A 7-Step Formal Asymmetric Total Synthesis of Strictamine via an Asymmetric Propargylation and Metal-Mediated Cyclization

Abstract

Herein is shown how a novel catalytic asymmetric propargylation of 3,4-dihydro-β-carboline, followed by a designed Au(I)/Ag(I)-mediated 6-endo-dig cyclization, can directly deliver the indolenine-fused methanoquinolizidine core of the akuammiline alkaloid strictamine in its native oxidation state, ultimately achieving a 7-step formal asymmetric total synthesis. Also demonstrated are how the cyclization products can rearrange into vincorine-type skeletons and a further use for the developed propargylation with the first catalytic asymmetric total synthesis of decarbomethoxydihydrogambirtannine.

Asymmetric Total Syntheses of the Akuammiline Alkaloids (−)‐Strictamine and (−)‐Rhazinoline

“…In 2016, Zhu's group reported a successful synthetic approach to (±)‐strictamine using a sequence of ring forming reactions; however, the final Ni‐mediated E‐ring formation suffered from low efficiency . Later, a few groups including Fujii/Ohno, Gaich,, and Snyder, as well as our group independently reported formal syntheses of strictamine by intercepting Zhu's intermediate. In 2017, Zu et al described the synthesis of (±)‐strictamine featuring a bioinspired late‐stage ring migration step .…”

Total Synthesis of (±)‐Corymine

“…Garg and co‐workers also introduced the elegant synthesis of picrinine ( 2 ) . The synthesis of strictamine ( 3 ) was achieved by the groups of Garg, Zhu, Ohno, Gaich,, and Snyder, and the synthesis of scholarisine A (not shown) was accomplished by the groups of Smith and Snyder …”

Heteroarene‐tethered Functionalized Alkyne Metamorphosis

“…Furthermore, asymmetric total synthesis of decarbomethoxydihydrogambirtannine 704 was also achieved from 698 via N ‐alkylation, thermally promoted intramolecular Diels–Alder/retro‐[4+2] reaction sequence (Scheme 170). [194] …”

“…Enantioenriched (+ +)-strictaminew as obtained after additional two-step transformation from 701.F urthermore, asymmetric total synthesis of decarbomethoxydihydrogambirtannine 704 was also achieved from 698 via N-alkylation, thermally promoted intramolecular Diels-Alder/retro-[4+ +2] reactions equence (Scheme 170). [194] Very recentlySnyder and co-workers reported an elegant approach for total synthesis of Kopsia indole alkaloid (+ +)-arborisidine 708.S tartingw ith the tryptamine, the racemic format involves seven steps whereas nine steps asymmetric version initiates from d-tryptophanm ethyl ester 705.T he key steps of…”