Retrosynthesis

Question 1

What is retrosynthesis?

Answer 1

Retrosynthesis, also known as the disconnection approach, is a process for devising a synthetic route to a target molecule by working backwards from that molecule

Question 2

How does retrosynthesis take place?

Answer 2

By breaking the molecule down into simpler fragments, these fragments are broken down further in to even more simple fragments etc, until we work back to fragments that are commercially available

Question 3

How does retrosynthesis work with complex molecules?

Answer 3

With complex molecules we can use retrosynthesis to come up with many possible ways of trying to make them, there is not just one right answer

Question 4

What is important about retrosynthesis with complex molecules?

Answer 4

When we have several possible synthetic routes we need to determine which is the best, the one with fewest steps, best yield, economic factors, costs of products and energy considerations, considerations of waste

Question 5

What a good bond to break in a ketone?

Answer 5

A good bond to disconnect is the C-C bond between the carbons that are alpha and beta to the ketone, we show which bond we are disconnecting with a wiggly line

Question 6

What needs to be considered when a bond is disconnected?

Answer 6

When we disconnect a bond w need to consider what happens to the electrons in that bond, the electrons could go to one of the fragments or the other

Question 7

What are the two possibilities of fragments called?

Answer 7

Synthons

Question 8

What are synthons?

Answer 8

Synthons are not real compounds, the are hypothetical compounds that would react together to form the desired bond if they existed

Question 9

What needs to be considered with synthons?

Answer 9

Once we have determined possible pairs of synthons, we have to consider if there are any real compounds that would react the same way

Question 10

Why can’t a primary carbocation exist as a synthon?

Answer 10

Too high energy and too unstable

Question 11

Real life equivalent of a primary alkyl cation?

Answer 11

A real life equivalent would be the corresponding alkyl halide eg an alkyl bromide and this would react by an SN2 mechanism

Question 12

What would the real life equivalent for a carbanion at the alpha position of a carbonyl?

Answer 12

The corresponding enolate, formed by deprotonation of that carbonyl

Question 13

How are enolates normally generated?

Answer 13

Enolates are normally generated by deprotonation of the corresponding carbonyl

Question 14

What is important about the base for generating an enolate?

Answer 14

The correct selection of the base for deprotonation is crucial to achieve a high concentration of the desired enolate, eg EtO- is only a good base for those substrates which are substantially more acidic than EtOH (pKa = 18)

Question 15

What are the typical bases used in generation of enolates?

Answer 15

Alkoxides (usually with Na as the couterion), alkali metal hydrides (NaH, KH), alkali metal amides (NaNH2, KNH2)

Question 16

What amides are especially useful in generation of enolates?

Answer 16

Particularly useful amides are those derived by deprotonation secondary amines, namely lithium diisoproplyamide (LDA), and lithium hexamehyldisilazide (LHMDS)

Question 17

Why are these amides especially useful in generation of enolates?

Answer 17

These are soluble in inert solvents such as THF, and are hindered and therefore non nucleophilic, strong bases

Question 18

Relation which bases and pKa?

Answer 18

Higher the pKa the stronger the base

Question 19

What is the problem with alkyllithiums?

Answer 19

They are very strong bases, they are commercially available but are not often used for enolate formation as they are also good nucleophiles, which leads to side reactions

Question 20

Picking a base for generating an enolate?

Answer 20

Pick a base with the same pKa or bigger

Question 21

Why are dicarbonyls easy to deprotonate?

Answer 21

Dicarbonyl species unusually easy to deprotonate, more resonance so more stable, so after deprotonation anion of this is very stable, the more stable anion is easier it’ll be to deprotonate

Question 22

What is the rate of alkylation of enolates dependent on?

Answer 22

The rate of alkylation of enolates is very solvent dependent

Question 23

Whats important about polar aprotic solvents in the alkylation of enolates?

