Protecting Groups in Organic Synthesis-1
Ready
Protecting Groups for Alcohols
Protecting groups are a sad fact of synthetic chemistry
4 major classes: silyl ethers, ethers, esters, acetals
They are usually needed, but rarely desired
Silyl Ethers
Many syntheses have stalled because of trouble
putting on or removing protecting groups
4 basic questions to address when choosing a P.G.:
1.
2.
3.
4.
Can I put it on where and only where I want?
Can I take it and only it off?
Will it survive all future reaction conditions?
Will it affect the reactivity of my substrate?
Your guide to these questions should be: Protective
Groups in Organic Synthesis by Theodora Greene and
Peter Wuts
An even better strategy is to plan your syntheses
to avoid protecting groups
Si
O
TMS
Si
O
TES
Si
O
Si
O
Si
O
TIPS
TBS or
TBDMS
TBDPS
TBS: Corey, JACS, 1972, 6190 (23rd most cited JACS paper)
ON:
OH
R3SiCl, Imidazole
DMF
OSiR3
+
R3Si
We will discuss general features of protecting groups,
for specific examples and exotic methods for attachment
or removal, see Greene
via
N
N
H
OH
R3SiOTf
2,6-lutidine, CH2Cl2
OSiR3
These transformations are very water sensitive.
Protecting Groups in Organic Synthesis-2
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Less Common methods for Silyl introduction:
LiO
O
SiMe2tBu
Brook Rearrangement
_
O
O
SiR3
X
O
OSiR3
_
R
bond
SiMe2tBu
Li
X
R
TBSO
Li
BDE (kcal/mol)
C Si
69
O Si
103
F Si
141
O
1/2 equiv.
I2
question: using approx. pKa values and the BDE above,
estimate Keq for different R's in the equation 1.
74%
O
TBSO
SiMe2tBu
HO
Ph
O
OtBu
OTBS
DBU
DMSO
OTBS
O
Ph
O
t
O Bu
Corey, JACS, 2002, 11290
TL, 1998, 5243
Other potential methods:
Hydrosilylation of ketones: always some stupid silyl group
Tamao oxidation of alkyl silanes: Silyl group rarely survives
Protecting Groups in Organic Synthesis- 3
silyl migrations
-smaller is faster
-1,2 and 1,3 most common
-good if planned; usually not planned
HO
OH
O
DBU
83% TBSO
OH
TBSO
Removal
Usually F- or H+
Usually, bigger is more stable
OH
O
Molander, JOC
1994, 7148
TBDPSO
OBn
NaH
OH
Br
C15H31
TBDPSO
>95%ee
OC16H33
OH- or H+
R OH
krel
H+
krel
OH
TMS
5,000,000
500,000
TES
100,000
50,000-5,000
TBDMS
250
5
TIPS
10
5
TBDPS
1
1
Silyl group
how does this happen?
OBn
R OSiR3
OH
HO
Note: 2 primary alcohols would make
selective protection difficult
Ready
0% ee
Welzel, Tet, 1987, 3803
Recall BDE: O-Si (~100 kcal/mol) vs F-Si (~140 kcal/mol)
Common F- sources:
Migrations likely via associative displacement:
-
O
OSiR3
O
Si O
pentavalent intermediate
R3SiO
O-
TBAF (nBu4NF)
HF-Pyridine
3HF-Et9N
HF
TASF [tris(dimethylamino)sulfonium
difluorotrimethylsilicate]
NMe2
S
Me2N
NMe2
F
F Si CH
3
H3C
CH3
Protecting Groups in Organic Synthesis-3
Conditions often need to be determined empirically
relative rates of Fluoride-induced cleavage:
AcO
Silyl group
OAc
O
O
20 min
TIPS
15 min
tHexDMS
15 min
TBDPS
50 min
TPS
2.5h
OAc
TBSO
1/2 life
TBS
Ready
OH
Ph
CH3
Cl2CCO2H
OTBS
90%
AcO
OAc
OAc
TBSO
O
O
OH
Ph
CH3
OH
Selective cleavage (review: Synthesis, 1996, 1065)
AcO
TESO
OTBDMS
OPiv
OH OTBDMS
2% HF, CH3CN
OAc
TBSO
O
O
OHCO2tBu
OPiv
Masamune, TL, 1985, 5239
Commercial TBAF is wet (to varying degrees).
