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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 this study, 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 the substrate scope to include up to 18 examples for dehalogenation 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 construction, offering efficient access to both enantiomers of chiral oxetanes and 1,3‐disubstituted alcohols. [ABSTRACT FROM AUTHOR]

Oxetane synthase (TmCYP1), a novel cytochrome P450 enzyme from Taxus×media cell cultures, has been functionally characterized to efficiently catalyse the formation of the oxetane ring in tetracyclic taxoids. Transient expression of TmCYP1 in Nicotiana benthamiana using 2α,5α,7β,9α,10β,13α‐hexaacetoxytaxa‐4(20),11(12)‐diene (1) as a substrate led to the production of a major oxetane derivative, 1β‐dehydroxybaccatin IV (1 a), and a minor 4β,20‐epoxide derivative, baccatin I (1 b). However, feeding the substrate decinnamoyltaxinine J (2), a 5‐deacetylated derivative of 1, yielded only 5α‐deacetylbaccatin I (2 b), a 4β,20‐epoxide. A possible reaction mechanism was proposed on the basis of substrate‐feeding, 2H and 18O isotope labelling experiments, and density functional theory calculations. This reaction could be an intramolecular oxidation‐acetoxyl rearrangement and the construction of the oxetane ring may occur through a concerted process; however, the 4β,20‐epoxide might be a shunt product. In this process, the C5‐O‐acetyl group in substrate is crucial for the oxetane ring formation but not for the 4(20)‐epoxy ring formation by TmCYP1. These findings provide a better understanding of the enzymatic formation of the oxetane ring in paclitaxel biosynthesis. [ABSTRACT FROM AUTHOR]

The (R,R)-Teth-TsDPEN-Ru(II) complex promoted the one-pot double C=O reduction of α-alkyl-β-ketoaldehydes through asymmetric transfer hydrogenation/dynamic kinetic resolution (ATH-DKR) under mild conditions. In this process, ten anti-2-benzyl-1-phenylpropane-1,3-diols (85:15 to 92:8 dr) were obtained in good yields (41–87%) and excellent enantioselectivities (>99% ee for all compounds). Notably, the preferential reduction of the aldehyde moiety led to the in situ formation of 2-benzyl-3-hydroxy-1-phenylpropan-1-one intermediates. These intermediates played a crucial role in enhancing both reactivity and stereoselectivity through hydrogen bonding. [ABSTRACT FROM AUTHOR]

We describe a catalyst, oxidant, and coupling‐reagent free strategy to access 4‐membered heterocycles, representing a unique example of visible‐light triggered intramolecular cyclization of propargylic alcohols and amines to access oxetanones and azetidinones respectively. Despite the direct 4‐endo‐dig cyclization from these starting materials has proven to be unfavorable, the formation of key p‐quinone methide intermediacy allows an efficient bypass for regioselective 4‐exo‐trig cyclization, resulting in the formation of the desired 4‐membered heterocycles. This mild and operationally simple protocol facilitates the synthesis of products with distinct substitution patterns such as quaternary α‐carbons, and enables late‐stage functionalization. [ABSTRACT FROM AUTHOR]

Reported herein is a Paternò–Büchi reaction of aromatic double bonds with quinones under visible light irradiation. The reactions of aromatics with quinones exposed to blue LED irradiation yielded oxetanes at −78 °C, which was attributed to both the activation of double bonds in aromatics and the stabilization of oxetanes by thiadiazole, oxadiazole, or selenadiazole groups. The addition of Cu(OTf)2 to the reaction system at room temperature resulted in the formation of diaryl ethers via the copper-catalyzed ring opening of oxetanes in situ. Notably, the substrate scope was extended to general aromatics. [ABSTRACT FROM AUTHOR]

This article discusses a study on the regioselective ring opening of oxetanes using zirconocene and photoredox catalysis. The researchers aimed to explore a less explored radical mechanism for ring opening and found that the regioselectivity of the reaction was different compared to previous methods. They also investigated the generality of the reaction and found that various functional groups were tolerated, producing moderate to good yields of the desired products. Ongoing investigations into the mechanism and other transformations using zirconocene and photoredox catalysis are being conducted, with support from the Materials Characterization Central Laboratory of Waseda University. [Extracted from the article]

A general approach to 3‐azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties. [ABSTRACT FROM AUTHOR]

Prenylation is a ubiquitous late‐stage modification in nature that often confers significantly improved bioactivity for secondary metabolites. While this lipophilic modification renders enhanced potency, the lipophilic tag(s) can diminish bioavailability and adversely alter drug transportation and metabolism. Thus, a functional‐group‐tolerant, mild, and selective late‐stage C−H functionalization of prenyl tags would present a great potential in drug discovery programs but could also impact other fields, such as agrochemistry and chemical biology. Herein we report an exocyclic‐strain‐driven cross‐metathesis reaction of prenyl tags, a formal double C−H oxidation protocol, that can be used for the selective late‐stage derivatization of prenylated compounds and natural products. This methodology avoids the need for prefunctionalization of target molecules and affords ready access to an unprecedented library of oxo‐ and aza‐prenylated complex molecules. Thus, in a broader context, this methodology extends late‐stage functionalization beyond that available to nature. [ABSTRACT FROM AUTHOR]

4-Membered heterocycles are low molecular weight polar scaffolds with intriguing potential for drug discovery. Despite their unquestionable value, methods to access such heterocycles remain scant. Here, we describe the generation of oxetane- and azetidine- benzylic carbocations as a general strategy to access valuable 3,3-disubstituted derivatives.

