Carbohydrates as multifunctional chiral scaffolds in combinatorial synthesis

Full text of DOI:10.1002/(SICI)1521-3773(19981002)37:18<2503::AID-ANIE2503>3.0.CO;2-R

COMMUNICATIONS
unaffected under the basic conditions of an ether synthesis.
The spectrum of protecting groups, thus limited, is further
reduced because benzyl ether protecting and other protecting
groups cleavable under heterogeneous conditions are not
applicable to solid-phase syntheses. Last but not least, an
anchoring group to the solid phase must be found which
remains stable during all protecting group and side-chain-
introducing manipulations, however, it must also allow the
detachment of the undestroyed target compound 2 from the
solid phase (Scheme 1).
Carbohydrates as Multifunctional Chiral
Scaffolds in Combinatorial Synthesis
Tobias Wunberg, Christopher Kallus, Till Opatz,
Stefan Henke, Wolfgang Schmidt, and Horst Kunz*
Dedicated to Professor Wolfgang Steglich
on the occasion of his 65th birthday
Combinatorial chemistry has incisively changed the search
for new biologically active substances in medicinal chemis-
try.[1] Owing to its roots in solid-phase peptide synthesis,[2]
combinatorial reaction sequences were first carried out on
solid phase to generate substance libraries (mixtures). Soon,
these procedures were supplemented by one-pot reactions on
nonprotected polyfunctional molecules[3] and by multicom-
ponent reactions in solution[4] as well as on solid phase,[1f]
likewise yielding mixtures of compounds. The parallel syn-
thesis of numerous single compounds is considered most
desirable nowadays and can be accomplished by sequential
couplings of building blocks to solid-phase-linked substrates,
if suitable combinations of protecting and anchoring groups
are applied.[1] Alternatively, multiply functionalized scaffolds
bound to solid phase are successively and regioselectively
coupled with side chains, a procedure which also requires a
tailor-made protecting and anchoring group technique.[5]
Besides peptides and amino acid derivatives,[1] functional-
ized aryl[6] and deoxycholic acid derivatives[7] have been
applied in this sense. In comparison to these scaffolds and to
the recently described squaric acid templates,[8] carbohydrates
constitute templates which not only offer more utilizable
functional groups but also numerous, alternative-
O
O
O
O
OSG1
A
OSG2
O
SG5O
SG4O
1.-4.: a–c
5.: d
P
O
O
OSG3
1
2
Scheme 1. Strategy of combinatorial synthesis with carbohydrate scaf-
folds: SG ˆ protecting group, A ˆ anchor, P ˆ polymer (carrier);
a) selective deprotection; b) functionalization; c) washing; d) cleavage of
the anchor.
For d-glucopyranose as an example of a carbohydrate
template, we have converted the 1,2,4,6-tetra-O-acetyl-3-O-
allyl-b-d-glucopyranose[10] 3 with succinic acid methyl ester-
monocysteamide 4 into the thioglucoside 5 (Scheme 2).
Â
Zemplen transesterification resulted in the selective deacety-
lation in the 4- and 6-position, whereas the 2-O-acetyl group
in 6 remained unaffected because of the neighboring equa-
O
ly addressable eligible stereogenic centers. On
the basis of a glucose derivative protected as the
benyzl ether in 2-, 3-, and 4-position, Hirschmann
et al. reported the synthesis of a biologically
efficient mimetic of somatostatin.[9]
HS
OMe
OAc
OAc
N
O
H
O
O
O
S
OMe
AcO
AllO
AcO
AllO
4
N
OAc
H
OAc
OAc
O
a
5
3
In order to apply carbohydrates as scaffolds in
solid-phase combinatorial synthesis, a strategy
based on orthogonally stable protecting groups
must be developed which allows the selective
deprotection at each hydroxylic group. More-
over, all other protecting groups must remain
unaffected during the subsequent introduction of
the potentially pharmacophoric side chains. Be-
cause side chains already linked to the scaffold
must also be stable during these condensations,
b
OTBDPS
O
O
OH
O
c
S
O
RO
AllO
S
N
HO
AllO
N
OAc
OAc
O
O
7, R = H
6
d
8, R = EE
the coupling of the side chain through an ether-
Scheme 2. Synthesis of carbohydrate scaffolds 8 equipped with orthogonally stable
protecting groups: a) BF3 ´ OEt2, CH2Cl2, 85%; b) NaOMe/MeOH, 90%; c) TBDPS-Cl,
DMAP,[12] CH2Cl2, 90%; d) EtOCH CH2, pyridinium-p-toluenesulfonate, CH2Cl2, 98%.
