Enantioselective Bronsted acid-catalyzed addition of carbon and nitrogen nucleophiles to imines

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Enantioselective Bronsted acid-catalyzed addition of carbon and nitrogen nucleophiles to imines

Material Information

Title:
Enantioselective Bronsted acid-catalyzed addition of carbon and nitrogen nucleophiles to imines
Creator:
Rowland, Gerald B
Place of Publication:
[Tampa, Fla]
Publisher:
University of South Florida
Publication Date:
Language:
English

Subjects

Subjects / Keywords:
Organocatalysis
Enantioselective catalysis
Aza-Friedel-Crafts
Aminal
Imines
Dissertations, Academic -- Chemistry -- Doctoral -- USF ( lcsh )
Genre:
non-fiction ( marcgt )

Notes

Summary:
ABSTRACT: The development of enantioselective reaction methodology has been at the forefront of research in both academic and industrial research laboratories due to the importance of chiral molecules in biological systems. An emerging area of research in the development of enantioselective reaction methodology has been the development of organocatalytic reactions. Organocatalysis, the use of small, chiral organic molecules as catalysts, has the advantage over traditional Lewis acid catalysis in that the reactions in general produce less toxic by-products. One recent breakthrough in the development of enantioselective methodology has been the development of chiral phosphoric acids as organocatalysts. Chiral phosphoric acids have been shown to be excellent catalysts for a wide variety of reactions. In this thesis chiral phosphoric acid-catalyzed enantioselective reaction methodologies have been developed for the addition of sulfonamides and indoles to imines.The development of Bronsted acid-catalyzed amidation of imines allows for an expedient route for the synthesis of N,N-aminals, which have been incorporated into a wide variety of biologically active compounds. Initial studies were undertaken to determine the practicality of a Bronsted acid-catalyzed method for the addition of amides to N-Boc protected imines. Over 20 achiral Bronsted acids were screened, and it was found that phenylphosphinic acid and trifluoromethanesulfinimide were both excellent catalysts for the addition of amides to a variety of imines giving the respective products in excellent yield. The methodology was extended to the development of an enantioselective method for the addition of sulfonamides to imines. It was found that a chiral phosphoric acid derived from the VAPOL ligand was suitable for this purpose.The developed methodology is capable of tolerating a wide variety of functional groups allowing for the preparation of the N, N-aminal products in excellent yield and enantioselectivities. An enantioselective phosphoric acid-catalyzed aza-Friedel-Crafts reaction between N-benzylindoles derivatives and N-benzoyl protected imines has been developed. A catalyst derived from the BINOL backbone was found to be the optimum catalyst for the enantioselective transformation. The developed methodology was capable of tolerating a wide variety of functional groups and provides an expedient route for the synthesis of chiral 3-indolylmethanamines.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2008.
Bibliography:
Includes bibliographical references.
System Details:
Mode of access: World Wide Web.
System Details:
System requirements: World Wide Web browser and PDF reader.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 146 pages.
General Note:
Includes vita.
Statement of Responsibility:
by Gerald B. Rowland.

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University of South Florida Library
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University of South Florida
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All applicable rights reserved by the source institution and holding location.
Resource Identifier:
002001166 ( ALEPH )
319637586 ( OCLC )
E14-SFE0002618 ( USFLDC DOI )
e14.2618 ( USFLDC Handle )

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Enantioselective Bronsted acid-catalyzed addition of carbon and nitrogen nucleophiles to imines
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ABSTRACT: The development of enantioselective reaction methodology has been at the forefront of research in both academic and industrial research laboratories due to the importance of chiral molecules in biological systems. An emerging area of research in the development of enantioselective reaction methodology has been the development of organocatalytic reactions. Organocatalysis, the use of small, chiral organic molecules as catalysts, has the advantage over traditional Lewis acid catalysis in that the reactions in general produce less toxic by-products. One recent breakthrough in the development of enantioselective methodology has been the development of chiral phosphoric acids as organocatalysts. Chiral phosphoric acids have been shown to be excellent catalysts for a wide variety of reactions. In this thesis chiral phosphoric acid-catalyzed enantioselective reaction methodologies have been developed for the addition of sulfonamides and indoles to imines.The development of Bronsted acid-catalyzed amidation of imines allows for an expedient route for the synthesis of N,N-aminals, which have been incorporated into a wide variety of biologically active compounds. Initial studies were undertaken to determine the practicality of a Bronsted acid-catalyzed method for the addition of amides to N-Boc protected imines. Over 20 achiral Bronsted acids were screened, and it was found that phenylphosphinic acid and trifluoromethanesulfinimide were both excellent catalysts for the addition of amides to a variety of imines giving the respective products in excellent yield. The methodology was extended to the development of an enantioselective method for the addition of sulfonamides to imines. It was found that a chiral phosphoric acid derived from the VAPOL ligand was suitable for this purpose.The developed methodology is capable of tolerating a wide variety of functional groups allowing for the preparation of the N, N-aminal products in excellent yield and enantioselectivities. An enantioselective phosphoric acid-catalyzed aza-Friedel-Crafts reaction between N-benzylindoles derivatives and N-benzoyl protected imines has been developed. A catalyst derived from the BINOL backbone was found to be the optimum catalyst for the enantioselective transformation. The developed methodology was capable of tolerating a wide variety of functional groups and provides an expedient route for the synthesis of chiral 3-indolylmethanamines.
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Organocatalysis
Enantioselective catalysis
Aza-Friedel-Crafts
Aminal
Imines
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E na nt i os e l e c t i ve B r ons t e d A c i d C a t a l yz e d A ddi t i ons of N i t r oge n a nd C a r bon N uc l e ophi l e s t o I m i ne s by G e r a l d B R ow l a nd, J r A di s s e r t a t i on s ubm i t t e d i n pa r t i a l f u l f i l l m e nt of t he r e qui r e m e nt s f or t he de g r e e of D oc t or of P hi l os ophy D e pa r t m e nt of C he m i s t r y C ol l e ge of A r t s a nd S c i e nc e s U ni ve r s i t y of S ou t h F l o r i da M a j or P r of e s s or : J on C A nt i l l a P h D R om a n M a ne t s c h, P h. D E dw a r d T u r os P h. D X P e t e r Z ha ng P h D D a t e of A ppr ova l : J ul y 3, 2008 K e yw or ds : or ga noc a t a l ys i s e na nt i os e l e c t i ve c a t a l y s i s a z a F r i e de l C r a f t s a m i na l i m i ne s C opyr i ght 2008 G e r a l d B R ow l a nd, J r

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I w oul d l i ke t o de di c a t e t h i s t o m y w i f e E m i l y, m y pa r e nt s m y s i s t e r a nd m y ne phe w s T ha nk you f o r a l l of t he l ove a nd s uppor t t ha t you ha ve gi v e n t o m e I n m e m or y of D av i d H B r adl e y P h D

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A c k n ow l e d ge m e n t s F i r s t I w oul d l i ke t o t ha nk D r J on A nt i l l a f o r t h e gui da nc e t ha t you ha ve gi ve n m e dur i ng m y gr a dua t e c a r e e r a nd f or a l l ow i ng m e t o pur s ue s om e of t he c r a z y i de a s t ha t I ha ve c om e up w i t h ove r t he ye a r s I w oul d l i ke t o t ha nk m y w i f e a nd l a b m a t e E m i l y R ow l a nd f or a l l of t he he l p a nd s uppor t t ha t you ha ve gi ve n t h r oughout t he ye a r s I w oul d l i ke t o t ha nk D r R om a n M a ne t s c h f or t he he l p t ha t you ha ve gi ve n, e s pe c i a l l y w h e n w e f i r s t a r r i ve d i n F l or i da a s w e l l a s t he h e l pf ul di s c us s i ons t ha t w e ha ve ha d ove r t he ye a r s I w oul d l i ke t o t ha nk D r P e t e r Z ha ng f or a l l o f t he he l pf ul di s c us s i ons on c a t a l yt i c pr oc e s s e s a nd f or a l l ow i ng m e t o us e S pa r t a n I w oul d l i ke t o t ha nk D r E dw a r d T ur os f or t he he l pf ul di s c us s i ons a nd de di c a t i on t o t he e duc a t i on of o r ga ni c gr a dua t e s t ude nt s I w oul d l i ke t o t ha nk a l l of t he pe opl e t ha t I ha ve w or ke d w i t h i n t he l a bor a t or y bot h w hi l e a t O l e M i s s a nd U S F I w oul d e s pe c i a l l y l i ke t o t ha nk t he pos t doc s t ha t I ha ve ha d t he pr i vi l e ge t o w or k w i t h a s a gr a dua t e s t ude nt I w oul d l i ke t o t ha nk D r H a i l e Z ha ng D r Y uxue L i a ng a nd D r G ui l ong L i f or a l l of t he he l pf ul di s c us s i ons a nd i de a s I w oul d a l s o l i ke t o t ha nk M i c he l l e C or t e s S a l va G a j e ndr a I ngl e a nd S ha w n L a r s on. I w oul d l i ke t o t ha nk J o s h R uppe l M a t t C r o s s a n d R ya n C or m i e r f or t he di s c us s i on s a bout c he m i s t r y a nd pr ov i di ng pe opl e t o t a l k t o w h e n I ne e de d t o ve nt

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i v T ab l e of C on t e n t s L i s t of T a bl e s i i i L i s t of F i gur e s v L i s t of S pe c t r a vi A b s t r a c t vi i i C ha pt e r 1. O r ga noc a t a l yt i c E na nt i os e l e c t i ve A ddi t i ons of N uc l e ophi l e s t o C O a nd C N D oubl e B onds 1 1. 1. E na m i ne C a t a l ys i s 3 1. 2. I m i ni um C a t a l ys i s 8 1. 3. H ydr oge n B ondi ng C a t a l ys i s 13 1. 3. 1 E na nt i os e l e c t i ve T hi ou r e a C a t a l ys i s 14 1. 3. 2 E na nt i os e l e c t i ve D i ol C a t a l ys i s 18 1. 3. 3 E na nt i os e l e c t i ve P hos phor i c A c i d C a t a l ys i s 21 C ha pt e r 2. E na nt i os e l e c t i ve B r ons t e d A c i d C a t a l yz e d A m i da t i on of I m i ne s 26 2. 1. R e t r o I nve r s o P e pt i de M i m i c s 27 2. 2. D e ve l opm e nt o f B r ons t e d A c i d C a t a l yz e d A m i da t i on of I m i ne s 28 2. 3. E na nt i os e l e c t i ve A ddi t i on of S ul f ona m i de s t o I m i ne s 34 2. 4. C onc l us i ons a nd F ut ur e W or k 38 C ha pt e r 3. B r ons t e d A c i d C a t a l yz e d E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on 40 3. 1. B a c kgr ound 40

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v 3. 2. E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on of I ndol e D e r i va t i ve s w i t h N B e nz oyl P r ot e c t e d I m i ne s 47 3. 3. C onc l us i ons 54 C ha pt e r 4. E xpe r i m e nt a l P r oc e dur e s 58 4. 1. S uppor t i ng I nf or m a t i on f o r C ha pt e r 2 58 4. 1. 1 G e ne r a l C ons i de r a t i ons 58 4. 1. 2 E xpe r i m e nt a l P r oc e d ur e s 4. 2. S uppor t i ng I nf or m a t i on f o r C ha pt e r 3 74 4. 2. 1 G e ne r a l C ons i de r a t i ons 74 4. 2. 2 E xpe r i m e nt a l P r oc e dur e s 75 4. 2. 3 X R a y C r ys t a l l ogr a phi c D a t a 89 C ha pt e r 5 1 H a nd 1 3 C S pe c t r a f or C om pounds 101 5. 1. 1 H a nd 1 3 C S pe c t r a f or C om pounds i n C ha pt e r 2 101 5. 2. 1 H a nd 1 3 C S p e c t r a f or C om pounds i n C ha pt e r 3 123 R e f e r e nc e s 139 A bout t he A ut hor E nd P a ge

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vi L i s t of T ab l e s T a bl e 1. 1 P r ol i ne C a t a l yz e d I nt e r m ol e c ul a r A l dol R e a c t i ons 5 T a bl e 1. 2 L i s t s P r ol i ne C a t a l yz e d, T hr e e C om pone nt M a nni c h R e a c t i on 6 T a bl e 1. 3 B a r ba s s P r ol i ne C a t a l yz e d, T hr e e C om pone nt M a nni c h R e a c t i on 7 T a bl e 1. 4 I m i di z ol i di none C a t a l yz e d E na nt i os e l e c t i ve D i e l s A l de r R e a c t i on 11 T a bl e 1. 5 C ount e r i on C a t a l yz e d R e duc t i on of U ns a t ur a t e d A l de hyde s 12 T a bl e 1. 6 T hi our e a C a t a l yz e d E na nt i os e l e c t i ve S t r e c ke r R e a c t i on 14 T a bl e 1. 7 T hi our e a C a t a l yz e d N A c yl P i c t e t S pe ngl e r R e a c t i on 16 T a bl e 1. 8 T hi our e a C a t a l yz e d A ddi t i ons t o O xoc a r be ni um I o ns 18 T a bl e 1. 9 T A D D O L C a t a l yz e d E na nt i os e l e c t i ve H e t e r o D i e l s A l de r R e a c t i on 19 T a bl e 1. 10 B I N O L C a t a l yz e d M or i t a B a yl i s s H i l l m a n R e a c t i on 20 T a bl e 1. 11 B i f unc t i ona l O r ga noc a t a l yt i c A z a M or i t a B a yl i s s H i l l m a n R e a c t i on 21 T a bl e 1. 12 A m m oni um S a l t C a t a l yz e d A z a H e nr y R e a c t i o n 22 T a bl e 1. 13 A ki ya m a s P hos phor i c A c i d C a t a l yz e d M a nni c h R e a c t i on 23 T a bl e 1. 14 T e r a da s P hos phor i c A c i d C a t a l yz e d M a nni c h R e a c t i on 24 T a bl e 2. 1 A c i d C a t a l ys t S c r e e ni ng 31 T a bl e 2. 2 V a r i a t i on of A m i de N uc l e ophi l e s 33 T a bl e 2. 3 V a r i a t i on of I m i ne S ubs t r a t e 34 T a bl e 2. 4 O pt i m i z a t i on of E na nt i os e l e c t i ve A ddi t i on o f S u l f ona m i de s t o I m i ne s 35

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vi i T a bl e 2. 5 V a r i a t i on of S ul f ona m i de N uc l e ophi l e s 37 T a bl e 2. 6 V a r i a t i on of I m i ne S ubs t r a t e 38 T a bl e 3. 1 J oha nns e n s E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on 42 T a bl e 3. 2 C oppe r C a t a l yz e d E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on 43 T a bl e 3. 3 E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on of F u r a ns w i t h I m i ne s 44 T a bl e 3. 4 A l ka l oi d C a t a l yz e d E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on 45 T a bl e 3. 5 P hos phor i c A c i d C a t a l yz e d E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on of I ndol e s w i t h E na m i ne s 46 T a bl e 3. 6 P hos phor i c A c i d C a t a l yz e d E na nt i os e l e c t i ve a z a F r i e de l C r a f t s R e a c t i on 47 T a bl e 3. 7 O pt i m i z a t i on of S ol ve nt a nd I ndol e P r ot e c t i ng G r o up 49 T a bl e 3. 8 O pt i m i z a t i on of a z a F r i e de l C r a f t s R e a c t i on 50 T a bl e 3. 9 V a r i a t i on of I m i ne E l e c t r ophi l e s 52 T a bl e 3. 10 V a r i a t i on of I ndol e S ubs t r a t e 54 T a bl e 3. 11 E na nt i os e l e c t i ve A ddi t i ons of P y r r ol e s t o I m i ne s 56

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vi i i L i s t of F i gu r e s F i gur e 1. 1 A l ka l oi d C a t a l yz e d A ddi t i on of M e t ha nol t o K e t e n e s 3 F i gur e 1. 2 C a t a l yt i c C yc l e f or E na m i ne C a t a l ys i s 4 F i gur e 1. 3 P r ol i ne M e di a t e d R obi ns on A nnul a t i on 5 F i gur e 1. 4 C a t a l yt i c C yc l e f or I m i ni um C a t a l ys i s 9 F i gur e 1. 5 W oodw a r d s P r ol i ne M e di a t e d D e r a c e m i z t i on of T hi a none I nt e r m e di a t e i n R out e t o t he S ynt he s i s of E r yt h r om yc i n 10 F i gur e 1. 6 M e c ha ni s m f or A c t i va t i on of E l e c t r oph i l e by T hi o ur e a C a t a l ys t s 15 F i gur e 1. 7 M e c ha ni s m of P i c t e t S pe ngl e r C yc l i z a t i on o f H ydr oxyl a c t a m 17 F i gur e 1. 8 C a t a l yt i c C yc l e of I m i ne A c t i va t i on by C hi r a l P ho s phor i c A c i ds 25 F i gur e 2. 1 R e t r o I nve r s o P e pt i de M i m i c s 27 F i gur e 2. 2 M e t hods f or t he S ynt he s i s of R e t r o I nve r s o P e pt i d e M i m i c s 28 F i gur e 2. 3 C onde ns a t i on of B e nz a l de hyde w i t h A c e t a m i de 29 F i gur e 2. 4 A ddi t i on of A m i de s t o C hl or a l D e r i ve d I m i ne s 29 F i gur e 2. 5 H ypot he s i s f or t he A m i da t i on of I m i ne s 30 F i gur e 2. 6 D e ve l opm e nt of V A P O L P hos phor i c A c i d 36 F i gur e 3. 1 N a t ur a l P r oduc t s C ont a i ni ng C hi r a l 3 I ndol yl m e t h a na m i ne s 40 F i gur e 3. 2 M ul t i pl e S ubs t i t ut i on of A m i nom e t hyl I nt e r m e di a t e s 41 F i gur e 3. 3 X R a y C r ys t a l D e t e r m i na t i on o f t he A bs ol ut e C onf i gur a t i on o f 137c 53 F i gur e 3. 4 A c i d C a t a l yz e d A ddi t i on of N uc l e ophi l e s t o R a c e m i c I ndol yl m e t ha na m i ne 57

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i x L i s t of S p e c t r a S pe c t r a 5. 1 1. 1 H a nd 1 3 C S pe c t r a f or C om pound 105a 101 S pe c t r a 5. 1 2. 1 H a nd 1 3 C S pe c t r a f or C om pound 105b 102 S pe c t r a 5. 1 3. 1 H a nd 1 3 C S pe c t r a f or C om pound 105c 103 S pe c t r a 5. 1 4. 1 H a nd 1 3 C S pe c t r a f or C om pound 105d 104 S pe c t r a 5. 1 5. 1 H a nd 1 3 C S pe c t r a f or C om pound 105e 105 S pe c t r a 5. 1 6. 1 H a nd 1 3 C S pe c t r a f or C om pound 105f 106 S pe c t r a 5. 1 7. 1 H a nd 1 3 C S pe c t r a f or C om pound 105g 107 S pe c t r a 5. 1 8. 1 H a nd 1 3 C S pe c t r a f or C om pound 105h 108 S pe c t r a 5. 1 9. 1 H a nd 1 3 C S pe c t r a f or C om pound 105i 109 S pe c t r a 5. 1 1 0. 1 H a nd 1 3 C S pe c t r a f or C om pound 105j 110 S pe c t r a 5. 1 11. 1 H a nd 1 3 C S pe c t r a f or C om pound 105k 111 S pe c t r a 5. 1 12. 1 H a nd 1 3 C S pe c t r a f or C om pound 105l 112 S pe c t r a 5. 1 13. 1 H a nd 1 3 C S pe c t r a f or C om pound 105m 113 S pe c t r a 5. 1 15. 1 H a nd 1 3 C S pe c t r a f or C om pound 105o 114 S pe c t r a 5. 1 16. 1 H a nd 1 3 C S pe c t r a f or C om pound 105p 115 S pe c t r a 5. 1 17. 1 H a nd 1 3 C S pe c t r a f or C om pound 105q 116 S pe c t r a 5. 1 18. 1 H a nd 1 3 C S pe c t r a f o r C om pound 105r 117 S pe c t r a 5. 1 19. 1 H a nd 1 3 C S pe c t r a f or C om pound 105s 118 S pe c t r a 5. 1 20. 1 H a nd 1 3 C S pe c t r a f or C om pound 105t 119 S pe c t r a 5. 1 21. 1 H a nd 1 3 C S pe c t r a f o r C om pound 105 u 120 S pe c t r a 5. 1 22. 1 H a nd 1 3 C S pe c t r a f or C om pound 105v 121

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x S pe c t r a 5. 1 23. 1 H a nd 1 3 C S pe c t r a f or C om pound 105w 122 S pe c t r a 5. 2 1. 1 H a nd 1 3 C S pe c t r a f or C om pound 137a 123 S pe c t r a 5. 2 2. 1 H a nd 1 3 C S pe c t r a f or C om pound 137b 124 S pe c t r a 5. 2 3. 1 H a nd 1 3 C S pe c t r a f or C om pound 137c 125 S pe c t r a 5. 2 4. 1 H a nd 1 3 C S pe c t r a f or C om pound 137d 126 S pe c t r a 5. 2 5. 1 H a nd 1 3 C S pe c t r a f or C om pound 137e 127 S pe c t r a 5. 2 6. 1 H a nd 1 3 C S pe c t r a f or C om pound 137f 128 S pe c t r a 5. 2 7. 1 H a nd 1 3 C S pe c t r a f or C om pound 137g 129 S pe c t r a 5. 2 8. 1 H a nd 1 3 C S pe c t r a f or C om pound 137h 130 S pe c t r a 5. 2 9. 1 H a nd 1 3 C S pe c t r a f or C om pound 137i 131 S pe c t r a 5. 2 10. 1 H a nd 1 3 C S pe c t r a f or C om pound 137j 132 S pe c t r a 5. 2 11. 1 H a nd 1 3 C S pe c t r a f or C om pound 137k 133 S pe c t r a 5. 2 12. 1 H a nd 1 3 C S pe c t r a f or C om pound 137l 134 S pe c t r a 5. 2 13. 1 H a nd 1 3 C S pe c t r a f or C om pound 137m 135 S pe c t r a 5. 2 14. 1 H a nd 1 3 C S pe c t r a f or C om pound 137n 136 S pe c t r a 5. 2 15. 1 H a nd 1 3 C S pe c t r a f or C om pound 137o 137 S pe c t r a 5. 2 16. 1 H a nd 1 3 C S pe c t r a f or C om pound 137p 138

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xi E n an t i os e l e c t i ve B r on s t e d A c i d C a t al yz e d A d d i t i on o f C ar b on an d N i t r oge n N u c l e op h i l e s t o I m i n e s G e r al d B R ow l an d Jr A B S T R A C T T he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy ha s be e n a t t he f or e f r ont o f r e s e a r c h i n bot h a c a de m i c a nd i ndu s t r i a l r e s e a r c h l a bor a t or i e s due t o t he i m por t a nc e of c hi r a l m ol e c ul e s i n bi ol ogi c a l s ys t e m s A n e m e r gi ng a r e a of r e s e a r c h i n t he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy ha s be e n t he de ve l opm e nt of or ga noc a t a l yt i c r e a c t i ons O r ga noc a t a l ys i s t he u s e of s m a l l c hi r a l or ga ni c m ol e c ul e s a s c a t a l ys t s ha s t he a dva nt a ge ove r t r a di t i ona l L e w i s a c i d c a t a l ys i s i n t ha t t he r e a c t i ons i n ge ne r a l pr oduc e l e s s t oxi c by pr oduc t s O ne r e c e nt br e a kt hr ough i n t he de ve l opm e nt of e na nt i os e l e c t i ve m e t hodol ogy ha s be e n t h e de ve l opm e nt of c hi r a l phos phor i c a c i ds a s or ga noc a t a l ys t s C hi r a l phos phor i c a c i ds ha ve b e e n s how n t o be e xc e l l e nt c a t a l ys t s f or a w i de va r i e t y of r e a c t i ons I n t hi s t he s i s c hi r a l pho s phor i c a c i d c a t a l yz e d e na nt i o s e l e c t i ve r e a c t i on m e t hodol ogi e s ha ve be e n de ve l ope d f or t he a ddi t i on of s ul f ona m i de s a nd i ndol e s t o i m i ne s T he de ve l opm e nt of B r ons t e d a c i d c a t a l yz e d a m i da t i on of i m i ne s a l l ow s f or a n e xpe di e nt r out e f or t he s ynt he s i s of N N a m i na l s w hi c h ha ve be e n i nc or por a t e d i nt o a w i de va r i e t y of bi o l ogi c a l l y a c t i ve c om pounds I ni t i a l s t udi e s w e r e unde r t a ke n t o de t e r m i ne t he pr a c t i c a l i t y of a B r ons t e d a c i d c a t a l yz e d m e t hod f or t he a ddi t i on of a m i de s

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xi i t o N B oc pr ot e c t e d i m i ne s O ve r 20 a c hi r a l B r o ns t e d a c i ds w e r e s c r e e ne d, a nd i t w a s f ound t ha t phe nyl phos phi ni c a c i d a nd t r i f l uor o m e t ha ne s ul f i ni m i de w e r e bot h e xc e l l e nt c a t a l ys t s f or t he a ddi t i on of a m i de s t o a va r i e t y of i m i ne s gi vi ng t he r e s pe c t i ve pr oduc t s i n e xc e l l e nt yi e l d. T he m e t hodol ogy w a s e xt e nde d t o t he de ve l opm e nt of a n e na nt i os e l e c t i ve m e t hod f or t he a ddi t i on of s ul f ona m i de s t o i m i ne s I t w a s f ound t ha t a c hi r a l phos phor i c a c i d de r i ve d f r om t he V A P O L l i ga nd w a s s ui t a bl e f or t hi s pu r pos e T he de ve l ope d m e t hodol ogy i s c a pa bl e of t ol e r a t i ng a w i de va r i e t y of f unc t i ona l gr oups a l l ow i ng f or t he pr e pa r a t i on of t he N N a m i na l pr oduc t s i n e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t i e s A n e na nt i os e l e c t i ve phos phor i c a c i d c a t a l yz e d a z a F r i e de l C r a f t s r e a c t i on be t w e e n N be nz yl i ndol e s de r i va t i ve s a nd N be nz oyl pr ot e c t e d i m i ne s ha s be e n de ve l ope d. A c a t a l ys t de r i ve d f r om t he B I N O L b a c kbone w a s f ound t o be t he opt i m um c a t a l ys t f or t he e na nt i os e l e c t i ve t r a ns f or m a t i on. T he de ve l op e d m e t hodol ogy w a s c a pa bl e of t ol e r a t i ng a w i de va r i e t y of f unc t i ona l gr oups a nd pr ovi de s a n e xpe di e nt r out e f or t he s ynt he s i s of c hi r a l 3 i ndol yl m e t ha na m i ne s

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1 C h ap t e r 1 O r gan oc at al yt i c E n an t i os e l e c t i ve A d d i t i on s o f N u c l e op h i l e s t o C O an d C N D ou b l e B on d s D ue t o t he ha nde dn e s s of t he m ol e c ul e s of l i f e s uc h a s a m i no a c i d s a nd D N A e na nt i om e r i c c om pounds of t e n di s pl a y va s t l y di f f e r e nt bi ol ogi c a l a c t i vi t i e s 1 A f e w e xa m pl e s of t he di f f e r e nt bi ol ogi c a l a c t i vi t y of e na nt i om e r i c c om pounds a r e t he pha r m a c e ut i c a l c om pounds i bupr of e n a nd t ha l i do m i de 2 I n t he c a s e of i bupr of e n, t he ( S ) e na nt i om e r w a s f ound t o be a c t i ve i n bot h i n v i t r o a nd i n v i v o t e s t i ng. T he ( R ) e na nt i om e r of i bupr o f e n ha s be e n s how n t o ha ve n one of t he be ne f i c i a l bi ol ogi c a l a c t i vi t y t ha t i s e xhi bi t e d by t he ( S ) e na nt i om e r A r e c e nt s ur ve y of s e ve r a l pha r m a c e ut i c a l c om pa ni e s s how e d t ha t 54% of t he ne w dr ug c a ndi da t e s i n de ve l opm e nt c ont a i n a t l e a s t one c hi r a l c e nt e r a nd a l l but t w o of t he dr ug c a ndi da t e s a r e b e i ng de ve l ope d a s e na nt i om e r i c a l l y pur e c om pounds 3 D ue t o t he c o m m on di f f e r e nc e i n bi o l ogi c a l a c t i vi t y of e na nt i om e r i c c om pounds t he de ve l opm e nt of m e t hods f or t he s ynt he s i s of e na nt i om e r i c a l l y pur e c om pounds ha s be e n a t t he f or e f r ont of r e s e a r c h i n m a ny i ndu s t r i a l a nd a c a de m i c r e s e a r c h l a bor a t or i e s A t t he pr e s e nt t i m e t he m os t c om m onl y us e d m e t hods f or t he s ynt he s i s of e na nt i opur e c om pounds a r e e m pl oyi ng t he c hi r a l pool c hi r a l a uxi l i a r i e s r e s ol ut i on, a nd e na nt i os e l e c t i ve c a t a l ys i s T he de v e l opm e nt of c a t a l yt i c e na nt i os e l e c t i ve r e a c t i on m e t hodol ogi e s ha s a m a j or a dva nt a ge ove r t he ot he r m e t hod s t ha t a r e c ur r e nt l y us e d i n t ha t onl y a c a t a l yt i c a m o unt of t he c hi r a l r e a ge nt i s r e qui r e d f or t he s ynt he s i s of e na nt i opur e c om pounds 4

