The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed epothilones including an epothilone B10 (3), epothilone F (5), 16-desmethylepothilone B (14), pyridine epothilones 57a-57g, dimeric epothilones 59 and 61, and benzenoid epothilones 63a-63g.

A brief introduction into the chemistry of diazonamide A (1) is followed by first-generation sequences to access the originally proposed structure for this unusual marine natural product. These explorations identified a route capable of delivering a model compound possessing the complete heteroaromatic core of the natural product, highlighting in the process several unanticipated synthetic challenges which led both to new methodology as well as an improved synthetic plan that was successfully applied to fully functionalized intermediates.

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Details of efficient syntheses of (9S,12S)-cycloisodityrosine (6) and a concise total synthesis of RA-VII (1) were described. An intramolecular SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-l-(3-hydroxy-4-methoxyphenylalanyl]-l-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)-l-(3,4-dihydroxyphenylalanyl)]-l-4-fluoro-3-nitrophenylalaninate ((9S,12S)-11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with l-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).

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