Vitamin isomerisation

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Ergosterol CjgH OH, a trebly unsaturated alcohol, is derived from the same ring system. It is produced in relatively large amounts by fungi, in particular by yeast, and on irradiation it is isomerised to the anti-rachitic vitamin, vitamin-D (Windaus). 

Scheme 8.2 Sensitised cis-trans isomerisation of vitamin A acetate...

The fluorinated ketoester shows some unusual chemistry the enol tautomer can be trapped directly with 1,3-dipoles [298], while alkylation occurs initially and reversibly at oxygen, followed by isomerisation to the C-adduct [299]. The Kumadaki group used the ketoester during syntheses of Vitamin E analogues Eq. 109 shows the preparation of a key enone [300]. 

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 major development in the study of EGB s is the recently reported measurements of rates of protonation by acids of known pK. The correlation of such rates with pK, the Bronsted relationship, also enables bases of determined pK to be used in the measurement of kinetic acidities of weak acids. This quantitative approach will eventually lead to the optimisation of reaction conditions for preparative reactions by providing data which can be used to match the acid/base pairs more exactly. In many organic reactions involving bases the base chosen is stronger than is strictly neccessary and consequently such reactions are often complicated by side reactions such as condensation reactions and isomerisations. The advantage of an EGB of moderate strength has been seen in the vitamin A preparation described in Scheme 18, where the facile cisftrans isomerisation is avoided. 

Photochemistry is used commercially in the synthesis of Vitamin A and Vitamin D3, Figure 3.14. Vitamin A is formed via a photochemical isomerisation process and the synthesis of Vitamin D3 involves a photochemical electrocyclic ring-opening step. The industrial relevance of this process is due to the lack of a viable thermal alternative and therefore, if unusual and useful chemistry is only possible via photochemistry, an industrial process may result, due to the high intrinsic value of the chemical product. 

By the Darzens reaction. -ionone afforded a C14 aldehyde which as the diethyl acetal underwent addition to ethyl vinyl ether in the presence of boron trifluoride etherate to yield a Cl6 acetal. After hydrolysis, loss of ethanol and formation of the diethyl acetal as before, reaction under acidic condiions with ethyl propenyl ether gave the unsaturated Cl9 aldehyde after hydrolysis and removal of ethanol. Reaction of two moles with ethyne dimagnesiuro bromide produced the C40 chain and dehydration of the diol, selective catalytic hydrogenation followed by isomerisation completed a remarkable technical synthesis of i-carotene. Further variations have involved the use of two moles of the C14 aldehyde and a Cl2 divinyl ether. An independent approach (ref.29) has utilised vitamin A (32) converted to a phosphonium salt, thence to the corresponding phosphoran, autoxidation of which afforded s-carotene ( scheme 16). 

The anti-rachitic factors resulting from the ultraviolet irradiation of cholesterol (40) and ergosterol (41) namely vitamin Dj (42) cholecalciferol and Dj, ergocalciferol (43) respectively are important dietary materials the chemistry of which was only elucidated by the investigations of many chemists (ref.41). Vitamin Dj is most easily derived by semi-synthesis from cholesterol through formation firstly of 7-dehydrocholesterol by reaction with N-bromosuccinimide followed by dehydrobromination with collidine. Ultraviolet light irradiation affords previtamin Dj which is thermally isomerised to the endo compound shown and thence to the exo... 

The lipidic vitamins (ref.84) include vitamin A (32), a substance intrinsic to the physiology of vision, vitamin E (83), a natural protective antioxidant, and vitamins K, (84) with Kj (85), antihemorrhagic compounds, each of which is derivable from an initial natural product intermediate. Although traditionally a -ionone obtained from citral (a major constituent of lemon grass oil) was used for the synthesis of vitamin A, a synthetic source has now replaced this in a process which also gives /g-carotene. In one method the Cl4 aldehyde in that process is reacted with a C6 eneyne component and selective hydrogenation followed by dehydration and isomerisation affords the final product (ref.85). 

Cis-trans isomerisation may be a cause of loss of potency of a dmg if the two geometric isomers have different therapeutic activities. Vitamin A (all-frans-retinol) is enzymatically... 

Loss of activity of solutions of some dmgs such as the tetracyclines can occur because of epimerisation of the dmg molecule, while others such as vitamin A lose activity because of geometrical isomerisation. 

The syntheses of methyl bixin (24) and other natural carotenoids were mentioned above. A biogenetically inspired synthesis of e-carotene used the titanium tetrachloride complex of lycopene (16). Dehydrolycopene was also isolated. Two more syntheses of ) -carotene (2) have been reported which use intermediates in the synthesis of vitamin A (see Scheme 2). Although ll-cis-j5-carotene was produced it is rapidly isomerised to the all-frons form. The cross-conjugated system (72) has a previously unknown chromophore. Another example of this system, but with an additional 4 -oxo-group, was synthesised by Surmatis et al. in a study of the synthesis of keto carotenoids. They prepared echinenone (73) and the two protected 3,3 -dioxo-j8-carotene compounds (74) and (75). Treatment of the ketal with sulphuric acid gave mainly 3,3 -dioxo- -carotene (76) while hydrochloric acid gave 3,3 -dioxo-c-carotene (77). Under both conditions the enol ether gave the latter product. 

