1.2- Dioxetanes preparation

Unfortunately, ultraviolet (UV) spectral data for most of the 1,2-dioxetanes prepared over the last decade have not been reported. In the previous version of this chapter, it was highlighted that the absorption maximum (Alna 4) of 1,2-dioxetanes occurs around 280-300 nm with very small extinction coefficients tailing up as far as 450 nm. Consequently, many 1,2-dioxetanes are pale yellow in color. 

In fact, the chemiluminescence of an authenic sample of trans- 3,4-diphenyl-1,2-dioxetane, prepared by Kopecky s procedure [118] and then added to the DCA-sensitized reaction on traws-stilbene (E° = 1.51 V vs SCE), totally disappears within a few minutes [119]. In spite of this elegant demonstration, the intermediacy of these short-lived compounds required further direct evidence. In this regard, although different mechanistic pathways can account for the reaction products [34,120,121], Schaap et al. [98] isolated in the DCA-sensitized photooxygenations of adamantylidene-adamantane (E° = 1.46 V vs SCE) 21 and/or of several substituted 2,3-diphenyl-5,6-dihydro-l,4-dioxins (Eox in the range 0.72-1.07 V vs SCE) 22a-f the correspopnding stable 1,2-dioxetanes 23, 24a-f [Eqs. (10,11)] in good yields. 

Electron-rich olefins, especially vinyl ethers, " ketene acetals, thioalkyl-substituted olefins,and enamines, " react readily with singlet oxygen to give dioxetane cleavage products. Under carefully controlled temperature conditions, the intermediary 1,2-dioxetanes can be isolated. The first 1,2-dioxetanes prepared in this manner were the cis and trans isomers (8a) and (8b), respectively (Eq. 14). 

The first 1,2-dioxetanes prepared in this way were the cis- 1,2-diethoxy (In) and trans- 1,2-diethoxy (lo) derivatives, obtained by photosensitized singlet oxygenation of the respective 1,2-diethoxyethylenes.34 The reaction is a stereospecific m-addition.34, c d However, when the same substrates are treated with triphenylphosphine ozonide, the cis- 1,2-dioxetane (In) is formed preferentially from either cis- or trans-olefin.34 A stepwise ionic mechanism was postulated to explain this stereoselective process [Eq. (8)]. 

The hydrolysis of p-nitrophenyl carboxylates has been studied using the model enzyme system, 10-hydroxy-1 l-hydroxyimino[20]paracyclophane with iVN-dime-thyl-iV-hexadecyl-iV-(4-imidazolium)methylammonium dichloride as co-factor. The 1,2-dioxetan prepared by the addition of 02 to 1-ethylthiocyclododene decomposes predominantly with C-C cleavage. ... 

In the past few years two rather distinct classes of chemiluminescent dioxetanes have become evident. Alkyl, alkoxy, and simple aryl substituted dioxetanes, which includes the earliest dioxetanes prepared, are characterized... 

Tetramethyl-l,2-dioxetane, prepared by treating the corresponding bromohydroperoxide with base, was a generous gift from Dr. K.R. Kopecky, University of Alberta, Department of Chemistry, Edmonton, Alberta, Canada. 

Classical chemiluminescence from lucigenin (20) is obtained from its reaction with hydrogen peroxide in water at a pH of about 10 Qc is reported to be about 0.5% based on lucigenin, but 1.6% based on the product A/-methylacridone which is formed in low yield (46). Lucigenin dioxetane (17) has been prepared by singlet oxygen addition to an electron-rich olefin (16) at low temperature (47). Thermal decomposition of (17) gives of 1.6% (47). 

The recently discovered preparative methods for the synthesis of 1.2-dioxetane derivatives (see Section V.) have made these compounds and their chemiluminescent decomposition the subject of especially intensive study. 

The past decade has seen significant achievements in stereoselective synthesis, with some pertinent developments also in dioxetane chemistry. Herein, we consider the most recent and prominent advances in the stereoselective preparation of chiral dioxetanes and their transformation into building blocks for asymmetric synthesis. 

The oxazolidinone-substituted olefin Ic (Scheme 3) constitutes another fortunate substrate for the diastereoselective synthesis of a chiral dioxetane , which is of preparative value for the enantiomeric synthesis of 1,2 diols . For example, the photooxygenation of the enecarbamate Ic produces the asymmetric dioxetane 2c in >95% jt-facial diastereoselectivity. The attack of the O2 occurs from the jt face anti to the isopropyl... 

As already hinted at above, chiral dioxetanes, obtained through the highly stereoselective [2 + 2] cycloaddition of singlet oxygen to the chiral enecarbamate, provide a convenient preparation of optically active 1,2 diols as building blocks for asymmetric synthesis (Scheme 5) . Reduction of the dioxetane 2c by L-methionine, followed by release of the oxazolidinone auxiliary by NaBH4/DBU reduction, affords the enantiomerically pure like-5 diol (for additional cases, see Table 4 in Reference 19e). 

Acetyl-protected 1,2,3,4-tetrahydropyrazines 105, which are prepared by treatment of 2,3-dihydropyrazine with acetic anhydride and zinc (Scheme 27), undergo photooxidation to produce new dioxetanes 106 <1995JA9690>. Upon thermolysis, the dioxetanes 106 decompose quantitatively to tetraacyl ethylenediamines 107. Dimethyldioxirane oxidation of tetrahydropyrazine 105 affords novel epoxide 108, which is also generated by deoxygenation of dioxetane 106 with dimethyl sulfide. In 2,3,4,5-tetrahydropyrazine 1-oxide 109, which is prepared... 

Ketenes have been converted into l,2-dioxetan-3-ones by triphenylphosphine ozonide (Scheme 14) (77JA5836, 80CC898). Dioxetanes and dioxetanones have been prepared (80CJC2089), e.g. by cyclization of the (3-bromohydroperoxide of 2-methyl-2-butene (Scheme 15). 

Biosystems) in dioxetane phosphate substrate buffer (see recipe), prepared just before use... 

Dioxetane phosphate visualization solution Prepare 0.1 mg/ml AMPPD or CSPD (Applied Biosystems) or 0.1 mg/ml Lumigen-PPD (Lumigen) substrate in dioxetane phosphate substrate buffer (see recipe). Prepare just before use. Lumi-Phos 530 (Boehringer Mannheim or Lumigen) is a ready-to-use solution and can be applied directly to the membrane. 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

The following four-membered ring structures containing two oxygen atoms are known. Of these, the 1,2-dioxetanes 1 are most common and will form the majority of this chapter. 1,2-Dioxetanones 2 (a-peroxy lactones) and dioxetanimines 3 are rare but have been prepared and will be mentioned where relevant. 1,2-Dioxetenes 4, methylene-1,2-dioxetanes 5, and l,2-dioxetane-3,4-dione 6 have not been prepared in stable form and will only be discussed from a theoretical viewpoint. The isomeric 1,3-dioxetanes 7, l,3-dioxetane-2,4-dione 8, and methylene-1,3-dioxetanes 9 have also received attention from the theoretical viewpoint however, creditable chemical evidence for their existence is still lacking. 

Mass spectrometry remains of limited use for the characterization of dioxetanes however, numerous relatively stable 1,2-dioxetanes have been prepared over the last decade allowing not only for the detection of their parent ions but also allowing for high-resolution mass spectrometry (HRMS) measurements to be taken. See references associated with structures depicted in Figure 1 or Table 1. 

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