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

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, T. Kurtán, Mary J. Garson, Christopher D. Vanderwal

Research output: Contribution to journalArticle

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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).

Original languageEnglish
Pages (from-to)13313-13323
Number of pages11
JournalJournal of Organic Chemistry
Volume82
Issue number24
DOIs
Publication statusPublished - Dec 15 2017

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Antimalarials
Catalysts
Molecular modeling
Chemical shift
Cyanides
Discrete Fourier transforms
Nuclear magnetic resonance
Parasites

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

White, A. M., Dao, K., Vrubliauskas, D., Könst, Z. A., Pierens, G. K., Mándi, A., ... Vanderwal, C. D. (2017). Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1. Journal of Organic Chemistry, 82(24), 13313-13323. https://doi.org/10.1021/acs.joc.7b02421

Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1. / White, Andrew M.; Dao, Kathy; Vrubliauskas, Darius; Könst, Zef A.; Pierens, Gregory K.; Mándi, Attila; Andrews, Katherine T.; Skinner-Adams, Tina S.; Clarke, Mary E.; Narbutas, Patrick T.; Sim, Desmond C.M.; Cheney, Karen L.; Kurtán, T.; Garson, Mary J.; Vanderwal, Christopher D.

In: Journal of Organic Chemistry, Vol. 82, No. 24, 15.12.2017, p. 13313-13323.

Research output: Contribution to journalArticle

White, AM, Dao, K, Vrubliauskas, D, Könst, ZA, Pierens, GK, Mándi, A, Andrews, KT, Skinner-Adams, TS, Clarke, ME, Narbutas, PT, Sim, DCM, Cheney, KL, Kurtán, T, Garson, MJ & Vanderwal, CD 2017, 'Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1', Journal of Organic Chemistry, vol. 82, no. 24, pp. 13313-13323. https://doi.org/10.1021/acs.joc.7b02421
White, Andrew M. ; Dao, Kathy ; Vrubliauskas, Darius ; Könst, Zef A. ; Pierens, Gregory K. ; Mándi, Attila ; Andrews, Katherine T. ; Skinner-Adams, Tina S. ; Clarke, Mary E. ; Narbutas, Patrick T. ; Sim, Desmond C.M. ; Cheney, Karen L. ; Kurtán, T. ; Garson, Mary J. ; Vanderwal, Christopher D. / Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1. In: Journal of Organic Chemistry. 2017 ; Vol. 82, No. 24. pp. 13313-13323.
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