Solid-phase synthesis of cyclic C-glycoside/amino acid hybrids by carbamate coupling chemistry and on-support cyclization

Article abstract of DOI:10.1002/ejoc.200500273

A solid-supported synthesis of cyclic C-glycoside/amino acid conjugates is described. For this purpose, N-(tert-butoxycarbonyl)-[6-O-(p- nitrophenoxycarbonyl)-2,3,4-tri-O-(p-toluoyl)-β-D-glycopyranosyl] methylamines derived from galactose and glucose were

Full text of DOI:10.1002/ejoc.200500273

FULL PAPER
Solid-Phase Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids by
Carbamate Coupling Chemistry and On-Support Cyclization
Johanna Katajisto*[a] and Harri Lönnberg[a]
Keywords: Solid-phase synthesis / C-glycosides / Amino acids / Cyclization
A solid-supported synthesis of cyclic C-glycoside/amino acid
conjugates is described. For this purpose, N-(tert-butoxycar-
mate immobilized through its γ-carboxy function to a SCAL
linker as a handle. On-support cyclization followed by cleav-
bonyl)-[6-O-(p-nitrophenoxycarbonyl)-2,3,4-tri-O-(p-toluoyl)- age from the support gave the desired conjugates. Removal
β-
D-glycopyranosyl]methylamines derived from galactose
of the p-toluoyl protections was carried out in solution phase
and glucose were prepared and used as activated monomers
together with appropriately protected amino acids. The solid
phase assembly of the linear precursor was conducted by
alternating peptide and carbamate coupling, using gluta-
by methoxide ion-catalyzed transesterification in methanol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
methylamine (2) 6-O-(p-nitrophenyl)carbonates (Figure 1)
have been prepared and used for solid-supported construc-
tion of cyclic tetrameric conjugates 20–22 consisting of
alternating sugar and amino acid constituents. Carbamate
and peptide couplings followed by PyBOP activated on-
support cyclization gave the desired conjugates in more
than 20% overall yield.
Introduction
Interactions of carbohydrates with proteins play a key
role in intercellular trafficking, receptor binding and signal-
ing.[1–6] To elucidate the underlying features of these inter-
actions, numerous carbohydrate-based mimics and molecu-
lar scaffolds, such as multiantennary glycoclusters,[7] glyco-
dendrimers,[8] glycopeptides,[9] cyclodextrin-based glycoclu-
sters and dendrimers,[10] and glycopolymers,[11] have been
synthesized. In most of these conjugates, nature-like syn-
thetic monomers are coupled to a polyfunctional scaffold.
In recent years, attention has increasingly been paid to
the synthesis of mixed conjugates that consist of structural
units of more than one type of biopolymers, usually sugars
and amino acids. Sugar amino acids,[12] in which the sugar
pyranose or furanose ring bears a carboxylate and an
amino function, have received particular interest. Such
monomers have been used to prepare linear and cyclic
homooligomers[12b,13] and sugar amino acid/amino acid
oligomers,[12b,14] which are expected to find applications as
conformationally constrained scaffolds and building blocks
in synthesis of multifunctional mimics of carbohydrates or
glycopeptides. These syntheses have been successfully ac-
complished both in solution and on solid-phase applying
traditional peptide chemistry. The cyclizations have usually
been performed in solution[13b–13c,13e,14b–14g] or achieved
upon release from the solid support.[14a]
Figure 1. The Glycosylmethylamine carbonates 1 and 2 used as
building blocks.
Results
Synthesis of the C-Glycoside Building Blocks 1 and 2: The
N-Boc-protected 2,3,4-tri-O-toluoyl-β-d-glycopyranosylme-
thylamine 6-O-(p-nitrophenyl) carbonates (1, 2) were syn-
thesized by combining several previously published meth-
ods, as outlined in Scheme 1. Commercially available per-
acetylated β-d-galactopyranose 3 was first converted to its
We now report on a novel protocol for preparation of
cyclic carbohydrate/amino acid hybrids on a solid support.
Fully protected β-d-galacto- (1) and β-d-glucopyranosyl-
1-deoxy-1-cyano analog
5
by trimethylsilyl cyanide
(TMSCN) treatment in nitromethane in the presence of bo-
ron trifluoride–diethyl ether (BF3·Et2O).[15] An analogous
reaction with peracetylated β-d-glucopyranose, however,
failed, as also reported previously in literature.[16] Only a
trace amount of the desired product was obtained and its
isolation was complicated by the formation of a cyanoethyl-
[a] Department of Chemistry, University of Turku,
20014 Turku, Finland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500273
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Solid-Phase Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids
FULL PAPER
Scheme 1. Conditions: (i) TMSCN, BF3·Et2O, MeNO2, 74%; (ii) Hg(CN)2, melt, 85 °C, 41%; (iii) LiAlH4, THF, (iv) Boc2O, 2 molL–1
NaOH, MeCN, H2O, 9: 53% (from 5), 10: 14% (from 6), (v) MMTrCl, NEt3, DMAP, DMF, 11: 69%,12: 77%; (vi) p-MeBzCl, pyridine,
13: 79%, 14: 52%;(vii) I2, MeOH, CH2Cl2, 15: 98%, 16: 97%; (viii) p-nitrophenyl chloroformate, DMAP, pyridine, 1: 52%, 2: 66%.
