Selective Protection of Secondary Alcohols by Using Formic Acid as a Mild and Efficient Deprotection Reagent for Primary tert -Butyldimethylsilyl Ethers

Article abstract of DOI:10.1055/s-0037-1611757

A mild, efficient, and environmentally friendly method for the selective protection of secondary hydroxyl groups is described. The method involves the protection of both primary and secondary hydroxyl groups as tert -butyldimethylsilyl (TBDMS) ethers and selective deprotection of the primary TBDMS group with formic acid in acetonitrile/water. The rates of desilylation of primary and secondary TBDMS ethers by different concentrations of formic acid are determined. Formic acid of 5-20% concentration is found to selectively deprotect primary TBDMS ethers while keeping more than 95% of their secondary counterparts intact.

Full text of DOI:10.1055/s-0037-1611757

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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
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Synlett
K. Sapkota, F. Huang
Letter
Selective Protection of Secondary Alcohols by Using Formic Acid
as a Mild and Efficient Deprotection Reagent for Primary tert-Bu-
tyldimethylsilyl Ethers
Krishna Sapkota
Faqing Huang*
TBDMSCl
OH Imidazole
O
Si
5–20% Formic acid
RT, MeCN/H2O
OH
DMF
O
Si
O
Si
R
OH
R
R
Department of Chemistry and Biochemistry, University of
Southern Mississippi, 118 College drive, Hattiesburg, MS,
>95% Chemoselectivity
78–90% isolated yields
39406, USA
6
examples of 1,2- and 1,3-diols
Faqing.huang@usm.edu
Received: 16.01.2019
Accepted after revision: 27.02.2019
Published online: 19.03.2019
noxazole A, Wipf and Lim protected primary and secondary
hydroxyl groups as TBDMS and TIPS ethers, respectively.
TBDMS ether was then selectively cleaved with LiOH in di-
DOI: 10.1055/s-0037-1611757; Art ID: st-2019-l0029-l
3
oxane/ethanol/water. Kadota and co-workers also protect-
Abstract A mild, efficient, and environmentally friendly method for
the selective protection of secondary hydroxyl groups is described. The
method involves the protection of both primary and secondary hydrox-
yl groups as tert-butyldimethylsilyl (TBDMS) ethers and selective depro-
tection of the primary TBDMS group with formic acid in acetonitrile/wa-
ter. The rates of desilylation of primary and secondary TBDMS ethers by
different concentrations of formic acid are determined. Formic acid of
ed primary and secondary hydroxyls as respective TBDMS
and TIPS ethers while pursuing the total synthesis of gam-
bierol. TBDMS ether was selectively desilylated with 10-
4
camphorsulfonic acid (CSA) in 75% yield.
Alternatively, a better strategy for selective protection
of secondary hydroxyls can be achieved by selective depro-
tection of primary TBDMS ethers after both types of hy-
droxyls are TBDMS-protected. Numerous investigations
have been made to achieve selective deprotection of prima-
5–20% concentration is found to selectively deprotect primary TBDMS
ethers while keeping more than 95% of their secondary counterparts in-
tact.
