Full text of DOI:10.1021/acs.orglett.8b00632

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereocontrolled Synthesis of 2‑Deoxy-galactopyranosides via
Isopropylidene-Protected 6‑O‑Silylated Donors
Dan-Mei Yang, Yue Chen, Ryan P. Sweeney, Todd L. Lowary, and Xing-Yong Liang*,†
†
,§
†,§
‡
‡
†
School of Chemistry Engineering, Sichuan University of Science & Engineering, Zigong 643000, China
‡
Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
*
S Supporting Information
ABSTRACT: The stereocontrolled synthesis of 2-deoxy-D-arabino-hexopyranosides (“galactopyranosides”) using 3,4-O-
isopropylidene-6-O-tert-butyldiphenylsilyl-protected glycosyl donors is reported. 2-Deoxy-thioglycoside 3e gives excellent α-
selectivity, while galactal 9 leads to, in a two-step protocol, 2-deoxy-β-glycosides in high stereoselectivity. The selectivity of both
reagents is believed to arise from the combination of the isopropylidene acetal spanning O-3 and O-4 together with the sterically
demanding silyl group on O-6. The utility of the method was demonstrated through the synthesis of a trisaccharide that contains
both 2-deoxy α- and β-D-galactopyranosyl residues.
a
2
-Deoxy-glycosyl residues are present in many biologically
Table 1. Glycosylation of Alcohol 5 with Donors 3a−e
active natural products and clinical agents, including anthracy-
Scheme 1. Preparation of Compounds 3a−e
b
c
entry
donor
product
yield (%)
α/β
1
2
3
4
5
3a
3b
3c
3d
3e
3e
6a
6b
6c
6d
6e
6e
91
84
86
75
83
81
3/1
3/2
7/2
9/2
10/1
d
6
α-only
a
All glycosylations were performed by treating the donor (1.2 equiv)
1
clines, angucyclines, and aureolic acid antibiotics. The lack of
and the acceptor (1.0 equiv) with NIS (1.5 equiv) and TfOH (0.1
neighboring-group participation from substituents at the C-2
position and the enhanced conformational flexibility derived
from the reduced number of substituents make it difficult to
equiv), in the presence of 4 Å molecular sieves in CH Cl , at −30 to 0
2
2
b
c
°C. Combined total yield of both isomers. Determined on the basis
of the H NMR of the corresponding mixture. TfOH (0.01 equiv).
1
d
2
achieve glycosylation in a stereoselective manner. Further-
more, the lack of an electron-withdrawing substituent at C-2
makes the resulting glycosides more acid labile.
Strategies for the stereocontrolled synthesis of 2-deoxy-
glycosides usually rely on indirect methods. Prominent among
hexopyranosides (“galactopyranosides”), using 3,4-O-isopropy-
lidene-6-O-TBDPS protected donors.
At the outset of this investigation, we envisioned applying the
1
4
3
4
5
hydrogen-bond-mediated aglycone delivery (HAD ) strategy
to synthesize 2-deoxy-β-D-galactopyranosides using a group at
O-6 to direct the attack of the nucleophile. Thus, we prepared a
donor modified at the primary position with a pyridine-2-
carboxylic (Pico) ester (3a, Scheme 1). Its preparation started
with thioglycoside 1, which was obtained from D-galactose as
these are reductive cleavage of a halogen, sulfur, oxygen,
6
7
nitrogen, or selenium functionality at C-2 of the glycoside
product. Direct synthesis of 2-deoxyglycosides using phos-
11
8
9
10
phate, phosphoroamidite, phosphite, phosphorodithioate,
1
2
13
thioglycoside, and (2-carboxyl)benzyl glycoside donors is
also known. Nevertheless, the synthesis of 2-deoxyglycosides
with high stereoselectivity still remains a challenge. Here, we
report two complementary methods for the synthesis, with high
stereocontrol, of either 2-deoxy-α- or 2-deoxy-β-D-arabino-
Received: February 21, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Glycosylation of Alcohols 7a−7j with 3e
Scheme 2. Proposed Pathway for Glycosylations with 3e and
9
15
described by Ye and co-workers. Acetalization of 1 with 2,2-
dimethoxypropane and PPTS afforded 2 in a yield of 71%.
Treatment with pyridine-2-carboxylic acid (PicoOH) and DCC
furnished 3a in 84% yield.