Answer 23

Polar aprotic solvents such as DMF, DMSO, HMPA are good cation solvates and therefore leave a naked, reactive anion

Question 24

Whats important about polar solvents in the alkylation of enolates?

Answer 24

Polar solvents such as THF and DME are still able to coordinate cations but with a smaller charge separation generating less reactive enolates

Question 25

When does C alkylation occur?

Answer 25

Small cations such as Li+ bind tightly to oxygen promoting C alkylation

Question 26

Why does O alkylation occur?

Answer 26

Larger cations such as K+ favour O alkylation

Question 27

What affects C and O alkylation?

Answer 27

The choice of alkylation agent is important

Question 28

Alkylating agent for O alkylation?

Answer 28

Oxygen derived leading groups promote O alkylation

Question 29

Alkylating agent for C alkylation?

Answer 29

For C alkylation use halides ie iodides or bromides

Question 30

What is OTs?

Answer 30

OTs is the shorthand for a para tolunesulfonate or 'tosylate', sultanates are leaving groups that can be synthesised in 1 step from the corresponding alcohol

Question 31

When is regioselective deprotonation important?

Answer 31

In non symmetrical ketones the question of which proton is removed is very important

Question 32

When does the kinetic enolate form?

Answer 32

The kinetic enolate is the fastest formed enolate usually formed by the removal of the least hindered proton

Question 33

What are conditions for forming the kinetic enolate?

Answer 33

Good conditions for this involve adding the ketone to an excess of a strong hindered base eg LDA at low temperature -78 degreesC, this avoids an equilibrium being set up

Question 34

What are conditions for forming the thermodynamic enolate?

Answer 34

The thermondynamic enolate can be formed by adding a strong base to the ketone often at room temperature or above to form the more substituted enolate, allows an equilibrium to be set up, the thing that there will be the most of is the most stable hence why thermodynamic enolate is present

Question 35

Why is the thermodynamic enolate more stable?

Answer 35

Stabilities effect of the methyl group on the C=C, it is more substituted and therefore the alkene is more stable

Question 36

How is an equilibrium set up in the thermodynamic enolate?

Answer 36

The pKa of the base and the proton on the methyl group are similar so can be protonated and deprotonated again and hence an equilibrium can be set up

Question 37

How selective is the kinetic enolate?

Answer 37

99:1 K/T, therefore it is very selective

Question 38

How selective is the thermodynamic enolate?

Answer 38

22:78 K/T, so not quite as selective

Question 39

How does enolate trapping work?

Answer 39

Mixtures of kinetic and thermodynamic enolates can be trapped as stable derivatives and then separated

Question 40

How can enolates be trapped?

Answer 40

A particualelry useful way of trapping enolates is to prepare silyl Enols ethers (also known as enol silanes) these are generated by trapping the enolate mixture with a trialklysilyl chloride, the most common is trimethylsilyl chloride (TMS-Cl)

Question 41

How can the resultant enol silanes be isolated?

Answer 41

The resultant enol silanes can be isolated and separated by distillation treatment with methyl lithium regenerates the enolate

Question 42

What is another method of achieving deprotonation at a specific position?

Answer 42

An alternative method to achieve deprotonation at a specific position is to introduce an activating group that increases the acidity of the desired proton, this is usually achieved by the introduction of a further EWG such as an ester, after alkylation the activating group can be removed by hydrolysis and then decarboxylation

Question 43

Where is the hydrogen atom locates in a beta-ketoacid?

Answer 43

In the beta-ketoacid the hydrogen is located between the two carbonyl due to intramolecular H bonding, at high temperature a pericyclic reactions occurs, extruding CO2 and forming the enol of the final product, this tautomerises to the ketone

Question 44

Why can there be problems with the direct alkylation of ketone?

Answer 44

Problems such as double alkylation and self condensation

Question 45

How can the problem with direct alkylation of ketones be avoided?

Answer 45

One solution is to use enamines, enols can react with themselves whereas enamines can't

Question 46

What are enamines?

