Asymmetric Reactions and Processes in Chemistry - American

8 Novel Approaches to the Asymmetric Synthesis of Peptides

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 5, 2018 | https://pubs.acs.org Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

IWAO OJIMA Sagami Chemical Research Center, Nishi-Ohnuma 4-4-1, Sagamihara, Kanagawa 229, Japan

A variety of dehydrodipeptides (N-protected free acids or methyl esters) have been hydrogenated with homogeneous rhodium catalysts bearing a variety of chiral diphosphine ligands. Diastereomer excess is frequently above 95%. The stereoselectivity of the reaction is, in a number of instances, quite dif ferent from that in hydrogenation of N-acyldehydro amino acids. The synthesis of acylphenylalanyl-α,β -d -alanine methyl ester as a nearly pure diastereomer (and enantiomer) is described. 2

Dipeptides have also been synthesized by cyclo -addition of azidoketene (formed in situ from azido acetyl chloride) to t-butyl esters of α-amino acids to give β-lactams which are then chromatographically resolved into diastereomers and cleaved by mild hy drogenolysis over palladium. By an extension of this method, t r i - , tetra- and higher oligopeptides can be obtained. A salient feature is the high solubility of the β-lactam intermediates in common organic solvents which facilitates chromatographic purifica tion. By an adaptation of this method, Leucine -Enkephalin (Tyr-Gly-Gly-Phe-Leu) t-butyl ester hydro chloride and its analog have been synthesized. Peptide linkages are g e n e r a l l y formed by the c o u p l i n g o f two o p t i c a l l y a c t i v e amino a c i d components through a c y l c h l o r i d e , a c y l a z i d e , mixed anhydride, carbodiimide, o r enzymatic methods. These methods have been developed f o r the s y n t h e s i s of n a t u r a l l y o c c u r r i n g p o l y p e p t i d e s w i t h minimum racemization. Recently, i t has been shown that s i g n i f i c a n t m o d i f i c a t i o n s of b i o l o g i c a l a c t i v i t i e s can be e f f e c t e d through i n v e r s i o n o f c o n f i g u r a t i o n a t one or more c h i r a l centers, o r through replacement o f one o r more " n a t u r a l " amino a c i d residues by " u n n a t u r a l " amino a c i d components i n a b i o 0097-6156/82/0185-0109$07.50/0 © 1982 American Chemical Society

Eliel and Otsuka; Asymmetric Reactions and Processes in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


