Conformational Lock of Glycosyl Donors Using Cyclic Carbamates

Article abstract of DOI:10.1002/ejoc.202001130

Axial rich glycosyl donors often display superior reactivity and stereoselectivity in glycosylations. In this study, a glucosamine glycosyl donor, locked in a ¹C₄ conformation by a six-membered carbamate ring, i.e. an oxazinone, is synthesized and studied. The 2N,4O carbamate is synthesized in one step from the corresponding azide. The glycosylation properties were studied by glycosylating different alcohols. Derivatives of the glycosyl donor were synthesized by introducing Ac, Troc, Ts, and Ms groups on the oxazinone nitrogen. The ring opening to give the glycoside in the ⁴C₁ conformation was found to proceed smoothly using Zemplén conditions.

Full text of DOI:10.1002/ejoc.202001130

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Glycosylation
Conformational Lock of Glycosyl Donors Using Cyclic
Carbamates
Jaime Moyano Villameriel[a] and Christian Marcus Pedersen*[a]
Abstract: Axial rich glycosyl donors often display superior reac- were studied by glycosylating different alcohols. Derivatives of
tivity and stereoselectivity in glycosylations. In this study, a the glycosyl donor were synthesized by introducing Ac, Troc, Ts,
1
glucosamine glycosyl donor, locked in a C4 conformation by a and Ms groups on the oxazinone nitrogen. The ring opening to
4
six-membered carbamate ring, i.e. an oxazinone, is synthesized give the glycoside in the C1 conformation was found to pro-
and studied. The 2N,4O carbamate is synthesized in one step ceed smoothly using Zemplén conditions.
from the corresponding azide. The glycosylation properties
Introduction
to manipulate the glycosyl donor reactivities.[12–15] According
to the hypothesis, axial hydroxyl groups, whether protected or
not, are less deactivating compared with their equatorial coun-
terparts. This means that developing a positive charge on the
anomeric position is becoming more feasible with more axial
hydroxyl groups, i.e. the axial rich glycosyl donor becomes more
reactive. As the stereochemistry has been settled by nature and
the protective groups only cover a certain span of reactivity,
the armed-disarmed concept has its limitations. Exceeding the
limitation could however be achieved by combining stereoelec-
tronic effects with less electron-withdrawing protective groups.
This led to the “superarmed” glycosyl donors,[16] where bulky
silyl ether protective groups induce a conformational change
leading to axial rich conformations and hence higher reactivity;
often more than a thousand times more reactive than armed
(perbenzylated) glycosyl donors with the same stereochemis-
try.[17] The same impressive rate enhancements could also be
achieved by tethering the 3,6 hydroxyl groups in manno,
galacto and glucosyl donors.[18] Surprisingly tethering the
2,4 hydroxyl groups in a glucosyl donor did not result in the
same dramatic reactivity boost.[19–21] Interestingly, Demchenko
found that introducing a 2-O-benzoyl group in a perbenzylated
glucosyl donor did increase the reactivity by anchimeric assist-
ance.[22,23] This concept, also termed superarmed,[24] was later
combined with the conformationally superarming, albeit result-
ing in slightly less reactive glycosyl donors.[25] As mentioned,
the 2,4-tethering of glycosyl donors did not increase the reac-
tivity, which is somewhat puzzling. Furukawa et al. have used
2,4-tethring for a glucuronyl donor and found the reactions to
be highly ꢀ-selective.[26] As a tethering group di-tert-butyl-
silylene was used and the bulkiness of this was sup-
posedly responsible for shielding the α-site of the glycosyl do-
nor. In this paper we return to 2,4 tethering, though focusing
on glucosamine derivatives. Cyclic carbamates have previously
been studied in glucosamine based glycosyl donors, with a few
reports on the 1,2 carbamates.[27] The 2,3-carbamates have re-
ceived some more attention, e.g. as a way to improve the nu-
Protective groups often have a decisive influence on the glyc-
osylation reaction.[1,2] The anomeric selectivity can be directed
by neighboring group participation, and the reactivity of the
glycosyl donor is determined by the protective groups.[3] The
connection between protective groups and reactivity was real-
ized in the 1970s by Paulsen, who recognized that benzyl ether-
protected glycosides were more reactive than the acetyl- or
benzoyl-protected analogues.[4,5] Fraser-Reid utilized this find-
ing in developing the armed-disarmed glycosylation ap-
proach.[6,7] As a rule of thumb, more electron-withdrawing
(EWD) protective groups, such as esters, reduce the reactivity
of the anomeric position, whereas less electron withdrawing
groups, such as ethereal protective groups, do not. Besides the
EWD properties of the protective group Fraser-Reid also found
that introducing a benzylidene protective group reduced the
reactivity and termed this effect torsional disarming.[8] The
change in reactivity is strongly related to the stability of the
glycosyl cation, which is the transient intermediate in most
glycosylation reactions. Manipulating the reactivity of glycosyl
donors has been used in one-pot oligosaccharide synthesis sav-
ing protective group manipulations.[3,9] Understanding the rela-
tionship between protective groups and anomeric reactivity is
obviously important, and there have been several studies trying
to pinpoint these long-range effects. Bols found that the differ-
ences in reactivity between epimeric glycosyl donors to a large
extend could be explained by stereoelectronic effects.[10,11] The
same effects could be confirmed in piperidine model systems,
and hence provided a strong platform for understanding how
[a] J. M. Villameriel, and Prof. C. M. Pedersen
Department of Chemistry, University of Copenhagen,
Universitetsparken 5, 2100 Copenhagen O, Denmark
E-mail: cmp@chem.ku.dk
https://www.ki.ku.dk
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001130.
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cleophilicity of the 4-OH,[28] and as glycosyl donors.[29,30] In this glucose 10 was used. The yield was again modest, but the se-
paper we synthesize and study the glycosylation properties of lectivity improved to a dr of 1:10. The significant drop in yield
2N,4O-tethered glucosaminyl donors.
when using more sterically hindered acceptors suggested that
the activated glycosyl donor decomposes. A way to stabilize an
intermediate could be to introduce a participating neighboring
group. As the nitrogen is already a part of a ring, participation
would lead to a tricyclic system, which from a geometrically
point of view seems unfavorable. Especially when taken the
formed positive charge, and thereby sp2 character of the
glycosyl cation into account. Introducing acetyl groups on the
2N,3O-oxazoline protected glycosyl donor was introduced by
Kerns.[32,33] Kerns[34] and Oscarson[35] later realized that the
anomeric selectivity was dependent on the exact amounts of
catalyst used. An in situ anomerisation was later found to be
the course of this.[36]
Results and Discussion
Introducing a 2,4-tethering was already studied when develop-
ing the super armed glycosyl donors, but as both the 2,4-O-
silylene tethered, as well as the 2N,4O-carbamate tethered were
cumbersome to synthesize and did not increase the reactivity
as expected, these donor types were abandoned at that time.
Recently, Furukawa et al. published the synthesis of 2,4-teth-
ered glycosyl donors showing interesting stereo directing prop-
erties, which inspired us to re-evaluate the use of this tethering
in glycosyl donors.[26] As a first priority, we wanted to simplify
the synthesis. A key reaction was the carbamate formation from
the azide and the 4-OH using PPh3 and CO2. This worked very
efficiently on a levoglucosane derivative and hence our first
approach was to investigate this reaction in an unrestricted all-
equatorial 2-azido-2-deoxyglycosyl-donor. Phenyl 2-azido-3,6-
Scheme 1. Introducing the oxazinone in one-pot from the corresponding
azide derivative.
di-O-benzyl-2-deoxy-1-thio-α- -glucopyranoside 2 was synthe-
D
sized from the corresponding benzylidene protected sugar 1
using known procedures.[18,31] With the mono-ol in hand the
carbamate forming reaction could be investigated.[27]
To study the influence of an additional protective group on
the nitrogen we decided to introduce an acetyl, which is the
most commonly used (Scheme 2). A Troc group was also intro-
duced, as it often gives good results when used as N-protection
in glycosylations.[37,38] Both the acetylation and the introduc-
tion of the Troc were found to give higher yield when adding
10 mol-% DMAP in DCM with DIPEA as the base, and AcCl or
TrocCl as the electrophilic reagents. Introducing other electro-
philes, such as Ts or Ms, did however not proceed under these
milder conditions and NaH in THF or DCM had to be used af-
fording the sulfonamides 6 and 7 (see SI for details).
The reaction sequence first involves the formation of an
iminophosphorane from the reaction between PPh3 and the
azido group (Scheme 1). Upon reaction with CO2 this is trans-
formed into the isocyanate. In order to form the intermolecular
tethering to the 4-OH, a conformational change of the pyranose
ring is required. Pleasingly, the reaction yielded 63 % isolated
yield, which is satisfactory taking into account the complexity
and number of steps involved. The conformation of the glycosyl
donor was analyzed by NMR spectroscopy, where the dihedral
3
angles in the pyranose ring can be evaluated from the J cou-
plings. As estimated, all the coupling constants were small, in
sharp contrast to the starting material, where all were ca. 8 Hz.
This abrupt change confirms the change from diaxial vicinal
protons to diequatorial. With access to grams of compound 3,
glycosylations could be studied. The first glycosyl acceptor,
2-methoxyethanol 8, is a primary hydroxyl group, so steric fac-
tors are small, but its electronic features resemble a saccharide-
based acceptor and hence it is a relevant model acceptor. First,
the standard conditions for activating thioglycosides, i.e. NIS
and TfOH, were used. Disappointingly, no product could be iso-
lated and decomposition of the donor seemed to a problem.
As a milder alternative, TfOH was exchanged by AgOTf and the
Scheme 2. N-Functionalization of the oxazinone nitrogen.
