Short Synthesis of Oxetane and Azetidine 3-Aryl-3-carboxylic Acid Derivatives by Selective Furan Oxidative Cleavage

Dubois, Maryne A. J.; Smith, Milo A.; White, Andrew J. P.; Jie, Alvin Lee Wei; Mousseau, James J.; Choi, Chulho; Bull, James A.

doi:10.1021/acs.orglett.0c01214

Cited by 32 publications

(21 citation statements)

References 29 publications

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“…The furan ring of cycloadduct 3o is oxidatively cleaved in 78% yield under mild conditions using a recent Ru-catalyzed protocol from Bull and co-workers (Scheme 5D). 47 This affords a versatile diacylated 2-oxaspiro [3.3]heptane building block (5d) with two orthogonal functional handlesa free carboxylic acid and a benzyl esterfor subsequent incorporation into drug candidates.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes

et al. 2021

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This paper describes an intermolecular crossselective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electrondeficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn-or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes

et al. 2021

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“…26,27 Initial investigations with acid 1 were based on a report by MacMillan in 201428 which generated C(sp 3 ) radicals under decarboxylative photoredox conditions and trapped these with electron deficient alkenes.29 Electron-rich oxetane acid 1 was used as model substrate and ethyl acrylate as radical acceptor. Notably,…”

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confidence: 99%

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

Dubois

Rojas

Sterling

et al. 2022

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4-Membered ring heterocycles oxetanes and azetidines offer exciting potential as small polar molecular motifs in medicinal chemistry but require further methods for their incorporation. Photoredox catalysis has emerged as a powerful method for the mild generation of alkyl radicals for C–C bond-forming reactions. However, the reactivity of radicals on strained rings is not well understood and there are few studies that address this question systematically. Furthermore, examples that use tertiary and benzylic radicals are rare, and their reactivity is challenging to harness and direct towards productive reaction pathways. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain on the reactivity of medicinally important small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precur- sors for the formation of tertiary benzylic oxetane/azetidine radicals with loss of CO2 and subsequent conjugate addition into activated alkenes. The process is shown to be tolerant of polar functional groups and heterocycles to generate medicinally relevant compounds bearing oxetane or azetidine motifs. We compare the reactivity of the oxetane radicals with that of other common benzylic systems. Computational studies indicate the Giese addition of benzylic radicals into acrylates to be generally reversible, resulting in lower yields and radical dimerization. However, the oxetane structure provides an overall exergonic process for the Giese addition step of the benzylic radical. Furthermore, strained ring structures benefit from lower spin density at the benzylic position, which is crucial to minimize radical dimerization. The lower spin density results from more extensive radical delocalization into the aromatic system which is rationalized on the basis of hybridization. The effect of radical acceptor on the distribution of products is investigated and a mechanism for the formation of side products of reduction is proposed based on experimental and computational evidence.

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“…Recently, the groups of Schreiber and Baran have showcased the use of directing groups at position 2 of stereodefined derivatives to promote a cis -selective functionalization at position 3 through C–H activation strategies (Scheme B) . In addition, efforts have recently been made toward the synthesis of 3-azetidinylcarboxylic acids …”

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confidence: 99%

Stereoselective Access to Azetidine-Based α-Amino Acids and Applications to Small Peptide Synthesis

et al. 2020

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Short Synthesis of Oxetane and Azetidine 3-Aryl-3-carboxylic Acid Derivatives by Selective Furan Oxidative Cleavage

Cited by 32 publications

References 29 publications

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

Stereoselective Access to Azetidine-Based α-Amino Acids and Applications to Small Peptide Synthesis

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