110

ASYMMETRIC

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

l o g i c a l l y a c t i v e polypeptide such as Enkephalin, Vasopressin, A n g i o t e n s i n I I , Gonadoliberin and other hormones (1). I n order t o o b t a i n such s y n t h e t i c polypeptides by the conventional methods mentioned above, i t i s indispensable t o prepare c h i r a l amino a c i d s with "unnatural" c o n f i g u r a t i o n or "unnatural" s u b s t i t u e n t s . As an approach to the s y n t h e s i s of c h i r a l o l i g o - and polypeptides with d e s i r e d s t r u c t u r e s , we have been t r y i n g t o develop f a c i l e approaches to o b t a i n i n g c h i r a l b u i l d i n g b l o c k s . We w i l l d e s c r i b e here such approaches i n v o l v i n g i ) c a t a l y t i c asymmetric hydrogénation, and i i ) the use of β-lactams as s y n t h e t i c intermediates. Synthesis o f C h i r a l Dipeptides by Means of Asymmetric Hydrogénation of Dehydrodipeptides As precursors of modified peptides, n a t u r a l l y o c c u r r i n g dehydropeptides may be i n t e r e s t i n g candidates s i n c e c a t a l y t i c asymmetric hydrogénation can, i n p r i n c i p l e , convert the dehydroamino a c i d residue i n t o an amino a c i d r e s i d u e with e i t h e r R o r S c o n f i g u r a t i o n . Indeed, the homogeneous asymmetric hydrogénation of dehydro-a-amino a c i d s c a t a l y z e d by rhodium complexes with c h i r a l d i phosphine l i g a n d s has turned out t o be q u i t e e f f e c t i v e f o r the synt h e s i s of c h i r a l α-amino a c i d s (2). An i n t e r e s t i n g p o i n t i n t h i s r e a c t i o n i s whether the c h i r a l center of the dehydrodipeptide ex e r t s a strong i n f l u e n c e on the asymmetric i n d u c t i o n , i . e . , whether the o p t i c a l p u r i t y of the newly formed c h i r a l center i s or i s not a f f e c t e d by the already e x i s t i n g c h i r a l center, and whether, i n f a c t , we can synthesize d i p e p t i d e s having the d e s i r e d c o n f i g u r a tions. N-acyldehydrodipeptides were r e a d i l y prepared e i t h e r by the condensation of N.-acyldehydro-a-amino a c i d s with α-amino a c i d e s t e r s or by the r e a c t i o n of the azlactones o f dehydro-a-amino a c i d with α-amino a c i d e s t e r s (eq. 1 ) . Asymmetric hydrogénation o f the N-acyldehydrodipeptides thus obtained (eq. 2) was c a r r i e d out by u s i n g rhodium complexes with a v a r i e t y of c h i r a l diphosphines such as £-Br-Phenyl-CAPP (3), Ph-CAPP (3), (-)BPPM (4_), (+)BPPM (4), (-)DIOP (5), (+)DI0P (5), diPAMP (6), Chiraphos (7), Prophos (8), BPPFA (9) and CBZ-Phe-PPM ( F i g . 1)(10). The c h i r a l c a t a l y s t s were prepared i n s i t u from c h i r a l diphosphine l i g a n d with [ R h ( N B D ) ] (NBD = norbornadiene). T y p i c a l r e s u l t s a r e summarized i n Tables I-V. As Table I shows, the e f f i c i e n c y of each c h i r a l diphosphine l i g a n d e x h i b i t e d i n the asymmetric hydrogénation of dehydrodipept i d e s i s c o n s i d e r a b l y d i f f e r e n t from that reported f o r the r e a c t i o n of N-acyldehydroamino a c i d s , e s p e c i a l l y i n the case o f Chiraphos and BPPFA, which a r e known to l e a d t o much b e t t e r e n a n t i o s e l e c t i v i t y than DIOP i n the dehydroamino a c i d case (2, 7_ 9 ) . When AcAPhe-(S)Phe-0H was employed as s u b s t r a t e , Chiraphos induced S^ conf i g u r a t i o n (Entry 17) and BPPFA l e d t o R c o n f i g u r a t i o n (Entry 19) with low s t e r e o s e l e c t i v i t i e s ; i n both cases, the d i r e c t i o n s o f asymmetric i n d u c t i o n are opposite t o those observed f o r a - a c e t +

CIO4"

2

9


8.

Asymmetric Synthesis of Peptides

OJIMA

tf NHCOR H^COOH 2

P MzN-CH-COOR^-! 3

w


111

+

R

2

+ H N-CH-COOR^-J 2

.1

Η

X

NHCORR3

CONH-CH-COOR* 1

Equation

R

W

N

H

C

O

R

R 3

H

1.

2

H^TONH-CH-COOR L*-Rh A

ÇH2R

1

R

3

RÔNH-CH-CONH-CH-COOR

4

Equation

2.


112

ASYMMETRIC

REACTIONS

" V · " Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 5, 2018 | https://pubs.acs.org Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

C=0

A N D PROCESSES

COO^Bu

(+)BPPM H

Mey04^-PPh Μ β ^ Ο φ — PPh Η

(+)DIOP

Ι*θ(.·

(-)BPPM H

2

2

Mey04^~PPh

MeÔ^v-pPh, Η

MeyPPh,

j ^ ^ ^ P h

Me^PPh

diPAMP

Chiraphos

2

Prophos Figure 1.

2

(-)DIOP

OMe

PPh

CHEMISTRY

V " V * COOû

Ph-CAPP

IN

Typical

2

^>-PPh

2

^ ^ - P P h

2

BPPFA chiral diphosphine

ligands.



