Asymmetric Reactions: A Challenge to the Industrial Chemist - ACS

10 Asymmetric Reactions: A Challenge to the Industrial Chemist

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.ch010

GABRIEL SAUCY and N O A L COHEN Hoffmann-La Roche Incorporated, Chemical Research Department, Nutley, NJ 07110

A variety of established industrial processes for the manufacture of and new synthetic approaches to certain optically active compounds such as pharmaceuticals, vitamins, and fine chemicals are surveyed. Among the techniques for obtaining optically pure intermediates covered in this review are classical or modified optical resolutions, the utilization of starting materials from the chiral pool, as well as stoichiometric and catalytic asymmetric transformations. The development o f p r a c t i c a l and economical processes f o r l a r g e s c a l e i n d u s t r i a l p r e p a r a t i o n of c e r t a i n o p t i c a l l y a c t i v e compounds such as pharmaceuticals, f i n e chemicals, and vitamins has been and continues to be a major challenge. H i s t o r i c a l l y , a number of e f f i c i e n t i n d u s t r i a l processes have evolved which are based on c l a s s i c a l r e s o l u t i o n (e.g. D - b i o t i n (1,2) and D-pantothenic a c i d (3)) o r the use of o p t i c a l l y a c t i v e s t a r t i n g m a t e r i a l s (e.g., v i t a m i n C (4)). More r e c e n t l y , a t t r a c t i v e processes utilizing asymmetric r e a c t i o n s have been designed (5). From an i n d u s t r i a l p o i n t o f view, the use o f c h i r a l c a t a l y s t s to generate asymmetry i s p a r t i c u l a r l y advantageous. Unfortunately, our l a c k of understanding o f the q u a n t i t a t i v e aspects which govern the degree o f asymmetry created i s a s e r i o u s problem. The development of c h i r a l c a t a l y s t s u s e f u l to i n d u s t r y i s p r e s e n t l y very much dependent on the e m p i r i c a l approach. New i n s i g h t and knowledge are needed to design r a t i o n a l approaches i n asymmetric s y n t h e s i s . T h i s review i s intended to show how i n d u s t r y has solved o r , at l e a s t , confronted the problem of producing c e r t a i n o p t i c a l l y a c t i v e t a r g e t compounds i n a p r a c t i c a l and economical manner, u s i n g s e l e c t e d examples from the area of pharmaceuticals, vitamins, and f i n e chemicals.

0097-6156/82/0185-0155$05.00/0 © 1982 American Chemical Society

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

156

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY


L-Dopa P r i o r to the p i o n e e r i n g development of the asymmetric hydrogénation process f o r producing L-Dopa by Knowles and coworkers at Monsanto (5), we had i n v e s t i g a t e d an a l t e r n a t i v e approach i n v o l v i n g hydrogénation of the c h i r a l s u b s t r a t e 1 using an a c h i r a l c a t a l y s t ( 6 ) . T h i s produced the mixture of epimeric amides 2 and 3 which could be converted, i n 89% o v e r a l l y i e l d , to the clesired isomer 3 v i a simultaneous base c a t a l y z e d e q u i l i b r a t i o n - c r y s t a l l i z a t i o n . Unfortunately, h y d r o l y s i s of ^ to L-Dopa gave unacceptably low y i e l d s , of the order of only 50%. 19-Norsteroids Very s u b s t a n t i a l asymmetric i n d u c t i o n at C-13 was found to take p l a c e upon condensation of the o p t i c a l l y a c t i v e hydroxy v i n y l ketone 4 (R=CsH5) with 2-methylcyclopentane-l,3-dione (5) g i v i n g predominantly the d i e n o l ether 6 (7). The e x p l o i t a t i o n of t h i s f o r t u i t o u s r e s u l t enabled us Ύο design s e v e r a l e f f i c i e n t routes to o p t i c a l l y a c t i v e 19-norsteroids and estrone (8). The key c h i r a l annulating agents 4 were secured by v a r i o u s schemes r e l y i n g on c l a s s i c a l r e s o l u t i o n s or microbio l o g i c a l r e d u c t i o n of δ-keto a c i d s g i v i n g o p t i c a l l y a c t i v e ό-lactones . Of p a r t i c u l a r i n t e r e s t i s the r e g i o - and e n a n t i o s p e c i f i c r e d u c t i o n of d i k e t o a c i d ^ with Margarinomyces bubaki a f f o r d i n g the keto l a c t o n e 8. The l a t t e r serves as the c h i r a l s t a r t i n g p o i n t i n an asymmetric t o t a l s y n t h e s i s (+)-estr-4-ene-3,17dione v i a key intermediate 9 (9). A most impressive example of c a t a l y t i c asymmetric s y n t h e s i s forms the b a s i s f o r s t i l l another and very e f f i c i e n t approach to 19-norsteroids (10,11). The exact mechanism r e s p o n s i b l e for the extremely high asymmetric i n d u c t i o n noted i n the c r u c i a l conversion of p r o c h i r a l to k e t o l 11 and (S)-enedione 12 s t i l l needs to be c l a r i f i e d (12,13). Nonetheless, these ôftlral a l d o l products serve very e f f e c t i v e l y as s t e r o i d CDr i n g synthons (8,14-21). Zeaxanthin Zeaxanthin, which occurs i n corn and many other p l a n t s , i s an important carotenoid. I t s s y n t h e s i s i n o p t i c a l l y a c t i v e form can be achieved on the b a s i s of the three approaches depicted. In the f i r s t case (22), o p t i c a l a c t i v i t y i s introduced by asymmetric r e d u c t i o n of the enedione ^ with yeast, g i v i n g dione Stereo- and r e g i o s e l e c t i v e r e d u c t i o n then produced the key k e t o l J ^ . In the second approach (23), the cyclohexa-



