Joshawna K. Nunnery1, Takashi L. Suyama1, Roger G. Linington2, and William H. Gerwick1. (1) Scripps Institution of Oceanography, University of California, San Diego, 9500 Gilman Drive, 0212, La Jolla, CA 92093-0212, (2) Department of Chemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064
The DHOYA (3-hydroxy-2,2-dimethyloctynoic acid) fragment was first identified in kulolide-1 in 1996. Recently, a number of biologically active marine natural products containing the DHOYA fragment, or a variant thereof, have been isolated from cyanobacteria. In Xu and colleagues’ total synthesis of yanucamide A, a natural product from Lyngbya majuscula, the DHOYA fragment was synthesized in nine steps (Org. Lett. 5:2821). Traditionally, preparation of an α,α-dimethyl-β-hydroxyl motif involved a Reformatsky reaction or an aldol reaction with a silyl enol ether catalyzed by a chiral borane species. The former requires synthesis of α-halo starting material, while the latter condition suffers from incompatibility with unsaturated aldehydes. The approach envisioned here explores the utility of Evans' chiral auxiliary for tertiary enolate aldol chemistry in the synthesis of DHOYA and similar motifs. At present, both the (3R) and the (3S) DHOAA (saturated DHOYA) fragments have been synthesized via this approach employing a titanium Lewis acid in three steps. These products have been utilized for the determination of the stereochemistry of the DHOYA unit in mantillamide A, a novel anti-malarial natural product from Lyngbya majuscula. Efforts to verify that the proposed route is applicable for the synthesis of DHOYA are ongoing. Studies are underway to better understand the tertiary aldol reaction and to improve the yield of this key step. The long-term goal of this research is to provide a more expedient route for manufacturing biologically active natural products that feature DHOYA or a similar motif.
