Total Synthesis of (+)-Aspicilin. The Naked Carbon Skeleton Strategy vs the Bioorganic Approach.
The advantages of the "naked carbon skeleton" strategy in the total synthesis of polyoxygenated natural products are demonstrated in the total synthesis of the 18-membered macrolide (+)-aspicilin, 1. This approach employs the easily prepared, nonfunctionalized carbon skeleton of the target molecule, hexadeca-1,3,15-triene, 2. All the required stereogenic carbinol centers are then introduced onto this partially unsaturated hydrocarbon chain using the Sharpless asymmetric dihydroxylation (AD) reaction. Thus, asymmetric synthesis of 1 is achieved in 14 steps and 11% overall yield. Three stereogenic carbinol centers are introduced with very high regio- and enantioselectivity (epimeric excess of 96% at positions 3, 4, and 86% at position 15) by using AD-mix-beta while the fourth is obtained using AD-mix-alpha. This approach is compared with an alternative synthesis of 1 (19 steps and 4.3% overall yield) using chiral building blocks derived from D-arabinose and from the enzymatic reduction of oct-7-yn-2-one, 34, with Thermoanaerobium brockii alcoholdehydrogenase (TBADH).
Sinha
Subhash C.
SC
The Scripps Research Institute, Department of Molecular Biology and the Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel.
Keinan
Ehud
E