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Chemoselectivity
Regioselectivity
which functional
where it will react
group will react
Which functional group reacts first
Reaction
condition
and Reagents
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niper_H
Reaction of di-anions
reacts first
protecting groups
Tactical Considerations
Stable throughout
reaction, work-up &
purification
niper_H
conditions
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Development
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niper_H
Methyl Ethers
Benzyl Ethers
P- Methoxy Benzyl Ethers
O- Nitro Bn Eters
P- Nitro Bn Ethers
Trityl Ethers
Alkoxy Ethers
MOM
MEM
BOM
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niper_H
Acetals
Esters
Tetrahydropyranyl
Ethers
Acetyl Chloride
Acetates
Pivaloates
Silyl
Ethers
t- BuDiMe Silyl
Tri IsoPro Silyl
t-Bu DiPh Silyl
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Formation:
R-OH
Methyl Ethers
Benzyl Ethers
CH2N2
BnOC(=NH)CCl3, CF3SO3H
R OH
MeI
R OCH2Ph
(Benzyl ether)
Me3O BF4
Cleavage:
Methyl Ethers
Me3SiI or BBr3,CH2Cl2
Benzyl Ethers
PhSe-
Protects from:
HBr
H2-Pd/C
BuLi, B(OMe)3
Na/NH3
CrO3
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niper_H
O R
MeO
Protection with
(PMBOC(=NH)CCl3)
Deprotection
with NBS
Deprotection with Na/ NH3
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niper_H
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niper_H
o-Nitrobenzyl ethers:
R OH
NaH, THF
OR
p-Nitrobenzyl ethers:
NO2
Cl
R OH
Cl
Hydrogenolysis, Electrochemically
R OCPh3
R OCH2OMe
CH3COCl, MeOH
OR
O2N
O2N
NO2
Alkoxyalkyl
niper_H
R OCH2OCH2CH2OMe
Formation: MeOCH CH OCH Cl, NaH,THF
2 2
2
MeOCH2CH2OCH2Cl,
CH2Cl2, i-Pr2EtN
Cleavage: Lewis acids such as
ZnBr2, TiCl4, Me2BBr
Formation:
Cleavage:
R OCH2OCH2Ph
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R OH
O
H+, PhH
RO
Diastereomers
formation
Cleavage
Protection of OH group with THP
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niper_H
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R OH
R OSiR'3
Cleavage: Acid
Increasing
stability towards
acids and base
Cleavage
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niper_H
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e. g.,
niper_H
R'
OH
R'
Cl
Cl
Acetates (Ac):
R OH
Formation: Ac2O,
R'
R OH
OR
R OAc
pyridine
Cleavage: K2CO3,
MeOH, reflux
NH3, MeOH
Pivaloates (Piv):
O
Cl
R OH
O
OR
Cleavage:
Properties:Stable to acid and mild base Not compatible with
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e. g.,
Protection of OH
group with BnCl
e. g., Protection
with TBDMS
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niper_H
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OH
R1
R2
R3
R4
Acid
Isopropylidenes (acetonides):
HO
OH
Acid
R1
R2
Acetone or
OMe
or
OMe
R1
R3
R4
R1
R2
Cycloalkylidene acetals:
O
R2
HO
OH
R1
R2
Acid
O
O
or
O
R1
O or O
R2
R1
O
R2
OMe
e. g.,
Benzylidene acetals:
Ph
HO
OH
R1
R2
Acid
CH(OMe)2
O
CHO
R1
O
R2
or
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niper_H
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p-Methoxybenzylidene acetals:
OMe
Acid
Cleavage:
HO
OH
R1
R2
CH(OMe)2
CHO
or
OMe
O
OMe
R1
R2
OH
R1
R2
Im2CO
O
R1
O
R2
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niper_H
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MeOH, H+
R2
R1
OMe
R2
OMe
O
R1
(CH2OH)2, H+
R2
H+
OH
R1
R2
Protected as cyclic
and acyclic ketals and
1,3-dioxanes
acetals
O
O
O
OH
O
O
R1
R2
O
O
Selective protection of
less hindered carbonyls
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niper_H
R1
R2
Stable to base
O
O
Stable
Product
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1,3-Dithiane derivative:
O
R1
HS
SH
R2
S
R1
S
R2
or
R1
R2
SH
SH
BF3.Et2O
Cleavage:
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Raney Ni
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RCOOH
OH
O
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Protecting group
Carboxylic Acids
2, 2, 2- trichloroethylesters
Allyl Esters
Photoclevage
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niper_H
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e. g.,
Protecting
Group
VarespladibPhospholipase
inhibitor
t-Butyl ester PG for Carboxylic acids
J. Med. Chem., 1996, 39, 5159
niper_H
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Protecting Groups
Protection of amines
Carbamates
R NH2
Formation:
R NHBoc
Cleavage:
3M HCl, EtOAc
AcCl, MeOH
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niper_H
CAN, CH3CN
P-TsOH, EtOH
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Mechanism of
BOC protection
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Formation:
Cleavage:
R NHFmoc
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Deprotection of Fmoc:
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Formation:
R NHCbz
Cleavage:
H2/ Pd-C
H2/ Pd-C, NH3
e. g.,
Pd-C, HCOONH4
BBr3, DCM
KOH, MeOH
Garenoxacin
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niper_H
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R NHTroc
R NHAlloc
Formation: CH2=CHCH2OCOCl, py
(CH2=CHCH2OCO)2O, DCM
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7. Phthalimides:
hydrogenolysis
P-Methoxybenzyl (PMB)
3,4Dimethoxybenzyl (DMPM)
p-methoxyphenyl (PMP)
ammonium cerium(IV)
nitrate (CAN)
Tosyl (Ts)
Acetyl (Ac)
Or Benzoyl (Bz)
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niper_H
Gemifloxacin
Boc Protecting group
niper_H
Oseltamivir Phosphate
32
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niper_H
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Orthogonality
Deprotection
Basic Hydrolysis
Acidic Hydrolysis
Dilute Acids
HBr-AcOH
TFA-DCM
Me3SiI, BBr3
PPTS
Dil. Acetic Acid-Temp.
Dilute Acid
Protection
Acetate Ester
Benzyl Ester
Pivaloate Ester
Trifluoro acetamide
Phthalimide
Trityl Ether/Ester
Benzyl Ether/Ester
t-Bu Ether/Ester
Alkyl Ethers
THP
MOM, MEM, BOM
Cyclic, Acyclic Acetal/Ketal
Heavy Metal
Fluoride Ion
NH3, K2SO4-MeOH
NH3, K2SO4-MeOH
NH2-NH2-EtOH
Substrate
R-OH
R-NH2
R-NH2
Carbonyl
R-OH
R-COOH
R-NH2
R-OH/R-COOH/R-NH2
R-OH/R-COOH
R-OH/R-COOH
R-OH/R-COOH
R-OH
R-OH
R-OH
Carbonyl
-Elimination
Piperidine/Morpholine-DMF Fmoc
R-NH2
Hydrogenolysis [H]-Pd/C/Cyclohexene/HCOOH Benzylic ethers/Esters/Carbamate(Cbz) R-OH/R-COOH/R-NH2
H2-Pd
BOM
R-OH
Oxidation
DDQ/Ceric Amm. Nitrate
Dissolving Metal Reduction
Na-NH3
SN2
LiI,Metal cyanide/Phenyl thiolate
Transition Metal
Pd(PPh3)4-Morpholine
Wilkinson Catalyst
Photocatalysis
UV Light
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niper_H
R-OH
R-OH/R-COOH
R-COOH
R-COOH
R-OH
R-COOH
R-COOH
R-COOH
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