Asymmetric Total Syntheses of Kopsane Alkaloids via a PtCl₂‐Catalyzed Intramolecular [3+2] Cycloaddition

Abstract

A concise and asymmetric total synthesis of five kopsane alkaloids that share a unique heptacyclic caged ring system was accomplished. The key transformation in the sequence involved a remarkable PtCl2‐catalyzed intramolecular [3+2] cycloaddition, which allowed for the rapid assembly of pentacyclic carbon skeletons bearing 2,3‐quaternary functionalized indoline. Expeditious construction of diverse indoline scaffolds with excellent control of diastereoselectivity demonstrated the broad scope and versatility of this key transformation.

Divergent Total Synthesis of Four Kopsane Alkaloids: N‐Carbomethoxy‐10,22‐dioxokopsane, Epikopsanol‐10‐lactam, 10,22‐Dioxokopsane, and N‐Methylkopsanone

“…Because no NMR data was provided in the isolation paper and this is the first reported total synthesis of 2 , we further confirmed its structure by X‐ray analysis and also provided its 1 H and 13 C NMR spectra. The data of 3 – 5 were in agreement with those reported [6, 14, 17a, 18, 26] …”

“…In 2018 and 2020, Ma and colleagues accomplished the synthesis of four kopsane alkaloids [17] . In 2020, the Ye group reported their synthesis of five kopsane alkaloids [18] . In connection with our ongoing studies towards the total synthesis of indole alkaloids, [19] herein, we report the divergent total synthesis of (+)‐ N ‐carbomethoxy‐10,22‐dioxokopsane ( 2 ), (−)‐epikopsanol‐10‐lactam ( 3 ), (+)‐10,22‐dioxokopsane ( 4 ) and (+)‐ N ‐methylkopsanone ( 5 ).…”

All-carbon [3 + 2] cycloaddition in natural product synthesis

“…The platinum-catalyzed intermolecular [3 + 2] cycloaddition of propargyl ether derivatives and vinyl ether producing polycyclic indoles was disclosed by Iwasawa and co-workers in 2011 [18,66] In 2020, Ye and co-workers used a platinum-catalyzed intramolecular [3 + 2] cycloaddition of a propargylic ketal derivative to complete the total synthesis of Kopsia indole alkaloids [67] (Scheme 11). The platinum-catalyzed intramolecular [3 + 2] Scheme 12: (A) Synthesis of phyllocladanol (21) features a Lewis acid-catalyzed formal intramolecular [3 + 2] cross-cycloaddition of cyclopropane 1,1-diesters with alkenes [68].…”

“…In 2020, Ye and co-workers used a platinum-catalyzed intramolecular [3 + 2] cycloaddition of a propargylic ketal derivative to complete the total synthesis of Kopsia indole alkaloids [ 67 ] ( Scheme 11 ). The platinum-catalyzed intramolecular [3 + 2] cycloaddition of propargylic ketal derivative 142 afforded indoline 143 in 58% yield, which possesses three contiguous stereocenters with vicinal all-carbon quaternary centers.…”

“… (A) Platinum-catalyzed intramolecular [3 + 2] cycloaddition of propargylic ketal derivative 142 to give indoline 143 [ 67 ]. (B) The proposed catalytic mechanism.…”