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。多诺霍小组(牛津大学)已经确定，五甲基苯乙酮是一种特权的羰基支架。芳香环的邻位取代基迫使其与羰基脱离共轭，然后这些取代基会立体地阻止酮作为亲电试剂，从而获得独特的反应性轮廓。环的富电子性质允许在添加溴时发生逆弗里德-克拉夫反应。这意味着，如果需要，该基团可以被揭开为高活性的酸性溴化物。这些性质在借氢(HB)中得到了最好的利用，在这里，过渡金属可以可逆地氧化衬底，得到一种可以转化的活性中间体，氢以高效的氧化还原过程返回。在HB羰基烷基化反应中，Ph*酮的性质限制了可用的氧化还原和羟醛还原过程，从而产生了单一的产物，而其他酮产生了各种C-C键形成和不同的氧化态。这可以在烯醇烷基化中替代有毒的烷基卤化物，或者在羟醛化学中需要化学计量的氧化剂和还原剂。在该基团中，HB中的1，4和1，5二醇已被用于在形式[N+1]环化反应中生成N-杂环和碳环。它们分别形成2C-N键或2C-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锅中形成C-C和C-N键来实现不同的环形成。以前关于环形成的工作表明，还原可能是高度立体选择性的。初步研究证实，α氨基苯酮可以在两步内合成为稳定的长凳油。多诺霍集团有合成精细天然产品的历史。这些环化反应将代表一种新的后合成断链，这可能允许以高度分散的方式合成具有医学意义的饱和N-杂环。该小组已经将HB化学用于小型天然产物(Lycorane g和Coniine)的新合成。在这项工作的基础上，我们希望将HB的战略用途、羰基化学选择性和裂解结合起来，这是Ph*酮允许我们在合成生物碱天然产物时所允许的。

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.