A study of the reactions of flavanoids with nucleophiles

Thesis

The reactions with nucleophiles of 4-substituted flavans variously methoxylated are studied. The partial epimerisation of 4β-acetoxyflavans in acetic acid/acetic anhydride mixtures and of flavan-4β-ols in aqueous acid, providing preparatively useful routes to 4α-acetoxyflavans and flavan-4α-ols, occur by an S_N1 mechanism. Reaction is greatly facilitated by methoxyl groups at the 5- and, especially, the 7-position. No effect of B-ring substitution on reaction rates was detected. Equilibrium mixtures of epimers studied contained 5–10% of the 4α-isomer.

2,3-Trans-3,4-trans-diacetoxy-5,7,3′,4′-tetramethoxyflavan (1) is considerably less reactive than 4β-acetoxy-5,7,3′,4′-tetramethoxyflavan (2). An equilibrium mixture of (1) with its 4-epimer contains ca. 16% of (1). Some puzzling reactions reported in the literature are explained by the results of this study or shown to be wrong.

The 4-carbocation generated by decomposition of (2) also reacts with phenols, providing the first satisfactory route to 4α-aryloxy-5,7,3′,4′-tetramethoxyflavans. The phenols (and yields of aryloxyflavan) are: phenol (60%), m-methoxyphenol (46%), m-benzoyloxyphenol (51%) and 3,5-dimethoxyphenol (9%). Generation of the necessary carbocation for synthetic purposes from flavanoids possessing a 3-oxygen substituent or lacking a 5-methoxyl substituent requires a better leaving group. Benzoate and p-nitrophenoxy are convenient for ease of preparation and reaction. Thus, 4α-phenoxy-7,3′,4′-trimethoxyflavan (39%) and 2,3-trans-3,4-cis-4-phenoxy-5,7,3′,4′-tetramethoxyflavan-3-ol (15%) and its 4-epimer (1%) are prepared.

7-Hydroxyflavanoids, intended to act as nucleophiles in syntheses of ether-linked flavanoid dimers (modelling postulated naturally occurring polymers) are synthesised with the aid of protection of the 7-hydroxyl group. Those which possess a 4-acyloxy group or 3,4-double bond are too labile, particularly in the presence of base, to be isolated. 7-Hydroxy-3′,4′-dimethoxyflavanone (3), 2,3-trans-3-benzoyloxy-3′,4′-dimethoxyflavan-7-ol (4) and also 2,3-trans-3′,4′-dimethoxyflavan-3,7-diol and 2,3-trans-3,4-cis-3′,4′-dimethoxyflavan-3,4,7-triol were isolated. The reagent osmium tetroxide/N-methylmorpholine-N-oxide was used to accomplish stereoselective bis-hydroxylation of flav-3-enes in high yield.

(3) And (4) react with 4β-(p-nitrophenoxy)-5,7,3′,4′-tetramethoxyflavan. 7-(5,7,3′,4′-tetramethoxyflavan-4α-yloxy)-3′,4′-dimethoxyflavan-4β-ol (formed by sodium borohydride reduction) and its acetate, and 7-(5,7,3′,4′-tetramethoxyflavan-4α-yloxy)-2,3-trans-3-benzoyloxy-3′,4′-dimethoxyflavan were isolated. Their structures are confirmed by n.m.r. and mass spectroscopy.

Authors: Attwood, M

• DOI: 10.5287/ora-6r8zzye9j
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford