organic chemistry retrosynthesis practice problems with answers

MCAT and Organic Chemistry Study Guides, Videos, Cheat Sheets, tutoring and more

A Simple Approach to Retrosynthesis in Organic Chemistry

November 17, 2016 By Leah4sci 15 Comments

While there isn’t a clear distinction, I like to think of synthesis as forward thinking and retrosynthesis as the reverse .

Synthesis is a topic that is typically introduced in Organic Chemistry 1, right after studying alkyne reactions. You’ll be utilizing it again and again as the number of reactions that you learn accumulate.

This is why it is important to review past topics prior to moving on to the next chapter. While learning the new topics, you may be asked to perform a retrosynthesis that involves retrieving five different reactions from five different chapters.

Let’s back up…

What is retrosynthesis?

Retro = Backwards Synthesis =  The process of combining simpler reactions to form a chemical compound/molecule.

In your Organic Chemistry course, this is presented in the form of a complex molecule that you are then asked to synthesize from a given starting molecule, or a set of reaction conditions. –>You may be given a specific reactant and asked to synthesize a product.

–> You may be asked to synthesize a product given a set of vague or specific reaction conditions.

For example: “Synthesize 2-butanone using any inorganic reagents. Use 2 carbon alkyl halides as your only carbon source.”

Have you seen similar questions in your homework, quizzes or practice exams?

What do you think?

Many students will look at the process and panic;

And in said panic started drawing everything and anything that comes to mind, without a clear process or idea of where they are headed.

I like to be systematic in my approach to problems. I like to plan my steps and know exactly what I have to do.

And more importantly, I trust that the process will help me get the correct results, again and again.

As quickly as possible!

The more systematic your approach, the more likely you’ll get every component of the reaction.  Therefore, the less likely you’ll miss something.

That’s the key. Get every component and minimize lost points on your exam.

Before even diving into the problems themselves, you need to know where you’re going.

You must ensure that what you do will ultimately pay off to give you your desired product.

These are my go-to Retrosynthesis questions:

• What’s the same?
• What’s different?
• How can I achieve this difference?

What’s the Same?

Before adding new groups to the molecule, you want to see what is already there to work with.

We’ll utilize the analysis taught in the synthesis tutorial  when analyzing what’s present on the reactant.

COUNT YOUR CARBONS!!!

(so many lose points due to lack of counting.) How many carbon atoms are present in the reactant and product ? This will help you identify chain elongation or cleavage reactions.

Look for any non-carbon atoms and functional groups .

What else is on the molecule in the reactant and product?

Look for location of reactivity on the molecule.

Reactivity on the molecule refers to the location of reactive atoms or functional groups.

For example, 2-chloropropane has reactivity on the second carbon. Cl is a good leaving group. This allows us to carry out a number of reactions:

• Elimination to create a pi bond (E1 or E2)
• Substitution to give us another functional group in the form of an incoming nucleophile (SN1 or SN2)
• We could turn the Cl into a Grignard for a super reactive organometallic

This is your clue regarding WHERE to start the reaction.

Compare each of these features to the final product.

Make careful note of anything that changes because our goal in carrying out retrosynthesis will be exactly that: figuring out HOW to carry out these transformations, which brings me to question 2.

What’s Different?

• If the number of carbon atoms changed, by how many?
• How many carbons were added or removed?
• If the functional groups or reactivity changed , what was replaced and by what?
• How many new groups were added?

Once we’ve identified what’s the same and what’s different, we ask the most important question:

HOW Can I Carry Out this Transformation?

This is a two-part question.

1)  For short synthesis problems the answer is simple.

Which ONE reaction will convert starting molecule x to end with product y ?

How can I carry out this transformation? Eliminate the halogen using a strong base for an E2 reaction  or even a weak base and heat for an E1 reaction. Both will provide the same product.

Quick tip: When in doubt select E2 over E1. It’s faster, more precise and has less competition ( E1 vs SN1 )  when conditions are set right. You can also control the product choosing to form a more (Zaitsev) or less substituted ( Big Bulky Base ) pi bond.

2) But your professor will likely not give you such a simple one-step transformation for retrosynthesis. Let’s crank it up a notch.

Still a relatively simple transformation, but we’re no longer looking at a simple one-step reaction. The same set of questions apply and will still guide you to the product.

What’s the same? We have a total of four carbons in the reactant and product. We have a single functional group in the reactant and product.

What’s different? The reactant has a halogen; the product has an alcohol. Reactivity on the molecule shifted from carbon #2 to carbon #1.

Which reactions do I know to carry out this transformation? Suddenly the answer is not as clear, but it is still not impossible.

In the previous example we were able to quickly answer this question. ONE single reaction transformed our starting molecule to our desired product. Here, not so much!

This is where the true power of retrosynthetic analysis comes into play.

Let’s break it down.

So let’s take it a step further or should I say take it a step back .

Retrosynthesis IS backwards thinking, so let’s start with the product.

If the product is an alcohol on the primary carbon, what reaction do I know that will GIVE ME an alcohol on the primary carbon?

Primary vs secondary tells me Anti-Markovnikov alcohol, which tells me I need to carry out an alkene addition reaction  under Anti-Markovnikov conditions.

Taking the product just one step back, I need an alkene.

Don’t worry about the reagents just yet. It’s much easier to think through the molecules first and then go back and fill in the missing reagents as explained in the synthesis tutorial .

Now we treat the alkene as our new product and ask the same question again.

Comparing the reactant to the alkene,

Do I know of a reaction that will either carry out this transformation or get me close?

Why absolutely yes, a simple elimination reaction as we’ve seen above.

Which reagent will carry out this ‘anti-Zaitsev’ or Hoffman elimination? We need a ‘triple B’ or Big Bulky Base Tert-butoxide

But let’s not worry about tert-butoxide right now, instead let’s simply acknowledge the fact that we CAN react 2-chlorobutane to form 1-butene and draw this transformation.

Once you have all of your intermediates drawn in from product to reactant, quickly follow the sequence from reactant to product to ensure it looks right and makes sense.

Now ask yourself this:

Which reagent will carry out each transformation?

Ask yourself this question one at a time as you fill in the reaction conditions and complete your retrosynthesis sequence.

We start with a secondary halogen and form a less substituted pi bond. This requires the strong base tert-butoxide as we already hinted above.

While some professors will accept this as is, others will require a full set of conditions.

And there we have it, a step by step transformation with reagents in place.

Retrosynthesis is Really a Combination of Forward and Reverse Thinking.

Synthesis + retrosynthetic analysis.

Start with backwards thinking whenever you can.

You know the expression “hindsight is 20/20?” That’s what we’re banking on.

By looking at your product and only keeping your reactant in mind, you’re able to ask the very, very important question:

What did this molecule look like just ONE step prior, so that I can form functional group x?

This form of retrosynthetic analysis will help you quickly identify one intermediate at a time, all the way back to your starting molecule.

Let’s try something a little more complex.

What’s different? The product is a disubstituted benzene. The substituents have an ortho relationship. We’ve added a carboxylic acid and a nitro group.

We can add the carboxylic acid through a Friedel Crafts Alkylation  followed by oxidation.

We can add the nitro group through EAS Nitration .

The groups are ortho to each other.

Both NO2 and carboxylic acid are EAS deactivating groups with meta directing effects.

Let’s think this through before we start reacting.

If the carboxylic acid comes from an FC Alkylation, the alkyl group prior to oxidation is an ortho/para director .

That’s good.

But how do we ensure that we wind up with the ortho rather than para position?

We need one more reaction that is not apparent in the product. We need a blocking group at the para position to ensure ortho is the only available group.

All these thoughts should quickly run through your head. There’s no need to write the reactions just yet, although I do like to mark up the molecules as a ‘note to self.’

Now that we know where we’re going, retrosynthesis is done and we can take this reaction from reactant to product directly.

We’ll start with a Friedel Crafts alkylation . The size of your carbon chain doesn’t matter since side chain oxidation will cut off the extra carbon atoms.

We now have an ortho para director, so let’s add the blocking group .

With para blocked we can carry out another reaction keeping in mind the following:

• Ethyl is still an ortho/para director but para is blocked!
• Sulfur is partially positive and a meta directing group.

BOTH groups direct to the #2 carbon near the ethyl group which is exactly what we want.

This is where many students lose points.

They get so excited for having thought of all this that they forget that this is not the desired product.

ALWAYS go back to the initial question to ensure you haven't forgotten anything.

What have we forgotten?

Ethyl is not our goal. We need a carboxylic acid.

Now that you have the basics for how to approach retrosynthesis, you will need a solid foundation. I recommend going back to review all the key reactions covered in your semester so you have them fresh and ready to utilize as needed.

Use my Syllabus Companion  to quickly find tutorials, videos and cheat sheets for typical organic chemistry reactions.

I’d love to hear from you

Do you feel better about retrosynthesis and staying on the right path to full credit for each problem? Let me know in the comments below.

January 14, 2019 at 12:51 pm

This is really usefull…

November 12, 2018 at 8:39 pm

Hi, just want to ask how do you know which reagents to use for each step of the way? While I find it easy to do retrosynthesis, by which I mean synthons and thus synthetic equivalent, what I find really difficult is knowing which reagents to put down in the forward synthesis. If you have any advice it would be a really big help. Thank you

June 2, 2018 at 5:21 pm

I am really grateful, this is so useful basic for retrosynthesis.Now i will follow careful my work to get this.. Thank you.. Hope I will know where am going.

March 28, 2018 at 3:14 am

thanks a lot

March 4, 2018 at 4:49 am

thanku so much can you send me a tutorial of organic synthesis and retro synthesis

January 30, 2018 at 6:41 pm

hi Leah4 do you give private tutorial?

January 17, 2018 at 7:21 am

How do I go about the retro synthetic analysis for 5 methyl hexen-2-al

December 29, 2017 at 9:50 pm

I would like to ask how if the question only give the desired product without giving any starting material? How to make it possible? For example, it want to produce a ketone and only give the clue for starting material(may use esters or any inorganic reagents such as PPh3, PBr3, H2CrO4, etc) Can you give me some hint how to solve this? Thanks a lot.

November 26, 2017 at 7:50 pm

I love your videos, thanks

April 1, 2017 at 2:46 am

Leah4sci thank you so much

November 8, 2017 at 12:12 pm

You’re very welcome

November 20, 2016 at 3:03 pm

thanks alot to u it seems so easy and resonable

November 20, 2016 at 7:05 pm

You’re very welcome Mohamad. My goal is to make this topic less intimidating

November 18, 2016 at 10:18 pm

On the solution to the F.C. alkylation of benzene in the above synthesis problem, was it supposed to be ethyl chloride / AlCl3 to add the ethyl to the benzene ring in the first step? If not, what happened to the C=O that was used in the first step? Where did the reduction come from to loose the oxygen?

Thank you!!

November 19, 2016 at 11:35 am

Tony: FC Alkylation adds just the alkyl (C+H) chain. FC Acylation will add a carbonyl. We chose alkylation in this case because the carbonyl would direct meta. We need an ortho directing group

Leave a Reply Cancel reply

Your email address will not be published. Required fields are marked *

Save my name, email, and website in this browser for the next time I comment.

Organic Chemistry Reference Material and Cheat Sheets

Alkene Reactions Overview Cheat Sheet – Organic Chemistry

The true key to successful mastery of alkene reactions lies in practice practice practice. However, … [Read More...]

Click for additional cheat sheets

MCAT Tutorials

Introduction To MCAT Math Without A Calculator

While the pre-2015 MCAT only tests you on science and verbal, you are still required to perform … [Read More...]

Click for additional MCAT tutorials

Organic Chemistry Tutorial Videos

Keto Enol Tautomerization Reaction and Mechanism

Keto Enol Tautomerization or KET, is an organic chemistry reaction in which ketone and enol … [Read More...]

