The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue

Abstract

A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained epothilone derivative 42.

Total Synthesis and Selective Activity of a New Class of Conformationally Restrained Epothilones

“…Attempts to rigidify the southern C-1-C-8 sector of the molecule have resulted in loss of biological activity. [17,18] Analogues made by rigidification of some parts of the northern C-9-C-13 sector have retained biological activity. [19][20][21] A series of conformationally rigidified analogues bridging the northern and southern sectors across the macrocycle were prepared recently.…”

The Epothilones: An Outstanding Family of Anti-Tumor Agents

“…Following Danishefsky's precedent, 298 was converted into tri-olefin 299 and then into intermediate 28b. (89)(90)(91)(92) The White group made novel contributions with respect to the formation of the (Z)-12,13-olefin moiety and the Wittig-olefination of phosphorane 308 and aldehyde 312 (Charts 49 and 50). The synthesis of 308 (Chart 49) started with a conjugate addition of the cuprate derived from vinyl iodide 300 to Evans'oxazolidinone 301 to give the C11-C16-fragment 302.…”

“…10) as a minor product in the fermentation of Sorangium cellulosum (86); this compound is 25-fold less active against the mouse fibroblast cell line L929 than Epo C. Mulzer and co-workers have described the synthesis of the conformationally constrained tricyclic analog VI-14 ( Fig. 10) (90), which was conceived based on the close proximity of the C4-(pro-R)-and the C6-methyl groups in the X-ray crystal structure of Epo B. The compound showed no biological activity, but it should be noted that the stereochemistry at C7 could not be rigorously established.…”

Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity

“…113,119,129 Another obvious modification, the ring closure of C27 with the thiazole ring, was first realized by the Novartis group only in 2000 with the synthesis of benzthiazole, benzoxazole, and quinoline analogs. 144 To rigidify the macrocycle and enforce certain conformations, 12,13-benzo, 145 10,11,12-benzo, 64,146 and 10,11-cyclopropano 108 analogs, and a C23, C24 ethanol bridged analog, 91 were synthesized. 142 Whereas 12,13-trans olefins and the epoxides derived from them were regularly unwanted byproducts in the ring-closing olefin metathesis, Altmann et al synthesized them in a stereoselective manner to prove their unexpected biological activity, 143 which had been observed earlier by Nicolaou and coworkers.…”