Phenolic lipids synthesis

Dihydric phenolic lipids of the cardol type are the most abundant in plant, fungal and bacterial kingdoms. The first species in which the members of the title subclass of phenolic lipids, resorcinolic lipids, were found was Ginkgo biloba (Ginkgoaceae) [6,9,10,17]. Later, the presence of resorcinolic lipids (5-n-alk(en)ylresorcinols) was shown also in other species, first, in the Anacardiaceae [14], which is an important source of various phenolic lipids, not only of alkylresorcinols but also of alkylphenols and alkylcatechols. For example, the cashew and the processing of cashew nuts are the main source of phenolic lipids for the formaldehyde-polymer industry. Aspects of Anacardium occidentale in relation to synthesis, semi-synthesis and chemical industry have been reviewed Tyman [1,11,14] as well as a recent book [2]. 

Prior to structural elucidation and possible eventual synthesis, the isolation of component phenolic lipids in a pure state is essential. The cold methods of thin layer chromatography (TLC), column chromatography (CC), flash chromatography, high performance liquid chromatography (HPLC) and hot methods (GC), often after derivatisation, are well established. Argentation versions of these separatory methods are less common but are desirable for the rapid separation of unsaturated constituents. 

Synthesis has often followed structural elucidation of a phenolic lipid to complete the characterisation process. However it may also become of greater significance in the study of biological properties, particularly in the involvement of structure/activity relationships. 

The synthesis of phenolic lipids of all types bearing saturated side-chains presents few problems and has been approached by the methodologies of classical organic chemistry [1,2,11,131]. 

With 3,5-dimethoxybenzoyl chloride used in the monoacylation of cyclohexanone to produce finally the same (MeO ArC synthon, an alternative synthesis of cardol 8(Z)-monene was developed [138]. Fig( 4)-49, Persoonol dimethyl ether (5-[(Z)-undec-3-enyl]resorcinol dimethyl ether) was synthesised from 3,5-dimethoxybenzyl alcohol [149], This same reactant has been employed for a range of 5-substituted resorcinols although its application to unsaturated phenolic lipids was not discussed [228]. Acetylenic methods have proved valuable for deriving phenolic lipidic double bonds in the Z-configurations and with advances in boration methodology [229] the corresponding E-isomers are accessible. 

The Wittig reaction approach provides an alternative route to the synthesis of the unsaturated phenolic lipids in urushiol in Rhus vernicifera, which contains three C15 isomeric trienes, the major constituent the semi-conjugated Fig (3)-4, 8(Z),11(E),13(Z), (55.4%), the trace corresponding 13(E) isomer (1.7%) and the non-conjugated Fig (3)-5, 8(Z), 11(E), 14 (7.4%) which is also the chief component in urushiol from Rhus toxicodendron. Scheme 1 shows the routes to the first and last constituents [230-233]. 

Subsequently, this approach to the synthesis of C15 phenolic lipids consisted in the route ArCi - ArCis. It has proved generally convenient for the synthesis of the unsaturated anacardic acids. From the methodological view it is also an aspect of the use of acyclic intermediates discussed in the next section since the starting material ethyl 2-methoxy-6-methylbenzoate is prepared from ethyl acetoacetate. 

Synthesis has been useful in the chemistry of phenolic lipids for structural confirmation and in enabling structure/property correlations to be made by the general applicability of syntheses to a range of non-natural isomers. With the polyunsaturated constituents synthesis is valuable since either argentation chromatography or preparative HPLC have usually proved laborious on the natural products and on transformed isomeric compounds required for evaluatory purposes in structure/activity studies. 

For the synthesis of polymethyl phenolic lipids such as a-leprosol and its isomer... 

The synthesis of 5-(2-oxoalky0resorcinols which are present in Cereale secale has been simply effected by the reaction of 3,5-dimethoxyphenylacetyl chloride with a dialkyl cadmium reagent in the folowing way (ref. 99). The 2-hydroxy compound shown as the final product is also present in the phenolic lipids of rye. 