Click for additional orgo tutorial videos

The following problems are meant to be useful study tools for students involved in most undergraduate organic chemistry courses.  The problems have been color-coded to indicate whether they are:

1.   Generally useful , 2.   Most likely to be useful to students in year long, rather than survey courses , 3.   Most likely to be useful only to students in courses for chemistry majors and/or honors students .

Some of these problems make use of a Molecular Editor drawing application.  To practice using this editor Click Here .

Most of these Interactive Organic Chemistry Practice Problems have been developed by Professor William Reusch. �1999 William Reusch, All rights reserved. Comments, questions and errors should be sent to [email protected] . The Virtual Text and some of the problems make use of either the CHIME plugin , or Jmol . Click on the name for information and a free copy. If possible, monitor resolutions of 1024 x 768 or 1152 x 870 should be used.

Department of Chemistry Michigan State University East Lansing, MI  48824

Chemistry Steps

Organic Chemistry

Organic synthesis problems.

Organic Chemistry Practice Problems can be found after each topic covered in Chemistry Steps. The list of topics can be found here , and below are some examples of what you will find.

Organic Chemistry 1 Synthesis Problems

Nucleophilic substitution and elimination reactions, practice problems.

Predict the mechanism as SN1, SN2, E1 or E2 and draw the major organic product formed in each reaction. Consider any regioselectivity and stereoselectivity where applicable:

Answers and Solutions

Reactions of Alkenes Practice Problems

This is a comprehensive problem that covers the following topics and will serve as a review of all of them:

Substitution and elimination reactions.  Particularly,  substitution and elimination reactions of alcohols , the  regio – and stereochemistry of E2 reactions, and E2 reaction of cyclohexanes .

Mesylation and tosylation in Substitution and elimination reactions. 

Hydrohalogenation of alkenes according to Markovnikov’s rule .

Radical hydrohalogenation of alkenes .

Hydroboration-Oxidation of Alkenes .

Halogenation of alkenes through halohydrin formation .

Syn and anti dihydroxylation of alkenes.

Elimination reactions: Zaitsev and Hoffman products .

Ozonolysis of Alkenes.

Attempt to solve the entire problem before accessing the answers!

The  answers  will give you the structure of the  final product(s) only . Use this as a hint to determine the compounds formed after the first and second reactions.

Complete the following synthesis by adding the missing reagent(s) for each step and the structures for compound A and B:

Reactions of Alkynes Practice Problems

On the following synthetic scheme, identify the reagents, in the correct order, that you would use to achieve the following synthetic transformations. Determine the structure of compounds A and B and the major organic products resulting from the alkyne.

Organic Chemistry 2 Practice Problems

Alcohols practice problems.

Predict the major organic product(s) for the following Grignard reactions of a ketone, aldehyde, ester, carbon dioxide and an epoxide:

The Diels-Alder Reaction Practice Problems

For each Diels–Alder reaction, predict the major product(s) with correct stereochemistry when each cyclic  diene is reacted with a dienophile:

Aromatic Substitution Practice Problems

Show how each compound can be synthesized from benzene and any other organic or inorganic reagents.

The order of reactions is very important!  So, before every step,  consider the ortho – ,  para – ,  or meta directing effect  of the current group on the aromatic ring.

Devise a synthesis of each of the following compounds using an arene diazonium salt. They all require more than one step and you may select the desired regioisomer (for example the para product from an ortho, para mixture) when needed.

Aldehydes and Ketones Practice Problems

Predict the major product(s) obtained when each of the following compounds undergoes hydrolysis in the presence of an acid:

 Carboxylic Acids and Their Derivatives Practice Problems

Predict the  major organic product(s)  for each of the following reactions. They  all involve carboxylic acid derivatives  such as  esters, acid chlorides, nitriles, anhydrides, and amides . You may also need to go over the reactions covered in earlier chapters, particularly, the  Grignard  and  Gilman  reagents,  oxidizing  and  reducing   agents  and  electrophilic aromatic substitutions .

A link to each topic encountered in a given problem will be provided in the answer tab.