We anticipated that the product of the coupling between 3a
and acceptor 5 should be the β-isomer due to the HAD effect.
However, we found that this reaction afforded product 6a as a
16
mixture (α:β, 3:1, entry 1, Table 1). In previous work, donor
4
(Scheme 1) has been successfully used in the stereoselective
17
synthesis of 2-deoxy-β-glycosides via HAD. The major
difference between 4 and 3a is the presence of a cyclic
protecting group on O-3 and O-4.
Based on these results, we hypothesized that the
isopropylidene acetal in 3a prevents the acceptor from
attacking the β-face of the donor. We further postulated that
additional tuning of the α-selectivity might be possible by the
choice of protecting group at O-6. Thus, a series of other
donors (3b−e) were synthesized from 2 (Scheme 1).
Treatment with benzoyl bromide in pyridine afforded 3b in
9
4% yield. Alkylation with benzyl bromide and sodium hydride
gave 3c in 92% yield. Introduction of a trityl ether by reaction
with trityl chloride in pyridine led to 3d in 81% yield. Finally,
reaction with TBDPSCl provided 3e in a yield of 83%.
Compounds 3a−e were obtained as a mixture of α and β
anomers. Although some of these anomers could be separated,
the mixtures were used in the glycosylations.
With these compounds in hand, their use in the glycosylation
of 6 was investigated (Table 1). The 6-O-Bz, 6-O-Bn, or 6-O-Tr
thioglycosides (3b−d) displayed modest α-selectivity, affording
disaccharides 6b−d in 75−84% yields as a mixture of anomers
(
3/2 to 9/2 α:β ratio, entries 2−4). These results are
comparable to those obtained with 3a (entry 1). However, to
our delight, the 6-O-TBDPS-protected thioglycoside 3e showed
significantly improved selectivity (83% yield α:β > 10:1, entry
5
). Interestingly, only the α-isomer was detected when the
amount of TfOH decreased from 0.1 to 0.01 equiv (entry 6).
Next, we surveyed the glycosylation of a variety of alcohols
18
with 3e. All reactions were run using the alcohol (7a−j, 1.0
equiv), thioglycoside 3e (1.2 equiv), NIS (1.5 equiv), and
TfOH (0.01 equiv), at −30 to 0 °C in CH Cl . As summarized
2
2
in Table 2, we were pleased to find that all acceptors reacted
very well with 3e, resulting in the corresponding glycoside
products 8a−j in 74−93% yields with the α-anomer as the
major product or sole product (α:β > 6:1). These included
glycosylation of the noncarbohydrate alcohols menthol (7a,
6
:1, α:β entry 1), 3-tert-butylphenol (7b, entry 2), and serine
derivative 7c (entry 3). In the cases of glycosyl acceptors, the
B
DOI: 10.1021/acs.orglett.8b00632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Glycosylation of 5, 7f−g, and 12−14 with 9
Scheme 3. Synthesis of the Trisaccharide 28
demanding TBDPS group on O-6 favors formation of the α-
glycoside, via α-selective attack of the alcohol on an
electrophilic intermediate formed upon activation of 3e
(
Scheme 2A).
The ability to convert 3e into α-glycosides with high
selectivity prompted us to design another glycosylation based
on the same general principles. We envisioned that galactal
19
derivative 9, which has the same protecting groups as 3e,
could be used to prepare 2-deoxy-β-glycosides with high
stereoselectivity via a two-step protocol. Treatment of 9 with
NIS would be expected to afford the cyclic iodonium ion
intermediate 10 (Scheme 2B). Nucleophiles would be expected
to attack this species from the top face, thus affording the 2-
deoxy-2-iodo-β-galactopyranoside 11. Subsequent reduction of
the C−I bond would give the 2-deoxy-glycoside.
With this in mind, we glycosylated a panel of alcohols with 9
(
Table 3). The glycosylation was promoted using the method
20
developed by Mong and co-workers (NIS and TMSOTf). As
expected, acceptor 5 reacted very well with 9, affording the
desired 2-deoxy-2-iodo-β-D-galactopyranoside 15 (determined
3
by the integration of NMR signals, J
= 9.6 Hz) in 92%
H1,H2
yield. The 2-deoxy-2-iodo-α-D-talopyranoside derivative was
not detected by TLC and NMR spectroscopy. Next, we carried
21
out similar glycosylations of alcohols 7e−f and 12−14. We
were pleased to find that all acceptors also reacted very well
with 9, thus resulting in the products 16−20 in 83−87% yields.
