Asymmetric Reactions and Processes in Chemistry - American

3 Asymmetric Synthesis of Chiral Tertiary Alcohols in High Enantiomeric Excess

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ERNEST L . ELIEL, JORMA K. KOSKIMIES, BRUNO LOHRI, W. JACK FRAZEE, SUSAN MORRIS-NATSCHKE, JOSEPH E . L Y N C H , and KENSO SOAI University of North Carolina, Department of Chemistry, Chapel Hill, NC 27514

Chiral 1,3-oxathianes have been used as adjuvants for highly stereoselective asymmetric syntheses. Acylation (direct or via an intermediate carbinol) proceeds to give exclusively equatorial products in which the chirality has been transferred to C(2) of the 1,3-oxathiane. Reaction of the acyl com pounds with Grignard reagents gives predominantly one diastereomer of a 2-oxathianylcarbinol bearing two different alkyl groups on the carbinol carbon, following Cram's rule. Conditions for maximum stereoselectivity have been worked out. Cleavage of the oxathiane (NCS/AgNO) leads to α-hydroxy aldehydes, RR'C(OH)CHO, from which glycols, RR'C (OH)CHOH, tertiary alcohols, RR'C(OH)CH and other derivatives can be prepared, generally in enantiomeric purity exceeding 90%. Suitable chiral 1,3-oxathianes can be conveniently derived from camphor (either enantiomer) or (+)-pulegone. 3

2

3

In 1971 we d i s c o v e r e d (1) t h a t the r e a c t i o n o f conforma t i o n a l ^ l o c k e d 2 - d i t h i a n y l l i t h i u m compounds with e l e c t r o p h i l e s (Corey-Seebach r e a c t i o n ) proceeds with remarkable s t e r e o s e l e c t i v i t y , g i v i n g v i r t u a l l y e x c l u s i v e l y the e q u a t o r i a l s u b s t i t u t i o n products, as e x e m p l i f i e d i n Scheme 1 (R=H). The preference f o r the l , 3 - d i t h i a n y l - 2 - c a r b a n i o n t o undergo e l e c t r o p h i l i c s u b s t i t u t i o n from the e q u a t o r i a l s i d e amounts t o over 6 kcal/mol ( 2 ) , corresponding t o a s e l e c t i v i t y f a c t o r i n excess o f 10,000. This high preference was subsequently shown (3) t o be due t o s t e r e o e l e c t r o n i c f a c t o r s , i n accord with t h e o r e t i c a l p r e d i c t i o n s (4, 5_, 6 ) . S t e r e o s e l e c t i v i t i e s o f such magnitudes resemble those found i n enzymatic r e a c t i o n s and we r e s o l v e d t o t r y t o apply the high

0097-6156/82/0185-0037$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.

ASYMMETRIC


38

REACTIONS

A N D PROCESSES IN

CHEMISTRY

Scheme 1 s e l e c t i v i t y t o the design o f a v e r y e f f i c i e n t asymmetric s y n t h e s i s . Before e n t e r i n g i n t o d e t a i l s , we wish t o s t a t e here the c o n d i t i o n s of an e f f e c t i v e asymmetric s y n t h e s i s i n g e n e r a l terms (7 ) :

1)

The s y n t h e s i s must be h i g h l y s t e r e o s e l e c t i v e .

2)

I f a c h i r a l adjuvant ( c h i r a l a u x i l i a r y reagent) i s b u i l t i n t o the s t a r t i n g m a t e r i a l , the c h i r a l center (or other c h i r a l element) c r e a t e d i n the asymmetric s y n t h e s i s must be r e a d i l y separable from the c h i r a l adjuvant without r a c e m i z a t i o n .

3)

The c h i r a l adjuvant i t s e l f must be r e c o v e r a b l e i n good y i e l d and without l o s s o f enantiomeric p u r i t y .

4)

The c h i r a l adjuvant should be r e a d i l y (cheaply) a v a i l a b l e i n e n a n t i o m e r i c a l l y pure form.

