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的福尔斯。含N、S和O的饱和杂环化合物在大量天然产物和其他生物活性化合物中具有特征;因此，与这种通用支架相关的基序被认为对药物工业具有高度吸引力。一个关键的结构特征涉及在三维空间中的变化，这样的基序可以占据，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效力的特征。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，并将其广泛纳入无金属催化剂的结构中。对于制备各种饱和杂环单元，存在许多有利可图的有机金属策略;许多饱和基序可以通过钯催化的Tsuji-Trost和其他铁和铟催化的活化烯丙醇环化有效地制备。此外，Willis及其同事最近已经在同一反应罐中通过经由铑（I）催化的加氢酰化形成的分子内N/O杂原子辅助的分子内环化制备了多种含N和O的饱和杂环支架。铑（I）催化的加氢酰化先前已经提供了从在低催化剂负载下使用醛跨越烯烃/炔的原子有效途径到烯酮。这些反应通常提供对区域选择性和对映体选择性的优异控制，然而不期望的还原脱羰途径的问题先前已经导致催化剂失活。这一限制可以通过使用醛系链来克服，醛系链能够螯合铑-金属中心并防止形成无活性的Rh（I）-CO complex. This Dphil project的最初目标是通过去氢酰化级联反应开发饱和杂环，将外消旋手性炔结合，产生非对映选择性的6-exo-candidate六元环闭合。该反应的初始旋转工作提供了成功的非对映选择性制备1，4-二氧杂环己烷。未来的工作将在这个初始的1，4-二氧六环系统的程度，取代基的变化，在所有潜在的位置周围形成的杂环，将影响反应的选择性。这也将是潜在的好处，改变杂原子，以扩大对吗啉和硫类似物的药物有价值的1，4-杂环基序的底物范围。吗啉类似物的手性保护的炔底物已显示可从容易获得的前体获得，然而环化dr不能通过粗1H NMR光谱容易地检测到。因此，为了量化吗啉形成的选择性，在未来的工作中改进环化步骤是至关重要的。至于目前的工作对硫类似物的制备，加氢酰化的SR保护的炔已经实现，但随后的脱保护/环化也必须refined.Another相当大的目的，这个项目将是展示这种方法的能力，另外利用5/7元环基序，通过底物，将形成烯酮中间体能够7-和5-exo-dichloro环关闭。利用手性炔对这些改变环的大小将提供洞察力的影响，相对环puckering约束环化博士。除了高博士，保留ee的产品，当从对映体纯的手性炔，在优化的反应条件下是同样有价值的。

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.