In all cases, none of the isomeric 2-deoxy-2-iodo-α-D-
talopyranosides were detected. Subsequent reduction of the
C−I bond with n-Bu SnH and AIBN led to the 2-deoxy-β-
3
galactopyranoside derivatives in excellent yield.
To demonstrate the power of these methods, we targeted the
preparation of a trisaccharide (28) that contained both 2-
deoxy-α- and 2-deoxy-β-galactopyranoside linkages (Scheme
a
All glycosylations were performed by treating 9 (1.0 equiv) and the
acceptor (1.5 equiv) with NIS (2.0 equiv), TMSOTf, (1.5 equiv), in
the presence of 4 Å molecular sieves in CH CN/CH Cl (v/v 2:1), at
−
3
). Thus, treatment of 5 and 9 with NIS and TMSOTf yielded
3
2
2
disaccharide 15 in 82% yield. Then, the iodine was removed by
b
50 to 0 °C. The yield based on the donor.
means of free radical reduction (n-Bu SnH, AIBN) to give
3
disaccharide 21. Subsequent desilylation via TBAF in THF
liberated the 6-OH of the β-2-deoxy-galactopyranosyl moiety,
thus affording 27 in 86% yield. Finally, the coupling between 27
and thioglycoside 3e produced 28 in 71% yield. The
stereochemistry of the trisaccharide was confirmed by the
combination of the J1,2 values and the chemical shift of the
reactions of 3e with 7d−j produced the expected α-linked
glycosides 8d−j with high diastereoselectivity (α:β > 15:1) and
in good yields (>74%). Reactions with primary acceptors 7d−g
provided, in general, the same α-selectivities as reactions with
more hindered secondary acceptors 7h−j (entries 4−7 vs
entries 8−10). Any sensitivity of the stereoselectivity to the
structure of the acceptor is not obvious. Taken together, these
results support our hypothesis that the combination of the
isopropylidene acetal on O-3 and O-4 and the sterically
16
anomeric carbon for these units.
In conclusion, we report two novel approaches for the
synthesis of 2-deoxy α- and β-D-galactopyranosides using the
3,4-O-isopropylidene-6-O-tert-butyldiphenylsilyl-protected do-
C
DOI: 10.1021/acs.orglett.8b00632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nors 3e and 9. The approach was successfully applied to the
synthesis of a protected trisaccharide derivative 28. Although
the exact mechanism of these transformations is unclear at
present, we believe the stereoselectivity results from the
protecting groups directing the attack of either an alcohol (in
the case of 3e) or iodonium ion (in the case of 9) to the α-face
of the molecule. Efforts to better understand the mechanism of
these processes and their application to the synthesis of other
(10) Hashimoto, S.-I.; Sano, A.; Sakamoto, H.; Ikegami, S. Synlett
1
995, 1995, 1271.
(11) Laupichler, L.; Sajus, H.; Thiem, J. Synthesis 1992, 1992, 1133.
(
12) (a) Sun, L.; Li, P.; Zhao, K. Tetrahedron Lett. 1994, 35, 7147−
7150. (b) Lear, M. J.; Yoshimura, F.; Hirama, M. Angew. Chem., Int. Ed.
2001, 40, 946−949. (c) Jaunzems, J.; Kirschning, A. Tetrahedron Lett.
2003, 44, 637−639.
(13) Kim, K. S.; Park, J.; Lee, Y. J.; Seo, Y. S. Angew. Chem., Int. Ed.
2
003, 42, 459.
2-deoxysugars are underway.
(14) (a) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012,
34, 20097−20102. (b) Yasomanee, J. P.; Demchenko, A. V. Angew.
1
ASSOCIATED CONTENT
* Supporting Information
Chem., Int. Ed. 2014, 53, 10453. (c) Liu, Q. W.; Bin, H. C.; Yang, J. S.
Org. Lett. 2013, 15, 3974.
■
S
(15) Lu, Y. S.; Ye, X. S. Synlett 2010, 2010, 1519.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00632.
