Full Papers
doi.org/10.1002/ejoc.202100808
the donor instead of excess acceptor (entry 14). The prolonged Experimental Section
reaction time is clearly resulting in a competing degradation of
All the chemicals and solvents were provided from commercial
the glycosyl donor. The same trend was seen with the
peracetylated cellubiosyl donor 5 (entry 15–18), where the
tosylated acceptors (8 and 11) gave prolonged reaction times
and lower yields (entry 15 and 16), which could be partly
improved by using excess of 5 (entry 17). The β-selectivities for
both 4 and 5 were maintained when having neighboring group
participation and no signs of the formation of N-acylorthoamide
were observed. As the ultimate test of our self-promoted
glycosylation the peracetylated GlcNAc glycosyl donor 6 was
attempted glycosylated using the same conditions, but no
product could be isolated. The low reactivity of the donor
combined with a favourable oxazoline formation of the donor is
making the N-glycosylation unachievable (not shown). This
observation is in line with Grundler and Schmidt’s synthesis and
attempted glycosylation with donor 6.[34] The donor has due to
this only sporadically been used since the work by Schmidt and
only to glycosylate reactive alcohols,[35,36] i.e. no carbohydrate
alcohols, amino acid alcohols[37] or weak nucleophiles like
amides. The inherent problem with glycosylation using a
GlcNAc donor could be overcome by using the N-Troc
protected donor 7, which gave good yields and high selectivity,
when using excess of the donor (entry 19 vs 20). The asparagine
acceptors were also effectively glycosylated by 7 and the
nosylated acceptor 12 was again found to give shorter reaction
times (entry 22).
With access to the glycosyl sulfonyl amides selective
desulfonylation became relevant. From our experience with the
orthogonal deprotection of the glycosyl sulfonyl carbamates,
where nosyl was found to be the most promising protective
group, as this could be deprotected under milder conditions
using thiolates. Exposing the glycosyl sulfonyl amides, under
these conditions did however result in cleavage of the amide
bond rather than the sulfonyl amide bond. Changing the base
used, solvents or the thiolate, did unfortunately not yield the
desired glycosyl amides and the nosyl group therefore should
be sought exchanged with a sulfonyl group, which can be
deprotected under less nucleophilic conditions. Returning to
the tosylated products, removal with Mg in MeOH was
attempted, but only traces of product could be observed.
Effective and selective deprotection of the sulfonyl groups will
have to be investigated further.
suppliers and used without further purification. Dry DCM,
acetonitrile, toluene, DMF and THF were obtained from an
Innovative Technology PSMD-05 solvent drying system. Other
solvents were dried with 4 Å molecular sieves. Thin layer chroma-
tography (TLC) was carried out using aluminum sheets coated with
silica gel (60F). TLC plates were visualized with UV-light or with a
10% solution of H2SO4 in ethanol and heat. Column chromatog-
raphy was performed using Kieselgel 230–400 mesh silica gel.
1
Optical rotations were measured on an Anton Paar polarimeter. H-
NMR and 13C-NMR spectra were recorded on a Bruker 500 MHz Ultra
Shield Plus spectrograph equipped with a cryo-probe. Chemical
shifts were reported relative to TMS (δ 0.00) or solvent residual
signals. High resolution mass spectra (HRMS) were obtained from a
Bruker SolariX XR 7T ESI/MALDI-FT-ICRMS instrument using matrix-
assisted laser desorption ionization (MALDI).
