Applications of Hypervalent Iodine Reagents in Organic Synthesis

Donohoe小组以前的工作导致了苯乙烯的立体专一性同位和杂位二聚化，以在正式的“[2+2]”反应中生成全反式环丁烷1。在温和的反应条件下，通过同位和异位二聚合成三取代和四取代环丁烷的能力表明，我们的方法比文献报道的方法更具优势。该项目旨在扩大方法学的范围，以促进添加更广泛的烯烃伙伴、重氮化合物和环丙烷。这些方法一旦得到优化，将导致合成具有生物活性的天然产品。这个项目属于EPSRC物理科学研究领域，特别是合成有机化学的主题。Donohoe小组最近报告了一种新的高价碘促进环丁烷的方法。在六氟异丙醇(HFIP)中使用5mol%(二乙酰氧基碘)苯(PIDA)促进了富含电子的苯乙烯的二聚，例如1，以良好到优异的产率作为单一(全反式)非对映异构体3(方案1)。此外，还实现了与富含电子和缺乏电子的苯乙烯的异二聚化反应，为以环丁烷为基础的化合物开辟了一条令人兴奋的先例。这项工作将致力于扩大这种形式的“[2+2]”环加成反应的范围，并导致新的相关合成方法的发展。目前，具有环丁烷部分的化合物只占药物库的一小部分。因此，葛兰素史克通过案例奖为该项目提供部分资金。这个项目还将与电化学和计算技术方面的专家合作进行，以形成一个全面的方法来理解这种新的化学反应模式。通过探索同时具有供电子和吸电子取代基的烯烃的用途，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转变为氮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一正式的“[2+2]”环加成反应的潜在合作伙伴(方案3)。所生产的重氮环丁烷将在药物发现计划中有重要的应用，我们的目标是裂解环，例如使用锌/氢+生成合成二胺9。总体而言，这代表了一种无金属脱氨反应，在有机合成中可能有很大的实用价值。推测富电子苯乙烯单电子氧化生成的自由基阳离子可能与环丙烷反应生成取代环戊烷。或者，也可以对富含电子的环丙烷进行单电子氧化，并将其与烯烃伙伴反应。6，7本项目将研究具有不同电子密度和空间位阻的多种环丙烷和苯乙烯类化合物。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和许多其他含有相关结构的物质。随着这一方法学的进一步发展，我们将展望生物活性天然产物的合成。

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.