Electrocatalytic Access to Azetidines via Intramolecular Allylic Hydroamination: Scrutinizing Key Oxidation Steps through Electrochemical Kinetic Analysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(28), P. 15360 - 15369

Published: July 10, 2023

Azetidines are prominent structural scaffolds in bioactive molecules, medicinal chemistry, and ligand design for transition metals. However, state-of-the-art methods cannot be applied to intramolecular hydroamination of allylic amine derivatives despite their underlying potential as one the most prevalent synthetic precursors azetidines. Herein, we report an electrocatalytic method sulfonamides access azetidines first time. The merger cobalt catalysis electricity enables regioselective generation key carbocationic intermediates, which could directly undergo C-N bond formation. mechanistic investigations including electrochemical kinetic analysis suggest that either catalyst regeneration by nucleophilic cyclization or second oxidation intermediate is involved rate-determining step (RDS) our protocol highlight ability electrochemistry providing ideal means mediate oxidation.

Language: Английский

---

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(22), P. 4553 - 4573

Published: Jan. 1, 2023

Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic pharmacological points of view, many researchers have focused efforts on development new methodologies for preparation transformation these interesting compounds. Over years, more ways obtain molecules bearing three-membered functional groups, which challenging due inherent reactivity, been described. Among them, several sustainable. In this review, we report recent advances biological chemical evolution derivatives, particular, variety described synthesis aziridines transformations leading formation such as 4-7 membered heterocycles pharmaceutical interest promising activities.

Language: Английский

---

Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(8), P. 5560 - 5592

Published: March 29, 2024

Cytochrome P450 BM3 monooxygenase is the topic of extensive research as many researchers have evolved this enzyme to generate a variety products. However, abundance information on increasingly diversified variants that catalyze broad array chemistry not in format enables easy extraction and interpretation. We present database categorizes by their catalyzed reactions includes details about substrates provide reaction context. This >1500 downloadable machine-readable instructions maximize ease gathering information. The allows rapid identification commonly reported substitutions, aiding who are unfamiliar with identifying starting points for engineering. For those actively engaged engineering BM3, database, along review, provides powerful user-friendly platform understand, predict, identify attributes variants, encouraging further enzyme.

Language: Английский

---

Rhodium‐Catalyzed One‐Carbon Ring Expansion of Aziridines with Vinyl‐N‐triftosylhydrazones for the Synthesis of 2‐Vinyl Azetidines

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(12)

Published: Jan. 29, 2024

Abstract Azetidines, being four‐membered N ‐heterocycles, possess significant potential in contemporary medicinal chemistry owing to their favorable pharmacokinetic properties. Regrettably, the incorporation of functionalized azetidines into pharmaceutical lead structures has been impeded by absence efficient synthetic methods for synthesis. In this study, a Rh‐catalyzed one‐carbon ring expansion aziridines with vinyl‐ ‐triftosylhydrazones is presented, which facilitates synthesis high value‐added 2‐alkenyl azetidine products. This research represents first example enabled vinyl carbenes. Additionally, one‐pot two‐step protocol, initiated from cinnamaldehyde, was successfully achieved, offering step‐economical and facile approach these compounds. The pivotal aspect successful transformation lies situ formation an alkenyl aziridinium ylide intermediate. Experimental investigations, coupled computational studies, suggest that diradical pathway involved reaction mechanism.

