Lipase-mediated enantioselective acylation of alcohols with functionalized vinyl esters: acyl donor tolerance and applications

Enzymatic acylation is commonly used for the kinetic resolution of alcohols and amines. The simple acyl group introduced during the enzymatic reaction is usually removed or replaced by another group. Retention of more complex acyl moieties as part of the target structures would be a more efficient strategy. We have studied the enantioselective acylation of a model alcohol substrate, 1-phenylethanol, with vinyl esters bearing various functionality on the acyl moieties in the presence of three lipases (Candida antarctica, Candida rugosa and Burkholderia cepacia) frequently used in organic synthesis. C. antarctica lipase is the most versatile lipase for this type of biotransformations. We applied this strategy to the synthesis of a protein kinase C ligand and a natural product, phoracantholide.

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(R)-1-Phenylethyl acetateC10H12O2Ee = >98% (Chiral GC)[α]D20=+43 (c 2.1, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl pivaloateC13H18O2Ee = 92% (Chiral HPLC)[α]D20=-5.8 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl pent-4-enoateC13H16O2Ee = 95% (Chiral HPLC)[α]D20=+64 (c 2.4, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl crotonateC12H14O2Ee = >98% (Chiral HPLC)[α]D20=+11 (c 1.2, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl methacrylateC12H14O2Ee = >98% (Chiral HPLC)[α]D20=+50 (c 0.88, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl benzoateC15H14O2Ee = 92% (Chiral HPLC)[α]D20=-2.3 (c 1.2, EtOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl cinnamateC17H16O2Ee = >98% (Chiral HPLC)[α]D20=-39 (c 1.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl N-Boc glycinateC15H21NO4Ee = >98% (Chiral HPLC)[α]D20=+15 (c 1.15, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(R)-1-Phenylethyl 2-(phenylthio)acetateC16H16O2SEe = 94% (Chiral HPLC)[α]D20=+49 (c 3.0, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (1R)

(S)-2-(4-(Benzyloxy)phenyl)-3-hydroxypropyl pivaloateC21H26O4Ee = >98% (Chiral HPLC)[α]D20=+12.9 (c 0.64, CHCl3)Source of chirality: enzymatic desymmetrizationAbsolute configuration: (2S)

(R)-Hept-6-en-yl pent-4-enoateC12H20O2Ee = 95% (Chiral GC)[α]D20=-5.51 (c 2.06, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (2R)

(S)-Hept-6-en-2-olC7H14OEe = 98%[α]D20=+10.2 (c 1.2, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (2S)

(R,Z)-10-Methyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-one (Phoracantholide J)C10H16O2Ee = 95%[α]D20=-31.9 (c 1.09, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (2R)

(R)-10-Methyloxecan-2-one (Phoracantholide I)C10H18O2Ee = 95%[α]D20=-33.5 (c 3.0, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (2R)