Protecting Groups: Additional Resources
Greene & Wuts: Protective Groups in Organic Synthesis Kocienski: Protecting Groups (see also: J. Chem. Soc., Perkin Trans. 1, 1999, 1589.) http://www.organic-chemistry.org/protectivegroups/
OHOH
OH
HOHO
OHMe
OOHO
OH
O
OH
O
OH
OHHO
OHO
OHH2N
OHOH
O
HO
OH
OHH
OH
OH
Me
OHOH
O
OH
OHHO
HO
HO
O
OHO
Me
Me Me OH
HO
O H
HOHOMeOH
OH
OH
OH
OHOH
NH
NH
Me
OH
OO
HO
palytoxin(1994, Kishi)
OH
OTBSOTBS
TBSO
TBSOTBSO
OTBSMe
OOO
OAc
O
OTBS
O
O
OTBSTBSO
OTBSO
OTBSNH
OTBSOTBS
O
TBSO
OTBS
OTBSH
OTBS
OTBS
Me
OAcOBz
O
OBz
OAcBzO
TBSO
BzO
OOBz
O
Me
Me Me OPMB
PMBO
O H
PMBOOPMBMe
OTBS
OPMB
OPMB
OPMB
OPMBOPMB
MeO
Me
OAc
O
palytoxin precursor:
OAc
TEOC
TEOC =
Me3Si O
O
Alcohol Protecting Groups: Ethers
• Methyl Ether ! ! ! ! !R-OH R-OMe
formation:
cleavage:
TBSO
OBnNaH, MeI THF, rt
OH OH
OPMB TBSO
OBnOMe OMe
OPMB
very robust, stable to strongly acid and basic conditions difficult to cleave, except in phenols
- NaH, MeI, THF - CH2N2, silica or HBF4
O
OOBz
OMe O
OOBz
OHAlBr3EtSH
- AlBr3, EtSH ! ! !- AlCl3, HSCH2CH2SH (large xs) !- BCl3, CH2Cl2, -20°C; Na2CO3 (aq) !- Me3SiI!
Alcohol Protecting Groups: Ethers
• Methoxymethyl Ether (MOM) ! ! ! !R-OH R-OCH2OMe
formation:
cleavage:
acetal type protecting group; stable to base and mild acid
- MeOCH2Cl, NaH, THF - MeOCH2Cl, iPr2NEt, CH2Cl2
- MeOCH2Cl, NaI, iPr2NEt, CH2Cl2 - CH2(OMe)2, P2O5, CH2Cl2
- TFA, CH2Cl2 ! ! !- Me2BBr2, CH2Cl2, -78°C!- 3% HCl, EtOH ! ! !- AcCl, MeOH, 0°C!
TBSO
OHMeOCH2Cl
iPr2NEt, CH2Cl2, 0°COMe OH
OBn TBSO
OMOMOMe OH
OBn
RO2C OMeOCH2Cl, NaI
iPr2NEt, DME, refluxOH
OSiMe3 RO2C O
OMOM
OSiMe3
Alcohol Protecting Groups: Ethers
• Tetrahydropyranyl Ether (THP) ! ! !R-OH R-OTHP
formation:
cleavage:
acetal type protecting group; base stable, cleaved with mild acid introduction can result in formation of diastereomers
- DHP (dihydropyran), pTsOH (cat), PhH - DHP, PPTS (cat), CH2Cl2
- HOAc/H2O ! ! !- CSA, MeOH!- PPTS, EtOH (aq) ! ! !- MgBr2, Et2O!
