Asymmetric Synthesis of Strained Multichiral Spirocyclobutanes through Cage-Confined Cross [2 + 2] Photocycloaddition

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

Chiral spirocycles possess the ability to undergo diverse modifications in three-dimensional space, offering advantages terms of physicochemical property and structural variability over conventional organic scaffolds holding promising potential for design biologically active molecules drugs. Among them, highly strained spirocyclobutanes with multiple chiral center-containing four-membered rings have attracted significant attention, but their viable efficient synthesis poses a great challenge. By virtue cage-confined asymmetric photocatalysis, we successfully construct spirocycle bispirocycle compounds containing quaternary tertiary carbon centers cyclobutane through cross [2 + 2] photocycloaddition visible-light-induced mild reactions. The mechanistic studies unveil that open pockets cage photoreactor facilitate dynamic bimolecular recognition render preferential heteromolecular cross-cycloaddition enhanced reactivity, unconventional enantioselectivity, good substrate tolerance, providing direction enzyme-mimetic catalyst challenging photochemical transformations.

Язык: Английский

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Regio‐ and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical‐Catalyzed (4+2) Cycloaddition

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(38)

Опубликована: Июнь 26, 2024

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines highly desirable. This work presents a radical (4+2) cycloaddition reaction synthesis of featuring dense substituents at 3,4,5-positions that not readily accessible by known methods. Using commercially available diboron(4) compounds 4-phenylpyridine as the catalyst precursors, boronyl radical-catalyzed between 3-aroyl azetidines various alkenes, including previously unreactive 1,2-di-, tri-, tetrasubstituted has delivered generally high yield diastereoselectivity. The also features modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts operation. utilization products demonstrated selective transformations. A plausible mechanism, with ring-opening azetidine rate-limiting step, proposed based on experimental computational results.

Язык: Английский

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Alkyl Azetidines Via Batch and Flow Photochemistry

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 4, 2025

Alkyl azetidines have been prepared by photochemical modifications of azetidine-2-carboxylic acids in batch and flow. The reaction has realized milligram, gram, even multigram quantities. obtained are valuable building blocks for drug discovery.

Язык: Английский

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Strained spiro heterocycles as potential bioisosteres: an update on the synthesis of heteroatom-containing spiro[2.3]hexanes and spiro[3.3]heptanes

Chemical Communications, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Developments in the synthesis and application of strained spiro heterocycles are discussed, given their potential as non-classical rigid three-dimensional bioisosteres drug development.

Язык: Английский

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Exploring Simple Drug Scaffolds from the Generated Database Chemical Space Reveals a Chiral Bicyclic Azepane with Potent Neuropharmacology

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 24, 2025

To assess how much structural diversity remains unexploited in simple drug scaffolds, we investigated ring systems functionalized with amine handles. Starting from the database GDB-4c, enumerated 1139 possible amines and diamines up to two five-, six-, or seven-membered rings. From 680 cases not listed PubChem, synthesized several unprecedented cis- trans-fused azepanes tested targets predicted using polypharmacology browser PPB2. this screening campaign, an N-benzylated azepane emerged as a potent inhibitor of monoamine transporters some selectivity toward norepinephrine (NET, SLC6A2) dopamine transporter (DAT, SLC6A3) inhibition (IC50 < 100 nM) combination σ-1R ≈ 110 nM). The vitro profile, favorable pharmacokinetic properties, preliminary behavioral metabolomic effects mice suggest potential bicyclic target neuropsychiatric disorders. These experiments highlight but still unexplored scaffolds for discovery.

Язык: Английский

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Discovery Process Chemistry: An Innovation Hub at the Interface of Academia, the Pharmaceutical Industry, and Contract Research Organizations

Synthesis, Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Abstract Discovery Process Chemistry (DPC) is an emerging intersectoral space that characterized by the development of new chemical reactions or syntheses enable efficient elucidation structure-activity relationships (SARs) and structure-property (SPRs) as well a rapid transition to process development. Drug discovery are accelerated such efforts this has led chemists in academia industry alike place increasing importance on these aims. In Short Review, we explore recent advances DPC impact it can have SAR/SPR interrogation downstream drug efforts. 1 Introduction 2 Enabling Interrogation with Bioisosteres 3 Couplings Diversifiable Reaction Partners 4 Late-Stage Functionalization 5 Conclusion Outlook

Язык: Английский

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Access to Alkenyl Cyclobutanols by Ni‐Catalyzed Regio‐ and Enantio‐selective syn‐Hydrometalative 4‐exo‐trig Cyclization of Alkynones

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Окт. 12, 2024

Abstract Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn ‐hydrometalative 4‐ exo ‐ trig cyclization 1,4‐alkynones to synthesize alkenyl cyclobutanols with tetrasubstituted stereocenter. This strategy features broad substrate scope, delivering variety trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields high enantioselectivities (up 84 % yield 98.5 : 1.5 er). The utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental computational mechanistic studies indicate that the reaction initiated by an active Ni−H species, carbonyl‐directed hydrometalation as key regioselective control. catalytic method provides general solution hydrofunctionalization alkynes represents efficient pattern assembling highly strained enantioenriched bioisosteres.

Язык: Английский

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1‐Oxa‐2,6‐diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow‐Assisted Preparation and Derivatisation by Strain‐Release of Azabicyclo[1.1.0]butanes

Advanced Synthesis & Catalysis, Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non‐strained aliphatic rings is highly sought after improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug‐likeness, target selectivity clinical success. Towards this goal, 1‐oxa‐2,6‐diazaspiro[3.3]heptane (ODASE) reported a potential SSH‐bioisostere. We demonstrate through theoretical studies the heterocycle to act bioisostere piperazine. have developed its synthesis from azabicyclo[1.1.0]butyl intermediate robust mild flow technology‐assisted two‐step protocol. Its tolerance stability towards medicinally relevant N ‐functionalisation protocols are studied, well reduction C3‐aminoalkylazetidinol motif found in anti‐cancer cobimetinib.

Язык: Английский

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Synthesis of Dispiro-Orthoester via an Acetal Oxo-Carbenium Ion

Chemical Communications, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

The first dispiro orthoester

Язык: Английский

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4-Azaspiro[2.3]hexane, an Overlooked Piperidine Isostere: Multigram Synthesis and Physicochemical and Structural Evaluation

The Journal of Organic Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 26, 2024

An expedient approach to the synthesis of 4-azaspiro[2.3]hexane derivatives is described. The synthetic scheme consists Tebbe olefination N-Boc-protected 2-azetidinone (including first use deuterated Petasis reagent Cp2Ti(CD3)2 in building block preparation) and cyclopropanation resulting intermediate. developed protocols allowed for preparation target blocks on a multigram scale (up 52 g). To illustrate potential obtained isosteric replacements drug discovery, their physicochemical structural characterization was performed, i.e., basicity (pKa) lipophilicity (Log P) measurements, X-ray diffraction studies, exit vector plot (EVP) analysis.

Язык: Английский

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