Glycosylation with the acetylated donor 5 and 2-methoxy-
amount of NIS lowered to a slight excess instead of 3 equiv. ethanol 8 resulted in a low yield and there seemed not to be
Under these conditions the primary acceptor could be glycosyl- an influence on the anomeric selectivity, which was 1:2 again
ated in an 86 % isolated yield and a dr of 1:2. To see the influ- (see Scheme 3 and Table 1). Turning to the more hindered ac-
ence of more sterically encumbered acceptors, yet more nu- ceptors 9 and 10 furnished no product. Instead, it was observed
cleophilic than 8, a secondary alcohol, cyclohexanol 9, was that the N-acetyl had been cleaved under the reaction condi-
tested next. With this acceptor, the yield took a hit down to tions and that the glycosylation product 12 was obtained in
30 %, whereas the selectivity remained similar. Clearly, introduc- yields similar to the glycosylation using the donor 3. Glycosyl-
ing another ring in the glycosyl donor makes the anomeric cen- ation using the Troc protected donor and methoxyethanol was
ter less accessible, but surprisingly the glycosylation not more performing slightly better, but still without a change in the ano-
selective. To combine steric hindrance and electronically dis- meric selectivity. The reaction using cyclohexanol 9 gave a
arming the hindered bicyclic glycosyl acceptor diacetone-
D
-
modest yield, but a surprisingly selective reaction. The glycosyl-
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ations suggest that there is not a benefit from neighboring amates and the unprotected 4-OH. All yields were in the range
group participation and that the EWGs reduce the reactivity 80–91 %. The anomeric ratios could then be confirmed for the
further.
glycosides containing the methoxyethanyl and diacetone
glycosyl aglycons, but rotamers caused by the methyl carb-
amate made assignments difficult and impossible when having
the cyclohexanol aglycon and dr are therefore given.
From these results our initial findings working on 2,4-teth-
ered glycosyl donors were supported. In contrast to 3,6 teth-
ering,[18] these donors are not to be considered very reactive
neither highly selective. The introduction of a 2N,4O tethering
can, however, be interesting in other aspects of carbohydrate
chemistry and the synthesis presented here allow easy access
to this motif.
Conclusion
In conclusion, we have developed a simple and straight forward
synthesis of the 2N,4O carbamate in a glucosaminyl donor. The
reaction involved the in situ formation of an isocyanate from
an azide and CO2 and a subsequent ring-formation to flip the
pyranose ring. The synthesized glycosyl donor was activated
with NIS and AgOTf catalysis, but only demonstrated modest
glycosylation properties, clearly suggesting that it is not always
enough to induce a ring flip in order to boost the reactivity and
selectivity of a glycosyl donor. Ring size and strain is decisive
and can overrule the stereoelectronical benefit achieved by a
ring flip.
Scheme 3. Glycosylation conditions and the donors and acceptors studied.
Table 1. Glycosylation reactions.
Entry
Glycosyl Donor N-R Glycosyl Acceptor Product Yield %,[a] (dr)[b]
1
2
3
4
5
6
7
8
9
H
H
H
Troc
Troc
Troc
Ac
Ac
Ac
8
9
10
8
9
10
8
9
11
12
13
14
15
16
17
18
19
85 (66:34)
30 (65:35)
31 (91:1)
30 (63:37)
43 (100:0)
0
24 (66:34)
0
0
Experimental Section
10
General working conditions
[a] Isolated yield. [b] Determined by NMR, specific stereochemistry was first
determined after opening of the oxazinone ring. For details, see SI.
All the chemical reagents have been employed directly and no ad-
ditional treatments were required. All the reactions were carried out
in flame-dried flasks, under N2 atmosphere and with dry solvents,
unless otherwise stated. The anhydrous solvents were obtained
from an Innovative Technology PS-MD-05 solvent drying system.
The TLCs were developed in silica-coated aluminum plates (60 F254)
and detection performed by UV-absorption (λ = 254 nm), and/or
by moistening with a staining solution (6 % vanillin and 3 % sulfuric
acid in ethanol) and subsequent charring with a heat gun. Flash
column chromatography purifications were conducted with silica
gel, SiO2 (40–63 μm) as stationary phase, and HPLC-grade solvents
as eluents, except heptane and petroleum ether (bp: 40–65 °C),
which were acquired in technical-grade. The NMR spectra (1H, 13C,
COSY and HSQC) were recorded on a Bruker 500 MHz spectrometer
equipped with autosampler. 1H-NMR spectra were recorded at
500 MHz and 13C at 126 MHz. Chemical shifts are listed in ppm and
the coupling constants in Hz. The NMR samples were prepared in
[D]chloroform (1H: 7.26 ppm, 13C: 77.16 ppm) or [D6]DMSO (1H:
2.50 ppm, 13C: 39.52 ppm), and chemical shifts referenced accord-
ing to the solvent peak. The HRMS samples were analyzed with a
Bruker SolariX XR 7T ESI/MALDI-FT-ICR-MS spectrometer employing
dithranol as matrix. The optical rotations were determined by an
Anton Paar MCP 200 Circular Polarimeter and were measured at
25.0 °C and a sodium lamp (λ = 589.3 nm) was used as light source.
A general problem working with conformationally flipped
glycosides is the assignment of the anomeric stereochemistry.
In this case, for gluco stereochemistry, the trans-diaxial protons
become trans-diequatorial, resulting in small 3J-couplings. In or-
der to confirm the stereochemistry beyond doubt, we decided
to open the carbamate bringing the glycosides back to their
4C1 conformation.
First, the glycosyl donor 3 was treated under Zemplén condi-
tions (Scheme 4). This gave the methyl carbamate in good yield.
Several attempts were made with BnOH as nucleophile, in order
to synthesize a Cbz protected glycosyl donor, but neither of
them afforded the desired product.
Phenyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-thio-
Scheme 4. Zemplén conditions to open the oxazinone.
α-
D-glucopyranoside (1)
The glycosylation products were therefore treated under
To a solution of compound SI-4 (150 mg, 0.39 mmol) in DMF
Zemplén conditions to give the corresponding methyl carb- (2.50 mL), BnBr (0.06 mL, 0.78 mmol, 2.0 equiv.) and NaH, as a 60 %
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suspension in mineral oil (24 mg, 0.59 mmol, 1.5 equiv.) were se- J = 4.9 Hz, 1H, NH), 5.34 (s, 1H, H1), 4.60 (d, J = 11.8 Hz, 1H, PhCH2),
quentially added at 0 °C. The mixture was allowed to stir for one 4.57–4.55 (m, PhCH2, H5), 4.52 (d, J = 11.8 Hz, 1H, PhCH2), 4.46 (d,
hour and upon completion, quenched by saturated aqueous NaH- J = 11.8 Hz, 1H, PhCH2), 4.41 (ddd, J = 3.7, 2.2, 1.6 Hz, 1H, H4), 4.10
CO3 (7 mL). The resulting mixture was extracted with Et2O (3 × (ddd, J = 4.0, 4.0, 1.2 Hz, 1H, H3), 3.88 (dd, J = 7.7 Hz, 10.4 Hz, 1H,
20 mL), washed with H2O (15 mL), dried with anhydrous MgSO4,
filtered and the solvents evaporated. The crude residue was purified
H6), 3.74 (dd, J = 6.4 Hz, 10.4 Hz, 1H, H6), 3.66–3.64 (m, 1H, H2)
ppm. 13C NMR (126 MHz, CDCl3) δ = 152.9 (carbamate-CO), 137.9
by flash column chromatography in silica gel (heptane/EtOAc, 3:1) (Ar), 136.4 (Ar), 133.5 (Ar), 131.6 (Ar), 129.3 (Ar), 128.9 (Ar), 128.7
to yield pure 1 (168 mg, 0.37 mmol, 94 %; approximate yield due (Ar), 128.6 (Ar), 127.9 (Ar), 127.7 (Ar), 79.7 (C1), 78.1 (C5), 73.3
to the presence of impurities on the sample, which could not be
removed by column chromatography) as a white solid. Rf (heptane/
EtOAc, 3:1) = 0.58 1H NMR (500 MHz, [D]Chloroform) δ 7.52–7.49
(m, 4H, ArH), 7.41–7.37 (m, 6H, ArH), 7.36–7.29 (m, 7H, ArH), 5.60 (s,
1H, PhCH), 5.57 (d, J = 4.7, 1H, H1), 4.98 (d, J = 10.9 Hz, 1H, PhCH2),
4.84 (d, J = 10.9 Hz, 1H, PhCH2), 4.43 (ddd, J = 9.9, 9.9, 4.9 Hz, 1H,
H5), 4.23 (dd, J = 10.4, 4.9 Hz, 1H, H6), 4.00–3.95 (m, 2H, H2, H4),
3.80–3.75 (m, 2H, H3, H6) ppm. 13C NMR (126 MHz, CDCl3) δ = 137.8
(Ar), 137.2 (Ar), 133.1 (Ar), 132.6 (Ar), 129.3 (Ar), 129.3 (Ar), 128.6
(Ar), 128.5 (Ar), 128.4 (Ar), 128.1 (Ar), 126.2 (Ar), 101.6 (PhCH), 88.0
(C1), 82.9 (C3), 78.0 (C2), 75.4 (PhCH2), 68.8 (C6), 64.0 (C5), 63.7 (C4)
ppm (missing signals due to overlaps: 4 aromatic (Ar) carbon sig-
nals). The NMR spectra are in accordance with the literature.[39]
(PhCH2), 72.7 (PhCH2), 70.0 (C3), 69.8 (C4), 67.5 (C6), 51.7 (C2) ppm
(missing signals due to overlaps: 5 aromatic (Ar) carbon signals).
Phenyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-oxazin-2-
one]-1-thio-2-N-[2,2,2-trichloroethoxycarbonyl]-α-D-glucopyr-
anoside (4)
To a stirred solution of compound 3 (40 mg, 0.11 mmol) in CH2Cl2
(3 mL) at 0 °C, iPr2NEt was added (60 μL, 0.32 mmol, 3.0 equiv.).
