An oxidation–amidation approach for the synthesis of glycuronamides

Article abstract of DOI:10.1002/ejoc.201600239

A route for the synthesis of glycuronamides via the variety of carbohydrate residues and protecting groups, was intermediacy of 6-S-tolyl-substituted glycosides and uronic acid used to synthesize the repeating unit of the E. coli K54 capsular thioesters, is reported. The route, which is compatible with a polysaccharide.

Full text of DOI:10.1002/ejoc.201600239

DOI: 10.1002/ejoc.201600239
Full Paper
Glycuronamide Synthesis
An Oxidation–Amidation Approach for the Synthesis of
Glycuronamides
Sicheng Lin,[a][‡] Roger A. Ashmus,[a][‡] and and Todd L. Lowary*[a]
Abstract: A route for the synthesis of glycuronamides via the variety of carbohydrate residues and protecting groups, was
intermediacy of 6-S-tolyl-substituted glycosides and uronic acid used to synthesize the repeating unit of the E. coli K54 capsular
thioesters, is reported. The route, which is compatible with a polysaccharide.
Introduction
Colwellia psychrerythraea 34H CPS has been suggested to be
important for the survival of the organism in subfreezing ma-
Glycuronamides, amidated uronic acid derivatives, are com- rine environments.[4] Other studies have shown that CPS pos-
monly found in bacterial lipopolysaccharides (LPS) and capsular sessing uronic acids amidated with amino acids are important
polysaccharides (CPS).[1–5] These structures frequently consist of in the induction of protective immunity against abscess forma-
glucuronic acid, galacturonic acid, mannuronic acid, or 2-acet- tion.[10] In addition, molecules containing these structures have
amido-2-deoxy-
different amines including ammonia,[1] ethanolamine,[6]
nine,[2] -serine,[3] -lysine,[7] -threonine,[4] and serinol.[8] Exam- glycuronamides is of interest.
ples include Escherichia coli K54 CPS, which has a repeating The conventional approach for glycuronamide synthesis in-
unit possessing a
-threonine-containing glucuronamide[9] and volves converting a uronic acid to a reactive intermediate (e.g.,
Proteus mirabilis O28 LPS, which contains two galacturonamide an activated ester or acyl halide) and then addition of an amine
D
-galacturonic acid amidated with a range of often been targeted in the development of vaccines.[7,11–13]
-ala- Consequently, the chemical synthesis of glycans possessing
L
L
L
L
L
residues, one incorporating L-lysine and the other L
-serine (Fig- (Scheme 1, compounds 1→2→6).[14–20] Recently, Crich and Sas-
ure 1).[7] Polysaccharides containing glycuronamide residues aki have developed an alternate method in which uronic acid
play essential roles in the organisms that produce them. For thiocarboxylates made in situ react with isocyanates or isothio-
instance, the
-threonine-containing galacturonamide in the cyanates to produce glycuronamides (1→3→6).[21] In another
L
Figure 1. Examples of polysaccharide repeating units containing glycuronamide residues.
alternate approach, treatment of 1,6- and 3,6-carbohydrate-
[a] Department of Chemistry and Alberta Glycomics Centre, The University of
Alberta,
based lactones with amines leads to the corresponding glucu-
ronamides (1→4/5→6).[22–24] These alternative approaches,
however have only been demonstrated on glucuronic acid resi-
dues. In addition, they are difficult to implement if the glycan
of interest contains more than one glycuronamide (e.g., the re-
peating unit found in P. mirabilis O28 LPS, Figure 1).
Edmonton, Alberta T6G 2G2, Canada
E-mail: tlowary@ualberta.ca
www.lowarylab.ca
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600239.
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water and acetone in the presence of Na2CO3, generate thioe-
sters.[39,40] These investigations prompted us to explore the pos-
sibility of preparing glycuronamides from 10 via the formation
of the uronic acid thioesters (e.g., 11) and then treatment with
amines (Scheme 2, b).
Results and Discussion
In a first series of experiments, we treated 6-S-tolyl-galactose
derivative 13 with sulfuryl chloride to produce the dichloro-
sulfide intermediate 14 (Scheme 3). Without purification, this
adduct was stirred with water in acetone in the presence of
NaHCO3, leading to the formation of thioester 15, which could
be isolated in 87 % yield. Subsequent treatment of 15 with p-
methoxybenzylamine in dichloromethane furnished the gluc-
uronamide 16 in 90 % isolated yield.
Having succeeded in applying this approach to 13, we then
examined the oxidation of various 6-S-tolyl-glycosides 17–21[41]
to the corresponding thioesters 22–26 as illustrated in
Scheme 4. In each case, the two-step conversion afforded the
desired product in good to excellent yield. Neither the electron-
withdrawing nature of the protecting groups, nor the carbo-
hydrate stereochemistry had a significant influence on the reac-
Scheme 1. Approaches for glycuronamide synthesis.
In recent efforts to synthesize glycoconjugates containing
glucuronamide residues using the conventional approach de-
scribed above (1→2→6), we encountered an unexpected prob-
lem: The generation of a glucuronic acid derivative, either by
hydrolysis of an ester or oxidation of a primary alcohol, led to
decomposition of the molecule. Thus, we required a method
for the formation of a glucuronamide that did not involve a
carboxylic acid intermediate. Although methods for the direct
conversion of primary alcohols to amides have been de-
scribed,[25–36] in our hands these were unsuccessful.
We then turned our attention to a report by Yu and co-work-
ers, which described the preparation of uronic acid esters from
6-S-phenyl-glycosides (Scheme 2, a).[37,38] In this approach, the
first step involves treatment of the sulfide precursor 7 with
sulfuryl chloride to generate the corresponding α,α-dichlorosul-
fide (8), which in a second step can be converted into the
uronic acid methyl ester (9). In other previous work, Fortes and
co-workers showed that α,α-dichlorosulfides, when treated with
Scheme 4. Synthesis of uronic acid thioesters from 6-S-tolyl-substituted glyc-
osides. Reagents and conditions: (a) pyridine, SO2Cl2, CCl4, 0 °C, 5 h; (b) NaH-
CO3, acetone/H2O (3:2), room temp., 18 h.
Scheme 2. a) Synthesis of uronic acid methyl esters by Yu and co-work-
ers.[37,38] b) proposed route to glycuronamides.
Scheme 3. Synthesis of galacturonamide 16 from thioether 13. Reagents and conditions: (a) pyridine, SO2Cl2, CCl4, 0 °C, 5 h; (b) NaHCO3, acetone/H2O (3:2),
room temp., 18 h; (c) p-methoxybenzylamine, CH2Cl2, room temp., 10 h.
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Table 1. Amidation of uronic acid thioesters with amines.
tion yield or reaction time. In addition, the reaction could also
be carried out in both milligram and gram scale without diffi-
culty. With the thioesters in hand, we explored their amidation
with various amines (Table 1).
In exploring the scope of the amidation reaction (Table 1),
we focused on the preparation of naturally occurring glycuron-
amides in their protected form. We found that varying the
carbohydrate residue and their electronic properties (i.e., the
electron-withdrawing or donating ability of the protecting
groups) did not affect the amidation yield or reaction rate.
When simple amines such as p-methoxybenzylamine (Entries
1, 10, 15, 18, 19) and ethanolamine (Entry 11) were used, the
amidation proceeded in good yields (> 82 %). Ammonia from
concentrated ammonium hydroxide could also be used as the
amine, albeit this afforded the glycuronamide 28 in somewhat
lower (66 %) yield and longer reactions times were required
(Entry 3). The use of amines derived from L-alanine, L-serine, L-
threonine as well as serinol, provided the corresponding glyc-
uronamides in 63–73 % yields.
The data in Table 1 also supports a general trend for the
reaction rate: simple amines (e.g., p-methoxybenzylamine, eth-
anolamine) > moderately bulky amines (e.g., protected
derivatives) > more sterically demanding amines (the serinol
analogue, -threonine derivatives, -serine derivatives). It was
discovered that for -threonine tert-butyl ester changing the sol-
L-alanine
L
L
L
vent from CH2Cl2 (Entry 13) to DMF (Entry 14) resulted in the
reaction rate increasing nearly twofold and a significantly im-
proved product yield. The same trend is observed with other
amino acid-derived amines (Entries 8, 16). In attempts to in-
crease the reaction rate, triethylamine was added (Entries 4, 5);
however, no increase in the rate or improvement of the yield
was observed. We also explored the use of 2,6-di-tert-butyl-4-
methylpyridine, but again no improvement in rate or product
yield was seen. Indeed, for substrates possessing acyl protect-
ing groups at O-4, the yield deceased (see next paragraph). It
was also evident that the free amine (Entry 7) is a substantially
better substrate than the corresponding hydrochloric salt, even
in the presence of an excess of triethylamine (Entry 6). Not sur-
prisingly, the data in entries 9, 11, and 13 demonstrate that
amidation will occur over esterification when competing alco-
hol nucleophiles are present.
It is important to note that when O-4 in the carbohydrate is
protected with an ester, significant elimination can occur in the
presence of an excess amine nucleophile or when triethylamine
is added to the reaction (Figure 2). Small amounts of the elimi-
nation adduct were also observed when a sterically demanding
amine was used in the amidation step. However, changing the
solvent from dichloromethane to DMF in the amidation of 23
with L-threonine tert-butyl ester (Entries 13, 14), led to less elim-
ination. In addition, by carefully controlling the amount of
amine in the reaction and avoiding the addition of triethyl-
amine, the formation of the elimination product with O-4 acyl-
ated substrates could be largely avoided (e.g., Table 1, Entry
10).
To demonstrate the applicability of the approach to glycan
synthesis, we used it to prepare the repeating unit of the E. coli
K54 CPS, a disaccharide possessing a glucuronamide residue
[a] 1.5 equiv. of amine except NH4OH (aq.). [b] Yield of isolated product. [c]
Triethylamine was added to the reaction.
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51 with sodium methoxide in methanol produced the disac-
charide 52 in 90 % yield.
Conclusions
In conclusion, an effective strategy for the preparation of
glycuronamides from 6-S-tolyl-glycosides was developed. The
method was compatible with a range of carbohydrate residues
and amines and the approach could be easily applied to the
synthesis of the E. coli K54 CPS repeating unit. To the best of
our knowledge, the route described here is the first of its kind
to completely avoid a carboxylic acid intermediate in the syn-
thesis of complex glycans containing glycuronamides. More-
over, staged introductions of 6-S-tolyl moieties into oligosac-
charides should allow the preparation of molecules containing
more than one uronic acid derivatives amidated to different
amines.
Figure 2. Example of the elimination product formed from O-4 acylated sub-
strates (e.g., 23) when an triethylamine is used in the amidation reaction.
linked to
-threonine (52, Scheme 5).[9] The synthesis started
L
with a TBSOTf-catalyzed glycosylation of glucosyl acceptor
43[42] with rhamnosyl donor 44,[43] which led to a 2:1 insepara-
ble mixture of 45 and its O-2 regioisomer in favor of the desired
adduct. Subsequent acetylation with acetic anhydride in pyrid-
ine and removal of the benzylidene acetal afforded disacchar-
ide 46 and its regioisomer 46a in 34 % and 17 % yield, respec-
tively, over three steps. Treatment of 46 with tolyl disulfide and
trimethylphosphine in pyridine selectively afforded the 6-S-tolyl
sulfide 47 in 95 % yield. Subsequent acetylation of 47 with
acetic anhydride in pyridine afforded an 95 % yield of 48. Oxid-
ation of 48 into thioester 49 proceeded in 85 % yield upon
treatment with sulfuryl chloride in carbon tetrachloride and
then with water in the presence of NaHCO3. The amidation of
Experimental Section
General Experimental Methods: All reagents were purchased from
commercial sources and were used without further purification un-
less noted. Reaction solvents were purified by successive passage
through columns of alumina and copper under argon. Unless stated
otherwise, all reactions were carried out at room temperature and
under a positive pressure of argon and were monitored by TLC
on Silica Gel G-25 F254 (0.25 mm). Visualization of the reaction
components was achieved using UV fluorescence (254 nm) and/or
by charring with acidified anisaldehyde solution in ethanol, acetic
acid and sulfuric acid. Organic solvents were evaporated under re-
duced pressure, and the products were purified by column chroma-
tography on silica gel (230–400 mesh). Optical rotations were meas-
ured in a microcell (1 cm, 1 mL) at 21 °C and are in units of de-
gree·mL/(g·dm). 1H NMR spectra were recorded at 400 MHz or
500 MHz and chemical shifts are referenced to residual CHCl3 (δ =
7.26 ppm, CDCl3) or CHD2OD (δ =3.30 ppm, CD3OD). 13C NMR spec-
tra were recorded at 125 MHz, and chemical shifts are referenced
to CDCl3 (δ =77.0 ppm) or CD3OD (δ =49.3 ppm). Reported splitting
patterns are abbreviated as s = singlet, d = doublet, t = triplet, m =
multiplet, br. = broad, app. = apparent. Assignments of NMR spectra
were based on two-dimensional experiments (1H–1H COSY, HSQC
and HMBC). High-resolution ESI-MS spectra (time-of-flight analyzer)
were recorded on samples suspended in THF or CH3OH and with
added NaCl.
thioester 49 with L-threonine benzyl ester afforded glycurona-
mide 50 in 83 % yield. With the disaccharide prepared, it was
deprotected by first hydrogenolysis of the benzyl ester over 5 %
Pd/C, which afforded the free acid 51. Subsequent treatment of
General Method 1: Preparation of 6-S-tolyl-Substituted Glycos-
ides:[37] To a stirred solution of the 6-hydroxy glycopyranoside
(1.0 mmol) in dry pyridine (5.0 mL) under argon were added (TolS)2
(2.0 mmol) and PMe3 (2.0 mmol, 1.0
M in THF). The reaction mixture
was stirred overnight at room temperature. Then, the reaction mix-
ture was concentrated, diluted with EtOAc (30 mL) and washed with
brine. The organic layer was dried with MgSO4, filtered and concen-
trated.