idine derivative as a major product. Hence, an alternative azasugar building blocks activated in situ with bis(4-ni-
reaction of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bro- trophenyl) carbonate.[22] In the present study, solid-sup-
mide (4) with Hg(CN)2 in melt[17] was applied to obtain the ported carbamate coupling and normal peptide coupling
desired cyanide 6. Reduction of the cyano group with Li- were utilized in an alternating manner to obtain cyclic tetra-
AlH4 in THF[18] afforded the free amines in a fully deacety- meric C-glycoside/amino acid-conjugates consisting of two
lated form (7, 8). No chromatographic purification was con- sugar and two amino acid units. The strategy employed is
ducted after the LiAlH4 reduction, but the crude products depicted in Scheme 2.
were subjected to selective protection of the amino function
The synthesis of cyclic C-glycoside/amino acid conjugate
with a Boc group, which gave 9 and 10 in an overall yield of 20 was started by immobilization of a safety catch acid-
53% and 14% from 5 and 6, respectively. A 4-methoxtrityl labile linker (SCAL, Figure 2)[23] to an aminomethyl-poly-
protection was then introduced at the primary hydroxy styrene support by 1-[bis(dimethylamino)methylene]-1H-
function[14c] (11, 12), and the secondary hydroxy functions 1,2,3-triazolo-[4,5-b]pyridinium hexafluorophosphate 3-ox-
were subsequently esterified with p-toluoyl chloride (13, ide (HATU)-promoted coupling.[24] The linker withstands
14). The toluoyl protective groups were chosen instead of a wide variety of conditions (including both Boc and Fmoc
the more common acetates, since upon the solid-phase syn- chemisty), but it may be converted cleavable by reduction
thesis they serve as chromophores allowing more efficient of the sulfoxide bonds. According to quantification of
detection of the synthesized conjugates and quantification benzofulvene released from the support-bound Fmoc-pro-
of each coupling step. The trityl protection was removed tected linker, the loading was 160 μmol g–1. After standard
with iodine in MeOH[19] (15, 16) and the exposed hydroxy Fmoc removal by 20% piperidine in DMF, a Nα-Fmoc-pro-
function was esterified with p-nitrophenyl chloroformate in tected allyl glutamate (Fmoc-Glu-OAll) was anchored
pyridine to obtain p-nitrophenyl carbonates 1 and 2.
through its γ-carboxy function to the exposed amino group
Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids: of the linker to obtain 17. The reaction was carried out in
Carbamate coupling chemistry has previously been applied DMF using 7-(azabenzotriazol-1-yl)-N-oxy-tris(pyrrolid-
to the solid-supported synthesis of oligourea- and oligocar- ino)phosphonium hexafluorophosphate (PyAOP)[25] as an
bamate-based analogs of peptides and carbohydrates. Such activator. The Fmoc-protection was again removed and the
oligomers are aimed at being resistant towards proteases first Boc-protected galactosyl 6-O-carbonate 1 was attached
and glycosidases. In addition, their hydrogen bonding prop- to obtain 18. N-Methylpyrrolidone (NMP) was used as a
erties and, hence, folding patterns differs from those of solvent in this carbamate coupling, 1-hydroxybenzotriazole
native peptides and oligosaccharides. Several oligourea-[20] (HOBt) as an auxiliary nucleophile and N,N-diisopropyl-
and oligocarbamate-based[21] peptidomimics have been pre- ethylamine (DIEA) as the base. For the next coupling, the
pared by solid phase synthesis using isocyanates,[20a] p-ni- conventional Boc chemistry was applied. Accordingly, the
trophenyl carbamates[20b–20e] and p-nitrophenyl carbon- Boc protection was removed acidolytically (25% TFA in
ates[21] as activated monomeric building blocks. Carbo- dichloromethane), and Boc-Ala-OH was coupled by the
hydrate mimics have, in turn, been obtained by coupling of PyAOP activation described above. The subsequent Boc de-
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J. Katajisto, H. Lönnberg
FULL PAPER
in AcOH (2 h at room temperature) and 50% TFA in
dichloromethane (2 h at room temperature), followed by se-
mipreparative HPLC purification, gave the desired amino
acid/carbohydrate conjugate 20 in a protected form. After
HPLC purification, conjugate 20 was characterized by
HRMS (Table 1; entry 1).
Figure 2. An aminomethyl-polystyrene support derivatized with a
SCAL linker.
The applicability of the protocol to the construction of
cyclic C-glycoside/amino acid conjugates was further veri-
fied by preparation of two additional cyclic conjugates 21
and 22 in a larger scale. The composition of the desired
fully protected conjugates was verified by HRMS from ana-
lytical HPLC samples (Table 1, entries 2–3). Semiprepar-
ative HPLC-purification of the crude products then gave 21
and 22 in overall 20 and 24% isolated yields, respectively
(based on the initial loading of the resin). In the case of
conjugate 22, the Fmoc protection of the lysine side chain
was, however, removed by piperidine treatment prior to the
cleavage from the support to facilitate the subsequent RP
HPLC purification. Finally, the purified conjugates were
1
further characterized by H NMR spectroscopy.
Conversion of the synthesized C-glycoside/amino acid
conjugates into a globally deprotected form was demon-
strated by using conjugate 21 as a model compound.
