A new method for cleavage of silicon-carbon linkers on glass plate supports with applications to solid-phase syntheses on silica resins

Article abstract of DOI:10.1016/j.tetlet.2010.01.042

We describe herein a novel and facile method for the cleavage of a silicon-based linker on solid-phase supports such as glass plates or silica resin. The linker was efficiently cleaved by oxidation of the silicon-carbon bond (Tamao-Kumada oxidation) to re

Full text of DOI:10.1016/j.tetlet.2010.01.042

Tetrahedron Letters 51 (2010) 1497–1499
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Tetrahedron Letters
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A new method for cleavage of silicon–carbon linkers on glass plate
supports with applications to solid-phase syntheses on silica resins
Takeshi Terauchi a, Sachiko Machida a, Shiro Komba a,b,
*
a Biomolecular Engineering Laboratory, National Food Research Institute, 2-1-12, Kannondai, Tsukuba, Ibaraki 305-8642, Japan
b PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein a novel and facile method for the cleavage of a silicon-based linker on solid-phase
supports such as glass plates or silica resin. The linker was efficiently cleaved by oxidation of the sili-
con–carbon bond (Tamao–Kumada oxidation) to release the functionalized molecule.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 October 2009
Revised 5 January 2010
Accepted 12 January 2010
Available online 18 January 2010
Keywords:
Glass substrate
Solid-phase synthesis
Cleavage of linker
Tamao–Kumada oxidation reaction
Recently, numerous reports concerning the research and devel-
opment of solid-phase synthesis on glass substrates have
appeared. Molecules immobilized on solid-phase supports have in-
cluded DNA,1 antibodies,2 proteins,3 peptides,4 lectins,5 sugar
chains,6 and other small molecules.7 In particular, the construction
technique based on a build-up approach using photolithography is
widely used in industry. As methods for the detection of functional
groups in immobilized molecules, a quantitative test for Fmoc-
could be cleaved directly, the special structures required for
cleavage of the linker systems in previous solid-phase syntheses
would become unnecessary. In addition, this strategy would be
more useful in that it would enable simplified preparation of the
linker and prevent unanticipated cleavage of linker in any of the
build-up steps because, unlike in previous strategies, the func-
tional group to be cleaved is not introduced initially.
Previous reports on the cleavage of silicon-connected linkers on
polymer beads have dealt with cleaving silicon–oxygen bonds,11
producing alkanes (as aryl compounds), or halides by cleavage of
silicon–carbon bonds through electrophilic reactions at the silicon
atom with HF,12h TBAF,13 CsF,14 halogens,15 or strong acids such as
TFA.12 While molecules can be removed with acid if they are bound
as arylsilane structures, silicon–carbon bonds fixed in an SiO2
structure are assumed to be very stable towards strongly acidic
conditions. In fact, treating a modified glass plate with TFA did
not result in the release of a cleavage product. HF gave a complex
mixture, but did not result in an appreciable amount of the product
of linker cleavage in our studies.
On the basis of these findings, we attempted to develop a new
cleavage strategy using a Tamao–Kumada oxidation16 reaction
under almost neutral conditions.
Using previously reported procedures, we first prepared ami-
nated pore-glass (VYCOR porous glass 7930, CORNING) by treat-
ment with (3-aminopropyl)triethoxysilane (APTES)17 in ethanol,
and then introduced several carboxylic acid moieties by condensa-
tion reactions (Scheme 1).
loaded resin8 and
a
colorimetric test9 have been used in
polymer-supported solid-phase synthesis. Whether monitoring
reactions for further elaboration or obtaining the finally
constructed target product, solid-phase synthesis usually requires
the cleaving of reactants from the resin matrix. To this end, many
linkers and corresponding cleavage protocols have hitherto been
developed and reported.10
However, despite the expected increase in the need and
demand for build-up technology on glass substrates that will
accompany the requirement for progress in biochemical analysis
tools, to the best of our knowledge, no reports on the cleavage of
immobilized molecules from glass substrates and their structural
determination have been published to date. Hence, we initiated a
study on the development of the cleavages of linkers aimed at rec-
ognizing the structures of covalently-linked molecules on glass
plates. For this, we planned to examine a cleavage method that re-
lies on the reactivity of the silicon atoms in the glass. The rationale
for this was that if a silicon–carbon linkage on a glass substrate
Before attempting to cleave the linker from the modified glasses
2a–e by a Tamao–Kumada oxidation, we examined cleavage rates in
* Corresponding author. Tel./fax: +81 29 838 7298.
E-mail address: skomba@affrc.go.jp (S. Komba).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.042

