Ethynyldiisopropylsilyl: A new alkynylsilane protecting group and click linker

Article abstract of DOI:10.1021/ol100968t

(Figure presented) A new silyl-based reagent has been developed for catch and release immobilization, combining click chemistry with silyl protection. The traditional all carbon attachment to solid supports in a silyl type linker was substituted with a stable triazole, easily assembled using the CuAAC reaction. The methodology introduces a novel ethynyldiiospropylchlorosilane reagent (EDIPS-Cl) as a functionalized protecting group linker.

Full text of DOI:10.1021/ol100968t

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2860-2863
Ethynyldiisopropylsilyl: A New
Alkynylsilane Protecting Group and
“Click” Linker
Pallavi Sharma and John E. Moses*
School of Chemistry, UniVersity of Nottingham, Nottingham, NG7 2RD
john.moses@nottingham.ac.uk
Received April 28, 2010
ABSTRACT
A new silyl-based reagent has been developed for “catch and release” immobilization, combining click chemistry with silyl protection. The
traditional “all carbon” attachment to solid supports in a silyl type linker was substituted with a stable triazole, easily assembled using the
CuAAC reaction. The methodology introduces a novel ethynyldiiospropylchlorosilane reagent (EDIPS-Cl) as a functionalized protecting group
linker.
Solid phase synthesis (SPS) has proven to be a powerful
tool in organic chemistry. This revolutionary technology has
enabled significant achievements in the fields of total
synthesis,1 split-pool synthesis,2 high-throughput screening,3
combinatorial chemistry,4 diversity oriented synthesis,5 and
more recently supported reagents for flow chemistry.6
driving the demand for the development of new and
innovative linkers.7 The ideal linker should be robust and
able to withstand a wide variety of reaction conditions, yet
should be readily cleaved under mild, chemoselective condi-
tions that do not degrade the products.7 For example, silyl
linkers, which are commonly used to attach alcohol-contain-
ing substrates, have proven highly valuable owing to their
inertness to a wide range of synthetic transformations, yet
are easily removed under selective conditions.
One of the key challenges in SPS involves immobilizing
the substrates (or reagents) onto the solid support, thus
The so-called “all carbon backbone silyl linkers”,8 such
as diisopropyl 1,9 n-alkyldiisopropyl linker 2,10 and the
recently introduced TBDAS-type silyl linker 38 (Figure 1)
are common. In such examples, the silane is generally first
attached to the resin followed by loading of the substrate.
Reactions such as lithiation of polystyrene followed by
trapping of the aryllithium intermediates with dialkyldichlo-
(1) (a) Hirose, T.; Sunazuka, T.; Sugawara, T.; Noguchi, Y.; Tanaka,
T.; Iguchi, K.; Yamamoto, Y.; Gouda, H.; Shiomi, K.; Omura, S. J. Antibiot.
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H. Chem. Commun. 2009, 1493–1495. (c) Nicolaou, K. C.; Pastor, J.;
Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998, 120, 5132–5133.
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M.; Dibo, G. Int. J. Pept. Protein Res. 1991, 37, 487–493. (c) Lam, K. S.;
Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W. M.; Knapp,
R. J. Nature 1991, 354, 82–84.
(3) Luo, J.; Zhang, H.; Xiao, W.; Kumaresan, P. R.; Shi, C.; Pan, C.-
X.; Aina, O. H.; Lam, K. S. J. Comb. Chem. 2008, 10, 599–604.
(4) Seeberger, P. H.; Hasse, W.-C. Chem. ReV. 2000, 100, 4349–4393.
(5) (a) Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma,
U.; Arya, P. Chem. ReV. 2009, 109, 1999–2060. (b) Pelish, H. E.; Westwood,
N. J.; Feng, Y.; Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001,
123, 6740–6741. (c) Schreiber, S. L. Science 2000, 287, 1964–1969.
(6) (a) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D.
Angew. Chem., Int. Ed. 2009, 48, 4017–4021. (b) Lu, J.; Toy, P. H. Chem.
ReV. 2009, 109, 815–838. (c) Baxendale, I. R.; Ley, S. V.; Smith, C. D.;
Tranmer, G. K. Chem. Commun. 2006, 4835–4837.
(7) For detailed reviews see: (a) Wills, A. J.; Balasubramanian, S. Curr.
Opin. Chem. Biol. 2003, 7, 346–352. (b) Guillier, F.; Orain, D.; Bradley,
M. Chem. ReV. 2000, 100, 2091–2157.
(8) DiBlasi, C. M.; Macks, D. E.; Tan, D. S. Org. Lett. 2005, 7, 1777–
1780.
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Soc. 1995, 117, 5712–5719.
(10) Tallarico, J. A.; Depew, K. M.; Pelish, H. E.; Westwood, N. J.;
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Chem. 2001, 3, 312–318.
10.1021/ol100968t  2010 American Chemical Society
Published on Web 05/20/2010

