Oxetane Formation Research Articles

Electronic Excited States Responsible for Dimer Formation upon UV Absorption Directly by Thymine Strands: Joint Experimental and Theoretical Study

The study addresses interconnected issues related to two major types of cycloadditions between adjacent thymines in DNA leading to cyclobutane dimers (T<>Ts) and (6-4) adducts. Experimental results are obtained for the single strand (dT)(20) by steady-state and time-resolved optical spectroscopy, as well as by HPLC coupled to mass spectrometry. Calculations are carried out for the dinucleoside monophosphate in water using the TD-M052X method and including the polarizable continuum model; the reliability of TD-M052X is checked against CASPT2 calculations regarding the behavior of two stacked thymines in the gas phase. It is shown that irradiation at the main absorption band leads to cyclobutane dimers (T<>Ts) and (6-4) adducts via different electronic excited states. T<>Ts are formed via (1)ππ* excitons; [2 + 2] dimerization proceeds along a barrierless path, in line with the constant quantum yield (0.05) with the irradiation wavelength, the contribution of the (3)ππ* state to this reaction being less than 10%. The formation of oxetane, the reaction intermediate leading to (6-4) adducts, occurs via charge transfer excited states involving two stacked thymines, whose fingerprint is detected in the fluorescence spectra; it involves an energy barrier explaining the important decrease in the quantum yield of (6-4) adducts with the irradiation wavelength.

Base-Controlled Selective Conversion of Michael Adducts of Malonates with Enones in the Presence of Iodine

An efficient base-controlled selective conversion of the Michael adducts of malonates with enones in the presence of iodine is reported. Highly functionalized cyclopropane, oxetane, and α-hydroxylmalonate derivatives are obtained selectively using DBU, Na(2)CO(3), and NaOAc as the base, respectively. O(2) was identified to be crucial to the formation of oxetane and α-hydroxylmalonate derivatives.

Hydroxy-group effect on the regioselectivity in a photochemical oxetane formation reaction (the Paternò-Büchi Reaction) of geraniol derivatives

The Paternò-Büchi (PB) reaction of geraniol derivatives 1, which contain allylic alcohol functionality and unfunctionalized double bonds, with benzophenone was investigated to see the effect of the hydroxyl group on the regioselectivity of the oxetane formation, i.e., 2/3. At low concentration of geraniol (1a), oxetanes 2a and 3a were formed in a ratio of 2a/3a = ca. 50/50. The oxetane 2a is derived from the PB reaction at the allylic alcohol moiety, whereas the PB reaction at the unfunctionalized double bond produces the oxetane 3a. The PB reaction of the hydroxy-protected methyl ether 1b and acetate 1c gave selectively oxetanes 3b,c derived from the reaction at the more nucleophilic double bond, 2/3∼ 15/85. The hydroxyl-group effect was found to be small, but apparently increased the formation of 2a in the PB reaction with geraniol (1a).

A Theoretical Rationale for Why Azetidine Has a Faster Rate of Formation Than Oxetane in TC(6–4) Photoproducts

The mechanism of formation of azetidine and oxetane in (6-4) photoproducts between thymine and imine-type cytosine is studied using the MPWB1K and B3LYP functionals together with the 6-31G(d,p) and 6-311++G(d,p) basis sets, in vacuum and bulk solvent. The photoinduced cycloaddition displays favorable energy barriers in the triplet excited state for formation of both azetidine and oxetane. The stepwise cycloaddition in the triplet excited state involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The distinguishing feature in the formation of azetidine compared to that of oxetane is an intermediate H3' back-transfer to N3', which is a low-barrier exothermic reaction, and thus shifts the energy balance toward azetidine formation.

Concentration and Temperature Dependency of Regio- and Stereoselectivity in a Photochemical [2 + 2] Cycloaddition Reaction (the Paternò−Büchi Reaction): Origin of the Hydroxy-Group Directivity