TBDPS ˆ tert-butyldiphenylsilyl; DMAP ˆ 4-dimethylaminopyridine.
type linkage constitutes the most general solu-
tion. As a consequence, all protecting groups in 1
except for the one to be removed first must be
ˆ
[*] Prof. Dr. H. Kunz, Dr. T. Wunberg, Dipl.-Chem. C. Kallus,
Dipl.-Chem. T. Opatz
torial substituents.[11] Reaction with tert-butyldiphenylsilyl
chloride (TBDPS-Cl) gave the 6-O-silyl ether 7, which was
treated with ethyl vinyl ether to form the 1-ethoxyethyl (EE)
ether group of the completely selectively deprotectable
building block 8.
Institut für Organische Chemie der Universität
J.-J.-Becher-Weg 18 ± 20, D-55099 Mainz (Germany)
Fax: (‡49)6131-39-4786
E-mail: hokunz@goofy.zdv.uni-mainz.de
Dr. S. Henke, Dr. W. Schmidt
Hoechst-Marion Roussel, Zentrale Pharmaforschung
Frankfurt am Main (Germany)
In this concept, the thioglycoside anchor functionalized in
the side chain is considered crucial. It must be stable during all
Angew. Chem. Int. Ed. 1998, 37, No. 18
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3718-2503 $ 17.50+.50/0
2503

COMMUNICATIONS
protecting group manipulations and alkylation reactions.[13] In
order to prove these prerequisites, the imide 8 was opened
and the product condensed with benzylamine.[14] Subsequent
treatment with hydrazine hydrate yielded model compound 9
(Scheme 3).
OTBDPS
O
O
a, b
c–e
EEO
S
7
O
N
OAc
O
12
OTBDPS
O
R''
O
EEO
S
N
OR2
O
O
N
O
R''
R'
OAc
a–c
EEO
AllO
O
S
N
8
N
13
OR1
R'
O
1. A
2. B
R1-X = CH3-I, PhCH2-Br, CH3CH2CH2-I,
CH3(CH2)6-I, o-CNC6H4CH2-Br
9, R1= H; R2 = TBDPS; R' = R'' = H 46 %
10, R1= Me; R2 = TBDPS; R', R'' = H, Me
d
e
R2-X = CH3-I, PhCH2-Br, (CH3)2CH-Br,
CH3(CH2)6-I, cyclo-C6H11CH2-Br,
o-CNC6H4CH2-Br
11, R1= Me; R2 = Bn; R', R'' = H, Me, Bn
OR2
O
O
R''
Scheme 3. a) LiOH, THF, H2O; b) Bn-NH2, DCC, N-hydroxysuccinimide;
c) hydrazine hydrate, DMF; d) 1. KOtBu, DMF; 2. CH3I; 63%; e) 1. TBAF,
THF, 80%; 2. KOtBu, DMF; 3. BnBr, TBAI, 57%. Bn ˆ benzyl; DCC ˆ
dicyclohexylcarbodiimide.
