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Biosynthesis

Selective cycloadditions

Nature Chemistry volume 15, pages 167–169 (2023)Cite this article

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2+2-cycloaddition reactions have long been considered key transformations in the biosynthesis of cyclobutane-containing natural products, but enzymes for these reactions have not yet been identified. Now, a 2+2 cyclase has been discovered, characterized and bioengineered to catalyse cycloadditions with different selectivity.

Cycloadditions are reactions where two or more unsaturated substrates (or parts of the same substrate) combine to form a ring system. They are considered the most powerful bond-forming reactions for the stereospecific construction of a wide range of carbocycles and heterocycles. Although these reactions have been proposed to be key transformations in the biosynthesis of many natural products, only a handful have been identified and characterized in the past decades, with the majority being 4+2 cyclases. The Diels–Alder (DA) reaction, which is formally a 4+2 cycloaddition and has been widely utilized in organic synthesis, is probably the most well-known and important cycloaddition reaction. The characterization of the first dedicated Diels–Alderase (DAase), SpnF (ref. 1) — involved in the biosynthesis of the commercial insecticide spinosyn A — opened the door for the discovery of other cyclases — for example, intramolecular and intermolecular DAases2, hetero-DAases3 and a 6+4 cyclase4 have now been identified in the biosynthesis of various natural products. No enzyme-catalysed 2+2 cycloadditions have been identified, although more than 300 cyclobutane natural products have been isolated5. Now, writing in Nature Chemistry, Wen Liu, Lifeng Pan, Kendall Houk and co-workers describe an enzymatic 2+2 cycloaddition reaction6.

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Fig. 1: Discovery of an enzymatic 2+2 cycloaddition.

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Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Chemistry and Biomedicine Inovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing, China

    Bo Zhang & Hui Ming Ge

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  1. Bo Zhang
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  2. Hui Ming Ge
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Correspondence to Hui Ming Ge.

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Zhang, B., Ge, H.M. Selective cycloadditions. Nat. Chem. 15, 167–169 (2023). https://doi.org/10.1038/s41557-022-01123-8

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