In a d d i t i o n , o f course, the s y n t h e s i s must proceed i n acceptable o v e r a l l chemical y i e l d . Statement 1) i s q u a l i t a t i v e and i t s t r a n s l a t i o n i n t o q u a n t i t a t i v e terms i s a matter o f t a s t e . Syntheses producing 85-90% enantiomeric excess (e.e.) u s u a l l y allow p u r i f i c a t i o n o f the c h i r a l product (or an intermediate on the way) t o enantiomeric p u r i t y by simple r e c r y s t a l l i z a t i o n . However, higher demands may be made i n cases o f syntheses of c h i r a l l i q u i d s when c r y s t a l l i n e intermediates are not a c c e s s i b l e . With r e s p e c t t o statements 2) and 3 ) , these c o n d i t i o n s are p a r t i c u l a r l y easy t o f u l f i l l i n c a t a l y t i c asymmetric s y n t h e s i s where 2) simply demands s e p a r a t i o n o f the c h i r a l product from the c h i r a l c a t a l y s t and 3) i s superseded by a requirement of reasona b l e turnover. (A turnover number of 100, modest by the standards of many c a t a l y t i c r e a c t i o n s , i s e q u i v a l e n t to a 99% recovery o f c h i r a l a u x i l i a r y reagent, which i s r a r e l y achieved!) Catalytic asymmetric syntheses are t h e r e f o r e p a r t i c u l a r l y a t t r a c t i v e , but, of course, they a r e o f t e n not a v a i l a b l e . Statement 3) may not apply when the c h i r a l a u x i l i a r y reagent i s v e r y cheap (e.g. sucrose). Contemplation o f Scheme 1 suggests t h a t i t s a p p l i c a t i o n t o asymmetric s y n t h e s i s should be f a c i l e i f R = CH. and the s t a r t i n g



3.

ELiEL E T AL.

39

Chiral Tertiary Alcohols

d i t h i o l i s r e s o l v e d . However, s e p a r a t i o n o f the new c h i r a l center (C-2) from the o r i g i n a l one (C-6) would appear t o be unachievable. We f e l t t h a t t h i s dilemma c o u l d be overcome by the use o f 1,3oxathianes i n s t e a d o f 1,3-dithianes and, indeed, i t was found t h a t the e l e c t r o p h i l i c r e a c t i o n s o f 2 - l i t h i o - l , 3 - o x a t h i a n e s are o f the same order o f s t e r e o s e l e c t i v i t y as those o f the corresponding d i t h i a n e s (8). However, an asymmetric s y n t h e s i s based on the s t e r e o s e l e c t i v e cleavage o f t h e C(2)-S bond f o l l o w e d by s c i s s i o n of the C(6)-0 l i n k a g e i n 2-alkyl-4,6,6-trimethyl-l,3-oxathianes gave d i s a p p o i n t i n g l y low o p t i c a l y i e l d s (9). A chance d i s c o v e r y p o i n t e d us toward the s u c c e s s f u l s y n t h e t i c approach. 2-Acyl-l,3-oxathianes can be obtained with e x c l u s i v e l y e q u a t o r i a l a c y l groups by a c y l a t i o n o f c o n f o r m a t i o n a l l y b i a s s e d 2 - l i t h i o - 1 , 3 - o x a t h i a n e s o r ( i n b e t t e r y i e l d ) by r e a c t i o n with aldehydes followed by Swern o x i d a t i o n (10). We d i s c o v e r e d (8) t h a t r e a c t i o n o f these ketones with Grignard reagents once again proceeds h i g h l y s t e r e o s e l e c t i v e l y g i v i n g one o f the two p o s s i b l e t e r t i a r y a l c o h o l s i n l a r g e excess over the other. The sequence of t h e two h i g h l y s t e r e o s e l e c t i v e steps i s shown i n Scheme 2. I t i s c l e a r t h a t s t a r t i n g from a c h i r a l 1,3-oxathiane such as ^, ^ T ^

s

^ 7

ι\ Bu L i - /7 Γ ^ T/ ^ ç U 1) 2) RCHO L ^ ^ D ' Ο 3) DMSO-TFAA' Et^N only isomer

^ r ^ ^ s - ^ T ^ c —

s

R l

— T ^ —

2

s

D R'MgX > 2° H

^ 7 — c

minor C pyridine C

I

TtO

12

11

1) B H 3 - T H F 2) N o O H - H 0 2 2

H C 3

OH

CH 1) oq.NoOH

3

'OH

2) H+

(R)-(-)-Mevak>loctone

2

« CHMgBr

3

3

T

2

OH

Scheme 10


52

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

Acknowledgement


This work was supported, i n p a r t , under NSF grants CHE7520052 and CHE78-28118. Acknowledgement i s a l s o made t o the Donors of the Petroleum Research Fund, administered by the American Chemical S o c i e t y , f o r p a r t i a l support o f t h i s r e s e a r c h .

