Unexpected Isomerization of Oxetane-Carboxylic Acids

Chalyk, Bohdan A.; Grynyova, Anastasiia; Filimonova, Kateryna; Rudenko, Tymofii V.; Dibchak, Dmitry; Mykhailiuk, Pavel K.

doi:10.1021/acs.orglett.2c01402

Cited by 21 publications

(10 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Cbz group could be readily removed from 13a by hydrogenolysis to generate a free N–H azetidine ( 14 ; 76% yield). Ester hydrolysis from the functionalized oxetane products under basic conditions using LiOH gave carboxylic acid 15 in 99% yield . This is the formal bis-homologation product of oxetane 1 , which was further characterized by X-ray crystallography (see Supporting Figure S33).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. 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 and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

show abstract

“…A general rule of thumb is that 3,3-disubstituted examples are more stable than other substitution patterns, but stability is nevertheless not guaranteed and could become a metabolic and/or chemical liability in vivo . For example, 3,3-disubstituted oxetanes with an internal nucleophile (e.g., alcohol or amine functionality) more readily ring-open under acidic conditions. , (4) Related to point 3, the potential instability of oxetane rings under harsh reaction conditions might become an issue for multistep large scale synthesis. In general, oxetane moieties were introduced only during the final stages of drug development to remediate problematic physicochemical properties such as insufficient solubility or metabolic stability (see section ).…”

Section: Discussionmentioning

confidence: 99%

“…Oxetanes substituted with electron-donating groups at C2 are likely to be unstable. Internal nucleophiles can also lead to cyclization processes, which can be synthetically productive. , …”

Section: Introductionmentioning

confidence: 99%

Oxetanes in Drug Discovery Campaigns

Rojas,

Bull

2023

J. Med. Chem.

View full text Add to dashboard Cite

The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity, and marked three-dimensionality. Oxetanes have garnered further interest as isosteres of carbonyl groups and as molecular tools to fine-tune physicochemical properties of drug compounds such as pK a, LogD, aqueous solubility, and metabolic clearance. This perspective highlights recent applications of oxetane motifs in drug discovery campaigns (2017–2022), with emphasis on the effect of the oxetane on medicinally relevant properties and on the building blocks used to incorporate the oxetane ring. Based on this analysis, we provide an overview of the potential benefits of appending an oxetane to a drug compound, as well as potential pitfalls, challenges, and future directions.

show abstract

“…The reaction was compatible with other aliphatic ketones (6-10) and aldehydes (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Among them were the chemically labile 3-oxetanone ( 6), [10] compounds with the ether group (9, 24, 25), and N-Boc protected azetidines/piperidines (8, 26, 27).…”

Section: Scopementioning

confidence: 99%

2‐Oxabicyclo[2.1.1]hexanes: Synthesis, Properties, and Validation as Bioisosteres of ortho‐ and meta‐Benzenes

Levterov,

Panasiuk,

Shablykin

et al. 2024

Angewandte Chemie

Self Cite

View full text Add to dashboard Cite

We have developed a general and practical approach towards 2‑oxabicyclo[2.1.1]hexanes with two and three exit vectors via an iodocyclization reaction. The obtained compounds have been easily converted into the corresponding building blocks for use in medicinal chemistry. 2‑Oxabicyclo[2.1.1]hexanes have been incorporated into the structure of five drugs and three agrochemicals, and validated biologically as bioisosteres of ortho‐ and meta‐benzenes.

show abstract

Unexpected Isomerization of Oxetane-Carboxylic Acids

Cited by 21 publications

References 40 publications

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

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

Oxetanes in Drug Discovery Campaigns

2‐Oxabicyclo[2.1.1]hexanes: Synthesis, Properties, and Validation as Bioisosteres of ortho‐ and meta‐Benzenes

Contact Info

Product

Resources

About