Afterwards, 2,2,2-trichloroethoxycarbonyl chloride (0.43 mL,
0.31 mmol, 3.0 equiv.) and DMAP (1 mg, 1.22 mmol, 0.1 equiv.)
were sequentially added, and the mixture was warmed up to room
temperature. After five hours, the reaction was quenched with 1
M
HCl (10 mL), washed with saturated aqueous NaHCO3 (2 × 10 mL),
dried with anhydrous MgSO4, filtered and the solvents evaporated.
The crude product was purified by flash column chromatography
in silica gel (EtOAc/PE, 1:1), resulting in an off-white viscous oil,
which corresponded to product 4 (50 mg, 0.23 mmol, 74 %; approx-
Phenyl 2-azido-3,6-di-O-benzyl-2-deoxy-1-thio-α-D-glucopyran-
oside (2)
To a stirred solution of compound 1 (600 mg, 1.20 mmol) in CH2Cl2
(10 mL) at 0 °C, Et3SiH (1.0 mL, 6.48 mmol, 5.4 equiv.) was added, imate yield due to the significant presence of impurities on the
followed by a dropwise addition of TFA (0.5 mL, 6.48 mmol, sample). Rf (EtOAc/PE, 1:3) = 0.67. [α]2D5 +26° (c 0.96, CHCl3) HRMS
5.4 equiv.) during 20 minutes. The mixture was allowed to stir for
three hours, after which the reaction was quenched by pouring
(HRMS/FT-ICR): m/z [M + Na]+ Calc. for C30H28Cl3NNaO7S+
674.05443, found 674.05525. 1H NMR (500 MHz, [D]Chloroform)
slowly saturated aqueous NaHCO3. The resulting mixture was sepa- δ 7.55–7.53 (m, 2H, ArH), 7.38–7.31 (m, 7H, ArH), 7.28–7.24 (m, 7H,
rated, extracted with CH2Cl2 (15 mL), washed with saturated aque- ArH), 5.53 (s, 1H, H1), 5.05 (d, J = 11.8 Hz, 1H, PhCH2), 4.91–4.88 (m,
ous NaHCO3 (2 × 10 mL), dried with anhydrous MgSO4, filtered and
the solvents evaporated. The crude product was purified by flash
column chromatography in silica gel (toluene/EtOAc, 9:1) to yield
2H, PhCH2, H3), 4.66 (dd, J = 11.8, 14.7 Hz, 2H, CH2CCl3), 4.52 (dd,
1H, J = 7.1, 6.8 Hz, H5), 4.50–4.49 (m, 1H, H2), 4.47 (d, d, J = 12.1 Hz,
1H, PhCH2), 4.37 (d, J = 11.8 Hz, 1H, PhCH2), 4.13 (ddd, J = 8.0, 3.8,
2.4 Hz, H4), 3.85 (dd, J = 10.5, 7.6 Hz, 1H, H6), 3.75 (dd, J = 10.3,
pure 2 (443 mg, 0.93 mmol, 74 %) as an off-white oil. Rf (EtOAc/
1
toluene, 1:9) = 0.63 H NMR (500 MHz, [D]Chloroform) δ 7.53–7.51 6.2 Hz, 1H, H6) ppm. 13C NMR (126 MHz, CDCl3) δ = 151.87 (carb-
(m, 2H, ArH), 7.44–7.38 (m, 5H, ArH), 7.35–7.31 (m, 7H, ArH), 7.28– amate-CO), 146.44 (C(O)OCH2CCl3), 137.72 (Ar), 135.93 (Ar), 133.28
7.27 (m, 4H, ArH), 5.58 (d, J = 5.4 Hz, 1H, H1), 4.96 (d, J = 11.1 Hz,
1H, PhCH2), 4.85 (d, J = 11.3 Hz, 1H, PhCH2), 4.59 (d, J = 11.9 Hz,
1H, PhCH2), 4.51 (d, J = 11.9 Hz, 1H, PhCH2), 4.34 (dd, J = 9.1, 4.7,
4.3 Hz, 1H, H5), 3.91 (dd, J = 10.2, 5.4 Hz, 1H, H2), 3.78–3.74 (m, 2H,
(Ar), 131.85 (Ar), 129.13 (Ar), 129.12 (Ar), 129.04 (Ar), 128.90 (Ar),
128.58 (Ar), 127.98 (Ar), 127.96 (Ar), 127.64 (Ar), 94.21 (CH2CCl3),
78.29 (C1), 77.53 (C2), 76.58 (PhCH2), 73.36 (PhCH2), 72.94 (CH2CCl3),
71.42 (C2), 69.39 (C4), 66.53 (C6), 54.11 (C3) ppm (missing signals
H4, H6), 3.70–3.66 (m, 2H, H3, H6), 2.53 (bs, 1H, OH) ppm. 13C NMR due to overlaps: 3 aromatic (Ar) carbon signals).
(126 MHz, CDCl3) δ = 138.0 (Ar), 137.8 (Ar), 133.5 (Ar), 132.3 (Ar),
Phenyl 2-N-acetyl-3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-
1,3-oxazin-2-one]-1-thio-α-D-glucopyranoside (5)
129.2 (Ar), 128.8 (Ar), 128.6 (Ar), 128.4 (Ar), 128.3 (Ar), 128.3 (Ar),
128.0 (Ar), 127.8 (Ar), 127.8 (Ar), 87.4 (C1), 81.5 (C3), 75.6 (PhCH2),
73.7 (PhCH2), 72.4 (C4), 71.1 (C5), 69.8 (C6), 63.7 (C2) ppm (missing
signals due to overlaps: two aromatic (Ar) carbon signals). The NMR
spectra are in accordance with the literature.[39]
Compound 3 (275 mg, 0.42 mmol, 1.0 equiv.) was dissolved in dry
CH2Cl2 (4 mL) at 0 °C, followed by the addition of iPr2EtN (0.33 mL,
1.91 mmol, 4.5 equiv.) and AcCl (0.14 mL, 1.91 mmol, 4.5 equiv.).
The mixture was warmed up to room temperature, and after five
Phenyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-oxazin-2-
one]-1-thio-α-D-glucopyranoside (3)
hours, the reaction was quenched with 1
M HCl (10 mL), washed
with saturated aqueous NaHCO3 (2 × 10 mL), dried with anhydrous
MgSO4, filtered and the solvents evaporated. The crude product
was purified by flash column chromatography in silica gel (toluene/
To a solution of compound 2 (1.149 g, 2.41 mmol) in THF (8.0 mL),
PPh3 (1.138 g, 4.34 mmol, 1.8 equiv.) was added, and the mixture
was allowed to stir for 2.5 hours. Afterwards, a stream of CO2, origi- EtOAc, 9:1) to yield pure 5 (200 mg, 0.39 mmol, 92 %) as a yellowish
nated from the sublimation of dry ice through a conical flask con-
taining CaCl2 as a drying agent, was bubbled through the solution
during 2.5 hours. Eventually, solvents were removed and the crude
residue purified by flash column chromatography in silica gel (tolu-
ene/EtOAc, 9:1 → EtOAc) to afford pure 3 (726 mg, 0.66 mmol,
63 %) as a white brittle solid. Rf (EtOAc) = 0.65 [α]2D5 +20° (c 0.98,
CHCl3) Mp (not recrystallized): 47.9 °C - 51.0 °C HRMS (HRMS/FT-ICR):
m/z [M + H]+ Calc. for C27H28NO5S+ 478.16827, found 478.16823. 1H
syrup. Rf (PE/EtOAc, 1:1) = 0.75. [α]2D5 +50 (c 0.11, CHCl3). HRMS
(HRMS/FT-ICR): m/z [M + H]+ Calc. for C29H30NO6S+ 520.17883,
found 520.18026. 1H NMR (500 MHz, [D]Chloroform) δ 7.55–7.53 (m,
2H, ArH), 7.36–7.30 (m, 7H, ArH), 7.25–7.16 (m, 10H, ArH), 5.52 (s,
1H, H1), 5.23–5.22 (m, 1H, H2), 4.68 (d, J = 11.8 Hz, 1H, PhCH2), 4.60
(d, J = 11.8 Hz, 1H, PhCH2), 4.49 (dd, J = 7.1, 6.8 Hz, 1H, H5), 4.46
(d, J = 11.7 Hz, 1H, PhCH2), 4.46 (dd, J = 4.0, 1.9,1H, H4), 4.36 (d, J =
11.8 Hz, 1H, PhCH2), 3.98 (ddd, J = 4.1, 4.0, 1.2 Hz, 1H, H3), 3.85 (dd,
NMR (500 MHz, [D]Chloroform) δ 7.53–7.51 (m, 2H, ArH), 7.35–7.30 J = 10.5, 7.7 Hz, 1H, H6a), 3.74 (dd, J = 10.5, 6.1 Hz, 1H, H6b), 2.67
(m, 6H, ArH), 7.28–7.26 (m, 5H, ArH), 7.23–7.21 (m, 2H, ArH), 5.78 (d,
(s, 1H, CH3) ppm. 13C NMR (126 MHz, CDCl3) δ = 173.2 (CH3CO),
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150.1 (carbamate-CO), 137.8 (Ar), 136.1 (Ar), 133.6 (Ar), 131.6 (Ar), (PhCH2), 73.3 (PhCH2), 71.7 (C2), 70.5 (C4), 66.6 (C6), 53.0 (C3), 41.7
129.2 (Ar), 129.1 (Ar), 129.0 (Ar), 128.8 (Ar), 128.6 (Ar), 128.4 (Ar), (CH3) ppm.
