Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, May 4, 2009
Douglass F. Taber
University of Delaware

The Carter Synthesis of (-)-Lycopodine

Rich G. Carter of Oregon State University described (J. Am. Chem. Soc. 2008, 130, 9238 DOI: 10.1021/ja803613w) the first enantioselective synthesis of the Lycopodium alkaloid (-)-lyopodine (3). A key step in the assembly of 3 was the diastereoselective intramolecular Michael addition of the keto sulfone of 1 to the enone, leading to the cyclohexanone 2.

The key cyclization substrate 1 bore a single secondary methyl group. While that could have been derived from a natural product, it was operationally easier to effect chiral auxiliary controlled conjugate addition to the crotonyl amide 4, leading, after methoxide exchange, to the ester 5. The authors reported that double deprotonation with LiTMP gave superior results, vs. LDA or BuLi, in the condensation of 6 with 5 to give 7. Metathesis with pentenone 8 gave the intramolecular Michael substrate 1.

The authors thought that they would need a chiral catalyst to drive the desired stereocontrol in the cyclization of 1 to 2. As a control, they tried an achiral base first, and were pleased to observe the desired diastereomer crystallize from the reaction mixture in 89% yield. The structure of 2 was confirmed by X-ray crystallography.

To prepare for the intramolecular Mannich condensation, the azide was reduced to give the imine, and the methyl ketone was converted to the silyl enol ether. Under Lewis acid conditions, the sulfonyl group underwent an unanticipated 1,3-migration, to give 11. Cyclization of 12 then delivered the crystalline 14. Reduction converted 14 to the known (in racemic form) ketone 15.

To complete the synthesis, the amine 15 was alkylated with 16 to give the alcohol 17. Oppenauer oxidation followed by aldol condensation delivered the cyclized enone, that was reduced with the Stryker reagent to give (-)-Lycopodine (3).

Both the cyclization of 1 to 2 and the cyclization of 9 to 14 are striking. It may be that the steric demand of the phenylsulfonyl group destabilizes the competing transition state for the cyclization of 1.

D. F. Taber, Org. Chem. Highlights 2009, May 4.