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Selective de-protection of silyl ethers
Tetrahedron Letters, Vo1.30, No.1, pp 19-22, 1989 Printed in Great Britain
SELECTIVE DE-PROTECTION
0040-4039/89 $3.00 + -00 Pergamon Press plc
OF SILYL ETHERS
Chandra Prakash, Samir Saleh, and Ian A. Blair Departments
of Pharmacology
Summary:
Pyridinium
selectively
in the
and Chemistry, Vanderbilt
p-toluenesulfonate
presence
has
been
of I-butyldiphenylsilyl
found ethers.
University, Nashville, TN 37232 to remove This
I-butyldimethylsilyl
methodology
should
ethers find
wide
applicability in complex organic synthesis. A large number as t-butyldimethylsilyl
of protecting
to their stability towards be accomplished
groups are available
(TBDMS) and l-butylcliphenylsilyl many reagents
and reaction
Often,
and tetraethyldiboroxane
more
products8-lo. essential
than
one protecting
Removal
hydrofluoric
in the presence group
of a selected
protection
of catalytic
group
are some problems
by treatment
De-protection
of silyl ethers can
fluoridelcT2, boron trifluoride
is often
amounts
of trimethylsilyl
the synthesis necessary
Tetrahydropyranyl
in dimethyl
in order
(THP)
for this purpose.
with tetrabutyiammonium
of complex
triflate7. natural
to reveal
an
ether derivatives
in
Selective
removal
of the
fluoride.
However, there
with the use of THP ether derivatives.
active alcohols results in the formation for interpretation
Silyl ethers such
acid 5, N-bromosuccinimide
has to be used during
with silyl ethers have been used extensively
silyl ether can be readily accomplished
the THP
aqueous
hydroxyl moiety during a complex synthesis.
combination
conditionsic.
using a variety of reagents such as tetrabutylammonium
etherate3, alkali metal tetrafluoroborate4, sulphoxide6
for free hydroxyl groups’.
(TBDPS) are among the most widely used due
For example, derivatization of optically of a mixture of diastereomers. This can be inconvenient both
of NMR spectra and for purification
derivative
is rather
labile
to acid and
by column chromatography is often
not
compatible
or HPLC.
Further,
with desired
reaction
conditions. Silyl ethers offer an attractive conditions
as noted above.
has been no convenient
alternative
because of their stability to a wide range of reaction
To date there has been no way to make use of this stability because there
way to distinguish
the different
silyl ethers.
We envisaged
that it may be
possible to distinguish the TBDMS group from the TBDPS because of the potential difference in reactivity of the two groups. Thus, a substrate containing the two protecting groups could cleave preferentially
at the least bulky silyl ether group (Scheme) to form the mono-TBDPS
(product type A)
rather than the mono-TBDMS (product type B). We report that this reaction occurs with pyridinium p-toluenesulfonate (PPTS) under mild conditions and so it is possible to use this methodology to selectively protect hydroxyl groups.
19
20
TBDMSO
/-OmY TE3DMSO hOEI
OTBDPS
Type B
TypeA Possible reaction products from l$-silyl ethers
Scheme:
The treatment
of l&silyl
1.2 to 2.0 h afforded isolated product
ethers with PPTS in ethanol
mono-silyl
either at room temperature
ethers in 80-92 % isolated
yield (Table).
‘H-NMR
or 55 “C for studies of the
showed a signal for the l-butyl group (6 I.06 ppm) from the t-butyldiphenyl
moiety
but the signals for the t-butyl group (6 0.88 ppm) and the two methyl groups (6 0.06 ppm) from the lbutyldimethylsilyl preferentially sensitivity
moiety
were absent.
This indicated
to completely
characterize
that the TBDMS
However,
by PP’IS to give type A products. the product
rH-NMR
Detailed
profile.
group had been
spectroscopy
studies were then carried out by
capillary column GC/electron
impact (EI) MS on the crude reaction products to determine
selectivity
The crude
of the reaction.
trimethylsilyl
(TMS) ethers
TBDMS) derivatives
in order
reaction
products
to improve
were
their GUMS
convertedi
peak areas corresponding
derivatives
(9-12 min).
