Chemoenzymatic synthesis of enantiomerically enriched α-chiral 3-oxy-propionaldehydes by lipase-catalyzed kinetic resolution and desymmetrization

Enantiomerically enriched phenylalanine- and leucine aldehyde analogues have been prepared by lipase catalyzed desymmetrization or kinetic resolution of 1,3-propanediol derivatives as key steps. Observations of unusual enantioselectivity were made, and most notably, Candida antarctica lipase B showed an opposite enantiopreference from other lipases, which was exploited in the synthesis. A thorough evaluation of chemoenzymatic routes to both enantiomers of the target α-chiral 3-oxy-propionaldehydes resulted in simple, inexpensive, and efficient procedures that provide the products in up to 92% enantiomeric excess and 55% total yield in five steps from easily accessible starting materials.

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(R)-2-Hydroxymethyl-3-phenyl-propyl acetateC12H16O3Ee = 96% by HPLC (Chiralpak AD-H) or GC (CP-Chirasil-DEX CB) after derivatization[α]D20=+29 (c 0.9, CHCl3)Source of chirality: Burkholderia cepacia lipase catalyzed desymmetrization by acetylationAbsolute configuration: R

(S)-2-Benzyl-3-((tert-butyldimethylsilyl)oxy)-propyl acetateC18H30O3SiEe = 96% by HPLC (Chiralcel OD-H)[α]D20=+5.2 (c 1.2, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: S

(S)-2-Benzyl-3-((tert-butyldimethylsilyl)oxy)-propanolC16H28O2SiEe = 96% by HPLC (Chiralcel OD-H)[α]D20=-16 (c 1.1, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: S

(R)-2-Benzyl-3((tert-butyldimethylsilyl)oxy)-propanalC16H26O2SiEe = 92% by GC (CP-Chirasil-DEX CB)[α]D20=-54 (c 0.80, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: R

(R)-2-Hydroxymethyl-4-methylpentyl acetateC9H18O3Ee = 96% by GC (CP-Chirasil-DEX CB) after derivatization[α]D20=+17 (c 0.99, CHCl3)Source of chirality: Pseudomonas fluorescence lipase catalyzed desymmetrization by acetylationAbsolute configuration: R

(S)-4-Methyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-pentyl acetateC15H32O3SiEe = 96% by GC (CP-Chirasil-DEX CB)[α]D20=-0.5 (c 1.0, CHCl3)Source of chirality: Pseudomonas fluorescence lipaseAbsolute configuration: S

(S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentanolC13H30O2SiEe = 92% by GC (CP-Chirasil-DEX CB)[α]D20=-17 (c 0.76, CHCl3)Source of chirality: Pseudomonas fluorescence lipaseAbsolute configuration: S

(R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentanalC13H28O2SiEe = 92% by GC (CP-Chirasil-DEX CB)[α]D20=-22 (c 0.83, CHCl3)Source of chirality: Pseudomonas fluorescence lipaseAbsolute configuration: R

(S)-2-(Acetyloxymethyl)-4-methylpentanoic acidC9H16O4Ee not determined (⩽88%)[α]D20=+4.3 (c 1.0, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: S

(S)-2-(tert-Butoxycarbonylamino)-4-methylpentyl acetateC13H25NO4Ee not determined (⩽88%)[α]D20=-28 (c 1.0, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: S

(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanolC11H23NO3Ee not determined (⩽88%)[α]D20=-22 (c 0.95, CHCl3)Source of chirality: Burkholderia cepacia lipaseAbsolute configuration: S