With hydride reagents such as dibal, Z-alkenes can be selectively obtained from alkynes in the phenolic lipid series (ref. 162), and related series of boron reagents greatly supplement the chemical methods of selective reduction and alkyiation. This selectivity has been achieved by the use of less reactive dialkylboranes such as bis(3-methyl-2-butyl)borane (di-isoamylborane), bis(2,3-dimethyl-2-butyl)borane (thexylborane), 9-boraUcyclo[3.kl]nonane (9-BBN) and dicyclohexylborane. Some applications in the polyethenoid field have been summarised (refs. 135,163) and the synthesis of alkenyl compounds generally reviewed (ref. 164). By the use of dibromoborane dimethylsulphide, an internal alkyne can be reduced selectively (ref. 165) as for example in the following way (R = n-alkyl). 

Since cardanols can be obtained from anacardic acids and cardols from orsellinic acids, the methods outlined have a general applicability to a range of phenolic lipids. Reference has been made largely to the phenols of the Anacardiacae but the methods are likely to be applicable to other phenolic systems, and those with methylene-interrupted structures at different side-chain positions. Alkynes and phosphorans have both proved invaluable in synthetic studies but attention should be drawn to the very elegant use of ailenic compounds in the polyethenoid (arachidonic) series (ref. 168) which has a potential application with phenolic lipids. Methods for the synthesis of leukotrienes are also relevant for the methylene group-interrupted structures of phenolic lipids (169). 

Tyman, J.H.P., and N. Visani, Synthesis of Polyunsaturated Constituents of Phenolic Lipids, Chem. Phys. Lipids 85 157-174 (1997). 

Ciprofibrate (48), a more potent lipid-lowering agent clofibrate, is prepared from Simmons-Smith product by Sandmeyer replacement of the amino group by a hydroxyl via the diazonium salt. Phenol undergoes the Reimer-Thiemann like process common to these agents upon alkaline treatment with acetone and chloroform to complete the synthesis of ci profib-rate (48). 

A plausible pathway is that the aromatisation of the cyclohexadienone 92 by a proton shift is accelerated in the presence of Ac20 under formation of acetate 93. The simultaneously generated acetic acid then cleaves the acetate to form the free phenol 94 (Scheme 44). This effect was observed for the first time during studies towards the total synthesis of the lipid-alternating and anti-atherosclerotic furochromone khellin 99 [64].The furanyl carbene chromium complex 96 was supposed to react with alkoxyalkyne 95 in a benzannulation reaction to give the densely substituted benzofuran derivative 97 (Scheme 45). Upon warming the reaction mixture in tetrahydrofuran to 65 °C the reaction was completed in 4 h, but only a dimerisation product could be isolated. This... 

Plant metabolism can be separated into primary pathways that are found in all cells and deal with manipulating a uniform group of basic compounds, and secondary pathways that occur in specialized cells and produce a wide variety of unique compounds. The primary pathways deal with the metabolism of carbohydrates, lipids, proteins, and nucleic acids and act through the many-step reactions of glycolysis, the tricarboxylic acid cycle, the pentose phosphate shunt, and lipid, protein, and nucleic acid biosynthesis. In contrast, the secondary metabolites (e.g., terpenes, alkaloids, phenylpropanoids, lignin, flavonoids, coumarins, and related compounds) are produced by the shikimic, malonic, and mevalonic acid pathways, and the methylerythritol phosphate pathway (Fig. 3.1). This chapter concentrates on the synthesis and metabolism of phenolic compounds and on how the activities of these pathways and the compounds produced affect product quality. 

Resveratrol has also been reported to offer protection against cardiovascular disease, such as coronary heart disease. The effects of resveratrol on factors implicated in the development of coronary heart disease - human platelet aggregation and the synthesis of eicosanoids (lipids) from arachidonate by platelets - were investigated and compared with the actions of other wine phenolics - catechin (1.39), epicatechin (7.18a), and quercetin (1.43) - and the antioxidants a-tocopherol (7.10a), hydroquinone and butylated hydroxytoluene. Resveratrol and quercetin demonstrated a dose-dependent inhibition of platelet aggregation, whereas the other compounds tested were inactive. Resveratrol also inhibited the synthesis of the eicosanoids in a dose-dependent manner, whereas the other phenolics were less effective of not effective at all. Removal of the alcohol from the wine did not diminish the effect on platelet aggregation (Pace-Asciak et al., 1995 Goldberg et al., 1995). 

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