Herein, we report a new catch and release click linker,
designed to facilitate mild loading and cleavage. We
envisioned that an azide-functionalized resin 5 and alkynyl-
silane-protected substrate 6 would be suitable partners for
this purpose (Scheme 1). The azido-functionalized resin could
readily be obtained from Merrifield resin upon treatment with
sodium azide,18 whereas the proposed ethynyldialkylchlo-
rosilane could in principle function as a silyl protecting
group, with the alkyne handle serving to immobilize the
substrate to the solid phase via CuAAC. The overall design
circumvents the need to introduce the alkyne functionality
just before loading. In addition, the characteristic IR azide
stretch (2100 cm-1) provides a convenient mode to monitor
the progress of resin loading.
Figure 1. Silyl ethers and triazole linkers.
rosilanes9,11,12 and hydrosilylation of resin bound olefins13
followed by the activation of the silyl hydride with triflic
acid,14 trichloroisocyanuric acid,10 or 1,3-dichloro-5,5-dim-
ethylhydantoin13 are widely employed. The target resin-
bound silyl ethers are then formed in situ by loading the
corresponding alcohol.8-10 The given cleavage conditions
depend upon the nature of the substituent but generally
involve fluoride sources or protic reagents.8,13
Scheme 1. “Click” Linker Design
Though a number of versatile silyl linkers are described
in the literature,7 our interest in click chemistry15 and in
particular the CuAAC reaction16 prompted us to design and
develop a complementary linker strategy. Our bifunctional
reagent would comprise a silyl core capable of reversibly
“tagging” a functional group, such as an alcohol and an
orthogonally reactive functional handle such as an alkyne,
ready for “capture” onto a solid phase.
Click chemistry has found previous application in SPS,
with the corresponding triazole “linker” functionality being
ideal due to its robust nature and inertness to a wide range
of conditions. Gmeiner et al. have reported a modified BAL
(Backbone Amide Linker),17 which involved reacting the
azido polystyrene with an appropriately laced alkyne sub-
strate. Cleavage of the amide group was achived by TFA
with loss of the aryl spacer group. The key to the success of
this methodology was the introduction of a suitable terminal
alkyne into the substrates for the 1,3-dipolar cycloaddition
(4, Figure 1).
Ethynyldiisopropylchlorosilane (EDIPS-Cl) (7) was chosen
as the first-generation alkynylchlorosilane for our investiga-
tion. Silyl chloride 7 was readily prepared by treating
commercially available chlorodiisopropylsilane 8 with ethy-
nylmagnesium bromide 9,19 affording 10, which upon
treatment with 1,3-dichloro-5,5-dimethylhydantoin (11) gave
target 7 (Scheme 2).13 The chlorination reaction was followed
using IR spectroscopy, which showed disappearance of the
distinctive Si-H stretch at 2100-2200 cm-1.
Scheme 2. Synthesis of 7
(11) For example, see: Farrall, M. J.; Frechet, J. M. J. J. Org. Chem.
1976, 41, 3877–3882
.
(12) (a) Schuster, M.; Blechert, S. Tetrahedron Lett. 1998, 39, 2295–
2298. (b) Schuster, M.; Lucas, N.; Blechert, S. Chem. Commun. 1997, 823–
824
.
(13) Hu, Y.; Porco, J. A.; Labadie, J. W.; Gooding, O. W. J. Org. Chem.
1998, 63, 4518–4521.
(14) (a) Hu, Y.; Porco, J. A. Tetrahedron Lett. 1999, 40, 3289–3292.
(b) Smith, E. M. Tetrahedron Lett. 1999, 40, 3285–3288.
Reagent 7 proved a good choice and could be reacted with
the hydroxyl group of several diverse substrates including
secondary, benzylic, and allylic alcohols, to give their
corresponding EDIPS protected silyl ethers 12-17, in good
to excellent yields (Scheme 3). Optimal conditions were
found with DCM as solvent, Et3N as base, and a catalytic
(15) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587–1590. (b) Barral,
K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811. (c)
Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.; Moore, M.; Neidle,
S.; Moses, J. E. J. Am. Chem. Soc. 2006, 128, 15972–15973.
(16) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornoe, C. W.;
Christensen, C.; Medal, M. J. Org. Chem. 2002, 67, 3057–3064. (c) Kolb,
H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004–2021. (d) Huisgen, R. Pure Appl. Chem. 1989, 61, 613–628. (e)
Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494–2507.
(17) Lo1ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5,
1753–1755.
(18) Arseniyadis, S.; Wagner, A.; Mioskowski, C. Tetrahedron Lett.
2002, 43, 9717–9719.
(19) Petit, M.; Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003,
5, 2037–2040.
Org. Lett., Vol. 12, No. 12, 2010
2861

