New methodologies for hydrogen borrowing cascades in the synthesis of amine scaffolds and its application in Natural product and drug synthesis

该项目属于 EPSRC 合成有机化学研究领域 Donohoe 小组（牛津大学）已确定五甲基苯基乙酮可作为一种特殊的羰基支架。芳环的邻位取代基迫使其脱离与羰基的共轭，然后这些取代基在空间上阻止酮充当亲电子试剂，从而提供独特的反应性特征。该环的富电子性质允许在添加溴时发生逆弗里德尔-克来福特反应。这意味着当需要时，该基团可以暴露为高反应性酰基溴。这些特性在氢借用（HB）中得到了最好的利用，其中过渡金属可以可逆地氧化底物，得到活性中间体，该中间体可以被转化，并且氢可以在有效的氧化还原过程中返回。在 HB 羰基烷基化中，Ph* 酮的特性限制了可用的氧化还原和醛醇缩合过程，从而产生单一产物，而其他酮则产生各种 C-C 键形成和可变的氧化态。这可以取代烯醇化烷基化中有毒的烷基卤化物或羟醛化学中对化学计量氧化剂和还原剂的需求。在该组中，HB 中使用 1,4 和 1,5 二醇已用于在正式的 [N 1] 环化中产生 N-杂环和碳环。它们分别形成 2 个 C-N 或 2 个 C-C 键。我们在这里提出，使用带有 Ph* 基序的氨基酮和二醇可以通过在一个罐中形成 C-C 和 C-N 键来允许形成多种环。先前关于环形成的研究表明，还原可能是高度立体选择性的。初步研究表明，α 氨基 Ph* 酮可以通过两步合成为实验室稳定油。Donohoe 团队拥有合成精细天然产物的历史。这些环化将代表一种新颖的逆合成断开，其可以允许医学相关的饱和N-杂环的高度发散的合成。该小组已经使用 HB 化学来合成小型天然产物（Lycorane g 和 Coniine）。在这项工作的基础上，我们希望将 HB、羰基化学选择性和 Ph* 酮允许我们合成生物碱天然产物的裂解结合起来。

This project falls within the EPSRC Synthetic Organic Chemistry research areaThe Donohoe group (University of Oxford) has established that pentamethylphenyl-ethanone acts as a privileged carbonyl scaffold. The Ortho substituents of the aromatic ring force it out of conjugation with the carbonyl, these substituents then sterically block the ketone from acting as an electrophile giving a unique reactivity profile. The electron rich nature of the ring allows for a retro-Friedel-Craft reaction to occur upon addition of bromine. This means the group can be unmasked as a highly reactive acid bromide when desired. These properties have been best utilised in hydrogen borrowing (HB), here transition metal can reversibly oxidise substrates to give an active intermediate which can be transformed and the hydrogen returned in a redox efficient process. In HB carbonyl alkylations The Ph* ketones properties limit the redox and aldol processes available giving single products where other ketones produce a variety of C-C bond formations and variable oxidation states. This can replaces toxic alkyl halides in enolate alkylation or the need for stoichiometric oxidants and reductants in aldol chemistry.Within the group the use of 1,4 and 1,5 diols in HB has been used to create N-heterocycles and carbocycles in formal [N+1] cyclizations. These form either 2 C-N or 2 C-C bonds respectively. We here propose that the use of amino ketones with the Ph* motif along with diols could allow for a diverse set of ring formations by the formation of both C-C and C-N bonds in a single pot. Previous work on ring formation suggests the reductions could be highly stereoselective. Preliminary research established that alpha amino Ph* ketone can be synthesised as a bench stable oil in 2 steps.The Donohoe group has a history of synthesising elaborate natural products. These cyclizations would represent a novel retrosynthetic disconnection which could allow for highly divergent synthesis of medicinally relevant saturated N-heterocycles. The group has already used HB chemistry for the novel synthesis of small natural products (Lycorane g and Coniine). To build on this work we hope to combine the strategic use of HB, carbonyl chemoselectivity and cleavage that the Ph* Ketone allows us in the synthesis of alkaloid natural products.