Alpha Carbon Chemistry – Enols and Enolates Practice Problems

This is a comprehensive practice problem  on the alpha carbon chemistry. The topics covered range from the simple halogenation reactions of enols to  multistep synthetic transformation .

To correctly answer these questions, you need to review the main principles of enolate chemistry – direct enolate alkylation, aldol condensation, crossed aldol condensation, alkylation using acetoacetic ester synthesis, malonic ester synthesis, the Stork enamine synthesis, Claisen condensation, Michael addition, and Robinson annulation.

CS Prime membership will also grant you access to multiple-choice quizzes !

If you are towards the end of your Organic 2 semester having covered most of the topics and ready for some more challenging synthesis problems – you are in the right place! In these practice problems, we will go over multistep organic synthesis.

Check also our new synthesis puzzles!

Go ahead and give it a try!

Determine the structure of each unknown in the following synthesis problems:

Keep in mind that it is rare to perform synthesis where only one product is formed and most often there is a need for isolating and purifying the desired product. So in this set of problems, you can choose a route where the target product is obtained as a mixture, even though it is desirable to design a synthesis where the yield of the target compound is in a reasonable range.

This content is for registered users only.

Click here to Register!

By joining Chemistry Steps, you will gain instant access to the answers and solutions for all the Practice Problems including over 20 hours of problem-solving videos, Multiple-Choice Quizzes, Puzzles, and t he powerful set of Organic Chemistry 1 and 2 Summary Study Guides .

Check Also:

• Carboxylic Acids and Their Derivatives Practice Problems
• Acetals as Protecting Groups for Aldehydes and Ketones
• How to Choose Molecules for Doing SN2 and SN1 Synthesis-Practice Problems
• Alkene Reactions Practice Problems
• Changing the Position of a Double Bond
• Changing the Position of a Leaving Group
• Alkenes Multi-Step Synthesis Practice Problems
• Alkyne Synthesis Reactions Practice Problems
• Radical Halogenation in Organic Synthesis
• Grignard Reaction in Organic Synthesis with Practice Problems
• Ortho Para Meta Directors in Electrophilic Aromatic Substitution with Practice Problems
• Orientation in Benzene Rings With More Than One Substituent

Leave a Comment Cancel reply

Notify me of followup comments via e-mail. You can also subscribe without commenting.

Have we been helpful? Please let us know in the Reviews section here.

WassUp 1.9.4.5 timestamp: 2024-05-22 07:56:40AM UTC (02:56AM) If above timestamp is not current time, this page is cached.

• school Campus Bookshelves
• menu_book Bookshelves
• perm_media Learning Objects
• login Login
• how_to_reg Request Instructor Account
• hub Instructor Commons

Margin Size

• Download Page (PDF)
• Download Full Book (PDF)
• Periodic Table
• Physics Constants
• Scientific Calculator
• Reference & Cite
• Tools expand_more
• Readability

selected template will load here

This action is not available.

INTERCHAPTER: Retrosynthetic analysis and metabolic pathway prediction

• Last updated
• Save as PDF
• Page ID 395046

• Tim Soderberg
• University of Minnesota Morris

\( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)

\( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)

\( \newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\)

( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\)

\( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

\( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\)

\( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)

\( \newcommand{\Span}{\mathrm{span}}\)

\( \newcommand{\id}{\mathrm{id}}\)

\( \newcommand{\kernel}{\mathrm{null}\,}\)

\( \newcommand{\range}{\mathrm{range}\,}\)

\( \newcommand{\RealPart}{\mathrm{Re}}\)

\( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

\( \newcommand{\Argument}{\mathrm{Arg}}\)

\( \newcommand{\norm}[1]{\| #1 \|}\)

\( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\AA}{\unicode[.8,0]{x212B}}\)

\( \newcommand{\vectorA}[1]{\vec{#1}}      % arrow\)

\( \newcommand{\vectorAt}[1]{\vec{\text{#1}}}      % arrow\)

\( \newcommand{\vectorB}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)

\( \newcommand{\vectorC}[1]{\textbf{#1}} \)

