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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Spiro-ring formation is catalyzed by a multifunctional dioxygenase in austinol biosynthesis
Yudai Matsuda1, Takayoshi Awakawa, Toshiyuki Wakimoto
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
Abstract:
Austinol, a fungal meroterpenoid derived from 3,5-dimethylorsellinic acid, has a unique chemical structure with a remarkable spiro-lactone ring system. Despite the recent identification of its biosynthetic gene cluster and targeted gene-deletion experiments, the process for the conversion of protoaustinoid A (2), the first tetracyclic biosynthetic intermediate, to the spiro-lactone preaustinoid A3 (7) has remained enigmatic. Here we report the mechanistic details of the enzyme-catalyzed, stereospecific spiro-lactone ring-forming reaction, which is catalyzed by a non-heme iron-dependent dioxygenase, AusE, along with two flavin monooxygenases, the 5'-hydroxylase AusB and the Baeyer-Villiger monooxygenase AusC. Remarkably, AusE is a multifunctional dioxygenase that is responsible for the iterative oxidation steps, including the oxidative spiro-ring-forming reaction, to produce the austinol scaffold.
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