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Enantioselective Br‚àö‚àènsted acid-catalyzed reaction methodology

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Material Information

Title:
Enantioselective Br‚àö‚àènsted acid-catalyzed reaction methodology Part a : enantioselective mannich reaction. Part b: enantioselective desymmetrization of meso-aziridines
Physical Description:
Book
Language:
English
Creator:
Rowland, Emily Bretherick
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
Publication Date:

Subjects

Subjects / Keywords:
Aziridine
Desymmetrization
Catalysis
Phosphoric acid
Bro‚àö‚àènsted Acid
Dissertations, Academic -- Chemistry -- Doctoral -- USF   ( lcsh )
Genre:
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: The synthesis of enantiomerically pure compounds is of vital importance. Most biologically active natural products are chiral and require asymmetric synthesis, chiral resolution, or the use of naturally chiral starting materials for their preparation. Organocatalytic enantioselective reaction methodology is a continuously growing area in organic chemistry. The use of organocatalysts as a potentially environmentally friendly alternative to metal catalysts is appealing to the pharmaceutical industry. In this dissertation an enantioselective Mannich reaction using an organocatalyst was investigated. The reaction was between a β-keto ester and an imine electrophile catalyzed by vaulted biphenanthrol (VAPOL) phosphoric acid. The reaction resulted in products with high yields, but low to moderate enantioselectivity and diastereoselectivity. The development of the first Brønsted acid-catalyzed desymmetrization of meso-aziridines was also investigated. This is one of the first instances where a phosphoric acid has been used to catalyze a reaction that did not involve an imine. It was shown that the chiral VAPOL phosphoric acid was an excellent catalyst for the reaction resulting in high yields and enantioselectivities for the chiral ring opened products. It was also shown, for the first time, that a vaulted binaphthol (VANOL) phosphoric acid can also catalyze the ring-opening of meso-aziridines with comparable results to the VAPOL phosphoric acid in some cases. Mechanistic NMR studies were used to probe the reaction, and it is believed that evidence leads one to conclude that a unique mechanism for phosphoric acid-catalysis is followed. The products that can be obtained from this reaction, 1,2-diamines, are of high value for synthetic chemists. They have been used as chiral auxiliaries, ligands, and precursors to natural products.
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.
Statement of Responsibility:
by Emily Bretherick Rowland.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 125 pages.
General Note:
Includes vita.

Record Information

Source Institution:
University of South Florida Library
Holding Location:
University of South Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 002001161
oclc - 319636932
usfldc doi - E14-SFE0002613
usfldc handle - e14.2613
System ID:
SFS0026930:00001


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E na nt i os e l e c t i ve B r ns t e d A c i d C a t a l yz e d R e a c t i o n M e t hodol ogy P a r t A : E na nt i os e l e c t i ve M a nni c h R e a c t i on P a r t B : E na nt i os e l e c t i ve D e 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 by E m i l y B r e t he r i c k R ow l a nd 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 K i r pa l B i s ht P h D R om a n M a ne t s c h, P h. D 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 : a z i r i di ne de s ym m e t r i z a t i on, c a t a l ys i s phos phor i c a c i d, B r ns t e d A c i d, M a nni c h, e na nt i os e l e c t i ve a s ym m e t r i c C opyr i ght 2008 E m i l y B r e t he r i c k R ow l a nd

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I w oul d l i ke t o de di c a t e t hi s t o m y hus ba nd, G e r a l d a n d m y f a m i l y. T ha nk you f or l ovi ng a nd s uppor t i ng m e

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A C K N O WL E D G E M E N T S I w oul d l i ke t o t ha nk m y r e s e a r c h a dvi s or D r J on A nt i l l a f or gi vi ng m e t he oppor t uni t y t o w or k i n hi s l a b a nd f or l ot s of gui da nc e I w oul d l i ke t o t ha nk m y hus ba nd, D r G e r a l d R ow l a nd, f or a l l o f t he s uppor t a nd he l p he ha s gi ve n m e I w oul d l i ke t o t ha nk m y c om m i t t e e m e m be r s D r R om a n M a ne t s c h, D r P e t e r Z ha ng, a nd D r K i r pa l B i s ht f o r t he i r t i m e a nd a s s i s t a nc e ove r t he l a s t f e w ye a r s I w a nt t o t ha nk a l l o f m y l a bm a t e s a t O l e M i s s a nd U S F 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 D r G ui l ong L i f or a l l of t he i r he l p i n t he l a b. I w oul d a l s o l i ke t o t ha nk Q i a ng Z ha ng, 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 S ha w n L a r s on, K i m be r l y L a w a nd C our t ne y S obe r s I w a nt t o t ha nk m y hi gh s c hool c he m i s t r y t e a c he r C a ndi c e G ol l i ve r be c a us e s he i s t he r e a s on I m a j or e d i n c he m i s t r y. I w a nt t o t ha nk m y unde r gr a dua t e c h e m i s t r y pr of e s s or s D r B r e nt O l i ve a nd D r T om M ur r a y f or t e a c hi ng m e t ha t e ve r yt h i ng w i l l w o r k out i f you t r y ha r d e nough a nd f or e nc our a gi ng m e t o go t o gr a dua t e s c hool I w a nt t o t ha nk m y ot he r unde r gr a dua t e pr o f e s s or s D r A nt hony B l os e a nd D r D ona l d R ous h f or a l l t he s uppor t t he y ga ve m e a s a n unde r gr a dua t e s t ude nt I w a nt t o t ha nk m y m om f or e ve r yt hi ng s he ha s done f or m e I w a nt t o t ha nk a l l of m y f a m i l y f or be i ng e xt r e m e l y s uppor t i ve w hi l e I ha ve pur s ue d m y de gr e e I w a nt t o t ha nk m y be s t f r i e nds J ul i e B r a c e y S a nd e r s on a nd J ohndr a U pt on f or a l w a ys b e i ng t he r e f or m e w he ne ve r I ne e de d s om e one t o t a l k t o.

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i T A B L E O F C O N T E N T S L I S T O F T A B L E S i i i L I S T O F F I G U R E S vi L I S T O F S P E C T R A vi i i A B S T R A C T x C H A P T E R 1: E N A N T I O S E L E C T I V E B R N S T E D A C I D C A T A L Y Z E D R E A C T I O N M E T H O D O L O G Y 1 1. 1 I nt r oduc t i on 1 1. 2 M a nni c h R e a c t i on 3 1. 3 A m i da t i on a nd I m i da t i on 5 1. 4 H ydr ophos phonyl a t i on 7 1. 5 F r i e de l C r a f t s R e a c t i on 8 1. 6 R e duc t i on C he m i s t r y 12 1. 7 C yc l oa ddi t i on R e a c t i ons 17 1. 8 B r ns t e d A c i ds us e d a s C ount e r i ons 21 1. 9 C onc l us i on 25 C H A P T E R 2: E N A N T I O S E L E C T I V E M A N N I C H R E A C T I O N 26 2. 1 I nt r oduc t i on 26 2. 2 E na nt i os e l e c t i ve O r ga noc a t a l yt i c M a nni c h R e a c t i on M e t hodol ogy 27 2. 3 I ni t i a l D e ve l opm e nt s of a n A s ym m e t r i c M a nni c h R e a c t i on 36 2. 4 C onc l us i on 42

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i i C H A P T E R 3: E N A N T I O S E L E C T I V E D E S Y M M E T R I Z A T I O N O F M E SO A Z I R I D I N E S 44 3. 1 I nt r oduc t i on 44 3. 2 M e t hodol ogy f or t he D e s ym m e t r i z a t i on o f m e s o A z i r i di ne s 46 3. 3 E na nt i os e l e c t i ve D e 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 M e t hodol ogy 49 3. 4 P hos phor i c A c i d C a t a l yz e d D e 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 53 3. 5 C onc l us i on 71 C H A P T E R 4: E X P E R I M E N T A L P R O C E D U R E S 72 4. 1 G e ne r a l I nf or m a t i on 72 4. 1 E xpe r i m e nt a l P r oc e dur e s f or C ha pt e r 2 73 4. 2 E xpe r i m e nt a l P r oc e dur e s f or C ha pt e r 3 78 C H A P T E R 5: S P E C T R A 96 5. 1 1 H a nd 1 3 C N M R f or C ha pt e r 2 96 5. 2 1 H a nd 1 3 C N M R f or C ha pt e r 3 101 R E F E R E N C E S 119 A B O U T T H E A U T H O R E nd P a ge

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i i i L I S T O F T A B L E S T a bl e 1. 1 A s ym m e t r i c I m i ne A m i da t i on 6 T a bl e 1. 2 A s ym m e t r i c I m i da t i on 7 T a bl e 1. 3 A ki ya m a s E na nt i os e l e c t i ve H ydr ophos phonyl a t i on 8 T a bl e 1. 4 T e r a da s E na nt i 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 9 T a bl e 1. 5 T e r a da s F r i e de l C r a f t s R e a c t i on of A l ke ne s 9 T a bl e 1. 6 Y ou s F r i e de l C r a f t s R e a c t i on 10 T a bl e 1. 7 A nt i l l a 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: V a r i a t i on of I m i ne 11 T a bl e 1. 8 A nt i l l a 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: V a r i a t i on of I ndol e 11 T a bl e 1. 9 R ue pi ng s O r ga noc a t a l yt i c R e duc t i on of I m i ne s 13 T a bl e 1. 10 L i s t s E na nt i os e l e c t i ve H ydr oge na t i on of K e t i m i ne s 14 T a bl e 1. 11 L i s t s R e duc t i ve A m i na t i on vi a D yna m i c K i ne t i c R e s ol ut i on 16 T a bl e 1. 12 A nt i l l a s R e duc t i on of I m i no E s t e r s 17 T a bl e 1. 13 R ue pi ng s A s ym m e t r i c S ynt he s i s of I s oqui nuc l i di ne s w i t h T w o B r ns t e d A c i ds 18 T a bl e 1. 14 G ong s D i r e c t A z a 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. 15 T e r a da s T a nde m A z a E ne R e a c t i on 20 T a bl e 1. 16 R ue pi n g s A s ym m e t r i c N a z a r ov C yc l i z a t i on 21 T a bl e 1. 17 R ue pi ng s A l kynl a t i on of I m i no E s t e r s 23

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i v T a bl e 2. 1 K oba ya s hi s E na nt i os e l e c t i ve M a nni c h T ype R e a c t i on 28 T a bl e 2. 2 L i s t s P r ol i ne C a t a l yz e d D i r e c t M a nni c h R e a c t i on 29 T a bl e 2. 3 J a c obs e n s T hi o ur e a c a t a l yz e d M a nni c h R e a c t i on 30 T a bl e 2. 4 B a r ba s s O r ga noc a t a l yt i c D i r e c t M a nni c h R e a c t i on w i t h A l i pha t i c A l de hyde s 30 T a bl e 2. 5 B a r ba s s O r ga noc a t a l yt i c D i r e c t M a nni c h R e a c t i on w i t h A r om a t i c A l de hyde s 31 T a bl e 2. 6 A ki ya m a s A s ym m e t r i c M a nn i c h R e a c t i on 32 T a bl e 2. 7 T e r a da s D i r e c t M a nni c h R e a c t i on 33 T a bl e 2. 8 G ong s A s ym m e t r i c M a nni c h R e a c t i on 34 T a bl e 2. 9 R ue pi ng s B r ns t e d A c i d A s s i s t e d E na nt i os e l e c t i v e B r ns t e d A c i d C a t a l yz e d D i r e c t M a nni c h R e a c t i on 35 T a bl e 2. 10 S c hne i de r s E na nt i os e l e c t i ve V i nl yl gous M a nni c h R e a c t i on 36 T a bl e 2. 11 I ni t i a l I nve s t i ga t i ons 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 B e t w e e n I m i ne s a nd K e t o E s t e r s 37 T a bl e 2. 12 B r ns t e d A c i d C a t a l yz e d A ddi t i on of K e t o E s t e r s t o I m i ne w i t h 4 F l uor o S ubs t i t ue nt on t he A r om a t i c R i ng 39 T a bl e 2. 13 B r ns t e d A c i d C a t a l yz e d A ddi t i on of A l l yl a c e t oa c e t a t e t o N B oc pr ot e c t e d I m i ne s 40 T a bl e 3. 1 Y a da v s I nC l 3 C a t a l yz e d O pe ni ng of A z i r i di ne s 47 T a bl e 3. 2 H ou s R i ng O pe ni ng of A z i r i di ne s w i t h T r i m e t hyl s i l yl C ya ni de 48 T a bl e 3. 3 M e s o A z i r i di ne O pe ni ng w i t h Z i nc C hl or i de a s a C a t a l ys t 49 T a bl e 3. 4 M e s o A z i r i di ne O pe ni ng w i t h T r i but yl phos phi ne a s a C a t a l ys t 49

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v T a bl e 3. 5 J a c obs e n s D e 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 50 T a bl e 3. 6 M ul l e r s D e s ym m e t r i z a t i on of m e s o N S ul f onyl a z i r i di ne s 51 T a bl e 3. 7 S hi ba s a ki s D e 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 w i t h T M S C N 52 T a bl e 3. 8 S hi ba s a ki s D e 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 w i t h T M S A z i de 53 T a bl e 3. 9 S c r e e ni ng of P r ot e c t i ng G r oup on N i t r oge n 56 T a bl e 3. 10 O pt i m i z a t i on of R e a c t i on of A z i r i d i ne 195a w i t h T M S A z i de 59 T a bl e 3. 11 O pt i m i z a t i on of R e a c t i on of A z i r i d i ne 195f w i t h T M S A z i de 61 T a bl e 3. 12 O pt i m i z a t i on of R e a c t i on of A z i r i d i ne 195h w i t h T M S A z i de 62 T a bl e 3. 13 S c ope of A z i r i d i ne S ub s t r a t e 64

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vi L I S T O F F I G U R E S F i gur e 1. 1 T ha l om i de a nd C a r vone 2 F i gur e 1. 2 H ydr oge n B ondi ng C a t a l yt s 3 F i gur e 1. 3 A ki ya m a s A s ym m e t r i c M a nni c h R e a c t i on 4 F i gur e 1. 4 T e r a da s A s ym m e t r i c M a nni c h R e a c t i on 4 F i gur e 1. 5 A nt i l l a s F r i e de l C r a f t s R e a c t i on of P y r r ol e s t o I m i ne s 12 F i gur e 1. 6 R upi ng s P r opos e d M e c ha ni s t i c C yc l e f or R e duc t i on of I m i ne s 13 F i gur e 1. 7 M a c M i l l a n s O r ga noc a t a l yt i c R e duc t i ve A m i na t i o n 15 F i gur e 1. 8 R e duc t i ve A m i na t i on P r opos e d M e c ha ni s m 16 F i gur e 1. 9 R ue pi ng s M e c ha n i s m f or S ynt he s i s of I s oqui nuc l i di ne s 18 F i gur e 1. 10 R ue pi ng s B r ns t e d A c i d a nd M e t a l C a t a l yz e d A l kynyl a t i on of I m i no E s t e r s 22 F i gur e 1. 11 T os t e s C ount e r i on M e di a t e d E na nt i os e l e c t i ve H ydr oa m i na t i on 24 F i gur e 1. 12 T os t e s C ount e r i on M e di a t e d H ydr oa l k oxyl a t i on 24 F i gur e 1. 13 L i s t s C a t a l yt i c A s ym m e t r i c a A l l yl a t i on of A l de hyde s 25 F i gur e 2. 1 D i r e c t a nd I ndi r e c t M a nni c h R e a c t i ons 27 F i gur e 2. 2 P r opos e d M e c ha ni s t i c C yc l e f or t he B r ns t e d A c i d A s s i s t e d A s ym m e t r i c B r ns t e d A c i d C a t a l yz e d M a nni c h R e a c t i o n 34 F i gur e 2. 3 I ni t i a l R e a s oni ng f or t he A ddi t i on of K e t o E s t e r s t o I m i ne s 37 F i gur e 2. 4 T a ut a m e r i z a t i on f r om V A P O L P hos phor i c A c i d 38 F i gur e 2. 5 N uc l e ophi l i c A ddi t i on t o I m i ne s 41

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vi i F i gur e 2. 6 S c ha us s A s ym m e t r i c S ynt he s i s of C yc l i c U r e t ha n e D e r i va t i v e s 42 F i gur e 3. 1 R i ng O pe ni ng of A z i r i d i ne i n t he S ynt he s i s of A c t i nom m yc i n D 45 F i gur e 3. 2 S t e ps i n t he S yn t he s i s of T a m i f l u 45 F i gur e 3. 3 C hi r a l D i a m i ne s 46 F i gur e 3. 4 P r e pa r a t i on of 6 ( 3, 5 B i s t r i f l uor om e t hyl be nz oyl ) 6 a z a bi c yc l o[ 3. 1. 0] he xa ne 57 F i gur e 3. 5 P r e pa r a t i on of c i s 1 ( 3 5 bi s t r i f l uor om e t hy l be nz oyl ) 2, 3 di phe nyl a z i r i di ne 57 F i gur e 3. 6 P r e pa r a t i on of 3 O xa 6 ( 3, 5 bi s t r i f l uor om e t hyl be nz oyl ) 6 a z bi c yc l o[ 3. 1. 0] he xa ne 58 F i gur e 3. 7 P r e pa r a t i on of 3 C a r bobe nz yl oxy 6 ( 3, 5 bi s t r i f l uor om m e t hyl be nz oyl ) 3, 6 d i a z bi c yc l o[ 3. 1. 0 ] he xa ne 58 F i gur e 3. 8 P r opos e d M e c ha ni s m f or t he P h os phor i c A c i d C a t a l yz e d D e 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 66 F i gur e 3. 9 1 H N M R R e a c t i on A r r a y: A r r ow s I ndi c a t e A z i r i di ne 186f 68 F i gur e 3. 10 1 H N M R R e a c t i on A r r a y: A r r ow s I ndi c a t e P r oduc t 196f 69 F i gur e 3. 11 1 H N M R R e a c t i on A r r a y: A r r ow s I ndi c a t e I nt e r m e di a t e 199f 70

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vi i i L I S T O F S P E C T R A S pe c t r a 5. 1 1 C om pound 136b 96 S pe c t r a 5. 1 2 C om pound 141b 97 S pe c t r a 5. 1 3 C om pound 136c 98 S pe c t r a 5. 1 4 C om pound 144a 99 S pe c t r a 5. 1 5 C om poun d 144b 100 S pe c t r a 5. 2 1 C om pound 186a 101 S pe c t r a 5. 2 2 C om pound 186b 102 S pe c t r a 5. 2 3 C om pound 186c 103 S pe c t r a 5. 2 4 C om pound 186d 104 S pe c t r a 5. 2 5 C om pound 186e 105 S pe c t r a 5. 2 6 C om pound 186f 106 S pe c t r a 5. 2 7 C om pound 186g 107 S pe c t r a 5. 2 8 C om poun d 186h 108 S pe c t r a 5. 2 9 C om pound 186i 109 S pe c t r a 5. 2 10 C om pound 196a 110 S pe c t r a 5. 2 11 C om pound 196b 111 S pe c t r a 5. 2 12 C om pound 196c 112 S pe c t r a 5. 2 13 C om pound 196d 113 S pe c t r a 5. 2 14 C om pound 196e 114 S pe c t r a 5. 2 15 C om pound 196f 115

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i x S pe c t r a 5. 2 16 C om pound 196g 116 S pe c t r a 5. 2 17 C om pound 196h 117 S pe c t r a 5. 2 18 C om pound 196i 118

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x E n an t i os e l e c t i ve B r n s t e d A c i d C a t al yz e d R e ac t i on M e t h o d ol ogy P ar t A : E n an t i os e l e c t i ve M an n i c h R e ac t i on P ar t B : E n an t i os e l e c t i ve D e s ym m e t r i z at i on of m e s o A z i r i d i n e s E m i l y B r e t h e r i c k R ow l an d A B S T R A C T 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 poun ds i s of vi t a l i m por t a nc e M os t bi ol ogi c a l l y a c t i ve na t ur a l pr oduc t s a r e c hi r a l a nd r e qui r e a s ym m e t r i c s ynt he s i s c hi r a l r e s ol ut i on, or t he us e of na t ur a l l y c hi r a l s t a r t i ng m a t e r i a l s f or t he i r pr e pa r a t i on. O r 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 i s a c ont i nuous l y gr ow i ng a r e a i n or ga ni c c he m i s t r y. T he us e of or ga noc a t a l ys t s a s a pot e nt i a l l y e nvi r onm e nt a l l y f r i e ndl y a l t e r na t i ve t o m e t a l c a t a l ys t s i s a ppe a l i ng t o t he ph a r m a c e ut i c a l i ndus t r y. I n t hi s di s s e r t a t i on 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 us i ng a n or ga noc a t a l ys t w a s i nve s t i ga t e d. T he r e a c t i on w a s be t w e e n a ke t o e s t e r a nd a n i m i ne e l e c t r ophi l e c a t a l yz e d by va ul t e d bi phe na nt hr ol ( V A P O L ) pho s phor i c a c i d. T he r e a c t i on r e s ul t e d i n pr oduc t s w i t h hi gh yi e l ds but l ow t o m ode r a t e e na nt i os e l e c t i vi t y a nd di a s t e r e os e l e c t i vi t y. T he de ve l opm e nt of t he f i r s t B r ns t e d a c i d c a t a l y z e d 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 w a s a l s o i nve s t i ga t e d. T hi s i s one of t he f i r s t i ns t a nc e s w he r e a phos phor i c a c i d ha s b e e n us e d t o c a t a l yz e a r e a c t i on t h a t di d n ot i nvol ve a n i m i ne I t w a s s how n t ha t t he c hi r a l V A P O L phos phor i c a c i d w a s a n e xc e l l e nt c a t a l ys t f or t he r e a c t i on r e s ul t i ng i n hi gh yi e l ds a nd e na nt i os e l e c t i vi t i e s f or t he c hi r a l r i ng ope ne d pr oduc t s I t w a s a l s o s how n, f or t he f i r s t t i m e t ha t a va ul t e d bi na pht h ol ( V A N O L ) phos phor i c a c i d c a n a l s o

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xi c a t a l yz e t he r i ng ope ni ng of m e s o a z i r i di ne s w i t h c om pa r a bl e r e s ul t s t o t he V A P O L phos phor i c a c i d i n s om e c a s e s M e c ha ni s t i c N M R s t udi e s w e r e us e d t o pr obe t he r e a c t i on, a nd i t i s b e l i e ve d t ha t e vi de nc e l e a ds on e t o c onc l ude t ha t a uni que m e c ha ni s m f or phos phor i c a c i d c a t a l ys i s i s f ol l ow e d. T he p r oduc t s t ha t c a n be obt a i ne d f r om t hi s r e a c t i on, 1 2 di a m i ne s a r e of hi gh va l ue f or s ynt he t i c c he m i s t s T he y ha ve be e n us e d a s c hi r a l a uxi l i a r i e s l i ga nds a nd p r e c ur s or s t o na t u r a l pr oduc t s

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1 C H A P T E R 1 E N A N T I O S E L E C T I V E B R O N S T E D A C I D C A T A L Y Z E D R E A C T I O N M E T H O D O L O G Y 1. 1 I n t r od u c t i on T he 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 ons i s a va l ua bl e s t r a t e gy f or m ode r n or ga ni c s ynt he s i s S e ve r a l r e s e a r c h l a bor a t or i e s a r ound t he w or l d ha ve f oc us e d on de ve l opi ng t he s e t ype s of r e a c t i ons 1 T he c hi r a l pr oduc t s obt a i ne d f r om s uc h c a t a l yt i c m e t hodol ogi e s ha ve be e n s how n t o be ke y s t e ps i n t he s ynt he s i s of nu m e r ous na t ur a l pr oduc t s 2 A l a r ge pe r c e nt a ge of bi ol ogi c a l l y a c t i ve c om pounds a r e c hi r a l i nc l udi ng t he na t ur a l l y oc c ur r i ng a m i no a c i ds a nd e nz ym e s 3 C hi r a l na t ur a l pr oduc t s a r e i m po r t a nt be c a us e of t he bi ol ogi c a l a c t i vi t y of one e na nt i om e r m a y be m uc h di f f e r e nt t ha n t he a c t i vi t y of t he ot he r e na nt i om e r 4 B y s ynt he s i z i ng onl y t he a c t i ve e na nt i om e r t he r e i s m uc h l e s s w a s t e pr oduc e d. T hi s a l s o ke e ps dow n t he c os t of dr ugs be c a us e t he r e i s not a s m uc h s t a r t i ng m a t e r i a l us e d i n t he r e a c t i on. I n s om e c a s e s s uc h a s t ha l i dom i de one e na nt i om e r w a s us e d t o de c r e a s e t he s ym pt om s of m or ni ng s i c kne s s a nd t he ot he r e na nt i om e r w a s f ound t o be t e r a t oge ni c 5 T he r e f or e by us i ng a n unt e s t e d r a c e m i c dr ug, de t r i m e nt a l s i de e f f e c t s f r om on e of t he e na nt i om e r s m a y be f ound. A not he r di s a dva nt a ge of us i ng r a c e m i c dr ugs i s t he dos a g e m a y ha ve t o be i nc r e a s e d s o t ha t t he a c t i ve e na nt i om e r i s gi ve n i n a n e f f e c t i ve c onc e nt r a t i on. I n s om e e xa m pl e s s uc h a s t ha l i dom i de i f one e na nt i om e r i s gi ve n a s a dr ug, i t m a y r a c e m i z e i n t he body. A not he r e xa m pl e w he r e e na nt i om e r s ha ve di f f e r e nt pr ope r t i e s i s c a r vone 6 T he ( S ) e na nt i om e r of

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2 c a r vone i s r e s pons i bl e f or t he f l a vor c a r a w a y a nd t he ( R ) e na nt i om e r i s r e s pons i bl e f or t he f l a vor s pe a r m i nt F i g u r e 1. 1 T h al i d o m i d e an d C ar von e C a t a l yt i c r e a c t i on m e t hodol ogy i s e xt r e m e l y i m po r t a nt i n or ga ni c s ynt he s i s T he us e of c a t a l y s t s t o pe r f or m or ga ni c t r a ns f or m a t i on s i s a n a r e a t ha t s e ve r a l r e s e a r c h gr oup s a r e de ve l opi ng. 2 6 F or m a ny r e a c t i ons t he pr e s e nc e of a c a t a l ys t l e a d s t o de c r e a s e d r e a c t i on t i m e i nc r e a s e d pr oduc t f or m a t i on a l l ow s f or m or e m ode r a t e r e a c t i on c ondi t i ons a nd a l s o i m pr ove d r e gi o a nd s t e r e os e l e c t i vi t y. U nt i l r e c e nt l y, c a t a l ys t s w e r e c l a s s i f i e d i nt o t w o m a i n c a t e gor i e s : e nz ym e s a nd m e t a l c om pl e xe s N ow t he r e i s a not he r c a t e gor y of c a t a l ys t s w hi c h m a ny r e f e r t o or ga noc a t a l yt s 7 O r ga noc a t a l ys i s c a n be de f i ne d a s t he us e of s m a l l or ga ni c m ol e c ul e s a s c a t a l ys t s a nd i t r e pr e s e nt s a n e m e r gi ng a r e a of or ga ni c m e t hodol ogy. T he us e of t he s e c a t a l ys t s ha ve t he pot e nt i a l t o be a n e nvi r on m e nt a l l y f r i e ndl y a l t e r na t i ve t o m e t a l c a t a l ys i s O r ga noc a t a l ys i s a ppe a l s t o l a r ge s c a l e s ynt he s i s b e c a us e of t he r e l a t i ve l a c k of t oxi c by pr oduc t s t ha t a r e c om m on l y a s s oc i a t e d w i t h s om e t ype s of m e t a l c a t a l ys i s O r ga noc a t l ys t s i n m a ny c a s e s a r e i ne xpe ns i ve r obus t a nd r e a di l y a va i l a bl e T he y a r e m os t l y be nc h s t a bl e a nd i n s om e c a s e s do not r e qui r e i ne r t a t m os phe r e s l ow t e m pe r a t ur e s or e xha us t i ve l y dr y s ol ve nt s l i ke m a ny m e t a l ba s e d s ys t e m s O ne s ub t ype of or ga noc a t a l ys t s a r e t he hydr oge n bondi ng c a t a l ys t s w hi c h a r e s how n i n F i gur e 1. 2.

