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Organic Chemistry Highlights

Total Synthesis

Monday, May 1, 2017
Douglass F. Taber
University of Delaware

The Boeckmann Synthesis of (-)-Nakadomarin A

Nakadomarin A (4), isolated from the marine sponge Amphimedon sp., inhibits cyclin-dependent kinase 4. Robert K. Boeckman, Jr. of the University of Rochester envisioned (Org. Lett. 2016, 18, 6136. DOI: 10.1021/acs.orglett.6b03137) setting the two new stereogenic centers of 3 by the conjugate addition of 1 to 2.

The preparation of the furan 3 followed earlier precedent. Alkylation of the dianion 6 with bromobutyne 5 followed by condensation with 7 delivered the enone 8. Cyclization to the furan followed by Swern oxidation led to 9, that was condensed with 10 to give 2.

The preparation of the azocine 17 began with the addition of the keto phosphonate 12 to the aldehyde 11 to give 13. Itsuno-Corey reduction set the absolute configuration of the secondary alcohol, that was activated as the carbonate 14. Cyclization proceeded with a 3:1 preference for the desired syn ester, that was reduced to the aldehyde 15. The derived imine 16 rearranged thermally to 17.

Deprotection followed by oxidation converted 17 into the lactam 18, that was carried on to 1. The addition to 2 mediated by 20 proceeded to only partial conversion, since the prospective catalyst was incorporated into the product. Instead, a stoichiometric quantity of 20 was used, the intermediate adduct was purified, and then reduced to 3 by exposure to BF3.OEt2 and Et3SiH. Selective reduction of the γ-lactam followed by cyclization led to 21, that was carried on via Mo-catalyzed ring-closing metathesis to (-)-nakadomarin A (4).

As always, it is instructive to compare the approach outlined here to previous syntheses of (-)-nakadomarin A. In that of Funk, for instance (The Funk Synthesis of (-)-Nakadomarin A 2011, July 4), which also employed Mo-catalyzed ring-closing alkyne metathesis, the eight-membered ring was assembled by Ru-catalyzed alkene metathesis.

D. F. Taber, Org. Chem. Highlights 2017, May 1.