A set of photochemical oxetane formation reactions, i.e., the Paternò-Büchi (PB) reactions, of tetrahydrobenzofuranol derivatives 1a-d with benzophenone (BP) was investigated to examine poorly understood hydroxy-group directivity on regio- and stereoselectivity. The selectivities of the PB reactions for allylic alcohols 1a,d were found to be largely dependent upon the concentration of the allylic alcohols and the reaction temperature. The temperature-dependent change of the regioselectivity at high concentrations of allylic alcohols was similar to that of the hydroxy-protected methyl ether 1b and tetrahydrobenzofuran (1c). The effect of concentration on regioselectivity can be explained by the hydrogen-bonded aggregates, which mimic the selectivities observed during the PB reaction of 1b,c. The hydroxy-directed cis-selectivity of the higher-substituted oxetane 3a,d formed at low concentration of 1a,d was found to be larger than that at the higher concentration of 1a,d. The cis-selectivity of 3a,d was found to be higher than that of the lower-substituted oxetane 2a,d. The regioselectivity of the cis-configured oxetanes was higher than that of the trans-configured oxetanes. These experimental results strongly suggest that hydroxy-group directivity, induced by hydrogen-bonding stabilization, plays a role in controlling the regio- and stereoselectivity of the PB reactions. The steric effect was also responsible for the diastereoselectivity, as shown by the fact that the cis selectivity in 3d was higher than that in 3a. Computational studies at the (U)MP2 and (U)DFT level of theory revealed that hydrogen-bonding stabilization becomes important only in the excited complex (exciplex) between the triplet excited state of carbonyls and alkenes, in which the charge transfer occurs from the alkene to the excited carbonyl to make the carbonyl oxygen nucleophilic. No significant stabilization energy was found in the intermediary triplet state of biradicals. The combined experimental and computational studies have clarified the origin of the poorly understood hydroxy-group effect on a high degree of regio- and stereoselectivity, i.e., the cooperative effect of hydrogen-bonding stabilization in exciplexes and the steric bulk of the substituents.

Paternò—Büchi reaction between furan and heterocyclic aldehydes: oxetane formation vs. metathesis

The photochemical reaction of 2-substituted heterocyclic aldehydes with furan gave the corresponding exo oxetane derivatives through the excited triplet state. However, in situ the oxetane derivatives were converted through a metathesis reaction into the corresponding Z,E-butadienyl formate derivatives. On the contrary, 3-substituted heterocyclic aldehydes gave the corresponding exo oxetane derivatives. The effect of 2-substituted heterocyclic ring in order to facilitate the metathesis reaction is explained considering the possible participation of the pi aromatic orbitals in the oxetane C-O bond cleavage.

Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors

Abstract Several syntheses of C-5-spirocycle-containing C-glycosides are discussed. A multigram-scale synthesis capitalizing on a one-pot aldol-Cannizzaro sequence is described. Spiro oxetane formation using an unprotected penta-ol C-glycoside as substrate is also exemplified. Functional assessment of these compounds for potency and selectivity was evaluated at human SGLT2 and SGLT1.

Unexpected formation of oxetanes from a geminal difluorinated δ-lactone

A perbenzylated 3,3-difluorinated hexono-1,5-lactone was prepared in several steps. Reaction of this lactone with MeOH/ p-TsOH followed by a treatment with ion-exchange resin led to the formation of an exocyclic oxetane derived vinylether. Similar reaction with ammonia gave the corresponding carboxamido substituted oxetane in good yields.

ChemInform Abstract: Recent Progress Regarding Regio‐, Site‐, and Stereoselective Formation of Oxetanes in Paterno—Buechi Reactions

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

ChemInform Abstract: Site‐ and Stereoselectivity in the Photochemical Oxetane Formation Reaction (Paterno—Buechi Reaction) of Tetrahydrobenzofuranols with Benzophenone: Hydroxy‐Directed Diastereoselectivity?

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

Site- and Stereoselectivity in the Photochemical Oxetane Formation Reaction (Paternò–Büchi Reaction) of Tetrahydrobenzofuranols with Benzophenone: Hydroxy-directed Diastereoselectivity?

Abstract The Paternò–Büchi reactions of tetrahydrobenzofuranols with benzophenone were investigated to reveal site- and stereoselectivity in oxetane formation reactions. Both selectivities were found to be largely dependent on the reaction temperature. The trans selectivity increased with a decrease in temperature, and the more-substituted oxetanes were selectively formed at high temperature.

Recent Progress Regarding Regio‐, Site‐, and Stereoselective Formation of Oxetanes in Paternò‐Büchi Reactions

AbstractRecently, the demand for synthetic oxetanes has increased because the highly strained structure allows specific biologic functions in vivo and also serves unique purposes in industrial materials. This review article summarizes recent progress in regio‐, site‐, and stereo‐selective formation of oxetanes via a photochemical process.

