May 2023

Iboga-type indole alkaloids are a promising compound group of potentially effective drugs. The common indole-fused pentacyclic skeleton is composed of an isoquinuclidine, and both enantiomers of this architecture are naturally present. In this study, we used enzymatic desymmetrization to obtain an optically active isoquinuclidine possessing four chiral carbon centers from a prochiral diester in one step. In addition, we synthesized a pentacyclic intermediate for catharanthine in an enantioenriched form through the late-stage construction of the common Iboga scaffold.

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug-discovery research. Herein, we report chemical diversification of carbocyclic pyrimidine nucleosides containing CF2 and CHF in place of the furanose oxygen to introduce ring unsaturation and 2′-epimers. Utilizing gram-scale access to 6′-(R)-monofluoro- and 6′-gem-difluorouridine, we explore the provision of 2′,3′-didehydro-2′,3′-dideoxy, and 1′,2′-didehydro-2′-deoxy analogues, alongside the first example of a 6′-(R)-fluoro arabino-carbauridine. Key stereochemistries and the presence of unsaturation are confirmed using X-ray crystallography and NMR, and an indicative conformational preference for a monofluoro 2′,3′-didehydro-2′,3′-dideoxy system is presented. This synthetic blueprint offers a potential to explore biological activity for these hitherto unavailable materials, including a direct comparison to established nucleoside analogue drugs.