Protecting Groups
Tactical Considerations
Cheap & commercially available
Easy & efficient introduction
Should not create any stereogenic center
Stable throughout reaction, work-up & purification
Efficient removal
By-products of the removal should be easily separated
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
1. Methyl ethers:
R OH
R OMe
Difficult to remove except for phenols
Formation:
CH2N2
NaH, MeI, THF
Cleavage:
BBr3, CH2Cl2
PhSePh2PMe3SiI
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
2. Methoxymethyl ethers (MOM):
R OH
R OCH2OMe
Stable to base and mild acid
Formation:
MeOCH2Cl, NaH, THF
MeOCH2Cl, CH2Cl2, i-Pr2EtN
Cleavage:
Me2BBr
HCl/ THF, reflux
CH3COCl, MeOH
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
3. Methoxyethoxymethyl ethers (MEM):
R OH
R OCH2OCH2CH2OMe
Stable to base and mild acid
Formation:
MeOCH2CH2OCH2Cl, NaH, THF
MeOCH2CH2OCH2Cl, CH2Cl2, i-Pr2EtN
Cleavage:
Lewis acids such as ZnBr2, TiCl4, Me2BBr2
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
4. Benzyloxymethyl ethers (BOM):
R OH
R OCH2OCH2Ph
Stable to base and mild acid
Formation:
PhCH2OCH2Cl, CH2Cl2, i-Pr2EtN
Cleavage:
H2, PtO2
Na/ NH3, EtOH
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
5. Tetrahydropyranyl ethers (THP):
R OH
O
H+, PhH
RO
Stable to base
Formation:
DHP, PPTS, CH2Cl2
Cleavage:
PPTS, EtOH
Amberlyst H-15, MeOH
Creates one more stereogenic center
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
6. Benzyl ethers (Bn):
R OH
Formation:
R OCH2Ph
NaH, BnBr, THF/ DMF/ DME
KH, BnCl, THF
BnOC(=NH)CCl3, CF3SO3H
Cleavage:
H2/ PtO2
Li/ NH3
H2/ Pd-C
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
7. p-Methoxybenzyl ethers (PMB):
Cl
MeO
O R
R OH
Formation:
MeO
KH, p-Methoxybenzyl chloride, THF
PMBOC(=NH)CCl3, CF3SO3H
Cleavage:
DDQ
CAN
H2/ Pd-C
Li/ NH3
PMP
OH
R
OPMB
DDQ
MS
O
R
DIBAL-H
PMBO
OH
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
R OH
Formation:
R OSiR3
R3SiCl, Pyridine, DMAP
R3SiCl, Imidazole, CH2Cl2/ DMF/ CH3CN,
DMAP
R3SiOTf, i-Pr2EtN, CH2Cl2
Cleavage:
Acid
F- (KF, CsF, HF, Py, n-Bu4NF)
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.1. Trimethylsilyl ethers (TMS):
Properties:
Acid and water labile
Useful for transient protection
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.2. Triethylsilyl ethers (TES):
Properties:
Considerably more stable than TMS
Can be selectively removed in presence
of more robust silyl ethers with F- or
mild acids
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.3. Triisopropylsilyl ethers (TIPS):
Properties:
More stable to hydrolysis than TMS
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.4. t-Butyldimethylsilyl ethers (TBS/ TBDMS):
Properties:
Stable to bases and mild acids
Under controlled condition it is selective
for primary alcohols
Formation:
t-Butyldimethylsilyl triflate, base
t-Butyldimethylsilyl chloride, base
OH
H2O/ AcOH/ THF
TESO
OTBS
O
OTBS
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.5. t-Butyldiphenylsilyl ethers (TBDPS):
Properties:
Stable to bases and mild acids
Selective for primary alcohols
Me3Si & i-Pr3Si groups can be selectively
removed in presence of TBS or TBDPS
TBS group can be selectively removed in
presence of TBDPS by acid hydrolysis
AcOH/ H2O
THF
OTBDPS
OTBS
OTBDPS
OH
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
8. Silyl ethers:
8.5. t-Butyldiphenylsilyl ethers (TBDPS):
Cleavage:
F-, n-Bu4F
HF/ H2O/ CH3CN
[Link]
