Photocatalyzed Epimerization of Quaternary Stereocenters

Abstract

Quaternary stereocenters play a crucial role in shaping both the molecular topology of small molecules and the outcome of stereoselective transformations. While considerable progress has been achieved in constructing highly substituted carbon centers with varied substitution patterns, the stereoselective synthesis of quaternary carbon centers remains a significant challenge. Here we report a protocol for the precise manipulation of quaternary stereocenters through epimerization. The critical design element of our ketone α-epimerization process was developing a photoactive imine, which circumvents the numerous deleterious pathways of carbonyl photochemistry. Excitation of this imine with visible light in the presence of a photocatalyst enables reversible C-C bond cleavage and reformation to vary the stereochemistry of the quaternary center. This approach allows us to override intrinsic stereochemical outcomes of C-C bond construction, therefore providing novel tactics for retrosynthetic planning. The broad utility of this protocol was demonstrated by the topological alteration of various classes of carbocyclic scaffolds bearing diverse functional groups.

Scheme 1. Epimerization of Quaternary Stereocenters Using an aza-Norrish Approach

Scheme 2. Development of a Photocatalytic Quaternary Center α-Epimerization

All reactions were conducted on 0.10 mmol scale with respect to 1a or 2a. Yields and diastereomeric ratios (dr) determined by ¹H NMR spectroscopy of the crude reaction mixtures utilizing CH₂Br₂ or 1,2-dibromoethane as the internal standard. Condensation performed using iodine (5.0 mol %) in DMF (0.1 M) at 90 °C for 72 h. Calculated by DFT at M06-2X/def2-TZVP/CPCM (DCE). n.d.: not determined.

Scheme 3. Substrate Scope

All reactions were conducted on 0.30 mmol scale with respect to the ketone (1). Isolated yields are based on the imine (2) unless otherwise noted; diastereomeric ratios (dr) were determined by ¹H NMR. Isolated yield in parentheses following a telescoped protocol without the isolation of 2; the yield is based on 1 (0.30 mmol). 5.0 mmol scale and 0.5 mol % PC1 was used. Condensation performed using 3.0 equiv THAQ.

Scheme 4. Late-Stage Epimerization of Steroidal Architectures

All reactions were conducted on 0.30 mmol scale with respect to the ketone (1). Isolated yields based on the imine (2) unless otherwise noted; diastereomeric ratios (dr) were determined by ¹H NMR. Yield and dr determined by ¹H NMR spectroscopy of the crude reaction mixture utilizing CH₂Br₂ as the internal standard. Isolated yield in parentheses following a telescoped protocol without the isolation of 2; the yield is based on 1 (0.30 mmol). Oxalic acid was utilized for the imine hydrolysis.

Scheme 5. Further Application of Quaternary Center Epimerization

Reaction was performed at 10 °C for 40 h. Reaction was performed at 10 °C for 26 h. Reaction was performed at 35 °C for 4 h.

Scheme 6. Mechanistic Investigations

Yield and dr determined by ¹H NMR spectroscopy of the crude reaction mixture utilizing CH₂Br₂ or TCE as the internal standard. See Supporting Information for experimental details.