O OH
OAc
OPPTS, CH2Cl2
O O
OAc
OH
OTHP
N
SOTBS
MgBr2 (3 eq)Et2O OH
N
SOTBS
Alcohol Protecting Groups: Ethers
• Benzyl Ether (R-OBn) ! ! ! !R-OH R-OCH2Ph
formation:
cleavage:
stable to acid and base; variety of cleavage protocols
- PhCH2Br, NaH, THF - PhCH2OC(=NH)CCl3, TfOH (cat), DCM
- H2, Pd/C, EtOH (also THF or EtOAc) !- H2, Pd(OH)2, MeOH!- Li/NH3 !! ! ! !- BCl3, CH2Cl2, 0°C
SEtNaH, BnBr
Bu4NI, THF, 0°COH OH
SEtOBn OBn
SEt SEt
BnO OMeH2, Pd/C
EtOHOMe
HO OMeOMe
Alcohol Protecting Groups: Ethers
• p-Methoxybenzyl Ether (R-OPMB) ! ! !R-OH R-OCH2PhOMe
formation:
cleavage:
base stable; more acid labile than benzyl ether can be cleaved selectively under oxidative conditions
- p-MeOPhCH2Cl, NaH, THF - p-MeOPhCH2OC(=NH)CCl3, TfOH (cat), DCM
- H2, Pd/C, EtOH (also THF or EtOAc) !- DDQ or CAN!- Li/NH3 !! ! ! !- TFA
O
OO
OH
Cl3C OPMB
NH
TfOH (cat), Et2O O
OO
OPMB
OBn
O
O
OPMB DDQCH2Cl2-H2O OBn
O
O
OH
Alcohol Protecting Groups: Ethers
• Silyl Ethers ! ! ! ! !R-OH R-OSiR’3
general stability in acidic media:
general stability in basic media:
stability to acid or base depends on specific silyl ether
- TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)
- TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)!
RO SiMe
MeMe
trimethylsilyl (TMS)
RO SiEt
EtEt
triethylsilyl (TES)
RO SiMe
MetBu
t-butyldimethylsilyl (TBS)
RO SiPh
PhtBu
t-butyldiphenylsilyl (TBDPS)
RO SiiPr
iPriPr
triisopropylsilyl (TIPS)
Alcohol Protecting Groups: Ethers
• Silyl Ethers ! ! ! ! !R-OH R-OSiMe3
J. Chem. Soc., Perkin Trans. 1 1992, 3043; J. Org. Chem. 1988, 53, 2602.
formation:
- R3SiCl, imidazole, DMF (or CH2Cl2 or CH3CN)
- R3SiOTf, iPr2NEt (or 2,6-lutidine), CH2Cl2 - R3SiCl, Et3N, DMAP, CH2Cl2 (selective protection of 1° alcohols)
cleavage:
- acid: !HCl, AcOH, CSA, pTSOH, PPTS, etc. – choice will depend on specific PG!- fluoride: Bu4NF (TBAF), HF-pyridine, HF, CsF, KF, etc.
Alcohol Protecting Groups: Ethers
• Silyl Ethers ! ! ! ! !R-OH R-OSiMe3
- very acid and water labile
- useful for transient protection
RO SiMe
MeMe
trimethylsilyl (TMS)
- stable to base and mild acid
- selective for 1° alcohols under controlled conditions
RO SiMe
MetBu
t-butyldimethylsilyl (TBS)
RO SiPh
PhtBu
t-butyldiphenylsilyl (TBDPS)
- stable to acid and base
- selective for 1° alcohols - also known as BPS
- TMS and TES groups can be cleaved in the presence of TBS and TBDPS - TBS can be cleaved under acide conditions in the presence of TBDPS (AcOH, THF/H2O)
Alcohol Protecting Groups: Ethers
• Silyl Ethers ! ! ! ! !R-OH R-OSiMe3
- TMS and TES groups can be cleaved in the presence of TBS and TBDPS - TBS can be cleaved under acidic conditions in the presence of TBDPS (AcOH, THF/H2O)
OOOH
TBDPSO
OTES
OTBS
OHOOH
TBDPSO
OH
OTBSPPTSEtOH
AcOH-THF-H2O(3:1:1)
OPv
H
HO
OTBDPS
TBSOCO2H
OPv
H
HO
OTBDPS
HOCO2H
Alcohol Protecting Groups: Esters
• Esters ! ! ! ! ! !R-OH R-O2CR’
relative reactivity:
stable to acid and mild base not compatible with strong base or strong nucleophiles
- Pv < Bz < Ac < chloroacetate < Ac’
(reactivity largely mirrors acidity of corresponding carboxylic acid)
O CH3
O
R
acetate (Ac)
O
O
R
pivaloate (Pv)
O
O
R
benzoate (Bz)
O
O
R
chloroacetate
O
O
R
trifluoroacetate (Ac')
F
F FCl
Alcohol Protecting Groups: Esters
• Esters ! ! ! ! ! !R-OH R-O2CR’
formation:
cleavage:
- (RCO)2O or RCOCl, pyridine - (RCO)2O or RCOCl, DMAP, Et3N, CH2Cl2
- K2CO3, MeOH ! ! !- NH3, MeOH!- LiOH, THF (aq) !! ! !- DIBAL, CH2Cl2 !
