Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B

Efficient syntheses of the title compounds have been developed. Several strategies for preparation of each of the naphthalene and tetrahydroisoquinoline (THIQ) portions were developed. Initial attempts to use benzyne plus furan cycloaddition reactions were thwarted by the unfavorable sense of the regiochemical outcome. An interesting annulation reaction of benzynes derived from 2,4-dibromophenol derivatives formed the core of the shortest naphthalene synthesis. An alternative annulation initiated by the addition of a benzylic sulfone anion to methyl crotonate led to an efficient naphthol synthesis amenable to large scale. The THIQ synthesis of Bringmann was used initially and subsequently complemented by a route whose key step involved the opening of N-tosyl-2-methylethyleneimine by a 3,5-dimethoxyphenylcuprate reagent. The results from a variety of aryl cross-coupling reactions are described. Suzuki coupling of the boronic acid derived from the naphthalene moiety with a THIQ-iodide was the most generally effective method for forming the hindered biaryl bond. The korupensamines and ancistrobrevine B were then revealed by deprotection. The oxidative coupling of several 4-aryl-1-naphthols to indigoids (cross ring naphthoquinones) with silver oxide effected the critical dimerization reaction needed to establish the michellamine skeleton. For the perbenzylated precursor, hydrogen over palladium on carbon both reductively bleached the indigoid and hydrogenolyzed the benzyl ethers and amines to release the free michellamines. The synthesis of several michellamine analogues, including ent-michellamines, is outlined. Results of anti-HIV assays are presented.