Question

Following is a synthesis for toremifene, a nonsteroidal estrogen antagonist whose structure is closely related to that of tamoxifen. (a) This synthesis makes use of two blocking groups, the benzyl (Bn) group and the tetrahydropyranyl (THP) group. Draw a structural formula of each group, and describe the experimental conditions under which it is attached and removed. (b) Discuss the chemical logic behind the use of each blocking group in this synthesis. (c) Propose a mechanism for the conversion of D to \(E\). (d) Propose a mechanism for the conversion of \(F\) to toremifene. (e) Is toremifene chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Short answer

Answer: The benzyl (Bn) group is used to protect the phenol group, and it can be attached using benzyl halide under basic conditions and removed by hydrogenation using Pd/C catalyst. The tetrahydropyranyl (THP) group protects the hydroxyl group and can be attached with dihydropyran under acidic conditions and removed using ethanol or TFA. These blocking groups allow for selective manipulation of other functional groups. The conversion of D to E occurs via an elimination reaction, while the conversion of F to toremifene occurs through a cyclization-dehydration reaction. Toremifene is chiral, and the synthesis can yield two possible stereoisomers: (S)-toremifene and (R)-toremifene, depending on the reaction conditions and stereochemistry of the starting materials.

Step-by-step solution

1. Draw the structural formulas for the benzyl (Bn) group and the tetrahydropyranyl (THP) group

Draw the following structures: Benzyl (Bn) group: An aromatic ring (benzene) attached to a CH2 group. Tetrahydropyranyl (THP) group: A pyran ring, which is a six-membered ring containing one oxygen atom and five saturated carbon atoms.

2. Describe the experimental conditions for attaching and removing the blocking groups

The benzyl (Bn) group can be attached to a compound by reacting it with a benzyl halide under basic conditions. It can be removed by hydrogenation, utilizing palladium on carbon (Pd/C) as a catalyst. The tetrahydropyranyl (THP) group can be attached by reacting a compound with dihydropyran under acidic conditions. It can be removed by using a specific reagent or a Lewis acid such as ethanol or TFA.

3. Discuss the chemical logic behind the use of each blocking group in this synthesis

Blocking groups are used to protect certain functional groups during a synthesis, allowing the chemist to selectively manipulate other groups. In the synthesis of toremifene, the benzyl (Bn) group protects the phenol group from reacting with other reagents. The tetrahydropyranyl (THP) group, on the other hand, protects the hydroxyl group from reacting with other reagents.

4. Propose a mechanism for the conversion of D to E

The conversion of D to \(E\) can be accomplished through an elimination reaction. A strong base can be used to abstract a proton from the alpha-carbon (carbon adjacent to the carbonyl group) in compound D, generating a carbanion. This carbanion can then attack the adjacent ester group, forming a cyclic intermediate. The intermediate can then undergo an intramolecular elimination reaction, leading to the formation of compound \(E\).

5. Propose a mechanism for the conversion of F to toremifene

The conversion of \(F\) to toremifene can be achieved through a cyclization-dehydration reaction. Compound \(F\) undergoes cyclization, whereby the phenol group attacks the carbon of the nitrile group, forming a new carbon-oxygen bond. This reaction generates an unstable imidate intermediate. This intermediate then undergoes dehydration (loss of water), forming a double bond between the nitrogen and the alpha-carbon, resulting in the formation of toremifene.

6. Determine if toremifene is chiral and identify which stereoisomers are formed if it is chiral

Toremifene is chiral, as it has a stereocenter at the position where the side chain with the aromatic ring is attached to the central carbon atom. The synthesis will potentially yield two possible stereoisomers: (S)-toremifene and (R)-toremifene. The specific stereochemistry of the product formed depends on the reaction conditions and the stereochemistry of the starting materials utilized in the reaction.

Key concepts

Blocking Groups in Organic Synthesis

In organic synthesis, blocking groups are essential for protecting specific functional parts of a molecule while the rest of it undergoes chemical transformations. The protection-deprotection strategy enables chemists to steer reactions toward desired products with high selectivity.

Two common blocking groups are the benzyl (Bn) and tetrahydropyranyl (THP) groups. The Bn group, comprised of an aromatic ring bonded to a CH2 group, is often attached under basic conditions using benzyl halide. Subsequent removal entails catalytic hydrogenation, typically with palladium on carbon (Pd/C). In the synthesis of therapeutic compounds like toremifene, this helps in guarding phenol functionalities from undesired side reactions.

The THP group is a six-membered ring with one oxygen and five carbon atoms offering protection to alcohol groups. Attaching it requires acidic conditions with a reagent such as dihydropyran, and it can be removed by reagents like ethanol or trifluoroacetic acid (TFA). Chemists use the THP group to prevent alcohol reactions that might interfere with other reactions progressing within the molecule. This precise control is critical in the medicinal chemistry field, where the synthesis of complex, biologically active substances like toremifene requires exact manipulation of molecular structure.

Mechanism of Esterification

The mechanism of esterification is a beautiful orchestration of atoms and bonds dancing to make new connections. In simple terms, it is a chemical reaction that transforms an alcohol and a carboxylic acid into an ester and water. The general form of the reaction is expressed as: \( \text{alcohol} + \text{carboxylic acid} \rightarrow \text{ester} + \text{water} \).

Delving into the mechanism, this process typically begins with the acid reacting with a strong acid catalyst, forming an activated acid that is more prone to attack by alcohol. The reaction proceeds through a series of steps, where the nucleophilic alcohol oxygen attacks the electrophilic carbonyl carbon of the acid. This forms a tetrahedral intermediate which, after a series of bond cleavages and re-arrangements, yields the ester product along with water.

Understanding esterification is crucial in organic chemistry because esters serve as protecting groups, flavors, fragrances, and are also intermediates in various synthetic routes—like the synthesis of toremifene, where alkoxides play a pivotal role. In advanced exercises, this could mean forming cyclic esters, utilizing the established mechanisms but in a more intricate set-up.

Chirality and Stereosiomers

Chirality is a geometric property where a molecule or its mirror image cannot be superimposed onto each other, akin to left and right hands. This characteristic has significant implications in chemistry, especially for molecules that have a center carbon connected to four different groups, known as a stereocenter or chiral center.

Each unique spatial arrangement of atoms around a chiral center gives rise to different stereoisomers. These are the same in molecular formula but differ in how their atoms are oriented in space. Stereosiomers include enantiomers, which are non-superimposable mirror images, and diastereomers, which are not mirror images. For many drugs, like toremifene, the specific arrangement of atoms can greatly affect how the drug interacts with biological targets.

The synthesis of toremifene can lead to two enantiomers: (S)-toremifene and (R)-toremifene. The chirality introduces complexity into synthetic processes as it requires careful control over reaction conditions to ensure the desired enantiomer is produced. This setting dictates which stereoisomer is formed, impacting the biological activity and efficacy of the final drug. As a consequence, understanding chirality and its control is paramount in the pharmaceutical industry.