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3 T he pr ol i ne c a t a l ys t s ha ve be e n us e d m os t s uc c e s s f ul l y f or a l dol r e a c t i ons 8 C hi r a l t hi our e a s ha ve pa r t i c ul a r l y s uc c e s s f ul hydr oge n bondi ng f r a m e w or ks us e d i n t he c a t a l ys i s of t he S t r e c ke r r e a c t i on, M a nni c h r e a c t i on, a z a H e nr y a s w e l l a s s e v e r a l ot he r s 9 H e t e r o D i e l s A l de r r e a c t i ons ha ve be e n c a t a l yz e d by T A D D O L a s i m pl e c hi r a l di ol 1 0 P hos phor i c a c i ds s uc h a s B I N O L phos phor i c a c i d, a r e a l s o hydr oge n bondi ng c a t a l ys t s 9 1 1 T he s e phos phor i c a c i ds a r e bi f unc t i o na l c a t a l ys t s t ha t c ont a i n a L e w i s ba s e a nd a B r ns t e d A c i d s i t e C hi r a l phos phor i c a c i ds ha ve be e n s how n t o be e xc e l l e n t c a t a l ys t s f or a w i de 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 F i gu r e 1. 2 H yd r oge n B on d i n g C at al ys t s 1. 2 M an n i c h R e ac t i on C a r bon c a r bon bond f or m i ng r e a c t i ons a r e one of t he m os t hi ghl y de ve l ope d r e a c t i ons i n or ga ni c c he m i s t r y. T he M a nni c h r e a c t i on i s a c a r bon c a r bon bond f o r m i ng r e a c t i on t ha t i nvol ve s t he r e a c t i on of a n e nol w i t h a n i m i ni um i on. 8 9 1 2 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 f i r s t e xa m pl e o f a c hi r a l phos phor i c a c i d c a t a l yz e d r e a c t i on. 1 3 I t w a s s how n t ha t a c hi r a l hi nde r e d B I N O L de r i ve d phos phor i c a c i d w a s a n e xc e l l e nt c a t a l ys t f or a n a s ym m e t r i c M a nni c h R e a c t i on. T he e na nt i os e l e c t i ve c a t a l yt i c a ddi t i on of s i l yl e nol e t he r s t o or t ho hydr oxy i m i ne s r e s ul t e d i n yi e l ds up t o 100% a nd e na nt i os e l e c t i vi t y up t o 96% e e a s s how n i n F i gur e 1. 3 be l ow

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4 F i gu r e 1. 3 A k i ya m a s A s ym m e t r i c M an n i c h R e ac t i on T e r a da a nd c o w or ke r s r e por t e d 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 a s w e l l T he a ddi t i on of a c e t yl a c e t one t o N B oc pr ot e c t e d I m i ne s r e s ul t e d i n yi e l ds up t o 99% a nd e na nt i os e l e c t i ve e xc e s s up t o 98% 1 4 T hi s w a s a not he r e xa m pl e of a c hi r a l B I N O L de r i ve d phos phor i c a c i d be i ng us e d a s a c a t a l ys t a s s how n i n F i gu r e 1 4 be l ow F i gu r e 1. 4 T e r ad a s A s ym m e t r i c M an n i c h R e ac t i on T he a bove e xa m pl e s a r e onl y t w o of s e ve r a l a s ym m e t r i c M a nni c h r e a c t i ons c a t a l yz e d by a phos phor i c a c i d. T he s e t w o a nd ot he r s w i l l be di s c us s e d i n m or e de t a i l i n c ha pt e r 2.

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5 1. 3 A m i d at i on an d I m i d at i o n O ur gr oup w a s t he f i r s t t o r e por t a c hi r a l phos 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 ddi t i on of a m i de s t o pr ot e c t e d i m i ne s w i t h s ul f ona m i de s 1 5 P r e vi ous w or k f or t he a ddi t i on of c a r bon nuc l e ophi l e s t o i m i ne s r e qui r e d e l e c t r on w i t hdr a w i ng gr oups on bot h t he i m i ne ni t r oge n a nd i m i ne c a r b on a t om s T he r e s ul t s f or t hi s V A P O L phos phor i c a c i d c a t a l y z e d a m i da t i on i ndi c a t e d t he r e a c t i on s c ope w a s f ound t o be qui t e ge ne r a l T he r e a c t i on t ol e r a t e d t he pr e s e nc e of e l e c t r on w i t hdr a w i ng a nd dona t i ng s ubs t i t ue nt s on t he i m i ne s ( T a bl e 1 1, e nt r i e s 9 12) a s w e l l a s t w o e xa m pl e s of he t e r oa r om a t i c s ubs t i t ue nt s T he a ddi t i on of a va r i e t y s ul f ona m i de s a l s o r e s ul t e d i n pr oduc t f or m a t i on w i t h hi gh yi e l ds a nd hi gh e na nt i os e l e c t i vi t i e s T hi s r e a c t i on c a n b e pot e nt i a l l y us e d t o s ynt he s i z e r e t r o i nve r s o pe pt i de m i m e t i c s popul a r i z e d by G oodm a n a nd c o w or ke r s 1 6 W i t h t he s uc c e s s of t he i m i ne a m i da t i on, t he m e t hodol ogy w a s e xt e nde d t o a n e na nt i os e l e c t i ve r e a c t i on be t w e e n i m i ne s a nd i m i de s 1 7 T hi s r e a c t i on a l s o t ol e r a t e d e l e c t r on w i t hdr a w i ng a nd dona t i ng s ubs t i t ue nt s on t he i m i ne S e ve r a l s ubs t i t ut e d i m i de s a l s o pr oduc e d e xc e l l e nt r e s ul t s T he V A P O L phos phor i c a c i d w a s s how n t o c a t a l yz e t he i m i ne i m i da t i on r e s ul t i ng 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 ( T a bl e 1 2)

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6 T ab l e 1. 1 A s ym m e t r i c I m i n e A m i d at i o n

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7 T ab l e 1. 2 A s ym m e t r i c I m i d at i on 1. 4 H yd r op h os p h on yl at i on A n e na nt i os e l e c t i ve hydr ophos phonyl a t i on w a s r e por t e d by A ki ya m a a nd c o w or ke r s r e qui r i ng t he a ddi t i on of a phos phi t e t o a n i m i ne w i t h a c hi r a l 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 1 8 T he phos phor i c a c i d h ydr oge n w a s us e d a s a B r ns t e d a c i d t o a c t i va t e t he a l di m i ne T he phos phor yl oxyge n w a s us e d a s a B r ns t e d ba s e t o c oor di na t e w i t h t he hydr oge n of t he pho s phi t e a nd a c t i va t e t h e oxyge n of t he phos phor yl T hi s l e a d t o t he hi gh yi e l ds a nd e na nt i os e l e c t i vi t i e s a s s how n i n T a bl e 1. 3 be l ow

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8 T ab l e 1. 3 A k i yam a s E n an t i os e l e c t i ve H yd r op h os p h on yl at i on 1. 5 F r i e d e l C r af t s R e ac t i on A t om e c onom i c a l r e a c t i ons a r e one goa l t ha t or ga ni c c he m i s t s t r y t o a c hi e ve T he s t r a t e gy s e r ve s t o m i ni m i z e w a s t e a nd u s e up a l l t he a va i l a bl e r e a c t a nt s T he a z a F r i e de l C r a f t s r e a c t i on i s on e e xa m pl e of t hi s t ype of a t o m e c onom i c a l r e a c t i on. 1 9 T he r e a c t i on c a n be u s e d t o s ynt he s i z e a w i de v a r i e t y of ni t r oge n c ont a i ni ng na t ur a l pr oduc t s a nd bi ol ogi c a l l y a c t i ve c om pounds S e ve r a l gr oups ha ve r e por t e d a z a F r i e de l C r a f t s r e a c t i ons us i ng c hi r a l B r ns t e d A c i d c a t a l ys t s T e r a da a nd c o w or ke r s de m ons t r a t e d a n 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 be t w e e n a f ur a n a nd N B oc pr ot e c t e d i m i ne 2 0 A l t hough t he r e w a s a w i de va r i e t y of s ubs t i t ue nt s on t he i m i ne onl y a s i ngl e f ur a n w a s us e d. B e c a us e of t hi s t he r e a c t i on di d not ha ve a w i de s c ope i n t e r m s o f t he nuc l e ophi l e T he r e a c t i on di d t ol e r a t e a va r i e t y of i m i ne s w i t h e l e c t r on dona t i ng a nd

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9 e l e c t r on w i t hdr a w i ng s ubs t i t ue nt s I m i ne s w e r e a l s o us e d t h a t c ont a i ne d he t e r oa r om a t i c s ubs t i t ue nt s T he r e a c t i on l e a d t o pr oduc t s w i t h yi e l ds up t o 95% a nd e na n t i os e l e c t i ve e xc e s s up t o 97% ( T a bl e 1. 4 ) T ab l e 1. 4 T e r ad a s E n an t i os e l e c t i ve F r i e d e l C r af t s R e ac t i on T e r a da a nd c o w or ke r s a l s o r e por t e d 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 a l ke ne s 2 1 A B I N O L de r i ve d phos phor i c a c i d w a s us e d a s t he c a t a l y s t I t w a s s how n t ha t t he s ys t e m a l l ow e d f or a va r i e t y o f i ndol e s w i t h e l e c t r on w i t hdr a w i ng a nd dona t i ng s ubs t i t ue nt s T he y r e por t e d 11 e xa m pl e s w i t h y i e l ds up t o 98% a nd e na nt i os e l e c t i ve e xc e s s up t o 96% ( T a bl e 1. 5 ) T ab l e 1. 5 T e r ad a s F r i e d e l C r a f t s r e ac t i on of A l k e n e s

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10 I n 2007 Y ou a nd c o w or ke r s r e por t e d t he a ddi t i o n of i ndol e t o N t os yl pr ot e c t e d i m i ne s 2 2 T he r e a c t i on r e qui r e d f i ve e qui va l e nt s of i ndol e a nd l ow t e m pe r a t ur e s T he r e a c t i on t ol e r a t e d e l e c t r on dona t i ng gr oups on t he i m i ne but a dr op i n e na nt i os e l e c t i vi t y w a s obs e r ve d w he n e l e c t r on w i t hdr a w i ng s ubs t i t u e nt s w e r e pr e s e nt ( T a bl e 1 6) T ab l e 1. 6 Y ou s F r i e d e l C r af t s R e ac t i on O ur gr oup de ve l ope d a n 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 be t w e e n s e ve r a l a r yl s ubs t i t ut e d N be n z oyl pr ot e c t e d i m i ne s a nd s ubs t i t ut e d i ndol e s c a t a l yz e d by a c hi r a l B I N O L de r i ve d phos phor i c a c i d. 2 3 T he r e a c t i on r e qui r e d t he us e of onl y 5 m ol % c a t a l ys t a nd 2 e qui va l e nt s of i m i ne T he r e a c t i on t ol e r a t e d 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 bot h t he i m i n e a nd on t he i ndol e T he onl y e xa m pl e t ha t di d not r e s ul t i n a 90% or gr e a t e r e na nt i os e l e c t i vi t y w a s t he r e a c t i on w i t h t he 2 M e i ndol e T hi s i s be l i e ve d t o b e be c a u s e of s t e r i c hi ndr a nc e of t he i ndol e T hi s F r i e de l C r a f t s r e a c t i on r e s ul t e d i n yi e l ds up t o 99% a nd e n a nt i os e l e c t i ve e xc e s s up t o 96%

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11 T ab l e 1. 7 A n t i l l a s 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 o n : V ar i at i on of I m i n e T ab l e 1. 8 A n t i l l a s 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 o n : V ar i at i on of I n d ol e

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12 A nt i l l a a nd c o w or ke r s a l s o e xt e nde d t hi s m e t hod ol ogy t o i nc l ude t he a ddi t i on of pyr r ol e s t o i m i ne s ( F i gur e 1. 5) w i t h y i e l ds up 97% a nd e na nt i os e l e c t i ve e xc e s s up t o 99% 2 4 T hi s r e a c t i on a l s o t ol e r a t e d a va r i e t y o f s ub s t i t ue nt s on t he i m i ne a nd pyr r o l e F i gu r e 1. 5 A n t i l l a s F r i e d e l C r af t s R e ac t i on of P yr r ol e s t o I m i n e s T he a bove r e a c t i ons m e nt i one d w e r e j us t a f e w F r i e de l C r a f t s r e a c t i ons s e ve r a l ot he r r e s e a r c h gr oups ha ve r e por t e d e na nt i 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 ons us i ng c hi r a l phos phor i c a c i d c a t a l ys t s a s w e l l 2 5 1. 6 R e d u c t i o n C h e m i s t r y C ur r e nt m e t hodol ogy f or t he a s ym m e t r i c r e duc t i o n of i m i ne s i nvol ve s t r a ns i t i on m e t a l c a t a l yz e d t r a ns f e r hydr oge na t i on, hi gh pr e s s ur e hydr oge na t i ons or hydr os i l yl a t i ons 2 6 S e ve r a l r e a c t i ons ha ve b e e n r e por t e d t ha t ut i l i z e nonm e t a l l i c c a t a l ys t s s uc h a s c hi r a l t hi our e a s di ol s a nd phos pha t e s f or e na nt i os e l e c t i ve or ga ni c t r a ns f or m a t i ons 2 7 R e c e nt l y s e ve r a l gr oups ha v e b e e n i nve s t i ga t i ng c hi r a l B r ns t e d a c i ds a s a n a l t e r na t i ve t o pr e vi ous l y r e por t e d m e t a l c a t a l ys i s I n 2005 R ue pi ng a nd c o w or ke r s i nve s t i ga t e d a B r ns t e d a c i d c a t a l yz e d t r a ns f e r hydr oge na t i on. 2 8 T hi s r e a c t i on ut i l i z e d a c hi r a l B I N O L phos phor i c a c i d ba s e d 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 of i m i ne s T he hydr oge n s our c e us e d f or t he r e duc t i on w a s H a nt z s c h di hydr opyr i di ne A s s how n i n T a bl e 1. 9, s e ve r a l a r om a t i c ke t i m i ne s w e r e r e duc e d r e s ul t i ng i n hi gh yi e l ds a nd

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13 e na nt i os e l e c t i vi t i e s T he m e c ha ni s m f or t he r e a c t i on w a s a l s o pr opos e d a s s how n i n F i gur e 1. 6. T he r e a c t i on pr oc e e ds vi a pr ot ona t i on of t he i m i ne w i t h t he pho s phor i c a c i d f ol l ow e d by hyd r oge n t r a ns f e r f r o m H a nt z s c h e s t e r T ab l e 1. 9 R u e p i n g s O r gan oc at al y t i c R e d u c t i on of I m i n e s F i gu r e 1. 6 R u e p i n g s P r op os e d M e c h an i s t i c C yc l e f or R e d u c t i on of I m i n e s L i s t a nd c o w or ke r s i nde pe nde nt l y r e por t e d a r e a c t i on pa r a l l e l t o t ha t of R ue pi ng s a s ym m e t r i c c a t a l yt i c hydr oge na t i on of ke t i m i ne s 2 9 A c hi r a l B I N O L

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14 phos phor i c a c i d ba s e d c a t a l ys t w a s us e d a s w e l l I m p r ove d r e s ul t s w e r e r e por t e d w i t h H a nt z s c h e s t e r s e r vi ng a s t he hydr i de s our c e f or t he e na nt i os e l e c t i ve c a t a l yt i c hydr oge na t i on of ke t i m i ne s w hi c h w a s s i m i l a r t o R ue pi ng s hydr oge na t i on. S e ve r a l i m i ne s w i t 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 w e r e r e a c t e d w i t h H a nt z s c h s e s t e r a nd t he phos phor i c a c i d, w hi c h r e s ul t e d i n yi e l ds up t o 98 % a nd e na nt i os e l e c t i ve e xc e s s up t o 88 % T ab l e 1. 10 L i s t s E n an t i os e l e c t i ve H yd r oge n at i o n of K e t i m i n e s I n 2006 M a c M i l l a n a nd c o w or ke r s r e por t e d t he f i r s t or ga noc a t a l yt i c r e duc t i ve a m i na t i on t ha t i nc l ude s a c oupl i ng be t w e e n ke t one s a nd a m i ne s 3 0 T he r e a c t i on pr oc e e ds vi a hydr oge n bodi ng be t w e e n a c hi r a l phos phor i c a c i d a nd t he s ubs t r a t e s a l ong w i t h H a nt z s c h s e s t e r a s a s our c e of hydr i de f or t he r e duc t i on of a n i m i ni um s pe c i e s pr oduc e d i n s i t u. I t w a s s how n t ha t a r om a t i c a nd a l kyl ke t one s w or ke d w e l l f or t he c oupl i ng a nd r e duc t i on w i t h a r om a t i c a m i ne s I t w a s a l s o s ho w n t ha t a r om a t i c ke t one s r e a c t e d w i t h he t e r oc yc l i c a m i ne s A l l of t he s e va r i a nt s f or t he r e a c t i on r e s ul t e d i n pr oduc t s w i t h hi gh y i e l d a nd e na nt i os e l e c t i vi t y a s s how n be l ow i n F i g ur e 1. 7

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15 F i gu r e 1. 7 M ac M i l l an s O r gan oc a t al yt i c R e d u c t i ve A m i n at i o n I n 2006 L i s t a nd c o w or ke r s publ i s he d a not he r r e duc t i ve a m i na t i on. T hi s r e por t de m ons t r a t e d a c oupl i ng r e a c t i on be t w e e n a n a l de hyde a nd a r om a t i c a m i ne w hi c h w a s r e duc e d vi a dyna m i c ki ne t i c r e s ol ut i on. 3 1 T he r e a c t i on pr oc e e de d t hr ough a n i m i m i um i nt e r m e di a t e w hi c h w a s r e duc e d w i t h a hydr i de pr oduc e d f r om H a nt z s c h s e s t e r a nd a s ubs t i t ut e d B I N O L phos phor i c a c i d c a t a l y s t w hi c h i s s how n i n F i gur e 1. 8 a s t h e pr opos e d m e c ha ni s m S e v e nt e e n e x a m pl e s w e r e r e por t e d a s s how n i n T a bl e 1. 11 be l o w w i t h yi e l ds up t o 96% a nd e e up t o 98%

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16 T ab l e 1. 11 L i s t s R e d u c t i ve A m i n at i on vi a D yn a m i c K i n e t i c R e s ol u t i on F i gu r e 1. 8 R e d u c t i ve A m i n a t i on P r op os e d M e c h an i s m I n 2007 our g r oup r e por t e d a n e na nt i os e l e c t i ve r e duc t i on of i m i no e s t e r s 3 2 T hi s w a s t he f i r s t r e por t of pho s phor i c a c i d c a t a l yz e d r e duc t i on w hi c h pr oduc e d a c yc l i c a m i no e s t e r s N a t ur a l a nd unna t ur a l a m i no a c i ds a r e hi ghl y i m por t a nt c om pound s i n pha r m a c e ut i c a l a nd bi ol ogi c a l i ndus t r i e s T hi s r e duc t i on w a s a not he r e xa m pl e of

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17 V A P O L phos phor i c a c i d c a t a l ys t r e s ul t i ng i n t he hi ghe s t yi e l ds a nd e na nt i os e l e c t i vi t y f or t he r e duc t i on of i m i no e s t e r s S e ve r a l ot he r gr o ups ha ve a l s o r e por t e d e na nt i os e l e c t i ve c a t a l yt i c r e duc t i ons of i m i ne s a s w e l l a s pyr i di ne s a nd ot he r he t e r oc yc l i c c om pounds 3 3 T ab l e 1. 12 A n t i l l a s R e d u c t i on of I m i n o E s t e r s 1. 7 C yc l oad d i t i on R e ac t i on s T he s ynt he s i s of he t e r oc yc l i c c om pounds i s of gr e a t i nt e r e s t t o c h e m i s t s N um e r ous e xa m pl e s of he t e r oc yc l i c na t ur a l pr o duc t s w i t h va s t bi ol ogi c a l i m po r t a nc e ha ve be e n i s ol a t e d. 3 4 M os t of t he s e na t ur a l pr o duc t s a r e c hi r a l 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 t o s ynt he s i s c hi r a l he t e r oc yc l e s i s of vi t a l i m por t a nc e C yc l oa ddi t i on r e a c t i ons a r e one r ou t e t o t he s ynt he s i s of he t e r oc yc l i c c om pounds 3 5 I n 2006 R ue pi ng a nd G ong i nde pe nde nt l y r e por t e d a B r ns t e d a c i d c a t a l yz e d a z a D i e l s A l de r r e a c t i on w i t h c yc l ohe xe none a nd a l di m i ne s 3 6 3 7 T he a z a D i e l s A l de r r e a c t i on i s a gr e a t m e t hod f or t he pr e pa r a t i on of pi pe r i di ne de r i va t i ve s A s s how n i n T a bl e 1. 13 R ue pi ng a nd c o w or ke r s pr e pa r e d i s oqui nuc l i di ne s us i ng a B I N O L de r i ve d c hi r a l B r ns t e d a c i d c a t a l ys t a l ong w i t h a c e t i c a c i d t o a s s i s t t he c a t a l yt i c c yc l e

