Neurokinins are peptides, which play an important role in human life: neurokinin G-protein-coupled receptors are involved in many pathological processes in the human body. Aprepitant (Emend®), which was developed by Merck, is the first selective neurokinin 1 (hNK1) receptor antagonist used to treat postoperative or chemotherapy-induced nausea and vomiting. In the course of further research by Merck to find effective analogues of aprepitant, a promising compound Merck12-a2-2 based on bicyclic aryl-substituted pyrrolidine was obtained. However, the synthesis of this molecule, presented by Merck, has a number of disadvantages, such as low regio- and diastereoselectivity of reactions, as well as the possibility of preparation of only one stereoisomer out of 16 possible.
As part of research on the complete synthesis of bioactive pyrrolidine derivatives, the scientists of laboratory № 9 of ZIOC RAS developed an asymmetric full synthesis of Merck12-a2-2, its epimer at the C-12 position and their enantiomers with a total yield of 5% at 10 stages. The key steps of the proposed approach are [4 + 2] cycloaddition, site selective CH-oxygenation using a tandem acylation/[3,3] rearrangement process, and reductive contraction of the 1,2-oxazine ring into the pyrrolidine ring. The absolute stereochemistry of the obtained stereoisomers was confirmed by X-ray diffraction analysis of the intermediates and the final compound. The strategy proposed by the researchers can be considered as a general method for the enantioselective synthesis of 3,4-disubstituted prolinols, which are important structural fragments of many bioactive molecules and organocatalysts.
Valentin S. Dorokhov, Yulia V. Nelyubina, Sema L. Ioffe, and Alexey Yu. Sukhorukov Asymmetric Synthesis of Merck’s Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides, J. Org. Chem., 2020, 85, 11060–11071, DOI: 10.1021/acs.joc.0c01322.