Dry TBAF is very basic; may need buffer:
AcO
O
RO
RO
O
TBAF
AcOH,
7d, 37%
CH3
HF
Cl3CO2H
HF-Et3N
TBAF
OAc
HO
OAc
HO
R = TBS
Ph
HF-Pyridine
CH3CN
90%
OR
OAc
O
O
CO
OH 2tBu
1
OAc
OAc
AcO
Ph
CH3
O
O
CO
OH 2tBu
Ph
CH3
+
1
R=H
Carreira, Du Bois JACS, 1995, 8106
Protecting Groups in Organic Synthesis-5
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allyl ether
Ethers
on: usually allyl Br/Cl + base. Usually easy
Ph
usually very robust, with orthogonal modes of removal
HO
usually:
Ph
OH
HO
O
HO
R OH +
R' LG
OH
R O R'
common ethers:
O
O
Bu2SnO
On: MeI, Me2SO4, Me3O BF4
Off: BBr3, TMSI,
O
R
CrO3
O
O
Ph
OH
O
O
HO
O
O
O
OH
95%
Ogawa, TL, 1988, 4097
Off: Isomerization with base or transition metal, then
hydrolysis:
Na/NH3
CrO3: via benzoate
HO
O
Br
HO
On: usually BnCl + base; somtimes with cat. I(do you know what I- does?)
Off: H2, Pd/C - competitive (usually slower) than
olefin reduction
Lewis Acid: SN1 mechanism
2e-, H+
O
O
"stanylene acetal"
Benzyl ether (Bn)
R
OH
O
Bu Sn
Bu
O
This is a general method for
monprotection of a 1,2 diol (not
limited to allyl). In this case,
note selective formation with
equitorial OH's.
Methyl ether: easy on, hard off. Usually only
good for phenols
O
HO
_
O
R
HO
R
R
O
O
R
-
OH
HO
R
O
B- or M
R
O
H3O+
R OH
Protecting Groups in Organic Synthesis-6
p-methoxybenzyl (PMB or MPM)
O
R
Off: hν
O
OH
R
o-nitrobenzyl
O
On: PMB-Cl, base
CF3
+
O
R
O
O
N
O
O
O
H+ or Lewis Acid
Ready
R
hν
N
O
H
O
+
NH
R
1,5 H abstraction
O
O
O
F3C
NH2
HO
example:
Off: Oxidation
O
R
[O]
O
O
R
+
R
O
+
O
O
[O] = DDQ, CAN, Ph3C BF4, Br2, NBS
OH
H2O
R
O
NO2
OH
H2O
N
O
O
H
N
Cl
N
CO2-
O
O
CO2-
non-fluorescent
365 nm hν
intermediate can be intercepted:
PMBO
OMe
OH
-
DDQ
HO
pKa ArOH = 5.1
O
O
O
H
N
Cl
+O
HO
CO2-
O
OH
OMe
N
Wen-Hong Li, JACS, 2004, 4653
Triphenyl Methyl (trityl)
O
HO
On: Ph3CCl, via SN1
O
Hoffman, ACIEE, 1993, 101
Off: Acid
CO2-
O
R
fluorescent
R
Protecting Groups in Organic Synthesis-7
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acetals
acetals of mono-ols:
Tetrahydropyranyl (THP)
R
many eg's of the form
O
O
R'
R
advantages:
O
Cl
R'
very active electrophile
likely forms
R'
O
+
OH
H+
+
O
O
OR
Easy on, easy off, cheap.
But get diastereomers with chiral molecues:
Methoxy Methyl (MOM)
HN
On:
Cl
O
'MOM-Cl' thought to be very toxic
even more toxic
Cl
Cl
O
Benzyloxy methyl (BOM)
Cl
O
Ph
Off: all the methods for removing Bn groups:
OTES
O
O
Ph
Li/NH3
OTES
O
OH
OTES
Masamune, TL, 1985, 5239
O
O
H
Off: Acid
On:
Ph
HO
OH
can complicate NMR spectra (and
sometimes chromatography)
Protecting Groups in Organic Synthesis-8
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acetal protection of diols
HO
Cyclic acetal are wonderful protecting groups for 1,2
and 1,3 diols.
OH
O
HO
OH
HO
OMe
cat. TsOH
HO
O OH
75%
O
HO H
O
Some of the most common:
Corey...Falck...JACS, 1978, 4620
O
O
O
O
O
O
O
reactions often under thermodynamic control:
O
'acetonide'
least stable
most stable
O
TsOH
O
O
HO
OH
Usually, 1,2 >1,3>1,4
OH OH
O
OH
O
O
HO
O
HO
O
H
1:10
TsOH
O
O
HO
OH
5
:
>100:1
1
oxonium intermediates can be intercepted
MeO
On:
OMe
Cat. H+
OMe
or
cat. H+
why not acetone + H+?