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18 I s oqui nuc l i di ne s a r e c om pounds t ha t a r e f ound i n na t ur a l l y oc c ur r i ng bi ol o gi c a l l y i m por t a nt a l ka l oi ds 3 6 T he pr opos e d c a t a l yt i c c yc l e a s s how n i n F i gur e 1 9 be l ow i nvol ve s t he a c e t i c a c i d he l pi ng t o e qui l i b r a t e t he c yc l ohe xe none t o t he e nol f o r m T he e nol t h e n r e a c t s w i t h t he i m i ni um i on t o f or m t he D i e l s A l de r pr oduc t A s s how n i n T a bl e 1. 13, s e ve r a l s ubs t i t ut e d i m i ne s w e r e r e a c t e d w i t h c yc l ohe xe none r e s ul t i ng i n m ode r a t e yi e l ds a nd e na nt i os e l e c t i vi t y. T ab l e 1. 13 R u e p i n g s A s ym m e t r i c S yn t h e s i s of I s oq u i n u c l i d i n e s w i t h T w o B r n s t e d A c i d s F i gu r e 1. 9 R u e p i n g s M e c h an i s m f or S yn t h e s i s of I s oq u i n u c l i d i n e s

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19 G ong a nd c o w or ke r s a z a D i e l s A l de r r e a c t i on a l s o us e d a c hi r a l B I N O L de r i ve d B r ns t e d a c i d t o c a t a l yz e t he r e a c t i on be t w e e n c yc l ohe xe none a nd a l di m i ne s 3 7 T he y r e por t e d t e n e xa m pl e s r e s ul t i ng i n m ode r a t e yi e l ds a nd e na nt i os e l e c t i vi t y. I t w a s a l s o s how n t ha t t he m a j or pr oduc t w a s i n t he e ndo c onf or m a t i on. T ab l e 1. 14 G on g s D i r e c t A z a H e t e r o D i e l s A l d e r R e ac t i on I n 2007 T e r a da a nd c o w or ke r s de ve l o pe d a t a nde m a z a e ne r e a c t i on t ha t pr oduc e d c hi r a l pi pe r i di ne s w hi c h ha ve s e ve r a l c hi r a l c e nt e r s 3 8 T he r e a c t i on w a s be t w e e n N a c yl i m i ne s a nd s ub s t i t ut e d e ne c a r ba m a t e s A c hi r a l B I N O L de r i ve d phos phor i c a c i d w a s u s e d a s t h e c a t a l ys t I t w a s o bs e r ve d t h a t t he m a j or pr oduc t w a s t he t r ans i s om e r a nd onl y t w o di a s t e r e om e r s w e r e o bt a i ne d. I t w a s s how n t ha t a r om a t i c he t e r oa r om a t i c a l i pha t i c a nd ot he r s ubs t i t ut e d a l di m i ne s a l l ga ve good t o e x c e l l e nt yi e l d s a nd e xc e l l e nt e na nt i os e l e c t i ve e xc e s s a s how n i n T a bl e 1. 15 be l ow

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20 T ab l e 1. 15 T e r ad a s T an d e m A z a E n e R e ac t i o n R ue pi ng a nd c o w or ke r s r e por t e d t he f i r s t e na nt i os e l e c t i ve or ga noc a t a l yt i c e l e c t r oc yc l i c r e a c t i on. 3 9 T he y i nve s t i ga t e d a n a s ym m e t r i c N a z a r ov c yc l i z a t i on. T he N a z a r ov c yc l i z a t i on i s a ve r s a t i l e m e t hod t o pr e pa r e f i ve m e m be r e d r i ngs w hi c h a r e ke y s t r uc t ur a l c om pone nt s of num e r ous na t ur a l p r odu c t s I t w a s s how n t ha t a c hi r a l B I N O L de r i ve d B r ns t e d a c i d c a t a l yz e d t he c yc l i z a t i on. S e ve r a l di f f e r e nt s ubs t i t ut e d di e none s w e r e s how n t o c yc l i z e i n t he pr e s e nc e of a phos p hor i c a c i d c a t a l ys t A s um m a r y of t he r e a c t i on i s s how n i n T a bl e 1 16. E l e ve n e xa m pl e s w e r e r e por t e d w i t h hi gh yi e l ds a nd m ode r a t e e na nt i os e l e c t i vi t i e s

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21 T ab l e 1. 16 R u e p i n g s A s ym m e t r i c N az ar ov C yc l i z at i on 1. 8 B r n s t e d A c i d s u s e d as C ou n t e r i on s M os t of t he pr e vi ous w or k w i t h B r ns t e d a c i d c a t a l ys i s ha s i nvol ve d i on pa i r f or m a t i on o r hydr oge n bondi ng be t w e e n t he c hi r a l phos phor i c a c i d a nd t he nuc l e ophi l e A ne w e m e r gi ng a r e a o f B r ns t e d a c i d c a t a l ys i s i nvol ve s c l a s s i c m e t a l c a t a l ys i s i n t he pr e s e nc e of c hi r a l c ount e r i ons T hi s m e t hodol ogy i nvol ve s a B r ns t e d a c i d a c t i va t i ng t he e l e c t r ophi l e a nd a m e t a l s a l t a c t i va t i ng t he nuc l e ophi l e R ue pi ng a nd c o w or ke r s pr opos e d a c a t a l yt i c m e c ha ni s m ( F i gur e 1. 10) f o r t he e na nt i os e l e c t i ve a l kynyl a t i on of i m i no e s t e r s a s s how n b e l ow 4 0 I n c yc l e A t he i m i ne a nd phos phor i c a c i d f or m a n i on pa i r I n c yc l e B t he a l kyne i s a c t i va t e d by a m e t a l s a l t T he n i on pa i r a nd a c t i va t e d a l kyne t he n pr oc e e d t o t he f i na l e na nt i os e l e c t i ve pr od uc t T he r e a c t i ons t ha t ha ve be e n de v e l ope d us i ng t hi s m e t hodol ogy w oul d ot he r w i s e not oc c ur w i t hout t he c om bi na t i on o f t he phos pha t e c ount e r i on a nd m e t a l c a t a l ys t

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22 F i gu r e 1. 10 R u e p i n g s B r n s t e d A c i d an d M e t a l C at al yz e d A l k y n yl at i on of I m i n o E s t e r s R ue pi ng a nd c o w or ke r s de ve l ope d a n e n a nt i os e l e c t i ve a l kynyl a t i on of i m i no e s t e r s 4 0 T he r e a c t i on i nvol ve d t he a ddi t i on of s e ve r a l a l kyne s t o p m e t hoxyphe nyl pr ot e c t e d i m i no e s t e r s us i ng a c hi r a l B r ns t e d a c i d i n c om bi na t i on w i t h s i l ve r a c e t a t e T he m i l d r e a c t i on c ondi t i ons a nd no ne e d t o pr e f or m t he c a t a l ys t a r e a ppe a l i ng. T hi s i s a l s o t he f i r s t t i m e a n or ga nom e t a l l i c c om pound ha d be e n a dde d t o a n a l di m i ne w i t h a B I N O L phos pha t e R ue pi ng r e por t e d e i ght e xa m pl e s w i t h yi e l ds up t o 93% a nd e na n t i os e l e c t i vi t y up t o 92%

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23 T ab l e 1. 17 R u e p i n g s A l k yn y l at i on of I m i n o E s t e r s A not he r e xa m pl e of c ount e r i on m e di a t e d r e a c t i on i s t he hydr oa m i na t i on r e por t e d by T os t e a nd c o w or ke r s i n 2007 4 1 T he y i nve s t i ga t e d r e a c t i ons t ha t ut i l i z e d a phos pha t e c ount e r i on de r i ve d f r om B I N O L w i t h a gol d c om pl e x. I t w a s s how n t ha t t he pr ot ona t e d phos pha t e t he phos phor i c a c i d, a l one di d not c a t a l yz e t he r e a c t i on a nd ne i t he r di d t he s i l ve r phos pha t e I t w a s a l s o s how n t ha t t he P h( C H 3 ) 2 P A uC l a l one di d not c a t a l y z e t he r e a c t i on, i t w a s a c om bi na t i on of a l l t hr e e of t he a bove r e a ge nt s T he pr oduc t s of t he hydr oa m i na t i on r e s ul t e d i n hi gh yi e l ds a nd e na nt i os e l e c t i vi t y, w hi c h i s s how n i n F i gur e 1. 11. T he s c ope of t he r e a c t i on w a s e xpa nde d t o a hydr oa l koxyl a t i on r e a c t i on, w i t h e i ght e xa m pl e s r e s ul t i ng i n yi e l ds up t o 96% a nd e e up t o 97% a s s how n i n F i gur e 1. 12

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24 F i gu r e 1. 11 T os t e s C ou n t e r i on M e d i a t e d E n an t i os e l e c t i ve H yd r oam i n at i on F i gu r e 1. 12 T os t e s C ou n t e r i on M e d i a t e d H yd r oal k oxyl at i on A n a s ym m e t r i c a l l yl a t i on of a l de hyde s w a s r e p or t e d by L i s t a nd c o w or ke r s i n 2007. 4 2 T hi s w a s a not he r e x a m pl e of a c ount e r i on i n m e t a l c a t a l ys i s I t w a s s how n t h a t c hi r a l phos phor i c a c i ds i nduc e d c hi r a l i t y i n a pa l l a di um c a t a l yz e d a l l yl a t i on. T hi s i s t he f i r s t e xa m pl e of a n a s ym m e t r i c c a t a l yt i c a l l yl a t i on of br a nc he d a l de yhde s T w e l ve e xa m pl e s w e r e r e por t e d w i t h yi e l ds up t o 89% a nd e e up t o 97 %

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25 F i gu r e 1. 13 L i s t s C at al y t i c A s ym m e t r i c A l l yl at i on o f A l d e h yd e s 1. 9 C on c l u s i on P hos phor i c a c i d c a t a l ys i s ha s be e n s how n t o be a ve r s a t i l e t ype of c a t a l ys i s f or a l a r ge num be r of o r ga ni c t r a ns f or m a t i ons T he s e or ga noc a t a l ys t s ha ve be e n de v e l ope d a s a n a l t e r na t i ve t o m e t a l c a t a l ys i s 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 i s hi ghl y i m por t a nt t o t he pha r m a c e ut i c a l a nd bi ol ogi c a l i ndus t r i e 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 i m pr e s s i ve c a t a l ys t s f or t he s ynt he s i s of a s ym m e t r i c pr oduc t s w i t h hi gh yi e l ds a nd e na nt i os e l e c t i vi t y. M os t of t he phos phor i c a c i d c a t a l ys i s m e t hodol ogy i nvol ve s t he t r a ns f o r m a t i ons of i m i ne s but r e c e nt l y t he m e t hodol ogy i s br a nc hi ng out t o i nc l ude ot he r t y pe s of c om pounds a s w e l l T he a bove e xa m pl e s a r e onl y a s m a l l a m ount of pho s phor i c a c i d c a t a l ys i s t ha t ha ve a l r e a dy be e n r e por t e d. T he r e i s s t i l l m uc h m or e i nve s t i ga t i on t o be done t o r e a l i z e t he bounda r i e s of a s ym m e t r i c phos phor i c a c i d c a t a l ys i s

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26 C H A P T E R 2 P A R T A : E N A N T I O S E L E C T I V E M A N N I C H R E A C T I O N 2 1 I n t r od u c t i on C a r bon c a r bon bond f or m i ng r e a c t i ons a r e hi gh l y us e f ul r e a c t i ons i n or ga ni c s ynt he s i s T he M a nni c h r e a c t i on, w hi c h i nvol ve s t he r e a c t i on of a n e nol w i t h a n i m i ni um ha s be e n hi ghl y i nve s t i ga t e d f or t he pa s t s e ve r a l ye a r s 4 3 I t i s ve r y us e f ul f o r t he pr e pa r a t i on of a m i no a c i d s a nd l a c t a m s w hi c h a r e bi ol ogi c a l l y i m por t a nt c om pounds 4 4 S e ve r a l r e s e a r c he r s ha ve e m p l oye d m e t a l ba s e d c a t a l ys t s f or t he e na nt i os e l e c t i ve c a t a l yt i c ve r s i on of t he M a nni c h r e a c t i on. R e c e nt l y, s e ve r a l gr oups ha ve be e n de ve l opi ng t he r e a c t i on w i t h or ga noc a t a l ys t s I ni t i a l l y, s t oi c he om e t r i c a m ount s of c hi r a l a c i ds w e r e u s e d, a nd t he n de ve l ope d f ur t he r w i t h c a t a l yt i c a m ount s of c hi r a l a c i d s O r ga noc a t a l ys t s s uc h a s pr ol i ne a nd t hi our e a ha ve be e n s how n t o be e xc e l l e nt c hi r a l c a t a l ys t s f or a s ym m e t r i c M a nni c h r e a c t i ons 8 9 C hi r a l phos phor i c a c i ds ha ve a l s o be e n s how n t o c a t a l yz e s e ve r a l a s ym m e t r i c M a nni c h r e a c t i ons 1 1 T w o m a j or va r i a t i ons of t he M a nni c h r e a c t i on ha ve be e n de ve l ope d. T he di r e c t va r i a nt i nvol ve s unm odi f i e d ke t one donor s a nd a m i ne s 8 T he i m i ni um i on i s f or m e d i n s i t u i n t he s e c a s e s T he i ndi r e c t va r i a nt i nvol v e s pr e f or m e d e nol a t e de r i va t i ve s a nd pr e f or m e d i m i ne s U nt i l r e c e nt l y, m os t of t he M a nni c h r e a c t i ons r e por t e d w e r e of t he i ndi r e c t t ype I n ge ne r a l i t w a s e a s i e r t o pr e f or m t he i m i ne s a nd t he n r e a c t t he m w i t h a n e nol a t e T he di r e c t M a nni c h r e a c t i ons s om e t i m e s l e a d t o unw a nt e d s i de pr oduc t s

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27 F i gu r e 2. 1 D i r e c t an d I n d i r e c t M an n i c h R e ac t i o n s 2. 2 E n an t i os e l e c t i ve O r gan oc at al yt i c M an n i c h R e ac t i on M e t h od ol ogy T he f i r s t t r ul y c a t a l yt i c e na nt i os e l e c t i ve M a nni c h t ype r e a c t i on w i t h a l d i m i ne s a nd s i l yl e nol a t e s w a s r e por t e d i n 1997 by K oba ya s hi a nd c o w or ke r s 4 5 T he y e m pl oye d a c a t a l yt i c a m ount of a c hi r a l z i r c oni um c om pl e x w hi c h w a s m a de i n s i t u. T he i r m e t hod w a s ba s e d on c hi r a l L e w i s a c i d c a t a l ys i s I t w a s s how n t ha t a r om a t i c a l di m i ne s a s w e l l a s he t e r oc yc l i c a nd a l i pha t i c a l di m i ne s w or ke d w e l l f or t he r e a c t i on. T he pr oduc t s obt a i ne d r e s ul t e d i n good t o hi gh yi e l d s a nd e n a n t i os e l e c t i ve e xc e s s I t w a s a l s o s how n t ha t t he M a nni c h r e a c t i on pr oduc t s w e r e e a s i l y c onve r t e d t o A m i no e s t e r s by m e t hyl a t i on of t he phe nol i c O H

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28 T ab l e 2. 1 K o b ayas h i s E n an t i os e l e c t i ve M an n i c h T yp e R e ac t i o n T he f i r s t e na nt i os e l e c t i ve or ga noc a t a l yt i c M a nni c h r e a c t i on w a s r e por t e d by L i s t a nd c o w or ke r s i n 2000. 4 6 I t w a s s how n t ha t ( L ) pr ol i ne w a s a n e xc e l l e n t c a t a l ys t f or a t hr e e c om pone nt di r e c t M a nni c h r e a c t i on. T he r e a c t i on w a s be t w e e n a ke t one a l de hyd e a nd p a ni s i di ne S e ve r a l a l de hyde s w e r e t e s t e d w i t h va r i ous s ubs t i t ue nt s r e s ul t i ng i n m ode r a t e yi e l ds a nd good t o e xc e l l e nt e na nt i os e l e c t i vi t y. T he a r o m a t i c a nd s t e r i c a l l y hi nde r e d a l de hyde s ( T a bl e 2. 2, e nt r i e s 1 3) r e s ul t e d i n hi ghe r e na nt i os e l e c t i vi t i e s t h a n t he ot he r a l de hyde s t e s t e d. T he obs e r ve d l ow yi e l ds w e r e due t o t he f o r m a t i on o f a l dol a nd c onde ns a t i on s i de pr oduc t s

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29 T ab l e 2. 2 L i s t s P r o l i n e C a t al yz e d D i r e c t M an n i c h R e ac t i on J a c obs e n a nd c o w or ke r s r e por t e d a n e na nt i os e l e c t i ve s ynt he s i s of a r yl a m i no a c i ds 4 7 T hi s M a nni c h r e a c t i on w a s be t w e e n a n e nol a t e e qui va l e nt a nd a r om a t i c N boc pr ot e c t e d i m i ne s A t hi our e a c a t a l ys t pr ovi de d e xc e l l e nt r e s ul t s f or t he r e a c t i on. L ow t e m pe r a t ur e s w e r e r e qui r e d f or opt i m um e na nt i os e l e c t i vi t y a nd onl y 5 m ol % of t he c hi r a l c a t a l ys t T he r e a c t i on t ol e r a t e d e l e c t r on w i t hdr a w i ng a nd dona t i ng s ubs t i t ue nt s i n t he or t ho m e t a a nd pa r a pos i t i on on t he a r om a t i c r i ng of t he i m i ne I t w a s a l s o s how n t ha t he t e r oa r om a t i c s ubs t i t ue nt s a l s o r e s ul t e d i n e x c e l l e nt e na nt i os e l e c t i vi t y a nd yi e l d s T he r e a c t i on w a s ve r y ge ne r a l w i t h r e s pe c t t o t he i m i n e s I t w a s de t e r m i ne d t ha t t he a m i no a c i d pr oduc t s w e r e e a s i l y de pr ot e c t e d w i t h m i l d c ondi t i ons F our t e e n e xa m pl e s w e r e r e por t e d w i t 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

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30 T ab l e 2. 3 Jac ob s e n s T h i ou r e a c at al yz e d M an n i c h R e ac t i on A di r e c t or ga noc a t a l yt i c M a nni c h r e a c t i on w a s de ve l ope d by B a r ba s a nd c o w or ke r s i n 2003. 4 8 T he r e a c t i on w a s be t w e e n a m i no e t hyl gl yoxyl a t e a nd s e ve r a l di f f e r e nt a l i pha t i c a l de hyde s c a t a l yz e d by L pr ol i ne A l l of t he e na nt i os e l e c t i vi t i e s w e r e e xc e l l e nt T he di a s t e r e o s e l e c t i vi t i e s w e r e ob s e r ve d t o be d e pe nde nt on t he s t e r i c s a n d c ha i n l e ngt h of t he a l de hyde s ub s t i t ue nt s T he l onge r t he c ha i n l e ngt h, t he hi ghe r t h e di a s t e r e os e l e c t i vi t y. T hi s r e a c t i on i s s how n be l ow i n T a bl e 2 4. T ab l e 2. 4 B ar b as s O r gan oc at al yt i c D i r e c t M an n i c h R e ac t i on w i t h A l i p h a t i c A l d e h y d e s

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31 B a r ba s a nd c o w or ke r s e xt e nde d t he i r m e t ho dol ogy t o a n or ga noc a t a l yt i c M a nni c h r e a c t i on t ha t ut i l i z e d a r om a t i c i m i ne s T he r e a c t i on r e qui r e d 30 m ol % L P r ol i ne a nd m ode r a t e l y l ow t e m pe r a t u r e s S e ve n di f f e r e nt a r om a t i c i m i ne s w e r e t e s t e d a nd a l l r e s ul t e d 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 y. A s s e e n w i t h t he a m i no gl yoxyl a t e t he di a s t e r e os e l e c t i vi t y f or t hi s r e a c t i on w a s a l s o de pe nde nt on t he c ha i n l e ngt h of t he a l i pha t i c a l de hyde A ga i n, t he gr e a t e r t he c ha i n l e ngt h, t he hi ghe r t he di a s t e r e os e l e c t i vi t y. F or e xa m pl e a n a l de hyde w i t h a pe nt a ne c ha i n r e s ul t e d i n a dr o f > 19: 1. T he a l de hyde s w i t h onl y m e t hyl s ubs t i t u e nt s r e s ul t e d i n a dr f r om onl y 3: 1 t o 10: 1. T ab l e 2. 5 B ar b as s O r gan oc at al yt i c D i r e c t M an n i c h R e ac t i on w i t h A r o m at i c A l d e h yd e s I n 2004 A ki ya m a a nd c o w or ke r s r e po r t e d t he f i r s t e xa m pl e of a phos phor i c a c i d c a t a l y z e d r e a c t i on. 1 3 I t w a s r e por t e d t ha t a c hi r a l B I N O L de r i ve d phos phor i c a c i d c a t a l yz e d a n a s ym m e t r i c M a nni c h t ype r e a c t i on. T he r e a c t i on w a s be t w e e n a s i l yl e nol a t e a nd or t ho hydr oxy i m i ne S e ve r a l B I N O L de r i ve d p hos phor i c a c i ds w e r e s c r e e ne d. I t w a s de t e r m i ne d t ha t t he 4 ni t r ophe nyl s ubs t i t ue nt i n t he 3, 3 pos i t i on r e s ul t e d i n t he hi ghe s t e na nt i os e l e c t i vi t y. T he r e a c t i on r e qui r e d onl y 10 m ol % phos phor i c a c i d c a t a l ys t a nd l ow

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32 t e m pe r a t ur e s t o pr oduc e t he opt i m um r e s ul t s T h e r e a c t i on t ol e r a t e d a va r i e t y o f gr oups on t he a r om a t i c r i ng a t t a c he d t o t he i m i ne c a r bon a nd pr ovi de d yi e l ds up t o 100% a nd e na nt i os e l e c t i vi t y up t o 96% a s s how n i n T a bl e 2. 6 be l ow T ab l e 2. 6 A k i yam a s A s ym m e t r i c M an n i c h R e ac t i on T e r a da a nd c o w or ke r s a l s o r e por t e d 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. A c e t yl a c e t one w a s a dde d t o N boc pr ot e c t e d i m i ne s 1 4 T he s c ope of t he i m i ne i s s how n i n T a bl e 2. 2 be l ow S i x e xa m pl e s w e r e r e por t e d w i t h a v a r i e t y of s ub s 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 T he r e a c t i on r e q ui r e d 2 m ol % o f a B I N O L de r i ve d phos phor i c a c i d a nd i t w a s pe r f or m e d a t r oom t e m pe r a t ur e T he r e a c t i on r e s ul t e d i n yi e l ds up t o 99% a nd e na nt i os e l e c t i ve e x c e s s up t o 98%

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33 T ab l e 2. 7 T e r ad a s A s ym m e t r i c M an n i c h R e ac t i on G ong a nd c o w or ke r s de ve l ope d a di r e c t e n a nt i os e l e c t i ve M a nni c h r e a c t i on i n 2007. 4 9 I t w a s s how n t ha t a c hi r a l B I N O L de r i ve d phos phor i c a c i d c a t a l y s t c oul d be u s e d t o c a t a l yz e t he r e a c t i on be t w e e n s i m pl e ke t one s a nd i m i ne s T he i m i ne s w e r e f or m e d i n s i t u f r om a n a r om a t i c a m i ne a nd a r om a t i c a l de hyd e T he m a j or pr oduc t f r om t he r e a c t i on w a s t he ant i s e l e c t i ve c onf or m a t i on. O t he r t ha n t he r e por t by B a r ba s a nd c o w or ke r s of a M a n ni c h r e a c t i on of a s i m pl e k e t one a nd i m i no e s t e r t hi s w a s t he f i r s t r e por t of a n ant i s e l e c t i ve di r e c t e na nt i o s e l e c t i ve M a nni c h r e a c t i on. 5 0 A s s how n be l ow s e ve r a l c yc l ohe xa none de r i va t i ve s a nd a va r i e t y of a r om a t i c a l de hyde s c ont a i ni ng bot h e l e c t r on do na t i ng a nd w i t hdr a w i ng s ubs t i t ue nt s r e s ul t e d i n good di a s t e r e o s e l e c t i vi t y a nd hi gh yi e l ds a nd e na nt i o s e l e c t i ve e x c e s s T he t e t r a hydr ot hi opyr a n 4 one ( e nt r y 6 8) w a s l e s s r e a c t i ve t ha n t he ot he r c yc l ohe xa none de r i va t i ve s a nd r e qui r e d t he us e of 2 m ol % c a t a l ys t P A 17 i n s t e a d of t he 0. 5 m ol % P A 13 u s e d f or a l l t he ot he r r e a c t i on s I t w a s a l s o not e d t ha t t he d i a s t e r e os e l e c t i vi t y w a s hi ghl y de pe nde nt on bot h t he a l de hyde a nd ke t one

