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

Lepadins A、B和C是从衣藻Clavelina lepadiformis中分离得到的，是第一个报道的具有十氢喹啉骨架的海洋天然产物，在体外对小鼠白血病和人类癌细胞具有显著的细胞毒作用。虽然这些化合物的分子结构和相对立体化学已被指认，但它们的绝对立体化学仍不清楚。本研究首次以分子内杂化Diels-Alder反应为基本策略合成了瘦素生物碱的不对称全合成，并确定了这些生物碱的绝对构型。根据我们以前的发现，我们设想在分子内酰基亚硝基杂化Diels-Alder反应中利用水相条件来提高立体选择性。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，该化合物自发地进行环加成反应得到具有高立体选择性的反式加合物。与Davis试剂的不对称羟基化和Aldol反应导致了十氢喹啉骨架的立体选择性构建，该骨架结合了合成Lepadins A、B和C所需的所有功能和正确的立体结构，因此可以作为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.