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2 U nt i l t he l a t e 1 990 s t he m a j or r e s e a r c h de ve l opm e nt of c a t a l yt i c e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy f oc us e d on t he e m pl oym e nt of c hi r a l m e t a l c om pl e xe s C hi r a l L e w i s a c i ds ha d t he m a j or a dva nt a ge of e m pl oy i ng s ubs t oi c hi om e t r i c a m ount s of t he of t e n e xpe ns i ve c hi r a l l i ga nd T he de ve l opm e nt of s uc h r e a c t i on m e t hodol ogy w a s not w i t hout i t s dr a w ba c ks T he m a j or dr a w ba c k of s u c h e na nt i os e l e c t i ve m e t hodol ogi e s w a s t he pr oduc t i on of of t e n t oxi c m e t a l by pr oduc t s D ue t o t hi s di s a dva nt a ge a nd e ve r t i ght e ni ng F D A gui de l i ne s r e s e a r c he r s l ooke d t o de ve l op ne w c a t a l yt i c r e a c t i on m e t hodol ogi e s t ha t di d not r e qui r e t he u s e of c hi r a l m e t a l c om pl e xe s f or e na nt i os e l e c t i ve c onve r s i ons T hi s a r e a of a s ym m e t r i c c a t a l ys i s ha s be c om e c om m onl y know n a s or ga noc a t a l ys i s A s ym m e t r i c or ga n oc a t a l y s i s i s t he us e of s m a l l c hi r a l or ga ni c m ol e c ul e s a s c a t a l ys t s f or e na nt i os e l e c t i ve t r a ns f or m a t i ons 5 A s ym m e t r i c or ga noc a t a l ys i s t r a c e s i t s r oot s ba c k t o w or k r e por t e d a bout one hundr e d ye a r s a go. I n 1912 B r e di g a nd F i s ke r e por t e d t ha t t he a ddi t i on of hyd r oge n c ya ni de t o be nz a l de hyde w a s a c c e l e r a t e d by t he pr e s e nc e of t he a l ka l oi ds qui ni ne a nd qui ni di ne 6 T he r e s ul t i ng c ya nohydr i n pr oduc t s w e r e f ound t o be f or m e d i n a n opt i c a l l y a c t i ve f or m T he opt i c a l pur i t y of t he pr oduc t s f or m e d f r om t hi s t r a ns f or m a t i on w a s f ound t o be l e s s t h a n 10% I n 1960, P r a c e j us a nd c o w or ke r s r e por t e d t h e e na nt i os e l e c t i ve a ddi t i on of m e t ha nol t o phe nyl m e t hyl ke t e ne 1 e m pl oyi ng onl y 1 m ol e pe r c e nt of O a c e t yl qui ni ne 3 a s t he c a t a l ys t T he r e s ul t i ng e s t e r 2 w a s f or m e d i n 74% e e ( F i gur e 1 1) 7 O ve r t he l a s t de c a de t he r e ha s be e n a n i nc r e a s e d i nt e r e s t i n t he de ve l opm e nt of e na nt i os e l e c t i ve or ga noc a t a l yt i c r e a c t i ons D ur i ng t hi s t i m e pe r i od s e ve r a l di f f e r e nt c l a s s e s of or ga noc a t a l ys t s ha v e be e n r e por t e d i n t he l i t e r a t u r e T he m a j or c l a s s e s of

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3 or ga noc a t a l ys t t ha t ha ve be e n r e por t e d i n t he l i t e r a t ur e c a n be di vi de d i nt o e na m i ne c a t a l ys t s i m i ni um c a t a l ys t s a nd hydr oge n bondi n g c a t a l ys t s F i gu r e 1. 1 A l k al oi d C at al yz e d A d d i t i on o f M e t h an ol t o K e t e n e s 1. 1 E n am i n e C at al ys i s E na m i ne c a t a l ys i s i nvol ve s t he us e of c hi r a l pr i m a r y or s e c onda r y a m i ne s a s c a t a l ys t s f or t he a ddi t i on of e l e c t r ophi l e s t o t he pos i t i on of a c a r bonyl c om pound ( F i gur e 1. 2 ) 8 T he r e a c t i ons pr oc e e d t hr ough a n e na m i ne i nt e r m e di a t e T he f o r m a t i on of t he i ni t i a l i m i ni um i on r e s ul t s i n a de c r e a s e i n t he e ne r gy of t he L U M O of t he c a r bonyl c om pound a s w e l l a s i nc r e a s e d a c i di t y of t he p r ot on. T hi s i nc r e a s e d a c i di t y of t he pr ot on r e s ul t s i n t he l os s of t he pr ot on a nd t he f or m a t i on of a n e na m i ne T he e na m i ne t he n a c t s a s a nuc l e ophi l e a ddi ng t o a n e l e c t r ophi l i c C O or C N doubl e bond. T hi s r e s ul t e d i n t he f o r m a t i on o f a ne w i m i ni um i on i nt e r m e di a t e w hi c h r e a di l y unde r goe s hydr ol ys i s t o gi ve t he f i na l pr oduc t 10

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4 F i gu r e 1. 2 C at al y t i c C yc l e f or E n am i n e C at al y s i s T he f i r s t r e por t of e na nt i os e l e c t i ve e na m i ne c a t a l y s i s w a s i n 1974. P a r r i s h a nd c o w or ke r s r e por t e d t ha t a c a t a l yt i c a m ount of L pr o l i ne w a s a bl e t o c a t a l yz e t he R obi n s on a nnul a t i on pr ovi di ng t he pr oduc t 13 i n qua nt i t a t i v e y i e l d a nd 93% e e ( F i gur e 1 3) 9 T h i s c he m i s t r y w a s r oot e d de e pl y i n t he w or k r e por t e d by S t o r k i nvol vi n g pr e f o r m e d, c hi r a l e na m i ne s f or di a s t e r e os e l e c t i ve s ynt he s i s 1 0 T he r e a c t i on be c a m e know n a s t he H a j os P a r r i s h E l de r S a ue r W i e c he r t r e a c t i on. T he r e a c t i on a l l ow e d f or a n e xpe di e nt e na nt i os e l e c t i ve r out e f or t he e na nt i os e l e c t i ve s ynt he s i s of a va r i e t y of i m por t a nt s ynt he t i c i nt e r m e di a t e s i nc l udi ng t he W i e l a nd M i s c hl e r ke t one 14

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5 F i gu r e 1. 3 P r ol i n e M e d i a t e d R ob i n s on A n n u l a t i on I t t ook m or e t ha n t w e n t y ye a r s f or t he ne xt m a j or br e a kt hr ough i n e na m i ne c a t a l ys i s t o oc c ur I n 2000, i n s pi r e d by t he w or k of B a r ba s a nd L e r ne r on C l a s s I a l dol a s e e nz ym e s 1 1 L i s t a nd c o w or ke r s r e por t e d t he a ppl i c a t i on of pr ol i ne a s a c a t a l y s t f or t he f i r s t o r ga noc a t a l yt i c i nt e r m ol e c ul a r a l dol r e a c t i on be t w e e n a l de hyde s a nd ke t one s ( T a bl e 1. 1) 1 2 T he r e a c t i on r e qui r e d c a t a l ys t l oa di ngs be t w e e n 10 a nd 30 m ol e pe r c e nt a nd pr ovi de d t he a l dol a dduc t s 17a f i n e na nt i os e l e c t i vi t i e s f r om 72% e e t o gr e a t e r t ha n 99% e e I n t he c a s e s w he r e t he f or m a t i on of di a s t e r e om e r s w a s pos s i bl e t he s y s t e m f a vor e d t he f or m a t i on of t he ant i di a s t e r e om e r T ab l e 1. 1. P r ol i n e C at al yz e d I n t e r m ol e c u l ar A l d ol R e ac t i on

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6 S oon a f t e r t he i ni t i a l r e por t of t he e na nt i os e l e c t i ve c r os s a l dol r e a c t i on L i s t a n d c o w or ke r s r e por t e d t he pr ol i ne c a t a l yz e d e na nt i os e l e c t i ve M a nni c h r e a c t i on ( T a bl e 1. 2) 1 3 T he r e a c t i on w a s a on e pot t hr e e c om pone nt r e a c t i on i nvol vi ng a ke t one a n a l de hyde a nd a n a m i ne T he r e a c t i on e m pl oye d 2 0 m ol % of ( S ) pr ol i ne a s a c a t a l ys t a nd r e s ul t e d i n t he f or m a t i on c hi r a l a m i ne s 19a e i n e xc e l l e nt e na nt i os e l e c t i vi t y. W he r e a s t he pr ol i ne c a t a l yz e d a l dol r e a c t i on f a vor e d t he f or m a t i on of t he ant i di a s t e r e om e r t he pr ol i ne c a t a l yz e d M a nni c h r e a c t i on f a vor e d t he f or m a t i on of t he s y n di a s t e r e om e r T he r e a c t i on c ondi t i ons w e r e a bl e t o t ol e r a t e a w i d e va r i e t y of ke t one s a l l ow i ng f or t he s ynt he s i s of hi ghl y f unc t i ona l i z e d a m i ne s A n e xa m pl e of t hi s i s t he us e of hydr oxy ke t one s a s t he nuc l e ophi l e s T he de ve l ope d m e t ho dol ogy a l l ow e d f or t he di r e c t s ynt he s i s of a m i no a l c ohol s T ab l e 1. 2. L i s t s P r ol i n e C at al yz e d T h r e e C o m p on e n t M an n i c h R e ac t i on

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7 S oon a f t e r t he i ni t i a l r e por t by L i s t a nd c o w or ke r s B a r ba s a nd c o w or ke r s i nde pe nde nt l y r e por t e d t he pr ol i ne c a t a l yz e d one pot t hr e e c om pone nt M a nni c h r e a c t i on ( T a bl e 1. 3 ) 1 4 S i m i l a r t o L i s t t he M a nni c h r e a c t i on r e por t e d by B a r ba s r e qui r e d hi gh c a t a l ys t l oa di ngs s om e up t o 35 m ol % of pr ol i ne T he r e a c t i on s c ope w a s f ound t o be br oa de r t ha n t he i ni t i a l r e por t by L i s t T he r e a c t i on w a s a bl e t o t ol e r a t e m or e di ve r s e f unc t i ona l i t y on t he ke t one c om pone nt of t he r e a c t i on. I t i s a l s o w or t h not i ng t ha t t he r e a c t i on c ondi t i ons pr ovi de d t he t he r m odyna m i c a l l y f a vor e d p r o duc t w he n s t e r i c a l l y l e s s de m a ndi ng a l de hyde s w e r e e m pl oye d. I n c a s e s w he r e s t e r i c a l l y m or e de m a ndi n g s ubs t i t ue nt s a r e pr e s e nt on t he a l de hyde t he r e a c t i on f a vor e d t he pr oduc t de r i ve d f r om t he ki ne t i c a l l y f a vor e d e na m i ne T hi s s e l e c t i vi t y i s m a i nl y due t o s t e r i c r e pul s i on T ab l e 1. 3. B ar b as s P r ol i n e C at al yz e d T h r e e C om p on e n t M an n i c h R e ac t i o n

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8 T he i ni t i a l r e por t s by t he L i s t a nd B a r ba s ha ve pa ve d t he w a y f o r t he a ppl i c a t i on of e na m i ne c a t a l ys i s t o a w i de va r i e t y of s ys t e m s 8 E na m i ne c a t a l ys i s ha s now b e e n s how n t o be a n e xc e l l e nt pl a t f o r m f or e na nt i os e l e c t i ve M i c ha e l a ddi t i on r e a c t i ons a nd f unc t i ona l i z a t i on of c a r bonyl c om pounds a s w e l l a s ot he r s 1 5 1 6 N e w c a t a l ys t s ha v e l e d t o t he de ve l opm e nt of ne w e na nt i os e l e c t i ve m e t hodo l ogy t ha t r e qui r e a m uc h l ow e r c a t a l ys t l oa di ng t ha n t he i ni t i a l r e por t s by B a r ba s a nd L i s t 1. 2. I m i n i u m C a t al ys i s I m i ni um c a t a l ys i s l i ke e na m i ne c a t a l ys i s e m pl oy s a c hi r a l pr i m a r y or s e c onda r y a m i ne a s a c a t a l y s t 1 7 I n t he c a s e of i m i ni um c a t a l ys i s how e ve r t he c a t a l y s t a c t i va t e s t h e c a r bonyl w hi c h i n t ur n a c t s a s a n e l e c t r ophi l e r a t he r t ha n a nuc l e ophi l e a s i s t he c a s e w i t h e na m i ne c a t a l ys i s C hi r a l s e c onda r y a m i ne s ha ve be e n t he pr i m a r y c hoi c e of c a t a l ys t due t o t he f a c t t ha t a c o c a t a l ys t i s not r e qui r e d f or i m i ni um i on f or m a t i on. T he r e s ul t i ng i m i ni um i ons a r e m or e e l e c t r ophi l i c t ha n e i t he r t he c or r e s pondi ng a l de hyde or ke t one I m i ni um c a t a l ys t s ha ve be e n w i de l y us e d f or t he a c t i va t i on of uns a t ur a t e d s ys t e m s ( F i gur e 1. 4) T he f i r s t s t e p of t he m e c ha ni s m i nvol ve s t he r e a c t i on of t he a m i n e c a t a l ys t 4 w i t h t he c a r bonyl c om pound 22 r e s ul t i ng i n t he f or m a t i on of t he i m i ni um i on 23 T hi s t ype of a c t i va t i on l ow e r s t he e ne r gy o f t he L U M O of t he c a r bonyl s ys t e m T he a ddi t i on of t he nuc l e ophi l e t o t he a c t i va t e d s y s t e m f ol l ow e d by hydr ol ys i s of t he i m i ni um pr ovi de s pr oduc t 26 a nd r e c ove r y of t he a m i ne c a t a l ys t I t i s i m por t a nt t o not e t ha t e a c h of t he di f f e r e nt t ype s of i m i ni um c a t a l yz e d r e a c t i on s ot he r t ha n t he c yc l oa ddi t i on r e a c t i ons w e r e r e por t e d i n s om e f o r m pr i or t o 1940

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9 F i gu r e 1. 4 C at al y t i c C yc l e f or I m i n i u m A c t i va t i on T he e a r l i e s t r e c or de d e xa m pl e of a r e a c t i on be i ng c a t a l yz e d by a n i m i ni um i on i s t he K noe ve na ga l c onde ns a t i on. 1 8 A f t e r t he i ni t i a l r e por t by K noe ve na ga l i n 1894, i t t ook 35 ye a r s f or B l a nc ha r d a nd c o w or ke r s t o s ugge s t t ha t po s i t i ve i ons pl a y a r ol e i n t he s e c onda r y a m i ne m e di a t e d K noe ve na ga l c onde n s a t i on. 1 9 I t w a s not unt i l 1951 t ha t C r ow e l l a nd P e c k di s c ove r e d e xpe r i m e nt a l e vi de nc e f or t he i nvol ve m e nt of t he i m i ni um i on. 2 0 T oda y t he r ol e o f t he i m i n i um i on i n t he K noe ve na ga l c onde ns a t i on i s w i de l y r e c ogni z e d. T he f i r s t r e por t of t he us e of a c hi r a l s e c onda r y a m i ne i n a n i m i ni um i on m e di a t e d r e a c t i on w a s by W oodw a r d a nd c o w or ke r s i n 1981 ( F i gu r e 1. 5 ) 2 1 T he r e s e a r c he r s r e por t e d t he us e of s t oi c hi om e t r i c a m ount s of D pr ol i ne f o r t he de r a c e m i z a t i on o f a t hi a none i nt e r m e di a t e i n r out e t o t he s ynt he s i s of e r yt hr om yc i n T he r e a c t i on f i r s t i nvol ve s t he f or m a t i on of a n e na m i ne f ol l ow e d by e l i m i na t i on of a s ul f i de t o f or m

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10 # uns a t ur a t e d i m i ni um i on 28 T he s ul f i de i on t he n a dds t o t he i m i n i um i on i n a M i c ha e l f a s hi on. T he r e s ul t i ng e na m i ne i nt e r m e di a t e 28 t he n unde r goe s a n i nt r a m ol e c ul a r a l dol r e a c t i on r e s ul t i ng i n t he f or m a t i on of bi c yc l i c pr oduc t 29 F i gu r e 1. 5. Woo d w ar d s P r ol i n e M e d i at e d D e r ac e m i z at i on of T h i an on e i n R ou t e t o t h e S y n t h e s i s E r yt h r om yc i n T he f i r s t c a t a l yt i c e na nt i os e l e c t i ve i m i ni um i on m e di a t e d r e a c t i on w a s r e por t e d i n 1991. Y a m a guc hi a nd c o w or ke r s r e por t e d t he pr ol i ne c a t a l yz e d c onj uga t e a ddi t i o n of m a l ona t e e s t e r s t o uns a t ur a t e d a l de hyde s 2 2 T he r e a c t i on ga ve t he pr oduc t i n e na nt i os e l e c t i vi t i e s r a ngi ng f r om t o 35 t o 77% e e T he ne xt m a j or br e a kt hr ough i n e na nt i os e l e c t i ve i m i ni um c a t a l ys i s w a s t he de ve l opm e nt of i m i di z ol i di none c a t a l ys t s by M a c M i l l a n a nd c o w or ke r s 2 3 M a c M i l l a n a nd c o w or ke r s f i r s t r e por t e d t he us e of c a t a l ys t s c ont a i ni ng t he i m i di z ol i di none ba c kbone f or t he f i r s t hi ghl y e na nt i os e l e c t i ve D i e l s A l de r r e a c t i on ( T a bl e 1. 4 ) 2 4 T he r e a c t i on i nvol ve d t he e na nt i os e l e c t i ve a ddi t i on o f bot h c yc l i c a nd a c yc l i c di e ne s t o uns a t ur a t e d a l de hyde s T he c r i t e r i a t ha t t he M a c M i l l a n gr oup f e l t w e r e i m por t a nt f o r a n e xc e l l e nt i m i ni um i on c a t a l ys t w e r e t he r a t e of i m i ni um i on f o r m a t i on, c ont r ol of t he i m i ni um i on ge om e t r y s e l e c t i ve di s c r i m i na t i on of t he ol e f i n $ f a c e a nd e a s e of c a t a l ys t pr e pa r a t i on. W i t h t he s e c r i t i c a l f a c t or s i n m i nd, c om put a t i ona l a nd ki ne t i c s s t udi e s l e d t o

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11 t he c onc l us i on t ha t c a t a l ys t ba s e d upon t he i m i di z ol i di none s c a f f ol d s houl d be e f f i c i e nt i m i ni um i on c a t a l ys t s T he e na nt i os e l e c t i ve D i e l s A l de r r e a c t i on of c yc l ope nt a di e ne w i t h uns a t ur a t e d a l de hyde s pr ovi de d t he p r oduc t s i n e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t y, how e ve r t he r a t i o of e ndo t o e xo pr oduc t f or m e d w a s onl y 1: 1. T he u s e c y c l ohe xa di e ne a s t he di e ne r e s ul t e d i n a m a r ke d i nc r e a s e i n e ndo : e xo r a t i o of t he pr oduc t up t o 14: 1 i n f a vor of t he e ndo pr oduc t w hi l e s i m i l a r yi e l ds a nd e na nt i os e l e c t i vi t i e s t o t he r e a c t i ons e m pl oyi ng c yc l ope nt a di e ne a s t he di e ne T ab l e 1. 4. I m i d i z ol i d i n on e C at al yz e d E n an t i os e l e c t i ve D i e l s A l d e r R e ac t i on C om put a t i ona l s t udi e s i ndi c a t e d t ha t t he i m i ni um i on c a t a l yz e d D i e l s A l de r r e a c t i on f ol l ow e d a n a s ync hr onous m e c ha ni s m r a t he r t ha n t he t r a di t i ona l l y a c c e pt e d

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12 c onc e r t e d m e c ha ni s m w he r e t he r a t e l i m i t i ng s t e p w a s a t t a c k of t he di e ne on t he c a r bon of t he i m i n i um i on T he s e l e c t i vi t y of t he r e a c t i on w a s be l i e ve d t o be c ont r ol l e d by a $ # $ i nt e r a c t i on be t w e e n t he be nz yl gr oup of t he c a t a l ys t a nd $ s y s t e m of t he i m i ni um i on. T he i m i da z ol i di none c a t a l ys t s ha ve b e e n s ho w n t o be e xc e l l e nt c a t a l y s t f or a w i de r a nge of e na nt i os e l e c t i ve t r a ns f or m a t i ons i nc l udi ng a l dol r e a c t i ons 2 5 a nd ha l oge na t i on of a l de hyde s 2 6 a s w e l l a s t he us e of t he a ppl i c a t i on of c a s c a de r e a c t i ons a s t he ke y s t e p on t he s ynt he s i s of s e ve r a l na t ur a l pr oduc t s 2 7 T ab l e 1. 5. C o u n t e r i on C at al yz e d R e d u c t i o n of U n s at u r at e d A l d e h yd e s A ne w a ppr oa c h t o t he de v e l opm e nt of e na nt i os e l e c t i ve i m i ni um i on c a t a l yz e d r e a c t i on m e t hodol ogy i s t he u s e of c hi r a l c oun t e r i ons i n a s s oc i a t i on w i t h a n a m i ne c a t a l ys t L i s t a nd c o w o r ke r s w e r e t he f i r s t t o r e por t s uc h a s t r a t e gy f or t he e na nt i os e l e c t i ve r e duc t i on of # uns a t ur a t e d a l de hyde s ( T a bl e 1. 5) 2 8 I n t he i ni t i a l

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13 r e por t m or phol i ne s a l t 35 of a c hi r a l pho s phor i c a c i d de r i ve d f r om B I N O L w a s f ound t o be a n e xc e l l e nt c a t a l ys t f or t he e na nt i os e l e c t i ve r e duc t i on e m pl oyi ng H a nt z s c h e s t e r de r i va t i ve 36 a s t he r e duc i ng a ge nt A w i de va r i e t y of a r om a t i c s ubs t i t ut e d # uns a t ur a t e d a l de hyde s w e r e t ol e r a t e d by t he c a t a l ys t s ys t e m A l l r e a c t i ons pr ovi de d a l de hyde pr oduc t s i n e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s 1. 3. H yd r oge n B on d i n g C at al ys i s H ydr oge n bondi ng i nt e r a c t i ons m a ke up a c l a s s of vi t a l l y i m por t a nt i nt e r a c t i ons i n na t ur e 2 9 S uc h i n t e r a c t i ons a r e r e s pons i bl e f or t he doubl e he l i x s t r uc t ur e o f D N A a s w e l l a s t he bi ndi ng of m a ny pha r m a c e ut i c a l a ge nt s t o t he a c t i ve s i t e of pr ot e i ns H ydr oge n bonds a r e a l s o r e s pon s i bl e f or t he s e c onda r y a nd t e r t i a r y s t r uc t ur e s of pr ot e i ns T he or i gi n of hydr oge n bondi ng c a n be t r a c e d ba c k t o t he e a r l y 1900 s w he r e hydr oge n bonds w e r e obs e r ve d i n s e v e r a l c he m i c a l s y s t e m s 3 0 I t w a s not unt i l 1931 t ha t t h e t e r m hydr oge n bond w a s f i r s t pr opo s e d by L i nus P a u l i ng i n hi s s t udi e s i nt o t he s t r uc t ur e of t he c he m i c a l bond. 3 1 P r i or t o t hi s r e por t hydr oge n bonds w e r e r e f e r r e d t o a s i nne r c om pl e x bui l di ng w e a k uni on a nd c he l a t i on U nl i ke c ova l e nt bonds bond a ngl e s bond di s t a nc e s a nd e ne r gy di s t r i but i ons c a n va r y gr e a t l y i n hyd r oge n bonde d s ys t e m s e ve n w i t hi n t he s a m e bondi ng pa r t ne r s H ydr oge n bondi ng c a t a l ys i s c a n t r a c e i t r oot s ba c k t o a l ka l oi d c a t a l yz e d c onj uga t e a ddi t i on r e a c t i ons I n 1981 W ynbe r g a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve a ddi t i on of t hi ol s t o uns a t ur a t e d ke t one s c a t a l yz e d by qui ni ne qui ni di ne c i nc honi ne a nd c i nc honi di ne 3 2 E a c h of t he s e a l ka l oi ds c ont a i ns a f r e e hydr ox yl gr oup i n c l os e pr oxi m i t y t o t he ba s i c qui nuc l i di ne ni t r oge n T h e us e 1 m ol % of t he a l ka l oi d c a t a l ys t a l l ow e d f or t he s ynt he s i s of t he p r oduc t i n up t o 75 % e e

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14 1. 3. 1 C h i r al T h i ou r e a C a t al ys i s W hi l e t he i ni t i a l r e po r t s of hyd r oge n bondi ng c a t a l ys i s w a s r e por t e d i n t he e a r l y 1980 s i t w a s not unt i l 1998 t ha t t he pr a c t i c a l a ppl i c a t i on of c hi r a l hydr oge n bondi ng c a t a l ys t s w a s f i r s t r e por t e d by J a c obs e n a nd c o w or ke r s ( T a bl e 1. 6) 3 3 D ur i ng t he s c r e e ni ng of a l i br a r y o f c hi r a l l i ga nds f o r t he a l u m i num c a t a l yz e d a ddi t i on of hydr oge n c ya ni de t o i m i ne s a l s o know n a s t he S t r e c ke r r e a c t i on, i t w a s di s c ove r e d t ha t c hi r a l ur e a a nd t hi our e a c om pounds w e r e c a pa bl e of c a t a l yz i ng t he r e a c t i on. T he de ve l ope d m e t hodol ogy ga ve t he p r oduc t i n bot h e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t y f or bo t h a r om a t i c a nd a l i pha t i c s ubs t i t ut e d i m i ne s T ab l e 1. 6. T h i ou r e a C at al yz e d E n an t i os e l e c t i ve S t r e c k e r R e ac t i on S i nc e t he i ni t i a l r e por t c hi r a l ur e a a nd t hi ou r e a c a t a l ys t s ha ve be e n s how n t o be e xc e l l e nt c a t a l ys t s f or t he a ddi t i on of a w i de r a nge of nuc l e ophi l e s i nc l udi ng t he e na nt i os e l e c t i ve a ddi t i ons of ni t r oa l ka ne s a nd s i l yl ke t e ne a c e t a l s t o i m i ne s 3 4 3 5 T he

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15 m e c ha ni s m f or t he r e a c t i on f i r s t i nvol ve s t he f or m a t i on of hydr oge n bonds be t w e e n t he c a t a l ys t a nd t he e l e c t r ophi l e ( F i gur e 1. 6 ) T he t h i our e a c a t a l ys t w a s f ound t o f or m t w o hydr oge n bonds w i t h t he e l e c t r ophi l e T he f or m a t i on of t w o hydr o ge n bonds be t w e e n t he e l e c t r ophi l e a nd t he c a t a l ys t a l l ow s f o r t he f or m a t i on of a r i gi d c hi r a l i nt e r m e di a t e I t w a s a l s o f ound t o b e i m por t a nt t ha t t he c a t a l ys t i s s ub s t i t ut e d w i t h gr oups t ha t a r e c a pa bl e of s e c onda r y i nt e r a c t i ons w i t h t he r e a c t a nt s F i gu r e 1. 6 M e c h an i s m f or A c t i va t i on o f E l e c t r op h i l e b y T h i ou r e a C at al ys t s T hi our e a de r i ve d c a t a l ys t s ha ve a l s o be e n s how n t o be e xc e l l e nt c a t a l ys t f or a va r i e t y of c yc l i z a t i on r e a c t i ons I n 2004 J a c obs e n a nd c o w or ke r s r e por t e d t he a ppl i c a t i on of a c hi r a l t hi our e a c a t a l ys t f or t he e na nt i os e l e c t i ve N a c yl P i c t e t S pe ngl e r r e a c t i on ( T a bl e 1. 7) 3 6 T he r e a c t i on i nvol ve d t he a c t i va t i on of a n i m i ne de r i ve d f r om t r ypt a m i ne w i t h a c e t yl c hl or i de T he t hi ou r e a c a t a l ys t w a s be l i e ve d t o hydr oge n bond t o t he N a c yl gr oup t o he l p a c t i va t e t he i m i ni u m i on T he r e s ul t i ng t e t r a hydr o c a r bol i ne pr oduc t s w e r e f or m e d i n hi gh yi e l d a nd e xc e l l e nt e e w he n t he i m i ne s w e r e de r i ve d f r om a l i pha t i c a l de hyde s T he us e of a r om a t i c s ubs t i t ut e d i m i ne s w a s not r e por t e d.