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34 T ab l e 2. 8 G o n g s D i r e c t A s ym m e t r i c M an n i c h R e ac t i on R ue pi ng a nd c o w or k e r s de ve l ope d t he f i r s t B r ns t e d a c i d a s s i s t e d a s ym m e t r i c B r ns t e d a c i d c a t a l yz e d di r e c t M a nni c h r e a c t i o n. 5 1 A m e c ha ni s m w a s pr opos e d a s s how n i n F i gur e 2 2. A n a c hi r a l B r ns t e d a c i d w a s us e d t o a c t i va t e t he ke t one by c onve r t i ng i t t o t he e nol f or m T hi s e nol i s t he n a b l e t o r e a c t w i t h t he i m i ni um i on, w hi c h w a s f or m e d f r om t he c hi r a l B r ns t e d a c i d, w hi c h w a s de r i ve d f r om B I N O L a nd t he i m i ne T he r e a c t i on w a s ve r y ge ne r a l a nd t ol e r a t e d a r om a t i c i m i ne s w i t h e l e c t r on dona t i ng a nd w i t hdr a w i ng s ub s t i t ue nt s a nd he t e r o a r om a t i c i m i ne s a s w e l l T he r e a c t i on pr oduc e d a m i no ke t one s w i t h m ode r a t e yi e l ds a nd good e na nt i os e l e c t i vi t i e s a s s ho w n i n T a bl e 2 9. F i gu r e 2. 2 P r op os e d M e c h an i s t i c C yc l e f or t h e B r n s t e d A c i d A s s i s t e d A s ym m e t r i c B r n s t e d A c i d C at al yz e d M an n i c h R e ac t i on

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35 T ab l e 2. 9 R u e p i n g s B r n s t e d A c i d A s s i s t e d E n an t i os e l e c t i ve B r n s t e d A c i d C at al yz e d M an n i c h R e ac t i on I n 2008 S c hne i de r a nd c o w or ke r s r e por t e d t he f i r s t e na nt i os e l e c t i ve vi nyl ogous M a nni c h r e a c t i on c a t a l yz e d by a B I N O L de r i ve d phos phor i c a c i d. 5 2 T he r e a c t i on w a s be t w e e n a c y c l i c s i l yl di e nol a t e s a nd pa r a m e t hoxy pr ot e c t e d i m i ne s T he r e a c t i on pr oduc e s # a m i no uns a t ur a t e d c a r boxyl i c e s t e r s L ow t e m pe r a t ur e s a nd onl y 5 m ol % phos phor i c a c i d w a s r e qui r e d f or t he opt i m um r e s ul t s F our t e e n e xa m pl e s w e r e s how n w i t h a r om a t i c i m i ne s t ha t c ont a i ne d e l e c t r on dona t i ng a nd w i t hdr a w i ng gr oups a s w e l l a s he t e r oa r om a t i c i m i ne s T he r e a c t i on r e s ul t e d i n yi e l ds up t o 94% a nd e na nt i os e l e c t i vi t y up t o 92% A s um m a r y of t he r e a c t i on i s s how n b e l ow i n T a bl e 2. 10

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36 T ab l e 2. 10 S c h n e i d e r s E n an t i os e l e c t i ve V i n yl og ou s M an n i c h R e ac t i on 2. 3 I n i t i al D e ve l op m e n t s of a n A s ym m e t r i c M an n i c h R e ac t i on B a s e d upon t he w or k of T e r a da a nd c o w or ke r s e na nt i os e l e c t i ve a ddi t i on of a c e t yl a c e t one t o i m i ne s w e f e l t t ha t c hi r a l ph os phor i c a c i ds c oul d be us e d f or t he e na nt i os e l e c t i ve a ddi t i on of ke t oe s t e r s t o i m i ne s T hi s w oul d a l l ow f or t he s ynt he s i s of s ynt he t i c a l l y m or e us e f ul pr oduc t s O u r vi s i on w a s t o e m pl oy t he r e s ul t i ng pr oduc t s f or t he s y nt he s i s of c hi r a l a m i no a l c ohol s T he r e s ul t i ng a m i no a l c ohol pr oduc t s ha ve b e e n us e d a s c hi r a l a uxi l i a r i e s a nd 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 r e a c t i on m e t hodol ogy. 5 3 T he r e s ul t i ng a l c ohol s c oul d a l s o unde r go i nt r a m ol e c ul a r c yc l i z a t i on. T hi s r out e w oul d a l l ow f o r t he e xpe di e nt e na nt i os e l e c t i ve s ynt he s i s of c hi r a l c yc l i c ur e t ha ne de r i va t i ve s T he s e c om pounds ha ve be e n s how n t o be us e f ul a s a nt i a r r hyt hm i c a nd a nt i f i br i l l a t o r y a ge nt s 5 4 T he e a r l i e r r e por t s a l l us e d B I N O L de r i ve d p hos phor i c a c i ds W e f e l t t ha t V A P O L phos ph or i c a c i d c oul d pr oduc e t he r e s ul t i ng pr oduc t s i n i nc r e a s e d yi e l ds a nd e na nt i os e l e c t i vi t i e s

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37 F i gu r e 2. 3 I n i t i al R e as on i n g f or t h e A d d i t i on of K e t o E s t e r s t o I m i n e s T ab l e 2. 11 I n i t i al I n ve s t i gat i on s of a n E n an t i o s e l e c t i ve M an n i c h R e ac t i on B e t w e e n I m i n e s an d K e t o E s t e r s O ur i ni t i a l i nve s t i ga t i ons i nt o t he a ddi t i on of ke t oe s t e r s t o a N B oc pr ot e c t e d i m i ne s s t a r t e d w i t h t he r e a c t i on of a phe nyl s ub s t i t ut e d i m i ne a s s how n i n T a bl e 2. 11. T he r e a c t i on of m e t hyl a c e t oa c e t a t e w i t h t he ph e nyl s ubs t i t ut e d i m i ne ge ne r a t e d t he pr oduc t i n m ode r a t e yi e l d but t he e na nt i os e l e c t i vi t y w a s ve r y l ow T he r e a c t i on of t he s a m e i m i ne w i t h e t hyl a c e t o a c e t a t e ga v e t he pr od uc t i n gr e a t e r t ha n 99% yi e l d, but t he pr oduc t c oul d not be s e pa r a t e d by H P L C F or t hi s r e a s on, w e ne xt s t a r t e d s c r e e ni ng t he r e a c t i on w i t h t he 4 m e t hoxyphe nyl s ubs t i t ut e d i m i ne A s s how n i n e nt r i e s 3 6 t he

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38 pr oduc t w a s f or m e d i n hi gh yi e l d a t r oom t e m pe r a t ur e but ve r y l ow e na nt i os e l e c t i vi t i e s a nd di a s t e r e os e l e c t i vi t i e s w e r e obs e r ve d. 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 40 C s how e d a m a r ke d 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 t o 47% but t he yi e l d de c r e a s e d t o 65% P he nyl phos phi ni c a c i d w a s u s e d t o c a t a l yz e t he r e a c t i on i n or de r t o pr oduc e t he r a c e m i c pr oduc t s T hi s us ua l l y r e s ul t e d i n m ode r a t e yi e l ds ( e nt r y 7) A l s o, t he phe nyl phos phi ni c a c i d pr oduc e d t he hi ghe s t di a s t e r e os e l e c t i vi t y. W e be l i e ve t ha t t hi s w a s pr oba bl y due t o phe nyl phos phi ni c a c i d be i ng a w e a ke r a c i d t ha n t he V A P O L phos phor i c a c i d. A s s how n i n F i gur e 2. 4, t he i nc r e a s e d a c i di t y of V A P O L phos phor i c a c i d l e a ds t o t he t a ut om e r i z a t i on of t he pr oduc t w hi c h r e s ul t s i n r a c e m i z a t i on of t he c hi r a l c e nt e r be t w e e n t he ke t one a nd t he e s t e r f unc t i ona l i t y. T hus r e s ul t i ng i n a de c r e a s e d di a s t e r e o s e l e c t i vi t y w he n c om pa r e d t o p he nyl phos phi ni c a c i d, w hi c h i s a m uc h w e a ke r a c i d. T hi s i s s ue c oul d be s ol ve d by s ubs t i t ut i ng one of t he hyd r oge ns i n t he ke t o e s t e r f or a not he r s ubs t i t ue nt or by us i ng a w e a ke r c hi r a l a c i d c a t a l ys t s o t ha t t he t a ut e r m i z a t i on doe s not oc c ur a s r e a di l y. F i gu r e 2. 4 T au t am e r i z at i on f r om V A P O L P h os p h or i c A c i d

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39 T ab l e 2. 12 B r n s t e d A c i d C at al yz e d A d d i t i on of K e t o E s t e r s t o I m i n e w i t h 4 F l u or o S u b s t i t u e n t o n t h e A r om at i c R i n g W i t h t he s e r e s ul t s i n ha nd, w e ne xt s c r e e ne d a n i m i ne w i t h a n e l e c t r on w i t hdr a w i ng f l uor i ne i n t he 4 pos i t i on on t he a r om a t i c r i ng. A s s how n i n T a bl e 2. 12, w i t h t he e l e c t r on w i t hdr a w i ng g r oup pr e s e nt t he e na nt i os e l e c t i vi t y di d not i nc r e a s e s i gni f i c a nt l y w he n t he V A P O L phos phor i c a c i d w a s us e d. I n e nt r i e s 1 3 w e r e a c t e d a c e t yl a c e t one w i t h i m i ne 139 s o w e c oul d c om pa r e t he V A P O L phos phor i c a c i d ( e nt r y 1) t o t he B I N O L de r i ve d phos phor i c a c i d ( e nt r y 3) t h a t T e r a da a nd c o w or ke r s e m pl oye d a n a s ym m e t r i c M a nni c h r e a c t i on. U s i ng T e r a da s s a m e c ond i t i ons our V A P O L phos phor i c a c i d c a t a l y z e d r e a c t i on r e s ul t e d i n a 79 % yi e l d a nd 5 0% e e a f t e r t w o hour s A t 20 C t he e na nt i os e l e c t i vi t y w a s i nc r e a s e d t o 70% w hi c h w a s t he hi ghe s t r e s ul t s o f a r R e pe a t i ng T e r a da s e xa c t r e a c t i on w i t h t he B I N O L de r i ve d a c i d, w e w e r e a bl e t o a l m os t r e pr oduc e t he i r w or k w i t h a 88% yi e l d a nd 94% e e T he y r e por t e d a 94% yi e l d a nd 96% e e us i ng t he s a m e i m i ne a nd a c e t yl a c e t one W e ne xt r e a c t e d e t hyl a c e t oa c e t a t e w i t h i m i ne 13 9 us i ng V A P O L phos phor i c a c i d a s t he c a t a l ys t a n d a t 20 C w e obt a i ne d a 83% e e but onl y a 40% yi e l d. B y us i ng t he B I N O L phos phor i c a c i d c a t a l ys t a nd e t hyl a c e t oa c e t a t e a

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40 77% yi e l d a nd 53% e e w a s obt a i ne d a t r oom t e m pe r a t ur e C ool i ng t o 40 C de c r e a s e d t he yi e l d dr a s t i c a l l y t o onl y 22% a nd a l s o l ow e r e d t he e e t o onl y 35% I t w a s d e t e r m i ne d f or t he e t hyl a c e t oa c e t a t e nuc l e ophi l e t he V A P O L phos phor i c a c i d l e a d t o m uc h s l ow e r r e a c t i on t i m e s a nd l ow e r yi e l d s a nd e na nt i os e l e c t i vi t i e s t ha n t he r e a c t i on r e por t e d b y T e r a da a nd c o w or ke r s T ab l e 2. 13 B r n s t e d A c i d C at al yz e d A d d i t i on of A l l y l ac e t oac e t at e t o N B oc p r ot e c t e d I m i n e s I n t he f i na l a t t e m pt s w e a l s o t r i e d t o a dd a l l yl a c e t oa c e t a t e t o t he N boc i m i ne w i t h a n e l e c t r on w i t hdr a w i ng gr oup a nd a n e l e c t r o n dona t i ng gr oup. T hi s r e s ul t e d i n l ow yi e l ds a nd l ow e na nt i os e l e c t i vi t y. T he r e w a s a l s o no i m pr ove m e nt i n t h e di a s t e r e os e l e c t i vi t y. S e ve r a l ot he r nuc l e ophi l e s w e r e t e s t e d a s s how n i n F i gur e 2. 3, but a l l r e s ul t e d i n no r e a c t i on w i t h t he phe nyl phos phi ni c a c i d c a t a l ys t T he r e a s on f o r t he a bs e nc e of r e a c t i vi t y i s due t o t he de c r e a s e d a c i di t y of t he p r ot ons on t he s e c om pounds U nl i ke t he ke t o e s t e r s w hi c h ha ve t w o c a r bonyl f unc t i ona l i t i e s t he s e c om pounds onl y ha ve one c a r bonyl t he r e f or e de c r e a s i ng t he a c i di t y of t he pr ot ons

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41 F i gu r e 2. 5 N u c l e o p h i l i c A d d i t i on t o I m i n e s O ur i ni t i a l i nt e nt i ons f or t hi s e n a nt i os e l e c t i ve M a n ni c h r e a c t i on of t he a ddi t i on of ke t o e s t e r s t o a r om a t i c i m i ne s w a s t o t r a ns f or m t he pr oduc t s obt a i ne d i nt o a m i no a l c ohol s w hi c h c oul d t he n unde r go i nt e r m ol e c ul a r c yc l i z a t i on t o f or m c yc l i c ur e t ha ne de r i va t i ve s S hor t l y a f t e r w e s t oppe d w or ki ng o n t hi s pr oj e c t S c ha us a nd c o w or ke r s r e por t e d a n a s ym m e t r i c M a nni c h r e a c t i on of ke t o e s t e r s w i t h a c r yl i m i ne s w hi c h w a s ve r y s i m i l a r t o our unpub l i s he d r e a c t i on. S c ha us e m pl oye d c i nc honi ne a s t he c hi r a l 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 ke t o e s t e r s t o N a c yl i m i ne s 5 5 T he ut i l i t y o f t he r e s ul t i ng pr oduc t s w a s de m ons t r a t e d by t he c onve r s i on t o c yc l i c ur e t ha ne de r i va t i ve s S e l e c t i ve r e duc t i on of t he ke t one w i t h Z n( B H 4 ) 2 f ol l ow e d by ba s e c a t a l yz e d i nt r a m ol e c ul a r c yc l i z a 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 i c ur e t ha ne d e r i va t i ve i n e xc e l l e nt yi e l d a nd w i t hout r a c e m i z a t i on a s s how n i n F i gur e 2. 6 be l ow

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42 F i gu r e 2. 6 S c h a u s s A s ym m e t r i c S yn t h e s i s of C yc l i c U r e t h an e D e r i vat i ve s 2. 4 C on c l u s i on T he de ve l opm e nt of c a r bon c a r bon bond f or m i ng r e a c t i ons i s a n i m por t a nt a s pe c t of or ga ni c s ynt he s i s T he E na nt i os e l e c t i ve M a nni c h r e a c t i on i s a t ype of c a r bon c a r bon bond f or m i ng r e a c t i on t ha t l e a ds t o hi ghl y us e f ul a m i no a c i ds a nd l a c t a m s T he or ga noc a t a l yt i c ve r s i on of t he M a nni c h r e a c t i on ha s r e c e nt l y r e c e i ve d m uc h i nt e r e s t O ur gr oup a t t e m pt e d t o de ve l op a n or ga noc a t a l yt i c e na nt i os e l e c t i ve M a nni c h r e a c t i on. W e i ni t i a l l y e nvi s i one d our pr e vi ous l y s uc c e s s f ul V A P O L phos pho r i c a c i d a s a c a t a l ys t f or t he a ddi t i on of ke t o e s t e r s t o a r o m a t i c i m i ne s T h i s w oul d l e a d t o hi ghl y us e f ul pr oduc t s t ha t c oul d be r e duc e d t o a m i no a l c ohol s T he a m i no a l c ohol s c oul d t he n be t r a ns f or m e d by a n i nt r a m ol e c ul a r c yc l i z a t i on r e a c t i on i nt o c yc l i c ur e t ha ne d e r i va t i ve s w hi c h ha ve be e n s how n t o ha ve a nt i a r r hyt hm i c a nd a nt i f i br i l l a t or y p r ope r t i e s T he V A P O L phos phor i c a c i d c a t a l ys t di d not c a t a l yz e t he r e a c t i on a s w e l l e xpe c t e d. T he yi e l ds w e r e m ode r a t e a nd t he e na nt i os e l e c t i vi t y w a s ve r y l ow T he di a s t e r e os e l e c t i vi t y w a s a l s o ve r y l ow w i t h t he V A P O L phos phor i c a c i d. W i t h phe nyl phos phi ni c a c i d e m pl oye d a s t he c a t a l ys t t h e di a s t e r e os e l e c t i vi t y w a s t he hi ghe s t a t 45: 1. T he r e a c t i on c oul d pos s i bl y be i m pr ove d by e m pl oyi ng a di f f e r e nt phos ph or i c a c i d or a not he r c hi r a l or ga noc a t a l ys t S c ha us a nd c o w or ke r s di d s how t he a ddi t i on of ke t o e s t e r s t o a c yl i m i ne s w i t h hi gh yi e l ds a nd e n a nt i os e l e c t i vi t y w i t h a c i nc hona a l ka l oi d

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43 c a t a l ys t I t w a s a l s o s how n t h a t t he r e s ul t i ng pr o duc t s c oul d be c onv e r t e d t o t he de s i r e d c yc l i c ur e t ha ne de r i va t i ve s T he r e i s s t i l l r oom f or i m pr ove m e nt f or t he or 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 on of ke t o e s t e r s t o i m i ne s

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44 C H A P T E R 3 D E S Y M M E T R I Z A T I O N O F M E S O A Z I R I D I N E S 3. 1 I n t r od u c t i on A z i r i di ne s a r e hi ghl y u s e f ul s ynt he t i c i nt e r m e di a t e s f or t he s ynt he s i s of na t ur a l pr oduc t s 5 6 T he s ynt he s i s of a c t i nom yc i n D i nvol ve s a s t e r e os e l e c t i ve r e gi os e l e c t i v e r i ng ope ni ng of a n a z i r i di ne ( F i gur e 3 1) T he n uc l e ophi l i c r i ng ope ni ng o f a z i r i di ne s w a s i nde pe nde nt l y e m pl oye d by C or e y 5 8 a nd S hi ba s a ki 5 9 ( F i gur e 3. 2 ) i n r out e t o t he s ynt he s i s of t he a nt i i nf l ue nz a dr ug t a m i f l u. T he de ve l opm e nt of ne w m e t hod s f or t he s ynt he s i s a nd r i ng ope ni ng of a z i r i di ne s ha s be e n a n e xt r e m e l y a c t i ve r e s e a r c h t opi c i n t he l a s t f e w ye a r s 5 6 A z i r i di ne s a r e hi gh l y s t r a i ne d, t hr e e m e m be r e d ni t r oge n c ont a i ni ng he t e r oc yc l e s T hi s s t r a i n on t he r i ng s ys t e m l e a ve s a r i ng t ha t i s e a s i l y ope ne d by nuc l e ophi l e s i n or de r t o r e l i e ve t he s t r a i n. S e ve r a l gr oups ha ve e m pl oye d ni t r oge n, oxyge n, a nd s ul f ur nuc l e ophi l e s f or t he r i ng ope ni ng of a z i r i di ne s how e ve r t he a z i r i di ne e m pl oye d i n t he s e r e a c t i ons w e r e e i t he r c hi r a l or r a c e m i c 6 0 T he pr oduc t s r e s ul t i ng f r om t he r i ng ope ni ng of a z i r i d i ne s w i t h ni t r oge n nuc l e ophi l e s c a n l e a d t o t he s ynt he s i s of vi c i n a l di a m i ne s w hi c h ha ve be e n w i de l y us e d a s c hi r a l l i ga nds a nd c hi r a l a uxi l i a r i e s a s s how n i n F i gur e 3. 3 6 1 C hi r a l vi c i na l d i a m i ne s c a n a l s o be f ound a s m a ny bi ol ogi c a l l y a c t i ve c om pounds a l ong w i t h a nt i c a nc e r a ge nt s a n d a nt i i nf l ue nz a d r ugs 5 7 5 8 5 9

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45 F i gu r e 3. 1 R i n g O p e n i n g o f A z i r i d i n e i n t h e S y n t h e s i s of A c t i n o m yc i n D F i gu r e 3. 2 S t e p s i n t h e S yn t h e s i s of T am i f l u

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46 F i gu r e 3. 3 C h i r al D i am i n e s S e ve r a l m e t hods ha ve be e n r e por t e d i n t he l i t e r a t ur e f or t he s ynt he s i s of c hi r a l vi c i na l di a m i ne s 6 1 O ne of t he m os t di r e c t m e t hods f or t he s ynt he s i s of c hi r a l vi c i na l di a m i ne s i s t he r i ng ope ni ng of a z i r i di ne s w i t h ni t r oge n nuc l e ophi l e s 6 2 A l t hough t he e xi s t i ng s t r a t e gi e s ha v e be e n s u c c e s s f ul l i t t l e a t t e nt i on ha s be e n gi ve n t o t h e 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 m e t h odol ogy f or t he 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 3. 2 M e t h od o l ogy f or t h e D e s ym m e t r i z at i on of m e s o A z i r i d i n e s T he r e ha ve be e n f e w e f f i c i e nt m e t hods de v e l ope d f or t he r i ng ope ni ng of m e s o a z i r i di ne s T he f i r s t m e t ho dol ogi e s f o r t he r i ng ope ni ng of m e s o a z i r i di ne s w e r e c a t a l yt i c but not e na nt i os e l e c t i ve S i m pl e a c hi r a l L e w i s a c i ds ha ve be e n s how n t o c a t a l yz e t he r i ng ope ni ng of a z i r i di ne s w i t h a va r i e t y of N uc l e ophi l e s

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47 Y a da v a nd c o w or ke r s r e por t e d f our e xa m pl e s of m e s o a z i r i di ne ope ni ng w i t h a L e w i s a c i d c a t a l y s t 6 3 I t w a s s how n t ha t 10 m ol % i ndi um c hl or i de c a t a l yz e d t he a ddi t i on of i ndol e a nd pyr r ol e t o m e s o N s ul f onyl a z i r i di ne s T hi s publ i c a t i on de m ons t r a t e d t ha t a s i m pl e L e w i s a c i d c oul d c a t a l yz e t he r i ng o pe ni ng of a z i r i di ne s w i t h he t e r oa r om a t i c c om pounds T he s e pr oduc t s a r e pot e nt i a l l y i m por t a nt pr e c ur s or s f or ni t r oge n c ont a i ni ng na t ur a l pr oduc t s T ab l e 3. 1 Y ad av s I n C l 3 C a t al yz e d O p e n i n g of A z i r i d i n e s H ou a nd c o w or ke r s r e por t e d a 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 w i t h t r i m e t hyl s i l yl c ya ni de 6 4 O r ga nos i l i c on c om pounds a r e know n f or t he i r ve r s a t i l e r e a c t i vi t y a nd t ol e r a nc e of a w i de r a nge of f unc t i ona l gr oups I n t hi s r e por t t e t r a but yl a m m oni um f l uor i de ( T B A F ) w a s us e d t o t r i gge r t he r e a c t i o n by br e a ki ng t he c a r bon s i l i c on bond. T hus m a ki ng t he c ya ni de m or e nuc l e ophi l i c I t w a s a l s o s how n t ha t a n a z i de c oul d a l s o ope n t he a z i r i di ne r i ng. T hi s r e a c t i on w a s not a s ym m e t r i c but i t w a s c a t a l yt i c T he pr oduc t s obt a i ne d w e r e r a c e m i c a nd i n t he t r ans c onf or m a t i on.

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48 T ab l e 3. 2 H o u s R i n g O p e n i n g o f A z i r i d i n e s w i t h T r i m e t h yl s i l yl C ya n i d e S e ve r a l t ype s of nu c l e ophi l e s ha ve b e e n s how n t o ope n a z i r i di ne s S om e e xa m pl e s of nuc l e ophi l e s us e d f or t he r i ng ope ni n g of a z i r i di ne s a r e t h i ol s a nd a l c ohol s I n 2001 H ou a nd c o w or ke r s r e por t e d t he a ddi t i o n of t hi ol s t o m e s o a z i r i di ne s 6 5 T he a m i no s ul f i de s pr oduc e d f r om t he a ddi t i on of t h i ol s t o a z i r i di ne s doe s ha ve s ynt he t i c i nt e r e s t t o or ga ni c c he m i s t s 6 6 A s s how n i n T a bl e 3. 4, onl y 5 m ol % z i nc c hl or i de w a s e m pl oye d t o c a t a l yz e t he r i ng ope ni ng of N b e nz oyl N boc a nd N t os yl pr ot e c t e d a z i r i di ne s T he z i nc c hl or i de s e r ve s a s a L e w i s a c i d a nd c oor di na t e s t o t he ni t r oge n of t he a z i r i di ne r i ng, w hi c h m a ke s t he c a r bon o f t he r i ng m or e e l e c t r ophi l i c a nd s ubj e c t t o a t t a c k f r om a nuc l e ophi l e T he a m i no s ul f i de s pr odu c e d f r om t he r e a c t i on w e r e obt a i ne d i n up t o 90% yi e l d.

