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

由铑催化加氢酰化级联非对映选择性制备饱和 S-N-和 O-掺入杂环

• 批准号: 1923180
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1923180
• 关键词: Diastereoselective; Preparation; Saturated; Incorporated; Heterocycles

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.

该项目属于EPSRC合成有机化学研究领域。含N， S和o的饱和杂环在大量天然产物和其他生物活性化合物中具有特色；因此，与这种通用支架相关的基序被认为对制药行业具有很高的吸引力。一个关键的结构特征涉及这些基序可以占据的三维空间的变化，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效力的特性。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，并将其广泛融入无金属催化剂的结构中。已经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；通过钯催化的Tsuji-Trost和其他铁、铟催化的活化烯丙醇环化反应可以有效地制备许多饱和基序。此外，Willis及其同事最近在相同的反应釜中，通过铑(I)催化的氢酰化形成的分子内N/O杂原子辅助分子内环化，制备了多种含N和O的饱和杂环支架。铑(I)催化的氢酰化以前为烯酮提供了原子高效的途径，通过在烯烃/炔上使用醛，在低催化剂负载下。这些反应通常对区域选择性和对映体选择性都有很好的控制，然而，由于不需要还原-脱碳途径，导致催化剂失活。这一限制可以通过使用醛系链来克服，醛系链能够螯合到铑金属中心，并防止形成无活性的Rh(I)-CO配合物。本博士项目的最初目标是通过氢酰化级联反应开发饱和杂环，结合外消旋手性炔，产生非对映选择性6-外三角六元环闭合。该反应的初始旋转工作成功地制备了1,4-二恶烷的非对映选择性。对这个初始的1,4-二氧六烷体系的未来研究将研究在形成杂环周围的所有潜在位置上取代基改变的程度将影响反应选择性。改变杂原子也有潜在的好处，以便将底物范围扩大到具有药用价值的1,4-杂环基序的啉和硫类似物。手性保护的炔烃底物可以从容易获得的前体中获得，但是环化反应不容易通过粗1H NMR光谱检测到。因此，在未来的工作中，完善环化步骤对于量化morpholine形成的选择性至关重要。至于目前在硫类似物制备方面所做的工作，已经实现了SR保护炔的氢化酰化，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该方法额外利用5/7元环基序的能力，通过底物形成能够关闭7和5外三角环的烯酮中间体。将手性炔用于这些改变的环尺寸将提供对相对环皱约束对环化的影响的见解。除了高dr外，在优化的反应条件下，从对映异构纯手性炔开始时，产物的ee保留率同样有价值。