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16 T ab l e 1. 7. T h i ou r e a C at al yz e d N A c yl P i c t e t S p e n gl e r R e ac t i on J a c obs e n a nd c ow or ke r s r e por t e d t ha t c hi r a l t hi o ur e a c a t a l ys t s w e r e c a pa bl e of c a t a l yz i ng t he P i c t e t S pe ngl e r r e a c t i on of hydr oxyl a c t a m s 3 7 T he de ve l ope d m e t hodol ogy w a s c a p a bl e of s ynt he s i z i ng bot h c hi r a l i ndol i z i di none s a nd qui nol i z i di none s i n bot h e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s T he r e a c t i on i nvol ve s t he c onv e r s i on of hydr oxy gr oup of hydr oxyl a c t a m s t o a c hl or i de w i t h T M S C l T he r e s ul t i ng ha l oge na t e d c om pound i s t he n t r e a t e d w i t h t he t hi our e a c a t a l ys t T hi s i s be l i e ve d t o r e s ul t i n t he f or m a t i on of a c hi r a l i on pa i r w hi c h t he n unde r goe s c yc l i z a t i on t o f or m t he r e s ul t i ng pr oduc t s ( F i gur e 1. 5 )

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17 F i gu r e 1. 7 M e c h an i s m o f P i c t e t S p e n gl e r C yc l i z at i on of H y d r oxyl ac t am I n 2008, J a c obs e n a nd c o w or ke r s e xt e nde d t he us e of t hi our e a s a s i on pa i r c a t a l ys t s t o t he e na nt i os e l e c t i ve a ddi t i on of s i l yl ke t e ne a c e t a l s t o oxoc a r be ni um i ons ( T a bl e 1. 8) 3 8 S uc h m e t hodol ogy ha d pl a ye d a m a j or r ol e i n t he de ve l opm e nt of c a r bohydr a t e m e t hodol ogy; how e ve r i t ha d not be e n e xpl oi t e d i n t he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy. T he oxoc a r be ni um i ons w e r e ge ne r a t e d by t r e a t m e nt of a # c hl or ogl yc os yl c om pound w i t h t he c hi r a l t hi our e a c a t a l ys t r e s ul t i ng i n t he f or m a t i on o f a c hi r a l i on pa i r T he s i l yl ke t e ne a c e t a l t he n a dds t o t he ge ne r a t e d oxoc a r be ni um i on r e s ul t i ng i n t he f or m a t i on o f t h e e t he r i n e xc e l l e nt yi e l d a nd e e T he r e a c t i on w a s c a pa bl e of t ol e r a t i ng a va r i e t y of s i l yl ke t e ne a c e t a l s

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18 T ab l e 1. 8. T h i ou r e a C at al yz e d A d d i t i on s t o O x oc ar b e n i u m I on s T hi our e a c a t a l ys t s ha ve ha d a br oa d i m p a c t on t he de ve l opm e nt of or ga noc a t a l yt i c e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy B e ds i de s t he r e a c t i ons di s c u s s e d he r e t hi our e a c a t a l ys t s h a ve be e n us e d f or t he de ve l opm e nt of e na nt i os e l e c t i ve M or i t a B a yl i s s H i l l m a n r e a c t i on, r e s ol ut i on of a z a l a c t one s a nd c ya nos i l yl a t i on of ke t one s a s w e l l a s m a ny ot he r r e a c t i ons 2 9 1. 3. 2 E n an t i os e l e c t i ve D i ol C at al ys i s C hi r a l di ol s ha ve h a d a l ong hi s t or y i n t he de ve l opm e nt of e na nt i os e l e c t i v e r e a c t i on m e t hodol ogy. 4 M a ny di ol s ha d be e n e m pl oye d a s c hi r a l l i ga nds f or t he de ve l opm e nt of e na nt i os e l e c t i ve L e w i s a c i d c a t a l yz e d r e a c t i on m e t hodol ogy m os t not a bl y t he a ppl i c a t i on o f t a r t r a t e s by S ha r pl e s s a n d c o w or ke r s f o r t he t i t a ni um c a t a l yz e d e poxi da t i on of a l l yl i c a l c ohol s I t w a s not unt i l 2 003 t ha t c hi r a l di ol s w e r e s how n t o be e xc e l l e nt c a t a l ys t s f or t he de ve l opm e nt of e na nt i os e l e c t i ve or ga n oc a t a l yt i c r e a c t i on

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19 m e t hodol ogy. I n t ha t ye a r R a w a l a nd c o w o r k e r s r e por t e d t he T A D D O L c a t a l yz e d, e na nt i os e l e c t i ve he t e r o D i e l s A l de r r e a c t i on be t w e e n a l de hyde s 16 a nd K oz m i n s di e n e 56 ( T a bl e 1. 9) 3 9 T he r e a c t i on w a s c a pa bl e of t ol e r a t i ng a w i de va r i e t y of s ubs t i t ue nt s on t he a l de hyde T he r e a c t i on r e s ul t e d i n t he f or m a t i on of t he c yc l oa dduc t s i n good yi e l d s a nd e xc e l l e nt e na nt i o s e l e c t i vi t i e s S oon a f t e r t h e i ni t i a l r e por t R a w a l a nd c o w or ke r s r e por t e d t ha t t he B A M O L l i ga nd w a s c a pa bl e of c a t a l yz i ng t he s a m e t r a ns f or m a t i on. T he B A M O L c a t a l ys t ga ve t he pr oduc t i n hi ghe r yi e l d t ha n t he r e a c t i on c a t a l yz e d by T A D D O L w i t h s i m i l a r e na nt i os e l e c t i vi t i e s 4 0 T ab l e 1. 9. T A D D O L C a t al yz e d E n an t i os e l e c t i v e H e t e r o D i e l s A l d e r R e ac t i on I n 2003, S c ha us a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve M or i t a B a yl i s H i l l m a n r e a c t i on be t w e e n a l de hyde s a nd c yc l i c e none s c a t a l yz e d by a c hi r a l B I N O L de r i va t i ve ( T a bl e 1. 10) 4 1 T he r e a c t i on ga ve t he B a yl i s H i l l m a n a dduc t i n e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t y f or a l i pha t i c s ubs t i t ut e d a l de hyde s T he p r e s e nc e of a r om a t i c s ubs t i t ue nt s on t he a l de hyde r e s ul t e d i n a de c r e a s e i n bot h t he yi e l d a nd e na nt i os e l e c t i vi t y of t he r e s ul t i ng pr oduc t I t i s a l s o w or t h not i ng t ha t w he n one of t he phe nol g r oups on t he

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20 c a t a l ys t i s pr ot e c t e d w i t h a m e t hyl gr oup i t r e s ul t s i n a m a r ke d de c r e a s e i n bot h t he yi e l d a nd e na nt i os e l e c t i vi t y. T ab l e 1. 10. B I N O L C at a l yz e d M or i t a B ayl i s H i l l m an R e ac t i o n A f e w ye a r s a f t e r t he i ni t i a l r e por t by S c ha us S a s a i a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve a z a M or i t a B a yl i s H i l l m a n r e a c t i on be t w e e n N t os yl i m i ne s a nd uns a t ur a t e d ke t one s ( T a bl e 1. 11) 4 2 T he c a t a l ys t e m pl oye d f or t he r e a c t i on w a s a B I N O L de r i va t i ve t ha t ha d bot h t he B r ons t e d a c i di c ph e nol gr oups a nd L e w i s ba s i c pyr i di ne s ubs t i t ue nt T hi s r e m ove s t he ne e d f or a s e pa r a t e nuc l e ophi l e t ha t i s r e qui r e d t o a c t i va t e t he ke t one V a r i a t i on of t he c a t a l y s t s t r uc t ur e s h ow e d a m a r ke d di f f e r e nc e i n bot h t he yi e l d a nd t he e na nt i os e l e c t i vi t y of t he pr oduc t R e m ova l of t he e l e c t r on dona t i ng s ubs t i t ue nt on t he pyr i di ne r i ng r e s ul t e d i n no r e a c t i on. I t w a s a l s o s how n t ha t pr ot e c t i on of t he phe nol gr oups of t he c a t a l y s t r e s ul t e d i n a n i na c t i ve c a t a l ys t T he c onc l u s i ons t ha t w e r e dr a w n ba s e d upon t he e xpe r i m e nt a l da t a w a s t ha t bot h t he B r ons t e d a c i d a nd L e w i s

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21 ba s i c c om pone nt s of t he c a t a l ys t w e r e r e qui r e d i n or de r t o obt a i n t he p r oduc t s i n e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s T ab l e 1. 11. B i f u n c t i on al O r gan oc at al y t i c A z a M or i t a B ayl i s s H i l l m an R e ac t i on 1. 3. 3 E n an t i os e l e c t i ve P h os p h or i c A c i d C a t al y s i s B r ons t e d a c i d s ha v e be e n s how n t o be e xc e l l e nt c a t a l ys t s f or a w i de va r i e t y of t r a ns f or m a t i ons s uc h a s a c e t a l f or m a t i on, e s t e r i f i c a t i on, a nd hydr ol ys i s 4 3 4 4 I t w a s not unt i l r e c e nt l y, how e ve r t ha t t he de ve l opm e nt of c hi r a l B r ons t e d a c i ds h a s b e e n e xpl oi t e d a s c a t a l y s t s f or e na nt i os e l e c t i ve r e a c t i ons W hi l e t he c hi r a l di ol s a nd T hi our e a c a t a l ys t s t ha t ha ve be e n pr e vi ous l y di s c us s e d a r e c ons i d e r e d t o be B r ons t e d a c i d c a t a l y s t s t he y a r e c ons i de r e d t o be ne ut r a l B r ons t e d a c i ds t ha t a r e ge ne r a l l y a s s oc i a t e d w i t h a c t i va t i on by hydr oge n bondi ng. W hi l e t he s e c a t a l ys t s ha ve be e n s how n t o be e xc e l l e nt c a t a l ys t f or a w i de va r i e t y of t r a ns f or m a t i ons m a ny r e a c t i ons r e qui r e t he us e of B r ons t e d a c i ds t ha t a r e be t t e r pr ot on donor s T he f i r s t r e po r t of a n e na nt i os e l e c t i ve t r a ns f or m a t i ons t ha t

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22 e m pl oye d a s t r onge r B r ons t e d a c i d w a s t he a z a H e nr y r e a c t i on by J ohn s t on a nd c o w or ke r s i n 2004 ( T a bl e 1. 12) 4 5 T he r e s e a r c he r s e m pl oye d a c hi r a l a m m oni um s a l t a s a B r ons t e d a c i d c a t a l y s t T he r e a c t i on pr ovi de d t he pr o duc t s r e s ul t i ng f r om t he a ddi t i on of ni t r oa l ka ne s t o N B oc pr ot e c t e d i m i ne s i n e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s T he r e a c t i on a l l ow s f or t he e xpe di e nt s ynt he s i s of c h i r a l vi c i na l di a m i ne s P e r r i n t i t r a t i on s t udi e s on t he c a t a l ys t l e d t o t he de t e r m i na t i on t ha t t he pK a o f t he c a t a l ys t w a s 5. 74. 4 6 T ab l e 1. 12. A m m on i u m S al t C a t al yz e d A z a H e n r y R e ac t i on I n 2004, A ki ya m a a nd c o w or ke r s r e por t e d t he us e of a c hi r a l phos phor i c a c i d de r i ve d f r om B I N O L f or t he de ve l opm e nt of a n e na nt i os e l e c t i ve M a nni c h r e a c t i on be t w e e n s i l yl ke t e ne a c e t a l s a nd i m i ne s ( T a bl e 1. 13) 4 7 T he phos phor i c a c i d c a t a l ys t a r e c ons i de r e d by s om e t o be bi f unc t i ona l i n na t ur e c ont a i ni ng bot h a B r ons t e d a c i di c hydr oge n a nd a L e w i s ba s i c oxyge n on t he phos ph or i c a c i d. T he B I N O L f r a m e w or k w a s e m pl oye d a s t he c hi r a l ba c kbone due t o t he e a s e i n w hi c h i t m a y be m odi f i e d i n o r de r t o

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23 t une bot h t he e l e c t r oni c s a s w e l l a s t he s t e r i c bul k of t he c a t a l ys t T he phos phor i c a c i d t ha t ga ve t he be s t r e s ul t s i n t e r m s of bot h yi e l d a nd e na nt i os e l e c t i vi t y of t he pr oduc t w a s a B I N O L phos phor i c a c i d t ha t w a s s ubs t i t ut e d i n t he 3 a nd 3 pos i t i on s w i t h a p t r i f l uor om e t hy l phe nyl gr oup. T he us e of e l e c t r on dona t i ng a r om a t i c s ubs t i t ue nt s on t he s e pos i t i ons s how e d a r e m a r ke d de c r e a s e i n bot h t he e na nt i os e l e c t i vi t y a nd yi e l d of t he r e s ul t i ng pr oduc t T he de ve l ope d m e t hodol ogy a l l ow s f or t he s ynt he s i s of c hi r a l a m i no a c i d de r i va t i ve s T he r e po r t e d m e t hodol ogy t ol e r a t e d a va r i e t y o f s ubs t i t ue nt s on bot h t he i m i ne a nd t he s i l yl ke t e ne a c e t a l r e a c t a nt s T ab l e 1. 13. A k i yam a s P h os p h or i c A c i d C at a l y z e d M an n i c h R e ac t i on S oon a f t e r t he i ni t i a l r e por t by A ki ya m a a nd c o w or ke r s T e r a da a nd c o w or ke r s r e por t e d t he M a nni c h r e a c t i on of a c e t yl a c e t one w i t h N B oc pr ot e c t e d i m i ne s c a t a l yz e d b y a phos phor i c a c i d c a t a l ys t de r i ve d f r om B I N O L ( T a bl e 1. 14 ) 4 8 I n t hi s c a s e a c a t a l ys t w i t h m or e s t e r i c a l l y de m a ndi ng s ubs t i t ue nt s i n t he 3, 3 pos i t i ons of B I N O L w e r e

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24 r e qui r e d i n or de r t o pr ovi de t he p r oduc t i n be s t yi e l d a nd e na nt i os e l e c t i vi t y. T he phos phor i c a c i d t ha t pr ove d t o be be s t f or t he r e a c t i on i n t e r m s of bot h yi e l d a n d e na nt i os e l e c t i vi t y ha d # na pht hyl C 6 H 4 s ub s t i t ue nt s i n t he 3 a nd 3 pos i t i ons of B I N O L T he r e a c t i on w a s a bl e t o t ol e r a t e a w i de v a r i e t y of a r om a t i c s ubs t i t ue nt s on t he i m i ne a l l r e s ul t i ng i n t he f or m a t i on o f t he pr oduc t i n g r e a t e r t ha n 94% yi e l d a nd 92% e e T he r e a c t i on e m pl oye d 2 m ol % of t he c hi r a l phos p hor i c a c i d, a de c r e a s e i n t he c a t a l ys t l oa di ng w he n c om pa r e d t o A ki ya m a s M a nni c h r e a c t i on. T ab l e 1. 14. T e r ad a s P h os p h or i c A c i d C at al yz e d M an n i c h R e ac t i on T he m os t w i de l y a c c e pt e d m e c ha ni s m f or t he a c t i va t i on of i m i ne s w i t h phos phor i c a c i ds ha s be e n t he t r a ns f e r of t he p r ot on f r om t he c a t a l ys t t o t he i m i ne ni t r oge n a t om ( F i gu r e 1. 8 ) T hi s r e s ul t s i n t he f or m a t i on of a c hi r a l i on pa i r w hi c h bl oc ks one f a c e of t he i m i ne f r om a t t a c k by t he nuc l e op hi l e T he nuc l e ophi l e t he n a t t a c ks t h e

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25 ope n f a c e of t he i m i ne r e s ul t i ng i n t he f or m a t i on of t he pr oduc t a nd r e f or m i ng t he a c i d c a t a l ys t s o t ha t i t m a y go t h r ough t he c a t a l yt i c c yc l e a ga i n. F i gu r e 1. 8 C at al y t i c C yc l e o f I m i n e A c t i vat i on b y C h i r al P h os p h or i c A c i d s S i nc e t he i ni t i a l r e por t s o f t he a ppl i c a t i on of c hi r a l phos phor i c a c i ds f or t he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t ho dol ogy, s e ve r a l ot he r r e s e a r c h gr oups ha ve s how n t h a t c hi r a l phos phor i c a c i ds m a y be e m pl oye d a s c a t a l ys t s f or a va r i e t y of e na nt i os e l e c t i ve t r a ns f or m a t i ons T he s e t r a ns f or m a t i ons i nc l ude t he a ddi t i on of nuc l e ophi l e s t o i m i ne s r e duc t i on of i m i ne s r e duc t i on of i m i no e s t e r s t he P i c t e t S pe ngl e r r e a c t i on, a nd va r i o us c yc l oa ddi t i on r e a c t i ons 4 4

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26 C h ap t e r 2 E n an t i os e l e c t i ve B r on s t e d A c i d C a t al yz e d A m i d at i on o f I m i n e s I m i ne s ha ve be e n s how n t o ve r s a t i l e i nt e r m e di a t e s f or t he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy. 4 T he a ddi t i ons of nuc l e ophi l e s t o i m i n e s a l l ow s f or t he e xpe di e nt s ynt he s i s of c hi r a l a m i ne s C hi r a l a m i ne s pl a y a n i m por t a nt r ol e i n m a ny bi ol ogi c a l l y a c t i ve c om pounds A r e c e nt s ur ve y of s e ve r a l pha r m a c e ut i c a l c om pa ni e s s how e d t ha t a ppr oxi m a t e l y 90% of t he ne w dr ug c a ndi da t e s c ont a i n a t l e a s t one ni t r oge n a t om 3 I n t he s a m e s ur ve y, i t w a s s how n t ha t 54% of t he dr ug c a ndi da t e s i n de ve l opm e nt c ont a i n a t l e a s t one c hi r a l c e nt e r A l l but t w o of t he dr ug c a ndi da t e s t ha t w e r e be i ng de ve l ope d w e r e be i ng s ynt he s i z e d a s s i ngl e e na nt i om e r s T o da t e t he m os t c om m on m e t hod ut i l i z e d by t he pha r m a c e ut i c a l c om pa ni e s f or t he s ynt he s i s of c hi r a l c om pounds ha s be e n t he r e s ol ut i on of r a c e m i c i nt e r m e di a t e s T hi s m e t hod, w hi l e be i ng t he m os t de pe nda bl e a nd c os t e f f i c i e nt m e t hod t o da t e ha s m a ny dr a w ba c ks w h e n c om pa r e d t o c a t a l yt i c e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy. I t pr oduc e s m or e w a s t e t ha n c a t a l yt i c m e t hodol ogy a nd i t a l s o r e qui r e s t he us e of s t oi c hi om e t r i c a m ount s of of t e n e xpe ns i ve c hi r a l r e a ge nt s A l l of t he pr e vi ous l y r e por t e d e na nt i os e l e c t i ve r e a c t i ons i nvol vi ng t he a ddi t i on of nuc l e ophi l e s t o i m i ne s e m pl oye d c a r bon nuc l e o phi l e s t o i m i ne s W e e nvi s i one d t h e de ve l opm e nt of a ne w a r e a of e na nt i o s e l e c t i ve r e a c t i on m e t hodol ogy e m pl oyi ng he t e r oa t om nuc l e ophi l e s T he f i r s t nuc l e ophi l e t ha t w e f oc u s e d our e f f or t s on w a s a m i de

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27 nuc l e ophi l e s T he r e s ul t i ng pr ot e c t e d N N a m i na l s ha d be e n s how n t o b e bi ol ogi c a l l y a c t i ve w he n i nc or por a t e d i nt o pe pt i de c ha i ns 2. 1. R e t r o I n ve r s o P e p t i d e M i m i c s I n t he l a t e 1970 s G oodm a n a nd c o w or ke r s r e por t e d t he de ve l opm e nt o f r e t r o i nve r s o pe pt i de m i m i c s ( F i gur e 2. 1) 4 9 R a t he r t ha n t he t ypi c a l m a nne r i n w hi c h pe pt i de s w e r e a s s e m bl e d, G oodm a n a nd c o w or ke r s pr e pa r e d pe pt i de s i n w hi c h t he or de r s of t he pe pt i de bonds w e r e r e ve r s e d. P e pt i de s s uc h a s 79 ha ve be e n s how n t o ha ve hi gh l e ve l s of bi ol ogi c a l a c t i vi t y. T he y ha ve be e n s how n t o be s om a t os t a t i ns gl yc os i da s e i nhi bi t or s a nd ha ve be e n i nc or por a t e d i nt o a r t i f i c i a l s w e e t e ne r s F i gu r e 2. 1 R e t r o I n ve r s o P e p t i d e M i m i c s S e ve r a l m e t hods w e r e s oon de ve l ope d f or t h e s ynt he s i s of t he r e t r o i nve r s o pe pt i de m i m i c s ( F i gur e 2 2) T he e a r l i e s t s y nt he t i c m e t hods e m pl oye d a C ur t i us r e a r r a nge m e nt of i s oc ya na t e s a nd H of m m a n t ype r e a r r a nge m e nt us i ng m i l d oxi di z i ng a ge nt s T hi s r e s ul t e d i n t he s ynt he s i s of t he a m i na l pr oduc t i n good yi e l d O t he r s ynt he t i c m e t hods f or t he s ynt he s i s of r e t r o i n ve r s o pe pt i de m i m i c s ha ve be e n t he a m i doa l kyl a t i on of t hi ol s a s w e l l a s t he be n z ot r i a z ol e m e di a t e d m e t hodol ogy de ve l ope d by K a t r i t z ky a nd c o w or ke r s 5 0 W hi l e t he s e m e t hods a r e a l l c a pa bl e of s ynt he s i z i ng a va r i e t y of N N a m i na l s t he y r e qui r e m ul t i pl e s t e ps s om e a s m a ny a s f our s t e ps ha r s h r e a c t i on c ondi t i ons a nd r e s ul t i n t he f or m a t i on o f t he a m i na l pr oduc t s i n r a c e m i c f or m T hi s a dds a n a ddi t i ona l s t e p on t o t he s ynt he s i s of t he a m i n a l pr oduc t s i n or de r t o obt a i n

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28 t he e na nt i om e r i c pur e a m i na l S ol i d pha s e m e t h ods ha ve a l s o be e n de ve l ope d f or t he s ynt he s i s of r e t r o i nve r s o pe pt i de m i m i c s V e r di ni a nd c o w or ke r s ha ve de ve l ope d s ol i d pha s e m e t hod s t ha t c a n b e ut i l i z e d t o c a r r y out o xi da t i ve H of m a nn t ype r e a r r a nge m e nt r e s ul t i ng i n t he f or m a t i on of t he r e t r o i nve r s o pe pt i de m i m i c i n e xc e l l e nt yi e l d. 5 1 F i gu r e 2. 2 M e t h od s f or t h e S y n t h e s i s of R e t r o I n ve r s o P e p t i d e M i m i c s 2. 2. D e ve l op m e n t of B r on s t e d A c i d C at al yz e d A m i d at i on of I m i n e s T h e a ddi t i on of a m i de s t o i m i ne s c a n be t r a c e d b a c k t o t he l a t e 1800 s I n 1870, R ot h r e por t e d t he s ynt he s i s of be n z yl i de ne di a c e t a m i de by he a t i ng a n e a t m i xt ur e of

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29 a c e t a m i de a nd be nz a l de hyde ( F i gur e 2. 3) 5 2 T he r e s ul t i ng a m i na l w a s f or m e d i n e xc e l l e nt yi e l d F i gu r e 2. 3 C on d e n s at i on of B e n z al d e h yd e w i t h A c e t am i d e S oon a f t e r t he r e por t by R ot h, B i s c hof f r e por t e d a s i m i l a r r e a c t i on be t w e e n ur e t ha ne a nd a s e r i e s of a l de hyde s 5 3 B i s hof f a l s o r e por t e d t he c onde ns a t i on of u r e t ha ne w i t h c hl or a l a nd br om a l H ow e ve r i n t he s e c a s e s a m i xt ur e of pr oduc t s w a s f or m e d T he pr oduc t s w e r e t he N N a m i na l pr oduc t a s w e l l a s t he N O a m i na l pr oduc t w hi c h f or m s by t he s i m pl e a ddi t i on of t he a m i de t o t he a l de hyde I n t he 1960 s D r a c h a nd c o w or ke r s r e por t e d t he a ddi t i o n o f a m i de nuc l e op hi l e s t o i m i ne s de r i ve d f r om c hl o r a l ( F i gur e 2 4) 5 4 F i gu r e 2. 4 A d d i t i on of A m i d e s t o C h l or al D e r i ve d I m i n e s A s one c a n s e e t he m e t hods r e por t e d i n t he l i t e r a t ur e ge ne r a l l y r e qui r e ha r s h r e a c t i on c ondi t i ons or t he us e of i m i ne s w i t h t w o e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s W e f e l t t ha t t he de ve l opm e nt a c a t a l yt i c m e t hod f or t he a ddi t i on of a m i de nuc l e ophi l e s t o i m i ne s w oul d a l l ow f or a n e xpe di e nt r out e f or t he s ynt he s i s of N N a m i na l s T he

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30 r e s ul t i ng a m i na l pr oduc t s c oul d ha ve pot e nt i a l f or i nc or por a t i on i nt o pe pt i de c ha i ns i n or de r t o de ve l op pot e nt i a l l y ne w r e t r o i nve r s o pe pt i de m i m i c s O ur a ppr oa c h t o t he de ve l opm e nt of a c a t a l yt i c m e t hod f or t he a ddi t i on of a m i de s t o i m i ne s w a s t o e m pl oy B r ons t e d a c i d c a t a l y s t s f or t he a ddi t i o n of a m i de s t o i m i ne s c ont a i ni ng a n a c yl t ype pr ot e c t i ng gr oup on t he ni t r oge n a t om of t he i m i ne W e s a w t hi s r e a c t i on t o be s om e w ha t a na l ogous t o t he c a t a l yt i c m e t hods f or t he M i c ha e l a ddi t i on of a m i de s t o e na l s a nd e none s t ha t ha d be e n pr e vi o us l y r e por t e d i n t he l i t e r a t ur e ( F i gur e 2. 5) 5 5 T he w or k of S pe nc e r a nd c o w or ke r s w a s e s pe c i a l l y not e w or t hy i n t hi s c a s e 5 5 a S pe nc e r a nd c o w or ke r s r e por t e d t he a ddi t i on of a m i de s t o a v a r i e t y of M i c ha e l a c c e pt or s c oul d be c a t a l yz e d by 10 m ol % of t he s t r ong B r on s t e d a c i d t r i f l uor om e t ha ne s ul f oni m i de T he r e a c t i on s how e d br oa d s c ope i n t e r m s of t h e a m i de nuc l e ophi l e s a nd t he M i c ha e l a c c e pt or s F i gu r e 2. 5 H yp o t h e s i s f or t h e A m i d a t i on of I m i n e s W e be ga n our i ni t i a l i nve s t i ga t i ons by s c r e e ni ng a va r i e t y of a c hi r a l B r ons t e d a c i ds f or t he a ddi t i on of a c r yl a m i de t o N B o c pr ot e c t e d i m i ne s i n e t he r a t r oom t e m pe r a t ur e ( T a bl e 2. 1 ) 5 6 T he r e a c t i on be t w e e n a c r yl a m i de a nd 1. 1 e qui va l e nt s of i m i ne pr ovi de d t he a m i na l pr oduc t i n 55% yi e l d. B y i nc r e a s i ng t he i m i ne r a t i o t o t w o e qui va l e nt s of i m i ne t he pr oduc t w a s f or m e d i n 9 5 % yi e l d. I t w a s de t e r m i ne d a f t e r t he

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31 s c r e e ni ng of t he B r ons t e d a c i d c a t a l ys t t ha t t r i f l uor o m e t ha ne s ul f oni m i de a nd phe nyl phos phi ni c a c i d w e r e e xc e l l e nt c a t a l y s t s f or t he a ddi t i ons of a m i de nuc l e ophi l e s t o i m i ne s C a r boxyl i c a c i d c a t a l ys t s r e s ul t e d i n t h e f or m a t i on of t he pr oduc t i n l ow t o m ode r a t e yi e l d. A s t h e pK a of t he a c i d d e c r e a s e d, t he r e a c t i on w a s f ound t o be m or e e f f i c i e nt T ab l e 2. 1. A c i d C at al ys t S c r e e n i n g H a vi ng de t e r m i ne d t he op t i m um c a t a l ys t a nd r e a c t i on c ondi t i ons w e ne xt s ought t o de t e r m i ne t he s c ope of t he r e a c t i on i n t e r m s of t he a m i de nuc l e ophi l e s ( T a bl e 2. 2) I t w a s s oon di s c ove r e d t ha t t he de ve l ope d c a t a l yt i c s ys t e m c oul d t ol e r a t e a va r i e t y of a m i de nuc l e ophi l e s T he a ddi t i on of m e t ha ne s ul f ona m i de a nd p t ol ue ne s ul f ona m i de t o N B oc pr ot e c t e d i m i ne s pr ovi de d t he r e s pe c t i ve a m i na l pr oduc t s i n 99% a nd 91% yi e l d ( E nt r i e s 1 2) T he de ve l ope d r e a c t i on w a s a l s o c a pa bl e of c a t a l yz i ng t he a ddi t i ons of c a r ba m a t e nuc l e ophi l e s t o N B oc pr ot e c t e d, a l l r e s ul t i ng i n t he f or m a t i on of t he a m i na l p r oduc t s i n

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32 e xc e l l e nt yi e l ds T he a ddi t i on of t he c a r ba m a t e nuc l e ophi l e ur e t ha ne ga ve t he a m i na l pr oduc t i n 91% yi e l d ( E nt r y 3) T he a ddi t i on o f be nz yl c a r ba m a t e pr ovi de d t he a m i na l pr oduc t i n 81% yi e l d ( E nt r y 4) T he a ddi t i on o f a m i de nuc l e ophi l e s w a s a l s o t ol e r a t e d by t he de ve l ope d c a t a l yt i c s y s t e m T he a ddi t i on of a c r yl a m i de a c e t a m i de f or m a m i de a nd be nz a m i de a l l ga v e t he a m i na l pr oduc t s i n e xc e l l e nt yi e l d ( E nt r i e s 5 8) T he us e of 3, 5 d i m e t hoxybe nz a m i de a s a nuc l e ophi l e r e s ul t e d i n t he f or m a t i on of t he a m i na l p r oduc t i n 84% yi e l d ( E nt r y 9) H ow e ve r t he e m pl oy m e nt of 3, 5 di ni t r obe nz a m i de a s t he nuc l e ophi l e s how e d a m a r ke d de c r e a s e i n t he yi e l d of t he a m i na l pr oduc t w he n c om pa r e d t o 3, 5 di m e t hoxybe nz a m i de ( E nt r y 10) T hi s w a s pr oba bl y due t o t he de c r e a s e d nuc l e ophi l i c i t y of t he 3, 5 di ni t r obe nz a m i de due t o t he pr e s e nc e e l e c t r on w i t hdr a w i ng ni t r o s ubs t i t ue nt s on t he a r om a t i c r i ng.