OHOH
OH
tBu Cl
O(1 equiv)
pyridine, CH2Cl2OPv
OH
OH
OAc
OPv
LiOHMeOH, 3.5 h
OH
OPv
1,2- & 1,3-Diol Protecting Groups: Acetals
• Acetals !
formation:
stable to base; cleaved with mild aqueous acid
- catalysts: pTsOH, CSA, PPTS, ZnCl2, etc. - use of a Dean-Stark trap or dessicant (4Å MS or anh. CuSO4) facilitates the reaction
- silylene acetal: tBu2SiCl2, Et3N, HOBT or tBu2Si(OTf)2, 2,6-lutidene
HO OH( )n O O
( )n
R'R
O O
R R'( )n
O O
R R'( )n
O O
R R'( )n
O OSi
R R'( )n
tButBu
acetonide(isopropylidene acetal)
benzylideneacetal
p-methoxybenzylideneacetal (PMP)
di-t-butylsilyleneacetal
OMe
O O
( )n
R'R
HO OH( )nR R'
O
R R'
OMeMeO
R'
OMe
(R = Me)or or
H+ catalyst, - H2O
1,2- & 1,3-Diol Protecting Groups: Acetals
• Acetals ! ! !
formation:
HO OH( )n O O
( )n
R'R
• acetonide formation in 1,2-diols is generally faster than that in 1,3-diols
• benzylidene acetals typically favor protection of the 1,3-diol
HOOHOH
acetonepTsOH
OHOHO
OOO +
5 : 1
• acetal formation from PMB ethers
PhCH(OMe)2pTsOH, 4Å MS
HOOHOH OHO
HOOO
O +
1 : 9
PhPh
DDQ4Å MS, CH2Cl2
ButO2COOH
ButO2COO
PMP
OH OHOMe ButO2C
OOH
OHOMe
1,2- & 1,3-Diol Protecting Groups: Acetals
• Acetals ! ! ! cleavage:
- H3O+, THF ! ! !- PPTS, MeOH!- TFA-H2O ! ! ! !- AcOH!- benzylidene acetals: H2, Pd/C ! !- silylene acetals: HF•pyridine!
HO OH( )n O O
( )n
R'R
• selective cleavage of benzylidene acetals
O O
OOBn
BnO
BnO Ar LiAlH4, AlCl3or DIBAL
O OH
OOBn
BnO
BnO Ar
Ar = Ph, PMP
O O
OOBn
MeO
BnO Ar NBSCCl4 O
Br
OOBn
MeO
BnO Ar
O Ar = Ph, PMP
OO
PMP
DDQAcOH (aq)HO
OHOHO
OMeO
Aldehyde & Ketone Protecting Groups: Acetals & Ketals
• Acetals ! ! !
formation:
- 2 ROH, dry HCl ! ! !- ROTMS, TMSOTf, CH2Cl2, -78°C!!
