Models oxetanes

It is clear from Fig. 8 and Table 1 that the angle 0 does indeed decrease as expected if the n-pair models and rule 1 were applicable. Moreover, the hydrogen bond non-linearity 9 decreases along the series B = oxirane, oxetane, 2,5-dihydrofuran. On the other hand, the values of 9 for oxirane- -ClF and 2,5-dihydrofuran- -ClF (included in Fig. 8) reveal that the halogen bond shows little propensity to be non-linear. 

Fig. 8 The n-pair models of 2,5-dihydrofuran, oxetane and oxirane (first column) and the experimental geometries of their complexes with HC1 (second column) and C1F (third column), each drawn to scale. The angle 0 is almost identical in B- HC1 and B- ClF for a given B but increases from 2,5-dihydrofuran, through oxetane, to oxirane, as expected from the model (see text). The non-linearity of the hydrogen bond increases monotoni-cally from 2,5-dihydrofuran to oxirane. See Fig. 1 for key to the colour coding of atoms...

In order to investigate the single electron donation process from a reduced flavin to a pyrimidine dimer or oxetane lesion, the photolyase model compounds 1-4 depicted in Scheme 4 were prepared [41, 42]. The first model compounds 1 and 2 contain a cyclobutane uracil (1) or thymine (2) dimer covalently connected to a flavin, which is the active electron donating subunit in photolyases. These model systems were dissolved in various solvents... 

Scheme 4 The four pyrimidine dimer and oxetane model compounds 1-4 with either a reduced and deprotonated flavin, or a pyrene as the electron donor. Depiction of the detected reaction products 5-7...

Whatever the reason may be behind the strict necessity to deprotonate the flavin donor, the reduced and deprotonated flavin was established in these model studies to be an efficient electron donor, able to reduce nucle-obases and oxetanes. In the model compounds 1 and 2 the pyrimidine dimer translates the electron transfer step into a rapidly detectable chemical cycloreversion reaction [47, 48], Incorporation of a flavin and of a cyclobutane pyrimidine dimer into DNA double strands was consequently performed in order to analyse the reductive electron transfer properties of DNA. 

Flavin-cyclobutane pyrimidine dimer and flavin-oxetane model compounds like 1-3 showed for the first time that a reduced and deprotonated flavin is a strong photo-reductant even outside a protein environment, able to transfer an extra electron to cyclobutane pyrimidine dimers and oxetanes. There then spontaneously perform either a [2n+2n cycloreversion or a retro-Paternd-Buchi reaction. In this sense, the model compounds mimic the electron transfer driven DNA repair process of CPD- and (6-4)-photolyases. 

There is always interest in the photochemistry of the pyrimidine nucleic acid bases and related simple pyrimidinones, due to its importance in genetic mutation. In addition to damaging DNA, photo-induced reactions may also repair the damage, as in the reduction, by FADH, of the thymine glycol 64 back to thymine <06JACS10934>. Another report related to repair of DNA involved a model study, by means of the linked dimer 65, of the involvement of tryptophan in the electron-transfer leading to reversion of thymine oxetane adducts <06OBC291>. 

This mechanistic question is one of the examples of the success of density functional theory methods in organometallic chemistry. Earlier work on the reaction mechanism could not discriminate between the two alternatives. Analysis of the different orbitals based on extended Hiickel calculations came to the result that the [3+2] pathway is more likely, but could not exclude the possibility of a [2+2] pathway [13]. Similar conclusions where obtained from the results of Hartree-Fock calculations in combination with QCISD(T) single point calculations [21], Attempts to use Ru04 as a model for osmium tetraoxide indicated that the formation of an oxetane is less favorable compared to the [3+2] pathway, but still possible [22, 23],... 

Initially, it was thought more likely that the electron poor metal atom would be involved in the electrophilic attack at the alkene and also the metal-carbon bond would bring the alkene closer to the chiral metal-ligand environment. This mechanism is analogous to alkene metathesis in which a metallacyclobutane is formed. Later work, though, has shown that for osmium the actual mechanism is the 3+2 addition. Molecular modelling lends support to the 3+2 mechanism, but also kinetic isotope effects support this (KIEs for 13C in substrate at high conversion). Oxetane formation should lead to a different KIE for the two alkene carbon atoms involved. Both experimentally and theoretically an equal KIE was found for both carbon atoms and thus it was concluded that an effectively symmetric addition, such as the 3+2 addition, is the actual mechanism [22] for osmium. 