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33 T ab l e 2. 2. V ar i at i on o f t h e A m i d e N u c l e op h i l e s W i t h t he r e a c t i on s how i ng br oa d s c ope i n t e r m s of t he a m i de nuc l e ophi l e w e ne xt t ur ne d our a t t e nt i on t o t he s c ope of t he r e a c t i on i n t e r m s of t he i m i ne e l e c t r ophi l e ( T a bl e 2. 3) T he r e a c t i ons w e r e s c r e e n e d e m pl oyi ng a c r yl a m i de a s t he nuc l e op hi l e a nd phe nyl phos phi ni c a c i d a s t he c a t a l ys t T he pr e s e nc e of e l e c t r on dona t i ng s ubs t i t ue nt s a l l r e s ul t e d i n t he f or m a t i on o f t he a m i na l pr oduc t s i n gr e a t e r t ha n 91% yi e l d ( E nt r i e s 2 a nd 4) E l e c t r on w i t hdr a w i ng gr oups on t he a r om a t i c r i ng of t he i m i n e a l s o r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n e xc e l l e nt yi e l d. F or e xa m pl e t he us e of t he 4 br om ophe nyl s ubs t i t ut e d N B oc pr ot e c t e d i m i ne r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n 94% yi e l d ( E nt r y 3) T he us e of he t e r oa r om a t i c s ub s t i t ue nt s on t he i m i ne e l e c t r ophi l e pr oduc e d t h e

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34 a m i na l i n e xc e l l e nt yi e l d. T he us e of t he 2 f u r yl a nd 2 t hi e nyl s ubs t i t ut e d ga ve t he r e s pe c t i ve a m i na l pr oduc t s i n 91 % a nd 99 % yi e l d ( E nt r i e s 4 5 ) T ab l e 2. 3. V ar i at i on o f I m i n e S u b s t r at e 2. 3. E n an t i os e l e c t i ve B r on s t e d A c i d C at al yz e d A m i d at i on o f I m i n e s N ow know i ng t ha t B r ons t e d a c i ds w e r e c a pa bl e of c a t a l yz i ng t he a ddi t i on of a va r i e t y of a m i de nuc l e ophi l e s t o i m i ne s w e ne xt s ought t o de ve l op a n e na nt i os e l e c t i ve m e t hod f or t he a ddi t i ons of a m i de s t o i m i ne s B a s e d upon t he w or k of T e r a da w e f i r s t s ought t o e m pl oy t he know n phos phor i c a c i ds de r i ve d f r om B I N O L T he r e a c t i ons of a m i de s a nd c a r ba m a t e s u s i ng B I N O L de r i ve d phos phor i c a c i d c a t a l ys t s r e s ul t e d i n t h e f or m a t i on of t he a m i na l pr oduc t s i n e xc e l l e nt yi e l ds b ut t he e na nt i os e l e c t i vi t i e s f or t he r e a c t i ons w a s e xt r e m e l y l ow W e s oon d i s c ove r e d t ha t t he a ddi t i on of p t ol ue ne s ul f ona m i de t o N B oc pr ot e c t e d i m i ne s s h ow e d s om e s e l e c t i vi t y ( 5 % e e ) w he n e m pl oyi ng B I N O L phos phor i c a c i d ( E nt r y 1 ) T h e us e of a B I N O L ph os phor i c a c i d w i t h 4 ( 2 na pht hyl ) phe nyl s ubs t i t ue nt s i n t he 3 a nd 3 pos i t i on s how e d a n i nc r e a s e i n t he

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35 e na nt i os e l e c t i vi t y of t he r e a c t i on t o 60% e e ( E nt r y 2) T he us e of t he m o r e s t e r i c a l l y de m a ndi ng 4 ( 1 na pht hyl ) phe nyl s ubs t i t ut e d B I N O L phos phor i c a c i d a l s o s how e d a n i nc r e a s e i n t he e na nt i os e l e c t i vi t y of t he r e a c t i on t o 71% e e ( E nt r y 3) T ab l e 2. 4. O p t i m i z at i on of E n an t i os e l e c t i ve A d d i t i on o f S u l f on am i d e s t o I m i n e s A t t hi s poi nt w e t hought t ha t a ne w phos phor i c a c i d c oul d pr ove t o be a be t t e r c a t a l ys t f or t he e na nt i os e l e c t i ve a ddi t i on of s ul f ona m i de s t o i m i ne s W e de ve l ope d a phos phor i c a c i d de r i ve d f r om t he c hi r a l V A P O L l i ga nd. W ul f f a nd c o w or ke r s a t t he U ni ve r s i t y of C hi c a go f i r s t de ve l ope d t he c hi r a l V A P O L ( V a ul t e d bi s P he nt hr O L ) l i ga n d ( F i gur e 2. 6 ) 5 7 V A P O L w a s t hought t o be s upe r i or t o s ubs t i t ut e d B I N O L s due t o t he f a c t i t ha d a r i gi d c hi r a l poc ke t r a t he r t ha n a f l e xi bl e c hi r a l poc ke t W ul f f a nd c o w or ke r s ha ve s how n t ha t c hi r a l m e t a l c om pl e xe s of V A P O L c oul d be us e d f or a v a r i e t y of e na nt i os e l e c t i ve t r a ns f or m a t i on, i nc l udi ng e na nt i os e l e c t i ve D i e l s A l de r r e a c t i ons a z i r i di na t i on of i m i ne s a nd a z a D i e l s A l de r r e a c t i ons 5 8 T he a ppl i c a t i on o f t he c hi r a l phos phor i c a c i d de r i ve d f r om V A P O L t o t he a ddi t i on of s ul f ona m i de nuc l e ophi l e s t o t h e

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36 phe nyl s ubs t i t ut e d N B oc pr ot e c t e d i m i ne r e s ul t e d i n t he f or m a t i on o f t he a m i na l pr oduc t i n 95% yi e l d a nd 94% e e ( E nt r y 4) T he r e a c t i on e m pl oye d 5 m ol % of t he c hi r a l phos phor i c a c i d i n e t he r F i gu r e 2. 6 D e ve l op m e n t of V A P O L P h os p h or i c A c i d W i t h t he opt i m i z e d r e a c t i on c ondi t i on i n h a nd, w e s ought t o c he c k t he s c ope of t he r e a c t i on i n t e r m s of t he s ul f ona m i de nuc l e ophi l e ( T a bl e 2. 4) T he a ddi t i on of m e t ha ne s ul f ona m i de t o t he phe nyl s ub s t i t ut e d N B oc pr ot e c t e d i m i ne s pr ovi de d t h e pr oduc t i n 86 % yi e l d a nd 93% e e ( E nt r y 1 ) T he pr e s e nc e of bot h e l e c t r on dona t i ng a nd e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s on t he s ul f ona m i de nuc l e ophi l e s w a s t ol e r a t e d by t he r e a c t i on c ondi t i ons T he a ddi t i on p m e t hoxybe nz e ne s ul f ona m i de t o t he i m i ne pr ovi de d t he a m i na l pr odu c t i n 89% yi e l d a nd 91% e e ( E nt r y 2) T he a ddi t i on o f p c hl or obe nz e ne s ul f ona m i de t o t he i m i ne pr oduc e d t he c hi r a l a m i na l i n 98% yi e l d a nd 95% e e ( E nt r y 4) T he a ddi t i on of o t ol ue ne s ul f ona m i d e t o t he i m i ne r e s ul t e d i n a de c r e a s e i n bot h t he yi e l d a nd t he e n a nt i os e l e c t i vi t y of t he pr oduc t ( E nt r y 3) T hi s w a s pr e s um a bl y due t o t he i nc r e a s e d s t e r i c a s s oc i a t e d w i t h t he nuc l e ophi l e

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37 T ab l e 2. 5. V ar i at i on o f S u l f o n am i d e N u c l e op h i l e s W e ne xt i nve s t i ga t e d t he e f f e c t of va r yi ng t he a r om a t i c s ubs t i t ue nt on t he i m i n e r e a c t a nt W e w e r e ha ppy t o di s c ove r t ha t t he r e a c t i on c ondi t i ons w e r e a bl e t o t ol e r a t e a va r i e t y of a r om a t i c s ubs t i t ue nt s on t he i m i ne I t s houl d be not e d t ha t e i t he r e t he r or t ol ue ne c oul d be us e d a s t he s ol ve nt f or t he r e a c t i on. I n s e ve r a l c a s e s r e a c t i ons pe r f or m e d t ol ue ne de m ons t r a t e d a n i nc r e a s e i n b ot h t he yi e l d a nd t he e n a nt i os e l e c t i vi t y w he n c om pa r e d t o t he s a m e r e a c t i on pe r f o r m e d i n e t he r a s t he s ol ve nt E l e c t r on dona t i ng s ubs t i t ue nt s on t he a r om a t i c gr oup of t he i m i ne r e s ul t e d i n t he f or m a t i on of t he p r oduc t i n e xc e l l e nt yi e l d a nd e e F o r e xa m pl e t he a ddi t i on of p t o l ue ne s ul f ona m i de t o t he 4 m e t hoxyphe nyl s ubs t i t ut e d i m i ne r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n 92% yi e l d a nd 90% e e ( E nt r y 12 ) E l e c t r on w i t hd r a w i ng s ubs t i t ue nt s a l l pr ovi de d t he a m i na l pr oduc t i n gr e a t e r t ha n 88% yi e l d a nd 92% e e ( E nt r i e s 9 11) T he he t e r oc yc l i c 2 t hi e nyl s ubs t i t ut e d i m i ne pr ovi de d t he a m i na l i n 94% yi e l d a nd 88% e e ( E nt r y 13 )

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38 T ab l e 2. 6. V ar i at i on o f I m i n e S u b s t r at e I t s houl d be not e d t ha t i n o r de r t o obt a i n t he p r oduc t i n bot h hi gh y i e l d a nd e na nt i os e l e c t i vi t y, i m i ne s of a t l e a s t 95% pur i t y m us t be us e d i n t he r e a c t i on. W e di s c ove r e d t ha t i n or de r t o s ynt he s i z e t he i m i ne s of hi gh e nough pur i t y, t he s ul f one i nt e r m e di a t e t ha t w a s c on ve r t e d t o i m i ne ha d t o b e dr i e d i n a n A bd e r ha l de n dr yi ng pi s t ol f or 12 hour s D r i e d, pow de r e d m ol e c ul a r s i e ve s w e r e f ound t o be s upe r i or t o s odi um s ul f a t e a s a dr yi ng a ge nt f or t he c onve r s i on of t he s ul f one t o t he i m i ne I m i ne s t ha t w e r e oi l s w e r e c ol l e c t e d us i ng S c hl e nk f i l t r a t i on m e t hods a nd c onc e nt r a t e d unde r hi gh va c uum T he s ol i d i m i ne s w e r e r e c r ys t a l l i z e d f r o m he xa ne s pr i or t o us e i n t he r e a c t i on. I t s houl d a l s o be not e d t ha t i t w a s r e qui r e d t ha t t he c a t a l ys t w a s a l s o dr i e d i n a n A bde r ha l de n dr yi n g pi s t ol ove r ni ght i n or de r t o obt a i n r e pr oduc i bl e yi e l ds a nd e na nt i os e l e c t i vi t i e s 2. 4. C on c l u s i on s W e ha ve de ve l op e d t he f i r s t c a t a l yt i c m e t hod f or t he a ddi t i on of c a r ba m a t e a m i de a nd s ul f ona m i de nuc l e ophi l e s t o N B oc pr ot e c t e d i m i ne s E i t he r phe nyl p hos phi ni c a c i d or t r i f l uor om e t ha ne s ul f i ni m i de c oul d be us e d a s c a t a l y s t s f or t he

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39 a ddi t i on of s uc h nuc l e ophi l e s t o t he i m i ne s T he r e a c t i on w a s c a pa bl e of s ynt he s i z i ng t he N N a m i na l pr oduc t s i n e xc e l l e nt yi e l ds W e ha ve a l s o de ve l op e d t he f i r s t hi ghl y e n a nt i os e l e c t i ve m e t hod f or t he a ddi t i on of s ul f on a m i de nuc l e ophi l e s t o N B oc pr ot e c t e d i m i ne s e m pl oyi ng a nove l phos phor i c a c i d de r i ve d f r om t he V A P O L l i ga nd. T he r e a c t i on w a s t ol e r a nt of a va r i e t y of s ub s t i t ue nt s on bot h t he s ul f ona m i de nuc l e ophi l e a nd t h e i m i ne e l e c t r ophi l e s S i nc e our i ni t i a l publ i c a t i on, our gr oup ha s e xt e nde d t he de s c r i be d m e t hodol ogy t o t he e na nt i os e l e c t i ve a ddi t i on of i m i de s t o i m i ne s 5 9 T he r e a c t i on e m pl oye d V A P O L phos phor i c a c i d a nd w a s c a pa bl e of f o r m i ng t he a m i na l pr oduc t s i n e x c e l l e nt yi e l d a nd e na nt i os e l e c t i vi t i e s O ur gr oup ha s a l s o de v e l ope d B r ons t e d a c i d c a t a l yz e d m e t hod s f or t he e na nt i os e l e c t i ve a ddi t i on of phos phor us nuc l e ophi l e s a nd a l c ohol s t o i m i ne s a s w e l l a s e m pl oyi ng t he V A P O L pho s phor i c a c i d f or t he e na nt i os e l e c t i v e r e duc t i on of i m i no e s t e r s a nd de s ym m e t r i z a t i on of m e s o a z i r i di ne s 6 0

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40 C h ap t e r 3 H i gh l y E n an t i os e l e c t i ve B r on s t e d A c i d C at al yz e d E n an t i os e l e c t i ve A z a F r i e d e l C r af t s R e ac t i on T he F r i e de l C r a f t s r e a c t i on i s undoubt e dl y one of t he m os t i m por t a nt c a r bon c a r bon bond f or m i ng r e a c t i ons i n or ga ni c s ynt he s i s 6 1 I t i s t he r e a c t i on of e l e c t r on r i c h a r om a t i c s pe c i e s w i t h e l e c t r ophi l e s T he r e a c t i on i s c ons i de r e d t o be a gr e e n r e a c t i on i n t ha t i t i s hi ghl y a t om e c onom i c a l a nd pr oduc e s no t oxi c by pr oduc t s T he e na nt i os e l e c t i ve a ddi t i on of i ndol e s t o i m i ne s a l l ow s f or t he e xpe di e nt s ynt he s i s of c hi r a l 3 i ndol yl m e t ha na m i ne s w hi c h a r e i m por t a nt i nt e r m e di a t e s i n t he s ynt he s i s of m a ny bi ol ogi c a l l y a c t i ve a l ka l oi d na t u r a l pr oduc t s s uc h a s t he D r a gm a c i di ns a nd kop s i ni ne 6 2 F i gu r e 3. 1 N at u r al P r od u c t s C on t ai n i n g C h i r a l 3 I n d ol yl m e t h a n am i n e s 3. 1 B ac k gr ou n d T he de ve l opm e nt of t he s t e r e os e l e c t i ve F r i e de l C r a f t s r e a c t i on da t e ba c k t o 1985. 6 1 I n t ha t ye a r S a r t o r r i a nd c o w or ke r s r e p or t e d t he e na nt i os e l e c t i ve a ddi t i on of phe nol s t o t r i c hl or oa c e t a l de hyde 6 3 T he r e a c t i on e m pl oye d a s t oi c hi om e t r i c a m ount of a c hi r a l r e a ge nt de r i ve d f r om di e t hyl a l um i num c hl o r i de a nd c hi r a l a l c ohol s T he r e a c t i on

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41 r e s ul t e d i n t he f or m a t i on of t he c hi r a l be nz yl i c a l c ohol s i n e xc e l l e n t yi e l ds a nd e na nt i os e l e c t i vi t i e s up t o 80% S i nc e t ha t t i m e s e ve r a l r e s e a r c h gr oups ha ve de v e l ope d hi ghl y e na nt i os e l e c t i ve m e t hods f or t he a ddi t i on of i ndol e s t o M i c ha e l a c c e pt or s c a t a l yz e d by bot h c hi r a l L e w i s a c i d c om pl e xe s a s w e l l a s or ga noc a t a l yt s 6 4 T he de ve l opm e nt of e na nt i os e l e c t i ve m e t hods f or t he a ddi t i ons of e l e c t r on r i c h a r om a t i c c om pounds t o i m i ne s ha s l a gge d be hi nd t he de ve l opm e nt of t he e na nt i os e l e c t i ve m e t hodol ogy f or t he a ddi t i on of s uc h a r om a t i c c om pounds t o M i c h a e l a c c e pt or s T he r e a s on f or t hi s l a g i s t ha t t he r e s ul t i ng p r oduc t f or t he a ddi t i on of e l e c t r o r i c h a r om a t i c s t o i m i ne s a nd a l de hyde s w a s t ha t t he pr oduc t s t e nd t o unde r go m ul t i pl e s ubs t i t ut i ons due t o t he i ns t a bi l i t y of t he r e s ul t i ng a m i nom e t hyl a nd hy dr oxym e t hyl gr oups ( F i gu r e 3. 2 ) F i gu r e 3. 2 M u l t i p l e S u b s t i t u t i on s o f A m i n om e t h yl I n t e r m e d i at e s T he f i r s t c a t a l yt i c e na nt i os e l e c t i ve m e t hod f or t h e a z a F r i e de l C r a f t s r e a c t i on of i m i ne s a nd i ndol e s w a s r e por t e d i n t he l i t e r a t ur e i n 1999. J oha nns e n e m pl oye d a c hi r a l L e w i s a c i d c a t a l ys t de r i ve d f r om c oppe r he xa f l uor ophos pha t e a nd T ol B I N A P t o c a t a l yz e t he r e a c t i on be t w e e n i ndol e a nd i m i ne s de r i ve d f r om e t hyl gl yoxyl a t e a nd p t ol ue ne s ul f ona m i de ( T a bl e 3. 1) 6 5 T he r e a c t i on e m pl oye d 10 m ol % of t he c hi r a l c oppe r c om pl e x a s t he c a t a l ys t a nd r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t y. A v a r i e t y of 5 s ubs t i t ut e d i n dol e de r i va t i ve s w e r e s c r e e ne d f or t he r e a c t i on. T he pr e s e nc e of e l e c t r on w i t hd r a w i ng gr oups on t he i ndol e r i ng r e s ul t e d i n a de c r e a s e i n bot h t he yi e l d a nd e na nt i os e l e c t i vi t y of t he pr oduc t s

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42 T ab l e 3. 1. Jo h an n s e n s E n an t i os e l e c t i ve az a F r i e d e l C r af t s R e ac t i on I t w a s not unt i l 2006 t h a t a m or e g e ne r a l m e t ho d f or t he e na nt i os e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on of i m i ne s w i t h i ndol e s w a s r e por t e d i n t he l i t e r a t ur e Z hou a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve a ddi t i on of i ndol e s of N t os yl pr ot e c t e d i m i ne s 6 6 T he r e a c t i ons e m pl oye d t he us e of a c a t a l ys t de r i ve d f r om c oppe r ( I I ) t r i f l a t e a nd a bi s oxa z ol i ne l i ga nd. T he us e of f i ve e qui va l e nt s of t he i ndol e r e a c t a nt w a s r e qui r e d i n or de r t o obt a i n t he pr oduc t i n bot h e xc e l l e nt yi e l d a nd e e T he r e a c t i on r e s ul t e d i n t he f or m a t i on of t he pr oduc t s i n e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s w he n e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s w e r e a t t a c he d t o t he a r om a t i c s ubs t i t ue nt of t he i m i ne T he pr e s e nc e of e l e c t r on dona t i ng s ubs t i t ue nt s on t he a r om a t i c r i ng o f t he i m i ne s how e d a ge ne r a l de c r e a s e i n t he yi e l d of t he r e s ul t i ng pr oduc t but t he e e of t he pr oduc t w a s s t i l l

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43 gr e a t e r t ha n 90% T he us e o f ot he r pr ot e c t i ng g r oups on t he ni t r oge n a t om of t he i m i ne r e s ul t e d i n a de c r e a s e i n bot h t he yi e l d a nd e na nt i os e l e c t i vi t y. T he a ut hor s r e por t e d t ha t t he r e a c t i on of N phe nyl pr ot e c t e d i m i ne s r e s ul t e d i n t he f or m a t i on of t he d e s i r e d pr oduc t i n 6 5% yi e l d a nd 0 % e e T ab l e 3. 2. C op p e r C a t al yz e d E n an t i os e l e c t i ve a z a F r i e d e l C r af t s R e ac t i on T he f i r s t or ga noc a t a l yt i c a z a F r i e de l C r a f t s r e a c t i on of a he t e r oc yc l e w i t h a n i m i ne w a s r e por t e d by T e r a da a nd c o w or ke r s i n 2 004. T e r a da a nd c o w or ke r s e m pl oye d a c hi r a l phos phor i c a c i d de r i ve d f r om B I N O L f or t he e na nt i os e l e c t i ve a ddi t i on of a s i ngl e e l e c t r on r i c h f ur a n t o N B oc pr ot e c t e d i m i ne s 6 7 O nl y 2 m ol % t he c hi r a l phos phor i c a c i d c a t a l ys t w a s r e qui r e d i n or de r t o f or m t h e pr oduc t i n e xc e l l e nt yi e l d a n d

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44 e na nt i os e l e c t i vi t y. T he us e of s t e r i c a l l y de m a ndi ng a r om a t i c s ubs t i t ue nt s on t he i m i ne r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n de c r e a s e d yi e l d, how e ve r t he e na nt i os e l e c t i vi t y of s uc h r e a c t i ons w a s not di m i ni s he d. T he s ynt he t i c ut i l i t y of t he r e a c t i on w a s de m ons t r a t e d by t he c onve r s i on of t he r e s ul t i ng pr oduc t s t o a % but e nol i de w i t h no l os s of e na nt i om e r i c e xc e s s T ab l e 3. 3. E n an t i os e l e c t i ve az a F r i e d e l C r af t s R e ac t i on of F u r an s w i t h I m i n e s I n 2006, D e ng a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on of N be nz e ne s ul f onyl pr ot e c t e d i m i ne s w i t h i ndol e us i ng a n or ga noc a t a l ys t 6 8 T he c a t a l ys t t ha t w a s e m pl oye d f or t he r e a c t i on w a s a t hi our e a de r i va t i ve of qui ni ne a nd qui ni di ne ( T a bl e 3. 4) T he r e a c t i on r e qui r e d t h e us e of 2 e qui va l e nt s of t he i ndol e nuc l e ophi l e i n or de r t o obt a i n t he 3 i ndol yl m e t ha na m i ne pr oduc t i n e xc e l l e nt yi e l d a n d e na nt i om e r i c e xc e s s T he r e a c t i on r e qui r e d l ong r e a c t i on t i m e s up t o 72 hour s i n or de r t o obt a i n t he pr oduc t i n hi gh yi e l d w he n t h e a r om a t i c s ubs t i t ue nt of t he i m i ne w a s s ubs t i t ut e d w i t h a n e l e c t r on w i t hdr a w i ng s ubs t i t ue nt T he pa pe r by D e ng a nd c o w or ke r s w a s t he f i r s t r e por t o f t he e na nt i os e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on of a l i pha t i c

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45 s ubs t i t ut e d i m i ne s w i t h i ndol e s T he yi e l d f or t he r e a c t i on of a n a l i pha t i c i m i ne w i t h i ndol e r e s ul t e d i n t h e p r oduc t i n a de c r e a s e t he yi e l d, but t he l e ve l of e na nt i om e r i c e xc e s s of t he pr oduc t w a s e qua l t o t he e na nt i om e r i c e xc e s s of t he pr oduc t s of t he a r om a t i c s ubs t i t ut e d i m i ne s D e ng a nd c o w or ke r s a l s o de m ons t r a t e d t ha t t he t o s yl pr ot e c t i ng gr oup of t he i m i ne c oul d be r e m ove d a nd r e pl a c e d w i t h a C bz pr ot e c t i ng gr oup w i t hout r a c e m i z a t i on. T ab l e 3. 4. A l k al oi d C at al yz e d E n an t i os e l e c t i ve az a F r i e d e l C r af t s R e ac t i on I n 2006, T e r a da a nd c o w or ke r s r e por t e d t he p hos phor i c a c i d c a t a l yz e d a z a F r i e de l C r a f t s r e a c t i on of e l e c t r on r i c h e na m i ne s w i t h i ndol e de r i va t i ve s ( T a bl e 3. 5 ) 6 9 T he c a t a l ys t t ha t w a s e m pl oye d f or t he r e a c t i on w a s B I N O L phos phor i c a c i d de r i va t i ve w i t h a 2, 4 6 t r i i s opr opyl phe nyl s ubs t i t ue nt s i n t he 3 a nd 3 pos i t i ons T he r e a c t i on r e s ul t e d i n t he f or m a t i on o f pr oduc t s i n good yi e l ds a nd e xc e l l e nt e na nt i os e l e c t i vi t i e s f or

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46 a va r i e t y of i ndol e de r i va t i ve s a nd e n a m i ne s T e r a da a nd c o w or ke r s s ugg e s t e d t ha t t h e r e a c t i on oc c ur r e d by f i r s t c onve r s i on of t he e na m i ne s t a r t i ng m a t e r i a l t o a n i m i ne vi a t a ut om e r i z a t i on. T he c hi r a l phos phor i c a c i d c a t a l ys t s t he n a c t i va t e d t he i m i ne i nt e r m e di a t e T he r e s ul t i ng i m i ni um i on t he n r e a c t e d w i t h t he i ndol e de r i va t i ve r e s ul t i ng i n t he f o r m a t i on o f t he f i na l pr oduc t T ab l e 3. 5. P h os p h or i c A c i d C at a l yz e d E n an t i os e l e c t i ve az a F r i e d e l C r af t s R e ac t i o n of I n d ol e s w i t h E n am i n e s I n 2007, Y ou a nd c o w or ke r s r e por t e d t he e na nt i os e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on of N t os yl pr ot e c t e d i m i ne s w i t h i ndol e de r i va t i ve s ( T a bl e 3. 6) 7 0 T he r e a c t i on e m pl oye d a phos phor i c a c i d c a t a l ys t w i t h 1 na pht hyl s ubs t i t ue nt s i n t he 3 a nd 3 pos i t i on of t he B I N O L T he r e a c t i on r e qui r e d t he u s e o f f i ve m ol a r e qui va l e nt s of t he i ndol e r e a c t a nt i n or de r t o a voi d t he f or m a t i on of t he m ul t i pl e a ddi t i on pr oduc t T he pr e s e nc e of e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s on t he a r om a t i c r i ng of t he i m i ne r e s ul t e d i n a s l i ght

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47 de c r e a s e i n bot h t he yi e l d a nd t he e na nt i om e r i c e xc e s s of t he pr oduc t T he s e r e a c t i ons a l s o r e qui r e d l onge r r e a c t i on t i m e s t ha n t he r e a c t i ons t ha t e m pl oye d i m i ne s w i t h e l e c t r on dona t i ng s ubs t i t ue nt s on t he i m i ne f r om a bout 10 m i nut e s f or t he i m i ne s w i t h e l e c t r on dona t i ng s ubs t i t ue nt s t o 24 hour s f or t he r e a c t i on of i ndol e w i t h i m i ne s t ha t ha d e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s T ab l e 3. 6 P h os p h or i c A c i d C at al yz e d E n an t i os e l e c t i ve A z a F r i e d e l C r af t s R e ac t i on 3. 2. E n an t i os e l e c t i ve az a F r i e d e l C r af t s R e ac t i on o f I n d ol e D e r i vat i ve s w i t h N B e n z oyl P r ot e c t e d I m i n e s W i t h t he s uc c e s s t ha t our gr oup ha d obt a i ne d f or t he e na nt i os e l e c t i ve a ddi t i on of s ul f ona m i de s t o N B oc pr ot e c t e d i m i ne s w e s ought t o e xt e nd t he de ve l ope d m e t hodol ogy t o t he r e a c t i on of nuc l e ophi l e s t o i m i ne s W e s oo n di s c ove r e d t ha t w e w e r e obt a i ni ng a m i xt ur e of pr oduc t s f r om t he r e a c t i on. C ha r a c t e r i z a t i on of t he obt a i ne d r e a c t i on pr oduc t s

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48 i ndi c a t e d t ha t a l ong w i t h t he i ndol e a ddi ng t o t he i m i ne by t he ni t r oge n a t om t he i ndol e w a s a l s o a ddi ng t o t he i m i ne vi a t he C 3 c a r bon. V a r i a t i on of t he r e a c t i on c ondi t i ons de m ons t r a t e d t ha t i t w a s pos s i bl e t o s om e w ha t c ont r ol w hi c h of t he t w o pr oduc t s w a s f or m e d a s t he m a j or pr oduc t s U pon f ur t he r l i t e r a t ur e s e a r c h, i t w a s s oon e vi de nt t ha t t he C 3 c a r bon of i ndol e w a s t he m os t nuc l e ophi l i c a t om on t he i ndol e r i ng s ys t e m 7 1 B a s e d upon t he e xpe r i m e nt a l a nd l i t e r a t ur e e vi de n c e t ha t w a s obt a i n e d, w e s ought t o de ve l op a phos phor i c a c i d c a t a l yz e d m e t hod f or t he e na nt i o s e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on of i ndol e de r i va t i ve s w i t h i m i ne s S i nc e w e ha d a l r e a dy obs e r ve d t he f or m a t i on o f a m i xt ur e of p r oduc t s f r om t he r e a c t i on of unpr ot e c t e d i ndol e de r i va t i ve s w i t h N B oc pr ot e c t e d i m i ne s c a t a l yz e d b y V A P O L phos phor i c a c i d, w e ne xt s ought t o c he c k t he e f f e c t of pr ot e c t i ng t he ni t r oge n a t om of t he i ndol e r i ng ( T a bl e 3. 7 ) T he f i r s t i ndo l e de r i va t i ve t ha t w a s s c r e e ne d w a s t he N m e t hyl i ndol e T he r e a c t i on w i t h t he B oc p r ot e c t e d i m i ne s pr ovi de d t he de s i r e d pr oduc t i n 94 % yi e l d a nd 15% e e ( E nt r y 2) T he us e of N be nz yl i ndol e ga ve t he de s i r e d pr oduc t i n 97 % yi e l d a nd a n i nc r e a s e i n t he e e t o 30% ( E nt r y 3 ) S o l ve nt s c r e e ns i ndi c a t e d t ha t ha l oge na t e d s ol ve nt s pr ovi de d t he pr oduc t s i n t he e na nt i om e r i c e xc e s s ( E nt r i e s 4 a nd 6) T he r e a s on f or t he hi ghe r e n a nt i os e l e c t i vi t i e s a nd yi e l ds t ha t w e r e obs e r ve d f or t he r e a c t i on pe r f o r m e d i n ha l oge na t e d s ol ve nt s w a s pr oba bl y due t o t he i nc r e a s e d s ol ubi l i t y of t he s t a r t i ng m a t e r i a l s i n t he ha l oge na t e d s ol ve nt s

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49 T ab l e 3. 7. O p t i m i z at i on of S ol ve n t a n d I n d ol e P r ot e c t i n g G r ou p W he n w e c ha nge d t he pr ot e c t i ng gr oup on t he ni t r oge n a t om of t he i m i ne f r om a B oc pr ot e c t i ng gr oup t o a be n z oyl pr ot e c t i ng g r oup, t he e na nt i om e r i c e xc e s s of t he pr oduc t i nc r e a s e d f r om 60% t o 86% us i ng V A P O L phos phor i c a c i d ( T a bl e 3. 8) I t s houl d be not e d t h a t t he r e a c t i vi t y of t he N B oc pr ot e c t e d i m i ne s w a s m uc h l ow e r t ha n t he r e a c t i vi t y of t he N be nz oyl pr o t e c t e d i m i ne s T he r e a c t i on of N B oc pr ot e c t e d i m i ne s a t 60 o C r e s ul t e d i n t he f or m a t i on of none of t h e de s i r e d pr oduc t be i ng f or m e d by t he r e a c t i on ( E nt r y 1) W i t h t he i nc r e a s e d e na nt i os e l e c t i vi t y t ha t w a s obs e r ve d by r e pl a c i n g t he B oc pr ot e c t i ng gr oup w i t h t he be nz oyl pr ot e c t i ng gr oup, w e de c i de d t o ne xt s c r e e n ot he r phos phor i c a c i d c a t a l ys t s ( E n t r y 2 ) L uc ky f or us t he ne xt phos phor i c a c i d c a t a l ys t t ha t w e s c r e e ne d pr ove d t o be t he c a t a l ys t t ha t r e s ul t e d i n t he f or m a t i on of t he de s i r e d pr oduc t i n t he hi ghe s t yi e l d a nd e na nt i om e r i c e xc e s s T he c a t a l y s t w a s a B I N O L de r i va t i ve t ha t ha d t r i phe nyl s i l yl s ubs t i t ue nt s i n t he 3 a nd 3 pos i t i ons T he c a t a l ys t w a s

