Biocatalytic synthesis of lactones and lactams

Abstract

Cyclic esters and amides (lactones and lactams) are important active ingredients and polymer building blocks. In recent years, numerous biocatalytic methods for their preparation have been developed including enzymatic and chemoenzymatic Baeyer-Villiger oxidations, oxidative lactonisation of diols, and reductive lactonisation and lactamisation of ketoesters. The current state of the art of these methods is reviewed.

Keywords: Baeyer-Villiger oxidation; biocatalysis; lactams; lactones; oxidative Lactonisation.

Scheme 1

Baeyer–Villiger monooxygenase (BVMO)‐catalysed oxidative lactonisation of cyclic ketones.

Scheme 2

Chemoenzymatic Baeyer–Villiger oxidations exploiting the perhydrolase pathway of hydrolases.

Scheme 3

Oxidative lactonisation of diols using alcohol dehydrogenases (ADHs).

Scheme 4

Reduction or reductive amination of ketoacids for the synthesis of lactones or lactams.

Scheme 5

Simplified representation of the catalytic mechanism of BVMOs.

Scheme 6

Sequential, redox‐neutral cascade combining ADHs and BVMOs to transform cycloalkanols into lactones.

Scheme 7

Common product removal strategies to alleviate inhibitory effects on BVMOs. A: in situ extraction of the product into a hydrophobic organic phase or to a resin; B: hydrolysis or oligomerisation of the lactone product.

Scheme 8

Representation of the wide substrate scope of BVMOs.

Scheme 9

Use of complementary BVMOs (from natural or man‐made diversity) to produce either the ‘normal’ or the ‘abnormal’ lactone.

Scheme 10

Asymmetric (enantioseletive and regiospecific) oxygenation of rac‐(cis)‐bicyclo[3.2.0]hept‐2‐en‐6‐one by BVMOs.

Scheme 11

DKR of α‐substituted ketones at alkaline pH benefitting from the high enantioselectvity of the BVMO for one enantiomer and the fast racemisation of the starting material.26a,26b

Scheme 12

BVMO‐catalysed Baeyer–Villiger oxidations with in situ generated cycloketones. A: from cycloalkanes with cytochrome P450 monooxygenase (CYP450)‐catalysed hydroxylation followed by ADH‐catalysed oxidation or B: from allylic alcohols by ADH‐catalysed oxidation and ene reductase (ER)‐catalysed reduction. Both pre‐cascades as redox‐neutral.

Scheme 13

Application of the 2LPS approach in oxidative lactonisation reactions.

Scheme 14

A convergent, redox‐neutral cascade combining an ADH and a BVMO for the synthesis of ϵ‐caprolactone.49b,49c

Scheme 15

TEMPO‐catalysed oxidative lactonisation of 1,5‐diols with aerobic, laccase‐catalysed regeneration of TEMPO.50

Scheme 16

Chemoenzymatic cascade transforming levulinic acid into enantiomerically pure (S)‐γ‐valerolactone. CPCR2: Carbonyl reductase 2 from Candida parapsilosis.

Scheme 17

Reductive lactamisation of some γ‐ or δ‐ketoesters using stereocomplementary transaminases. Both enantiomers were obtained essentially enantiomerically pure.53