Full scanning
to the total ion currents of the individual
program
the absolute corresponding
The type B (mono-
times (3-S min) compared
analysisi
was carried out and
products were calculated
using the
The mass spectra of the products were
automated
integration
confirmed
by comparison
proceeded
to give > 99.7 % of type A products in which the TBDMS group had been removed.
selectivity was apparent
with authentic
system (entry
(entries
It was shown that in most cases the reaction
standards.
even when a primary
present in the same molecule I,5pentane
of the GC/MS data system.
to their
characteristics.
eluted from the column13 with relatively short retention
with the type A (mono-TBDPS)
removed
lacked sufficient
TBDPS group and a secondary
6 and 7).
The poorest
1) where 3.5 % of product
TBDMS
selectivity was observed
type B was observed.
This
group were
in the case of
The reason
for this
discrepancy is not apparent at this time. With longer chain lengths selectivity was always 5 99 %. General procedure: The b&.ilyl
ether (1.0 mmol) was dissolved
mmol) was added in one portion. 1.2-2 h (see Table).
in absolute
ethanol
(5 ml) and PPTS (75 mg, 0.3
The reaction mixture was stirred at room temperature
The solvent was removed h m
(or 55 “C) for
and the residue was dissolved in ethyl acetate.
The organic solution was washed with saturated aqueous brine, water and then dried (MgSO,). The solvent was evaporated in vacua and the crude product was purified on a silica-gel column using hexane:ethyl acetate (9:l) as solvent.
21
Table: Reaction of &-silyl Entry
Substra@
ethers with PPTS.
1
TBDPSO-O’IBDMS
Product
Reaction conditions Time @I
Tern
erature P“C)
2.0
22
96.5
3.5
88.0
2
TBDPSO-“*DMS
1.5
22
99.1
0.9
92.0
3
TBDPSOeoTBDMs
1.2
22
99.8
0.2
92.0
4
l-f$DPSOwoTBDMS
1.2
22
99.9
0.1
90.0
TBDPSO-OTBDMS
2.0
22
99.8
0.2
82.0
‘IBDMSO
2.0
55
99.6
0.4
82.0
2.0
55
99.7
0.3
80.0
1.8
22
99.7
0.3
84.0
1.8
22
99-4
0.6
84.0
5
bOl-33DPS
TBDMSO -0TBDPS
TBDPSO hOTBDMS
9
TBDPSO &OlBDMS
22
In summary, conditions the presence
have been established
of a TBDPS ether.
Secondary
if the TBDPS is in a primary position.
where selective protection
that allow selective removal of a TBDMS ether in
TBDMS ethers can be removed with high selectivity even
This reaction
should find wide application
in organic synthesis
of hydroxyl groups is required. ACKNOWLEDGEMENTS
We acknowledge
the support of NIH grants GM 15431, GM 31304 and ES 00267 and thank Dr. D.F.
Taber for useful discussions. REFERENCES 1.
AND NOTES
Groups in Organic Synthesis”, John Wiley & Sons, New York, 1981.
(a) Green, T.W., “Protective
(b) Calvin, E.W., Chem. Sot. Rev., 2:35, 1978. (c) Corey, A.J., Venkateswarlu, Sot., 94:6190, 1972. (d) Barton, T.J., Tully, CR., J. Ore. Chem., a:3649,
A., J. Amer. Chem.
1978.
(e) Prakash, C.,
Roberts, L.J., Saleh, S., Taber, D.F. and Blair, IA. Adv. Prost. Thromb. Leuk. Res., 17:781, 1987. 2.
Corey, E.J., and Snider, B.B. J. Amer. Chem. Sot., 9&2549, 1972.
3.
Kelly, D.R., Roberts, S.M., and Newton, R.F. Svnth. Commun.. P:279, 1979.
4.
Metcalf, B.W., Burkhart, J.P., and Jund, K. Tetrahedron
5.
Newton, R.F., Reynolds, a:3981,
Lett., a:35
1980.
D.P., Finch, M.A.W., Kelly, D.R., and Roberts, SM.
