Removal of benzyl protecting groups from solid-supported compounds by hydrogenolysis using palladium nanoparticles

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4545::AID-ANIE4545>3.0.CO;2-V

As mild and effective as the widely accepted solution-phase hydrogenolysis: Palladium nanoparticles can be used as catalysts to deprotect benzyl groups on carbohydrates attached to a solid support. The use of a UV-active linker to connect benzyl protected

Full text of DOI:10.1002/1521-3773(20001215)39:24<4545::AID-ANIE4545>3.0.CO;2-V

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problems of using such metal clusters is that the small
particles become unstable as they aggregate together. To
overcome this problem, polymers, especially poly<N-vinyl-2-
pyrrolidone) <PVP),[12] are often used to stabilize metal
nanoparticles through coordination to the metal cluster and
for protection against aggregation.[13] Recently, a fast reduc-
tion process was developed, in which a solution of H2PdCl4 in
ethanol in the presence of PVP was refluxed to produce
monodispersed Pd nanoparticles witha mean diameter
ranging from 17 to 21 Š and witha narrow distribution < s <
5 Š) [Eq. <1)].[10a]
Removal of Benzyl Protecting Groups from
Solid-Supported Compounds by
Hydrogenolysis Using Palladium
Nanoparticles**
Osamu Kanie,* Gijsbert Grotenbreg, and
Chi-Huey Wong*
One of the major problems currently encountered in solid-
phase synthesis, especially in the synthesis of oligosaccharides,
is the lack of a mild and effective debenzylation reaction on
solid supports. The benzyl protecting group has been widely
used in organic synthesis as a result of its stability and ease of
mild and selective deprotection by catalytic hydrogenolysis.[2]
Hydrogenolysis using particle catalysts, however, can not be
applied to solid-phase organic synthesis because of steric and
mass-transport problems.[3] Although palladium<ii) acetate
has been successfully used in the hydrogenolysis of benzyl
groups in peptide synthesis, the Pd<0) particles formed in situ
immediately precipitate in the Merrifield-type resin. In
addition, there are no alternative mild methods available for
the deprotection of the benzyl group under conditions
compatible withacid-sensitive acetal groups and also that
are applicable to the changes in the polarity of the substrate in
the final stage of the synthesis.[4, 5] Current efforts to address
this issue focus on replacing the benzyl group with substituted
H2PdCl4 ‡ EtOH À! Pd<0) ‡ CH3CHO ‡ 4HCl
<1)
We therefore decided to evaluate the Pd nanoparticles as
catalysts for the hydrogenolysis of benzyl ether groups on
solid supports.
Before attempting solid-phase hydrogenolysis, we tested a
reaction of 2,3,4,6-tetra-O-benzyl-d-glucopyranose[14] witha
colloidal Pd nanoparticle solution and, for comparison, with
10% Pd on charcoal. The colloidal Pd solution was prepared
according to the procedure reported previously.[10a, 15] The
solution was concentrated and redissolved in EtOH for
hydrogenolysis. The reaction with perbenzyl glucose using
0.1 atom equivalent of the nanoparticle solution proceeded
muchfaster <approximately 10 times faster) than the corre-
sponding reaction of Pd on charcoal, and was completed in 2 h
to give d-glucose. Having found that the Pd nanoparticles
could be used as hydrogenolysis catalysts, we turned our
attention to the solid-phase reaction.
benzyl ethers, which are removable by relatively mild
[6]
conditions, suchas acid
witha Lewis acid,
or oxidative[7] hydrolysis, reaction
[8]
a two-step reduction ± oxidation proc-
ess[9], or treatment withfluoride anions.
[7b]
However, these
new substituted benzyl ethers are unstable under certain
reaction conditions, which makes synthetic planning some-
times troublesome.