10.

SAUCY

Asymmetric

AND COHEN

157

Reactions

COOH NH H 2

CNHR

L-DOPA

H NHCCH, 9

II

CNHR H

CH 03

Ο 2

NoOt-Bu

NHCCH 'Pd/C

CH 03

Ο

3

II

0

0

CNHR

L 3° CH

(R*

*

H

0^ ")

CH3O

Η

NHCCH, u

3

Ο


0


158

ASYMMETRIC

^NJA.

A N D PROCESSES

IN

CHEMISTRY

L-Proline

u— 10

REACTIONS

6

catalytic °"

(prochiral) \ \

I' A ' X ο/ ~ ~ 9 3%e.e. Y =100% L-Proline/HCI0

. # /

/

'2 8 7 % e.e. Y=87%

4


SAUCY A N D COHEN

Asymmetric

Reactions


10.


159

ASYMMETRIC


160

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

diene 16, a v a i l a b l e from s a f r a n a l , i s subjected to an asymmetric hydroboration with (+)-diisopinocampheylborane g i v i n g i n t e r mediate Γ7. In t h i s context, i t should be noted that asym metric hydroboration of dienes has a l s o been a p p l i e d at HoffmannLa Roche i n a s y n t h e s i s of p r o s t a g l a n d i n intermediates having i n d u s t r i a l p o t e n t i a l (24). The t h i r d approach to zeaxanthin (25) e x p l o i t s the s p e c i a l f e a t u r e s of keto a c e t a l which i s t h e o r e t i c a l l y a v a i l a b l e i n q u a n t i t a t i v e y i e l d s t a r t i n g from the diketone ^ and (2R,3R)2,3-butanediol. F o r t u n a t e l y , 19b i s c r y s t a l l i n e and l e s s s o l u b l e than i t s epimer 19a. E q u i l i b r a t i o n with sodium hydroxide thus favors the d e s i r e d epimer. Diastereomer )£b i s then transformed i n t o the d i o l 20 i n two s t e r e o s p e c i r i c steps. Pantothenic A c i d The present i n d u s t r i a l processes used to produce the c r u c i a l intermediate (R)-(-)-pantolactone (22) are based on r e s o l u t i o n of racemic m a t e r i a l ( 3 ) . A d i f f e r e n t and very promising approach has been reported by a Japanese group (26). Independently, Roche workers a l s o i n v e s t i g a t e d t h i s approach which i n v o l v e s asymmetric r e d u c t i o n of ketolactone %1 u s i n g rhodium c a t a l y s t s d e r i v e d from c h i r a l phosphines (27;. In t h i s manner, 22 can be obtained i n very high chemical and optical yie l d ^ D-Biotin The o r i g i n a l s y n t h e s i s of D - b i o t i n , which i n v o l v e s a c l a s s i c a l r e s o l u t i o n w i t h e f f i c i e n t r e c y c l i n g of the unwanted enantiomer (1), has r e c e n t l y been advantageously modified (28). The key. f e a t u r e of the new Sumitomo route i n v o l v e s p r e p a r a t i o n of the c h i r a l imide 24 from symmetrical d i a c i d 23. Hydride r e d u c t i o n of 24 occurs wî€h h i g h asymmetric i n d u c t i o n , generating hydroxy amîâe 25 having e x c e l l e n t o p t i c a l p u r i t y , i n 65% y i e l d . Treatment with HC1 converts ^ to the corresponding γ-lactone and u l t i m a t e l y D - b i o t i n by the e s t a b l i s h e d route. The c h i r a l aminopropanediol (R*) i s recovered and r e c y c l e d . Other novel approaches to D - b i o t i n have been s t u d i e d at Hoffmann-La Roche i n recent years (29,30). f

