Vitamin racemization

Vitamin K compounds ate yellow solids or viscous liquids. The natural form of vitamin is a single diastereoisomer with 2 (E), 7 (R), ll (R) stereochemistry. The predominant commercial form of vitamin is the racemate and a 2 (E)j (Z) mixture. Table 1 fists some physical and spectral properties of vitamin K. ... 

Although the predominant commercial form of vitamin is the racemate, natural (2 (E), 7 (R), 1 h(R))—vitamin is accessible either from a... 

The biologically active form of vitamin Bg is pyridoxal-5-phosphate (PEP), a coenzyme that exists under physiological conditions in two tautomeric forms (Figure 18.25). PLP participates in the catalysis of a wide variety of reactions involving amino acids, including transaminations, a- and /3-decarboxylations, /3- and ") eliminations, racemizations, and aldol reactions (Figure 18.26). Note that these reactions include cleavage of any of the bonds to the amino acid alpha carbon, as well as several bonds in the side chain. The remarkably versatile chemistry of PLP is due to its ability to... 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

Scheme 8 presents the sequence of reactions that led to the synthesis of the B-ring of vitamin B12 by the Eschenmoser group. An important virtue of the Diels-Alder reaction is that it is a stereospecific process wherein relative stereochemical relationships present in the diene and/or the dienophile are preserved throughout the course of the reaction.8 Thus, when the doubly activated dienophile 12 (Scheme 8) is exposed to butadiene 11 in the presence of stannic chloride, a stereospecific reaction takes place to give compound 27 in racemic form. As expected, the trans relationship between... 

The a-tocopherol, P-carotene (ATBC) Cancer Prevention study was a randomised-controlled trial that tested the effects of daily doses of either 50 mg (50 lU) vitamin E (all-racemic a-tocopherol acetate), or 20 mg of P-carotene, or both with that of a placebo, in a population of more than 29,000 male smokers for 5-8 years. No reduction in lung cancer or major coronary events was observed with any of the treatments. What was more startling was the unexpected increases in risk of death from lung cancer and ischemic heart disease with P-carotene supplementation (ATBC Cancer Prevention Study Group, 1994). Increases in the risk of both lung cancer and cardiovascular disease mortality were also observed in the P-carotene and Retinol Efficacy Trial (CARET), which tested the effects of combined treatment with 30 mg/d P-carotene and retinyl pahnitate (25,000 lU/d) in 18,000 men and women with a history of cigarette smoking or occupational exposure to asbestos (Hennekens et al, 1996). 

An enantioselective hydrogenation of this type is also of interest in the production of a-tocopherol (vitamin E). Totally synthetic a-tocopherol can be made in racemic form from 2,3,5-trimethylhydroquinone and racemic isophytol. The product made in this way is a mixture of all eight possible stereoisomers. 

D-Pantolactone and L-pantolactone are used as chiral intermediates in chemical synthesis, whereas pantoic acid is used as a vitamin B2 complex. All can be obtained from racemic mixtures by consecutive enzymatic hydrolysis and extraction. Subsequently, the desired hydrolysed enantiomer is lactonized, extracted and crystallized (Figure 4.6). The nondesired enantiomer is reracemized and recycled into the plug-flow reactor [33,34]. Herewith, a conversion of 90-95% is reached, meaning that the resolution of racemic mixtures is an alternative to a possible chiral synthesis. The applied y-lactonase from Fusarium oxysporum in the form of resting whole cells immobilized in calcium alginate beads retains more than 90% of its initial activity even after 180 days of continuous use. The biotransformation yielding D-pantolactone in a fixed-bed reactor skips several steps here that are necessary in the chemical resolution. Hence, the illustrated process carried out by Fuji Chemical Industries Co., Ltd is an elegant way for resolution of racemic mixtures. 

These enzymes invariably involve a cofactor, pyridoxal phosphate (vitamin B6). In addition, pyridoxal phosphate is also required for most decarboxylations, racemizations, or elimination reactions in which an amino acid is a substrate. Pyridoxal phosphate is not involved in decarboxylations in which the substrate is not an amino acid. So if a question... 

