Hydroxy chalcones cyclization

The condensation of 2-hydroxyacetophenone with benzaldehyde yielded exclusively 2 -hydroxy-chalcone, and the cyclization to flavanone was not observed. An investigation of the species adsorbed on the catalyst (289) suggested that CS condensation on the Ba(OH)2 surface occurs via a very rigid transition state, whereby the OH group of 2-hydroxyacetophenone is bonded to the catalyst surface and placed at great distance from the carbonyl carbon atom of the aldehyde, making the cyclization of 2 -hydroxy-chalcone to flavanone difficult. Deactivation of the catalyst was not observed in the presence of moderate amounts of organic acids, such as benzoic, acrylic, or trichloroacetic acid. 

Farkas et al., [123] synthesised different natural isoflavanones (255) and isoflavans (256) by oxidative rearrangement of 2-hydroxy chalcones (254) with thallium nitrate in methanol followed by acid-catalyzed cyclization as shown in Fig. (11). 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

The cyclization of 2 -amino- and 2 -hydroxy-chalcones (12a,b) (Scheme 1.9) using silica-supported sodium hydrogen sulfate (NaHS04-Si02) was accomplished by Kumar and Perumal (2006). Preparation of tetrahydroquinolones and flavonones is a matter of great interest as these compounds display various pharmacological... 

The stereospecific cyclization of chalcones to (2S)-flavanones is a prerequisite for the synthesis of the majority of fiavonoid subclasses derived from this branch point metabolite. This reaction is catalyzed by chalcone isomerase (CHI, CFI EC 5.5.1.6). CHI exists in two forms, one that accepts only 6 -hydroxychalcones and another that accepts both 6 -hydroxy-(naringenin chalcone) and 6 -deoxychalcones (isoliquirgentin), the latter generally found in legumes. Although 6 -hydroxychalcones will spontaneously convert to a racemic flavanone mixture, the CHI-catalyzed reaction proceeds at a rate 36 million-fold faster and is highly stereoselective for the formation of (25)-flavanones [60]. Spontaneous isomerization of 6 -deoxychalcones does not substantially occur without enzyme catalysis. 

Ring closure is enhanced by a 6 -hydroxy group in the chalcone, whereas a substituent in the 6-position apparently hinders cyclization (62TL593). Chalcone O-glycosides are isomer-ized under mild conditions (69CB785). 

Chalcone synthase (CHS) and chalcone reductase (CHR) convert 4-coumaro-yl-CoA (15) and 3 mol malonyl-CoA (16) to trihydroxychalcone (a chalcone) (17) via tetrahydroxychalcone (a chalcone) (18). Chalcone isomerase (CHI) converts trihydroxychalcone (a chalcone) (17) into liquiritigenin (7,4/-dihydroxyllavanone, a flavanone) (19). Isoflavone synthase (IFS) converted flavanone (19) to isoflavones (20) such as daidzein (21) and genis-tein (22). Isoflavone 2/-hydroxylase (I2 H) hydroxylated isoflavones (20) to 4/-methoxyisoflavones (23). Isoflavone 2 -hydroxylase (I2 H) hydroxylated 4/-methoxyisoflavones (23) into 2/-hydroxy-4/-methoxyisoflavones (24). Isoflavone reductase (IFR) reduced 2/-hydroxy-4/-methoxyisoflavones (24) to 2/-hydroxy-4/-methoxyisoflavonones (25). Finally, vestitone reductase (VR) and 4/-methoxyisoflavanol dehydrogenase (DMID) cyclized 2/-hydroxy-4/-methoxyisoflavonones (25) to form isoflavonoids (26) such as medicarpin (27) (Fig. 4) [23,24]. 

Cyclization conditions also seem to be of paramount importance in determining the products from the ring closure of o-hydroxy-a-acylchalcone (10).15 Treatment of 10 with hydroxylamine hydrochloride in pyridine furnishes the oxime (11 X = NOH) of the o-hydroxybenzoylisoxazoline (11 X = O), the product from the action of hydroxylamine hydrochloride and sodium acetate on the chalcone. In contrast, with ethanolic hydroxylamine hydrochloride, 10 yields only the indoxazene (12 R = Ac, Ar = Ph). 

Type I and Type II PKSs catalyze multiple rounds of reactions by catalytic modules encoded either by a single polypeptide (PKS I) or on separate polypeptides (PKS II) by analogy to FAS-I and FAS-II. In contrast, PKS Ills are dimers of KASs that catalyze multiple condensation reactions in one active site and include chalcone synthase, stilbene synthase, and 2-pyrone synthase (see Chapters 1.05, 1.07, and 1.04). In the case of chalcone synthase, three consecutive condensation reactions each utilizing malonyl-CoA, followed by a cyclization reaction, lead to the formation of 4, 2, 4, 6 -tetrahydroxychalcone from 4-hydroxycinnamoyl-CoA (Figure 3). Recruitment of a reductase leads to the formation of a product lacking the 6 -hydroxy group, a reaction that requires an intermediate in the synthesis of chalcone to dissociate from the synthase active site. 

Mechanisms for the formation of homoisoflavanones have been thoroughly discussed by Dewick (79). In analogy to flavonoid biosynthesis 32) an intermediate (93) produced from a chalcone (92) could be formed. The latter would cyclize to the chromanone (95) giving the homoisoflavanones (94) or (97) either by elimination of a proton or by hydride transfer. Addition of water to (94) or hydroxylation of (97) would finally lead to the 3-hydroxy derivative (96). 

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