Gem-difluorocyclopropane

Table 1. gem-Difluorocyclopropanes from Bromo(difluoromethyl)-triphenylphosphonium Bromide... 

Table 2. gem-Difluorocyclopropanes from Alkenes and Hexafluoropropylene Oxide... 

Dolbier WR, Sellers SF (1982) J. Am. Chem. Soc. 104 2494. A review of the authors works on thermal rearrangements of gem-difluorocyclopropanes covering, inter alia, cyclopropane thermolysis, methylene cyclopropane and spiropentane rearrangements, vinyl-cyclopropane and cyclopropylcarbinyl isomerizations has been published Dolbier WR (1981) Acc. Chem. Res. 14 195... 

The cis/trans isomerization of l,l-difluoro-2,3-dimethylcyclopropane (2) has an activation energy about lOkcal mol-1 lower than that of the parent hydrocarbon.5 Unlike the parent hydrocarbon, competing cyclopropane to propene rearrangement is not observed, a generalization that extends to other gem-difluorocyclopropanes studied in the Dolbier laboratories.1... 

While the cyclopropane to propene isomerization is not observed in the thermal rearrangements of gem-difluorocyclopropanes (vide supra), this is the principal reaction of polyfluorocy-clopropanes in the presence of Lewis acids.23 Perfluoro(alkylcyclopropanes) 27 isomerize to perfluoroalkenes 28 in high yield, despite the harsh conditions (100°C) required in some cases. It should be noted that double-bond migration under these reaction conditions occurs readily (see Section 5.1.2.2.). 

Fig. 68 Mesogenic dimer with a rigid gem-difluorocyclopropane based spacer unit (77° C) [363]...

There is one example of a fluorine spectrum of an epoxide that incorporates a CF2 group (Scheme 4.23). As was the case with gem-difluorocyclopropanes, the three-membered ring of the epoxide gives rise to significant shielding of the CF2 fluorines relative to those of an RCF2OR ether ( -79ppm). 

Figure 12,3 Biologically active gem-difluorocyclopropane F2CBI as a duocarmycin analogue.

Figure 12.6 Examples of biologically active gem-difluorocyclopropanes (simple molecules).

Figure 12.7 Nucleoside-type biologically active gem-difluorocyclopropanes prepared by the Csuk group.

Scheme 12.1 Synthesis of gem-difluorocyclopropane through diastereoselective Michael reaction followed by radical coupling.

Scheme 12.2 Preparation of gem-difluorocyclopropanes through addition of difluorocarbene to olefin.

Scheme 12.3 summarizes typical examples for the synthesis of gem-difluorocyclopropanes via difluorocarbene addition to olefins. Although high temperature is necessary to generate difluorocarbene by pyrolysis of ClCF2COONa, addition of difluorocarbene to carbon-carbon double bonds proceeds in a stereospecific cis manner... 

Scheme 12.3 Typical examples of the synthesis of gem-difluorocyclopropanes using difluo-rocarbene addition to olefin.

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

Scheme 12.4 Preparation of optically active gem-difluorocyclopropanes using enzymatic resolution.

As described above, gem-d II non>cycl opropane analogues of structurally complex biologically active natural products reported to date have not shown enhanced activities [8, 14], while rather simple synthetic gm-difluorocyclopropanes have shown interesting biological activities [15, 16, 18-22], We recently reported the synthesis of gem-difluorocyclopropanes that showed a strong DNA-cleaving property switched on by photoirradiation [22],... 

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