Synthesis Of Oxetanes Research Articles

Stereoselective Synthesis of Oxetanes Catalyzed by an Engineered Halohydrin Dehalogenase.

Although biocatalysis has garnered widespread attention in both industrial and academic realms, the enzymatic synthesis of chiral oxetanes remains an underdeveloped field. Halohydrin dehalogenases (HHDHs) are industrially relevant enzymes that have been engineered to accomplish the reversible transformation of epoxides. In our work, a biocatalytic platform was constructed for the stereoselective kinetic resolution of chiral oxetanes and formation of 1,3-disubstituted alcohols. HheC from Agrobacterium radiobacter AD1 was engineered to identify key variants capable of catalyzing the dehalogenation of γ-haloalcohols (via HheC M1-M3) and ring opening of oxetanes (via HheC M4-M5) to access both (R)- and (S)-configured products with high stereoselectivity and remarkable catalytic activity, yielding up to 49% with enantioselectivities exceeding 99% ee and E>200. The current strategy is broadly applicable as demonstrated by expansion of substrate scope to include up to 18 examples for dehalogenations and 16 examples for ring opening. Additionally, the functionalized products are versatile building blocks for pharmaceutical applications. To shed light on the molecular recognition mechanisms for the relevant variants, molecular dynamic (MD) simulations were performed. The current strategy expands the scope of HHDH-catalyzed chiral oxetane ring constructions, offering efficient access to both enantiomers of chiral oxetanes and 1,3-disubstituted alcohols.

Stereoselective Synthesis of Oxetanes Catalyzed by an Engineered Halohydrin Dehalogenase

Although biocatalysis has garnered widespread attention in both industrial and academic realms, the enzymatic synthesis of chiral oxetanes remains an underdeveloped field. Halohydrin dehalogenases (HHDHs) are industrially relevant enzymes that have been engineered to accomplish the reversible transformation of epoxides. In our work, a biocatalytic platform was constructed for the stereoselective kinetic resolution of chiral oxetanes and formation of 1,3‐disubstituted alcohols. HheC from Agrobacterium radiobacter AD1 was engineered to identify key variants capable of catalyzing the dehalogenation of γ‐haloalcohols (via HheC M1‐M3) and ring opening of oxetanes (via HheC M4‐M5) to access both (R)‐ and (S)‐configured products with high stereoselectivity and remarkable catalytic activity, yielding up to 49% with enantioselectivities exceeding 99% ee and E>200. The current strategy is broadly applicable as demonstrated by expansion of substrate scope to include up to 18 examples for dehalogenations and 16 examples for ring opening. Additionally, the functionalized products are versatile building blocks for pharmaceutical applications. To shed light on the molecular recognition mechanisms for the relevant variants, molecular dynamic (MD) simulations were performed. The current strategy expands the scope of HHDH‐catalyzed chiral oxetane ring constructions, offering efficient access to both enantiomers of chiral oxetanes and 1,3‐disubstituted alcohols.

Ketyl Radical Enabled Synthesis of Oxetanes

AbstractOxetanes, 4-membered oxygen-containing heterocycles, were identified to have pharmaceutical applications after the discovery of the chemotherapeutic drug taxol (Paclitaxel) and its analogues. Furthermore, oxetanes have been identified as bioisosteres for several common functional groups and are present in a number of natural products. However, oxetanes are one of the least common oxygen-containing heterocycles in active pharmaceutical ingredients on the market, which can be attributed, in part, due to challenges with their synthesis. Previous strategies rely on nucleophilic substitutions or [2+2]-cycloadditions, but are limited by the stepwise buildup of starting material and limitations in scope resulting from requirements for activated substrates. To address these limitations, we envisioned activating simple carbonyls to their corresponding α-oxy iodides to promote ketyl radical formation. These radicals can then undergo atom-transfer radical addition with alkenes followed by one-pot nucleophilic substitution to produce oxetanes. Herein, we present a proof-of-principle of this strategy in which fluoroalkyl carbonyls are successfully converted into the corresponding fluoroalkyl oxetanes.

Cobalt-Catalyzed Synthesis of Oxetanes and Azetidines

Key words pyridines - oxetanes - azetidines - cobalt catalysis - cycloisomerization

Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols.

Oxetanes and azetidines continue to draw significant interest in medicinal chemistry, as small, polar and non-planar motifs. Oxetanes also represent interesting surrogates for carbonyl-containing functional groups. Here we report a synthesis of 3,3-disubstituted oxetane- and azetidine-ethers, with comparisons made to the ester functional group. The tertiary benzylic alcohols of the 4-membered rings are selectively activated using Brønsted acid catalysis and reacted with simple alcohols to form the ethers and maintain the oxetane ring intact. This approach avoids the use of strong bases and halide alkylating agents and allows alcohol libraries to be leveraged. Oxetane ethers demonstrate excellent chemical stability across a range of conditions and an improved stability vis-à-vis analogous esters under basic and reducing conditions.

Photoinduced synthesis of functionalized oxetanes via diradical-mediated ring contraction

A photochemical ring contraction is reported for the synthesis of oxetanes from dihydrofurans and diazo compounds under catalyst-free conditions.

Synthesis of Oxetanes

Synthesis of Oxetanes

Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions.

Intermolecular [2+2] photocycloadditions represent a powerful method for the synthesis of highly strained, four-membered rings. Although this approach is commonly employed for the synthesis of oxetanes and cyclobutanes, the synthesis of azetidines via intermolecular aza Paternò-Büchi reactions remains highly underdeveloped. Here we report a visible-light-mediated intermolecular aza Paternò-Büchi reaction that utilizes the unique triplet state reactivity of oximes, specifically 2-isoxazoline-3-carboxylates. The reactivity of this class of oximes can be harnessed via the triplet energy transfer from a commercially available iridium photocatalyst and allows for [2+2] cycloaddition with a wide range of alkenes. This approach is characterized by its operational simplicity, mild conditions and broad scope, and allows for the synthesis of highly functionalized azetidines from readily available precursors. Importantly, the accessible azetidine products can be readily converted into free, unprotected azetidines, which represents a new approach to access these highly desirable synthetic targets.

