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 \(\mathrm{D}\) to \(\mathrm{E}\). (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 blocking groups, such as benzyl (Bn) and tetrahydropyranyl (THP), serve to protect functional groups and direct the reactions selectively. Mechanisms for conversions involve the formation of intermediates, such as enolate anions, and nucleophilic attacks, such as that of Grignard reagents. Toremifene is chiral with one stereocenter, allowing for the formation of two possible stereoisomers: (R)-toremifene and (S)-toremifene. The synthesis process may result in a racemic mixture of these stereoisomers if there is no preferential formation.

Step-by-step solution

(a) Blocking Groups: Benzyl (Bn) and Tetrahydropyranyl (THP)

The benzyl (Bn) and the tetrahydropyranyl (THP) are two blocking groups used in the synthesis of toremifene. 1. Benzyl (Bn) Group - Structural Formula: \[\mathrm{C_6H_5-CH_2}\] - Attached under the experimental conditions: Nucleophilic addition of a benzyl alcohol to the unprotected functional group. - Removed under experimental conditions: Hydrogenolysis with hydrogen gas and a palladium catalyst. 2. Tetrahydropyranyl (THP) Group - Structural Formula: \[\mathrm{C_5H_9O}\] - Attached under the experimental conditions: Treatment with DHP (3,4-dihydro-2H-pyran) and an acid catalyst. - Removed under experimental conditions: Treatment with an acid, usually aqueous hydrochloric acid (HCl), or an acidic resin.

(b) Chemical Logic Behind the Use of Blocking Groups

The use of each blocking group in this synthesis is to control the reactivity of the functional groups and direct the reactions selectively. These protecting groups are added to the functional groups, which need to be temporarily blocked from undergoing reactions. Later, they can be removed to reveal the original functional groups under controlled conditions. - Benzyl (Bn) Group: This blocking group is mainly used to protect hydroxyl groups (OH) during synthesis to prevent undesired reactions from occurring. The Bn group sterically shields the hydroxyl group and makes it less nucleophilic. - Tetrahydropyranyl (THP) Group: This blocking group is also used to protect hydroxyl groups, but it is usually temporary and easier to remove than the benzyl group. The THP group shields the hydroxyl group from reacting with electrophiles, which allows other functional groups to react selectively.

(c) Mechanism for the Conversion of D to E

The conversion of D to E involves the attack of a strong base (e.g., LDA or lithium diisopropylamide) on the ketone at the \(\alpha\)-carbon position, by deprotonating the acidic \(\alpha\)-hydrogen (in what is called an aldol condensation). This leads to the formation of an enolate anion as an intermediate. Subsequently, an intramolecular nucleophilic attack of the enolate oxygen atom onto the bromine atom occurs. The bromine atom leaves as a leaving group, forming a bromide ion, and the five-membered cyclic ether E is formed.

(d) Mechanism for the Conversion of F to Toremifene

The conversion of F to toremifene includes the reaction of F with a Grignard reagent. The aryl magnesium bromide, acting as a nucleophile, attacks the carbonyl carbon in F. This results in the breaking of the carbon-oxygen (C=O) bond and formation of a new carbon-carbon bond. After the addition of the aryl group, the reaction is quenched by the addition of an acidic workup, which protonates the oxygen, generating the desired toremifene product.

(e) Chirality of Toremifene and Stereoisomers Formed

Toremifene is a chiral molecule because it has at least one stereocenter (carbon with four distinct substituents). The stereocenter is at the tetrahydrofuran ring junction. Since there is only one stereocenter, toremifene can have two possible stereoisomers: (R)-toremifene and (S)-toremifene. In this synthesis, both isomers can be formed, depending on the facial selectivity of the aldol reaction in step c. If there is no preferential formation of one isomer over the other, a racemic mixture of the two possible stereoisomers will be obtained.