Celebrating 20 Years of SYNLETT - Special Account On the Merits of Biocatalysis and the Impact of Arene cis-Dihydrodiols on Enantioselective Synthesis

Abstract

This account is a tribute to Professor David Gibson in recognition of his discovery of enzymatic dihydroxylation of aromatic compounds four decades ago. Here are highlighted some of the milestones in microbiology, biochemistry, molecular biology, and synthetic organic chemistry connected with this unique reaction. Gibson’s discovery greatly contributed to advancing biocatalysis as a discipline with major impact on synthesis of optically pure compounds. Personal recollections of several chemists who have embraced this technology in their own work, along with the authors’ recollections of the early days of research involving the cis-dihydrodiols, are provided as Notes at the end of the article.

1 Introduction: History of Biocatalysis

2 The Discovery of Enzymatic Dihydroxylation

3 Processing of Arenes by Oxidoreductase Enzymes

4 Considerations of the Mechanism

5 Diversity of Metabolites

6 cis-Dihydrodiols as Synthetic Intermediates: Analysis of Reactivity and Symmetry Options

7 Historically Important Milestones in Applications to Synthesis

8 Outlook

9 Notes

Key words

biocatalysis - enzymatic dihydroxylation of aromatics - arene cis-dihydrodiols - enantioselective synthesis - enantiopure metabolites

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31

Aldrich catalog numbers for cis-dihydrodiols derived from various aromatic compounds: bromobenzene (48-949-2), chlorobenzene (48,950-6), biphenyl (48,963-8), and naphthalene (49,032-6).

48

Safety notice: There are some hazards in handling and storage, especially for the cis-dihydrodiol derived from β-bromobenzene. This particular compound cannot be stored in solid form free of solvent. On several occasions it exploded on vacuum drying and on one occasion a bottle with about 25 g of crystalline solid exploded and burned in a freezer at -78 ˚C. The aromatization of this material is highly exothermic and catalyzed by trace amounts of phenol; therefore, the isolation and handling of cis-dihydrodiols in amounts over 5-10 g must be attended to with caution. Ethyl acetate extracts must be washed with saturated carbonate solution to remove any trace amounts of the corresponding phenols, which may catalyze aromatization. In our own experience, we have encountered no problems with the cis-dihydrodiols derived from chloro- and bromobenzene; however, it is advisable to handle larger amounts in solution rather than in solid state.

53

For more detailed discussion of enantiodivergent design see references 47c, 47e, 83a, and 90.

85

‘Bibliometric Analysis for Papers on Topics Related to Pollution Prevention (P2)’ can be accessed at http://es.epa.gov/ncer/publications/bibliometrics/p2_bibliometric_032905.html, 2005.