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50 f i r s t r e por t e d i n t he l i t e r a t u r e by M a c M i l l a n a nd c o w or ke r s f or t he e na nt i os e l e c t i ve r e duc t i on of i m i ne s w i t h H a nt z c h s e s t e r 7 2 T he f i r s t r e a c t i on t ha t w a s pe r f o r m e d w i t h t hi s c a t a l ys t w a s a t 60 C a nd r e s ul t e d i n t he f or m a t i on of t he pr oduc t i n 92% yi e l d a nd 97% e e ( E nt r y 6) T he r e a s on f or t he i nc r e a s e d e n a nt i os e l e c t i vi t y c oul d be t ha t t he B I N O L de r i ve d c a t a l ys t w a s m or e bul ky t ha n t he V A P O L de r i ve d c a t a l y s t I t a l s o c oul d be du e t o t he f l e xi bi l i t y of t he c hi r a l poc ke t of t he B I N O L de r i ve d c a t a l ys t W e w e nt ba c k a nd l ooke d a t t he e f f e c t of va r yi ng t he r e a c t i on t e m pe r a t ur e w i t h t he ne w c a t a l ys t s y s t e m A t r oom t e m pe r a t ur e t he r e a c t i on f or m e d t he de s i r e d pr od uc t i n 99% y i e l d a nd 80 % e e ( E nt r y 3 ) L ow e r i ng t he r e a c t i on t e m pe r a t ur e t o 30 C r e s ul t e d i n t he opt i m a l r e a c t i on c ondi t i on ( E n t r y 5 ) T he de s i r e d p r oduc t w a s f or m e d i n 99% yi e l d a nd 94% e e T ab l e 3. 8. O p t i m i z at i on f or t h e az a F r i e d e l C r af t s R e ac t i on W i t h t he r e a c t i on c ondi t i ons now opt i m i z e d, w e ne xt t ur ne d a t t e nt i on t o c he c ki ng t he s c ope of t he r e a c t i on i n t e r m s of t he i m i ne e l e c t r ophi l e ( T a bl e 3. 9) W e f i r s t s c r e e ne d

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51 a s e r i e s of i m i ne s w i t h e l e c t r on w i t hdr a w i ng s u bs t i t ue nt s on t he par a po s i t i on of t he a r om a t i c r i ng o f i m i ne T he r e a c t i on of t he i m i n e w i t h t he s t r ong e l e c t r on w i t hdr a w i ng ni t r o s ubs t i t ue nt i n t he par a pos i t i on of t he i m i ne r e s ul t e d i n t he f or m a t i on o f t he p r oduc t i n 99% yi e l d a nd 94% e e ( E nt r i e s 2 5) T he pr e s e nc e of ha l oge n s ubs t i t ue nt s on t he pa r a pos i t i on of t he a r om a t i c r i ng of t he i m i ne w a s a l s o w e l l t ol e r a t e d by t he r e a c t i on ( E nt r i e s 3 5) A l l r e a c t i ons w i t h s uc h s ubs t r a t e s r e s ul t e d i n t he f or m a t i on o f t he de s i r e d pr oduc t s i n gr e a t e r t ha n 92% yi e l d a nd gr e a t e r t ha n 95% e e T he a bs ol ut e c onf i gur a t i on of t he p c hl or i na t e d pr oduc t w a s de t e r m i ne d t o be ( R ) by x r a y c r ys t a l l ogr a phi c a na l ys i s T hi s w a s a f i r s t f or a n or ga noc a t a l yt i c a z a F r i e de l C r a f t s r e a c t i on. T he m e t hodol ogi e s r e por t e d by D e ng a nd Y ou s how e d a de c r e a s e i n bo t h t he e na nt i om e r i c e xc e s s a nd t h e yi e l ds of t he r e s ul t i ng pr oduc t s w he n i m i ne s c ont a i ni ng e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s w e r e e m pl oye d i n t he r e a c t i on. T he pr e s e nc e of e l e c t r on dona t i ng s ubs t i t ue nt s on t h e a r om a t i c r i ng of t he i m i ne a l s o r e s ul t e d i n t he f or m a t i on of t he de s i r e d pr oduc t s i n e xc e l l e nt yi e l ds a nd e na nt i os e l e c t i vi t i e s ( E nt r i e s 6 9) T he 4 m e t hoxy s ubs t i t ut e d i m i ne r e s ul t e d i n t he f o r m a t i on o f t he de s i r e d pr oduc t s i n e xc e l l e nt yi e l d a nd e na nt i os e l e c t i vi t i e s ( E nt r y 7) S t e r i c a l l y hi nde r e d i m i ne s a l s o r e s ul t e d i n t he f or m a t i on of t he pr oduc t s i n e x c e l l e nt yi e l ds a nd e n a nt i os e l e c t i vi t i e s ( E nt r i e s 9 a nd 10) F or e xa m pl e t he phos phor i c a c i d c a t a l yz e d a ddi t i on of N be nz yl i ndol e w i t h t he 1 na pht hyl s ubs t i t ut e d i m i ne f ur ni s he d t he pr oduc t i n 99% yi e l d a nd 95% e e ( E nt r y 10)

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52 T ab l e 3. 9. V ar i at i on o f I m i n e E l e c t r op h i l e W e ne xt t ur ne d our a t t e nt i on t o t he e f f e c t of ha vi ng s ubs t i t ue nt s on t he i ndol e r i ng s ys t e m ( T a bl e 3. 10) W e f i r s t s c r e e ne d a s e r i e s of 5 s ubs t i t ut e d i ndol e s ubs t r a t e s T he pr e s e nc e of e l e c t r on w i t hdr a w i ng gr oups on t he 5 pos i t i on of t he i ndol e r i ng ga ve t he de s i r e d pr oduc t s i n e xc e l l e nt yi e l d a nd e na nt i om e r i c e xc e s s ( E nt r i e s 1 2) T he 5

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53 c a r boxym e t hyl a nd 5 br om o s ubs t i t ut e d i ndol e s p r ovi de d t he pr oduc t s i n s l i ght l y l ow e r y i e l ds a nd e na nt i os e l e c t i vi t i e s w he n c om pa r e d t o t he i ndol e w i t h no s ubs t i t ue nt s on t h e r i ng. T hi s i s pr oba bl y due t o t he de c r e a s e d nuc l e ophi l i c i t y of t he i ndol e due t o t he l ow e r i ng of t he e l e c t r on de ns i t y of t he i ndol e r i ng s ys t e m T he pr e s e nc e of t he e l e c t r on dona t i ng m e t hoxy a nd m e t hyl s ubs t i t ue nt s on t he C 5 c a r bon of t he i ndol e r e s ul t e d i n t he f or m a t i on of t he de s i r e d pr oduc t s i n e xc e l l e nt yi e l ds a nd e na nt i o s e l e c t i vi t i e s ( E nt r i e s 3 4) T he r e a c t i on of t he 7 m e t hyl s ubs t i t ut e d i ndol e ga ve t he d e s i r e d pr oduc t i n 98% yi e l d a nd 96% e e ( E nt r y 5 ) T he onl y i ndol e s ubs t r a t e t ha t r e s ul t e d i n a s ha r p de c r e a s e i n t he e na nt i om e r i c e xc e s s of t he pr oduc t w a s 2 m e t hyl i ndol e T he r e a c t i on o f 2 m e t hyl i ndol e w i t h t he N be nz oyl i m i ne pr ovi de d t he pr oduc t i n 91% yi e l d but t he e na nt i om e r i c e xc e s s of t he pr oduc t w a s onl y 64% ( E nt r y 6) T he de c r e a s e i n t he e e w a s pr e s um a bl y due t o de t r i m e nt a l s t e r i c hi nd r a nc e F i gu r e 3. 3 X R ay C r ys t al D e t e r m i n at i o n of A b s ol u t e C on f i gu r at i on o f 137c ( R )

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54 T ab l e 3. 10. V ar i at i on o f I n d ol e S u b s t r at e 3. 3. C on c l u s i on s W e ha ve de ve l op e d a hi ghl y e na nt i os e l e c t i ve m e t hod f or a ddi t i on of N be nz yl i ndol e t o N be nz oyl p r ot e c t e d i m i ne s c a t a l yz e d by a c hi r a l B I N O L phos phor i c a c i d w i t h t r i phe nyl s i l yl s ubs t i t ue nt s on t he 3 a nd 3 pos i t i ons of t he B I N O L r i ng. T he r e a c t i on m e t hodol ogy t ha t w a s de v e l ope d w a s c a pa bl e of s ynt he s i z i ng of a v a r i e t y of s ubs t i t ut e d 3 i ndol yl m e t ha na m i ne s T he de ve l ope d m e t ho dol ogy ha d m a ny be ne f i t s ove r t he

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55 m e t hodol ogy t ha t ha d be e n pr e vi ous l y r e por t e d i n t he l i t e r a t ur e T he de ve l ope d m e t hodol ogy e m pl oye d t he i ndol e r e a c t a nt a s t he l i m i t i ng r e a ge nt T h i s w a s be ne f i c i a l due t o t he f a c t t ha t t he s ub s t i t ut e d i ndol e s t a r t i ng m a t e r i a l s w e r e t he m or e e xpe ns i v e of t he t w o s t a r t i ng m a t e r i a l s A not he r m a j or a dva nt a ge t ha t t he de v e l ope d m e t hodol ogy ha d ove r t he r e por t e d m e t hods w a s t ha t t he r e a c t i o n w a s a bl e t o t ol e r a t e t he pr e s e nc e of e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s on e i t he r t he i n dol e r i ng or t he a r om a t i c s ubs t i t ue nt of t he i m i ne T he l a s t m a j or be ne f i t t ha t t he de ve l op e d m e t hodol ogy ha d w a s t he us e of t he N be nz oyl pr ot e c t i ng gr oup on t he ni t r oge n of t he i m i ne I n ge ne r a l i t i s e a s i e r t o r e m ove t he be nz oyl pr ot e c t i ng gr oup t ha n t he t os yl pr ot e c t i ng gr oup t ha t ha s be e e m pl oye d f or a l l of t he r e por t e d m e t hodol ogi e s f or t he e na nt i os e l e c t i ve a ddi t i on of i ndol e t o a r om a t i c i m i ne s T he de ve l ope d m e t hodol ogy doe s ha ve a dr a w ba c k w he n c om pa r e d t o t he l i t e r a t ur e m e t hods W e ha d t o us e t he N be nz yl pr ot e c t i ng gr oup on t he ni t r oge n a t om of t he i ndol e r i ng i n or de r t o obt a i n t h e d e s i r e d pr od uc t i n e xc e l l e nt yi e l d a nd e na nt i om e r i c e xc e s s w hi l e t he ot he r m e t hods r e por t e d i n t he l i t e r a t ur e do not r e qui r e a pr o t e c t i ng gr oup on t he i ndol e r i ng. S i nc e w e r e por t e d t he m e t h odol ogy f or t he e na nt i os e l e c t i ve a z a F r i e de l C r a f t s r e a c t i on s e ve r a l ot he r r e s e a r c h gr ou ps ha ve r e por t e d c hi r a l phos phor i c a c i d c a t a l yz e d a z a F r i e de l C r a f t s r e a c t i ons 7 3 S i nc e our i ni t i a l r e por t our gr oup ha s a l s o de ve l ope d t he f i r s t hi ghl y e na nt i os e l e c t i ve m e t hod f or t he e na nt i os e l e c t i v e a ddi t i on of pyr r ol e de r i va t i ve s t o i m i ne s 7 4 T he r e a c t i on e m pl oys t he s a m e i m i ne s a nd c a t a l ys t t ha t w e r e u s e d f or t he e na nt i os e l e c t i ve a ddi t i on of i ndol e s t o i m i ne s T he r e a c t i on e m pl oye d 2 e qui va l e nt s of t he i m i ne i n o r de r t o ke e p f r om f o r m i ng a n u nw a nt e d s i de pr oduc t T he r e a c t i on

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56 pr oduc e d t he de s i r e d pr oduc t i n e xc e l l e nt yi e l d a n d e na nt i om e r i c e xc e s s f or i m i ne s w i t h bot h e l e c t r on dona t i ng a nd e l e c t r on w i t hd r a w i ng s ubs t i t ue nt s T ab l e 3. 11. E n an t i os e l e c t i ve A d d i t i on o f P yr r ol e s t o I m i n e s A pr oj e c t t ha t c oul d be de ve l ope d out t he m e t ho dol ogy t ha t w a s de ve l ope d w a s t he a ppl i c a t i on of c hi r a l phos phor i c a c i d c a t a l y s t s t o t he e n a nt i os e l e c t i ve a ddi t i on of nuc l e ophi l e s t o r a c e m i c 3 i ndol yl m e t ha na m i ne s A r a c e m i c f or m of s uc h a pr oc e s s w a s r e por t e d by K oba ya s hi i n 2005. 7 5 T he r e a c t i on s houl d pr oc e e d by pr ot ona t i on of t he ni t r oge n of t he 3 i ndol yl m e t ha na m i ne T he l os s of t he a m i de f unc t i ona l i t y w oul d r e s ul t i n t he f or m a t i on of a uns a t ur a t e d i m i ni um i on. T he phos pha t e c ount e r i on s houl d b e a bl e t o f or m a c hi r a l i on pa i r w i t h t he r e s ul t i ng i m i ni um i on. T he a ppl i c a t i on of c hi r a l phos pha t e c ount e r i ons f or t he de ve l opm e nt of e na nt i os e l e c t i ve r e a c t i on m e t hodol ogy ha s be e n r e por t e d by L i s t a nd c o w or ke r s f or t he e na nt i os e l e c t i ve r e duc t i on of

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57 uns a t ur a t e d e none s a nd e na l s 2 8 I t s houl d be pos s i bl e f or nuc l e ophi l e s t o a dd t o t he c hi r a l i on pa i r w i t h s om e l e ve l o f e na nt i oc ont r ol F i gu r e 3. 4 A c i d C at al yz e d A d d i t i on of N u c l e op h i l e s t o R ac e m i c 3 I n d ol yl m e t h an am i n e s

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58 C h ap t e r 4 E xp e r i m e n t al P r oc e d u r e s 4. 1. S u p p or t i n g I n f or m at i o n f or C h ap t e r 2 4. 1. 1 G e n e r al C on s i d e r at i on s A l l r e a c t i ons w e r e c a r r i e d out i n f l a m e dr i e d or o ve n dr i e d s c r e w c a p t e s t t ube s a nd r un unde r a dr y a r gon a t m os phe r e w i t h m a gne t i c s t i r r i ng. E t he r w a s pur c ha s e d a nhydr ous f r om F i s he r a nd di s t i l l e d ove r s odi u m / be nz ophe none unde r a dr y a r gon a t m os phe r e V A P O L w a s s ynt he s i z e d a c c or di ng t o t he l i t e r a t ur e pr oc e dur e 5 7 A l l i m i ne s w e r e s ynt he s i z e d a c c or di ng t o t he l i t e r a t ur e p r o c e dur e e xc e pt S c hl e nk f i l t r a t i on w a s r e qui r e d f or i m i ne s of hi gh pur i t y t o be i s ol a t e d. 3 5 A m i de s s ul f ona m i de s a nd B I N O L w e r e pur c ha s e d f r om c om m e r c i a l s our c e s a n d us e d w i t hout f ur t he r pur i f i c a t i on. S ubs t i t ut e d B I N O L phos phor i c a c i ds w e r e pr e pa r e d a c c or di ng t o t he know n l i t e r a t ur e pr oc e dur e 4 8 T hi n l a ye r c hr o m a t ogr a phy w a s pe r f or m e d on M e r c k T L C pl a t e s ( s i l i c a ge l 60 F 2 5 4 ) F l a s h c ol um n c hr om a t ogr a phy w a s pe r f or m e d w i t h I C N s i l i c a g e l ( 230 400 m e s h) or M e r c k s i l i c a ge l ( 230 400 m e s h) I R s pe c t r a w e r e r e c or de d on a P e r ki n E l m e r P a r a gon 500 F T I R i ns t r um e nt f or a l l pr e vi ous l y u nknow n c om pounds ( K B r pe l l e t ) E na nt i om e r i c e xc e s s ( e e ) w a s de t e r m i ne d us i ng a H e w l e t t P a c ka r d 1050 S e r i e s H P L C f i t t e d w i t h D a i c e l C hi r a l c e l O D H or O J H c hi r a l c ol um n a t 254. 4 nm ( e l ue nt a nd f l ow r a t e s s how n be l ow ) O pt i c a l r ot a t i ons w e r e pe r f or m e d on a R udol ph R e s e a r c h A na l yt i c a l A ut opol I I I pol a r i m e t e r ( & 589 ) us i ng a 1 m L c e l l w i t h a pa t h l e ngt h of 1 dm M e l t i ng poi nt s w e r e de t e r m i ne d us i ng a M E L T E M P 3 0 i n s t r um e nt 1 H N M R a nd 1 3 C N M R w e r e

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59 r e c or de d on a B r uke r A va nc e D R X 500 ( 500 M H z ) i ns t r um e nt w i t h c he m i c a l s hi f t s r e por t e d r e l a t i ve t o t e t r a m e t hyl s i l a ne ( T M S ) T h e H R M S da t a w e r e m e a s ur e d on a n A gi l e nt M S D / T O F m a s s s p e c t r om e t e r w i t h e l e c t r os pr a y i oni z a t i on. C om pounds de s c r i be d i n t he l i t e r a t ur e w e r e c ha r a c t e r i z e d by c o m pa r i ng t he i r 1 H N M R 1 3 C N M R a nd m e l t i ng poi nt ( m p) t o t he r e por t e d va l ue s G e n e r al p r oc e d u r e f or t h e B r n s t e d ac i d c at al y z e d am i d at i o n o f i m i n e s T he B oc i m i ne ( 1 m m ol ) a m i de or s ul f ona m i de ( 0. 5 m m ol ) a nd B r ns t e d a c i d ( 0. 5 20 m ol % ) w e r e w e i ghe d i nt o a dr y, r e s e a l a bl e t e s t t ube w i t h s e pt a a nd s t i r ba r T he t ube w a s e va c ua t e d a nd ba c k f i l l e d w i t h a r gon a nd r e p e a t e d t hr e e t i m e s T o t he m i xt u r e w a s a dde d 2 m L of d r y e t he r vi a s yr i nge a nd t he m i xt ur e w a s s t i r r e d vi gor ous l y f o r t he de s i r e d r e a c t i on t i m e A c e t one ( 2 3 m L ) a nd a s c oop of s i l i c a ge l w e r e a dde d a nd t he s ol ve nt w a s r e m ove d by r ot a r y e va por a t i on t o gi ve a c r ude s ol i d m i xt ur e t ha t w a s pur i f i e d by c ol um n c hr om a t og r a phy t o pr ovi de p r oduc t 3 ( ) t e r t b u t yl m e t h yl s u l f on a m i d o( p h e n yl ) m e t h yl c ar b am at e ( 105a) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 99% yi e l d. M p = 161 163 C I R ( K B r c m 1 ) : 3340 ( s N H ) 3268 ( s N H ) 1686 ( s C = O ) 1519 ( P h) 1329 ( s S O 2 ) 1153 ( s S O 2 ) 1 H N M R ( 500M H z C D C l 3 ) : 1. 48 ( s 9H 3C H 3 ) 3. 03 ( s 3H C H 3 ) 5. 58 ( s 1H N H ) 5 59 ( s 1H N H ) 6. 14 ( s 1H C H ) 7. 28 7. 48 ( m 5H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 7 ( C H 3 ) 42. 4 ( C H 3 ) 64. 3 ( C H ) 81. 4 [ C ( C H 3 ) 3 ] 126. 5 129. 1,

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60 129. 3, 138 6, 155 2 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 3 H 2 0 N 2 N a O 4 S ( [ M + N a ] + ) 323. 1042, F ound 323. 1076 ( ) t e r t b u t yl ( 4 m e t h yl p h e n yl s u l f on am i d o) ( p h e n yl ) m e t h yl c ar b a m at e ( 105 b ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 91% yi e l d. M p = 179 180 C I R ( K B r c m 1 ) : 3362 3 230, 1684, 1524, 1335, 1163. 1 H N M R ( 500M H z C D C l 3 ) : 1 37 ( s 9H 3C H 3 ) 2 44 ( s 3H C H 3 ) 5. 32 ( s br 1H N H ) 5 76 ( s br 1H N H ) 5 97 ( t J = 8 0 H z 1H C H ) 7. 28 7 35 ( m 7H A r H ) 7 78 ( d, J = 8 2 H z 2H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 21. 93 ( C H 3 ) 28 6 ( C H 3 ) 64. 2 ( C H ) 80 7 [ C ( C H 3 ) 3 ] 126 4, 127 6, 128 8, 129 0, 130 0, 138 2, 138. 9 143. 8 154. 7 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 9 H 2 4 N a N 2 O 4 S ( [ M + N a ] + ) 399 13 54 F ound 399. 1340 ( ) t e r t b u t yl u r e t h a n yl ( p h e n yl ) m e t h yl c ar b am at e ( 105c ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 97% yi e l d. M p = 156 157 C I R ( K B r c m 1 ) : 3315 1700 1654 1545, 1511. 1 H N M R ( 500M H z C D C l 3 ) : 1 25 ( t J = 6 8, 3H C H 3 ) 1 44 ( s 9H 3C H 3 ) 4 15 ( q J = 6. 8, 2 H C H 2 ) 5 56 ( s br 2H 2N H ) 6 17 ( s 1H C H ) 7. 31 7 41 ( m 5H A r H ) 1 3 C N M R ( 12 5M hz C D C l 3 ) : 14. 9 ( C H 2 C H 3 ) 28. 7

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61 ( C H 3 ) 61 6 ( C H ) 62 1 ( C H 2 C H 3 ) 81 0 [ C ( C H 3 ) 3 ] 126. 2 128. 4 12 9. 0 139. 9, 155. 1( C = O ) 156. 1 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 5 H 2 2 N 2 N a O 4 ( [ M + N a ] + ) 317. 147 8, F ound 317. 14 87 ( ) t e r t b u t yl b e n z yl c ar b am at o ( p h e n yl ) m e t h yl c ar b am at e ( 105d ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 81% yi e l d. M p = 138 139 C I R ( K B r c m 1 ) : 3323 1670 1654 154 3, 1508. 1 H N M R ( 500M H z C D C l 3 ) : 1. 46 ( s 9H 3C H 3 ) 5 16 ( s 2H C H 2 ) 5. 56 ( s b r 1H N H ) 5 78 ( s br 1H N H ) 6. 2 2 ( s 1H C H ) 7. 29 7 43 ( m 10H ) 1 3 C N M R ( 125 M H z C D C l 3 ) : 28. 7 ( C H 3 ) 62 2 ( C H ) 67. 4 ( O C H 2 ) 80. 8 [ C ( C H 3 ) 3 ] 126. 2 ( A r C ) 128. 6 ( A r C ) 128. 9 ( A r C ) 129. 1 ( A r C ) 136. 6 ( A r C ) 139. 6, 155 1 ( C = O ) 155. 8 ( C = O ) H R M S ( E S I ) C a l c d f or C 2 0 H 2 4 N a N 2 O 4 ( [ M + N a ] + ) 379. 1634 F ound 379. 1634 ( ) t e r t b u t yl ac r yl am i d o ( p h e n yl ) m e t h yl c ar b am at e ( 105e ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 97% yi e l d. M p = 162 163 C I R ( K B r c m 1 ) : 3421, 3327 1690, 1657, 1628 154 8. 1 H N M R ( 500 M H z C D C l 3 ) : 1. 44 ( s 9H 3C H 3 ) 5. 70 ( d J = 10. 6, 1H C H ) 5. 72 ( s br 1H N H ) 6. 15 ( dd J = 10. 6, J = 17. 0, 1H C H ) 6. 32 ( d J = 17. 0, 1H C H ) 6. 35 ( s 1H C H ) 6. 87 ( s b r N H ) 7. 28 7 47

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62 ( m 5H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 2 8. 7 ( C H 3 ) 60 7 ( C H ) 80. 9 [ C ( C H 3 ) 3 ] 126. 2 ( A r C ) 127. 9 ( C H = C H 2 ) 128. 4 ( A r C ) 129 1 ( A r C ) 131. 5 ( C H = C H 2 ) 139. 4 ( A r C ) 155. 4 ( C = O ) 165. 5 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 5 H 2 0 N a N 2 O 3 ( [ M + N a ] + ) 299. 1372, F ound 299 1371. ( ) t e r t b u t yl f or m a m i d o( p h e n yl ) m e t h yl c ar b am at e ( 105f ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 87% y i e l d. M p = 144 145C I R ( K B r c m 1 ) : 3319, 1691, 1543, 1508 1 H N M R ( 500M H z C D C l 3 ) : 1. 44 ( s 9H 3C H 3 ) 5. 42 ( s N H ) a nd 5. 79 r ot a m e r 6. 20 ( s N H ) a nd 6. 40 r ot a m e r 6. 78 ( s N H ) a nd 7. 02 r ot a m e r 7 26 7 55 ( m 5H A r H ) 8. 28 ( s C H O ) a nd 8. 40 r o t a m e r 1 3 C N M R ( 125M H z C D C l 3 ) : 28 7, 59. 4 81 0, 126 2, 128. 7 129 1, 1 29. 4, 129 6, 137. 9 138 9, 155 3, 160. 9 165. 1 H R M S ( E S I ) C a l c d f or C 1 3 H 1 8 N 2 N a O 3 ( [ M + N a ] + ) 273. 1215 F ound 273. 12 27 ( ) t e r t b u t yl ac e t am i d o( p h e n y l ) m e t h yl c ar b am at e ( 105g) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 91% yi e l d. M p = 161 163 C I R ( K B r c m 1 ) : 3327 ( s N H ) 1699 ( s C = O ) 1653 ( s C = O ) 1552, 1509, 1368 ( m C H 3 ) 1 H N M R ( 500M H z C D C l 3 ) : 1. 45 ( s 9H 3C H 3 ) 2. 02 ( s 3H C H 3 ) 5. 93 ( s br N H ) 6. 31 ( s br N H ) 7 10 ( s 1H C H ) 7. 29 7 36 ( m 5H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) :

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63 23. 6 ( C H 3 ) 28. 7 ( C H 3 ) 60. 4 ( C H ) 80. 7 [ C ( C H 3 ) 3 ] 126. 2, 128 3, 129. 6 139. 7, 155. 5 ( C = O ) 170. 4 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 4 H 2 0 N a N 2 O 3 ( [ M + N a ] + ) 287. 1372 F ound 287. 1369. ( ) t e r t b u t yl b e n z am i d o( p h e n yl ) m e t h yl c ar b am at e ( 105h ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 91% yi e l d. M p = 154 156 C I R ( K B r c m 1 ) : 3313, 1689 1638 1542 1509 1 H N M R ( 500M H z C D C l 3 ) : 1 43 ( s 9H 3C H 3 ) 6. 24 ( s br 1H N H ) 6. 51 ( s 1H C H ) 7. 2 3 7. 49 ( m 8H A r H ) 7. 81 ( d J = 7. 5 H z 2H A r H ) 7 95 ( s b r 1H N H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28 7 ( C H 3 ) 61 0 ( C H ) 80. 9 [ C ( C H 3 ) 3 ] 126. 3 ( A r C ) 127 7 ( A r C ) 128. 3 ( A r C ) 129. 0 ( A r C ) 129 6 ( obs c ur e d A r C ) 132 2 ( A r C ) 134. 3 ( A r C ) 139 8 ( A r C ) 155. 7 ( C = O ) 169 9 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 9 H 2 2 N a N 2 O 3 ( [ M + N a ] + ) 349. 1528 F ound 349 1572. ( ) t e r t b u t yl ( 3, 5 d i m e t h oxy b e n z am i d o) ( p h e n yl ) m e t h yl c ar b am a t e ( 105i ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he p r oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 84% yi e l d. M p =

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64 186 187 C I R ( K B r c m 1 ) : 3323 ( m N H ) 1692 ( s C = O ) 1637, 1597, 1509, 1159. 1 H N M R ( 500M H z C D C l 3 ) : 1. 44 ( s 9H 3C H 3 ) 3. 81 ( s 6H C H 3 ) 5. 89 ( s br 1H N H ) 6. 49 ( s br 1H N H ) 6 59 ( t 1H J = 2. 0 H z C H ) 6. 95 ( d J = 1. 9 H z 2H A r H ) 7. 29 7. 45 ( m 6H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 8 ( C H 3 ) 56. 0 ( O C H 3 ) 61 2 ( C H ) 81. 0 [ C ( C H 3 ) 3 ] 104. 6 ( A r C ) 105. 5 ( A r C ) 126 3 ( A r C ) 128. 5 ( A r C ) 129 1 ( A r C ) 136. 6 ( A r C ) 139. 7 ( A r C ) 155 7 ( A r C ) 161. 4 ( C = O ) 167. 3 ( C = O ) H R M S ( E S I ) C a l c d f or C 2 1 H 2 6 N a N 2 O 5 ( [ M + N a ] + ) 409. 1739 F ou nd 407. 177 ( ) t e r t b u t yl ( 3, 5 d i n i t r ob e n z am i d o) ( p h e n yl ) m e t h yl c ar b am at e ( 105j ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 49% yi e l d. M p = 206 207 C I R ( K B r c m 1 ) : 3402 ( w N H ) 3332 ( m N H ) 1687 ( s C = O ) 1654 ( s C = O ) 1545, 1496, 1344 ( s N O 2 ) 1 H N M R ( 500M H z D M S O ) : 1. 42 ( s 9H 3C H 3 ) 6 59 ( t J = 7. 1 H z 1H C H ) 7. 32 7 47 ( m 5H A r H ) 7. 8 0 ( s 1H N H ) 8 97 ( t 1H J = 2 0 H z A r H ) 9. 12 ( d J = 2 0 H z 2H A r H ) 9 87 ( d, J = 7. 2 H z 1H N H ) 1 3 C N M R ( 125M H z D M S O ) : 28. 1 ( C H 3 ) 60. 4 ( C H ) 78. 5 [ C ( C H 3 ) 3 ] 121 0, 126. 6 127. 6 127. 8 127. 9, 128. 2, 136. 6 139. 5 148. 1 ( C = O ) 161. 6 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 0 N a N 4 O 7 439. 123 F ound 439 1271.