Tetrahedron
Lett.,
1979.
6.
Batten, R.J., Dixon, AJ., Taylor, R.J.&, and Newton, R.F. Synthesis, 234, 1980.
7.
Dahlhoff, W.V., and Taba, K.M. Synthesis, 561, 1986.
8.
Jones, S.S. and Reese, C.B. J. Amer. Chem. Sot., m:7399,1979.
9.
Corey, E.J., Wollenberg,
10.
Prakash, C., Roberts,
R.H. and William, D.R. Tetrahedron
I_&., 2243,1977.
L.J., Saleh, S., Taber, D.F. and Blair, I.A.
,I. Chem Sot Perkin I, 1988 in
press. 11.
McDougal, P.G., Rico, J.G., Oh, Y.I., and Condon, B.D. J. Ore. Chem., 2:3388,1986.
12.
Trimethylsilyl
ethers
were
prepared
trimethylsilyl-trifluoroacetamide 13.
of the
crude
reaction
product
with &-
GC/MS analysis was carried out on a 10 m SPB-1 fused silica capillary column (0.32 mm id; 0.25 pm coating thickness)
using helium as carrier gas at a flow rate of 1 ml mm-‘.
made
mode.
in the splitless
programmed 14.
by treatment
at 60 OCfor 1 h.
The column
temperature
were
to 300 OC at 15 *C/min.
Full scan EI mass spectra of the TMS derivatives scanning
Injections
was held at 60 OC for 2 min then
time of 1.5 sec.
The silyl derivatives
were obtained
from n& 30 to r&
all showed characteristic
600 with a
M-57 ions corresponding
to M-I-Bu. 15.
Mono-silyl
ethers
were prepared
by treatment
of the corresponding
sodium hydride followed by reaction with the appropriate prepared
from the corresponding
mono-silyl
ethers.
dials with 1.1 equiv. of
silyl chloride (11). &-silyl
Satisfactory
analytical
all new compounds. 16.
Products were characterized (Received
in
USA
by MS and ‘H-NMR.
3 August
1988)
ethers were
data was obtained
Yields refer to isolated compounds.
on
SELECTIVE DE-PROTECTION
0040-4039/89 $3.00 + -00 Pergamon Press plc
OF SILYL ETHERS
Chandra Prakash, Samir Saleh, and Ian A. Blair Departments
of Pharmacology
Summary:
Pyridinium
selectively
in the
and Chemistry, Vanderbilt
p-toluenesulfonate
presence
has
been
of I-butyldiphenylsilyl
found ethers.
University, Nashville, TN 37232 to remove This
I-butyldimethylsilyl
methodology
should
ethers find
wide
applicability in complex organic synthesis. A large number as t-butyldimethylsilyl
of protecting
to their stability towards be accomplished
groups are available
(TBDMS) and l-butylcliphenylsilyl many reagents
and reaction
Often,
and tetraethyldiboroxane
more
products8-lo. essential
than
one protecting
Removal
hydrofluoric
in the presence group
of a selected
protection
of catalytic
group
are some problems
by treatment
De-protection
of silyl ethers can
fluoridelcT2, boron trifluoride
is often
amounts
of trimethylsilyl
the synthesis necessary
Tetrahydropyranyl
in dimethyl
in order
(THP)
for this purpose.
with tetrabutyiammonium
of complex
triflate7. natural
to reveal
an
ether derivatives
in
Selective
removal
of the
fluoride.
However, there
with the use of THP ether derivatives.
active alcohols results in the formation for interpretation
Silyl ethers such
acid 5, N-bromosuccinimide
has to be used during
with silyl ethers have been used extensively
silyl ether can be readily accomplished
the THP
aqueous
hydroxyl moiety during a complex synthesis.
combination
conditionsic.
using a variety of reagents such as tetrabutylammonium
etherate3, alkali metal tetrafluoroborate4, sulphoxide6
for free hydroxyl groups’.
(TBDPS) are among the most widely used due
For example, derivatization of optically of a mixture of diastereomers. This can be inconvenient both
of NMR spectra and for purification
derivative
is rather
labile
to acid and
by column chromatography is often
not
compatible
or HPLC.
