Chemoenzymatic Total Synthesis of Natural Products

Abstract

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...

State-of-the-Art Biocatalysis

“… 7 In particular, the sustainability profile of enzymatic transformations has motivated their adoption. 17 In contrast to the organometallic catalysts developed using precious metals, which are being rapidly depleted from the Earth’s crust, 18 enzymatic catalysts can be produced without the worry of exhausting limited resources. These advantages poise biocatalysis for adoption into the mainstream synthetic repertoire.…”

Properties and Mechanisms of Flavin-Dependent Monooxygenases and Their Applications in Natural Product Synthesis

“…Then 1 underwent a second oxidation catalyzed by non heme iron monooxygenase 2-oxoglutarate-dependent dioxygenase (TropC). The researchers speculated that the mechanism of this process might be the rearrangement reaction containing one electron, followed by the rebound and elimination of oxygen, and finally the double electron rearrangement reaction and the elimination reaction participated by iron, leading to the net ring expansion and finally the formation of Stipitatic aldehyde 3 [ 71 ].…”

Two-Phase Biocatalysis in Microfluidic Droplets

“…The use of enzymes for chemical transformations often grants unparalleled chemo-, regio- and stereoselectivity, and even enables transformations that would be impossible to achieve with conventional chemical methods [ 1 , 2 , 3 , 4 ]. Owing to these advantages, recent years have witnessed a growing popularity of strategic enzymatic steps in the preparation of pharmaceuticals, natural products, and other fine chemicals [ 5 , 6 , 7 , 8 , 9 , 10 ]. By reducing the length of synthetic routes and the demand for laborious purification processes, biocatalytic transformations typically exhibit more favorable green chemistry metrics than their corresponding chemical counterparts [ 11 , 12 ].…”