\( \newcommand{\vectorD}[1]{\overrightarrow{#1}} \)

\( \newcommand{\vectorDt}[1]{\overrightarrow{\text{#1}}} \)

\( \newcommand{\vectE}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{\mathbf {#1}}}} \)

Imagine that you are a biological chemist doing research on bacterial metabolism. You and your colleagues isolate an interesting biomolecule from a bacterial culture, then use mass spectrometry, NMR, and other analytical techniques to determine its structure. Using your 'toolbox' of known organic reaction types - nucleophilic substitution, phosphorylation, aldol additions, and so forth - can you figure out a chemically reasonable pathway by which your compound might be enzymatically synthesized from simple metabolic precursors? In other words, can you fill in the missing biochemical steps (or at least some of them) to come up with a potential new metabolic pathway, which can then be used a hypothesis for future experimental work to try to find and study the actual enzymes involved?

An actual example approximating this scenario is shown below. A complete biosynthetic pathway for isopentenyl diphosphate (IPP), the building block molecule for all isoprenoi d compounds, has been known since the 1960's. This pathway, which begins with acetyl-CoA, was shown to be active in yeast, plants, and many other species including humans. However, researchers in the late 1980s uncovered evidence indicating that the known pathway is not present in bacteria, although they clearly use IPP as a building block molecule just as other forms of life do.

Over the next several years, the researchers conducted a number of experiments in which bacteria were grown on a medium containing glucose 'labeled' with the 13 C isotope. With the results from these experiments, combined with their knowledge of common biological organic reaction types, the researchers were able to correctly predict that the bacterial pathway starts with two precursor molecules (pyruvate and glyceraldehyde phosphate instead of acetyl CoA) and they also correctly predicted the first two enzymatic steps of the newly discovered bacterial pathway. This accomplishment eventually led to elucidation of every step in the pathway, and isolation of the enzymes catalyzing them. ( Biochem J . 1993 , 295 , 517; J. Am. Chem. Soc. 1996 , 118 , 2564; Lipids 2008 , 43 , 1095)

Why weren't they able to predict the whole pathway? It turns out that several of the later steps were somewhat unusual, unfamiliar reaction types - but discovery of these reactions hinged upon the correct prediction of the more familiar first two steps.

Multi-step transformation problems of this type offer an unparalleled opportunity to use our knowledge of biological organic chemistry combined with creative reasoning to solve challenging, relevant scientific puzzles. At this point in your organic chemistry career, you have not yet accumulated quite enough tools in your reaction toolbox to tackle most real-life biochemical pathway problems such as the one addressed above - but by the time we finish with oxidation and reduction chemistry in chapter 15, you will be able to recognize most of the reaction types that you will encounter in real metabolism, and will be challenged to predict some real pathways in the end-of-chapter problems.

You do, however, have right now enough of a bioorganic repertoire to begin to learn how multi-step pathway problems can be approached, using for practice some generalized, hypothetical examples in which the reaction types involved are limited to those with which you are already familiar.

Imagine that you want to figure out how an old-fashioned mechanical clock is put together. One way to do this is to start with a working clock, and take it apart piece-by-piece. Alternatively, one could start with all of the disassembled pieces, plus a lot of other small parts from different clocks, and try to figure out how to put together the specific clock you are interested in. Which approach is easier? The answer is intuitively obvious - it's usually easier to take things apart than to put them back together.

The same holds true for molecules. If we want to figure out the biosynthetic pathway by which a large, complex biomolecule might be made in a cell, it makes sense to start with the finished product and then mentally work backwards, taking it apart step-by-step using known, familiar reactions, until we get to simpler precursor molecules. Starting with a large collection of potential precursor molecules and trying to put the right ones together to make the target product would be a formidable task.

Retrosynthetic analysis - the concept of mentally dismantling a molecule step by step all the way back to smaller, simpler precursors using known reactions - is a powerful and widely-used intellectual tool first developed by synthetic organic chemists. The approach has also been adapted for use by biological chemists in efforts to predict pathways by which known biomolecules could be synthesized (or degraded) in living things.

