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. 2009 Dec 7;15(47):12978-92.
doi: 10.1002/chem.200902172.

The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: reaction development, scope, and applications

David C Ebner  1 , Jeffrey T Bagdanoff, Eric M Ferreira, Ryan M McFadden, Daniel D Caspi, Raissa M Trend, Brian M Stoltz
Affiliations

The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: reaction development, scope, and applications

David C Ebner et al. Chemistry. .

Abstract

The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23 degrees C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-to-excellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.

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Figures

Figure 1
Figure 1
Ligands evaluated in Table 1.
Figure 2
Figure 2
Enantioenriched ketones obtained from the kinetic resolution.
Figure 3
Figure 3
Examples of alcohols displaying poor reactivity.
Figure 4
Figure 4
Examples of alcohols oxidized with poor selectivity.
Figure 5
Figure 5
Polyether natural products potentially accessible by meso-diol desymmetrization.
Scheme 1
Scheme 1
Uemura’s oxidation of alcohols.
Scheme 2
Scheme 2
Proposed mechanism for the palladium-catalyzed alcohol oxidation.
Scheme 3
Scheme 3
Initial conditions for the Pd-catalyzed enantioselective oxidation of alcohols.
Scheme 4
Scheme 4
Potential role of excess sparteine and base.
Scheme 5
Scheme 5
Stabilization of the β-hydride elimination transition state by resonance and a β-silicon.
Scheme 6
Scheme 6
Formation of inactive Pd complex 13.
Scheme 7
Scheme 7
Model for kinetic resolution selectivity.
Scheme 8
Scheme 8
Secondary alcohols as drug intermediates.
Scheme 9
Scheme 9
Conversion of a resolved alcohol to a functionalized tetrahydrofuran.
Scheme 10
Scheme 10
Desymmetrization of diol 41.
Scheme 11
Scheme 11
Preparation of meso-diols from a common starting material.
Scheme 12
Scheme 12
Oxidative desymmetrization of meso-diols.
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