Assistance of the C-7,8-Picoloyl Moiety for Directing the Glycosyl Acceptors into the α-Orientation for the Glycosylation of Sialyl Donors

Article abstract of DOI:10.1021/acs.orglett.7b01658

An efficient α-sialylation method for many primary hydroxyl acceptors that include 6-OH glycosides has been developed. 7,8-Di-O-picoloyl sialyl glycoside was used as the glycosyl donor, and α-glycoconjugation was controlled by using the 7,8-di-O-picoloyl

Full text of DOI:10.1021/acs.orglett.7b01658

Letter
pubs.acs.org/OrgLett
Assistance of the C‑7,8-Picoloyl Moiety for Directing the Glycosyl
Acceptors into the α‑Orientation for the Glycosylation of Sialyl
Donors
Yu-Fa Wu and Yow-Fu Tsai*
Department of Chemistry, Chung Yuan Christian University, Chung Li District, Taoyuan 32023, Taiwan
*
S Supporting Information
ABSTRACT: An efficient α-sialylation method for many
primary hydroxyl acceptors that include 6-OH glycosides has
been developed. 7,8-Di-O-picoloyl sialyl glycoside was used as
the glycosyl donor, and α-glycoconjugation was controlled by
using the 7,8-di-O-picoloyl moiety in CH Cl . The method-
2
2
ology was successfully applied to the total synthesis of ganglioside Hp-s1 possessing neuritogenic activity.
ialic acids are a diverse family of carboxylated sugars with a
skeleton of nine carbon atoms. As sialic acids are widely
best result was obtained with the glycosylation of 7,8-di-O-
1
S
picoloyl donor 1d with acceptor 2 at −40 °C, in which the
coupling product 3d was obtained in 70% yield with excellent
stereoselectivity (α only) along with glycal 4d in 27% yield
(entry 4). 8-O-Picoloyl donor 1b also exhibited high α-
stereoselectivity (α/β = 8:1) and moderate yield (62%) for
disaccharide 3b, with glycal 4b observed in 24% yield (entry 2).
7-O-Picoloyl donor 1a (entry 1) and 4,9-di-O-picoloyl donor 1c
(entry 3) showed no significant stereoselectivity for dis-
accharides 3a (α/β = 1:1.2, 57% yield) and 3c (α/β = 1.3:1,
43% yield), and glycals 4a and 4c were obtained in 40% and
49% yield, respectively. Per-O-benzoyl donor 1e gave
disaccharide 3e in excellent yield (90%) but with poor α-
expressed on the cell surfaces of all animals and are frequently
located at the terminal position of glycoconjugates on the cell
1
a,c,2
surface,
they can play important functional roles in various
biological and pathological processes, such as cell−cell adhesion
and recognition, cell differentiation, signal transduction, and
3
tumor metastasis. Hence, sialic acid glycosides and their
4
oligomers have potential applications in medicine, and the
synthesis of glycoconjugates containing sialic acid is very
important.
Natural sialosides have an α-anomeric structure. Because of
the presence of the C-1 carboxyl group at the tertiary anomeric
center and the lack of a stereocontrolling group at C-3 to direct
α-stereoselective sialylation, achieving high α-stereoselectivity
of the glycosylation of sialic acid donors with high product yield
remains a challenge. Despite previously reported studies on
elegant strategies and methodologies, such as the application of
13
stereoselectivity (α/β = 1:3.3) (entry 5). We also explored
the glycosylation of the 7,8-di-O-nicotinoyl (3-pyridinecarbon-
yl, Nico), and 7,8-di-O-isonicotinoyl (4-pyridinecarbonyl,
iNico) sialyl donors with acceptor 2. The results revealed
excellent α-stereoselectivity (α only) for the corresponding
disaccharides, albeit with very poor product yields (see Table
S1 for the detailed results).
5
6
7
various leaving groups, solvents, and promoters as well as
8
9
10
structural modification at C-1, C-3, and C-5, it is imperative
to develop efficient strategies and methodologies for α-
sialylation from the biological viewpoint as well as for potential
applications in medicine.
To optimize the conditions for glycosylation, the glyco-
conjugation of sialyl donor 1d with acceptor 2 was conducted
using various solvents and temperatures (Table 2). First, the
effect of temperature was investigated. Using NIS/TfOH as the
11
Recently, Yasomanee and Demchenko reported a novel
methodology for stereodirected glycosylation. The stereo-
selectivity of glycosylation was controlled by the picolinyl (2-
pyridylmethyl, Pic) and picoloyl (2-pyridinecarbonyl, Pico)
substituents via intermolecular H-bond tethering between the
glycosyl donor and glycosyl acceptor counterparts. However, to
the best of our knowledge, no related studies describing the
application of this method to the glycosylation of sialic acid
promoter and conducting the glycosylation in CH Cl at −20
2
2
°
C, we observed low stereoselectivity (α/β = 5.3:1) and poor
product yield (24%) (entry 1). When the reaction temperature
was decreased to −60 °C (entry 2), the yield (69%) and α-
stereoselectivity (α only) of disaccharide 3d were as good as
those at −40 °C. Next, the effect of the solvent was examined.