127.9 (Ar), 127.9 (Ar), 127.7 (Ar), 127.6 (Ar), 125.4 (Ar), 78.3 (C1), 77.6
(C5), 73.4 (PhCH2), 72.8 (PhCH2), 71.5 (C4), 69.7 (C3), 66.6 (C6), 49.9
Glycosylation general procedure
To a flame-dried round-bottomed flask, the glycosyl donor
(1.0 equiv.) and acceptor (1.5 equiv.) were added, coevaporated with
toluene (2 × 2 mL) and dried under vacuum. Glycosyl acceptors, 2-
methoxyethanol 8 and cyclohexanol 9 did not require such a proce-
dure, as they have been dried with 3Å MS prior use. Afterwards, the
reagents are dissolved in dry CH2Cl2 (2 mL) and 3Å MS (100 mg)
were added. The resulting mixture was stirred for 1 hour at room
temperature and, eventually, cooled to 0 °C. Afterwards, NIS and
catalytic amounts of AgOTf were sequentially added to the solution
and the reaction monitored by TLC. Upon completion, the glycosyl-
ations were quenched with Et3N (0.7 mL), diluted with EtOAc and
filtered through Celite. The mixture was washed with a 10wt.-%
(C2), 26.9 (CH3) ppm.
Phenyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-oxazin-2-
one]-2-N-[p-toluenesulfonyl]-1-thio-α-D-glucopyranoside (6)
To a solution of compound 3 (177 mg, 0.35 mmol) in THF (4.5 mL)
at 0 °C, NaH, as 60wt.-% dispersion in mineral oil (55 mg, 1.49 mmol,
4.25 equiv.), and TsCl (112 mg, 0.56 mmol, 1.6 equiv.) were sequen-
tially added. The solution was warmed up progressively to room
temperature and was stirred for 5 h. Afterwards, the reaction was
quenched with 1
with Et2O (2 × 20 mL). The combined organic layers were washed
with additional 1 HCl (2 × 20 mL), dried with anhydrous MgSO4,
M HCl and the resulting mixture was extracted
M
filtered and the solvent was removed under vacuum. The crude
residue was purified by flash column chromatography (toluene) to
furnish the final product 6 (183 mg, 0.29 mmol, 82 %) as a transpar-
ent syrup. Rf (EtOAc/PE, 1:1) = 0.79. [α]2D5 +39° (c 0.42, CHCl3). HRMS
aqueous Na2S2O3 solution (2 × 15 mL), HCl 1
M (2 × 15 mL) and
saturated aqueous NaHCO3 (2 × 15 mL). The organic phase was
dried with anhydrous MgSO4, filtered, concentrated under vacuum
and purified by flash column chromatography (PE/EtOAc or tolu-
ene/EtOAc).
(HRMS/FT-ICR): m/z [M + H]+ Calc. for C34H33NO7S2 632.17712,
+
1
found 654.15906. H NMR (500 MHz, [D]Chloroform) δ 8.03 (d, J =
2-Methoxyethyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-
8.4 Hz, 2H, tolyl-ArH), 7.63–7.61 (m, 2H, tolyl-ArH), 7.42–7.40 (m, 3H,
ArH), 7.37–7.25 (m, 15H, ArH), 7.21–7.17 (m, 2H, ArH), 5.52 (s, 1H,
H1), 5.00 (dd, J = 0.7, 3.1 Hz, 1H, H2), 4.70 (d, J = 11.8 Hz, 1H,
PhCH2), 4.66 (d, J = 11.8 Hz, 1H, PhCH2), 4.48 (d, J = 11.8 Hz, 1H,
PhCH2), 4.45 (m, 1H, H5), 4.40–4.38 (m, 1H, H4), 4.37 (d, J = 12.0 Hz,
1H, PhCH2), 4.00–3.98 (m, 1H, H3), 3.85 (dd, J = 7.9, 10.5 Hz, 1H, H6),
3.72 (dd, J = 6.0, 10.5 Hz, 1H, H6), 2.44 (s, 3H, CH3) ppm. 13C NMR
(126 MHz, CDCl3) δ = 147.9 (carbamate-CO), 145.3 (Ar), 138.0 (Ar),
137.7 (Ar), 135.8 (Ar), 135.2 (Ar), 133.9 (Ar), 131.8 (Ar), 129.8 (Ar),
129.3 (Ar), 129.1 (Ar), 129.1 (Ar), 129.0 (Ar), 128.9 (Ar), 128.5 (Ar),
128.3 (Ar), 128.1 (Ar), 127.9 (Ar), 127.8 (Ar), 127.6 (Ar), 125.4 (Ar),
78.3 (C1), 77.6 (C5), 73.3 (PhCH2), 72.9 (PhCH2), 71.3 (C4), 70.4 (C3),
66.6 (C6), 54.0 (C2), 21.8 (CH3) ppm (missing signals due to overlaps:
4 aromatic carbons).
oxazin-2-one]-D-glucopyranoside (11)
Glycosyl donor 3 (80 mg, 0.17 mmol), 2-methoxyethanol (18 mg,
0.24 mmol, 1.5 equiv.), NIS (53 mg, 0.24 mmol, 1.5 equiv.) and AgOTf
(5.1 mg, 0.02 mmol, 0.1 equiv.) were used. Full conversion was ob-
served after 45 minutes. Aqueous workup and flash column chro-
matography (EtOAc/PE, 1:1 → EtOAc) furnished a yellowish oil that
corresponded to the mixture of anomers of the final product 11
(48 mg, 0.11 mmol, 86 %). Rf (EtOAc) = 0.28 [α]2D5 –1.1° (c 1.96,
CHCl3) HRMS (HRMS/FT-ICR): m/z [M + Na]+ Calc. for C24H29NO7Na+
466.18362, found 466.18352. dr = 66:34 1H NMR (500 MHz, [D]Chlo-
roform) δ 7.36–7.32 (m, 8H, ArH), 7.31–7.27 (m, 6H, ArH), 7.26–7.23
(m, 4H, ArH; overlapped with CHCl3), 6.79 (bs, 1H, NH), 5.66 (d, J =
3.9 Hz, 1H, NH), 4.93 (s, 1H, H1), 4.82 (s, 1H, H1), 4.78 (d, J = 11.0 Hz,
1H, PhCH2), 4.59 (d, J = 11.8 Hz, 1H, PhCH2), 4.58 (d, J = 11.8 Hz,
1H, PhCH2), 4.54–4.51 (m, 3H, PhCH2, H4, H5), 4.45 (d, J = 11.0 Hz,
1H, PhCH2), 4.43 (app. bs, 1H, PhCH2), 4.41 (ddd, J = 1.6, 1.8, 3.6 Hz,
1H, H4), 4.34 (dd, J = 7.3, 7.2 Hz, 1H, H4), 4.15 (ddd, J = 1.1, 3.9,
3.9 Hz, 1H, H3), 4.11 (d, J = 3.8, 3.6 Hz, 1H, H3), 3.97–3.90 (m, 2H,
H6, H6), 3.82–3.74 (m, 3H, H2, H6, H6), 3.66–3.61 (m, 2H, CH2), 3.59–
3.55 (m, 2H, CH2), 3.54–3.53 (m, 1H, CH2), 3.51–3.47 (m, 2H, CH2),
3.47–3.41 (m, 2H, CH2), 3.36 (s, 3H, CH3), 3.29 (s, 3H, CH3) ppm. 13C
NMR (126 MHz, CDCl3) δ = 154.1 (carbamate-CO), 153.4 (carbamate-
CO), 138.2 (ipso-Ar), 137.9 (ipso-Ar), 137.3 (ipso-Ar), 136.5 (ipso-Ar),
128.8 (Ar), 128.6 (Ar), 128.6 (Ar), 128.5 (Ar), 128.5 (Ar), 128.0 (Ar),
127.9 (Ar), 127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 99.8 (C1), 93.5 (C1), 77.5
(C5), 75.1 (C5), 73.3 (PhCH2), 73.2 (PhCH2), 72.5 (PhCH2), 71.8
(CH2CH2OMe), 71.6 (CH2CH2OMe), 71.4 (C4), 70.5 (C3), 70.2 (C6), 69.8
(C4), 68.3 (C3), 68.3 (CH2CH2OMe), 68.0 (CH2CH2OMe), 67.7 (C6), 59.1
(CH3), 59.0 (CH3), 50.3 (C2), 46.9 (C2) ppm (missing signals due to
overlaps: 6 aromatic carbons).
