Transcript Hydroxyl Protecting Groups Stability

PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
Intensive Program 31388-IC-11-2005-1-GR-ERASMUS-IPUC-1
SYNAPS: Synthesis and Retrosynthesis in the Chemistry
of Natural Products
NATURAL PRODUCT CHEMISTRY
Module 2
Retrosynthetic Approaches Towards the Synthesis of Natural Products
Prof. H. E. Katerinopoulos
Education, Audiovisual & Culture Executive Agency
Hydroxyl Protecting Groups Stability
MOM-OR
Methoxymethyl ether, MOM ether
THP-OR
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Tetrahydropyranyl ether, THP ether
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 49-54, 708-711.
Hydroxyl Protecting Groups Stability
t-Butyl ether
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Allyl ether
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 49-54, 708-711.
Hydroxyl Protecting Groups Stability
Bn-OR
Benzyl ether
TBDMS-OR
TBDPS-OR
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
t-Butyldimethylsilyl ether, TBDMS ether
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
t-Butyldiphenylsilyl ether, TBDPS ether
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 49-54, 708-711.
Hydroxyl Protecting Groups Stability
Ac-OR
Pv-OR
Bz-OR
Acetic acid ester, Acetate ester, Acetate
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Pivalic acid ester, Pivlate ester, Pivalate
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Benzoic acid ester, Benzoate ester, Benzoate
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 49-54, 708-711.
Hydroxyl Protecting Groups Stability
1,2- and 1,3-diols
Acetonide
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Benzylidene acetal
T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 49-54, 708-711.
Carboxyl Protecting Groups Stability
Methyl ester
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
t-Butyl ester
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Carboxyl Protecting Groups Stability
Benzyl ester
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
2-Alkyl-1,3-oxazoline
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Carbonyl Protecting Groups Stability
Dimethyl acetal
1,3-Dioxanes
1,3-Dioxolanes
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Carbonyl Protecting Groups Stability
1,3-Dithiolanes
1,3-Dithianes
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
N,N-Dimethylhydrazone
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Amino Protecting Groups Stability
Fmoc-NR
BOC-NR2
9-Fluorenylmethyl carbamate, FMOC amino, FMOC amine, FMOC amide
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
Electrophiles
:
Reduction:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2/CH2Cl2
t-Butyl carbamate, BOC amine, BOC amino, BOC amide
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Benzyl carbamate
Cbz-NR2 / Z-NR2
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Amino Protecting Groups Stability
Acetamide
Ac-NR2
Trifluoroacetamide
Phthalimide
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Amino Protecting Groups Stability
Bn-NR2
Tr-NR2
Ts-NR2
Benzylamine
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
Triphenylmethylamine (Tritylamine)
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2
p-Toluenesulfonamide, Tosylamide
H2O:
pH < 1, 100°C
pH = 1, RT
pH = 4, RT
pH = 9, RT
pH = 12, RT
pH > 12, 100°C
Bases:
LDA
NEt3, Py
t-BuOK
Others:
DCC
SOCl2
Nucleophiles:
RLi
RMgX
RCuLi
Enolates
NH3, RNH2
NaOCH3
Electrophiles:
RCOCl
RCHO
CH3I
Others:
:CCl2
Bu3SnH
Reduction:
H2 / Ni
H2 / Rh
Zn / HCl
Na / NH3
LiAlH4
NaBH4
Oxidation:
KMnO4
OsO4
CrO3 / Py
RCOOOH
I2, Br2, Cl2
MnO2 / CH2Cl2