Highly sulphated cellulose: a versatile, reusable and selective desilylating agent for deprotection of alcoholic TBDMS ethers

Article abstract of DOI:10.1039/c8ob01438h

A mild, efficient and rapid protocol was developed for the deprotection of alcoholic TBDMS ethers using a recyclable, eco-friendly highly sulphated cellulose sulphate acid catalyst in methanol. This acid catalyst selectively cleaves alcoholic TBDMS ethers in bis-TBDMS ethers containing both alcoholic and phenolic TBDMS ether moieties.

Full text of DOI:10.1039/c8ob01438h

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ARTICLE
Highly sulphated cellulose: A versatile, reusable and selective
desilylating agent for deprotection of alcoholic TBDMS ethers
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
b
Soma Shekar Dachavaram, Narsimha R. Penthala, Julie L. Calahan, Eric J. Munson, Peter A.
a
Crooks *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild, efficient and rapid protocol was developed for the deprotection of alcoholic TBDMS ethers using a recyclable, eco-friendly
highly sulphated cellulose sulphate acid catalyst in methanol. This acid catalyst selectively cleaves alcoholic TBDMS ethers in bis-
TBDMS ethers containing both alcoholic and phenolic TBDMS ether moieties.
The cleavage of TBDMS ethers proceeds mainly by reaction with
fluoride anion or under mild acid conditions. It is well-known that
Introduction
1
-5
fluoride-mediated deprotection of TBDMS ethers proceeds through
Protection and deprotection sequences are commonly utilized in
the total synthesis of natural products, in multi-step synthesis of
complex organic molecules, and in the synthesis of small molecules
in medicinal chemistry. As the complexity of synthetic targets are
increasing, the ability to protect multiple hydroxy groups in the
same molecule, and the sequential deprotection of selective
moieties has become essential.
23, 24
a pentavalent-silicon intermediate pathway,
permitted by
hybridization with silicon's vacant 3d orbital. Among the many
desilylating agents, TBAF is most often used as the source of
1
5
fluoride anion for desilylation. Patel et al. has described the
mechanism for the desilylation of TBDMS ethers utilizing
tetrabutylammonium tribromide (TBATB) in MeOH as being due to
2
5
the released HBr ; however, TBATB is not a selective reagent for
deprotection of alcoholic TBDMS ethers, since it also deprotects
phenolic TBDMS ethers.
Protection of hydroxyl groups by formation of silyl ethers has been
extensively utilized in organic synthesis to achieve the target
6
-12
molecule,
due to facile synthetic procedures for preparing silyl
In addition to the above reported literature methods, a variety of
Lewis acids and other reagents have also been developed for the
ethers. Silyl ethers are resistant to oxidation and have good thermal
stability and low viscosity; they are also easily deprotectable to
afford the desired parent compound.
2
6
27
desilylation of various TBDMS ethers, which include BF
3
,
BCl
3
,
2
8
29
30
31
32
33
BiBr
acid (CSA),
2
Fe(OTs) .6H O. All these reagents are noble desilylating agents,
3
,
CuBr
2
,
ZnBr
2
,
NIS, FeCl
3
,
3
Bi(OTf) ,
camphor sulfonic
34
35
36
37
NaAuCl
4
.2H
2
O,
KF.2H
2
O,
LiOAc.2H
2
O,
and
Although numerous silylating protection methods are currently
38
1
3, 14
3
being utilized in organic synthesis
, the tert-butyldimethylsilyl
however, some have limitations, which include being non-
ecofriendly reagents, having poor selectivity and non-recyclability,
(
TBDMS) moiety has earned a place of prominence. Commercially
available tert-n-butyldimethylsilyl chloride (TBDMS-Cl) was initially
3
9
and involving tedious workup procedures.
used as a silylating agent by Corey for the mild conversion of
1
5
various alcohols to TBDMS ethers. In multi-step organic syntheses,
functional group protection, as well as subsequent deprotection,
with TBDMS groups without affecting other functional groups in the
Previously, our research group reported the applications of
cellulose sulphuric acid (CSA) as a catalyst in various organic
4
0
1
6
reactions the Bignelli reaction, the Pechman condensation
same molecule is often challenging. Corey was able to achieve the
rapid cleavage of TBDMS ethers to alcohols by treatment with 2-3
4
1
42
reaction,
the
synthesis
of
xanthenes ,
thiadiazolo
4
3
44
1
5
benzimidazoles,
1-oxo-hexahydroxanthenes,
and in the
eq. of tetra-n-butylammonium fluoride (TBAF) in THF at 25°C.