Answer 46

These can be considered as the nitrogen analogues of enols

Question 47

How are enamines formed?

Answer 47

By the reaction of a secondary amine with a carbonyl compound in the presence of an acid catalyst, pyrrolidine and morpholine are commonly used amines

Question 48

How do enamines react?

Answer 48

Enamines are nucleophilic at the beta position, they react with alkyl halides and can then be hydrolysed to regenerate the carbonyl compound

Question 49

What are the advantages to using enamines?

Answer 49

No base is used so no self condensation occurs Monoalkylation is usually observed (the intermediate mono alkylenamines are unreactive towards further reaction) Alkylation of unsymmetrical ketones is regioselective the major enamine is less substituted (steric inhibition of resonance)

Question 50

Where is the most thermodynamically acidic proton at the enolate of the alpha beta unsaturated ketone?

Answer 50

The most thermodynamically acidic proton is at the thermodynamically stable anion

Question 51

Where are the three nucleophilic sites on the enolate of the alpha beta unsaturated ketone?

Answer 51

The enolate has three potentially nucleophilic sites - the oxygen atom, the alpha and gamma carbons

Question 52

Where does kinetic alkylation take place on the enolate of the alpha beta unsaturated ketone?

Answer 52

Kinetic alkylation (ie fastest) takes place at the alpha positions, the most kinetically acidic proton is at the alpha position

Question 53

What is the real life equivalent of the cation to alpha to a ketone synthon?

Answer 53

The real life equivalent of the cation to alpha to a ketone synthon is an alpha halo ketone - these undergo nucleophilic displacement in a particularly facile manner

Question 54

How are Grignard reagents formed?

Answer 54

They are formed from the corresponding alkyl or aryl halide and magnesium metal

Question 55

How do Grignard reagents react?

Answer 55

Grignard reagents act as a carbon nucleophile and react with many different electrophiles for example they react with aldehydes and ketones to give the corresponding alcohols

Question 56

What does aldehyde plus Grignard reagent make?

Answer 56

Gives secondary alcohol

Question 57

What does ketone plus Grignard reagent make?

Answer 57

Gives tertiary alcohol

Question 58

Why are Grignards more often used than corresponding alkyllithiums?

Answer 58

Grignard reagents are much more commonly used as carbon nucleophiles than the corresponding alkyllithiums as these are very basic which often leads to side reactions

Question 59

What are alkyllithiums normally used as?

Answer 59

Alkyllithiums are mainly just used as strong irreversible bases

Question 60

What are Grignard reagents normally used for in retrosynthesis?

Answer 60

They give a method for disconnecting the C-C bond next to the secondary or tertiary alcohol, Grignard reagents are also useful for opening strained rings

Question 61

What is a problem with the alpha halo ketone?

Answer 61

The alpha halo ketone is an ambient electrophile, a nucleophile can react with it in more than one place - since the nucleophile (ie the Grignard reagent) could attack in more than one place we need to know about the selectivity of the nucleophilic carbon species

Question 62

What is the selectivity of the Grignard reagent?

Answer 62

The Grignard reagent will attack the ketone in preference to the alpha carbon, so a Grignard is not a good choice of real life reagent for the alpha halo ketone

Question 63

What type of nucleophilic carbon species is a Grignard reagent?

Answer 63

A Grignard is a hard nucleophilic carbon species, which are small and highly charged with electrostatic interactions, so it reacts with the carbonyl carbon as this is the harder electrophilic site

Question 64

What are soft nucleophilic carbon species?

Answer 64

Soft nucleophiles are likely to be found further down the group on the periodic table with orbital overlap, some soft carbon nucleophiles would also be useful, as they would show complementary reactivity to Grignards

Question 65

What is a softer kind of organometallic nucleophile?

Answer 65

An organocopper reagent or "cuprate"

Question 66

How are cuprates made?

