Enantioconvergent Alkylation of Ketones with Racemic

Key roles:

Protection of the carbonyl against nucleophilic attackReduction of the carbonylPrevention against dimerisation

Highly crystalline material

Enantioconvergent Alkylation of Ketones with Racemic Secondary Alcohols via Hydrogen Borrowing Catalysis

Daniella Maria Jia-Yi Cheang, Roly J. Armstrong, Wasim M. Akhtar and Timothy J. Donohoe*University of Oxford, Department of Chemistry ● E: daniella.cheang@chem.ox.ac.uk ● W: http://donohoe.chem.ox.ac.uk

An enantioconvergent hydrogen borrowing strategy enables the catalytic asymmetric alkylation of ketone enolates with unactivated, racemic secondary alcohols.

Traditional Enolate Alkylation

Hydrogen Borrowing offers a powerful alternative strategy: a one-pot, three-step process

Two Main Challenges

1. Forming isomerically pure enone intermediate2. Using a single catalyst with three roles: oxidation, reduction and

enantioselectivity.

asymmetric reduction of the enone intermediate

Advantages Overall redox neutral process Sole by-product: water High atom economy Non toxic alcohols Reaction with 2° electrophiles

Acknowledgments: D. M. J. C is grateful to the EPSRC Centre for Doctoral Training in Synthesis forBiology and Medicine (EP/L015838/1) for a studentship. D.M.J.C. is also grateful for an Oxford-RadcliffeScholarship

Increasing electron density

Increasing steric bulk Combining both factors

Varying the backbone

References: [1] D. M. J. Cheang, R. J. Armstrong, W. M. Akhtar, T. J. Donohoe, Chem. Commun. 2020, 56, 3543–3546. [2] A. Corma, J. Navas, M. J. Sabater, Chem. Rev. 2018, 118, 1410–1459. [3] W. M. Akhtar, R. J. Armstrong, J. R. Frost, N. G. Stevenson, T. J. Donohoe, J. Am. Chem. Soc. 2018, 140, 11916–11920. [4] R. J. Armstrong, W. M. Akhtar, T. A. Young, F. Duarte, T. J. Donohoe, Angew. Chem. Int. Ed. 2019, 58, 12558–12562.

orthogonal aromatic group

Ph* provides the optimum steric hindrance

Ph* enables stereoselective crystallisation on gram scale

Ph* cleavage with bromine forms the corresponding acid bromide via retro-Friedel-Crafts acylation.

The Re-transition state is strongly disfavoured by steric clash with the P-Ar group of the ligand.

enantioconvergent alkylation · racemic alcohols · versatile Ph* ketones

Ph* cleavage enabled determination of absolute stereochemistry

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1Introduction Importance of the Ph* group

Optimisation – Ligand Effects

Substrate Scope

References & Acknowledgements

Absolute Stereochemistry and Rationale

Derivatisation

Summary

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A visual representation of the C=O IR stretches

Carbonyl IR stretchesPentamethylphenyl Group

The Ph* group is cleaved via ipso-substitution of bromine to form the acid bromide

The acid bromide provides a versatile handle to derivatise the Ph* products

Ph* cleavage proceeds with no epimerization at the ß- stereogeniccentre.

As the aromatic group moves out of conjugation with the carbonyl, a change in IR stretch is observed.