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49 T ab l e 3. 3 M e s o A z i r i d i n e O p e n i n g w i t h Z i n c C h l or i d e as a C a t al ys t H ou a nd c o w or ke r s de ve l ope d a not he r r i ng ope ni ng of m e s o a z i r i di ne s i n 2002. 6 7 I t w a s s how n t ha t t r i but yl phos phi ne c oul d s e r ve t o c a t a l yz e t he r i ng ope ni ng of m e s o a z i r i di ne s w i t h phe nol s a nd t hi ol s T he r o l e of t h e t r i but yl phos phi ne w a s t o de p r ot ona t e t he nuc l e ophi l e l e a vi ng t he nuc l e ophi l e w i t h a n e ga t i ve c ha r ge s o i t c a n e a s i l y a t t a c k a nd pr oc e e d t o ope n t he a z i r i di ne r i ng T he s e S N 2 t ype r e a c t i ons l e a d t o t he r i ng ope ne d pr oduc t s t ha t a r e i n t he t r ans c onf or m a t i on. T he pr oduc t s obt a i ne d f r om t he t r i but yl phos phi ne c a t a l yz e d r i ng ope ni ng of m e s o a z i r i di ne s r e s ul t e d i n up t o 95% yi e l d. T ab l e 3. 4 M e s o A z i r i d i n e O p e n i n g w i t h T r i b u t y l p h os p h i n e as a C at al ys t 3. 3 E n an t i os e l e c t i ve D e s ym m e t r i z at i on o f m e s o A z i r i d i n e s M e t h od ol ogy T he f i r s t r e por t of e na nt i os e l e c t i ve c a t a l yt i c r i ng ope ni ng of m e s o a z i r i di ne s w a s r e por t e d by J a c obs e n a nd c o w or ke r s i n 1999. 6 8 T he y r e por t e d t he de s ym m e t r i z a t i on of

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50 m e s o a z i r i di ne s w i t h a z i dot r i m e t hyl s i l a ne us i ng a c hi r a l c hr om i um c om pl e x. T he c hr om i um c om pl e x w a s a t r i de nt a t e S c hi f f ba s e de r i ve d f r om 1 a m i no 2 i nda nol T he t r i de nt a t e c om pl e x, w hi c h i s not a s bul ky a s t he s a l e n t ype t e t r a de nt a t e c om pl e xe s w hi c h w e r e s how n t o c a t a l yz e e poxi de ope ni ng 6 9 w or ke d w e l l f or t he a z i r i di ne ope ni ng S i nc e e poxi de s do not ha ve a s ub s t i t ue nt on t he oxyg e n l i ke t he s ub s t i t ue nt on t he ni t r oge n of a n a z i r i di ne t he y a r e not a s bul ky a s a z i r i di ne s T he r e f or e t he a z i r i di ne ope ni ng r e qui r e d a s m a l l e r c a t a l ys t c om pl e x f or t he r i ng ope ni ng. F i ve e xa m pl e s of t he r i ng ope ni ng of m e s o a z i r i di ne s w e r e r e por t e d w hi c h r e s ul t e d i n good yi e l ds a nd e na nt i os e l e c t i vi t y a s s how n i n T a bl e 3 5. T ab l e 3. 5 Jac ob s e n s D e s ym m e t r i z at i on o f m e s o A z i r i d i n e s

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51 I n 2001 M ul l e r a nd c o w or ke r s de ve l ope d a r i ng ope ni ng of m e s o N s ul f onyl a z i r i di ne s w i t h G r i gna r d r e a ge nt s 7 0 I t w a s s how n t h a t a c hi r a l c oppe r l i ga nd c om pl e x c a t a l yz e d t he r e a c t i on be t w e e n t he m e s o a z i r i di ne a nd G r i gna r d r e a ge nt s S e ve r a l l i ga nds w e r e t e s t e d, but t he one t ha t pr oduc e d t he opt i m um r e s ul t s w a s t he on e s how n i n T a bl e 3. 7. S e ve r a l G r i gna r d r e a ge nt s w e r e a l s o s c r e e ne d a nd g a ve va r i a bl e r e s ul t s F our t e e n e xa m pl e s w e r e r e por t e d w i t h yi e l ds r a ngi ng f r o m 28 89% a nd e na nt i os e l e c t i ve e xc e s s r a ngi ng f r om 0 72% T ab l e 3. 6 M u l l e r s D e s ym m e t r i z at i on of m e s o N S u l f on yl az i r i d i n e s I n 2005 S hi ba s a ki a nd c o w or ke r s r e por t e d t he r i n g ope ni ng of m e s o a z i r i di ne s us i ng a c a r bon nuc l e ophi l e 7 1 T r i m e t hyl s i l yl c y a ni de w a s s how n t o be a n e xc e l l e nt nuc l e ophi l e f or t he a ddi t i on t o m e s o a z i r i di ne s T he r e a c t i on e m pl oye d a c hi r a l ga dl i ni um c om pl e x a s t he c a t a l ys t M os t of t he r e a c t i ons w e r e done a t r oom t e m pe r a t ur e but s om e ha d t o be he a t e d up t o 60 C t o obt a i n t h e opt i m um r e s ul t s T r i f l uo r oa c e t i c a c i d w a s us e d a s a n a ddi t i ve f or t he r e a c t i on. I t i s be l i e ve d t o he l p br i dge t he ga dl i ni um a t om s a nd s t a bi l i z e t he c hi r a l c om pl e x. I t w a s d e m o ns t r a t e d t ha t t he pr oduc t s obt a i ne d f r om t he a ddi t i on of c ya ni de t o t he a z i r i di ne c oul d be r e a di l y c onve r t e d t o a m i no a c i ds w i t h r e t e nt i on of s t e r e oc he m i s t r y. T hi s r e a c t i on w a s s how n t o be a ne w m e t hod f or t he

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52 pr e pa r a t i on of a m i no a c i ds A s s how n i n T a bl e 3. 8, s e ve r a l e xa m pl e s w e r e r e por t e d w i t h pr oduc t s r e s ul t i ng i n hi gh 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 3. 7 S h i b as ak i s D e s ym m e t r i z at i on of m e s o A z i r i d i n e s w i t h T M S C N I n 2006 S hi ba s a ki a nd c o w or ke r s a l s o r e por t e d t he r i ng ope ni ng of m e s o a z i r i di ne s w i t h T M S N 3 c a t a l yz e d by a c hi r a l yt t r i um c om pl e x a s s how n i n T a bl e 3. 8. 7 2 T hi s m e t hodol ogy w a s e m pl oye d i n r out e t o t he s ynt he s i s of T a m i f l u. T he s ynt he s i s i nvol ve d a n e na nt i os e l e c t i ve r i ng ope ni ng of a m e s o a z i r i di ne T e n di f f e r e nt m e s o

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53 a z i r i di ne s w e r e s c r e e ne d a nd a l l r e s ul t e d i n pr odu c t f or m a t i on w i t h yi e l ds up t o 99% a nd e na nt i os e l e c t i vi t y up t o 96% T ab l e 3. 8 S h i b as ak i s D e s ym m e t r i z at i on of m e s o A z i r i d i n e s w i t h A z i d ot r i m e t h yl s i l an e 3. 4 P h os p h or i c A c i d C at al yz e d D e s ym m e t r i z at i on of m e s o A z i r i d i n e s 7 3 O r ga noc a t a l ys i s ha s be e n a popul a r a r e a of r e s e a r c h ove r t he pa s t de c a de S e ve r a l gr oups ha ve r e por t e d t he u s e of pho s phor i c a c i d c a t a l ys t s f or a l a r ge num be r 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 t ha s be e n s ho w n t ha t phos phor i c a c i ds a r e ve r s a t i l e c a t a l ys t s f or t he a ddi t i on of va r i ous nuc l e ophi l e s t o i m i ne s 1 1 W i t h t he pr e vi ous s uc c e s s of phos phor i c a c i d c a t a l yz e d r e a c t i ons w i t h i m i ne s w e e nvi s i one d a r e a c t i on t ha t c oul d

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54 ut i l i z e a c hi r a l pho s phor i c a c i d c a t a l ys t t o ope n a n a z i r i di ne O ur gr oup ha s de ve l ope d t he f i r s t phos phor i c a c i d c a t a l yz e d 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 I t w a s a l s o t he f i r s t e xa m pl e of a phos phor i c a c i d c a t a l yz e d r e a c t i on w i t h a non i m i ne ba s e d e l e c t r ophi l e O ur i ni t i a l i nve s t i ga t i on i nvol ve d t e s t i ng a s m a l l num be r of di f f e r e nt nuc l e ophi l e s a nd phos phor i c a c i d c a t a l ys t s unt i l w e f ound a c om bi na t i on t ha t w oul d ope n a m e s o a z i r i di ne W e f ound t ha t t r i m e t hyl s i l yl a z i de ( T M S N 3 ) r e a c t e d w e l l w i t h a c yc l ohe xa ne de r i ve d a z i r i di ne w i t h a 4 ni t r obe nz oyl pr ot e c t i ng gr oup on t he ni t r oge n of t he a z i r i di ne ( T a bl e 3. 9, e nt r y 3) w i t h V A P O L phos phor i c a c i d. W i t h t hi s pr om i s i ng r e s ul t i n ha nd, w e ne xt c hos e t o c he c k t he e f f e c t of va r yi ng 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 a z i r i di ne T he us e of a N C bz a nd N B oc pr ot e c t e d c yc l ohe xa ne de r i ve d a z i r i di ne r e s ul t e d i n r a c e m i c pr oduc t s ( T a bl e 3 10, e nt r i e s 1 2) W e a l s o s c r e e ne d a c yc l ohe xa ne de r i ve d a z i r i di ne w i t h a N be nz oyl 2 3, 4 5, 6 f l uo r o a nd N C bz pr ot e c t i ng g r oup, w hi c h r e s ul t e d i n ve r y l ow yi e l ds a nd l i t t l e t o no e na nt i os e l e c t i vi t y S i nc e t he 4 ni t r obe nz oyl pr ot e c t i ng gr oup r e s ul t e d i n a good yi e l d w e t he n t e s t e d t he 3, 5 di ni t r obe nz oyl pr ot e c t i ng gr oup on t he ni t r oge n of t he a z i r i di ne a nd t hi s r e s ul t e d i n hi gh yi e l d s a nd up t o 77% e na nt i os e l e c t i v e e xc e s s W e t he n s c r e e ne d t h e r e a c t i on of T M S N 3 a nd t he 3, 5 di ni t r obe nz oyl c yc l ohe xa ne de r i ve d a z i r i di ne w i t h s e ve r a l s ol ve nt s ( e nt r i e s 4 5) a l ong w i t h t he s ol ve nt s N N di m e t hyl f or m a m i de ( D M F ) di m e t hyl s ul f oxi de ( D M S O ) 1, 3 D i m e t hyl t e t r a hydr opyr i m i d i n 2 ( 1 H ) one ( D M P U ) a nd N m e t hyl pyr r ol i done ( N M P ) T he D M F D M S O D M P U a nd N M P r e s ul t e d i n no r e a c t i on pr oba bl y be c a us e t he s e s ol ve nt s a r e t oo pol a r f or t he r e a c t i on. A l t hou gh t he di c hl or om e t ha ne t ol ue ne a nd

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55 a c e t oni t r i l e di d gi ve good yi e l ds t he 1, 2 di c hl or oe t ha ne r e s ul t e d i n a hi gh yi e l d a nd a 77% e e ( e nt r y 8) W e ne xt s c r e e ne d s e ve r a l di f f e r e nt m ol a r r a t i os of a z i r i di ne t o a z i de unt i l w e f ound t he opt i m um c ondi t i on o f 1. 0 e qui va l e nt a z i r i di ne t o 1 5 e qui va l e nt a z i de H a vi ng t he s e opt i m i z e d c ondi t i on s i n ha nd, w e t he n t e s t e d t he e f f e c t of ha vi ng a 3, 5 bi s t r i f l uor om e t hyl be nz oyl c hl or i de p r ot e c t i ng gr o up on t he ni t r oge n. W e w a nt e d t o e xa m i ne t he e f f e c t s of 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 a z i r i di ne I t w a s de t e r m i ne d t ha t t he 3, 5 bi s t r i f l uor om e t hyl be nz oyl c hl or i de pr ot e c t i ng gr oup r e s ul t e d 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. T h i s i s pr oba bl y due t o t he pi i nt e r a c t i on be t w e e n t he f l uor i ne a t om s a nd t he a r o m a t i c r i ngs of t he V A P O L phos phor i c a c i d. W e t he n t e s t e d s e ve r a l s ol v e nt s a nd m ol a r r a t i os T he be s t r e s ul t a ga i n, w a s t he 1, 2 di c hl or oe t ha ne a s t he s ol ve nt a nd 1. 5 e q. a z i r i di ne t o 1. 0 e q T M S N 3 r e s ul t i ng i n 97% yi e l d a nd 95% e e ( e nt r y 10)

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56 T ab l e 3. 9 S c r e e n i n g of P r ot e c t i n g G r ou p on N i t r oge n 6 4 W e de t e r m i ne d t ha t t he 3, 5 bi s t r i f l uor om e t hyl be nz oyl pr ot e c t i ng gr oup on t h e ni t r oge n of t he a z i r i di ne r e s ul t e d i n t he hi ghe s t e na nt i os e l e c t i vi t y w i t h t he V A P O L phos phor i c a c i d c a t a l y s t W i t h t he s e r e s ul t s i n ha nd w e t he n ne e d e d t o pr e pa r e ot he r a z i r i di ne s w i t h t hi s s a m e pr ot e c t i ng gr oup. T he m e s o a z i r i di ne s c ont a i ni ng t he 3, 5 di ni t r obe nz oyl pr ot e c t i ng gr oup ha d be e n r e po r t e d i n t he l i t e r a t ur e A l t hough s e ve r a l of t he a z i r i di ne s w e w a nt e d t o pr e pa r e w i t h t he 3, 5 t r i f l uor om e t hyl be nz oyl pr ot e c t i ng gr oup c oul d be pr e pa r e d f ol l ow i ng t he s a m e pr oc e dur e a s t he a z i r i di ne s w i t h t he 3, 5 di ni t r obe nz oyl gr oup, s om e of t he m ha d t o be pr e pa r e d us i ng a m odi f i e d m e t hod. T he y a r e de s c r i be d i n s hor t be l ow bu t t he de t a i l e d pr oc e dur e c a n be f ound i n C ha pt e r 4.

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57 A z i r i di ne 186d w a s pr e pa r e d by c onve r t i ng a n e poxi de t o a n a z i do a l c ohol f ol l ow e d by s e ve r a l s t e p s a nd t he n pr ot e c t i on of t he ni t r oge n a s s how n i n F i gur e 3. 4 be l ow F i gu r e 3. 4 P r e p ar at i o n of 6 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 6 az ab i c yc l o[ 3. 1. 0] h e xan e A z i r i di ne 186g w a s pr e pa r e d by c onve r t i ng t he e poxi de t o t he a z i do a l c ohol T r i phe nyl phos phi ne w a s a dde d r e s ul t i ng i n i nt e r m e di a t e 189 f ol l ow e d by t he a ddi t i on of a c e t i c a c i d a nd t he n s odi um hydr oxi de r e s ul t i ng i n a z i r i di ne 190 A z i r i di ne 190 w a s t he n pr ot e c t e d w i t h t he 3, 5 bi s t r i f l uor o m e t hyl be nz oyl c hl or i de a s s how n i n F i gur e 3 5 be l ow F i gu r e 3. 5 P r e p ar at i on of c i s 1 ( 3 5 b i s t r i f l ou or m e t h yl b e n z oyl ) 2, 3 d i p h e n yl az i r i d i n e

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58 A z i r i di ne 186h w a s pr e pa r e d by f i r s t pe r f or m i ng e poxi da t i on on a l ke ne 191 t he n c onve r t i ng i t t o a z i do a l c ohol 192 f ol l ow e d by r e d uc t i on w i t h hydr oge n a nd pa l l a di um on c a r bon. T he ni t r oge n w a s t he n pr ot e c t e d w i t h t he be nz oyl gr oup a s s how n i n F i gur e 3. 6 be l ow F i gu r e 3. 6 P r e p ar at i on of 3 O xa 6 ( 3 4 b i s t r i f l u or om e t h yl b e n z oyl ) 6 az b i c yc l o[ 3. 1. 0] h e x an e A z i r i di ne 186i w a s pr e pa r e d by c onve r t i ng t he e p oxi de t o t he a z i do a l c ohol T he a z i do a l c ohol w a s t he n c onv e r t e d a z i r i di ne 195 f o l l ow e d by pr ot e c t i on w i t h t he be nz oyl c hl or i de a s s how n i n F i gu r e 3 7 be l ow F i gu r e 3. 7 P r e p ar at i on o f 3 C ar b ob e n z yl ox y 6 ( 3, 5 b i s t r i f l u or om e t h yl b e n z oyl ) 3 6 d i az b i c yc l o[ 3. 1. 0] h e xan e

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59 T he s t r uc t ur e s of t he a z i r i di ne s us e d i n t hi s i nve s t i ga t i on a r e ve r y di f f e r e nt S om e c ont a i n e l e c t r one ga t i ve a t om s a nd ot he r s onl y ha ve hydr oc a r bon s ubs t i t ue nt s c onne c t e d t o t he a z i r i di ne r i ng c a r bon a t om s T he r e f or e t he opt i m i z e d c ondi t i on de t e r m i ne d f or t he c yc l ohe xa ne de r i ve d a z i r i di ne w a s not ne c e s s a r i l y t he opt i m i z e d c ondi t i ons e m pl oye d f or t he ot he r a z i r i di ne s T he opt i m i z a t i on of s om e of t he ot he r a z i r i di ne s ubs t r a t e s w i l l now be di s c us s e d. F or s e ve r a l of t he a z i r i di ne s one m a j or f a c t or a f f e c t i ng t he yi e l d a nd e na nt i os e l e c t i vi t y w a s t he r a t i o of a z i r i di ne t o a z i de T hi s pr oduc e d t he gr e a t e s t c h a nge i n e na nt i os e l e c t i vi t y. T hi s i s pr oba bl y due t o t h e s t r uc t ur e of t he V A P O L phos phor i c a c i d a nd t he s t r uc t ur a l a r r a nge m e nt o f t he a z i r i di ne w i t h t he phos phor i c a c i d. T he r e a c t i on t i m e w a s a ppr oxi m a t e l y t he s a m e f or a l l r e a c t i ons a nd di d not gr e a t l y a f f e c t t he yi e l d or e na nt i os e l e c t i vi t y. T ab l e 3. 10 O p t i m i z at i on o f R e ac t i o n of A z i r i d i n e 195a w i t h T M S N 3

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60 T he opt i m i z a t i on o f t he c yc l ohe xa ne de r i ve d a z i r i di ne ( 195a ) i s s how n i n T a bl e 3. 10. O f t he f e w phos phor i c a c i ds s c r e e ne d, t he V A P O L phos phor i c a c i d ga v e t he be s t r e s ul t s w i t h t he V A N O L phos phor i c a c i d ( P A 19 ) ha vi ng c om pa r a bl e yi e l d a nd e na nt i os e l e c t i vi t y ( e nt r y 4) A B I N O L de r i ve d phos phor i c a c i d ( e nt r y 2) w a s a l s o s c r e e ne d but pr oduc e d onl y a t r a c e a m ount o f p r o duc t S e ve r a l di f f e r e nt r a t i os ( e nt r i e s 1 6 10) of a z i r i di ne t o a z i de w e r e t e s t e d w i t h 1. 5 e qui va l e nt s of a z i r i di ne pr oduc i ng t he hi ghe s t yi e l d a nd e na nt i os e l e c t i vi t y f or t he c yc l ohe xa ne de r i ve d a z i r i di ne S e ve r a l s ol ve nt s w e r e s c r e e ne d f or t he c yc l oh e xa ne de r i ve d a z i r i di ne r e a c t i on, i nc l udi ng di c hl or om e t ha ne ( e nt r y 5 ) a nd i t w a s de t e r m i ne d t ha t t he 1 2 di c hl or oe t ha ne w a s t he s ol ve nt of c hoi c e t ha t r e s ul t e d i n t he opt i m i z e d e n a nt i os e l e c t i vi t y. T he di c hl or om e t ha ne di d gi ve t he hi ghe s t yi e l d, but i t w a s onl y 2 % hi ghe r t ha n t he yi e l d f or t he 1, 2 di c hl or oe t ha ne T he s m a l l di f f e r e nc e i s t he pol a r i t y of t he t w o s ol ve nt s s e e m e d t o m a ke a s m a l l di f f e r e nc e i n t he e na nt i os e l e c t i vi t y of t hi s r i ng ope ne d pr oduc t T he 1 2 di c hl or oe t ha ne di d m a ke a l a r ge r di f f e r e nc e i n t he e na nt i os e l e c t i vi t y w i t h s om e of t he ot he r a z i r i di ne s s c r e e ne d.

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61 T ab l e 3. 11 O p t i m i z at i on of R e ac t i on o f A z i r i d i n e 195f w i t h T M S N 3 A s s ho w n i n T a bl e 3. 11, t he a z i r i di ne c ont a i ni ng t he m e t hyl s ubs t i t ue nt s ( 186f ) ha d s i m i l a r opt i m i z a t i on c ondi t i ons a s t he c yc l oh e xa ne de r i ve d a z i r i di ne A f t e r t e s t i ng s e ve r a l r a t i os f or t he r e a c t i on of t he m e t hyl s ubs t i t ut e d a z i r i di ne i t w a s de t e r m i ne d t ha t 1. 5 e qui va l e nt s of a z i r i di ne r e s ul t e d i n t he opt i m i z e d e na nt i os e l e c t i vi t y of 86% T he yi e l d w a s good, but w e he a t e d t h e r e a c t i on t o s e e i f t he yi e l d c oul d be i nc r e a s e d. H e a t i ng a t 40 C di d i nc r e a s e t he yi e l d t o 9 1% but t he e n a nt i os e l e c t i vi t y w a s de c r e a s e d t o 83% ( e nt r y 2) w hi c h i s w h a t i s e xpe c t e d w i t h he a t i ng. A l s o, 10 m ol % V A P O L w or ke d w e l l f or t he r e a c t i on a nd by e m pl oyi ng 5 m o l % c a t a l y s t t he yi e l d a nd e na nt i os e l e c t i vi t y w a s s i gni f i c a nt l y de c r e a s e d.