Answer 66

Unlike Grignard reagents they aren't made by directly combining copper metal with an alkyl or aryl halide instead we take an organometallic reagent that we have pre formed (eg a Grignard or an organolithium) and carry out a transmetallation ie swapping one metal for another

Question 67

What is used in the transmetallation to form a cuprate?

Answer 67

Various copper (I) salts can be used for the transmetallation: Cl, Br, I, CN etc

Question 68

How can the structure of the curate be derived?

Answer 68

In the case of the cuprate derived from a Grignard reagent this has been written as R-Cu as the precise structure is ill defined, the structure of the cuprate derived from two equivalents of organolithium is better defined

Question 69

Where do cuprates react on a molecule?

Answer 69

Generally speaking curates do not react with carbonyls directly at the carbonyl carbon as this carbon is too hard an electrophile

Question 70

What is the one exception where cuprate will react directly at the carbonyl carbon?

Answer 70

Acid chlorides, a cuprate will react with an acid chloride once displacing the chloride

Question 71

How is an acid chloride made?

Answer 71

Acid chlorides can be made by reacting the corresponding carboxylic acid with thionyl chloride or with oxalyl chloride/DMF

Question 72

What is important about the solvent when making an acid chloride?

Answer 72

Usually a polar parotid solvent used but actually gets involved in the reaction mechanism

Question 73

What do cuprates do in retrosynthesis?

Answer 73

The reaction between cuprates and acid chlorides gives us more options in terms of which bond to disconnect when undertaking retrosynthesis Cuprates are very good at conjugate addition to alpha beta unsaturated carbonyl systems ie 1, 4-addition, (Grignard effect 1, 2-addition)

Question 74

When can organocopper be used catalytically?

Answer 74

When you use an organocopper species derived from a Grignard you can use the copper catalytically

Question 75

What bond does conjugate addition technology allow us to break?

Answer 75

Conjugate additions allows us to disconnect a third bond - the one between the beta and gamma carbons

Question 76

What other molecules undergo conjugate addition?

Answer 76

Heteroatom nucleophiles can undergo conjugate addition toe nones - this is a powerful method for C-X bond formation

Question 77

What ring system can cuprates open?

Answer 77

Just like Grignard reagents can be used to open epoxides, cuprates can be used to open aziridines (the nitrogen equivalent of epoxides)

Question 78

In the case of cuprate mediated aziridine opening the reaction does not work well is R2 = H so how do you get round this if you want R2 to be H?

Answer 78

The solution is to use a R2 substituent on the nitrogen that you can remove after the cuprate has been added. In general installing a functional group in a molecule temporarily to allow a particle reaction to be carried out (and the removing that group) is called using a protecting group, various protecting groups can be used to protect an aziridine nitrogen prior to the ring opening with a cuprate

Question 79

Boc as a protecting group?

Answer 79

Not appropriate in acidic conditions since it comes off when you don't want it to

Question 80

How does dissolving metal reduction remove Ts group?

Answer 80

Dissolving metal reduction passes an electron to naphthalene which reduces it which is the reactive reductant so passes another electron onto the nitrogen-sulfur bond (reductive cleavage) sodium mercury amalgam can be used as well, this is effective at removing the Ts group

Question 81

What is the conditions for removing the protecting group?

Answer 81

Orthogonal conditions - in the context of protecting groups this mean you want each one to be removed under different reaction conditions than the others

Question 82

What is important about protecting groups?

Answer 82

For each functional group many different protecting groups have been developed each of which is stable to different conditions and is removed by different conditions

Question 83

What is important about complicated synthesis and protecting groups?

Answer 83

If you are carrying out a very complex synthesis you may need several different types of protecting group for different parts of the molecules - ideally you want these protecting groups to be orthogonal

Question 84

Why are protecting groups useful?

Answer 84

Protecting groups are very useful in that they allow you to use disconnections that would not work otherwise they greatly expand the synthetic toolkit

Question 85

What is a problem with protecting groups?