Key words selective deprotection, TBDMS ethers, formic acid, sec-
ondary alcohol protection, desilylation
5
6
ry TBDMS ethers. Various acids including HCl, HF, acetic
7,8
9
10
acid, CSA, toluenesulfonic acid (TsOH), and trifluoro-
acetic acid (TFA)1 have been investigated. Smith and Liu
used 1% HCl in ethanol to selectively deprotect primary
TBDMS ethers while performing the total synthesis of dis-
1
Complex synthetic targets in modern organic chemistry
often require different strategies for selective protection
and deprotection of various functional groups to facilitate
site-specific reactions. tert-Butyldimethylsilyl (TBDMS) is
one of the most reliable and commonly used groups for hy-
droxyl protection because of its easy installation and re-
5
codermolide. However, inorganic acids such as HCl and HF
are poorly selective and produce a complex mixture of the
desired primary alcohol, undesired secondary alcohol, and
globally deprotected alcohol.1
2,13
Ogilvie and co-workers
1
moval. Both primary and secondary hydroxyl groups can
used aqueous acetic acid to selectively desilylate the 5′-
TBDMS group of protected nucleosides.14 Acetic acid was
also used by Battistini and co-workers for selective depro-
tection of primary TBDMS ethers during the total synthesis
be protected as TBDMS ethers without difficulty. Many bio-
molecules and bioactive therapeutics contain both primary
and secondary hydroxyl groups. During the synthesis of
complex natural products and biopharmaceuticals, there
are many instances in which selective protection of second-
ary hydroxyls is required without affecting primary hy-
7
of cyclopentadienyl-carboxylic amino acid. However, this
method suffers from poor selectivity, low yield (50–60%),
requirement for high concentration (80%), and very long re-
action time (>24 h). While strong acids such as TsOH and
CSA can be used to deprotect TBDMS ethers with much
lower concentration and short time, they are less selective
against secondary TBDMS ethers, resulting in <60% yield.
2,3
droxyl groups. However, this cannot be achieved directly
because primary hydroxyls also react under the conditions
that secondary hydroxyl groups are protected. Given that
primary and secondary hydroxyls exhibit different chemi-
cal reactivity, they may be orthogonally protected so that
one can be selectively deprotected over the other. For ex-
ample, during the synthesis of marine natural product He-
TFA is another widely used acid for selective desilyla-
tion.1
1,13,15
Yokokawa and co-workers compared various
desilylating reagents including HF, acetic acid, and TFA for
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
K. Sapkota, F. Huang
Letter
selective desilylation of primary TBDMS ethers during the
total synthesis of micropeptin T-20.12 HF produced a com-
plex mixture due to the selectivity problem. Acetic acid and
TFA deprotected the desired primary TBDMS ether in 28%
and 54% yield, respectively. In another report, Gu and Sil-
verman used 90% TFA at room temperature to selectively
O
O
5%–20% Formic acid
MeCN/H2O, RT, 0.5 h–12 h
OH
O
Si
H3C
O
9
H3C
H3C
O
1
5%
2
O
5%–20% Formic acid
MeCN/H2O, RT, 0.5 h–12 h
O
O
Si
OH
O
3
H C O
CH3
CH3
11
3
deprotect primary TBDMS ether in 70% yield. Partially de-
activated neutral alumina was used by Guerrero and co-
workers to achieve the selective deprotection of TBDMS
ethers in the presence of other acid labile protecting
groups. However, this method lacks regioselectivity among
primary and secondary TBDMS ethers and yields globally
4
<
5%
Scheme 1 Model compounds for the study of desilylation rates and se-
lectivity with 5, 10, and 20% formic acid, and with acetic acid and TFA
The desilylation reaction was initiated by incubating
model compounds 1 and 3 with the desilylation reagent in
1:10 ratio by volume. Three formic acid concentrations
16
deprotected alcohol. Metal Lewis acid hafnium triflate has
recently been shown to deprotect silyl ethers including
17
TBDMS ether under mild conditions. In all these exam-
ples, while primary TBDMS ethers are preferentially depro-
tected, secondary TBDMS ethers are also cleaved to various
degrees, resulting in undesired byproducts and low yields.
Whereas optimal deprotection conditions for achieving
high selectivity and yield may exist for specific target mole-
cules, it is by no means a simple task – involving searching
for different acids, concentrations, temperature, and reac-
tion time.
were prepared by mixing formic acid/H O/MeCN in ratios of
2
1:3:16 for 5%, 2:3:15 for 10% and 4:3:13 for 20%. Addition-
ally, we included acetic acid and TFA as desilylation re-
agents for comparison with formic acid. The reaction was
quenched at different reaction times with 1 equivalent of
2
0
NaOH and the mixture was analyzed by HPLC. The
amounts of 1 and 3 at different reaction time was deter-
mined from peak integration and used to calculate desilyla-
tion kinetic curves. The half-lives of TBDMS ethers under
different deprotection conditions are presented in Table 1.
