Synthesis of the E and Z isomers of the
antiestrogen Tamoxifen.
David W.Robertson and John A.
Katzenellenbogen.
Journal of Organic Chemistry 1982 , 47,
Pages 2387-2393.
An early synthesis of Tamoxifen :
Production of non stereo specific products.
For easy of understanding the complete synthesis has been
broken down into a number of steps.
Step 1.
Step 1.
This step shows use of a simple friedel-craft acylation
involving Anisole(A) and Phenylacetic acid (B). The acylating agent
in this process was a mixture of PCl5 / SnCl4. The ketone C was
formed in a 78% yield.
Step 2.
Step 2.
Alkylation was promoted by treating the ketone C with
Sodium hydride (NaH). This removed the acidic protons (located on the
position alpha to the carbonyl group) to produce the enolate ion.
This could be isolated as the sodium enolate of the ketone treatment
of this with ethyl iodide resulted in the formation of compound (D)
in a 94% yield. The Ethyl iodide was chosen as the acylating agent
probably as it contains the iodide ion , which is an excellent
leaving group. It can therefore facilitate an SN2 substitution
reaction with relative easy.
Step 3.
Step 3.
The phenol was deprotected using Lithium ethanthiolate in
DMF ( Dimethyl This facilitated the removal of the methyl group and
replaced it with a H to form a hydroxl group. Thus forming compound
(E) in a 96% yield.
This is a key step as it has left a chink in the armour of
the molecule. This can then be used to build up a characteristic part
of the Tamoxifen molecule. (eg the (diemthylamino)ethyl group can be
added easily from here)
Step 4.
Step 4.
Then product E can be alkylated by treatment with
2-(dimethylamino) ethy chloride. The most facile site of alklation is
the OH group on the phenyl ring. This can be interpreted roughly by
using HSAB theory. e.g Hard and Soft acid/base theory. The carbon
adjacent to the chloride ion of the reactant 2-(dimethylamino)ethyl
chloride is made slightly harder due to the process of symbiosis.
This can rationalise the formation between the hard oxygen atom to
the normally soft carbon atom. In this case the carbon atom has
become slightly harder due to the presence of the hard chorine atom.
Hence the interaction is favourable by HSAB theory. The above
reaction gives product F via a SN2 substitution reaction in 70%
yield.
Step 5.
Step5.
F on treatment with PhMgBr forms the tertiary alcohol (G).
Formation of the Grignard reagent can be achieved via
reaction of PhBr + Mg -----> PhMgBr. The Grignard reagent has
effectively formed a carbanion species eg C delta negative (-ve).
This is due to the presence of the C-Mg bond. the fact that Magnesium
is a more electropositive element thus making the Carbon atom the
more electronegative element and hence acquiring a negative charge.
As a result of the negative nature of the carbon atom it can now
attack the delta positive (+ve) Carbon atom of the carbonyl group.
Step 6.
Step 6.
The dehydration of F was initiated by treatment of
methanoic hydrogen chloride. this gives the required structure of
Tamoxifen. However it gives a racemic mixture of both cis and trans
isomers.
The ratio of the Cis / Trans isomers was (1.3 / 1). These
isomers of Tamoxifen can be separated by Silica gel thin layer
chromatography with benzene / triethylamine (9:1) as the developing
solvent. Analysis of this technique revealed that the Z (Trans)
isomer was more mobile than the E (Cis) isomer.
Comments.
The above series of steps seem to enforce many of the
reactions and concepts developed during my short undergraduate
career.this is both surprising and satisfying as I am able to
interpret the synthesis of this important compound.
The Achilles heal of this synthesis is the fact that it
produces a mixture of both isomers which must then be separated. This
is a potentially difficult and time consuming process which should be
avoided if possible. In this respect this synthesis shows it's age
(it is nearly 20 years old) due to the fact that it is non
stereospecific.