General Method 2: Preparation of Thio-uronates:[39,40] To a solu-
tion of the thioether (1.0 mmol) in dry CCl4 (15 mL) at 0 °C under
argon were added anhydrous pyridine (2.0 mmol) and then SO2Cl2
(2.0 mmol). The reaction mixture was stirred for 5 h at 0 °C, then
diluted with CH2Cl2 and the mixture was washed with brine. The
organic layer dried with MgSO4, filtered and concentrated. The
crude residue was dissolved in 3:2 acetone/H2O (20 mL), and solid
NaHCO3 (4.0 mmol) was added. The reaction mixture was stirred for
Scheme 5. Reagents and conditions: (a) 4 Å MS, TBSOTf, CH2Cl2, –78 °C, 20 min
(inseparable, 46:46a = 2:1); (b) Ac2O, pyridine, DMAP, 3 h; (c) 80 % CH3COOH/
H2O, 80 °C, 2 h (separable, 47:47a = 2:1); (d) (TolS)2, Me3P in THF, pyridine,
room temp., overnight; (e) Ac2O, pyridine, DMAP, 3 h; (f) pyridine, SO2Cl2,
CCl4, 0 °C, 5 h; (g) NaHCO3, acetone/H2O (3:2), room temp., 18 h; (h)
nine benzyl ester, CH2Cl2, room temp., 44 h; (i) 5 % Pd/C, CH3OH, room temp.,
overnight; (j) 50 m NaOCH3/CH3OH, room temp., 4 h.
L-threo-
M
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18 h at room temperature, diluted with brine, and then extracted
residue was purified by flash chromatography (5:1→4:1 hexane/
with EtOAc (3 × 30 mL). The organic layer was dried with MgSO4, EtOAc) to afford 17 (542 mg, 95 %) as a clear viscous oil. The 1H
filtered and concentrated.
NMR spectroscopic data for the product was consistent with that
reported in the literature.[45]
General Method 3: Preparation of Uronamides: To a solution of
the thioester (0.1 mmol) in CH2Cl2 (or DMF) (1 mL) was added the
amine (0.15 mmol). The reaction mixture was monitored by TLC
until the consumption of starting material and then diluted with
Methyl 2,3,4-Tri-O-benzoyl-6-thio-6-S-p-tolyl-α-
ide (18): Scale 1.0 mmol. Prepared from methyl 2,3,4-tri-O-benzoyl-
α-
-glucopyranoside[46]as described in general method 1. The
D-glucopyranos-
D
CH2Cl2 (5 mL), washed with satd. NH4Cl (aq.) and brine. The organic crude residue was purified by flash chromatography (5:1→4:1 hex-
layer dried with MgSO4, filtered and concentrated.
ane/EtOAc) to afford 18 (576 mg, 94 %) as a clear viscous oil. Rf =
0.44 (4:1 hexane/EtOAc). [α]D = +40.8 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 8.00–7.98 (m, 2 H, Ar), 7.96–7.94 (m, 2 H, Ar),
7.88–7.86 (m, 2 H, Ar), 7.57–7.51 (m, 2 H, Ar), 7.46–7.38 (m, 5 H, Ar),
7.32–7.26 (m, 4 H, Ar), 7.06 (d, J = 7.9 Hz, 2 H, Ar), 6.11 (app. t, J =
9.8 Hz, 1 H, 3-H), 5.49 (app. t, J = 9.7 Hz, 1 H, 4-H), 5.29 (dd, J =
10.2, 3.7 Hz, 1 H, 2-H), 5.24 (d, J = 3.7 Hz, 1 H, 1-H), 4.24 (ddd, J =
9.5, 9.4, 2.5 Hz, 1 H, 5-H), 3.50 (s, 3 H, OCH3), 3.23 (dd, J = 14.0,
2.5 Hz, 1 H, 6-Ha), 3.13 (dd, J = 14.0, 9.1 Hz, 1 H, 6-Hb), 2.33 (s, 3 H,
ArCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.8 (2 × C=O), 165.5
(C=O), 136.6 (Ar), 133.5 (Ar), 133.4 (Ar), 133.1 (Ar), 132.3 (Ar), 130.2
(Ar), 130.0 (Ar), 129.9 (Ar), 129.8 (Ar), 129.7 (Ar), 129.3 (Ar), 129.1
(Ar), 128.0 (Ar), 128.4 (2 × Ar), 128.3 (Ar), 96.8 (C-1), 72.3 (C-4), 72.2
(C-2), 70.4 (C-3), 68.9 (C-5), 55.5 (OCH3), 36.6 (C-6), 21.0 (ArCH3) ppm.
HRMS (ESI) calcd. for [M + Na] C25H32NaO8S: 635.1710, found
635.1707.
1,2:3,4-Di-O-isopropylidene-6-thio-6-S-p-tolyl-α-D-galactopyr-
anose (13): Scale 1.0 mmol. Prepared as described in general
method 1. The crude residue was purified by flash chromatography
(5:1→4:1 hexane/EtOAc) to afford 13 (330 mg, 90 %) as a clear vis-
cous oil. Rf = 0.39 (4:1 hexane/EtOAc). [α]D = –84.3 (c = 0.4, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.33–7.31 (m, 2 H, Ar), 7.11–7.09 (m,
2 H, Ar), 5.53 (d, J = 5.0 Hz, 1 H, 1-H), 4.61 (dd, J = 7.9, 2.4 Hz, 1 H,
3-H), 4.39 (dd, J = 7.9, 1.8 Hz, 1 H, 4-H), 4.29 (dd, J = 5.0, 2.4 Hz, 1
H, 2-H), 3.83 (td, J = 7.0, 1.7 Hz, 1 H, 5-H), 3.14 (d, J = 7.0 Hz, 2 H,
6-H), 2.31 (s, 3 H, ArCH3), 1.47 [s, 3 H, C(CH3)2], 1.36 [s, 3 H, C(CH3)2],
1.30 [s, 3 H, C(CH3)2], 1.26 [s, 3 H, C(CH3)2] ppm. 13C NMR (125 MHz,
CDCl3): δ = 136.4 (Ar), 131.9 (Ar), 130.4 (Ar), 129.7 (Ar), 109.3
[C(CH3)2], 108.6 [C(CH3)2], 96.7 (C-1), 71.3 (C-4), 70.9 (C-3), 70.6 (C-
2), 66.2 (C-5), 34.0 (C-6), 26.0 [C(CH3)2], 25.6 [C(CH3)2], 25.0 [C(CH3)2],
24.5 [C(CH3)2], 21.0 (ArCH3) ppm. HRMS (ESI) calcd. for [M + Na]
C19H26NaO5S: 389.1393, found 389.1397.
Methyl 2,3,4-Tri-O-acetyl-6-thio-6-S-p-tolyl-α-
ide (19): Scale 1.0 mmol. Prepared from methyl 2,3,4-tri-O-acetyl-
α-
-galactopyranoside[47] as described in general method 1. The
D-galactopyranos-
S-p-Tolyl Thio(1,2:3,4-Di-O-isopropylidene-α-D-galactopyran-
D
ose)uronate (15): Scale: 1.0 mmol. Prepared as described in general
method 2. The crude residue was purified by flash chromatography
(4:1 hexane/EtOAc) to afford 15 (331 mg, 87 %) as a white amor-
phous solid. Rf = 0.29 (4:1 hexane/EtOAc). [α]D = –179.5 (c = 0.7,
crude residue was purified by flash chromatography (3:2→2:1 hex-
ane/EtOAc) to afford 19 (363 mg, 85 %) as a clear viscous oil. Rf =
0.44 (2:1 hexane/EtOAc). [α]D = +82.7 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.29 (d, J = 8.1 Hz, 2 H, Ar), 7.13 (d, J = 7.9 Hz,
2 H, Ar), 5.49 (dd, J = 3.4, 1.2 Hz, 1 H, 4-H), 5.33 (dd, J = 10.9, 3.4 Hz,
1 H, 3-H), 5.15 (dd, J = 10.9, 3.6 Hz, 1 H, 2-H), 5.00 (d, J = 3.6 Hz, 1
H, 1-H), 4.05 (ddd, J = 7.8, 5.5, 1.0 Hz, 1 H, 5-H), 3.39 (s, 3 H, OCH3),
3.07 (dd, J = 13.8, 8.0 Hz, 1 H, 6-Ha), 2.90 (dd, J = 13.8, 5.4 Hz, 1 H,
6-Hb), 2.35 (s, 3 H, ArCH3), 2.15 (s, 3 H, COCH3), 2.09 (s, 3 H, COCH3),
2.00 (s, 3 H, COCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.4 (C=
O), 170.3 (C=O), 169.9 (C=O), 137.0 (Ar), 131.6 (Ar), 130.6 (Ar), 129.9
(Ar), 97.2 (C-1), 69.6 (C-3), 68.2 (C-2), 67.8 (C-4), 67.5 (C-5), 55.4
(OCH3), 35.2 (C-6), 21.0 (COCH3), 20.8 (COCH3), 20.7 (COCH3) ppm.
HRMS (ESI) calcd. for [M + NH4] C20H30NO8S: 444.1687, found
444.1679.
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.35–7.32 (m, 2 H, Ar), 7.24–
7.22 (m, 2 H, Ar), 5.75 (d, J = 4.9 Hz, 1 H, 1-H), 4.69 (dd, J = 7.7,
2.6 Hz, 1 H, 3-H), 4.65 (dd, J = 7.7, 2.2 Hz, 1 H, 4-H), 4.49 (d, J =
1.9 Hz, 1 H, 5-H), 4.43 (dd, J = 4.9, 2.5 Hz, 1 H, 2-H), 2.39 (s, 3 H,
ArCH3), 1.56 [s, 3 H, C(CH3)2], 1.55 [s, 3 H, C(CH3)2], 1.38 [s, 3 H,
C(CH3)2], 1.36 [s, 3 H, C(CH3)2] ppm. 13C NMR (125 MHz, CDCl3): δ =
197.9 (C-6), 139.5 (Ar), 134.7 (Ar), 130.0 (Ar), 123.6 (Ar), 110.1
[C(CH3)2], 109.3 [C(CH3)2], 96.7 (C-1), 74.2 (C-5), 72.3 (C-4), 70.8 (C-
3), 70.7 (C-2), 26.1 [C(CH3)2], 26.0 [C(CH3)2], 24.8 [C(CH3)2], 24.6
[C(CH3)2], 21.4 (ArCH3) ppm. HRMS (ESI) calcd. for [M + Na]
C19H24NaO6S: 403.1186, found 403.1186.
N-(4-Methoxybenzyl) 1,2:3,4-Di-O-Isopropylidene-α-D-galacto-
Methyl 2,3,4-Tri-O-benzyl-6-thio-6-S-p-tolyl-α-
oside (20): Scale 1.0 mmol. Prepared from methyl 2,3,4-tri-O-
benzyl-α-
-galactopyranoside[48] as described in general method 1.
D-galactopyran-
pyranosiduronamide (16): Scale 0.1 mmol. Prepared as described
in general method 3. The crude residue was purified by flash chro-
matography (2:1 hexane/EtOAc) to afford 16 (35 mg, 90 %) as a
white solid. Rf = 0.18 (2:1 hexane/EtOAc). [α]D = –78.2 (c = 0.5,
D
The crude residue was purified by flash chromatography (6:1→4:1
hexane/EtOAc) to afford 20 (479 mg, 82 %) as a clear viscous oil.
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.24–7.21 (m, 2 H, Ar), 6.85–
1
Rf = 0.44 (4:1 hexane/EtOAc). [α]D = –13.0 (c = 0.3, CHCl3). H NMR
6.82 (m, 2 H, Ar), 6.78 (app. t, J = 5.5, 5.5 Hz, 1 H, CONHCH2), 5.54
(d, J = 4.9 Hz, 1 H, 1-H), 4.72 (dd, J = 7.9, 2.1 Hz, 1 H, 3-H), 4.68–
4.64 (m, 2 H, 4-H, NHCH2Ar), 4.34 (m, 2 H, 2-H, 5-H), 4.23 (dd, J =
14.8, 4.7 Hz, 1 H, NHCH2Ar), 3.78 (s, 3 H, ArOCH3), 1.51 [s, 3 H,
C(CH3)2], 1.39 [s, 3 H, C(CH3)2], 1.35 [s, 3 H, C(CH3)2], 1.32 [s, 3 H,
C(CH3)2] ppm. 13C NMR (175 MHz, CDCl3): δ = 168.2 (C-6), 158.9 (Ar),
130.0 (Ar), 128.9 (Ar), 113.9 (Ar), 109.4 [C(CH3)2], 109.2 [C(CH3)2], 96.2
(C-1), 71.6 (C-3), 70.7 (C-2), 70.4 (C-4), 68.8 (C-5), 55.3 (ArOCH3), 42.2
(NHCH2Ar), 26.0 [C(CH3)2], 25.9 [C(CH3)2], 24.8 [C(CH3)2], 24.2
[C(CH3)2] ppm. HRMS (ESI) calcd. for [M + Na] C20H27NNaO7:
416.1680, found 416.1678.
(400 MHz, CDCl3): δ = 7.40–7.26 (m, 15 H, Ar), 7.18–7.16 (m, 2 H,
Ar), 7.07 (d, J = 8.3 Hz, 2 H, Ar), 5.00 (d, J = 11.4 Hz, 1 H, PhCH2O),
4.87 (d, J = 11.7 Hz, 1 H, PhCH2O), 4.82 (d, J = 12.1 Hz, 1 H, PhCH2O),
4.75 (d, J = 11.7 Hz, 1 H, PhCH2O), 4.69–4.65 (m, 2 H, PhCH2O, 1-H),
4.55 (d, J = 11.4 Hz, 1 H, PhCH2O), 4.02 (dd, J = 10.0, 3.6 Hz, 1 H, 2-
H), 3.97 (d, J = 2.5 Hz, 1 H, 4-H), 3.89 (dd, J = 10.0, 2.5 Hz, 1 H, 3-
H), 3.77–3.73 (m, 1 H, 5-H), 3.32 (s, 3 H, OCH3), 3.07 (dd, J = 13.4,
6.5 Hz, 1 H, 6-Ha), 2.89 (dd, J = 13.4, 7.1 Hz, 1 H, 6-Hb), 2.31 (s, 3 H,
ArCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.8 (Ar), 138.5 (2 ×
Ar), 136.2 (Ar), 132.4 (Ar), 129.8 (Ar), 129.6 (Ar), 128.4 (3 × Ar), 128.3
(Ar), 128.1 (Ar), 127.7 (2 × Ar) 127.6 (Ar), 127.5 (Ar), 98.9 (C-1), 79.4
Methyl 2,3,4-Tri-O-benzyl-6-thio-6-S-p-tolyl-α-
ide (17): Scale 1.0 mmol. Prepared from methyl 2,3,4-tri-O-benzyl-α- (C-5), 55.3 (OCH3), 34.7 (C-6), 21.0 (ArCH3) ppm. HRMS (ESI) calcd.
