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

Abstract

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.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…[14][15][16][17][18][19] Studying such reactions computationally not only enriches our understanding of thesep rocesses but also creates opportunities to improvetheir efficiency. [20][21][22][23][24][25][26][27] In continuationo fo ur efforts to understandt he stereoselectivity of organocatalyzed reactions, [29] particularly in the context of KRs, [30,31] we have examined the KR of axially chiral biaryls reported by Sibi and co-workersi n2 014 (Scheme 1). [28] In this reaction, chiral DMAP catalyst A serves as ah ighly selective catalystw hen paired with isobutyric anhydride as the acylating agent.A lthough there have been previousc omputational studieso fo therK Rs of alcohols, [10,[32][33][34][35] the reactioni n Scheme 1p resents an umber of unique features.F irst, it is the seminale xample of an organocatalyzed KR that providese xcellent selectivities for axially chiral alcohols, yet has not been explored computationally.S econd, it exhibits high degreeso fs electivity despite the use of ah ighly-fluxional chiral catalyst.…”

Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach

“…Computational mechanistic studies (e.g., using density functional theory) have previously aided the optimization of phosphoramidite ligands used in metal-catalyzed asymmetric transformations. 35,36 However, these approaches are significantly more expensive and require prior detailed knowledge of mechanism and competing stereodetermining transition structures. Impressive predictive accuracies of ∼2 kJ/mol have been obtained using QSSR models, which should be viewed in a favorable light when compared with the bounds of chemical accuracy attainable by quantum chemical calculations of around ∼4 kJ/mol.…”

Rhodium‐Catalyzed Pauson–Khand‐Type Cyclization of 1,5‐Allene‐Alkynes: A Chirality Transfer Strategy for Optically Active Bicyclic Ketones

“…Based on the X‐ray diffraction analysis of ( R )‐ 2 a and previous reports, a mechanism of the Rh‐catalyzed APKR is proposed (Scheme ). Firstly, [RhCl(CO) 2 ] 2 reacts with AgSbF 6 to generate cationic catalyst [Rh(CO) 2 ] + SbF 6 − .…”

“…On the other hand, in principle, chiral cyclopentenone compounds could be accessed by chirality transfer when the optically active axially chiral allenynes are used. To our knowledge, there are only limited examples on the APKR of chiral allenynes . In 2002, Brummond et al.…”