Among the alternative methods tested, the conventional
base-catalyzed transesterification in 50 mmol·L–1 meth-
anolic sodium methoxide (24-h treatment at room tempera-
ture)[7i] proved to be the method of choice. The deprotected
conjugate was isolated by analytical RP HPLC in a 71%
yield, and the composition of the purified product 23 was
verified by HRMS (see Supporting Information; for details
see also the footnote on the first page of this article). The
Scheme 2. Conditions: (i) Piperidine, DMF, (ii) Fmoc-Glu-OAll,
PyAOP, DIEA, DMF; (iii) 1, DIEA, HOBt, NMP; (iv) TFA,
CH2Cl2; (v) Boc-Ala-OH, PyAOP, DIEA, DMF; (vi) Pd(OAc)2,
Bu3SnH, PPh3, AcOH, CH2Cl2; (vii) PyBOP, DIEA, DMF; (viii)
0.1% HBr in AcOH, TFA, CH2Cl2.
protection was followed by coupling of the second galacto- reaction conditions, however, required special attention,
syl carbonate 1 to give the linear resin-bound precursor 19. since cleavage of the ester bonds was unexpectedly readily
According to HPLC analysis of small aliquots released accompanied by hydrolysis of the carbamate bonds under
from the support, both of the carbamate couplings were aqueous conditions. While under strictly anhydrous condi-
virtually quantitative, consistent with the reports in litera- tions the toluoyl esters were cleanly removed without any
ture.[21,22] Deprotection of the C-terminal allyl ester by a sign of hydrolysis side products, treatment with sodium me-
palladium-catalyzed cleavage reaction[26] and subsequent thoxide in aqueous methanol or with 33% aq. ammonia
Boc removal from the N-terminus then allowed cyclization resulted in complete hydrolysis of the carbamate bonds. In
on a solid support. (Benzotriazol-1-yl)-N-oxy-tris(pyrrolid- dry methanolic ammonia no carbamate bond cleavage took
ino)phosphonium hexafluorophosphate (PyBOP)[27] as a place, but the ammonolysis of the ester bonds was sluggish.
coupling reagent at fivefold excess in the presence of DIEA After treatment for 24 h, the deprotection was still incom-
(10 equiv.) gave an almost quantitative cyclization, as plete. Similar results were obtained when a lower concentra-
shown by the RP HPLC analysis of the crude product (Fig- tion of sodium methoxide (20 mmol·L–1) was used.
ure 3). No marked difference was observed when PyAOP
An analogous Fmoc-protected galactosyl 6-O-carbonate
was employed as a coupling reagent, while HATU as the building block was also prepared and used in the solid-sup-
activator increased the amount of side products. Cleavage ported synthesis similarly to 1. The coupling of the carbon-
from the support by consecutive treatments with 0.1% HBr ate was successful, but introduction of the next building
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Solid-Phase Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids
FULL PAPER
Figure 3. RP HPLC profile of crude 20. Hypersil Hypurity C18 (150×4.6 mm, 5 μm), gradient from aqueous 0.1% TFA to acetonitrile
in 30 min, flow 1.0 mL min–1, detection at 215 nm.
Table 1. The synthesized C-glycoside/amino acid conjugates 20–22 and their calculated (Mcalcd.) and found (Mfound) LC/ESI-HRMS
molecular masses.
Entry Conjugate
Sequence
[(M + 2H+)/2]found
[(M + 2H+)/2]calcd.
1
2
3
20
21
22
Cyclo[Glu-Gal(Tol)3-Ala-Gal(Tol)3]
Cyclo[Glu-Glc(Tol)3-Ala-Gal(Tol)3]
Cyclo[Glu-Glc(Tol)3-Lys(Fmoc)-Glc(Tol)3]
673.7588
673.7578
813.3210
673.7550
673.6550
813.3180
block, whether it was another sugar carbonate or an ordi- cyclic carbohydrate/amino acid hybrids. Exploitation of
nary amino acid, proved to be unsuccessful. Kaiser ninhyd- urethane coupling for introduction of the C-glycoside units
rin test[28] indicated that no free amino groups were present, appears advantageous for two reasons. Firstly, the alternat-
which, according to our opinion, probably results from the ing urethane/amide backbone is in all likelihood less sus-
OǞN acyl migration upon the basic Fmoc removal.
ceptible to enzymatic degradation than a peptide backbone.
In summary, a novel solid-phase protocol for preparation Secondly, preparation of C-glycoside building blocks as
of cyclic C-glycoside/amino acid hybrids has been devel- active carbonates is more straightforward than their conver-
oped. The key building blocks are N-Boc-protected glycos- sion to carboxylic acids, and the risk of elimination to a
ylmethylamines bearing a 4-nitrophenoxycarbonyl group 4,5-ene upon removal of the toluoyl protections by base-
on the primary sugar hydroxy function. While the active catalyzed transesterification is diminished compared to
carbonate ester readily reacts with a solid-supported amino sugar ligands bearing a carbonyl group at C5. Insertion of
group by formation of a stable urethane linkage, the meth- an amino acid between the two sugar units also plays a
ylamino group allows chain elongation with commercially dual role. The use of commercially available amino acids
available N-Boc-protected amino acids. Accordingly, a lin- increases the chemical diversity, but more importantly, their
ear precursor consisting of alternating sugar and amino side chain functionalities allow post-synthetic conjugation
acid units may be conveniently assembled on a γ-carboxy- of the cyclic constructs. Two or more tetrameric macro-
immobilized glutamic acid handle and cyclized on-support cycles may be linked to a chain-like structure with the aid
in high yield. To the best of our knowledge, this is first appropriate bifunctional tethers or they may be attached to
entirely on-resin techniques introduced for the preparation a multipodal scaffold to benefit from a cluster effect. Alter-
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J. Katajisto, H. Lönnberg
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N-(tert-Butoxycarbonyl-[6-O-(4-methoxytrityl)-2,3,4-tri-O-(p-toluoyl)-
β-D-galactopyranosyl]methylamine (13): Compound 11 (700 mg,
natively, the side-chain functionalities may be used for con-
jugation to peptides or oligonucleotides.
