Enantioselective Total Synthesis of (+)-Gliocladine C: Convergent Construction of Cyclotryptamine-Fused Polyoxopiperazines and a General Approach for Preparing Epidithiodioxopiperazines from Trioxopiperazine Precursors

Abstract

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11), in ten steps and 11% overall yield from isatin, is reported. In addition, the ETP natural product (+)-gliocladine C (6) is prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of (+)-gliocladine C (6) constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.

Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

“…130 Known 2-indolinone 215 (prepared from isatin and indole) was reduced and Boc-protected to afford compound 216 . Conversion to the oxindole ester ( 217 ) proceeded efficiently upon treatment with 2,2,2-trichloro-1,1-dimethylethyl chloroformate, triethyl amine, and 10 mol % of Fu's ( S )-(–)-4-pyrrolidinopyrindinyl-(pentamethylcyclopentadienyl)iron catalyst.…”

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…9a). 78 In this study, the practicality of Fu’s method was highlighted by the formation of 86 in 96% yield and 96% ee on multigram scales. In a quite different approach to generating chiral carbon electrophiles, iminium activation developed by the MacMillan group has been used for the enantioselective construction of 3a-substituted pyrrolidinoindolines and featured in the synthesis of (−)-flustramine B.…”

“…a , The Steglich rearrangement of indole carbonate 85 in the presence of Fu’s planar-chiral catalyst 88 to give 3,3-disubstituted oxindole 86 in route to (+)-gliocladin C. 78 Boc, tert -butoxycarbonyl; Me, methyl; THF, tetrahydrofuran. b , The copper-catalyzed β-arylation of indole 89 and concomitant cyclization to form 3a-arylpyrrolidinoindolinone 90 .…”

Total syntheses of chaetocin and ent-chaetocin

“…10 For example, Kishi and Fukuyama reported seminal work on the ETP alkaloids in 1970s, including total syntheses of gliotoxin and sporidesmines. 11 Quite recently, Overman et al achieved the first total synthesis of gliocladine C. 12 Fig . 1 shows the dimeric ETP alkaloids for which total syntheses have been achieved.…”