1498
T. Terauchi et al. / Tetrahedron Letters 51 (2010) 1497–1499
R
O
NH2
NH
RCOOH
O
DIC
APTES
DMAP
HO
N
H
R
Vycor porous glass
Si
Si
CH2Cl2
3 h
EtOH
120 ºC / 1 h
3a-e
1
2a-e
R=
H
N
O
O Si
O
O
d
a
c
e
b
Scheme 1.
the absence of any oxidants as a preliminary control. Exposure of 2a
to bases including saturated aqueous NaHCO3, K2CO3, and 1 N NaOH,
in the presence or absence of an FÀ source such as KF, for 24 h re-
sulted in the formation of a small amount of a mixture of alcohol
3a and the corresponding trihydroxysilane. This suggested that the
presence of oxygen or reactive oxygen species in solution caused
partial oxidation, but in order to acquire the desired alcohol as effi-
ciently as possible, we continued with more thorough examinations
to optimize the reaction conditions with oxidants (Table 1).18
The use of a peroxycarboxylic acid (entries 5, 6) as an oxidant
accelerated the reaction, and the reaction rates were observed to
reach a plateau after 1 h. Acceleration of this reaction with increas-
ing basicity of additives was also observed (entry 8), but rates for
the cleavage of substrate 2e bearing an Fmoc group were found
to decrease (entry 23).19
in Figure 1. In the same manner, acid-labile 2c and fluorescent 2d
were also efficiently cleaved. Thus, although the application of alka-
li-labile or oxidation-susceptible substrates is considered to be lim-
ited to some extent, the typical conditions for carrying out the
Tamao–Kumada reaction in solution were found to be similarly
applicable to cleaving the linker on glass plates.
100
80
60
40
20
0
The cleavage also occurredin theabsence of fluoride ion (entry 9),
and even silyl ether 3b was released from 2b by selective cleavage of
the C–Si bond fixed in SiO2 (entry 17). After further investigation, we
found thatheating(entries12–14)acceleratedthereactionto a great
extent. The time course for oxidative cleavage of 2a at 60 °C is shown
0
2
4
6
8
10
12
Time (h)
Figure 1. Time course of oxidative cleavage of 2a at 60 °C.
Table 1
Results of oxidative cleavage of the silicon-based linkers on modified glasses 2a–e
Entry
Substrate
Oxidant
Fluoride
Additive
Solvent
Temperature
Time (h)
Overall yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2a
30% H2O2
30% H2O2
30% H2O2
30% H2O2
m-CPBA
KF
KF
KF
KF
KF
KF
KF
KF
—
KF
KF
KF
KF
KF
KF
—
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2HPO4
KHCO3
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
DMF
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
THF–MeOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60 °C
60 °C
60 °C
rt
2
4
12
24
1
12
24
24
24
24
24
2
6b
11b
28b
35b
10b
13b
18b
68b
32b
26b
46b
25b
51b
96a
40c
44c
71a
92a
73a
25d
45a
7d
m-CPBA
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
NaHCO3
—
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
KHCO3
4
12
12
12
12
12
12
2
22
2
22
2b
rt
—
60 °C
60 °C
60 °C
rt
rt
60 °C
rt
2c
2d
2e
KF
KF
KF
KF
KF
KF
18d
Isolated yields based on the loading determined by the Fmoc release UV assay.8
Yields were calculated from the ratio of analytical HPLC integration values based on the corresponding isolated yields of entries 14, 17, and 21, respectively.
a
b–d