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62 T ab l e 3. 12 O p t i m i z at i on of R e ac t i on of A z i r i d i n e 195h w i t h T M S N 3 T he f ur a n de r i ve d a z i r i di ne ( 186h ) r e qui r e d s e ve r a l a t t e m pt s a t opt i m i z a t i on T he pr e s e nc e of t he oxyge n i n t he f ur a n r i ng s e e m e d t o be hi nde r i ng t he r e a c t i on ( T a bl e 3 12, e nt r i e s 1, 2) I t c oul d ha ve be e n be c a us e e i t h e r t he phos phor i c a c i d w a s hydr oge n bondi ng t o t he oxyge n i n t he r i ng or t he T M S gr oup w a s c oor di na t i ng w i t h t he oxyge n i ns t e a d of pr oc e e di ng i n t he c a t a l yt i c c yc l e B e c a us e of t hi s t w o or m or e e qui va l e nt s of a z i de w e r e r e qui r e d s o t ha t t he a z i de ha d a gr e a t e r c ha nc e of r e a c t i ng w i t h t he V A P O L phos phor i c a c i d. T hi s w i l l be di s c us s e d f ur t he r i n t he s e c t i on on t he m e c ha ni s t i c c yc l e f or t he r e a c t i on. T hi s w a s a l s o obs e r ve d w i t h t he a z i r i di ne ( 195i ) t ha t c ont a i ne d a C bz gr oup i n t he c yc l ope nt a ne r i ng o f t he a z i r i di ne H e a t i ng t he r e a c t i on of T M S N 3 w i t h t he f ur a n de r i ve d a z i r i di ne d i d not g r e a t l y i nc r e a s e t he yi e l d of t he de s i r e d pr oduc t ( e nt r i e s 3, 5, 7) T he c onc e nt r a t i on of t he r e a c t i on w a s i nc r e a s e d a nd de c r e a s e d i n or de r t o i m pr ove t he yi e l d a nd e na nt i os e l e c t i vi t y. I n ge ne r a l i nc r e a s i ng t he c onc e nt r a t i on s houl d

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63 l e a d t o a n i nc r e a s e i n r e a c t i vi t y, but f o r t hi s r e a c t i on i t di d not i m p r ove t he yi e l d a s m uc h a s de s i r e d. U s u a l l y by de c r e a s i ng t he c onc e nt r a t i on of a r e a c t i on, t he r e a c t i on t i m e i s de c r e a s e d a nd t he e na nt i os e l e c t i vi t y i s i nc r e a s e d. T he r e f or e by de c r e a s i ng t he c onc e nt r a t i on t o 0. 25 M t he e na nt i os e l e c t i vi t y w a s 85% but t he yi e l d w a s m uc h l ow e r ( e nt r y 9) T he be s t c ondi t i ons f o r t he hi ghe s t e n a nt i os e l e c t i vi t y w a s a c onc e nt r a t i on of 1. 0 M a t r oom t e m pe r a t ur e w hi c h r e s ul t e d i n pr oduc t f or m a t i on up t o 49 % yi e l d a nd 87% e na nt i os e l e c t i vi t y. S e ve r a l ot he r a z i r i di ne s w i t h t he 3, 5 t r i f l uor om e t hyl be nz oyl pr ot e c t i ng gr oup w e r e opt i m i z e d a s s how n i n T a bl e 3 13 be l o w S e ve r a l di f f e r e nt h ydr oc a r bon r i ng s i z e s w e r e s c r e e ne d. T he f i ve s i x, a nd s e ve n m e m be r e d r i ngs a l l r e s ul t e d i n good yi e l ds a nd e na nt i os e l e c t i vi t i e s T he c yc l ohe pt a n e r i ng di d r e s ul t i n a l ow e r e n a nt i os e l e c t i vi t y, but t hi s c oul d ha ve be e n b e c a us e t he r i ng w a s not a s r i gi d a s t he s m a l l e r r i ngs I t m a y not ha ve a l i gne d a s w e l l w i t h t he c hi r a l c a t a l ys t t o p r oduc e hi ghe r e na nt i os e l e c t i vi t y. T he bul ky s i z e of t he di hydr o na pht ha l e ne de r i ve d a z i r i di ne w a s pr oba bl y t he r e a s on t hi s a z i r i di ne onl y r e s ul t e d i n a 70% e e ( e nt r y 8) T he m e t hyl a nd s t i l be ne de r i ve d a z i r i di ne s ( e nt r i e s 9, 10) bot h r e s ul t e d i n h i gh yi e l ds a nd g ood e na nt i os e l e c t i vi t i e s A s di s c us s e d e a r l i e r t he a z i r i di ne s i n e nt r y 11 a nd e nt r y 12 r e s ul t e d i n good yi e l ds a nd e na nt i os e l e c t i vi t i e s

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64 T ab l e 3. 13 S c op e of A z i r i d i n e S u b s t r a t e 6 4 T he a c c e pt e d m e c ha ni s m of phos phor i c a c i d c a t a l yz e d nuc l e ophi l i c a ddi t i on i nvol ve d a nuc l e ophi l e t ha t ga v e up a pr ot on t o b e r e us e d i n t he c a t a l yt i c c yc l e 7 4 W i t h t he T M S N 3 t he r e w a s no s uc h pr ot on t o g i ve up. F o r t hi s r e a s on, w e t he n i nve s t i ga t e d t he m e c ha ni s m of t he a ddi t i on o f T M S N 3 t o m e s o a z i r i di ne s O ur i nve s t i ga t i on be ga n w i t h t e s t i ng t he ne e d f or t he T M S gr oup. T he r e a c t i on of t e t r a but yl a m m oni um a z i de a nd

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65 s odi um a z i de i n t he pr e s e nc e of t he phos phor i c a c i d r e s ul t e d i n no r e a c t i on H ow e ve r t he r e a c t i on di d oc c ur w i t h s odi um a z i de a nd T M S C l T hi s s e e m e d t o be e vi de nt t ha t t he T M S gr oup w a s ne c e s s a r y f or t he r e a c t i on t o oc c u r I t ha s be e n know n t ha t P = O doubl e bond c a n a c t i va t e s i l a ne c om pounds P r e l i m i na r y 1 H N M R s t udi e s i ndi c a t e d t he pr e s e nc e of a ne w c om pound W e be l i e ve t hi s c om pound w a s i nt e r m e di a t e 199 be l ow A s i ndi c a t e d i n F i gur e 3. 6, i n m e c ha ni s m A w e be l i e ve d t he T M S c om bi ne d w i t h t he phos phor i c a c i d r e l e a s i ng hydr a z oi c a c i d ( H N 3 ) T he n i n t e r m e di a t e 197 r e a c t e d w i t h t he a z i r i di ne f o r m i ng 198 I nt e r m e di a t e 198 t h e n r e a c t e d w i t h t he H N 3 r e s ul t i ng i n c om pound 199 C om pound 199, w hi c h i s hi ghl y u ns t a bl e w a s pr ot ona t e d dur i ng w or kup t o pr oduc e t he f i na l p r oduc t 196 A s e c ond pos s i bl e m e c ha ni s m B i s a l s o s how n be l ow I n t hi s m e c ha ni s m t he a z i r i di ne i s f i r s t pr ot ona t e d by t he phos phor i c a c i d f or m i ng t he i on pa i r 200 T he pr ot ona t e d a z i r i di ne i s t he n a t t a c ke d by t he a z i de f or m i ng i nt e r m e di a t e 199 I n bot h of t he a bove m e c ha ni s m s t he i nt e r m e di a t e 199 i s f or m e d.

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66 F i gu r e 3. 8 T w o P os s i b l e P r op os e d M e c h an i s m s f or t h e P h os p h or i c A c i d C a t al yz e d D e s ym m e t r i z at i on of m e s o A z i r i d i n e s A s di s c u s s e d e a r l i e r t he m e c ha ni s m s s how n a bov e w oul d e xpl a i n w hy t he f ur a n de r i ve d a z i r i di ne ha d t o ha ve t w o or m or e e qui va l e nt s of a z i de f or t he pr oduc t t o f or m I f t he T M S gr oup c oor di na t e s w i t h t he oxyge n i n t h e f ur a n r i ng i ns t e a d of t he phos phor i c a c i d t o f or m c om pound 197 t he n t he r e a c t i on w o ul d not oc c ur I n t e r m e di a t e 198 w oul d ne ve r f or m a nd t he H N 3 w oul d not ha ve a nyt hi ng t o r e a c t w i t h. T he hi gh yi e l d f or t he

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67 pr oduc t of t he r e a c t i on of T M S N 3 w i t h a z i r i d i ne 196i c oul d be due t o t he T M S gr oup be i ng c oor di na t e d t o bot h c a r bonyl oxyge ns I f t hi s ha ppe ne d t he n t he a z i r i di ne w oul d be a c t i va t e d s o i t c oul d be a t t a c ke d by t he H N 3 T he l ow e na nt i os e l e c t i vi t y c oul d be due t o t he a r r a nge m e nt of t he c hi r a l a c i d w i t h r e s pe c t t o t he a z i r i di ne F i gur e 3. 9, 3 10, a nd 3. 11 i s t he 1 H N M R e xpe r i m e nt f r om a n a r r a y t ha t w e r a n f or s e ve r a l hour s of t he r e a c t i on be t w e e n t he a z i r i di ne a nd T M S N 3 T he a r r ow s i n F i gur e 3. 7 i ndi c a t e d t he pe a k s f r om t he a z i r i di ne T he a r r ow s i n F i gur e 3. 8 i ndi c a t e d t he pe a ks f r om t he f i na l pr oduc t I n F i gur e 3. 9 t he a r r ow s i ndi c t e d w h a t w e be l i e ve d t o b e i nt e r m e di a t e 199 T he 1 9 F N M R w a s a l s o i ndi c a t i ve of a di f f e r e nt s pe c i e s T he 1 9 F N M R of t he a z i r i di ne c ont a i ne d a pe a k a t 61. 771 ppm T he pr oduc t c ont a i ne d a p e a k a t 61. 652 ppm W e r a n a n a r r a y f or s e v e r a l hour s o f t he r e a c t i on t o ge t t he 1 9 F N M R da t a A f t e r a f e w hour s a t hi r d pe a k w a s a t 61. 717 ppm T hi s t hi r d pe a k w a s pr oba bl y i nt e r m e di a t e 199 A 3 1 P N M R of t he c a t a l ys t c ont a i ne d a pe a k a t 0. 28 ppm C om bi ni ng t he c a t a l ys t w i t h t he T M S N 3 a ne w c om pound p e a k a ppe a r e d a t 13. 4 ppm A f t e r t he c om pl e t i on t i m e of t he p r ot on a nd f l uo r i ne a r r a ys w e a dde d w a t e r t o bot h of t he s a m pl e s a nd c he c ke d t h e s pe c t r a a ga i n. T he a ddi t i on o f w a t e r t o t he N M R t ube r e s ul t e d i n c om pl e t e c onve r s i on of t he i nt e r m e di a t e s pe c i e s t o t he f i na l pr oduc t i n bot h t he p r ot on N M R s p e c t r um a nd f l uor i ne N M R s pe c t r um W e be l i e ve t hi s e vi de n c e s ugge s t e d t he m e c ha ni s m w e pr opos e d w a s c ons i s t e nt w i t h t he o bs e r va t i ons

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68 F i gu r e 3. 9 1 H N M R R e ac t i on A r r ay: A r r ow s I n d i c at e A z i r i d i n e 186f 1 0 2 9 5 8 5 7 5 6 7 5 6 0 5 2 5 4 5 3 7 5 3 0 2 2 5 1 5 0 7 5 0 0 0 T i m e h

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69 F i gu r e 3. 10 1 H N M R R e ac t i o n A r r ay: A r r ow s I n d i c at e P r od u c t 196f 1 0 2 9 5 8 5 7 5 6 7 5 6 0 5 2 5 4 5 3 7 5 3 0 2 2 5 1 5 0 7 5 0 0 0 T i m e h

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70 F i gu r e 3. 11 1 H N M R R e ac t i on A r r ay: A r r ow s I n d i c at e I n t e r m e d i at e 199f 1 0 2 9 5 8 5 7 5 6 7 5 6 0 5 2 5 4 5 3 7 5 3 0 2 2 5 1 5 0 7 5 0 0 0 T i m e h

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71 3. 5 C on c l u s i on O ur gr oup de ve l ope d t he f i r s t e na nt i o s 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 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 T he r e a c t i on be t w e e n T M S a z i de a nd a z i r i di ne w a s c a t a l yz e d by V A P O L phos phor i c a c i d. A l t hough s e ve r a l of t he a z i r i di ne s w e r e pr e pa r e d by l i t e r a t u r e pr oc e dur e s s om e of t he m ha d t o be pr e pa r e d by ne w m odi f i e d m e t hods T he pr oduc t s obt a i ne d f r om t he V A P O L phos phor i c a c i d c a t a l yz e d r e a c t i on r e s ul t e d i n hi gh yi e l d s a nd e na nt i os e l e c t i vi t i e s A m e c ha ni s m f or t he r e a c t i on w a s pr opos e d a nd pr e l i m i na r y m e c ha ni s t i c s t udi e s w e r e pe r f or m e d. T he m e c ha ni s t i c s t udi e s i ndi c a t e d t ha t t he pr opos e d m e c ha ni s m w a s pr oba bl e F u r t he r s t u di e s s houl d be c om pl e t e d f or m or e e vi de nc e of t he p r opos e d m e c ha ni s m

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72 C H A P T E R 4 E X P E R I M E N T A L P R O C E D U R E S 4. 1 G e n e r al I n f or m at i on 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 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 nhyd r ous 1, 2 di c hl or oe t ha ne w a s pur c ha s e d f r om c om m e r c i a l s our c e s A l l ot he r 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 on s C hi r a l phos phor i c a c i d c a t a l y s t P A 5 a nd P A 19 w e r e pr e p a r e d by l i t e r a t ur e pr oc e dur e s 7 5 A l l ke t oe s t e r s 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 nd di s t i l l e d be f or e us e T hi n l a ye r c hr om a t ogr a phy w a s p e 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 og r 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 y s 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 u s 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 21 0 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 A S H A D H or O 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 how 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 V X R 300 ( 300 M H z ) or a V a r i a n I nova 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 r e s i dua l c hl or 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 g i l e nt 1100 s e r i e s 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 om 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 n t ( m p) t o t he r e por t e d va l ue s

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73 4. 2 E xp e r i m e n t al P r oc e d u r e s f or C h ap t e r 2 A l l i m i ne s 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 7 6 G e ne r a l P r oc e dur e f o r R a c e m i c P r oduc t s T he i m i ne ( 0. 5 m m ol ) a nd phe nyl phos phi ni c a c i d ( 0. 025 m m ol ) w e r e w e i ghe d i nt o a f l a m e dr i e d t e s t t ube T he a i r w a s r e m ove d unde r va c uum a nd r e pl a c e d w i t h a r gon T he b di ke t one ( 0. 25 m m ol ) w a s a dde d vi a s yr i n ge t o t he t e s t t ube f ol l ow e d by C H 2 C l 2 ( 2. 0 m L ) 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 unt i l pr oduc t f or m a t i on w a s s i gni f i c a nt w hi c h w a s m oni t or e d by T L C T h e 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 G e ne r a l P r oc e dur e f o r 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 o a f l a m e dr i e d t e s t t ube w a s a dde d c hi r a l phos phor i c a c i d c a t a l ys t ( 10 m o 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. D i c hl o r om e t ha ne ( 0. 25 2. 0 m L ) w a s a dde d a nd t he s ol ut i on w a s c ool e d t o t he de s i r e d t e m pe r a t ur e ( 78C t o r oom t e m pe r a t u r e ) T he ke t oe s t e r ( 0. 25 1. 1 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube T he i m i n e ( 0. 1 0 5 m m ol ) w a s a dde d qui c kl y t o t he t e s t t u be a nd t he r e a c t i on w a s s t i r r e d a t t he de s i r e d t e m pe r a t ur e a nd m oni t or e d by T L C 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 2 ( t e r t B u t oxyc ar b on yl am i n o p h e n yl m e t h yl ) 3 oxo b u t yr i c ac i d e t h y l e s t e r ( 136b )

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74 T o a f l a m e dr i e d t e s t t ube w a s a dde d i m i ne ( 0 10 3 g, 0 5 m m o l ) a nd ( R ) V A P O L phos phor i c a c i d ( 0. 006 g 10 m ol % ) 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 D i c hl or om e t ha ne ( 2. 0 m L ) w a s a dde d f ol l ow e d by E t hyl a c e t oa c e t a t e ( 32 L 0 25 m m ol ) vi a s yr i nge t o t he t e s t t ube 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 20 h. T he r e a c t i on w a s di l ut e d w i t h e t hyl a c e t a t e 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 w i t h he xa ne s / e t hyl a c e t a t e R e c ove r e d w hi t e s ol i d ( 0. 08 g, 99% ) H P L C a na l ys i s : C oul d not s e pa r a t e 1 H N M R ( 500 M H z C D C l 3 bot h di a s t e r e om e r s r e por t e d) : # 1. 15 ( m 6H ) 1 27 ( s 18H ) 2. 18 ( s 6H ) 4 02 ( m 2H ) 4 13 ( m 4H ) 5 45 ( s 2H ) 5 85 ( m 2H ) 7. 25 7 41 ( m 5H ) 1 3 C N M R ( 125M H z C D C l 3 one di a s t e r e om e r r e por t e d) : # 13. 7 28 1, 53. 7 61 7, 63. 6 79 7, 126. 1 126 8, 1 28. 2, 128. 9 139 7, 154. 9 167 3 203. 2 2 [ t e r t B u t oxyc ar b on yl am i n o ( f l u or o p h e n yl ) m e t h yl ] 3 oxo b u t yr i c ac i d e t h yl e s t e r ( 141b ) T o a f l a m e dr i e d t e s t t ube w a s a dde d ( R ) V A P O L phos phor i c a c i d ( 0. 006 g, 10 m ol % ) 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. D i c hl or om e t ha ne ( 1. 0 m L ) w a s a dde d a nd t he s ol ut i on w a s c ool e d t o 20 C E t hyl a c e t oa c e t a t e ( 14 L 0. 11 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube T he i m i ne ( 0. 0 22 g, 0 1 m m ol ) w a s a dde d qui c kl y t o t he t e s t t ube a nd t he r e a c t i on w a s s t i r r e d a t 20 C f or 15 h. T he r e a c t i on w a s di l ut e d w i t h e t hyl a c e t a t e c onc e nt r a t e d on s i l i c a g e 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 w i t h he xa ne s / e t hyl a c e t a t e R e c ove r e d w hi t e s ol i d ( 0. 014 g, 40% )

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75 H P L C a na l ys i s : C hi r a l c e l A S 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 95 m i n a nd 12. 48 m i n, t r m i n o r 9. 28 m i n a nd 11. 23 m i n. 1 H N M R ( 500M H z C D C l 3 bot h di a s t e r e om e r s r e por t e d) : # 1. 19 ( m 6H ) 1 20 ( s 18H ) 2. 18 ( s 6H ) 3 99 ( m 2H ) 4 14 ( m 4H ) 5 39 ( s 2H ) 5. 86 ( m 2H ) 7. 00 ( m 4H ) 7. 29 ( m 4H ) 1 3 C N M R ( 125M H z C D C l 3 one di a s t e r e om e r r e por t e d) : # 13. 9 28 2, 53 4, 61 7, 63. 6 79 9, 115. 9 128 6, 13 5. 7, 154. 9 161 1, 163. 0 167 1, 203. 0 2 [ t e r t B u t oxyc ar b on yl am i n o ( 4 m e t h oxyp h e n y l ) m e t h yl ] 3 oxo b u t yr i c ac i d e t h yl e s t e r ( 136c ) T o a f l a m e d r i e d t e s t t ube w a s a dde d ( R ) V A P O L phos phor i c a c i d ( 0 006 g 10 m ol % ) 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. D i c hl or om e t ha ne ( 1. 0 m L ) w a s a dde d a nd t he s ol ut i on w a s c ool e d t o 40 C E t h yl a c e t oa c e t a t e ( 14 L 0 11m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube T he i m i ne ( 0. 024 g, 0. 1 m m ol ) w a s a dde d qui c kl y t o t he t e s t t ube a nd t h e r e a c t i on w a s s t i r r e d a t 40 C f or 19 h. T he r e a c t i on w a s di l ut e d w i t h e t hyl a c e t a t e 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 w i t h he xa ne s / e t hyl a c e t a t e R e c ove r e d w hi t e s ol i d ( 0. 024g 65% ) H P L C a na l ys i s : C hi r a l c e l A 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 16. 56 m i n a nd 23. 69 m i n t r m i n o r 19. 17 m i n a nd 27. 01 m i n. 1 H N M R ( 500M H z C D C l 3 bot h di a s t e r e om e r s r e por t e d) : # 1 H N M R ( 500M H z C D C l 3 bo t h di a s t e r e om e r s r e por t e d) : # 1 18 ( m 3H ) 1. 27 ( s 3H ) 1 40 ( s 18H ) 2. 19 ( s 6H ) 3 78 ( s 6 H ) 4 07 ( m 2H ) 4 13 ( m 4H ) 5 38 ( s 2H ) 5. 76 ( m 2H ) 6 84 ( m 4H ) 7. 22 ( m 4 H ) 1 3 C N M R ( 125M H z C D C l 3 one di a s t e r e om e r r e por t e d) :

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76 # 13. 8 28 1, 55. 1 61 6, 63. 9 7 9 6, 113. 2 113 9, 1 27. 3, 127. 9 131 8, 154. 9 158 8, 167. 3 203. 2 2 [ t e r t B u t oxyc ar b on yl am i n o ( 4 m e t h oxy p h e n yl ) m e t h yl 3 oxo b u t yr i c ac i d al l yl e s t e r ( 144a) T o a f l a m e dr i e d t e s t t ube w a s a dde d ( R ) V A P O L phos phor i c a c i d ( 0. 006 g, 10 m ol % ) 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. D i c hl or om e t ha ne ( 1. 0 m L ) w a s a dde d a nd t he s ol ut i on w a s c ool e d t o 20 C A l l yl a c e t oa c e t a t e ( 15 L 0. 11 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube T he i m i ne ( 0. 0 24 g, 0 1 m m ol ) w a s a dde d qui c kl y t o t he t e s t t ub e a nd t he r e a c t i on w a s s t i r r e d a t 20 C f or 20 h. T he r e a c t i on w a s di l ut e d w i t h e t hyl a c e t a t e c onc e nt r a t e d on s i l i c a g e 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 w i t h he xa ne s / e t hyl a c e t a t e R e c ove r e d w hi t e s ol i d ( 0. 019 g, 50% ) H P L C a na l ys i s : C h i r a l c e l A 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 17. 99 m i n a nd 28. 32 m i n, t r m i n o r 21. 45 m i n a nd 29. 67 m i n. 1 H N M R ( 500M H z C D C l 3 bot h di a s t e r e om e r s r e por t e d) : # 1. 34 ( s 9H ) 136 ( s 6 H ) 1 41 ( s 9H ) 2 17 ( s 4H ) 2. 25 ( s 1H ) 3. 71 ( s 6H ) 4. 01 ( m 1H ) 4. 47 ( m 3H ) 4 83 ( s 2H ) 5. 14 ( m 3H ) 5. 35 ( s 1H ) 5. 73 ( m 1H ) 5. 95 ( s 1H ) 6. 80 ( m 4H ) 7. 18 ( m 4H ) 1 3 C N M R ( 125M H z C D C l 3 one di a s t e r e om e r r e por t e d) :

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77 # 29. 9 54 9, 64. 4 65 5, 79. 1 113 5, 113. 8 118 6, 127. 4, 128. 0 131 2, 154. 8 156 5, 158. 8, 166 8, 202. 8 2 [ t e r t B u t oxyc ar b on yl am i n o ( 4 f l u or o p h e n yl ) m e t h yl ] 3 oxo b u t yr i c ac i d al l yl e s t e r ( 144b ) T o a f l a m e dr i e d t e s t t ube w a s a dde d ( R ) V A P O L phos phor i c a c i d ( 0. 006 g, 10 m ol % ) 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. D i c hl or om e t ha ne ( 1. 0 m L ) w a s a dde d a nd t he s ol ut i on w a s c ool e d t o 20 C A l l yl a c e t oa c e t a t e ( 15 L 0. 11 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube T he i m i ne ( 0. 0 22 g, 0 1 m m ol ) w a s a dde d qui c kl y t o t he t e s t t ube a nd t he r e a c t i on w a s s t i r r e d a t 20 C f or 20 h. T he r e a c t i on w a s di l ut e d w i t h e t hyl a c e t a t e c onc e nt r a t e d on s i l i c a g e 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 w i t h he xa ne s / e t hyl a c e t a t e R e c ove r e d w hi t e s ol i d ( 0. 014 g, 38% ) H P L C a na l ys i s : C hi r a l c e l A 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. 47 m i n a nd 15. 53 m i n, t r m i n o r 14. 80 m i n a nd 15. 53 m i n. 1 H N M R ( 500M H z C D C l 3 bot h di a s t e r e om e r s r e por t e d) : # 1. 40 ( m 18H ) 2. 19 ( s 6H ) 4. 02 ( s 2H ) 4. 56 ( s 2H ) 5. 23 ( m 2H ) 5. 39 ( s 2H ) 5. 82 ( m 2H ) 5. 86 ( m 2H ) 7. 00 ( m 4H ) 7 29 ( m 4H ) 1 3 C N M R ( 125M H z C D C l 3 one di a s t e r e om e r r e por t e d) : # 28. 3 54 4, 63. 6 66 3, 79. 9 115 5, 127. 9 128 6, 130. 9, 135. 6 154 9, 161. 1 163 1, 166. 8, 202 7.