1.24 mmol) was coevaporated twice with dry pyridine, and dis-
solved in dry pyridine (20 mL). p-Toluoyl chloride (737 μL,
5.57 mmol) was added, and the reaction mixture was shaken over-
night at 50 °C. The mixture was poured into ice-cold water, ex-
tracted with dichloromethane, washed with saturated NaHCO3,
and dried with Na2SO4. The solution was concentrated in vacuo
and coevaporated to dryness with toluene. The oily residue was
purified by silica gel chromatography (CH2Cl2) to give 13 as a white
amorphous solid in a 79 % yield (870 mg). 1H NMR (CDCl3,
400 MHz): δ = 7.96 (t, 2 H, H-Tol), 7.68 (t, 2 H, H-Tol), 7.11–7.31
(m, 18 H, H-Tol, H-MMTr), 7.04 (d, 2 H, H-Tol), 6.67 (d, 2 H, H-
MMTr), 6.06 (br. s, 1 H, NH), 5.60–5.64 (m, 2 H, H-3,4), 5.54 (t,
J = 9.8 Hz, 1 H, H-2), 4.03 (m, 1 H, H-6), 3.67–3.72 (m, 4 H,
MMTrOCH3, H-5), 3.76, 3.57, 3.43, 3.22 (each m, each 1 H, H-
1,6Ј,7,7Ј), 2.29, 2.35 and 2.46 (each s, each 3 H, TolCH3), 1.44 (s,
9 H, tBu) ppm. 13C NMR (CDCl3, 100 MHz): δ = 165.8, 165.2
(C=O, Tol), 158.5 (C=O, Boc), 144.2, 143.7, 134.9, 130.3, 130.1,
129.9, 129.4, 129.1, 128.9, 128.3, 128.1, 127.8, 127.7 (MMTrC,
TolC), 113.2 (MMTrC), 86.6 (Cq, MMTr), 79.4 (Cq, Boc), 75.9 (C-
5), 72.6, 69.4, 68.5, 68.2 (C-1,2,3,4), 60.8 (C-6), 55.0
(MMTrOCH3), 41.8 (C-7), 28.4 (Boc CH3), 21.7, 21.6 (Tol CH3)
ppm. HRMS (ESI) [M + Na]+ calcd. 942.3779, obsd. 942.3824.
Experimental Section
General: See electronic supporting information for detailed infor-
mation. The NMR spectra were recorded with Bruker 400, 500
0r 600 MHz in deuteriochloroform, unless otherwise stated. The
chemical shifts are given in ppm from internal TMS, and the coup-
ling constants are reported in Hertz. The mass spectra were re-
corded with Applied Biosystems Mariner System 5272 mass spec-
trometer using ESI ionization method. Analytical and semiprepar-
ative RP HPLC analyses were performed with a Hypersil Hypuri-
tyTM Elite C18 columns (150×4.6 mm, 5 μm or 250×10 mm, 5 μm,
respectively), applying a gradient elution from 0.1% aq. TFA to
acetonitrile in 30 min (flow rates 1.0 mL min–1 or 3.0 mL min–1,
respectively). Eluent detection was monitored by UV absorbance
at 215 nm.
2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl Cyanide (5): Com-
pound 5 was prepared according to the procedure reported pre-
viously.[15] The product was obtained as a white crystalline solid in
a 75% yield. The 1H and 13C NMR spectra were in accordance
with published data.[16]
N-(tert-Butoxycarbonyl-[2,3,4-tri-O-(p-toluoyl)-β-D-galactopyrano-
(β-D-Galactopyranosyl)methylamine (7): Compound 7 was prepared
syl]methylamine (15): Compound 13 (870 mg, 0.95 mmol) was dis-
solved in a mixture of methanolic iodine (5 mL, 1 % iodine in
MeOH) and dichloromethane (1 mL). After stirring the mixture
overnight at room temperature, excess of dichloromethane was
added and the solution was extracted twice with neutral aq.
Na2SO3 (10%, m/v). The organic phase was dried with Na2SO4
and the solvents evaporated to dryness. The product was separated
by silica gel chromatography (0% to 5% MeOH in CH2Cl2) to yield
according to a previously published procedure starting from com-
pound 5 (3.30 g, 9.24 mmol).[18] The yield of a white solid powder
was 61% (1.10 g). The 13C NMR spectrum was identical with the
data published by Bhat and Gervay–Hague.[16]
N-(tert-Butoxycarbonyl)-(β-D-galactopyranosyl)methylamine
(9):
Compound 7 (1.10 g, 5.69 mmol) was dissolved in a mixture of
acetonitrile (20 mL) and water (5 mL), and aq. NaOH (2 mol·L–1,
4.3 mL, 8.54 mmol) and Boc2O (1.24 g, 5.69 mmol) were added.
The mixture was left to stand overnight at ambient temperature.
The solvents were removed in vacuo, the solid residue was extracted
several times with boiling methanol and the hot extracts were fil-
tered through Celite. The combined extracts were evaporated to
dryness and the residue was purified by silica gel chromatography
(10% to 20% MeOH in CH2Cl2) to yield 9 as a white solid in a
86% yield (1.47 g). 1H NMR (D2O, 500 MHz): δ = 3.84 (br. s, 1
H, 5-H), 3.37–3.64 (complex, 6 H, H-1,2,3,6,6Ј,7), 3.21 (m, 1 H,
H-4), 3.10 (m, 1 H, H-7Ј), 1.33 (s, 9 H, tBu) ppm. 13C NMR (D2O,
100 MHz): δ = 158.3 (C=O, Boc), 81.1 (Cq, Boc), 80.1, 78.5 (C-
1,5), 73.8, 69.1, 68.5 (C-2,3,4), 61.5 (C-6), 41.3 (C-7), 27.6 (Boc
CH3) ppm. HRMS (ESI) [M + H]+ calcd. 294.1547, obsd.