Bz-APhe-(S)Phe-OMe

Ac-APhe-(SI)Phe-0H

1 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20

1 1 1 5 5 10 5 5 5 1 5 10 10 5 5 5 10 10 50 10

Ph-CAPP (-)BPPM (+)BPPM (-)DIOP (+)DI0P diPAMP Chiraphos Prophos BPPFA dppb

40°C, 40°C, 40°C, 25°C, 25°C, 50°C, 40°C, 40°C, 40°C, 40°C, 40°C, 50°C, 50°C, 40°C, 40°C, 50°C, 50°C, 50°C, 50°C, 50°C,

atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm,

20h 20h 20h 20h 20h 20h 20h 20h 20h 20h

3h lh lh 18h 18h 15h lOh 10b 10b 5h 98.0/2.0 96.2/3.8 0.6/99.4 81.8/18.2 5.9/94.1 1.4/98.6 39.1/60.9 18.8/81.2 61.2/38.8 34.1/65.9 100 100 97 100 89 86 96 95 23 99 6

99.2/0.8 98.7/1.3 0.9/99.1 84.1/15.9 15.0/85.0 2.2/97.8 85.1/14.9 4.1/95.9 18.7/81.3 37.8/62.2

Dipeptide (R,S)/(S,S)*

100 100 100 100 100 100 82 99 51 85

b

Conversion Conditions (%) (H2 p r e s s . , Temp., Time)

p-Br-phenyl-CAPP (-)BPPM (+)BPPM (-)DIOP (+)DI0P diPAMP Chiraphos Prophos BPPFA dppb

Ligand

-4 of the s u b s t r a t e and 5.0 x 10" mol of the c a t a l y s t a A l l r e a c t i o n were run with 5.0 x 10 mol b Determined by HPLC.

Substrate

a

E f f i c i e n c y of C h i r a l Diphosphine Ligands i n the Asymmetric Hydrogénation o f T y p i c a l Dehydrodipeptides

Entry

Table I.



114

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

amidocinnamic a c i d . Prophos induced high s t e r e o s e l e c t i v i t y with Bz-APhe-(S)Phe-OMe (Entry 8) whereas i t was no longer a very good c h i r a l l i g a n d f o r Ac-APhe-(S)Phe-OH (Entry 18). Pyrrolidinodiphosphines and diPAMP achieved extremely high s t e r e o s e l e c t i v i ties. There seems to be a trend that the c h i r a l l i g a n d s which form seven membered r i n g c h e l a t e s w i t h rhodium give r i s e to much b e t t e r r e s u l t s than those forming r i g i d f i v e membered r i n g c h e l a t e s or q u a s i f i v e membered r i n g c h e l a t e s except diPAMP. The r e s u l t s may imply that the seven membered r i n g c h e l a t e has f l e x i b i l i t y f o r " i n d u c e d - f i t " a c t i o n l i k e an enzyme, which i s q u i t e an important f a c t o r f o r a c h i r a l complex c a t a l y s t when the s u b s t r a t e i s p o l y f u n c t i o n a l (11). As f o r the i n f l u e n c e of the c h i r a l center i n the s u b s t r a t e on asymmetric i n d u c t i o n , c o n s i d e r a b l e double asymmetric i n d u c t i o n was observed on u s i n g a dehydrodipeptide bearing a f r e e a c i d terminus such as Ac-APhe-(S)Phe-OH (see Entry 12, 13, and 14, 15). To r e a l i z e the extent of double asymmetric i n d u c t i o n