The isolation of the biologically active metabolite of vitamin D3 in a pure state, and the determination of its structure as 25-hydroxycholecalciferol (401) has been rapidly followed by its synthesis via irradiation of 25-hydroxycholesta-5,7-dien-3j -ol by three independent groups. The first synthesis of pre-calciferola (405) has been achieved by reaction of the lithium derivative of the chloro-ketone (402) with the en-yne (403) to give (404) which was treated with bis(ethylenediamine)chromium(ii) and then partially reduced catalytically. The thermal isomerisation of (405) (as 3,5-dinitrobenzoate) to vitamin D3 represents the first non-photochemical synthesis. 

Adenosyl-cobalamine isomerisation (hydrogen-shift) vitamin Bi2... 

The role of retinal (18, vitamin A aldehyde) in the visual process, involving cis/trans isomerisation of the sterically hindered C-11,12 double bond, is well established [28,29]. Besides the important function of retinal in visual signal transduction in animals is the function of energy production in halophilic bacteria, where the retinal-based bacterio-rhodopsin takes part in a light driven proton pump [30]. 

Vitamin Biji Adenosyl eobalamin metliyl o>tMlamin Isomerisations and methyl group transfers 73S... 

Starting from their experience in manufacturing /3-ionone, Hoffmann-La Roche initially favoured acetylene as the universal building block for further syntheses. The reaction of methyl vinyl ketone with lithium acetylide in ammonia gives a tertiary alcohol, which is isomerised with sulfuric acid into a mixture of the (Eland (Z)-isomers of 3-methylpent-2-en-4-ynol. The isomers can be separated by distillation. Whereas the main component, the (Z)-isomer, is used for the production of Vitamin A, the (E)-isomer finds application in carotenoid synthesis. 

The synthesis of Vitamin D3 in vivo takes place in the skin. UV-B radiation ( = 290-315 nm) cleaves 7-dehydrocholesterol, an intermediate product of cholesterol metabolism, in the epidermis, which isomerises spontaneously at body temperature to cholecalciferol. While the photolysis is very efficient, it is subject to seasonal and climatic fluctuations. Strong pigmentation and aged skin lead to a considerably reduced capacity to produce Vitamin D. 

Present in red palm oil and very widely distributed in leaves, etc. Dark red plates or prisms. M.p. 187° corr. [a]oa + 380° inCgHg. Absorption oands in CSj, 511, 478, 446 mu SbClg in CHCI3 —> blue col. with absorption band at 542 mp. Possesses only half the vitamin A activity of p-carotene. Isomerises slowly in sol. to neocarotene which gives neo-a-carotene on cryst. 

C17H20N4O9P 455.34 The prosthetic group of various flavine enzymes. Enzyme co-factor, vitamin. Sodium salt used as dietary and nutrient supplement. Yellow cryst. + 2H2O. Tends to isomerise to isomeric phosphates. 

Fig. 117. Evidence of thermal isomerisation in TLC. Separation of 400 [xg samples of pure vitamin Dg before (i) and after warming in chloroform solution (2.5 h at 60° C in the dark) (2) on silica gel GF254 with cyclo-hexane-ether (50 + 50). Photograph inUV light (254 nm) [8]...

Numerous papers deal with the chemistry of vitamin B]2> cobalamins, cobinamides, and their synthetic models, the cobaloximes [Co(dmgH)2(R)(L)], including the synthesis of new species,225-228 structural studies,229-239 the stereochemistry of formation and isomerisation,240-244 and reactivity.245-248 jhe effects of viscosity,249 pressure, temperature,250,25l and base coordination252... 

Vitamin B12 was first identified as the antipernicious anaemia factor, present in whole liver. Only recently has it been shown that, in common with other members of the B group of vitamins, a derivative of cyanocobalamin (having the cyanide group replaced by adenosine) is a cofactor for certain enzymes, in particular, those catalysing the isomerisation of glutamate to jS-meAyl aspartate (bacteria) and of the methylmalonyl derivative of coenzyme A (Figure 29) to succinyl It has been suggested that both... 

Ketoisophorone (KIP) is a key intermediate in the production of nutritional products (e.g. vitamins and carotenoids) and in the flavours and fragrances industries. One option for a technical access to KIP is the catal5rtic oxidation of isophorone (Fig. 16.13). For good selectivity and yield in the oxidation step a thermal isomerisation of a-isophorone to /1-isophorone is necessary. However, in order to avoid this additional step and because the isomerisation equilibrium is strongly in favour of the a-isomer, a direct oxidation of a-isophorone to KIP would clearly be preferred. 

The isolation and identification of the metabolites of vitamin D have been followed by a keen interest in the chemical synthesis of the D vitamins. Clinical use of these new compounds has stimulated the development of more efficient syntheses (9). A popular approach to the synthesis of vitamin D metabolites involves the preparation of a suitably hydroxylated or substituted provitamin, conversion of this to the equivalent previtamin, followed by thermal isomerisation to the vitamin D, but other sophisticated procedures have been used where the molecule is synthesised in two halves (10-13). 

Compounds belonging to the vitamin D group are oxylabile, similar to other Hpophihc vitamins. It would therefore be expected that these compounds yield autoxidation products. Thermal transformation (at temperatures around 200 °C) produces both pyroi-somers and isopyroisomers of vitamins D (Figure 5.4), isomerisation in acidic media provides isovitamins D and isotachysterols (Figure 5.5). 

Isbell made use of this reaction to S3mthesise vitamin C from L-galactono-y-lactone. The latter was first converted into the 2-0x0 derivative (see p. 83). A commercial synthesis of ascorbic acid is also based on this isomerisation. Bertrand s sortose bacterium, Acetobacter xylinium, converts sorbitol to L-sorbose (XCI) and this on condensation with acetone yields the 2,3 4,5-di-O-isopropyhdene derivative (XCII). Oxidation and hydrolysis of this... 

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