Abstract:
This thesis describes synthetic efforts towards the bisindole alkaloid (+)-sciodole (209). Isolated from the pungent fruit bodies of the mushroom species Tricholoma sciodes,1 this alkaloid contains a bond between the nitrogen of an indole and C7 of a tetrahydroindole unit bearing an alkoxyalkene. The synthesis of the natural product 209 required a supply of the ‘lower half’, specifically 5- methoxy-2,4-dimethylindole (185), which led to a scalable route to this indole. Reduction of o-quinone methide (o-QM) 258, itself generated from Mannich base 257, enabled installation of the key C4-methyl group. Selective O-methylation gave the desired indole 185 in gram quantities. Two additional Tricholoma-derived 2-methylindoles (186 and 187) were also attainable via the same o-QM. Using 5-methoxy-2,4-dimethylindole (185), various C7-H activated derivatives (273, 290, 295) were synthesised and an assortment of cross-coupling reactions were attempted; disappointingly Chan-Evans-Lam, Ullmann and Buchwald-Hartwig coupling reactions all failed to produce the key carbon-nitrogen bond. Using the indoline 317 in a Buchwald-Hartwig coupling did lead to the desired compound 322, but in very poor yields that were not synthetically viable. Given the failure of the cross-coupling routes, we considered the biosynthesis of sciodole. We suspected that lascivol, 195, a bitter component isolated from Tricholoma lascivum, likely produced as a deterrent to predation, is the precursor to 209. Revealingly, lascivol (195) has been shown to degrade into indole 185, presumably via dimethoxydihydroindole 198.2 We posit that coupling of the N-H of indole 185 to 198 via either an SN1 or SN2 addition followed by an alkene tautomerisation could generate this sciodole (209) in vivo. Tetrahydroindole 402, accessed in six steps from pyrrole 332, was ultimately chosen as a bioinspired coupling partner to react with indole 185. Synthesis of an electrophile (409) required to explore the SN2-based route failed to produce any of the desired product 408. Alternatively, SN1 conditions proceeding via azafulvenium 412, readily formed the C3'-linked dimer 414. Since dimer 414 had formed based on a biomimetic disconnection, we suspected that sciodole (209) could in fact be a C3'-linked regioisomer. Allylic oxidation of 414 afforded dimer 415 (the anti diastereomer as the major product), the spectroscopic data of which was inconsistent with that reported for sciodole (209). In an effort to eliminate C3-attack, indoline 317 was investigated as the nucleophile under both SN1 and SN2 conditions; disappointingly no N-linked compounds were observed. Although the total synthesis of sciodole (209) was not achieved, this work has laid the foundations for the eventual synthesis of this unique alkaloid.