Activation cyclobutanes

Diazafluorenes such as 129 have found use as cognition enhancers <1995USP5424430> and biologically active cyclobutane oligodeoxyribonucleotides such as 130 have been prepared using a photochemical cycloaddition reaction <2003W0070741>. 

Asymmetric [2 + 2] cycloaddition reaction affords a practical means of synthesis of optically active cyclobutanes, which can be used as useful intermediates in organic synthesis [138]. Narasaka reported that asymmetric [2 -i- 2] cycloaddition between acryloyl oxazolidinone derivatives and bis(methylthio)ethylene proceeded with high enantios-electivity when catalyzed by TADDOL-derived titanium complex (Sch. 58) [139]. The cyclobutane product was transformed into carbocyclic oxetanocin analogs or (-n)-grand-isol [140]... 

In photocycloadditions of 1,2-dioxine-4-ones A derived from menthone with unsymmetrically substituted alkenes moderate regioselectivity was observed. However, the cycloaddition reaction with cyclopentene proceeded highly stereoselective. " Chiral bicyclic lactams diastereoselectively react with ethylene furnishing optically active cyclobutanes. ... 

Use For the synthesis of camphor and insecticides, as solvents for waxes, and as softeners for plastics. Oxidative cleavage of the double bond in a-R leads to optically active cyclobutane derivatives that can be us as starting materials in the synthesis of cyclobutanoid natural products. 

Abstract. The asymmetric synthesis of chiral polymers by topochemically controlled polymerization in chiral crystals is discussed. Following a short survey of topochemical polymerization in the solid state and some comments on chiral crystals, we present the requirements for the performance of asymmetric polymerization based on [2+2]-photocycloaddition. The planning and execution of two successful polymerizations of this sort are described. In the first, we start with a chiral non-racemic monomer and obtain optically active cyclobutane oligomers. The optical yields of the dimer and trimer were quantitative on the scale of N.M.R. sensitivity. In the second reaction we start with a racemate, and by the processes of crystallization in a chiral structure and solid-state reaction we generate an optically active polymer, in the absence of any outside chiral agent. The possible application of this novel method to additional systems is discussed. 

The development of asymmetric reactions has been one of the main themes of modern synthetic organic chemistry, and currently much effort is being directed toward the development of catalytic asymmetric reactions. Cyclopropane and cyclohexane frameworks have been constructed enantioselectively by the catalytic asymmetric cyclopropanation and Diels-Alder reaction, respectively. On the other hand, there exist a few practical catalytic methods for the synthesis of optically active cyclobutanes, although chiral substances possessing a cyclobutane skeleton are found often in nature and serve as key intermediates in routes to biologically and medicinally important synthetic targets [17,18]. 

The complementary relationship between thermal and photochemical reactions can be illustrated by considering some of the same reaction types discussed in Chapter 11 and applying orbital symmetry considerations to the photochemical mode of reaction. The case of [2ti + 2ti] cycloaddition of two alkenes can serve as an example. This reaction was classified as a forbidden thermal reaction (Section 11.3) The correlation diagram for cycloaddition of two ethylene molecules (Fig. 13.2) shows that the ground-state molecules would lead to an excited state of cyclobutane and that the cycloaddition would therefore involve a prohibitive thermal activation energy. 

For the 2-1-2 pathway the FMO sum becomes (ab — ac) = a b — c) while for the 4 -I- 2 reaction it is (ab-I-ab) — a (2b). As (2b) > (b — c), it is clear that the 4 + 2 reaction has the largest stabilization, and therefore increases least in energy in the initial stages of the reaction (eq. (15.1), remembering that the steric repulsion will cause a net increase in energy). Consequently the 4 - - 2 reaction should have the lowest activation energy, and therefore occur easier than the 2-1-2. This is indeed what is observed, the Diels-Alder reaction occurs readily, but cyclobutane formation is not observed between non-polar dienes and dieneophiles. 

At high temperatures, the decomposition of cyclobutane is a first-order reaction. Its activation energy is 262kJ/mol. At 477°C, its half-life is 5.00 min. What is its half-life (in seconds) at 527°C ... 

More detailed and theoretical explanations of the role of the catalyst, based on this scheme, have appeared (72, 74, 77-82). In order to obtain experimental evidence for this scheme, some investigators did experiments in which 1,2-dimethylcyclobutane or cyclobutane were brought into contact with an active metathesis catalyst. However, 1,2-dimethylcyclobutane was stable under conditions where propene gave a high conversion to ethene and 2-butene (63). The experiments with cyclobutane led to the same conclusion (83). From this, and from the fact that cyclobutanes are not reaction products, although this can be expected thermodynamically, it follows that cyclobutanes are not free intermediates. This prompted Lewandos and Pettit (83) to propose a tetramethylene complex as the key intermediate ... 

Thermal dimerization of ethylene to cyclobutane is forbidden by orbital symmetry (Sect 3.5 in Chapter Elements of a Chemical Orbital Theory by Inagaki in this volume). The activation barrier is high E =44 kcal mof ) [9]. Cyclobutane cannot be prepared on a preparative scale by the dimerization of ethylenes despite a favorable reaction enthalpy (AH = -19 kcal mol" ). Thermal reactions between alkenes usually proceed via diradical intermediates [10-12]. The process of the diradical formation is the most favored by the HOMO-LUMO interaction (Scheme 25b in chapter Elements of a Chemical Orbital Theory ). The intervention of the diradical intermediates impfies loss of stereochemical integrity. This is a characteric feature of the thermal reactions between alkenes in the delocalization band of the mechanistic spectrum. 