As can be seen from the table, although 5–20% formic acid
can deprotect both primary and secondary TBDMS ethers,
there is a strong preference of 40–60 times for the primary
over the secondary. While acetic acid also displays such a
preference, it takes a long time to deprotect the primary
TBDMS ether at similar concentration. TFA, on the other
hand, can desilylate both primary and secondary TBDMS
ethers much faster. However, the preference for primary
over secondary TBDMS ethers decreases dramatically to
about 3 times.
Despite being a subject of numerous investigations, a
simple, high yielding, and environmentally friendly proce-
dure for selective desilylation of primary TBDMS ethers is
not available. Consequently, development of such a proce-
dure will be of great utility for synthetic organic, medicinal,
and bioorganic chemists. When examining various proce-
dures for selective deprotection of TBDMS ethers in the lit-
erature, it came to our attention that the medium strength
formic acid is rarely used, while both stronger (TsOH, CSA,
HCl, TFA) and weaker (acetic acid) acids are often utilized.
To our knowledge, there are only two reports of TBDMS
deprotection with formic acid. Kawahara and co-workers
investigated the 2′-O desilylation of nucleotides and found
that 20–40% formic acid can be used to effectively deprotect
Table 1 Half-Lives of Primary and Secondary TBDMS Desilylation Reac-
tion under Different Conditions
2
′-O TBDMS from protected oligoribonucleotides.18 In an-
other report, Kende and colleagues used 30% formic acid to
deprotect secondary TBDMS ethers during the synthesis of
Desilylation reagent
formic acid
Concentration (%)
Half-life (min)
Primary
Secondary
19
lankacidin C macrolide. While formic acid can be used to
globally deprotect TBDMS ethers at high concentrations
5
150
52
8600
2300
630
1
2
5
1
2
5
1
0
(>30%), its utility at lower concentrations for selective
0
17
deprotection of primary TBDMS ethers has not been ex-
plored. We hereby report the desilylation rates of primary
and secondary TBDMS ethers with 5–20% formic acid in
acetonitrile/water, thus establishing formic acid as an excel-
lent reagent for selective desilylation of primary TBDMS
ethers.
We used TBDMS-glycolate methyl ester 1 and TBDMS-
lactate methyl ester 3 as model compounds to represent
primary and secondary TBDMS ethers, as shown in Scheme 1.
acetic acid
TFA
3465
990
385
34
>18,000
~18,000
~9,000
110
0
0
0
12
36
20
4
12
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K. Sapkota, F. Huang
Letter
The significant difference in half-lives of primary and
secondary TBDMS ethers under different formic acid con-
centrations can be exploited to achieve the selective desil-
ylation of one over the other. The deprotection regioselec-
tivity of TBDMS ethers can be determined by the relative
amount of primary and secondary alcohols under defined
conditions of desilylation reagent concentration and reac-
tion time. As shown in Table 2, 5–20% formic acid can be
used to achieve 95% deprotection of primary TBDMS ethers
with <5% secondary TBDMS desilylation; i.e., a desilylation
regioselectivity of ca. 95:5. In comparison, TFA of 5–20% can
reach only about 95:40 regioselectivity.
taining both primary and secondary alcohols, as shown in
Table 3. All the hydroxyls were fully protected as TBDMS
ethers, which were treated with 10% formic acid in acetoni-
trile/water for 4 h at room temperature to achieve selective
deprotection of primary TBDMS groups. As can be seen
from Table 3, the treatment procedure yielded the corre-
sponding primary alcohols in excellent yields for all TBDMS
protected diols. After a simple ethyl acetate extraction pro-
cedure, the mono TBDMS protected diols were isolated in
1
high purity, as confirmed by H NMR spectroscopy (see the
Supporting Information).
