CHAPTER 1

RETROSYNTHETIC ANALYSIS

Every organic synthesis problem actually begins at the end of the story, a targetmolecule. The goal is to design a reasonable synthesis that affords the targetmolecule as the major product. In the interest of saving both time and money,an ideal synthesis will employ readily available starting materials and will be asefficient as possible. The planning of a synthesis involves imagining the possiblereactions that could give the desired target molecule product; this process iscalled doing a retrosynthesis or performing a retrosynthetic analysis of a targetmolecule. A special arrow is used to denote a retrosynthetic step. The arrowleading away from the target molecule represents the question "What startingmaterials could I use to make this product?" and points to an answer to thatquestion. The analysis begins by identifying a functional group (FG) present onthe target molecule and recalling the various reactions that are known to giveproducts containing that functional group (or pattern of FGs). The process iscontinued by analyzing the functional groups in the proposed starting materialand doing another retrosynthetic step, continuing to work backwards towardsimple, commercially available starting materials. Once the retrosynthetic analysisis complete, then the forward multistep synthesis can be evaluated, beginningwith the proposed starting materials and treating them with the necessaryreagents to eventually transform them into the desired target molecule.A retrosynthesis involves working backwards from the given target molecule(work done in our minds and on paper), while the synthesis is the forward pathleading to the target molecule (experimental work done in the lab). Performinga retrosynthetic analysis is challenging since it not only requires knowledgeof an enormous set of known organic reactions, but also the ability to imaginethe experimental conditions necessary to produce a desired product. This challengebecomes more manageable by developing a systematic approach tosynthesis problems.

When evaluating a given target molecule, it is important to consider howthe functional groups present in the target molecule can be formed. There aretwo possibilities for creating a given functional group: by conversion from adifferent functional group (called a functional group interconversion or FGI),or as a result of a bond-forming reaction (requiring a retrosynthetic "disconnection").In order to synthesize a target molecule (or transform a given startingmaterial into a desired product),a combination of FGIs and carbon–carbonbond-forming reactions will typically be required. While the key to the "synthesis"of complex organic molecules is the formation of new carbon–carbonbonds, the synthetic chemist must also be fully capable of swapping one functionalgroup for another.

RETROSYNTHESIS BY FUNCTIONAL GROUPINTERCONVERSION (FGI)

Each functional group has a characteristic reactivity; for example, it might beelectron-rich, electron-deficient, acidic, or basic. In order to synthesize organiccompounds, we must construct the desired carbon framework while locatingthe required functional groups in the appropriate positions. This necessitatesthat the chemist is familiar not only with the reactivities of each functionalgroup, but also the possible interconversions between functional groups. Suchfunctional group interconversions enable the chemist to move along a syntheticpathway toward a desired target.

Let's consider a carboxylic acid target molecule (RCO₂H). There are manyways to generate a carboxylic acid functional group, so there are many possiblesyntheses to consider (often, there may be more than one good solution to agiven synthesis problem!). One reaction that gives a carboxylic acid productis the hydrolysis of a carboxylic acid derivative, such as a nitrile. Therefore, apossible retrosynthesis of a carboxylic acid target molecule (What startingmaterials are needed?) is to consider a functional group interconversion andimagine a nitrile starting material. In other words, if we had a nitrile in ourhands, we could convert it to a carboxylic acid, leading to a synthesis of thetarget molecule.

Choice of Reagents

There is almost always more than one reagent that can be used to achieve anygiven transformation. In fact, a quick look at a book such as ComprehensiveOrganic Transformations by Richard Larock reveals that there may be dozensof possibilities. Why have so many methods been developed over the years fororganic reactions? Because not every molecule—or every chemist—has thesame needs. The most obvious reason any "one size fits all" approach fails isthat complex synthetic targets contain a wide variety of functional groups. Themolecule as a whole must tolerate the reaction conditions used, and side reactionswith other functional groups must be kept to a minimum. For example,chromic acid oxidation (Na₂Cr₂O₇, H₂SO₄) of a 2° alcohol to give a ketonewould not be useful if the starting material contains any functional groups thatare sensitive to acidic conditions. In such a case, the Swern oxidation might bepreferred (DMSO, ClCOCOCl, Et₃N). New reagents, catalysts, and methodsare continuously being developed, with goals of having better selectivity, bettertolerance for certain functional groups, being "greener" with less waste orlower toxicity, requiring fewer steps, being more efficient and/or less expensive,and so on.

The focus of this book is on the strategies of organic synthesis; it isnot intended to be comprehensive in the treatment of modern reagents.Instead, reagents used are those that are typically found in undergraduateorganic chemistry textbooks. Hopefully, these reagents will be familiar to thereader, although they would not necessarily be the ones selected when thesynthesis moves from paper to the laboratory. Furthermore, experimentaldetails have largely been omitted from this book. For example, osmiumtetroxide oxidation of an alkene is given simply as "OsO₄." In reality, thisexpensive and toxic reagent is used in catalytic amounts in conjunction withsome other oxidizing agent (e.g., NMO), so the precise reagents and experimentalreaction conditions are much more complex than what is presentedherein.

RETROSYNTHESIS BY MAKING A DISCONNECTION

Rather than being created via a functional group interconversion, a functionalgroup (or pattern of functional groups) may be created as a result ofa reaction that also forms a carbon–carbon sigma bond. In that case, theretrosynthesis involves the disconnection of that bond. In a typical carbon–carbonbond-forming reaction, one of the starting material carbons must havebeen a nucleophile (Nu:, electron-rich), and the other must have been anelectrophile (E⁺, electron-deficient). While this is certainly not the only wayto make a carboncarbon bond (e.g., organometallic coupling reactions),the pairing of appropriate nucleophiles and electrophiles serves as an importantfoundation to the logic of organic synthesis, and such strategies will solvea wide variety of synthetic problems. Therefore, the disconnection of thecarboncarbon bond is made heterolytically to give an anion (nucleophile)and a cation (electrophile). These imaginary fragments, called "synthons," arethen converted into reasonable starting...