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78 4. 2 E xp e r i m e n t al P r oc e d u r e s f or C h ap t e r 3 P r oc e dur e f o r t he P r e pa r a t i on of A z i r i di ne S ubs t r a t e s C au t i on A z i d e s ar e p ot e n t i al l y e xp l os i ve e s p e c i al l y w h e n c on c e n t r at e d A z i r i di ne s 181a 181b a nd 181c w e r e p r e pa r e d by l i t e r a t ur e pr oc e dur e 7 7 A z i r i di ne s 181d 186a 186b 186c 186e a nd 186f w e r e pr e pa r e d by t he l i t e r a t ur e pr oc e dur e 7 8 6 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 6 az ab i c yc l o[ 3. 1. 0 ] h e xan e ( 186d ) w a s pr e pa r e d by t he f ol l ow i ng m odi f i e d p r oc e dur e of t he r e por t e d m e t hod. 7 8 7 9 T o a s ol ut i on of 3: 1 M e O H : H 2 O ( 300 m L ) w a s a dde d c yc l ope nt e ne oxi de ( 184 ) ( 13 m L 149. 0 m m ol ) f ol l ow e d by t he a ddi t i on of N a N 3 ( 19. 4 g, 298. 0 m m ol ) a nd N H 4 C l ( 12. 4 g, 223. 5 m m ol ) T he m i xt u r e w a s he a t e d a t 60 C f or 13 h. M os t of t he M e O H w a s e va por a t e d i n va c uo a nd t he n e xt r a c t e d t hr e e t i m e s w i t h C H 2 C l 2 w a s he d w i t h br i ne d r i e d ove r N a 2 S O 4 a nd c onc e n t r a t e d t o a f f o r d 2 a s a t a n oi l ( 17. 7 g, 94% ) A z i do a l c ohol 185 ( 5. 0 g 39 3 m m ol ) w a s a dde d t o a f l a m e dr i e d f l a s k. 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 nhydr ous T H F ( 40. 0 m L ) w a s a dde d f ol l ow e d by P P h 3 ( 12. 3 g, 47. 0 m m ol ) a nd he a t e d unde r r e f l ux f or 15 h. M o s t of t he T H F w a s r e m ove d i n va c uo a t a m bi e nt t e m pe r a t ur e A dde d 10% N a O H ( 50 m L ) a nd r e f l uxe d f or

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79 12 h t he n e xt r a c t e d t hr e e t i m e s e a c h w i t h e t he r t he n C H 2 C l 2 w a s he d w i t h br i ne dr i e d ove r M gS O 4 a nd c onc e nt r a t e d a t a m bi e nt t e m pe r a t ur e l e a vi ng a bout 100 m L C H 2 C l 2 B e nz oyl a t i on w a s c om pl e t e d i n C H 2 C l 2 f ol l ow i ng t he r e por t e d l i t e r a t ur e pr oc e dur e 7 8 C a l c ul a t i ons f or t he be nz oyl a t i on w e r e ba s e d on us i ng 18. 1 m m ol 3, 5 bi s ( t r i f l uo r om e t hyl ) be nz oyl c hl or i de c i s 1 ( 3 5 B i s t r i f l u or om e t h yl b e n z oy l ) 2, 3 d i p h e n yl az i r i d i n e ( 186g) w a s pr e pa r e d b y t he f ol l ow i ng m odi f i e d p r oc e dur e of t he r e por t e d m e t hod. 7 8 8 0 T o a s ol ut i on of 3: 1 M e O H : H 2 O ( 40 m L ) w a s a dde d c i s s t i l be ne oxi de ( 187 ) ( 5 2 g, 27. 0 m m ol ) f ol l ow e d by t he a ddi t i on of N a N 3 ( 3 5g, 54 m m ol ) a nd N H 4 C l ( 2 2 g, 40. 5 m m ol ) T he m i xt ur e w a s he a t e d a t 60 C f or 13 h. M os t of t he M e O H w a s e va por a t e d i n va c uo a nd t he n e xt r a c t e d t hr e e t i m e s w i t h C H 2 C l 2 w a s he d w i t h br i ne dr i e d ove r N a 2 S O 4 a nd c onc e nt r a t e d t o a f f o r d a t a n oi l ( 6 g, 76% ) A z i do a l c ohol 188 ( 4. 0 g 13. 6 m m ol ) w a s a dde d t o a f l a m e dr i e d f l a s k. 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 nhydr ous C H 3 C N ( 16. 0 m L ) w a s a dde d f ol l ow e d by P P h 3 ( 3. 6 g, 13. 6 m m ol ) a nd a l l ow e d t o s t i r f or 1 h a t a m bi e nt t e m pe r a t ur e a nd t he n pl a c e d i n a 2 0 C f r e e z e r ove r ni ght A w hi t e pr e c i pi t a t e f or m e d w hi c h w a s r e c ove r e d by f i l t r a t i on T he c r ys t a l s w e r e put i n C H 2 C l 2 ( 6. 0 m L ) a nd c onc e nt r a t e d a c e t i c

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80 a c i d ( 12 m L ) w a s a dde d a nd s t i r r e d f or 30 m i n. T he s ol ut i on w a s di l ut e d w i t h e t he r ( 100 m L ) a nd e xt r a c t e d t w i c e w i t h 2M H C l A dde d 2M N a O H t o t he H C l l a ye r unt i l ba s i c a nd e xt r a c t e d t w i c e w i t h C H 2 C l 2 dr i e d ove r N a 2 S O 4 a nd c onc e nt r a t e d. T he be nz oyl a t i on w a s c om pl e t e d i n C H 2 C l 2 f ol l ow i ng t he r e por t e d l i t e r a t ur e pr oc e dur e 7 8 C a l c ul a t i ons f or t he be nz oyl a t i on w e r e ba s e d on us i ng 18 1 m m ol 3, 5 bi s ( t r i f l uo r om e t hyl ) be nz oyl c hl or i de 3 O xa 6 ( 3, 5 B i s t r i f l u or o m e t h yl b e n z oyl ) 6 az b i c yc l o[ 3. 1. 0] h e xan e ( 186h ) w a s pr e pa r e d by t he f ol l ow i ng m odi f i e d pr oc e dur e o f t he r e por t e d m e t hod 7 8 8 1 8 2 8 3 2, 4 D i hydr of u r a n ( 191 ) ( 5. 3 m L 71. 3 m m ol ) w a s a dde d t o a 500 m L r ound bot t om f l a s k c ont a i ni ng C H 2 C l 2 ( 250 m L ) m C P B A w a s a dde d a nd t he s ol ut i on s t i r r e d a t a m bi e nt t e m pe r a t ur e f or t w o da ys T he s ol ut i on w a s w a s h e d t w i c e w i t h a que ou s N a 2 S 2 O 3 t he n s a t N a 2 C O 3 a nd dr i e d ove r N a 2 S O 4 T he o r ga ni c l a ye r w a s t he n c onc e nt r a t e d t o a f f or d t he e poxi de a s a c ol or l e s s oi l ( 3 7 g 66% ) N a N 3 ( 11. 2 g 172 m m ol ) a nd N H 4 C l ( 3. 6 g, 64. 5 m m ol ) w e r e a dde d t o 80 m L 95% M e O H i n H 2 O a nd s t i r r e d unt i l m os t di s s ol ve d. T he a bove e poxi de ( 3. 7 g, 43 m m ol ) w a s a dde d a nd t he s ol ut i on w a s he a t e d a t 75 C f or 20 h I t w a s t he n c ool e d t o r oom t e m pe r a t ur e a nd f i l t e r e d t o r e m ove e xc e s s N a N 3 T he f i l t r a t e w a s di l ut e d w i t h w a t e r

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81 a nd e xt r a c t e d f our t i m e s w i t h E t O A c dr i e d ove r N a 2 S O 4 a nd c onc e nt r a t e d t o a f f or d a z i do a l c ohol 192 a s a t a n oi l ( 4 3 g 78 % ) T o a f l a m e dr i e d 100 m L r ound bot t om f l a s k unde r a r gon w a s a dde d 10% P d/ C ( 304 m g) f ol l ow e d by M e O H ( 15 m L ) w hi l e s t i r r i ng. A dde d a z i do a l c ohol 192 vi a s yr i nge a nd s t i r r e d unde r a n a t m os phe r e of hydr oge n f o r 48 h. R e a c t i on w a s m oni t or e d by T L C unt i l c om pl e t i on a nd f i l t e r e d ove r a pa d of c e l i t e a nd c onc e nt r a t e d t o a f f or d t he a m i no a l c ohol a t a n s ol i d ( 1. 5 g, 94% ) T he a m i no a l c ohol ( 1 5 g, 14. 5 m m o l ) w a s a dde d t o a 100 m L r ound bot t om f l a s k. A ppr oxi m a t e l y 4 m L H 2 O w a s a dde d a nd t he m i xt ur e c ool e d t o 0 C C onc e nt r a t e d H 2 S O 4 ( 0 78 m L ) i n H 2 O ( 1. 8 m L ) w a s a dde d dr op w i s e a nd t he m i xt ur e s t i r r e d a t 0 C f or 1 h. T he H 2 O w a s r e m ove d by di s t i l l a t i on a nd c ont i nue d he a t i ng a t 100 C f or 1 h A dde d 20% N a O H a nd he a t e d a t 100 C ove r ni ght T he s ol ut i on w a s c ool e d t o r oom t e m pe r a t ur e a nd e xt r a c t e d f our t i m e s w i t h C H 2 C l 2 a nd dr i e d ove r N a 2 S O 4 M os t of t he s ol ve nt w a s r e m ove d c a r e f ul l y i n va c uo ( t he r e s ul t i ng a z i r i di ne i s vol a t i l e ) T he be nz oyl a t i on w a s c om pl e t e d i n C H 2 C l 2 f ol l ow i ng t he r e por t e d l i t e r a t u r e pr oc e dur e 3 C a l c ul a t i ons f or t he be nz oyl a t i on w e r e ba s e d on us i ng 18. 1 m m ol 3, 5 bi s ( t r i f l uo r om e t hyl ) be nz oyl c hl or i de 3 C ar b ob e n z yl oxy 6 ( 3, 5 B i s t r i f l u or om e t h yl b e n z oyl ) 3, 6 d i az b i c yc l o[ 3. 1. 0 ] h e xan e ( 186i ) w a s pr e pa r e d by t he f ol l ow i ng m odi f i e d pr o c e dur e of t he r e por t e d m e t hod. 7 8 8 4

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82 T o a s ol ut i on of 4: 1 M e O H : H 2 O w a s a dde d e p oxi de 193 ( 4. 8 g 22. 0 m m o l ) f ol l ow e d by t he a ddi t i on of N a N 3 ( 2. 86 g, 44. 0 m m ol ) a nd N H 4 C l ( 1. 8 g, 33 0 m m ol ) w hi l e s t i r r i ng. T he m i xt u r e w a s he a t e d a t 70 C f or 20 h a nd t he n di l ut e d w i t h H 2 O e xt r a c t e d t hr e e t i m e s w i t h C H 2 C l 2 a nd dr i e d ove r N a 2 S O 4 T he or ga ni c l a ye r w a s c onc e nt r a t e d t o a f f or d a r e d oi l w hi c h w a s c a r r i e d on t o t he ne xt s t e p. T he a i r w a s r e m ove d f r om t he f l a s k a nd r e pl a c e d w i t h a r gon. P yr i di ne ( 13. 0 m L ) w a s a dde d a n d c ool e d t o 0 C M e t ha ne s ul f onyl c hl or i de ( 1 9 m L 24. 2 m m ol ) w a s a dde d s l ow l y dr opw i s e vi a s yr i nge T he s ol ut i on w a s a l l ow e d t o w a r m t o a m bi e nt t e m pe r a t ur e a nd s t i r r e d f or 20 h. T he r e a c t i on m i xt u r e w a s p our e d ove r i c e c ol d H 2 O a nd e xt r a c t e d w i t h C H 2 C l 2 t w i c e a nd t he n w a s he d w i t h t w o 50 m L p or t i ons of 1M H C l f ol l ow e d by br i ne T he or ga ni c pha s e w a s c onc e nt r a t e d t o a f f o r d a r e d oi l ( 6 1 g 82% ) w hi c h w a s di l ut e d w i t h E t O H ( 60 m L ) a nd a dde d t o a 500 m L f l a s k c ont a i ni ng a 0 C s ol ut i on of C oB r 2 H 2 O ( 0. 92 g 4 m m ol ) a nd 2 2 di py r i dyl ( 2. 2 g, 14 m m ol ) i n 300 m L a bs ol ut e E t O H S odi um bor ohydr i de ( 3. 1 g, 82. 0 m m ol ) w a s a dd e d ve r y s l ow l y i n s m a l l por t i ons ove r 1 h w hi l e ke e pi ng a t 0 C T he m i xt ur e w a s a l l ow e d t o s l ow l y w a r m t o a m bi e nt t e m pe r a t ur e a nd s t i r r e d f o r a n a ddi t i ona l 2 h T he m i xt ur e w a s t he n s l ow l y pour e d ove r H 2 O ( 1000 m L ) a nd e xt r a c t e d t hr e e t i m e s w i t h C H 2 C l 2 dr i e d ove r N a 2 S O 4 a nd

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83 c onc e nt r a t e d t o a f f or d a br ow n oi l w hi c h w a s pur i f i e d by f l a s h c ol um n c hr om a t ogr a phy w i t h C H 2 C l 2 a nd M e O H R e c ove r e d 3 77 g 97% of a z i r i di ne 195 A z i r i di ne 195 ( 2. 0 g, 9 2 m m ol ) w a s a dde d t o a n ove n dr i e d f l a s k. 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. C H 2 C l 2 ( 20 m L ) w a s a dde d f ol l ow e d by E t 3 N ( 1 4 m L 10. 1 m m ol ) a nd c ool e d t o 0 C A bubbl e r w a s a t t a c he d t o t he f l a s k a nd 3, 5 B i s ( t r i f l uo r om e t hyl ) be nz oyl c hl or i de ( 1. 64 m L 9 2 m m ol ) i n C H 2 C l 2 ( 6 0 m L ) w a s a dde d s l ow l y dr opw i s e T he S ol ut i on w a s s t i r r e d a t 0 C f or 1 h. H 2 O ( 20 m L ) w a s a dd e d a nd l e t w a r m t o a m bi e nt t e m pe r a t ur e a nd e xt r a c t e d t hr e e t i m e s w i t h C H 2 C l 2 w a s he d w i t h br i ne dr i e d ove r N a 2 S O 4 c onc e nt r a t e d 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 w i t h 6: 1 he xa ne s : a c e t one t o a f f o r d a 186 i a s a c ol o r l e s s oi l ( 1. 8 g, 47% ) 7 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 7 az ab i c yc l o[ 3. 1. 0 ] h e p t a n e ( 186a) w hi t e s ol i d M p = 39. 7 40 5 C 1 H N M R ( 500M H z C D C l 3 ) : # 1. 3 8 ( m 2H ) 1 57 ( m 2H ) 1. 94 ( m 2H ) 2. 02 ( m 2H ) 2. 81 ( m 2H ) 8 02 ( s 1H ) 8. 41 ( s 1H ) ( d, J = 7. 3 H z 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 19. 8 23 7, 37. 9 1 21 5, 121 9, 124. 0 125 7, 1 26. 5 129 1, 132. 0 ( q, J = 34 H z ) 135. 6 177 0. H R M S ( E S I ) C a l c d f o r C 1 5 H 1 3 F 6 N O ( [ M + H ] + ) 338. 0974 F ound 338. 0972

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84 7 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 7 az ab i c yc l o[ 4. 1. 0 ] h e p t 3 e n e ( 186b ) w hi t e s ol i d. M p = 85. 3 85. 9 C 1 H N M R ( 500 M H z C D C l 3 ) : # 2. 52 ( d, J = 17. 9 H z 2H ) 2. 63 ( d, J = 17. 9 H z 2H ) 2. 96 ( s 2H ) 5. 58 ( s 2H ) 8 02 ( s 1H ) 8. 39 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 23. 9, 37 0, 121 8, 122 2, 124 0, 125. 8 126. 2, 129 1, 132 0 ( q, J = 34 H z ) 135. 7, 176. 6 H R M S ( E S I ) C a l c d f o r C 1 5 H 1 1 F 6 N O ( [ M + H ] + ) 336. 0818 F ound 336. 0819 8 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 8 az b i c yc l o[ 5. 1. 0] oc t an e ( 186c ) w hi t e s ol i d M p = 33. 8 34. 8 C 1 H N M R ( 500M H z C D C l 3 ) : # 1. 29 ( m 1H ) 1. 65 ( m 5H ) 2 00 ( m 4H ) 2. 76 ( s 2H ) 8. 01 ( s 1H ) 8 38 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 2 5. 3, 2 8. 8, 31. 2 42. 6, 119 7, 121. 8 1 24 0, 125. 6 126 2, 128. 0 13 2. 0 ( q J = 34 H z ) 135 5, 176. 8 H R M S ( E S I ) C a l c d f o r C 1 6 H 1 5 F 6 N O ( [ M + H ] + ) 352 1131 F ound 352. 1131 6 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 6 az ab i c yc l o[ 3. 1. 0 ] h e xan e ( 186 d ) c ol o r l e s s oi l 1 H N M R ( 500M H z C D C l 3 ) : # 1. 68 1. 78 ( m 4H ) 2. 10 2. 14 ( m 2H ) 3. 24 ( s 2H ) 8. 01 ( s 1H ) 8. 38 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 1 9. 4, 26. 9 44. 4 1 19. 7, 121 9, 124. 0 125. 7, 1 26. 2 128. 8, 132 0 ( q, J = 34 H z ) 1 35 6, 174. 9 H R M S ( E S I ) C a l c d f or C 1 4 H 1 1 F 6 N O ( [ M + H ] + ) 324. 0818 F ound 324 0817

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85 N ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 2, 3 i m i n ot e t r al i n ( 186e ) w hi t e s ol i d M p = 119. 5 120. 8 C 1 H N M R ( 500M H z C D C l 3 ) : # 3. 20 3. 2 5 ( m 4H ) 3. 34 ( m 2H ) 7. 08 ( m 2H ) 7. 20 ( m 2H ) 8 00 ( s 1H ) 8 25 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 29. 5 37 8, 121 8, 123. 9, 125 7, 127. 2 128 8, 128. 9 129 2, 131. 8 1 31. 9, 132 1, 135. 6 175 9 H R M S ( E S I ) C a l c d f or C 1 9 H 1 3 F 6 N O ( [ M + H ] + ) 386. 0974 F ound 386. 0973 c i s 1 ( 3, 5 B i s t r i f l u or om e t h yl b e n z oyl ) 2 3 d i m e t h yl az i r i d i n e ( 186f ) w hi t e s ol i d M p = 42. 3 43. 3 C 1 H N M R ( 500M H z C D C l 3 ) : # 1 3 8 ( m 6H ) 2 68 ( m 2H ) 8. 02 ( s 1H ) 8. 40 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 12 6, 38. 102 119. 7 121 9, 124 0, 125. 8 126. 2, 129 1, 132 0 ( q J = 34 H z ) 135. 5, 176 9 H R M S ( E S I ) C a l c d f or C 1 3 H 1 1 F 6 N O ( [ M + H ] + ) 312. 0818 F ound 312 0820 c i s 1 ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) 2, 3 d i p h e n yl az i r i d i n e ( 186g) w hi t e s ol i d. M p = 94. 0 95. 5 C 1 H N M R ( 500M H z C D C l 3 ) : # 4 15 ( s 2H ) 7 21 7 26 ( m 10H ) 8. 02 ( s 1H ) 8 50 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 4 7 3, 121. 7 123. 8 126 3, 126. 5 127. 8, 127. 9 128. 2 128. 9, 129 3, 132 2, ( q J = 34 H z ) 132. 7, 134. 5, 176 5. H R M S ( E S I ) C a l c d f or C 2 3 H 1 5 F 6 N O ( [ M + H ] + ) 436. 1130 F ound 436. 1122

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86 3 O xa 6 ( 3, 5 B i s t r i f l u or o m e t h yl b e n z oyl ) 6 az b i c yc l o[ 3. 1. 0] h e xan e ( 186h ) w hi t e s ol i d. M p = 85. 0 85 8 C 1 H N M R ( 500M H z C D C l 3 ) : # 3 51 ( s 2H ) 3 59 ( d J = 10 5 H z 2H ) 3 96 ( d J = 10 0 H z 2H ) 8 02 ( s 1 H ) 8. 36 ( s 1H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 4 1 6, 65. 9 1 19 6, 1 21. 8 1 23. 9 125 8, 126. 1 128 4, 132. 1 ( q, J = 35 H z ) 135. 6, 173. 2 H R M S ( E S I ) C a l c d f o r C 1 3 H 9 F 6 N O 2 ( [ M + H ] + ) 326. 0610 F ound 326. 0619 3 C ar b ob e n z yl oxy 6 ( 3, 5 B i s t r i f l u or om e t h yl b e n z oyl ) 3, 6 d i az b i c yc l o[ 3. 1. 0 ] h e xan e ( 186i ) c ol or l e s s oi l 1 H N M R ( 500M H z C D C l 3 ) : # 3. 42 ( m 4H ) 3. 99 ( m 2H ) 5. 06 ( m 2H ) 7. 30 ( m 5H ) 8. 04 ( s 1H ) 8. 33 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 41. 6, 46. 0 46. 5, 67. 2 119. 5 121. 7, 123 9, 126 0, 126. 2 127. 9, 128. 1, 128 5, 128. 7 132. 3 ( q, J = 34 H z ) 134. 9, 136. 2, 154. 8 173. 7. H R M S ( E S I ) C a l c d f or C 2 1 H 1 6 F 6 N 2 O 3 ( [ M + N a ] + ) 481. 0957 F ound 481 0961. G e ne r a l P r oc e dur e f o r t he P r e pa r a t i on of R a c e m i c P r oduc t s T he a z i r i di ne ( 0 25 m m ol ) phe nyl phos phi ni c a c i d, T f 2 N H o r a m i xt u r e of ( R ) a nd ( S ) V A P O L phos phor i c a c i d ( 10 t o 100 m ol % ) w e r e w e i ghe d i nt o a t e s t t ube T he a i r w a s r e m ove d unde r va c uum a nd r e pl a c e d w i t h a r gon. T M S N 3 ( 0 67 4 e qui v. ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by ( C H 2 C l ) 2 or C H 2 C l 2 ( 0. 5 m L ) 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 u r e t o 60 C unt i l p r oduc t f or m a t i o n w a s s i gni f i c a nt w hi c h w a s

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87 m oni t or e d by T L C 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. P r oc e dur e s f or t he D e s ym m e t r i z a t i on o f m e s o A z i r i di ne s T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 25 0. 38 m m ol ) a nd a c i d c a t a l ys t ( 10 m ol % ) 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. T M S N 3 ( 0. 25 1 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 25 1 0 m L ) 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 t o 60 C a nd m oni t or e d by T L C 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. 1 A z i d o 2 [ N ( 3 5 B i s t r i f l u or om e t h yl b e n z oyl ) a m i n o] c yc l oh e xan e ( 196a) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 128 g, 3. 38 m m ol ) a nd ( S ) P A 5 ( 15m g 10 m ol % ) 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 T M S N 3 ( 33 L 0. 25 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f o r 21 h T h e 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 w i t h he xa ne s / E t O A c R e c ove r e d w hi t e s ol i d ( 0. 093 g, 97 % ) M p = 138. 9 139. 4 C H P L C a na l ys i s : C hi r a l c e l A S 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 6. 15 m i n, t r m a j o r 8. 65 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 1 28 1 41 ( m 3H ) 1. 47 1 55 ( m 1H ) 1 76 ( m 1H ) 1 87 ( m 1H ) 2 16 ( m 2H ) 3. 27 ( m 1H ) 3. 95 ( m 1H ) 6. 34 ( d, J = 7. 7 H z 1H ) 7. 98 ( s 1H ) 8. 19 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 24. 1, 24. 2 30 6, 31. 9 53 7, 63. 5 119. 7

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88 121. 8, 123 9, 125. 0 125 4, 127. 3 132 1 ( q J = 34 H z ) 136 6, 164. 6 H R M S ( E S I ) C a l c d f or C 1 5 H 1 4 F 6 N 4 O ( [ M + H ] + ) 381 1145 F ound 381. 1 140 [ ] 2 9 D + 63 8 ( c = 1 04, C H C l 3 ) 4 A z i d o 5 [ N ( 3 5 B i s t r i f l u or o m e t h yl b e n z oyl ) a m i n o] c yc l oh e xe n e ( 196b ) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 127 g, 0. 38 m m ol ) a nd ( S ) P A 5 ( 15m g 10 m ol % ) 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 T M S N 3 ( 33 L 0. 25 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f o r 21 h T h e 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 w i t h he xa ne s / E t O A c R e c ove r e d w hi t e s ol i d ( 0. 080 g, 8 4% ) M p = 126. 3 128. 4 C H P L C a na l ys i s : C hi r a l c e l A S H ( he xa ne / i P r O H = 95 / 5 1. 0 m L / m i n ) t r m i n o r 11. 33 m i n, t r m a j o r 18. 73 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 2 16 2 25 ( m 2H ) 2. 49 2 59 ( m 2H ) 3 72 ( m 1H ) 4 20 ( m 1H ) 5. 62 ( m 2H ) 7. 24 ( d J = 8. 0H z 1H ) 7. 90 ( s 1H ) 8. 16 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 2 9. 9, 30. 8, 49. 8 59. 2, 119 5, 121. 7 123. 8, 124. 6 124. 9 126. 0, 127. 4, 127 4, 132 0, ( q, J = 34 H z ) 136. 3 165. 2 H R M S ( E S I ) C a l c d f or C 1 5 H 1 2 F 6 N 4 O ( [ M + H ] + ) 379. 0988 F ound 379. 0997 [ ] 2 9 D + 70. 3 ( c = 1 10, C H C l 3 ) t r an s 1 A z i d o 2 [ N ( 3, 5 B i s t r i f l u or om e t h yl b e n z oyl ) am i n o] c yc l oh e p t an e ( 196c ) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 088 g, 0. 25 m m o l ) a nd ( S ) P A 5 ( 15m g, 10

