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

水介质中的新型串联脱硫和羟基化（致力于新型有效抗癌剂的不对称合成）

基本信息

批准号：
15550031
负责人：
YODA Hidemi
金额：
$ 2.43万
依托单位：
Shizuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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.

该实验室最近的公开内容已经证明了SmI_2促进的串联脱硫以及芳香族内酰胺与羰基化合物的高赤选择性偶联反应，因此，尽管在推进硫取代内酰胺的多功能性方面已经取得了重大进展，但缺乏有关的研究。除了乳醇类型的化合物之外，对简单路易斯酸的反应性是令人惊讶的。在此，我们希望报告我们在开发新型路易斯酸介导的方面所做出的成功努力。苯硫基取代的脂环族和芳香族内酰胺在水介质中进行串联反应，得到γ-羟基化产物，该过程进一步应用于异吲哚苯并氮杂环天然产物chilenine的便捷全合成。而与FeCl_3和CuI的反应则得到所需的γ -羟基化产物，但收率较低，分别使用 CuCl 或 CuBr 对速率有显着影响，并且几乎在几乎我们很高兴地发现，通过更换溶剂系统，在使用含有脂肪族和芳香族烷基侧链的季铵定量取代的苯基硫代内酰胺的反应中再次获得了相同的有益结果。 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可以方便地进行反应，以相当低的速度得到相应的脱硫羟基内酰胺。鉴于上述成果，我们将注意力转向开发新型、便捷的异吲哚苯并氮杂生物碱Chilenine的合成方法，并实现了天然Chilenine的全合成，该工艺将广泛应用于其他稠合生物碱的合成。天然产物如新型抗肿瘤抗生素UCS 1025系列含有α位氮上的季羟基。