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）已经确定，五甲基苯基乙烷作为一种特殊的羰基支架。芳香环的邻位取代基迫使它与羰基偶联，这些取代基然后在空间上阻止酮作为亲电试剂，从而形成独特的反应性。环的富电子性质允许在添加溴时发生反弗里德尔-克拉夫特反应。这意味着当需要时，该基团可以作为高活性的酸溴化物被揭开。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底物，产生一种活性中间体，该中间体可以在氧化还原有效的过程中转化和氢气返回。在HB羰基烷基化中，Ph*酮的性质限制了氧化还原和醛醇过程，产生单一产物，而其他酮产生各种C-C键形成和可变氧化态。这可以取代烯醇烷基化中有毒的烷基卤化物，或取代醇化学中需要的化学计量氧化剂和还原剂。在该基团中，在HB中使用1,4和1,5二醇已被用于在正式的[N+1]环化中生成N-杂环和碳环。它们分别形成2个碳氮键或2个碳碳键。我们在这里提出，使用具有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键来形成不同的环。先前关于环形成的工作表明，还原可能具有高度的立体选择性。初步研究表明，α氨基Ph*酮可在两步内合成出稳定的油。多诺霍集团在合成复杂的天然产物方面有着悠久的历史。这些环化将代表一种新的反合成断开，它可以允许高度分散的合成医学相关的饱和n -杂环。该小组已经将HB化学用于小型天然产物（Lycorane g和Coniine）的新型合成。在这项工作的基础上，我们希望结合HB的战略性使用，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。

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.