Protecting Groups in Synthesis
IMPORTANT. You are not expected to remember the structures of the molecules that
are used as examples in this course! There will NOT be an exam question that, for
example, requires you to recall the structure in Figure 1-1!
IMPORTANT. References are provided for your interest and completeness – they are
not compulsory to the course unless indicated.
Introduction
In your organic synthesis modules to date the examples have mostly focussed on
relatively small structure without a large number of functional groups in the final
molecule. As we want to make more complex target molecules we have a problem
that functionality one part of the molecule can start interfering with our ability to
manipulate another part of the molecule in the synthetic route. For example, a total
synthesis of the molecule Leutroducsin B has been reported.1
Figure 0-1 The structure of Leutroducsin B – The functional group complexity is apparent
It is immediately apparent there are numerous challenges in making this molecule –
for example how will we control the reactions of the different oxygen containing
functional groups? One group needs to be phosphorylated, one has a long chain ester
others are free OH. How do we do reactions in the presence of the NH2 group without
the nucleophilic nitrogen interfering with our desired chemistry? If we look at the final
step of the published synthesis then the scheme looks rather odd.
1
B. Trost, B. Biannic, C. Brindle, M. O’Keefe, T. Hunter, and M.-Y. Ngai, J. Am. Chem. Soc., 2015, 137.
Figure 0-2 The final step of the synthesis of Leutroducsin B.
Many of the reactive groups are clearly modified but with slightly odd acronyms rather
than proper formulae. These are protecting groups. They are functionality that has
been added during the synthesis to stop cross reactivity of one part of the molecule
with another. Of course, no one wants to use protecting groups. By masking a
functional group and then revealing it later in the route two steps are added to the
synthesis however as molecules become more complex their use is hard to avoid.
Because of their near ubiquitous presence in modern chemistry an understanding of
protecting groups (and their nomenclature and abbreviations) is essential. Following
the language of protecting groups is also key to being able to follow and understand
the latest developments in the chemical literature.
Professor Philip Kocieński FRS, who you will still see around the School of Chemistry
at Leeds wrote a seminal reference work on the use or protecting groups in organic
syntheses.
In his introduction “Death Taxes and Protecting Groups” he points out that the use of
protecting groups is a necessary expedient, a tacit confession that organic chemists
can still not control reactivity in poly-functional molecules but that we will continue to
depend upon them for the foreseeable future.
Because of their wide use and abbreviation in chemical structures having a grasp of
protecting groups chemistry is key to following literature syntheses which is why we
are dealing with this topic in the first few lectures.
Features of Protecting Groups
Groups that are generally protected in synthesis are those that can interfere with other
reactions such as those that are strongly acidic ( e.g. carboxylic acids), nucleophilic
(alcohols and amines) or electrophilic (e.g. carbonyl groups) – exactly which groups
you need to protect depends on the rest of your synthetic scheme.
Kocieński defined 7 key features of a protecting group:
1. The protecting group should be easily and efficiently introduced
2. Reagents to introduce it should be cheap and readily available
3. It should be easy to characterise and avoid such complications as the
creation of new chiral centres
4. It should be stable to chromatography
5. It should be stable to widest possible range of reaction conditions
6. It should be removed selectively and efficiently under highly specific
conditions
7. The by-products of deprotection should be easily separated from their
substrate
Not all protecting groups in common use meet all of these conditions (for example
some are more expensive to use than desirable) but the most common have a good
attempt at meeting most of these criteria.
Protection of Alcohols.
Alcohol functions are one the most common groups that require protection. The
alcohol is both nucleophilic and the OH is acidic enough to interfere with reactions that
have a strong base in them (eg a Grignard reagent would deprotonate an alcohol
before it attacks a carbonyl group). There are several strategies to mask an alcohol.
ETHER PROTECTION
Making an ether makes the oxygen of the alcohol virtually completely unreactive and
thus provides excellent protection. Simple alkyl ethers are however very difficult to
cleave selectively - the key is some special reactivity shown by some special ether
functions:
Benzyl ethers are easily prepared from alcohols using a typical SN2 reaction of the
alkoxide with benzyl bromide. Removal is most often effected by hydrogenation.
Interestingly a bond to a heteroatom next to the aromatic ring is labile to these
reductive conditions with the by-products being toluene and the alcohol.
