The synthesis of compounds related to naturally occurring flavanoids

Flavanoid compounds exist in many parts of plant life and assume various roles which are not yet fully understood. A study of flavanoids based on the flavan-3-ol (I : R=OH, R′=H) and the flavan-3:4-diol (I : R=R′=OH) skeleton, is essential for investigation of the functions fulfilled by flavanoids in plants. The synthesis of such flavanoids of particular stereochemistry requires the development of stereospecific methods. Until recently, confusion existed in the knowledge of the stereochemistry of the heterocyclic ring in flavanoids, and particularly the configurations and conformations existing in flavan-4-ols (I : R=H, R′=OH).
A number of simple flavan-4-ols have been synthesised, and their benzoates shown, by a strict examination by nuclear magnetic resonance spectroscopy, to exist in a "half chair" conformation, with the oxygen function axial in the α-flavanols and equatorial in the β-flavanols. Accurate data and interpretation in the α-series has not previously been available; the results for compounds in the β-series are in excellent agreement with those found by other workers.
Flavan-4α-ols were synthesised by the oxime route which has been little used. The route has been shown to be the most reliable of the methods available for the synthesis of flavan-4α-ols. Synthesis of racemic tri-O-methylpeltogynol (II : R=CH3) has been accomplished. (+)-Peltogynol and its isomer peltogynol B, (II : R=H), occur in "purple heart", Peltogyne porphyrocardia, a rare Amazonian tree. The critical stage in the synthesis was the specific oxidation of the secondary benzylic hydroxyl group, at the 4-position in the triol (III) to the flavan-4-one (IV) leaving the primary benzylic hydroxyl group present, unoxidised. This was achieved with activated manganese dioxide under the conditions described by Turner. Dehydration and reduction yielded racemic tri-O-methylpeltogynol shown by melting point, infra-red spectroscopy and mass-spectrometry to be structurally identical with the methylated natural product.
Synthesis of tri-O-methylcyanomaclurin (V) which occurs unmethylated in jackwood, Artocarpus integrifolia, was attempted. Failure of phloracetophenone-4:6-dimethyl ether (VI : R=H) to condense with β-resorcyl aldehyde-4-methyl ether (VII : R=H) or with the easily hydrolysed benzoate of the aldehyde (VII : R=COPh) under alkaline conditions, is attributed to the reduction of aldehydic character by the o-phenoxide ion. Condensation was found to occur under acid conditions to yield the flavylium salt (VIII : R=H). A similar flavylium salt (VIII : R=OCH3) was prepared by condensation of ω-methoxyphloracetophenone-4:6-dimethyl ether (VI : R=OCH3) with the aldehyde (VII : R=H) under acid conditions. These compounds may be important intermediates in future work on the synthesis of tri-O-methyl-cyanomaclurin.
The condensation of catechins with phenols under acid conditions may be operative in the natural formation of some tannins. Recent studies on such condensations have included the condensation of (+)-catechin with phloroglucinol to yield a complex condensate, C21H18O8, whose structure could not be determined at that time. Two mechanisms were postulated for its formation, each of which would give rise to a different product. In a similar experiment, simpler starting materials, 3-hydroxy-4′-methoxyflavan and phenol, were used and the product treated with dimethyl sulphate and potassium carbonate. The product analysed approximately for the molecular formula C23H22O3, which represents the flavan (IX) and also the coumaran (X), these structures arising from each of the two mechanisms postulated for this kind of condensation. The flavan (IX) was synthesised and found to be different from the "methylated condensation product". The coumaran (X) has now been synthesised by the hydrogenation and hydrogenolysis of the carbinol (XI), which was prepare by Grignard reaction of ethyl coumarilate (XII) with anisyl magnesium bromide. Ethyl coumarilate (XII) was prepared by condensation of salicylaldehyde with ethyl bromoacetate.
Several attempts had been made to synthesise the coumaran (X) by other routes. In one, attempted oxidation of 2:2-di-anisylethanol (XIII : R=CH 2 OH) to 2:2-dianisylacetaldehyde (XIII : R=CHO) yielded 1:1-dianisylethylene (XIV : X=CH2); in another, attempted formation of the Grignard reagent (XIII : R=MgBr) from the bromide (XIII : R=Br) and carbonation yielded 4:4′-dimethoxybenzophenone (XIV : X=O); and in another, rearrangement of hydroanisoïn (XV) on treatment with sulphuric acid yielded desoxyanisoïn (XVI) and not the aldehyde (XIII : R=CHO).
The coumaran (X) was found to be different from the "methylated condensate". Consequently, the latter was examined by n.m.r. spectroscopy, which revealed that condensation had not taken place and that simple dehydration had given rise to the flav-2-ene (XVII). This was hydrogenated at room temperature to yield the known compound, 4′-methoxyflavan (XVIII).
While this work was in progress, the complex product obtained by condensation of (+)-catechin and phloroglucinol was being investigated and its structure established as a coumaran (XIX) by chemical and mass-spectrometric evidence. The mechanism of its formation was shown to be attack of phloroglucinol on the carbon atom at C2 in (+)-catechin, opening the heterocyclic ring, followed by dehydration involving the 3-hydroxyl group and one of the o-hydroxyl groups in the phloroglucinol group, a mechanism which would not operate with the simpler starting materials used by Warren.
A convenient route to simple flavans (e.g., (XX) ) is by the reduction of 2-hydroxychalcones (e.g., (XXI) with lithium aluminium hydride-aluminium chloride. In the reduction of 2-hydroxy-4′-methoxychalcone (XXI) with this reagent, 4′-methoxyflavan (XX) was isolated in 23% yield, together with an alcohol m.p. 136-7° (49%) obtained only when methyl formate was used in the isolation procedure. Reduction of the tosylate of this alcohol with lithium aluminium hydride yielded the methylflavan, C17H18O2, m.p. 106-7°. Investigations into the nature of the methylflavan, m.p. 106-7° suggested that it might be a 2:3-trans-3 -or a4-methylflavan. The 4′-methoxy-4-methylflavans (XXII), isomeric at the 4-position, have been synthesised as an inseparable mixture, by two methods, both of which involved reduction of the flavan-4-ol (XXIII) and which gave a 1:1 mixture of isomers. The n.m.r. spectrum of the mixture shows two discernible superimposed spectra, which confirm the structures (XXII), and which are quite unlike the spectrum of the methylflavan, m.p. 106-7°. However this spectrum is not of sufficient quality to make exact assignments. Accordingly, the spectrum was measured afresh, and an excellent spectrum obtained, which establishes the structure of the methylflavan (XXIV). This is isomeric with the 3-methylflavan previously prepared (XXV). The future unambiguous synthesis of this 2:3-trans-3-methylflavan will no doubt confirm the structure (XXIV).
[For the diagrams to accompany this abstract, please consult the PDF.]