Previtamins

Irradiation of steroidal 3,7-dienes with ultraviolet light may result in ring opening and formation of various trienes. The most important reaction of this type is the conversion of ergosterol to previtamin Dj. 

Fig. 3. Photochemical and thermal reactions of previtamin D2 where the quantum yields for photochemical reactions are given by the arrow. R is as shown...

Fig. 4. Time course for uv-irradiation of 7-dehydtocholesterol ( ) (o), previtamin D (x), lumisterol (-), tachysterol.

Formation, % Vitamin D from previtamin D Previtamin D from vitamin D ... 

The equihbtium composition is normally ca 80% vitamin D and 20% previtamin D. This reaction is an intramolecular 1 7 Ft sigmatropic shift... 

Commercially, the irradiation of the 5,7-diene provitamin to make vitamin D must be performed under conditions that optimize the production of the previtamin while avoiding the development of the unwated isomers. The optimization is achieved by controlling the extent of irradiation, as well as the wavelength of the light source. The best frequency for the irradiation to form previtamin is 295 nm (64—66). The unwanted conversion of previtamin to tachysterol is favored when 254 nm light is used. Sensitized irradiation, eg, with fluorenone, has been used to favor the reverse, triplet-state conversion of tachysterol to previtamin D (73,74). 

The molecular extinction coefficients (at various wavelengths) of the four main components of the irradiation are shown in Table 5. The absorption of light above 300 nm is favored by tachysterol. A yield of 83% of the previtamin at 95% conversion of 7-dehydrocholesterol can be obtained by irradiation first at 254 nm, followed by reirradiation at 350 nm with a yttrium aluminum garnet (YAG) laser to convert tachysterol to previtamin D. A similar approach with laser irradiation at 248 nm (KrF) and 337 nm (N2) has also been described (76). 

Synthetic dienynes like (43) are semihydrogenated to form previtamin D and are then rearranged to the D stmcture (152—155). 

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). 

Intriguingly, the conical intersection model also suggests that E,Z-isomerization of acyclic dienes might be accompanied by conformational interconversion about the central bond, reminiscent of the so-called Hula-Twist mechanism for the efficient ,Z-photo-isomerization of the visual pigment rhodopsin in its rigid, natural protein environment101. A study of the photochemistry of deuterium-labelled 2,3-dimethyl-l,3-butadiene (23-d2) in low temperature matrices (vide infra) found no evidence for such a mechanism in aliphatic diene E,Z -photoisomerizations102. On the other hand, Fuss and coworkers have recently reported results consistent with the operation of this mechanism in the E,Z-photoisomerization of previtamin D3 (vide infra)103. 

The E,Z-photoisomerization of previtamin D to tachysterol has also received recent attention. Jacobs and coworkers examined the process in various solvents at 92 K and found evidence for the formation of a triene intermediate which converts thermally (Ea ca 6.5 kcal mol 1) to the more stable tEc rotamer of tachysterol (tEc-T equation 58)230. The rate of this conversion is viscosity dependent. They identified this intermediate as the cEc rotamer, produced by selective excitation of the cZc rotamer of previtamin D. In a re-examination of the low temperature ,Z-photoisomerization of previtamin D as a function of excitation wavelength, Fuss and coworkers have suggested an alternative mechanism, in which tEc-1 is produced directly from cZc-P and cEc-T directly from tZc-P (equation 59)103. This mechanism involves isomerization about both the central double bond and one of its associated single bonds—the hula-twist mechanism of Liu and Browne101 — and involves a smaller volume change than the conventional mechanism for ,Z-isomerization. The vitamin D system has also been the subject of recent theoretical study by Bemardi, Robb and Olivucci and their co workers232. 

In solution, vitamin D (both D2 and D3) isomerizes to previtamin D and forms a temperature-dependent equilibrium mixture [520], which leads to quantification problems. Previtamin D is difficult to quantify because of interference from co-eluted contaminants. The reversibility of the isomerization is very slow, therefore the percentage of previtamin can be considered constant during the entire analysis. The quantification of the potential vitamin D can be performed using an external standard that has undergone saponification procedure as the sample [521]. Vitamin D2 and D3 can be used as an internal standard to quantify the other one. Indeed, the isomerization rates of vitamins D2 and D3 are virtually the same thereby the previtamin D/vitamin D ratio will be the same for both vitamers at any temperature. The isomerization problem can be resolved by... 

An important group of conjugated diene/triene systems are those in the vitamin D series. The key reactions in the commercial manufacture of vitamin D (and probably also in its formation in skin exposed to daylight) are a photochemical, conrotatory electrocydic ring-opening in the provitamin, and a thermal 1.7-shift of hydrogen in the previtamin so formed (2.23). High conversions to the vitamin are not normally possible because all three species absorb appreciably at the... 

Continuous processes if photochemical (and thermal) reactors are installed in series. Such an arrangement could be useful in the production of previtamin D (PD), where tachysterol (T) produced as a secondary product (Figure 21) may be recovered by a subsequent triplet sensitized cis-trans isomerization [2, 3, 75-77]. 

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

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