General approach for the synthesis of sarpagine indole alkaloids.: Enantiospecific total synthesis of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, (+)-Na-methylvellosimine, and (+)-Na-methyl-16-epipericyclivine

The first total synthesis of (+)-N-a-methyl-16-epipericyclivine (9) was completed [from D-(+)tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[alpha](D) +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[alpha](D) 0 (c 0.50, CHCl3)](47) was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q(3), (-)-panarine, and (+)-N-a-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the C-13 NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q(3). In this approach, the key templates, (-)-N-a-H,N-b-benzyltetracyclic ketone 15a and (-)-N-a-methyl,N-b-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.