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

“…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 ).…”

Emerging computational approaches for the study of regio- and stereoselectivity in organic synthesis

“…It was found that the intramolecular [3 + 2] cycloaddition is a crucial step that provided a stereopure product in mild conditions. 48 Moreover, ligand-free PtCl 2 was used as a catalyst in dichloroethane solvent. The authors employed computational simulations to model the reaction focusing on the cyclization step.…”

Applications of ultrasound in total synthesis of bioactive natural products: A promising green tool

“…In 2020, asymmetric and concise total syntheses of five kopsan alkaloids were disclosed by Ye and co-workers via deprotection of the tosyl group under ultrasonic irradiation as a key step [137] . Kopsine the first isolated member of Kopsia indole alkaloids family, as well as many kopsane alkaloids contain an indoline fused to a strained carbocyclic cage [138] , [139] , [140] .…”

“…Kopsine the first isolated member of Kopsia indole alkaloids family, as well as many kopsane alkaloids contain an indoline fused to a strained carbocyclic cage [138] , [139] , [140] . The structure of kopsane alkaloids namely (-)-kopsanone , (+)-kopsanol, (-)-epikopsanol, (+)-10,22-dioxokopsane and (+)- N -methyl-10,22-dioxokopsane share a unique heptacyclic skeleton having six stereogenic centers, of which two are vicinal and quaternary [137] . This family of natural products has drawn continuous attention from the synthetic organic and biological community due to their interesting structural pattern and attracting biological activities including cholinergic, antirheumatism, and anti-inflammation effects [141] .…”