Synthesis, conformation analysis, and characterization of physiologically important flavonoids and isoflavonoids

Abstract

This work contains two parts of study: Synthesis of a series of homoisoflavonoid analogues in order to investigate a difference between 6- and 8- homoisoflavanone which isolated from Scilla Natalensis and Part II contains conformational analysis of C-ring substituted flavans and analogues. While the novel homoisoflavanone isolated from Scilla natalensis as the peracetate has unambiguously been proven by synthesis to have the 5,7,4’-triacetoxy-8-methoxy structure during this investigation. The control of the substituents (protecting groups) is determined the Aring of a homoisoflavanone which has also been pointed out that great care should be taken in the assignment of the structures of these compound by comparison of proton chemical shifts. This is especially true when a single methoxy group is situated on a trioxygenated A-ring as there might not be an nOe association between the methyl protons and any aromatic hydrogen. The situation may further be aggravated by the fact that natural products may be isolated as derivatives, like peracetates, of the naturally occurring free phenolic analogues due to separation difficulties. Although only two of the possible 6 A-ring trioxygenated homoisoflavanones have been synthesised e.g. 5,7,4’-trihydroxy-6-methoxyhomoisoflavanone and 5,7,4’-trihydroxy-8- methoxyhomoisoflavanone, it is envisaged that the remaining four compounds will also be prepared so the 1H and 13C NMR data of all these compounds both as free phenols and peracetates can be reported. This will be a valuable tool to assist researchers during the isolation and structure elucidation of this class of natural product during future phytochemical investigations. In an effort to divulge the effect of the individual stereocenters form each other, and thus the combined effet obtained by ECD, it was decided to investigate the chromophore based method of VCD as measurement of absolute configuration at the different stereogenic centres. If a correlation between the IR absorption band(s) at certain wave numbers and a specific chromophore in a molecule could be established, it should, in principle, be possible to define the absolute comfiguration at that point in the molecule by VCD. In order to find a possible relationship between chromophores and IR absorption bands in flavonoids and related molecules, a molecular modelling study to determine the preferred conformation of the heterocyclic ring of these compounds as well as establish a possible correlation between the chromophore present in the molecule and IR band(s) was embarked upon. In this regard, the preferred conformation(s) of the series of heterocyclic molecules with increasing order of complexity, i.e. no substituent to three heterocyclic substituents, were determined and correlated with the respective modelled IR frequencies as well as the experimental absorption bands in the IR spectrum. In this study a complete conformational surface of oxane, chromane, flavan, flavan-3-ols, 4- arylflavan and 4-arylflavan-3-ols is presented to give the global and local minima which reulted in finding the most stable conformations. However, the most stable conformations for these compounds are the chair, 2,5-twisted boat and 1,4-twisted boat (oxane); half chair (chromane); [(2R)-equatorial and (2S)-equatorial (flavan)]; [(2S)-equatorial, (3S)-axial and (2S)-equatorial, (3R)-equatorial (flavan-3-ol)]; [(2S)-equatorial, (4R)-axial and (2S)-equatorial, (4S)-equatorial (4-arylflavan)] and {[(2S)-axial, (3S)-equatorial, (4R)-axial], [(2S)-axial, (3S)-equatorial, (4S)-equatorial], [(2S)-equatorial, (3R)-equatorial, (4R)-equatorial] and [(2S)-equatorial, (3R)-equatorial, (4S)-axial] (4-arylflavan-3-ols)}. The assignment of IR absorption from theoretical spectra is presented and the excellent match between theoretical and experimental IR analysis is achieved. It’s evidently concluded that the method of using TDDFT calculations together with infrared spectroscopy to determine the most stable or preferred conformation was achieved for flavonoid compounds. The determining of absolute configuration at a chiral centre in selected flavonoid compounds and understanding of its IR spectra is currently under investigation with the same approach. The calculated VCD spectrums of the highest populated conformations are presented e.g. [(2R)- equatorial (flavan)]; [(2S)-equatorial, (3S)-axial and (2S)-equatorial, (3R)-equatorial (flavan-3- ol)]; [(2S)-equatorial, (4R)-axial and (2S)-equatorial, (4S)-equatorial (4-arylflavan)] and {[(2S)- axial, (3S)-equatorial, (4R)-axial], [(2S)-axial, (3S)-equatorial, (4S)-equatorial], [(2S)- equatorial, (3R)-equatorial, (4R)-equatorial] and [(2S)-equatorial, (3R)-equatorial, (4S)-axial] (4-arylflavan-3-ols)} were also achieved successfully.