Asymmetric propargylic substitution (APS) reactions play a crucial role in synthesizing the fundamental structural units found in natural drug molecules and macromolecules. However, achieving both high yields and enantioselectivity in the synthesis of asymmetric alkynyl propyl compounds remains a formidable challenge. In this study, we present a comprehensive computational study of asymmetric alkynyl propyl hydroxyaminations catalyzed by a chiral phosphine-nickel complex. The entire catalysis can be outlined as three stages: (i) Propargylic carbonate 1a activation by the (S)-L1/Ni(0)-catalyst, results in the Ni(II)-intermediate IM2A. (ii) IM2A undergoes decarboxylation process, leading to the Ni(II)-complex IM5A. (iii) IM5A suffers asymmetric propargylic substitution with N-hydroxyphthalimide 2a gives the more stable Ni(0)-complex IM7A, followed by product (S)-3a liberation and IM1A regeneration for the next catalytic cycle with the assistance of another equiv 1a. The asymmetric propargylic substitution step, with a barrier of 21.4 kcal/mol, should be the rate-determining step and enantioselectivity-determining step during the whole catalysis. EDA-NOCV analysis revealed that the origins of the enantioselectivity of product (S)-3a lies in the combination effects of the ligand-substrate electrostatic interactions, orbital interactions, Pauli repulsions, and dispersion interactions. Based on mechanistic study, new biaryl bisphosphine ligand (i.e., (S)-L6) affording higher enantioselectivity was designed, which will help to improve current catalytic systems and facilitate the development of new Ni-catalyzed asymmetric alkynyl propyl hydroxyaminations.

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