Mechanistic possibilities for oxetane formation in the biosynthesis of Taxol’s D ring

Three mechanistic possibilities for the formation of the oxetane (D ring) of Taxol were examined at various levels of theory [B3LYP/6-31+G(d,p), mPW1PW91/6-31+G(d,p), and MP2/6-31+G(d,p)] including one mechanism involving an unusual oxabicyclobutonium ion intermediate. The mechanisms examined differ considerably in terms of their predicted inherent activation barriers, and the requirements for acceleration of each by an enzyme active site are outlined. Our calculations provide an important starting point for future studies in this area. Also examined were previously published calculations on simple oxabicyclobutonium ions, as well as the all-carbon analog of the pathway involving the oxabicyclobutonium ion.

Paternò-Büchi reaction between aromatic carbonyl compounds and 1-(3-furyl)alkanols

The photochemical reaction between aromatic carbonyl compounds and 3-furylmethanol derivatives occurs with high regioselectivity. In most of the experiments formation of oxetanes occurs at the hydroxyalkylated double bond. With chiral 1-(3-furyl)alkanols the reaction occurs with good-high stereoselectivity. In the case of 1-(3-furyl)-benzyl alcohol the stereoselectivity can be explained on the basis of the conformers of the reagent, assuming the formation of a complex between the carbonyl compound and the hydroxyl group.

Characterization, reactivity and photosensitizing properties of the triplet excited state of α-lapachone

alpha-Lapachone is a natural 1,4-naphthoquinone with promising biological activity. The fused dihydropyran ring present in its structure, acting as formal 2-alkoxy and 3-alkyl substituents to the quinone moiety, endows this compound with milder redox properties and lower toxicity, when compared with other bioactive 1,4-quinones. Its photochemistry, here reported, seems to originate from the triplet state, which shows pipi* character. Triplet quenching in acetonitrile solution with added hydrogen-atom donors such as 1,4-cyclohexadiene or 2-propanol is inefficient, independent of solvent polarity, and leads to formation of the semiquinone radical. With phenol and indole, quenching rate constants are two orders of magnitude higher, but smaller than the value for triethylamine. In the first two cases the semiquinone radical can be detected by laser flash photolysis and in the last case, the anion radical derived from alpha-lapachone is readily detected. The semiquinone radical can also be observed in the quenching of triplet alpha-lapachone by 2'-deoxyguanosine and by the methyl esters of L-tryptophan and L-tyrosine, whereas for L-cysteine methyl ester the quenching rate constant is very slow. Triplet alpha-lapachone is not quenched by thymine, thymidine, 2'-deoxycytosine or 2'-deoxyadenosine; this is probably due to its pipi* character and low energy, which prevents oxetane formation and triplet-triplet energy transfer, respectively. Steady-state photolysis of aerated solutions of these compounds in the presence of alpha-lapachone does not show evidence of decomposition, whereas similar experiments with 2'-deoxyguanosine result in efficient consumption of the nucleoside. Singlet oxygen is formed from triplet alpha-lapachone, and a quantum yield of 0.68 is measured.

Modeling Thymine Photodimerizations in DNA: Mechanism and Correlation Diagrams

The basic mechanistic traits of the main photochemical reactions in DNA, the formation of the cyclobutane and oxetane thymine dimerization adducts, are established with the help of CASSCF and CASPT2 calculations for a gas-phase model of two stacked thymines. Both reactions go through conical intersections between the ground and the excited state that are connected through minimum energy paths to the corresponding products. This explains the ultrafast formation of the cyclobutane adduct detected experimentally, and it suggests that the oxetane formation also occurs on that time scale. Moreover, the states responsible for the photoproduct formation correlate with two high-lying states of the pair in its ideal B-DNA conformation. These states are different from the delocalized states resulting from coupling of the localized ones, which suggests that the origin of the reactive electronic states lies in the pi stacking. Formation of the photoproducts requires population of these states, by direct excitation of favorable conformations, or preceded by a localized excitation.

