Diastereoselective Preparation of Saturated S- N- and O- Incorporated Heterocycles from a Rhodium Catalysed Hydroacylation Cascade

该项目属于EPSRC合成有机化学研究领域。N-、S-和O-饱和杂环存在于大量的天然产物和其他生物活性化合物中；因此，与这一通用支架相关的主题被认为对制药行业具有极大的吸引力。一个关键的结构特征涉及这些基序在三维空间中的变化，受相对环取代基构型的影响；这是一个非常有利于酶活性位点结合的选择性和有效性的特征。其他关键资产包括高水溶性，从而增强相关药物分子的药代动力学特征，并将它们广泛并入无金属催化剂的结构中。有许多有利可图的有机金属策略来制备各种饱和杂环单元；许多饱和基元可以通过钯催化的Tsuji-trost和其他铁和铟催化的活性烯丙醇环化来有效地制备。此外，Willis和他的同事最近通过分子内N/O杂原子辅助的分子内环化反应在同一反应罐中制备了一系列含N和O的饱和杂环支架。以前，Rh(I)催化的氢酰化反应提供了一条原子高效的路线，通过在低催化剂载量下通过烯烃/炔烃上的醛来合成烯酮。这些反应通常能够很好地控制区域选择性和对映体选择性，然而，不受欢迎的还原-脱甲基化途径的问题以前曾导致催化剂失活。这一限制可以通过使用能够与Rh(I)-金属中心螯合并防止形成非活性Rh(I)-CO络合物的乙醛链条来克服。DPhil项目的最初目标是通过胸腺酰化级联反应来开发饱和杂环，其中包括外消旋手性炔，从而产生非对映选择性的6-外三角六元环闭合。该反应的初始旋转工作成功地实现了1，4-二恶烷的非对映选择性制备。未来关于这个最初的1，4-二恶烷系统的工作将考察形成杂环周围所有潜在位置的取代基改变对反应选择性的影响程度。改变杂原子也将是潜在的好处，以便将底物范围扩大到具有药用价值的1，4-杂环基元的吗啉和硫类似物。用于吗啉类似物的手性保护的炔底物已被证明可以从容易获得的前体中获得，但是环化DR不能通过粗略的1H核磁共振谱容易地检测到。因此，为了量化吗啉形成的选择性，在未来的工作中完善环化步骤是至关重要的。至于目前在硫磺类似物制备方面所做的工作，受SR保护的炔烃的氢酰化反应已经实现，但随后的去保护/环化还必须改进。该项目的另一个重要目标是展示这种方法的能力，即通过底物额外利用5/7元环基序，底物将形成能够关闭7-和5-外三角环的烯酮中间体。利用手性炔来改变这些环的大小，将提供对相对环折叠限制对环化的影响的洞察力。在优化的反应条件下，除了高DR外，当从对映体纯手性炔开始时，ee到产物的保留率也是同样重要的。

This project falls within the EPSRC Synthetic Organic Chemistry research area.N-, S- and O-containing saturated heterocycles feature in a vast array of natural products and other bioactive compounds; motifs associated with this general scaffold are therefore considered highly attractive to drug industry. A key structural feature involves the variation in 3-dimensional space such motifs can occupy, influenced by relative ring substituent configuration; this is a trait highly beneficial to selectivity and potency in enzyme active-site binding. Other key assets include high aqueous solubility, leading to enhanced pharmacokinetic profiles for related drug molecules and their extensive incorporation into the structures of metal-free catalysts. There have been numerous lucrative organometallic strategies towards the preparation of various saturated heterocyclic units; many saturated motifs can be effectively prepared through palladium-catalysed Tsuji-Trost and other iron and indium catalysed activated allylic alcohol cyclisations. Furthermore, a diverse range of N- and O- containing saturated heterocyclic scaffolds have been recently prepared by Willis and co-workers, through an intramolecular N/O heteroatom assisted intramolecular cyclisation formed via a rhodium(I) catalysed hydroacylation, in the same reaction pot. Rhodium(I) catalysed hydroacylations have previously offered atom-efficient routes towards enones, from the employment of aldehydes across alkenes/alkynes, at low catalyst loadings. These reactions generally deliver excellent control of both regio- and enantioselectivity, however issues with undesired a reductive-decarbonylation pathway have previously led to catalyst deactivation. This limitation can be overcome by use of aldehyde tethers, capable of chelating to the rhodium-metal centre and prevent formation of inactive Rh(I)-CO complex.The initial aim of this Dphil project is to develop saturated heterocycles through thydroacylation cascade reaction, incorporating racemic chiral alkynes that produce diastereoselective 6-exo-trig six-membered ring closure. Initial rotation work on this reaction delivered the successful diastereoselective preparation of 1,4-dioxanes. Future work on this initial 1,4-dioxane system will look into the degree of which substituent alterations, at all potential positions around the forming heterocycle, will affect reaction selectivity.It would also be of potential benefit to alter the heteroatom, in order to expand the substrate scope towards morpholine and sulfur analogues of the medicinally valuable 1,4-heterocyclic motif. Chiral protected alkyne substrates for the morpholine analogues have shown to be obtainable from a readily available precursor, however cyclisation dr could not be easily detected via crude 1H NMR spectroscopy. Accordingly, refining the cyclisation step in future work is thus critical in order to quantify selectivity for morpholine formation. As for the present work done towards sulfur analogue preparation, hydroacylation of SR protected alkynes has been achieved but subsequent deprotection/cyclisation must also be refined.Another considerable aim for this project would be to showcase this methods ability to additionally harness 5/7-membered cyclic motifs, by substrates that would form enone intermediates capable of 7- and 5-exo-trig ring closure. Utilising chiral alkynes towards these altered ring sizes would provide insight to the effect of relative ring puckering constraints upon cyclisation dr. Alongside high dr, retention of ee to product, when starting from an enantiomerically pure chiral alkyne, under the optimised reaction conditions is equally valuable.