Subsequently, several literature methods for the deprotection of
4
5
synthesis of quinoxalines. Cellulose sulphuric acid (CSA) is partially
sulphated cellulose prepared by the reaction of cellulose (1) with
chlorosulphonic acid in hexanes (analytical data for CSA is given in
4
TBDMS ethers were reported.
A variety of acid-catalyzed
desilylation methods were also reported for the cleavage of the Si-
O bond of TBDMS ethers to their respective alcohols utilizing
4
0, 46, 47
the supporting information).
1
7
18
19
20
21
reagents such as CCl
3
COOH,
HF, AcOH, TsOH, HCl, and
22
To address the above issues of other acid catalysts in the selective
deprotection of alcoholic TBDMS ethers we attempted the
deprotection of alcoholic TBDMS ethers using chlorosulphonic acid-
derived CSA as a mild acid catalyst in methanol. Unfortunately, this
CSA did not deprotect alcoholic TBDMS ethers.
TFA.
b
Department of Pharmaceuticals Sciences, University of Kentucky, Lexington, KY, 40536, USA.
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Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x.
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Journal Name
attributable to
a
C
6
-sulphated hydroxyl moiety, no proton
3
In the present study we investigate the use of a highly sulphated resonance at 4.97 ppm (indicative of the absence of a C -sulphated
cellulose sulphate (HS-cellulose sulphate; 2) as a potential catalyst hydroxyl moiety) was observed. However, these investigators
for deprotection of alcoholic TBDMS ethers in molecules which concluded from their studies that the structure of their product
2
contain both phenolic and alcoholic bis-TBDMS ether moieties. To could not be determined, since the NMR spectrum was run in D O,
the best of our knowledge, HS-cellulose sulphate has not been which affords a broad signal that would mask the expected proton
reported previously as a catalyst for the selective deprotection of resonance at 4.83 ppm attributable to a cellulose product that was
alcoholic TBDMS ethers.
sulphated at the C
2
-hydroxyl group. These data are consistent with
O as the NMR solvent,
HS-Cellulose sulphate is an inexpensive, non-toxic, eco-friendly and indicate that H-NMR data alone when run in D O does not
catalyst which can be prepared easily from the most abundant, present enough information to determine whether the C -hydroxyl
our own NMR data, since we also utilized D
2
1
2
2
4
8
naturally occurring biopolymer, α-cellulose (1). We found that HS- is sulphated or not. When elemental sulphur combustion analysis
cellulose sulphate-mediated heterogeneous catalysis can cleave the was carried out on the sodium salt of 2 a value of 15.42% was
Si-O bond in TBDMS ethers very efficiently to afford the desired obtained, i.e. 88.06% of theoretical for 2,6-disubstituted cellulose
desilylated product. When compared to currently used sulphate sodium (C H S O Na ), indicating that the product is
6
8
2
11
2
homogeneous catalysts, this mild catalytic methodology offers predominantly the disulphated cellulose rather than the
major advantages, such as facile separation of catalyst from the monosulphated cellulose (see Supporting Information for more
reaction mixture, reusability, and minimal environmental pollution data).
on disposal.
Elemental sulphur content of chlorosulphonic acid-derived CSA
Results and discussion
afforded only 0.42% (equivalent to 2.04% sulphation of α-cellulose),
indicating a comparatively much higher sulphate content in the
sulphuric acid-derived HS-cellulose 2.