Table 3 Selective Deprotection of Disilylated Alcohols with 10% For-
mic Acid for 4 h at Room Temperature
Table 2 Desilylation Selectivity of 5–20% Formic Acid and 5–10% TFA
Desilylation re- Concentration
Reaction time
(h)
Yield (%)
Primary
Entry Reactant
1
Product
Isolated
yield (%)
agent
(%)
Secondary
OTBDMS
OTBDMS
78
Formic acid
5
10.5
4
95
95
95
95
95
95
<5
<5
<5
40
36
45
TBDMSO
HO
HO
1
2
5
1
2
0
2
81
0
1.2
2.5
0.8
0.25
N
OTBDMS
N
TBDMSO
TFA
OTBDMS
0
0
3
4
TBDMSO
TBDMSO
O
86
88
OTBDMS
OH
O
Our data suggest that the desilylation rate and selectivi-
ty between primary and secondary TBDMS ethers are de-
pendent on both acid strength and concentration. While
TFA exhibits relatively high desilylation rates, it has poor se-
lectivity. On the other hand, slow deprotection of primary
TBDMS ethers can be effected by acetic acid. As secondary
TBDMS ethers are practically stable in 5–20% acetic acid, it
has a high desilylation selectivity between primary and
secondary TBDMS ethers. Given that formic acid lies be-
tween TFA and acetic acid in terms of acid strength, it came
as no surprise that we found formic acid to be an ideal desi-
lylation reagent for optimal desilylation rate and selectivity.
Our experiments showed water as an important component
in the desilylation reagent for TBDMS ethers. No reaction
was observed when a primary TBDMS ether was treated
overnight with 5–10% formic acid in anhydrous acetonitrile.
To demonstrate the broad utility of formic acid as a sim-
ple and efficient reagent for selective desilylation of prima-
ry TBDMS ethers, we investigated six different diols con-
3
H C
3
H C
TBDMSO
TBDMSO
O
O
O
OTBDMS
OH
O
5
6
TBDMSO
O
85
90
TBDMSO
O
OTBDMS
OH
Cl
Cl
OTBDMS
OTBDMS
TBDMSO
HO
Finally, we applied this method in one of our ongoing
projects involving the chemical synthesis of dephospho-co-
enzyme A.21 We needed to selectively protect the two sec-
ondary hydroxyls of pantethine while keeping the two pri-
mary hydroxyl groups available for phosphorylation. As
shown in Scheme 2, after the global TBDMS protection of
O
O
TBDMSCl,
Imidazole
DMF, RT, 8 h
10% Formic acid
MeCN/H2O,
O
O
HO
O
O
RT, 4 h
N
N
S
Si
O
H
H
N
N
S
HO
OH
H
H
N
N
S
2
O
H
H
2
O
Si
2
5
6
7
Si
90%
95%
Scheme 2 Synthesis of secondary hydroxyl protected pantethine by selective desilylation of primary TBDMS ether with 10% formic acid
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K. Sapkota, F. Huang
Letter
the four hydroxyls of pantethine 5, selective desilylation of
tetra-TBDMS pantethine 6 with 10% formic acid yielded the
disilylated pantethine 7 in 90% isolated yield.
(3) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(
4) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Satake,
M.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 11893.
5) Smith, A. B.; Xian, M.; Liu, F. Org. Lett. 2005, 7, 4613.
6) Reiff, E. A.; Nair, S. K.; Henri, J. T.; Greiner, J. F.; Reddy, B. S.;
Chakrasali, R.; David, S. A.; Chiu, T.-L.; Amin, E. A.; Himes, R. H. J.
Org. Chem. 2009, 75, 86.
22
(
(
In summary, selective protection of secondary hydroxyl
groups in the presence of primary hydroxyls is of consider-
able interest in chemical synthesis. However, a simple and
efficient procedure is not currently available. Various meth-
ods explore either orthogonal protection/deprotection or
global protection followed by deprotection under condi-
tions with different acids, concentrations, and reaction
time, with varying degrees of success. In contrast, our selec-
tive desilylation of primary TBDMS ethers with 5–20% for-
mic acid in MeCN/water offers a simple, efficient, remark-
ably mild, and environmentally friendly method. With its
acid strength between those of TFA and acetic acid, formic
acid displays an optimal balance between the desilylation
rate and selectivity for primary over secondary TBDMS
ethers. As a result, high yields of primary alcohols with sec-
ondary alcohol protected by TBDMS can be achieved with-
out difficulty.
