Synthesis of Vitamin D (Calciferol)-Application of Pericyclic Reaction

Pericyclic Reactions in organic chemistry is one of the most intriguing featured chemical reaction, in contrast
to polar or radical structural transformation of molecules – are one step processes proceed through a cyclic
transition-state structure . Here it can be said that the term Pericyclic means electron moves round the
periphery of a circle. The concept of pericyclic reactions are classical because the basis of the reaction is
determined by Symmetry of the Molecular Orbitals participating in the chemical reaction – so called HOMO
and LUMO according to Frontier Molecular Orbital (FMO) concept. Different types of pericyclic reaction are
there based on the reaction mechanistic course like; 1. Electrocyclic Reaction 2. Cycloaddition Reaction 3.
Sigmatropic Rearrangements. These various types of pericyclic reactions are associated with versatile
application. Especially in the field of drug synthesis and several natural product synthesis pericyclic reactions
are important. It is well known that in human skin in presence of sunlight vitamin-D is synthesised –in fact it is
associated with two consecutive different types of pericyclic reaction. In plant kingdom several metabolites are
made via pericyclic reactions also. In fact in industrial field several compounds like Captan an agricultural
fungicide is prepared by Diels-Alder reaction. In fact several compounds like Adamentane, Twistane can be
synthesised by the means of pericyclic reactions.

Among several applications, here the synthesis of vitamin-D in human skin which occurs via pericyclic
reactions is explained; the formation of vitamin-D3 from 7-dehydrocholesterol is accompanied by a photo
chemically induced , Conrotatory cycloreversion of the steroid ring - followed by a thermally allowed
[1,7]-Sigmatropic H-shift.

The seco-B-steroid 1,25-D3(Fig.1.), an essential hormonal regulator in higher animals, is produced by the
metabolic pathway shown in Figure 2. The natural vitamin D3 (5, D3) is produced in skin upon ultraviolet
irradiation of 7-dehydrocholesterol (2, 7-DHC; also called provitamin D3) or is absorbed from the diet. The
reaction in skin is believed to be a purely photochemical process, not requiring enzymes or proteins.58 7-DHC
absorbs ultraviolet light, which effects an electrocyclic rupture of the 9,10 bond to produce previtamin D3 (3,
Pre-D3). The latter is likely a biologically inert compound, which is thought to spontaneously isomerize to D 3.
initially producing the 6-s-cis form 4 which rapidly rotates about its 6,7 single bond to its more commonly
depicted (and more stable) 6-s-trans conformer 5 [Fig.2.]. A plasma protein, vitamin D binding protein (DBP),
subsequently transports D3 to the liver where metabolic alteration required for hormonal function is initiated.
The conversion of D3 to 25- hydroxyvitamin D3 (6, 25-D3) in liver is carried out by a microsomal system
requiring NADPH, molecular oxygen, a flavoprotein, and a cytochrome P-450. The metabolite 25-D 3, the major
circulating form of the vitamin D in serum, is then further metabolized to 1,25-D3 in the kidney.

1
 Fig.1. 1α-25- dihydroxyvitamin D3

The corresponding reaction protocol can be diagrammatically represented as –

Reaction sequence of production of Vitamin-D3 on skin

In this assignment, the mechanism of formation of 6-s-cis Vitamin-D3 is highlighted.

Here there are two pericyclic reactions in the 1 st two steps. First one is Electrocyclic ring opening and the
second one is [1,7] Sigmatropic rearrangement. The two reactions can be explained via WOODWARD
2
HOFFMANN’S rule of Electrocyclic reactions and [1,7] Sigmatropic shift of hydrogen; these can be
represented as –
For Electrocyclic reaction ,

7-Dehydrocholesterol (7-DHC) Previtamin D3 (Pre-D3)

Fig.2. The Electrocyclic Reaction

No. of participating electron Thermal reaction course. Photochemical reaction

pair course
Even conrotation Disrotation
Odd Disrotation Conrotation

Here the no. of participating electron pair is 3. Under photochemical reaction course conrotation occurs. And
we have the product in accordance with the WOODWARD-HOFFMANN rule. The orbital picture of
conrotation –

Fig.3. Orbital picture of Conrotation in 6π eectron system under Photochemical condition

In the [1,7] sigmatropic migration of hydrogen we have the following rule,

3
 No. of participating electron Thermal reaction pathway Photochemical reaction
pairs: (1+j)/2 pathway
Even Antarafacial Suprafacial
Odd Suprafacial Antarafacial

Here the no. participating electron pair is 4. Under thermal reaction condition the reaction is proceed via
Antarafacial manner we have the following diagram----

Previtamin D3 (Pre-D3) 6-s-cis-Vitamin D3(6-s-cis-D3)

Fig.4. The [1,7] Sigmatropic Shift of hydrogen

Now, this 6-s-cis D3 isomerises to its trans conformer and further reaction happens.