Figure 0-1 Use of a benzyl group in the synthesis of a glycosidase inhibitor
Figure 0-1 shows the use of benzyl protecting groups in the synthesis of a glycosidase
inhibitor.2 The hydroxyl groups that are present in the final target are actually also
present in the starting material but would interfere with the other synthetic steps. They
are protected as benzyl ethers and the benzyl groups are removed as the last step
which also conveniently removes a double bond.
Glycosidase inhibitors are used particular in the antiviral area but also as anticancer
agents as they alter the processing of cell surface carbohydrates which can be an
essential feature particularly in viral cell entry and release.
Other common ether protecting groups that you will find are the PMB group –
(paramethoxybenzyl) which is cleaved under oxidative conditions and the allyl
protecting group, which is cleaved using transition metal catalysis. The trityl ether is a
bulky protecting group that can be used for the selective protection of primary alcohols
and is cleaved using acid with an SN1 mechanism as you would anticipate given the
highly stable carbocation (Figure 0-2).
Figure 0-2 the structures of Allyl, PMB and Tr protecting groups
J. Boisson, A. Thomasset, E. Racine, P. Cividino, T. Sainte-Luce, J.-F. Poisson, J.-B. Behr, and S. Py, Organic Letters,
2015, 17, 3662–3665.
2
Abbreviation
Bn
PMB
All
Tr
NMR
 7.3 (5H, m), 4.5 (2H s, or 2 x d if
diasterotopic)
 7.3 (2H, d, J= 8Hz), 6.9 (2H, d,
J=8Hz), 4.4 (2H s or 2x d if
diasterotopic), 3.8 (3H, s)
 5.7( 1H, ddt, J=17,10,5Hz), 5.25
(1H,dd, J=17,1), 5.18 (1H,dd,J =
10,1), 3.8 (2H, m)
7.3 (15H, m)
Table 1 NMR characteristics of ether protecting groups
Allyl and paramethoxybenzyl ethers are used elegantly in Ferigna’s model system
which shows unidirectional rotary motion driven by chemical reactions (Figure 0-3).3
The PMB and allyl group can be removed without affecting the other group ( PMB and
allyl are said to be orthogonal protecting groups). The clever part of this scheme is
the selective reduction reaction which gives only one specific twist of the biaryl ring.
Selective protection of the phenol (driven by the different pKa of the phenol and alcohol
is followed by oxidation of the primary alcohol to an acid – deprotection of the PMB
group using the oxidising agent ceric ammonium nitrate [Ce(NH4)2(NO3)6] is followed
by lactone formation. The process is then repeated with selective reduction but this
time PMB protection, oxidation, allyl deprotection with transition metal catalysis and
cyclisation. The net effect is rotation of the aromatic ring around the biaryl axis (follow
the atom labelled 1 in the figure). (Figure 0-3)
Why try so hard to create a molecule that can rotate like this? Chemically driven
rotational motors are everywhere in biology. Rotational motors such ATPase are
critical to life itself and also power the movement of features such as bacterial flagella
which let bacteria ‘swim’
3
Fletcher, Science, 2005, 310, 80–82.
Figure 0-3 Ferigna’s unidirectional rotation driven by reaction.
The mechanism for PMB and allyl deprotection are both driven by oxidation of the
carbon next to the ether oxygen, in the case of PMB using an oxidising agent whereas
for the allyl group this occurs via double bond isomerisation.
Figure 0-4 Deprotection mechanisms for PMB and allyl protecting groups
Selective protection of a tritylether is shown in Figure 0-5. The reaction proceeds via
and SN1 mechanism and the bulky trityl cation selects the primary position
Figure 0-5 Selective trityl protection
Trityl groups are deprotected using acidic conditions usually using acids such as
trifluoroacetic acid or HCl. A trityl protecting group was used in the synthesis of the
anti HIV medicine AZT. Selective protection of the primary position enables the
subsequent selective installation of the azide group at the 3 – position of the ribose
ring (Figure 1-8)
Figure 1-8 Use of a trityl protecting group in the synthesis of AZT.
An even more acid labile variant of the trityl group – dimethoxytrityl is key in the solid
phase synthesis of oligonucleotides which we will explore later in course.