Solid-state photocycloaddition of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones with benzophenone

Photocycloaddition reactions of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones ( 4a– c) with benzophenone ( 2a) by mixing in the solid state (solid solution) afforded the corresponding oxetane derivatives ( 5a– c; 1:2 adducts) with high site- and regioselectivity across the C5–C6 and C5′–C6′ double bonds in 4 via the triplet excited state of benzophenone. The oxetane formation proceeded more effectively in the solid state than in solution. The reaction mechanism was inferred by MO methods to be initiated by electrostatic interaction between the C6 position of 4a– c and the carbonyl oxygen of 2a in their ground states. The solid-state interaction may be enhanced by the electron density at the carbonyl oxygen of the triplet 2a. The transition state (TS) analysis of the [2+2] cycloaddition reactions also suggested some triplet complexes and high regioselectivity. The hydrogen-bonding interaction between 2a and 4a– c and the triplet reaction mechanism were also explained by the IR analyses and the quenching experiments, respectively.

Preferred 4-exo Ring Closure in the Intramolecular Coupling of Vinyl Bromides with Alcohols

A novel direct and selective access to oxetanes via a Cu(I)-catalyzed intramolecular ring-closure reaction of vinyl bromides and alcohols is presented. Remarkably, the formation of the four-membered oxetanes is preferred to five- or six-membered ring formation. This preference is opposed to the Pd(II)-catalyzed ring-closure reactions.

The Long-Lived Triplet Excited State of an Elongated Ketoprofen Derivative and Its Interactions with Amino Acids and Nucleosides

The aim of the present work was to find a ketoprofen (KP) equivalent suitable for time-resolved studies on the interactions of its KP-like triplet state with biomolecules or their simple building blocks, under physiologically relevant conditions. Such a compound should fulfill the following requirements: (i) it should be soluble in aqueous media; (ii) its triplet lifetime should be longer than that of KP, ideally in the microsecond range; and (iii) its photodecarboxylation should be slow enough to avoid interference in the time-resolved studies associated with formation of photoproducts. Here, the glycine derivative of ketoprofen (KPGly) has been found to fulfill all the above requirements. In a first stage, the attention has been focused on the photophysical and photochemical properties of KPGly, and then on its excited-state interactions with key amino acids and nucleosides. In acetonitrile, the typical benzophenone-like triplet-triplet absorption (3KPGly) with lambda(max) at 520 nm and a lifetime of 5.3 micros was observed. This value is very close to that of 3KP (5.6 micros) obtained under the same conditions. In methanol, the 3KPGly features were also close to those of 3KP with detection of a short-lived triplet state that evolves to give a ketyl radical. By contrast with the behavior of KP, in deaerated aqueous solutions at pH = 7.4, the transient detected in the case of KPGly displayed two bands at lambda(max) at 330 and 520 nm, very similar to those observed in acetonitrile solution but with a lifetime of 7.5 micros at 520 nm. Hence, it was assigned to the KPGly triplet. In the case of KP, efficient decarboxylation occurs in the subnanosecond time scale, via intramolecular electron transfer. This process gives rise to a detectable carbanion intermediate (lifetime approximately 250 ns) and prevents detection of the shorter-lived 3KP signal. In a second stage, the attention has been focused on the excited-state interactions between 3KPGly and amino acids or nucleosides; for this purpose, 2'-deoxyguanosine (dGuo), thymidine (Thd), tryptophan (Trp), and tyrosine (Tyr) have been chosen as photosensitization targets. In general, efficient quenching (rate constant kq > 109 M(-1) x s(-1)) was observed; it was attributed for dGuo, Tyr, and Trp to a photochemical reaction involving initial electron transfer from the biological target to 3KPGly, followed by proton transfer from the amino acid or the nucleoside radical cation to KPGly-*. As a matter of fact, ketyl radical together with guanosinyl, tyrosinyl, or tryptophanyl radicals were detected; this supports the proposed mechanism. The results with Thd were somewhat different, as the efficient 3KPGly quenching was ascribed to oxetane formation by a Paterno Büchi photocycloaddition.

Minimum electrophilicity principle in photocycloaddition formation of oxetanes

AbstractThe regio‐ and stereoselectivity of some Paternó–Büchi reactions are studied within a density functional framework with B3LYP exchange‐correlation energy functional and 6‐31G** basis set. It is shown that although in most cases the Minimum Polarizability and the Maximum Hardness Principles (MPP and MHP) successfully predict the major oxetane products of these reactions, but in all of the considered reactions, with no exception, the main products have the lesser electrophilicity values than the minor isomers, and therefore the Minimum Electrophilicity Principle (MEP) correctly predicts the most stable stereoisomer of the reaction. Copyright © 2007 John Wiley &amp; Sons, Ltd.