i n a q u a n t i t a t i v e manner, one has to look not a t the d i f f e r e n c e of the r e l a t i v e amounts of diastereomers i n percent but a t the r a t i o of two d i a s t e reomers, which i s r e l a t e d to MG*: For BPPM, (R,S)/(S,S) =25.3 (Entry 12, (-)BPPM), (S,S)/(R,S) = 165.7 (Entry 13, (+)BPPM); f o r DIOP, (R,S)/(£,S) = 4.49 (Entry 14, (-)DIOP), (S^S)/(R,S.) = 15-9 (Entry 15, (+)DIOP). Thus, the extent of double asymmetric induc t i o n turns out to be more pronounced f o r BPPM than f o r DIOP a l though the apparent d i f f e r e n c e i n o p t i c a l p u r i t y i s much s m a l l e r f o r BPPM compared with that f o r DIOP. The r e s u l t s concerning the double asymmetric i n d u c t i o n i n d i c a t e t h a t the formation of the (]L,S)-isomer i s p r e f e r r e d i n these systems. An experiment u s i n g an a c h i r a l diphosphine l i g a n d , bis(diphenylphosphino)butane (dppb), gave a c o n s i s t e n t r e s u l t (Entry 20), i . e . 31.8% asymmetric induc t i o n f a v o r i n g the formation of the (S,S)-isomer o f Ac-Phe-Phe-OH was observed. On the other hand, when dehydrodipeptide methyl e s t e r s were employed, o n l y a s l i g h t e f f e c t of the e x i s t i n g c h i r a l center was observed as f a r as DIOPs were concerned, e.g., Bz-PhePhe-OMe: (+)DI0P, (R,S)/(£,S) = 16.4/83.6, (-)DIOP, (R,S)/(S,,S) - 84.1/15.9; Ac-Phe-Phe-OMe: (+)DI0P, (R,S)/(£,S) = 19.4/80.6, (-)DIOP, (R,S)/(£,S) * 81.6/18.4; Bz-Phe-Val-OMe: (+)DI0P, (R,S)/ (S,S) = '20.6/79.4, (-)DIOP, (R,£)/(S_,S) = 83.0/17.0. The r e s u l t s could be i n t e r p r e t e d by assuming e x c l u s i v e coor d i n a t i o n of the N-acyldehydroamino a c i d moiety w i t h the rhodium com p l e x i n which the r e s t of the molecule, i . e . the α-amino e s t e r moie t y , i s l o c a t e d i n the outer sphere of the c h i r a l c o o r d i n a t i o n s i t e : t h i s may be the reason why v i r t u a l l y no double asymmetric i n d u c t i o n was observed. However, a simple asymmetric hydrogénation u s i n g dppb as a c h i r a l l i g a n d (Entry 10) d i s c l o s e d p r e f e r e n t i a l formation of Bz-(S)Phe-(S)Phe-OMe with 24.4% asymmetric i n d u c t i o n , which i s c o n s i s t e n t with the r e s u l t u s i n g Ac-APhe-(S)Phe-0H as s u b s t r a t e (Entry 20). A c c o r d i n g l y , i t seems t h a t the r e s u l t s of u s i n g DIOPs are r a t h e r e x c e p t i o n a l . In t h i s context, we f u r t h e r looked a t the e f f e c t of the c h i r a l center on the c a t a l y t i c asymmetric i n d u c t i o n



