Part I: The first regio- and atropdiastereoselective total synthesis of the dimeric indole alkaloid (+)-dispegatrine, as well as the first total synthesis of the sarpagine alkaloids (+)-spegatrine, lochvinerine, (+)-lochneram and an improved total synthes

Part I. The first regio- and atropdiastereoselective total synthesis of the bisquatemary alkaloid (+)-dispegatrine (2) has been accomplished in an overall yield of 8.3% (12 reaction vessels from 5-methoxy-D-tryptophan ethyl ester (13). A crucial late-stage thallium(III) mediated oxidative coupling was employed in the formation of the C9-C9' biaryl axis in 2. The complete stereocontrol observed in this key biaryl coupling step can be entirely attributed to the natural sarpagine configuration of the monomer lochnerine (6) which was also confirmed by model studies on the beta-carboline 37. The axial chirality of the lochnerine dimer 45a and in turn dispegatrine (2) was established by X-ray crystallography and was determined to be P(S). Additionally the first total synthesis of the monomeric indole alkaloids lochvinerine (7), (+)-spegatrine ( 1), (+)-lochneram (11) and an improved total synthesis of (+)-10-methoxyvellosimine (5), (+)-loclmerine (6) and (+)-sarpagine (8) was also completed via the common intermediate 34. 5-Methoxy-D-(+)-tryptophan ethyl ester which served both as the chiral auxiliary and the starting material was synthesized on a large scale via the regiospecific bromination route. The stereospecific conversion of 13 into the key pentacyclic framework 34 followed the general route developed in Milwaukee for the synthesis of sarpagine alkaloids.;Part II An enantiospecific, stereospecific approach toward the total synthesis of the C-19 methyl substituted sarpagine alkaloid, macrosalhine chloride (1) as well as macroline related alkaloids macrocarpine A, B and C was developed. Although the total synthesis of 1 was not completed, this was the first approach which set the stereochemistry of the methyl group at C-19 in a sterospecific fashion. The lipase mediated kinetic resolution of the racemic TIPS-acetylenic alcohol 38 was developed on 104 gram scale and produced the (R)-TIPS acetate 39 in 45.8% yield and 95% ee. The key C-19 stereocenter was set by an SN2 reaction of the optically active tosylate 29 with the amine 30. The acetylenic moiety 28 was modified to the key vinyl iodide 27 by silylstannation and haloboration reactions. Initial attempts at haloboration were accompanied by inconsistent reproducibility, purification problems and very low yield, which were circumvented by modification of the reaction conditions and the use of a superior haloborating agent (dicyclohexyliodoborane). The key intermediate 49, synthesized from the pentacyclic ketone 26 via a sequence of chemical reactions which included a Wittig reaction, a regioselective hydroboration and oxidation, could now be employed to complete the total synthesis of macroline related alkaloids 17, 20 and 21. The ring-A oxygenated analog 15 could also be synthesized similarly from 5-methoxy-D-(+)-tryptophan ethyl ester, which is also the northern hemisphere of bisindoles 12-14 . The approach developed here provides a general entry, it is felt, into a whole series of biosynthetically important monoterpene C-19 substituted indole alkaloids.