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的福尔斯。多诺霍小组（牛津大学）已经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试剂，从而产生独特的反应性特征。环的富电子性质允许在添加溴时发生逆弗里德尔-克拉夫特反应。这意味着当需要时，该基团可以作为高反应性的酰基溴被暴露。这些特性在氢借用（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以产生活性中间体，该活性中间体可以在氧化还原有效过程中转化并返回氢。在HB羰基烷基化反应中，Ph* 酮的性质限制了氧化还原和羟醛缩合过程，从而产生单一产物，而其他酮产生各种C-C键形成和可变氧化态。这可以取代烯醇化物烷基化中的有毒烷基卤化物或羟醛化学中对化学计量的氧化剂和还原剂的需要。在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，使用具有Ph* 基序的氨基酮与二醇一起沿着，可以通过在一个锅中形成C-C和C-N键来允许多种环形成。先前关于环形成的工作表明还原可能是高度立体选择性的。初步研究表明，α-氨基苯甲酮可以通过两个步骤合成为一种稳定的油。Donohoe集团在合成精细天然产品方面有着悠久的历史。这些环化反应将代表一种新的逆合成断开，其可以允许高度发散的医学相关的饱和N-杂环的合成。该小组已经将HB化学用于小天然产物（Lycorane g和Coniine）的新合成。为了建立在这项工作，我们希望联合收割机的HB，羰基化学选择性和切割的战略用途的Ph* 酮允许我们在生物碱天然产物的合成。

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.