Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1

Abstract

Three new isocyanoditerpenes (5-7) have been characterized from Australian specimens of the nudibranch Phyllidiella pustulosa. The planar structure and (3R,6S,7R) absolute configuration of pustulosaisonitrile-1 were deduced by spectroscopic analyses at 900 MHz informed by molecular modeling, DFT calculations, and computational NMR chemical shift predictions and by comparison of experimental electronic circular dichroism (ECD) data with TDDFT-ECD calculations for the truncated model compound 8. A catalyst-controlled enantio- and diastereoselective total synthesis of the two most likely diastereomeric candidates for the structure of 5 solidified its (3R,6S,7R,10S,11R,14R) absolute configuration. Three individual enantioselective methods provided stereochemical control at key positions, permitting an unambiguous final structural assignment. Isocyanide 5 and synthetic diastereomers 5a and 5c showed activity against Plasmodium falciparum malaria parasites (IC ∼1 μM).

Terpenoids in Marine Heterobranch Molluscs

“…P. pustulosa from Vietnam also contains these compounds and some sterols [129]. Three isonitriles, pustulosaisonitriles-1 (50), -2, and -3 ( Figure 7) are also found in P. pustulosa from Australia, with pustulosaisonitrile-1 exhibiting moderate levels of antimalarial activity in vitro [188]. The aeolid Spurilla sp.…”

Marine natural products

“…623 Three new isonitriles, pustulosaisonitriles-1 1403, -2 1404 and -3 1405 were isolated from 14 specimens of the nudibranch Phyllidiella pustulosa. 624 Absolute conguration was assigned to the cyclohexene subunit of 1403 by NOESY in combination with TDDFT-ECD calculations of structurallysimpler model compounds, while stereocontrolled synthesis established the absolute conguration of the complete molecule. The isolated NP 1403, synthesised NP and a stereoisomer all exhibited similarly moderate levels of antimalarial activity in vitro.…”

High-value compounds from the molluscs of marine and estuarine ecosystems as prospective functional food ingredients: An overview

“…A bromo-chloro-diterpenoid dolabellol A 178 was identified from D. auricularia , and its structure and absolute configuration were confirmed through X-ray diffraction ( MacHida, Matsumoto, Fusetani, & Nakao, 2017 ). The isonitriles, named as pustulosaisonitriles 1–3 179 – 181 were isolated from Phyllidiella pustulosa ( White et al, 2017 ). Spurilla neapolitana from Bay of Naples afforded cyclohexenyl terpenoid, named as spurillin A 182 , whereas Spurilla sp.…”