Introduction to Strategies for Organic Synthesis - Softcover

Starkey, Laurie S.

Softcover

ISBN 10: 0470484098 ISBN 13: 9780470484098

Publisher: Wiley, 2012

Synopsis

The stepping-stone text for students with a preliminary knowledge of organic chemistry looking to move into organic synthesis research and graduate-level coursework

Organic synthesis is an advanced but important field of organic chemistry, however resources for advanced undergraduates and graduate students moving from introductory organic chemistry courses to organic synthesis research are scarce. Introduction to Strategies for Organic Synthesis is designed to fill this void, teaching practical skills for making logical retrosynthetic disconnections, while reviewing basic organic transformations, reactions, and reactivities.

Divided into seven parts that include sections on Retrosynthesis and Protective Groups; Overview of Organic Transformations; Synthesis of Monofunctional Target Molecules; Synthesis of Target Molecules with Two Functional Groups; Synthesis of Aromatic Target Molecules; Synthesis of Compounds Containing Rings; and Predicting and Controlling Stereochemistry, the book covers everything students need to successfully perform retrosynthetic analyses of target molecule synthesis.

Starting with a review of functional group transformations, reagents, and reaction mechanisms, the book demonstrates how to plan a synthesis, explaining functional group analysis and strategic disconnections. Incorporating a review of the organic reactions covered, it also demonstrates each reaction from a synthetic chemist's point of view, to provide students with a clearer understanding of how retrosynthetic disconnections are made.

Including detailed solutions to over 300 problems, worked-through examples and end-of-chapter comprehension problems, Introduction to Strategies for Organic Synthesis serves as a stepping stone for students with an introductory knowledge of organic chemistry looking to progress to more advanced synthetic concepts and methodologies.

About this title

About the Author

Laurie S. Starkey, PHD, is a Full Professor of Chemistry at California State Polytechnic University, Pomona, where she has been teaching organic chemistry and organic synthesis since 1996. Dr. Starkey earned the College of Science's Distinguished Teaching Award in 2000 and the Provost's Award in Teaching Excellence at Cal Poly Pomona in 2013. Her research interests lie in the area of chemical education, including the development and assessment of online learning tools and the creation of educational videos for YouTube and Educator.com.

Organic synthesis is an advanced but important field of organicchemistry, however resources for advanced undergraduates andgraduate students moving from introductory organic chemistrycourses to organic synthesis research are scarce. Introductionto Strategies for Organic Synthesis is designed to fill thisvoid, teaching practical skills for making logical retrosyntheticdisconnections, while reviewing basic organic transformations,reactions, and reactivities.

Divided into seven parts that include sections on Retrosynthesisand Protective Groups; Overview of Organic Transformations;Synthesis of Monofunctional Target Molecules; Synthesis of TargetMolecules with Two Functional Groups; Synthesis of Aromatic TargetMolecules; Synthesis of Compounds Containing Rings; and Predictingand Controlling Stereochemistry, the book covers everythingstudents need to successfully perform retrosynthetic analyses oftarget molecule synthesis.

Starting with a review of functional group transformations,reagents, and reaction mechanisms, the book demonstrates how toplan a synthesis, explaining functional group analysis andstrategic disconnections. Incorporating a review of the organicreactions covered, it also demonstrates each reaction from asynthetic chemist's point of view, to provide students with aclearer understanding of how retrosynthetic disconnections aremade.

Including detailed solutions to over 300 problems,worked-through examples and end-of-chapter comprehension problems,Introduction to Strategies for Organic Synthesis serves as astepping stone for students with an introductory knowledge oforganic chemistry looking to progress to more advanced syntheticconcepts and methodologies.

Excerpt. © Reprinted by permission. All rights reserved.

Introduction to Strategies for Organic Synthesis

By Laurie S. Starkey

John Wiley & Sons

Copyright © 2012 John Wiley & Sons, Inc.
All rights reserved.

ISBN: 978-0-470-48409-8

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 materials. By being familiar withcommon nucleophiles and electrophiles, we can make logical disconnections.The example below shows the logical disconnection of an ether target molecule,affording recognizable alkyl halide E⁺ and alkoxide Nu: startingmaterials.

Disconnecting that same carbonoxygen bond in the other direction (withboth electrons going to the carbon) would be an illogical disconnection, sinceit leads to an electrophilic oxygen synthon for which there is no reasonableequivalent reagent.

Let's consider once again a carboxylic acid target molecule. We've seen thata carboxylic acid can be prepared by an FGI if the carbon chain is alreadyin place, but it is also possible to create new carbon–carbon bonds in a carboxylicacid synthesis. For example, the reaction of a Grignard reagent withcarbon dioxide generates a carboxylic acid functional group, so this presentsa possible disconnection for the target molecule's retrosynthesis. The logicaldisconnection is the one that moves the electrons away from the carbonyl,giving reasonable synthons and recognizable starting materials (RMgBr Nu:and CO₂ E⁺).

What Makes a Good Synthesis?

The fact that multiple retrosynthetic strategies usually exist means that therewill often be more than one possible synthesis of a desired target molecule.How can we determine which synthesis is best? This depends on many factors,but there are some general rules that can help us devise a good plan to synthesizethe simple target molecules found in this book.

1. Start with reasonable starting materials and reagents. A good synthesisbegins with commercially available starting materials. Most of these startingmaterials will have a small number of functional groups (just one ortwo), although some complex natural products are readily available andinexpensive (e.g., sugars and amino acids). A quick check in any chemicalsupplier catalog can confirm whether a starting material is ordinary (i.e.,available and inexpensive) or exotic (i.e., expensive or not listed).

2. Propose a reaction with a reasonable reaction mechanism. Look forfamiliar nucleophiles and electrophiles to undergo predictable reactions.A poor choice for a bond disconnection can lead to impossible synthons(and impossible reagents). However, we will learn that certain seeminglyimpossible synthons are, in fact, possible with the use of syntheticequivalents.

3. Strive for disconnections that lead to the greatest simplification. It is badpractice to put together a 10-carbon target molecule one carbon at a time(an example of a linear synthesis). Remember, the synthetic schemesdrawn on paper represent reactions that will be performed in the lab.While this book will not be focusing on experimental details, we shouldrecognize that the more steps in a reaction sequence, the lower theoverall yield of product will be. Starting with a nine-carbon starting material,which is nearly as big and possibly as complicated as a 10-carbontarget molecule, also would not be a good synthesis. The most efficientsynthesis would be one that links together two five-carbon structures, orperhaps one that combines a four-carbon with a six-carbon compound(described as a convergent synthesis). The more nearly equal the resultingpieces, the better the bond disconnection. One useful strategy is tolook for branch points in a target molecule for good places to make adisconnection. In the example below, the starting materials resultingfrom disconnection "a" are not only more simple molecules, but also thebutanal starting material (butyraldehyde) is one-tenth the price of thealdehyde in disconnection "b" (2-methylbutyraldehyde).

(Continues...)

Excerpted from Introduction to Strategies for Organic Synthesis by Laurie S. Starkey. Copyright © 2012 John Wiley & Sons, Inc.. Excerpted by permission of John Wiley & Sons.
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Edition details

• Publisher: Wiley
• Publication date: 2012
• ISBN 10: 0470484098
• ISBN 13: 9780470484098
• Binding: Paperback
• Language: English
• Edition number: 1
• Number of pages: 360