EEO
S
N
O
N
OR1
R'
O
14
f, g
OR2
Deprotonation of potassium tert-butylate (3 equiv) in
dimethylformamide and reaction with methyl iodide (4 equiv)
furnished the 2-O-methyl compound 10 without affecting the
thioglycoside structure. In this reaction partial N-methylation
of the amide grouping occurred. This effect as well as loss
during purification are not relevant to the combinatorial
synthesis on solid phase. The removal of the TBDPS group by
using tetrabutylammonium fluoride (TBAF) and the subse-
quent formation of the 6-O-benzyl ether 11 were achieved
again without affecting the thioglycoside. After these test
reactions, the carbohydrate scaffold 8 was used for combina-
torial multistep reactions. Because preliminary experiments
had shown that the cleavage of allyl ethers on solid phase in
contrast to the corresponding reactions in solution by treat-
ment with [(PPh3)3RhCl],[15] PdCl2,[16] or the zirconocene
reagent[17] were accompanied by side reactions, for example
hydrogenation, the allyl ether 7 was converted into the propyl
ether using diimine[18] prior to the introduction of the 1-
ethoxyethyl group to give 12 (Scheme 4). The imide group was
opened and coupled to aminomethyl polystyrene (AMPS,
O
HO
O
OR
OR1
15, R = Me, Et, iPr, Bn
ˆ
ˆ
Scheme 4. a) KOOCN NCOOK, AcOH, MeCN; b) EtOCH CH2,
TsOH; c) LiOH, THF/H2O; d) N,N'-diisopropylcarbodiimide/N-hydroxy-
succinimide/AMPS, CH2Cl2; e) hydrazine hydrate, DMF; A: 1. KOtBu,
DMF; 2. R1-X; B: 1. TBAF, THF; 2. KOtBu, DMF, 3. R2-X; f) 1.
pyridinium-p-toluenesulfonate; 2. Br2, CH2Cl2, 2,6-di-tert-butylpyridine; g)
R-OH, cyclohexene, Et4NBr. AMPS ˆ aminomethylpolystyrene; Ts ˆ p-
toluenesulfonyl.
ucts were isolated after filtration, elution from a short column
of silica, and evaporation of the volatile components in high
vacuum. They are obtained as mixtures of anomers (a:b ꢀ
5:1) and are identified by analytical HPLC and FAB mass
spectrometry. The anomeric configuration was determined for
compounds 15 (R ˆ R1 ˆ Me, R2 ˆ Bn), 16a, and 17a from 1H
NMR spectra (400 MHz). As a rule, the purity of the mixtures
of anomers according to RP-HPLC ranges from 75 to 95%;
the remainder of di-tert-butyl-pyridine formed the major
component of the impurities. Out of an array of 28 compounds
15 (Scheme 4), 25 mixtures of anomers 15 have been obtained
after five reactions on solid phase and the subsequent
glycosylation reaction in overall yields of 30 to 80%.
The diversity of the single compound libraries is expanded
by involving the 4-position. The EE-protecting group was
removed by a transacetalization reaction (Scheme 5). The
fourth variable substituent can be introduced into these
compound libraries not only by alkylations to give compounds
of type 16, but also by reactions with isocyanates to form 17.
The developed strategy thus provides the generation of
libraries of large diversity already on the basis of the four
functional groups used so far. By means of carbamate
formations, branched and heterocyclic substituents can be
introduced, in particular, if not only commercially available
reagents are applied. The inclusion of the fifth function and
1
1.3 mmolg ) to yield the solid-phase anchored carbohydrate
scaffold 13 (0.6 mmol carbohydrate per gram resin).[19] In
parallel syntheses, deprotonations were carried out using
KOtBu (10 equiv) while shaking at room temperature, and
alkylations were performed by using alkyl halide (30 equiv) in
dimethylformamide at room temperature within 2 h. The
TBDPS group was removed by using TBAF (10 equiv) in
tetrahydrofuran at room temperature within 16 h. After every
reaction, the resin was washed several times with dimethyl-
formamide, toluene, and the solvent of the subsequent
conversion (Scheme 4).
After combinatorial substitution at the 2- and 6-position,
the thioglycoside anchor was cleaved by using a 1m solution of
bromine in dichloromethane (3 equiv) under addition of 2,6-
di-tert-butyl-pyridine (7.5 equiv). To this mixture, a 25%
solution of the alcohol to be glycosylated (20 equiv) in
dichloromethane containing tetraethylammonium bromide
(1 equiv) and cyclohexene (6 equiv) were added. The prod-
2504
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3718-2504 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 18

COMMUNICATIONS
[18] S. Hünig, H. R. Müller, W. Thier, Angew. Chem. 1965, 77, 368; Angew.
Chem. Int. Ed. Engl. 1965, 4, 271.
14
a–c
a, d, c
O
[19] The loading was determined by elemental analysis (sulfur) and
gravimetrically.
OR2
O
OR2
O
R3O
R4NH
O
[20] For
a thioglycoside anchor in oligosaccharide synthesis and an
O
O
OR
OR
OR1
OR1
alternative cleavage: J. Rademann, R. R. Schmidt, Tetrahedron Lett.
