Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy

Abstract

The total syntheses of epothilones A (1) and B (2) and several analogues thereof are described. The reported strategy relies on a macrolactonization approach and features selective epoxidation of the macrocycle double bond in precursors 3 and 4 (Scheme ), respectively, as well as high convergency and flexibility. Building blocks 9−12 and 15 were constructed by asymmetric processes and coupled via Wittig, aldol, and macrolactonization reactions to afford the basic skeleton of epothilones and that of several of their analogues by a relatively short route. The utilization of intermediate 14, obtained via a stereoselective Wittig reaction and its Enders coupling to SAMP hydrazone 13 (Scheme ), in combination with a stereoselective aldol reaction with the modified substrate 69 (Scheme ) improved the stereoselectivity and efficiency of the total synthesis of these new and highly potent microtubule binding antitumor agents.

The Formal Total Synthesis of Epothilone A

“…N- -oxazolidinone 23 was selectively methylated to give 24, thus establishing the desired tate. The final coupling steps follow the procedure employed by Nicolaou et al [11] in their total synthesis of epostereochemistry. Reduction with LiAlH 4 [10] and subsequent oxidation generated the required (2S)-methyl-6-heptenoic thilone A (1) (Scheme 9).…”

“…TBS triflate and 2,6-lutidine in dichloromethane. duced at the end of this reaction sequence, to make this Selective deprotection of the primary ether with CSA [11] in sequence suitable for the introduction of different heteromethanol followed by DessϪMartin oxidation of the result-cyclic side chains in a combinatorial manner. ant alcohol 33 completed the synthesis of aldehyde 3.…”

Recent Methods for the Synthesis of (E)‐Alkene Units in Macrocyclic Natural Products

“…A better strategy for this total synthesis includes the formation of the (Z)-alkene on a linear precursor, and a macrolactonization to close the 16-membered ring. [28] Another study concerning the influence of remote substituents was reported by Fürstner et al in the course of their approach towards the synthesis of salicylihalamides A and B (Scheme 9). [29] The free phenol 21 a, in the presence of catalyst 10 in toluene at 80 8C, furnished the Z isomer of 22 a exclusively.…”

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

“…Compound 10 was synthesized as reported earlier. [32] Selective reduction of the aldehyde group of 10 with NaBH 4 gave the primary alcohol 11 as a mixture with its hemiacetal 12, and was converted to the bis-silyl ether 4 with TBSCl and imidazole.…”