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Organic Chemistry Highlights

Total Synthesis

Monday, May 6, 2013
Douglass F. Taber
University of Delaware

The Dixon Synthesis of Manzamine A

The pentacyclic alkaloid Manzamine A (4), isolated from a sponge collected in the Okinawa Sea, displays a range of anti-bacterial, anti-cancer and anti-malarial activity. The preparation of 4 reported (J. Am. Chem. Soc. 2012, 134, 17482 DOI: 10.1021/ja308826x) by Darren J. Dixon of the University of Oxford showcases the versatility of the nitro group in organic synthesis.

The nitro alkene 2 was prepared from the commercial bromide 5. Displacement with acetate followed by Swern oxidation led to the aldehyde 6, that was condensed with nitromethane to give 2.

Lactam 1 was an intermediate in Professor Dixon's synthesis (The Dixon Synthesis of (-)-Nakadomarin A 2010, May 3) of (-)-Nakadomarin A. Lactam 1 was prepared from the tosylate 7, that was derived from pyroglutamic acid.

The addition of 1 to the nitroalkene 2 delivered 3 as the dominant diastereomer of the four possible. Mannich condensation with formaldehyde and the amine 12 gave 13.

The nitro group of 13 was removed by free radical reduction. Exposure of the reduced product to trimethylsilyl iodide gave, via ionization of the ketal, the primary iodide, that was carried on to the nitro compound 14. Dibal selectively reduced the δ-lactam. Partial reduction of the γ-lactam then gave an intermediate that engaged in Mannich condensation with the nitro-activated methylene to give 15. While there are many protocols for the conversion of a nitro compound to a ketone, most of those were not compatible with the functional groups of 15. Fortunately, Ti(III) was effective. Ce-mediated addition of the Grignard reagent 16 to the ketone followed by deprotection and protection then delivered the silyl ether 17.

Remarkably, the ketone 17 could be deprotonated and carried on to the enol triflate 18 without eliminating the TMSO-group. Coupling with the stannane 19 then completed the synthesis of Manzamine A (4). One-carbon homologation of 18 led to Ircinol A, Ircinal A, and Methyl Ircinate (not illustrated).

D. F. Taber, Org. Chem. Highlights 2013, May 6.