Epoxides, chalcone derivatives

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

For a similar series of chalcone derivatives the use of aqueous sodium hypochlorite in a two phase system (with toluene as the organic solvent) and the quinine derivative (32) as a chiral phase-transfer catalyst, produces epoxides with very good enantiomeric excesses and yields1981. 

The asymmetric epoxidation reaction with polyleucine as catalyst may be applied to a wide range of a, 3-unsaturated ketones. Table 4.1 shows different chalcone derivatives that can be epoxidized with poly-L-leucine. The substrate range included dienes and tctracncs151. Some other examples were reported in a previous edition161 and by M. Lastcrra-Sanchcz171. 

A research team from Bloemfontein (South Africa) have also taken advantage of the Julia and Colonna oxidation in elegant research aimed at the synthesis of optically active flavonoids. Bezuidenhoudt, Ferreira et al. have oxidised a range of chalcone derivatives using poly-(L)-alanine in the three phase system to afford optically active epoxides 4 which were readily cyclised to target compounds of the dihydroflavinol type 5, (Scheme 3) [16]. 

The catalytic asymmetric epoxidation of electron-deficient olefins has been regarded as one of the most representative asymmetric PTC reactions, and various such systems have been reported (Scheme 3.12). Lygo reported the asymmetric epoxidation of chalcone derivatives through the use of NaOCl [30,31], while Shioiri and Arai used aqueous H202 as an oxidant, their results indicating hydrogen bonding between the catalyst and substrates because an OH functionality in the catalyst was essential... 

The Wang group also reported the asymmetric epoxidation of chalcone derivatives with their polymer-supported dimeric PTC 61 using fert-butyl hydroperoxide as an oxidant (Scheme 4.18) [23]. 

The water suspension method described in Section 15.2.13 can also be applied to epoxidation reactions of chalcones 70 with NaOCl or Ca(C10)2. A mixture of 70a, 72 and commercially available 11 % aqueous NaOCl was stirred at room temperature for 24 h. The reaction product was filtered and dried to give 76a in quantitative yield [34]. This procedure was applied to various kinds of chalcone derivatives, and 70b-j were oxidized efficiently giving the corresponding epoxides 76b-j respectively, in good yields (Table 15-20) [34]. In the case of 70h and 70i, the oxidation reaction proceeds very fast. This organic solvent-free reaction procedure is much more simple and convenient in comparison with the usual solvent procedure [37]. Ca(OCl)2 can also be used for this epoxidation reaction in water suspension (Table 15-20) [34]. In the case of 70g and 70h, the reaction proceeds extremely quickly. However, the reaction product must be isolated from water-insoluble Ca(OCl)2 by extraction with organic solvent. Furthermore, in the case of 70d-f and 70j, the reaction products were not extracted with ether from the reaction mixture (Table 15-20). 

The Julih-Colonna epoxidation uses poly-I.-leucine and hydrogen peroxide to effect enantioselective epoxidation of chalcone derivatives such as 12. In a pair of back-to-back papers Tetrahedron Lett. 2004,45,5065 and 50691, H.-Christian Mililzer of Bayer Healthcare AG, Wuppertal, reports a detailed optimization of thi.s procedure. In the following paper (Tetrahedron Lett. 2004.45, 5073), Stanley Robert.s of the University of Liverpool reports the extension of this procedure to imsaturated sulfones such as 14. 

Dixon, C. E. Pyne, S. G. Synthesis of Epoxidated Chalcone Derivatives. /. Chem. Educ. 1992, 69, 1032-1033. 

Roberts has shown that the asymmetric epoxidation of chalcone can be catalysed by polyamino acid derivatives under non-aqueous conditions [13]. This improved reaction involves the use of a urea-hydrogen peroxide complex in THF, in the presence of an organic base (DBU) and immobilized poly-(L)-leucine. Under these conditions, the reaction of chalcone derivatives and related substrates provided the corresponding epoxides in 70-99% yield and 83-95% ee within 30 min. Several substrates with enolisable enones have also been epoxidized successfully [14]. 

C. Morisseau, G. Du, J. W. Newman, B. D. Hammock, Mechanism of Mammalian Soluble Epoxide Hydrolase by Chalcone Oxide Derivatives , Arch. Biochem. Biophys. 1998, 356, 214 - 228 C. Morisseau, M. H. Goodrow, D. Dowdy, J. Zheng, J. F. Greene, J. R. Sanborn, B. D. Hammock, Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases , Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8849 - 8854. 

Epoxidation of amino chalcone 17, followed by regioselective ring opening of the epoxide unit, demonstrates the formation of optically active lactam derivatives of type 18, which are highly important structures for use within the pharmaceutical industry. The reaction proceeds in good yield and without loss of stereochemical integrity (Scheme 15). 

Lygo and Wainwright recently reported a detailed study of the asymmetric phase-transfer mediated epoxidation of a variety of acyclic a,P-unsaturated ketones of the chalcone type. The third-generation cinchona-derived quats (8c and 7c), related to those discussed earlier in the alkylation section and Scheme 10.4, gave the best inductions (89% ee, 88 to 89, Scheme 10.13 and 86% ee for the pseudoenantiomeric catalyst 7c to give, as product, the enantiomer of 89). 

There are also a few examples of poly-amino add catalyzed epoxidation of non-linear enones. These indude tetralone derivatives 47, which can be epoxidized with good yields and enantiomeric excesses the best results were achieved for R = p-02N-QH4 and n = 1 (85% 96% ee) [84]. Other examples are the epoxidation of "iso-chalcone 48 (78% 59% ee) [69] or of bis-benzylidene cyclohexanone 49, which affords the corresponding bis-epoxide of good optical purity [69]. 

The mechanism of the polyleucine-catalyzed epoxidation is still under investigation [74]. Kinetic studies indicate that the reaction proceeds via the reversible addition of chalcone to a polyleucine-bound hydroperoxide [75]. Recent discussions have included studies of asymmetric amplification polyleucine derived from non-enantiopure amino acid shows highly amplified epoxide enantiomeric excess, and the results fit a mathematical model requiring the active catalyst to have five terminal homochiral residues, as rationalized by molecular modeling studies [76]. 

Similar conditions are also effective for the direct enantioselective epoxidation of a,p-unsaturated carbonyls, as exemplified by the conversion of chalcone (30) to the corresponding ft,/ -epoxide in 97% yield and 84% ee using the 4-iodophenyl cinchonine derivative 32 <02T1623>. Alternatively, the novel polyethylene glycol-supported oligo(L-leucine) catalyst... 

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