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Organic Chemistry Highlights

Total Synthesis

Monday, September 5, 2016
Douglass F. Taber
University of Delaware

The Takao Synthesis of (+)-Cytosporolide

(+)-Cytosporolide A (4), isolated from the fungus Cytospora, showed significant activity against gram-positive bacteria. Ken-ichi Takao assembled (J. Am. Chem. Soc. 2015, 137, 15971. DOI: 10.1021/jacs.5b11438) 4 by the hetero Diels-Alder reaction of 2 with 1 to give 3.

The unstable o-quinone methide 2 was generated in situ by thermolysis of 9. The assembly of 9 began with the enantiomerically-pure epoxide 5, prepared by Jacobsen hydrolysis of the racemate. Addition of 6 led to 7, that was deprotected and carboxylated to give 8. Esterification of 8 followed by condensation with triethyl orthoformate then gave 9.

The ester 1 is in fact a protected form of (-)-fuscoatrol A (18), the preparation of which followed the authors’ previous synthesis (Angew. Chem. Int. Ed. 2008, 47, 3426, DOI: 10.1002/anie.200800253; J. Org. Chem. 2009, 74, 6452, DOI: 10.1021/jo9012546) of the closely-related pestalotiopsin A. Kinetic quench following conjugate reduction of the 2+2 adduct 10 incorporating the Oppozler camphorsultam auxiliary proceeded with high diastereocontrol to give, after reduction and cyanide coupling, the nitrile 11. Release of the protected ketone followed by the addition of vinyl magnesium bromide and nitrile hydrolysis led to the lactone 12. Sharpless asymmetric dihydroxylation proceeded with poor diastereocontrol, but monoprotection of the resulting diol mixture followed by oxidation and reduction delivered, after protection, the lactone 13. Aldol reaction with 14 followed by MOM protection gave 15. Nozaki-Hiyama-Kishi (NHK) cyclization of the derived aldehyde led to 16, that was deprotected and deoxygenated to give 17. Reduction to the lactol followed by β-elimination and reduction completed the synthesis of (-)-fuscoatrol A (18), that was protected to give 1.

Thermolysis of 9 in the presence of 1 led transiently to the o-quinone methide 2, that, following the biosynthetic hypothesis, added to the more strained E alkene of 1 to give 3. Deprotection then completed the synthesis of (+)-cytosporolide A (4).

D. F. Taber, Org. Chem. Highlights 2016, September 5.