Question

During the synthesis of the antiasthmatic drug montelukast (Singulair), a silyl ether protecting group is used to mask the reactivity of an OH group. The silyl group chosen is the tert-butyldimethylsilyl (TBDMS) group. Draw the product of the following transformation, assuming the TBDMS-Cl reagent reacts only once with the starting material. Briefly explain your answer.

Short answer

Question: Provide the structure of the product formed during the synthesis of montelukast when a tert-butyldimethylsilyl (TBDMS) protecting group is used to mask an OH group. Also provide a brief explanation of the process. Answer: In montelukast synthesis, the OH group reacts with a tert-butyldimethylsilyl chloride (TBDMS-Cl) reagent. The reaction occurs once, causing the OH group to be replaced by a tert-butyldimethylsilyl group, forming a silyl ether. This protects the OH group during the synthesis process. The final product will have the structure of montelukast with the OH group replaced by the TBDMS group.

Step-by-step solution

Identify the starting material and reagent structure

To draw the final product, we first need to know the structure of the starting material and TBDMS-Cl. After looking up the structure of montelukast, identify the OH group that needs to be protected by the TBDMS group. Similarly, determine the structure of the tert-butyldimethylsilyl chloride (TBDMS-Cl) reagent. Step 2:

Identify the reaction site

Now, identify where the OH group on montelukast will react with the TBDMS-Cl. Since we know that the TBDMS-Cl reagent reacts only once with the starting material, we need to find only one site of reaction on the molecule. Step 3:

Draw the product

Once the site of reaction is identified, draw the product showing the attachment of the TBDMS group to montelukast by replacing the OH group with the tert-butyldimethylsilyl group. Step 4:

Provide a brief explanation

Write a brief explanation of the process, describing the reaction between montelukast's OH group and the TBDMS-Cl reagent to form a silyl ether, resulting in the protection of the OH group during synthesis. Remember that the product you draw must properly reflect the structures of montelukast and the TBDMS group, as well as show the result of the reaction between them. Follow these steps, and you will be able to draw the desired product and provide a brief explanation of the process.

Key concepts

Montelukast Synthesis

Montelukast is a medication popularly used to manage the symptoms of asthma and to relieve the signs of seasonal allergies. The synthesis of montelukast in the laboratory is complex due to its intricate molecular structure which includes multiple reactive functional groups. One of the primary hurdles in the synthesis process is to avoid unwanted reactions that could derail the production of the correct molecule. For this reason, chemists often employ protecting groups, which are chemical groups attached to reactive sites to prevent them from engaging in unwanted chemical processes.

During the synthesis of montelukast, an OH (hydroxyl) group is particularly reactive and could interfere with sequential synthetic steps. To prevent this, chemists use a silyl ether protecting group, specifically the tert-butyldimethylsilyl (TBDMS) group. By selectively reacting the TBDMS group with the OH group, it becomes temporarily inert, allowing other parts of the montelukast molecule to be constructed or modified without interference. Once the other synthetic steps are complete, the protecting group can be removed to reveal the active OH group once more. This strategy is a crucial aspect of producing montelukast in a controlled and efficient manner.

TBDMS-Cl Reagent

The tert-butyldimethylsilyl chloride (TBDMS-Cl) reagent is a silicon-based compound widely used in organic synthesis to protect hydroxyl groups as silyl ethers. It is especially useful due to its stability and the ease with which it can be introduced and later removed from the molecule without affecting other functional groups.

The structure of TBDMS-Cl comprises a silicon atom bonded to a chloride (Cl), a tert-butyl group (C₄H₉), and two methyl (CH₃) groups. In the presence of a mild base, TBDMS-Cl reacts specifically with hydroxyl (-OH) groups in a process known as silylation, where the chloride group is displaced by the hydroxyl group to form a silyl ether bond. This conversion temporarily masks the reactivity of the hydroxyl group during synthetic steps where it could otherwise react indiscriminately. This selective protection is instrumental in the stepwise construction of complex molecules such as montelukast, offering chemists precise control over the synthesis process.

Organic Synthesis Protection

Chemical Shielding

Organic synthesis often requires the use of protection strategies to guard sensitive functional groups from undesirable reactions. A protecting group such as the TBDMS group acts as a chemical shield, preventing the hydroxyl group from taking part in reactions until the suitable stage in the synthesis is reached.

Selectivity and Reversibility

Key features of any protecting group include selectivity—ensuring it reacts only with the target functional group—and reversibility, which allows it to be removed under specific conditions without damaging the molecule.

• Selectivity ensures that the protecting group does not react with other functional groups on the molecule, thus preserving the integrity of the target functional group.
• Reversibility allows chemists to deprotect the functional group once its safety from unintended reactions is no longer needed, which is usually accomplished by introducing specific reagents or changing reaction conditions.

Chemists must carefully select a protecting group, like TBDMS, to successfully navigate the complex paths of organic synthesis and ultimately arrive at the desired product with high purity and yield.