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[reaction: see text] In this Letter, we describe a general method for preparing the dianions of cyclopropene carboxylic acids, and we show that their subsequent reactions with electrophiles provide a general means for selectively introducing diverse types of functional groups. This provides a general method for the synthesis of chiral 1,2-disubstituted cyclopropenes, and opens new avenues for the enantioselective preparation of cyclopropenes.

P2X receptors on dorsal root ganglion (DRG) neurons have been strongly implicated in pathological nociception after peripheral nerve injuries or inflammation. However, nothing is known of a role for purinergic receptors in neuropathic pain produced by a chronic compression of DRG (CCD) -an injury that may accompany an intraforaminal stenosis, a laterally herniated disc or other disorders of the spine leading to radicular pain. In a rat model of DRG compression, hyperexcitable neurons retain functioning axonal connections with their peripheral targets. It is unknown whether such hyperexcitability might enhance chemically mediated nociceptive stimulation of the skin. In this study, CCD facilitated the nocifensive behavior and mechanical hyperalgesia-induced by the P2X 3 agonist, α,β-methylene ATP (α,β-meATP). An injection of α,β-meATP into the hind paw of CCD rats resulted in a significantly greater decrease in the mean threshold to von Frey stimuli and a greater duration of paw lifts than in sham-operated control rats. CCD also increased the levels of P2X 3 receptor protein and the number of P2X 3 immunoreactive, small diameter DRG neurons in the compressed ganglion. P2X 3 receptors were co-labeled with the isolectin IB4, consistent with a role in nociception. In addition, a α,β-meATP induced significantly larger fast-inactivating currents in CCD-than in sham-operated acutely dissociated DRG neurons. These currents were accompanied by the generation of action potentials -but only in the CCD neurons. U0126, a specific inhibitor of the MEK1/2, greatly down-regulated the enhanced current. Taken together, these observations suggest that enhanced purinergic responses after CCD are mediated by P2X 3 receptors.

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Directed carbometallation reactions of cyclopropenes are powerful reactions for the construction of functionalized cyclopropanes 1 -structures that have manifold applications in synthesis. 2 A number of effective carbomagnesation procedures have been described in recent years, 3 but a limitation has been the reactivity of Grignard reagents toward many functional groups. Most conspicuous has been the intolerance toward the ester functions of cyclopropenes (1) that are available from transition metal-catalyzed reactions of alkynes with α-diazo esters (Scheme 1). 4 Described herein are carbozincation reactions of cyclopropenes that are directed by ester or oxazolidinone substituents. This straightforward approach to cyclopropane synthesis proceeds with a stereochemical outcome that is complementary to that generally observed in catalytic cyclopropanation reactions of diazo compounds with alkenes. 5 It is well established that Cu-complexes can catalyze the conjugate addition reactions of organozinc reagents, and mechanistic proposals have invoked the cooperative action of Cu and Zn (Scheme 2a). 6 As cycloprop-2-ene carboxylates are homologs of α,β-unsaturated carbonyl compounds, it was hypothesized that esters would direct the carbozincation of cyclopropenes by analogy (Scheme 2b). Work by Gevorgyan, Rubin and Orchin has established that esters can be used as syn-directing groups 7 in catalytic hydroboration reactions 7a and in hydroformylation 7b-d reactions of cyclopropenes. Pioneering work by Negishi 8 and Nakamura 9 has established that allylzinc reagents add to cyclopropene derivatives. Nakamura has described an enantioselective Fe-catalyzed system for the addition of diorganozinc reagents to cyclopropenone ketals, 3c and Richey has described additions of Et 2 Zn to spiro[2.5]oct-1-enes. 10 However, facially selective carbozincations of cyclopropenes were unknown.From an optimization study directed toward the preparations of 3a-c, it was determined that additions of diorganozinc reagents could be effectively catalyzed by a variety of Cu(I) salts (see Supporting Information). CuI and CuCN were the most effective catalysts, and led to carbometallation products with excellent selectivity. Low conversions were observed and large excesses of organozinc reagents were required for additions carried out in the absence of a catalyst. An exception was 4b, which was formed in high yield with or without a catalyst. Solvent choice was an essential parameter: toluene was most effective, whereas the use of THF or diethyl ether lead to carbometallation products with low diastereoselectivity. The reactions with Ph 2 Zn were most effective in terms of reagent economy: 3c was obtained in 83% and 70% yields with 1.0 equiv and 0.6 equiv of Ph 2 Zn, respectively (Table 1). Larger amounts of Me 2 Zn (4.0 equiv) and Et 2 Zn (2.5 equiv) were required for optimal reactivity, as decreasing the amount of these organozinc reagents led to lower yields and increased side product formation.jmfox@udel.edu. Supporting Information Available: Fu...