294.1558.
1
566 mg (98%) 15 as a clear oil. H NMR (CDCl3, 400 MHz): δ =
8.01 (d, 2 H, H-Tol), 7.79 (d, 2 H, H-Tol), 7.69 (d, 2 H, H-Tol),
7.44 (d, 2 H, H-Tol), 7.04 (d, 2 H, H-Tol), 6.85 (d, 2 H, H-Tol),
5.81 (d, J = 2.9 Hz, 1 H, H-4), 5.73 (t, J = 9.8 Hz, 1 H, H-2), 5.63
(dd, J = 3.2 and 10.0 Hz Hz, 1 H, H-3), 5.30 (br. s, 1 H, NH), 4.02
(m, 1 H, H-6), 3.76–3.81 (m, 3 H, H-1,5,6Ј), 3.70 (br. s, 1 H, OH-
6), 3.58, 3.21 (each m, each 1 H, H-7, H,7Ј), 2.29, 2.37 and 2.47
(each s, each 3 H, TolCH3), 1.45 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 167.1, 166.0, 165.6 (C=O, Tol and Boc),
144.6, 144.3, 144.0, 130.1, 129.9, 129.8, 129.4, 129.2, 129.0 (C-Tol),
79.4 (Cq, Boc), 77.6 (C-5), 72.5, 69.5, 68.0, 67.5, 60.9, 52.0 (C-
1,2,3,4,6), 41.5 (C-7), 28.4 (Boc CH3), 21.7 (Tol CH3) ppm. HRMS
(ESI) [M + H]+ calcd. 648.2770, obsd. 648.2803.
N-(tert-Butoxycarbonyl-[6-O-(p-nitrophenoxycarbonyl)-2,3,4-tri-O-
N-(tert-Butoxycarbonyl)-[6-O-(4-methoxytrityl)-β-D-galactopyrano- (p-toluoyl)-β-D-galactopyranosyl]methylamine (1): Compound 15
syl]methylamine (11): Compound 11 was prepared according to a
previously published prodecure using compound 9 (1.80 g,
6.14 mmol) as a starting material.[14c] The yield of the white solid
foam after isolation by silica gel column chromatography (2 to 10%
(400 mg, 0.62 mmol) was dried by repeated coevaporations with
dry pyridine and dissolved in dry pyridine (10 mL). p-Nitrophenyl
chloroformate (149 mg, 0.74 mmol) and a catalytic amount of
DMAP were added. The mixture was left to stand overnight at
MeOH in CH2Cl2) was 69% (2.40 g). 1H NMR (CDCl3, 400 MHz): ambient temperature. The solution was poured into ice-cold
δ = 7.46 (d, 3 H, H-MMTr), 7.17–7.35 (m, 9 H, H-MMTr), 6.84 1 mol·L–1 aq. HCl, extracted with ethyl acetate, washed with water,
(d, 2 H, H-MMTr), 5.53 (br. s, 1 H, NH), 5.05, 4.40, 4.16 (each m,
and dried with Na2SO4. The residue was applied onto a short dried
each 1 H, OH-2,3,4), 3.80 (s, 3 H, MMTrOCH3), 3.63, 3.58, 3.35, silica gel column and the pure compound was isolated by eluting
3.26 (each m, each 2 H, H-1,3,4,5,6,6Ј,7,7Ј), 3.05 (m, 1 H, H-2),
1.45 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 100 MHz): δ = 158.6
(MMTrC), 157.9 (C=O, Boc) 144.3, 135.4, 130.4, 128.4, 127.9,
with a gradient of ethyl acetate (10% to 30%) in hexane. Carbonate
1 was obtained as a white amorphous solid in a 52 % yield
(260 mg). 1H NMR (CDCl3, 400 MHz): δ = 8.27 (d, 2 H, H-
127.0, 113.1 (MMTrC), 86.57 (Cq, MMTr), 80.4 (Cq, Boc), 79.3 (C- PhNO2), 7.95 (d, 2 H, H-Tol), 7.82 (d, 2 H, H-Tol), 7.65 (d, 2 H,
5), 74.16, 68.9, 67.3 (C-1,2,3,4), 62.4 (C-6), 55.2 (MMTrOCH3), H-Tol), 7.38 (d, 2 H, H-PhNO2), 7.29 (d, 2 H, H-Tol), 7.15 (d, 2
41.2 (C-7), 28.3 (Boc CH3) ppm. HRMS (ESI) [M + Na]+ calcd. H, H-Tol), 7.03 (d, 2 H, H-Tol), 5.94 (d, J = 2.6 Hz, 1 H, H-4),
588.2568, obsd. 588.2561. 5.71 (t, J = 10.0 Hz, 1 H, H-2), 5.60 (dd, J = 3.1 and 10.2 Hz, 1
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Solid-Phase Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids
FULL PAPER
H, H-3), 5.15 (br. s, 1 H, NH), 4.40–4.49 (m, 2 H, H-5,6), 4.28,
3.89, 3.73, 3.29 (each m, each 1 H, H-1,6Ј,7,7Ј), 2.30, 2.35 and 2.46
(each s, each 3 H, Tol CH3), 1.46 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 166.2, 166.0 (C=O, Tol), 162.0, 156.0
(C=O, Boc and PhNO2), 155.5, 152.0 (C-PhNO2), 144.7, 144.2,
144.0, 129.9, 129.8, 129.1, 126.2, 125.9, 125.4 (C-Tol), 121.76, 115.6
(C-PhNO2), 80.0 (Cq, Boc), 72.5 (C-5), 68.0, 67.5, 66.0 (C-
1,2,3,4,6), 41.5 (C-7), 28.4 (Boc CH3), 21.6 (Tol CH3) ppm. HRMS
(ESI) [M + H]+ calcd. 813.2865, obsd. 813.2873.
