ALDOL CONDENSATION OF EVANS CHIRAL ENOLATES WITH ACETOPHENONES - ITS APPLICATION TO THE STEREOSELECTIVE SYNTHESIS OF HOMOCHIRAL ANTIFUNGAL AGENTS

The results of the aldol condensation of Evans chiral imide enolates with a series of acetophenones are reported. Activated acetophenones, such as 2,4-difluoroacetophenone, alpha-chloroacetophenone, and alpha-chloro- and alpha-bromo-2,4-difluoroacetophenone, reacted with the lithium enolate of 5 with good levels of enolate facial diastereoselectivity toward the (2R)-isomers (> 10:1) but with low anti:syn selectivity (ca. 3:2). Sodium and potassium enolates of 5 were also tested. The nature of the solvent influenced the degree of diastereofacial biases. Less activated ketones, such as acetophenone, reacted only to a ca. 50% extent without facial or anti:syn stereoselectivities. Chairlike pericyclic transition states are believed to govern the reaction. When alpha-bromoacetophenones were used, longer reaction times and higher temperatures resulted in the selective formation of the S-2 epoxide (syn-(2R,3R), 11) with good levels of selectivity. Equilibration studies performed in THF with the corresponding metal aldolates generated in situ by deprotonation of the aldol adducts indicated that an aldol/retroaldol process was first established followed by a slower formation of the epoxide. Stereoselection is thought to originate by a faster oxirane formation of the syn bromohydrins as compared to the anti due to steric interactions between the alpha-group and the leaving bromide. Optimum retroaldol-epoxide formation rates were obtained using the sodium enolate in ether at -78 degrees C. Under these conditions the S-1:S-2:A(1)A(2) ratio of epoxides was 6:83:10:0.3 and the major isomer was isolated by recrystallization in 79% yield. An improved synthesis of amino alcohol 3, an advanced intermediate in the preparation of orally active antifungal agents, using a tandem of this new ketone-aldol technology and a Curtius rearrangement, is reported. The new sequence proceeds with an overall yield of 53% and does not require chromatographic purifications.