Building-Block Approach for Organic Synthesis

化学家创造具有精确形状和功能的分子的能力对从医学到材料的许多研究学科的发展和壮大至关重要。从工业生产中得知，模块化过程通常是高效和灵活的，这就是为什么大自然通过在类似流水线的过程中连接一组非常有限的小分子(所谓的积木)来构建大多数分子，从而创造出数量惊人的各种天然化合物。因此，两块积木被激活，然后结合在一起，形成新的化学键。这是大自然以非常高的精度以顺序的方式完成的。对于最突出的情况(DNA/RNA/蛋白质)，化学家已经开发出复制自然界积木方法的过程，对科学和技术产生了重大影响。虽然氨基酸(蛋白质)和核苷酸(DNA/RNA)之间的联系相当直接，但碳链的受控增长却更具挑战性，碳链是制造有机分子的核心。因此，合成复杂的有机分子对专家来说仍然是一项艰巨的任务，对于每个单一分子，必须从头开始设计一条新的合成路线。这项拟议的研究项目的目的是开发一种策略，采用积木方法合成高度复杂的有机分子，即所谓的聚酮。聚酮类化合物是一个非常广泛和多样的天然产物家族，具有许多重要的生物活性，导致在许多药物和农用化学品(抗生素、抗真菌药物、杀虫剂等)中的应用。这就是为什么积木方法是可取的，因为它将使这些非常重要的分子的合成变得更容易和更快(高效率)。当使用一套标准的积木时，即使是非专业人员也可以制备大多数聚酮结构。重要的是，这种模块化策略将使修饰分子和研究分子结构如何影响生物活性变得容易得多，最终导致分子具有更好的性质(高灵活性)。第一步是设计积木，并确定符合条件的化学转化，以高精度选择性地激活它们。该组积木包括具有用于连接的一个手柄的端子单元和具有两个手柄的双功能端子单元。接下来，将以高效和可重复的方式合成所设计的积木。然后，这组积木将用于以高效的方式从聚酮家族合成两种抗生素。这种积木策略具有巨大的潜力，可以向更广泛的科学家群体开放有机合成领域。

The ability of chemists to create molecules with precise shape and functionality is central to development and growth for many research disciplines from medicine to materials. As known from industrial production modular processes are usually highly efficient and flexible, that is why Nature builds most molecules by connecting a very limited set of small molecules (so called building-blocks) in an assembly-line like process, hereby creating an unbelievable amount of diverse natural compounds. Therefore two building-blocks are activated and then brought together so that they form a new chemical bond. This is done by Nature with very high precision in a sequential way. For the most prominent cases (DNA/RNA/proteins) chemists already developed processes to copy the building-block approach from Nature with significant impact in science and technology. While the connection of amino acids (proteins) and nucleotides (DNA/RNA) is rather straightforward the controlled growth of carbon chains, which is central for making organic molecules, is much more challenging. Thus, synthesis of complex organic molecules remains a demanding task for specialists and for every single molecule a new route for the synthesis has to be designed from scratch. The aim of the proposed research project is to develop a strategy to adopt the building-block approach for the synthesis of highly complex organic molecules, the so called polyketides. Polyketides are a very large and diverse natural product family with many important biological activities leading to application in many pharmaceuticals and agrochemicals (antibiotics, antifungals, insecticides, etc.). That is why a building-block approach is desirable since it will allow the synthesis of these very important molecules much easier and faster (high efficiency). When using a standard set of building-blocks most polyketide structures can be prepared even by non-specialists. Importantly, this modular strategy will make it much easier to modify the molecules and study how the structure of the molecule affects the biological activity, finally leading to molecules with better properties (high flexibility). The first step is to design building-blocks and identify an eligible chemical transformation to selectively activate them in high precision. The set of building-blocks includes terminal units with one handle for connection and bifunctional ones with two handles. Next, the designed building-blocks will be synthesized in an efficient and reproducible way. This set of building-blocks will then be used for the synthesis of two antibiotics from the polyketide family in a highly efficient manner. This building-block strategy has great potential to open the field of organic synthesis to a much broader pool of scientist.