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

含有环状原子排列的有机化合物，其中环中至少一个原子是碳以外的原子，被称为杂环。杂环基序存在于许多天然和人造的生物活性化合物中，例如药物和功能性有机材料，例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新电子设备的组成部分，这类有机分子对我们的生活质量都有巨大的影响。因此，开发新的化学工艺，使杂环结构以简洁的方式构建，具有重大的国际重要性，并且是一个高度竞争的科学领域，这并不奇怪。我们实验室的最新发现意味着我们在该领域处于独特的地位，可以利用我们的初步成果，并在该领域处于领先地位。有机合成的巨大挑战-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，以最小的中间体纯化生产目标化合物。在这个项目中，我们将开发策略，使重要的杂环结构快速建立，使用新的化学反应，包括“级联”反应，和分离技术，以减少对传统的纯化技术，如色谱的需要。级联反应是指在一个反应瓶中发生多个化学变化的化学反应，从而节省了时间和资源。我们将用于形成杂环的新化学反应是通过添加或失去硫醇（醇的硫类似物）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，并提供短路线的化合物，显示重要的生物活性（如抗肿瘤剂）或显示有价值的物理特性（半导体器件的组成部分，显示出更好的稳定性）。加入巯基单元后，我们可以对中间体进行修饰，并快速纯化，从而避免传统色谱法的费用。该项目的特点是合成两个天然产物家族的类似物，即海鞘素和螺前列腺素。天然产物，顾名思义，是天然存在的有机分子，通常具有重要的药用价值。最著名的例子之一是从太平洋紫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。海鞘素和spirotryprostatin也具有重要的抗癌活性，迫切需要大量的这些稀缺的天然产物的类似物进行评估。我们还将使用我们的新策略来收集具有令人兴奋的半导体特性的“非天然产物”吲哚并咔唑。开发这些天然和非天然产物的有利途径是特别及时的，因为这些家族中分子结构和活性之间的联系尚不清楚。由于目前达到这些目标的途径有限，因此研究材料很少。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，并随后改善世界各地的生活质量。

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.