Total Synthesis of Palmerolide A

Winbush, Susann

Abstract

Palmerolide A is a marine natural product isolated from the Antarctic tunicate Synoicum adareanum, and has been reported to exhibit significant cytotoxic activity. Palmerolide A was screened against the National Cancer Institute's (NCI) 60 cell line panel, and demonstrates potent activity against melanoma (e.g., UACC-62, LC50= 6.5 nM) with three orders of magnitude greater sensitivity relative to other cell lines. Melanoma is the least common, but most deadly skin cancer. Traditional treatment options include surgery, chemotherapy, radiation and biologic therapy. The selectivity index demonstrated by palmerolide identifies it as a premiere candidate for anti-melanoma treatment. With limited access to the natural product from natural sources, chemical synthesis remains the only viable option to acquire quantities of palmerolide to be used in various biological studies. Our proposal for the total synthesis of palmerolide focuses on the construction of the C(1)-C(15) fragment using a highly diastereoselective double allylboration reaction to install the C(7)-C(11) triol unit. We anticipate that access to the triol unit as a direct result of the new allylboration reaction would be conceivable if the intermediate allylboronate (following the first allylation) is modified with a silyl or boronate group at the terminal olefin. Following the allylboration of this silyl or boryl substituted olefin, the resultant silicon and/or boron containing-1,5-diol would be converted to the triol by oxidation of the metal-carbon bond. A complimentary approach involves use of a chiral stannane allylboration sequence. Upon employing both strategies all four diastereomers of the C(1)-C(15) segment of palmerolide will be accessible. Upon generating various stereoisomers of the C(1)-C(15) fragment, we will then synthesize the enamide side chain by a concise route employing a diastereoselective chiral allenylborane or stannane addition and copper catalyzed amidation reaction. Coupling of the C(1)-C(15) fragment with the enamide side chain will then proceed by a cross-coupling andmacrolactonization sequence to access the natural product. Our synthetic proposal to palmerolide should provide access to various stereo and structural isomers that could be used for biological evaluation in an effort to maximize selectivity and potency of the cytotoxic parent compound (-)-palmerolide A. Public Health Relevance: Quantities of (-)-palmerolide generated during this study will be submitted for ongoing biological studies. Stereo and structural isomers of palmerolide will be evaluated for their biological activity in regard to therapuetic potential as anti-melanoma agents.