Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)‐Haplophytine by Direct Coupling and Late‐Stage Oxidative Rearrangement

Abstract

A bioinspired convergent total synthesis of (+)-haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described. This synthesis involves the direct coupling of the two segments in a AgNTf -mediated Friedel-Crafts reaction and construction of the diazabicyclo[3.3.1]nonane skeleton through late-stage chemoselective aerobic oxidation of the 1,2-diaminoethene moiety and a sequential semipinacol-type rearrangement.

Synthetic Studies toward Dimeric Indole Alkaloids Based on Convergent Synthetic Strategy

“…After extensive investigation, the coupling between 27 and an aniline derivative as an alternative to the right-hand unit was achieved via the introduction of an iodo leaving group followed by treatment of the iodoindolenine intermediate 28 with silver trifluoromethanesulfonate (AgOTf) in the presence of 2,3-dimethoxyl aniline 29. 22,41) In this coupling reaction, trans-31 was obtained preferentially, presumably due to steric repulsion between 29 and the side chain at the C-1 position. Fortunately, a mixture of diastereomers of 31 was readily separated using a silica chromatography column.…”

“…With this synthetic background, our group undertook synthetic studies of haplophytine, which seems to be one of the most synthetically difficult dimeric indole alkaloids. Herein, I report the first total synthesis of haplophytine 22) via a silver salt-mediated coupling reaction between two indole units and its second-generation synthesis 23) through a convergent synthetic route. Furthermore, we applied the silver bis(trifluoromethanesulfonyl) imide (AgNTf 2 )-mediated coupling reaction discovered in the synthesis of haplophytine to the introduction of aryl moiety into pyrroloindoline 24) and total syntheses of T988s.…”

“…The characteristic structural features of 1 are as follows: i) the lefthand unit comprising a unique diazabicyclo[3.3.1] nonane skeleton including a bridged ketone and aminal functionalities, ii) the right-hand unit comprising a hexacyclic aspidosperma alkaloid, and iii) a quaternary carbon center connecting the two indole units at the bridgehead position. Although much synthetic effort was devoted to the synthesis of 1, its formidable structural complexity precluded successful chemical synthesis until our first total synthesis of 1, 22) even though seven total syntheses of (−)-aspidophytine (5) have been reported. [45][46][47][48][49][50][51][52][53][54] A few months after our report, Nicolaou and Chen's group also achieved the total synthesis of 1.…”

“…5). First, formylation of 7-benzyloxyindole 21 22) was conducted under Vilsmeiyer-Haack conditions 57) followed by the addition of nitromethane to afford nitroalkene 22. Reduction of nitroalkene followed by acylation with succinic anhydride gave the tryptamide, which was converted to methyl ester 24 with SOCl 2 in MeOH.…”

“…Based on the altered synthetic strategy, the total synthesis of aspidophytine was set as our initial goal to validate the synthetic utility of Fischer indole synthesis with the tricyclic ketone prepared by our inventive synthetic route. 22) Heating a mixture of tricylic ketone 40 and 2,3-dimethoxyphenyl-hydrazine (41) in refluxing benzene gave the corresponding hydrazone, which was subjected to Fischer indole synthesis conditions using acetic acid as the solvent at 100°C to afford the desired indolenine compound 42. Compound 5 was then converted from indolenine 42, according to a previously reported procedure 46,47) with a slight optimization ( Fig.…”