Hint: Consider pKa's of protonated ketones vs ethers
CH2OBn
H
O
H
O
CH2OBn
Me3Al
O
CH2OBn
H
OtBu
H
OH
CH2OBn
TL 1988, 1823
O
H
Protecting Groups in Organic Synthesis-9
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Ph
benzylidene acetals
O
O
H
H
On: PhCHO/H+ or Lewis acid
Me
Ph
HAlR2
O
O
H
Off: H3O+ or H2 Pd/C
OP
Can be converted to benzyl:
MeO2C
CO2Me
do you know how?
H
Ph
O
O
i
Bn
Bu2AlH
H
H
AlR2
O
OH
Me
Ph
O
H
O
H
H
>20:1
OP
H
Ph
H
OP
OP
H
Me
1.404A
Bn
O
OH
O
O
H
1.417A
OP
from X-ray
OP
Schreiber, TL, 1988, 4085.
Usually see protection of less hindered OH
For protection of more hindered OH by a similar
reaction, see Yamamoto, TL, 1988, 1947-1950
Protecting Groups in Organic Synthesis-10
Ready
in situ generated active ester
diols can be protected as diacetals:
N
carbodiimides:
R"
O
O
OH
O
OMe
OH
O
HO
OO
OH CSA, CH(OMe)3
OH
OH
MeOH
OMe
OH
O
R
OH
+ R'
O
via
R
O
In general, ease of introduction and removal is
function of sterics and electronics
N
usually:
N
R'
N
N
N
R
LG
O
R'
O
Cl
R'
O
O
O
O
R'
R'
Cl
EDCI - can
extract urea
with acid
O
Cl
Cl
'Yamaguchi conditions'
more often for
macrolactonizations
Include CH2N2
DCC - mp=34oC
reported sensitizer
increased solubility
DIC - liquid at rt,
easy to use on
small scale
egs
O
N
O
O
R'
+ "RHN
NHR"
R''
O
N
N
OH +
O
rxn is 'self-drying'
removal of urea can be trouble
most common egs:
Esters as protecting groups
R'
R
OH
OMe
Ley, Perkin 1, 1997, 2023
R
"R
O
N
O
BOP-Cl:
O
O
R
OH
+ R'
OH
O
O
P
N
N
O
Cl
Et3N
synthesis, 1980, 547
O
R
O
R'
NHR"
Protecting Groups in Organic Synthesis- 11
Cleavage: base hydrolysis rates depend on sterics
and electronics
desymmetrization
OAc
stability to base
O
OR
OR
MeO
Bz
O
O
O
OR
Piv
Cl
OR
OR F3C
Ac
OR
TFA
less stable
more stable
Lipases: ester (usually Ac) on or off under mild
conditions; often enantioselectively
O
kinetic resolution
O
O
O
O
Ac2O
Lipase
O
O
(rac)O
OAc
lipase
O
O
Ready
OH
OAc
44%, 100%ee
OH
OH
O
O
O
O
OH
OH
54%, 88%ee
TL, 1992, 1911
OAc
OH
96%ee
for references, see Greene, 3rd ed.p156
Protecting Groups in Organic Synthesis-12
Dimethyl Thiocarbamate
Carbonates
similar deal as with esters, but more stable to base. Also,
some alternative cleavage methods possible.
cleavage
B
group
O
RO
O
O
Ready
RO
on:
R
S
NaH; Me2N
or
OH
Cl
S
RO
S
H
N
N
N
NMe2
N ; Me2NH
O
pKa ~ 10
Fmoc
B= Et3N, T1/2=20min
O
RO
O
Cl
O
Zn(0)
Cl
Cl
RO
O
Cl
Troc
Cl
Zn
Cl
S
RO
NMe2
stable to: Cr(VI); EtMgBr; DIBAL; LiAlH4; BH3;
nBuLi; Wittig; TBAF; DDQ; TiCl4
OFF:
LA
O
RO
O
SiMe3
LA=lewis acid
O
RO
OH
S
NaIO4
SiMe3
O
RO
NMe2
or
Teoc
O
RO
O
RO
cat Pd(0)
O
O
PdII
NuH
Alloc
Nu
SiMe3
NuH
F-
+ ROH + CO2
S
RO
H2O
NMe2
+
or NaOH/H2O2
Falck, Org. Lett., 2003,4755
ROH
Protecting Groups in Organic Synthesis-13
Protection for carboxylate
Mostly, same deal as ester and carbonate
protected substrate
O
R
ortho esters: not electophilic, no acidic protons
step 1
OH
O
O
KOH, ∆
+
EtO
HO
deprotection
OEt
HO
OH
step 2
common Eg's
Ready
O
R
O
various
ways
R
BF3 Et2O
O
OH
R
O
K2CO3/MeOH
CF3
R
+
H (TFA, HCl, TsOH)
eg
Br
O
O
1. BF3 Et2O
2. PPh3
3. KN(TMS)3
H
O
Pd(0), NuH
O
O
Ph3P
O
R
H
O
H2 Pd/C or Li/NH3
Ph
O
O
O
O
OMe
OMe
O
O
H
as before, enzymes can work
PLE
96%ee
O
O
OO
O
1. LiAlH4
2. o-NO2C6H4SeCN
Bu3P
3. mCPBA
H
H
OH
OMe
CO2Me
CO2H
cat H2SO4
O
O
PLE = pig liver esterase
When enzymes work, they're nearly perfect.