Further,
with desired
reaction
conditions. Silyl ethers offer an attractive conditions
as noted above.
has been no convenient
alternative
because of their stability to a wide range of reaction
To date there has been no way to make use of this stability because there
way to distinguish
the different
silyl ethers.
We envisaged
that it may be
possible to distinguish the TBDMS group from the TBDPS because of the potential difference in reactivity of the two groups. Thus, a substrate containing the two protecting groups could cleave preferentially
at the least bulky silyl ether group (Scheme) to form the mono-TBDPS
(product type A)
rather than the mono-TBDMS (product type B). We report that this reaction occurs with pyridinium p-toluenesulfonate (PPTS) under mild conditions and so it is possible to use this methodology to selectively protect hydroxyl groups.
19
20
TBDMSO
/-OmY TE3DMSO hOEI
OTBDPS
Type B
TypeA Possible reaction products from l$-silyl ethers
Scheme:
The treatment
of l&silyl
1.2 to 2.0 h afforded isolated product
ethers with PPTS in ethanol
mono-silyl
either at room temperature
ethers in 80-92 % isolated
yield (Table).
‘H-NMR
or 55 “C for studies of the
showed a signal for the l-butyl group (6 I.06 ppm) from the t-butyldiphenyl
moiety
but the signals for the t-butyl group (6 0.88 ppm) and the two methyl groups (6 0.06 ppm) from the lbutyldimethylsilyl preferentially sensitivity
moiety
were absent.
This indicated
to completely
characterize
that the TBDMS
However,
by PP’IS to give type A products. the product
rH-NMR
Detailed
profile.
group had been
spectroscopy
studies were then carried out by
capillary column GC/electron
impact (EI) MS on the crude reaction products to determine
selectivity
The crude
of the reaction.
trimethylsilyl
(TMS) ethers
TBDMS) derivatives
in order
reaction
products
to improve
were
their GUMS
convertedi
peak areas corresponding
derivatives
(9-12 min).
Full scanning
to the total ion currents of the individual
program
the absolute corresponding
The type B (mono-
times (3-S min) compared
analysisi
was carried out and
products were calculated
using the
The mass spectra of the products were
automated
integration
confirmed
by comparison
proceeded
to give > 99.7 % of type A products in which the TBDMS group had been removed.
selectivity was apparent
with authentic
system (entry
(entries
It was shown that in most cases the reaction
standards.
even when a primary
present in the same molecule I,5pentane
of the GC/MS data system.
to their
characteristics.
eluted from the column13 with relatively short retention
with the type A (mono-TBDPS)
removed
lacked sufficient
TBDPS group and a secondary
6 and 7).
The poorest
1) where 3.5 % of product
TBDMS
selectivity was observed
type B was observed.
This
group were
in the case of
The reason
for this
discrepancy is not apparent at this time. With longer chain lengths selectivity was always 5 99 %. General procedure: The b&.ilyl
ether (1.0 mmol) was dissolved
mmol) was added in one portion. 1.2-2 h (see Table).
in absolute
ethanol
(5 ml) and PPTS (75 mg, 0.3
The reaction mixture was stirred at room temperature
The solvent was removed h m
(or 55 “C) for
and the residue was dissolved in ethyl acetate.
The organic solution was washed with saturated aqueous brine, water and then dried (MgSO,). The solvent was evaporated in vacua and the crude product was purified on a silica-gel column using hexane:ethyl acetate (9:l) as solvent.
21
Table: Reaction of &-silyl Entry
Substra@
ethers with PPTS.
1
TBDPSO-O’IBDMS
Product
Reaction conditions Time @I
Tern
erature P“C)
2.0
22
96.5
3.5
88.0
2
TBDPSO-“*DMS
1.5
22
99.1
0.9
92.0
3
TBDPSOeoTBDMs
1.2
22
99.8
0.2
92.0
4
l-f$DPSOwoTBDMS
1.2
22
99.9
0.1
90.0
TBDPSO-OTBDMS
2.0
22
99.8
0.2
82.0
‘IBDMSO
2.0
55
99.6
0.4
82.0
2.0
55
99.7
0.3
80.0
1.8
22
99.7
0.3
84.0
1.8
22
99-4
0.6
84.0
5
bOl-33DPS
TBDMSO -0TBDPS
TBDPSO hOTBDMS
9
TBDPSO &OlBDMS
22
In summary, conditions the presence
have been established
of a TBDPS ether.
