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

• Applicant: Dr. Simon Allmendinger
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277159957

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor David W. C. MacMillan, Ph.D.