Novel Tandem Desulfurization and Hydroxylation in Aqueous Media (Towards the Asymmetric Synthesis of New and Effective Anti-cancer Agents)

该实验室最近的发现表明，smi_2促进了芳香内酰胺与羰基化合物的串联脱硫和高红选择性偶联反应。因此，尽管在推进硫取代内酰胺的多功能性方面取得了重大进展，但令人惊讶的是，除了乳酸菌类化合物外，缺乏对简单路易斯酸反应性的研究。在此，我们成功地开发了新的Lewis酸介导的苯硫代脂环和芳香族内酰胺在水介质中的串联反应，得到了γ-羟基化产物，并进一步应用于异吲哚苯并氮平天然产物儿童碱的便捷全合成。而与FeCl_3和CuI反应得到所需的γ-羟基化产物，但产率都很低，而使用CuCl或cur在这些温和且容易获得的条件下，对速度有显著影响，并能顺利地以几乎定量的产率生成目标化合物。我们很高兴地发现，用含脂肪和芳香烷基侧链的季代苯硫内酰胺取代溶剂体系，再次得到了同样有益的结果。我们进一步发现，使用β-取代和α，β-二取代的γ-苯基硫内酰胺以及芳香族内酰胺进行方便的反应，可以得到相应的脱硫羟基内酰胺，收率相当高。基于以上结果，我们将注意力转向了异吲哚苯并氮卓类生物碱——儿童碱的新颖便捷合成方法的开发，并完成了天然儿童碱的全合成。该工艺将广泛适用于其他融合生物碱天然产物的合成，如新型抗肿瘤抗生素ucs1025系列含有一个季羟基α到氮。

Recent disclosures from this laboratory have demonstrated SmI_2-promoted tandem desulfurization and high erythro-selective coupling reactions of aromatic lactams with carbonyl compounds. Although significant progress, thus, has been made in advancing the versatility of sulfur-substituted lactams, the lack of studies concerning the reactivity toward simple Lewis acids is surprising except the lactol type of compounds. Herein we wish to report our successful efforts for the development of novel Lewis acid-mediated tandem reaction of phenylthio-substituted alicyclic and aromatic lactams in aqueous media, leading to the γ-hydroxylated products, whose process was further applied to the convenient total synthesis of isoindolobenzazepine natural product, chilenine.Whereas the reactions with FeCl_3 and CuI gave the desired γ-hydroxylated product, but in low yield, respectively, use of CuCl or CuBr had a dramatic effect on the rate and smoothly brought about the taget compound in almost quantitative yields under these mild and readily available conditions. We were delighted to find that the same beneficial results were again obtained in reaction employing quaternary substituted phenylthiolactams containing aliphatic and aromatic alkyl side chains by replacement of the solvent system. We further found that the use of β-substituted and α,β-disubstituted γ-phenylthiolactams as well as the aromatic one underwent convenient reactions to afford the corresponding desulfurized hydroxylactams in quite high yields. In light of the above outcome, we turned our attention to the development of novel and convenient synthetic method of isoindolobenzazepine alkaloid, chilenine and accomplished the total synthesis of natural chilenine. This process will be widely applicable to the synthesis of other fused alkaloidal natural products such as new antitumor antibiotics, UCS 1025 series containing a quaternary hydroxyl group α to the nitrogen.