Organocatalytic direct α-selective N-glycosylation of amide with glycosyl trichloroacetimidate

Article abstract of DOI:10.1248/cpb.c18-00255

Through the synergistic catalytic effect of the halogen bond (XB) donor and thiourea catalyst, a direct α-selective N-glycosylation of the amide residue of asparagine derivative was achieved using readily accessible glycosyl trichloroacetimidate. n-Butyl methyl ether was found to be the most suitable solvent for the α-selectivity.

Full text of DOI:10.1248/cpb.c18-00255

768
Chem. Pharm. Bull. 66, 768–770 (2018)
Vol. 66, No. 7
Note
Organocatalytic Direct α-Selective N-Glycosylation of Amide with
Glycosyl Trichloroacetimidate
,a,b
Shanji Li,a Yusuke Kobayashi,b and Yoshiji Takemoto*
a Graduate School of Advanced Integrated Studies in Human Survivability, Kyoto University; 1 Yoshida-Naka-Adachi-
b
cho, Sakyo-ku, Kyoto 606–8306, Japan: and Graduate School of Pharmaceutical Sciences, Kyoto University; 46–29
Yoshida-Shimo-Adachi, Sakyo-ku, Kyoto 606–8501, Japan.
Received April 1, 2018; accepted April 16, 2018
Through the synergistic catalytic effect of the halogen bond (XB) donor and thiourea catalyst, a direct
α-selective N-glycosylation of the amide residue of asparagine derivative was achieved using readily acces-
sible glycosyl trichloroacetimidate. n-Butyl methyl ether was found to be the most suitable solvent for the
α-selectivity.
Key words glycosylation; organocatalyst; halogen bond; hydrogen bond; green chemistry
N-Glycosides are found in a variety of bioactive com- non-halogenated azolium 5 did not furnish 2a at all (entry
pounds, including natural products.1) Sugar moieties are 4), indicating that XB interaction would play an important
known to extend the diversity of molecules, altering their role. The chemical yields were slightly improved using XB2
property, structure, and biological activities.2) However, syn- and XB3 (entries 5 and 6), whereas the undesired glycosyl
thetic methods for N-glycosides have not been well devel- trichloroacetamide 4 was obtained in these cases. Further
oped,3–8) as compared with the preparation of O-glycosides. investigation was carried out with XB3 from the viewpoint of
In particular, stereoselective synthesis of α-N-glycosides is its easy preparation.17) A slight improvement of α/β-selectivity
one of the most challenging issues despite their potentials (α:β=65:35) was observed when diethyl ether was used as
as therapeutic compounds.9–11) In 2003, DeShong’s group solvent (entry 7).18) Encouraged by this result, we next in-
has reported a highly α-selective synthesis of N-glycosides vestigated several other etheric solvents (entries 8–12), and
through a Cu-mediated acylation of glycopyranosyl isoxazo- found that dimethoxyethane (DME) and n-butyl methyl ether
line intermediates generated from the corresponding azides,5) improved α/β-selectivity (α:β=80:20) (entries 11 and 12). The
while anomerization of 1-aminoglycopyranosyl derivatives is anomeric configuration of major product was unambiguously
generally a significant problem.4) Direct N-glycosylation of determined as α-isomer (α-2a) by an X-ray crystallographic
amides has emerged as an alternative approaches,6–8) but those analysis.17)
reports relied on the neighboring group participation to give
β-N-glycosides (Chart 1a).
With the suitable catalyst and solvent in hand, we next
Herein, we report the first direct α-N-glycosylation of amide
with glycosyl trichloroacetimidate12) using halogen bond (XB)
donor13)/Schreiner thiourea14) co-catalytic system. We envi-
sioned that α-selectivity would be achieved through the double
inversion strategy (Chart 1b). The initial SN2 addition of an
appropriate solvent, such as etheric solvent, and/or additive15)
to α-donor 1 would form a β-linked intermediate A, to which
the following SN2 attacked by an employed amide would af-
ford the desired α-linked product. As in our previous report,8)
we have chosen an XB-donor/thiourea co-catalytic system for
the activation of the leaving group (LG) of 1, mainly due to
the following reasons: 1) XB interaction would be effective
in relatively polar etheric solvent, and 2) tuning of both HB
donor and XB donor would improve their ability to trap the
LG via anion binding,16) preventing the undesired rearrange-
ment of the LG.
We first screened the reaction conditions for the direct
α-N-glycosylation of asparagine derivative 3 with glycosyl
donor 1 (Table 1). According to our previous work, 2-iodo-
imidazolium salt (XB1)13) was examined in conjunction with
HB1 in dichloromethane.8) As we expected, the combina-
tion of HB1 and XB1 was essential for the production of
desired N-glycoside 2a (entries 1–3), although almost no α/β
selectivity was observed (entry 3). A control experiment with
Chart 1. Strategy for α-N-Glycoside
*To whom correspondence should be addressed. e-mail: takemoto@pharm.kyoto-u.ac.jp
© 2018 The Pharmaceutical Society of Japan