-glucopyranoside[44] as described in general method 1. The crude
for [M + NH4] C35H42NO5S: 588.2778, found 588.2764.
D-glucopyranos- (C-3), 76.3 (C-2), 75.7 (C-4), 74.9 (PhCH2O), 73.5 (2 × PhCH2O), 69.4
D
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Full Paper
Methyl 2,3,4-Tri-O-benzoyl-6-thio-6-S-p-tolyl-α-
oside (21): Scale: 1.0 mmol. Prepared from methyl 2,3,4-tri-O-ben-
zoyl-α-
-mannopyranoside[49] as described in general method 1.
The crude residue was purified by flash chromatography (6:1→2:1
D
-mannopyran-
ppm. 13C NMR (125 MHz, CDCl3): δ = 195.0 (C-6), 170.3 (C=O), 169.8
(C=O), 169.5 (C=O), 140.1 (Ar), 134.5 (Ar), 130.2 (Ar), 122.6 (Ar), 97.8
(C-1), 74.2 (C-5), 68.8 (C-4), 67.9 (C-2), 67.2 (C-3), 56.3 (OCH3), 21.4
(COCH3), 20.8 (COCH3), 20.6 (COCH3), 20.5 (ArCH3) ppm. HRMS (ESI)
D
hexane/EtOAc) to afford 21 (594 mg, 97 %) as a white amorphous calcd. for [M + NH4] C20H28NO9S: 458.1479, found 458.1472.
solid. Rf = 0.42 (4:1 hexane/EtOAc). [α]D = –112.0 (c = 1.0, CHCl3).
S-p-Tolyl Thio(methyl 2,3,4-Tri-O-benzyl-α-D-galactopyran-
1H NMR (400 MHz, CDCl3): δ = 8.13–8.11 (m, 2 H, Ar), 7.96–7.94 (m,
2 H, Ar), 7.84–7.82 (m, 2 H, Ar), 7.64–7.38 (m, 7 H, Ar), 7.28–7.24 (m,
4 H, Ar), 7.05 (d, J = 8.0 Hz, 2 H, Ar), 5.87–5.80 (m, 2 H, H3, H4), 5.67
(app. t, J = 1.7 Hz, 1 H, 2-H), 4.99 (d, J = 1.7 Hz, 1 H, 1-H), 4.27–4.22
(m, 1 H, 5-H), 3.53 (s, 3 H, OCH3), 3.29 (dd, J = 13.8, 2.5 Hz, 1 H, 6-
Ha), 3.20 (dd, J = 13.8, 8.7 Hz, 1 H, 6-Hb), 2.31 (s, 3 H, ArCH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 165.7 (C=O), 165.6 (C=O), 165.4 (C=
O), 136.5 (Ar), 133.5 (2 × Ar), 133.1 (Ar), 132.3 (Ar), 130.2 (Ar), 130.0
(Ar), 129.9 (2 × , Ar), 129.8 (Ar), 129.4 (Ar), 129.2 (Ar), 129.0 (Ar),
128.6 (Ar), 128.5 (Ar), 128.2 (Ar), 98.5 (C-1), 70.6 (C-2), 70.0 (2 × C3 &
C4), 69.7 (C5), 55.4 (OCH3), 36.8 (C-6), 21.0 (ArCH3) ppm. HRMS (ESI)
calcd. for [M + Na] C35H32NaO8S: 635.1710, found 635.1706.
osid)uronate (25): Scale 1.0 mmol. Prepared as described in gen-
eral method 2. The crude residue was purified by flash chromatog-
raphy (4:1 hexane/EtOAc) to afford 25 (439 mg, 75 %) as a clear
viscous oil. Rf = 0.42 (4:1 hexane/EtOAc). [α]D = –41.0 (c = 0.2,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.40–7.29 (m, 15 H, Ar), 7.23–
7.21 (m, 4 H, Ar), 4.92 (d, J = 11.1 Hz, 1 H, PhCH2O), 4.91 (d, J =
3.6 Hz, 1 H, 1-H), 4.88 (d, J = 12.0 Hz, 1 H, PhCH2O), 4.84 (d, J =
11.7 Hz, 1 H, PhCH2O), 4.75 (d, J = 11.7 Hz, 1 H, PhCH2O), 4.71 (d,
J = 12.0 Hz, 1 H, PhCH2O), 4.56 (d, J = 11.1 Hz, 1 H, PhCH2O), 4.43
(d, J = 1.4 Hz, 1 H, 5-H), 4.39 (dd, J = 2.8, 1.4 Hz, 1 H, 4-H), 4.16 (dd,
J = 10.1, 3.6 Hz, 1 H, 2-H), 3.97 (dd, J = 10.1, 2.8 Hz, 1 H, 3-H), 3.49
(s, 3 H, OCH3), 2.40 (s, 3 H, ArCH3) ppm. 13C NMR (125 MHz, CDCl3):
S-p-Tolyl Thio(methyl 2,3,4-Tri-O-benzyl-α-
D-glucopyran- δ = 198.2 (C-6), 139.8 (Ar), 138.5 (Ar), 138.4 (2 × Ar), 134.8 (Ar), 130.1
osid)uronate (22): Scale 1.0 mmol. Prepared as described in gen- (Ar), 128.4 (Ar), 128.1 (2 × Ar), 127.8 (Ar), 127.6 (Ar), 127.5 (2 × Ar),
eral method 2. The crude residue was purified by flash chromatog-
raphy (6:1→4:1 hexane/EtOAc) to afford 22 (456 mg, 78 %) as a
colorless oil. Rf = 0.40 (4:1 hexane/EtOAc). [α]D = +15.5 (c = 1.0,
123.4 (Ar), 99.4 (C-1), 78.3 (C-3), 76.4 (C-4), 76.1 (2×C-5, C-2), 75.6
(PhCH2O), 73.9 (PhCH2O), 73.2 (PhCH2O), 56.1 (OCH3), 21.4 (ArCH3)
ppm. HRMS (ESI) calcd. for [M + NH4] C35H40NO6S: 602.2571, found
602.2557.
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.38–7.25 (m, 19 H, Ar), 4.97
(d, J = 10.9 Hz, 1 H, PhCH2O), 4.86 (d, J = 10.9 Hz, 1 H, PhCH2O),
4.85 (d, J = 12.4 Hz, 1 H, PhCH2O), 4.78 (d, J = 10.4 Hz, 1 H, PhCH2O),
4.73 (d, J = 3.5 Hz, 1 H, 1-H), 4.69 (d, J = 12.4 Hz, 1 H, PhCH2O), 4.68
(d, J = 10.4 Hz, 1 H, PhCH2O), 4.37 (d, J = 9.7 Hz, 1 H, 5-H), 4.05
(app. t, J = 9.3 Hz, 1 H, 3-H), 3.82 (dd, J = 9.7, 9.3 Hz, 1 H, 4-H), 3.62
(dd, J = 9.3, 3.5 Hz, 1 H, 2-H), 3.49 (s, 3 H, OCH3), 2.40 (s, 3 H, ArCH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 195.4 (C-6), 140.0 (Ar), 138.6
(Ar), 138.0 (2 × Ar), 134.5 (Ar), 130.2 (Ar), 128.6 (Ar), 128.4 (2 × Ar),
128.2 (Ar), 128.1 (2 × Ar), 128.0 (Ar), 127.8 (Ar), 127.7 (Ar), 123.1 (Ar),
98.8 (C-1), 81.5 (C-3), 79.9 (C-4), 79.3 (C-2), 76.0 (PhCH2O), 75.5 (C5),
75.3 (PhCH2O), 73.7 (PhCH2O), 55.9 (OCH3), 21.4 (ArCH3) ppm. HRMS
(ESI) calcd. for [M + NH4] C35H40O6S: 602.2571, found 602.2572.
S-p-Tolyl Thio(methyl 2,3,4-Tri-O-benzoyl-α-D-mannopyran-
osid)uronate (26): Scale 1.0 mmol. Prepared as described in gen-
eral method 2. The crude residue was purified by flash chromatog-
raphy (4:1→3:1 hexane/EtOAc) to afford 26 (464 mg, 74 %) as a
white amorphous solid. Rf = 0.31 (4:1 hexane/EtOAc). [α]D = –100.5
(c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.21–8.19 (m, 2 H,
Ar), 8.01–7.99 (m, 2 H, Ar), 7.90–7.88 (m, 2 H, Ar), 7.66–7.45 (m, 5 H,
Ar), 7.40–7.28 (m, 6 H, Ar), 7.24 (d, J = 8.0 Hz, 2 H, Ar), 6.20 (app. t,
J = 9.7 Hz, 1 H, 4-H), 5.96 (dd, J = 9.7, 3.2 Hz, 1 H, 3-H), 5.77 (dd,
J = 3.2, 2.2 Hz, 1 H, 2-H), 5.21 (d, J = 2.2 Hz, 1 H, 1-H), 4.76 (d, J =
9.7 Hz, 1 H, 5-H), 3.65 (s, 3 H, OCH3), 2.38 (s, 3 H, ArCH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 194.9 (C-6), 165.50 (C=O), 165.35 (C=O),
S-p-Tolyl Thio(methyl 2,3,4-Tri-O-benzoyl-α-
osid)uronate (23): Scale 1.0 mmol. Prepared as described in gen- (Ar), 130.1 (Ar), 129.9 (Ar), 129.8 (Ar), 129.2 (2 × Ar), 129.0 (Ar), 128.7
eral method 2. The crude residue was purified by flash chromatog- (Ar), 128.4 (Ar), 122.7 (Ar), 99.1 (C-1), 75.4 (C-5), 69.9 (C-2), 69.4 (C-
raphy (dry loading) (4:1→3:1 hexane/EtOAc) to afford 23 (539 mg, 3), 67.8 (C-4), 56.3 (OCH3), 21.4 (ArCH3) ppm. HRMS (ESI) calcd. for
D-glucopyran- 165.29 (C=O), 140.0 (Ar), 134.8 (Ar), 133.7 (Ar), 133.3 (2 × Ar), 130.2
86 %) as a white amorphous solid. Rf = 0.31 (4:1 hexane/EtOAc).
[α]D = +52.9 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.03–
[M + NH4] C35H34NO9S: 644.1949, found 644.1935.
1
N-(4-Methoxybenzyl) (Methyl 2,3,4-Tri-O-benzyl-α-D-gluco-
8.01 (m, 2 H, Ar), 7.97–7.95 (m, 2 H, Ar), 7.93–7.90 (m, 2 H, Ar), 7.57–
7.30 (m, 11 H, Ar), 7.22 (dd, J = 8.5, 0.6 Hz, 2 H, Ar), 6.21 (app. t, J =
9.8 Hz, 1 H, 3-H), 5.85 (app. t, J = 9.7 Hz, 1 H, 4-H), 5.44 (d, J =
3.6 Hz, 1 H, 1-H), 5.38 (dd, J = 10.1, 3.6 Hz, 2-H), 4.71 (d, J = 9.7 Hz,
1 H, 5-H), 3.59 (s, 3 H, OCH3), 2.37 (s, 3 H, ArCH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 194.7 (C-6), 165.8 (C=O), 165.6 (C=O), 165.1
(C=O), 140.0 (Ar), 134.8 (Ar), 133.5 (Ar), 133.3 (Ar), 133.2 (Ar), 130.2
(Ar), 130.0 (Ar), 129.9 (Ar), 129.7 (Ar), 129.1 (Ar), 129.0 (Ar), 128.9
(Ar), 128.5 (Ar), 128.3 (2 × Ar), 122.6 (Ar), 97.6 (C-1), 74.0 (C-5), 71.6
(C-2), 70.1 (C-4), 69.9 (C-3), 56.4 (OCH3), 21.4 (ArCH3) ppm. HRMS
(ESI) calcd. for [M + Na] C35H30NaO9S: 649.1503, found 649.1497.
pyranosid)uronamide (27): Scale 0.1 mmol. Prepared as described
in general method 3. The crude residue was purified by flash chro-
matography (2:1 hexane/EtOAc) to afford 27 (51 mg, 85 %) as a
white solid. Rf = 0.18 (2:1 hexane/EtOAc). [α]D = –6.1 (c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.38–7.25 (m, 15 H, Ar), 7.15 (d, J =
8.6 Hz, 2 H, Ar), 6.82 (d, J = 8.6 Hz, 2 H, Ar), 6.33 (app. t, J = 5.5 Hz,
1 H, CONHCH2), 4.97 (d, J = 10.9 Hz, 1 H, PhCH2O), 4.85 (d, J =
10.9 Hz, 1 H, PhCH2O), 4.82 (d, J = 12.0 Hz, 1 H, PhCH2O), 4.78 (d,
J = 10.5 Hz, 1 H, PhCH2O), 4.67 (d, J = 12.0 Hz, 1 H, PhCH2O), 4.64–
4.61 (m, 2 H, 1-H, PhCH2O), 4.43 (dd, J = 14.4, 5.5 Hz, 1 H, NHCH2Ar),
4.34 (dd, J = 14.4, 5.5 Hz, 1 H, NHCH2Ar), 4.10 (d, J = 9.9 Hz, 1 H, 5-
S-p-Tolyl Thio(methyl 2,3,4-Tri-O-acetyl-α-D-galactopyran- H), 4.02 (app. t, J = 9.3 Hz, 1 H, 3-H), 3.79 (s, 3 H, ArOCH3), 3.63 (dd,
osid)uronate (24): Scale 1.0 mmol. Prepared as described in gen- J = 9.9, 9.3 Hz, 1 H, 4-H), 3.57 (dd, J = 9.3, 3.5 Hz, 1 H, 2-H), 3.40 (s,
eral method 2. The crude residue was purified by flash chromatog- 3 H, OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.6 (C-6), 159.1
raphy (2:1 hexane/EtOAc) to afford 24 (396 mg, 90 %) as a clear (Ar), 138.6 (Ar), 138.0 (Ar), 137.9 (Ar), 129.8 (Ar), 129.3 (Ar), 128.5
viscous oil. Rf = 0.36 (2:1 hexane/EtOAc). [α]D = +72.8 (c = 1.0,
(Ar), 128.4 (3 × Ar), 128.2 (Ar), 128.1 (2 × Ar), 128.0 (Ar), 127.8 (Ar),
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.27–7.23 (m, 4 H, Ar), 5.82 127.7 (Ar), 114.1 (Ar), 98.5 (C-1), 81.5 (C-3), 80.3 (C-4), 79.2 (C-2), 75.9
(dd, J = 3.3, 1.6 Hz, 1 H, 4-H), 5.43–5.39 (m, 1 H, 3-H), 5.27–5.24 (m, (PhCH2O), 75.2 (PhCH2O), 73.6 (PhCH2O), 70.8 (C-5), 55.8 (OCH3), 55.3
2 H, 1-H, 2-H), 4.66 (d, J = 1.6 Hz, 1 H, 5-H), 3.55 (s, 3 H, OCH3), 2.39 (ArOCH3), 43.0 (NHCH2Ar) ppm. HRMS (ESI) calcd. for [M + H]
(s, 3 H, ArCH3), 2.12 (s, 6 H, COCH3, COCH3), 2.00 (s, 3 H, COCH3) C36H40NO7: 598.2799, found 598.2790.