Although ether protection is useful the conditions to remove the protecting group are
sometimes a little harsh for other parts of the molecule for example hydrogenation to
remove a benzyl group would be completely incompatible with double bonds in the
rest of the molecule. What would be ideal is a protecting group with the stability of an
ether protecting group but with a set of deprotection conditions that are much less
likely to affect the rest of the molecule. The most important class of such groups are
the silyl ethers.
SILYL ETHER PROTECTION
An example silyl ether is shown in
Figure 0-6. As you can see it involves a link
from the oxygen atom to trialkylsilane to give the silyl ether group.
Figure 0-6 A silyl ether
Just as with a normal ether the removal of the oxygen significantly reduces the
reactivity of the oxygen. As silicon is electropositive the bond to oxygen is rather
strong. The key to the silyl ethers popularity as a protecting group comes from the
deprotection conditions. Silicon has a strong affinity for fluorine and so the group can
be cleaved with a fluoride source which is very unlikely to attack anything else in most
molecules. The most common fluoride sources are a solution of HF in pyridine (which
buffers the solution) or a fluoride source that is soluble in organic solvents, the most
common being tetra-n-butyl ammonium fluoride (Bu4NF) which is commonly
abbreviated as TBAF. Some silyl ethers are also easy to cleave under acidic
conditions.
The synthesis is by substitution, usually of the silyl chloride, but take care! The
mechanism is not an SN2 reaction. The tertiary silicon atom is too hindered for such
a process, however silicon can access pentavalent intermediates as d-orbitals are
available for bonding. The mechanism is addition elimination usually catalysed by the
weakly basic imidazole (Figure 0-7).
Figure 0-7 Protection of an alcohol with a trialkylsilylchloride
Cleavage occurs via similar mechanism either using fluoride or, in some case aqueous
acid (Figure 0-8).
Figure 0-8 Silyl deprotection mechanisms with fluoride and acid.
One really interesting thing about silyl protecting groups is that the ease of
deprotection is controlled by the steric crowding around the silicon atom. This means
that by changing the R-groups, we can alter the stability for the protecting group. Small
groups such as methyl groups in a trimethylsilylether do not protect the silicon very
much and so cleavage is very easy in both fluoride and acid – indeed a TMS ether will
often fall off on an acidic silica chomatography column, however by increasing the size
of the groups the stability increases. Common protecting groups include triethlyl silyl,
tertbutyldimethyl silyl and triisopropyl silyl protecting groups. Silyl groups are virtually
always abbreviated in reaction schemes and their structures and abbreviations are
shown below in order of increasing stability (Table 2).
group
Abbreviation
Trimethylsilyl
TMS
Triethylsilyl
TES
Tert-butyldimethylsilyl
TBS or TBDMS
Triisopropylsilyl
TIPS
Tert-butyldiphenylsilyl
TBDPS
Structure
Table 2 common silyl protecting groups
The wide variety of silicon protecting groups means that more than one silylether group
can be installed into a molecule in a synthesis and deprotection reactions performed
sequentially. 4
4
D. Crouch, Tetrahedron, 2013, 69, 2383–2417.
Figure 0-9 Selective deprotection of silyl ethers using acid (top) and fluoride (bottom)5
conditions
Another interesting feature of the silicon group is because it is bulky it can often be
used to selectively protect a primary alcohol in the presence of a secondary alcohol:
Figure 0-10 Synthesis of an intermediate using selective primary protection
Protons on carbons which are attached to silicon have a very characteristic small NMR
chemical shift (remember tetramethylsilane is the definition of 0 ppm in proton NMR).
This is often useful as the silyl protecting group signals often do not obscure other
features of the NMR spectrum (
Table 3).
5
Abbreviation
NMR
TMS
 0.01 (9H,s)
TES
 0.6 (6H, q, J=7Hz), 0.9 (9H, t, J=7Hz)
TBS or TBDMS
 0.1 (6H, s), 0.9 (9H, s)
TIPS
 1.0 (18H, d, J=7Hz), 0.9 (3H, sept, J=7Hz)
TBDPS
 0.9 (9H, s), 7.0-7.3 (10H, m)
A. Hamajima and M. Isobe,Organic Letters, 2006, 8, 1205–1208.
Table 3 NMR characteristics of silyl protecting groups
Silyl ethers can also be used to modulate reactivity. For example Silyl-enol ethers
are enolate equivalents that can be used in aldol reaction that you learned about last
year. As silyl enol ethers are less reactive than enolates a Lewis acid is added to
promote the aldol reaction. Figure 1-13b shows the synthesis of gingerol which is
one on flavour components of ginger from vanillin.
