An Introduction to Organic Synthesis

Organic synthesis is the construction of complex organic compounds from simple starting compounds by a series of chemical reactions. The compounds synthesized in nature are called natural products. Nature provides a plethora of organic compounds and many of these possess interesting chemical and pharmaceutical properties. Examples of natural products include cholesterol (1.1), a steroid found in most body tissues limonene (1.2), a terpene found in lemon and orange oils caffeine (1.3), a purine found in tea leaves and coffee beans and morphine (1.4), an alkaloid found in opium. 

The compound to be synthesized may have a small carbon framework such as vanillin (1.5) (vanilla flavouring) or have more complex carbon frameworksuch as penicillin G (1.6) (an antibiotic) and taxol (1.7) (used for the treatment of certain types of cancer). However, three challenges must be met in devising a synthesis for a specific compound (1) the carbon atom framework or skeleton that is found in the desired compound must be assembled  

in order to understand the synthesis of a complex molecule, we need to understand the carbon-carbon bond forming reactions, functional groups interconversions and stereochemistry aspects. 

Therefore, carbon-carbon bond forming reactions, asymmetric synthesis, the design of new chiral ligands, environmental-friendly reactions and atom economical syntheses are the major aims of present-day research. 

Some of the syntheses we plan may seem trivial. Here s an example  

Strategy Compare the product with the starting material, and catalog the differences. In this case, we need to add three carbons to the chain and reduce the triple bond. Since the starting material is a terminal alkyne that can be alkylated, we might first prepare the acetylide anion of 1-pentyne, let it react with 1-bromopropane, and then reduce the product using catalytic hydrogenation. 

The synthesis route just presented will work perfectly well but has little practical value because you can simply buy octane from any of several dozen 

Let s work several more examples of increasing complexity. 

Synthesize c/s-2-hexene from 1-pentyne and any alkyl halide needed. More than one step is required. 

Practice Problem 8.1 Prepare octane from 1-pentyne. 

Strategy Compare the product with the starting material, and catalog the differences. In this case, we need to add three carbons and reduce the triple bond. 

Solution First alkylate the acetylide anion of 1-pentyne with 1-bromopropane to add three carbons, and then reduce the product using catalytic hydrogenation  

Although the synthesis route just presented will work perfectly well, it has little practical value because a chemist can simply buy octane from any of several dozen chemical supply companies. The value of working the problem is that it makes us approach a chemical problem in a logical way, draw on our knowledge of chemical reactions, and organize that knowledge into a workable plan—it helps us learn organic chemistry. 

Problem 8.10 Show the terminal alkync and alkj l halide from which each of the following products can be obtained. If two routes look feasible, list both. 

Problem 8.11 How would you prepare cts-2-butene starting from propync, an alkyl halide, and any other reagents needed This problem can t be worked in a single step. You ll have to carry out more than one reaction. 

The mechanism for this reduction, shown in the preceding box, involves successive electron transfers from lithium (or sodium) atoms and proton transfers from amines (or ammonia). In the first step, a lithium atom transfers an electron to the alkyne to produce an intermediate that bears a negative charge and has an unpaired electron, called a radical anion. In the second step, an amine transfers a proton to produce a vinylic radical. Then, transfer of another electron gives a vinylic anion. It is this step that determines the stereochemistry of the reaction. The trawi-vinylic anion is formed preferentially because it is more stable the bulky alkyl groups are farther apart. Protonation of the trani-vinylic anion leads to the trans-alkene. 

Write the structure of compound A, used in this synthesis of the perfume ingredient (Z)-jasmone. 

You have learned quite a few tools to this point that are useful for organic synthesis. Among them are nucleophilic substitution reactions, elimination reactions, and the hydrogenation reactions covered in Sections 7.13-7.15. Now we will consider the logic of organic synthesis and the important process of retrosynthetic analysis. Then we will apply nucleophilic substitution (in the specific case of alkylation of alkynide anions) and hydrogenation reactions to the synthesis of some simple target molecules. 

A very simple organic synthesis may involve only one chemical reaction. Others may require from several to 20 or more steps. A landmark example of organic synthesis is that of vitamin B12, announced in 1972 by R. B. Woodward (Harvard) and A. Eschenmoser (Swiss Federal Institute of Technology). Their synthesis of vitamin B12 took 11 years, required more than 90 steps, and involved the work of nearly 100 people. We will work with much simpler examples, however. 

Sometimes it is possible to visualize from the start aU the steps necessary to synthesize a desired (target) molecule from obvious precursors. Often, however, the sequence of transformations that would lead to the desired compound is too complex for us to see a path from the beginning to the end. In this case, since we know where we want to finish (the target molecule) but not where to start, we envision the sequence of steps that is required in a backward fashion, one step at a time. We begin by identifying immediate precursors that could react to make the target molecule. Once these have been chosen, they in turn become new intermediate target molecules, and we identify the next set of precursors that could react to form them, and so on, and so on. This process is repeated until we have 

There are many reasons for carrying out the laboratory synthesis of an organic compound. In the pharmaceutical industry, new organic molecules are designed and synthesized in the hope that some might be useful new drugs. In the chemical industry, syntheses are done to devise more economical routes to known compounds. In academic laboratories, the synthesis of complex molecules is 

The product in this case is a cis-disubstituted aikene, so the first question is, What is an immediate precursor of a cis-disubstituted aikene We know that an aikene can be prepared from an aikyne by reduction and that the right choice of experimentai conditions wiii aiiow us to prepare either a trans-disubstituted aikene (using iithium in iiquid ammonia) or a cis-disubstituted aikene (using cataiytic hydrogenation over the Lindiar cataiyst). Thus, reduction of 2-hexyne by cataiytic hydrogenation using the Lindiar cataiyst should yield c/s-2-hexene. 

Next ask, What is an immediate precursor of 2-hexyne We ve seen that an internal aikyne can be prepared by alkylation of a terminal aikyne anion. In the present instance, we re told to start with Tpentyne and an alkyl halide. Thus, alkylation of the anion of Tpentyne with iodomethane should yield 2-hexyne. 

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G. H. Posner, Org. Reactions 22, 253 (1975) G. H. Posner, An Introduction to Organic Synthesis Using Organocopper Reagents. Wiley, New York, 1980. 

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