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Organic Chemistry Highlights

Total Synthesis

Monday, October 7, 2013
Douglass F. Taber
University of Delaware

The Evans Synthesis of (-)-Nakadomarin A

(-)-Nakadomarin A (4), isolated from the marine sponge Amphimedon sp. off the coast of Okinama, shows interesting cytotoxic and antibacterial activity. David A. Evans of Harvard University prepared (J. Am. Chem. Soc. 2013, 135, 9338. DOI: 10.1021/ja404673s) 4 by coupling the enantiomerically-pure lactam 2 with the prochiral lactam 1.

The preparation of 1 began with the aldehyde 5. Following the Comins protocol, addition of lithio morpholine to the carbonyl gave an intermediate that could be metalated and iodinated. Protection of the aldehyde followed by Heck coupling with allyl alcohol gave the aldehyde 7. Addition of the phosphorane derived from 8 followed by deprotection gave 9 with the expected Z selectivity. Addition of the phosphonate 10 was also Z selective, leading to the lactam 1.

The preparation of 2 began with the enantiomerically-pure imine 12. The addition of 13 was highly diastereoselective, setting the absolute configuration of 15. Alkylation with the iodide 16 delivered 17, that was closed to 2 under conditions of kinetic ring-closing metathesis, using the Grubbs first generation Ru catalyst.

The condensation of 1 with 2 gave both of the diastereomeric products, with a 9:1 preference for the desired 3. Experimentally, acid catalysis alone did not effect cyclization, suggesting that the cyclization is proceeding via silylated intermediates. The diastereoselectivity can be rationalized by a preferred extended transition state for the intramolecular Michael addition.

Selective activation of 3 followed by reduction gave 18, that underwent Bischler-Napieralski cyclization to give an intermediate that could be reduced to (-)-Nakadomarin A (4). It was later found that exposure of 3 to Tf2O and 19 followed by the addition of Redal gave direct conversion to 4.

It is instructive to compare this work to the two previous syntheses of 4 that we have highlighted, by Dixon (The Dixon Synthesis of (-)-Nakadomarin A 2010, May 3) and by Funk (The Funk Synthesis of (-)-Nakadomarin A 2011, July 4). Together, these three independent approaches to 4 showcase the variety and dexterity of current organic synthesis.

D. F. Taber, Org. Chem. Highlights 2013, October 7.