Previtamin synthesis

A domino RCM of an ene-yne was also used by Granja and coworkers [250] for their synthesis of the B-bishomo-steroid analogue 6/3-70. Reaction of the substrate 6/3-69 with the ruthenium catalyst 6/3-13 led to 6/3-70 in 48% yield as a 6.5 l-mix-ture of the two C-10-epimers (Scheme 6/3.20). The aim of this study was to prepare haptenes for the production of catalytic monoclonal antibodies that could be used to study the mechanism of the physiologically important transformation of previtamin D3 into vitamin D3 [251]. 

The photoequilibrium between 1,3-cyclohexadienes and 1,3,5-hexatrienes 3t5,3i6) s key step jn synthesis of vitamin D, as shown in the formation of vitamin D3 (R = C8H17) via a [l,7]sigmatropic H-shift from previtamin D which is obtained by irradiating provitamin D (3.9) 317). 

Figure 21. Principal photochemical reactions of the previtamin D synthesis (for a complete scheme of photochemical and thermal isomerizations, see [2, 3]).

Previtamin D3 is thermodynamically unstable and rearranges its double bonds to form the more thermodynamically stable vitamin D3. After synthesis, vitamin D3 is transported to the liver by a vitamin D-binding protein, which is an a-globulin. 

Irradiation of the 5,7-diene gave the previtamin, which was isomerized and saponified to give la-hydroxy-vitamin D3. For the last synthesis of la-hydroxy-7-dehydrocholesterol recorded here, cholesta-l,4,6-triene-3-one was again used as starting steroid.122 Deconjugation of this trienone with strong base followed by immediate reduction with calcium borohydride led to the unstable 3/3-hydroxycholesta-l,5,7-triene which, without isolation, was converted into the 1,4-addition product (265) upon reaction with 4-phenyl-l,2,4-triazoline-3,5-dione. 

CH(Me)(CH2)2CH=CMe2 and CH(Me)(CH2)3C(Me)=CH2. The 25-hydroxy-group was restored at the end of the synthesis. Successive acetylation, bromination, dehydrobromination, saponification, and irradiation when applied to la,25-dihydroxycholesterol convert it either into la,25-dihydroxy-previtamin D3128 or into a la,25-dihydroxy-vitamin D3,129 depending on reaction conditions. 

Sunlight is not strictly essential for cutaneous synthesis of cholecalciferol, because UV-B penetrates clouds reasonably well complete cloud cover reduces the available intensity by about 50%. It also penetrates light clothing. However, low-intensity irradiation (below 20 ml per cm in vitro) does not result In significant photolysis of 7-dehydrocholesterol to previtamin D. Acute whole-body exposure to UV-B irradiation below 18 ml per cm does not result in any detectable increase in plasma cholecalciferol or calcidiol. In temperate regions (beyond about 40°N or S), the intensity of UV-B is below this threshold in winter, so there is unlikely to be any significant cutaneous synthesis of the vitamin in winter, and plasma concentrations of calcidiol show a marked seasonal variation in temperate regions (Holick, 1995 see Table 3.2). 

By contrast, the retro electrocyclization by photochemical irradiation is well known. For example, the photochemical transformation (6e conrotato ring opening) of provitamin D (5) to previtamin D (3) and then thermal isomerization (1,7-H shift) of the latter is a well-established sequence leading to vitamin D (4). It is a sequence involved in vitamin D biosynthesis and in the laboratory synthesis of vitamin D. Moreover, the process is used commercially. 

Biochemistry. Vitamin D is introduced into the bloodstream either from the skin after natural synthesis by the irradiation of 7-dehydrocholesterol stored in the epidermis (172) or by ingestion and absorption of vitamin D2 or vitamin D through the gut wall (40). Between 60 and 80% of the vitamin introduced in the blood is taken up by the Hver, where cholecalciferol is transferred from chylomicrons to a vitamin D-binding protein (DBF), an OC-globulin specific for vitamin D and its metaboHtes but one which does not bind with previtamin D in the skin (173). Cholecalciferol is hydroxylated in the Hver at the C-25 position (51,141,174). This hydroxylation occurs in the endoplasmic reticulum and requires NADPH, a flavoprotein, cytochrome P-450, Mg ", and O2 (175). 25-Hydroxylation also occurs in intestinal homogenates of chicks (176), but does not appear to occur outside the... 

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... 

Another important hormone derived from cholesterol is vitamin D. This steroid-like hormone is involved in regulating calcium and phosphorus metabolism. The complete synthesis of vitamin D requires ultraviolet light to convert 7-dehydrocholesterol to previtamin Dj. The reaction scheme is shown in Figure 34-3. The active hormone 1,25-dihydroxycholecalciferol (calcitriol)... 

Synthesis of previtamin Ds. The reagent, bis(ethylenediamine)chromium(II), was employed by a British group8 in the first total synthesis of previtamin D3, the immediate product of irradiation of 7-dehydrocholesterol. Condensation of the lithium derivative of the trimethylsilyl ether of the enyne (2) with the chloroketone (1) gives the chlorohydrin (3). This is converted into the enynene (4) by reaction with bis(ethylenediamine)chromium(II). Semihydrogenation with Lindlar s catalyst completes the synthesis. The overall yield from (1) is over 25%. 

Oxidation of la-hydroxycholecalciferol and la,25-dihydroxycholecalciferol with Mn02 gave the corresponding 1 -oxo-previtamins which could be reduced with LiAlH4 at —25 °C in each case to give a mixture of la-hydroxy- and IjS-hydroxy-previtamins in which the IjS-epimers (285) and (286) predominated. Thermal equilibration allowed the isolation of the 1/3-hydroxy-cholecalciferol and l/ ,25-dihydroxycholecalciferol. A similar independent synthesis of 1/3-hydroxycholecalciferol employed NaBH4 for the reduction... 

Partial Synthesis with Photochemical Formation of Previtamin D... 

Vitamin D3 (7a) is obtained commercially by partial synthesis. This partial synthesis begins with inexpensive cholesterol and its transformation into provitamin D3 (la). It ends with light-induced ring opening to previtamin D3 (5a) and its thermally induced 1,7-H-shift to vitamin D3 (7a, see Scheme 3). Since 5 reacts back to 1 and onwards to 2 and 6, the result is a photostation-ary mixture. UV Irradiation of 1 is expediently carried out at 0°, to largely exclude isomerization of 5 into 7. This is important for the prevention of further reaction of 7 into the so-called over-irradiation products ), the components of which would appreciably raise the diversity of the irradiated mixture. 

Photochemical synthesis of previtamin D A simple design procedure... 

As shown in Figure 11.6, the steroid 7-dehydrocholesterol (an intermediate in the synthesis of cholesterol that accumulates in the skin but not other tissues), undergoes a non-enzymic reaction on exposure to UV light, yielding previtamin D. This undergoes... 

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). 

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