Language: Английский

---

Triftosylhydrazone in Single-Atom Skeletal Editing

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

ConspectusIn the past decade, single-atom skeletal editing, which involves precise insertion, deletion, or exchange of single atoms in core skeleton a molecule, has emerged as promising synthetic strategy for rapid construction diversification complex molecules without laborious de novo processes. Among them, carbene-initiated editing is particularly appealing due to ready availability and diverse reactivities carbene species. The initial endeavors modify heteroarenes through carbon-atom insertion could date back 1881, when Ciamician Denstedt described conversion pyrroles pyridines by trapping haloform-derived free carbene. Despite its potential value, general applicability this one-carbon seen limited progress poor yields harsh reaction conditions. Significant advances via were achieved only 3 years Levin, Ball, Xu, Song, Glorius, others. hallmark these approaches facile halocyclopropanation followed regioselective ring opening facilitated expulsion halide ion. Consequently, specially designed α-halocarbene precursors, such haloform derivatives, α-halodiazoacetates, chlorodiazirines, α-chlorodiazo oxime esters, can be employed achieve Ciamician–Denstedt-type editing. This not limits types functional groups installed on expansion products but also prevents their widespread adoption, especially late-stage contexts. enduring quest develop environmentally friendly versatile superior group compatibility, application diversifications investigation mechanistic insights into carbon reactions remain fundamental objective.In our over 5 years, we have developed o-trifluoromethylbenzenesulfonylhydrazones (named Triftosylhydrazones) operationally safe easily decomposable diazo surrogates explored various challenging catalytic transfer reactions. Recently, put great efforts expanding scope unlocking triftosylhydrazones precursors Since 2018, realized range acyclic 1,3-dicarbonyls with silver carbenes access 1,4-dicarbonyls, proceeding cyclopropanation/ring-opening process. Inspired results, recently demonstrated series transition-metal-catalyzed highly selective medicinally interesting like pyrroles, indoles, 1,2-diazoles carbenic insertion. We then strained three-membered nitrogen- oxygen-containing heterocycles single-carbon atoms. In Account, present an overview achievements heterocycles, organized based three situ-generated key intermediates, cyclopropane, N-ylide, O-ylide from focus scopes, features, applications. hope that Account will provide valuable contribute development new methodologies both chemistry fields.

Language: Английский

---

Catalyzing the future: recent advances in chemical synthesis using enzymes

Current Opinion in Chemical Biology, Journal Year: 2024, Volume and Issue: 83, P. 102536 - 102536

Published: Oct. 5, 2024

Language: Английский

---

Precision single-atom editing: new frontiers in nitrogen insertion and substitution for the generation of N-heterocycles

Organic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 11(14), P. 4041 - 4053

Published: Jan. 1, 2024

This paper primarily focuses on the editing of nitrogen atoms, encompassing insertion N, substitution C with and utilization 15 N in place 14 for construction N-heterocycles.

Language: Английский

---

Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 19, 2024

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than century research, Ciamician-Dennstedt (C-D) rearrangement limited to halocarbene precursors. Herein, we report general methodology reaction using α-halogen-free carbenes generated situ from N-triftosylhydrazones. This one-pot, two-step protocol enables various carbenes, including those previously unexplored C-D chemistry, indoles/pyrroles scaffolds access 3-functionalized quinolines/pyridines. Mechanistic studies reveal pathway involving intermediacy 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative form different carbon-atom products. Ciamician–Dennstedt authors

Language: Английский

---

Substituent-Controlled Regiodivergent Rearrangement of Gramine Ammonium Ylide

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

The complicated mechanism makes the regiodivergent rearrangement of ammonium ylide seem to be out reach. Herein, we reported a gramine well controlled by substituents. Density functional theory studies reveal that with more steric hindrance substituent 2-diazo-2-arylacetate goes through stepwise yield both kinetically and thermodynamically preferred [1,2]-rearrangement product. In contrast, less ethyl diazoacetate concerted generate [2,3]-rearrangement product, which is favored as result release ring strain in transition state. This study would open up avenues grasp ylide, will promote application skeletal editing synthesis complex natural products.

Language: Английский

---

MicroED Structure of a Protoglobin Reactive Carbene Intermediate

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(13), P. 7159 - 7165

Published: March 22, 2023

Microcrystal electron diffraction (MicroED) is an emerging technique that has shown great potential for describing new chemical and biological molecular structures. Several important structures of small molecules, natural products, peptides have been determined using ab initio methods. However, only a couple novel protein thus far derived by MicroED. Taking advantage recent technological advances, including higher acceleration voltage low-noise detector in counting mode, we the first structure Aeropyrum pernix protoglobin (ApePgb) variant MicroED AlphaFold2 model phasing. The revealed mutations introduced during directed evolution enhance carbene transfer activity reorienting α helix ApePgb into dynamic loop, making catalytic active site more readily accessible. After exposing tiny crystals to substrate, also trapped reactive iron-carbenoid intermediate involved this engineered ApePgb's new-to-nature activity, challenging from diazirine via putative metallo-carbene. bound discloses how enlarged pocket stabilizes heme iron and, presumably, transition state formation key intermediate. This work demonstrates improved technology advancement prediction now enable investigation was previously beyond reach.

Language: Английский

---