Title
Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1
Author
Andrew M. White, Kathy Dao, Darius Vrubliauskas, Zef A. Könst, Gregory K. Pierens, Attila Mándi, Katherine T. Andrews, Tina S. Skinner-Adams, Mary E. Clarke, Patrick T. Narbutas, Desmond C.-M. Sim, Karen L. Cheney, Tibor Kurtán, Mary J. Garson, Christopher D. Vanderwal
Year
2017
Journal
The Journal of Organic Chemistry
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 (IC50 ∼1 μM).
Full Article
Instrument
J-810
Keywords
Circular dichroism, Absolute configuration, Natural products, Pharmaceutical