Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and

 

Total Synthesis

Monday, September 7, 2015
Douglass F. Taber
University of Delaware

The Smith Synthesis of (-)-Nodulisporic Acid D

The nodulisporic acids, isolated from the endophytic fungus Nodulisporium sp., show promising insecticidal activity. Amos B. Smith III of the University of Pennsylvania envisioned (J. Am. Chem. Soc. 2015, 137, 7095. ) the construction of the central indole of Nodulisporic Acid D (4) by the convergent coupling of the chloroaniline 1 with the enol triflate 2.

The preparation of 2 began (Org. Process Res. Dev. 2007, 11, 19. ) with the monoketal 5 of the Wieland-Miescher ketone, available in enantiomerically-pure form by organocatalyzed Robinson annulation. Condensation with thiophenol and formaldehyde gave 6, which under dissolving metal conditions was reduced to an enolate that was trapped as the silyl enol ether 7. Condensation again with formaldehyde gave 8, that was converted by reduction and protecting group exchange to the ketone 9. Pd-catalyzed formylation of the derived enol triflate led to 10.

The Cu-meditated conjugate addition of vinyl magnesium bromide to the unsaturated aldehyde 10 was carefully optimized to maximize equatorial addition, away from the angular methyl group. Subsequent C-methylation of the aldehyde was achieved by generating the Li enolate and carrying out the alkylation in diglyme.

With 11 in hand, the third carbocyclic ring was assembled by 1,2-addition of vinyl magnesium bromide to the aldehyde followed by ring closing metathesis and oxidation to give 12. Hydrogenation followed by functional group interconversion then completed the assembly of the enol triflate 2.

The stereogenic center of 1 was established by Enders alkylation of 13 with the iodide 14. The ketone 15 was best liberated by ozonolysis under non-epimerizing conditions. The critical Barluenga indole construction that formed 3 also required careful optimization in a model study, the key observation being the value of the Buchwald ligand RuPhos. The conditions developed were found, remarkably, to be compatible with the aldehyde functional group, so subsequent Horner-Wadsworth-Emmons condensation with 16 could be carried out directly, to complete the synthesis of Nodulisporic Acid D (4).

D. F. Taber, Org. Chem. Highlights 2015, September 7.
URL: https://www.organic-chemistry.org/Highlights/2015/07September.shtm