Vitamin Ε ((2R,4'R,8 R)-α-Tocopherol) The development of a p r a c t i c a l t o t a l s y n t h e s i s of n a t u r a l (2R,4 R,8'R)-α-tocopherol (^) i s a major c h a l l e n g e . While much progress has been made i n t h i s area, a t e c h n i c a l l y f e a s i b l e s y n t h e t i c approach to t h i s form of v i t a m i n Ε remains an e l u s i v e goal and i s o l a t i o n from soybean o i l continues to be the major source of 26 (31). f


10.

SAUCY A N D COHEN

Asymmetric

Reactions

161


QH H

H

υπ ft ^ v | 4 y K k ^ '0

0

C

0

0

H

PANTOTHENIC ACID

21

22

Ketoloctone

(R)-H-Pontoloctone

D-BIOTIN

tf^A^tf HOOC

COOH

23

tf-^T^NT^j!

NoBH

4

o^N^O 1



162

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

Much of our s y n t h e t i c work aimed at has been summarized i n a recent review (32) and w i l l not be covered i n d e t a i l here. The two homologous s t r a t e g i e s employed are depicted by the bond d i s s e c t i o n s "a" and "b". In the former, a C14chroman u n i t i s coupled with a C i s - s i d e chain intermediate i n the penultimate step while i n the l a t t e r , Cis-chroman and C 1 4 s i d e chain synthons are u n i t e d . Regarding the s i d e chain, recent developments i n our l a b o r a t o r i e s i n v o l v e a p p l i c a t i o n s of asymmetric hydride reductions (e.g., 27 + 29 and 31) to provide c h i r a l C l a i s e n rearrangement substrates ^ ^ , a n d ^ which, i n turn, a f f o r d o p t i c a l l y a c t i v e e s t e r ^ or i t s enantiomer ^ with e s s e n t i a l l y complete c h i r a l i t y t r a n s f e r (33). In another approach, c a t a l y t i c asymmetric hydrogénation of geranic a c i d (38) y i e l d s the C 1 0 intermediate ^ i n 70% e.e. (34). Man$%ther, o f t e n q u i t e ingenious routes to c h i r a l s i d e chain precursors have been reported r e c e n t l y by v a r i o u s groups (35-39). Progress has a l s o been made with regard to the a c c e s s i b i l i t y of key chroman intermediates. Thus methods were developed which allow u t i l i z a t i o n of the unwanted enantiomers of chroman2 - c a r b o x y l i c and chroman-2-acetic a c i d s ( 4 $ ^ 42c) obtained along with the d e s i r e d antipodes (41b, 42b) by'^cî'assical r e s o l u t i o n of the racemic forms ({flffl* (enantioconvergence 40, 41). For example, a four s t a g e l n v e r s i o n sequence provides a route f o r transforming 41c i n t o the (S)-enantiomer required for synthesis (42). S i m i l a r l y , the homologous, unwanted (R)-chroman-2-acet"îc a c i d 42c can be u t i l i z e d by means of a r a c e m i z a t i o n - r e c y c l i n g process (43). While these approaches s t i l l r e l y on c l a s s i c a l r e s o l u t i o n s , the m o d i f i c a t i o n s incorporated s u b s t a n t i a l l y improve the o v e r a l l e f f i c i e n c y i n terms of o b t a i n i n g o p t i c a l l y pure intermediates. A s i g n i f i c a n t o f f s h o o t of our s y n t h e t i c s t u d i e s aimed at 26 has been the e x p l o i t a t i o n of the r e s u l t i n g methodology f o r preparing a l l seven stereoisomers of 26 (44). Employing a v a r i a t i o n of a gas chromatographic metnod r e c e n t l y developed f o r separating the diastereomers of α-tocopherol (45), we were able to demonstrate that a l l of our s y n t h e t i c stereoisomers were of high (93-99%) diastereomeric p u r i t y (44). The a v a i l a b i l i t y of these compounds i n pure form w i l l now allow a p r e c i s e determination of the r e l a t i o n s h i p between s t e r e o chemistry and v i t a m i n Ε biopotency i n the α-tocopherol molecule. During the course of t h i s work, i t was e s t a b l i s h e d f o r the f i r s t time that n a t u r a l l y o c c u r r i n g d-a-tocopherol from soybean o i l i s a s i n g l e enantiomer (2R,4 R,8'R), that s y n t h e t i c d.,JL-atocopherol i s an equimolar mixture of four racemates, and that n a t u r a l ( E ) - ( 7 R , l l R ) - p h y t o l i s e n a n t i o m e r i c a l l y homogeneous (44). f



