Chalcone, epoxidation

The first enantioselective synthesis of cis- and trans- 3-hydroxyflavanones is based on the Lewis-acid-catalysed reaction of phenylmethanethiol with chalcone epoxides <96CC2747>. Further support for the intermediacy of epoxides in the Algar-Flynn-Oyamada flavone synthesis has been provided by the isolation of epoxides in the corresponding preparation of 3-hydroxy-2-phenylquinol-4-ones <96JCS(P2)269>. 

In the first of these techniques the lanthanoid complex (33) (5-8 mol%) is used as the organometallic activator in cumene hydroperoxide or tert-butyl hydrogen peroxide-mediated oxidation of chalcone (epoxide yield 99 % 99 % ee) or the ketone (34) (Scheme 20)[1001. 

The publication (70) in 1976 of the preparation of optically active epoxyketones via asymmetric catalysis marked the start of an increasingly popular field of study. When chalcones were treated with 30% hydrogen peroxide under (basic) phase-transfer conditions and the benzylammonium salt of quinine was used as the phase-transfer catalyst, the epoxyketones were produced with e.e. s up to 55%. Up to that time no optically active chalcone epoxides were known, while the importance of epoxides (arene oxides) in metabolic processes had just been discovered (71). The nonasymmetric reaction itself, known as the Weitz-Scheffer reaction under homogeneous conditions, has been reviewed by Berti (70). 

Structural and Solvent Effects in the Asymmetric Induction of Chalcone Epoxides... 

The effect of additives on Shibasaki s lanthanide-BINOL catalysts has been investigated by Inanaga and coworkers. From a variety of additives, triphenylphosphine oxide turned out to be the best one improving, for example, the obtained ee for the chalcone epoxide from 73% to 96% (Table 16) . The explanation for the positive effect of the additive was the disruption of the oligomeric structure of the catalyst by coordination of the phosphine oxide. As a consequence, epoxidation takes place in the coordination sphere of the ytterbium where the reaction site might become closer to the chiral binaphthyl ring due to the phosphine oxide ligand with suitable steric buUdness. In contrast to the Shibasaki... 

An alternative method for the epoxidation of enones was developed by Jackson and coworkers in 1997 , who utilized metal peroxides that are modified by chiral ligands such as diethyl tartrate (DET), (5,5)-diphenylethanediol, (—)-ephedrine, ( )-N-methylephedrine and various simple chiral alcohols. The best results were achieved with DET as chiral inductor in toluene. In the stoichiometric version, DET and lithium tert-butyl peroxide, which was generated in situ from TBHP and n-butyllithium, were used as catalyst for the epoxidation of enones. Use of 1.1 equivalent of (-l-)-DET in toluene as solvent afforded (2/f,35 )-chalcone epoxide in 71-75% yield and 62% ee. In the substo-ichiometric method n-butyllithium was replaced by dibutylmagnesium. With this system (10 mol% Bu2Mg and 11 mol% DET), a variety of chalcone-type enones could be oxidized in moderate to good yields (36-61%) and high asymmetric induction (81-94%), giving exactly the other enantiomeric epoxide than obtained with the stoichiometric system (equation 37). 

Solvent evaporation in a rotary evaporator afforded the crude product, which was further purified by column chromatography (silica gel, CH2CI2) to give the ( )-(2S,3/ )-chalcone epoxide (0.23 g, 99% yield, >99% de, 90% ee). (/f)-BINOL was recovered almost quantitatively in the last fractions. 

When dienones such as 55 are subjected to the epoxidation conditions the electron-poorer C=C double bond is selectively epoxidized. The other C=C bond can be functionalized further, for example, it can be dihydroxylated, as shown in the synthesis of the lactone 56 (Scheme 10.11) [82]. Stannyl epoxides such as 57 (Scheme 10.11, see also Table 10.8, R1 = n-Bu3Sn) can be coupled with several electrophiles [72], reduction of chalcone epoxide 58 and ring opening with alkyl aluminum compounds provides access to, e.g., the diol 59 and to phenylpropionic acids (for example 60). Tertiary epoxy alcohols such as 61 can be obtained with excellent diastereoselectivity by addition of Grignard reagents to epoxy ketones [88, 89]. 