T. Terauchi et al. / Tetrahedron Letters 51 (2010) 1497–1499
1499
PhCO2H
30% H2O2
NaHCO3
KF
DIC
O
O
DMAP
NH2
HO
N
H
N
H
Si
Si
THF-MeOH
CH2Cl2
3 h
4
5
3a
60 ºC / 12 h
84% over all yield
Scheme 2.
5. (a) Hsu, K.-L.; Pilobello, K. T.; Mahal, L. K. Nat. Chem. Biol. 2006, 2, 153–157; (b)
Lee, M.-r.; Park, S.; Shin, I. Bioorg. Med. Chem. Lett. 2006, 16, 5132–5135.
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7967–7968; (b) Hergenrother, P. J.; Depew, K. M.; Schreiber, S. L. J. Am. Chem.
Soc. 2000, 122, 7849–7850; (c) He, X. G.; Gerona-Navarro, G.; Jaffrey, S. R. J.
Pharmacol. Exp. Ther. 2005, 313, 1–7.
We next attempted to apply this method for solid-phase synthe-
sis in the case of silica resin (Scheme 2). Commercially available 3-
aminopropyl-functionalized silica gel 4 (Sigma–Aldrich, si-amine,
loading: 1.08 mmol/g) was treated with benzoic acid, as in the prep-
aration of 2a, to produce benzamide 5. Finally, the desired alcohol 3a
was obtained in 84% yield based on starting resin 4, along with resid-
ual 5, using the above oxidative cleavage conditions.
8. Gude, M.; Ryf, J.; White, P. D. Lett. Pept. Sci. 2002, 9,
203–206.
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Tetrahedron Lett. 2001, 42, 6691–6693; (f) Komba, S.; Sasaki, S.; Machida, S.
Tetrahedron Lett. 2007, 48, 2075–2078.
In conclusion, we have demonstrated that functionalized mole-
cules connected through silicon–carbon bonds to glass plates or
silica resin can be efficiently cleaved by a new method based on
a Tamao–Kumada oxidation reaction. The approach described here
does not require special structures to be incorporated into the lin-
ker to permit its cleavage, and the resulting terminal hydroxyl
group is stable, convertible, and manageable. Thus, this approach
should prove effective for applications in solid-phase syntheses.
10. For example, see: Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100, 2091–
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Ellman, J. A. J. Org. Chem. 1997, 62, 2885–2893; (f) Schuster, M.; Lucas, N.;
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14. See Ref. 12g.
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Acknowledgments
This work was supported by the Program for the Promotion of
Basic Research Activities in Innovative Bioscience (PROBRAIN)
and by the Precursory Research for Embryonic Science and Tech-
nology (PRESTO) program. We thank Dr. H. Ono and his staff for
NMR measurements, and Dr. M. Kameyama and her staff for ESI-
FT-MS measurements. In addition, we also thank K. Yuhara for
technical assistance.
16. Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2, 1694–
1696; Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599–7662.
17. Commercially available aminopropylated glass slides were found to have lower
loading levels than those required for our purpose, so we independently
fabricated them by the aminopropylation of unmodified porous glass slides.
Our protocol for this was based on the results of an examination of the
immobilization conditions with a selection of materials. For an example of a
similar aminoalkylation protocol, see Ref. 4a.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.042.
18. A typical procedure for the oxidative cleavage was as follows. The following
References and notes
were added to modified glass 2a (438 mg of a glass plate, 12.3
l
mol, amino-
l), saturated aqueous
l), and 30% aqueous H2O2
loading: 28.2
NaHCO3 (877
l
mol/g): THF (877
ll), MeOH (877 l
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1991, 251, 767–773; (b) Pease, A. C.; Solas, D.; Sullivan, E. J.; Cronin, M. T.;
Holmes, C. P.; Fodor, S. P. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5022–5026; (c)
Singh-Gasson, S.; Green, R. D.; Yue, Y.; Nelson, C.; Blattner, F.; Sussman, M. R.;
Cerrina, F. Nat. Biotechnol. 1999, 17, 974–978.
2. (a) Angenendt, P.; Glökler, J.; Murphy, D.; Lehrach, H.; Cahill, D. J. Anal. Biochem.
2002, 309, 253–260; (b) Angenendt, P.; Glökler, J.; Sobek, J.; Lehrach, H.; Cahill,
D. J. J. Chromatogr., A 2003, 1009, 97–104.
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Zhong, Z.; Feijen, J. Biomacromolecules 2007, 8, 1775–1789.
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346–353; (b) Panicker, R. C.; Huang, X.; Yao, S. Q. Comb. Chem. High Throughput
Screening 2004, 7, 547–556. see also Ref. 1a.
l
l), saturated aqueous KF (877
l
(877 ll). After warming at 60 °C for 12 h, the reaction mixture was allowed to
cool to room temperature and then diluted with water (10 ml). The resulting
mixture was extracted with EtOAc (2 Â 5 ml), and the combined organic
phases were concentrated and dried in vacuo to yield a slurry (2.46 mg). The
crude product was purified by reversed-phase HPLC to produce 3a (2.12 mg,
95.5% from 1) as a colorless oil.
19. In order to assess the stability of 3e to the oxidative conditions, we subjected it
to several oxidative or basic conditions, including those of entries 21 and 23 in
Table 1, in the liquid phase. Partial Fmoc cleavage was observed in most cases;
an increase in basicity or temperature-accelerated Fmoc cleavage, while the
presence of KF or H2O2 had hardly any influence.