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PROBLEM SOLVING STRATEGY
Organic Synthesis

In solving multistep synthetic problems, it is often helpful to analyze the problem backward: Begin with the desired product (called the target compound) and see how it might be mentally changed or broken down to give the starting materials. This backward approach to synthesis is called a retrosynthetic analysis.

Some problems allow you to begin with any compounds that meet a certain restriction;for example, you might be allowed to use any alcohols containing no more than four carbon atoms. A retrosynthetic analysis can be used to break down the target compound into fragments no larger than four carbon atoms; then those fragments could be formed from the appropriate alcohols by functional group chemistry

The following suggestions should help you solve synthesis problems.

1. Do not guess a starting material and try every possible reaction to convert it to the target compound. Rather, begin with the target compound and use a retrosynthetic analysis to simplify it.

2. Use simple equations, with reagents written above and below the arrows, to show the reactions. The equations do not have to be balanced, but they should include all the reagents and conditions that are important to the success of the reaction.

3. Focus your attention on the functional groups, since that is generally where reactions occur. Do not use any reagents that react with a functional group you don?t intend to modify.

In solving multistep synthesis problems, you will rarely be able to ?see? the solution immediately. These problems are best approached systematically, working backward and considering alternative routes.

Consider the synthesis of the following compound from alkenes containing up to five carbon atoms.
Refer fig 1

1. Review the functional groups and carbon skeleton of the target compound.
The target compound is an ether. One alkyl group is a five-carbon cyclopentane ring with two oxygen atoms situated trans. The other group has three carbons containing a reactive epoxide ring.

2. Review the functional groups and carbon skeletons of the starting materials (if specified), and see how their skeletons might fit together in the target compound.
The synthesis is to begin with alkenes containing up to five carbon atoms, so all the functional groups in the product must be derived from alkenes. Most likely, we will start with cyclopentene to give the five-carbon ring and propene to give the three-carbon chain.

3. Compare methods for synthesizing the functional groups in the target compound, and select the reactions that are most likely to give the correct product.This step may require writing several possible reactions and evaluating them. Ethers canbe synthesized by nucleophilic reactions between alkyl halides and alkoxides .The target compound might be formed by S_N2 attack of an alkoxide ion on an alkyl halide in either of two ways:(refer fig 2)
The first reaction is better because the S_N2 attack is on a primary alkyl halide, while the second is on a secondary halide. Also, in the second reaction the alkoxide might simply deprotonate the alcohol on the left and cause the reaction to fail.

4. In general, reactive functional groups are best put into place toward the end of a synthesis. The target compound contains a reactive epoxide ring. Epoxides react with acids and bases, and the epoxide might not survive the crucial ether-forming reaction shown above. Perhaps the epoxide is best added after formation of the ether. That gives us the following final two steps in the synthesis:
(Refer fig 3)

5. Working backward through as many steps as necessary, compare methods for synthesizing the reactants needed for the final step. This process may require writing several possible reaction sequence and evaluating them, keeping in mind the specified starting materials. Two reactants are needed to form the ether: an allylic halide and an alkoxide ion. Alkoxide ions are commonly formed by the
reaction of an alcohol with sodium metal:(Refer fig 4)

The alkoxide needed in the final step is formed by adding sodium to a trans diol. Trans diols are formed by epoxidation and hydrolysis of alkenes(fig 5)

The other piece we need is an allylic bromide. Allylic bromides are formed by allylic bromination of alkenes.(fig 6)

6. Summarize the complete synthesis in the forward direction, including all steps and all reagents, and check it for errors and omissions.

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