quantity of DMAP. The successful formation of 7 was
pleasing since the functionalized silanes not only served to
protect the alcohol moiety but at the same time offered a
handle for “capturing”.
Table 1. Optimization of Solid Phase Silyl Cleavage
Scheme 3
.
Synthesis of Ethynyldiisopropylsilyl (EDIPS)
Protected Alcohols
entry
reagents (2 equiv)
temp (°C)
time
2 h
2 h
2 h
cleavagea
1
2
3
4
HF·pyridine
TBAF, THF
NH4F, THF
6:6:1 AcOH:THF:H2O
25
25
25
25
72%
16%
9%
2 days
44%
a Percent cleavage was determined by the weight of the isolated product
after passing through a plug of silica gel.
marized in Table 2. Gratifyingly, all entries showed good to
moderate loading and cleavage, thereby proving the general-
ity of the protocol.
Table 2. Loading and Cleavage of 12-17
entry
substrate
loadinga
cleavageb
a 2,6-lutidene was employed as a base.
1
2
3
4
5
6
12
13
14
15
16
17
70%
45%
76%
75%
65%
73%
72%
65%
85%
80%
60%
78%
The solid phase investigation began by loading silyl-
protected menthol 12 onto the azidomethyl polystyrene (5)
using the conditions of Gmeiner et al. (Cu(I), DIPEA in 1:1
THF:DMF).17 The reaction was followed by filtering the
resin and extensive washing with Py, MeOH, THF, and
DCM. The resin was dried under high vacuum to afford the
triazole linked substrate. The positive increase in the weight
of resin after the reaction indicated successful loading (70%).
Cleavage conditions were next investigated, screening with
both protic and fluoride sources (Table 1). HF·pyridine8 at
room temperature gave the best results. The liberated alcohols
were recovered after removal of excess cleavage reagent by
addition of methoxytrimethylsilane and evaporation of
residual solvent. Passing the residue through a plug of silica
gel afforded pure products which were identified by 1H NMR
spectroscopy. Though TBAF also led to substrate cleavage,
the yields were comparatively low. On the other hand, a 6:6:1
acetic acid:THF:H2O system13 effected smooth cleavage in
moderate yields, thereby providing an alternative to the
HF·pyridine system.
a Loading was estimated based on an increase in weight of the resin.
b Percent cleavage was determined by weight of the isolated compound
after passing through a plug of silica gel.
To demonstrate the inertness of the silyl “click” linker,
representative reactions on aldehyde 20 were performed on
the solid phase. As illustrated in Scheme 4, the resin bound
aldehyde 20 could be converted to the (E)-alkene 21 via
Wittig olefination or to the secondary alcohol 22 via methyl
Grignard addition, whereas oxime formation 23 was observed
on reaction with o-benzhydroxylamine. HF·Py-mediated
cleavage provided the liberated (E)-alkene 24 in 62%, the
alcohol 25 in 51%, and the oxime 26 in 48% overall yield,
respectively.
In conclusion, we have developed a new alkynylsilane
reagent (EDIPS-Cl) which functions as a hydroxyl protecting
group, equipped with an alkyne handle for a catch and release
strategy. We have shown that protected substrates can be
readily loaded onto a solid support via a triazole linkage using
To test the scope of the protocol, the variously substituted
aryl, alkyl, and vinyl alcohols (Scheme 3) were loaded onto
the resin and subsequently cleaved. The results are sum-
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Org. Lett., Vol. 12, No. 12, 2010

Scheme 4. Representative Reactions on 20 and Subsequent Cleavage
the CuAAC reaction and that the corresponding linker is
stable to a variety of reaction conditions and chemical
transformations. Monitoring of sample loading is made
simple by examination of the distinctive azide stretch (2100
cm-1) in the IR spectrum. Subsequent cleavage of the
corresponding substrates was readily achieved under mild
conditions. We believe the present linker-functionalized
protecting group will find wide application in SPS, drug
discovery, affinity chromatography, and related areas, and
we are currently exploring the scope of this methodology.
Acknowledgment. P.S. and J.E.M. would like to thank
EPSRC and The University of Nottingham for financial
spport.
Supporting Information Available: Experimental pro-
cedures and analytical data for 7, 10, and 12-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100968T
Org. Lett., Vol. 12, No. 12, 2010
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