Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

Abstract

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin–Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

Stereoselective Production of Imino‐d‐ribitol and C‐Azanucleosides through Electrochemical C−H Functionalization

“…Glycosidation with 7‐nitroindole and continuous Pd/C reduction and Boc protection gave 7‐aminoindolyl C ‐glycoside 14 . The final full deprotection by acid treatment yielded 15 without the decomposition of the C ‐glycoside moiety, despite the presence of an acid‐sensitive vinylogous aminal moiety (pseudo‐aminal) [9] . From these results, it can be deduced that our synthetic method of C ‐azanucleosides worked well, because highly stereocontrolled reactions did not require a complicated isomer separating process and mild reaction conditions avoided any decomposition or epimerization of the benzylic C ‐glycosidic bond.…”

Six-Step Total Synthesis of (±)-Conolidine

“…Conolidine ( 2 ), a 5-nor-stemmadenine-type alkaloid (Figure ), − was isolated from the stem bark of Tabernaemontana divaricata by Kam and co-workers in 2004 . This alkaloid possesses a strained 1-azabicyclo[4.2.2]­decane framework with an E -exocyclic trisubstituted double bond.…”