Total synthesis of (+)-ambruticin.

Abstract A convergent total synthesis of the novel antifungal agent ambruticin S ( 1 ) has been completed from the assembly of intermediates 18 , 33 and 52 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 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31 E to complete a formal synthesis of 1 , there were several inefficiencies associated with the preparation of 9a . A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh2[5(S)-MEPY]4. Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19 . Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35 . The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48 , which was prepared in three steps from the known epoxide 45 , followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52 . A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S ( 1 ). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.