The Biosynthesis of the Benzoxazole in Nataxazole Proceeds via an Unstable Ester and has Synthetic Utility. Issue 15 (11th February 2020)

• Record Type: Journal Article
• Authors: Song, Haigang; Rao, Cong; Deng, Zixin; Yu, Yi; Naismith, James H.
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 15(2020)
• Page Start: 6054
• Page End: 6061
• Publication Date: 2020-02-11
• Subjects: benzoxazole -- enzyme catalysis -- heterocycles -- structural biology -- structure–activity relationships; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201915685
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Heterocycles, a class of molecules that includes oxazoles, constitute one of the most common building blocks in current pharmaceuticals and are common in medicinally important natural products. The antitumor natural product nataxazole is a model for a large class of benzoxazole‐containing molecules that are made by a pathway that is not characterized. We report structural, biochemical, and chemical evidence that benzoxazole biosynthesis proceeds through an ester generated by an ATP‐dependent adenylating enzyme. The ester rearranges via a tetrahedral hemiorthoamide to yield an amide, which is a shunt product and not, as previously thought, an intermediate in the pathway. A second zinc‐dependent enzyme catalyzes the formation of hemiorthoamide from the ester but, by shuttling protons, the enzyme eliminates water, a reverse hydrolysis reaction, to yield the benzoxazole and avoids the amide. These insights have allowed us to harness the pathway to synthesize a series of novel halogenated benzoxazoles. Abstract : Benzoxazole biosynthesis, a key step in the biosynthesis of the antitumor agent nataxazole, proceeds via a hemiorthoamide intermediate that arises from an unstable ester. NatL2 catalyzes the formation of this ester that spontaneously rearranges into an off‐pathway amide. In the presence of NatAM, the ester is converted to benzoxazole via a hemiorthoamide intermediate. These enzymes are used to synthesize a series of novel halogenated benzoxazoles.