Answer 85

Every protecting group you use will add at least two steps to the synthesis (one to introduce it and one to remove it) and as these steps are unlikely both to have yield of 100% this will inevitable reduce the overall yield for your synthesis

Question 86

What is the most common strategy for protecting groups?

Answer 86

The most common strategy for protecting alcohols is use of silyl ethers

Question 87

How can silyl ethers be formed?

Answer 87

These can be formed from the alcohols by using the corresponding silyl chloride (the more steric bulk around the silicon the more stable the silyl ether)

Question 88

How are silyl ethers removed?

Answer 88

Silyl ethers are stale to most reaction conditions but are removed by treatment with acid or with a source of fluoride (Si-F is a very strong bond) - using several different silyl ethers in the same molecule can allow for their selective removal

Question 89

What protecting group can be used for alcohols?

Answer 89

A different protecting groups strategy for alcohols is the use of tetrahydropyranyl ether (THP ether) these are installed under acid catalysis and removed the same way (it is an equilibrium), as THP ethers can be cleaved by acid but not by fluoride they can be seen as orthogonal to silyl ethers

Question 90

What is the most common way of protecting aldehydes and ketones?

Answer 90

The most common way of protecting an aldehyde is to use an acetal and to protect a ketone is a ketal, these are formed by treating the carbonyl in question with a diol and catalytic acid

Question 91

Why is water needed to be removed in the formation of acetals and ketals?

Answer 91

As the reaction is an equilibrium it is important to remove the water that is formed with a Dean Stark strap to drive the equilibrium to the right, in order to remove these protecting groups we need to drive the equilibrium to the left so we need to deliberately add lots of water

Question 92

How can the reaction be used to protect a diol?

Answer 92

If you look at the reaction the other way round it can also be used to protect a diol, this time we are adding an aldehyde or ketone, commonly acetone or benzaldehyde

Question 93

What is an example of where protecting groups are necessary?

Answer 93

In the formation of Grignard reagents that would not be accessible otherwise, if we disconnect the molecules to two synthons the electrophile is ok but the Grignard is not viable if we try to form it it will instantly react with itself as there is an electrophilic ketone elsewhere in the same molecules, the solution is to use a metal protecting group - in the protected compound the former ketone carbon is no longer electrophilic so we can from the Grignard reagent without any problems carry out the additions into the aldehyde then remove the protecting group

Question 94

How else do protecting groups allow access to Grignard reagents?

Answer 94

Protecting groups can allow access to Grignard reagents containing masked alcohols, we have disconnected adjacent to one of the alcohols giving a cationic synthon which correspond to a ketone and an anionic synthon corresponding to an unstable Grignard reagent, the problem is that the Grignard reagent is a strong base as well as a strong nucleophile and there is an acidic proton elsewhere in the molecule on the -OH, so it will deprotonate itself and the Grignard reagent will be quenches

Question 95

What are the two retrosynthetic steps?

Answer 95

A retrosynthetic step can either be a bond disconnection or a functional group interconversion

Question 96

When is an interconversion used?

Answer 96

When both pairs of synthons have problems such as no real life equivalent or selectivity issues

Question 97

What FGI can be used to make a ketone from the alcohol?

Answer 97

We can make the ketone from the alcohol by oxidation so we can disconnect the alcohol instead, this maps on to the use of an epoxide and gives us two valid, compatible real life reagents, PCC is pyridinium chlorochromate which is an oxidising agent

Question 98

What are possible oxidising agents?

Answer 98

The most powerful is Jones reagent, whereas PCC and PDC are milder reagents that have solubility in organic solvents, all these reagents will oxidise a secondary alcohol to a ketone, in the case of a primary alcohols PCC and PDC will oxidise it once to an aldehyde whereas the Jones reagent will oxidise it further to a carboxylic acid

Question 99

What is a problem with chromium (VI) reagents?

Answer 99

They are all toxic and carcinogenic and the waste is expensive to dispose of