Figure 13 shows the structure and absolute configuration of (2R,3S)-(-) vitamin K3 epoxide. This epoxide, prepared in optically active form by us (70) in 1976, had been known as a racemate since 1939 (78). It has recently been implicated (79) in prothrombin biosynthesis (80). The absolute configuration as shown in Figure 13 is based on the work of Snatzke (76) and the absolute rotation is [ ]436 = — 124° (acetone) and [a] = 0° ( ) (acetone). 

Optically active EP is an important C3 chiral building block for the synthesis of chiral pharmaceuticals such as j9-adrenergic blockers [11 -13], vitamins [14,15], pheromones [16], natural products [17], and new materials such as ferro-electric crystals [18]. Racemic EP can be made via 2,3-DCP and l,3-dichloro-2-pro-panol (1,3-DCP) synthesized from propylene by organic synthesis [19] however, a practical production method for optically active EP has not yet been established. Racemic 2,3-DCP, which is easily synthesized by the chemical... 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

Pyridoxal phosphate is the coenzyme for the enzymic processes of transamination, racemization and decarboxylation of amino-acids, and for several other processes, such as the dehydration of serine and the synthesis of tryptophan that involve amino-acids (Braunstein, 1960). Pyridoxal itself is one of the three active forms of vitamin B6 (Rosenberg, 1945), and its biochemistry was established by 1939, in considerable part by the work of A. E. Braunstein and coworkers in Moscow (Braunstein and Kritzmann, 1947a,b,c Konikova et al 1947). Further, the requirement for the coenzyme by many of the enzymes of amino-acid metabolism had been confirmed by 1945. In addition, at that time, E. E. Snell demonstrated a model reaction (1) for transamination between pyridoxal [1] and glutamic acid, work which certainly carried with it the implication of mechanism (Snell, 1945). 

Under the denomination of vitamin E are collected eight different isomers that are present in nature and particularly in oils commonly used as food, The synthetic vitamin E is the all racemic a-tocopherol (ART), whereas the natural vitamin E is the RRR a-tocopherol (RRRT). 

Table 6 Clinical/epidemioloqical studies with Vitamin E as all racemic a-tocopherol (ART), or as RRR-a tocopherol (RRRT)...

Vitamins, cofactors, and metals have the potential to broaden the scope of antibody catalysis considerably. In addition to hydrolytic and redox reactions, they facilitate many complex functional group interconversions in natural enzymes.131 Pyridoxal, for example, plays a central role in amino acid metabolism. Among the reactions it makes possible are transaminations, decarboxylations, racemizations, and (3,y-eliminations. It is also essential for ethylene biosynthesis. Not surprisingly, then, several groups have sought to incorporate pyridoxal derivatives into antibody combining sites. 

Vitamin B6 enzyme models that can catalyze five types of reactions - transamination, racemization, decarboxylation, P-elimination and replacement, and aldolase-type reactions - have been reviewed. There are also five approaches to construct the vitamin B6 enzyme models (i) vitamin B6 augmented with basic or chiral auxiliary functional groups (ii) vitamin B6 having an artificial binding site (iii) vitamin B6-surfactant systems (iv) vitamin B6-polypeptide systems (v) polymeric and dendrimeric vitamin B6 systems. These model systems show rate enhancement and some selectivity in vitamin B6-dependent reactions, but they are still primitive compared with the real enzymes. We expect to see improved reaction rates and selectivities in future generations of vitamin B6 enzyme models. An additional goal, which has not received ade-... 

The catabolism of certain amino acids (e.g., valine, isoleucine, methionine) and odd-chain fatty acids (17 0) produces propionyl-CoA. Propionyl-CoA enters the TCA (citric acid) cycle following conversion to succinyl-CoA, as shown in Fig. 28-7. Propionyl-CoA is first carboxylated to produce D-methylmalonyl-CoA, which in turn is then racemized to L-methylmalonyl-CoA. In an intramolecular rearrangement reaction catalyzed by L-methylmalonyl-CoA mutase, a vitamin B12-... 

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

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