Chiral Synthesis of New Biologically Active Alkaloids Utilizing Hetero Diels-Alder Reaction

点击翻译按钮获取中文摘要

Lepadins A,B,and C,isolated from tunicate Clavelina lepadiformis, are the first repoted example of marine natural products with a decahydroquinoline skeleton, and exhibit significant in vitro cytotoxixity against murine leukemia and human cancer cell lines. Although molecular structures and relative stereochemistry of these compounds have been assigned, their absolute stereochemistries still remain unknown. The present investigations were aimed at the first asymmetric total synthesis of lepadin alkaloids by utilizing intramolecular hetero Diels-Alder reaction as a basic strategy and also determining the absolute configuration of these alkaloids.According to our previous findings, we envisioned the use of aqueous conditions for enhancement of stereoselectivity in intramolecular acylnitroso hetero Diels-Alder reaction. Thus, the chiral hydroxamic acid derived from L-malic acid was oxidized by the periodate salt to generate the acylnitroso compound, which spontaneously underwent cycloaddition to afford the trans-adduct with high stereoselectivity. Asymmetric hydroxylation with Davis reagent followed by aldol reaction resulted in the stereoselective construction of the decahydroquinoline frame work, which incorporates all functionalities and right stereostructure required for the synthesis of Lepadins A,B,and C,and thus, can be utilized as a common key synthetic intermediate for the target compounds.