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 prototypical single-molecule magnet (SMM) molecule [Mn12O12(O2CCH3)16(OH2)4] was incorporated under mild conditions into a highly porous metal-organic framework (MOF) matrix as a proof of principle for controlled nanostructuring of SMMs. Four independent experiments revealed that the SMM clusters were successfully loaded in the MOF pores, namely synchrotron-based powder diffraction, physisorption analysis, and in-depth magnetic and thermal analyses. The results provide incontrovertible evidence that the magnetic composite, SMM@MOF, combines key SMM properties with the functional properties of MOFs. Most importantly, the incorporated SMMs exhibit a significantly enhanced thermal stability with SMM loading advantageously occurring at the periphery of the bulk MOF crystals with only a single SMM molecule isolated in the transverse direction of the pores.

The use of enzyme-mediated reactions has transcended ancient food production to the laboratory synthesis of complex molecules. This evolution has been accelerated by developments in sequencing and DNA synthesis technology, bioinformatic and protein engineering tools, and the increasingly interdisciplinary nature of scientific research. Biocatalysis has become an indispensable tool applied in academic and industrial spheres, enabling synthetic strategies that leverage the exquisite selectivity of enzymes to access target molecules. In this Outlook, we outline the technological advances that have led to the field’s current state. Integration of biocatalysis into mainstream synthetic chemistry hinges on increased access to well-characterized enzymes and the permeation of biocatalysis into retrosynthetic logic. Ultimately, we anticipate that biocatalysis is poised to enable the synthesis of increasingly complex molecules at new levels of efficiency and throughput.

Metrics & MoreArticle Recommendations CONSPECTUS: The total synthesis of structurally complex natural products has challenged and inspired generations of chemists and remains an exciting area of active research. Despite their history as privileged bioactivity-rich scaffolds, the use of natural products in drug discovery has waned. This shift is driven by their relatively low abundance hindering isolation from natural sources and the challenges presented by their synthesis. Recent developments in biocatalysis have resulted in the application of enzymes for the construction of complex molecules. From the inception of the Narayan lab in 2015, we have focused on harnessing the exquisite selectivity of enzymes alongside contemporary small molecule-based approaches to enable concise chemoenzymatic routes to natural products.We have focused on enzymes from various families that perform selective oxidation reactions. For example, we have targeted xyloketal natural products through a strategy that relies on a chemo-and site-selective biocatalytic hydroxylation. Members of the xyloketal family are characterized by polycyclic ketal cores and demonstrate potent neurological activity. We envisioned assembling a representative xyloketal natural product (xyloketal D) involving a biocatalytically generated ortho-quinone methide intermediate.The non-heme iron (NHI) dependent monooxygenase ClaD was used to perform the benzylic hydroxylation of a resorcinol precursor, the product of which can undergo spontaneous loss of water to form an ortho-quinone methide under mild conditions. This intermediate was trapped using a chiral dienophile to complete the total synthesis of xyloketal D.A second class of biocatalytic oxidation that we have employed in synthesis is the hydroxylative dearomatization of resorcinol compounds using flavin-dependent monooxygenases (FDMOs). We anticipated that the catalyst-controlled site-and stereoselectivity of FDMOs would enable the total synthesis of azaphilone natural products. Azaphilones are bioactive compounds characterized by a pyranoquinone bicyclic core and a fully substituted chiral carbon atom. We leveraged the stereodivergent reactivity of FDMOs AzaH and AfoD to achieve the enantioselective synthesis of trichoflectin enantiomers, deflectin 1a, and lunatoic acid. We also leveraged FDMOs to construct tropolone and sorbicillinoid natural products. Tropolones are a structurally diverse class of bioactive molecules characterized by an aromatic cycloheptatriene core bearing an α-hydroxyketone moiety. We developed a two-step biocatalytic cascade to the tropolone natural product stipitatic aldehyde using the FDMO TropB and a NHI monooxygenase TropC. The FDMO SorbC obtained from the sorbicillin biosynthetic pathway was used in the concise total synthesis of a urea sorbicillinoid natural product.Our long-standing interest in using enzymes to carry out C−H hydroxylation reactions has also been channeled for the late-stage diversification of complex scaffolds. For example, we have used Rieske oxygenases to h...