American Chemical Society
ja7b07121_si_003.cif (528.74 kB)

Computationally Guided Catalyst Design in the Type I Dynamic Kinetic Asymmetric Pauson–Khand Reaction of Allenyl Acetates

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posted on 2017-10-11, 21:04 authored by Lauren C. Burrows, Luke T. Jesikiewicz, Gang Lu, Steven J. Geib, Peng Liu, Kay M. Brummond
The Rh­(I)-catalyzed allenic Pauson–Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh­(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh­(I) catalyst that provided α-acyloxy cyclopentenone product in up to 14:86 er. Enantioselectivity of the Rh­(I)-(S)-MonoPhos-alkene catalyst was rationalized using ligand-substrate steric interactions and distortion energies in the computed transition states. This asymmetric APKR of allenyl acetates is a rare example of a Type I DyKAT reaction of an allene, the first example of DyKAT in a cyclocarbonylation reaction, and the first catalyst-controlled enantioselective APKR.