Phenyl 3,6-di-O-benzyl-2-deoxy-2-N-methylsulfonyl-2N,4O-
[[2,3,4-c,d]-1,3-oxazin-2-one]-1-thio-α-D-glucopyranoside (7)
To a solution of compound 3 (63 mg, 0.13 mmol) in THF (1.0 mL)
at 0 °C, NaH, as 60wt.-% dispersion in mineral oil (63 mg, 1.68 mmol,
12.7 equiv.), and MsCl (49.5 μL mg, 0.63 mmol, 4.8 equiv.) were
sequentially added. The solution was warmed up progressively to
room temperature and stirred for 24 h. Afterwards, the reaction was
quenched carefully with 1
extracted with Et2O (2 × 20 mL). The combined organic layers were
washed with additional 1 HCl (2 × 20 mL), dried with anhydrous
M HCl and the resulting mixture was
M
MgSO4, filtered and the solvent was removed under vacuum. The
crude residue was purified by flash column chromatography (tolu-
ene/EtOAc, 2:1) to furnish the final product 7 (48 mg, 0.09 mmol,
69 %) as a transparent syrup (since some impurities could not be
removed by column chromatography, the yield is approximate). Rf
(EtOAc/PE, 1:1) = 0.28. [α]D25 –16° (c 0.064, CHCl3). HRMS (HRMS/FT-
ICR): m/z [M + Na]+ Calc. for C34H33NO7S2 578.12776, found
+
Cyclohexyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-
oxazin-2-one]-1-O-D-glucopyranoside (12)
578.12672. 1H NMR (500 MHz, [D]Chloroform) δ 7.64–7.63 (m, 2H,
ArH), 7.43–7.37 (m, 7H, ArH), 7.33–7.30 (m, 10H, ArH), 7.26–7.25 (m,
1H, ArH), 5.52–5.51 (m, 1H, H1), 4.90 (m, 1H, H3), 4.76–4.73 (m, 1H,
PhCH2), 4.69–4.66 (m, 1H, PhCH2), 4.54 (m, 1H, H5), 4.51 (d, J =
11.6 Hz, 1H, PhCH2), 4.51 (m, 1H, H2), 4.19 (d, J = 3.9, 7.6 Hz, 1H,
H4), 3.90–3.86 (m, 1H, H6), 3.80–3.79 (m, 3H, CH3), 3.76–3.72 (m, 1H,
H6) ppm.13C NMR (126 MHz, CDCl3) δ = 149.0 (carbamate-CO), 137.7
Glycosyl donor 1 (81 mg, 0.17 mmol), cyclohexanol 9 (18 mg,
0.26 mmol, 1.5 equiv.), NIS (57 mg, 0.23 mmol, 1.4 equiv.) and AgOTf
(6 mg, 0.02 mmol, 0.1 equiv.) were employed. Full conversion was
observed after 45 minutes. After aqueous workup and flash column
chromatography purification (EtOAc/PE, 1:3 → EtOAc), a mixture of
(Ar), 135.9 (Ar), 132.8 (Ar), 132.0 (Ar), 129.3 (Ar), 129.2 (Ar), 129.2 anomers, which corresponded to product 9, was obtained as a col-
(Ar), 129.1 (Ar), 129.0 (Ar), 128.6 (Ar), 128.4 (Ar), 128.2 (Ar), 128.0 orless oil (23 mg, 0.09 mmol, 30 %; approximate yield due to the
(Ar), 128.00 (Ar), 127.6 (Ar), 125.4 (Ar), 78.0 (C1), 78.0 (C5), 73.4
presence of impurities on the sample that could not be removed
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by column chromatography). Rf (EtOAc) = 0.89. [α]2D5 +6.0° (c 0.17, 2-Methoxyethyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-
CHCl3). HRMS (HRMS/FT-ICR): m/z [M + H]+ Calc. for C27H34NO6
468.23806, found 468.23876. dr = 67:33. 1H NMR (500 MHz, [D]Chlo-
roform) δ 7.36–7.32 (m, 10H, ArH), 7.31–7.28 (m, 7H, ArH), 7.27–7.22
(m, 6H, ArH; overlapped with CHCl3), 6.89 (d, J = 5.0 Hz, 1H, NH),
5.54 (d, J = 3.9 Hz, 1H, NH), 4.99 (s, 1H, H1), 4.93 (s, 1H, H1), 4.79 (d,
J = 11.0 Hz, 1H, PhCH2), 4.63 (d, J = 11.8 Hz, 1H, PhCH2), 4.57–4.45
(m, 7H, 3 × PhCH2, H4, H5), 4.42–4.41 (m, 2H, H4, PhCH2), 4.32 (dd,
J = 7.5, 6.9 Hz, 1H, H5), 4.16–4.15 (m, 1H, H3), 4.12–4.10 (m, 1H, H3),
4.07 (dd, J = 9.5, 8.2 Hz, 1H, H6), 3.88 (dd, J = 6.5, 9.4 Hz, 1H, H6),
3.82–3.76 (m, 2H, H6), 3.70–3.61 (m, 3H, H2, 2 × cyclohexyl-OCH),
3.36–3.35 (m, 2H, H2), 1.93–1.84 (m, 2H, CH2), 1.80–1.69 (m, 8H,
CH2), 1.55–1.47 (m, 2H, CH2), 1.38–1.30 (m, 3H, CH2) ppm. 13C NMR
(126 MHz, CDCl3) δ = 154.5 (carbamate-CO), 153.6 (carbamate-CO),
138.2 (Ar), 138.0 (Ar), 137.4 (ipso-Ar), 136.7 (ipso-Ar), 128.9 (Ar),
128.6 (Ar), 128.6 (Ar), 128.5 (Ar), 128.4 (Ar), 128.0 (Ar), 127.9 (Ar),
127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 96.7 (C1), 90.9 (C1), 77.2
(C5), 76.4 (cyclohexyl-OCH), 75.6 (cyclohexyl-OCH), 74.8 (C5), 73.3
(PhCH2), 72.6 (PhCH2), 71.4 (C4), 71.3 (PhCH2), 70.9 (C3), 70.5 (C6),
69.7 (C4), 68.4 (C3), 67.9 (C6), 51.2 (C2), 47.5 (C2), 33.6 (CH2), 33.2
(CH2), 31.9 (CH2), 31.0 (CH2), 25.8 (CH2), 25.7 (CH2), 24.1 (CH2), 24.1
(CH2), 23.8 (CH2) ppm (missing signals due to overlaps: 9 aromatic
(Ar), one benzylic (PhCH2) and one cyclohexyl-CH2 carbons).
oxazin-2-one]-2-N-[2,2,2-trichloroethoxycarbonyl]-D-glucopyr-
+
anoside (14)
The reaction was carried out with 4 (70 mg, 0.11 mmol) as glycosyl
donor, 2-methoxyethanol 8 (18 mg, 0.17 mmol, 1.5 equiv.) as glyc-
osyl acceptor, NIS (38 mg, 0.17 mmol, 1.5 equiv.) and AgOTf (5 mg,
0.01 mmol, 0.1 equiv.). Full conversion was achieved after 40 min-
utes. After aqueous workup flash column chromatography purifica-
tion (toluene/EtOAc, 3:1 → EtOAc), the anomeric mixture of the
final product 14 was obtained as a yellowish oil (50 mg, 0.04 mmol,
30 %) (some impurities could not be removed by column chroma-
tography; the yield is approximate). Rf (EtOAc/PE, 1:1) = 0.63.
[α]2D5 –6.8° (c 0.11, CHCl3). HRMS (HRMS/FT-ICR): m/z [M + H]+ Calc.
for C26H32NO8 486.21224, found 486.21465. dr = 63:37. 1H NMR
+
(500 MHz, [D]Chloroform) δ 7.65–7.64 (m, 1H, ArH), 7.46–7.43 (m,
1H, ArH), 7.27–7.13 (m, 36H, ArH; overlapped with CHCl3), 4.97 (s,
1H, H1), 4.88 (s, 1H, H1), 4.84 (d, d, J = 11.9 Hz, J = 11.7 Hz, 1H,
PhCH2), 4.73 (d, d, J = 11.9 Hz, J = 11.7 Hz, 1H, PhCH2), 4.65–4.62
(m, 2H, PhCH2), 4.59–4.55 (m, 3H, PhCH2, H4), 4.45–4.39 (m, 6H, H4,
H5, CH2CCl3), 4.38–4.32 (dd, 4H, J = 17.8, 12.2 Hz, CH2CCl3), 4.25 (dd,
J = 7.4, 7.0 Hz, 1H, H5), 4.11–4.07 (m, 2H, H3, H5), 4.03–4.01 (m, 1H,
H3), 3.96 (dd, J = 9.6, 8.0 Hz, 1H, H6), 3.87–3.82 (m, 2H, H6), 3.80–
3.76 (m, 1H, H6), 3.71–3.68 (app. d, J = 7.2 Hz, 1H, H6), 3.56–3.46
(m, 4H, CH2), 3.42–3.35 (m, 4H, CH2), 3.23 (s, 3H, CH3), 3.21 (s, 3H,
CH3) ppm (missing signals due to overlaps: one H5 proton). 13C
NMR (126 MHz, CDCl3) δ = 151.1 (carbamate-CO), 150.9 (carbamate-
CO), 147.3 (C(O)CH2CCl3), 146.8 (C(O)CH2CCl3), 138.0 (ipso-Ar), 137.7
(ipso-Ar), 136.8 (ipso-Ar), 132.3 (Ar), 129.2 (Ar), 129.0 (Ar), 128.8 (Ar),
128.7 (Ar), 128.7 (Ar), 128.7 (Ar), 128.6 (Ar), 128.5 (Ar), 128.3 (Ar),
128.2 (Ar), 128.2 (Ar), 128.2 (Ar), 128.0 (Ar), 127.9 (Ar), 127.8 (Ar),
127.9 (Ar), 127.9 (Ar), 127.8 (Ar), 125.5 (Ar), 98.1 (C1), 94.4 (CCl3),
94.2 (CCl3), 93.1 (C1), 76.8 (C5), 76.4 (PhCH2), 74.4 (C5), 73.4
(CH2CCl3), 73.3 (CH2CCl3), 73.2 (PhCH2), 72.8 (PhCH2), 71.9 (CH2), 71.8
(C4), 71.6 (PhCH2), 71.2 (CH2), 70.8 (C4), 69.8 (C3), 69.6 (C6), 67.8
(C3), 67.8 (CH2), 67.2 (C6), 59.0 (CH3), 59.0 (CH3), 53.0 (C2), 51.0 (C2)
ppm (missing signals due to overlaps: one C5 carbon).
