Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products

Abstract

Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with anticipated site- and stereoselectivity, this predictability does not extend to enzymes. Further, the lack of access to catalysts that provide complementary selectivity creates a challenge in the application of biocatalysis in synthesis. Here, we report an approach for accessing biocatalysts with complementary selectivity that is orthogonal to protein engineering. Through the use of a sequence similarity network (SSN), a number of sequences were selected, and the corresponding biocatalysts were evaluated for reactivity and selectivity. With a number of biocatalysts identified that operate with complementary site- and stereoselectivity, these catalysts were employed in the stereodivergent, chemoenzymatic synthesis of azaphilone natural products. Specifically, the first syntheses of trichoflectin, deflectin-1a, and lunatoic acid A were achieved. In addition, chemoenzymatic syntheses of these azaphilones supplied enantioenriched material for reassignment of the absolute configuration of trichoflectin and deflectin-1a based on optical rotation, CD spectra, and X-ray crystallography.

The Hitchhiker's guide to biocatalysis: recent advances in the use of enzymes in organic synthesis

“…[197][198][199] Chemoenzymatic approaches have also proved useful in the synthesis of natural products. [200][201][202][203] A recent important publication by Lipshutz and coworkers has shown that the formation of micelles in the reaction medium can facilitate the combination of chemo-and bio-catalysis in a single reactor as the substrates, products and catalysts partition into the different compartments. 204 For an extensive review of the recent literature on biocatalytic cascade reactions see Kroutil and coworkers.…”

Recent advances in the chemistry and biology of azaphilones

“…General synthetic protocol for azaphilones scaffolds had been concluded in 2013. 3 Recently, several synthetic strategies of signicance have been developed for these novel diversied azaphilones, which mainly focused on stereoselectivity, 29 complementary biocatalysts, 93 and the formation of angular lactone and chiral azaphilone dimers. 94 In general, cazisochromene and dioxinone have been employed as important intermediates and precursors, whilst AzaH and AfoD have been applied in synthesis as common biocatalysts.…”

“…94 In general, cazisochromene and dioxinone have been employed as important intermediates and precursors, whilst AzaH and AfoD have been applied in synthesis as common biocatalysts. 93,95 The recently reported chemical synthetic study of azaphilones were summarized herein.…”

“…Total synthesis of trichoectin (262), (S)-deectin-1a (263), and lunatoic acid A (264) were accomplished using complementary biocatalysts. 93 The synthesis of trichoectin (262) was initiated through a ve-step route to enone 265. Dearomatization of 265 afforded azaphilone scaffold (R)-266 in high yield.…”

Frontiers in Biocatalysis: Profiling Function across Sequence Space

“…In other studies, SSNs have proven useful for profiling other classes of FAD-dependent enzymes to identify biocatalysts appropriate for target-oriented synthesis. 10…”