Prenyl vitamins

Animals caimot synthesize the naphthoquinone ring of vitamin K, but necessary quantities are obtained by ingestion and from manufacture by intestinal flora. In plants and bacteria, the desired naphthoquinone ring is synthesized from 2-oxoglutaric acid (12) and shikimic acid (13) (71,72). Chorismic acid (14) reacts with a putative succinic semialdehyde TPP anion to form o-succinyl benzoic acid (73,74). In a second step, ortho-succmY benzoic acid is converted to the key intermediate, l,4-dihydroxy-2-naphthoic acid. Prenylation with phytyl pyrophosphate is followed by decarboxylation and methylation to complete the biosynthesis (75). 

Tabushi et al. (1979) have shown that p-cyclodextrin in aqueous alkaline solution allows highly selective one-step synthesis of vitamin Kj (or K2) analogues here the key step is alkylation of 2-methyl hydronaphthoquinone with allyl, crotyl, methallyl, or prenyl bromide. 

Another important family of quinones, related in structure to those already discussed, are the vitamins K (Fig. 15-24, Box 15-F). These occur naturally as two families. The vitamins K, (phylloquinones) have only one double bond in the side chain and that is in the prenyl unit closest to the ring. This suggests again the possibility of chromanol formation. In the vitamin K2 (menaquinone) series, a double bond is present in each of the prenyl units. A synthetic compound menadione completely lacks the polyprenyl side chain and bears a hydrogen in the corresponding position on the ring. Nevertheless, menadione serves as a synthetic vitamin K, apparently because it can be converted in the body to forms containing polyprenyl side chains. 

The vitamins K and other naphthoquinones arise from O-succinylbenzoate84 86 whose synthesis from chorismate and 2-oxoglutarate depends upon a thiamine diphosphate-bound intermediate, as indicated in Fig. 25-4. Elimination of pyruvate yields O-succinylbenzoate. The remaining reactions of decarboxylation, methylation, and prenylation (Fig. 25-4) resemble those of ubiquinone synthesis. 

This article is a summary of our recent extensive study of tumor specificity (TS) and the type of cell death induced by N-containing heterocycles such as 4-trifluoromethylimidazole [22] and phenoxazine derivatives [23], by O-containing heterocycles such as 3-formylchromone [24] and coumarin derivatives [25,26], and by other compounds such as vitamin K2 and prenyl-alcohols [27]. 

Cross-coupling ofallyl bromides with allyltins (cf. 10, 26). The coupling of prenyl bromide with the tin reagent 1 in the presence of 10% ZnCh gives myrcene (2) in high yield. This coupling also provides a synthesis of vitamin K, (3). ... 

Retinoids. A new procedure has been described for the synthesis of vitamin A [retinol (95)] and related compounds via ir-allyl Pd complexes. Thus prenyl acetate (96) with PdCl2 gave the complex (97), the structure of which was... 

In addition to cholesterol and its derivatives, a remarkable array of biomolecules are synthesized from isopentenyl pyrophosphate, the basic five-carbon building block. The hydrocarbon side chains of vitamin K2, coenzyme Qjq, and chlorophyll are extended chains constructed from this activated C5 unit. Prenyl groups that are derived from this activated intermediate target many proteins to membranes. 

The Ru catalyst can also be successfully applied to the sequential introduction of chirality into the prenyl side chain of vitamin E [20]. In this case, a Ru complex with a 2-furyl MeOBIPHEP ligand is used for the hydrogenation of unsaturated ketones to give saturated ketones in 94 ... 

A review of the biosynthesis of Vitamin K and other naturally occurring naphthoquinones and an outline of recent work on the induction of biosynthesis, metabolic turnover, and kinetics of formation of this vitamin and other prenyl lipids have appeared. The prenylation of 4-hydroxybenzoate has been further studied.A cell-free extract of Euglena gracilis could synthesize nona- and octa-prenyltoluquinol from homogentisate and a Micrococcus luteus extract that had been pre-incubated with IPP. The same system produced 2-deca-, 2-nona-, and 2-octa-prenyl forms of 4-carboxy-2-polyprenylphenoI when p-hydroxybenzoate... 

Several important biomolecules are composed of nonterpene components attached to isoprenoid groups (often referred to as prenyl or isoprenyl groups). Examples of these biomolecules, referred to as mixed terpenoids, include vitamin E (a-tocopherol) (Figure 10.22a), ubiquinone (Figure 10.3), vitamin K, and some cytokinins (plant hormones) (Figure 11.11). 