A strong acceptor TCNE undergoes [2+2] rather than [4+2] cycloaddition reactions even with dienes. 1,1-Diphenylbutadiene [20] and 2,5-dimethyl-2,4-hexadiene (Scheme 5) [21] afford mainly and exclusively vinyl cyclobutane derivatives, respectively. In the reactions of 2,5-dimethyl-2,4-hexadiene (1) the observed rate constant, is greater for chloroform solvent than for a more polar solvent, acetonitrile (2) the trapping of a zwitterion intermediate by either methanol or p-toluenethiol was unsuccessful (3) radical initiators such as benzyl peroxide, or radical inhibitors like hydroquinone, have no effect on the rate (4) the entropies of activation are of... 

The HPLC-MS/MS assay was also successfully applied to the measurement of UV-induced dimeric pyrimidine photoproducts [123, 124]. The latter lesions were released from DNA as modified dinucleoside monophosphates due to resistance of the intra-dimer phosphodiester group to the exonuclease activity during the hydrolysis step [125, 126]. The hydrolyzed photoproducts exhibit mass spectrometry and chromatographic features that allow simultaneous quantification of the three main classes of photolesions, namely cyclobutane dimers, (6-4) photoproducts, and Dewar valence isomers, for each of the four possible bipyrimidine sequences. It may be added that these analyses are coupled to UV detection of normal nucleosides in order to correct for the amount of DNA in the sample and obtain a precise ratio of oxidized bases or dimeric photoproducts to normal nucleosides. 

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... 

The product of simple addition across the double bond is only weakly acidic whereas the final product has a hydrogen activated by two carbethoxy groups and is removed from the equilibrium by conversion to the enolate salt. The stability of the final salt serves to drag the reaction over the barrier that the cyclobutane intermediate must represent. 

Vink, A. A. et al., The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers, Proc. Natl. Acad, Sci. USA 94, 5255-5260, 1997. 

Reaction of [Pd(pica)(H20)2]2+ (pica = 2-picolylamine) with cbdc, cyclobutane-1,1-dicarboxylate, to give [Pd(pica)(cbdc)(H20)], containing monodentate cbdc, is characterized by an activation volume close to zero, indicating a balance between a negative contribution from associative activation and a positive contribution from solvational changes associated with transition state formation (256). 

Several other types of photochemical reactions involving unsaturated carbohydrates have been reported. One of these is38 photochemical, E -Z isomerization of the groups attached to a double bond (see Scheme 5). A second is the internal cycloaddition between two double bonds connected by a carbohydrate chain.39-41 Although the carbohydrate portion of the molecule is not directly involved in this cycloaddition, its presence induces optical activity in the cyclobutane derivatives produced photochemically. Finally, a group of acid-catalyzed addition-reactions has been observed for which the catalyst appears to arise from photochemical decomposition of a noncarbohydrate reactant.42-44... 

The cyclodimerisation of fluorinated alkenes and formation of cyclobutane from alkenes activated by electron withdrawing groups has formed great application in laboratory and industry... 

The nature of the substituents on the allene can have an impact on the outcome of a [2 + 2] cycloaddition reaction, as was illustrated by the Lewis acid catalyzed cycloadditions of l-thioaryl-3,3-dimethylallene (24) and 1 -methyl- 1-trimethylsilylallene to various 2-alkoxy-p-benzoquinones 25 (e.g. equation 8)17. The reactions were considered to proceed via carbocation intermediates formed by nucleophilic attack of the thioallene on the Lewis acid activated quinone. At lower temperatures, these carbocations closed to cyclobutanes 26, whereas at higher temperatures, the thermodynamically more stable benzofurans 27 were formed. 

Calculations based on this second model give the observed value for the entropy of activation. In addition, this model may be used to account for the observed isotope effect (Benson and Nangia, 1963). If the tetra-methylene biradical is involved then it is to be expected that appropriately substituted cyclobutanes might undergo cis-trans isomerization reactions. This will be referred to again later. One final point should be mentioned in connection with biradical intermediates in both cyclopropane and cyclobutane reactions. This concerns the absence of any effect of radical inhibitors on these systems, when it might be expected that they would interact with the biradicals. In fact calculations show that, under the conditions of formation, the biradicals have extremely short lifetimes sec) and hence, unless radical inhibitors are... 

A number of other cyclobutanes have been studied in which this effect, i.e. stabilization of the biradical intermediate, results in a lowering in the energy of activation of the reaction. These include... 

The values of these Arrhenius parameters contrast dramatically with those obtained for the bicyclo[2,2,0]hexane isomerization. In this compound there is no weak bridgehead bond, and hence the reaction path is more closely akin to that for cyclobutane itself. The similarity of the A factors for this reaction and that for other simple cyclobutanes supports this contention. If this is so, then the lowering of the energy of activation in this bicyclic compound by some 7 kcal mole from that observed in the alkylcyclobutanes is to be attributed to extra strain energy in this molecule. 

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