4 Acyclic Stereoselection via the Aldol Condensation C L A Y T O N H . HEATHCOCK
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University of California, Department of Chemistry, Berkeley, CA 94720
The aldol condensation, one of the oldest organic reactions, is emerging as a powerful method for control of relative and absolute stereochemistry in the syn thesis of conformationally flexible compounds. Some of the research which has been carried out at Berkeley over the past five years is reviewed in this article. Points discussed are the factors that control simple erythro, threo diastereoselection, the use of double stereodifferentiation to influence the "Cram's rule" preference shown by chiral aldehydes, and some recent experiments that shed light on the role that the sol vent and other nucleophilic ligands play in determining the stereochemistry of the reaction. I t has been q u i t e apparent f o r some time t h a t c o n t r o l o f s t e r e o s t r u c t u r e i n the s y n t h e s i s o f a c y c l i c and other conformationa l l y mobile compounds i s a problem f o r which s y n t h e t i c chemists have few s o l u t i o n s . For example, i n h i s 1956 a r t i c l e i n "Perspect i v e s i n Organic Chemistry," the l a t e P r o f e s s o r R.B. Woodward c h a r a c t e r i z e d the macrolide a n t i b i o t i c erythromycin as a s y n t h e t i c challenge which i s " . . . q u i t e h o p e l e s s l y complex, e s p e c i a l l y i n view o f i t s p l e t h o r a o f asymmetric c e n t e r s . " ( J , 2 ) I n f a c t , i t was t h i s
erythromycin-A
0097-6156/82/0185-0055$05.00/0 © 1982 American Chemical Society
In Asymmetric Reactions and Processes in Chemistry; Eliel, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY
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molecule and the above mentioned quote from the master o f organic s y n t h e s i s which planted the seed o f the p r o j e c t which i s discussed i n t h i s a r t i c l e . In c a s t i n g about f o r a method which might be used to a t t a c k the s y n t h e t i c problem posed by erythromycin, I came across a statement by another master — o f the f i e l d o f b i o s y n thesis. In f a c t , i t was a l s o i n " P e r s p e c t i v e s i n Organic Chemis t r y " that J.W. C o r n f o r t h wrote: "Nature, i t seems, i s an organic chemist having some p r e d i l e c t i o n f o r the a l d o l and r e l a t e d conden s a t i o n s . . . " (3.) Thus, the erythromycin aglycone i s presumably con s t r u c t e d by Nature by a s e r i e s o f a l d o l - t y p e condensations o f pro pionate u n i t s :
CH0
In 1976 we began an i n v e s t i g a t i o n o f the a l d o l condensation with the u l t i m a t e goal o f l e a r n i n g enough about i t s stereochemistry t o use i t as the s o l e method f o r c o n s t r u c t i n g the aglycone o f erythromycin-Α and, a t the same time, c o n t r o l l i n g the r e l a t i v e stereochemistry o f i t s t e n c e n t e r s o f c h i r a l i t y . Here, f o l l o w i n g a b r i e f review o f our e a r l y work, I s h a l l d i s c u s s some recent unpub l i s h e d experiments t h a t p e r t a i n to the c o o r d i n a t i o n chemistry o f the enolate c o u n t e r i o n and how t h a t can i n f l u e n c e the stereochemis t r y o f the a l d o l condensation. In e v a l u a t i n g the a l d o l condensation as a method f o r b u i l d i n g acyclic molecules containing many stereocenters, such as e r y t h r o n o l i d e - A , there a r e two types o f d i a s t e r e o s e l e c t i o n which must be considered. The f i r s t i s r e f e r r e d to as simple d l a s t e r e o -
erythro
thrêo
s e l e c t i o n and a r i s e s from the f a c t t h a t two newly-created chiral c e n t e r s may be formed w i t h e i t h e r the e r y t h r o o r threo r e l a t i v e
In Asymmetric Reactions and Processes in Chemistry; Eliel, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
4.
HEATHCOCK
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Acyclic Stereoselection
c o n f i g u r a t i o n . * I t i s now c l e a r t h a t simple d i a s t e r e o s e l e c t i o n i s c o n t r o l l e d by two f a c t o r s — the c o n f i g u r a t i o n (E or 1) o f the enol a t e and the o r i e n t a t i o n o f the enolate and aldehyde i n the t r a n s i t i o n s t a t e o f the a l d o l r e a c t i o n i t s e l f . Deprotonation o f an e t h y l carbonyl compound can g i v e e i t h e r a t r a n s - o r a c i s - e n o l a t e : *
x**-
g
«
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