(Boc CH3), 21.7, 21.6 (Tol CH3) ppm. HRMS (ESI) [M + H]+
calcd. 648.2803, obsd. 648.2776.
N-(tert-Butoxycarbonyl)-[6-O-(p-nitrophenoxycarbonyl)-2,3,4-tri-O-
(p-toluoyl)-β-D-glucopyranosyl]methylamine (2): Compound 2 was
synthesized as described for 1 using compound 16 (566 mg,
0.87 mmol) as a starting material. The carbonate 2 was obtained as
a clear oil in a 66% yield (470 mg). 1H NMR (CDCl3, 400 MHz): δ
= 8.28 (d, 2 H, H-PhNO2), 7.81 (d, 4 H, H-Tol), 7.69 (d, 2 H, H-
Tol), 7.41 (d, 2 H, H-PhNO2), 7.16 (t, 4 H, H-Tol) 7.06 (d, 2 H,
H-Tol), 5.92 (t, J = 9.5 Hz, H-3), 5.58 (t, J = 9.3 Hz, 1 H, H-4),
5.42 (t, J = 9.8 Hz, 1 H, H-2), 5.09 (br. s, 1 H, NH), 4.44–4.54 (m,
2 H, H-6,6Ј), 4.05, 3.88, 3.68, 3.27 (each m, each 1 H, C-1,5,7,7Ј),
2.36 (s, 6 H, Tol CH3), 2.28 (s, 3 H, Tol CH3), 1.44 (s, 9 H, tBu)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 166.0, 165.7, 156.0 (C=O,
Tol, Boc, PhNO2), 155.5, 152.3 (C-PhNO2), 145.4, 144.3, 144.1,
129.9, 129.1, 126.1, 125.3 (C-Tol), 121.8, 115.4 (C-PhNO2), 80.0
(Cq, Boc), 75.5 (C-5), 73.6, 69.8, 68.9, 60.5 (C-1,2,3,4,6), 41.5 (C-
7), 28.3 (Boc CH3), 21.7 (Tol CH3) ppm. HRMS (ESI) [M + Na]+
calcd. 835.2685, obsd. 835.2705.
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl Cyanide (6): Compound
6 was prepared from 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl
bromide reacting with Hg(CN)2 in melt at 80 °C under argon, ap-
plying the method reported previously.[17] The 1H and 13C NMR
spectra were in accordance with published data.[16]
(β-D-Glucopyranosyl)methylamine (8): Compound 8 was obtained
from 6 (6.00 g, 16.8 mmol) by a previously published procedure.[18]
The yield of the white solid product was 79% (2.55 g). The 13C
NMR spectrum was identical with the data published by Gervay–
Hague et al.[16]
Loading of the Resin with SCAL Linker: Aminomethyl-polystyrene
employed as a solid support was first acylated with a Fmoc-pro-
tected SCAL linker by treating the resin (300 mg) with Fmoc-
SCAL (3 equiv.), HATU (3 equiv.) and DIEA (6 equiv.) in DMF
(2 mL) for 5 h at room temperature. According to UV spectro-
scopic quantification of benzofulvene released from the linker, a
loading of 160 μmolg–1 was obtained. The support was filtered,
washed with DMF, dichloromethane and MeOH, and dried under
reduced pressure. The unreacted amino groups were capped with
Ac2O in THF containing N-methylimidazole and lutidine.
N-(tert-Butoxycarbonyl)-(β-D-glucopyranosyl)methylamine (10):
Compound 10 was prepared as described for 9, using compound 8
(2.55 g, 13.2 mmol) as the starting material. The yield of the white
solid was 18% (700 mg). The 1H and 13C NMR spectra were in
accordance with published data.[14c]
N-(tert-Butoxycarbonyl-[6-O-(4-methoxytrityl)-β-D-glucopyranosyl]-
methylamine (12): Compound 12 was obtained from 10 (700 mg,
2.39 mmol) by a previously published procedure.[14c] The yield of
the white solid foam after isolation by silica gel column chromatog-
1
raphy (2 to 10% MeOH in DCM) was 77% (1.00 g). The H and
13C NMR spectra were in accordance with published data.[14c]
Synthesis of C-Glycoside/Amino Acid Conjugates 20–22: The Fmoc
group was first removed from the linker with piperidine in DMF
(1:4, v/v, 10 min at room temperature). The exposed amino func-
tion was then coupled with the side chain carboxyl group of Fmoc-
Glu-OAll by adding 10 equiv. of Fmoc-Glu-OAll, 10 equiv. PyAOP
and 20 equiv. of DIEA to a suspension of the solid support (50 to
150 mg) in DMF (1 mL). The mixture was shaken for 3 h at ambi-
ent temperature. The solid support was filtered, washed with DMF,
dichloromethane and MeOH, and dried in vacuo. The Fmoc group
was again removed as described above, and then the first Boc-pro-
tected glycosyl 6Ј-O-p-nitrophenyl carbonate (1 or 2; 5 equiv.) and
DIEA (5 equiv.) were added to a suspension of the solid support
in 100 μmol·L–1 solution of HOBt in NMP (1 mL). After shaking
the mixture for 5 h at room temperature, the resin was filtered off,
washed with NMP, dichloromethane and MeOH, and dried in