(
16) Paul, S.; Jayaraman, N. Carbohydr. Res. 2007, 342, 1305. The
1
stereochemistry was determined by H NMR spectroscopy. In the α-
glycosides, the anomeric hydrogen appeared as a doublet with a J1,2 of
3.0−4.0 Hz; the H-2 protons resonated between 2.30 and 1.85 ppm,
1
Experimental procedures, characterization data, and H,
H
appeared as a doublet of triplets, and H appeared as a doublet
13
2ax
2eq
C NMR spectra for all new compounds (PDF)
of doublets. The chemical shift of the anomeric carbon in the α-
anomer resonated at 96−98 ppm. In comparison, in all β-isomers the
AUTHOR INFORMATION
Corresponding Author
E-mail: levesonk@163.com.
H-1 resonance appeared as a double of doublets, with J1 = 8.0−10.0
,2ax
■
*
Hz and J1,2b = 2.0−3.0 Hz. The H-2 resonances appeared between 2.20
and 1.60 ppm. The resonances for H2 appeared as a doublet of
ax
doublet of doublets, and H2eq appeared as a multiplet. The chemical
shift of the anomeric carbon in the β-anomer resonated at 98−101
ppm.
ORCID
Todd L. Lowary: 0000-0002-8331-8211
Xing-Yong Liang: 0000-0003-0328-6019
Author Contributions
§D.-M.Y. and Y.C. contributed equally.
(
17) Ruei, J. H.; Venukumar, P.; Mong, K.-K. T. Chem. Commun.
2015, 51, 5394.
18) Alcohols 7a, 7b, and 7h are commercially available. All others
(
were prepared by reported methods. 7c: Arnaud, O.; Koubeissi, A.;
Ettouati, L.; Falson, P. J. Med. Chem. 2010, 53, 6720. 7d: Reference
Notes
15c. 5, 7e−f: Liptak
721. 7g, 7j: Wouters, A. Synthesis 2013, 45, 2222. 7i: Capozzi, G. J.
Org. Chem. 2001, 66, 8787.
19) Marcaurelle, L. A.; Bertozzi, C. R. Org. Lett. 2001, 3, 3691.
(20) Pradhan, T. K.; Mong, K.-K. T. Org. Lett. 2014, 16, 1474.
(21) 12 and 13: Ishikawa, T.; Shimizu, Y. Org. Lett. 2003, 5, 3879.
14: Completo, G. C.; Lowary, T. L. J. Org. Chem. 2008, 73, 4513.
́ ́
, A.; Imre, J.; Neszmelyi, A. Tetrahedron 1982, 38,
3
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
NSFC-21402131), Sichuan University of Science & Engineer-
■
(
ing (2014RC06, LYJ4204), and the China Scholarship Council
and the Canadian Glycomics Network for financial support.
REFERENCES
■
(
1
1) (a) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr. Chem.
997, 188, 1. (b) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14,
9
9. (c) Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
(
2) (a) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385−
417. (b) Veyrieres, A. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, 2000; p
67. (c) Hou, D.; Lowary, T. L. Carbohydr. Res. 2009, 344, 1911.
d) Kharel, M. K.; Rohr, J. Nat. Prod. Rep. 2012, 29, 264. (e) Borovika,
A.; Nagorny, P. J. Carbohydr. Chem. 2012, 31, 255.
3) (a) Thiem, J.; Gerken, M.; Weigand, J. Carbohydr. Res. 1987, 164,
8
́
3
(
(
3
1
27. (b) Horton, D.; Priebe, W.; Sznaidman, M. Carbohydr. Res. 1989,
87, 149. (c) Costantino, V.; Fattorusso, E.; Imperatore, C.; Mangoni,
A. Tetrahedron Lett. 2002, 43, 9047.
4) (a) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 2723.
b) Roush, W. R.; Briner, K.; Gustin, D. J. J. Org. Chem. 1996, 61,
098.
5) Sato, K.; Yoshitomo, A.; Takai, Y. Bull. Chem. Soc. Jpn. 1997, 70,
85.
6) Capozzi, G.; Dios, A.; Franck, R. W.; Tamarez, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 777.
7) (a) Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75.
b) Nicolaou, K. C.; Mitchell, H. J.; Suzuki, H.; Rodriguez, R. M.
Angew. Chem., Int. Ed. 2000, 39, 1089.
8) Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J. Org. Chem.
993, 58, 1083.
9) Hao, L.; Meijin, C.; Kang, Z. Tetrahedron Lett. 1997, 38, 6143.
(
(
6
(
8
(
(
(
(
1
(
D
DOI: 10.1021/acs.orglett.8b00632
Org. Lett. XXXX, XXX, XXX−XXX