1
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1
Methyl 2,3,4-Tri-O-benzyl-α-
Scale 0.1 mmol. Prepared as described in general method 3. The
D
-glucopyranosiduronamide (28):
[α]D = +11.3 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.39–
7.25 (m, 15 H, Ar), 7.02 (d, J = 7.8 Hz, 1 H, CONHCH), 4.94 (d, J =
crude residue was purified by flash chromatography (1:2 hexane/ 10.8 Hz, 1 H, PhCH2O), 4.83 (d, J = 10.8 Hz, 1 H, PhCH2O), 4.83 (d,
EtOAc) to afford 28 (32 mg, 66 %) as a white solid. Rf = 0.24 (1:2
J = 12.3 Hz, 1 H, PhCH2O), 4.78 (d, J = 10.2 Hz, 1 H, PhCH2O), 4.73
(d, J = 10.3 Hz, 1 H, PhCH2O), 4.68 (d, J = 3.5 Hz, 1 H, 1-H), 4.68 (d,
hexane/EtOAc). [α]D = –8.2 (c = 1.0, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.39–7.28 (m, 15 H), 6.12 (br. s, 1 H, CONHa), 5.79 (br. s, J = 12.3 Hz, 1 H, PhCH2O), 4.65–4.62 (m, 1 H, NHCHCH2), 4.15 (d, J =
1 H, CONHb), 4.98 (d, J = 10.9 Hz, 1 H, PhCH2O), 4.87–4.81 (m, 3 H, 9.9 Hz, 1 H, 5-H), 4.02 (app. t, J = 9.3 Hz, 1 H, 3-H), 3.77 (dd, J = 8.8,
PhCH2O), 4.71–4.65 (m, 3 H, PhCH2O, 1-H), 4.12 (d, J = 9.7 Hz, 1 H,
5-H), 4.02 (app. t, J = 9.5 Hz, 1 H, 3-H), 3.61 (dd, J = 9.7, 9.5 Hz, 1 H,
2.9 Hz, 1 H, CHCH2O), 3.63 (app. t, J = 9.4 Hz, 1 H, 4-H), 3.59–3.57
(m, 2 H, 2-H, CHCH2O), 3.42 (s, 3 H, OCH3), 1.48 [s, 9 H, C(CH3)3],
4-H), 3.57 (dd, J = 9.5, 3.5 Hz, 1 H, 2-H), 3.41 (s, 3 H, OCH3) ppm. 1.11 [s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 169.2 (C=
13C NMR (125 MHz, CDCl3): δ = 171.4 (C-6), 138.5 (Ar), 138.0 (Ar), O), 168.7 (C=O), 138.7 (Ar), 138.1 (2 × Ar), 128.5 (Ar), 128.4 (Ar), 128.3
137.7 (Ar), 128.6 (Ar), 128.5 (2 × Ar), 128.4 (2 × Ar), 128.3 (Ar), 128.2 (2 × Ar), 128.2 (Ar), 128.0 (2 × Ar), 127.6 (Ar), 98.4 (C-1), 82.0
(3 × Ar), 128.1 (Ar), 128.0 (Ar), 127.9 (Ar), 127.7 (Ar), 98.4 (C-1), 81.6 [C(CH3)3], 81.5 (C-3), 80.6 (C-3), 79.3 (C-2), 76.0 (PhCH2O), 75.1
(C-3), 80.2 (C-4), 79.2 (C-2), 75.9 (PhCH2O), 75.4 (PhCH2O), 73.6 (PhCH2O), 73.6 (PhCH2O), 73.0 [C(CH3)3], 70.9 (C-5), 62.1 (CHCH2O),
(PhCH2O), 70.0 (C-5), 55.8 (OCH3) ppm. HRMS (ESI) calcd. for [M +
55.7 (OCH3), 53.1 (NHCH), 28.1 [C(CH3)3], 27.4 [C(CH3)3] ppm. HRMS
H] C28H32NO6: 478.2224, found 478.2217.
(ESI) calcd. for [M + H] C39H52NO9: 678.3637, found 678.3631.
2-N-(Methyl 2,3,4-Tri-O-benzyl-α-D-glucopyranosiduronoyl)-1,3- N-(Methyl 2,3,4-Tri-O-benzyl-α-D-glucopyranosiduronoyl)-L-
di-O-benzyl-2-deoxy-glycerol (29): Scale 0.1 mmol. Prepared as
described in general method 3. The crude residue was purified by
flash chromatography (4:1→2:1 hexane/EtOAc) to afford 29 (47 mg,
64 %) as a white solid. Rf = 0.24 (2:1 hexane/EtOAc). [α]D = –6.3 (c =
threonine tert-Butyl Ester (32): Scale 0.1 mmol. Prepared as de-
scribed in general method 3. The crude residue was purified by
flash chromatography (2:1 hexane/EtOAc) to afford 32 (40 mg,
63 %) as a oil. Rf = 0.22 (2:1 hexane/EtOAc). [α]D = –14.6 (c = 1.0,
1
1
1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.40–7.26 (m, 25 H, Ar),
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.39–7.25 (m, 15 H, Ar), 6.97
6.49 (d, J = 8.4 Hz, 1 H, CONHCH), 4.96 (d, J = 10.9 Hz, 1 H, PhCH2O),
4.85–4.82 (m, 2 H, PhCH2O), 4.74 (d, J = 10.6 Hz, 1 H, PhCH2O), 4.69–
(d, J = 8.6 Hz, 1 H, CONHCH), 4.96 (d, J = 10.8 Hz, 1 H, PhCH2O),
4.84 (d, J = 10.8 Hz, 1 H, PhCH2O), 4.83 (d, J = 12.4 Hz, 1 H, PhCH2O),
4.64 (m, 3 H, PhCH2O, 1-H), 4.52–4.44 (m, 4 H, PhCH2O), 4.37–4.33 4.78–4.74 (m, 2 H, PhCH2O), 4.68 (d, J = 12.4 Hz, 1 H, PhCH2O), 4.68
(m, 1 H, NHCH), 4.07 (d, J = 9.9 Hz, 1 H, 5-H), 4.01 (app. t, J = 9.3 Hz, (d, J = 3.5 Hz, 1 H, 1-H), 4.54 (dd, J = 8.6, 2.9 Hz, 1 H, NHCHCH),
1 H, 3-H), 3.65–3.56 (m, 4 H, CHCH2OBn, 2-H, 4-H), 3.53 (dd, J = 9.3,
4.30–4.29 (m, 1 H, CHCHOH), 4.20 (d, J = 10.0 Hz, 1 H, 5-H), 4.04
5.9 Hz, 1 H, CHCH2OBn), 3.46 (dd, J = 9.3, 5.9 Hz, 1 H, CHCH2OBn), (app. t, J = 9.2 Hz, 1 H, 3-H), 3.65 (dd, J = 9.8, 9.0 Hz, 1 H, 4-H), 3.58
3.40 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.7 (C- (dd, J = 9.7, 3.5 Hz, 1 H, 2-H), 3.41 (s, 3 H, OCH3), 2.05 (s, 1 H, CHOH),
6), 138.7 (Ar), 138.1 (2 × Ar), 138.0 (2 × Ar), 128.5 (Ar), 128.4 (2 × Ar), 1.49 [s, 9 H, C(CH3)3], 1.21 (d, J = 6.4 Hz, 3 H, CHCH3) ppm. 13C NMR
128.3 (Ar), 128.2 (Ar), 128.0 (3 × Ar), 127.7 (4 × Ar), 127.6 (Ar), 98.5 (125 MHz, CDCl3): δ = 169.8 (C=O), 169.7 (C=O), 138.6 (Ar), 138.0
(C-1), 81.5 (C-3), 80.4 (C-4), 79.2 (C-2), 75.9 (PhCH2O), 75.1 (PhCH2O), (2 × Ar), 128.6 (Ar), 128.4 (Ar), 128.3 (Ar), 128.2 (2 × Ar), 128.1 (Ar),
73.6 (PhCH2O), 73.1 (2 × PhCH2O), 70.9 (C-5), 68.3 (CHCH2OBn), 68.2 127.9 (Ar), 127.7 (Ar), 127.6 (Ar), 98.4 (C-1), 82.7 [C(CH3)3], 81.5 (C-3),
(CHCH2OBn), 55.8 (OCH3), 48.4 (NHCH) ppm. HRMS (ESI) calcd. for
[M + H] C45H50NO8: 732.3531, found 732.3516.
80.6 (C-4), 79.2 (C-2), 76.0 (PhCH2O), 75.2 (PhCH2O), 73.6 (PhCH2O),
70.6 (C-5), 68.4 (CHCHOH), 57.5 (NHCH), 55.8 (OCH3), 28.0 [C(CH3)3],
20.0 (CHCH3) ppm. HRMS (ESI) calcd. for [M + H] C36H46NO9:
636.3167, found 636.3161.
N-(Methyl 2,3,4-Tri-O-benzyl-α-D-glucopyranosiduronoyl)-L-
alanine tert-Butyl Ester (30): Scale 0.1 mmol. Prepared as de-
scribed in general method 3. The crude residue was purified by
flash chromatography (2:1 hexane/EtOAc) to afford 30 (43 mg,
N-(4-Methoxybenzyl) (Methyl 2,3,4-Tri-O-benzoyl-α-
D-gluco-
pyranosid)uronamide (33): Scale 0.1 mmol. Prepared as described
71 %) as a viscous oil. Rf = 0.27 (2:1 hexane/EtOAc). [α]D = –4.64 in general method 3. The crude residue was purified by flash chro-
1
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.39–7.27 (m, 15 H, matography (3:2→1:1 hexane/EtOAc) to afford 33 (55 mg, 86 %) as
Ar), 6.83 (d, J = 7.0 Hz, 1 H, CONHCH), 4.96 (d, J = 10.9 Hz, 1 H,
a clear viscous oil. Rf = 0.43 (1:1 hexane/EtOAc). [α]D = +99.7 (c =
PhCH2O), 4.85 (d, J = 11.8 Hz, 1 H, PhCH2O), 4.83 (d, J = 12.7 Hz, 1 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.04–7.99 (m, 4 H, Ar),
H, PhCH2O), 4.76 (d, J = 10.3 Hz, 1 H, PhCH2O), 4.73 (d, J = 10.4 Hz,
1 H, PhCH2O), 4.67 (d, J = 12.1 Hz, 1 H, PhCH2O), 4.66 (d, J = 3.5 Hz,
7.91–7.89 (m, 2 H, Ar), 7.56–7.50 (m, 2 H, Ar), 7.48–7.38 (m, 5 H, Ar),
7.34–7.30 (m, 2 H, Ar), 7.29–7.26 (m, 2 H, Ar), 6.93–6.91 (m, 2 H, Ar),
1 H, 1-H) 4.46 [dt, J = 14.2, 7.2 Hz, 1 H, NHCHCO2C(CH3)3], 4.11 (d, 6.71 (app. t, J = 5.6 Hz, 1 H, CONHCH2), 6.20 (app. t, J = 9.9 Hz, 1 H,
J = 9.9 Hz, 1 H, 5-H), 4.02 (app. t, J = 9.3 Hz, 1 H, 3-H), 3.61 (dd, J = 3-H), 5.68 (app. t, J = 9.9 Hz, 1 H, 4-H), 5.30 (d, J = 3.6 Hz, 1 H, 1-H),
9.9, 8.9 Hz, 1 H, 4-H), 3.56 (dd, J = 9.7, 3.5 Hz, 1 H, 2-H), 3.41 (s, 3
H, OCH3), 1.48 [s, 9 H, NHCHCO2C(CH3)3], 1.36 (d, J = 7.1 Hz, 3 H,
5.24 (dd, J = 10.2, 3.6 Hz, 1 H, 2-H), 4.56 (d, J = 10.2 Hz, 1 H, 5-H),
4.49 (dd, J = 14.5, 6.0 Hz, 1 H, NHCH2Ar), 4.35 (dd, J = 14.5, 5.4 Hz,
CHCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.0 (C=O), 168.5 (C= 1 H, NHCH2Ar), 3.84 (s, 3 H, ArOCH3), 3.50 (s, 3 H, OCH3) ppm. 13C
O), 138.7 (Ar), 138.0 (Ar), 138.0 (Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar),
128.3 (Ar), 128.2 (Ar), 128.0 (Ar), 127.9 (Ar), 127.7 (Ar), 127.6 (Ar), 165.5 (C=O), 159.2 (Ar), 133.5 (Ar), 133.2 (Ar), 133.1 (Ar), 130.0 (2 ×
98.4 (C-1), 82.2 [NHCHCO2C(CH3)3], 81.5 (C-3), 80.4 (C-4), 79.2 (C-2), Ar), 129.8 (Ar), 129.7 (Ar), 129.4 (Ar), 129.3 (Ar), 129.2 (Ar), 128.9 (Ar),
75.9 (PhCH2O), 75.2 (PhCH2O), 73.6 (PhCH2O), 70.7 (C-5), 55.8 (OCH3), 128.5 (Ar), 128.3 (2 × Ar), 114.2 (Ar), 97.2 (C-1), 71.9 (C-2), 70.4 (C-4),
48.5 [NHCHCO2C(CH3)3], 28.0 [NHCHCO2C(CH3)3], 18.6 (CHCH3) ppm. 69.8 (C-3), 68.7 (C-5), 56.2 (OCH3), 55.3 (ArOCH3), 42.7 (NHCH2Ar)
HRMS (ESI) calcd. for [M + Na] C35H43NNaO8: 628.2881, found ppm. HRMS (ESI) calcd. for [M + H] C36H34NO10: 640.2168, found
NMR (125 MHz, CDCl3): δ = 166.9 (C=O), 165.9 (C=O), 165.6 (C=O),
628.2876.
