Total Syntheses of (−)‐Minovincine and (−)‐Aspidofractinine through a Sequence of Cascade Reactions

Abstract

We report 8‐step syntheses of (−)‐minovincine and (−)‐aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta‐ and hexacyclic frameworks. These cascade transformations included organocatalytic Michael‐aldol condensation, a multistep anionic Michael‐S N 2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo‐ and regioselective transformations.

Enantioselective construction of cis-hydroindole scaffolds via an asymmetric inverse-electron-demand Diels–Alder reaction: application to the formal total synthesis of (+)-minovincine

“…25,26 However, there are few examples in the literature for the enantioselective total synthesis of (−)-minovincine. 27–29 Based on our present approach and interest in synthesis of natural alkaloids, 30 the cis -hydroindole scaffold present in minovincine inspired us to develop a concise synthetic route for the enantioselective formal total synthesis of the naturally occurring enantiomer (+)-minovincine. As shown in Scheme 3, the enantiomerically pure product 3a was readily reduced to 4 in 92% yield with 97% ee by treatment with 5 mol% Crabtree's catalyst under a hydrogen atmosphere.…”

“…The absolute configuration of 10 was determined to be opposite to that reported by Soós, and then it could be converted into (+)-minovincine in three steps according to a known procedure. 29…”

Iodide-Mediated [3 + 2]-Cycloaddition Reaction with N-Tosylaziridines and α,β-Unsaturated Ketones

“…Stepwise addition–cyclization methods, including isolation of the aziridine-opened intermediates, have been reported by using the NH-free aziridine and α,β-unsaturated ketones . Recently, a cascade reaction including the S N 2 reaction of NH-free aziridine to an alkyl halide, aziridine-opening chlorination, and intramolecular conjugate addition of the resulting NH group was achieved in the total synthesis of (−)-minovincine and (−)-aspidofractinine . In our course of synthetic studies on alkaloids, we found that lithium iodide mediated the [3 + 2] addition reaction of nonsubstituted N -tosylaziridine with an α,β-unsaturated ketone to achieve the direct construction of N -tosylpyrrolidine.…”

Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification

“…Recently, our laboratory developed a short and scalable (60g) synthetic route for the stereoselective synthesis of Aspidosperma tricyclic ketone core 7 with C-5 methoxycarbonyl group and employed this advanced intermediate for the concise syntheses of (−)-minovincine ( 2 ) and (−)-aspidofractinine ( 3 ) ( Scheme 1 ). 7 A key element of these syntheses was the rapid buildup of much of the complexities of the targets through the sequence of organocascade and anionic cascade reactions. These routes are strategically aligned with the Stork–Dolfini synthesis 3a of aspidospermidine but delivering C-20 oxidized intermediates and natural products.…”