Cope rearrangement Subject

Along with a very wide synthetic application the Cope rearrangement continues to be a subject of intense debates. The key mechanistic question is whether the rearrangement of 1,5-hexadiene derivatives is concerted and passes via a six-electron aromatic transition state, or whether it involves the formation of a diradical intermediate, i.e. a cyclization-cleavage mechanism. In the former case, bond making and bond breaking occur synchronously (a survey of this question has been published210). 

Three isomers of the substituted cyclobutanes 33, 34 and 35 are obtained by the [2+2] cycloaddition of isoprene, and separated at low temperature from other cooligomers without undergoing Cope rearrangement. When the mixture was subjected to hydroboration and oxidation, the alcohol 37 was obtained from the isomer 34, and easily separated from 35 and the diol 36. The alcohol 37 is a pheromone called grandisol [11]. Although overall yield was 15%, this is the shortest synthetic route to this pheromone. 

An interesting example of the transfer of center chirality to helicity is the work by Ogawa et al., based on an asymmetric aromatic oxy-Cope rearrangement to provide nonracemic [5]helicenes (Fig. 15.8) [75]. The starting material with center chirality, bicyclo[2,2,2]ketone (-)-21 (>98% ee), was obtained by enzymatic resolution. In the annelation step, the phenanthrene derivative was subjected to aromatic oxy-Cope rearrangement, to afford a pentacyclic product in 47 % yield. The corresponding [5]helicene 22 was obtained in 7 % overall yield (> 98 % ee) after six steps. 

The reaction mechanism was rationalized as an Lewis acid-induced ring opening of the carbohydrate. This iminium cation is subjected to an aza-Cope-rearrangement. 

Inversion of configuration at the phosphane phosphorus atom of 3a is most likely due to 3lP NMR spectroscopically monitored dynamic phenomena. Keeping 3a at 60°C for 3 hours leads to an irreversible thermodynamically more stable 4aE. The energy of activation is calculated to 80.5 kJ/mol. According to X-ray structure determinations of 3a and 4aE the SS stereoisomeric compound is subject to a Cope rearrangement, resulting in the EE stereoisomeric form (Scheme 9). 

An experimental aspect of the Cope rearrangement particularly important in synthesis is the feature that it is frequently subject to catalysis. We have already seen that in the anionic oxy-Cope rearrangement enormous rate enhancements are realized by the incorporation of an alkoxide ion in the substrate. In many Cope rearrangements similar rate enhancements are achieved by the addition of catalysts, particularly acids and metals. ... 

The success of the Claisen-Cope rearrangement need not be limited to the production of aldehydes via enol ethers. Allylic alcohol (58) is successively transposed into a mixture of allylic isomers (59 Scheme 4), and is subjected to an orthoester Claisen rearrangement at 150 "C to provide ester (61). The moderate temperature of the Claisen step permits the isolation of an intermediate (c/. Scheme 3) prior to the final Cope rearrangement (195 C) to. y-unsaturated esters (60). The esters (60) are a 55 45 mixture of ( )- and (Z)-double bond isomers owing to the near equal steric bulk of the methyl and acetic acid residues in the transition state for the Cope rearrangement. ... 

Photochemical rearrangements have also been reported, as shown in equation (53). " Transition metal catalyzed rearrangement [palladium(O)] of a dienylaziridine has been reported in one case, and a radical opening of a dienylaziridine led to pyrroline formation under the conditions of radical initiation with AIBN/PhsSnH (equation 54). For those vinylaziridines that contain additional unsaturation, the corresponding aza equivalent of a divinylcyclopropane Cope rearrangement is the usual pathwayThe subject of heterodivinylcyclopropane Cope rearrangement is covered in detail elsewhere." The... 

Therefore several reactions were subjected to various antibody catalyses, e. g., ester and enol ether cleavage, transesteiification, ketone reduction. Cope rearrangement, ring closure via epoxide opening, or Diels-Alder cycloaddition [74, 75]. An exceptional reaction is the antibody-catalyzed Robinson annulation of triketone 28 to the Wieland-Miescher ketone 29 on a preparative scale. Surprisingly, even the alkylation of diketone 27 with methyl vinyl ketone was catalyzed by the same antibody, but at moderate rates (Scheme 15) [76]. 

In the laboratory of R.D. Rychnovsky, the segment-coupling Prins cyciization was utilized for the total synthesis of (-)-centrolobine. This approach avoided the common side reactions, such as side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement, associated with other Prins cyciization reactions. The substrate -acetoxy ether was subjected to SnBr4 in DCM, which brought about the formation of the all-equatorial tetrahydropyran in good yield. 

The Cope rearrangement of 1,2-divinylcyclopropane systems in which one of the vinyl groups is part of an a, -unsaturated ketone moiety has found considerable use in synthesis. A significant number of substrates have been prepared and subjected to thermal rearrangement and some of the products have been employed effectively for natural product syntheses. 

The route developed by Fowler and his associates (287) involved an ingenious application of the aza-Cope rearrangement, in which the bridged hydroxamic acid derivative 468, prepared as shown in Scheme 48, was subjected to flash vacuum thermolysis. The product, the enol ether 469, was not isolated but immediately hydrolyzed to the ketone 470, which was then hydrogenated and cyclized to the racemic ketone 466. This appears to be the first application of the aza-Cope rearrangement in synthetic chemistry, since the reaction is normally not thermodynamically favored when C-1 is replaced by nitrogen. However, it is clearly successful when the nitrogen is acylated, as in the present example. 

Reduction of prochiral 1,3-diketone A with baker s yeast gives hydroxy ketone B of 99% ee.10 The ketone B was converted to unsaturated ketone C, which was treated with (Z)-l-propenylmagnesium bromide in the presence of cerium(III) chloride to give a mixture of D and E. This mixture was directly subjected to oxy-Cope rearrangement to give F from D. The exo-isomer E was recovered unchanged. 

The rearrangements of 4a and 4c were best conducted in acetonitrile or ben7ene. b 4b was formed as a minor product in the preparation of 3b and was not subjected to Cope rearrangement. 

Eight-membered rings can be obtained by [4+4]-cycloadditions of 1,3-dienes [1] via diradicals or other intermediates. Synthesis of such compounds has been achieved by thermal, [2] photochemical, [3] and by metal-catalyzed [4] processes these reactions have been the subject of extensive mechanistic [5] and theoretical [5c] studies. Their strategic applications in natural product synthesis have been reviewed. [5d] The thermal version has generated little interest, except in orthoquino-dimethane dimerizations and in cycloreversions the Cope rearrangement of 1,2-divinyl-cyclobutanes [3] is more commonly used. [4+4]-Cycloadditions are also used with 1,3-dipoles or mesoionic heterocycles for the synthesis of six- and seven-membered rings. Sometimes also [6+4]-cycloadditions are... 

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