Charting the Evolution of Chemoenzymatic Strategies in the Syntheses of Complex Natural Products

Abstract

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase in popularity and utility. This Perspective explores the integration of enzymes into multistep chemical syntheses, highlighting the unique potential of biocatalytic transformations to streamline the synthesis of complex natural products. In particular, we identify four primary conceptual approaches to chemoenzymatic synthesis and illustrate each with a number of landmark case studies. Future opportunities and challenges are also discussed.

Controllable skeletal reorganizations in natural product synthesis

“…Chemoenzymatic approaches that combine chemical transformations with enzymatic oxidation appear to be an attractive solution to this challenge, owing to the boom in research on enzyme engineering. 186–192 Moreover, integration of functionalization and rearrangement processes into a single transformation can result in synthetic routes that are much more concise and direct. The thriving field of transition-metal catalysis is sure to facilitate such integration because transition-metal catalysts can activate C–H and C–C bonds that are traditionally considered to be inert and can also mediate various C–C bond forming reactions.…”

Simplification of Corticosteroids Biosynthetic Pathway by Engineering P450BM3

“…7−9 Nevertheless, given the abundance of inert C− H bonds in steroids, achieving precise single or multiple oxidations of the steroid backbone without generating excess byproducts remains a formidable task in synthetic chemistry. 10,11 Thus, targeting the oxidation of steroid backbones to synthesize high-value steroidal pharmaceuticals in the process of producing hydroxyl-rich corticosteroids involves immense challenges such as numerous reaction steps, generation of substantial undesired byproducts, and elevated synthesis costs. 8,12 Cytochrome P450 enzymes (CYP450), a vast group of heme-binding proteins found across various organisms, play a crucial role in metabolizing a range of drugs and endogenous compounds owing to their ability to catalyze numerous oxidative transformations.…”

“…Steroids, composed of a complex cyclopentane-polyhydrophenanthrene structure, present anti-inflammatory and immunosuppressive effects and are used for treating various clinical diseases, including acute infections, inflammatory aftermath, autoimmune disorders of connective tissues, COVID-19, and acquired immunodeficiency syndrome (AIDS). , Introduction of the hydroxyl groups into the steroid backbone in a regioselective and stereoselective manner is an essential step for achieving ideal solubility as well as the physiological and pharmacological activity of steroids. − For instance, hydrocortisone, a typical corticosteroid with a progesterone (PG) skeleton and modified with three hydroxylations at C11β, C17α, and C21, possesses potent anti-inflammatory and immunosuppressive properties, making it an ideal choice for treating conditions such as allergies, dermatitis, and adrenal dysfunction. − Nevertheless, given the abundance of inert C–H bonds in steroids, achieving precise single or multiple oxidations of the steroid backbone without generating excess byproducts remains a formidable task in synthetic chemistry. , Thus, targeting the oxidation of steroid backbones to synthesize high-value steroidal pharmaceuticals in the process of producing hydroxyl-rich corticosteroids involves immense challenges such as numerous reaction steps, generation of substantial undesired byproducts, and elevated synthesis costs. , …”

Engineering Peroxygenase Activity into Cytochrome P450 Monooxygenases through Modification of the Oxygen Binding Region

“…When H 2 O 2 is used to support catalysis, costly nicotinamide cofactors (e.g., NAD­(P)­H) and additional electron transfer partner proteins are no longer required . However, the majority of CYPs are unable to use H 2 O 2 efficiently. , Peroxides can also destroy the heme or oxidize the heme-bound cysteine ligand, resulting in loss of activity. − If CYPs could be engineered to use H 2 O 2 more efficiently, it would enable them to be more widely used in synthetic procedures, which require C–H bond oxidations and complement existing chemical and biocatalytic methods and enable new highly selective reactions on a broader range of substrates. − …”