Question

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.

Short answer

Answer: The two key reactions needed to convert compound A into tamoxifen are: 1. Converting the phenol group to a vinyl group using a series of reactions involving TBDPSCl and imidazole, DMP, and diethyl Methylphosphonate and KOtBu. 2. Introducing the dialkylaminoethoxyl substituent to the aromatic ring by first removing the phenol protecting group with TBAF and then performing an etherification reaction with 2-(N,N-dimethylamino)ethyl chloride and K2CO3.

Step-by-step solution

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.

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

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

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.

Key concepts

Estrogen Antagonists

Nonsteroidal estrogen antagonists are pivotal in the medical field, particularly for conditions like breast cancer. These compounds interact with estrogen receptors yet thwart the effects of both natural and synthetic estrogens. Imagine them as molecular blockers, stopping estrogen in its tracks. One hallmark of these antagonists is their unique chemical structure, often incorporating a 1,2-diphenylethylene unit. A substituent, such as a dialkylaminoethoxyl group, is attached to one of the benzene rings. This specific configuration enhances the ability to block estrogen receptors effectively.

The importance of estrogen antagonists in treatment regimens, especially for post-menopausal women, cannot be overstated. By reducing estrogen's influence, these drugs can slow or halt the growth of certain cancers. When designing these molecules, scientists focus on achieving a balance: maximizing receptor blockage while minimizing unwanted side effects.

Key points to remember about estrogen antagonists:

• They prevent estrogen from binding to its receptor.
• Key structural features are crucial for their function.
• Continuous study is leading to improved versions with fewer side effects.

Tamoxifen Synthesis

Tamoxifen is a groundbreaking drug used in breast cancer therapy. It's synthesized using a series of reactions designed to create its unique structure. The end goal is to achieve a molecule with an aromatic ring linked to an ethylene double bond, crucial for its activity as an estrogen receptor blocker.

The synthesis journey begins with a compound that holds a phenol group. Chemistry involves carefully altering this structure to form the required features of tamoxifen. The two main tasks entail changing this phenol group into a vinyl group and adding a dialkylaminoethoxyl group onto the aromatic ring.

Steps involved in synthesizing tamoxifen include:

• Protecting the phenol group, ensuring it's safe during later transformations.
• Oxidizing and transforming the adjacent carbon to create a vinyl link.
• Finally, introducing the needed dialkylaminoethoxyl group to complete the transformation.

These steps ensure that the final product, tamoxifen, is ready to function effectively against breast cancer, offering hope to many patients worldwide.

Horner-Wadsworth-Emmons Reaction

The Horner-Wadsworth-Emmons (HWE) reaction is a chemist's tool for crafting carbon-carbon double bonds, crucial in synthesizing compounds like tamoxifen. This reaction stands out for its ability to reliably produce geometric isomers, meaning it can give a mixture of two different spatial arrangements of the same molecule.

In tamoxifen synthesis, once the benzylic carbon adjacent to the phenol group is transformed to an aldehyde, the HWE reaction can proceed. This involves the use of reagents like diethyl methylphosphonate and a strong base such as potassium tert-butoxide (KOtBu).

Key aspects of the Horner-Wadsworth-Emmons reaction:

• Allows precise formation of the vinyl group from an aldehyde.
• Produces both E and Z isomers, useful in varying scientific contexts.
• Essential for constructing complex molecular structures quickly and efficiently.

Phenol Protection and Deprotection

In organic synthesis, protecting groups are employed like shields. They safeguard functional groups during reactions that could otherwise disrupt the molecule's delicate structure. Phenol groups, in particular, need protection, especially when undergoing intricate multi-step syntheses, such as tamoxifen production.

During tamoxifen synthesis, phenol protection is achieved using tert-butyldiphenylsilyl chloride (TBDPSCl). This creates a protective layer around the phenol group, ensuring the rest of the synthesis proceeds smoothly. Once the desired transformations are achieved, the phenol is then deprotected. Reagents like tetrabutylammonium fluoride (TBAF) gently remove the shielding, allowing the phenol to participate in further reactions.

Why protect phenol groups?

• Prevents unwanted reactions during key synthetic steps.
• Ensures the accuracy and success of complex syntheses.
• Facilitates the introduction of new functionalities to enhance drug efficacy.

This strategy demonstrates the careful planning involved in organic synthesis, particularly in pharmaceutical applications.