640.2177.
N-(Methyl 2,3,4-Tri-O-benzyl-α-
D
-glucopyranosiduronoyl)-O-
N-(2-Hydroxyethyl) (Methyl 2,3,4-Tri-O-benzoyl-α-D-gluco-
tert-butyl-L-serine tert-Butyl Ester (31): Scale 0.1 mmol. Prepared pyranosid)uronamide (34): Scale 0.1 mmol. Prepared as described
as described in general method 3. The crude residue was purified
by flash chromatography (4:1→2:1 hexane/EtOAc) to afford 31
(42 mg, 70 %) as a clear viscous oil. Rf = 0.47 (2:1 hexane/EtOAc).
in general method 3. The crude residue was purified by flash chro-
matography (20:1 CH2Cl2/CH3OH) to afford 34 (48 mg, 86 %) as a
clear viscous oil. Rf = 0.31 (1:1 CH2Cl2/CH3OH). [α]D = +75.0 (c = 1.0,
Eur. J. Org. Chem. 2016, 2653–2664
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Full Paper
1
CHCl3). H NMR (600 MHz, CDCl3): δ = 8.01–7.99 (m, 4 H, Ar), 7.90– +116.5 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.24–7.21 (m,
7.88 (m, 2 H, Ar), 7.56–7.50 (m, 2 H, Ar), 7.46–7.38 (m, 5 H, Ar), 7.32– 2 H, Ar), 6.90–6.87 (m, 2 H, Ar), 6.81 (app. t, J = 5.8 Hz, 1 H,
7.29 (m, 2 H, Ar), 6.89 (app. t, J = 5.8 Hz, 1 H, CONHCH2), 6.22 (app. CONHCH2), 5.88 (dd, J = 3.4, 1.7 Hz, 1 H, 4-H), 5.44 (dd, J = 10.5,
t, J = 9.9 Hz, 1 H, 3-H), 5.62 (app. t, J = 9.9 Hz, 1 H, 4-H), 5.34 (d, J =
3.6 Hz, 1 H, 1-H), 5.29 (dd, J = 10.1, 3.6 Hz, 1 H, 2-H), 4.50 (d, J =
3.4 Hz, 1 H, 3-H), 5.12–5.08 (m, 2 H, 1-H, 2-H), 4.62 (dd, J = 14.6,
7.0 Hz, 1 H, NHCH2Ar), 4.51 (d, J = 1.6 Hz, 1 H, 5-H), 4.22 (dd, J =
10.2 Hz, 1 H, 5-H), 3.84–3.81 (m, 1 H, CH2CH2OH), 3.71–3.69 (m, 1 14.6, 5.0 Hz, 1 H, NHCH2), 3.82 (s, 3 H, ArOCH3), 3.43 (s, 3 H, OCH3),
H, CH2CH2O), 3.60 (dddd, J = 14.2, 5.8, 5.8, 3.2 Hz, 1 H, NHCH2CH2),
3.50 (s, 3 H, OCH3), 3.30 (dddd, J = 13.9, 8.1, 5.6, 3.4 Hz, 1 H,
NHCH2CH2), 2.76 (s, 1 H, CH2OH) ppm. 13C NMR (125 MHz, CDCl3):
2.10 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3), 1.95 (s, 3 H, COCH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.5 (C=O), 169.7 (C=O), 169.3 (C=
O), 166.3 (C=O), 159.2 (Ar), 130.1 (Ar), 129.2 (Ar), 114.1 (Ar), 97.5 (C-
δ = 168.2 (C=O), 166.1 (C=O), 165.9 (C=O), 165.6 (C=O), 133.6 (Ar), 1), 69.5 (C-5), 69.0 (C-4), 68.0 (C-2), 67.1 (C-3), 56.1 (OCH3), 55.3
133.4 (Ar), 133.2 (Ar), 130.0 (2 × Ar) 129.7 (Ar), 129.1 (Ar), 128.9 (Ar), (ArOCH3), 42.5 (NHCH2), 20.8 (COCH3), 20.6 (COCH3), 20.4 (COCH3)
128.8 (Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 97.3 (C-1), 71.9 (C-2),
ppm. HRMS (ESI) calcd. for [M + Na] C21H27NNaO10: 476.1527, found
71.0 (C-4), 69.5 (C-3), 69.1 (C-5), 61.2 (CH2CH2O), 56.2 (OCH3), 42.2 476.1516.
(NHCH2CH2) ppm. HRMS (ESI) calcd. for [M + H] C30H30NO10
564.1864, found 564.1859.
:
N-(Methyl 2,3,4-Tri-O-acetyl-α-
D-galactopyranosiduronoyl)-O-
tert-butyl- -serine tert-Butyl Ester (38): Scale 0.1 mmol. Prepared
L
2-N-(Methyl 2,3,4-Tri-O-benzoyl-α-
D
-glucopyranosiduronoyl)-
as described in general method 3. The crude residue was purified
1,3-di-O-benzyl-2-deoxy-glycerol (35): Scale 0.1 mmol. Prepared
by flash chromatography (3:2→1:1 hexane/EtOAc) to afford 38
as described in general method 3. The crude residue was purified
by flash chromatography (2:1 hexane/EtOAc) to afford 35 (56 mg, [α]D = +101.8 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.29
(34 mg, 64 %) as a clear viscous oil. Rf = 0.48 (1:1 hexane/EtOAc).
1
73 %) as a clear viscous oil. Rf = 0.23 (2:1 hexane/EtOAc). [α]D
+70.6 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.03–7.99 (m, 5.44 (dd, J = 10.7, 3.4 Hz, 1 H, 3-H), 5.18 (dd, J = 10.7, 3.6 Hz, 1 H,
4 H, Ar), 7.92–7.90 (m, 2 H, Ar), 7.57–7.30 (m, 19 H, Ar), 6.88 (d, J = 2-H), 5.15 (d, J = 3.6 Hz, 1 H, 1-H), 4.63 (app. dt, J = 8.6, 3.0 Hz, 1 H,
=
(d, J = 8.1 Hz, 1 H, CONHCH), 5.87 (dd, J = 3.4, 1.6 Hz, 1 H, 4-H),
1
8.5 Hz, 1 H, CONHCH), 6.20 (app. t, J = 9.9 Hz, 1 H, 3-H), 5.63 (app.
NHCHCH2), 4.51 (d, J = 1.5 Hz, 1 H, 5-H), 3.82 (dd, J = 8.8, 3.1 Hz, 1
t, J = 9.9 Hz, 1 H, 4-H), 5.34 (d, J = 3.6 Hz, 1 H, 1-H), 5.29 (dd, J = H, CHCH2O), 3.48 (dd, J = 8.8, 3.0 Hz, 1 H, CHCH2O), 3.47 (s, 3 H,
10.2, 3.6 Hz, 1 H, 2-H), 4.62 (d, J = 12.0 Hz, 1 H, PhCH2O), 4.59 (d, OCH3), 2.12 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.00 (s, 3 H, COCH3),
J = 12.0 Hz, 1 H, PhCH2O), 4.54 (d, J = 12.0 Hz, 1 H, PhCH2O), 4.51 1.49 [s, 9 H, C(CH3)3], 1.19 [s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz,
(d, J = 12.0 Hz, 1 H, PhCH2O), 4.50 (d, J = 10.1 Hz, 1 H, 5-H), 4.31–
4.28 (m, 1 H, NHCH), 3.73 (dd, J = 9.3, 3.9 Hz, 1 H, CHCH2OBn), 3.69
(dd, J = 9.4, 4.3 Hz, 1 H, CHCH2OBn), 3.65 (dd, J = 9.3, 6.2 Hz, 1 H,
CDCl3): δ = 170.5 (C=O), 169.7 (C=O), 169.3 (C=O), 169.0 (C=O), 166.2
(C=O), 97.4 (C-1), 82.0 [OC(CH3)3], 73.2 [OC(CH3)3], 69.3 (C-5), 68.9
(C-4), 68.0 (C-2), 67.3 (C-3), 62.5 (CHCH2O), 56.1 (OCH3), 52.9
CHCH2OBn), 3.56 (dd, J = 9.4, 5.9 Hz, 1 H, CHCH2OBn), 3.50 (s, 3 H, (NHCHCH2), 28.0 [C(CH3)3], 27.4 [C(CH3)3], 20.8 (COCH3), 20.7
OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.9 (C=O), 165.9 (C= (COCH3), 20.6 (COCH3) ppm. HRMS (ESI) calcd. for [M + H]
O), 165.6 (C=O), 165.4 (C=O), 138.2 (Ar), 138.1 (Ar), 133.5 (Ar), 133.2
(Ar), 133.1 (Ar), 130.0 (2 × Ar), 129.7 (Ar), 129.3 (Ar), 129.2 (Ar), 128.9
(Ar), 128.5 (Ar), 128.4 (2 × Ar), 128.3 (2 × Ar), 127.8 (Ar), 127.7 (2 ×
Ar), 127.6 (Ar), 97.2 (C-1), 73.2 (PhCH2O), 73.1 (PhCH2O), 71.9 (C-2),
70.4 (C-4), 69.9 (C-3), 68.8 (C-5), 68.2 (CHCH2OBn), 68.1 (CHCH2OBn),
56.2 (OCH3), 48.2 (NHCH) ppm. HRMS (ESI) calcd. for [M + H]
C45H44NO11: 774.2909, found 774.2893.
C24H40NO12: 534.2545, found 534.2538.
N-(Methyl 2,3,4-Tri-O-acetyl-α- -galactopyranosiduronoyl)-L-
alanine tert-Butyl Ester (39): Scale 0.1 mmol. Prepared as de-
scribed in general method 3. The crude residue was purified by
flash chromatography (3:2→1:1 hexane/EtOAc) to afford 39 (29 mg,
D
63 %) as a clear viscous oil. Rf = 0.20 (3:2 hexane/EtOAc). [α]D
=
+92.7 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.15 (d, J =
7.6 Hz, 1 H, CONHCH), 5.84 (dd, J = 3.4, 1.7 Hz, 1 H, 4-H), 5.44 (dd,
J = 10.1, 3.4 Hz, 1 H, 3-H), 5.16–5.12 (m, 2 H, 1-H, 2-H), 4.52–4.46
(m, 2 H, 5-H, NHCHCH3), 3.45 (s, 3 H, OCH3), 2.11 (s, 3 H, COCH3),
2.07 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3), 1.49 [s, 9 H, C(CH3)3], 1.38
(d, J = 7.1 Hz, 3 H, CHCH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
N-(Methyl 2,3,4-Tri-O-benzoyl-α-D-glucopyranosiduronoyl)-L-
threonine tert-Butyl Ester (36): Scale 0.1 mmol. Following the
general method 3, the crude residue was purified by flash chroma-
tography (3:2→1:1 hexane/EtOAc) to afford 36 (28 mg, 41 %) as a
clear viscous oil. Rf = 0.52 (1:1 hexane/EtOAc). [α]D = +67.1 (c = 1.0,
1
CHCl3). H NMR (600 MHz, CDCl3): δ = 8.02–7.97 (m, 4 H, Ar), 7.90– 171.7 (C=O), 170.5 (C=O), 169.7 (C=O), 169.2 (C=O), 165.9 (C=O),
7.88 (m, 2 H, Ar), 7.56–7.36 (m, 7 H, Ar), 7.32–7.29 (m, 2 H, Ar), 7.23
97.5 (C-1), 82.3 [C(CH3)3], 69.4 (C-5), 69.0 (C-4), 68.0 (C-2), 67.1 (C-
(d, J = 8.7 Hz, 1 H, CONHCH), 6.21 (app. t, J = 9.9 Hz, 1 H, 3-H), 5.68 3), 56.1 (OCH3), 48.3 (NHCHCH3), 28.0 [C(CH3)3], 20.8 (COCH3), 20.6
(app. t, J = 9.9 Hz, 1 H, 4-H), 5.37 (d, J = 3.6 Hz, 1 H, 1-H), 5.31 (dd,
J = 10.2, 3.6 Hz, 1 H, 2-H), 4.56 (d, J = 10.2 Hz, 1 H, 5-H), 4.47 (dd,
J = 8.7, 3.2 Hz, 1 H, NHCH), 4.31–4.30 (m, 1 H, CHCHOH), 3.52 (s, 3
H, OCH3), 2.27 (s, 1 H, CHOH), 1.50 [s, 9 H, C(CH3)3], 1.31 (d, J =
6.5 Hz, 3 H, CHCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 169.6 (C=
O), 167.7 (C=O), 165.8 (C=O), 165.7 (C=O), 165.6 (C=O), 133.5 (Ar),
133.2 (2 × Ar) 130.0 (Ar), 129.7 (Ar), 129.1 (2 × Ar), 128.9 (Ar), 128.5
(Ar), 128.4 (Ar), 128.3 (2 × Ar), 97.3 (C-1), 82.8 [C(CH3)3], 71.8 (C-2),
70.7 (C-4), 69.8 (C-3), 68.9 (2 × C-5, CHCHOH), 57.5 (NHCH), 56.3
(OCH3), 28.0 [C(CH3)3], 20.1 (CHCH3) ppm. HRMS (ESI) calcd. for [M
+ H] C36H40NO12: 678.2545, found 678.2531.
