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Chapter 12:

Multistep Syntheses and Retrosynthetic Analysis

In previous chapters, you have been learning how to conduct functional group transformations that are generally 1 or 2 steps in length.  Each of these transformations represents a small overall change to the molecule as a whole and is important.  In real life, however, syntheses require many “small” steps to arrive at the desired, or needed, product.  Often, a compound is discovered in nature and a chemist’s job is to determine how to synthesize this compound beginning with small, inexpensive reagents.  The compound is built by using multiple, individual chemical transformations.  In this chapter, we are going to learn how to combine all the individual transformations you have been studying efficiently in multi-step syntheses.  We are going to learn that the easiest method to carry out this task is often by working backward, beginning with a product and breaking the skeletal structure down in small steps to arrive at simple starting reagents.  This method of working backward is called Retrosynthetic Analysis.  It may be a slightly different way ofthinking, but you will find this technique extremely helpful.

Let us use an example from Chapter 11 to begin our study of multi-step syntheses.  The compound below is known as the Wieland-Miescher Ketone which is used by many natural product chemists as a precursor in the synthesis of steroidal backbones.

Wielend-Miescher Ketone

In Chapter 11, you learned how to form one of the 6-membered rings of this compund by an intra-molecuar Aldol condensation.  That technique is very powerful indeed, but how would you build the rest of this molecule?  It is most often synthesized from 2-ketohexanal shown below:

retrosynthetic analysis general

The question now that needs to be answered is..”How is the product obtained from the starting material shown?”  It cannot be accomplished in one step, so we need to work out multiple steps in this journey.  A popular synthesis of the molecule is shown below:

Wielend-Miescher forward

The synthesis shown requires 7 steps to go from starting reagent to final product.  One of the reagents needs to have a protected carbonyl functional group as shown in step 5, so there are actually 8 required transformations.  This synthesis is considered fairly simple to organic synthetic chemists.  However, if you were given the starting material shown and told to form the desired product, there appears to be no straightforward methodology for the steps used.  In hindsight, they seem obvious, but how is that particular pathway decided upon?  With all the reactions you have learned, and all the reagents you know, going forward from 2-ketohexanal could be a journey among many possible pathways leading to innumerable products.  It is almost impossible to “see” how to go from the starting material to product.  At each step, the complexity of the compound increases, and there are more chemical issues for you to be concerned with, including protecting groups, reagent incompatibility, side product formation, etc.  Every step forward becomes more complex and difficult.

It is much easier to begin with the product and work backward toward starting material.  Working backward allows you to begin with the most complex molecule, working your way back toward more and more simple compounds.  Each step should become increasingly easier, and the  reaction systems more simple .  You will find that retrosynthetic analysis allows you to readily construct the most difficult looking molecules in an efficient, and simple manner.

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