Literature Cited 1. Eliel, E.L.; Hartmann, A.A. J.Am.Chem.Soc. 1971, 93, 2572. 2. Eliel, E.L.; Hartmann, Α.Α.; Abatjoglou, A.G. J.Am.Chem.Soc. 1974, 96, 1807. 3. Abatjoglou, A.G.; Eliel, E.L.; Kuyper, L.F. J.Am.Chem.Soc. 1977, 99, 8262. 4. Bernardi, F.; Csizmadia, I.G.; Mangini, A.; Schlegel, H.B.; Whanbo, M.-H.; Wolfe, S. J.Am.Chem.Soc. 1975, 97, 2209. 5. Lehn, J.-M.; Wipff, G. J.Am.Chem.Soc. 1976, 98, 7498. 6. Epiotis, N.D.; Yates, R.L.; Bernardi, F.; Wolfe, S. J.Am.Chem.Soc. 1976, 98, 5435. 7. Eliel, E.L. Tetrahedron 1974, 30, 1503. 8. Koskimies, J.K. Ph.D. Dissertation, University of North Carolina, Chapel Hill, NC, 1976. 9. Eliel, E.L.; Koskimies, J.K.; Lohri, B. J.Am.Chem.Soc. 1978, 100, 1614. 10. Omura, K.; Sharma, A.K.; Swern, D. J.Org.Chem. 1976, 41, 957. 11. Cram, D.J.; Kopecky, K.R. J.Am.Chem.Soc. 1959, 81, 2748. 12. cf. Ho, T.-L. "Hard and Soft Acids and Bases"; Academic Press: New York, 1977; Ho, T.-L. Chem.Rev. 1975, 75, 1. 13. For example: Cram, D.J.; Wilson, D.R. J.Am.Chem.Soc. 1963, 85, 1245; Stocker, J.H.; Sidisunthorn, P.; Benjamin, B.M.; Collins, C.J. J.Am.Chem.Soc. 1960, 82, 3913; Stocker, J.H. J.Org.Chem. 1964, 29, 3593; Angiolini, L.; Costa-Bizzari, P.; Tramontini, M. Tetrahedron 1969, 25, 4211; Méric, R.; Vigneron, J.-P. Bull.Soc.Chim.France 1973, 327; Nicolaou, K.C.; Charemon, D.A.; Barnette, W.E. J.Am.Chem.Soc. 1980, 102, 6611; Still, W.C.; McDonald, III, J.H. Tetrahedron Lett. 1980, 1031 and refs. there cited. 14. Morris-Natschke, Susan Ph.D.Dissertation, University of North Carolina, Chapel Hill, NC, 1981. 15. Owen, L.N.; Sultanbawa, M.U.S. J.Chem.Soc. 1949, 3098. 16. Hagberg, C.E.; Allenmark, S. Chem.Scripta 1974, 5, 13. 17. cf. Greene, T.W. "Protective Groups in Organic Synthesis"; Wiley-Interscience: New York, 1981; pp. 133-140. 18. Takano, S.; Hatekeyama, S.; Ogasawara, K. J.Chem.Soc.Chem. Commun. 1977, 68; Fetizon, F.; Jurion, M. ibid. 1972, 382. 19. Mizurro, H.; Yamada, S.-i. Chem.Pharm.Bull. 1975, 23, 527. 20. Eliel, E.L.; Frazee, W.J. J.Org.Chem. 1979, 44, 3598. 21. Eliel, E.L.; Lynch, J.E. Tetrahedron Lett. 1981, 22, 2855. 22. Müller, N.; Eliel, E.L. unpublished observations.


3. ELIEL ET AL.

Chiral Tertiary Alcohols


23. 24. 25. 26.

53

Lynch, J.Ε.; Eliel, E.L. unpublished observations. Eliel, E.L.; Soai, K. Tetrahedron Lett. 1981, 22, 2859. Corey, E.J.; Erickson, B.W. J.Org.Chem. 1971, 36, 3553. Regarding the rotation and configuration of 9b, see Mitsui, S.; Imaizumi, S.; Senda, Y.; Konno, K. Chem.Ind.(London) 1964, 233. 27. Regarding previous reports on chiral 10a and 10b, cf. Richter, W.J. Justus Leibigs Ann.Chem. 1975, 401 and Zeiss, H.H. J.Am.Chem.Soc. 1951, 73, 2391. 28. Mukaiyama, T.; Sakito, Y.; Asami, M. Chem.Lett. 1978, 1253; 1979, 705. 29. Inch, T.D.; Lewis, G.J.; Sainsbury, G.L.; Sellers, D.J. Tetrahedron Lett. 1969, 3657; Inch, T.D. Synthesis 1970, 466. 30. Inch, T.; Ley, R.V.; Rich, P. J.Chem.Soc.(C) 1968, 1693. 31. cf. Krull, I.S. Advances in Chromatography 1978, 16, 175; see also the article by Pirkle, W.H.; Finn, J.M.; Hamper, B.C.; Schreiner, J . ; Pribish, J.R. in this volume. 32. Abushanab, E.; Reed, D.; Suzuki, F.; Sih, C.J. Tetrahedron Lett. 1978, 3415. 33. Kogure, T.; Eliel, E.L. unpublished observations. RECEIVED December 14, 1981.


Asymmetric Reactions and Processes in Chemistry - American

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