SiF4. CH2Cl2
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
9. o-Nitrobenzyl ethers:
NaH, THF
OR
R OH
Cl
NO2
NO2
Formation:
o-Nitrobenzyl chloride, NaH, THF
Cleavage:
Photolysis at 320 nm
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
10. p-Nitrobenzyl ethers:
NaH, THF
OR
R OH
O2N
O2N
Cl
Formation:
p-Nitrobenzyl chloride, NaH, THF
Cleavage:
Selective removal with DDQ
Hydrogenolysis
Electrochemically
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Ethers
11. Trityl ethers (Tr= CPh3):
R OH
R OCPh3
Selective for primary alcohols, stable to base
Formation:
Ph3C-Cl, pyridine, DMAP
Ph3C+BF4-
Cleavage:
Mild acid
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Esters
O
R OH
Formation:
R'
Activated acid, base, solvent
Chem. Soc. Rev. 1983, 12, 129
Angew. Chem. Int. Ed. Engl. 1978, 17, 569
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Esters
1. Via acid chlorides:
R'
O
OH
R'
Cl
R'
Cl
R OH
R'
OR
Formation:
SOCl2
PCl5
(COCl)2
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Esters
2. Acetates (Ac):
R OH
Properties:
R OAc
Stable to acid and mild base
Not compatible with strong nucleophiles
such as organometallic reagents
Formation:
Ac2O, pyridine
Acetyl chloride, pyridine
Cleavage:
K2CO3, MeOH, reflux
KCN, EtOH, reflux
NH3, MeOH
LiOH, THF, H2
Enzyme hydrolysis (Lipase)
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Esters
3. Pivaloates (Piv):
O
Cl
R OH
O
OR
Selective for primary alcohols
Formation:
t-Butylacetyl chloride
t-Butylacetic anhydride
Cleavage:
Mild base
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Protection of 1,2 & 1,3-diols
O
HO
OH
R1
R2
R4
R3
Acid
R3
R4
R1
R2
1. Isopropylidenes (acetonides):
HO
OH
Acid
R1
R2
Acetone or
OMe
or
OMe
R1
O
R2
OMe
1,2-acetonide formation is usually favored over 1,3-acetonides
Cleavage:
Mild aqueous acid
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Protection of 1,2 & 1,3-diols
2. Cycloalkylidene acetals:
HO
R1
OH
R2
Acid
O
O
O
R1
O
R2
or
O
R1
O
R2
or
Cyclopentylidenes are slightly easier to cleave than acetonides
Cyclohexylidenes are slightly harder to cleave than acetonides
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Protection of 1,2 & 1,3-diols
3. Benzylidene acetals:
Ph
HO
OH
R1
R2
Acid
CH(OMe)2
O
CHO
R1
O
R2
or
1,3-Benzylidene formation is usually favored over 1,2Benzylidene
Benzylidenes are usually hydrogenolyed slower than benzyl
ethers or olefins
Cleavage:
Acid hydrolysis or hydrogenolysis
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Protection of 1,2 & 1,3-diols
4. p-Methoxybenzylidene acetals:
OMe
HO
OH
R1
R2
Acid
CH(OMe)2
CHO
O
or
OMe
Cleavage:
R1
O
R2
OMe
Hydrolyzed about 10 times faster
than regular benzylidenes
Can be oxidatively removed with CAN
CH-423
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Protecting Groups
Hydroxyl Protecting Groups
Protection of 1,2 & 1,3-diols
5. Carbonates:
HO
OH
R1
R2
Im2CO
O
R1
O
R2
Stable to acid & more difficult to hydrolyze than esters
Formation:
Im2CO or phosgene or triphosgene
Cleavage:
Removed with base
CH-423
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Protecting Groups
Protection of ketones and aldehydes
O
R1
MeOH, H+
R2
(CH2OH)2, H+
H+
R1
OMe
R2
OMe
R1 O
R2
R1
R2
OH
1,3-dioxolanes
1,3-dioxanes
O
OH
Ketones and aldehydes are generally protected as cyclic
and acyclic ketals and acetals
Stable to base
CH-423
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Protecting Groups