Figure1-13b syntehsis of gingerol
ESTER PROTECTION
Formation of an ester also protects an alcohol efficiently. Acetate and Benzoate
protecting groups are the most common, cheap to prepare and are easily cleaved,
usually with mild base catalysis (eg NaOMe, K2CO3 or NH3 in MeOH) although acid
catalysed ester hydrolysis is also possible as is removal by reduction. As esters are
still susceptible to reactions with stronger nucleophiles they must be used with care.
Figure 0-11 Synthesis of Levofloxacin using an acetate protecting group.
Levofloxain is a DNA gyrase inhibitor used as an ant-bacterial and lamivudine is and
HIV-reverse transcriptase inhibitor.
Figure 0-12 Synthesis of lamivudine using a benzoate protecting group
There are several other types of protecting groups for alcohols and we will explore
acetals as diol protecting groups later in the course.
Protection of Carboxylic Acids
Carboxylic acids are usually carried in protected from throughout syntheses. Their
acidic nature complicates other transformations and also makes them difficult to
purify. They are normally protected as esters. Ester formation is mostly by the
classical method, either by an acid catalysed reaction with the alcohol or via
intermediate formation of the acid chloride Simple esters such as methyl and ethyl
esters are cleaved under basic conditions. Alternatively several protecting groups
that are usually used to protect an alcohol can also be used to protect the OH of the
acid. Although silyl esters are not usually sufficiently stable, benzyl esters can be
cleaved hydrogenolytically, and allyl esters can be cleaved using transition metal
catalysis.
Figure 0-1 part of Nicolaou’s synthesis of Thiostrepton6 which uses both allyl and
methyl esters
Figure 0-1 Shows part of the synthesis of Thiostrepton. Early installation of the
methyl ester is by a classical route – following extensive elaboration of the core the
authors managed to selectively deprotect the methyl ester in the presence of the allyl
6
Nicolaou, Angew. Chem. Int. Ed., 2012, 51.
ester protecting group – this is not a general result but in this molecule the methyl
ester is more reactive due to the neighbouring pyridine ring. Later in the synthesis
the allyl ester is removed using transition metal catalysis. Note the TBS groups are
unaffected throughout these manipulations.
As Tert-butanol is not nucleophilic tert-butyl esters must be made using a different
process, by alkylation of the carboxylic acid. tert-Butyl esters are cleaved under
strongly acidic conditions (via an SN1 type mechanism) and are important in peptide
synthesis where they are commonly used in side chain protection. Sometime
scavenger reagents are added to the cleavage cocktail to prevent reactive tert-butyl
cation from reacting with other parts of the molecule.
Figure 0-2 Use of tert-butyl ester protection in the synthesis of Quinapril
Quinapril is one of a number of drugs which inhibit angiotensin converting enzyme
which are used to treat high blood pressure.
Figure 0-3 Mechanism of cleavage of tert-butyl esters
Protection of Amines
Basic amine groups can be particularly intrusive during synthesis, their basic and
nucleophilic nature causing complications in many reactions and also making
purification challenging by column chromatography. The most important amine
protecting groups make the nitrogen significantly less basic and nucleophilic by
conjugation of the nitrogen lone pair. The most common protecting group are the
carbamates which are generally prepared from the corresponding chloroformate or
equivalent.
Figure 0-1 The structures of common carbamate protecting groups
Figure 0-2 Carbamate protection with Fmoc, using the chloroformate7 and Boc using
the anhydride like equivalent.
The top example in Figure 1 20 is from Andy Wilson’s syntheses of inhibitors of
protein : protein interactions
You may well guess from the structure of parts of these protecting groups that the
deprotection reaction involves initial cleavage of the group attached to the carbamate
oxygen – subsequent decarboxylation then give the unprotected amine.
N. Murphy, P. Prabhakaran, V. Azzarito, J. Plante, M. Hardie, C. Kilner, S. Warriner, and A. Wilson, Chem. Eur. J.,
2013, 19.