The benzyl-protected glycosides of glucose <1), fucose <4),
and lactose <7) attached to a solid support were chosen as
In our endeavor to find a suitably mild benzyl-deprotection
method applicable to solid-phase synthesis, we considered Pd
nanoparticles witha size equivalent to small organic mole-
cules <10 ± 40 Š diameter) as potential catalysts for the
hydrogenolysis reaction. Recent developments in Pd nano-
particles[10] have proven to be successful in making mono-
dispersed Pd nanoparticles witha controlled size that could be
used in the hydrogenation of olefins,[10c, 11, 12] although no
hydrogenolysis of benzyl groups was reported. One of the
OR2
O
OR1
OR2
H3C
O
R2O
R2O
OR1
OR2
OR2
R2O
4 : R1 = X1, R2 = Bn
5 : R1 = X2, R2 = Bn
6 : R1 = X2, R2 = H
1 : R1 = X1, R2 = Bn
2 : R1 = X2, R2 = Bn
3 : R1 = X2, R2 = H
OR2
OR2
R2O
R2O
O
O
R2O
OR1
OR2
O
OR2
[*] Dr. O. Kanie,[‡] Prof. C.-H. Wong,[‡‡] G. Grotenbreg
Frontier ResearchProgram
7 : R1 = X1, R2 = Bn
8 : R1 = X2, R2 = Bn
9 : R1 = X2, R2 = H
The Institute of Physical and Chemical Research <RIKEN)
2-1 Hirosawa, Wako-shi, Saitama 351-0198 <Japan)
E-mail: kokanee@libra.ls.m-kagaku.co.jp, wong@scripps.edu
O
OX1 =
O
‡
N
H
[ ] Current address:
Y
O
Glycoscience Laboratory
Mitsubishi Kasei Institute of Life Sciences
Minamiooya 11, Machida-shi, Tokyo 194-8511 <Japan)
Fax : <‡81)42-724-6317
O
Y = TentaGel or PEGA resin
O
OX2 =
O
N
H
‡‡
[
] Permanent address:
OH
Department of Chemistry
O
The Scripps Research Institute
10550 N. Torrey Pines Road, La Jolla, CA 92037 <USA)
Fax : <‡1)858-784-2409
representatives for the study. The syntheses of these materials
were conducted as follows. Perbenzyl thioglycosides of d-
glucose, l-fucose, and lactose[16±18] were coupled withteh
linker methyl 4-[<6-hydroxyhexyl)amino]carbonyl benzoate
[**] This work was presented in part at the XV International Symposium
on Glycoconjugates, August 22 ± 27, 1999, Tokyo, Japan.[1] This
research was supported in part by the Science and Technology Agency
of the Japanese Government.
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in a mixture of dichloromethane and diethyl ether in the
presence of N-iodosuccinimide <NIS) and a catalytic amount
of trifluoromethanesulfonic acid <TfOH)[19] at 08C. The linker
was designed to serve as a chromophore for the HPLC
analysis of the reaction after cleavage of the products from the
solid support. Anomeric mixtures <ca. 1:1) were used to test if
there was, for example, any difference in their reactivity or
accessibility to the catalyst particle. After saponification of
each methyl ester, the acids <2, 5, and 8) were converted into
the corresponding acid chloride using Vilsmeierꢁs reagent and
treated withthe OH group of a solid support <Y) to give 1, 4,
and 7, respectively. Two types of solid support, TentaGel and
PEGA resin, were used to investigate the effect of pore size.
When Pd nanoparticles were used for the reaction with
polystyrene beads it was observed that palladium particles
were slowly precipitated in the bead. This undesirable
precipitation was perhaps a consequence of the steric
stabilization of Pd nanoparticles followed by aggregation
inside the pore. This problem could, however, be overcome by
using an excess amount of PVP <100 monomer equivalents) to
further stabilize the nanoparticles.
In conclusion, we have shown that Pd nanoparticles can be
used in the hydrogenolysis of benzyl protecting groups on
carbohydrates attached to solid supports such as TentaGel
and PEGA resins. It was shown for the first time that
hydrogenolysis is possible on solid and in solution phase using
Pd nanoparticles, although there is still room for improve-
ment. As this method is as mild and effective as the widely
accepted solution-phase hydrogenolysis, it may have great
potential in solid-phase synthesis, especially when biological
assays are to be carried out withcompounds on a resin for
high-throughput screening. Work is in progress to optimize
the reactions and to prepare a carbohydrate library for
screening.
Received: May 2, 2000
Revised: August 28, 2000 [Z15059]
[1] See abstract: G. Grotenbreg, O. Kanie, C.-H. Wong, Glycoconjugate J.
1999, 16, S161-S162.
[2] a) M. Schelhaas, H. Waldmann, Angew. Chem. 1996, 108, 2192 ± 2219;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2056 ± 2083; b) T. Ziegler in
Carbohydrate Chemistry <Ed.: G.-J. Boons), Blackie Academic &
Professional, London, 1998, pp. 21 ± 45.
Thus, the hydrogenolysis of the benzyl protecting groups of
solid-supported compounds was examined at 408C and was
shown to be successful, in all cases, on the basis of HPLC
analysis[20] of the materials released from the support.
Precipitation of Pd nanoparticles was not observed in the
case of the reaction using TentaGel. The HPLC profile of the
glucose derivative showed that the peaks corresponding to the
partially debenzylated compounds <17 ± 30 min) appeared in
addition to the starting material 2 <37.8 and 41.1 min) and the
fully deprotected compound 3 <11.9 min) was formed gradu-
ally. Formation of the product was confirmed by co-injection
with the authentic sample in the HPLC and mass spectrom-
etry analyses after isolation of each compound. Although the
reaction was not complete after 60 h<85% yield), [21] peaks of
2 <a, b) were still present, it seems that no further con-
sumption of 2 would occur. Interestingly, very small amounts
of partially debenzylated intermediates remained at this stage,
probably because of the presence of sites in TentaGel that
were inaccessible to the Pd nanoparticles. In addition, it was
found from the HPLC profile that compound 3 exists as an
anomeric mixture with the same ratio as that of 2. Further-
more, the color, clarity, and catalytic activity of the Pd
nanoparticles remained unchanged.
Since the reaction could not be completed using the
Merrifield-type resin, the reactions using a PEGA resin were
next examined to see the effect of pore size. Absorption of
almost all Pd nanoparticles into the pores of the resin was
observed <from the color of the reaction mixture and the
resin); however, the hydrogenolysis proceeded smoothly and
reached completion within 36 h to give the glucoside 3 and
fucoside 6, respectively. In the case of lactoside 7, formation of
product 9 was confirmed, but the reaction was still incomplete
<yield ca. 95%). The possible reason for the observed
adsorption of Pd particles to the support is perhaps because
of the presence of amide functions on the solid support;
removal of the Pd nanoparticles from the product mixture of
solution-phase hydrogenolysis is a difficult problem and these
amide functions may be useful.
[3] J. M. Schlatter, R. H. Mazur, O. Goodmonson, Tetrahedron Lett. 1977,
33, 2851 ± 2852.
[4] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis,
2nd ed., Wiley, New York, 1991.
[5] An interesting approachwas reported for a solution-phase debenzy-
lation using a radical-mediated two-phase system which was shown to
be mild and selective; see: M. Adinolfi, G. Barone, L. Guariniello, A.
Iadonisi, Tetrahedron Lett. 1999, 40, 8439 ± 8441.
[6] L. Yan, D. Kahne, Synlett 1995, 523 ± 524.
[7] a) Y. Oikawa, Y. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982, 23,
885 ± 888; b) L. Jobron, O. Hindsgaul, J. Am. Chem. Soc. 1999, 121,
5835 ± 5836.
Â
[8] A. Bouzide, G. Sauve, Synlett 1997, 1153 ± 1154.