Acidic hydrolysis of benzoylepoxides 1087 provides an asymmetric route to 2-alkylchromanA-oncs (Equation 426) <1999JOC3489>. During treatment of (/. )-2 -hydroxyA-rncthoxychalcone with DMDO in a reaction medium buffered to pH 4.4, a chalcone epoxide is implicated as the 6-exo-trig cyclization precursor that leads to an anti-2,3-dihydroflavonol <1997T8491>. 

H202 are required [72]. These authors also investigated the effect of the method used for the preparation of polyleucine, and found that material made by high-temperature polymerization gave the best results. Much lower loadings of polyleucine can now be used (down to 0.5 mol% for chalcone epoxidation). The same group has carried out the process on the 100-g scale [73]. Although these conditions have not yet been tested as widely as the Roberts biphasic ones, a non-chalcone substrate was reported (Scheme 12.16). 

The use of numerous polymer-supported optically active phase transfer catalysts was further extended by Kelly and Sherrington11351 in a range of phase transfer reactions including a variety of displacement reactions, such as sodium borohydride reductions of prochiral ketones, epoxidation of chalcone, addition of nitromethane to chalcone and the addition of thiophenol to cyclohexanone. Except in the chalcone epoxidation, all the examined resin catalysts proved to be very effective. However, with none of the chiral catalyst system examined was any significant ee achieved. The absence of chiral induction is a matter of debate, in particular over the possible reversibility of a step and the minimal interaction within an ion pair capable of acting as chiral entities in the transition state and/or the possible degradation of catalysts and leaching. 

A cycloaddition methodology has been exploited in the cation radical-mediated reactions between electron-rich chalcone epoxides 287 and A -aryl imines 286 using tris(4-bromophenyl)aminium hexachloroantimonate (TBPA -SbCle ) as the radical initiator to generate substituted 1,3-oxazolidines 288a and 288b in good yields (Equation 21) <2005SL161>. 

The first catalytic asymmetric version of the Darzens reaction was achieved in 1978 by J. Hummelen and H. Wynberg [41]. The treatment of p-chlorobenzaldeh ydc and phenacylchloride with the strong base NaOH in the presence of the benzyl quini-nium chloride 86 as a chiral catalyst (6 mol%) afforded the trans-chalcone epoxide 98 in 68% yield. However, the optical yield achieved was only in the range of 7-9% ee (Scheme 8.33). 

Wroblewski, A.E., and Karolczak, W., Chalcone epoxide derived hydroxyphosphonates. Synthesis, stereochemistry and ring opening reactions, Pol. J. Chem., 72, 1160, 1998. 

Kee S, Gavriiliidis A (2007) Batch versus continuous mg-scale synthesis of chalcone epoxide with soluble polyethylene glycol poly-L-leucine catalyst. J Mol Catal A Chem 263(1-2) 156-162... 

Flavans.—The presence or absence of a 6 -substituent in chalcone epoxides plays an important part in the course of the reaction which leads to a flavanol only for 6 -unsubstituted epoxides. Reduction of 2 -(benzyloxy)chalcone epoxides (181) with LiAlH4 and AICI3 led to flavan-2,3-rran5-3,4-m-diols or the 2,3-trans-3,4-trans-dio s, depending on the substitution pattern of the benzene ring adjacent to the carbonyl group. 

Flavones are built by oxidation. The enzyme catalyzing the reaction needs molecular oxygen. It is not yet elucidated whether a chalcone epoxide is an intermediate. 

Fig. 315. Possible formation of dihydroflavonols from chalcone epoxides...

The absolute configuration of chalcone epoxide (17) has been assigned by chemical correlation studies,and a detailed study of the Rasoda synthesis of dihydroflavonols undertaken. A total synthesis of the important naturally occurring epoxide picrotoxinin has been published. The important epoxidation reaction of (18) proceeds stereospecifically to yield (19), which is readily converted into picrotoxinin (Scheme 19). 

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