Applications of Hypervalent Iodine Reagents in Organic Synthesis

高价碘试剂在有机合成中的应用

• 批准号: 1809808
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1809808
• 关键词: Applications; Hypervalent; Iodine; Reagents; Organic

Previous work in the Donohoe group has led to the stereospecific homo- and hetero-dimerisation of styrenes to yield all-trans cyclobutanes in a formal "[2+2]" reaction.1 The ability to synthesise tri- and tetra-substituted cyclobutanes by both homo- and heterodimerisation under mild reaction conditions demonstrates the advantages of our methodology over those previously reported in the literature. This project aims to broaden the scope of the methodology to facilitate addition of a broader range of alkene partners, diazo compounds and cyclopropanes. These methodologies, once optimised, will lead to the synthesis of biologically active natural products. This project falls within the EPSRC Physical Sciences research area, specifically within the theme of Synthetic Organic Chemistry.A novel hypervalent iodine-promoted approach to cyclobutanes has recently been reported by the Donohoe group.1 Use of 5 mol% (diacetoxyiodo)benzene (PIDA) in hexafluoroisopropanol (HFIP) facilitates the dimerisation of electron rich styrenes e.g. 1 in good to excellent yields as a single (all-trans) diastereoisomer 3 (Scheme 1). Furthermore, hetero-dimerisation reactions with both electron rich and electron deficient styrenes have also been achieved setting an exciting precedent for a versatile route towards cyclobutane based compounds. This work will focus on expandingthe scope of this formal "[2+2]" cycloaddition reaction and lead to the development of new related synthetic methodologies. Currently, compounds featuring a cyclobutane moiety make up a tiny fraction of pharmaceutical libraries. As a consequence of this GlaxoSmithKline is part funding this project through a CASE Award. This project will also be conducted in collaboration with specialists in both electrochemical4 and computational5 techniques to form a holistic approach towards understanding this novel mode of chemical reactivity.By exploring the use of alkenes featuring both an electron donating and an electron withdrawing substituent, we hope to expand the scope of partner alkenes beyond the class of styrenes currently used. Variation of the heteroatom X to nitrogen would facilitate access to unnatural cyclobutane amino acids, with potentially interesting biological activities.This project will investigate diazo compounds as potential partners in this formal "[2+2]" cycloaddition reaction (Scheme 3). Thediazocyclobutanes produced will have important applications in drug discovery programmes, and we aim to cleave the ring e.g. using Zn/H+ to yield the syn-diamine 9. Overall this represents a metal free deamination and is likely to be of great utility in organic synthesis. It has been postulated that the radical cation produced from the one electron oxidation of an electron rich styrene may react withcyclopropanes to yield substituted cyclopentanes. Alternatively, it may be possible to perform a one electron oxidation of an electronrich cyclopropane and react it with alkene partners.6,7 This project will investigate a broad range of cyclopropane and styrenesubstrates with varying electron density and steric hindrance. The development of successful conditions would lead to a mode ofreactivity without precedent in the literature. There are in excess of 1,500 natural products containing a cyclobutane core and many others containing related structures. Following further development of this methodology we will look towards the synthesis of biologically active natural products.

Donohoe小组先前的工作已经导致苯乙烯的立体特异性均聚和杂二聚，以在正式的“[2+2]”反应中产生全反式环丁烷。1在温和的反应条件下通过均聚和杂二聚合成三取代和四取代的环丁烷的能力证明了我们的方法相对于文献中先前报道的方法的优势。该项目旨在扩大该方法的范围，以便于添加更广泛的烯烃伙伴、重氮化合物和环丙烷。这些方法，一旦优化，将导致生物活性天然产物的合成。该项目属于EPSRC物理科学研究领域的福尔斯，Donohoe小组最近报道了一种新的高价碘促进的环丁烷方法。1使用5摩尔%的碘，在六氟异丙醇（HFIP）中的（二乙酰氧基碘）苯（PIDA）促进富电子苯乙烯例如1的二聚，以良好至优异的产率作为单一的二聚物。（全反式）非对映异构体3（方案1）。此外，还实现了与富电子和缺电子苯乙烯的杂二聚反应，为环丁烷基化合物的多用途路线创造了令人兴奋的先例。本工作将致力于拓展这种形式的“[2+2]”环加成反应的范围，并导致新的相关合成方法学的发展。目前，具有环丁烷部分的化合物构成了药物库的一小部分。因此，葛兰素史克通过案例奖为该项目提供部分资金。该项目还将与电化学4和计算5技术的专家合作进行，以形成理解这种化学反应性的新模式的整体方法。通过探索具有供电子和吸电子取代基的烯烃的使用，我们希望将伙伴烯烃的范围扩大到目前使用的苯乙烯类之外。将杂原子X改变为氮原子将有助于获得非天然的环丁烷氨基酸，具有潜在的生物活性。本项目将研究重氮化合物作为这种形式的“[2+2]”环加成反应的潜在伙伴（方案3）。所产生的重氮环丁烷将在药物发现计划中具有重要的应用，并且我们的目标是例如使用Zn/H+裂解环以产生顺式二胺9。总的来说，这代表了无金属的脱氨基作用，并且可能在有机合成中具有很大的实用性。据推测，由富电子苯乙烯的单电子氧化产生的自由基阳离子可以与环丙烷反应产生取代的环戊烷。或者，也可以对富电子环丙烷进行单电子氧化，并使其与烯烃伙伴反应。6，7该项目将研究具有不同电子密度和空间位阻的广泛的环丙烷和苯乙烯基质。成功条件的发展将导致一种在文献中没有先例的反应模式。有超过1，500种天然产物含有环丁烷核心，还有许多其他含有相关结构的天然产物。随着这种方法的进一步发展，我们将着眼于生物活性天然产物的合成。