Erythronolide A seco-acid

A stereoselective osmylation approach was applied to the synthesis of C(l)—C(7) and C(7)—C(13) subunits of erythronolide A41. A key synthon of the erythronolide A seco acid, 30, was prepared in an enantiomerically pure form by utilizing a stereoselective osmylation of the chiral hydroxy (Z, )-diene ester 31 and subsequent hydrogenation of the resulting butenolide 32 (equation 24). 

RB Woodward, E Logusch, KP Nambiar, K Sakan, D Ward, B-W Au-Yeung, P Balaram, LJ Browne, PJ Card, CH Chen, RB Chenevert, A Fliri, K Frobel, H-J Gais, DG Garrat, K Hayakawa, W Heggie, DP Hesson, D Hoppe, 11 loppe et al. Asymmetric total synthesis of erythromycin. 1. Synthesis of erythronolide A seco acid derivative via asymmetric induction. J Am Chem Soc 103 3210-3213, 1981. 

A unique approach to the stereochemical complexities of erythronolide A was developed by Deslongchamps as outlined in Scheme 2,19. The methyl ester of erythronolide A seco acid (212) was dehydrated to form the cyclic ketal 213. A multistep oxidation of the side chain then gave aldehyde 214 which, when condensed with the zirconium enolate of methyl propionate, afforded a 10 1 ratio of aldol diastereomers, the major being 213. Furthermore, aldehyde 214 could easily be converted into the y-lactone 215. 

The lactonization of erythronolide A seco acid to form a 14 membered lactone has a cumbersome and instructive history. The Woodward group tested a plethora of protecting group patterns at the seco acid stage until cyclization was finally realized [13] with 38. The success has been traced to the 9(S) configuration of the cyclization precursor 38. 

Erythronolide A (8) is a 14-membered macrolide, with ten chiral centres. Because a 14-membered ring is not only as flexible as a linear open-chain, but also prone to experience several kinds of transannular interactions, any kind of stereochemical control must be exerted in the corresponding open-chain derivative,20 i.e. in the seco-acid 9, or in the linear fragments resulting from its disconnection, which should be immobihsed or "frozen" in someway. 

Hikota, M., Tone, H., Horita, K., Yonemitsu, O. Chiral synthesis of polyketide-derived natural products. 31. Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of seco-acid. Tetrahedron 1990, 46, 4613 628. 

Martin, S.F., Lee, W.-C., Pacofsky, G.J. et a(. (1994) Strategies for macrolide synthesis. A concise approach to protected seco-acids of erythronolides A and B. Journal of the American Chemical Society, 116, 4674-4688. 

Compound 89 was converted into 91 through epimerization at C5 of the ketone 90. The aldehyde 93 reacted with the lithium enolate of ethyl trityl ketone to give the desired aldol 94 as a sole product, which was converted into the (R)-sulfoxide 95 through the epimerization of the (S)-sulfoxide. The lithiated 95 was added to the ketone 91, followed by desulfurization and desilylation, to give the adduct 96. The seco-acid derived from 96 was cyclized by Corey s method followed by deprotection to give (9S)-9-dihydroerythronolide B, which was converted to erythronolide B (55) after 3,5-0-benzylidenation, oxidation and debenzylidenation. 

In anticipation of the final carbon-carbon bond construction that is required to prepare the intact seco acid of erythronolide B using a directed aldol reaction to form the C(10)-C(l 1) bond, it was first necessary to prepare the requisite chiral aldehyde 80. Although the synthesis of 80 had been previously reported, we elected to devise an alternative route to access this material that commenced with the addition of the chiral boron enolate 37 0 to propionaldehyde to furnish 81 (Scheme 12). The sequential protection of the secondary hydroxyl group and removal of the chiral auxiliary gave 82, which was then converted to 80 by over-reduction followed by reoxidation under Swem conditions. 

Upon examination of the reactions outlined in Schemes 9, 11, and 12, it is evident that the present route to the seco acid of erythronolide B is remarkably concise, involving a longest linear sequence of a mere 14 chemical operations from the commercially available 2-ethylfuran (64). Even counting the steps required for the preparation of the aldehyde 80, the total number of operations is only 19. We anticipate that the analogous aldol reaction of the enolate derived from 79 with the... 

The methods described above should allow an efficient assembly of the molecular skeleton of erythronolide A. This would involve six chain elongation steps leading to the seco-acid 24 of 9(S)-dihydroerythronolide A. 

How does one then attain an axial orientation of C8 at C9/C11 dioxane ring This requires the aryl-residue Ar in 41 to be placed in an equatorial position, which is unfortunately the thermodynamically less stable situation. As soon as equilibration becomes possible, 41 is converted into 42, which goes over into the twist boat conformation 43 [36] in which all the major residues are equatorially arranged. Erythronolide seco acid derivatives with such an arrangement have a... 

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