STRATEGIES FOR MACROLIDE SYNTHESIS - A CONCISE APPROACH TO PROTECTED SECO-ACIDS OF ERYTHRONOLIDE-A AND ERYTHRONOLIDE-B

Concise syntheses of protected derivatives of the seco-acids of erythr onolides A and B, 5 and 6, respectively, have been completed wherein t he longest linear sequence requires only 13 chemical steps from 5-ethy lfuraldehyde (15). The syntheses commenced with the asymmetric aldol c ondensation of 15 according to the Evans protocol to afford the optica lly pure syn adduct 16, thereby establishing the critical stereocenter s at C(4) and C(5) of the erythromycin backbone. Reductive removal of the chiral auxiliary from 16 gave the diol 17, which was converted to the bicyclic enone 18 by an one-pot process involving sequential oxida tion of the furan ring and acid-catalyzed bicycloketalization. Stereos elective elaboration of 18 to the tertiary alcohol 19 was achieved in two steps by sequential treatment with lithium dimethylcuprate and met hyllithium in the presence of cerium trichloride. Compound 19 underwen t facile acid-catalyzed reorganization to the isomeric ketal 21, which was transformed into 24 by a Swern oxidation and a second asymmetric aldol condensation. However, the necessary refunctionalization of 24 i nto a ketone that would participate in the requisite aldol reaction to append the C(11)-C(15) segment of the erythronolide backbone could no t be induced. On the other hand, transthioketalization of 19 gave the triol 26, which was converted to 28 by the thermodynamically-controlle d formation of an acetonide of the 1,2-diol array. Deprotection of the C(9) ketone function followed by Swern oxidation produced the keto al dehyde 31, which underwent chemoselective, Lewis acid-mediated additio n of tri-n-butylcrotylstannane to the aldehyde function to furnish a m ixture (4:1) of the homoallylic alcohols 32 and 33; the major product 32 comprises the C(1)-C(10) subunit common to the seco-acids of both e rythronolides A and B. Diastereoselective aldol condensation of the en olate derived from 32 with 40 gave 42 as the major adduct; oxidative p rocessing of the terminal olefin then delivered the erythronolide B se co-acid derivative 46. The proposed structure of 42 was initially base d upon its conversion into the polyol 48, which was identical to that derived from natural erythronolide B (49). Subsequent to this chemical correlation, the X-ray structure of 50, which was prepared from 42, u nequivocally verified this assignment. In experiments directed toward the preparation of the seco-acid of erythronolide A, the directed aldo l reactions of 32 with the aldehydes 59 and 60 were examined. Although the addition of the enolate of 32 to 59 produced none of the requisit e adduct, its reaction with 60 gave a mixture (1:5) of 62 and 64. Ster eoselective reduction of the C(9) carbonyl function of 62 followed by oxidative cleavage of the double bond and global deprotection gave the polyol 62, which was identical with the polyol derived from natural e rythromycin A (1).