Using CH CN (entry 3) or CHCl (entry 4), we got excellent
3
3
12
α-stereoselectivity, but the yield of disaccharide 3d was not
satisfactory (56% or 20%, respectively). Interestingly, using
toluene as the solvent (entry 5) did not result in the
glycosylation of sialyl donor 1d with acceptor 2; 1d was
have been reported apart from De Meo’s results. In that
study, α-stereoselectivity for the sialylation of hydroxyl aglycone
assisted by the Pico group was described.
To seek a potential glycosyl donor, the glycosylation of
phenyl thiosialosides 1a−e (see the Supporting Information for
the corresponding preparation) with glycosyl acceptor 2 in the
presence of NIS/TfOH in CH Cl was explored (Table 1). The
Received: June 1, 2017
2
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01658
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Organic Letters
Letter
Table 1. Exploring the Glycosylation of Sialyl Donors 1a−e with Glucosyl Acceptor 2
a
b
1
Isolated through chromatography. Determined by H NMR spectroscopy.
Table 2. Screening of the Optimized Conditions for the
Glycosylation of Sialyl Donor 1d with Glucosyl Acceptor 2
OP(OEt) , OP(O)(OPh) , and OPico were examined under
the optimal conditions (i.e., use of NIS/TfOH as the promoter
2
2
in CH Cl at −40 °C). However, the results (see Table S3)
2
2
were not better than that for SPh as the leaving group.
To further evaluate the scope of glycosylation for sialyl donor
1d under the optimized reaction conditions (Table 3), various
glycosyl acceptors were prepared according to a previously
reported method (see the Supporting Information). The
glycoconjugation of sialyl donor 1d with primary alcohol 5a
afforded the corresponding disaccharide 6a in 97% yield as a
single α-stereoisomer (entry 1). For the sialylation of primary
alcohol 5b with donor 1d, the coupling product 6b was
obtained in excellent yield (98%), albeit with moderate α-
stereoselectivity (α/β = 2.8:1) (entry 2). The coupling of
primary alcohols 5c and 5d containing carbohydrates with 1d
also furnished the desired coupling products 6c and 6d in good
yields (68% and 73%, respectively) with excellent stereo-
selectivity (α only) (entries 3 and 4). Using secondary sugars
b
b
temp
time
(h)
yield (%) cof 3d
yield (%) of
a
entry
solvent
(°C)
(α/β)
4d
1
2
3
4
5
CH Cl2
−20
−60
−40
−40
−40
0.5
5.0
0.5
0.5
2.0
24 (5.3:1)
70
25
44
76
0
2
CH Cl2
69 (α only)
56 (α only)
20 (α only)
2
CH CN
3
CHCl3
toluene
d
−
a
b
Promoter: NIS (2 equiv)/TfOH (1.5 equiv). Isolated through
chromatography. Determined by H NMR spectroscopy. The
c
1
d
starting material was recovered.
(
e.g., 5e) as acceptors, we did not obtain the corresponding
14
disaccharides (e.g., 6e) but obtained only the glycal side
product 4d, possibly because of the strong steric hindrance in
these acceptors (entry 5). Detailed results for the glycosylation
of 1d with other acceptors are provided in Table S4. The
stereochemistry of disaccharides 3d and 6a−d was determined
by comparing the chemical shifts of the de-O-acylated
recovered quantitatively after 2 h. The reason for this result is
not clear. As to the effects of promoters and some solvents,
detailed results are shown in Table S2.
To understand the effects of the leaving group on the
stereoselectivity of glycosylation and the yield of the final
product, other leaving groups such as S-benzoxazolyl (SBox),
B
DOI: 10.1021/acs.orglett.7b01658
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a
Table 3. Evaluation of the Glycosylation Scope of Sialyl Donor 1d with Various Acceptors
a
b
The reaction was carried out under the following conditions: NIS (2 equiv), TfOH (1.5 equiv), CH Cl , −40 °C. Isolated by chromatography.
2
2
c
1
Determined by H NMR spectroscopy.
Scheme 1. Total Synthesis of Ganglioside Hp-s1 Possessing Neuritogenic Activity
disaccharides with those of the corresponding compounds
reported in the literature (see Tables S5−S7 for the detailed
results). The sialylation of primary alcohols containing
carbohydrates, e.g., 2 and 5c, with 7,8-di-O-picoloyl-Neu5Gc
as the donor was also investigated, and good yields of the
corresponding disaccharides as single α-stereoisomers were
observed (see Table S8 for the detailed results).