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

Four-membered rings remain underexplored motifs despite offering attractive physicochemical properties for medicinal chemistry. Arylacetic acids bearing oxetanes, azetidines, and cyclobutanes are prepared in two steps: a catalytic Friedel-Crafts reaction from four-membered ring alcohol substrates, followed by mild oxidative cleavage. The suitability of the products as building blocks is reflected in their facile purification and amenability to derivatization. Examples include heteroaromatics and aryltriflates, as well as oxetane-derived profen drug analogues and a new endomorphin derivative containing an azetidine amino acid residue.

Visible-Light-Driven [2 + 2] Photocycloadditions between Benzophenone and C═C Bonds in Unsaturated Lipids.

The [2 + 2] photocycloaddition of alkenes and carbonyls is of fundamental interest and practical importance, as this process is extensively involved in oxetane-ring constructions. Although individual carbonyl group or alkene moiety has been utilized as photoactive species for oxetane formations upon ultraviolet photoexcitation, direct excitation of the entire noncovalent complex involving alkene and carbonyl substrates to achieve [2 + 2] photocycloadditions is rarely addressed. Herein, complexes with noncovalent interactions between benzophenone and C═C bonds in unsaturated lipids have been successfully characterized, and for the first time a [2 + 2] cycloaddition leading to the formation of oxetanes has been identified under visible-light irradiation. The mechanism of this reaction is distinctly different from the well-studied Paternò-Büchi reaction. The entire complexes characterized as dimeric proton-bonded alkene and carbonyl substrates can be excited under visible light, leading to electron transfer from the alkene moiety in fatty acyls to the carbonyl group within the complex. These results provide new insight into utilizing noncovalent complexes for the synthesis of oxetanes in which the excitation wavelength becomes independent of each individual substrate.

Machine assisted reaction optimization: A self-optimizing reactor system for continuous-flow photochemical reactions

A methodology for the synthesis of oxetanes from benzophenone and furan derivatives is presented. UV-light irradiation in batch and flow systems allowed the [2 + 2] cycloaddition reaction to proceed and a broad range of oxetanes could be synthesized in manual and automated fashion. The identification of high-yielding reaction parameters was achieved through a new self-optimizing photoreactor system.

ChemInform Abstract: Synthesis of Oxetane‐ and Azetidine‐Containing Spirocycles Related to the 2,5‐Diketopiperazine Framework.

AbstractSpirocyclic analogues of the diketopiperazine nucleus are prepared by a two‐step sequence consisting of conjugate addition of chiral α‐amino esters to nitroalkenes followed by nitro group reduction with spontaneous cyclization.

Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework

A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or <i>N</i>-Boc-azetidin-3-one, followed by nitro group reduction provides, after spontaneous cyclization, the spirocycles in good overall yields. These rigid scaffolds can be functionalized by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines.

Catalytic Asymmetric Synthesis of Oxetanes

Catalytic Asymmetric Synthesis of Oxetanes

Oxetane synthesis via cyclisation of aryl sulfonate esters on polystyrene and PEG polymeric supports

The addition of suitably protected pentaerythritols to polymer supported sulfonyl chloride with subsequent alkoxide formation and intramolecular cyclisation to generate oxetanes is described. This convenient method for the preparation of oxetanes has several advantages over analogous solution phase reactions and the methodology is extended to the preparation and use of a novel PEG-sulfonyl chloride.

ChemInform Abstract: The Stereoselective Synthesis of Oxetanes; Exploration of a New, Mitsunobu‐Style Procedure for the Cyclization of 1,3‐Diols.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The stereoselective synthesis of oxetanes; exploration of a new, Mitsunobu-style procedure for the cyclisation of 1,3-diols

A solution of 2-methyl-3-[1-(phenylsulfanyl)cyclohexyl]propane-1,3-diol 1 in toluene treated with triphenylphosphine, Ziram® 2 and DEAD, gave 3-methyl-2-[1-(phenylsulfanyl)cyclohexyl]oxetane 3 in 85% yield. A mechanistic study has been undertaken, optimal conditions have been found and the range of substrates for which the reaction is useful has been explored. We include the results of an X-ray study which shows that compound 33 (the oxidation product of diol 1) is a sulfone rather than a sulfoxide as previously reported.

Photochemical formation of oxetanes derived from aromatic ketones and substituted thiophenes and selenophenes

The photochemical formation of oxetanes from different heterocycles have been investigated for many years in this laboratory. Thus far, only correlation between quenching effect of the heterocycles and capability of forming oxetanes have been established but no attempts have been made to elucidate from these data the different mechanistic pathways that lead from starting materials to product in various cases. In the light of kinetic as well as ionization potential information an attempt is made in this review to establish the mechanisms involved in these reactions. By means of the studies of the Stern‐Volmer plots, the quenching constants of the reaction of Paternò‐Büchi between substituted thiophene and selenophene with aromatic ketones and their relationship with the potentials of ionization of these heterocycles we can infer in the efficient synthesis of oxetanes.

ChemInform Abstract: Synthesis of Oxetanes with Perfluorinated Alkyl Substituents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of oxetanes with perfluorinated-alkyl substituents

Perfluoroalkylated oxetanes have been obtained exclusively, in 36% yield, by reduction of perfluoroalkylated β-ketoester, followed by iodination and dehydroiodination.