(COCH3), 20.4 (COCH3), 18.7 (CHCH3) ppm. HRMS (ESI) calcd. for [M
+ Na] C20H31NNaO11: 484.1789 Found 484.1779.
N-(4-Methoxybenzyl) (2,3,4-Tri-O-benzyl-α-D-galactopyran-
osid)uronamide (40): Scale 0.1 mmol. Prepared as described in
general method 3. The crude residue was purified by flash chroma-
tography (2:1 hexane/EtOAc) to afford 40 (50 mg, 83 %) as a clear
viscous oil. Rf = 0.20 (2:1 hexane/EtOAc). [α]D = +60.1 (c = 1.0,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.39–7.26 (m, 15 H, Ar), 7.11
(d, J = 8.5 Hz, 2 H, Ar), 6.79 (app. t, J = 5.6 Hz, 1 H, CONHCH2), 6.73
(d, J = 8.6 Hz, 2 H, Ar), 4.92 (d, J = 10.9 Hz, 1 H, PhCH2O), 4.85 (d,
J = 12.1 Hz, 1 H, PhCH2O), 4.81 (d, J = 11.8 Hz, 1 H, PhCH2O), 4.76
(d, J = 11.8 Hz, 1 H, PhCH2O), 4.70–4.67 (m, 2 H, PhCH2O, 1-H), 4.58
N-(4-Methoxybenzyl) (Methyl 2,3,4-Tri-O-acetyl-α-D-galacto-
pyranoside)uronamide (37): Scale 0.1 mmol. Prepared as de- (d, J = 10.9 Hz, 1 H, PhCH2O), 4.48–4.42 (m, 2 H, 3-H, NHCH2Ar),
scribed in general method 3. The crude residue was purified by
flash chromatography (3:2 EtOAc/hexane) to afford 37 (41 mg,
4.35–4.29 (m, 2 H, NHCH2Ar, 5-H), 4.05–3.98 (m, 2 H, 2-H, 4-H), 3.76
(s, 3 H, ArOCH3), 3.36 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz, CDCl3):
δ = 168.6 (C-6), 159.0 (Ar), 138.7 (Ar), 138.5 (2 × Ar), 129.7 (Ar), 129.1
91 %) as a clear viscous oil. Rf = 0.25 (3:2 EtOAc/hexane). [α]D
=
Eur. J. Org. Chem. 2016, 2653–2664
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(Ar), 128.4 (2 × Ar), 128.2 (Ar), 128.1 (Ar), 128.0 (Ar), 127.8 (Ar), 127.6 5.27 (m, 9 H), 5.20 (d, J = 1.5 Hz, 2 H, 1′-H of 45), 5.07 (t, J = 10.0 Hz,
(Ar), 127.5 (2 × Ar), 114.0 (Ar), 99.2 (C-1), 78.4 (C-4), 76.6 (C-3), 75.7 1 H), 4.97 (t, J = 10.0 Hz, 2 H), 4.49 (d, J = 7.7 Hz, 1 H, 1-H of 45a),
(C-2), 75.4 (PhCH2O), 73.7 (PhCH2O), 73.0 (PhCH2O), 71.3 (C-5), 55.9 4.40–4.32 (m, 7 H), 4.20 (dq, J = 9.9, 6.3 Hz, 2 H), 4.03–3.74 (m, 9 H),
(OCH3), 55.3 (ArOCH3), 42.6 (NHCH2Ar) ppm. HRMS (ESI) calcd. for 3.66–3.54 (m, 9 H), 3.51–3.38 (m, 4 H), 2.71 (d, J = 2.8 Hz, 1 H), 2.41
[M + H] C36H40NO7: 598.2799, found 598.2790.
(d, J = 2.7 Hz, 1 H), 2.14 (s, 3 H), 2.13 (s, 6 H), 2.03 (s, 3 H), 1.99 (s,
6 H), 1.97 (s, 3 H), 1.95 (s, 6 H), 1.20 (d, J = 6.3 Hz, 3 H), 1.06–0.92
(m, 6 H), 0.85 (d, J = 6.2 Hz, 6 H), 0.04 (s, 9 H), 0.03 (s, 18 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.2, 170.2, 170.2, 170.0, 169.9,
137.2, 137.0, 129.3, 129.0, 128.4, 128.0, 126.3, 126.2, 103.0 (C-1 of
45), 101.8, 101.7 (C-1 of 45a), 101.6, 97.7 (C-1′ of 45), 97.6 (C-1′ of
45a), 80.7, 79.0, 77.1, 76.4, 75.7, 74.9, 71.3, 71.17, 69.7, 69.7, 69.3,
69.3, 68.8, 68.7, 68.2, 68.0, 66.8, 66.4, 66.0, 65.9, 21.0, 21.0, 20.8, 20.8,
18.5, 18.3, 17.3, 16.8, –1.4, –1.5 ppm. HRMS (ESI) calcd. for [M + Na]
N-(4-Methoxybenzyl) (2,3,4-Tri-O-benzoyl-α-D-mannopyran-
osid)uronamide (41): Scale 0.1 mmol. Prepared as described in
general method 3. The crude residue was purified by flash chroma-
tography (3:2→1:1 hexane/EtOAc) to afford 41 (63 mg, 98 %) as a
clear viscous oil. Rf = 0.43 (1:1 hexane/EtOAc). [α]D = –19.0 (c = 1.0,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 8.07–8.05 (m, 4 H, Ar), 7.87
(d, J = 7.4 Hz, 2 H, Ar), 7.64–7.39 (m, 7 H, Ar), 7.31–7.26 (m, 4 H, Ar),
6.89 (d, J = 8.5 Hz, 2 H, Ar), 6.80 (app. t, J = 5.5 Hz, 1 H, CONHCH2),
6.04 (dd, J = 10.0, 10.0 Hz, 1 H, 4-H), 5.93 (dd, J = 10.1, 3.2 Hz, 1 H,
3-H), 5.69 (dd, J = 2.9, 1.9 Hz, 1 H, 2-H), 5.04 (d, J = 1.3 Hz, 1 H, 1-
H), 4.58 (d, J = 10.0 Hz, 1 H, 5-H), 4.50 (dd, J = 14.5, 6.0 Hz, 1 H,
NHCH2Ar), 4.38 (dd, J = 14.6, 5.4 Hz, 1 H, NHCH2Ar), 3.82 (s, 3 H,
ArOCH3), 3.55 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
167.3 (C=O), 165.7 (C=O), 165.41 (C=O), 165.37 (C=O), 159.1 (Ar),
133.6 (Ar), 133.3 (Ar), 133.1 (Ar), 130.0 (Ar), 129.9 (2 × Ar), 129.8 (Ar),
129.5 (Ar), 129.2 (2 × Ar), 129.1 (Ar), 128.7 (Ar), 128.4 (Ar), 128.3 (Ar),
114.2 (Ar), 98.8 (C-1), 70.2 (C-2), 69.7 (C-5), 69.5 (C-3), 67.8 (C-4), 56.1
(OCH3), 55.3 (ArOCH3), 42.6 (NHCH2Ar) ppm. HRMS (ESI) calcd. for
[M + H] C36H34NO10: 640.2177 Found 640.2163.
C
30H44NaO13Si: 663.2443, found 663.2440.
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
(1→3)-2-O-acetyl-4,6-O-benzylidene-ꢀ- -glucopyranoside (S1)
and 2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α- -rhamnopyran-
osyl-(1→2)-3-O-acetyl-4,6-O-benzylidene-ꢀ- -glucopyranoside
L
-rhamnopyranosyl-
D
L
D
(S1a): To a solution of 45/45a (904 mg, 1.41 mmol) in pyridine
(14 mL) and Ac2O (7 mL) was added DMAP (17 mg, 0.14 mmol).
The reaction mixture was stirred for 3 h at room temperature, then
the Ac2O was quenched by addition of CH3OH (7 mL). Then, the
mixture was co-concentrated with toluene (3 ×). The crude residue
was purified by flash chromatography (1:1 hexane/EtOAc) to afford
S1/S1a (934 mg, 97 %, S1:S1a = 2:1) as a white solid, which was
an inseparable mixture. Rf = 0.56 (1:1 hexane/EtOAc). 1H NMR
(500 MHz, CDCl3): δ = 7.50–7.48 (m, 5 H), 7.45–7.43 (m, 2 H), 7.38–
7.33 (m, 11 H), 5.57 (s, 2 H), 5.48 (s, 1 H), 5.40 (t, J = 9.4 Hz, 1 H),
5.34–5.29 (m, 4 H), 5.11–5.05 (m, 5 H), 5.04 (d, J = 1.9 Hz, 1 H, 1′-H
of S1a), 4.99 (dd, J = 3.4, 1.8 Hz, 2 H), 4.95 (t, J = 9.9 Hz, 2 H), 4.91
(d, J = 1.7 Hz, 2 H, 1′-H of S1), 4.57 (d, J = 7.6 Hz, 1 H, 1-H of S1a),
4.49 (d, J = 8.0 Hz, 2 H, 1-H of S1), 4.41–4.37 (m, 3 H), 4.32 (dq, J =
10.2, 6.3 Hz, 1 H), 4.10 (dq, J = 10.0, 6.2 Hz, 2 H), 4.04–3.88 (m, 5 H),
3.87–3.75 (m, 3 H), 3.75–3.62 (m, 4 H), 3.62–3.44 (m, 6 H), 2.15 (s, 3
H), 2.14 (s, 6 H), 2.14 (s, 3 H), 2.12 (s, 6 H), 2.05 (s, 3 H), 2.02 (s, 3 H),
2.00 (s, 6 H), 1.98 (s, 6 H), 1.21 (d, J = 6.2 Hz, 3 H), 1.05–0.89 (m, 6
H), 0.68 (d, J = 6.2 Hz, 6 H), 0.06 (s, 9 H), 0.03 (s, 18 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 170.0, 170.0, 169.8, 169.4, 137.1, 136.9,
129.2, 129.0, 128.2, 128.1, 126.4, 126.1, 102.0, 101.7 (C-1 of S1a),
101.4, 101.0 (C-1 of S1), 97.7 (C-1′ of S1a), 97.6 (C-1′ of S1), 79.1,
78.7, 73.9, 73.5, 71.4, 71.4, 70.6, 70.3, 68.8, 68.7, 68.6, 68.4, 68.1, 67.6,
66.6, 66.6, 66.3, 66.2, 25.0, 20.9, 20.9, 20.8, 20.8, 20.8, 18.4, 18.1, 17.3,
16.5, –1.42, –1.49 ppm. HRMS (ESI) calcd. for [M + Na]
N-(4-Methoxybenzyl) (Methyl 2,3-Di-O-Benzoyl-4-deoxy-ꢀ-L-
threo-hex-4-enopyranosid)uronamide (42): To a solution of 23
(63 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added p-methoxybenzyl-
amine (19 μL, 0.15 mmol), followed by triethylamine (62 μL,
0.45 mmol). The reaction mixture was stirred for 10 h at room tem-
perature, then diluted with CH2Cl2 (10 mL), washed with satd. NH4Cl
(aq.), brine, dried with MgSO4 and concentrated. The crude reside
was purified by flash chromatography (2:1→3:2 hexane/EtOAc) to
afford 42 (39 mg, 75 %) as a clear viscous oil. Rf = 0.19 (2:1 hexane/
EtOAc). [α]D = +75.3 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
8.06–8.01 (m, 4 H, Ar), 7.59–7.54 (m, 2 H, Ar), 7.46–7.41 (m, 4 H, Ar),
7.29–7.26 (m, 2 H, Ar), 6.93–6.90 (m, 2 H, Ar), 6.80 (app. t, J = 5.8 Hz,
1 H, CONHCH2), 6.30 (d, J = 3.0 Hz, 1 H, 4-H), 6.13 (dd, J = 8.0,
3.0 Hz, 1 H, 3-H), 5.54 (dd, J = 8.0, 2.5 Hz, 1 H, 2-H), 5.35 (d, J =
2.6 Hz, 1 H, 1-H), 4.57 (dd, J = 14.6, 6.1 Hz, 1 H, NHCH2Ar), 4.46 (dd,
J = 14.6, 5.5 Hz, 1 H, NHCH2Ar), 3.83 (s, 3 H, ArOCH3), 3.54 (s, 3 H,
OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.8 (C=O), 165.6 (C=
O), 160.5 (C=O), 159.2 (Ar), 143.7 (C-5), 133.6 (Ar), 133.3 (Ar), 130.0
(Ar), 129.8 (Ar), 129.8 (Ar), 129.5 (Ar), 129.3 (Ar), 129.0 (Ar), 128.5
(Ar), 128.4 (Ar), 114.2 (Ar), 104.9 (C-4), 98.9 (C-1), 69.9 (C-2), 66.8 (C-
3), 57.1 (OCH3), 55.3 (ArOCH3), 43.0 (NHCH2Ar) ppm. HRMS (ESI)
calcd. for [M + Na] C29H27NNaO8: 540.1629, found 540.1633.
C
32H46NaO14Si: 705.2549, found 705.2541.
