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; Tibor Kurtán; Mary J. Garson; Christopher D. Vanderwal

doi:10.1021/acs.joc.7b02421

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, Tibor Kurtán, Mary J. Garson^*, Christopher D. Vanderwal

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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 language	English
Pages (from-to)	13313-13323
Number of pages	11
Journal	Journal of Organic Chemistry
Volume	82
Issue number	24
DOIs	https://doi.org/10.1021/acs.joc.7b02421
Publication status	Published - 15 Dec 2017
Externally published	Yes

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White, A. M., Dao, K., Vrubliauskas, D., Könst, Z. A., Pierens, G. K., Mándi, A., Andrews, K. T., Skinner-Adams, T. S., Clarke, M. E., Narbutas, P. T., Sim, D. C. M., Cheney, K. L., Kurtán, T., Garson, M. J., & 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

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title = "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 (IC50 ∼1 μM).",

author = "White, {Andrew M.} and Kathy Dao and Darius Vrubliauskas and K{\"o}nst, {Zef A.} and Pierens, {Gregory K.} and Attila M{\'a}ndi and Andrews, {Katherine T.} and Skinner-Adams, {Tina S.} and Clarke, {Mary E.} and Narbutas, {Patrick T.} and Sim, {Desmond C.M.} and Cheney, {Karen L.} and Tibor Kurt{\'a}n and Garson, {Mary J.} and Vanderwal, {Christopher D.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = dec,

day = "15",

doi = "10.1021/acs.joc.7b02421",

language = "English",

volume = "82",

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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

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AU - White, Andrew M.

AU - Dao, Kathy

AU - Vrubliauskas, Darius

AU - Könst, Zef A.

AU - Pierens, Gregory K.

AU - Mándi, Attila

AU - Andrews, Katherine T.

AU - Skinner-Adams, Tina S.

AU - Clarke, Mary E.

AU - Narbutas, Patrick T.

AU - Sim, Desmond C.M.

AU - Cheney, Karen L.

AU - Kurtán, Tibor

AU - Garson, Mary J.

AU - Vanderwal, Christopher D.

PY - 2017/12/15

Y1 - 2017/12/15

N2 - 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).

AB - 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).

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

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