A5086426097- Synthesis and Catalytic Reactions
- Asymmetric Hydrogenation and Catalysis
- Cyclopropane Reaction Mechanisms
- Catalytic C–H Functionalization Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pharmacogenetics and Drug Metabolism
- Metal-Catalyzed Oxygenation Mechanisms
- Catalysis for Biomass Conversion
- Catalytic Alkyne Reactions
- Amino Acid Enzymes and Metabolism
- Chemical Reactions and Isotopes
- Organoboron and organosilicon chemistry
- CO2 Reduction Techniques and Catalysts
- Radical Photochemical Reactions
- Catalytic Cross-Coupling Reactions
- Enzyme Catalysis and Immobilization
California Institute of Technology
2020-2024
Moderna Therapeutics (United States)
2024
Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes reported for their synthesis, methods that directly install free amine group into C(sp3)–H bonds remain unprecedented. Here, we report set new-to-nature enzymes catalyze the direct amination with excellent chemo-, regio-, enantioselectivity, using readily available hydroxylamine derivative as nitrogen source. Directed evolution genetically encoded cytochrome...
Selective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation bonds is well established, the analogous nitrogen still unknown; nature reliant on preoxidized compounds for incorporation. Likewise, synthetic methods selective derivatization unbiased remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points directed evolution enzymes...
Hydroxylamine-derived reagents have enabled versatile nitrene transfer reactions for introducing nitrogen-containing functionalities in small-molecule catalysis, as well biocatalysis. These reagents, however, result a poor atom economy and stoichiometric organic waste. Activating hydroxylamine (NH
Abstract Directed evolution of heme proteins has opened access to new‐to‐nature enzymatic activity that can be harnessed tackle synthetic challenges. Among these, reactions resulting from active site iron‐nitrenoid intermediates present a powerful strategy forge C−N bonds with high site‐ and stereoselectivity. Here we report biocatalytic, intermolecular benzylic C−H amidation reaction operating at mild scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic...
In nature and synthetic chemistry, stereoselective [2 + 1] cyclopropanation is the most prevalent strategy for synthesis of chiral cyclopropanes, a class key pharmacophores in pharmaceuticals bioactive natural products. One extensively studied reactions organic chemist's arsenal, cyclopropanation, largely relies on use stereodefined olefins, which can require elaborate laboratory or tedious separation to ensure high stereoselectivity. Here, we report engineered hemoproteins derived from...
Boronic acids and esters are highly regarded for their safety, unique reactivity, versatility in synthesizing a wide range of small molecules, bioconjugates, materials. They not exploited biocatalytic synthesis, however, because enzymes that can make, break, or modify carbon–boron bonds rare. We wish to combine the advantages boronic molecular assembly with biocatalysis, which offers potential unsurpassed selectivity efficiency. Here, we introduce an engineered protoglobin nitrene...
Nature harnesses exquisite enzymatic cascades to construct N-heterocycles and further uses these building blocks assemble the molecules of life. Here we report an platform important chiral N-heterocyclic products, pyrrolidines indolines, via abiological intramolecular C(sp3)–H amination organic azides. Directed evolution cytochrome P411 (a P450 enzyme with serine as heme-ligating residue) yielded variant P411-PYS-5149, capable catalyzing insertion alkyl nitrene into bonds build pyrrolidine...
Engineered hemoproteins can selectively incorporate nitrogen from nitrene precursors like hydroxylamine,
α-Amino esters are precursors to noncanonical amino acids used in developing small-molecule therapeutics, biologics, and tools chemical biology. α-C-H amination of abundant inexpensive carboxylic acid through nitrene transfer presents a direct approach α-amino esters. Methods for nitrene-mediated the protic bonds esters, however, underdeveloped. This gap arises because hydrogen atom abstraction (HAA) C-H by electrophilic metal-nitrenoids is slow: preferentially react with polarity-matched,...
Selective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation bonds is well established, the analogous nitrogen still unknown; nature reliant on pre-oxidized compounds for incorporation. Likewise, synthetic methods selective derivatization unbiased remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points directed evolution enzymes...
Intermolecular functionalization of tertiary C–H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance directing groups, state-of-the-art catalysts struggle introduce chirality racemic sp3-carbon centers. Direct asymmetric such is worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from bacterial cytochrome P450, that capable aminating...
Abstract Directed evolution of heme proteins has opened access to new‐to‐nature enzymatic activity that can be harnessed tackle synthetic challenges. Among these, reactions resulting from active site iron‐nitrenoid intermediates present a powerful strategy forge C−N bonds with high site‐ and stereoselectivity. Here we report biocatalytic, intermolecular benzylic C−H amidation reaction operating at mild scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic...
Abstract In nature and synthetic chemistry, stereoselective [2+1] cyclopropanation is the most prevalent strategy for synthesis of chiral cyclopropanes, a class key pharmacophores in pharmaceuticals bioactive natural products. One extensively studied reactions organic chemist’s arsenal, cyclopropanation, largely relies on use stereodefined olefins, which require elaborate laboratory or tedious separation to ensure high stereoselectivity. Here we report engineered hemoproteins derived from...