Literature known energetic oxetane derivatives have a nitrogen content of up to 49.98 %. Through the introduction of azide and tetrazole functionalities attached to an oxetane ring, energetic oxetanes with higher nitrogen contents than previously reported in the literature were obtained. The newly synthesized oxetane derivatives were extensively characterized via 1H NMR, 13C{1H} NMR, 14N NMR, 15N NMR, 1H‐15N HMBC, FT‐IR spectroscopy and/or DTA. Their crystal structures were elucidated using X‐ray diffraction, their sensitivities towards impact, friction and electrostatic discharge were determined and their energetic properties were calculated using the EXPLO5 code. [ABSTRACT FROM AUTHOR]

Oxetanocin A and albucidin are two oxetane natural products. While the biosynthesis of oxetanocin A has been described, less is known about albucidin. In this work, the albucidin biosynthetic gene cluster is identified in Streptomyces. Heterologous expression in a nonproducing strain demonstrates that the genes alsA and alsB are necessary and sufficient for albucidin biosynthesis confirming a previous study (Myronovskyi et al. Microorganisms2020, 8, 237). A two‐step construction of albucidin 4′‐phosphate from 2′‐deoxyadenosine monophosphate (2′‐dAMP) is shown to be catalyzed in vitro by the cobalamin dependent radical S‐adenosyl‐l‐methionine (SAM) enzyme AlsB, which catalyzes a ring contraction, and the radical SAM enzyme AlsA, which catalyzes elimination of a one‐carbon fragment. Isotope labelling studies show that AlsB catalysis begins with stereospecific H‐atom transfer of the C2′‐pro‐R hydrogen from 2′‐dAMP to 5′‐deoxyadenosine, and that the eliminated one‐carbon fragment originates from C3′ of 2′‐dAMP. [ABSTRACT FROM AUTHOR]

The catalyst-free [2 + 2] photocycloaddition between benzils and simple olefins is reported. The adoption of visible light proved essential for the transformation, as shorter wavelengths led to uncontrolled decomposition. When cyclic olefins were used, the reaction occurred smoothly to afford the expected oxetanes regio- and stereoselectively after 24 h of irradiation. In contrast, in the case of acyclic olefins, longer reaction times were typically required and small amounts (ca. 20%) of [4 + 2] photocycloadducts and by-products deriving from competitive hydrogen atom abstraction were observed. The selectivity of the transformation could be consistently improved by decreasing the reaction temperature, thus restoring the desired [2 + 2] reactivity. An overall mechanistic picture is also offered based on the chemical and photophysical quenching experiments and the stereochemical output is rationalized based on Griesbeck models. [ABSTRACT FROM AUTHOR]

[Display omitted] A novel free fatty acid mimetic based on the spirocyclic oxetane pyrazolone 1-oxa-6,7-diazaspiro[3.4]oct-7-en-5-one scaffold has been obtained in seven steps. The key stages are based upon the toolbox of diazo chemistry, including the F SAFE diazo transfer and RhII-catalyzed O–H insertion followed by base-triggered oxetane closing. [ABSTRACT FROM AUTHOR]

The compact and versatile oxetane motifs have gained significant attention in drug discovery and medicinal chemistry campaigns. This review presents an overview of the diverse applications of oxetanes in clinical and preclinical drug candidates targeting various human diseases, including cancer, viral infections, autoimmune disorders, neurodegenerative conditions, metabolic disorders, and others. Special attention is given to biologically active oxetane-containing compounds and their disease-related targets, such as kinases, epigenetic and non-epigenetic enzymes, and receptors. The review also details the effect of the oxetane motif on important properties, including aqueous solubility, lipophilicity, pKa, P-glycoprotein (P-gp) efflux, metabolic stability, conformational preferences, toxicity profiles (e.g., cytochrome P450 (CYP) suppression and human ether-a-go-go related gene (hERG) inhibition), pharmacokinetic (PK) properties, potency, and target selectivity. We anticipate that this work will provide valuable insights that can drive future discoveries of novel bioactive oxetane-containing small molecules, enabling their effective application in combating a wide range of human diseases. [Display omitted] • Summarize the disease-related targets for oxetane-containing (pre)clinical drug candidates. • Highlight the contribution of an oxetane motif towards potency, target selectivity and drug-like properties. • Provide important insights that can drive future discoveries of novel bioactive oxetane-containing small molecules. [ABSTRACT FROM AUTHOR]

[Display omitted] Diels–Alder adducts of levoglucosenone with isoprene, butadiene and piperylene in the presence of AlCl 3 smoothly react with acetaldehyde or benzaldehyde to give products of the ene reaction, the hydroxy group of the primary intermediates participating in the formation of semiketal moiety. The yields of the reaction products depend both on the Lewis acid used (AlCl , BF ·Et O, ZnBr , SnCl or EtAlCl 2) and on the nature of the substrate. [ABSTRACT FROM AUTHOR]

[Display omitted] • First reported multigram scale synthesis of seven new building blocks of 1-oxaspiro[3.3]heptane family. • Operationally simple methods were used at each step. • 2D NMR spectra of 1-oxaspiro[3.3]heptan-6-one and 1-oxaspiro[3.3]heptan-6-amine were studied in detail. A decagram-scale synthesis of seven new building blocks of 1-oxaspiro[3.3]heptane family is described. This general approach requires 6 to 13 operationally simple steps starting from commercially available and inexpensive 3-oxocyclobutane-1-carboxylic acid. Expedient synthetic routes enable the straightforward access to these novel modules. Finally, the generation of virtual combinatorial library using the LLAMA software showed that building blocks described here demonstrated the high propensity to populate the lead-like chemical space. Like pigeons delivering letters, the newly 1-oxaspiro[3.3]heptane family scaffolds could deliver their functionality to drug-like compounds that are expected to be important in drug discovery and design. [ABSTRACT FROM AUTHOR]