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
(1→3)-2-O-acetyl-ꢀ- -glucopyranoside (46) and 2-(Trimethyl-
silyl)ethyl 2,3,4-Tri-O-acetyl-α- -rhamnopyranosyl-(1→3)-3-O-
-rhamnopyranosyl- acetyl-ꢀ- -glucopyranoside (46a): To a solution of S1/S1a
L-rhamnopyranosyl-
D
L
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
(1→3)-4,6-O-benzylidene-ꢀ- -glucopyranoside and 2-(Trimeth-
ylsilyl)ethyl 2,3,4-Tri-O-acetyl-α- -rhamnopyranosyl-(1→2)-4,6-
O-benzylidene-ꢀ-
L
D
D
(767 mg, 1.12 mmol) in 80 % CH3COOH/H2O (10 mL) was heated at
80 °C for 2 h and then cooled to room temperature. The mixture
L
D
-glucopyranoside (45/45a): A mixture of tri- was concentrated and then co-evaporated with toluene (3×). The
chloroacetimidate 44[43] (854 mg, 1.96 mmol), alcohol 43[42] crude residue was purified by flash chromatography (1:1→1:2 hex-
(869 mg, 2.36 mmol), and 4 Å molecular sieves (4 g) in CH2Cl2 ane/EtOAc) to afford 46 (326 mg, 49 %) as a white amorphous solid
(80 mL) was stirred for 30 min at room temperature under an argon
atmosphere. The mixture was cooled to –78 °C, then TBSOTf (46 μL,
0.2 mmol) was added. The reaction mixture was stirred for 20 min
and 46a (166 mg, 25 %) as a white amorphous solid. Data for 46:
Rf = 0.45 (1:2 hexane/EtOAc). [α]D = –17.7 (c = 1.5, CHCl3). H NMR
(500 MHz, CDCl3): δ = 5.22 (dd, J = 10.1, 3.3 Hz, 1 H, 3′-H), 5.15 (dd,
1
at –78 °C, then the TBSOTf was quenched by the addition of Et3N J = 3.3, 2.1 Hz, 1 H, 2′-H), 5.11 (app. t, J = 9.9 Hz, 1 H, 4′-H), 4.96
(28 μL). The mixture was filtered through Celite and concentrated. (dd, J = 9.5, 8.1 Hz, 1 H, 2-H), 4.90 (d, J = 2.0 Hz, 1 H, 1′-H), 4.47 (d,
The crude residue was purified by flash chromatography (2:1 hex-
ane/EtOAc) to afford 45/45a (904 mg, 72 %, 45:45a = 2:1) as a
white solid, which was an inseparable mixture. Rf = 0.27 (2:1 hex-
J = 8.1 Hz, 1 H, 1-H), 4.15 (dq, J = 9.8, 6.5 Hz, 1 H, 5′-H), 4.00–3.93
[m, 2 H, 6-Ha, OCH2CH2Si(CH3)3], 3.84 (ddd, J = 11.7, 7.4, 4.8 Hz, 1
H, 6-Hb), 3.65 (app. td, J = 9.0, 2.4 Hz, 1 H, 4-H), 3.61–3.54 [m, 3 H,
ane/EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.49–7.45 (m, 6 H), 7.39– 3-H, OCH2CH2Si(CH3)3, 4-OH], 3.38 (ddd, J = 8.2, 4.6, 3.4 Hz, 1 H, 5′-
7.36 (m, 3 H), 7.34–7.31 (m, 6 H), 5.55 (s, 2 H), 5.51 (s, 1 H), 5.35–
H), 2.16 (s, 3 H, COCH3), 2.16 (s, 3 H, COCH3), 2.09 (t, J = 7.2 Hz, 1
Eur. J. Org. Chem. 2016, 2653–2664
www.eurjoc.org
2661
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
H, 6-OH), 2.06 (s, 3 H, COCH3), 2.00 (s, 3 H, COCH3), 1.26 (d, J =
6.3 Hz, 3 H, 6′-H), 0.98 [ddd, J = 14.1, 10.6, 6.7 Hz, 1 H,
tion mixture was stirred for 3 h at room temperature, then the Ac2O
was quenched by addition of CH3OH (1 mL). Then the mixture was
OCH2CH2Si(CH3)3], 0.91 [ddd, J = 14.0, 10.2, 5.6 Hz, 1 H, co-concentrated with toluene (3×). The crude reside was purified
OCH2CH2Si(CH3)3], 0.03 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 13C NMR by flash chromatography (2:1 hexane/EtOAc) to afford 48 (145 mg,
(125 MHz, CDCl3): δ = 170.1 (C=O), 169.9 (C=O), 169.6 (C=O), 169.4 95 %) as a white amorphous solid. Rf = 0.19 (2:1 hexane/EtOAc).
1
(C=O), 100.3 (C-1), 99.1 (C-1′), 85.9 (C-3), 75.1 (C-5), 71.3 (C-2), 70.6 [α]D = –10.7 (c = 0.3, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.28–
(C-4′), 70.2 (C-4), 69.8 (C-2′), 68.6 (C-3′), 67.9 (C-5′), 67.4
[OCH2CH2Si(CH3)3], 62.4 (C-6), 20.9 (COCH3), 20.8 (COCH3), 20.7
7.26 (m, 2 H, Ar), 7.12–7.10 (m, 2 H, Ar), 5.12–5.09 (m, 2 H, 3′-H, 2′-
H), 5.03 (dd, J = 9.7, 8.1 Hz, 1 H, 2-H), 5.02 (app. t, J = 9.8 Hz, 1 H,
(COCH3), 20.7 (COCH3), 18.0 [OCH2CH2Si(CH3)3], 17.5 (C-6′), –1.4 4′-H), 4.98 (app. t, J = 9.4 Hz, 1 H, 4-H), 4.80 (d, J = 1.2 Hz, 1 H, 1′-
[OCH2 CH2 Si(CH3 )3] ppm. HRMS (ESI) calcd. for [M + Na] H), 4.38 (d, J = 8.0 Hz, 1 H, 1-H), 3.93–3.86 [m, 2 H, 5′-H,
C
25H42NaO14Si: 617.2236 found 617.2228. Data for 46a: Rf = 0.42 OCH2CH2Si(CH3)3], 3.75 (app. t, J = 9.3 Hz, 1 H, 3-H), 3.55 [td, J =
(1:2 hexane/EtOAc). [α]D = –28.0 (c = 3.2, CHCl3). 1H NMR (500 MHz,
9.9, 6.6 Hz, 1 H, OCH2CH2Si(CH3)3], 3.46 (ddd, J = 9.7, 8.3, 3.4 Hz, 1
CDCl3): δ = 5.27 (dd, J = 10.1, 3.4 Hz, 1 H, 3′-H), 5.08 (app. t, J = H, 5-H), 3.05 (dd, J = 14.0, 8.2 Hz, 1 H, 6-Ha), 2.99 (dd, J = 13.9,
10.1 Hz, 1 H, 4′-H), 5.06 (dd, J = 3.7, 1.8 Hz, 1 H, 2′-H), 5.02 (app. t, 3.4 Hz, 1 H, 6-Hb), 2.33 (s, 3 H, Ar-CH3), 2.16 (s, 3 H, COCH3), 2.15 (s,
J = 9.4 Hz, 1 H, 3-H), 5.00 (d, J = 1.8 Hz, 1 H, 1′-H) 4.48 (d, J = 7.8 Hz, 3 H, COCH3), 2.11 (s, 3 H, COCH3), 2.05 (s, 3 H, COCH3), 1.96 (s, 3 H,
1 H, 1-H), 4.33 (dq, J = 10.1, 6.2 Hz, 1 H, 5′-H), 3.98 [td, J = 9.8, COCH3), 1.16 (d, J = 6.2 Hz, 3 H, 6′-H), 0.96 [ddd, J = 13.9, 10.3,
8.1 Hz, 1 H, OCH2CH2Si(CH3)3], 3.93 (dd, J = 11.9, 3.5 Hz, 1 H, 6-Ha),
3.83 (dd, J = 11.9, 4.7 Hz, 1 H, 6-Hb), 3.65–3.60 [m, 3 H, 2-H, 4-H,
OCH2CH2Si(CH3)3], 3.41 (ddd, J = 9.5, 4.6, 3.7 Hz, 1 H, 5-H), 3.16 (br.
s, 1 H, 4-OH) 2.18–2.14 (m, 7 H, 2× COCH3, 6-OH), 2.04 (s, 3 H,
COCH3), 2.01 (s, 3 H, COCH3), 1.19 (d, J = 6.2 Hz, 3 H, 6′-H), 1.04–
6.8 Hz, 1 H, OCH2CH2Si(CH3)3], 0.90 [ddd, J = 14.0, 10.0, 5.8 Hz, 1 H,
OCH2CH2Si(CH3)3], 0.02 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.2 (C=O), 170.1 (C=O), 169.8 (C=O), 169.5
(C=O), 169.4 (C=O), 136.5 (Ar), 132.5 (Ar), 130.1 (Ar), 129.7 (Ar), 100.1
(C-1), 99.5 (C-1′), 81.9 (C-3), 73.5 (C-5), 73.2 (C-4), 71.9 (C-4′), 70.6 (C-
0.98 [m, 2 H, OCH2CH2Si(CH3)3], 0.04 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 2), 69.9 (C-2′), 68.9 (C-3′), 67.5 (C-5′), 67.1 [OCH2CH2Si(CH3)3], 36.5
13C NMR (125 MHz, CDCl3): δ = 172.7 (C=O), 170.1 (C=O), 170.0 (C= (C-6), 21.3 (COCH3), 21.0 (Ar-CH3), 20.9 (COCH3), 20.8 (COCH3), 20.8
O), 169.9 (C=O), 101.0 (C-1), 97.6 (C-1′), 78.8 (C-3), 76.1 (C-2), 75.6
(COCH3), 20.6 (COCH3), 17.9 [OCH2CH2Si(CH3)3], 17.2 (C-6′), –1.4
(C-5), 71.3 (C-4′), 70.2 (C-2′), 70.2 (C-4), 68.7 (C-3′), 67.9 [OCH2 CH2 Si(CH3)3] ppm. HRMS (ESI) calcd. for [M + Na]
[OCH2CH2Si(CH3)3], 66.5 (C-5′), 62.3 (C-6), 20.9 (COCH3), 20.9
(COCH3), 20.8 (COCH3), 20.7 (COCH3), 18.4 [OCH2CH2Si(CH3)3], 17.3
(C-6′), –1.5 [OCH2CH2Si(CH3)3] ppm. HRMS (ESI) calcd. for [M + Na]
C25H42NaO14Si: 617.2236, found 617.2230.
C
34H50NaO14SSi: 765.2583, found 765.2580.
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
(1→3)-S-p-tolyl Thio(2,4-di-O-acetyl-ꢀ-
uronate (49): To a solution of 48 (136 mg, 0.18 mmol) in dry CCl4
L
-rhamnopyranosyl-
D
-glucopyranosid)-
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-Acetyl-α-
(1→3)-2-O-acetyl-6-thio-6-S-p-tolyl-ꢀ- -glucopyranoside (47):
To a stirred solution of 46 (128 mg, 0.216 mmol) in dry pyridine
L-rhamnopyranosyl- (2.7 mL) at 0 °C were added anhydrous pyridine (29 μL, 0.36 mmol)
D
followed by the addition of SO2Cl2 (29 μL, 0.36 mmol) under argon.
The reaction mixture was stirred for 5 h at 0 °C and then diluted
(1.1 mL) were added (TolS)2 (108 mg, 0.44 mmol) and P(CH3)3 with CH2Cl2 and was washed with brine. The organic layer was dried
(0.44 mL, 0.44 mmol, 1.0 in THF) under argon. The reaction mix- with MgSO4, filtered and concentrated. The crude residue was dis-
ture was stirred overnight at room temperature. Then, the reaction solved in 3:2 acetone/H2O (3.6 mL), and solid NaHCO3 (60.5 mg,
mixture was concentrated, diluted with EtOAc (30 mL) and washed 0.72 mmol) was added. The reaction mixture was stirred overnight
M
with brine. The organic layer was dried with MgSO4, filtered and at room temperature, diluted with brine and then extracted with
concentrated. The crude residue was purified by flash chromatogra- EtOAc (3 × 5 mL). The organic layer was dried with MgSO4, filtered
phy (2:1 hexane/EtOAc) to afford 47 (144 mg, 95 %) as a viscous oil.
and concentrated. The crude residue was purified by flash chroma-
Rf = 0.18 (2:1 hexane/EtOAc). [α]D = +1.7 (c = 0.3, CHCl3). 1H NMR tography (2:1 hexane/EtOAc) to afford 49 (116 mg, 85 %) as a white
(500 MHz, CDCl3): δ = 7.34–7.32 (m, 2 H, Ar), 7.12–7.09 (m, 2 H, Ar), amorphous solid. Rf = 0.45 (1:1 hexane/EtOAc). [α]D = –66.8 (c = 0.6,
1
5.22 (dd, J = 10.0, 3.3 Hz, 1 H, 3′-H), 5.14 (dd, J = 3.2, 2.1 Hz, 1 H,
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.31–7.29 (m, 2 H, Ar), 7.25–
2′-H), 5.10 (app. t, J = 9.9 Hz, 1 H, 4′-H), 4.98 (dd, J = 9.1, 8.4 Hz, 1 7.23 (m, 2 H, Ar), 5.32 (dd, J = 9.7, 9.3 Hz, 1 H, 4-H), 5.16 (dd, J =
H, 2-H), 4.87 (d, J = 2.1 Hz, 1 H, 1′-H), 4.39 (d, J = 8.1 Hz, 1 H, 1-H), 9.3, 7.9 Hz, 1 H, 2-H), 5.13–5.11 (m, 2 H, 2′-H, 3′-H), 5.04 (app. t, J =
4.12 (dq, J = 9.8, 6.3 Hz, 1 H, 5′-H), 3.92 [td, J = 9.9, 5.7 Hz, 1 H, 9.8 Hz, 1 H, 4′-H), 4.86 (d, J = 1.5 Hz, 1 H, 1′-H), 4.56 (d, J = 7.9 Hz,
OCH2CH2Si(CH3)3], 3.57–3.41 [m, 6 H, OCH2CH2Si(CH3)3, 3-H,4-H,5- 1 H, 1-H), 4.08 [td, J = 9.6, 6.7 Hz, 1 H, OCH2CH2Si(CH3)3], 3.99 (d,
H,6-Ha, 4-OH], 3.09 (dd, J = 13.7, 7.7 Hz, 1 H, 6-Hb), 2.33 (s, 3 H, Ar-
J = 9.9 Hz, 1 H, 5-H), 3.92 (dq, J = 9.7, 6.1 Hz, 1 H, 5′-H), 3.86 (app.