7
You can already guess the conditions for most of these deprotection reactions as
they are the same as for the corresponding alcohol deprotections! Thus Boc is
deprotected in acid, Alloc with transition metal catalysis and CBz by hydrogenation.
The only special protecting group is the Fmoc protecting group which is cleaved by a
secondary amine with an E1cb mechanism. The Fmoc group critical to solid phase
peptide synthesis – which we will review later in the course.
Figure 0-3 The mechanism of Fmoc cleavage.
Protection of the Carbonyl Group
Ketones and aldehydes can react easily with many nucleophiles and will often have
to be protected in more complex syntheses. One solution is to carry the oxygen
functionality as a protected alcohol and then oxidise to the desired carbonyl group at
the appropriate time in the synthesis. Direct protection of ketones and aldehydes is
usually achieved by formation of an acetal. To give added stability a diol is
frequently used to create a cyclic structure. Formation is usually by acid catalysed
reaction with the diol under dehydrating conditions. As would be expected the
cleavage is the reverse process involving acid catalysed hydrolysis. Figure 0-1
Figure 0-1 protection of a ketone using an acetal and deprotection.
Acetal protection of diols
The formation of a cyclic acetal can also be used in the inverse manner to selectively
protect two alcohols at the same time within a molecule. The formation conditions
are identical to those used in the protection of carbonyls, although sometimes an
acetal is used as the precursor rather than a carbonyl compound. Figure 0-1,Figure
0-2
Figure 0-1 Protection of a 1,2 diol as a cyclic acetal.
Figure 0-2 Protection of a 1,3 diol as an acetal. The subsequent silyl deprotection is
followed by a Swern oxidation which will be considered below.
The interesting thing about acetal protection is that the formation processes are
under thermodynamic control so the most stable acetal is formed. This means that
in substrates containing several hydroxyl groups selective protection can be
achieved. The selectivity depends on the size and sometimes stereochemistry of the
ring being formed.
By being able to selectively protect polyol starting materials it means chemists do not
have to build them up step by step to get the desired protection profile saving many
steps in a synthetic route.
When aldehydes are used to form the acetal selective protection of 1,3 diols is the
preferred option given a choice. The selectivity arises from the formation of the 6membered ring and the acetal substituent is placed in the equatorial position. Figure
0-3
If ketones are used to form the acetal then 1,2 diol protection is preferred if this
relationship is available, forming a 5 membered ring. The 6-membered cyclic product
suffers from a 1,3 diaxial clash in this case which destabilises the 6-membered ring
relative to the 5-membered alternative. Figure 0-4
Figure 0-3 Selective protection is steered by the choice of reagent
Figure 0-4 The switch in selectivity can be explained from the 1,3 diaxial clashes in
the 6-membered ring when a ketone is used as the protecting reagent.
There are numerous examples where acetals can be used to selectively protect
polyols and are particularly useful in carbohydrate chemistry8 and for the use of
carbohydrates as starting materials. In the example in , protection with an aldehyde
selectively blocks the 4 and 6 positions, whereas sue of a ketone gives a completely
different pattern, protecting the 3 and 4 positions. The 2,3 protected product is
disfavoured by the strain that is produced if a 5 and 6 membered ring are fused with
a trans ring junction. Figure 0-5
Figure 0-5 Selective protection of a galactose sugar by choice of protecting group.
8
V. Noorden and Richard, Nature, 2010, 466.
Selective protection is key to the chemical synthesis of carbohydrates but is much
more complex than that required for peptide or nucleic acid synthesis as the variety
of different linkages possible in carbohydrate structures make them far harder to
prepare. While automated peptide and nucleic acid synthesis is routine,
oligosaccharide assembly remains challenging although some progress towards
automated routes has been made.3
Summary
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Protecting groups are an essential feature of modern synthesis
There are many protecting groups used which are often abbreviated within
structures in the chemistry literature. Understanding the language of protecting
groups will help you understand modern research papers.
Silyl ethers are a particularly important class of protecting group as their
deprotection is highly orthogonal to other types of reaction condition.
Carbamate protecting groups for nitrogen cleave in a two step process
releasing the oxygen first then CO2
Acetals can be used to protect 2 alcohols at the same time and also
selectively protect polyols