The on-off switch: Synthesis of functional heterocycles mediated by the capture and release of thiols

含有原子的循环排列的有机化合物，其中环中至少有一个原子是碳以外的原子，称为杂环。杂环基序存在于许多天然和人工生物活性化合物中，如药物，以及功能有机材料，如有机半导体和液晶。无论这些杂环化合物是新药的成分，还是构成新电子设备的元件，这类有机分子都对我们的生活质量产生了巨大的影响。因此，能够以简明的方式构建杂环结构的新化学工艺的开发具有重大的国际重要性，是一个竞争激烈的科学领域，这一点也就不足为奇了。我们研究实验室的最新发现意味着我们处于独特的地位，可以利用我们在这一领域的初步成果并在该领域处于领先地位。有机合成中的重大挑战-从简单的有机分子构建复杂的有机分子-是开发高效的路线，使用很少的化学反应，以最少的中间体纯化生产目标化合物。在这个项目中，我们将开发能够快速构建重要杂环结构的策略，使用新的化学反应，包括级联反应和分离技术，以减少对传统纯化技术(如层析)的需求。级联反应是指在一个反应瓶中发生许多化学变化，从而节省时间和资源的化学反应。我们将用来形成杂环的新化学反应是由原料中的硫醇--醇的硫磺类似物--的添加或丢失而引发的。我们将‘耦合’这些新的化学反应，使它们以协同的方式工作，并提供通往显示重要生物活性(例如抗肿瘤制剂)或显示有价值的物理特性(显示出更高稳定性的半导体设备的成分)的化合物的短路线。合并后，硫醇单元将帮助我们修改中间体，并使我们能够快速纯化它们，从而避免传统层析的费用。该项目将以合成两个天然产品家族的类似物为特色，即外膜前列腺素和螺旋前列腺素。顾名思义，天然产品是天然产生的有机分子，通常具有重要的药用价值。最著名的例子之一是从太平洋红豆杉树皮中分离出来的天然产品紫杉醇，现在是一种领先的抗癌药物。降钙素和前列腺素也具有重要的抗癌活性，迫切需要这些稀缺天然产物的更大数量的类似物进行评估。我们还将使用我们的新策略来收集吲哚咔唑，这是一种具有令人兴奋的半导体特性的“非天然产品”。由于分子结构与其在这些家族中的活性之间的联系尚不清楚，开发获得这些天然和非天然产品的便捷途径尤其及时。由于现有获取这些目标的途径有限，可供研究的材料很少。最终，我们的研究可能会导致新的杂环药物和有机电子设备，并随后在世界范围内改善生活质量。

Organic compounds containing a cyclic arrangement of atoms, where at least one atom in the ring is an atom other than carbon, are refered to as heterocycles. Heterocyclic motifs are found in many natural and man-made biologically active compounds, for example drugs, and functional organic materials, such as organic semiconductors and liquid crystals. Whether these heterocyclic compounds are the constituents of new medicines or make up components of new electronic devices, this class of organic molecule has a tremendous impact on our quality of life. It is not surprising then that the development of new chemical processes that allow heterocyclic architectures to be constructed in a concise fashion is of major, international importance and is a highly competitive area of science. Recent discoveries in our research laboratories mean that we are uniquely placed to exploit our preliminary results in this area and to take a lead in the field.The grand challenge in organic synthesis - the construction of complex organic molecules from simple ones - is the development of efficient routes, using few chemical reactions, that produce the target compounds with minimum purification of intermediates. In this project we will develop strategies that allow important heterocyclic structures to be built quickly, using new chemical reactions, including 'cascade' reactions, and separation technology to reduce the need for traditional purification techniques such as chromatography. Cascade reactions are chemical reactions were a number of chemical changes happen in one reaction flask thus saving time and resources.The new chemical reactions we will use to form heterocycles are triggered by either the addition or the loss of a thiol - the sulfur analogue of an alcohol - from starting materials. We will 'couple' these new chemical reactions so that they work in a synergistic fashion and provide short routes to compounds that display either important biological activity (e.g. anti-tumour agents) or exhibit valuable physical properties (the constituents of semiconductor devices that show improved stability). When incorporated, the thiol unit will help us modify intermediates and will allows us to purify them quickly thus avoiding the expense of traditional chromatography.The project will feature the synthesis of analogues of two natural product families, the ecteinascidins and the spirotryprostatins. Natural products are, as the name suggest, naturally occuring organic molecules that often have important medicinal properties. One of the most famous examples is the natural product Taxol that was isolated from the bark of the Pacific Yew tree and is now a leading anti-cancer drug. The ecteinascidin and spirotryprostatin also have important anti-cancer activity and there is an urgent need for larger amounts of analogues of these scarce natural products for evaluation. We will also use our new strategies to make collections of indolocarbazoles, 'unnatural products' that have exciting semiconductor properties.Developing expedient routes to these natural and unnatural products is particularly timely as the link between the molecule's structure and its activity in these families is not clear. As existing access to these targets is limited, material for study is scarce. Ultimately, our research may lead to new heterocyclic drugs and organic electronic devices, and subsequently, to improvements in the quality of life, worldwide.