Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

Abstract

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.

A Unique (3+2) Annulation Reaction between Meldrum's Acid and Nitrones: Mechanistic Insight by ESI‐IMS‐MS and DFT Studies

“…[1] Since the seminali nvestigations of Huisgen,[2] ag reat deal of research has been performed not only to extend the scope of these useful annulation processes but also to ascertain whether the exact mechanism of action is based on concerted or nonconcerted events. [4] This novel methodology highlighted 1) the practical use of Meldrum's acid derivatives 1 as a ketene equivalent or C2 synthon; [5] 2) af acile addition reaction of rather acidic Meldrum's acid derivatives 1 (pK a = 4.93 in water for R 1 = H) to nitrones 2 under organocatalytic Brønsted base (R 3 N) conditions despite the poor nucleophilic nature of anion intermediate 4 (step I); [6, 5c] and 3) ad omino reaction likely encompassing af ormal (3 + 2) annulation-fragmentation-decarboxylation-protonations equence towards the formation of product 3 (steps I-III). [4] This novel methodology highlighted 1) the practical use of Meldrum's acid derivatives 1 as a ketene equivalent or C2 synthon; [5] 2) af acile addition reaction of rather acidic Meldrum's acid derivatives 1 (pK a = 4.93 in water for R 1 = H) to nitrones 2 under organocatalytic Brønsted base (R 3 N) conditions despite the poor nucleophilic nature of anion intermediate 4 (step I); [6, 5c] and 3) ad omino reaction likely encompassing af ormal (3 + 2) annulation-fragmentation-decarboxylation-protonations equence towards the formation of product 3 (steps I-III).…”

Oxa–diketopiperazines: Access and Conformational Analysis of Potential Turn Inducers

“…It could be assumed that lower temperature coefficient values < 5 Dppb/DK were related to inaccessible protons to the solvent. [22,23] Temperature coefficient in CDCl 3 and titration experiments were unfortunately unachievable since the carbamate "NH" proton signal superimposed with aromatic protons signals. The calculated coefficient in DMSO-d 6 revealed a value of 4.10 and 3.72 Dppb/DK for 4 c and 4 g, respectively, indicating the inaccessibility of the carbamate proton engaged in H-bonding with an oxygen atom.…”

“…According to the notable success of heterocycles in our pharmacopeia, there is a recent enthusiasm to pursue the development of compounds containing both nitrogen and oxygen as adjacent atoms . In this sense, the biological potential of oxadiazine as antibacterial or pesticide, makes its skeleton relevant for organic chemists and drug designers.…”

“…According to the notable success of heterocycles in our pharmacopeia, there is a recent enthusiasm to pursue the development of compounds containing both nitrogen and oxygen as adjacent atoms. [1][2][3] In this sense, the biological potential of oxadiazine as antibacterial or pesticide [4,5] makes its skeleton relevant for organic chemists and drug designers. The conformational restriction implied by the insertion of such scaffold into peptides led us to freshly describe innovative peptidomimetics based on the 1,2,4-oxadiazine-3,6-diones moiety.…”

Oxazole and Isoxazole Chemistry in Crop Protection

“…The oxazoles and isoxazoles constitute a fascinating class of five‐membered heterocyclic compounds with one nitrogen and one oxygen ring atom, chemically related to the other azoles, such as imidazole, pyrazole, thiazole, and isothiazole. The process in preparative investigations on oxazoles , isoxazoles , oxazolines , isoxazolines , oxazolidines , isoxazolidines , oxazolones , isoxazolones , benzoxazoles , and benzisoxazoles has been summarized in exhaustive reviews. Also, the application of most of these heterocyclic scaffolds in medicinal chemistry has been reviewed recently, just to mention the broad pharmacological (e.g., anticancer, antimicrobial, antidiabetic, anti‐inflammatory, and anticonvulsant) activity of benzoxazoles or the specific significance of isoxazoles for neuropsychiatric therapeutics .…”