CH3), 2.16 (s, 3 H, COCH3), 2.15 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3), t, J = 9.2 Hz, 1 H, 3-H), 3.68 [td, J = 9.5, 6.8 Hz, 1 H, OCH2CH2Si(CH3)3],
2.00 (s, 3 H, COCH3), 1.25 (d, J = 6.3 Hz, 3 H, 6′-H), 0.96 [ddd, J = 2.39 (s, 3 H, Ar-CH3), 2.19 (s, 3 H, COCH3), 2.15 (s, 3 H, COCH3), 2.06
14.0, 10.3, 6.8 Hz, 1 H, OCH2CH2Si(CH3)3], 0.90 [ddd, J = 13.7, 9.9, (s, 3 H, COCH3), 2.05 (s, 3 H, COCH3), 1.98 (s, 3 H, COCH3), 1.16 (d,
5.6 Hz, 1 H, OCH2CH2Si(CH3)3], 0.02 [s, 9 H, OCH2CH2Si(CH3)3] ppm. J = 6.2 Hz, 3 H, 6′-H), 1.03 [ddd, J = 14.0, 9.4, 6.8 Hz, 1 H,
13C NMR (125 MHz, CDCl3): δ = 170.0 (C=O), 169.9 (C=O), 169.5 (C= OCH2 CH2 Si(CH3 )3 ], 0.99 [ddd, J = 14.0, 9.4, 6.8 Hz, 1 H,
O), 169.4 (C=O), 136.1 (Ar), 132.9 (Ar), 129.8 (Ar), 129.7 (Ar), 100.0
OCH2CH2Si(CH3)3], 0.06 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 13C NMR
(C-1), 99.2 (C-1′), 86.3 (C-3), 74.7 (C-5), 72.7 (C-4), 71.4 (C-2), 70.6 (C- (125 MHz, CDCl3): δ = 195.5 (C-6), 170.2 (C=O), 170.1 (C=O), 169.5
4′), 69.8 (C-2′), 68.6 (C-3′), 67.9 (C-5′), 67.0 [OCH2CH2Si(CH3)3], 36.2 (C=O), 169.4 (C=O), 169.3 (C=O), 139.9 (Ar), 134.8 (Ar), 130.2 (Ar),
(C-6), 21.0 (Ar-CH3), 20.9 (COCH3), 20.8 (COCH3), 20.7 (COCH3), 20.7 122.8 (Ar), 100.2 (C-1), 99.4 (C-1′), 81.1 (C-3), 77.7 (C-5), 71.4 (C-2),
(COCH3), 17.9 [OCH2CH2Si(CH3)3], 17.5 (C-6′), –1.4 [OCH2CH2Si(CH3)3] 70.8 (C-4), 70.6 (C-4′), 69.9 (C-2′), 68.8 (C-3′), 67.5 [OCH2CH2Si(CH3)3],
ppm. HRMS (ESI) calcd. for [M + Na] C32H48NaO13SSi: 723.2477, 67.5 (C-5′), 21.4 (Ar-CH3), 21.0 (COCH3), 21.0 (COCH3), 20.8 (COCH3),
found 723.2472.
20.8 (COCH3), 20.7 (COCH3), 18.0 [OCH2CH2Si(CH3)3], 17.3 (C-6′), –1.3
[OCH2CH2Si(CH3)3] ppm. HRMS (ESI) calcd. for [M + NH4]
C34H52NO15SSi: 774.2807 Found 774.2821.
2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
L
-rhamnopyranosyl-
-glucopyranoside
(48): To a solution of 47 (143.6 mg, 0.205 mmol) in pyridine (2 mL)
and Ac2O (1 mL) was added DMAP (2.6 mg, 0.021 mmol). The reac- yl-(1→3)-(2,4-di-O-acetyl-ꢀ-
(1→3)-2,4-di-O-acetyl-6-thio-6-S-p-tolyl-ꢀ-
D
N-[2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
L-rhamnopyranos-
D
-glucopyranosiduronoyl)]-
L-threo-
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nine Benzyl Ester (50): To a solution of 49 (79.8 mg, 0.105 mmol) NaOCH3 in CH3OH (1 mL, 0.1
in CH2Cl2 (2.1 mL) was added -threonine benzyl ester (33.1 mg,
0.158 mmol). The reaction mixture was stirred for 44 h at room Amberlite® IR-120 (H+) cation exchange resin. The mixture was fil-
temperature, then diluted with CH2Cl2 (10 mL), washed with satd. tered and the filtrate was concentrated. The residue was dissolved
M). The reaction mixture was stirred
L
for 4 h at room temperature and then neutralized by addition of
NH4Cl (aq.) and brine. The organic layer was dried with MgSO4, in water and then lyophilized to afford 52 (39.0 mg, 90 %) as a
filtered and concentrated. The crude residue was purified by flash white solid. Rf = 0.24 (1:2:4 H2O/2-propanol/EtOAc). [α]D = –53.2
chromatography (2:1→1:1 hexane/EtOAc) to afford 50 (73.5 mg, (c = 0.3, CH3OH). 1H NMR (500 MHz, CD3OD): δ = 5.18 (d, J = 1.6 Hz,
83 %) as a white amorphous solid. Rf = 0.29 (1:1 hexane/EtOAc).
[α]D = –23.1 (c = 0.6, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.38–
1 H, 1′-H), 4.45 (br. s, 1 H, NHCHCO2H), 4.39 (d, J = 7.9 Hz, 1 H, 1-
H), 4.36 (br. s, 1 H, HOCHCH3), 4.07 (dq, J = 9.6, 6.2 Hz, 1 H, 5′-H),
1
7.31 (m, 5 H, Ar), 7.19 (d, J = 8.8 Hz, 1 H, NHCHCO2Bn), 5.22 (d, J = 4.00 [ddd, J = 11.0, 9.7, 6.0 Hz, 1 H, OCH2CH2Si(CH3)3], 3.92 (dd, J =
12.3 Hz, 1 H, CH2Ph), 5.17 (d, J = 12.3 Hz, 1 H, CH2Ph), 5.14 (app. t, 3.3, 1.7 Hz, 1 H, 2′-H), 3.87 (d, J = 9.3 Hz, 1 H, 5-H), 3.71–3.65 [m, 2
J = 9.4 Hz, 1 H, 4-H), 5.11–5.06 (m, 3 H, 2-H, 2′-H, 3′-H), 5.01 (app. H, 3′-H, OCH2CH2Si(CH3)3], 3.59 (app. t, J = 8.7 Hz, 1 H, 3-H), 3.54
t, J = 9.7 Hz, 1 H, 4′-H), 4.86 (d, J = 1.2 Hz, 1 H, 1′-H), 4.55 (dd, J = (app. t, J = 9.0 Hz, 1 H, 4-H), 3.37 (app. t, J = 9.7 Hz, 1 H, 4′-H), 3.34
8.7, 3.3 Hz, 1 H, NHCHCO2Bn), 4.50 (d, J = 8.0 Hz, 1 H, 1-H), 4.29 (dd, J = 8.5 Hz, 1 H, 2-H), 1.23 (d, J = 6.2 Hz, 3 H, 6′-H), 1.19 (d,
(ddq, J = 6.3, 5.5, 3.7 Hz, 1 H, HOCHCH3), 3.97 [td, J = 9.7, 6.4 Hz, 1 J = 6.3 Hz, 3 H, HOCHCH3), 1.05 [ddd, J = 13.8, 11.0, 5.8 Hz, 1 H,
H, OCH2CH2Si(CH3)3], 3.91–3.84 (m, 3 H, 5′-H, 3-H, 5-H), 3.58 [td, J =
9.6, 6.8 Hz, 1 H, OCH2CH2Si(CH3)3], 2.16 (s, 3 H, COCH3), 2.13 (s, 3 H,
COCH3), 2.10 (s, 3 H, COCH3), 2.06 (d, J = 5.5 Hz, 1 H, HOCHCH3),
2.02 (s, 3 H, COCH3), 1.95 (s, 3 H, COCH3), 1.24 (d, J = 6.4 Hz, 3 H,
OCH2CH2Si(CH3)3], 0.99 [ddd, J = 13.8, 11.0, 6.0 Hz, 1 H,
OCH2CH2Si(CH3)3], 0.03 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 13C NMR
(125 MHz, CD3OD): δ = 173.4 (C=O), 172.2 (C-6), 103.8 (C-1), 102.5
(C-1′), 83.0 (C-3), 76.0 (C-5), 75.5 (C-2), 74.1 (C-4′), 72.4 (C-4), 72.4 (C-
HOCHCH3), 1.14 (d, J = 6.2 Hz, 3 H, 6′-H), 0.97 [ddd, J = 14.2, 9.7, 2′), 72.3 (C-3′), 69.9 (C-5′), 68.6 [OCH2CH2Si(CH3)3], 68.4 (HOCHCH3),
6.7 Hz, OCH2CH2Si(CH3)3], 0.92 [ddd, J = 14.4, 10.0, 6.6 Hz, 58.6 (NHCHCO2H), 20.6 (HOCHCH3), 19.2 [OCH2CH2Si(CH3)3], 17.9 (C-
OCH2CH2Si(CH3)3], 0.02 [s, 9 H, OCH2CH2Si(CH3)3] ppm. 13C NMR 6′), –1.4 [OCH2CH2Si(CH3)3] ppm. HRMS (ESI) calcd. for [M – H]
(125 MHz, CDCl3): δ = 170.1 (C=O), 170.1 (C=O), 170.0 (C=O), 169.9
(C=O), 169.6 (C=O), 169.4 (C=O), 167.6 (C-6), 135.2 (Ar), 128.65 (Ar),
128.50 (Ar), 128.2 (Ar), 100.2 (C-1), 99.1 (C-1′), 80.4 (C-3), 72.8 (C-5),
71.7 (C-2), 71.1 (C-4), 70.6 (C-4′), 69.9 (C-2′), 68.8 (HOCHCH3), 68.5
(C-3′), 68.0 [OCH2CH2Si(CH3)3], 67.4 (C-5′), 67.3 (CH2Ph), 57.2
(NHCHCO2Bn), 21.0 (COCH3), 20.9 (COCH3), 20.8 (COCH3), 20.8
(COCH3), 20.7 (COCH3), 19.9 (HOCHCH3), 18.0 [OCH2CH2Si(CH3)3],
17.3 (C-6′), –1.4 [OCH2CH2Si(CH3)3] ppm. HRMS (ESI) calcd. for [M +
Na] C38H55NNaO18Si: 864.3081, found 864.3076.
C21H38NO13Si: 540.2118, found 540.2113.
Acknowledgments
This work was supported by the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) and the Alberta Gly-
comics Centre. R. A. A. thanks Alberta Innovates Health Solu-
tions for a studentship award.
N-[2-(Trimethylsilyl)ethyl 2,3,4-Tri-O-acetyl-α-
L
-rhamnopyranos-
Keywords: Synthetic methods · Oxidation · Amidation ·
Polysaccharides · Glycuronamides
yl-(1→3)-(2,4-di-O-acetyl-ꢀ- -glucopyranosiduronoyl)]-
D
L-threo-
nine (51): To a solution of 50 (67.4 mg, 0.08 mmol) in CH3OH was
added palladium on charcoal (5 %, 10 mg). The flask was flushed
with H2 gas, and then the reaction mixture was stirred at room
temperature overnight under a H2 atmosphere. The mixture was
filtered through Celite, and the filtrate was concentrated to afford
51 (60.2 mg, quant.) as a white solid. Rf = 0.30 (5:1 CH2Cl2/CH3OH).
[α]D = –30.2 (c = 1.6, CHCl3). 1H NMR (500 MHz, CD3OD): δ = 5.14
(app. t, J = 9.6 Hz, 1 H, 4-H), 5.08 (dd, J = 3.3, 2.0 Hz, 1 H, 2′-H), 5.04
(dd, J = 10.1, 3.3 Hz, 1 H, 3′-H), 5.00 (dd, J = 9.6, 8.1 Hz, 1 H, 2-H),
4.96 (app. t, J = 9.6 Hz, 1 H, 4-H) 4.92 (d, J = 1.9 Hz, 1 H, 1′-H), 4.68
(d, J = 8.1 Hz, 1 H, 1-H), 4.31–4.28 (m, 2 H, NHCHCO2H, HOCHCH3),
4.07 (app. t, J = 9.5 Hz, 1 H, 3-H), 4.04 [td, J = 9.8, 5.9 Hz, 1 H,
OCH2CH2Si(CH3)3], 4.02 (d, J = 9.9 Hz, 1 H, 5-H), 3.85 (dq, J = 9.7,
6.2 Hz, 1 H, 5′-H), 3.64 [td, J = 9.6, 6.7 Hz, 1 H, OCH2CH2Si(CH3)3],
2.12 (s, 3 H, COCH3), 2.12 (s, 3 H, COCH3), 2.06 (s, 3 H, s, 3 H, COCH3),
2.02 (s, 3 H, s, 3 H, COCH3), 1.93 (s, 3 H, s, 3 H, COCH3), 1.19 (d, J =
6.3 Hz, 3 H, HOCHCH3), 1.12 (d, J = 6.2 Hz, 3 H, 6′-H), 0.97 [ddd, J =
14.0, 9.9, 6.7 Hz, 1 H, OCH2CH2Si(CH3)3], 0.89 [ddd, J = 14.0, 9.6,
5.8 Hz, 1 H, OCH2CH2Si(CH3)3], 0.02 [s, 9 H, OCH2CH2Si(CH3)3] ppm.
13C NMR (125 MHz, CD3OD): δ = 174.5 (C=O), 171.7 (C=O), 171.7
(C=O), 171.4 (C=O), 171.4 (C=O), 171.3 (C=O), 169.6 (C-6), 101.3 (C-
1), 100.6 (C-1′), 81.9 (C-3), 73.7 (C-5), 73.4 (C-2), 72.5 (C-4), 71.9 (C-
4′), 71.1 (C-2′), 70.3 (C-3′), 68.7 (HOCHCH3), 68.6 [OCH2CH2Si(CH3)3],
58.9 (NHCHCO2H), 21.4 (COCH3), 21.1 (COCH3), 20.7 (COCH3), 20.6
(COCH3), 20.6 (COCH3), 20.3 (HOCHCH3), 18.9 [OCH2CH2Si(CH3)3],
17.7 (C-6′), –1.3 [OCH2CH2Si(CH3)3] ppm. HRMS (ESI) calcd. for [M +
Na] C31H49NNaO18Si: 774.2611, found 774.2600.
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N-[2-(Trimethylsilyl)ethyl α-
Glucopyranosiduronoyl)]- -threonine (52): To a solution of 51
(60.2 mg, 0.08 mmol) in CH3OH (1 mL) was added a solution of
L
-Rhamnopyranosyl-(1→3)-(ꢀ-
D-
L
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Received: March 1, 2016
Published Online: May 3, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim