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

Efficient syntheses of the title compounds have been developed. Several str ategies for preparation of each of the naphthalene and tetrahydroisoquinoli ne (THIQ) portions were developed. Initial attempts to use benzyne plus fur an cycloaddition reactions were thwarted by the unfavorable sense of the re giochemical outcome. An interesting annulation reaction of benzynes derived from 2,4-dibromophenol derivatives formed the core of the shortest naphtha lene synthesis. An alternative annulation initiated by the addition of a be nzylic sulfone anion to methyl crotonate led to an efficient naphthol synth esis amenable to large scale. The THIQ synthesis of Bringmann was used init ially and subsequently complemented by a route whose key step involved the opening of N-tosyl-2-methylethyleneimine by a 3,5-dimethoxyphenylcuprate re agent. The results from a variety of aryl cross-coupling reactions are desc ribed. Suzuki coupling of the boronic acid derived from the naphthalene moi ety with a THIQ-iodide was the most generally effective method for forming the hindered biaryl bond. The korupensamines and ancistrobrevine B were the n revealed by deprotection. The oxidative coupling of several 4-aryl-1-naph thols to indigoids (cross ring naphthoquinones) with silver oxide effected the critical dimerization reaction needed to establish the michellamine ske leton. For the perbenzylated precursor, hydrogen over palladium on carbon b oth reductively bleached the indigoid and hydrogenolyzed the benzyl ethers and amines to release the free michellamines. The synthesis of several mich ellamine analogues, including ent-michellamines, is outlined. Results of an ti-HIV assays are presented.