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

Lepadins A、B和C是首次报道的具有十氢喹啉骨架的海洋天然产物，它们在体外对小鼠白血病和人癌细胞系具有显著的细胞毒性。虽然这些化合物的分子结构和相对立体化学已被指定，但它们的绝对立体化学仍然未知。本研究以分子内杂Diels-Alder反应为基本策略，首次不对称全合成了lepadin生物碱，并确定了该类生物碱的绝对构型，在此基础上，展望了利用水相条件提高分子内酰基亚硝基杂Diels-Alder反应的立体选择性.因此，由L-苹果酸衍生的手性异羟肟酸被高碘酸盐氧化生成酰基亚硝基化合物，该酰基亚硝基化合物自发地进行环加成，得到具有高立体选择性的反式加合物。用Davis试剂进行不对称羟基化，然后进行羟醛缩合反应，导致十氢喹啉骨架的立体选择性构建，其包含了合成Lepadins A、B和C所需的所有官能团和正确的立体结构，因此可以用作目标化合物的共同关键合成中间体。

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.