Exercises in Organic Synthesis Based on Synthetic Drugs

Concepts involving retrosynthesis were and are essential to the development of organic synthesis as science and art. Therefore, the first four exercises are based on this concept. These exercises were subdivided into themes and degrees of increasing difficulty so that the reader could gradually progress and become familiar with their concepts. Thus, the first exercise begins with the retrosynthetic analysis of drugs based on the identification of only two synthons and their respective synthetic equivalents (reagents and substances) necessary for their synthesis. Exercises 2, 3, and 4 are thematic and based on the identification of epoxides, piperazines, and aldehydes, used in the synthesis of drugs and bioactive substances as well as other synthons and their respective synthetic equivalents present in the exercises.

In this chapter, the exercises below are based on two themes. First, exercises based on the synthesis of several drugs and bioactive compounds used to treat various diseases. Therefore, several reaction conditions are presented. However, these conditions are disordered, and it is up to the reader to order them. The other theme is to identify reagents used for the preparation of a specific target molecule. This type of training is essential because it allows the reader to contact different types of reagents and chemical transformations and use them in a sequentially correct way.

In this chapter, the exercises below are also based on two themes. The first has an objective of the identification of the structure of the drugs having information of the starting materials and reagents used. This activity also enables the reader to become familiar with different classical chemical transformations used in medicinal chemistry and with varying types of reagents, reaction conditions, and necessary intermediates. In the second theme, the exercises are based on a series of gaps in the synthesis of different drugs. Therefore, it is up to the reader to complete them. This type of exercise is a combination of the themes previously presented. It is necessary to identify the reagents' use, the reaction conditions employed, and the intermediates formed, besides the use of the concept of retrosynthesis.

Heteroaromatics are substances having one or more atoms in the aromatic ring other than the carbon atom. This class of compounds is fundamental in developing new drugs, being present in a large number of drugs and bioactive compounds. Some of these cores are listed below, and it is worth noting that due to their immense structural variety, we mentioned only the most common ones. The exercises of this item we based on the formation of different heteroaromatic substances, and it is up to the reader to identify the respective nuclei.

The chemical hydrazine (NH2NH2) and its derivatives have several applications being also responsible for a large number of chemical transformations. This class has applications as rocket fuel and being present in the composition of explosives, in the control of corrosion, and the area of polymers. They also have full use in the development of bioactive substances being of great importance in medicinal chemistry. In the exercises of this chapter, we can synthesize several rings using hydrazine and its derivatives, and it is up to the readers to identify them.

Nitrile is a chemical function found in several drugs in the market for different kinds of diseases and can be transformed into several other functional groups such as ketones, aldehydes, carboxylic acids, amines, amides, and other functional groups. The use of nitriles is also advantageous in forming heteroaromatic nuclei with important applications in medicinal chemistry. In this chapter, the exercises are based on the use of nitriles to form a different nucleus.

Combinatorial chemistry is a methodology developed based on the synthesis of many compounds (hundreds, thousands, or even millions) in a simple chemical process building libraries of these compounds. In medicinal chemistry, an essential factor is the number of different molecules to be produced. For obtaining a leading compound and later a candidate drug, the biological evaluation of thousands of compounds is necessary. Therefore, the exercises below are based on combinatorial chemistry.

Multicomponent reaction (MCR) is a type of reaction based on a mixture of three or more compounds or reagents leading only to one or a major molecule being able to form complex molecules with a high degree of control of the stereogenic centers in only one step. This methodology is also a useful tool in medicinal chemistry to produce a diversity of compounds for biological evaluation. Due to its importance, the exercises below focus on this technique.

The most famous reaction, based on the click chemistry concept, is to obtain 1,2,3-triazoles, employing the 1,3-dipolar cycloaddition reaction between azides and alkynes. This reaction raised intense interest in academics and industrialists and was discovered independently by Sharpless and the Danish Morten Meldal in the year 2002. They demonstrated that the addition of copper as a catalyst has several advantages, such as an increase in the speed of the reaction, regioselectivity, high yields, and reactions are easy to elaborate. Due to its importance in drug discovery, the exercises below are based on this concept.

Fluorine chemistry is an important area that made a significant impact on drug discovery development, which can be seen by a large number of drugs in the market containing this chemical element. The success of drugs containing fluorine atoms in its structures is due to its chemical properties compared to the other elements, providing several advantages in drug discovery. Some of these advantages are better metabolic stability, avoiding undesired metabolizations, and improving the bioavailability of the drugs, among others. Due to its importance in drug discovery, the exercises below are focused on fluorine chemistry.