Epothilones macrolactonization strategy

Nicolaou et al. were the first to report the successful use of RCM to prepare the 16-membered macrolactone nucleus of the epothilones and present a strategy for their total synthesis based on this reaction. The approach involved formation of the C12,C13 olefin and is outlined in Scheme 2 [12,13]. 

In order to overcome the problem, the inverse strategy was followed. Chromium-Reformatsky reaction between 76-derived C8 aldehyde and a 68-derived ester afforded all four possible C6,C7-diastereomers, which can be independently processed to epothilone D5 diastereomers (including the natural one) by the macrolactonization route. 

A Stille type coupling strategy has been utilised to complete a total synthesis of epothilone E. The vinyl iodide 30 and the thiazole stannane 31 were coupled to give the macrolactone 32 which is a precursor to natural epithilone E. The thiazole stannane 31 was prepared from 4-bromo-2-hydroxymethylthiazole via treatment of the lithiated protected 4-bromO 2-hydroxymethylthiazole with tributylstannyl chloride. This Stille coupling approach was also used to prepare a range of epothilone B analogues <99BMC665>,... 

For the cyclization to the 16-membered macrolactone structure of epothilones C and D (= desoxyepothilones A and B, resp. [26]), three different strategies have been used successfully so far (1) Ring-closing olefin metathesis (RCM) between C12 and Cl3. RCM is a comparably new method in total synthesis and underwent enor-... 

A convergent strategy was chosen, which allows the introduction of modifications at nearly every position of the macrolactone. During the research more than 350 active epothilone analogues were synthesized and it was found that the side chains at C-15 and C-6 are responsible for the tolerability and efficacy. ... 

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

Nicolaou KC, Einlay MRV, Ninkovic S, Sarabia F. Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998 54 7127 7166. 

The basics and the synthetic potential of olefin metathesis has been recently presented in a comprehensive handbook and several reviews [58]. Thus, this chapter will be restricted to demonstrate the scope and flexibility of this type of reaction in the total synthesis of a complex natural product skeleton such as epothilone. The first total syntheses of these antitumor-active 16-membered macrolactones were based on a ringclosing metathesis (RCM) strategy (Scheme 11.36) [73]. Grubbs catalyst 143 has been used for the construction of the endocydic 1,2-disubstituted C12-C13 double bond in epothilone C 148 that, after epoxidation, affords epothilone A 150 [74]. In this approach, ruthenium carbene 143 is more efiident than Schrock molybdenum catalyst 142b [75a[. However, the RCM-route to epothilone D 149, the desoxy precursor of epothilone B 151 bearing a trisubstituted C=C bond, requires the molybdenum carbene catalyst 142b attempts to initiate ring-closure with 143 failed [75]. 

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