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A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product. A second set of conditions were found to flip the selectivity of the C-H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C-H activation pathway.

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 starting 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 hydroxylate the tricyclic core common to paralytic shellfish toxins. The systemic toxicity of these compounds can be reduced by adding hydroxyl and sulfate groups, which improves their properties and potential as therapeutic agents. The enzymes SxtT, GxtA, SxtN, and SxtSUL, were used to carry out selective C–H hydroxylation and O-sulfation in saxitoxin and related structures. We conclude this account with a discussion of existing challenges in biocatalysis and ways we can currently address them.

BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C–H functionalization at C-5 was invented, enabling the efficient synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle in only six steps from commodity chemicals. The scope of the C–H activation was further investigated, and the generality of the transformation across a series of bicyclic aromatic heterocycles was explored.

Generation of reactive intermediates and interception of these fleeting species under physiological conditions is a common strategy employed by Nature to build molecular complexity. However, selective formation of these species under mild conditions using classical synthetic techniques is an outstanding challenge. Here, we demonstrate the utility of biocatalysis in generating o-quinone methide intermediates with precise chemoselectivity under mild, aqueous conditions. Specifically, α-ketoglutarate-dependent non-heme iron enzymes, CitB and ClaD, are employed to selectively modify benzylic C-H bonds of o-cresol substrates. In this transformation, biocatalytic hydroxylation of a benzylic C-H bond affords a benzylic alcohol product which, under the aqueous reaction conditions, is in equilibrium with the corresponding o-quinone methide. o-Quinone methide interception by a nucleophile or a dienophile allows for one-pot conversion of benzylic C-H bonds into C-C, C-N, C-O, and C-S bonds in chemoenzymatic cascades on preparative scale. The chemoselectivity and mild nature of this platform is showcased here by the selective modification of peptides and chemoenzymatic synthesis of the chroman natural product (-)-xyloketal D.

Generation of reactive intermediates and interception of these fleeting species in a cascade is a common strategy employed by Nature. However, formation of these species under mild conditions using traditional synthetic techniques can present a challenge. Here, we demonstrate the utility of biocatalysis in generating ortho-quinone methide intermediates under aqueous conditions and at reduced temperatures. Specifically, we applied an α-ketoglutarate-dependent non-heme iron enzyme, CitB, in the selective modification of benzylic C–H bonds of ortho-cresol substrates to afford a benzylic alcohol product which, under the reaction conditions, is in equilibrium with the corresponding ortho-quinone methide. Interception of the ortho-quinone methide by a nucleophile or a dienophile allows for one-pot conversion of benzylic C–H bonds into C–C, C–N, C–O, and C–S bonds in a chemoenzymatic cascade.

A new Au(I)-catalyzed method for the preparation of trisubstituted indolizines from easily accessible 2-propargyloxy-pyridines is reported. The reaction tolerates a wide range of functionality, allowing for diversity to be introduced in four distinct regions of the product (R, R

N-Alkyl 2-pyridones and other enolizable heterocycles are important synthetic constructs, due to their prevalence in natural products and pharmaceutical targets and their capacity to serve as models for a number of biological and chemical processes. The disclosed Au(I)-catalyzed reaction utilizes 2-propargyloxypyridines to access N-alkylated 2-pyridone products derived from both 5-exo and 6-endo addition of the nitrogen to the pendent alkyne. Experimental and computational studies suggest that the desired 5-exo N-alkenyl 2-pyridonyl ethers are formed reversibly in the transformation. After extensive optimization, biaryl Au(I) catalyst 21 was found to overcome the inherent preference for the 6-endo pathway and provide the highest combination of 5-exo selectivity and yield. Herein, we report the application of this new Au(I)-catalyzed C-N bond formation to the preparation of a variety of N-alkenyl 2-pyridonyl ether analogues, which have the potential to serve as an entry point for the synthesis of complex N-alkyl 2-pyridone-containing frameworks.