Retinol reactions

The triplet state of the unpaired electrons of oxygen play a key role in both the photon excitation and the potential relaxation mode of the excited chromophores of vision. The paramagnetic properties of oxygen provide a definitive method of determining whether oxygen is present in the chromophores of vision, a condition that would eliminate the Shiff-base theory of retinol reaction with opsin to form rhodopsin. The evaluation of the electron paramagnetic resonance of the chromophores of vision is discussed in Chapter 7. 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

In intestinal cells, carotenoids can be incorporated into CMs as intact molecules or metabolized into mainly retinol (or vitamin A), but also in retinoic acid and apoc-arotenals (see below for carotenoid cleavage reactions). These polar metabolites are directly secreted into the blood stream via the portal vein (Figure 3.2.2). Within intestinal cells, retinol can be also esterified into retinyl esters. 

Four deuteriated retinols, 26-29, with 3 to 5 deuterium atoms have been synthesized29 for metabolism of vitamin A studies in humans30. Deuterium has been introduced into appropriate intermediates, used in the reaction scheme shown in equation 12, by base-catalysed exchange with 2H20 or perdeuterioacetone. The numbering system for retinol (vitamin A alcohol) is shown in equation 12. 

This reaction was also used in a synthesis of 13-cis-retinoic acid.2 Thus reduction of 3 under the same conditions gives the triethylsilyl ether (4) of 13-cis-retinol, with retention of the geometry of the terminal double bond. This product can be converted to 13-cis-retinoic acid by deprotection and oxidation (60% yield). 

Figure 15.11 The biochemical reactions that result in the conversion of trans-retinal to ds-retinal, to continue the detection of light To continue the process, trans-retinal must be converted back to c/s-retinal. This is achieved in three reactions a dehydrogenase converts trans-retinal to trans-retinol an isomerase converts the trans-retinol to c/s-retinol and another dehydrogenase converts c/s-retinol to c/s-retinal. To ensure the process proceeds in a clockwise direction (i.e. the process does not reverse) the two dehydrogenases are separated. The trans-retinal dehydrogenase is present in the photoreceptor cell where it catalyses the conversion of trans-retinal to trans-retinol which is released into the interstitial space, from where it is taken up by an epithelial cell. Here it is isomerised to c/s-retinol and the same dehydrogenase catalyses its conversion back to c/s-retinal. This is released by the epithelial cell into the interstitial space from where it is taken up by the photoreceptor cell. This c/s-retinal then associates with the protein opsin to produce the light-sensitive rhodopsin to initiate another cycle. The division of labour between the two cells may be necessary to provide different NADH/NAD concentration ratios in the two cells. A high ratio is necessary in the photoreceptor cell to favour reduction of retinal and a low ration in the epithelial cell for the oxidation reaction (Appendix 9.7).

This enzyme [EC 2.3.1.76], also referred to as retinol fatty-acyltransferase, catalyzes the reaction of an acyl-CoA derivative with retinol to generate coenzyme A and the retinyl ester. The CoA derivative can be palmi-toyl-CoA or other long-chain fatty-acyl derivatives of coenzyme A. 

Although the majority of analytes do not possess natural fluorescence, the fluorescence detector has gained popularity due to its high sensitivity. The development of derivatization procedures used to label the separated analytes with a fluorescent compound has facilitated the broad application of fluorescence detection. These labeling reactions can be performed either pre- or post-separation, and a variety of these derivatization techniques have been recently reviewed by Fukushima et al. [18]. The usefulness of fluorescence detectors has recently been further demonstrated by the Wainer group, who developed a simple HPLC technique for the determination of all-trani-retinol and tocopherols in human plasma using variable wavelength fluorescence detection [19]. 

Retinol Derivatives. Aryl sulphones have been used in two new syntheses in the vitamin A series. Reaction of /8-cyclocitryl phenyl sulphone (102) with the bromo-compound (103) gives the intermediate sulphone (104), which on base-catalysed elimination affords methyl retinoate (98). Alternatively retinol (99) has been prepared in high yield by condensation of the C15 bromide (105) with the C5 hydroxy-sulphone (106), followed by elimination of sulphinic acid. The syntheses... 