8.

OJIMA

Asymmetric

Synthesis

of

Peptides

115

by using Ac-APhe-(R)Phe-OMe and Ac-APhe-(S)Phe-OMe as s u b s t r a t e s , and CBZ-(S)Phe-PPM (3^), CBZ-(S)Val-PPM Q £ ) and CBZ-(S)Pro-PPM (M) as c h i r a l l i g a n d s f o r the c a t i o n i c rhodium complex. The r e s u l t s are l i s t e d i n Table I I . As Table I I shows, there i s only a s l i g h t d i f f e r e n c e between the two s u b s t r a t e s i n percent asymmetric i n d u c t i o n from a s y n t h e t i c p o i n t of view, s i n c e the r e a c t i o n s achieve q u i t e high s t e r e o s e l e c t i v i t i e s , yet there i s a s i g n i f i c a n t d i f f e r e n c e i n MG* s i n c e i t i s observed that the (R,R)/(S,R) r a t i o i s three to four times l a r g e r than the (R,S!)/ CS,S) r a t i o i n every case examined. Moreover, s i m i l a r r e s u l t s were obtained i n the asymmetric hydrogénation of Ac-APhe-(R)Phe-OMe by using (-)BPPM and (+)BPPM as shown i n Table I I I . Thus, the r e a c t i o n using (-)BPPM l e d to 99.6% production of Ac-(R)Phe-(R)Phe-OMe while that using (+)BPPM produced 98.5% of the (S,R)-isomer: (R,R)/(S,R) = 249 f o r (-)BPPM: (S^R)/(R,R) = 65.7 f o r (+)BPPM. Consequently, i t may be s a i d that there i s a s i g n i f i c a n t extent of double asymmetric i n d u c t i o n f o r the r e a c t i o n of dehydrodipeptide methyl e s t e r s , too, and the case of DIOP i s r a t h e r e x c e p t i o n a l . Table I I I summarizes t y p i c a l r e s u l t s f o r the asymmetric hydrogénation of a v a r i e t y of N-acyldehydrodipeptides with p y r r o l i d i n o diphosphines and diPAMP. As Table I I I shows, (R,S), (S,S.), (S,R) or (R,R)-dipeptides i n high o p t i c a l p u r i t i e s can be r e a d i l y synt h e s i z e d by using these c h i r a l l i g a n d s , and, i n one r e c r y s t a l l i z a tion, e a s i l y lead to o p t i c a l l y pure d i p e p t i d e s . Since c a t a l y t i c asymmetric hydrogénation can generate e i t h e r S or R c o n f i g u r a t i o n at the p o s i t i o n of the dehydroamino a c i d r e s i d u e , t h i s method could be p o t e n t i a l l y u s e f u l f o r the s p e c i f i c l a b e l i n g of c e r t a i n amino a c i d residues i n a p o l y p e p t i d e . The r e g i o s p e c i f i c and s t e r e o s e l e c t i v e l a b e l i n g of an amino a c i d r e s i due i s d i f f i c u l t to achieve with the conventional stepwise peptide s y n t h e s i s . We c a r r i e d out the d i d e u t e r a t i o n of Ac-APhe-(S)Ala-0Me with the use of the c a t i o n i c rhodium complexes w i t h (-)BPPM and (+)BPPM (Scheme 1 ) , which gave Ac-(R,R)Phe(d2)-(S)Ala-0Me [(R,R,S)/ (S,£,S) = 98.7/1.3] and Ac-(S,£)Phe(^)-(S)Ala-OMe [ (R,R,S1)/(S,S,£) «0.5/99.5], r e s p e c t i v e l y , without any scrambling of deuterium. As i t has been shown that the i n t r o d u c t i o n of deuterium a t the c h i r a l center of c e r t a i n amino a c i d s , e.g., 3 - f l u o r o - 2 - d e u t e r i o (R)-alanine, changes b i o l o g i c a l a c t i v i t y remarkably (12), t h i s s t e r e o s e l e c t i v e d i d e u t e r a t i o n may provide a convenient device f o r t h i s kind of m o d i f i c a t i o n of b i o l o g i c a l a c t i v i t y . Since p y r r o l i d i n o d i p h o s p h i n e s , e.g., Ph-CAPP, 2,-Br-Phenyl-CAPP and BPPM, gave e x c e l l e n t s t e r e o s e l e c t i v i t i e s , we prepared a s e r i e s of new c h i r a l p y r r o l i d i n o d i p h o s p h i n e s , i n which the n i t r o g e n atom of PPM (4, 11) i s l i n k e d up with a v a r i e t y of α-aminoacyl groups. The rhodium complexes with these l i g a n d s may serve as good b i o mimetic models of reductase when they are anchored on polymers e s p e c i a l l y polyamides. α-Aminoacyl-PPMs Q ) were prepared by the condensation o f PPM with an N-CBZ-α-amino a c i d or an N-CBZ-dipept i d e i n the presence of d i c y c l o h e x y l c a r b o d i i m i d e (DCC) and 1-hyd r o x y b e n z t r i a z o l e (HOBT)(eq. 3 ) .



b

a

Ac-APhe- (S) Phe-OMe Ac-APhe- (R) Phe-OMe Ac-APhe- (S)Phe-OMe Ac-APhe- (R) Phe-OMe

CBZ- (S)Pro-PPM(^J)

CBZ- (S)Pro-PPM(^J)

CBZ- (S)Val-PPM(^)

CBZ- (S)Val-PPM(^)

3

4

5

6

98.9/1.1

98.1/1.9

98.0/2.0

96.2/3.8

99.5/0.5

99.5/0.5

Ac-Phe-Phe-OMe ( R , S ) / ( S , S ) * or ( R , R ) / ( S , R ) *

on S t e r e o s e l e c t i v i t y

A l l r e a c t i o n s were run with 5.0 * 10 mol the s u b s t r a t e and 5.0 x 10 mol Of the c a t a l y s t a t 40°C and 1 atm of hydrogen f o r 2h. Conversion was 100% f o r every case examined. Determined by HPLC.

Ac-APhe- (R) Phe-OMe

CBZ- (S)Phe-PPM(^)

2

fc

, ^ Substrate

Ac-APhe- (S) Phe-OMe

0

CBZ- (S)Phe-PPM(^.)

