Total synthesis of (+)-ambruticin S

A convergent total synthesis of the novel antifungal agent ambruticin S () has been completed from the assembly of intermediates , and that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of via a route that featured oxidation of the dihydroxy furan and elaboration of the dihydropyranone derived therefrom. Although served as a precursor of E to complete a formal synthesis of , there were several inefficiencies associated with the preparation of . A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde and produced in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone was initiated with the enantioselective cyclopropanation of catalyzed by Rh2[5(S)-MEPY]4. Ring opening of the resultant lactone followed by a series of refunctionalizations gave in a total of seven steps and 46% yield from . Coupling of the A- and B-ring precursors and was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate . The dihydropyran core of the C-ring subunit precursor was formed from the ring closing metathesis of the diene , which was prepared in three steps from the known epoxide , followed by oxidation. A chelation-controlled addition to the methyl ketone set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol that was then transformed in two steps to the sulfone . A traditional Julia coupling of and proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.