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b<s:1> chi型酮的快速合成，它应该作为合成Vindoline的关键中间体。然而，这个目标代表了通向长春碱的中间步骤。这个项目现在包括合成这种天然产物的第二个片段，它比现在复杂得多，并显示出有希望的生物活性。这可以通过光氧化还原-和镍催化合并形成的新型不对称C(sp3)-C（sp3）交叉偶联来实现。然而，这个关键的转变仍然是难以捉摸的，重要的优化是必要的，以达到合成有用的产量和选择性。这个任务在我们看来是更大的挑战，因此应该先解决这个部分的项目。烷基-烷基交叉偶联通常是构建碳框架的一种强大方法，当以不对称方式进行时甚至更有效。现有系统的主要缺点是需要预功能化的起始材料，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，处理这些往往是困难的，从而阻碍了它们的适用性。在过去的几个月里，我们建立了这种转化的外消旋变体，并发表了这些结果。我们的工艺从稳定的羧酸和烷基溴开始。该反应通过镍和光氧化还原催化的协同组合进行。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的前所未有的反应模式。我们介绍的改造通过利用台架稳定的起始材料的可能性而脱颖而出，这些材料不需要额外的预激活步骤，从而提高了效率，并最大限度地减少了努力和浪费。此外，由于采用良性反应条件，该方案表现出特殊的官能团耐受性。通过外消旋反应，我们可以证明它的活性。在实现这一目标之后，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.