, Ligand

E f f e c t of C h i r a l Center i n Dehydrodipeptides

1

Entry

Table I I .


d

40°C, 40°C,

10 atm, 10 atm, 1 atm, 1 atm, 1 atm, 1 atm, 5 atm, 10 atm, 1 atm, 5 atm, 5 atm, 5 atm,

Ph-CAPP diPAMP (-)BPPM (+)BPPM (-)BPPM (+)BPPM (-)BPPM diPAMP CBZ-(S)Phe-PPM Ph-CAPP Ph-CAPP (+)BPPM

Ac-APhe-(£)Val-OH

Bz-ALeu- (S) Phe-OMe

Ac-APhe-(R)Phe-OMe

Ac-APhe- (R)Phy-0Me

Bz-APhe- (R) Phe-OMe

Eliel and Otsuka; Asymmetric Reactions and Processes in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1982. r

64h

24h

24h

lh

24h 24h

2h 2h

24h 16h

20h 20h

20h 20h

46h lh

20h 24h

3h lh

100

100

100

100

100 100

100 100

100 100

100 100

100 100

100 100

100 100

100 100

fc

h

0.9/99.1

99.4/0.6

99.8/0.2^

99.5/0.5

h

h

95.7/4.3 2.6/97.4°

99.6/0.4 , 1.5/98.5°

fc

95.3/4.7 3.6/96.4

96.3/3.7 3.0/97.0

98.0/2.0 0.6/99.4

99.0/1.0 0.6/99.4

98.0/2.0 1.0/99.0

99.2/0.8 0.9/99.1

a Determined by HPLC. (R,S)/(S,S) unless otherwise noted, b (R,R)/(S,R). a (Ac)Tyr = 4-acetoxyt y r o s y l . d (AcO)(MeO)Phe = 3-methoxy-4-acetoxyphenylalanyl. e (F)Phe = 4 - f l u o r o p h e n y l a l a n y l .

Ac-A(F)Phe-(S)Leu-0Me

6

Ac-A(AcO) (MeO)Phe-(R)Ala-OMe

40 °C,

40°C,

40°C, 40°C,

40°C, 40°C,

40°C, 40°C,

50°C, 50°C,

40 °C, 40°C,

5 atm, 10 atm,

Ph-CAPP (+)BPPM

Ac-APhe-(S)Phe-OH

40°C, 40°C,

1 atm, 1 atm,

40°C, 40°C,

Ph-CAPP (+)BPPM

10 atm, 10 atm,

£-Br-phenyl-CAPP diPAMP

Bz-APhe-(S)Val-OMe

40°C, 40°C,

Ac-APhe- (S) Phe-OMe

1 atm, 1 atm,

2-Br-phenyl-CAPP (+)BPPM

Ac-A (Ac) T y r - (R) Ala-OMe^

n

Dipeptide Conditions Conversion Ph-^^NH^CO^Bul

-122.6*(MeOH)

B

7g

° *

s

rj^^Me

N 4 - f - P h H /10«/.Pd-C ^ N ^ - f o h H /10*/.Pd-C J-N υ MeOH, r.t. * J - N f _MeOH(Haaq), 50*C O' vple ry vp< C02BU CO2B1A 7b 8b

3

N -H-Ph

2

Chbci * -78-C-r.t.

3

2

* Et N

3

N CH Coa

2

(S)-PhCH°N^CQ Bui

3

H H N 4-f-Ph


OJIMA


8.

N

Asymmetric

3 W

A

Synthesis

of

ο

r

Jr-W C0 R Y

131

Peptides

Ho

2

2

HSUc*

Dipeptide

" V > "

Tripeptide

A

r 1

R X-NH-^CONH^Âr Υ1* ^ C 0 3

Γ

v

R

2

2

P P d

c

Β

N Âr 3

P^CONHy-jAr' 0

Ri

"2 > Tetrapeptide

P C0 R v

Ο ^ Υ ^ ' J-N C0 Y

K

3

P d

2

2

"

C

- ρ ϊ Τ

T r i

P*P

t i d

2

D Scheme 9.


*

132

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

ω ο ι Ο < ι

X


2 LO

I φ α. ι

CN CN

I

Χ ο Σ Ο CO

CM Q I

s

α

CSI I

Ph 3

H

2

c T V

Asymmetric Reactions and Processes in Chemistry - American

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