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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...

The discovery of the (+)-α-thujone and (-)-β-thujone stereoisomers in the essential oil of sage (Salvia officinalis L.) and dietary supplements is documented for the first time. The detection was accomplished using a chiral resolution protocol of racemic α-/β-thujone on headspace solid-phase microextraction-gas chromatography-mass spectrometry. Because the previously unreported stereoisomers, (+)-α-thujone and (-)-β-thujone, are not commercially available, a three-step synthesis of racemic thujone from commercially available starting materials was developed. Thermolysis studies demonstrated that no racemization at the cyclopropane stereocenters occurs, corroborating that the detection is not an artifact from the hydrodistillation process. The developed chiral resolution of thujone was also used to provide evidence for the absence of the (+)-α-thujone and (-)-β-thujone enantiomers in other common thujone-containing essential oils.

Biocatalysis offers compelling advantages in synthesis, often becoming the method of choice based on sustainability, safety, and selectivity considerations. Despite these advantages, enzymes in synthesis are typically dedicated to functional group intercon versions in linear synthetic sequences and have not been broadly integrated into the retrosynthetic logic for carbon skeleton assembly. In this article, we disclose a biocatalytic platform for fragment coupling to assemble target molecules convergently. Specifically, we report a strategy for biocatalytic phenolic cross-coupling through oxidative C-C bond formation. Using cytochrome P450 enzymes, we demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates and further demonstrate the ability to tune these catalysts to possess the desired reactivity, site-, and atroposelectivity. This streamlined method for constructing sterically-hindered biaryl bonds provides an engineerable platform for assembling molecules with programmable catalyst-controlled reactivity and selectivity unprecedented with small molecule catalysts.Convergent synthetic strategies enable the efficient construction of carbon frameworks, quickly generating complexity by stitching individual building blocks together. 1 Chemists depend on transformations, such as cross-coupling reactions, that can reliably be programmed into synthetic routes for convergent approaches. 2 Ideally, reactions planned for the assembly phase of a convergent synthesis are both perfectly selective and tolerate a breadth of functional groups to minimize the production of undesired products, installation of protecting groups, or unnecessary redox manipulations. 3 These qualities are common in biocatalytic reactions due to the catalyst-controlled selectivity possible with large molecule catalysts; 4 however, the enzymatic transformations most commonly applied in synthesis are confined to functional group interconversions, not convergent steps within a synthetic route. [5][6][7][8][9][10][11] To enable convergent biocatalytic strategies, a handful of biocatalytic methods have recently been developed, [12][13][14][15] foreshadowing the potential of convergent biocatalysis in synthesis. Based on the paucity of enzyme-mediated methods for uniting substantial fragments, we developed an intense interest in expanding the repertoire of biocatalysts capable of convergent fragment couplings. As a first step toward this goal, we sought to develop a platform for the biocatalytic assembly of carbon frameworks through oxidative cross-coupling reactions, thus providing a solution for this transformation's outstanding reactivity and selectivity challenges through biocatalysis and enabling convergent synthetic routes (Figure 1a).We chose to target biaryl bond formation as a model transformation for convergent cross-coupling reactions, given the ubiquitous nature of biaryl scaffolds in drugs, materials, and ligands for asymmetric catalysis (Figure 1b) and the fundamental synthetic challenges presented by the...

a b s t r a c tThe catalyst-free, regioselective synthesis of 4 0 -O-substituted pyridoxine derivatives under solventless conditions is described. The methodology relies on the highly regioselective formation of the orthopyridinone methide from pyridoxine and subsequent oxa-Michael addition of alcohol nucleophiles. This methodology provides good to excellent yields for primary and secondary alcohols and moderate yields for tertiary alcohols.