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Organic Chemistry Highlights

Total Synthesis

Monday, May 3, 2010
Douglass F. Taber
University of Delaware

The Dixon Synthesis of (-)-Nakadomarin A

(-)-Nakadomarin A (4), isolated from the sponge Amphimedon sp. off the coast of Okinama, shows interesting antifungal and antibacterial activity. The key step in the total synthesis of 4 reported (J. Am. Chem. Soc. 2009, 131, 16632. DOI: 10.1021/ja908399s) by Darren J. Dixon of the University of Oxford was the diastereoselective addition of the enantiomerically-pure ester 1 to the prochiral nitroalkene 2.

The assembly of 2 began with the linchpin ketophosphonate 5. Alkylation of the dianion of 5 with allyl bromide followed by direct condensation of the resulting monoanion with the diacetate 6 gave 7. On exposure to aqueous acid, 7 cyclized to the furan. Oxidation of the liberated primary alcohol followed by condensation with nitromethane then completed the preparation of 2.

The starting material for the synthesis of 1 was the enantiomerically-pure pyroglutamate derivative 8. Sulfide displacement followed by N-alkylation with the bromide 10 delivered 11. Oxidation followed by deprotection then set the stage for the intramolecular Julia-Kocienski cyclization, that gave 12 with the expected (eight-membered ring) high geometric control.

Addition of the ester 1 to Michael acceptors proceeded across the open face of the lactam, but it was still necessary to control the face of the nitro alkene 2 to which the lactam anion added. Catalysis of the addition with the urea 13 delivered 3 with 10:1 diasterocontrol.

Mannich condensation of the nitroalkane 3 with formaldehyde and the amine 14 gave the bis-lactam 15, conveniently as a single diastereomer. After free radical removal of the nitro group, it was necessary to achieve selective reduction of the δ-lactam in the presence of the γ-lactam. Low temperature LiAlH4 was found to be effective. Direct reduction of the resulting hemiaminal with formic acid led to the monolactam 16. The hemiaminal from monoreduction of 16 was found to be unstable and sensitive to over-reduction. Nevertheless, exposure of 16 to Dibal at low temperature followed by acid-mediated cyclization delivered the diamine 17.

Cyclization of the free base of 17 with the first generation Grubbs catalyst gave (-)-Nakadomarin A (4) as the minor component of a 40:60 Z/E mixture. Carrying out the cyclization on the camphorsulfonate salt improved the ratio to 63:37 Z/E.

D. F. Taber, Org. Chem. Highlights 2010, May 3.