Question

Verapamil (Effexor), a coronary artery vasodilator, is used in the treatment of angina caused by insufficient blood flow to cardiac muscle. Even though its effect on coronary vasculature tone was recognized over 30 years ago, only recently has its role as a calcium channel blocker become understood. Following is a retrosynthetic analysis leading to a convergent synthesis; it is convergent because (A) and (B) are made separately and then combined (i.e., the route converges) to give the final product. Convergent syntheses are generally much more efficient than those in which the skeleton is built up stepwise. (a) Given this retrosynthetic analysis, propose a synthesis for verapamil from the four named starting materials. (b) Two steps are required to convert (D) to (C). The first is treatment of (D) with ethyl chloroformate. What is the product of this first step? What reagent can be used to convert this product to (C)? (c) How do you account for the regioselectivity of the nucleophilic displacement involved in converting (C) to (B)?

Short answer

Question: Propose a convergent synthesis of Verapamil from the four named starting materials using the given retrosynthetic analysis, and explain the regioselectivity of the nucleophilic displacement involved in converting (C) to (B). Identify the product of the first step of conversion of (D) to (C) and the required reagents to complete the conversion.

Step-by-step solution

(a) Convergent synthesis of Verapamil

A convergent synthesis of Verapamil involves making intermediates (A) and (B) separately and then combining them. The strategy is to build the intermediates from the given starting materials and then couple them to obtain the target molecule, Verapamil. 1. Synthesis of Intermediate (A): i. Starting from material I, perform a Friedel-Crafts alkylation with t-butyl chloride and aluminum chloride (AlCl3) to obtain intermediate (A). 2. Synthesis of Intermediate (B): i. Convert material (D) to intermediate (C) using the steps described in part (b) of the exercise. ii. Perform a nucleophilic displacement on intermediate (C) using sodium azide to form intermediate (B). 3. Coupling reaction between (A) and (B): i. React intermediate (A) with thionyl chloride and pyridine to form the corresponding acid chloride. ii. Perform an amide coupling reaction between the acid chloride of (A) and intermediate (B) using a suitable base like triethylamine to form Verapamil.

(b) Conversion of (D) to (C) - First step product and reagents

In the first step of the conversion of (D) to (C), (D) is treated with ethyl chloroformate. This results in the formation of a 3° carbamate ester. Thus, in the first step, the product will be the corresponding carbamate ester derived from (D). For the second step, to convert the carbamate ester to intermediate (C), we will need to use a suitable nucleophile to displace the ethyl group from the carbamate ester. Sodium phenoxide (NaOPh) can be used as the nucleophile to perform this conversion.

(c) Regioselectivity of nucleophilic displacement in the conversion of (C) to (B)

The regioselectivity of the nucleophilic displacement in the conversion of (C) to (B) can be justified based on the hard-soft acid-base (HSAB) principle. In this case, the nucleophile sodium azide (NaN3) is a hard nucleophile. This hard nucleophile is more likely to attack the more electropositive and sterically accessible carbon atom of the carbamate ester, which is also a better leaving group. As a result, the nucleophilic substitution preferentially occurs at the carbamate ester, leading to the formation of intermediate (B) with the observed regioselectivity.

Key concepts

Convergent Synthesis

Convergent synthesis is a method in organic chemistry education that prioritizes the assembly of complex molecules from simpler ones through separate synthetic paths that eventually converge. This approach contrasts with linear synthesis, where compounds are constructed step by step in a sequential manner, often leading to inefficiencies and higher chances of failure as the complexity of the molecule increases.

With convergent synthesis, intermediate (A) and intermediate (B) are synthesized independently and then coupled to form the final product, such as Verapamil, which is used to treat angina. This strategy not only simplifies the synthesis process but also improves the overall yield and can be critical when creating molecules like calcium channel blockers, where precision and efficiency are crucial.

Understanding the value of convergent synthesis allows for appreciation of the work that goes into developing compounds with specific and potent therapeutic effects, such as Verapamil.

Friedel-Crafts Alkylation

The Friedel-Crafts alkylation reaction is a key transformation in organic synthesis. This reaction involves the addition of an alkyl group to an aromatic ring, facilitated by a strong Lewis acid catalyst, typically aluminum chloride (AlCl3).

For instance, when synthesizing intermediate (A) for Verapamil, starting material I undergoes Friedel-Crafts alkylation using t-butyl chloride to attach the t-butyl group to the aromatic ring. However, this reaction must be carefully controlled to achieve the desired regioselectivity and prevent polysubstitution, a common issue with this method.

The ability to perform such reactions with high precision is vital, as the placement of the alkyl group can significantly influence the pharmacological properties of drugs like Verapamil.

Regioselectivity

Regioselectivity refers to the preference of a chemical reaction to occur at one directional site over other possible sites on a molecule. This concept is crucial when aiming to achieve specific structural outcomes in complex organic syntheses.

In the context of Verapamil synthesis, regioselectivity is crucial when converting intermediate (C) to (B) through nucleophilic displacement. The reaction must occur at the correct position on the molecule to produce the desired intermediate that will eventually become a part of the Verapamil structure. By applying the hard-soft acid-base (HSAB) principle, chemists can predict and manipulate these outcomes to ensure that the nucleophile attacks the most electropositive and accessible carbon atom.

This underlines the importance of understanding molecular electronic environments and steric hindrances, which are central to achieving high regioselectivity in the preparation of pharmaceuticals.

Nucleophilic Displacement

Nucleophilic displacement is a fundamental reaction type where a nucleophile, a species rich in electrons, displaces another group within a compound. This reaction is important in the synthesis of various organic molecules, including pharmaceuticals.

In Verapamil's synthesis, a nucleophilic displacement is used to transform intermediate (C) to (B). Sodium azide acts as the nucleophile, targeting the carbamate ester within the compound due to its electropositive character and accessibility. The choice and control of nucleophiles, in this case, are integral to achieving the correct molecular architecture required for Verapamil to function as a calcium channel blocker.

Proficient application of nucleophilic displacement reactions is a valuable skill for chemists, particularly in designing drugs with precise modes of action.

Calcium Channel Blockers

Calcium channel blockers are a class of medications that disrupt the movement of calcium through calcium channels in the heart and blood vessel walls. Verapamil, the focus of our synthetic exercise, is one such drug. It helps in relaxing blood vessels and reducing heart rate, thereby improving blood flow and decreasing blood pressure.

Calcium channel blockers are often used in the treatment of hypertension, angina, and some arrhythmias. The interesting part about drugs like Verapamil is their role at the cellular level, affecting the voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle. The synthesis of Verapamil, therefore, is not only an exercise in chemical ingenuity but also an application of pharmacological principles.

Educationally, it's vital for students to link the chemical structure of drugs like Verapamil to their biological function, appreciating the synthesis's final goal, which extends beyond the bench to impact patient care.