(7) Battistini, L.; Curti, C.; Zanardi, F.; Rassu, G.; Auzzas, L.;
Casiraghi, G. J. Org. Chem. 2004, 69, 2611.
(8) Sekine, M.; Aoyagi, M.; Ushioda, M.; Ohkubo, A.; Seio, K. J. Org.
Chem. 2005, 70, 8400.
(9) Lee, J.; Panek, J. S. Org. Lett. 2009, 11, 4390.
(
10) (a) Reddy, C. R.; Dharmapuri, G.; Rao, N. N. Org. Lett. 2009, 11,
5730. (b) Ramachandran, P. V.; Srivastava, A.; Hazra, D. Org. Lett.
2007, 9, 157.
(11) Gu, W.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287.
(12) Yokokawa, F.; Inaizumi, A.; Shioiri, T. Tetrahedron 2005, 61,
1459.
(
(
13) Crouch, R. D. Tetrahedron 2013, 69, 2383.
14) Ogilvie, K. K.; Schifman, A. L.; Penney, C. L. Can. J. Chem. 1979,
57, 2230.
(
15) (a) Zhu, X.-F.; Williams, H. J.; Scott, A. I. J. Chem. Soc., Perkin
Trans. 1 2000, 2305. (b) Nelson, T. D.; Crouch, R. D. Synthesis
1996, 1031.
(
(
(
(
(
16) Feixas, J.; Capdevila, A.; Camps, F.; Guerrero, A. J. Chem. Soc.,
Funding Information
Chem. Commun. 1992, 1451.
17) Zhengh, X.-A.; Kong, R.; Huang, H.-S.; Wei, J.-Y.; Chen, J.-Z.;
Gong, S.-S.; Sun, Q. Synthesis 2019, 51, 944.
This work was supported by development fund from the University of
Southern Mississippi, Hattiesburg, MS, USA.()
18) Kawahara, S.-i.; Wada, T.; Sekine, M. J. Am. Chem. Soc. 1996, 118,
9461.
19) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am. Chem.
Soc. 1995, 117, 8258.
Supporting Information
20) HPLC conditions: Gemini C18 4.6 × 50 mm column, flow-rate 1
mL/min. The column was run in isocratic mode at 40% MeCN
and 10% 40 mM KH PO for 1 h. Under these conditions, the
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611757.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
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orit
n
g Inform ati
o
n
2
4
retention time for TBDMS-glycolate and TBDMS-lactate were
.2 min and 3.5 min, respectively. The same amount of each of
the reactions at time 0 were injected and used as a control. The
area of peaks of 1 and 3 at different time points of reaction were
quantified using EZChrom Elite software.
3
References and Notes
(
(
1) Corey, E.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
2) (a) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1993, 58, 5130.
b) Nicolaou, K.; Rutjes, F.; Theodorakis, E.; Tiebes, J.; Sato, M.;
(
(
21) Sapkota, K.; Huang, F. Bioorg. Chem. 2018, 76, 23.
(
1
22) Di-TBDMS-pantethine: H NMR (400 MHz, CDCl ):  = 7.07 (t, J =
Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173. (c) Berks, A. H.
Tetrahedron 1996, 52, 331. (d) Chandrasekhar, S.; Mohanty, P.
K.; Takhi, M. J. Org. Chem. 1997, 62, 2628. (e) Kadota, I.;
Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J.
Am. Chem. Soc. 2003, 125, 46. (f) Marshall, J. A.; Ellis, K. C. Org.
Lett. 2003, 5, 1729. (g) Ghosh, A. K.; Li, J. Org. Lett. 2009, 11,
3
6.2 Hz, 4 H), 6.87 (t, J = 5.9 Hz, 4 H), 3.98 (s, 2 H), 3.57 (s, 4 H),
3.44–3.35 (m, 4 H), 2.80 (t, J = 6.5 Hz, 4 H), 1.00 (s, 6 H), 0.95 (s,
18 H), 0.91 (s, 12 H), 0.80 (s, 6 H)
4164.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D