Protection of ketones and aldehydes
Cleavage rate of substituted 1,3-dioxanes
R1
R2
R1
R2
R1
R2
O
O
Ketal formation of ,-unsaturated carbonyls are usually
slower than for the saturated case
O
(CH2OH)2
H+
O
CH-423
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Protecting Groups
Protection of ketones and aldehydes
1. Fluoride cleavable ketal:
O
O
LiBF4
Me3Si
2. Base cleavable ketal:
O
R1
SO2Ph
SO2Ph
HO
R2
pTSA
DBU, DCM
OH
O
R1
R2
CH-423
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R1
R2
30
Protecting Groups
Protection of ketones and aldehydes
3. 1,3-Dithiane derivative:
O
R1
HS
SH
R2
R1
R2
or
R1
R2
Aldehydes are selectively protected in presence of ketones
Formation:
HS(CH2)nSH, BF3.Et2O, DCM, 25 oC
In ,-unsaturated ketones, double bond does not migrate to
the ,-positions
O
S
O
CH-423
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Protecting Groups
Protection of ketones and aldehydes
3. 1,3-Dithiane derivative:
1,3-dioxolanes and 1,3-dioxanes can be readily
converted into 1,3-dithiolanes and 1,3-dithianes
SH
SH
BF3.Et2O
Cleavage:
Hg(ClO)4, MeOH, CHCl3, 25 oC
NBS, acetone, 0 oC
I2, DMSO
CAN, aq. CH3CN
m-CPBA, Ac2O
DDQ, aq. CH3CN
CH-423
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Protecting Groups
Protection of carboxylic acids
Esters
1. Alkyl esters:
Formation:
Fischer esterification (RCOOH + ROH + H+)
Acid chloride + ROH, pyridine
t-Butyl esters: Isobutylene & acid
Methyl esters: Diazomethane
Cleavage:
LiOH, THF, H2O
Enzyme hydrolysis
t-Butyl esters are cleaved with aq. acid
Bu2SnO, PhH, reflux
CH-423
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Protecting Groups
Protection of carboxylic acids
Esters
2. 9-Fluorenylmethyl esters (Fm):
DCC
RCOOH
OH
O
CH-423
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Protecting Groups
Protection of amines
Carbamates
1. t-Butyl carbamate (Boc):
R NH2
Formation:
R NHBoc
(Boc)2O, NaOH, H2O, 25 oC
(Boc)2O, TEA, MeOH/ DMF
BocN3, DMSO
Cleavage:
3M HCl, EtOAc
TFA, PhSH, DCM
AcCl, MeOH
CAN, CH3CN
CH-423
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Protecting Groups
Protection of amines
Carbamates
2. Allyl carbamate (Alloc):
R NH2
Formation:
R NHAlloc
CH2=CHCH2OCOCl, py
(CH2=CHCH2OCO)2O, DCM
Cleavage:
Pd(Ph3P)4, TBTH, AcOH
Pd(Ph3P)4, Dimedone, THF
CH-423
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Protecting Groups
Protection of amines
Carbamates
3. Benzyl carbamate (Cbz or Z):
R NH2
Formation:
R NHCbz
BnOCOCl, Na2CO3, H2O
(BnOCO)2O, dioxane, H2O
Cleavage:
H2/ Pd-C
H2/ Pd-C, NH3
Pd-C, HCOONH4
BBr3, DCM
KOH, MeOH
CH-423
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Protecting Groups
Protection of amines
Carbamates
4. 9-Fluorenylmethyl carbamate (Fmoc):
R NH2
Formation:
R NHFmoc
Fmoc-Cl, NaHCO3, aq. Dioxane
Fmoc-OC6F5, NaHCO3, acetone
Cleavage:
Amine bases
Piperidine, morpholine, diisopropylethyl amine
TBAF, DMF
CH-423
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Protecting Groups
Protection of amines
Carbamates
5. 2,2,2-Trichloroethyl carbamate (Troc):
R NH2
R NHTroc
Formation:
Cl3CCH2OCOCl, Py or aq. NaOH
Cleavage:
Zn, THF, H2O, pH= 4.2
Zn-Pb couple, 4:1 THF/ 1M NH4OAc
CH-423
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Protecting Groups
Protection of amines
Carbamates
6. 2-Trimethylsilylethyl carbamate (Teoc):
Formation:
TMSCH2CH2OCOCl (Teo-Cl) or Teoc-N3
Teoc-OC6H4-4-NO2, NaOH
Teoc-OSu, TEA
CH-423
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