SAUCY A N D C O H E N

Asymmetric

Reactions

(2R,4'R,8'R) - c c - Tocopherol

X

LiAIH, "CH

1

27

3

HC

,

H

>P

H

H

3

~P h~C h v ^f * l

OH

2

N(CH ) 3

9

®

2

28

Li A I H

^

4

HO,

H

H C 3

R

Γ^Ί

HO

N(CH3)

Η

31 (S) 2

3 0 (R)



ASYMMETRIC

3

AND

PROCESSES

IN

CHEMISTRY

H \ OH

pH

H C

REACTIONS

33

(S-E)

EtO

34

HO

H

ÇH

3


31


10.

SAUCY

AND

COHEN

Asymmetric

Reactions

165

410j R ' , R » C H , C 0 H ( ± ) 2

3

4lb

2

R' » C H , R « C 0 H ( S ) 2

;

41C;

3

2

R' » C O H , R « C H ( R ) 2

2

3

42ÛÎ R',R «CH ,CH CO H(±) 2

3

2

2

42b;

R'»CH ;

42C;

R'»CH C0 H; R »CH (R)

3

R «CH C0 H(S) 2

2

2

2

2

2

3


ASYMMETRIC

166

REACTIONS

A N D PROCESSES

IN

CHEMISTRY


Conclusions For many reasons, the pharmaceutical i n d u s t r y w i l l continue to r e q u i r e f a c i l e s y n t h e t i c routes to d i a s t e r e o i s o m e r i c a l l y and e n a n t i o m e r i c a l l y pure c h i r a l molecules. In order t o achieve these goals, new asymmetric processes, e s p e c i a l l y c a t a l y t i c asymmetric r e a c t i o n s , w i l l be needed. A l t e r n a t i v e l y , there i s great p o t e n t i a l f o r the development of i n d u s t r i a l l y u s e f u l b i o t r a n s f o r m a t i o n s to produce complex o p t i c a l l y a c t i v e compounds. Genetic engineering w i l l probably p l a y an important r o l e i n such approaches. Nonetheless, the challenge to the organic chemist w i l l remain. Acknowledgment We a r e g r a t e f u l to the Research Management of Hoffmann-La Roche Inc. f o r the opportunity to prepare t h i s review which covers the m u l t i d i s c i p l i n a r y e f f o r t s of v a r i o u s research groups i n the U.S.A. (Nutley, N. J.) and Switzerland ( B a s l e ) .

Literature Cited 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14.

Sternbach, L. H. in "Comprehensive Biochemistry"; Vol. 11, Florkin, M.; Stotz, Ε. H.; Elsevier: New York, 1963; p. 66. Gerecke, M.; Zimmermann, J.-P.; Aschwanden, W. Helv. Chim. Acta 1970, 53, 991. Robinson, F. A. "The Vitamin Co-factors of Enzyme Systems", Pergamon Press: London, 1966, p. 415; Paust, J.; Pfohl, S.; Reif, W.; Schmidt, W. Ann. Chem. 1978, 1024. Reichstein T.; Grüssner, A. Helv. Chim. Acta 1934, 17, 311. Koenig, K. E.; Sabacky, M. J.; Bachman, G. L . ; Christopfel, W. C.; Barnstorff, H. D.; Friedman, R. B.; Knowles, W. S.; Stults, B. R.; Vineyard, B. D.; Weinkauff, D. J. Ann. N. Y. Acad. Sci. 1980, 333, 16 and references cited therein. Perry, C.; Saucy, G. unpublished results. Saucy, G.; Borer, R. Helv. Chim. Acta 1971, 54, 2517. Cohen, N. Acc. Chem. Res. 1976, 9, 412 and references cited therein. Rosenberger, M.; Borer, R.; Saucy, G. J. Org. Chem. 1978, 43, 1550. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496. Buchschacher, P.; Cassal, J.-M.; Fürst, Α.; Meier, W. Helv. Chim. Acta 1977, 60, 2747. Brown, K. L . ; Damm, L . ; Dunitz, J. D.; Eschenmoser, Α.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108. Eder, U. J. Steroid Biochem. 1979, 11, 55 and references cited therein.


