Modeling a Macrocyclic Bis[spirodiepoxide] Strategy to Erythronolide A

Abstract

A concise route to functionalized 14-membered macrolides related to erythronolide A was achieved. Key steps include the simultaneous formation of bis[allenic] substrates, efficient macrolactonization, highly stereoselective oxidation to the corresponding bis[spirodiepoxide], and nucleophilic spirodiepoxide opening. The structure and reactivity of these macrolides, and the strategy that led to their evaluation, are discussed.

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…[40] The literature describes numerous examples of synthesis, in which additional fragments to the already prepared Macroheterocycles Functionalization Accompanied by Preservation and Changing Their Size dioxirane (DMDO) in synthesis of epothilone A and B, [51] their analogues, [52] and antibiotic erythromycin derivatives A. [53] Thus, synthesis of erythronolide A (54) derivatives that are macroheterocycles (55-58) with potentially antibiotic properties [53] was carried out by the interaction between DMDO and cyclic bis-allenes (59) and (60) (61) and (62). Subsequent addition of methyl cuprate to compound (61) leads to chiral macroheterocycle (55) with four stereocenters and side rearrangement product with C4-C6 oxetane fragments (63).…”

The conversion of allenes to strained three-membered heterocycles

“…Initial studies were carried out on a model substrate containing chirality only at the two allenes (Scheme 43). 62 Epoxidation of both allenes, followed by addition of methyl cuprate, gave the ring-opened product in modest yield; however, ring-opening with thiobenzamide resulted in higher yields. If fewer equivalents of oxidant were used, one allene was preferentially reacted over the other, allowing for multiple nucleophiles to be incorporated into the macrocyclic framework.…”

The chemistry of bisallenes

“…In Scheme 108 it is shown how a compound of type 329 (Scheme 76) was used by Williams and co-workers to develop the synthetic methodology for the efficient preparation of various compounds related to erythronolide A [190,256]. Model system 480 was first oxidized with dimethyldioxirane (DMDO), and the resulting bis(spiro)diepoxide derivative 481 was subsequently opened by a nucleophile (a cuprate in this case) to 482 .…”