−40 °C to afford the α-stereoisomer disaccharide 9 in 76%
yield. Compound 9 was coupled with protected phytoceramide
11 in the presence of a promoter such as AgOTf in anhydrous
CH Cl at 0 °C, and only the β-anomer was obtained for
2
2
protected Hp-s1 12, albeit in poor yield (25%). Fortunately,
when 9 was first treated with Cu(OAc) in MeOH at −10 °C
2
16
to selectively remove the picoloyl group and then protected
phytoceramide 11 was glycosylated with the resulting
disaccharide 10 (93% yield) under the same conditions as
those described for disaccharide 9, the desired Hp-s1 analogue
13 was obtained in high yield (87%) with excellent stereo-
selectivity (β only). Finally, protected Hp-s1 analogues 12 and
13 were subjected to sequential deprotection reactions
Finally, to confirm the utility of this aforementioned
methodology, it was extended to the synthesis of the natural
product ganglioside Hp-s1, which exhibits neuritogenic activity
1
5
(
8
Scheme 1). The sialylation of S-thiazolyl (STaz) acceptor
1
5b
with sialyl donor 1d was performed using NIS/TfOH as
the promoter in CH Cl with powdered 3 Å molecular sieves at
2
2
C
DOI: 10.1021/acs.orglett.7b01658
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
involving deisopropylidenenation, debenzylation, deacetylation,
and saponification to furnish the desired ganglioside Hp-s1 in
(c) Haberman, J. M.; Gin, D. Y. Org. Lett. 2001, 3, 1665. (d) Takahashi,
T.; Tsukamoto, H.; Yamada, H. Tetrahedron Lett. 1997, 38, 8223.
(9) (a) Hossain, N.; Magnusson, G. Tetrahedron Lett. 1999, 40, 2217.
7
5% and 89% yield, respectively, in three steps.
In summary, 7,8-di-O-picoloyl sialyl donors can be applied in
(b) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schmidt, R. R. J. Am.
Chem. Soc. 1998, 120, 5434. (c) Martichonok, V.; Whitesides, G. M. J.
Am. Chem. Soc. 1996, 118, 8187.
the α-sialylation of most primary hydroxyl acceptors such as 6-
OH glycosides. The α-stereocontrolled glycosylation was best
(10) (a) Corcilius, L.; Payne, R. J. Org. Lett. 2013, 15, 5794. (b) Chu,
achieved using the 7,8-di-O-picoloyl moiety in CH Cl . A
2
2
K.-C.; Ren, C.-T.; Lu, C.-P.; Hsu, C.-H.; Sun, T.-H.; Han, J.-L.; Pal, B.;
Chao, T.-A.; Lin, Y.-F.; Wu, S.-H.; Wong, C.-H.; Wu, C.-Y. Angew.
Chem., Int. Ed. 2011, 50, 9391. (c) De Meo, C.; Priyadarshani, U.
Carbohydr. Res. 2008, 343, 1540. (d) Crich, D.; Li, W. J. Org. Chem.
2007, 72, 2387. (e) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am.
Chem. Soc. 2006, 128, 7124.
further advantage of this method is the facile preparation of the
,8-di-O-picoloyl sialyl donors. This methodology was success-
7
fully applied to the total synthesis of ganglioside Hp-s1 via
chemoselective glycosylation. This developed method can be
used to efficiently synthesize various glycoconjugates possessing
an α(2−6) disaccharide segment. The investigation of the
mechanism of glycosylation is also in progress, and the results
will be reported in due course.
(11) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012,
1
34, 20097.
(12) Escopy, S.; Geringer, S.; De Meo, C. Org. Lett. 2017, 19, 2638.
(
13) Premathilake, H. D.; Gobble, C. P.; Pornsuriyasak, P.;
Hardimon, T.; Demchenko, A. V.; De Meo, C. Org. Lett. 2012, 14,
1126.
(14) De Meo, C.; Farris, M.; Ginder, N.; Gulley, B.; Priyadarshani,
U.; Woods, M. Eur. J. Org. Chem. 2008, 2008, 3673.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01658.
(15) (a) Chen, W.-S.; Sawant, R. C.; Yang, S.-A.; Liao, Y.-J.; Liao, J.-
W.; Badsara, S. S.; Luo, S.-Y. RSC Adv. 2014, 4, 47752. (b) Tsai, Y.-F.;
Shih, C.-H.; Su, Y.-T.; Yao, C.-H.; Lian, J.-F.; Liao, C.-C.; Hsia, C.-W.;
Shui, H.-A.; Rani, R. Org. Biomol. Chem. 2012, 10, 931. (c) Yamada, K.;
Tanabe, K.; Miyamoto, T.; Kusumoto, T.; Inagaki, M.; Higuchi, R.
Chem. Pharm. Bull. 2008, 56, 734.
Detailed experimental procedures for the preparation and
characterization of all compounds (PDF)
(
16) Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Org. Lett.
AUTHOR INFORMATION
Corresponding Author
■
2
014, 16, 716.
*tsaiyofu@cycu.edu.tw
ORCID
Yow-Fu Tsai: 0000-0002-8175-8408
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the
Ministry of Science and Technology, Taiwan (MOST 105-
■
2113-M-033-003).
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DOI: 10.1021/acs.orglett.7b01658
Org. Lett. XXXX, XXX, XXX−XXX