Total Synthesis of (+)-Isatisine A

Abstract

Total synthesis of (+)-isatisine A is described based on the application of a silyl-directed Mukaiyama-type [3+2]-annulation for the preparation of a fully substituted furan core. The indole branch forming the quaternary carbon center at C2 was constructed by addition to an intermediate N-acyliminium ion derived from aminal 4. In addition, the fused tetracyclic framework including furan core was built up using modified Buchwald amidation conditions.

Total Synthesis of (−)‐Isatisine A

“…The absolute configuration of these two bisindole alkaloids was established by the first total synthesis of (+)-isatisine A (ent-1), which was reported by Karadeolian and Kerr (Scheme 1), [3] and later was confirmed by the total synthesis of ent-1 by Lee and Panek (Scheme 2). [4] Apart from the challenging structural features of isatisine A (1), its uncharacterized bioactivity makes this compound an unusually appealing synthetic target. Isatisine A acetonide (2), the abundant artifact which arises from the isolation process of isatisine A, was shown to be cytotoxic against C8166 (CC 50 = 302 mm) and also displayed anti-HIV-1 IIIB activity (EC 50 = 37.8 mm).…”

“…Subsequently, the second indole moiety was installed by a nucleophilic addition to a rather reactive acyl iminium ion to prepare ent-1. [3,4,6] Herein, we report our total synthesis of (À)-isatisine A (1), the natural enantiomer of the alkaloid. Our synthetic strategy was inspired by the multiple hydroxy groups and their relative stereochemistry on the tetrahydrofuran core of 1, which reminded us of d-ribose.…”

Total Synthesis of (−)‐Isatisine A

“…Extensive NMR spectroscopic analyses and X‐ray crystallographic analysis of 2 revealed that isatisine A ( 1 ) features an unprecedented fused tetracyclic framework with five contiguous stereogenic centers, two of which are fully substituted, and a densely functionalized tetrahydrofuran core. The absolute configuration of these two bisindole alkaloids was established by the first total synthesis of (+)‐isatisine A ( ent ‐ 1 ), which was reported by Karadeolian and Kerr (Scheme ),3 and later was confirmed by the total synthesis of ent ‐ 1 by Lee and Panek (Scheme ) 4…”

“…Subsequently, the second indole moiety was installed by a nucleophilic addition to a rather reactive acyl iminium ion to prepare ent ‐ 1 3. 4, 6…”

Catalytic Function of Cu (I) and Cu (II) in Total Synthesis of Alkaloids

“…[111] In the following, Panek et al in 2011 reported another method for the synthesis of (+)-isatisine A. [112] The total synthesis of (+)-isatisine A was started with the reaction of silane anti-148 and (E)-2-bromo-3-phenylacrylaldehyde (149) to produce furan 150 via [3 + 2]-annulation. After several steps, 150 was converted into indole adduct 151 as a single diastereomer.…”