Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids

Abstract

Reported is the enantioselective total syntheses of mavacuran alkaloids,( + +)-taberdivarine H, (+ +)-16-hydroxymethyl-pleiocarpamine,a nd (+ +)-16-epi-pleiocarpamine,a nd their postulated biosynthetic precursor 16-formyl-pleiocarpamine.This family of monoterpene indole alkaloids is atarget of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline.I nspired by the biosynthetic hypothesis,a no xidative coupling approach from the geissoschizine framework to form the N1ÀC16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I 2 as it masks the nucleophilicity of the aliphatic nitrogen center and locksi nt he required cis conformation.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Zuschriften Scheme 3. Synthesis of (+ +)-16-deformyl-geissoschizine [(+ +)-22], (+ +)-geissoschizine [(+ +)-1], and the geissoschizine malonate (À)-23 according to our previous work. [13] AIBN = 2,2'-azobisisobutyronitrile, Boc = tert-butoxycarbonyl, COD = 1,5-cyclooctadiene, DMAP = 4-(N,Ndimethylamino)pyridine, LDA = lithium diisopropylamide, TFA = trifluoroacetica cid.Scheme 4. Total synthesis of (+ +)-16-epi-pleiocarpamine [(+ +)-5]a nd (+ +)-16-hydroxymethyl pleiocarpamine[(+ +)-3]byN 1 ÀC16 oxidative cyclization from N4-PMB-geissoschizinium derivatives. DIBAL-H = diisobutylaluminum hydride, DMF = N,N-dimethylformamide, PMB = pmethoxybenzyl, TMS = trimethylsilyl.

Biosynthetically Relevant Reactivity of Polyneuridine Aldehyde

“…This spontaneous reaction is biosynthetically relevant as deformylation events are common in the sarpagan‐type and related alkaloids biosynthesis. [ 7,8 ]…”

“…In the context of the bio‐inspired synthesis of mavacuran alkaloids [ 6,7 ] we first investigated the possibility to convert 3 back into geissoschizine ( 2 ) via a retro‐biomimetic process (Scheme 2). Stirring 3 in acetic acid at 65 °C afforded tetradehydro‐geissoschizine ( 8 ) with a 75 % yield.…”

“…[ 2,3 ] Then, divergent routes lead to the large diversity of this family of alkaloids. From corynan‐type geissoschizine ( 2 ), [ 4 ] intramolecular oxidative couplings explain inter‐alia the formation of akuammilan‐type, [ 5 ] mavacuran‐type [ 6,7 ] and sarpagan‐type alkaloids. [ 3,8 ] Concerning the latter group, the first biosynthetic member is polyneuridine aldehyde ( 3 ).…”

The chemistry of mavacurane alkaloids: a rich source of bis-indole alkaloids

“…The latter was removed in three steps to obtain (+)-16-deformyl-gessoschizine (145) which was converted into (+)-geissoschizine (51) after a formylation step and to C16-malonate 146 via protection and deprotection of the indole nitrogen. 65,68…”

Bioinspired Divergent Oxidative Cyclizations of Geissoschizine: Total Synthesis of (–)‐17‐nor‐Excelsinidine, (+)‐16‐epi‐Pleiocarpamine, (+)‐16‐Hydroxymethyl‐Pleiocarpamine and (+)‐Taberdivarine H

“…Our collaborative work recently led to the total synthesis of (–)‐17‐nor‐excelsinidine ( 7 ), [ 16 ] (+)‐16‐ epi ‐pleiocarpamine ( 16 ), (+)‐16‐hydroxymethyl‐pleiocarpamine ( 14 ) and (+)‐taberdivarine H ( 18 ). [ 17 ]…”