Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, December 6, 2004
Douglass Taber
University of Delaware

Synthesis of Amphidinolide T1

The amphidinolides are a class of structurally diverse and physiologically potent natural products. The key step in the total synthesis of enantiomerically-pure amphidinolide T1 3 recently reported (J. Am. Chem. Soc. 2004, 126, 998. DOI: 10.1021/ja039716v) by Timothy Jamison of MIT, the Ni-mediated cyclization of 1 to 2, clearly illustrates the power of organometallic C-C bond formation in organic synthesis.

The alcohol fragment of 1 was prepared by Evans alkylation of 4 to give, after reduction and protection, the alkyne 5. Ni-mediated coupling of the alkyne 5 with the enantiomerically-pure epoxide 6, following the procedures developed by the Jamison group, led to the alcohol 7 with high regio- and geometric control.

The acid portion of 1 was assembled by enantio- and diastereocontrolled addition of Z-crotyl borane to the aldehyde 8, following the Brown protocol. Hydroboration and oxidation led to 9, which was condensed with the allenyl silane 10 to give 11 with high diastereocontrol. Conversion of the alcohol to the iodide followed by three-carbon homologation by the Myers procedure then led to 1, which was cyclized with > 10:1 regio- and diasterocontrol to give 12. Ozonolysis and methylenation of the less hindered ketone then delivered 3.

In both of the Ni-mediated steps in this synthesis, the Ni-alkyne complex is acting as an acyl anion, in one case opening an epoxide and in the other case adding to the aldehyde in an intramolecular sense. Such Ni-reduced phenylalkynes are among the easiest to prepare and least expensive of acyl anion equivalents.

D. F. Taber, Org. Chem. Highlights 2004, December 6.