Nα-(2,2,2-trichloroethoxycarbonyl)-N-(tosyl)-l-asparagine benzyl
ester (10) A solution of TsNH2 (0.41 g, 2.38 mmol) and DIPEA
(0.8 ml, 4.77 mmol) in abs. CH2Cl2 (20 ml) was cooled down to
°
À 20 C. Then a solution of the acyl chloride S14 (0.99 g, 2.38 mmol)
in abs. CH2Cl2 (20 ml) was added dropwise. The reaction mixture
was slowly allowed to warm up and stirred at r.t. overnight. After
this time the resulting solution was diluted with CH2Cl2 (100 ml)
and washed with 1 M HCl (2×100 ml). The organic layer was dried
over Na2SO4 and evaporated to dryness. The crude product was
pourified by column chromatography (1:5!1:2 Acetone/
Cyclohexane) to yield the compound 10 (0.64 g, 1.17 mmol, 49%)
as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H, NH),
7.90 (d, J=8.6 Hz, 2H, ArTs), 7.40–7.29 (m, 5H, ArBn), 7.26–7.21 (m,
2H, ArTs), 6.00 (d, J=8.3 Hz, NH), 5.12 (d, J=12.2 Hz, CH2Bn), 5.06 (d,
J=12.2 Hz, CH2Bn), 4.68 (s, 2H, CH2Troc), 4.59 (dt, J=8.6, 4.5 Hz, 1H,
CHAsn), 3.04 (dd, J=17.1, 4.5 Hz, 1H, CH2Asn), 2.88 (dd, J=17.1, 4.5 Hz,
1H, CH2Asn), 2.44 (s, 3H, CH3Ts) ppm. 13C NMR (500 MHz, Chloroform-
d) δ 169.78 (C=OAmide/Ester), 168.21 (C=OAmide/Ester), 154.53 (C=OCarbamate),
145.62 (iArTs/Bn), 135.46 (iArTs/Bn), 134.89 (iArTs/Bn), 129.93 (2×ArBn),
128.80 (2×ArBn), 128.74 (ArBn), 128.44 (2×ArTs), 128.39 (2×ArTs),
95.23 (CCl3), 74.90 (CH2Troc), 68.14 (CH2Bn), 50.48 (CHAsn), 38.03
Ts
(CH2Asn), 21.87 (CH3
)
ppm. HRMS (MALDI+): Calculated for
C21H21Cl3N2O7SNa+ m/z 573.0033; found m/z 573.0033. [α]D
=
589
°
37.0 (c=0.7, CHCl3).
Nα-(alloxycarbonyl)-N-(tosyl)-l-asparagine benzyl ester (11)
A
solution of TsNH2 (0.47 g, 2.75 mmol) and DIPEA (0.9 ml, 5.01 mmol)
°
in abs. CH2Cl2 (18 ml) was cooled down to 0 C. Then a solution of
the acyl chloride S16 (0.82 g, 2.50 mmol) in abs. CH2Cl2 (15 ml) was
added dropwise. The reaction mixture was slowly allowed to warm
up and stirred at r.t. for 1 h. After this time the resulting solution
was diluted with CH2Cl2 and washed with 1 M HCl (2×100 ml). The
organic layer was dried over Na2SO4 and evaporated to dryness.
The crude product was pourified by column chromatography
(1:5!1:2 Acetone/Cyclohexane) to yield the compound 11 (0.90 g,
1
1.95 mmol, 78%) as a pale-yellow solid. H NMR (500 MHz, Chloro-
Conclusion
form-d) δ 8.82 (s, 1H, NH), 7.90 (d, J=8.6 Hz, 2H, ArTs), 7.39-7.28 (m,
5H, ArBn), 7.25 (d, J=8.6 Hz, 2H, ArTs), 5.92-5.79 (m, 1H, =CHAlloc), 6.79
(d, J=8.0 Hz, NH), 5.27 (broad d, J=17.1 Hz, =CH2Alloc), 5.19 (broad
d, J=10.2 Hz, =CH2Alloc), 5.12 (d, J=12.1 Hz, CH2Bn), 5.05 (d, J=
12.1 Hz, CH2Bn), 4.60–4.48 (m, 3H, CHAsn, CH2Alloc), 2.97 (broad d, J=
16.6 Hz, 1H, CH2Asn), 2.86 (broad d, J=16.6 Hz, 1H, CH2Asn), 2.42 (s,
3H, CH3Ts) ppm. 13C NMR (500 MHz, Chloroform-d) δ 170.4 (C=O),
168.6 (C=O), 156.2 (C=O), 145.3 (Ar), 135.7 (Ar, 135.1 (All), 132.4 (Ar),
129.8 (Ar), 128.7 (Ar), 128.6 (Ar), 128.3 (Ar), 118.1 (=CH2Alloc), 67.9
(CH2Bn), 66.3 (CH2Alloc), 50.4 (CH2Asn), 38.4 (CH2Asn), 21.8 (Me) ppm.
In conclusion, we have developed a self-promoted glycosylation
of sulfonyl amides, which is performed at elevated temper-
atures without any additives. Various solvents can be used, but
dichlorobenzene was found to be superior at higher temper-
atures. The synthesized glycosyl sulfonyl amides were found to
be more labile than the corresponding sulfonyl carbamates and
milder desulfonylation methods, or other sulfonyl groups, have
therefore to be developed to access the glycosyl amides in
practical yields. Our method gives easy access to β-N-glycosides
at mild conditions with a minimal use of chemicals.
HRMS (MALDI+): Calculated for C22H24N2O7SNa+ m/z 483.1202;
589
°
found m/z 483.1197. [α]D =39.4 (c=0.6, CHCl3).
Eur. J. Org. Chem. 2021, 1–6
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