MK biosynthesis by the OSB pathway has been elucidated on the basis of isotopic tracer experiments, isolation of mutants blocked in the various steps, isolation and identification of intermediates accumulated by the mutants, and by enzyme assays. Early isotopic tracer experiments with various bacteria established that methionine and prenyl PPi contribute to the methyl and prenyl substituents of the naphthoquinone. The early isotopic tracer studies and other work have been reviewed by Bentley and Meganathan. " In 1964, Cox and Gibson observed that [G- " C] shikimate was incorporated into both MK and ubiquinone by E. coli, thus providing the first evidence for the involvement of the shikimate pathway." Chemical degradation of the labeled isolated menaquinone (MK-8) showed that essentially all of the radioactivity was retained in the phthalic anhydride. It was concluded that the benzene ring of the naphthoquinone (sic) portion of vitamin K2 arises from shikimate in E. coli The authors further suggested that shikimate was first converted to chorismate before incorporation into MK. A more complete chemical degradation of the MK derived from... 

Isoprenylated Quinones.—A book has been published dealing with biomedical and clinical aspects of coenzyme Q [ubiquinone (203)]. Other reviews have appeared on the chemistry and biochemistry of ubiquinone,vitamin K [phyl-loquinone (204) and menaquinone (205)], and plastoquinone (206) and on the chemical methods for prenylation of quinones. ... 

An easy synthesis of prenyl naphthoquinones, e.g. menaquinone-2 (205 n = 2), was achieved by coupling the appropriate prenyl halide with an organo-copper derivative of the electrochemically derived quinone bisacetal (216). Menaquinone-2 and phylloquinone (204) were also obtained in good yields by reaction of 2-methyl-1,4-naphthoquinone (205 n =0) with geranyl and phytyl halides in the presence of metal dust. A one-step method for the preparation of vitamin K analogues uses cyclodextrin inclusion catalysts.Thus reaction of the diol (217) with allyl bromide in the presence of oxygen and/3-cyclodextrin at pH 9 afforded the menaquinone analogue (218). 

Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K, and vitamin Kj. Vitamin K or phylloquinone (phytonadione) is 2-methyl-3-phytyl-l,4-naphthoquinone it is found in plants and is the only natural vitamin K available for therapeutic use. Vitamin K is actually a series of compounds (the mena-quinones) in which the phytyl side chain of phylloquinone has been replaced by a side chain built up of 2 to 13 prenyl units. Considerable synthesis of menaquinones occurs in Gram-positive bacteria indeed, intestinal flora synthesize the large amounts of vitamin K contained in human and animal feces. In animals menaquinone-4 can be synthesized from the vitamin precursor menadione (2-methyl-l,4-naphtho-quinone), or vitamin Kj. Depending on the bioassay system used, menadione is at least as active on a molar basis as phylloquinone. 

FIGURE 54-6 The vitamin K cycle y-glutamyl carboxy lotion of vitamin K-dependentpr( eins. The enzyme -glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin Kj or K2, to -carboxylation of Glu residues on vitamin K-dependent proteins, generating the epoxide of vitamin K (KO) and 7-carboxyglutamate (Gla) residues in vitamin K-dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on tiie vitamin K molecule represents a 20-carbon phytyl side chain in vitamin and a 5- to 65-carbon prenyl side chain in vitamin K2. 

Collectively known as vitamin E, tocotrienols are identical in structure to tocopherols except for the degree of satmation in their side chain. The prenyl side chain of tocotrienol has been postulated to be responsible for the differential membrane distribution and metabolism of tocotrienols when compared with tocopherols. Fntnre investigations need to examine the molecular mechanism of action of tocotrienols in order to achieve a more comprehensive understanding of their complex bnt beneficial effects on cancer. 

Typical of the methods available for the preparation of 7t-allylpalladium complexes is the preparation of the crystalline compound 70 by heating prenyl acetate 71 in acetic acid with PdCl2 in the presence of copper(II) chloride, followed by chromatographic purification. Alkylation of 70 with the anion derived from the Ci5-sulphone 72 is then carried out in DMF in the presence of at least four equivalents of triphenylphosphine (two per Pd) and gives the crystalline C2o-sulphone 73 from which vitamin A may be obtained by ethoxide-catalysed elimination of phenylsulphinic acid [40] (Scheme 16). Despite the moderate yield (52%) in the alkylation step and the use of stoichiometric amounts of palladium, this synthesis of vitamin A (7) avoids the lengthy functionalization process that is often necessary with more conventional methods of carbon-carbon bond formation. 

A palladium complex 18 is obtained by reaction of an acetic acid/acetic anhydride solution of prenyl acetate with palladium (II) chloride in the presence of sodium chloride, sodium acetate and cupric chloride. This complex is employed in alkylation of the anion derived from the Ci5-sulphone 7 to give the precursor sulphone 12 (Scheme 5) [6]. Use of a large excess of PPhs (4 equiv. per Pd) in DMF as solvent is needed for smooth coupling and gives a 52% yield of (alI- )-y2. Exposure of 12 to NaOEt in boiling MeOH affords an 81% yield of vitamin A (17), which contains 67% of the (all-E)-isomer. 

Vitamins of the K series ("Coagulation" vitamins) are chemically classified as prenyl-1,4-naphthoquinones. They are ingested with food originating from all green plants, are involved in oxidative phosphorylation during respiration processes and... 

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