The enantiospecific stereospecific total synthesis of the enantiomers of the indole alkaloids N(a)-methylvellosimine, affinisine and macroline as well as the total synthesis of the indole alkaloids triervine, alstophylline and the antimalarial bisindol

The total synthesis of several indole alkaloids [trinervine 75 and alstophylline 1, as well as the enantiomers ( 71En, 72En and 3En, respectively) of N_a-methylvellosimine, affinisine and macroline] was accomplished via the asymmetric Pictet-Spengler reaction. During the synthesis of the enantiomer 72En of affinisine, the enantiomer 40En of the tetracyclic ketone required for the synthesis of the antipodes of the natural occurring alkaloids was constructed efficiently from L-tryptophan on large scale. By modification of the original Pd(0) catalyzed(enolate driven) intramolecular cyclization, the enantiospecific stereospecific total synthesis of the enantiomer 72En of affinisine was accomplished (from L-tryptophan methyl ester 85) in 7 reaction vessels in 22% overall yield. The development of a regioselective hydroboration/oxidation sequence permitted the total synthesis of the enantiomer 3En of macroline 3 (from L-tryptophan methyl ester 85) with 11 isolated intermediates (13 reaction vessels) and an overall yield of 12.3%. The Pd0 intramolecular cyclization strategy coupled with the modified entry into the tetracyclic ketone (40En) provided the four chiral centers for the enantiomer 3En of macroline 3, stereospecifically. The N_a-H macroline equivalent 76 was synthesized (from D-tryptophan methyl ester) in only 13 reaction vessels and in 17.5% overall yield by following the same sequence. Completion of the total synthesis of the enantiomer 3En of macroline 3 and the N _a-H macroline equivalent 76 provided these macroline units for the preparation of bisindole alkaloids. Therefore, natural or unnatural bisindole alkaloids as well as mismatched pairs can be obtained by this chemistry. This will provide additional tools with which to study drug resistance in Plasmodia falciparum (K1 vs. T9-96 strain) malaria. The same hydroboration/oxidation protocol was employed to complete the total synthesis of trinervine 75 in enantiospecific fashion in an overall yield of 20% (from ketone 83) in 10 reaction vessels.; In an effort to synthesize the ring-A methoxylated indole alkaloid alstophylline 1, a new efficient route to the parent 6-methoxy-D-tryptophan ethyl ester 166 was developed. This process was scaled up to 300 grams via a palladium catalyzed heteroannulation process. The regiospecific synthesis of the template, 11-methoxy tetracyclic ketone 174, was executed enantiospecifically via the asymmetric Pictet-Spengler reaction. A two-pot synthesis of this key template 174 was developed in 46% overall yield in 5 reaction vessels (from the iodoaniline 163).; The synthesis of 16-epi-Na methylgardnera1 188, 16-epi-N _a methylgardnerine 189 and the 11-methoxymacroline equivalent 194 has been accomplished in high yield and in stereospecific fashion. Although these bases have not been isolated from natural sources, to date, it was felt they will be implicated in the future as key biogenetic or synthetic intermediates on the route to bisindoles or to ajmaline alkaloids such as rauflexine 197. The final step in the synthesis of alstophylline 1 was achieved by the recently developed IBX chemistry of Nicolaou. This served as the first total synthesis of alstophylline. The coupling of alstophylline 1 and macroline 3 was carried out previously by LeQuesne, Cook et al, consequently, this completed the total synthesis of the antimalarial bisindole macralstonine 64.