PROTECTING GROUPS
AND SHIELDED BY
PROTECTING
THEIR DEPROTECTION GROUP
REACTIVE
FUNCTIONAL
GROUP
Submitted by
Roshen Reji Idiculla
ID MS14/11
REAGENTS
Introduction- the need for
selectivity in retrosynthetic analysis
of target molecule
• Chemoselectivity which functional group
will react with reagent.
• Regioselectivity where will reagent reacts
• Stereoselectivity
Regioselectivity where will reagent
reacts
• The problem of regioslectivity can be improved by,
Chemoselectivity revisited
• 1st disconnection
• Molecule has two nucleophiles so electrophile can attack either of them (the
oxygen as desired or the nitrogen).
• This is the 1st problem of chemoselectivity.
• There can be a 2nd disconnection.
• Here, the electrophilic carbon can react with two nucleophiles (O as
desired or N in intramolecular attack of the amine, leading to aziridine
formation by cyclisation).
• 2ND problem of chemoselectivity.
Every Problem Has a Chemical
(Creative) Solution
• 1st solution – use better disconnection – 3rd disconnection
• But here the disconnection do not split the molecule to half.
• 2nd solution – prevent the N to act as nucleophile in synthons of 1st and 2nd
disconnection.
• 2nd solution – prevent the N to act as nucleophile in synthons of 1st and 2nd
disconnection.
• This can be achieved by introducing a bulky and electron withdrawing group in N
moiety.
• Let’s consider the reaction using RNH-Boc. ( Boc = Tert Butyloxycarbonyl group)
• The amine attacks a carbonyl C on di-tert-butyl dicarbonate (Boc2O) with tert-
butyl carbonate leaving as a leaving group.
• Tert-butyl carbonate picks up the proton from the protonated amine.
• Tert-butyl bicarbonate breaks down into CO2 (gas) and tert-butanol.
• 2nd solution – prevent the N to act as nucleophile in synthons of 1st and 2nd
disconnection.
• But , we must remove the Boc group from amine.
We must remove the Boc group from amine.
• The tert-butyl carbamate becomes protonated.
• Loss of the tert-butyl cation results in a carbamic acid.
• Decarboxylation of the carbamic acid results in the free amine.
Protecting groups
• Here Boc group protected amine from undergoing reaction.
• So this group is termed protecting group.
• So Protecting groups are usually used to temporarily mask a functional
group which may interfere with a certain reaction.
• The addition of protecting groups to functional groups is termed
‘protection’ and removal of protecting group is ‘deprotection’.
• Protecting group (PG) is a small molecule, which has the capability to
protecting temporarily the a specific functional group of a molecule from
undergoing reaction, allowing the rest of the functional groups present in the
molecule to react without affecting the original reactivity and leave from the
host molecule without affecting the rest of the functional groups.
A good protecting group
• should react with the desired functional group quickly,
• should form the protected compound in good yield,
• the protected compound should have good stability when stored for a
long time.
• should have a minimum functional group to avoid side reaction during
the course of the main reaction
• should not create a new chiral centre at the molecule.
• At the time of deprotection, should cleave under mild reaction
condition, should give good yield and the purification must be simple.
• Protected compound must be highly hydrophobic, thus enabling
extractive work-ups easier, and if the product is crystalline, so as to
provide suitable purification
General facts on protection
• Generally there are 5 types of functional groups , having –OH, -SH, -
COOH, -C=O, NH.
• Alcoholic and phenolic hydroxyl groups and its sulphur analogues (thiols
and thiophenols) are protected as ethers or esters.
• Carboxylic acids are protected as esters or amides.
• Adehydes and ketones are protected as acetals or ketals.
• The amino group was protected as carbamates, amides or imines.
Protecting Groups for Alcohols- Ester
protection (alcohol to ester)
protection strategy eliminates the acidic proton on the alcohol,
and also reduces the nucleophilicity and basicity of the oxygen
atom by steric hindrance and / or electronic effects.
• 2,2,2-Trichloroethyl carbonate (Troc) –
• The alcohol attacks the acyl chloride or acyl anhydride , nucleophilic addition
followed by elimination of chloride or acetate. The deprotonation gives
protected alcohol group.
Protecting Groups for Alcohols- Ester
protection (alcohol to ester)
• Acetate (Ac)
• Benzoate (Bz)
In general, the susceptibility of esters to base-catalyzed hydrolysis increases
with the acidity of the product acid.
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• Advantages:
• Relatively stable in harsh conditions (acidic, basic, reflux, etc.)
• Enhance the reactivity due to electron-donating effect
• More compatible to the conditions needed for deoxygenation or amino (azido)
substitution
• Selective protection is possible
• Disadvantages:
• Relatively harder to remove (deprotect)
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• Methyl ether
removal is not as difficult with phenols, using BBr3 to deprotect.