Vol. 66, No. 7 (2018)
Chem. Pharm. Bull.
769
Table 1. Initial Screening for α-2a
Table 2. Effect of Additives and HB Donors
investigated several additives and HB donors in order to im-
prove the α/β-selectivity, and to suppress the undesired glyco-
syl trichloroacetamide 4 (Table 2).
Experimental
When 1.0 equiv of thiophene was added, the yield of 2a
To a solution of glycosyl donor 1 (41.1mg, 0.06mmol), gly-
increased to 64% along with the decrease of byproduct 4, cosyl acceptor 3 (15.3mg, 0.05mmol), and thiophene (4.2mg,
and the α/β-selectivity has reached to 82:18 (entry 1). Ten 0.05mmol) in n-butyl methyl ether (1.0mL) were successively
equiv of thiophene, however, diminished the yield of 2a, added activated MS4Å (100.0mg), XB3 (3.3mg, 0.005mmol),
probably due to the inhibition of the catalysts (entry 2). To and HB1 (2.5mg, 0.005mmol), and the reaction mixture was
our disappointment, further improvement was not observed, stirred at room temperature for 24h. Direct purification on
although several different thiophene derivatives (entries 3–8) silica gel column chromatography gave α-2a (21.9mg, 53%)
and other nucleophilic additives, such as N,N-dimethylamino- and β-2a (4.8mg, 11%) as white solid (Table 2, entry 1).
pyridine-N-oxide (DMAPO), N-formylmorpholine (NFM),15)
triphenylphosphine oxide, and tri(2-thienyl)phosphine (entries
Acknowledgments This work is supported in part by
9–12), were screened as additives. Then, we examined the Takeda Science Foundation and Grants-in-Aid for Scientific
HB donors HB219) and HB317) bearing superior HB-donating Research (16H06384) from Ministry of Education, Culture,
abilities (entries 13 and 14). The ratio of the desired product Sports, Science and Technology (MEXT) of Japan.
2a to the byproduct 4 was improved, presumably because of
their stronger anion binding abilities, while there is still room
Conflict of Interest The authors declare no conflict of
for improvement of the α/β-selectivity. It is worthy to note that interest.
trimethylsilyl trifluoromethanesulfonate (TMSOTf), one of the
most commonly used Lewis acids, was not effective to obtain
Supplementary Materials The online version of this ar-
N-glycoside 2a, and the undesired glycosyl trichloroacetamide ticle contains supplementary materials.
4 was just produced in high yield (entry 15).
In conclusion, we have found that XB donor/ thiourea co-
catalytic system was effective even in polar solvent, enabling
a direct α-selective N-glycosylation of amide with glycosyl
trichloroacetimidate. We believe that this methodology would
be applied to the synthesis of a variety of α-N-glycosides.
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