Catalyst preparation and structure determination
To a cooled solution of EtOH (58 mL) at -10°C was added H SO (45
2
4
mL) drop-wise over a period of 5 minutes and the reaction mixture
13
,
HS-cellulose sulphate sodium was also characterized by C-NMR,
was stirred vigorously for a further 15 min, followed by addition of
13
and solid-state C-NMR. In addition, HS-cellulose sulphate and HS-
α-cellulose (4g). The reaction mixture was then stirred at -5°C to -
cellulose sulphate sodium
were analyzed
by FT-IR
1
0°C for 5h, the heterogeneous reaction mixture was filtered, and
spectrophotometry (see Supporting Information).
the resulting solid was washed with ethanol (3x100 mL) and dried,
49
to afford HS-cellulose sulphate as a white solid (Scheme 1).
Deprotection of TBDMS ethers with HS-cellulose sulphate catalyst
TBDMS ethers 3a-3j and 5a-5d were prepared from
alcohols/phenols (4a-4j and 6a-6d) using a known standard
8
procedure. Alcohols/phenols (4a-4j and 6a-6d) were reacted with
TBDMS chloride in the presence of imidazole in DCM to afford their
8
respective TBDMS ethers. The TBDMS ethers of 3k, 5e, 5f were
5
2
synthesized by the Barbier allylation procedure. Compound 3l was
prepared by the reduction of methyl 8-(4-chlorophenyl)-1,4-
dioxaspiro[4.5]dec-7-ene-7-carboxylate using lithium aluminum
hydride (LAH) as reducing agent to afford 4l. Compound 4l was
converted to its TBDMS ether (3l) by reaction with TBDMS chloride
Scheme 1 Synthesis of HS-cellulose sulphate (2) from α-cellulose
1).
(
Solution-state NMR analysis of HS-cellulose sulphate 2 was not
possible, due to its insolubility in all available deuterated solvents.
To solve this insolubility problem, the HS-cellulose sulphate was
suspended in deionized water under vigorous stirring over a period
of 30 min, and the pH of the mixture adjusted to 9 with 2M sodium
hydroxide solution (100 mL) at room temperature. The above
8
1
13
and imidazole in DCM. H-NMR, C-NMR and mass spectral data
for all new TBDMS ethers and for new alcohols are provided in the
Supporting Information.
Method
reaction mass was filtered to remove insoluble material, and the Initially, we carried out the deprotection of TBDMS ether groups
sodium salt of HS-cellulose sulphate was precipitated from the attached to both primary and secondary hydroxyl moieties of
filtrate by adding EtOH (200 mL). The filtered solid was then dried various organic molecules utilizing cellulose sulphate as catalyst.
to afford HS-cellulose sulphate sodium, which is readily soluble in Treatment of simple alcoholic TBDMS ethers (3a-3l) with a catalytic
H
D
2
O and is amenable to characterization by solution-state NMR in amount of HS-cellulose sulphate in methanol at room temperature
2
O.
for 0.5 to 1.5 h (Tables 1 and 2) afforded the corresponding
desilylated products (4a-4l) in generally good yields (Scheme 2).
1
The H NMR spectral data of cellulose sulphate 2 is consistent with
1
the H NMR spectrum of a cellulose sulphate reported by Zeng et
5
0
51
al and Kamide et al. While the NMR spectrum of the Zeng
cellulose sulphate shows proton resonance (4.39 ppm)
a
2
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3
4
0
5
75
82
Scheme 2 Desilylation of alcoholic TBDMS ethers (3a-3l) utilizing
HS-cellulose sulphate catalyst.
We also attempted the deprotection of alcoholic TBDMS ethers that
incorporated the acid-sensitive ethylene glycol (3l) protecting group
within the same molecule utilizing HS-cellulose sulphate as catalyst
and found that ethylene glycol protection was not affected during
the TBDMS ether deprotection process (Table 1).
4
5
91
Table 1. Desilylation of different alcoholic TBDMS ethers (3a-3l) to
a
their corresponding alcohols (4a-4l) using HS-cellulose sulphate
acid catalyst.
b
c
Substrate
Product
Time
min)
Yield
a
b
d
5 % w/w of HS-cellulose sulphate acid catalyst was used; 100 mg of TBDMS
(
(%)
c
ether in 1 ml methanol, TLC monitoring time (ethyl acetate/n-hexane 1:10),
d
isolated yields.
