Development of an asymmetric C(sp3)-C(sp3) cross-coupling using a merger of Photoredox- and Nickel-catalysis

第一个应用描述了所谓的Büchi-型酮的快速合成，它应该作为长春花碱合成的关键中间体。然而，这个目标代表着迈向长春花碱的中间一步。该项目现在包括合成这种天然产物的第二个片段，到目前为止，它要复杂得多，并显示出良好的生物活性。这应该通过一种新型的不对称C(SP3)-C(SP3)交叉偶联来实现，通过光氧化还原和镍催化剂的合并来实现。然而，这一关键的转化仍然是难以捉摸的，为了获得综合有用的产率和选择性，有必要进行重大的优化。在我们看来，这项任务是更大的挑战，因此应该首先解决该项目的这一部分。通常，烷基-烷基交叉偶联是构建碳框架的一种强有力的方法，如果以不对称的方式进行，效果会更好。现有系统的主要缺点是需要预官能化的起始材料，通常是有机金属化合物。由于它们对水分和空气的固有敏感性，它们的处理往往很困难，因此阻碍了它们的应用。在过去的几个月里，我们能够建立这种转化的外消旋变体并发表这些结果。我们的过程从稳定的羧酸和烷基溴化物开始。该反应通过镍和光氧化还原催化的协同作用进行。后者描述了应用特殊催化剂的概念，这种催化剂可以通过吸收可见光来激发。这种激发态现在有能力激活有机底物，实现前所未有的反应模式。我们介绍的改造通过使用工作台稳定的起始材料的可能性而与众不同，这些起始材料不需要额外的预活化步骤，从而提高了效率，并将工作量和浪费降至最低。此外，由于采用了良性的反应条件，该协议表现出了特殊的官能团耐受性。通过以外消旋的方式进行该反应，我们可以证明其可行性。在实现这一目标后，下一步是解决对映选择性变体，它的价值更高。这种立体选择性转化将应用于复杂天然产物的合成。

The first application described rapid synthesis of the so-called Büchi-type-ketones, which should act as the key intermediate in the synthesis of Vindoline. This goal, however, represents an intermediate step on the way to Vinblastine. This project now includes the synthesis of the second fragment of this natural product, which is by far more complex and exhibits promising biological activity. This should be accessed via a novel asymmetric C(sp3)-C(sp3) cross-coupling via the merger of Photoredox- and Nickel catalysis.Nevertheless, this key transformation remains elusive and significant optimization is necessary to reach synthetically useful yields and selectivities. This task is in our opinion the bigger challenge, therefore this part of the project should be addressed first.Alkyl-alkyl cross-couplings in general represent a powerful method to build carbon frameworks and are even more effective when conducted in an asymmetric fashion. The major drawback of established systems is the need for prefunctionalized starting materials, often organometallic compounds. The handling of these tends to be difficult due to their inherent sensitivity towards moisture and air, thus hampering their applicability.Over the last months we were able to establish a racemic variant of this transformation and publish these results. Our process starts from stable carboxylic acids and alkyl bromides. The reaction proceeds via a synergistic combination of nickel and photoredox catalysis. The latter describes the concept of applying special catalysts, which can be excited through the absorption of visible light. This excited state now has the ability to activate organic substrates for unprecedented modes of reactivity. The transformation we introduced distinguishes itself through the possibility of utilizing bench stable starting materials, which do not need an additional step for preactivation, thereby leading to enhanced efficiency as well as minimized effort and waste. Furthermore, this protocol exhibits exceptional functional group tolerance due to the benign reaction conditions employed.By performing this reaction in a racemic fashion we could prove its viability. After achieving this goal the next step is to address the enantioselective variant, which is even higher in value. This stereoselective transformation then shall be applied in the synthesis of complex natural products.