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65 ( ) t e r t b u t yl ac r yl am i d o( o t ol yl ) m e t h yl c ar b am at e ( 105k ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he p r oduc t w a s obt a i ne d a s a w hi t e s o l i d i n 98% yi e l d. M p = 162 164 C I R ( K B r c m 1 ) : 3301, 1692, 1657, 1171 1 H N M R ( 500M H z C D C l 3 ) : 1. 46 ( s 9H 3C H 3 ) 2. 42 ( s 3H C H 3 ) 5. 36 ( s b r N H ) 5. 71 ( d, J = 1 0. 4 H z 1H C H ) 5 88 ( s br 1H N H ) 6. 13 ( q, dd, 1H J = 10. 3 H z J = 16. 9 H z C H ) 6 62 ( s 1H C H ) 7. 20 7. 29 ( m 4H A r H ) 7 42 7. 43 ( m 1H N H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 19 5 ( C H 3 ) 28. 6 ( C H 3 ) 58. 8 ( C H ) 80. 9 [ C ( C H 3 ) 3 ] 125. 3 126. 7 127. 9 128 8, 130 7, 131 4, 136 2, 137. 6 154. 9 ( C = O ) 164. 9 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 6 H 2 2 N a N 2 O 3 ( [ M + N a ] + ) 313. 1528 F ound 313. 1532. ( ) t e r t b u t yl ac r yl am i d o ( 4 b r om op h e n y l ) m e t h yl c ar b a m at e ( 105l ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 94% yi e l d M p = 184. 5 185. 0 C I R ( K B r c m 1 ) : 3321, 1689 1627, 1546 1 H N M R ( 500M H z C D C l 3 ) : 1. 44 ( s 9H 3C H 3 ) 5 74 ( d J = 10 4 H z 1H ) 5 83 ( s br 1H N H ) 6. 15 ( q dd 1H J = 10. 4 H z J = 16. 6 H z C H ) ; 6. 28 ( s b r 1H C H ) 6. 33 ( d, J = 16. 6 H z 1H C H ) 6. 86 ( s b r 1H N H ) 7. 27 ( d, J = 9. 3 H z 2H A r H ) 7. 48 ( d, J = 8 5 H z 2H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 7 ( C H 3 ) 60. 3 ( C H ) 80 8 [ C ( C H 3 ) 3 ] 122. 1 127. 6 128. 0, 130. 6 132. 2,

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66 138. 5, 155 1 ( C = O ) 165 1 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 5 H 1 9 B r N a N 2 O 3 ( [ M + N a ] + ) 377. 0477, F ound 377 0482. ( ) t e r t b u t yl ac r yl am i d o( 4 m e t h oxyp h e n yl ) m e t h yl c ar b am at e ( 105m ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 91% yi e l d. M p = 167 169 C I R ( K B r c m 1 ) : 3320, 1689, 1658, 1511. 1 H N M R ( 500M H z C D C l 3 ) : 1. 43 ( s 9H 3C H 3 ) 3 78 ( s 3H 3C H 3 ) 5. 68 ( d, J = 10. 2 H z 1H C H ) 5. 87 ( s br 1H N H ) 6 12 6. 17 ( q, dd, J = 16. 9 J = 10. 2, 1H C H ) 6. 34 ( d, 2H J = 16. 9, C H C H ) 6. 85 6. 87 ( m 2H A r H ) 6 87 ( s br N H ) 7. 27 7 30 ( m 2H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28 3 ( C H 3 ) 55. 3 59. 9 ( C H ) 80. 3 [ C ( C H 3 ) 3 ] 114. 0 1 27. 0, 127. 4 130. 5 131. 2 155. 0, 159 3 ( C = O ) 165. 0 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 6 H 2 2 N 2 N a O 4 ( [ M + N a ] + ) 329. 1477 F ound 329. 14 83. ( ) t e r t b u t yl ac r yl am i d o ( t h i o p h e n 2 yl ) m e t h yl c ar b am at e ( 105 n ) F o l l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i n e d a s a w hi t e s ol i d i n 91% yi e l d. M p = 166 168 C I R ( K B r c m 1 ) : 3318 3268 1695 166 4, 1167. 1 H N M R ( 500M H z C D C l 3 ) : 1. 45 ( s 9H 3C H 3 ) 5 74 ( d, J = 10. 2 H z 1H C H ) 5. 9 ( s br 1H N H ) 6. 13 ( q dd, J = 10. 2 H z J = 16. 9 H z 1H C H ) 6. 35 ( d J = 16 9 1H C H ) 6 53 ( s br 1H C H ) 6. 95

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67 7. 26 ( m 3H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28 7 ( C H 3 ) 57. 8 ( C H ) 81 2 [ C ( C H 3 ) 3 ] 125. 1, 125. 7 127. 4, 128 3, 130. 7 143. 9 155. 2 ( C = O ) 165. 3 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 3 H 1 8 N a N 2 O 3 S ( [ M + N a ] + ) 305. 0936 F ound 3 05. 0945. ( ) t e r t b u t yl ac r yl am i d o ( f u r an 2 yl ) m e t h yl c ar b am at e ( 105o) U s i ng t he ge ne r a l pr oc e dur e t he p r oduc t w a s obt a i ne d a s a w hi t e s o l i d i n 99% yi e l d. M p = 162 163 C I R ( K B r c m 1 ) : 3301 ( m N H ) 1691 ( s C = O ) 16 58 ( w C = O ) 1560, 1511. 1 H N M R ( 500M H z C D C l 3 ) : 1. 45 ( s 9H 3C H 3 ) 5. 72 ( d, J = 10. 2 H z 1H C H ) 5. 8 ( s b r 1H N H ) 6. 15 ( dd, J = 10. 2 H z J = 16. 9 H z 1H C H ) 6 34 6. 37 ( m 3H ) 6. 87 ( s br N H ) 7. 28 ( s 1H C H ) 7 37 ( s 1H C H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28 7 ( C H 3 ) 55 7 ( C H ) 81. 0 [ C ( C H 3 ) 3 ] 107. 4 111. 0 128. 2, 13 0. 7, 142. 6 151. 5, 155 1( C = O ) 165. 3 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 3 H 1 8 N a N 2 O 4 ( [ M + N a ] + ) 289. 1164, F ound 289. 1172 G e n e r al p r oc e d u r e f or c h i r al V A P O L p h os p h or i c ac i d c at al yz e d am i d at i o n of i m i n e s T he B oc i m i ne ( 2 e qui v. ) nuc l e oph i l e ( 1e qui v) a nd t he V A P O L phos phor i c a c i d ( 4 10m ol % ) w e r e w e i ghe d i nt o a dr y t ube a nd unde r A r gon, i nj e c t e d i nt o dr y di e t hyl e t he r or t ol ue ne ( 1 2 m L ) T he r e a c t i on m i xt ur e w a s s t i r r e d a t a m bi e nt t e m pe r a t ur e unt i l m a xi m um s ol i d pr e c i pi t a t e d. A dde d a c e t o ne a nd t r a ns f e r t he r e s ul t i ng m i xt ur e t o bi g gl a s s w a r e a nd t he n a dde d s i l i c a ge l ( a bout h a l f s poon) T he s ol ve nt w a s e va por a t e d a nd t he pr oduc t w a s i s ol a t e d by c ol um n c hr om a t ogr a p hy a s w hi t e s ol i d. T he e e of t he pr oduc t w a s de t e r m i ne d by c hi r a l H P L C a na l y s i s

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68 t e r t b u t yl m e t h yl s u l f o n am i d o ( p h e n yl ) m e t h yl c ar b am at e ( 105a) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 86 % yi e l d a nd 93% e e H P L C a na l ys i s : C hi r a l c e l O J H ( he xa ne / i P r O H = 85/ 15 1. 0 m L / m i n ) t r m i n o r 14. 1 m i n t r m a j o r 15. 9 m i n. I R ( K B r c m 1 ) : 3340 ( s N H ) 3268 ( s N H ) 1686 ( s C = O ) 1519 ( P h) 1329 ( s S O 2 ) 1153 ( s S O 2 ) 1 H N M R ( 500M H z C D C l 3 ) : 1. 48 ( s 9H 3C H 3 ) 3. 03 ( s 3H C H 3 ) 5. 58 ( s 1H N H ) 5 59 ( s 1H N H ) 6. 14 ( s 1H C H ) 7. 28 7. 48 ( m 5H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 7 ( C H 3 ) 42. 4 ( C H 3 ) 64. 3 ( C H ) 81. 4 [ C ( C H 3 ) 3 ] 126. 5 129. 1, 129. 3, 138 6, 155 2 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 3 H 2 0 N 2 N a O 4 S ( [ M + N a ] + ) 323. 1042, F ound 323. 1076 ( ) t e r t b u t yl ( 4 m e t h yl p h e n yl s u l f on am i d o) ( p h e n yl ) m e t h yl c ar b a m at e ( 105b ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 9 5 % yi e l d a nd 94% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10 1. 0 m L / m i n ) t r m a j o r 10 6 m i n t r m i n o r 12 1 m i n [ a ] 2 0 D = 10. 4 ( c = 0. 23, C H C l 3 ) I R ( K B r c m 1 ) : 3362, 3230, 1684, 1524 1335, 1163 1 H N M R ( 500M H z C D C l 3 ) : 1. 37 ( s 9H 3C H 3 ) 2 44 ( s 3H C H 3 ) 5 32 ( s br 1H N H ) 5. 76 ( s br 1H N H ) 5 97 ( t J = 8. 0 H z 1H C H ) 7 28 7. 35 ( m 7H A r H ) 7 78 ( d J = 8 2 H z 2H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 21. 93 ( C H 3 ) 28. 6 ( C H 3 ) 64. 2 ( C H ) 80. 7 [ C ( C H 3 ) 3 ] 12 6. 4, 127. 6 128. 8, 129. 0 130. 0, 138. 2 138. 9, 143 8, 154 7 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 9 H 2 4 N a N 2 O 4 S ( [ M + N a ] + ) 399. 1354 F ound 399. 1340

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69 ( + ) t e r t b u t yl ( 4 m e t h oxyp h e n yl s u l f on am i d o) ( p h e n yl ) m e t h y l c ar b am at e ( 105p ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr od uc t w a s obt a i ne d a s a w hi t e s ol i d i n 89 % yi e l d a nd 91% e e H P L C a na l ys i s : C hi r a l c e l O J H ( he xa ne / i P r O H = 90/ 10 1. 0 m L / m i n ) t r m i n o r 23. 43 m i n t r m a j o r 30. 72 m i n [ a ] 2 0 D = 1 86 ( c = 0. 4 C H C l 3 ) M p = 159 160 C I R ( K B r c m 1 ) : 3302 1688, 1156 1 H N M R ( 500M H z C D C l 3 ) : 1 37 ( s 9H 3C H 3 ) 3. 87 ( s 3H C H 3 ) 5. 28 ( s br 1H N H ) 5. 52 ( s br 1H N H ) 5 9 3 ( t J = 7. 6 H z 1H C H ) 6. 94 ( d J = 8. 9H z 2 H A r H ) 7. 28 7 32 ( m 5H A r H ) 7. 7 9 ( d, J = 8. 9 H z 2H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 4 ( C H 3 ) 55. 7 ( C H 3 ) 64. 1 ( C H ) 80. 7 [ C ( C H 3 ) 3 ] 114. 3 126. 2, 128. 7, 128 9, 129. 6 132 3, 138. 4 155 0, 16 3. 1 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 5 S ( [ M + N a ] + ) 415. 1303 F ound 415 1 231. ( + ) t e r t b u t yl ( 2 m e t h yl p h e n yl s u l f on am i d o) ( p h e n yl ) m e t h yl c ar b a m at e ( 105 q ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 80 % yi e l d a nd 73% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10, 1. 0 m L / m i n, t r m i n o r 8. 02 m i n, t r m a j o r 10. 38 m i n [ a ] 2 0 D = + 7 ( c = 0. 4, C H C l 3 ) M p = 147 148 C I R ( K B r c m

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70 1 ) : 3353 1692 1161 1 H N M R ( 500M H z C D C l 3 ) : 1 3 5 ( s 9H 3C H 3 ) 2. 63 ( s 3H C H 3 ) 5 3 6 ( s br 1H N H ) 5. 83 ( s b r 1H N H ) 5. 88 ( t J = 7. 7 H z 1H C H ) 7. 2 3 7 29 ( m 7H A r H ) 7. 45 ( t 1H J = 9. 2 H z A r H ) 7. 8 7 ( d, J = 7. 8 H z 1 H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 2 0. 4 ( C H 3 ) 28. 3 ( C H 3 ) 64. 2 ( C H ) 80. 7 [ C ( C H 3 ) 3 ] 126. 1 12 6. 4 128. 6 12 8 8, 129 6 132. 5 132. 9 137 1, 138 0, 1 38. 7, 154 4 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 4 S ( [ M + N a ] + ) 399. 1354 F ound 3 99. 1337. ( ) t e r t b u t yl ( 4 c h l or op h e n yl s u l f on a m i d o) ( p h e n yl ) m e t h yl c ar b a m at e ( 105r ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 98% yi e l d a nd 94 % e e H P L C a na l y s i s : C hi r a l c e l O D H ( he x a ne / i P r O H = 90/ 10, 1. 0 m L / m i n t r m a j o r 8. 79 m i n, t r m i n o r 11. 26 m i n [ a ] 2 0 D = 4. 56 ( c = 0. 9, C H C l 3 ) M p = 166 167 C I R ( t hi n f i l m c m 1 ) : 33 61, 3221 1679 116 5 1 H N M R ( 3 00M H z C D C l 3 ) : 1 38 ( s 9H 3C H 3 ) 5. 31 ( s br 1H N H ) 5 77 ( s br 1H N H ) 6 02 ( t J = 7. 9 H z 1H C H ) 7. 32 ( m 5H A r H ) 7 45 ( d 2H J = 8. 6 H z A r H ) 7 78 ( d J = 8. 6 H z 1 H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 2 ( C H 3 ) 64. 0 ( C H ) 80. 8 [ C ( C H 3 ) 3 ] 126. 0, 128 6 128. 7, 12 8. 8 129. 2 137. 9 139. 2 139. 3 154. 3 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 4 S ( [ M + N a ] + ) 397. 0991 F ound 397 0988.

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71 ( + ) t e r t b u t yl ( 4 c h l or op h e n yl ) ( 4 m e t h yl p h e n yl s u l f on am i d o) m e t h yl c ar b am at e ( 105s ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr od uc t w a s obt a i ne d a s a w hi t e s ol i d i n 88% yi e l d a nd 95 % e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10, 1. 0 m L / m i n t r m a j o r r 8. 48 m i n, t r m i n o r 13. 30 m i n [ a ] 2 0 D = + 2. 84 ( c = 1. 07 C H 2 C l 2 ) M p = 168 169C I R ( t hi n f i l m c m 1 ) : 3334, 3266, 1681 1520, 1444, 1347, 116 0 1 H N M R ( 300M H z C D C l 3 ) : 1 33 ( s 9H 3C H 3 ) 2 44 ( s 3H C H 3 ) 5. 36 ( s br 1H N H ) 5 89 ( s br 2H N H C H ove r l a p) 7. 27 ( d, 2H A r H ) 7. 7 2 ( t 1H J = 9. 2 H z A r H ) 7. 87 ( d, J = 7. 8 H z 1 H A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 21. 6 ( C H 3 ) 28 2 ( C H 3 ) 63 6 ( C H ) 80. 8 [ C ( C H 3 ) 3 ] 127. 2, 127. 6 128. 8, 129. 7 134. 4, 136. 8 137. 7, 143. 7 154. 2 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 9 H 2 4 N a N 2 O 4 S ( [ M + H ] + ) 411. 1147 F ound 411 1145 ( ) t e r t b u t yl ( 4 b r om op h e n yl ) ( 4 m e t h yl p h e n y l ) m e t h yl c ar b am a t e ( 105t ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 96% y i e l d a nd 91 % e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10, 1. 0 m L / m i n, t r m a j o r 8 65 m i n, t r m i n o r 16. 74 m i n [ a ] 2 0 D = 3. 45 ( c = 1. 1 C H C l 3 ) M p = 172 173 C I R ( K B r c m 1 ) :

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72 33 39 3262, 1685 1519 1319 1158 1 H N M R ( 5 00M H z C D C l 3 ) : 1 37 ( s 9H 3C H 3 ) 2. 46 ( s 3H C H 3 ) 5 35 ( s b r 1H N H ) 5. 82 ( s br 1H N H ) 5 87 ( t 1H J = 7. 7 H z C H ) 7. 20 ( d 2H J = 8 4 H z A r H ) 7. 30 ( d 2H J = 8. 3 H z A r H ) 7 43 ( d, 2H J = 8. 5 H z A r H ) 7. 73 ( d, 2H J = 8. 2 H z A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 2 1. 6 ( C H 3 ) 28. 2 ( C H 3 ) 63. 6 ( C H ) 80 8 [ C ( C H 3 ) 3 ] 122 6, 12 7. 2, 127 9, 129 8, 131 8, 137. 3 137. 7 143. 7, 154 3 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 4 S ( [ M + H ] + ) 455. 0644 F ound 455. 0640 ( ) t e r t b u t yl ( 2 m e t h yl p h e n yl s u l f o n am i d o ) ( 4 ( t r i f l u or om e t h yp h e n yl ) m e t h yl c ar b a m at e ( 105u ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 99 % yi e l d a nd 99 % e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10, 1. 0 m L / m i n, t r m a j o r 7. 00 m i n, t r m i n o r 11. 50 m i n [ a ] 2 0 D = 4 29 ( c = 1. 0 D M S O ) M p = 185 186 C I R ( K B r c m 1 ) : 3441 1654 1317, 1163 1 H N M R ( 500M H z C D C l 3 ) : 1 36 ( s 9H 3C H 3 ) 2 43 ( s 3H C H 3 ) 5 41 ( s br 1H N H ) 5 84 ( s br 1H N H ) 5. 92 ( t 1H J = 8. 2 H z C H ) 7. 27 ( d 2H J = 9 43, A r H ) 7. 44 ( d 1H J = 8. 2 H z A r H ) 7. 54 ( d, 2H J = 8. 2 H z A r H ) 7. 70( d 2H J = 8. 3) 1 3 C N M R ( 125M H z D M S O ) : 2 0. 9 ( C H 3 ) 28. 0 ( C H 3 ) 62 6 ( C H ) 78. 5 [ C ( C H 3 ) 3 ] 125. 2 126. 5, 127 2, 128 2 128. 5 129. 2 138 8, 142 3, 1 44. 2, 154 4 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 4 S ( [ M + H ] + ) 445 1410 F ound 44 5. 1409

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73 ( ) t e r t b u t yl ( 4 m e t h oxyp h e n yl ) ( 4 m e t h yl p h e n yl s u l f on am i d o) m e t h yl c ar b am at e ( 105v) F ol l ow i ng t he ge ne r a l pr oc e dur e t he p r od uc t w a s obt a i ne d a s a w hi t e s ol i d i n 92% yi e l d a nd 90 % e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10, 1. 0 m L / m i n t r m a j o r 14 116 m i n, t r m i n o r 26 924 m i n [ a ] 2 0 D = 3. 36 ( c = 1 0 C H C l 3 ) M p = 151 152C I R ( K B r c m 1 ) : 3337 3283 1684, 1512, 1367, 1306, 1161. 1 H N M R ( 500M H z C D C l 3 ) : 1 3 8 ( s 9H 3C H 3 ) 2 44 ( s 3H C H 3 ) 3. 80 ( s 3H O C H 3) 5. 23 ( s b r 1H N H ) 5. 56 ( s br 1H N H ) 5. 90 ( t J = 7. 7 H z 1 H C H ) 6 82( d J = 8. 8 H z 2H A r H ) 7. 22( d, J = 8. 8 H z 2H A r H ) 7. 29( d J = 7. 7 H z 2H A r H ) 7. 75 ( d, J = 8. 3 H z 2H A R H ) 1 3 C N M R ( 75M H z C D C l 3 ) : 21 5 ( C H 3 ) 28 2 ( C H 3 ) 55. 3 ( O C H ) 80 7 [ C ( C H 3 ) 3 ] 114 0, 127 3, 127 3, 129 6, 137. 7 143. 4 5, 154. 2 159. 6 4 ( C = O ) H R M S ( E S I ) C a l c d f or C 1 9 H 2 4 N a N 2 O 4 S ( [ M + H ] + ) 407 1643 F ou nd 407. 1641 ( + ) t e r t b u t yl ( 4 m e t h yl p h e n yl s u l f on am i d o) ( t h i op h e n 2 y l ) m e t h yl c ar b am at e ( 105w ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 94% yi e l d a nd 8 7 % e e H P L C a na l y s i s : C hi r a l c e l O D H ( he x a ne / i P r O H = 90/ 10, 1. 0 m L / m i n t r m a j o r 8. 86 m i n, t r m i n o r 12. 15 m i n [ a ] 2 0 D = + 7 ( c = 0. 4, C H C l 3 ) M p = 172 173 C I R ( K B r c m 1 ) : 335 1 3214 1676, 1332, 1161 1 H N M R ( 500M H z C D C l 3 ) : 1. 3 8 ( s 9H 3C H 3 ) 2. 45

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74 ( s 3H C H 3 ) 5 40 ( s br 1H N H ) 5. 95 ( s br 1 H N H ) 6. 14 ( t J = 8. 1 7 H z 1H C H ) 6. 94 ( t 1H J = 5 4, A r H ) 6. 97 ( s b r 1H A r H ) 7. 24 ( d 1H J = 4. 9 H z A r H ) 7. 31 ( d, 2H J = 8. 1 H z A r H ) 1 3 C N M R ( 125M H z C D C l 3 ) : d 21. 6 ( C H 3 ) 28. 2 ( C H 3 ) 61. 2 ( C H ) 80. 7 [ C ( C H 3 ) 3 ] 125. 2 125 9, 127 2, 127 2, 129 7, 137 8, 143. 0 143. 6 154 0 ( C = O ) H R M S ( E S I ) C a l c d f o r C 1 9 H 2 4 N a N 2 O 4 S ( [ M H ] ) 381 0942 F ound 381 0998 4. 2. S u p p or t i n g I n f or m at i o n f or C h ap t e r 3 4. 2. 1 G e n e r al C on s i d e r at i on s A l l r e a c t i ons w e r e c a r r i e d out i n f l a m e d r i e d s c r e w c a p t e s t t ube s f i t t e d w i t h a s e pt um a nd pe r f or m e d unde r a dr y a r gon a t m os phe r e w i t h m a gne t i c s t i r r i ng. A l l s ol ve nt s w e r e pur i f i e d by pa s s i ng t he de ga s s e d s ol ve nt t hr ough a c ol um n of a c t i va t e d a l um i na pr i or t o us e i n r e a c t i ons T he i ndo l e s ubs t r a t e s us e d f or t he r e a c t i ons w e r e pr e pa r e d by f ol l ow i ng l i t e r a t ur e pr oc e dur e s 6 4 d C hi r a l phos phor i c a c i d c a t a l y s t P A 5 5 7 a nd P A 6 7 2 w e r e p r e pa r e d by l i t e r a t ur e p r oc e dur e s T hi n l a ye r c hr om a t ogr a phy w a s pe r f or m e d on M e r c k T L C pl a t e s ( s i l i c a ge l 60 F 2 5 4 ) F l a s h c ol um n c hr om a t ogr a phy w a s pe r f or m e d w i t h a n I s c o T e l e dyne C om pa ni on 4X c hr om a t ogr a phy s ys t e m E na nt i om e r i c e xc e s s ( e e ) w a s de t e r m i ne d us i ng a V a r i a n P r os t a r H P L C s ys t e m w i t h a P r os t a r 210 bi na r y pum p a nd P r os t a r 335 di ode a r r a y de t e c t or w i t h D a i c e l C hi r a l c e l O D H or A D H c hi r a l c ol um n ( e l ue nt a nd f l ow r a t e s s ho w n be l ow ) 1 H N M R a nd 1 3 C N M R w e r e r e c or de d on a V a r i a n I nova 400 or a V a r i a n I nov a 500 i ns t r um e nt w i t h c he m i c a l s hi f t s r e por t e d r e l a t i ve t o r e s i dua l c hl o r of or m T he H R M S da t a w e r e m e a s ur e d on a n A gi l e nt 1100 s e r i e s M S D / T O F m a s s s pe c t r om e t e r w i t h e l e c t r os pr a y i oni z a t i on. C om pounds de s c r i be d i n t he l i t e r a t ur e w e r e c ha r a c t e r i z e d by c o m pa r i ng t he i r 1 H N M R 1 3 C N M R a nd

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75 m e l t i ng poi nt ( m p) t o t he r e por t e d va l ue s 4. 2. 2 E xp e r i m e n t al P r oc e d u r e s 1) G e n e r al p r oc e d u r e f or t h e p r e p ar at i on o f N ac yl i m i n e s F ol l ow i ng a m odi f i e d pr oc e dur e of T e r a da 7 7 N B e nz oyl 1 m e t hoxy 1 a r yl m e t hyl a m i ne ( 10 m m ol ) ove n dr i e d K 2 C O 3 a nd ove n dr i e d N a 2 S O 4 w e r e w e i ghe d i nt o a n ove n dr i e d 200 m L R B f l a s k. T ol ue ne ( 100 m L ) w a s a dde d t o t he f l a s k a nd t h e r e s ul t i ng s u s pe n s i on w a s he a t e d t o r e f l ux f or 12 h. T he s u s pe n s i on w a s c ool e d t o a m bi e nt t e m pe r a t ur e f i l t e r e d t hr ough c e l i t e a nd c onc e nt r a t e d i n va c uo. T he r e s i due w a s t r i t ur a t e d w i t h he xa ne unt i l t he r e s i due w a s a uni f or m s ol i d. T he r e s ul t i ng i m i ne s w e r e us e d i n r e a c t i on s w i t hout f ur t he r pu r i f i c a t i on. 2) G e n e r al p r oc e d u r e f or t h e p r e p ar at i on o f r a c e m i c 3 i n d ol yl m e t h an am i n e s T he i m i ne ( 0. 50 m m o l ) N b e nz yl i ndol e ( 0. 25 m m ol ) a nd phe nyl phos phi ni c a c i d ( 4 m g, 0. 025 m m ol ) w e r e w e i ghe d i nt o a t e s t t ube T h e a i r w a s r e m ove d und e r va c uum a nd r e pl a c e d w i t h a r gon. C H 2 C l 2 ( 2 m L ) w a s a dde d t o t he t e s t t ube vi a s yr i nge a nd t he r e a c t i on w a s s t i r r e d a t r oom t e m pe r a t ur e f or 1 hour T he r e a c t i on w a s di l ut e d w i t h C H 2 C l 2 c onc e nt r a t e d on s i l i c a ge l a nd pur i f i e d by f l a s h c ol um n c hr om a t ogr a phy 3) G e n e r al p r oc e d u r e f or t h e e n a n t i os e l e c t i ve a z a F r i e d e l C r af t s r e ac t i on T o a f l a m e dr i e d t e s t t ube c ont a i ni ng 200m g of a c t i va t e d, pow de r e d 4 m ol e c ul a r s i e ve s a nd a m a gn e t i c s t i r ba r w a s a dde d i m i ne ( 0. 50 m m ol ) a nd a c i d c a t a l ys t ( 11. 0m g, 0. 013 m m ol ) T he a i r w a s r e m ove d w i t h va c uum a nd r e pl a c e d w i t h a r gon, a nd 1 m L of C H 2 C l 2 w a s a dde d t o t he t e s t t ube vi a s yr i nge T he r e s ul t i ng s ol ut i on w a s pl a c e d i nt o a 30 o C ba t h a nd a l l ow e d t o s t i r f or 5 m i nut e s N be nz yl i ndol e ( 0. 25 m m ol ) w a s w e i ghe d i nt o a s e pa r a t e f l a m e dr i e d vi a l T he a i r w a s r e m ove d a nd r e pl a c e d w i t h a r gon, a nd 1 m L of C H 2 C l 2 w a s a dde d t o t he vi a l v i a s yr i nge T he r e s ul t i ng i ndol e s ol ut i on w a s t r a ns f e r r e d t o

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76 t he t e s t t ube c ont a i ni ng t he i m i ne a nd c a t a l ys t b y dr opw i s e a ddi t i on ove r a pe r i od of a ppr oxi m a t e l y 1 m i nut e T he r e s ul t i ng s ol ut i on w a s a l l ow e d t o s t i r f o r 16 h a t 30 o C a t w hi c h poi nt t he r e a c t i on m i x t ur e w a s di l ut e d w i t h C H 2 C l 2 c onc e nt r a t e d on s i l i c a ge l a nd pur i f i e d by f l a s h c ol um n c hr om a t ogr a phy. ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( p h e n y l ) m e t h yl ) b e n z am i d e ( 137a ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 99% yi e l d a nd 94% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 85 / 15 1. 0 m L / m i n ) t r m a j o r 15 80 m i n t r m i n o r 20. 16 m i n [ ] 2 5 D = 66. 1 ( c = 1. 0, C H C l 3 ) M p = 203. 3 204. 9 C I R ( s ol i d, c m 1 ) : 3317, 3234, 3029, 1629, 1521, 1490, 1350, 1336, 798, 699. 1 H N M R ( 500M H z C D C l 3 ) : 5. 28 ( s 2H ) 6. 79 ( m 3H ) 7 13 ( m 3H ) 7. 23 ( t J = 8. 3 H z 1H ) 7. 30 ( m 5H ) 7. 40 ( t J = 7. 8 H z 2H ) 7. 45 ( t J = 7. 8 H z 2H ) 7. 51 ( m 3H ) 7. 60 ( d, J = 7. 8 H z 1H ) 7. 84 ( d, J = 7. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 5 0. 4, 51 2, 110 4, 116. 7 119. 9 120 1, 122. 7, 126 9, 127. 0 127 3, 127. 3 127 6, 127. 9 1 28. 1, 128 8, 128. 9 129 1, 131. 8 134 7, 137. 4, 137 5, 141 6, 166. 7 H R M S ( E S I ) C a l c d f or C 2 9 H 2 4 N 2 N a O ( [ M + N a ] + ) 439. 1781 F ound 439. 1785