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17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

SAUCY

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COHEN

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Reactions

167

Neef, G.; Eder, U.; Haffer, G., Sauer, G.; Wiechert, R. Chem. Ber. 1977, 110, 3377. Eder, U.; Cleve, G.; Haffer, G.; Neef, G.; Sauer, G.; Wiechert, R.; Fürst, A.; Meier, W. Chem. Ber. 1980, 113, 2249. Pandit, U. K.; Bieräugel, H. Rec. Trav. Chim. 1976, 95, 223. Kametani, T.; Matsumoto, H.; Nemoto, H.; Fukumoto, K. J. Am. Chem. Soc. 1978, 100, 6218. Crabbé, P.; Bieber, L . ; Nassim, B. J.C.S. Chem. Comm. 1980, 472. Tsuji, J.; Shimizu, I.; Suzuki, H.; Naito, Y. J. Am. Chem. Soc. 1979, 101, 5070. Shimizu, I.; Naito, Y.; Tsuji, J. Tetrahedron Lett. 1980, 21, 487. Leuenberger, H. G. W.; Boguth, W.; Widmer, E . ; Zell, R. Helv. Chim. Acta 1976, 59, 1832. Rütimann, Α.; Mayer H. Helv. Chim. Acta 1980, 63, 1456. Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am. Chem. Soc. 1973, 95, 7171. Saucy, G.; Weber G. Paper presented at the ACS/CSJ Chemical Congress, Honolulu, Hawaii, April 1-6, 1979; Abstr. ORGN 200. Ojima, I.; Kogure, T.; Terasaki, T.; Achiwa, K. J. Org. Chem. 1978, 43, 3444. Townsend,J; Valentine, D., Jr. unpublished results; Valentine, D., Jr.; Sun, R. C.; Toth, K. J. Org. Chem. 1980, 45, 3703. Aoki, Y.; Suzuki, H.; Akiyama, H.; Okano, S. Chem. Abstr. 1974, 80, 95951z (U. S. Patent no. 3,876,656 - Sumitomo). Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar, D.; Uskokovic, M. R. J. Am. Chem. Soc. 1975, 97, 5936. Vasilevskis, J.; Gualtieri, J. S.; Hutchings, S. D.; West, R. C.; Scott, J. W.; Parrish, D. R.; Bizzarro, F. T.; Field, G. F. J. Am. Chem. Soc. 1978, 100, 7423. Rubel, T., "Vitamin Ε Manufacture", Noyes Development Corp.: Park Ridge, N. J. 1969. Saucy, G.; Cohen, N. in "New Synthetic Methodology and Biologically Active Substances"; Yoshida, Z. Ed.; Kodansha (Tokyo); Elsevier (New York), 1981; Ch. 9, p. 155. Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org. Chem. 1980, 45, 582. Valentine, D. Jr.; Johnson, Κ. K.; Priester, W.; Sun, R. C.; Toth, K; Saucy, G. J. Org. Chem. 1980, 45, 3698. Takahashi, J.; Mori, K.; Matsui, M. Agric. Biol. Chem. 1979, 43, 1605. Bödeker, C.; de Waard, E. R.; Huisman, H. O. Tetrahedron 1981, 37, 1233. Sato, T.; Kawara, T.; Nishizawa, Α.; Fujisawa, T. Tetra hedron Lett. 1980, 3377.



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38. Fujisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. Tetrahedron Lett. 1981, 22, 4823. 39. Trost, B. M.; Klun, T. J. Am. Chem. Soc. 1981, 103, 1864. 40. Trost, B. M.; Timko, J. M.; Stanton, J. L. J.C.S. Chem. Commun. 1978, 436. 41. Fischli, A. Chimia 1976, 30, 4. 42. Cohen, N.; Lopresti, R. J.; Neukom, C. J. Org. Chem. 1981, 46, 2445. 43. Cohen, N.; Banner, B. L . ; Neukom, C. Synthetic Commun., in press. 44. Cohen, N.; Scott, C. G.; Neukom, C.; Lopresti, R. J.; Weber, G.; Saucy, G. Helv. Chim. Acta 1981, 64, 1158. 45. Slover, H. T.; Thompson, R. Η., Jr. Lipids 1981, 16, 268. RECEIVED December 28, 1981.


Asymmetric Reactions: A Challenge to the Industrial Chemist - ACS

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