Secondary
if the TBDPS is in a primary position.
where selective protection
that allow selective removal of a TBDMS ether in
TBDMS ethers can be removed with high selectivity even
This reaction
should find wide application
in organic synthesis
of hydroxyl groups is required. ACKNOWLEDGEMENTS
We acknowledge
the support of NIH grants GM 15431, GM 31304 and ES 00267 and thank Dr. D.F.
Taber for useful discussions. REFERENCES 1.
AND NOTES
Groups in Organic Synthesis”, John Wiley & Sons, New York, 1981.
(a) Green, T.W., “Protective
(b) Calvin, E.W., Chem. Sot. Rev., 2:35, 1978. (c) Corey, A.J., Venkateswarlu, Sot., 94:6190, 1972. (d) Barton, T.J., Tully, CR., J. Ore. Chem., a:3649,
A., J. Amer. Chem.
1978.
(e) Prakash, C.,
Roberts, L.J., Saleh, S., Taber, D.F. and Blair, IA. Adv. Prost. Thromb. Leuk. Res., 17:781, 1987. 2.
Corey, E.J., and Snider, B.B. J. Amer. Chem. Sot., 9&2549, 1972.
3.
Kelly, D.R., Roberts, S.M., and Newton, R.F. Svnth. Commun.. P:279, 1979.
4.
Metcalf, B.W., Burkhart, J.P., and Jund, K. Tetrahedron
5.
Newton, R.F., Reynolds, a:3981,
Lett., a:35
1980.
D.P., Finch, M.A.W., Kelly, D.R., and Roberts, SM.
Tetrahedron
Lett.,
1979.
6.
Batten, R.J., Dixon, AJ., Taylor, R.J.&, and Newton, R.F. Synthesis, 234, 1980.
7.
Dahlhoff, W.V., and Taba, K.M. Synthesis, 561, 1986.
8.
Jones, S.S. and Reese, C.B. J. Amer. Chem. Sot., m:7399,1979.
9.
Corey, E.J., Wollenberg,
10.
Prakash, C., Roberts,
R.H. and William, D.R. Tetrahedron
I_&., 2243,1977.
L.J., Saleh, S., Taber, D.F. and Blair, I.A.
,I. Chem Sot Perkin I, 1988 in
press. 11.
McDougal, P.G., Rico, J.G., Oh, Y.I., and Condon, B.D. J. Ore. Chem., 2:3388,1986.
12.
Trimethylsilyl
ethers
were
prepared
trimethylsilyl-trifluoroacetamide 13.
of the
crude
reaction
product
with &-
GC/MS analysis was carried out on a 10 m SPB-1 fused silica capillary column (0.32 mm id; 0.25 pm coating thickness)
using helium as carrier gas at a flow rate of 1 ml mm-‘.
made
mode.
in the splitless
programmed 14.
by treatment
at 60 OCfor 1 h.
The column
temperature
were
to 300 OC at 15 *C/min.
Full scan EI mass spectra of the TMS derivatives scanning
Injections
was held at 60 OC for 2 min then
time of 1.5 sec.
The silyl derivatives
were obtained
from n& 30 to r&
all showed characteristic
600 with a
M-57 ions corresponding
to M-I-Bu. 15.
Mono-silyl
ethers
were prepared
by treatment
of the corresponding
sodium hydride followed by reaction with the appropriate prepared
from the corresponding
mono-silyl
ethers.
dials with 1.1 equiv. of
silyl chloride (11). &-silyl
Satisfactory
analytical
all new compounds. 16.
Products were characterized (Received
in
USA
by MS and ‘H-NMR.
3 August
1988)
ethers were
data was obtained
Yields refer to isolated compounds.
on