Syntheses and biological studies of marine terpenoids derived from inorganic cyanide

Abstract

Isocyanoterpenes (ICTs) are marine natural products biosynthesized through an unusual pathway that adorns terpene scaffolds with nitrogenous functionality derived from cyanide. The appendage of nitrogen functional groups–isonitriles in particular–onto stereochemically-rich carbocyclic ring systems provides enigmatic, bioactive molecules that have required innovative chemical syntheses. This review discusses the challenges inherent to the synthesis of this diverse family and details the development of the field. We also present recent progress in isolation and discuss key aspects of the remarkable biological activity of these compounds.

Synthesis of the Privileged 8-Arylmenthol Class by Radical Arylation of Isopulegol

“…1 Chiral catalysts, reagents and auxiliaries, for example, can be sourced from cyclic monoterpenes, 2 which are usually inexpensive, abundant and easily removed from reaction mixtures. During recent studies of the isocyanoterpene (ICT) class, 3 we required access to aryl derivatives of the broadly-applicable chiral controller, 8-phenylmenthol ( 1 ). 4 The widely applied parent alcohol (−)- 1 or (+)- 1 can be appended to carboxylic acids to effect highly stereoselective reactions, as shown in Figure 1a,b.…”

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20‐Diisocyanoadociane

“…[1] This family includes ar ange of complex polycyclic architectures (Figure 1a)t hat has inspired our group to develop au nified strategy toward seemingly topologically disparate ICT diterpenes.A mong them, 7,20-diisocyanoadociane (DICA, 1)arguably stands out as the most stereochemically complex. [1] This family includes ar ange of complex polycyclic architectures (Figure 1a)t hat has inspired our group to develop au nified strategy toward seemingly topologically disparate ICT diterpenes.A mong them, 7,20-diisocyanoadociane (DICA, 1)arguably stands out as the most stereochemically complex.…”

Stereocontrolled Synthesis of Kalihinol C

“…1,2 Kalihinol A 3a also exhibits the highest reported potency of the ICTs against P. falciparum , 3b killing with an EC 50 of 1 nM, but the mechanism of action has not been rigorously assigned. Proposed mechanisms to explain phenotypic effects of the ICTs include inhibition of heme detoxification 4 or copper chelation, 5 but these proposals do not fully account for the structure-activity relationships and life-cycle activities reported.…”

“…6 Copper chelation is simply not possible for congeners with distant isonitriles. As part of a program to investigate the biological activity of ICTs, we have begun to develop effective chemical syntheses 2,6,7 and associated methods 8 to produce and modify three main structural classes: amphilectenes, adocianes, and kalihinols. 1,2 Prior syntheses 9 of the kalihinol class have fought to control stereochemistry in the functionally dense scaffolds, and each contains at least one uncontrolled ( ca.…”

“…Addition of a methyl group prior to decarboxylation preserved the trans -decalin geometry, whereas the corresponding ketone weakly favored the cis -decalin after lactone cleavage. Preferential formation of the disfavored trans -decalin (of 11 ) has remained unsolved in prior work, 2,9,10 and in this case is enabled by the fused lactone, which locks the geometry. Through this short process, multigram quantities of decalone 11 could be generated in a single pass for elaboration to protokalihinol 2a and the metabolite itself ( 1 ).…”