Estrogens are female sex hormones, the most potent of which is \(\beta\)-estradiol. In recent years, chemists have focused on designing and synthesizing molecules that bind to estrogen receptors. One target of this research has been nonsteroidal estrogen antagonists, compounds that interact with estrogen receptors and block the effects of both endogenous and exogenous estrogens. A feature common to one type of nonsteroidal estrogen antagonist is the presence of a 1,2 -diphenylethylene with one of the benzene rings bearing a dialkylaminoethoxyl substituent. The first nonsteroidal estrogen antagonist of this type to achieve clinical importance was tamoxifen, now an important drug in the treatment of breast cancer. Tamoxifen has the \(Z\) configuration as shown here. Propose reagents for the conversion of A to tamoxifen. Note: The final step in this synthesis gives a mixture of \(E\) and \(Z\) isomers.

Step by step solution

01

Identify the necessary changes and reagents

First, analyze the structure of compound A and compare it to tamoxifen. Compound A has a phenol group attached to a benzylic carbon, while tamoxifen has an aromatic carbon directly bonded to an ethylene double bond. Moreover, compound A is missing the dialkylaminoethoxyl substituent found in tamoxifen. To convert compound A into tamoxifen, we need to perform two key reactions: 1. Convert the phenol group to a vinyl group. 2. Introduce the dialkylaminoethoxyl substituent to the aromatic ring.

02

Phenol to vinyl group conversion

To convert the phenol group into a vinyl group, we can perform a series of reactions. First, we can protect the phenol group by converting it to its tert-butyldiphenylsilyl (TBDPS) ether using tert-butyldiphenylsilyl chloride (TBDPSCl) and imidazole as the reagents. Next, the benzylic carbon can be oxidized to the corresponding aldehyde using DMP (Dess-Martin periodinane) as the oxidizing reagent. Then, we can utilize the Horner-Wadsworth-Emmons (HWE) reaction for the formation of the vinyl group. To accomplish the HWE reaction, we need to treat the aldehyde with diethyl Methylphosphonate and a suitable base like potassium tert-butoxide (KOtBu). This step gives a mixture of the \(E\) and \(Z\) isomers. TDBPSCl and imidazole→ DMP → diethyl Methylphosphonate and KOtBu

03

Introduction of the dialkylaminoethoxyl substituent

To introduce the dialkylaminoethoxyl substituent, we need to remove the phenol protecting group first. To accomplish this, we can use tetrabutylammonium fluoride (TBAF) as a reagent. Then, we can perform an etherification reaction with 2-(N,N-dimethylamino)ethyl chloride to introduce the dialkylaminoethoxyl substituent. Lastly, we can use potassium carbonate (K2CO3) as a base to facilitate the etherification reaction. TBAF → 2-(N,N-dimethylamino)ethyl chloride and K2CO3

04

Summary of the steps

Here is the summary of the steps: 1. Protect phenol with TBDPSCl and imidazole. 2. Oxidize benzylic carbon to aldehyde using DMP. 3. Convert aldehyde to vinyl group via Horner-Wadsworth-Emmons reaction with diethyl Methylphosphonate and KOtBu. 4. Remove the phenol protecting group with TBAF. 5. Etherification reaction with 2-(N,N-dimethylamino)ethyl chloride and K2CO3 to introduce the dialkylaminoethoxyl substituent. The final product obtained is tamoxifen with a mixture of E and Z isomers.

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