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89 m ol % ) 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. T M S N 3 ( 66 L 0 50 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f or 91 h. 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 o m a t ogr a phy w i t h he xa ne s / E t O A c R e c ove r e d w hi t e s ol i d ( 0. 063 g, 64% ) M p = 139. 3 140. 9 C H P L C a na l ys i s : C hi r a l c e l A S 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 5. 35 m i n, t r m a j o r 8. 27 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 1. 51 1. 57 ( m 3H ) 1. 60 1 81 ( m 5H ) 1. 89 1 99 ( m 2H ) 3. 53 ( m 1H ) 4 02 ( m 1H ) 7 17 ( d J = 7 8, 1H ) 7. 91 ( s 1H ) 8 17 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 22. 9 23 8, 27 3, 30 5, 31 8, 56. 5, 66 5, 119 5, 121 7, 128. 9 124. 8 126. 0, 127 4, 131 9 ( q J = 34 H z ) 136 5, 164 6 H R M S ( E S I ) C a l c d f or C 1 6 H 1 6 F 6 N 4 O ( [ M + H ] + ) 395. 1301 F ound 395. 1302 [ ] 2 9 D + 36. 9 ( c = 1 04, C H C l 3 ) t r an s 1 A z i d o 2 [ N ( 3, 5 B i s t r i f l u or o m e t h yl b e n z oyl ) am i n o] c yc l op e n t an e ( 196d ) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 12 g 0. 38 m m ol ) a nd ( S ) P A 5 ( 1 5m g 10 m ol % ) 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. T M S N 3 ( 33 L 0 25 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f or 48 h. 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 w i t h he xa ne s / E t O A c R e c ove r e d c ol or l e s s oi l ( 0. 063 g, 84% ) M p = 99. 5 100. 5 C H P L C a na l ys i s : C hi r a l c e l A S H ( he xa ne / i P r O H = 95 / 5 1. 0 m L / m i n ) t r m i n o r 12. 16 m i n, t r m a j o r 14. 04 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 1. 62 1. 82 ( m 4H ) 2. 02 2 08 ( m 1H ) 2. 14 2 22 ( m 1H ) 3. 90 ( q, J = 6. 7H z 1H ) 4 25 ( m 1H ) 7. 41 ( d, J = 7. 7 H z 1H ) 7. 86 ( s 1H ) 8. 12 ( s 2H ) 1 3 C N M R ( 125 M H z C D C l 3 ) : # 16. 9, 18. 7, 49. 5 61. 7, 119. 6 121. 8, 1 23. 9 125. 1, 127. 2

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90 132. 2 ( q J = 34 H z ) 136 4, 164 3. H R M S ( E S I ) C a l c d f or C 1 4 H 1 2 F 6 N 4 O ( [ M + H ] + ) 367. 0988 F ound 367 0988 [ ] 2 9 D + 40 2 ( c = 1 01, C H C l 3 ) t r an s 2 A z i d o 3 [ N ( 3, 5 B i s t r i f l u or o m e t h yl b e n z oyl ) am i n o] t e t r al i n ( 196e ) T o a f l a m e dr i e d t e s t t u be w a s a dde d a z i r i di ne ( 0. 096 g, 0. 25 m m o l ) a nd ( S ) P A 5 ( 15m g, 10 m ol % ) 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. T M S N 3 ( 66 L 0 50 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 1. 0 m L ) T he r e a c t i on w a s s t i r r e d a t a m b i e nt t e m pe r a t ur e f or 48 h. 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 w i t h he xa ne s / C H 2 C l 2 R e c ove r e d w hi t e s ol i d ( 0. 096 g, 90% ) M p = 146. 8 147. 6 C H P L C a na l ys i s : C hi r a l c e l A S 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 05 m i n t r m a j o r 15 71 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 2. 89 ( m 1H ) 3 0 ( m 1H ) 3 23 ( dd 11. 4 5. 3 H z 1H ) 3. 39 ( dd 11 3, 5. 4 H z 1H ) 3 98 ( m 1H ) 4. 41 ( m 1H ) 6 62 ( d, J = 7 6H z 1H ) 7 05 7. 18 ( m 4H ) 7. 97 ( s 1H ) 8 18 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 33. 1, 33. 9 50. 3 59. 4, 119 5, 121. 7 123. 9 125 2, 126. 0 126. 9 12 7. 3, 128 9, 128. 9 132. 3 ( q J = 34 H z ) 136. 2, 164 9. H R M S ( E S I ) C a l c d f or C 1 9 H 1 4 F 6 N 4 O ( [ M + H ] + ) 429. 1145 F ound 429 1146 [ ] 2 9 D + 53 3 ( c = 1 07, C H C l 3 )

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91 an t i 2 A z i d o 3 [ N ( 3, 5 B i s t r i f l u or o m e t h yl b e n z o yl ) am i n o] b u t an e ( 196f ) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 118 g, 0. 38 m m ol ) a nd ( S ) P A 5 ( 15m g 10 m ol % ) 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 T M S N 3 ( 33 L 0. 25 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f o r 21 h T h e 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 w i t h he xa ne s / E t O A c R e c ove r e d c ol or l e s s oi l ( 0. 077 g, 88 % ) M p = 50. 7 51. 4 C 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 = 95 / 5 1 0 m L / m i n ) t r m i n o r 5. 76 m i n, t r m a j o r 6. 96 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 1. 31 ( m 6H ) 3 74 ( m 1H ) 4 29 ( m 1H ) 6. 3 4 ( br s 1H ) 7. 98 ( s 1H ) 8 17 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 16. 9 18 7, 49. 5 61 7, 119. 6 121. 8, 123 9, 125. 1 127. 2 132. 2 ( q, J = 34 H z ) 136. 4, 164. 3 H R M S ( E S I ) C a l c d f or C 1 3 H 1 2 F 6 N 4 O ( [ M + H ] + ) 355 0988 F ound 355 0985 [ ] 2 9 D + 28 3 ( c = 1 15, C H C l 3 ) an t i 1 A z i d o 2 [ N ( 3, 5 B i s t r i f l u or o m e t h yl b e n z o yl ) am i n o] 1, 2 d i p h e n yl e t h an e ( 196g ) T o a f l a m e dr i e d t e s t t ube w a s a dd e d a z i r i di ne ( 0. 16 g, 0. 38 m m ol ) a nd ( S ) P A 5 ( 15m g, 10 m ol % ) 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. T M S N 3 ( 33 L 0. 25 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 1 0 m L ) T he r e a c t i on 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 f or 48 h. 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 w i t h he xa ne s / E t O A c R e c ove r e d w hi t e s ol i d ( 0. 113 g, 95% ) M p = 140. 3 11. 0 C H P L C a na l ys i s : C hi r a l c e l A S H ( he xa ne / i P r O H = 98 / 2 1. 0 m L / m i n ) t r m a f o r 13 49 m i n t r m i n o r 20. 61 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 4. 97 ( d J = 6. 1 H z 1H ) 5. 48 ( t J = 6. 6 H z 1H ) 7. 21 7 31 ( m 10H ) 7 44 ( br s 1H ) 7. 90 ( s 1H ) 8. 09 ( s 2H ) 1 3 C N M R ( 125M H z

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92 C D C l 3 ) : # 58 8, 71. 6 119 5, 121. 6 123 8, 125. 1 1 25. 9, 126 9, 127. 1 127 3, 127. 3 128 1, 128. 6, 128 8, 132 0 ( q J = 34 H z ) 136 2, 164 5 H R M S ( E S I ) C a l c d f or C 2 3 H 1 6 F 6 N 4 O ( [ M + N a ] + ) 501. 1121 F ound 501. 1128 [ ] 2 9 D + 33. 0 ( c = 1 05, C H C l 3 ) t r an s 3 A z i d o 4 [ N ( 3, 5 B i s t r i f l u or o m e t h yl b e n z oyl ) am i n o] t e t r ah yd r of u r an ( 196h ) T o a f l a m e d r i e d t e s t t ube w a s a dde d a z i r i di ne ( 0 081 g, 0 25 m m ol ) a nd ( S ) P A 5 ( 15m g 10 m ol % ) 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. T M S N 3 ( 132 L 1. 0 m m ol ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1, 2 di c hl or oe t ha ne ( 0 25 m L ) T he r e a c t i on 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 f or 48 h. 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 w i t h C H 2 C l 2 / e t he r R e c ove r e d w hi t e s ol i d ( 0 045 g 49% ) M p = 103. 3 104 6 C H P L C a na l ys i s : C hi r a l c e l A S H ( he xa ne / i P r O H = 98 / 2 0. 75 m L / m i n ) t r m i n o r 30 39 m i n t r m a j o r 32. 55 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 3. 68 ( dd, J = 6. 8H z 1H ) 3 89 ( m 1H ) 4 03 4. 07 ( m 1H ) 4. 11 4. 18 ( m 1H ) 4 19 ( m 1H ) 4. 56 ( m 1H ) 7 01 ( b r s 1H ) 7 98 ( s 1H ) 8 21 ( s 2H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 57. 4 66 2, 70. 9 71 5, 119. 1 121 7, 123. 8, 125 4 126. 0 127. 4 132. 2 ( q, J = 34 H z ) 135. 4, 164. 7 H R M S ( E S I ) C a l c d f or C 1 3 H 1 0 F 6 N 4 O 2 ( [ M + H ] + ) 369. 0781 F ound 369. 078 1 [ ] 2 9 D + 42 7 ( c = 1 04, C H C l 3 )

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93 t r an s 1 C ar b o b e n z yl oxy 3 az i d o 4 [ N ( 3 5 B i s t r i f l u or om e t h y l b e n z oyl ) am i n o] p yr r ol i d i n e ( 196i ) T o a f l a m e dr i e d t e s t t ube w a s a dde d a z i r i di ne ( 0. 110 g, 0. 25 m m ol ) a nd ( S ) P A 5 ( 15m g, 10 m ol % ) 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. T M S N 3 ( 132 L 1. 0 m m o l ) w a s a dde d vi a s yr i nge t o t he t e s t t ube f ol l ow e d by 1 2 di c hl or oe t ha ne ( 0. 5 m L ) T he r e a c t i on 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 f or 96 h 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 w i t h C H 2 C l 2 / e t he r R e c ove r e d w hi t e s ol i d ( 0. 122 g, 96% ) M p = 47. 0 48 4 C 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 = 95 / 5 1. 0 m L / m i n ) t r m a j o r 10 79 m i n t r m i n o r 28 65 m i n 1 H N M R ( 500M H z C D C l 3 ) : # 3 52 4. 01 ( m 4H ) 4. 25 4 39 ( m 1H ) 4 63 4. 71 ( m 1H ) 4. 89 4. 99 ( m 1H ) 513 5. 24 ( m 1H ) 7. 22 7. 24 ( m 3H ) 7. 83( d J = 5. 5 H z 1H ) 8 09 ( m 2H ) 8 51 ( m 3H ) 1 3 C N M R ( 125M H z C D C l 3 ) : # 41. 6, 48. 9, 49. 2 54. 6, 54 9, 63. 1, 64. 0 67. 3 67. 8, 119. 6 121. 8 123. 9, 125 3, 126. 2 127. 6 128. 2 128. 4 128. 5 13 2. 1 ( q, J = 35 H z ) 135 1, 154 9, 164 6. H R M S ( E S I ) C a l c d f or C 2 1 H 1 7 F 6 N 5 O 3 ( [ M + H ] + ) 5 02. 1310 F ound 502. 1312 [ ] 2 9 D + 5. 73 ( c = 1. 03 C H C l 3 ) P r oc e dur e f o r t he D e t e r m i na t i on o f A bs ol ut e S t e r e oc he m i s t r y T he a bs ol ut e s t e r e oc he m i s t r y w a s d e t e r m i ne d by t he r e por t e d l i t e r a t ur e m e t hod. 7 8 C om pound 196a ( 80% e e ) ( R ) P A 5 us e d a s c a t a l ys t ) w a s c onv e r t e d t o t he know n 1, 2 di a m i noc yc l ohe xa ne di hydr oc hl or i de T he opt i c a l r ot a t i on w a s c om pa r e d t o t he l i t e r a t ur e va l ue a nd c om pound 196a w a s de t e r m i ne d t o b e ( 1 R 2 R ) [ ] 2 9 D 8. 65 ( c = 1. 0, H 2 O ) L i t e r a t ur e va l ue [ ] D 15 8 ( c = 2 53, H 2 O ) f or ( 1 R 2 R ) 1 2 di a m i noc yc l ohe xa ne di hydr oc hl or i de

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94 P r e l i m i na r y N M R I nve s t i ga t i on of R e a c t i on M e c ha ni s m P r oc e dur e : A n ove n d r i e d N M R t ube w a s f i t t e d w i t h a s e pt um a nd dr i e d unde r hi gh va c uum T he t ube w a s f i l l e d w i t h a r gon. T he a z i r i di ne ( 40 m g, 0 13 m m ol ) a nd c a t a l ys t P A 5 ( 5 0 m g 0 01 m m ol ) w e r e w e i ghe d i n t o t he N M R t ube T he s e pt um w a s pl a c e d on t he t ube a nd t he a i r w a s r e m ove d by hi gh v a c uum T he N M R t ube w a s f i l l e d w i t h a r gon. T he s ol ve nt w a s a dd e d t o t he t ube vi a s yr i nge T hi s s a m pl e w a s t a ke n a s t h e i ni t i a l s pe c t r um T he T M S N 3 ( 25 L 0. 19 m m ol ) w a s a dde d t o t he t ube vi a s yr i nge A pr ot on N M R s pe c t r um w a s t a k e n a s s oon a s t he s a m pl e w a s pl a c e d i n t he s pe c t r om e t e r a ppr oxi m a t e l y 2 m i nut e s a f t e r t he i nj e c t i on of t he a z i de P r ot on N M R s pe c t r a ( 8 s c a n s ) w e r e t a ke n e ve r y 15 m i nut e s f or t he f i r s t 7. 5 hour s of t he r e a c t i on, f ol l e w e d by i nt e r va l s of 20 m i nut e s f or t he ne xt 2. 3 hour s a nd f i na l l y 40 m i nut e s f or t he ne xt 2 6 hou r s A na l ys i s : T he N M R s pe c t r um i ndi c a t e d t he pr e s e nc e of 186a 196a a nd a ne w c om pound t ha t w e be l i e ve t o be i n t e r m e di a t e 199 T he pr oc e dur e f or t he 1 9 F N M R w a s t he s a m e a s t he 1 H N M R s pe c t r a

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95 I n t e r m e d i at e 199 1 H N M R ( 300 M H z ) # 0. 28 ( s ) 1. 18 ( d, 6. 3 H z ) 1. 27 ( d, 6 3 H z ) 3. 47 ( m ) 3 77 ( m ) 7 91 ( s ) 8 30 ( s ) 1 9 F N M R ( 3 00 M H z ) # 61. 717 ( s ) 3 1 P N M R

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96 C H A P T E R 5 S P E C T R A 5. 1 1 H an d 1 3 C N M R F or C h ap t e r 2 S p e c t r a 5. 1 1 C om pound 136b

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97 S p e c t r a 5. 1 2 C om pound 141b

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98 S p e c t r a 5. 1 3 C om pound 136c

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99 S p e c t r a 5. 1 4 C om pound 144a

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100 S p e c t r a 5. 1 5 C om pound 144b

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101 5. 2 1 H an d 1 3 C N M R F or C h ap t e r 3 S p e c t r a 5. 2 1 C om pound 186a 0000

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102 S p e c t r a 5. 2 2 C om pound 186b

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103 S p e c t r a 5. 2 3 C om pound 186c

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104 S p e c t r a 5. 2 4 C om pound 1 86d

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105 S p e c t r a 5. 2 5 C om pound 186e

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106 S p e c t r a 5. 2 6 C om pound 186f

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107 S p e c t r a 5. 2 7 C om pound 186g

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108 S p e c t r a 5. 2 8 C om pound 186h

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109 S p e c t r a 5. 2 9 C om pound 186i

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110 S p e c t r a 5. 2 10 C om pound 196a

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111 S p e c t r a 5. 2 11 C om pound 196b

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112 S p e c t r a 5. 2 12 C om pound 196c

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113 S p e c t r a 5. 2 13 C om pound 196d

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114 S p e c t r a 5. 2 14 C om pound 196e

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115 S p e c t r a 5. 2 15 C om pound 196f

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116 S p e c t r a 5. 2 16 C om pound 196g

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117 S p e c t r a 5. 2 17 C om pound 196h

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118 S p e c t r a 5. 2 18 C om pound 196i

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119 R E F E R E N C E S 1. 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 S pr i nge r : B e r l i n G e r m a ny, 1 999, V ol s I I I I 2. a ) R a he e m I T ; G oodm a n, S N ; J a c obs e n, E N ; J A m C he m Soc 2004 126 706. b) T hom ps on, C F ; J a m i s on, T F ; J a c ob s e n, E N J A m C he m Soc 2000 122 10482 c ) B a l s kus E ; J a c obs e n, E N ; Sc i e nc e 2007 317 1736. 3. 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 4. 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 ouk, 1990. 5. 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 l s e vi e r A m s t e r da m : 1993 6. L e i t e r e g, T J ; G ua da gni D G ; M on, T R ; T e r a ni s hi R J A gr i c F ood C he m 1971 19 785 7. a ) D a l ko, P ; M oi s a n, L A nge w C he m I nt E d 2004 43 5138. b ) D a l ko, P ; M oi s a n, L A nge w C he m I nt E d 2001 40 3726. c ) A s y m m e t r i c O r ganoc at al y s i s F r om B i om i ne t i c C onc e pt s t o A ppl i c at i ons i n A s y m m e t r i c Sy nt he s i s : B e r ke s s e l A ; G r oge n, H a r a l d W i l e y V C H : W e i nhe i m 2005. d) E nant i os e l e c t i v e O r ganoc at al y s i s : R e ac t i ons and E x pe r i m e nt al P r oc e dur e s : D a l ko, P I W i l e y V C H W e i nhe i m 2007. 8. M ukhe r j e e S ; Y a ng, J W ; H of f m a nn, S ; L i s t B C he m R e v 2007 107 5471 9. T a yl or M S ; J a c obs e n, E N ; A nge w C he m I nt E d 2006 45 1520

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120 10. H ua ng, Y ; U nni A K ; T ha da ni A N ; R a w a l V H N at ur e 2003 424 146. 11. a ) A ki ya m a T C he m R e v 2007 107 5744 b) C o nnon, S J A nge w C he m I nt E d. 2006 45 3909. 12. N ot z W ; T a na ka F ; B a r ba s D F I I I A c c C he m R e s 2004 37 580. 13. A ki ya m a T ; I t oh, J ; Y okot a K ; F uc hi be K A nge w C he m I nt E d 2004 1566. 14. U r a guc hi D ; T e r a da M J A m C he m Soc 2004 126 5356 15. R ow l a nd, G B ; Z ha ng, H ; R ow l a nd, E B ; C he nna m a dha vuni S ; W a ng Y ; A nt i l l a J C J A m C he m Soc 2005 127 15696 16. C hor e v, M ; G ood m a n, M A c c C he m R e s 1993 26 266 17. L i a ng, Y ; R ow l a nd, E B ; R ow l a nd, G B ; P e r m a n, J A ; A nt i l l a J C C he m C om m un. 2007 43 4477. 18. A ki ya m a T ; M or i t a H ; I t oh, J F uc hi be K O r g. L e t t 2005 7 2583 19. B a r di ni M ; M e l l oni A ; U m a ni R onc hi A A ng e w C he m I n t E d 2004 43 550. 20. U r a guc hi D ; S o r i m a c hi K ; T e r a da M J A m C he m Soc 2004 126 11804. 21. T e r a da M ; S or i m a c hi K J A m C he m Soc 2007 129 292 22. K a ng, Q ; Z ha o Z A ; Y ou S L J A m C he m So c 2007 129 1484. 23. R ow l a nd, G B ; R ow l a nd, E B ; L i a ng, Y ; P e r m a n, J A ; A nt i l l a J C O r g. L e t t 2007 9 2609 24. L i G ; R ow l a nd, G B ; R ow l a nd, E B ; A nt i l l a J C O r g. L e t t 2007 9 4065.

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A B O U T T H E A U T H O R E m i l y B r e t he r i c k R ow l a nd w a s bor n i n F l o r e nc e A l a ba m a on O c t obe r 12, 1980. S he gr e w up on a f a r m i n G r e e nhi l l A l a ba m a w i t h he r pa r e nt s D a nny a nd P a t r i c i a B r e t he r i c k a nd he r ol de r br ot he r J os h B r e t he r i c k. S he l ove s a ni m a l s a nd ha s a l w a y s ha d s e ve r a l dogs hor s e s r a bbi t s duc ks a nd num e r ou s ot he r pe t s E m i l y a t t e nde d R i ve r hi l l e l e m e nt a r y s c hool a nd t he n R oge r s H i gh S c hool W hi l e i n hi gh s c hool s he j oi ne d t he ba nd a nd l e a r ne d t o pl a y t he F r e nc h H or n ve r y w e l l a nd w on s e v e r a l a w a r ds f or he r t a l e nt E m i l y gr a dua t e d hi gh s c hool i n 1999 a nd a t t e nde d t he U ni ve r s i t y of N or t h A l a ba m a w he r e s he m a j or e d i n c he m i s t r y. S he ha d s e ve r a l gr e a t unde r gr a dua t e pr of e s s or s t ha t i ns pi r e d he r t o w a nt t o be a pr o f e s s or a s w e l l I n he r t hi r d ye a r a t U N A s he m e t he r hus ba nd, G e r a l d R ow l a nd, w ho w a s a l s o m a j or i ng i n c h e m i s t r y. A f t e r gr a dua t i ng m agna c um l aude w i t h a B S de gr e e i n c he m i s t r y, s he t he n s t a r t e d gr a dua t e s c hool a t t he U ni ve r s i t y of M i s s i s s i ppi w he r e s he j oi ne d P r of e s s or J on A nt i l l a s r e s e a r c h gr oup. D r A nt i l l a t he n m ove d t o t he U ni ve r s i t y of S out h F l o r i d a w he r e E m i l y e a r ne d he r P h. D i n o r ga ni c c he m i s t r y.


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Rowland, Emily Bretherick.
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Enantioselective Brnsted acid-catalyzed reaction methodology :
b Part a : enantioselective mannich reaction. Part b: enantioselective desymmetrization of meso-aziridines
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by Emily Bretherick Rowland.
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[Tampa, Fla] :
University of South Florida,
2008.
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Dissertation (Ph.D.)--University of South Florida, 2008.
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ABSTRACT: The synthesis of enantiomerically pure compounds is of vital importance. Most biologically active natural products are chiral and require asymmetric synthesis, chiral resolution, or the use of naturally chiral starting materials for their preparation. Organocatalytic enantioselective reaction methodology is a continuously growing area in organic chemistry. The use of organocatalysts as a potentially environmentally friendly alternative to metal catalysts is appealing to the pharmaceutical industry. In this dissertation an enantioselective Mannich reaction using an organocatalyst was investigated. The reaction was between a §-keto ester and an imine electrophile catalyzed by vaulted biphenanthrol (VAPOL) phosphoric acid. The reaction resulted in products with high yields, but low to moderate enantioselectivity and diastereoselectivity. The development of the first Brnsted acid-catalyzed desymmetrization of meso-aziridines was also investigated. This is one of the first instances where a phosphoric acid has been used to catalyze a reaction that did not involve an imine. It was shown that the chiral VAPOL phosphoric acid was an excellent catalyst for the reaction resulting in high yields and enantioselectivities for the chiral ring opened products. It was also shown, for the first time, that a vaulted binaphthol (VANOL) phosphoric acid can also catalyze the ring-opening of meso-aziridines with comparable results to the VAPOL phosphoric acid in some cases. Mechanistic NMR studies were used to probe the reaction, and it is believed that evidence leads one to conclude that a unique mechanism for phosphoric acid-catalysis is followed. The products that can be obtained from this reaction, 1,2-diamines, are of high value for synthetic chemists. They have been used as chiral auxiliaries, ligands, and precursors to natural products.
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Aziridine
Desymmetrization
Catalysis
Phosphoric acid
Bronsted Acid
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