Abstract
AbstractA highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.
Highlights
Tertiary alcohols and their derivatives are present within many natural products and bioactive molecules, their synthesis in enantiopure form remains a significant challenge.[1]
One potentially general solution is immobilization of the organocatalyst on a heterogeneous support, provided that the catalyst maintains activity and displays high stability.[21,22]. We recently addressed this issue through the development of a polymer-supported isothiourea catalyst (32), which could be applied for the kinetic resolution (KR) of alcohols in batch and flow with no reduction in either activity or selectivity observed upon recycling.[23]
The absolute configuration of the recovered alcohol within each substrate class [aryl/alkyl (5,20); alkenyl/alkyl (29); alkyl/ alkyl (31)] was determined by comparison of specific rotations to reported values.[14]. Based on these data and previous computational studies,[5h,10h,q] we propose that the ester functionality operates as a recognition motif within the acylation transition states of this KR by engaging in a stabilizing C=O···isothiouronium interaction with the acylated catalyst (Figure 3 b)
Summary
Tertiary alcohols and their derivatives are present within many natural products and bioactive molecules, their synthesis in enantiopure form remains a significant challenge.[1]. The challenges associated with the KR of tertiary alcohols are two-fold: 1) tertiary alcohols are sterically hindered, reducing their nucleophilicity; and 2) the catalyst is required to differentiate between three non-hydrogen substituents at the stereogenic carbinol centre. In contrast to our previous work on the KR of heterocyclic alcohols,[5h] the additional conformational flexibility of acyclic substrates (Figure 2 b) presents additional challenges to overcome: 1) increased steric hindrance at the carbinol centre attenuating the rate of acylation; and 2) the potential for the other carbinol substituents to act as competitive recognition motifs, resulting in reduced enantiodiscrimination. We report the development of the acylative KR of acyclic tertiary alcohols using isothiourea catalysis Key to this transformation is the incorporation of a suitable carbonyl donor adjacent to the tertiary stereogenic carbinol centre to act as a recognition motif for the acylated catalyst
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