[9] a) K. Fukase, M. Hashida, S. Kusumoto, Tetrahedron Lett. 1991, 32,
3557 ± 3558; b) K. Fukase, T. Yoshimura, M. Hashida, S. Kusumoto,
Tetrahedron Lett. 1991, 32, 4019 ± 4022.
[10] a) T. Teranishi, M. Miyake, Chem. Mater. 1998, 10, 594 ± 600; b) H.
Hirai, N. Yakura, Y. Seta, S. Hodoshima, React. Funct. Polym. 1998, 37,
121 ± 131; c) For a review, see L. N. Lewis, Chem. Rev. 1993, 93, 2693 ±
2730.
[11] a) G. Schmid, Clusters and Colloids, VCH, Weinheim, 1994; b) Y.
Volokitin, J. Sinzig, L. J. de Jong, G. Schmid, M. N. Vargaftik, I. I.
Moiseev, Nature 1996, 384, 621 ± 623.
[12] H. Hirai, Y. Nakao, N. Toshima, J. Macromol. Sci. Chem. 1978, A12,
1117 ± 1141; N. Toshima, M. Harada, T. Yonezawa, K. Kushihashi, K.
Asakura, J. Phys. Chem. 1991, 92, 7448 ± 7453; A. Henglein, J. Phys.
Chem. 1993, 97, 5457 ± 5471; H. Thiele, H. S. von Levern, J. Colloid Sci.
1965, 20, 679 ± 694.
[13] H. Hirai, N. Toshima in Catalysis by Metal Complexes, Tailored Metal
Catalysts <Ed.: Y. Iwasawa), Reidel, Dordrecht, 1986.
[14] C. P. J. Glaudemans, H. G. Fletcher, Jr., Methods Carbohydr. Chem.
1972, 6, 373 ± 376.
[15] Preparation of Pd nanoparticles: A 0.6 mm solution of H2PdCl4
containing 40% ethanol and 100 monomeric molar equivalents of
PVP <average Mw ˆ 6000) was refluxed under N2 to obtain mono-
dispersed Pd nanoparticles <presumably witha mean diameter of
ca. 17 Š as reported in ref. [10b]).
[16] I. Nakagawa, T. Hata, Tetrahedron Lett. 1975, 1409 ± 1412.
[17] a) L. Yan, D. Kahne, J. Am. Chem. Soc. 1996, 118, 9239 ± 9248; b) R. T.
Ferrier, R. H. Furneaux in Methods in Carbohydrate Chemistry,
Vol. VIII <Eds.: J. N. Bemiller, R. L. Whistler), Academic Press, New
York, 1980, p. 251.
[18] A. K. Choudhury, N. Roy, Synth. Commun. 1996, 26, 3937 ± 3945.
[19] a) P. Konradsson, D. R. Mootoo, R. E. McDevitt, B. Fraser-Reid, J.
Chem. Soc. Chem. Commun. 1990, 270 ± 272; b) G. H. Veenemann,
4546
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S. H. van Leeuwen, J. H. van Boon, Tetrahedron Lett. 1990, 31, 1331 ±
1334.
dialkylsubstituted nTs <x ˆ 1, 2), and b-alkyl-substituted PTs,
where optimized carrier mobilities <0.1 ± 0.6 cm2 VÀ1 sÀ1) and
on/off ratios <>106) approach those of amorphous silico-
n.[1e, 2a,c,e, 3] Without exception, these systems behave as p-type
semiconductors, presumably because the electron-richness of
the thiophene renders negative carriers susceptible to trap-
ping by more electronegative residual impurities suchas
oxygen. On the other hand, developing and understanding
new n-type materials would enable applications,[4] suchas
bipolar transistors, p-n junction diodes, and complementary
circuits, as well as to afford a better fundamental under-
standing of charge transport in molecular solids. The major
barrier to progress, however, is that most n-type organics are
either environmentally sensitive, have relatively low field
mobilities, lack volatility for efficient film growth, and/or are
difficult to synthesize.[4, 5, 6]
[20] HPLC conditions: column: Millipore NovaPak C18, 4.6 Â 150 mm;
flow: 1.00 mLminÀ1; detection: 254 nm; RT; solvents A: 10% CH3CN
in H2O with0.1% TFA, B: 10% H 2O in CH3CN with0.1% TFA,
solvent gradient: 0 min <100% A), 5 min <50:50 A:B), 35 min <30:70
A:B), 45 ± 55 min <100% B). Retention time: 2 <37.8 and 41.1 min), 3
<11.9 min), 5 <30.5 and 31.8 min), 6 <16.2 min), 8 <56.3 and 58.1 min), 9
<7.6 min).
[21] The yield was estimated from the peak area of the HPLC chromato-
gram and the molar absorbance of the benzyl and terephthalate
groups.
We report here the facile, efficient synthesis of the first
n-type sexithiophene conductor, a,w-diperfluorohexylsexi-
thiophene <DFH-6T; 1), for TFTs. DFH-6T was synthesized
Tuning the Semiconducting Properties of
Sexithiophene by a,w-SubstitutionÐ
a,w-Diperfluorohexylsexithiophene:
The First n-Type Sexithiophene for Thin-Film
Transistors**
Antonio Facchetti, Yvonne Deng, Anchuan Wang,
Yoshihiro Koide, Henning Sirringhaus, Tobin J. Marks,*
and Richard H. Friend*
aa'-Conjugated thiophene oligomers <nTs) and polymers
<PTs) have attracted great interest as semiconducting ele-
ments in organic thin-film transistors <TFTs).[1, 2] To be useful
by a Pd0-catalyzed Stille coupling of 5-bromo-5'-perfluoro-
hexyl-dithiophene <6) with5,5 '-di<tributylstannyl)dithio-
phene <Scheme 1). This route affords DFH-6T <1) in high
purity and yield after multiple gradient sublimation. Although
monosubstituted perfluoroalkyl thiophene oligomers with up
to three units have been reported, synthetic yields were
typically about 10%.[7]
in suchstructures, teh organic material must support a
channel of holes or electrons <p- or n-type semiconductor,
respectively) created by the gate electrode bias, which
switches the device ªonº. Furthermore, the charge mobility
of the material must be sufficiently large to increase the
source ± drain on-conduction by many orders of magnitude
over the ªoffº state. The most important examples of this
family of compounds are unsubstituted, a,w-, and b,b'-
[*] Prof. T. J. Marks, Dr. A. Facchetti, Dr. A. Wang, Dr. Y. Koide
Department of Chemistry and the Materials Research Center
Northwestern University
2145 Sheridan Road, Evanston, IL, 60208-3113 <USA)
Fax : <‡1)847-491-2290
Scheme 1.
E-mail: tjmarks@casbah.acns.nwu.edu
Prof. R. H. Friend, Y. Deng, Dr. H. Sirringhaus
CavendishLaboratory, Department of Physics
University of Cambridge
The comparative thermal properties of DFH-6T <1) and
DH-6T <2) were investigated by differential scanning calo-
rimetry <DSC) and thermal gravimetric analysis <TGA). The
DSC trace of compound 1 exhibits a distinct crystal-to-liquid
crystal <LC) transition at 2928C and a LC-to-isotropic
transition at 3098C, while the crystal-to-LC transition of 2
<3008C) falls just below the melting point, 308 ± 3138C.[8]
These mesophase-formation events are not surprising in view
Madingley Road, Cambridge CB3 0HE <UK)
Fax : <‡44)1223-353297
E-mail: rhf10@cam.ac.uk
[**] We thank DARPA <N00421-98-1187) and the NSF-MRSEC program
through the Northwestern Materials Research Center <DMR-
9632472) for support of this research. H.S. thanks the Royal Society
for a University ResearchFellowship <URF).
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