3
0
97
90
In order to evaluate the effect of various solvents on the
desilylation of alcoholic TBDMS ethers utilizing HS-cellulose
sulphate, the desilylation reaction was carried out for the synthesis
of compound 4a in the following solvents: dichloromethane,
tetrahydrofuran (THF), dioxane, dimethyl formamide (DMF),
methanol, ethanol and isopropyl alcohol. The relative rates of
deprotection of the TBDMS ether moiety under these conditions
was methanol > ethanol > isopropyl alcohol, and is likely due to the
more polar nature of methanol compared to either ethanol and
isopropyl alcohol. It is well documented in the literature that a
more protic medium such as methanol favors the desilylation of OH
2
0
2
2
0
0
90
90
2
5
groups. Among the solvents utilized, methanol was found to be
the optimal solvent for efficient desilylation.
3
3
0
0
82
85
Table 2. Effect of different solvents on the desilylation of alcoholic
TBDMS ether 3a.
Solvents
Reaction time (h)
Yield (%)
nil
Water
12.0
0.5
Methanol
97.0
11.0
77.0
4.0
Ethanol
12.0
24.0
12.0
24.0
12.0
12.0
12.0
12.0
Ethanol
Isopropanol
Isopropanol
Dichloromethane
Tetrahydrofuran
Dioxane
2
5
85
30
nil
nil
nil
Dimethylformamide
nil
3
2
0
0
88
92
A plausible mechanism for the deprotection of TBDMS ethers by
HS-cellulose sulphate initially involves silyl ether protonation by
abstraction of hydronium ion from the HS-cellulose sulfate catalyst,
followed by cleavage of the silyl oxygen bond by methanol, to
afford the deprotected alcohol, as illustrated in Figure 1.
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Examples of the chemoselective desilylation of alcoholic TBDMS
ethers in the presence of phenolic TBDMS ethers (5a-5f) utilizing
HS-cellulose sulphate as the acid catalyst are presented in Table 3.
Table 3. Chemoselective deprotection of alcoholic TBDMS ethers
a
over phenolic TBDMS ethers with HS-cellulose sulphate as acid
catalyst.
b
c
Substrate
Product
Time
min)
Yield
d
(%)
(
6
0
93
92
Fig 1. Plausible mechanism for the deprotection of TBDMS ethers by
HS-cellulose sulphate
As part of this study, we investigated the selectivity of HS-cellulose
sulphate as a suitable reagent for the selective deprotection of
alcoholic TBDMS ethers in the presence of phenolic TBDMS ethers
3
0
(
5a-5f) (Scheme 3). Interestingly, HS-cellulose sulphate efficiently
deprotected alcoholic TBDMS ethers without effecting phenolic
TBDMS ethers, in a subset of compounds that incorporated both
alcoholic and phenolic TBDMS ether moieties, demonstrating the
chemoselective nature of this catalyst.
90
80
82
The above chemoselective TBDMS ether deprotection mechanism
likely results from the alkyl TBDMS ether moiety being more
favorable than the aryl TBDMS ether moiety to protonation by the
HS-cellulose sulfate catalyst, facilitating selective deprotection of
alkyl TBDMS ethers over aryl TBDMS ethers. Considering that both
alcoholic and phenolic hydroxyl groups exist in the structures of
many complex natural products, the differential deprotection of
alcoholic and phenolic silyl ethers is of considerable interest.
OH
9
0
H3CO
OCH3
OTBDMS
6d
OTBDMS
OTBDMS
5
0
90
88
Several literature methods and reagents are also available for the
selective deprotection of alcoholic silyl ethers in the presence of
5
3
54
18
phenolic silyl ether moieties, i.e. Selectfluor, TMSCl, HF and
5
5
56
TMSBr , dicationic ionic liquid. However, most of these reagents
are hazardous, toxic and require special care in their use. We
believe that the use of HS-cellulose sulphate in place of the above
reagents constitutes a superior, simple, rapid, inexpensive and
more environmentally friendly method for the chemoselective
desilylation of alcoholic TBDMS ethers in the presence of phenolic
TBDMS ethers.
