Chalcone derivatives

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

The aforementioned section described the synthesis of a wide range of biologically important heterocyclic derivatives of combretastatin. The next part of this chapter will focus on the synthesis of heterocyclic 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. 

The synthetic approach to the benzo[fo]furan is similar to that of the thiophenes described in Scheme 39. The synthetic approach was described by Flynn et al. [73], and an example synthesis is given in Scheme 40. The appropriate iodophenol 104 is coupled to the aryl alkyne 111. The intermediate 155 is subsequently cyclized in the presence of an appropriately substituted aryl iodide, e.g., 107 under an atmosphere of carbon monoxide gas, to give the benzo[fr]furan chalcone derivative 156. Deprotection of the hydroxyl produces the target compound 157. 

Similarly, Scheme 44 indicates that Selvan et al. utilized -hydroxy enones (e.g., 169) to synthesize pyrazoles (e.g., 170) [87]. Although this example is a cur cumin analog and not a chalcone derivative, it has been included as this class of compounds exhibited anti-oxidant and COX-l/COX-2 activity. 

This section has illustrated a number of chalcone-derived analogs of com-bretastatins. For the most part there have been limited biological studies with these compounds however, the synthesis was included for completeness and to indicate that they warrant further investigation. 

The synthesis of biologically important heterocyclic stilbene and chalcone derivatives of combretastatins has been discussed. Combretastatins have been shown to be inhibitors of tubulin polymerization. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. It is the author s opinion that a great number of the compounds contained within this review are worthy of further investigation as potential tubulin binders. 

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 number of substituted chalcones were synthesised by base catalysed condensation of substituted aromatic aldehyde with substituted acetophenone in good yield. These chalcones derivatives were further condensed withortho-phenylene diamine to yield Benzol,5-diazepine derivatives in moderate yield. All the compounds were characterized by 1H-NMR spectral data. These compounds may have good pharmacological activity against bacteria. 

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]. 

Based on the results with chalcones, Sods expanded their substrate pool to look at a,p-unsaturated A -acyl pyrroles (137) as a chalcone derivative [81], Utility of the products formed was demonstrated in the concise syntheses of the anti-inflammatory drng (/ )-rolipram (Scheme 31). 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

In our analysis of the chemical structures which are active tur-inducers (41) it was found that the compounds fell into four groups (1) acetophenones and related structures, (2) monolignols, (3) hydroxycinnamic acids and their esters, and (4) chalcone derivatives (Fig. 1). Each compound had either a guaiacyl or a syringyl nucleus, and with the exception of the monolignols, possessed a carbonyl group. Most were of common occurrence in vascular plants. 

Matsumoto, J. et al., Components of Broussonetia papyrifera. I. Structures of the two new isoprenylated flavonols and two chalcone derivatives, Chem. Pharm. Bull, 33, 3250, 1985. 

Tanaka, T et al.. Dimeric chalcone derivatives from Mallotus philippensis. Phytochemistry, 48, 1423, 1998. 

Tuchinda, P. et al.. Anti-inflammatory cyclohexenyl chalcone derivatives in Boesenbergia pandurata, Phytochemistry, 59, 169, 2002. 

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