3,6-Di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-oxazin-2-one]-
D
-glucopyranoside (1 → 3)-1,2;5,6-di-O-isopropylidene-α-
D-glu-
cofuranose (13)
The reaction was carried out with 3 (80 mg, 0.17 mmol) as glycosyl
donor, diacetone- -glucose 10 (66 mg, 0.26 mmol, 1.5 equiv.) as
D
glycosyl acceptor, NIS (57 mg, 0.23 mmol, 1.4 equiv.) and AgOTf
(6 mg, 0.02 mmol, 0.1 equiv.). Full conversion had occurred after
one hour. After aqueous workup and flash column chromatography
purification (toluene/EtOAc, 3:1 → EtOAc), the mixture of anomers
of the final product 13 was obtained as a colourless oil (31 mg,
0.09 mmol, 31 %) (since some impurities could not be removed by
column chromatography, the yield is approximate). Rf (EtOAc) =
0.49. [α]2D5 –33° (c 0.70, CHCl3). HRMS (HRMS/FT-ICR): m/z [M + Na]+
Cyclohexyl 3,6-di-O-benzyl-2-deoxy-2N,4O-[[2,3,4-c,d]-1,3-
oxazin-2-one]-2-N-[2,2,2-trichloroethoxycarbonyl]-
anoside (15)
1
Calc. for C33H41NO11Na+ 650.25718, found 650.25812. dr = 91:9. H
D-glucopyr-
NMR (500 MHz, [D]Chloroform) δ 7.36–7.27 (m, 17H, ArH), 7.25–7.24
(bd, J = 5.3 Hz, 2H, ArH), 5.87 (d, J = 3.9 Hz, 1H, H1′), 5.79 (d, J =
3.9 Hz, 1H, H1′), 5.08 (s, 1H, H1), 5.04 (1H, H1), 4.72–4.70 (m, 1H,
H4), 4.66 (d, J = 11.0 Hz, 1H, PhCH2), 4.58–4.56 (m, 3H, H2′, H2′, H4),
4.46 (d, J = 11.5 Hz, 1H, PhCH2), 4.40–4.35 (m, 3H, H5, H5, H4′, H4′
), 4.46 (dd, J = 9.8, 9.8 Hz, 1H, H6), 4.19–4.14 (m, 1H, H3), 4.13–4.09
(m, 3H, H3, H5′, H5′), 3.95 (dd, J = 4.1, 8.7 Hz, 1H, H6′), 3.84 (dd, J =
Glycosyl donor 4 (63 mg, 0.10 mmol), cyclohexanol 9 (15 mg,
0.15 mmol, 1.5 equiv.), NIS (43.0 mg, 0.25 mmol, 2.5 equiv.) and
AgOTf (10 mg, 0.02 mmol, 0.2 equiv.) were used. Full conversion
was observed after 90 minutes. The final product 15 was obtained
as a yellowish oil (27 mg, 0.04 mmol, 43 %; approximate yield
5.9, 9.9 Hz, 1H, H6), 3.73 (dd, J = 6.1, 8.6 Hz, 1H, H6′), 3.60–3.58 (m, due to the presence of impurities on the sample that could
1H, H2), 3.47 (m, 1H, H2) ppm (missing signals due to overlaps: two
not be removed by column chromatography), after aqueous
workup and flash column chromatography purification (EtOAc/PE,
H3′, one H4′, two H6, two H6′ and two benzylic (PhCH2) protons).
13C NMR (126 MHz, CDCl3) δ = 154.5 (carbamate-CO), 154.3 (carb- 1:3 → EtOAc) as a single anomer. Rf (EtOAc) = 0.67. [α]2D5 –45°
amate-CO), 138.4 (Ar), 138.2 (Ar), 136.8 (Ar), 136.5 (Ar), 128.9 (Ar), (c 0.55, CHCl3). HRMS (HRMS/FT-ICR): m/z [M + H]+ Calc. for
128.9 (Ar), 128.7 (Ar), 128.7 (Ar), 128.7 (Ar), 128.6 (Ar), 128.6 (Ar), C26H32NO8 486.21224, found 486.21465. dr = 20:1. 1H NMR
+
128.6 (Ar), 128.5 (Ar), 128.3 (Ar), 128.0 (Ar), 127.9 (Ar), 127.9 (Ar), (500 MHz, [D]Chloroform) δ 7.37–7.32 (m, 6H, ArH), 7.31–7.30 (m,
127.8 (Ar), 127.8 (Ar), 127.7 (Ar), 127.5 (Ar), 127.4 (Ar), 112.1 (C1′),
112.0 (C1′), 109.3 (isopropylidene-C), 109.3 (isopropylidene-C), 105.6
(isopropylidene-C), 104.7 (isopropylidene-C), 96.8 (C1), 94.6 (C1),
1H, ArH), 7.30–7.29 (m, 1H, ArH), 7.29–7.26 (m, 1H, ArH), 7.24 (m,
1H, ArH), 7.22 (m, 1H, ArH), 5.07 (s, 1H, H1), 4.90 (dd, J = 15.1,
12.1 Hz, 2H, CH2CCl3), 4.81 (d, J = 11.3 Hz, 1H, PhCH2), 4.67 (ddd,
81.5 (C2′), 81.2 (C2′), 80.7 (C4′), 79.5 (C4′), 75.1 (C5), 74.8 (C5), 73.4 J = 3.6, 2.2, 1.7 Hz, 1H, H3), 4.59 (ddd, J = 3.4, 1.8, 1.8 Hz, 1H, H2),
(PhCH2), 73.1 (PhCH2), 72.5 (PhCH2), 72.1 (PhCH2), 71.5 (C5′), 70.6 4.54 (d, J = 11.9 Hz, 1H, PhCH2), 4.45 (d, J = 11.2 Hz, 1H, PhCH2),
(C6′), 70.2 (C3), 69.6 (C6), 68.3 (C4), 67.2 (C6), 50.0 (C2), 47.5 (C2), 4.41 (d, J = 11.8 Hz, 1H, PhCH2), 4.34–4.31 (m, 1H, H5), 4.15 (dd, J =
27.2 (isopropylidene-CH3), 27.0 (isopropylidene-CH3), 26.8 (iso-
9.3, 8.8 Hz, 1H, H6), 4.11–4.10 (m, 1H, H4), 3.87 (dd, J = 9.5, 6.3 Hz,
propylidene-CH3), 26.6 (isopropylidene-CH3), 26.3 (isopropylidene- 1H, H6), 3.72–3.67 (m, 1H, cyclohexyl-OCH), 1.90–1.85 (m, 1H, CH2),
CH3), 26.0 (isopropylidene-CH3), 25.6 (isopropylidene-CH3), 25.4 (iso-
propylidene-CH3) ppm (missing signals due to overlaps: 2 aromatic
(Ar), one C3, two C3′, one C4, one C5′ and one C6′ carbons).
1.82–1.77 (m, 1H, CH2), 1.73–1.67 (m, 2H, CH2), 1.56–1.48 (m, 2H,
CH2) ppm (missing signals: 4 cyclohexyl CH2 protons; expected shift:
1.39–1.21 ppm). 13C NMR (126 MHz, CDCl3) δ = 151.1 (CO), 147.0
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(C(O)OCH2CCl3), 138.0 (ipso-Ar), 136.8 (ipso-Ar), 128.7 (Ar), 128.5 (Ar), (CH3) (missing signals due to overlaps: one aromatic (Ar) carbon
128.3 (Ar), 127.9 (Ar), 127.9 (Ar), 127.8 (Ar), 95.2 (C1), 94.2 (CCl3),
76.3 (cyclohexyl-OCH), 76.3 (CH2CCl3), 74.1 (C5), 73.4 (PhCH2), 72.3
(C3), 71.6 (PhCH2), 69.8 (C6), 67.8 (C5), 51.5 (C2), 33.1 (CH2), 31.2
(CH2), 29.9, 25.7, 24.0 (CH2), 23.8 (CH2) ppm (missing signals due to
overlaps: 2 aromatic (Ar) and 2 cyclohexyl CH2 carbons).
signal).
General ring opening procedure of the glycosylation products
under Zemplén conditions
The corresponding glycoside was dissolved in dry MeOH and excess
NaOMe, as 25wt.-% solution in MeOH, were sequentially added. The
mixture was either stirred at either room temperature or refluxed
until full conversion was appreciated. The reaction was then diluted
2-Methoxyethyl 2-N-acyl-3,6-di-O-benzyl-2-deoxy-2N,4O-
[[2,3,4-c,d]-1,3-oxazin-2-one]-D-glucopyranoside (17)
in EtOAc, washed with 1
NaHCO3, dried with anhydrous MgSO4, filtered and concentrated
under vacuum.
M HCl, neutralised with aqueous saturated
The reaction was carried out with 5 (50 mg, 0.10 mmol) as glycosyl
donor, methoxyethanol 8 (11 mg, 0.15 mmol, 1.5 equiv.) as glycosyl
acceptor, NIS (33.8 mg, 0.15 mmol, 1.5 equiv.) and AgOTf (3 mg,
0.01 mmol, 0.1 equiv.). Full conversion was observed after 30 min- 2-Methoxyethyl 3,6-di-O-benzyl-2-deoxy-2-N-[methoxycarbon-
utes. The aqueous workup and flash column chromatography (tolu-
ene/EtOAc, 5:1 → EtOAc) afforded the final mixture of anomers 17
as a yellowish oil (14 mg, 0.03 mmol, 24 %) (some impurities could
not be removed by column chromatography; the yield is approxi-
mate). Rf (EtOAc) = 0.31. [α]2D5 –1.1° (c 0.19, CHCl3). HRMS (HRMS/
yl]-D-glucopyranoside (21)
Glycoside 11 (94 mg, 0.22 mmol) was dissolved in dry MeOH
(1.5 mL) and NaOMe solution (0.19 mL, 0.67 mmol, 3.0 equiv.) was
added. The mixture was mixture stirred and refluxed at 45 °C for 4
hours. Eventually, a greyish oil was obtained (83 mg, 0.17 mmol,
89 %), which corresponded to product 21. Rf (EtOAc/PE, 1:1) = 0.54
[α]2D5 +146° (c 0.61, CHCl3) HRMS (HRMS/FT-ICR): m/z [M + Na]+ Calc.
