Kinetic resolution of racemic tertiary allylic alcohols through SN2' reaction using a chiral bisphosphoric acid/silver(i) salt co-catalyst system

Abstract

A highly efficient kinetic resolution (KR) of racemic tertiary allylic alcohols was achieved through an intramolecular allylic substitution reaction using a co-catalyst system composed of chiral bisphosphoric acid and silver carbonate. This reaction afforded enantioenriched diene monoepoxides along with the recovery of tertiary allylic alcohols in a highly enantioselective manner, realizing an extremely high s-factor in most cases. The present method provides a new access to enantioenriched tertiary allylic alcohols, multifunctional compounds that are applicable for further synthetic manipulations.

Scheme 1. KR of enantiomeric tertiary allylic alcohols through an intramolecular S_N2′ reaction.

Scheme 2. (a) Enantioselective intramolecular S_N2′ reaction catalysed by (R)-1a (previous work). (b) Catalytic KR of racemic tertiary alcohols through the intramolecular S_N2′ reaction developed in the present study.

Fig. 1. Prediction of stereochemical outcomes in the present KR of racemic (E)-4 through the intramolecular S_N2′ reaction using the (R)-1a/additive co-catalyst system. The transition states in the absence of an additive are illustrated for clarity. (a) The reaction of (S,E)-4. (b) The reaction of (R,E)-4.

Scheme 3. Large-scale experiment to demonstrate the utility of the present KR.

Scheme 4. (a) Derivatization of enantioenriched epoxide cis-(2S,3R)-5a into allylic alcohol (S,E)-7. (b) Hydrolysis of enantioenriched (R,E)-4a into allylic alcohol (R,E)-7.

Scheme 5. Intramolecular S_N2′ reaction of racemic (E)-4a using the co-catalyst system of (R)-1b (G = H) and PhB(OH)₂ in chloroform.

Fig. 2. 3D structures and schematic representation models of the most energetically favourable transition states for the C–O bond cleavage step, TS-S_model and TS-R_model. The 3D structures of the fragments are represented as follows: phosphoric acid units and atoms involved in the bond recombination sequence and the hydrogen bonding interaction: “ball and bond type” model; and the other atoms, such as bisphosphoric acid backbone and substrate: “tube” model. The ortho-position of the phenyl ring is indicated by circles, where the substituent is introduced in the actual catalytic system. Relative free energies (kcal mol⁻¹) of the optimized structures at the B97D/6-31G(d) level in the gas phase are shown in parentheses. Relative free energies (kcal mol⁻¹) obtained by single-point energy calculations at the same level are shown for the optimized transition states in the solution phase according to the SCRF method based on CPCM (ether). Hydrogen bond lengths are indicated in blue (angstroms) and cleaved and formed C–O bond lengths are indicated in red (angstroms): (a) TS-S_model generated from (R)-1b (G = H) and (S,E)-4a. (b) TS-R_model generated from (R)-1b (G = H) and (R,E)-4a.