1996, 37, 3989.
16a, R1 = R3 = Bn; R2 = R = Me
17a, R1 = R2 = Bn; R4 = 2-CF3C6H4; R = Me
17b, R1 = R2 = Bn; R4 = 4-CNC6H4; R = Me
16b, R1 = Bn; R2 = Me,
R3 = CH2COOtBu, R = Me
Scheme 5. a) MeOH, dioxane, pyridinium-p-toluenesulfonate; b) KOtBu,
DMF, R3-X; c) Br2, CH2Cl2, 2,6-di-tert-butylpyridine, ROH, Et4NBr,
CH2Cl2, cyclohexene; d) R4-NCO, DMAP, dioxane.
Evidence for Selective Association of
‡
Tetrahedral BO4 Units with Na and of Trigonal
translation of the combinatorial synthesis to stereoisomers of
the glucose scaffold (galactose, mannose) are presently under
investigation.
‡
BO3 Units with H in Dehydrated Zeolite
B-ZSM-5 from Solid-State NMR Spectroscopy**
Received: March 23, 1998
Supplemented version: June 22, 1998 [Z11622IE]
German version: Angew. Chem. 1998, 110, 2620 ± 2622
Christian Fild, Hellmut Eckert, and Hubert Koller*
The study of local structure and bonding in zeolites is of
fundamental interest for a better mechanistic understanding
of their catalytic function. One of the unresolved questions
regards the stabilization of boron in different coordination
states in the zeolite framework. Typically, only boron centers
tetrahedrally coordinated by O atoms (B[4]) are present in
hydrothermally synthesized zeolites, some of which are
transformed into trigonally coordinated centers (B[3]) when
the organic structure directing agent is removed by calcina-
tion.[1±4] The negative charge of the BO4=2 groups in as-
synthesized zeolites is balanced by sodium and quaternary
ammonium cations, while the counterions in the calcined
Keywords: carbohydrates ´ combinatorial chemistry ´ pro-
tecting groups ´ solid-phase synthesis ´ thioglycosides
[1] Reviews: a) L. A. Thomson, J. A. Ellman, Chem. Rev. 1996, 96, 555;
b) J. S. Früchtel, G. Jung, Angew. Chem. 1996, 108, 19; Angew. Chem.
Int. Ed. Engl. 1996, 35, 17; c) F. Balkenhohl, C. von dem Bussche-
Hünnefeld, A. Lansky, C. Zechel, Angew. Chem. 1996, 108, 2436;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2288; d) A. Netzi, J. M. Ostresh,
R. A. Houghten, Chem. Rev. 1997, 97, 449.
[2] a) ªHighlight of Modern Biochemistryº: A. Furka, F. Sebesteyn, M.
Asgedom, G. Dibo, Proc. 14th Int. Congress Biochem., Utrecht
(Netherlands), 1988, 5, 47; b) H. M. Geysen, R. H. Meloen, S. J.
Barteling, Proc. Natl. Acad. Sci. USA 1984, 81, 3998; c) R. A.
Houghten, Proc. Natl. Acad. Sci. USA 1985, 82, 5131.
[3] a) T. Carell, E. A. Winter, A. Bashir-Hashemi, J. Rebek, Jr., Angew.
Chem. 1994, 106, 2159; Angew. Chem. Int. Ed. Engl. 1994, 33, 2161;
b) H. An, L. L. Cummins, R. H. Griffey, R. Bharadwaj, B. D. Haly,
A. S. Fraser, L. Wilson-Lingardo, L. M. Risen, J. R. Wyatt, P. D. Cook,
J. Am. Chem. Soc. 1997, 119, 3696.
‡
‡
zeolite are Na and H . Quantum-chemical calculations
suggest that the bond between boron and protonated frame-
work oxygen atoms is much weaker than the Al ± O bond in
Al-O(H)-Si groups; hence, the existence of three-coordinate
boron centers in calcined zeolites is plausible.[5]
Here we show that in calcined B-ZSM-5 the B[3] units
[4] M. Goebel, I. Ugi, Tetrahedron Lett. 1995, 36, 6043.
[5] Siehe z.B.: M. Patek, B. Drake, M. Lebl, Tetrahedron Lett. 1994, 35,
9169.
‡
‡
selectively associate with H , and the B[4] units with Na
counterions. The zeolites were prepared hydrothermally with
tetrapropylammonium (TPA) cations as structure-directing
agent. The content of sodium cations in the zeolites was varied
by changing the gel composition in the syntheses. The TPA
was subsequently removed from the zeolite channels by
calcination, and the samples were dehydrated in vacuum at
elevated temperature. The 11B MAS NMR spectra of the
calcined and dehydrated samples show that the B[4]/B[3] ratio
increases with increasing sodium content, and this suggests
that sodium cations are associated with B[4] units (MAS ˆ
magic angle spinning; rotation of the probe in a magnetic field).
More direct evidence for this association can be obtained
on the basis of the heteronuclear dipole interaction between
[6] See for example: J. Green, J. Org. Chem. 1995, 60, 4287.
[7] a) G. Wess, K. Bock, H. Kleine, M. Kurz, W. Guba, H. Hemmerle, E.
Lopez-Calle, K.-H. Baringhaus, H. Glombik, A. Ehnsen, W. Kramer,
Angew. Chem. 1996, 108, 2363; Angew. Chem. Int. Ed. Engl. 1996, 35,
2222; b) R. Boyce, G. Li, H. P. Nestler, T. Suenaga, W. C. Still, J. Am.
Chem. Soc. 1994, 116, 7955.
[8] P. A. Tempest, R. W. Armstrong, J. Am. Chem. Soc. 1997, 119, 7607.
[9] R. Hirschmann, K. C. Nicolaou, S. Pietramico, J. Salvino, E. M. Lealy,
W. C. Shakespeare, P. S. Spengler, P. Hamley, A. B. Smith, T. Reisine,
K. Raynor, C. Donaldson, W. Vale, L. Maechler, R. M. Freidinger,
C. D. Strader, J. Am. Chem. Soc. 1993, 115, 12550; siehe auch: K. C.
Nicolaou, J. I. Trujillo, K. Chibale, Tetrahedron 1997, 53, 8751.
[10] K. Takeo, T. Nakaji, K. Shinmitsu, Carbohydr. Res. 1984, 133, 275.
[11] Z. Szurmai, A. Liptak, G. Snatzke, Carbohydr. Res. 1990, 200, 201; M.
Kaltenbach, Dissertation, Universität Mainz, 1994.
[12] G. Höfle, W. Steglich, H. Vorbrüggen, Angew. Chem. 1978, 90, 602;
Angew. Chem. Int. Ed. Engl. 1978, 17, 569.
[*] Dr. H. Koller, C. Fild, Prof. H. Eckert
Institut für Physikalische Chemie der Universität
Schlossplatz 4/7, D-48149 Münster (Germany)
Fax: (‡49)251-83-29159
[13] This is a crucial point, because thioglycosides can be activated by
electrophiles, in particular, alkylating reagents: a) H. Lönn, Carbo-
hydr. Res. 1985, 139, 115; b) H. B. Meregata, V. R. Kulkarni, D. Ravi,
G. V. Sharma, B. V. Rao, G. B. Reddy, Tetrahedron 1992, 48, 545; c) K.
Toshima, K. Tatsuta, Chem. Rev. 1993, 93, 1503.
[14] F. Weygand, D. Hoffmann, E. Wünsch, Z. Naturforsch. B 1966, 21, 426.
[15] E. J. Corey, J. W. Suggs, J. Org. Chem. 1973, 38, 3224.
[16] T. Ogawa, S. Nakabayashi, T. Kitajima, Carbohydr. Res. 1983, 114, 225.
[17] Y. Hanzawa, H. Ito, T. Taguchi, Synlett 1995, 299.
E-mail: hkoller@uni-muenster.de
[**] We thank Arne Fischer for the ICP/AES analysis and Dr. Leo
van Wüllen for valuable discussions. Financial support by the Fonds
der Chemischen Industrie, the Bundesministerium für Bildung,
Wissenschaft, Forschung und Technologie, and the Deutsche For-
schungsgemeinschaft (KO 1817/1-1) is gratefully achkowledged.
Angew. Chem. Int. Ed. 1998, 37, No. 18
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3718-2505 $ 17.50+.50/0
2505