The Exploitation of Enzymatically‐Derived cis‐1,2‐Dihydrocatechols and Related Compounds in the Synthesis of Biologically Active Natural Products

Abstract

The title compounds of the general form 1 can be produced at large scale and in essentially enantiomerically pure form (when X≠H) through the whole cell biotransformation of the corresponding aromatic. The "dense" and varied functionality associated with these metabolites mean that they have become increasingly useful chirons for the total synthesis of a range of natural product types. This personal account details the outcomes of a nearly three-decade long campaign within our group to exploit these compounds in the synthesis of a diverse range of small molecule natural product targets. The work is subdivided according to the key transformation(s) employed in each synthesis. The development of newer chirons that "complement" the utility of the cis-1,2-dihydrocatechols are also described.

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

“…The absolute stereochemistry in 7 is incorporated via microbial dihydroxylation of phenethyl acetate 8 in the whole-cell fermentation with toluene dioxygenase, overexpressed in E. coli JM109(pDTG601A) [32]. The enzymatically derived arene cis -dihydrodiols such as 7 have found widespread use in enantioselective synthesis of natural products [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].…”

Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation

“…Ring-hydroxylating dioxygenase (DO)-catalyzed cis-dihydroxylation of similar substrates A can, however, produce more stable cis-dihydrodiols C. Despite their limited stability, cis-dihydrodiol metabolites have been widely used in the chemoenzymatic synthesis of natural products and other metabolites [4][5][6][7][8][9].…”

“…Many enantiopure cis-dihydrodiol metabolites from arene and heteroarene substrates are used in the synthesis of natural products [4][5][6][7][8][9], including arene oxides [44]. The potential use of thiophene cis-dihydrodiols in the future chemoenzymatic synthesis of thiophene epoxide metabolites produced during monooxygenase-catalyzed oxidations is explored herein.…”

A Chemoenzymatic Formal Synthesis of Epoxyquinols A and B

“…Enzymatically derived cis-dihydro diols have been increasingly utilized by organic chemists in syntheses of natural products, including a number of epoxyquinoids. 3,4,[26][27][28] Here we report the chemoenzymatic formal synthesis of epoxyquinols A (1) and B (2) through the preparation of the disilylated enone 4. 25 In this new asymmetric approach to the core of this family of epoxyquinols, chirality is derived from a biocatalytic ipso,ortho cis-dihydroxylation of benzoic acid.…”