Total Synthesis Highlights

procedure, exposure of the diene 12 to BF 3 etherate led directly to 14, accompanied by minor
amounts of the methyl ether 13.
51. The Ready Synthesis of (-)-Nigellamine A 2
The nigellamine alkaloids, represented by (-)-nigellamine (3), dolabellane diterpenes isolated from
black cumin, apparently have lipid metabolism promoting activity. Joseph M. Ready of UT
Southwestern Medical Center has described (J. Am. Chem. Soc. 2006, 128, 7428.) the first
synthesis of a nigellamine, (-)-nigellamine A 2 (3). Key steps in the synthesis include an
enantioselective cyclization to prepare 1, and the Cr-mediated cyclization of the aldehyde 2.
(-)-Nigellamine A 2 (3) has an angularly substituted trans ring fusion. The key to the synthesis was
the preparation of the angularly-substituted cis-fused lactone 1. The absolute configuration of 1
was set by the Pd-mediated S N 2' cyclization of the malonate 6, which proceeded in 95% ee.
Equally important was the seemingly mundane iodine-mediated cyclization of 7 to 8. This one
transformation differentiated the two esters of 6, secured the relative configuration of one of the
two secondary alcohols of 3, and established the requisite cis ring fusion of the lactone 1.
Nucleophilic displacement of the iodide 8 failed, but two-carbon homologation to the alkyne could
be accomplished by the free radical Fuchs procedure.
There were intial difficulties with the Negishi methylation/iodination of the terminal alkyne, as the
Cp 2 ZrCl 2 reacted preferentially with the lactol. Remarkably, repeating the reaction in the presence