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77 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( 4 n i t r op h e n yl ) m e t h yl ) b e n z am i d e ( 137b ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 99% y i e l d a nd 94% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 32. 96 m i n, t r m i n o r 44. 56 m i n [ ] 2 5 D = 49 1 ( c = 1. 0 C H C l 3 ) M p = 176 0 177 7 C I R ( s ol i d, c m 1 ) : 3316, 3062, 2978, 1626 1508, 1486, 13 35, 1177, 1026, 739, 691. 1 H N M R ( 500M H z C D C l 3 ) : 5. 28 ( d, J = 3. 4 H z 2H ) 6. 7 7 ( m 2H ) 7. 14 ( m 3H ) 7 28 735 ( m 4H ) 7. 43 7. 60 ( m 6H ) 7. 65 ( d, J = 8. 7 H z 2H ) 7. 83 ( d, J = 7. 3 H z 2H ) 8 23 ( d J = 8. 7 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 110. 7, 115 1, 119. 3, 120. 6 123. 1 124. 3 126. 5, 127 9, 128. 0 128 2, 129. 0 129 1, 129. 1 1 32. 2, 133 9, 137. 0 147 5, 149. 2 167 0. H R M S ( E S I ) C a l c d f o r C 2 9 H 2 3 N a N 3 O 3 ( [ M + N a ] + ) 484. 1632 F ound 484 1630 ( + ) ( R ) N ( ( 1 b e n z yl 1 H i n d o l 3 yl ) ( 4 c h l or op h e n yl ) m e t h yl ) b e n z am i d e ( 137c ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 97% yi e l d a nd 96% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he x a ne / i P r O H = 85 / 1 5, 1. 0 m L / m i n ) t r m a j o r 17. 28 m i n, t r m i n o r 23. 29 m i n [ ] 2 5 D = 80. 4 ( c = 1. 0, C H C l 3 ) M p = 236. 7 237. 9 C I R ( s ol i d, c m 1 ) : 3305 1629, 1515, 1482 1343, 1177, 1085, 824, 732, 718 1 H N M R ( 500M H z C D C l 3 ) : 5 26 ( s 2H ) 6 68 6. 77 ( m 3 H ) 7 11 7 56 ( m 16H ) 7. 81 ( d, J = 7. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 4, 5 0. 7, 110. 4 116. 1, 119. 6 120. 3, 122. 8 126. 7, 126 9, 127. 3 127 9, 128. 0 128 6, 128. 9 1 28. 9, 129 0, 131. 9 133 2, 134. 4 137 3, 137. 4, 14 0 1, 166 7. H R M S ( E S I ) C a l c d f or C 2 9 H 2 3 C l N 2 N a O ( [ M + N a ] + ) 473. 1391 F ound 473. 1390

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78 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( 4 b r om o p h e n yl ) m e t h yl ) b e n z am i d e ( 137d ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 92% y i e l d a nd 96% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 13. 69 m i n, t r m i n o r 17. 65 m i n [ ] 2 5 D = 74 3 ( c = 1. 1 C H C l 3 ) M p = 220 3 221 3 C I R ( s ol i d, c m 1 ) : 3291 2966 1629, 5024, 1485 1468 10 89, 1073, 10 11, 735 713. 1 H N M R ( 500 M H z C D C l 3 ) : 5. 24 ( s 2H ) 6 65 ( d, J = 7. 3 H z 1H ) 6. 73 ( m 2H ) 7. 08 ( m 2H ) 7. 14 7. 34 ( m 8H ) 7. 39 7 53 ( m 6H ) 7. 78 ( d J = 7. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50 5, 50. 8 110 5, 116. 0 119 7, 120. 3 1 21. 4, 122 8, 126. 8 127 0, 127. 3 128 0, 1 28. 0, 128 9, 129. 0 129 1, 131. 9 132 0, 134. 4 1 37. 3, 137 4, 140. 7 166 8. H R M S ( E S I ) C a l c d f or C 2 9 H 2 3 B r N 2 N a O 3 ( [ M + N a ] + ) 517. 0886 F ound 517. 0881 ( + ) N ( ( 1 b e n z yl 1 H i n d o l 3 yl ) ( 4 f l u or op h e n yl ) m e t h yl ) b e n z am i d e ( 137e ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 97% y i e l d a nd 95% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 11. 60 m i n, t r m i n o r 15. 49 m i n [ ] 2 5 D = 75 1 ( c = 1. 0 C H C l 3 ) M p = 194 5 195 3 C I R ( s ol i d,

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79 c m 1 ) : 3344, 3064, 2926, 1628 1511, 1487, 12 48, 1179, 1029, 738, 692. 1 H N M R ( 500M H z C D C l 3 ) : 5 28 ( s 2H ) 6 78 ( m 3H ) 7. 07 ( t J = 8. 3 H z 2H ) 7 12 ( m 3H ) 7. 23 ( t J = 7. 3 H z 1H ) 7. 31 ( m 4H ) 7 45 ( m 4 H ) 7. 54 ( m 2H ) 7. 83 ( d, J = 7 3 H z 2H ) 1 3 C N M R ( 12 5M H z C D C l 3 ) : 50. 5, 50. 6 110. 5, 115 6 ( d J = 21. 6 H z ) 116. 4 119. 8, 120 3, 122 8, 126 9, 127 0, 127 3, 127 9, 128. 0 ( d, J = 8 6 H z ) 128 8, 128 9, 129. 1, 131 9, 134. 5 137 4 ( d J = 2 9 H z ) 137 5, 162. 0 ( d J = 245 5 H z ) 166 8. H R M S ( E S I ) C a l c d f o r C 2 9 H 2 3 F N 2 N a O ( [ M + N a ] + ) 457. 168 7 F ound 457. 1683 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( p t o l yl ) m e t h yl ) b e n z am i d e ( 137f ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 96% yi e l d a nd 97% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he x a ne / i P r O H = 80/ 20 1 0 m L / m i n ) t r m a j o r 10 95 m i n t r m i n o r 13. 55 m i n [ ] 2 5 D = 66. 7 ( c = 1. 1, C H C l 3 ) M p = 212. 4 215. 5 C I R ( s ol i d, c m 1 ) : 3335, 3063 1622, 1519 1486, 1335 1173, 821 747, 692. 1 H N M R ( 500M H z C D C l 3 ) : 2. 38 ( s 3H ) 5. 28 ( s 2H ) 6 73 ( d J = 7. 8 1H ) 6. 77 ( d, J = 7 8, 1H ) 6. 82 ( s 1H ) 7 11 ( m 2H ) 7. 21 ( m 3H ) 7. 26 ( m 3H ) 7 38 ( d J = 8. 3 H z 3H ) 7. 44 ( t J = 7. 8 H z 3H ) 7. 51 ( t J = 7. 3 H z 1H ) 7. 59 ( d J = 7. 8 H z 1H ) 7. 83 ( d J = 6. 8 H z 2H ) 1 3 C N M R ( 125M hz C D C l 3 ) : 21. 4, 50 4, 50 9, 110. 3 11 6. 8, 119. 9 120. 1 122. 6 126. 9 127. 127. 2, 127 3, 127. 9 128 0, 128. 8 129 0, 129. 4 1 31. 8, 134 8, 137. 2 137 4, 137. 5 138 6, 166. 7. H R M S ( E S I ) C a l c d f o r C 3 0 H 2 6 N 2 N a O ( [ M + N a ] + ) 453. 1937 F ound 453. 1938

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80 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( 4 m e t h oxyp h e n yl ) m e t h yl ) b e n z am i d e ( 137g) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 93% yi e l d a nd 94% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0 / 20, 1. 0 m L / m i n ) t r m a j o r 1 8 00 m i n t r m i n o r 23. 45 m i n. [ ] 2 5 D = 72 1 ( c = 1. 0, C H C l 3 ) M p = 232. 6 233 1 C I R ( s ol i d, c m 1 ) : 3325 3064, 1625, 1530, 1513 124 7, 1176, 1027, 750 732 693. 1 H N M R ( 500M H z C D C l 3 ) : 3. 83 ( s 3H ) 5 28 ( s 2H ) 6 72 ( d, J = 7. 8 H z 1H ) 6. 76 ( d J = 6. 8 H z 1H ) 6 83 ( s 1H ) 6. 92 ( d, J = 6 8 H z 2H ) 7. 11 ( m 3H ) 7. 22 ( t J = 7 3 H z 1H ) 7. 31 ( m 4H ) 7. 42 ( m 4H ) 7. 51 ( m 1H ) 7. 57 ( d J = 7. 8 H z 1H ) 7. 83 ( d, J = 7. 8 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 1, 50 4, 55. 3, 110. 1 113. 9 116. 6 119. 8 122 3 126. 7, 126 7, 126. 8 127 0, 127. 7 128 2, 128. 6 1 28. 8, 131 5, 133. 5 134 5, 137. 2 142 9, 158. 8, 166. 4 H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 K O 2 ( [ M + K ] + ) 485. 1628 F ound 485. 1628 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( 3 m e t h oxyp h e n yl ) m e t h yl ) b e n z am i d e ( 105h ) w hi t e s ol i d. H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 14. 88 m i n, t r m i n o r 23. 05 m i n [ ] 2 5 D = 69. 1 ( c = 1. 0, C H C l 3 ) M p = 194. 8 195. 2 C I R ( s ol i d, c m 1 ) : 3366, 3026 2918, 1629, 1517 1488, 1466, 1350, 1283, 1240 1165

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81 1037, 791, 771 741, 695 1 H N M R ( 500 M H z C D C l 3 ) : 3 81 ( s 3H ) 5 27 ( s 2H ) 6 78 ( m 1H ) 6 84 ( m 3H ) 7. 08 7. 62 ( m 15H ) 7. 84 ( d J = 7. 8 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 4, 51. 1, 55 5, 110. 4 112. 8, 113 3, 1 16. 6, 119. 7 119. 9, 120 2, 122. 7 127. 0, 127. 1, 127 4, 128. 0 128 1, 128. 9 129 1, 12 9. 8 1 31. 8, 134 7, 137. 4 137 5, 143. 3 160 0, 166. 8. H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 N a O 2 ( [ M + N a ] + ) 469. 1887 F ound 469 1881 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( 2 m e t h oxyp h e n yl ) m e t h yl ) b e n z am i d e ( 137i ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i n e d a s a w hi t e s ol i d i n 97% yi e l d a nd 95% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 12. 09 m i n, t r m i n o r 15. 20 m i n [ ] 2 5 D = 90. 9 ( c = 1. 0, C H C l 3 ) M p = 195. 5 196. 4 C I R ( s ol i d, c m 1 ) : 3338, 3062 2975, 1633 1515, 1 4 90, 1350, 1243 1177, 1026 732, 693 1 H N M R ( 500M H z C D C l 3 ) : 3. 82 ( s 3H ) 5 24 ( d, J = 5. 3 H z 2H ) 6 70 ( s 1H ) 6 99 ( m 3H ) 7. 10 ( m 3H ) 7 19 ( t J = 6. 8 H z 1H ) 7. 24 7. 32 ( m 6H ) 7. 43 7 50 ( m 4H ) 7. 72 ( d J = 7. 8 H z 1H ) 7. 83 ( m 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 48 3, 50. 2 55 8, 110. 1, 111 6, 116. 4 119 9, 120 1, 121. 2 122 3, 1 26. 9, 127 127. 3 127 3, 127 8, 128. 8 128. 9, 128. 9 129. 0 129. 6, 131. 6 135. 1 137. 3, 1 37. 8, 157. 7 166. 3 H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 N a O 2 ( [ M + N a ] + ) 469. 1887 F ound 46 9. 1882

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82 ( + ) N ( ( 1 b e n z yl 1 H i n d ol 3 yl ) ( n ap h t h al e n 1 yl ) m e t h yl ) b e n z am i d e ( 137 j ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 99% y i e l d a nd 95% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0/ 2 0 1. 0 m L / m i n ) t r m a j o r 11. 41 m i n, t r m i n o r 16 09 m i n [ ] 2 5 D = 113. 9 ( c = 1. 0 C H C l 3 ) M p = 227. 8 228. 9 C I R ( s ol i d, c m 1 ) : 3272 2980, 1627 1577, 1538, 1381 116 2, 953, 745, 696 1 H N M R ( 500M H z D M S O ) : 5. 18 ( s 1H ) 6. 50 ( s 1H ) 6 84 ( d J = 7. 5, 1H ) 7. 01 ( d J = 6. 0 H z 2H ) 7. 13 ( t J = 7 1 H z 1H ) 7. 26 ( m 6H ) 7. 45 ( m 7H ) 7 65 ( m 2H ) 7 85 ( d J = 7 3 H z 2H ) 7. 89 ( d, J = 8. 1 H z 2H ) 8. 11 ( d, J = 8. 2 H z 1H ) 1 3 C N M R ( 125M H z D M S O ) : 48. 2, 50. 3, 110 4, 116. 4 119 9, 120 2, 122. 7 124 0, 12 4. 5, 12 5 6, 126. 0 126 5, 126 8, 127. 2 127. 4, 127 9, 128. 5 128 6, 128. 9 128 9, 129. 0 1 31. 5, 131 9, 134. 3 134 6, 132. 7 137 4, 137. 5, 166. 6 H R M S ( E S I ) C a l c d f o r C 3 3 H 2 6 N 2 N a O 489. 1937 F ound 489 1931 ( + ) N ( ( 1 b e n z yl 5 m e t h yl 1 H i n d ol 3 yl ) ( p h e n y l ) m e t h yl ) b e n z am i d e ( 137k ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 97% yi e l d a nd 95% e e H P L C a na l y s i s : C hi r a l c e l A D H ( he xa ne / i P r O H = 85 / 1 5, 1. 0 m L / m i n ) t r m i n o r 13. 32 m i n t r m a j o r 14. 44 m i n [ ] 2 5 D = 60. 1 ( c = 1. 0, C H C l 3 ) M p = 187. 0 188. 1 C I R ( s ol i d, c m 1 ) : 3338 3029, 2982, 1633, 1515 125 1, 1170, 1026, 795 740 692. 1 H N M R ( 500M H z C D C l 3 ) : 2. 41 ( s 3H ) 5 22 ( s 2H ) 6 73 ( d, J = 4. 3 H z 2H ) 6. 79 ( d J = 7. 8 H z 1H ) 7. 03 ( d J = 8. 3 H z 1H ) 7. 09 ( d J = 7. 3 H z 2H ) 7. 16 ( d J = 8. 3 H z 1H ) 7. 26 7. 32 ( m 4H ) 7 38 ( m 3H ) 7. 43 ( m 2H ) 7 50 ( m 3H ) 7. 83 ( d, J = 6 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 21. 4, 50. 1 50. 8, 10 9. 8, 115. 8 119. 1 124. 0, 126 6, 126 9,

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83 127. 0, 127 0, 127. 2 127 6, 127. 9 128 5, 128. 5 1 28. 7, 129 2, 131. 5 134 4, 135. 5 137 3, 141. 4, 166. 5 H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 N a O ( [ M + N a ] + ) 453. 1937 F ound 453. 1937 ( + ) N ( ( 1 b e n z yl 5 b r om o 1 H i n d ol 3 yl ) ( p h e n yl ) m e t h yl ) b e n z am i d e ( 137l ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 94% y i e l d a nd 92% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 85/ 15 1. 0 m L / m i n ) t r m a j o r 18. 68 m i n, t r m i n o r 22 19 m i n. [ ] 2 5 D = 35 5 ( c = 1. 0 C H C l 3 ) M p = 184 8 186. 2 C I R ( s ol i d, c m 1 ) : 3301, 3059 2975, 1626 1523, 1 4 86, 1343, 1269 1207, 1052 747, 699 1 H N M R ( 500M H z C D C l 3 ) : 5. 24 ( s 2H ) 6. 72 ( d, J = 7. 8 H z 1H ) 6. 78 ( d, J = 7. 8 H z 1H ) 6 85 ( s 1H ) 7. 08 ( d, J = 6. 8 H z 2H ) 7 14 ( d, J = 8 8 H z 1H ) 7. 24 7 34 ( m 4H ) 7. 40 ( t J = 6. 8 H z 2H ) 7. 46 ( m 5 H ) 7. 53 ( m 1 H ) 7. 67 ( d J = 1. 4 H z 1H ) 7. 84 ( d J = 6. 8 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 6, 50. 9 110. 1 111. 9 113. 5 116. 2 122. 4, 125 6, 126. 8 127 3, 127. 3 127 8, 128. 1 1 28. 7, 128 9, 129. 1 129 1, 132. 0 134 6, 136. 1, 137 0, 141 2, 166. 8 H R M S ( E S I ) C a l c d f o r C 2 9 H 2 3 B r N 2 N a O ( [ M + N a ] + ) 517. 0886 F ound 517. 0884 ( + ) m e t h yl 1 b e n z yl 3 ( p h e n y l ( p h e n yl a m i d o) m e t h yl ) 1 H i n d ol e 5 c ar b oxyl a t e ( 137m ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he p r o duc t w a s obt a i ne d a s a w hi t e s ol i d i n

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84 89% yi e l d a nd 90% e e H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 8 0 / 20, 1. 0 m L / m i n ) t r m a j o r 16. 44 m i n t r m i n o r 21. 27 m i n [ ] 2 5 D = 26. 7 ( c = 1. 0 C H C l 3 ) M p = 195. 2 196. 3 C I R ( s ol i d c m 1 ) : 3313, 3026 2919, 1714 1626, 1519, 1486 1350, 1302 1247, 1181k 1026, 732 696 1 H N M R ( 500M H z C D C l 3 ) : 3 88 ( s 3H ) 5. 29 ( s 2H ) 6 78 6. 80 ( m 2H ) 6. 91 ( s 1H ) 7. 11 ( d J = 6. 3 H z 2H ) 7 29 7 52 ( m 12H ) 7. 84 ( d J = 7. 3 2H ) 7. 92 ( d, J = 8. 7 1H ) 8. 33 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 6 51. 1 52. 1 110. 1, 118 1, 122. 3 122 7, 124. 1 126 5, 127. 0 1 27. 3, 127 3, 127. 8 128 2, 128. 9 128 9, 129. 2, 129 3, 131 9, 134. 6 136. 8 139. 9 141 3, 167. 9, 168 1. H R M S ( E S I ) C a l c d f or C 3 1 H 2 6 N 2 N a O 3 ( [ M + N a ] + ) 497. 1836 F ound 497. 18 37 ( + ) N ( ( 1 b e n z yl 5 m e t h oxy 1 H i n d ol 3 yl ) ( p h e n yl ) m e t h yl ) b e n z am i d e ( 105n ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 95% yi e l d a nd 98% e e . H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 90/ 10 1. 0 m L / m i n ) t r m a j o r 25. 75 m i n, t r m i n o r 30. 35 m i n [ ] 2 5 D = 5 6. 1 ( c = 1. 0, C H C l 3 ) M p = 176. 8 177. 9 C I R ( s ol i d, c m 1 ) : 3327, 3051, 2930 1640 1523 14 86, 1343, 1269, 1207 1052 747 699. 1 H N M R ( 500M H z C D C l 3 ) : 3. 76 ( s 3H ) 5 23 ( s 2H ) 6 74 ( d J = 6. 6 H z 2H ) 6. 80 ( d, J = 7. 8 H z 1H ) 6. 86 ( m 1H ) 7. 03 ( d, J = 2. 0 H z 1H ) 7. 10 ( d, J = 6. 8 H z 2H ) 7. 16 ( d J = 8. 7 H z 1H ) 7 32 ( m 3H ) 7. 41 ( m 5H ) 7. 51 ( m 3H ) 7. 84 ( m 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 50. 6 51 1, 56. 0 101 3, 111 3, 113. 0 116. 2 126 9, 127 3, 127. 3, 127 5, 127. 6 127 9, 128. 6 1 28 8, 128. 9 1 29. 0, 131 8, 132. 5 134 7, 137. 6 141 5, 154. 5, 166. 9 H R M S ( E S I ) C a l c d f o r C 3 0 H 2 7 N 2 O 2 ( [ M + H ] + ) 447 2067 F ound 447 2067

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85 ( + ) N ( ( 1 b e n z yl 7 m e t h yl 1 H i n d ol 3 yl ) ( p h e n y l ) m e t h yl ) b e n z am i d e ( 137o) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 98% yi e l d a nd 96% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 85/ 15 1. 0 m L / m i n ) t r m a j o r 13 32 m i n t r m i n o r 19. 85 m i n. [ ] 2 5 D = 84 3 ( c = 1. 1, C H C l 3 ) M p = 214. 0 215 4 C I R ( s ol i d, c m 1 ) : 3326, 3074 29 71, 1629 1526, 14 90, 1449, 1352 1303, 1169 785, 770 703, 623. 1 H N M R ( 500M H z C D C l 3 ) : 2. 53 ( s 3 H ) 5. 52 ( s 2H ) 6 71 ( s 1H ) 6. 79 ( m 2H ) 6. 94 ( t J = 7. 8 H z 3H ) 7 03 ( t J = 6. 8 H z 1H ) 7. 25 7. 53 ( m 12H ) 7 84 ( d J = 8. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 19. 6, 51. 0, 52. 4, 116. 6 117. 8, 120. 5 121. 7, 125. 5, 125 6, 127. 3 127 3, 127. 5 127 6, 128. 0 1 28. 8, 128 8, 129. 1 129 9, 131. 8 134 7, 136. 2, 139 6, 141 6, 166. 8 H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 N a O ( [ M + N a ] + ) 453. 1937 F ound 453. 1938 ( + ) N ( ( 1 b e n z yl 2 m e t h yl 1 H i n d ol 3 yl ) ( p h e n y l ) m e t h yl ) b e n z am i d e ( 137p ) F ol l ow i ng t he ge ne r a l pr oc e dur e t he pr oduc t w a s obt a i ne d a s a w hi t e s ol i d i n 91% yi e l d a nd 64% e e H P L C a na l y s i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 85 / 1 5, 1. 0 m L / m i n ) t r m a j o r 11. 79 m i n t r m i n o r 17. 67 m i n [ ] 2 5 D = 81. 2 ( c = 1. 0, C H C l 3 ) M p = 76. 2 77. 3 C I R ( s ol i d, c m 1 ) : 3374 3027, 2925, 1640, 1579 147 9, 1341, 1028, 737 714 695. 1 H N M R

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86 ( 500M H z C D C l 3 ) : 2. 49 ( s 3H ) 5 37 ( s 2H ) 6 85 ( d, J = 7. 3 H z 1H ) 6. 96 ( d J = 7. 8 H z 1H ) 7. 03 ( m 3H ) 7 14 ( t J = 6 8 H z 1H ) 7. 25 7. 36 ( m 8H ) 7. 43 7. 54 ( m 6H ) 7. 86 ( d, J = 6. 8 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 11. 0, 47. 0 50. 3, 109 9, 111. 8 118. 0, 120 0, 121. 5 126 3, 126. 9 127 2, 127. 3 1 27. 7, 128 7, 128. 9 129 1, 131. 8 1 34 7, 135. 3, 137 3, 137 7, 141. 7 166. 9 H R M S ( E S I ) C a l c d f or C 3 0 H 2 6 N 2 N a O ( [ M + N a ] + ) 453. 1937 F ound 453 1939 t e r t b u t yl ( 1 b e n z yl 1 H i n d o l 3 yl ) ( 4 m e t h oxyp h e n yl ) m e t h yl c ar b a m at e w hi t e s ol i d. H P L C a na l ys i s : C hi r a l c e l A D H ( he xa n e / i P r O H = 80 / 20, 1. 0 m L / m i n ) t r m a j o r 9. 17 m i n t r m i n o r 19. 21 m i n M p = 194. 8 195. 2 C I R ( s ol i d, c m 1 ) : 3391, 3030, 2964, 1675, 1508, 1390, 1241, 1164, 1028, 813 742, 726, 635 1 H N M R ( 500M H z C D C l 3 ) : 1. 49 ( s 9H ) 3. 83 ( s 3H ) 5. 26 ( d J = 3. 4 H z 2H ) 6 22 ( s 1H ) 6. 7 8 ( s 1H ) 6 91 ( d, J = 8. 8 H z 2H ) 7. 12 ( m 3H ) 7. 21 ( t J = 8. 3 H z 1H ) 7. 26 7 37 ( m 7H ) 7. 54 ( d J = 7. 8 H z 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 28. 7, 50 3, 51 4, 55. 5 79. 7, 110 2, 114 0, 119 8, 120. 1 122. 4 126. 9, 127 5, 127. 8 128 1, 128. 3 128 9 129. 0 1 37. 4, 137 6, 155. 4 158 9. H R M S ( E S I ) C a l c d f or C 2 8 H 3 0 N 2 N a O 3 ( [ M + N a ] + ) 465. 2149 F ou nd 465. 2145

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87 N ( ( 1 H i n d ol 3 y l ) ( p h e n yl ) m e t h yl ) b e n z am i d e w hi t e s ol i d. H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 80 / 20 1 0 m L / m i n ) t r m a j o r 7 64 m i n, t r m i n o r 9. 53 m i n M p = 189. 1 190. 2 C I R ( s ol i d, c m 1 ) : 3385 3295 3053 1607, 1529 1490 1337 735 698 1 H N M R ( 500M H z C D C l 3 ) : 6. 75 ( d J = 7. 8 H z 1H ) 6. 80 ( d, J = 8. 3 H z 2H ) 7 12 ( t J = 7. 8 H z 1H ) 7 24 ( t J = 8. 3 H z 1H ) 7 28 7. 59 ( m 10H ) 7 83 ( d J = 8 3 H z 2H ) 8. 24 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 51. 2, 1 11. 7, 117. 5 119. 6 120. 3, 122 8, 124. 0 126. 3, 127 3, 127. 3 127 6, 128. 8 128 9, 131. 8 1 34. 6, 137 0, 141. 5 166 8 H R M S ( E S I ) C a l c d f or C 2 2 H 1 8 N 2 N a O ( [ M + N a ] + ) 349 1311 F ou nd 349. 13 21 N ( ( 1 m e t h yl 1 H i n d ol 3 yl ) ( p h e n y l ) m e t h yl ) b e n z am i d e w hi t e s ol i d. H P L C a na l ys i s : C hi r a l c e l O D H ( he xa ne / i P r O H = 80 / 20 1. 0 m L / m i n ) t r m a j o r 8 41 m i n, t r m i n o r 9. 47 m i n M p = 189. 7 191. 2 C I R ( s ol i d c m 1 ) : 3385 329 5, 3053, 1607 1529 1490, 13 37 735 698. 1 H N M R ( 500M H z C D C l 3 ) : 3 74 ( s 3H ) 6. 68 ( s 1H ) 6. 74 ( d, J = 7. 8 H z 1H ) 6. 78 ( d, J = 7. 3 1H ) 7 13 ( t J = 7. 8 H z 1H ) 7 24 7. 59 ( m 11H ) 7 86 ( d J = 8. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : 33. 0 51. 1, 1 09. 8, 116. 0 119. 7, 119. 9 122. 4 126. 7, 127. 2, 127 5, 127. 6 128 8, 128. 8 129 0, 131. 8 1 34. 6, 137 8, 141. 7 166 7. H R M S ( E S I ) C a l c d f or C 2 3 H 2 0 N 2 N a O ( [ M + N a ] + ) 363 1468 F ou nd 363. 1462

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88 4. 2. 3 X R ay C r ys t al l ogr ap h i c D a t a T a bl e 1. C r ys t a l da t a a nd s t r uc t ur e r e f i ne m e nt f or gr pc l 1. I de nt i f i c a t i on c ode gr pc l 1 E m pi r i c a l f or m ul a C 29 H 23 C l N 2 O F or m ul a w e i ght 450. 94 T e m pe r a t ur e 100( 2) K W a ve l e ngt h 0. 71073 C r ys t a l s ys t e m O r t hor hom bi c S pa c e gr oup P 2( 1) 2( 1 ) 2( 1) U ni t c e l l di m e ns i ons a = 4. 9615( 1 5) a = 90. b = 9. 864 ( 3) b = 9 0. c = 46. 603( 1 5) g = 90. V ol um e 2280. 7( 12) 3 Z 4 D e ns i t y ( c a l c ul a t e d) 1. 313 M g/ m 3 A bs or pt i on c oe f f i c i e nt 0. 192 m m 1 F ( 000) 944 C r ys t a l s i z e 0. 80 x 0. 06 x 0 05 m m 3 T he t a r a nge f o r da t a c ol l e c t i on 0. 87 t o 26. 58 I nde x r a nge s 5< = h< = 6, 6< = k< = 12, 56< = l < = 58 R e f l e c t i ons c ol l e c t e d 13342 I nde pe nde nt r e f l e c t i ons 4748 [ R ( i nt ) = 0 0624] C om pl e t e ne s s t o t he t a = 26. 58 99. 7 % A bs or pt i on c or r e c t i on S A D A B S M a x. a nd m i n. t r a ns m i s s i on 1. 000 a nd 0 727 R e f i ne m e nt m e t hod F ul l m a t r i x l e a s t s qua r e s on F 2 D a t a / r e s t r a i nt s / pa r a m e t e r s 4748 / 0 / 298 G oodne s s of f i t on F 2 1. 167 F i na l R i ndi c e s [ I > 2s i gm a ( I ) ] R 1 = 0. 0737 w R 2 = 0 1512 R i ndi c e s ( a l l da t a ) R 1 = 0. 0912 w R 2 = 0 1628 A bs ol ut e s t r uc t ur e pa r a m e t e r 0. 09( 14) L a r ge s t di f f pe a k a nd hol e 0. 337 a nd 0. 385 e 3

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89 T a bl e 2 A t om i c c oor di na t e s ( x 10 4 ) a nd e qui va l e nt i s ot r opi c d i s pl a c e m e nt pa r a m e t e r s ( 2 x 10 3 ) f or g r pc l 1. U ( e q) i s de f i ne d a s one t hi r d of t he t r a c e of t he o r t hogona l i z e d U i j t e ns or ____________ _________ ________ _________ __ ____________ _________ ______ __ __ x y z U ( e q) ____________ _________ ________ _________ __ ____________ _________ ________ __ C l ( 1) 345( 3) 7980( 1) 1690( 1) 37( 1) O ( 1) 6540( 5) 937( 3) 1789( 1) 21( 1) N ( 1) 2203( 6) 1432( 3) 1688( 1) 13( 1) N ( 2) 1107( 7) 369( 3) 868( 1) 14( 1) C ( 1) 640( 10) 6317( 4) 1603( 1) 25( 1) C ( 2) 827( 9) 5623( 4) 1399( 1) 23( 1) C ( 3) 83( 9) 4295( 4) 1337( 1) 21( 1) C ( 4) 2011( 9) 3673( 4) 1478( 1) 15( 1) C ( 5) 3455( 9) 4413( 4) 1681( 1) 21( 1) C ( 6) 2782( 10) 5745( 4) 1743( 1) 24( 1) C ( 7) 2771( 8) 2195( 4) 1427( 1) 14( 1) C ( 8) 4132( 8) 945( 4) 1859( 1) 14( 1) C ( 9 ) 3266( 8) 418( 4) 2145( 1) 13( 1) C ( 10) 4637( 9) 647( 4) 2273( 1) 23( 1) C ( 11) 3912( 9) 1092( 4) 2542( 1) 25( 1) C ( 12) 1865( 9) 455( 4) 2692( 1) 22( 1) C ( 13) 547( 9) 628( 4) 2573( 1) 22( 1) C ( 14) 1209( 8) 1054( 4) 2298( 1) 19( 1) C ( 15) 1510( 8) 1572( 4) 1165( 1) 12( 1) C ( 16) 2246 ( 8) 1901( 4) 874( 1) 13( 1) C ( 17) 4154( 8) 2762( 4) 750( 1) 14( 1) C ( 18) 4384( 9) 2809( 4) 457( 1) 19( 1) C ( 19) 2711( 8) 2013( 5) 280( 1) 17( 1) C ( 20) 800( 8) 1165( 4) 395( 1) 15( 1) C ( 21) 556( 9) 1124( 4) 694( 1) 16( 1) C ( 22) 532( 8) 661( 4) 1151( 1) 15( 1) C ( 23) 3178( 8) 561( 4) 763( 1) 18( 1) C ( 24) 2078( 8) 1846( 4) 633( 1) 16( 1) C ( 25) 7( 10) 2566( 4) 761( 1) 27( 1)