Hard to get ent-PLE
O
CHO
CO2Me
O
R
O
Corey, TL 1983, 5571
O
O
R
O
O
OMe
O
H
OH
O
H
0.3M NaOH
HO
H
Corey, JACS,
1985, 4339
Protecting Groups in Organic Synthesis-14
Ready
Group
Protection for amines
Removal
O
Mostly carbamates; same deal as ester and carbonate
R2N
O
On:
O
RO
OR
O
N
OBt
R2NH
OR
O
N
N
O
Cl
R2N
Teoc
O
O
O
O
N
F- (TBAF most
common)
SiMe3
O
OR
+
-OSu
Boc
O
O
acid (TFA most
common)
O
O
OR
F
O
OR
F
R2N
O
Pd(0), NuH
alloc
O
O
F
F
O
O
O
F
Group
R2N
O
Removal
R2N
O
O
NaOH; PrSLi
Ph
Cbz
R2N
amine base (piperidine
most common)
O
O
R2N
Fmoc
CF3
TFA
O
R2N
H2, Pd/C; Na/NH3
OMe
O
O
CCl3
Troc
Zn(0)
Meldrum's
acid; common
NuH
NaOH
Protecting Groups in Organic Synthesis- 15
Benzyl groups for amine protection
Sulfonates
Tosyl: Easy on (TsCl); can be difficult to remove
Nosyl (Ns) nice alternative:
On:
C8H17
simple alkylation can be difficult
NH2 + BnCl
R
R
NHBn + R
2 step method
BzCl
R
Ready
NBn2 + R
NBn3
Cl-
O
NH2
R
N
H
Ph
LiAlH4
R
N
H
Ph
Ns
C8H17
CO2Me
HN O
S
O
O
N
O
HO
Ns
N
3
CO2Me
Br
N
5
Ns
DEAD, PPh3
Ns
N
Br
5
reductive amination
NH2
R
AcOH, NaCNBH3
O
+
R
Ph
N
H
Ph
C8H17
C8H17
H
N
N
O
Ns
N
Schiff's bases:
Many examples, benzhydryl one of most common
Ns
R
NH2
Ph
Ph
H+ +H2O
R
Ph
OH
O
S
S
O
O
N
O
HN
Ns
Br
5
C8H17
N
Ph
N
OH
DBU
H -H2O
O
Ns
HN
Ns
Ns
+
O
+
N
0.1M
86%
N
HS
H
N
Cs2CO3
-3 SO2
H
N
NH O
NH
-3 RSAr
Nucleophilic aromatic substitution
HN
Review: Fukuyama
Chem Comm. 2004, 353
Protecting Groups in Organic Synthesis-16
Protection of carbonyl group
mostly of the form:
X
Y
Cleavage: usually hydrolysis or transketalization.
Relative rate usually follows cation (oxonium) stability
X and Y = OR, SR, NR, CN
O
O
R
R
O
O
H
OMe
O
R
R
dimethyl acetal
MeS
O
O
R
1,3 dioxane
O
O
R
R
O
O
PPTS, acetone
H2O, ∆
Most common:
MeO
Ready
H
100%
O
O
1,3 dioxolane
O
1M HCl
O
71%
SMe
S
R
R
S
R
1,3 dithiane
dimethyl thioacetal
S
S
R
R
O
O
O
1,3 dithiolane
Dithioacetals
MeO
HS
Formation:
HO
MeO
CN
acetals:
(CH2)n
OH + ketone
OMe O
TsOH or HCl
relative rates: for the ketone, relative rates same as normal
addition to carbonyls: aldehyde>acylic
ketone~cyclohexanone>cyclpentanone>enone>>aromatic
ketone
SH
BF3-Et2O
S
S
MeO
most common conditions
other lewis acids work, too
90%
CH3I
MeO
MeOH, H2O
MeO
CO2Et
>
OH OH
HO
OH
>
MeO
OH OH
Many variations on this theme; in practice, consult Greene
CN
O
MeO
S
S
CO2Et
Weinreb, JOC, 1978, 4172
Other Offs: Sulfur-loving metals (HgII), [O] (IBX, NBS, I2)