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• Benzyl ether (Bn)
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• 2-Methoxyethoxymethyl ether (MEM)
• Selective protection is possible
• Can be incorporated at relatively weak basic conditions (3° amine) but needs
• relatively strong acid (TFA) to remove
• Stable in basic conditions
• The reagent, MEMCl, is considered carcinogenic
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• 2-Naphthylmethyl ether (Nap)
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• 4-Methoxybenzyl ether (PMB)
Protecting Groups for Alcohols- Ether
protection (Alcohol to ether)
• Tetrahydropyranyl ether(THP)
Protecting Groups for Alcohols- Acetal
protection (alcohol to acetal)
Protecting Groups for Alcohols- Ether
silyl protection
• tert-Butyldimethylsilyl ether (TBS, TBDMS)
• Silyl groups are typically deprotected with a source of fluoride ion. The Si–F bond
strength is about 30 kcal/mol stronger than the Si–O bond.
Protecting Groups for Alcohols- Ether
silyl protection
• Trimethylsilyl ether (TMS)
• Triethylsilyl ether (TES)
• Triisopropylsilyl ether (TIPS)
Protecting Groups for Alcohols- Ether
silyl protection
• tert-Butyldiphenylsilyl ether (TBDPS)
• the stability of silyl ethers towards acidic media increases as indicated:
• TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)
Protecting Groups for amines Amine
protection
• Benzylamine (Bn)
Protecting Groups for amines Amine
protection
• p-Methoxyphenyl amine (PMP)
Protecting Groups for amines Amide
protection
• Formamide
• Acetamide (Ac)
Protecting Groups for amines Amide
protection
• Trifluoroacetamide (TFA)
• Trichloroacetyl amide
Protecting Groups for amines
Phthalimide protection
Protecting Groups for amines
Carbamate protection
• 1-Chloroethyl carbamate (ACE)
• Benzyloxy carbamate (CBz)
• Methyl carbamate
• tert-Butoxy carbamate (Boc) – discussed early
• Vinyloxycarbonyl (Voc)
• Allyloxycarbonyl (Alloc)
• 9-Fluorenylmethyloxycarbonyl (Fmoc)
Protecting Groups for amines
Carbamate protection
1-Chloroethyl carbamate (ACE)
Benzyloxy carbamate (CBz)
Methyl carbamate
tert-Butoxy carbamate
(BocVinyloxycarbonyl (Voc)
Allyloxycarbonyl (Alloc)
9-Fluorenylmethyloxycarbonyl (Fmoc
Protecting Groups for amines
Sulfonamide protection
• 4-Methoxybenzenesulfonamide
• Tosyl (Ts) sulfonamide
• Nosyl (Ns) sulfonamide
Protection of Carboxylic acid Ester
protection
• Benzyl ester
• Methyl ester
Protection of Carboxylic acid Silyl Ester
protection
Protection of Carboxylic acid Oxazoline
protection
Protection of Aldehyde, Ketone
Acetal protection
Ketones and aldehydes have π* orbitals as the lowest unoccupied
molecular orbitals.
Nucleophiles interact with this orbital by doing 1,2 addition
Bases interact with this orbital by deprotonation at the alpha position.
Protection of Aldehyde, Ketone
Acetal protection
• Diethyl acetal
• Dimethyl acetal
Protection of Aldehyde, Ketone
Acetal protection
• Ethylene glycol acetal (1,3-Dioxane)
• Neopentyl glycol acetal (1,3-Dioxolanes)
Protection of Aldehyde, Ketone
Trimethylsilyl cyanohydrin protection
Protection of Aldehyde, Ketone
Thio-acetal protection
• 1,3-Dithiane
• S, S'-dialkyl acetals serve as an
umpolung synthon in the construction of
carbon-carbon bonds.
• 1,3-Dithiolane
Can be deprotected in the presence of
ketals and can survive ketal
deprotection
Protection of 1,2-Diol
Acetonide protection
• Benzaldehyde acetal
• Acetonide
Protection of 1,3-Diol
• Benzaldehyde acetal
• di-tert-Butyl dioxasilinane
1,3 diols are usually protected with
benzaldehyde but why is acetone is
used only for 1,2 diols ?
• The formation of the six-membered cyclic acetal is less favourable with
acetone than it is for benzaldehyde, because with acetone one methyl
group is being axial
Two types of protecting groups:
• Permanent protecting group
• Some functional groups require no manipulation and just want 'masking' to
prevent their interfering in intermediate steps.
• These protecting groups need to survive many steps (early introduction,
late removal). Example. Methyl ether protection
• temporary protecting group
• connect and remove it easily and selectively unaffecting more permanent
protecting groups.- (Orthogonal Protecting Group strategy)
Orthogonality in protection strategy
• remove one set of protecting groups, using reagents and conditions without
affecting the protecting groups in other sets.
• Manipulation of different functional groups using different sets of protecting
groups is achieved by their different reactivities.
• The hemicacetal hydroxyl is most reactive. (1-OH)
• The next most reactive hydroxyl is primary hydroxyl group. (2-OH)
• Equatorial hydroxyl group is most reactive than axial hydroxyl group
• Equatorial OH with vicinal axial OH (or OR) > Equatorial OH without vicinal
axial OH (or OR) (2-OH > 3-OH ~ 4-OH)
Estimated order of nucleophilicity
D - Glucose : 1-OH > 6-OH > 2-OH > 3-OH ~ 4-OH
Acetonide protection of 1,2 diols in
Carbohydrate Based Chirons