for C25H33NO8SNa+ 498.20984, found 498.20957. α/ꢀ = 4.3:1 1H
NMR (500 MHz, [D]Chloroform) δ 7.62–7.57 (m, 1H, ArH), 7.49–7.46
(m, 1H, ArH), 7.40–7.37 (m, 1H, ArH), 7.31–7.19 (m, 16H, ArH), 5.09
(d, J = 9.3 Hz, 1H, NHα), 4.98 (d, J = 7.8 Hz, 1H, NHꢀ), 4.75 (d, J =
3.2 Hz, 1H, H1α), 4.72 (m, H1ꢀ), 4.67 (d, 2H, J = 11.9 Hz, PhCH2),
4.55–4.47 (m, 3H, PhCH2), 3.92 (ddd, J = 2.9, 9.7, 9.9 Hz, 1H, H2α),
3.86 (ddd, J = 4.3, 7.1, 8.8 Hz, 1H, H6ꢀ), 3.76–3.72 (m, 2H, H4α, H5ꢀ,
H6α), 3.68 (dd, J = 2.4, 4.3 Hz, 2H, CH2ꢀ), 3.65 (dd, J = 4.5, 8.6 Hz,
3H, CH2α), 3.62 (bd, J = 1.8 Hz, 1H, H2α), 3.60 (s, 3H, C(O)CH3α),
3.58 (s, 2H, C(O)CH3ꢀ), 3.56–3.52 (m, 3H, H6α, CH2α), 3.50 (bd, J =
3.0 Hz, 1H, H3α), 3.44–3.38 (m, 1H, H4ꢀ, H5α), 3.23 (bdd, J = 5.5,
3.2 Hz, 1H, H2ꢀ) 3.29 (s, 3H, OCH3α), 3.28 (s, 2H, OCH3ꢀ) ppm. 13C
NMR (126 MHz, CDCl3) δ 171.3 (carbamate-COꢀ), 156.8 (carbamate-
COα), 138.6 (Ar), 138.5 (Ar), 138.0 (Ar), 137.9 (Ar), 132.2 (Ar), 132.1
(Ar), 132.1 (Ar), 132.0 (Ar), 128.7 (Ar), 128.6 (Ar), 128.5 (Ar), 128.5
(Ar), 128.2 (Ar), 127.9 (Ar), 127.9 (Ar), 127.8 (Ar), 127.8, 127.7 (Ar),
100.9 (C1ꢀ), 98.6 (C1α), 81.1 (C3ꢀ), 80.9 (C3α), 75.4 (C4ꢀ), 74.5 (C5α),
74.4 (PhCH2), 74.0 (PhCH2), 73.8 (PhCH2), 73.7 (PhCH2), 70.6 (C4α),
70.0 (CH2), 68.7 (C6α), 67.3 (C6ꢀ), 60.5 (C5ꢀ), 59.0 (OCH3α), 57.3
(OCH3ꢀ), 54.4 (C2α), 52.3 (C(O)CH3α), 52.2 (C(O)CH3ꢀ) ppm (missing
signals due to overlaps: seven aromatic, one C2ꢀ and three meth-
oxyethyl CH2 carbons).
+
FT-ICR): m/z [M + H]+ Calc. for C26H32NO8 486.21224, found
486.21465. dr = 66:34. 1H NMR (500 MHz, [D]Chloroform) δ 7.35–
7.33 (m, 18H, ArH), 7.31–7.28 (m, 1H, ArH), 7.25–7.20 (m, 9H, ArH),
5.06 (s, 1H, H1), 4.95 (bs, 1H, H2), 4.86 (d, 1H, J = 11.2 Hz, PhCH2)
4.71 (s, 1H, H1), 4.64–4.63 (m, 1H, H4), 4.57–4.55 (m, 2H, PhCH2),
4.51–4.47 (m, 6H, PhCH2, H5, H3), 4.44–4.40 (m, 3H, PhCH2), 4.37–
4.31 (m, 2H, H5), 4.15–4.14 (m, 2H, H4), 4.01–3.99 (m, 2H, H3), 3.95–
3.90 (m, 4H, H6), 3.87–3.75 (m, 4H, H6), 3.61–3.55 (m, 4H, CH2), 3.51–
3.40 (m, 4H, CH2), 3.34 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 2.62 (s, 3H,
C(O)CH3) ppm (missing signals due to overlaps: one H2 proton).
13C NMR (126 MHz, CDCl3) δ = 173.1 (C(O)CH3), 154.0 (carbamate-
CO), 150.4 (carbamate-CO), 138.3 (Ar), 138.1 (Ar), 137.8 (Ar), 137.1
(Ar), 136.2 (Ar), 129.7 (Ar), 129.5 (Ar), 129.1 (Ar), 129.0 (Ar), 128.9
(Ar), 128.8 (Ar), 128.7 (Ar), 128.6 (Ar), 128.5 (Ar), 128.5 (Ar), 128.2
(Ar), 128.0 (Ar), 128.0 (Ar), 127.9 (Ar), 127.9 (Ar), 127.8 (Ar), 127.1
(Ar), 127.0 (Ar), 125.9 (Ar), 97.9 (C1), 93.7 (C1), 74.6 (C5), 73.4 (PhCH2),
73.3 (PhCH2), 72.6 (PhCH2), 72.4 (C4), 71.7 (PhCH2), 71.6 (CH2), 71.5
(CH2), 71.4 (CH2), 71.2 (C4), 71.1 (C5), 69.7 (C6), 68.4 (C6), 68.3 (CH2),
68.2 (C3), 61.7 (C3), 59.3 (OCH3), 59.1 (OCH3), 29.9 (C(O)CH3), 27.1
(C(O)CH3) ppm [missing signals due to overlaps: two C2 carbons].
Phenyl 3,6-di-O-benzyl-2-deoxy-2-N-[methoxycarbonyl]-1-thio-
α-D-glucopyranose (20)
To a stirred solution of glycoside 3 (80 mg, 0.17 mmol) in dry MeOH
(0.6 mL), NaOMe, as 25wt.-% solution in MeOH (0.14 mL, 0.50 mmol,
3.0 equiv.), was added. The mixture was mixture was allowed to
stir at room temperature for 24 h. Once the conversion had been
complete, the mixture was neutralised with AmberliteTM IR-120
resin and filtered. The solvent was eliminated under vacuum to ob-
tain a whitish oil (68 mg, 0.13 mmol, 79 %), which corresponded to
Cyclohexyl 3,6-di-O-benzyl-2-deoxy-2-N-[methoxycarbonyl]-D-
glucopyranoside (22)
Compound 12 (53 mg, 0.11 mmol) was dissolved in dry MeOH
(1.5 mL) and NaOMe solution in MeOH (0.12 mL, 0.55 mmol,
5.0 equiv.) was added. The mixture was mixture stirred and refluxed
product 20. Rf (EtOAc) = 0.85 [α]2D5 +146° (c 0.56, CHCl3) HRMS at 50 °C for 24 h. Eventually, a yellowish oil was obtained (45 mg,
(HRMS/FT-ICR): m/z [M + H]+ Calc. for C27H31NO4S+ 510.19448,
found 510.19486. 1H NMR (500 MHz, [D]Chloroform) δ 7.46–7.45 (m,
0.09 mmol, 80 %), which corresponded to product 22 (since some
impurities could not be removed by column chromatography, the
2H, ArH), 7.38–7.30 (m, 10H, ArH), 7.26–7.25 (m, 3H, ArH; overlapped yield is approximate). Rf (EtOAc) = 0.76 [α]2D5 +2.7° (c 0.38, CHCl3).
with CHCl3), 5.60 (d, J = 4.1 Hz, 1H, H1), 4.84 (d, J = 8.8 Hz, 1H, NH),
HRMS (HRMS/FT-ICR): m/z [M + Na]+ Calc. for C28H37NO7SNa+
4.81 (d, J = 11.5 Hz, 1H, PhCH2), 4.77 (d, J = 11.5 Hz, 1H, PhCH2), 522.24622, found 522.24535. dr = 79:21 1H NMR (500 MHz,
4.62 (d, J = 11.9 Hz, 1H, PhCH2), 4.54 (d, J = 11.9 Hz, 1H, PhCH2), [D]Chloroform) δ 7.26 (m, 10H, ArH), 7.22–7.21 (m, 3H, ArH), 7.19–
4.31 (ddd, J = 9.3, 4.8, 4.3 Hz, 1H, H5), 4.24–4.19 (m, 1H, H2), 3.84–
3.82 (m, 1H, H4), 3.80 (dd, J = 10.3, 4.5 Hz, 1H, H6a), 3.74 (dd, J =
10.3, 4.2 Hz, 1H, H6b) 3.67 (s, 3H, CH3), 3.47 (dd, J = 9.8, 9.2 Hz, 1H,
7.18 (m, 1H, ArH), 4.85 (bs, 2H, H1, H1′), 4.74 (d, J = 10.6 Hz, 1H,
NH), 4.69 (bd, J = 11.9 Hz, 2H, PhCH2), 4.55–4.46 (m, 3H, PhCH2),
3.88 (bdd, J = 10.1, 9.6 Hz, 1H, H2), 3.79–3.77 (m, 1H, H5, H5′), 3.67–
H3), 2.72 (bs, 1H, OH). 13C NMR (126 MHz, CDCl3) δ = 156.5 (carb- 3.63 (m, 4H, H4, H4′, H6, H6′), 3.59 (bs, 3H, CH3), 3.57 (bs, 2H,
amate-C(O)CH3), 138.3 (Ar), 137.9 (Ar), 134.0 (Ar), 132.3 (Ar), 132.2
CH3′), 3.55–3.44 (m, 3H, H3, H3′, cyclohexyl-OCH, cyclohexyl-OCH′),
(Ar), 131.8 (Ar), 129.2 (Ar), 128.8 (Ar), 128.7 (Ar), 128.6 (Ar), 128.1 1.80 (bd, J = 9.3 Hz, 2H, CH2), 1.71 (bs, 1H, CH2), 1.61 (bs, 3H, CH2),
(Ar), 128.0 (Ar), 127.9 (Ar), 127.7 (Ar), 89.6 (C1), 80.3 (C3), 74.5
(PhCH2), 73.8 (PhCH2), 72.7 (C4), 71.5 (C5), 70.2 (C6), 54.6 (C2), 52.6
1.46–1.43 (m, 2H, CH2), 1.34- 1.26 (m, 4H, CH2), 1.06–0.94 (m, 2H,
CH2) ppm (missing signals: one NH proton). 13C NMR (126 MHz,
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CDCl3) δ = 156.7 (carbamate-CO), 156.5 (carbamate-CO), 138.6 (Ar),
3.74 (dd, J = 5.2, 10.0 Hz, 3H, H6), 3.75–3.72 (m, 5H, H2), 3.65–3.64
138.5 (Ar), 138.3 (Ar), 138.3 (Ar), 138.1 (Ar), 138.0 (Ar), 137.9 (Ar), (bd, J = 2.1 Hz, 4H, H2), 3.59–3.56 (m, 6H, H6), 3.52–3.41 (m, 102H,
137.8 (Ar), 98.6 (C1′), 96.4 (C1), 81.5 (C3), 81.1 (C3′), 76.0 (cyclohexyl-
OCH), 74.5 (PhCH2), 73.7 (PhCH2), 73.5 (PhCH2), 73.5 (PhCH2), 71.8
H5, 4 × methoxyethyl-CH2), 3.22 (s, CH3), 3.19 (s, CH3) ppm. 13C NMR
(126 MHz, DMSO) δ = 152.5 (carbamate-CO), 152.3 (carbamate-CO),
(C4), 70.9 (C6), 70.3 (C5), 70.1 (C6′), 69.8 (C5′), 69.4, 57.8, 55.2 (C2′), 138.4 (Ar), 138.3 (Ar), 138.0 (Ar), 137.5 (Ar), 128.5 (Ar), 128.4 (Ar),
54.2 (C2), 52.4 (C(O)CH3), 52.3 (C(O)CH3′), 37.5 (CH2), 37.2 (CH2), 33.5
(CH2), 31.7 (CH2), 25.6 (CH2), 24.0 (CH2) ppm (missing signals due to
overlaps: two carbamate ester carbonyls (C(O)CH3), 16 aromatic and
four cyclohexyl CH2 carbons).
128.4 (Ar), 128.3 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 127.6 (Ar),
127.6 (Ar), 99.6 (C1), 93.4 (C1), 75.3 (C4), 72.2 (CH2CCl3), 72.2
(CH2CCl3), 71.3 (PhCH2), 71.2 (PhCH2), 71.1 (methoxyethyl-CH2), 70.6
(PhCH2), 70.3 (C4), 70.2 (C6), 69.2 (C3), 68.7 (C3), 68.0, 67.7 (methoxy-
ethyl-CH2), 67.6, 67.1 (C6), 58.3 (OCH3), 58.2 (OCH3), 48.8 (C5), 45.9
(C2) ppm (missing signals due to overlaps: two Troc carbonyls, 11
aromatic, two CCl3, one C2, one C5 carbons and two carbamate
ester methyl (C(O)CH3) signals).
3,6-O-benzyl-2-deoxy-2-N-[methoxycarbonyl]-
D-glucopyran-
ose-(1 → 3)-1,2;5,6-di-O-isopropylidene-α- -glucofuranose (23)
D
Compound 13 (40 mg, 0.064 mmol) was dissolved in dry MeOH
(3.0 mL) and NaOMe solution (0.08 mL, 0.34 mmol, 5.0 equiv.) was
added. The mixture was mixture stirred at room temperature for
24 h. Finally, a yellowish oil was obtained (38 mg, 0.058 mmol,
91 %), which corresponded to product 23 (since some impurities
could not be removed by column chromatography, the yield is ap-
proximate). Rf (EtOAc) = 0.67. [α]2D5 +2.7° (c 0.38, CHCl3). HRMS
(HRMS/FT-ICR): m/z [M + Na]+ Calc. for C34H45NO12SNa+ 682.28340,
found 682.28423. α/ꢀ = 1:5.2. 1H NMR (500 MHz, [D]Chloroform)
δ 8.10 (d, J = 7.5 Hz, 2H, ArH), 7.60 (t, J = 7.3 Hz, 1H, ArH), 7.47 (t,
J = 7.5 Hz, 1H, ArH), 7.38–7.28 (m, 19H, ArH), 5.85 (d, J = 3.5 Hz, 1H,
H1′ꢀ), 5.82 (d, J = 3.8 Hz, 1H, H1′α), 4.82 (d, J = 3.5 Hz, 1H, H1α),
4.78–4.75 (m, 2H, H1ꢀ, PhCH2), 4.72 (d, J = 11.7 Hz, 1H, PhCH2), 4.63
(d, J = 12.2 Hz, 1H, PhCH2), 4.59–4.50 (m, 5H, H2′, PhCH2), 4.38 (d,
J = 12.2 Hz, 1H, PhCH2), 4.34–4.31 (m, 1H, H5), 4.28 (bdd, J = 3.5,
2.7 Hz, 1H, H3′), 4.25–4.20 (m, 1H, H3′), 4.10 (dd, J = 8.8, 2.9 Hz, 1H,
H4′), 4.06–4.00 (m, 2H, H4, H4), 3.95 (ddd, J = 3.2, 6.3, 13.2 Hz,
H5′), 3.89 (bs, 1H, H5′), 3.81 (dd, J = 3.1, 11.3 Hz, 2H, H6′), 3.73 (bd,
J = 9.6 Hz, 1H, H6), 3.68 (s, 3H, C(O)CH3), 3.67–3.62 (m, 5H, H3, H3,
H6, H6′), 3.40 (bs, 1H, H2), 3.17 (bs, 1H, H2), 1.46 (bdd, J = 7.4,
7.5 Hz, 6H, CH3), 1.30–1.16 (m, 18H, CH3) ppm (missing signals: two
NH, one H4′ and one H5 protons). 13C NMR (126 MHz, CDCl3) δ =
170.5 (carbamate-C(O)CH3), 138.2 (Ar), 137.4 (Ar), 133.7 (Ar), 130.3
(Ar), 129.6 (Ar), 128.8 (Ar), 128.8 (Ar), 128.7 (Ar), 128.7 (Ar), 128.7
(Ar), 128.7 (Ar), 128.7 (Ar), 128.6 (Ar), 128.6 (Ar), 128.3 (Ar), 128.3
(Ar), 128.2 (Ar), 128.1 (Ar), 128.0 (Ar), 127.9 (Ar), 127.8 (Ar), 112.3
(isopropylidene-C), 112.2 (isopropylidene-C), 112.1 (isopropylidene-
C), 111.8 (isopropylidene-C), 105.4 (C1′), 105.2 (C1′), 83.7 (C2′), 83.0
(C3′), 82.8, 81.7, 80.5 (C3′), 80.3 (C4′), 74.8 (PhCH2), 74.7 (PhCH2),
74.4 (PhCH2), 74.2, 74.0, 73.9 (PhCH2), 73.1 (C5), 72.1, 70.4 (C6), 69.8
(C6), 68.4 (C5′), 64.6 (C6′), 57.5 (C2), 56.9 (C2), 52.6 (C(O)CH3), 52.5
(C(O)CH3), 32.1 (CH3), 29.8 (CH3), 29.5 (CH3), 26.9 (CH3), 26.7 (CH3),
26.4 (CH3), 25.4 (CH3), 22.8 (CH3) ppm (missing signals due to over-
laps: one carbamate ester carbonyl (C(O)CH3), 3 aromatic (Ar), C1,
one C2′, two C3, two C4 and one C4′ carbons).
Keywords: Glycosylation · Conformational restriction ·
Cyclic carbamate · Protective groups
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2-Methoxyethyl 3,6-di-O-benzyl-2-deoxy-2-N-[methoxy-
carbonyl]-2-N-[2,2,2-tricholorethoxycarbonyl]-D-glucopyranos-
ide (24)
Compound 14 (31 mg, 0.050 mmol) was dissolved in dry MeOH
(2.0 mL) and NaOMe solution (0.11 mL, 0.50 mmol, 10.0 equiv.) was
added. The mixture was mixture stirred and refluxed at 50 °C for
24 h, to furnish a yellowish oil (25 mg, 0.040 mmol, 81 %), which
corresponded to compound 24. Rf (EtOAc) = 0.21 [α]2D5 +6.6° (c 0.62,
DMS O) HR MS (H RM S/ FT-I CR ): m/ z [ M + N a ] + Ca l c. fo r
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1
C28H34Cl3NO10Na+ 672.11450, found 672.11414. dr = 60:40 H NMR
(500 MHz, DMSO) δ 7.79 (bd, J = 5.3 Hz, 2H, ArH), 7.72–7.64 (m, 3H,
ArH), 7.36–7.22 (m, 23H, ArH), 4.81 (s, 1H, H1), 4.73 (d, J = 11.4 Hz,
1H, PhCH2), 4.68 (s, 1H, H1), 4.64 (d, J = 12.1 Hz, 1H, PhCH2), 4.60
(d, J = 11.7 Hz, 1H, PhCH2), 4.53 (d, J = 12.1 Hz, 1H, PhCH2), 4.48–
4.45 (m, 4H, H3), 4.40–4.39 (m, 3H, 2 × CH2CCl3), 4.15–4.09 (m, 5H,
H4, H4), 3.99 (dd, J = 8.1, 10.0 Hz, 1H, H6), 3.86–3.78 (m, 6H, H6),
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Eur. J. Org. Chem. 2020, 6459–6467
www.eurjoc.org
6466
© 2020 Wiley-VCH GmbH

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doi.org/10.1002/ejoc.202001130
EurJOC
European Journal of Organic Chemistry
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Received: August 19, 2020
Eur. J. Org. Chem. 2020, 6459–6467
www.eurjoc.org
6467
© 2020 Wiley-VCH GmbH