vacuo. The Boc group was removed with 25% TFA in dichloro-
methane (1 mL, 1 h at room temperature) and the filtered support
was washed with 10% pyridine in dichloromethane, and consecu-
tively with DMF, dichloromethane and MeOH, and dried under
reduced pressure. A coupling solution containing the appropriate
N-(tert-Butoxycarbonyl-[6-O-(4-methoxytrityl)-2,3,4-tri-O-(p-toluoyl)-
β-D-glucopyranosyl]methylamine (14): Compound 14 was synthe-
sized as described for 13, using compound 12 (1.00 g, 1.77 mmol)
as the starting material. The product was obtained as a clear oil in
1
a 52% yield (830 mg). H NMR (CDCl3, 400 MHz): δ = 7.84 (t, 2
H, H-Tol), 7.74 (d, 2 H, H-Tol), 7.26–7.35 (m, 11 H, H-Tol, H-
MMTr), 7.18 (m, 7 H, H-Tol, H-MMTr), 7.07 (d, 2 H, H-Tol), 6.84
(d, 2 H, H-MMTr), 5.93 (t, J = 9.6 Hz, H-3), 5.40 (m, 2 H, H-2,4),
5.19 (br. s, 1 H, NH), 3.81–3.87 (m, 5 H, MMTrOCH3, H-6,6Ј),
3.66–3.75 (m, 3 H, H-1,5,7), 3.20 (m, 1 H, H-7Ј), 2.37, 2.36 and
2,29 (each s, each 3 H, Tol CH3), 1.44 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 166.4, 166.0, 165.9 (C=O, Tol), 158.7
(C=O, Boc), 147.1, 144.6, 143.9, 139.3, 130.0, 129.9, 129.7, 129.2,
129.1, 129.0, 127.9, 127.2, 126.3, 125.8 (MMTrC, TolC), 113.2
(MMTrC), 81.7 (Cq, MMTr), 79.5 (Cq, Boc), 78.6 (C-5), 73.7, 70.2,
69.5, 61.4 (C-1,2,3,4,6), 55.3 (MMTrOCH3), 41.3 (C-7), 28.4 (Boc
CH3), 21.7 (Tol CH3) ppm. HRMS (ESI) [M + Na]+ calcd.
942.3824, obsd. 942.3858.
N-(tert-Butoxycarbonyl)-[2,3,4-tri-O-(p-toluoyl)-β-D-glucopyranosyl]- amino acid (10 equiv., Boc-Ala-OH or Boc-Lys(Fmoc)-OH),
methylamine (16): Compound 16 was synthesized as described for
15 using compound 14 (830 mg, 0.90 mmol) as the starting mate-
rial. The product was obtained as a clear oil in a 97 % yield
PyAOP (10 equiv.) and DIEA (20 equiv.) in DMF (1 mL) was then
added, and the mixture was shaken for 5 h at ambient temperature.
The resin was filtered, washed with DMF, dichloromethane, and
MeOH, and dried under reduced pressure. The Boc deprotection
1
(566 mg). H NMR (CDCl3, 400 MHz): δ = 7.83 (t, 4 H, H-Tol),
7.71 (d, 2 H, H-Tol), 7.18 (t, 4 H, H-Tol), 7.06 (d, 2 H, H-Tol), and subsequent coupling of the second Boc-protected glycosyl p-
5.93 (t, J = 11.1 Hz, 1 H, H-3), 5.40 (q, J = 9.7 Hz, 2 H, H-2,4), nitrophenyl carbonate were then carried out as described above to
5.20 (br. s, 1 H, NH), 3.84 (m, 2 H, H-6,6Ј), 3.66–3.75 (m, 3 H, H-
1,5,7), 3.20 (m, 1 H, H-7Ј), 2.36 (s, 6 H, Tol CH3), 2.29 (s, 3 H, Tol
furnish the support-bound linear precursor. The completeness of
all couplings of the Boc-protected building blocks was checked by
CH3), 1.43 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 100 MHz): δ = releasing the product from an aliquot of the resin and analyzing
166.4, 165.9, 165.7 (C=O, Tol), 155.9 (C=O, Boc), 144.6, 144.2,
143.9, 130.0, 129.9, 129.7, 129.2, 129.1, 128.9 (C-Tol), 79.6 (Cq, minus was removed by palladium-catalyzed hydrostannolysis by
Boc), 78.6 (C-5), 73.6, 70.2, 69.5, 61.4 (C-1,2,3,4,6), 41.3 (C-7), 28.4
Bu3SnH.[26] Accordingly, a mixture of Pd(OAc)2 (2 equiv.) and
the samples by HPLC. Next, the allyl protection from the C-ter-
Eur. J. Org. Chem. 2005, 3518–3525
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3523

J. Katajisto, H. Lönnberg
FULL PAPER
PPh3 (12 equiv.) in dichloromethane (1 mL) and AcOH (12 equiv.)
was added onto the resin, and then Bu3SnH (12 equiv.) was added.
The mixture was left to stand at room temperature for 20 min. The
resin was filtered, washed/neutralized with 10% pyridine in dichlo-
(400 μL), and the reaction was allowed to proceed at room tem-
perature for 24 h. Sodium methoxide was neutralized with
DOWEX 50WXB-200 (H+). After filtration of the resin, methanol
was removed under reduced pressure, and the dried residue was
romethane, and consecutively washed several times with DMF, dissolved in water, extracted with diethyl ether and evaporated un-
dichloromethane and MeOH, and dried in vacuo. After standard der reduced pressure. The crude product was diluted with 0.1% aq.
Boc removal from the N-terminus, PyBOP (5 equiv.) and DIEA TFA and purified by RP HPLC (for the chromatographic condi-
(10 equiv.) were added onto the resin swelled in DMF (1 mL), and
the cyclization was allowed to proceed overnight at room tempera-
ture. The support was filtered, washed with DMF, dichloromethane
and MeOH, and dried under reduced pressure. At this stage, a
small aliquot of the solid support was withdrawn from the synthesis
column, and the authenticity of 20–22 was verified by HRMS
(Table 1) of the analytical HPLC samples. An additional piperidine
treatment was conducted at the end of the synthesis of conjugate
22 to remove the Fmoc protection from the side chain amino func-
tion of the lysine residue prior the cleavage from the support. The
cyclic conjugates were then cleaved from the solid support. The
resin was first swollen with a small amount of dichloromethane
and 1 mL of 0.1% HBr in AcOH was added. The mixture was
shaken for 2 h at room temperature. The support was filtered,
washed with dichloromethane and MeOH, and dried in vacuo. The
resin was suspended in a mixture of TFA in dichloromethane
(1 mL, 1:1, v/v). After shaking for 2 h at room temperature, the
solution was collected by filtration and the solvents evaporated to
dryness, affording 20–22 as crude reaction products. The residues
were diluted with a mixture of 0.1% aq. TFA and EtOH and puri-
fied by HPLC. The conjugates 21 and 22, which were prepared in
a larger quantity, were further characterized by 1H NMR spec-
troscopy. PDQF and HMBC spectra were also utilized.
tions, see Supporting Information) to afford 23 in a 71 % yield
(0.6 mg). HRMS (ESI) [M + Na]+ calcd. 660.2335, obsd. 660.2358.
Acknowledgments
The authors wish to thank Dr. Jari Sinkkonen for performing the
1H NMR analysis on Bruker 600 NMR spectrometer and Dr. Harri
Hakala for performing the HRMS analysis.
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Cyclo[Glu-Glc(Tol)3-Ala-Gal(Tol)3] (21): The overall isolated yield:
20%: 1H NMR ([D6]DMSO, 600 MHz): δ = 7.89 (dd, 2 H, H-Tol),
7.73–7.81 (m, 7 H, H-Tol), 7.65 (br. s, 1 H, NH), 7.60 (m, 2 H, H-
Tol), 7.52 (m, 2 H, H-Tol), 7.40, 7.26–7.31 (m, 7 H, H-Tol), 7.19
(m, 2 H, H-Tol), 7.14 (d, 2 H, H-Tol), 6.78 (m, 1 H, NH), 6.69 (m,
1 H, NH), 5.88 (m, J = 9.5 Hz, GlcH-3), 5.76 (m, 2 H, NH, GalH-
3), 5.53 (t, J = 9.3 Hz, 1 H, GlcH-4), 5.42 (m, 2 H, GalH-2,4), 5.14
(t, J = 9.5 Hz, GlcH-2), 4.23 (m, 1 H, GlcH-5), 3.99–4.09 (m, 6 H,
GalH-1,5,6, GlcH-1,6, AlaH-α), 3.82 (m, 2 H, GalH-6Ј, GluH-α),
3.75 (m, 1 H, GalH-7), 3.50 (br. s, H2O residual peak), 3.33 (m, 1
H, GlcH-6Ј), 3.28 (m, 1 H, GlcH-7), 3.10 (m, 1 H, GlcH-7Ј), 2.97
(m, 1 H, GalH-7Ј), 2.42 (s, 3 H, Tol CH3), 2.33 (m, 9 H, Tol CH3),
2.26 (m, 6 H, Tol CH3), 1.98 (m, 2 H, GluH-γ), 1.75 (m, 1 H,
GluH-β), 1.65 (m, 1 H, GluH-βЈ), 1.15 and 0.98 (two d, 3 H, AlaH-
β) ppm. The 1H NMR spectrum also exhibited smaller peaks at
5.99, 5.91, 5.24 and 1.50 as well as smaller overlapping peaks at
4.35 and 1.78 ppm, presumably due to slow conformational ex-
change at ambient temperature.
Cyclo[Glu-Glc(Tol)3-Lys-Glc(Tol)3] (22): The overall isolated yield:
1
24%: H NMR ([D6]DMSO, 600 MHz): δ = 7.75 (m, 8 H, H-Tol),
7.68 (m, 2 H, NH), 7.59 (m, 4 H, NH), 7.53 (t, 2 H, NH), 7.28 (m,
10 H, H-Tol), 7.20 (m, 6 H, H-Tol), 5.92 (m, J = 8.2 and 9.5 Hz Hz,
2 H, GlcH-3), 5.60 (q, J = 8.2 and 9.5 Hz Hz, 2 H, GlcH-4), 5.15
(t, J = 9.5 Hz, 2 H, GlcH-2), 4.18 (t, J = 10.1 Hz, 2 H, GlcH-5),
4.03–4.13 (m, 4 H, GlcH-1,7), 3.78–3.84 (m, 4 H, LysH-α, GluH-
α), 3.66 (br. s, H2O residual peak), 3.26–3.42 (m, 4 H, GlcH-6,7Ј),
3.17–3.24 (m, 2 H, GlcH-6Ј), 2.73 (m, 2 H, LysH-ε), 2.33 (br. s, 12
H, Tol CH3), 2.28 (br. s, 6 H, Tol CH3), 1.91–2.10 (m, 2 H, GluH-
γ), 1.83 (m, 1 H, GluH-β), 1.72 (m, 1 H, GluH-βЈ), 1.63 (m, 1 H,
LysH-β), 1.48 (m, 3 H, LysH-βЈ,δ), 1.23 (br. s, 2 H, LysH-γ) ppm.
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3524
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Solid-Phase Synthesis of Cyclic C-Glycoside/Amino Acid Hybrids
FULL PAPER
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Received: April 18, 2005
Published Online: July 4, 2005
Eur. J. Org. Chem. 2005, 3518–3525
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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