- 1,2- or 1,3-diol, pTsOH (cat), PhH, Δ (-H2O e.g. with Dean Stark or dessicant)!
stable to base; cleaved with aqueous acid
O OR'R
O OR R'
MeO OMe
R R'
dimethyl acetal 1,3-dioxane 1,3-dioxolane
R R'
O
orORRO OO( )n
O OR'R R R'
O O OR R'
HO OHpTsOH (cat), -H2O
OHpTsOH (cat), -H2OHO
MeOHdry HCl R'R
OMeMeO
R R'
O
Aldehyde & Ketone Protecting Groups: Acetals & Ketals
• Acetals ! ! ! R R'
O
orORRO OO( )n
formation:
• selective protection of saturated ketones
• selective protection of unsaturated ketones (steric)
O
O
HO OHpTsOH (cat), -H2O
O O
O
O
O
TMSO OTMSTMSOTf, CH2Cl2, -78°C
O
OO
• migration of double bond may occur (favored by stonger acid catalysts)
O
HO OHpTsOH (cat), -H2O O
O
cleavage:
- 1M HCl, THF ! ! !- PPTS, acetone, H2O, Δ
pTsOH pKa <1 (db isomerization) fumaric acid pKa = 3.03 (no isom)
J. Org. Chem. 1985, 50, 3946.
Aldehyde & Ketone Protecting Groups: Thioacetals & Ketals
• Thioacetals ! ! !
cleavage:
- Hg(ClO4)2, MeOH (or other Hg2+ salts) !- mCPBA; Et3N, Ac2O, H2O!- IBX, DMSO (aq) !! ! !- CF3CO2)2IPh, H2O, CH3CN !
R R'
O
stable to mild acid and base; not typically cleaved with aqueous acid can be difficult to remove
S SR'R
S SR R'
1,3-dithiane 1,3-dithiolane
formation:
S SR'R
or S SR R'
O
HS SHS
SBF3•OEt2, CH2Cl2
- HS(CH2)2SH or HS(CH2)3SH, BF3•OEt2, CH2Cl2 ! !!- TMSS(CH2)2STMS or TMSS(CH2)3STMS, ZnI2, Et2O!
no isomerization
Carboxylic Acid Protecting Groups: Esters
• Esters ! ! ! ! ! !R-CO2H R-CO2R’
formation:
cleavage:
- Fisher esterification: ROH, H2SO4 (good for simple alcohols) - methyl esters: CH2N2 - t-butyl ester: isobutylene, H2SO4, Et2O - allyl ester: allyl bromide, Cs2CO3, DMF - R’OH, EDC•HCl or DCC, DMAP (very general) - 1. SOCl2, 2. ROH, pyridine (very general)
- LiOH, THF (aq) ! ! !- t-butyl ester: TFA, CH2Cl2 !!- allyl ester: Pd(PPh3)4, RSO2Na, CH2Cl2 !- benzyl ester: H2, Pd/C!
R OH
O R'OHconditions R OR'
O
R OMe
O
R OtBu
O
methyl ester t-butyl ester
R O
O
benzyl ester
Ph R O
O
allyl ester
Amine Protecting Groups: Carbamates
• Carbamates ! ! ! ! !R2-NH
formation:
cleavage:
- BOC: !HCl or TFA!or TMSI ! !!- Fmoc: !piperidine or morpholine or dicyclohexylamine!!- Cbz: !H2, Pd/C or TMSI!
R NR
O R'O
R2N OtBu
O R O
O
t-butyl carbamate(BOC)
9-fluorenylmethyl carbamate(Fmoc)
R2N O
O
benzyl carbamate(Cbz)
Ph
R2N H Cl OR'
O
R'O OR'
Oor
R2N OR'
O
Et3N, DMAP or pyridine
amines are also often protected as benzyl or allyl ethers, acetates, and tosylates. Latter two may be difficult to cleave.