Most of the work reported with these complexes has been concerned with kinetic measurements and suggestions of possible mechanisms. The [Ru(HjO)(EDTA)] / aq. HjOj/ascorbate/dioxane system was used for the oxidation of cyclohexanol to cw-l,3-cyclohexanediol and regarded as a model for peroxidase systems kinetic data and rate laws were derived [773], Kinetic data were recorded for the following systems [Ru(Hj0)(EDTA)]702/aq. ascorbate/dioxane/30°C (an analogue of the Udenfriend system cyclohexanol oxidation) [731] [Ru(H20)(EDTA)]70j/water (alkanes and epoxidation of cyclic alkenes - [Ru (0)(EDTA)] may be involved) [774] [Ru(HjO)(EDTA)]702/water-dioxane (epoxidation of styrenes - a metallo-oxetane intermediate was postulated) [775] [Ru(HjO)(EDTA)]7aq. H O /dioxane (ascorbic acid to dehydroascorbic acid and of cyclohexanol to cyclohexanone)... 

Fully as expected from the inspection of molecular models, the generation of the oxetane ring has the effect of heightening the structural curvature in compounds such as 85 and 86. Reagent approach from the exterior should materialize under kinetically controlled conditions. These features are reflected in the catalytic hydrogenation of 86, which results in saturation of the double bond from the (3 surface along with reductive debromination to furnish 87. The lesson learned here is that the oxetane ring should be released or not formed at all if an opportunity to approach C9 from the a direction has any chance to take place. 

A pentacyclic diterpene 1 called dictyoxetane contains a most unusual subunit, a 2,7-dioxatricyclo[4.2.1.03>8 ]nonane. During model studies designed to provide access to this key subunit the bicyclic ether 2 was synthesised in the hope that Sn displacement would generate the unsaturated tricyclic oxetane. There was no reaction when 2 was treated with base. Reaction with a catalytic amount of p-toluenesulfonic acid in DMF at 75°C for 24 hours resulted only in formation of 4-methylacetophenone. The hydroxy mesylate 2 is also reported to decompose to 4-methylacetophenone on storage. 

A few theoretical studies of oxetanes and oxetanones have been reported since CHEC-II(1996). Building upon a study of the oxetane- -HCl complex studied by rotational spectroscopy, MP2 calculations were used to investigate the axial and equatorial HCl arrangement, and to try and explain why for oxetane- -HCl only one conformer was observed <2001CPL250, 2002CPL123>. The amine-catalyzed aldol reaction via enamine intermediates has been explored using density functional theory (DFT) (B3LYP/6-31G ) and conductor-like polarizable continuum model... 

NMR analysis of. sm>-D-ring taxane analogues <1999BML3041, 2000JNP726> supports the hypothesis that the oxetane serves to rigidify the overall molecular backbone (see Section 2.06.12.3). NOE and nuclear Overhauser effect spectroscopy (NOESY) experiments have been used to establish stereochemistry in taxanes, their synthetic precursors, and model structures <2005JOC3484, 2001S1013>. Fluorescence spectroscopy and rotational-echo double... 

Fig. 8 Overlap of the three pharmacophores representing the interactions found for paclitaxel in the 1JFF structure (A), epothilone A in the NMR-derived structure (B), and epothilone A in the QSAR model from Botta and co-workers (C), respectively. Blue C7-OH (epothilones) oxetane ring (paclitaxel) red C13 carbon (epothilones) phenyl ring (paclitaxel) yellow Cl carbonyl oxygen (epothilones) Cl carbonyl oxygen (paclitaxel) purple thiazole ring (epothilone) C3 benzamide (paclitaxel). (3-tubulin monomer is represented as a green cartoon and residues involved in hydrogen bonds are in orange (hydrogens are omitted for sake of clarity)...

Griesbeck and colleagues proposed a reliable model that would predict the stereoselectivity in the PB reaction of the dihydrofuran derivatives (Scheme 7.16). Thus, the Griesbeck Model [33] explains the stereoselectivity of oxetanes formed in the PB reactions of cyclic alkenes. 

Scheme 7.16 Endo-selective formation of oxetanes in the PB reaction of dihydrofuran with benzaldehyde (the Criesbeck Model).

Bach and coworkers observed both regioselective and stereoselective oxetane formation during the PB reaction of acyclic vinyl ethers (Scheme 7.26) [15n], The stereoselectivity observed for such photochemical reactions cannot be explained using the Griesbeck Model, even though triplet, 14-biradicals were proposed as intermediates. Thus, the stereoselectivity was proposed to be largely dependent on product stability. 

The reaction affords two products, an oxolane Pi and an oxetane P2, which exhibit a mirror-image relationship of their CIDNP patterns. The three most strongly polarized signals, of Hi, H7, and H7, with intensity ratios of about —2 to + 3 to +3.5, have been shown in the figure all the other protons are also polarized, but more weakly. The observed pattern is found to be in excellent agreement with the relative proton hyperfine coupling constants of the neutral benzosemiquinone radical and of the tert-butoxybicyclo[2.2.1]heptenyl radical, which were tested as model compounds for the two radical moieties.The biradical BRi is thus the source of the polarizations. It is formed in a triplet state, its singlet exit channel produces the oxolane Pi, and its triplet exit channel the oxetane P2. 

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