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90 C ( 26) 874( 10) 3766( 5) 641( 1) 34( 1) C ( 27) 277( 10) 4269( 5) 395( 1) 35( 1) C ( 28) 2312( 10) 3542( 5) 261( 1) 31( 1) C ( 29) 3219( 10) 2342( 5) 385( 1) 27( 1) ____________ _________ __ ______ _________ __ ____________ _________ ________ __

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91 T a bl e 3 B ond l e ngt hs [ ] a nd a ngl e s [ ] f or g r p c l 1. ____________ _________ ________ _________ __ ____________ C l ( 1) C ( 1) 1. 760( 4) O ( 1) C ( 8) 1. 239( 5) N ( 1) C ( 8) 1. 336( 5) N ( 1) C ( 7) 1. 459( 5) N ( 2) C ( 21) 1 376( 5) N ( 2) C ( 22) 1. 379( 5) N ( 2) C ( 23) 1. 461( 5) C ( 1) C ( 6) 1. 370( 6) C ( 1) C ( 2) 1. 379( 6) C ( 2) C ( 3) 1. 391( 6) C ( 3) C ( 4) 1. 375( 6) C ( 4) C ( 5) 1. 393( 6) C ( 4) C ( 7) 1. 525( 5) C ( 5) C ( 6) 1. 385( 6) C ( 7) C ( 15) 1. 501( 5) C ( 8) C ( 9) 1. 493( 5) C ( 9) C ( 10) 1. 386( 6) C ( 9) C ( 14) 1. 393( 6) C ( 10) C ( 11) 1. 374( 5) C ( 11) C ( 12) 1. 384( 6) C ( 12) C ( 13) 1. 370( 6) C ( 13) C ( 14) 1. 388( 5) C ( 15) C ( 22) 1. 356( 5) C ( 15) C ( 16) 1. 444( 5) C ( 16) C ( 17) 1. 397( 5) C ( 16) C ( 21) 1. 412( 5) C ( 17) C ( 18) 1. 370( 5) C ( 18) C ( 19) 1. 408( 6) C ( 19) C ( 20) 1. 372( 6) C ( 20) C ( 21) 1. 397( 5) C ( 23) C ( 24) 1. 509( 6) C ( 24) C ( 29) 1. 375( 6) C ( 24) C ( 25) 1. 390( 6)

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92 C ( 25) C ( 26) 1. 377( 6) C ( 26) C ( 27) 1. 374( 7) C ( 27) C ( 28) 1. 388( 7) C ( 28) C ( 29) 1. 392( 6) C ( 8) N ( 1) C ( 7 ) 123. 1( 3) C ( 21) N ( 2) C ( 22 ) 109. 1( 3) C ( 21) N ( 2) C ( 23 ) 124. 4( 3) C ( 22) N ( 2) C ( 23 ) 126. 5( 3) C ( 6) C ( 1) C ( 2 ) 122. 3( 4) C ( 6) C ( 1) C l ( 1 ) 119. 2( 3) C ( 2) C ( 1) C l ( 1 ) 118. 5( 4) C ( 1) C ( 2) C ( 3 ) 118. 1( 4) C ( 4) C ( 3) C ( 2 ) 121. 4( 4) C ( 3) C ( 4) C ( 5 ) 118. 7( 4) C ( 3) C ( 4) C ( 7 ) 122. 5( 4) C ( 5) C ( 4) C ( 7 ) 118. 7( 4) C ( 6) C ( 5) C ( 4 ) 121. 0( 4) C ( 1) C ( 6) C ( 5 ) 118. 5( 4) N ( 1) C ( 7) C ( 15 ) 112. 7( 3) N ( 1) C ( 7) C ( 4 ) 108. 3( 3) C ( 15) C ( 7) C ( 4 ) 114. 6( 3) O ( 1) C ( 8) N ( 1) 122. 4( 3) O ( 1) C ( 8) C ( 9 ) 120. 7( 4) N ( 1) C ( 8) C ( 9 ) 116. 9( 3) C ( 10) C ( 9) C ( 14 ) 118. 8( 4) C ( 10) C ( 9) C ( 8 ) 120. 4( 4) C ( 14) C ( 9) C ( 8 ) 120. 6( 4) C ( 11) C ( 10) C ( 9 ) 120. 4 ( 4) C ( 10) C ( 11) C ( 12 ) 120. 5( 4) C ( 13) C ( 12) C ( 11 ) 120. 0( 4) C ( 12) C ( 13) C ( 14 ) 119. 9( 4) C ( 13) C ( 14) C ( 9 ) 120. 5( 4) C ( 22) C ( 15) C ( 16 ) 106. 9( 3) C ( 22) C ( 15) C ( 7 ) 128. 6( 3)

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93 C ( 16) C ( 15) C ( 7 ) 124. 5( 3) C ( 17) C ( 16) C ( 21 ) 119. 1( 3) C ( 17) C ( 16) C ( 15 ) 134. 2( 3) C ( 21) C ( 16) C ( 15 ) 106. 7( 3) C ( 18) C ( 17) C ( 16 ) 119. 3( 4) C ( 17) C ( 18) C ( 19 ) 120. 9( 4) C ( 20) C ( 19) C ( 18 ) 121. 3( 3) C ( 19) C ( 20) C ( 21 ) 117. 8( 4) N ( 2) C ( 21) C ( 20 ) 130. 9( 4) N ( 2) C ( 21) C ( 16 ) 107. 4( 3) C ( 20) C ( 21) C ( 16 ) 121. 6( 4) C ( 15) C ( 22) N ( 2 ) 109. 9( 3) N ( 2) C ( 23) C ( 24 ) 114. 0( 3) C ( 29) C ( 24) C ( 25 ) 119. 1( 4) C ( 29) C ( 24) C ( 23 ) 119. 2( 4) C ( 25) C ( 24) C ( 23 ) 121. 7( 4) C ( 26) C ( 25) C ( 24 ) 119. 8( 4) C ( 27) C ( 26) C ( 25 ) 121. 2( 5) C ( 26) C ( 27) C ( 28 ) 119. 5( 4) C ( 27) C ( 28) C ( 29 ) 119. 1( 4) C ( 24) C ( 29) C ( 28 ) 121. 2( 5) ____________ _________ ________ _________ __ __ __________ _________ S ym m e t r y t r a ns f or m a t i ons us e d t o ge ne r a t e e qui va l e nt a t om s :

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94 T a bl e 4 A ni s ot r opi c di s pl a c e m e nt pa r a m e t e r s ( 2 x 10 3 ) f or g r pc l 1. T he a ni s ot r opi c di s pl a c e m e nt f a c t or e xpone nt t a ke s t he f o r m : 2 p 2 [ h 2 a 2 U 11 + . + 2 h k a b* U 12 ] ____________ _________ ________ _________ __ ____________ _________ ________ __ U 11 U 22 U 33 U 23 U 13 U 12 ____________ _________ ________ _________ __ ____________ _________ ________ __ C l ( 1) 64( 1) 14( 1) 32( 1) 4( 1) 8( 1) 4( 1) O ( 1) 9( 2) 35( 2) 20( 1) 7( 1) 1( 1) 1( 1) N ( 1) 8( 2) 17( 2) 13( 1) 3( 1) 3( 1) 0( 1) N ( 2) 12( 2) 16( 2) 15( 1) 3( 1) 1( 1) 3( 2) C ( 1) 41( 3) 15( 2) 18( 2) 1( 2) 18( 2) 4( 2) C ( 2) 24( 2) 24( 2) 21( 2) 1( 2) 4( 2) 6( 2) C ( 3) 18( 2) 25( 2) 20( 2) 4( 2) 2( 2) 3( 2) C ( 4) 17( 2) 16( 2) 13( 2) 3( 2) 5( 2) 2( 2 ) C ( 5) 20( 2) 24( 2) 18( 2) 5( 2) 2( 2) 1( 2) C ( 6) 37( 3) 22( 2) 14( 2) 7( 2) 3( 2) 5( 2) C ( 7) 11( 2) 15( 2) 16( 2) 3( 2) 4( 2) 1( 2) C ( 8) 12( 2) 16( 2) 14( 2) 3( 1) 0( 2) 3( 2) C ( 9) 11( 2) 15( 2) 12( 2) 0( 2) 4( 2) 3( 2) C ( 10) 19( 2) 26( 2) 24( 2) 5( 2) 1( 2) 4( 2 ) C ( 11) 25( 3) 19( 2) 30( 2) 11( 2) 7( 2) 1( 2) C ( 12) 24( 2) 28( 2) 13( 2) 7( 2) 3( 2) 9( 2) C ( 13) 19( 2) 26( 2) 20( 2) 4( 2) 5( 2) 3( 2) C ( 14) 21( 2) 20( 2) 15( 2) 3( 2) 3( 2) 4( 2) C ( 15) 16( 2) 8( 2) 12( 2) 1( 1) 0( 2) 0( 2) C ( 16) 12( 2) 14( 2) 12( 2) 5( 2) 1( 2) 5( 2) C ( 17) 11( 2) 16( 2) 16( 2) 3( 2) 3( 2) 1( 2) C ( 18) 19( 2) 18( 2) 18( 2) 2( 2) 2( 2) 2( 2) C ( 19) 14( 2) 25( 2) 13( 2) 1( 2) 2( 2) 1( 2) C ( 20) 13( 2) 18( 2) 14( 2) 3( 2) 2( 2) 3( 2) C ( 21) 16( 2) 12( 2) 21( 2) 1( 2) 0( 2) 10( 2) C ( 22) 17( 2) 14( 2) 15( 2) 1( 2) 3( 2) 0( 2) C ( 23) 15( 2) 18( 2) 20( 2) 3( 2) 4( 2) 6( 2) C ( 24) 13( 2) 18( 2) 18( 2) 2( 2) 4( 2) 3( 2) C ( 25) 28( 3) 24( 2) 30( 2) 2( 2) 1( 2) 2( 2) C ( 26) 26( 3) 23( 2) 52( 3) 1( 2) 4( 2) 4( 2)

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95 C ( 27) 34( 3) 23( 2) 46( 3) 15( 2) 17( 2) 5( 2) C ( 28) 31( 3) 33( 3) 29( 2) 19( 2) 6( 2) 11( 2) C ( 29) 24( 3) 28( 3) 28( 2) 5( 2) 1( 2) 7( 2) ____________ _________ ________ _________ __ ____________ _________ ________ __

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96 T a bl e 5 H ydr oge n c oor di na t e s ( x 10 4 ) a nd i s ot r opi c di s pl a c e m e nt pa r a m e t e r s ( 2 x 10 3 ) f or g r pc l 1. ____________ __ _______ ________ _________ __ ____________ _________ ________ __ x y z U ( e q) ____________ _________ ________ _________ __ ____________ _________ ________ __ H ( 1N ) 415 1401 1746 19 H ( 2) 2302 6039 1303 28 H ( 3) 1043 3807 1194 25 H ( 5) 4922 3999 1778 25 H ( 6) 3785 6250 1880 29 H ( 7) 4803 2085 1388 21 H ( 10) 6085 1072 2175 28 H ( 11) 4823 1842 2625 30 H ( 12) 1373 768 2877 26 H ( 13) 816 1086 2678 26 H ( 14) 251 1786 2213 22 H ( 17) 5281 3309 867 17 H ( 18) 5690 3387 372 22 H ( 19) 2908 2063 78 21 H ( 20) 318 625 276 18 H ( 22) 1433 2 80 1311 18 H ( 23A ) 4294 11 627 27 H ( 23B ) 4388 695 906 27 H ( 25) 832 2231 931 33 H ( 26) 2294 4255 731 40 H ( 27) 316 5108 318 42 H ( 28) 3076 3859 86 37 H ( 29) 4653 1857 297 32 ____________ _________ ________ _________ __ ____________ _________ ________ __

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97 T a bl e 6 T or s i on a ngl e s [ ] f or gr pc l 1 ____________ _________ ________ _________ __ ____________ _________ ___ C ( 6) C ( 1) C ( 2 ) C ( 3) 0. 2( 6) C l ( 1) C ( 1) C ( 2 ) C ( 3) 178. 1( 3) C ( 1) C ( 2) C ( 3 ) C ( 4) 1. 4( 6) C ( 2) C ( 3) C ( 4 ) C ( 5) 2. 0( 6) C ( 2) C ( 3) C ( 4 ) C ( 7) 176. 5( 4) C ( 3) C ( 4) C ( 5 ) C ( 6) 0. 9( 6) C ( 7) C ( 4) C ( 5 ) C ( 6) 177. 7( 4) C ( 2) C ( 1) C ( 6 ) C ( 5) 1. 3( 6) C l ( 1) C ( 1) C ( 6 ) C ( 5) 177. 0( 3) C ( 4) C ( 5) C ( 6 ) C ( 1) 0. 7( 6) C ( 8) N ( 1) C ( 7 ) C ( 15) 123. 4( 4) C ( 8) N ( 1) C ( 7 ) C ( 4) 108. 8( 4) C ( 3) C ( 4) C ( 7 ) N ( 1) 113. 2( 4) C ( 5) C ( 4) C ( 7 ) N ( 1) 65. 3( 4) C ( 3) C ( 4 ) C ( 7 ) C ( 15) 13. 6( 5) C ( 5) C ( 4) C ( 7 ) C ( 15) 167. 9( 3) C ( 7) N ( 1) C ( 8 ) O ( 1 ) 10. 3( 6) C ( 7) N ( 1) C ( 8 ) C ( 9) 168. 8( 3) O ( 1) C ( 8) C ( 9 ) C ( 10) 32. 8( 6) N ( 1) C ( 8) C ( 9 ) C ( 10) 148. 0( 4) O ( 1) C ( 8) C ( 9 ) C ( 14) 142. 1( 4) N ( 1) C ( 8) C ( 9 ) C ( 14) 37. 1( 5) C ( 14) C ( 9) C ( 10 ) C ( 11) 2. 1 ( 6) C ( 8) C ( 9) C ( 10 ) C ( 11) 177. 1( 4) C ( 9) C ( 10) C ( 11 ) C ( 12) 2. 1( 7) C ( 10) C ( 11) C ( 12 ) C ( 13) 0. 1( 7) C ( 11) C ( 12) C ( 13 ) C ( 14) 2. 2( 6) C ( 12) C ( 13) C ( 14 ) C ( 9) 2. 1( 6) C ( 10) C ( 9) C ( 14 ) C ( 13) 0. 0( 6) C ( 8) C ( 9) C ( 14 ) C ( 13) 175. 0( 4) N ( 1) C ( 7) C ( 15 ) C ( 22) 18. 3( 6) C ( 4) C ( 7) C ( 15 ) C ( 22) 106. 1( 5) N ( 1) C ( 7) C ( 15 ) C ( 16) 164. 3( 3)

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98 C ( 4) C ( 7) C ( 15 ) C ( 16) 71. 3( 5) C ( 22) C ( 15) C ( 16 ) C ( 17) 179. 6( 4) C ( 7) C ( 15) C ( 16 ) C ( 17) 1. 7( 7) C ( 22) C ( 15) C ( 16 ) C ( 21) 0. 8( 4) C ( 7) C ( 15) C ( 16 ) C ( 21) 178. 6( 4) C ( 21) C ( 16) C ( 17 ) C ( 18) 1. 5( 6) C ( 15) C ( 16) C ( 17 ) C ( 18) 178. 1( 4) C ( 16) C ( 17) C ( 18 ) C ( 19) 0. 6( 6) C ( 17) C ( 18) C ( 19 ) C ( 20) 0. 0( 7) C ( 18) C ( 19) C ( 20 ) C ( 21) 0. 4( 6) C ( 22) N ( 2) C ( 21 ) C ( 20) 178. 2( 4) C ( 23) N ( 2) C ( 21 ) C ( 20) 3. 2( 6) C ( 22) N ( 2) C ( 21 ) C ( 16) 0. 7( 4) C ( 23) N ( 2) C ( 21 ) C ( 16) 179. 3( 3) C ( 19) C ( 20) C ( 21 ) N ( 2) 178. 6( 4) C ( 19) C ( 20) C ( 21 ) C ( 16) 1. 4( 6) C ( 17) C ( 16) C ( 21 ) N ( 2) 179. 7( 3) C ( 15) C ( 16) C ( 21 ) N ( 2) 0. 0( 4) C ( 17) C ( 16) C ( 21 ) C ( 20) 1. 9( 6) C ( 15) C ( 16) C ( 21 ) C ( 20) 177. 8( 4) C ( 16) C ( 15) C ( 22 ) N ( 2) 1. 2( 4) C ( 7) C ( 15) C ( 22 ) N ( 2) 179. 0( 4) C ( 21) N ( 2) C ( 2 2 ) C ( 15) 1. 2( 4) C ( 23) N ( 2) C ( 22 ) C ( 15) 179. 8( 4) C ( 21) N ( 2) C ( 23 ) C ( 24) 72. 3( 5) C ( 22) N ( 2) C ( 23 ) C ( 24) 109. 4( 4) N ( 2) C ( 23) C ( 24 ) C ( 29) 138. 2( 4) N ( 2) C ( 23) C ( 24 ) C ( 25) 43. 8( 5) C ( 29) C ( 24) C ( 25 ) C ( 26) 0. 8( 6) C ( 23) C ( 24) C ( 25 ) C ( 26) 177. 2( 4) C ( 24) C ( 25) C ( 26 ) C ( 27) 0. 3( 7) C ( 25) C ( 26) C ( 27 ) C ( 28) 1. 4( 7) C ( 26) C ( 27) C ( 28 ) C ( 29) 2. 5( 7) C ( 25) C ( 24) C ( 29 ) C ( 28) 0. 4( 6) C ( 23) C ( 24) C ( 29 ) C ( 28) 178. 4( 4)

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99 C ( 27) C ( 28) C ( 29 ) C ( 24) 2. 1( 7) ____________ _________ ________ _________ __ ____________ _________ ___ S ym m e t r y t r a ns f or m a t i ons us e d t o ge ne r a t e e qui va l e nt a t om s :

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100 T a bl e 7 H ydr oge n bonds f or gr pc l 1 [ a nd ] ____________ _________ ________ _________ __ ____________ _________ ________ __ D H . A d( D H ) d( H . A ) d( D . A ) < ( D H A ) ____________ _________ ________ _________ __ ___ _________ _________ ________ __ N ( 1) H ( 1N ) . O ( 1) #1 0. 93 1. 99 2. 890( 4) 164. 2 ____________ _________ ________ _________ __ ____________ _________ ________ __ S ym m e t r y t r a ns f or m a t i ons us e d t o ge ne r a t e e qui va l e nt a t om s : #1 x 1, y z

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101 C h ap t e r 5 1 H an d 1 3 C S p e c t r a f or C om p o u n d 5. 1. 1 H an d 1 3 C S p e c t r a f or C o m p ou n d s i n C h a p t e r 2 S p e c t r a 5 1. 1 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05a

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102 S p e c t r a 5 1. 2 1 H a nd 1 3 C S pe c t r a f or C om pound 1 05b

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103 S p e c t r a 5 1. 3 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05c

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104 S p e c t r a 5 1. 4 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05d

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105 S p e c t r a 5 1. 5 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05e

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106 S p e c t r a 5 1. 6 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05f

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107 S p e c t r a 5 1. 7 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05g

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108 S p e c t r a 5 1. 8 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05h

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109 S p e c t r a 5 1. 9 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 05i

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110 S p e c t r a 5 1. 10 1 H a nd 1 3 C S pe c t r a f o r C om pound 105j

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111 S p e c t r a 5. 1 11. 1 H a nd 1 3 C S pe c t r a f or C om pound 105k

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112 S p e c t r a 5 1. 12 1 H a nd 1 3 C S pe c t r a f o r C om pound 105l

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113 S p e c t r a 5 1. 13 1 H a nd 1 3 C S pe c t r a f o r C om pound 105m

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114 S p e c t r a S p e c t r a 5 1. 15 1 H a nd 1 3 C S pe c t r a f o r C o m pound 105o

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115 S p e c t r a 5 1. 16 1 H a nd 1 3 C S pe c t r a f o r C om pound 105p

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116 S p e c t r a 5 1. 17 1 H a nd 1 3 C S pe c t r a f o r C om pound 105q

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117 S p e c t r a 5 1. 18 1 H a nd 1 3 C S pe c t r a f o r C om pound 105r

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118 S p e c t r a 5 1. 19 1 H a nd 1 3 C S pe c t r a f or C om pound 105s

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119 S p e c t r a 5 1. 20 1 H a nd 1 3 C S pe c t r a f or C om pound 105t

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120 S p e c t r a 5 1. 21 1 H a nd 1 3 C S pe c t r a f o r C om pound 105u

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121 S p e c t r a 5 1. 22 1 H a nd 1 3 C S pe c t r a f o r C om pound 105v

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122 S p e c t r a 5 1. 23 1 H a nd 1 3 C S pe c t r a f o r C om pound 105w

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123 5. 2. 1 H an d 1 3 C S p e c t r a f or C o m p ou n d s i n C h a p t e r 3 S p e c t r a 5 2 1 1 H a nd 1 3 C S pe c t r a f or C om pound 1 37a

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124 S p e c t r a 5 2. 5 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37b

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125 S p e c t r a 5 2. 2 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37c

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126 S p e c t r a 5 2. 3 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37d

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127 S p e c t r a 5 2. 4 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37e

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128 S p e c t r a 5 2. 6 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37f

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129 S p e c t r a 5 2. 7 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37g

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130 S S p e c t r a 5 2. 8 1 H a nd 1 3 C S pe c t r a f o r C om pound 137h

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131 S p e c t r a 5 2. 9 1 H a nd 1 3 C S pe c t r a f o r C om pound 1 37i

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132 S p e c t r a 5 2. 10 1 H a nd 1 3 C S pe c t r a f o r C om pound 137j

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133 S p e c t r a 5 2. 11 1 H a nd 1 3 C S pe c t r a f o r C om pound 137k

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134 S p e c t r a 5 2. 12 1 H a nd 1 3 C S pe c t r a f o r C om pound 137 l S p e c

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135 S p e c t r a 5 2. 13 1 H a nd 1 3 C S pe c t r a f o r C om pound 137m

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136 S p e c t r a 5 2. 14 1 H a nd 1 3 C S pe c t r a f o r C om pound 137 n

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137 S p e c t r a 5 2. 15 1 H a nd 1 3 C S pe c t r a f o r C om pound 130o

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138 S p e c t r a 5 2. 16 1 H a nd 1 3 C S pe c t r a f o r C om pound 130p

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139 R e f e r e n c e s 1) a ) T he I m pac t of St e r e oc he m i s t r y on D r ug D e v e l opm e nt and U s e : A boul E ne i n, H Y E d. ; W i l e y: N e w Y or k, 1997. b) C hi r al i t y i n D r ug Sy nt he s i s : B r ow n, C E d. ; A c a de m i c : N e w Y or k, 1990 2) a ) C he n C S ; S hi e h W R ; L u P H ; H a r r i m a n S ; C he n C Y B i oc hi m B i ophy s A c t a. 1991 1078, 411 7. b) T e r at oge ns : C he m i c al s W hi c h C aus e B i r t h D e f e c t s K ol b, V M E d ; E l s e ve i r A m s t e r da m : 1993 3) C a r e y, J S ; L a f f a n D ; T hom s on, C ; W i l l i a m s M T O r g. B i o. C he m 2006 4 2337. 4) C om pr e he n s i v e A s y m m e t r i c C at al y s i s : J a c obs e n, E N ; P f a l t z A ; Y a m a m ot o H E ds ; S p r i nge r : H e i de l be r g, 1 999. 5) a ) D a l ko, P I ; M oi s a n, L A nge w C he m I nt E d. 2001 40 3726. b) D a l ko, P I ; M oi s a n, L A nge w C he m I nt E d 2004 43 5138 6) B r e di ng, G ; F i s ke P S B i oc he m Z 1912 46 7 7) P r a c e j us H J us t us L i e bi gs A nn. C he m 1960 634 9. 8) a ) N ot z W ; T a na ka F ; B a r ba s C F I I I A c c C he m R e s 2004 37 580 b) L i s t B A c c C he m R e s 2004 37 548. c ) M ukhe r j e e S ; Y a ng, J W ; H of f m a n, S ; L i s t B C he m R e v 2007 107 5471 9) H a j os Z G ; P a r r i s h, D R J O r g. C he m 1974 3 9 1615 10) S t or k G ; T e r r e l l R ; S z m us z kovi c z J J A m C h e m Soc 1954 76 2029. 11) a ) B a r ba s C F I I I ; H e i ne A ; Z hong, G ; H of f m a n, T ; G r a m a t i kova S ; B j or ns t e dt R ; L i s t B ; A nde r s on, J ; S t ur a E A ; W i l s on, L ; L e r ne r R A

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140 Sc i e nc e 1997 278 208 5. b ) T ur ne r J ; B ui T ; L e r ne r R A ; B a r ba s C F I I I ; L i s t B C he m E ur J 2000 6 2772 12) N ot z W ; L i s t B J A m C he m Soc 2000 122 7 386. 13) L i s t B J A m C he m Soc 2000 122 9336. 14) C how da r i N S ; R a m a c ha r y, D B ; B a r ba s C F I I I Sy nl e t t 2003 1906 15) R os s i t e r B E ; S w i ngl e N M C he m R e v 1992 92 771 16) M a r i go, M ; J r ge s e n, K A C he m C om m un. 200 6 2001 17) E r kki t a A ; M a j a nde r I ; P i hko, P M C he m R e v 2007 107 5416 18) K noe ve na ge l I C he m B e r 1894 27 2345 19) B l a nc ha r d K C ; K l e i n, D L ; M a c D ona l d, J J A m C he m Soc 1931 53 2809. 20) C r ow e l l T I ; P e c k, D W J A m C he m Soc 195 3 75 1075 21) W oodw a r d, R B ; L ogus c h, E ; N a m bi a r K P ; S a ka n, K ; W a r d, D E ; A u Y oung, B W ; B a l a r a m P ; B r ow ne L J ; C a r d, P J ; G a r r a t D J ; H a ya ka w a K ; H e ggi e W ; H e s s on, D P ; H oppe D ; H op pe L ; H ya t t J A ; I ke da D ; J a c obi P A ; K i m K S ; K obuke Y ; K oj i m a K ; K r ow i c ki K ; L e e V J ; L a ut e r t I ; M a l c he nko, S ; M a r t e ns J ; M a t t he w s R S ; O ng, B S ; P r e s s J B ; R a j a n B a bu, T V ; R ous s e a u, G ; S a ut e r H M ; S uz uki M ; T a t s ut a K ; T ol be r t L M ; T r ue s da l e F A ; U c hi da I ; U e da Y ; U yc ha r a T ; V a s e l l a A T ; V l a duc hi c k, W C ; W a de P A ; W i l l i a m s R M ; W ong, H N C J A m C he m Soc 1981 103 3210. 22) Y a m a guc hi M ; Y okot a N ; M i na m i T J C he m Soc C he m C om m un. 1991 1088.

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A b ou t t h e A u t h or G e r a l d B R ow l a nd J r w a s bor n on S e pt e m be r 10 1980 i n B oone vi l l e M S H e w a s t he s e c ond c hi l d ( be hi nd s i s t e r E uni c e ) of M a y a n d G e r a l d R ow l a nd. G e r a l d a t t e nde d H i l l s C ha pe l E l e m e nt a r y S c hool a nd N e w S i t e H i gh S c hool U pon c om pl e t i on of hi gh s c hool G e r a l d e nr ol l e d i n c ol l e ge a t N or t he a s t M i s s i s s i ppi C om m uni t y C ol l e ge a s a s c i e n c e e duc a t i on m a j or U pon c om pl e t i on of hi s a s s o c i a t e de gr e e he e nr ol l e d a t t he U ni ve r s i t y of N or t h A l a ba m a a s a pr of e s s i ona l c he m i s t r y m a j or ( A C S c e r t i f i e d) w he r e he r e c e i ve d hi s B S de gr e e i n 2003. I n 2003, he j oi ne d t he r e s e a r c h gr oup of P r of e s s or J on C A nt i l l a a t t he U ni ve r s i t y of M i s s i s s i ppi I n 2005, G e r a l d m a r r i e d hi s w onde r f ul w i f e a nd l a b m a t e E m i l y B r e t he r i c k. I n 2006, G e r a l d m ove d w i t h P r of e s s or A nt i l l a t o t he c he m i s t r y de pa r t m e nt a t t he U ni ve r s i t y of S out h F l o r i da I n A ugus t 2008, G e r a l d w i l l be m ovi ng t o C a m br i dge M A w he r e he h a s a c c e pt e d a pos t doc t or a l pos i t i on i n t he l a bor a t or y of G r e gor y C F u a t t he M a s s a c hu s e t t s I ns t i t ut e of T e c hnol ogy


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Cras ut cursus ante, a fringilla nunc. Mauris lorem nunc, cursus sit amet enim ac, vehicula vestibulum mi. Mauris viverra nisl vel enim faucibus porta. Praesent sit amet ornare diam, non finibus nulla.

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Cras efficitur magna et sapien varius, luctus ullamcorper dolor convallis. Orci varius natoque penatibus et magnis dis parturient montes, nascetur ridiculus mus. Fusce sit amet justo ut erat laoreet congue sed a ante.

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Phasellus ornare in augue eu imperdiet. Donec malesuada sapien ante, at vehicula orci tempor molestie. Proin vitae urna elit. Pellentesque vitae nisi et diam euismod malesuada aliquet non erat.

WIKIPEDIA

Nunc fringilla dolor ut dictum placerat. Proin ac neque rutrum, consectetur ligula id, laoreet ligula. Nulla lorem massa, consectetur vitae consequat in, lobortis at dolor. Nunc sed leo odio.