In the first Section, the dolichol pathway of protein glycosylation is introduced, and the reader is made familiar with the various reactions in the formation of the lipid and carbohydrate moieties of lipid-linked saccharides. Three different classes of compound are known so far (a) isoprenoid alcohol esters of monosaccharide monophosphates, such as D-mannosyl and D-glucosyl (dolichol phosphate), (b) such isoprenoid alcohol esters of saccharide diphosphates as dolichol diphosphate linked to 2-acetamido-2-deoxy-D-glucose and to oligosaccharides, and (c) retinol (D-mannosyl phosphate). The dolichol-linked sugars occur in all eukaryotes. 

Chabardes developed a process for the preparation of vitamin A and its intermediates, from cyclogeranylsulfone and Cio aldehyde-acetals [30]. For example, chlorocitral reacted with ethylene glycol, HC(OMe)3 and pyridinium tosylate to provide the chloroacetal (40%), as a mixture of two isomers. Reaction of this allylchloride with A-methylmorpholine oxide (NMO) and Nal furnished the aldehyde, as a mixture of four isomers. These compounds underwent condensation with P-cyclogeranylsulfone. Further chlorination of the sulfone-alkoxide salts, led to a mixture of sulfone-chloride acetals and their products of hydrolysis in 45-50% yield. Double elimination of the chloride and the sulfone, followed by hydrolysis with pyridinium tosylate (PPTS) gave retinal, as a mixture of all E and 13Z isomers (78/22). The overall yield from the chloroacetal was 18%. In another one-pot example, retinal was obtained in 52% yield from the aldehyde, and was then isomerised and reduced to retinol (all E 95.5, 13Z 4, 9Z 0.5) Fig. (8). 

A highly stereoselective synthesis of retinol via a Cm + C6 route was depicted by De Lera et al. [52]. A Suzuki reaction of a C14 alkenyliodide with a Cg alkenylboronic acid afforded retinol in 83% yield, with retention of the geometries of the coupling partners. The alkenyliodide was obtained by a zirconium-mediated methylalumination and a subsequent Al/I exchange by slow addition of ICN. Coupling with the C6 boronic acid (12 hrs to reach completion), afforded retinol in 83% yield [53], Fig. (21). 

The Wittig reaction of lithium a-(dimethylamino)-alkoxydes and a C15 alkyltriphenylphosphonium salt was used by Wang et al. to elaborate the ethylenic linkage of retinol [79]. This in situ method offers the unique advantage in its application to labile aldehydes, which otherwise would become isomerised or self-condensed, Fig. (44). 

Do we know all of the special chemistry of vitamin A that is involved in its functions Retinal could form Schiff bases with protein groups as it does in the visual pigments. Redox reactions could occur. Conjugative elimination of water from retinol to form anhydroretinol is catalyzed nonenzymatically by HC1. Anhydroretinol occurs in nature and... 

Figure 23-44 Reactions of retinol and the retinal cycle of mammalian rod cells. After Palczewski et al.5i3...

Oxygenation of allylic alcohols. This Ru(II) complex, as well as RuBr2[P(C6H5)3]3 and RuH(OAc)[P(C6H5)3]3, catalyzes the oxidation of allylic alcohols to 2,/J-unsaturated ketones or aldehydes by molecular oxygen with retention of configuration. The oxidation of retinol to retinal (second example) requires addition of 2,6-dimethylpyridine to prevent side reactions.2... 

Other antioxidant species are synthesized by cells like uric acid, ubiquinol or thiols (cystein, homocystein, etc.). In addition, many compounds found in food display antioxidant properties retinol (vitamin A) and its precursor /(-carotene, and polyphenols (flavonoids, etc.). Figure 8.2 shows the apparent standard potential of some LMWA and ROS explaining the spontaneous oxido-reduction reactions at the origin of the antioxidant protection system. 

A number of geometric isomers of retinol exist because of the possible cis-trans configurations around the double bonds in the side chain. Fish liver oils contain mixtures of the stereoisomers synthetic retinol is the all-trans isomer. Interconversion between isomers readily takes place in the body. In the visual cycle, the reaction between retinal (vitamin A aldehyde) and opsin to form rhodopsin only occurs with the 11 -cis isomer. 

Figure 6.6 indicates the various reactions typical of vitamin Av Retinoic acid, oxidized trans-retinal, is apparently involved in epithelial cell physiology. Retinol phosphate, trans-retinol esterified with a phosphate residue, associates with various membrane structures through its hydrophobic isoprenoid residue, leaving its hydrophilic phosphate group in contact with the aqueous environment. It serves as an anchor for growing oligosaccharide chains in the same manner as dolichol phosphate does (see Chapter 18). 

---