In retrosynthesis, we think about a series of reactions in reverse. A backwards (retro) chemical step is symbolized by a 'thick' arrow, commonly referred to as a retrosynthetic arrow , and visually conveys the phrase ' can be formed from '.

Consider a simple, hypothetical example: starting with the target molecule below, can we come up with a chemically reasonable pathway starting from the precursors indicated?

A first step is to identify the relevant disconnection : a key bond (usually a carbon-carbon bond) that must be formed to make the target product from smaller precursors. We search our mental 'toolbox' of common biochemical reaction types, and remember that the only way we know of (so far!) to make a new carbon-carbon bond is through an aldol addition reaction, which takes place at an alpha-carbon. Therefore, we can make a likely disconnection next to the alpha-carbon in the target molecule.

Next, we need to recognize that the aldol addition reaction results in a beta-hydroxy ketone. But our target molecule is beta- methoxy ketone! Working backwards, we realize that the beta-methoxy group could be formed from beta-hydroxy group by a SAM methylation reaction. This is our first retrosynthetic (backwards) step.

The second retro step (aldol) accounts for the disconnection we recognized earlier, and leads to the two precursor molecules.

Now, consider the more involved (but still hypothetical) biochemical transformation below:

Often the best thing to do first in this type of problem is to count the carbons in the precursor compounds and product - this allows us to recognize when extra carbons on either side must at some point be accounted for in our solution. In this case, one carbon (labeled 'f'') has been gained in the form of a methyl ether in the product. This is easy to account for: we know that the coenzyme S -adenosyl methionine (SAM) often serves as the methyl group donor in enzymatic O - or N -methylation reactions. So, we can propose our first backwards (retro) step: the product as shown could be derived from SAM-dependent methylation of an alcohol group on a proposed intermediate I.

Retrosynthetic step 1:

How do we know that the methylation step occurs last? We don't - remember, we are proposing a potential pathway, so the best we can do is propose steps that make chemical sense, and which hopefully can be confirmed or invalidated later through actual experimentation. For now, we'll stick with our initial choice to make the methylation step the last one.

Now that we have accounted for the extra carbon, a key thing to recognize regarding the transformation in question is that two linear molecules are combining to form a cyclic product. Thus, two connections need to be made between reactants A and B, one to join the two, the other to close the circle. Our primary job in the retro direction, then, is to establish in the product the two points of disconnection : in other words, to find the two bonds in the product that need to be taken apart in our retrosynthetic analysis. Look closely at the product: what functional groups do you see? Hopefully, you can identify two alcohol groups, a methyl ether, and (critically) a cyclic hemiketal . We've already accounted for the methyl ether. Identifying the cyclic hemiketal is important because it allows us to make our next 'disconnection': we know how a hemiketal forms from a ketone and an alcohol , so we can mentally work backwards and predict the open-chain intermediate II that could cyclize to form our product.

Now, starting with the R 1 group and working along the carbon chain, we can account for carbons a-e on the two precursors.

Thus, the next disconnection is between carbons b and c. Here's where our mastery of biological organic reactivity really comes into play: the OH at carbon c of intermediate II is in the beta position relative to carbonyl carbon a. Aldol addition reactions result in beta-hydroxy ketones or aldehydes. Therefore, we can work backward one more step and predict that our intermediate II was formed from an aldol addition reaction between intermediate III (as the nucleophile) and precursor molecule A (as the electrophile).

We are most of the way home - we have successfully accounted for given precursor A. Intermediate III, however, is not precursor B. What is different? Both III and B have a carbonyl and two alcohol groups, but the positioning is different: III is an aldehyde, while B is a ketone. Think back to earlier in this chapter: intermediate III could form from isomerization of the carbonyl group in compound B. We have now accounted for our second precursor - we are done!

In the forward direction, a complete pathway diagram can be written as follows:

A full 'retrosynthesis' diagram for this problem looks like this:

Practice problems for retrosynthesis/pathway prediction

Organic Chemistry With a Biological Emphasis by  Tim Soderberg  (University of Minnesota, Morris)