Combination of Novozym 435–Catalyzed Hydrolysis and Mitsunobu Reaction for Production of (R)-γ-Lactones

Abstract

Chiral γ-lactones of both enantiomers were synthesized with more than 90% optical purities. The key step was Novozym 435–catalyzed hydrolysis of racemic N-benzyl-4-acetoxyalkylamides. Additionally, because (R)-γ-lactones are predominant in apricot, mango, peach, passion fruit, and strawberry, synthesis was attempted using only one enantiomer selectively. The (R)-enantimer was synthesized with more than 80% total yield and more than 90% optical purity by a combination of Novozym 435–catalyzed hydrolysis and the Mitsunobu reaction.

Keywords:

• Enzymatic resolution
• Mitsunobu reaction
• optical purity
• (R)-γ-lactone

ACKNOWLEDGMENTS

We are grateful to Novozymes A/S for the generous gift of Novozym 435. Financial support from Meiji University (Grant-in-Aid for Young Scientists of Meiji University) is gratefully acknowledged.

Notes

^a Substrate: 1.0 mmol, MeOH: 3.0 mmol, Novozym 435: 0.4 g, Pr₂O: 20 ml, 60 °C.

^b Determined by GC using Chirasil-Dex CB column.

^c E =ln[1 − c (1 + ee_p)]/ln[1 − c (1 − ee_p)], where c = ee_s/(ee_s + ee_p), ee_s = enantiomeric excess of (R)-1, ee_p = enantiomeric excess of (S)-1.

^a Substrate: 1.0 mmol, MeOH: 3.0 mmol, Novozym 435: 0.4 g, ⁱ Pr₂O: 20 ml, 60 °C.

^b Nucleophile: 1.0 mmol, PPh₃: 1.0 mmol, DIAD: 1.0 mmol, solvent: 5 ml, rt.

^c Total yield based on rac-2.

^d Determined by GC using Chirasil-Dex CB column.