Synthesis of the C29-C44 portion of spongistatin 1 (altohyrtin A).
Two synthetic approaches to the C29-C44 portion of spongistatin 1 (altohyrtin A) have been developed. The key step of the first approach relies on the Claisen rearrangement of glucal 18 to provide ester 20a. This intermediate was advanced to silyl enol ether 30, which was coupled under Mukaiyama aldol conditions with aldehyde 3. Cyclization of this aldol adduct completed our first synthesis of the C29-C44 portion of spongistatin 1, requiring 25 total steps and occurring in 2.4% yield over the longest linear sequence (21 steps). We have also developed a second-generation approach based on the C-glycosidation of glucal 43. Through equilibration of the corresponding C-glycosides 49a/b and 50a/b the desired C-glycoside (50a) was obtained in good yield. Aldol condensation of this ketone provided cyclization precursor 67, which undergoes acid-catalyzed ketalization to close the E-ring of the spongistatins. An oxidation/reduction protocol was employed to set the C37 stereocenter. Protection of the C37 carbonol and selective unmasking of the C44 carbonol completed our second generation synthesis. This approach requires 27 steps and occurred in 13.2% yield over the longest linear sequence (18 steps).
Wallace
G A
GA
Department of Chemistry, University of California, Berkeley, California 94720, USA.
Scott
R W
RW
Heathcock
C H
CH
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D008968:Molecular Conformation; D015394:Molecular Structure; D000095702:Polyether Toxins
D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D007202:Indicators and Reagents; D007783:Lactones; D018942:Macrolides; C083856:spongistatin 1; D000095702:Polyether Toxins