A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments1

Abstract

Our continued interest in the anticancer agent paclitaxel is driven by the desire to understand the structural features and spatial arrangement necessary for tubulin binding2 and stabilization of microtubule dynamics.3 The recently reported class of natural products, epothilone, now provides us with compounds structurally distinct from taxol and taxol analogues but with similar biological activity. In addition, epothilones have much greater activity against multi-drug resistant cell lines.4 After independently determining the relative stereochemistry of epothilone A we reported our synthetic approach, Figure 1, which includes a late-stage macrocyclic olefin metathesis.5 Our initial publication presented an enantioselective preparation of thiazole fragment C and the successful application of a ring-closing olefin metathesis reaction to an epothilone model system. Concurrently, three other synthetic groups reported similar approaches to epothilone A all of which have culminated in total synthesis.6-10 Herein we report the details of our independent, enantioselective preparation of the ketone fragment B and aldehyde A. Ketone B has been prepared from a sequence which is highlighted by a samarium-mediated Reformatsky reaction11 originally developed by Molander, Scheme 1. The sequence begins with racemic alcohol 2 readily prepared in one step from propionaldehyde and 3-methyl-2-butenylmagnesium chloride. Enzymatic resolution in methyl tert-butyl ether using Altus Biologics12 Chiro-CLECPC(which is reusable without significant loss of activity) provided an efficient route to gram quantities of (R)-2 after purification and deacylation. The enantioselectivity of the resolution at 47% conversion was determined to be >20:1 by Mosher ester methodology13 and chiral capillary gas chromatography (see Experimental Section for details). The enantiomeric excess was found to be dependent upon percent conversion (97% ee at 15% conversion and 92% ee at 48% conversion). The unreacted alcohol 2 can be easily recycled by a two-step oxidationreduction sequence. Acylation of the secondary hydroxyl occurred readily with bromoacetyl bromide in the presence of N,N-dimethylaniline to provide ester 3 in excellent yield. Ozonolytic cleavage of the terminal olefin yielded the necessary Reformatsky precursor which under exposure to freshly prepared SmI2 provided the lactone 4 in quantitative yield with >20:1 diastereose-