Vitamin cascade reactions

Figure 17.6 A cascade reaction column with multiple agitators for the synthesis of the vitamin carbol (after Wiedeskehr, 1988).

Another impressive example of dienamine-iminium cascade catalysis was developed during the total synthesis of a-tocopherol 59 by Liu et al. [31]. This natural product is a member of the vitamin E family and possesses remarkable biological activity. The key step in the total synthesis of this natural product involved an organocatalytic aldol/oxa-Michael cascade reaction for construction of the core... 

Recent studies revealed that (2S)-tocopherols have no antioxidant effect in biological systems because they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. As a result, the enantioselective synthesis of the a-tocopherol became attractive, and several groups have reported on its asymmetric synthesis. In addition, Tietze and co-workers reported on an enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction (Scheme 21.15). ° In their study, reaction of 64 with methyl acrylate in CH2CI2 with catalytic amounts of Pd(TFA)2 (TEA = trifluoroacetate), the chiral ligand (5,5)-Bn-BOXAX 65, and p-benzoquinone afforded the desired chroman 66 with 96% ee in 84% yield. The enantioselective cascade reaction described therein provided the efficient construction of the chroman firamework of vitamin E 67 with concomitant introduction of part of the side chain in high yields and high enantioselectivities. 

FIGURE 18.40 The glutamyl carboxylase reaction is vitamin K-dependent. This enzyme activity is essential for the formation of 7-car-boxyglutamyl residues in several proteins of the blood-clotting cascade (Figure 15.5), accounting for the vitamin K dependence of coagulation. 

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

Monoamine oxidase, tyrosine hydroxylase, and L-amino acid oxidase generate hydrogen peroxide as their reaction product. Hydrogen peroxide is also produced by auto-oxidation of catecholamines in the presence of vitamin C. Moreover, phospholipase A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX), the enzymes associated with arachidonic acid release and the arachidonic acid cascade,... 

Antioxidants 43 Arachidonic acid cascade 44 Radical reactions with DNA 44 Ribonucleotide reductases 45 Vitamin B12 46 Nitric oxide 47 Cytochrome P-450 48 AcetylCoA dehydrogenase 48... 

A number of proteins of the blood clotting (coagulation) cascade (including prothrombin, and a number of other clotting factors) undergo post-translational modification in a reaction catalysed by a vitamin K-dependent carboxylase, which transforms specific Glu residues into y-carboxyglutamic acid, Gla (Fig. 4.1). In the reaction (Fig. 4.2), the dihydroquinone (reduced) form of vitamin K, KH2, is oxidised to the epoxide form, KO, by O2. The... 

The well-publicized substance known as Coenzyme QIO, or CoQlO, receives favorable mention as an anticancer agent in an article by Christi Yerby appearing in the October 2005 issue of Life Extension. He states that low levels of CoQlO were found in patients with myeloma, lymphoma, and cancers of the breast, lung, prostate, pancreas, colon, kidney, head, and neck. In one case study, a woman with breast cancer experienced a stabilized tumor from taking 90 mg/day of CoQlO. When the daily dose was increased to 390 mg, the tumor disappeared. It was mentioned that CoQlO is synthesized from the amino acids tyrosine and phenylalanine in a cascade of reactions that involve vitamin C and the B vitamins B2, B3, B5, B6, B12, plus folic acid. Although the body produces CoQlO naturally, this is sometimes not enough. An earlier reference is S.T. Sinatra s The Coenzyme QIO Phenomenon, published in 1998. 

First, phospholipid bilayers which mimic cellular membrane and platelet factor 3, on which several blood clotting factors bind in order to generate the more efficient cascade of enzymatic reactions (J ). They are the vitamin K-dependent proteins II, X and IX which are... 

Abstract The in vitro enzyme-mediated polymerization of vinyl monomers is reviewed with a scope covering enzymatic polymerization of vitamin C functionalized vinyl monomers, styrene, derivatives of styrene, acrylates, and acrylamide in water and water-miscible cosolvents. Vitamin C functionalized polymers were synthesized via a two-step biocatalytic approach where vitamin C was first regioselectively coupled to vinyl monomers and then subsequently polymerized. The analysis of this enzymatic cascade approach to functionalized vinyl polymers showed that the vitamin C in polymeric form retained its antioxidant property. Kinetic and mechanistic studies revealed that a ternary system (horseradish peroxidase, H2O2, initiator fS-diketone) was required for efficient polymerization and that the initiator controls the characteristics of the polymer. The main attributes of enzymatic approaches to vinyl polymerization when compared with more traditional synthetic approaches include facile ambient reaction environments of temperature and pressure, aqueous conditions, and direct control of selectivity to generate functionalized materials as described for the ascorbic acid modified polymers. 

Vitamin E is a collective term for all tocopherols and tocotrienols. In 2005, the group of Tietze described a new enantioselective total synthesis of vitamin E via a palladium-catalyzed enantioselective Wacker oxidation/Heck reaction cascade sequence as the key step, which allowed the formation of the chiral chroman framework with an enantioselectivity of 96% ee and the introduction of part of the side chain in one step (Scheme 13.22) [27]. 

Scheme 13.22 Total synthesis of vitamin E (149) employing a palladium-catalyzed enantios-elective Wacker oxidation/Heck reaction cascade sequence.

D-Arabinose is the starting material in a synthesis of la,2P-dihydroxyvitamin D3 (78). The derivative 75 is converted to the protected eneyne 76 in seven steps. This undergoes a palladium-catalysed cascade process on reaction with vinyl bromide to give 77, yielding, after deprotection, the vitamin D3 analogue (Scheme 14). (See Vol 27, p.317 for synthesis of a similar chiron from D-mannitol). 

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