5e
30
a
b
5
% w/w of HS-cellulose sulphate acid catalyst was used; 100 mg of TBDMS
c
ether in 1 ml methanol, TLC monitoring time (ethyl acetate/n-hexane 1:10),
d
isolated yields.
To assess the selective deprotection of TBDMS ethers utilizing
+
standard H sources such as TFA, HCl or H2SO4 (0.1 eq),
Scheme 3 Chemoselective desilylation of alcoholic TBDMS ethers in
the presence of phenolic TBDMS ethers (5a-5f) utilizing HS-cellulose
sulphate catalyst.
deprotection of compound 5a in methanol (10 vol) at room
temperature for 20 minutes was also carried out. In every case,
desilylation resulted in deprotection of both the phenolic and
alcoholic TBDMS groups in 5a.
4
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To evaluate the reusable efficiency of HS-cellulose sulphate as a 1.
desilylating agent we recovered the catalyst from the reaction mass
P. G. M. Wuts, Greene's Protective Groups in Organic
Synthesis, 5th edn., 2014.
P. J. Kocienski, Protecting Groups, Thieme, 2005.
K. Jarowicki and P. Kocienski, J. Chem. Soc., Perkin Trans.
2
3
.
.
after the synthesis of compound 6a. The synthesis of compound 6a
from 5a was repeated thrice by recovering HS-cellulose sulphate
each time, and we observed that the catalyst could be
quantitatively recovered and reused in these three successive
TBDMS deprotection reactions without considerable loss of
catalytic activity, and with minimal change in the yield of product
1
, 2001, DOI: 10.1039/B103282H, 2109-2135.
4
5
.
.
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6
.
(99.0%, 97.5% and 96.5%). We also determined that the chemical
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1
13
HS-cellulose sulphate and comparing the spectra with that of the
9
1
1
.
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34, 19234-19239.
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1.
1
Conclusions
1
In conclusion, HS-cellulose sulphate prepared from commercially
available α-cellulose, is an efficient, thermally stable and
recoverable acid catalyst that can be used for the deprotection of
alcoholic TBDMS ethers in methanol at 25°C. Selective desilylation
of TBDMS ethers of alcohols in the presence of TBDMS phenolic
1
1
2.
3.
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4.
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ethers can also be achieved. This protocol is the first report of the 15.
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considerable loss of catalytic activity and without any significant
1
7.
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above features, we believe that this catalyst could be an excellent
choice for selective alcohol group deprotection in both lab-scale
and manufacturing scale chemistries.
3
04-309.
1
1
2
2
2
8.
9.
0.
1.
2.
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To a solution of TBDMS ether (1 mmol) in methanol (5 mL) was
added HS-cellulose sulphate (2; 5% w/w). The heterogenous
reaction mixture was stirred at 25°C for 0.5 to 1.5 hrs. Progress of
the deprotection reaction was monitored by TLC. After completion
of the reaction the catalyst was separated by filtration and the
filtrate was concentrated under reduced pressure to remove
4
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2
3.
4.
methanol to afford the corresponding deprotected crude alcohol. 25.
The crude product was purified by silica gel column
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Conflicts of interest
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Notes and references
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB01438H
Table of Contents
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. Manuscript
. Cover letter
. Supporting information
. Graphical Abstract

Organic & Biomolecular Chemistry
Page 8 of 8
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DOI: 10.1039/C8OB01438H
Graphical Abstract
Highly sulphated cellulose: A versatile, reusable and selective desilylating agent for
deprotection of alcoholic TBDMS ethers
Soma Shekar Dachavaram, Narsimha R. Penthala, Julie L. Calahan, Eric J. Munson,
Peter A. Crooks
A mild, efficient and rapid protocol was developed for the deprotection of alcoholic TBDMS ethers using a
recyclable, eco-friendly highly sulphated HS-cellulose sulphate acid catalyst in methanol. This acid catalyst
selectively cleaves alcoholic TBDMS ethers in bis-TBDMS ethers containing both alcoholic and phenolic
TBDMS ether moieties.