Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the synthesis of the carbohydrate portion of antibiotic hygromycin A

Article abstract of DOI:10.1016/j.tetlet.2017.02.079

An efficient methodology for the synthesis of aryl 1,2-cis-furanosidic linkages has been developed with 2-quinolinecarbonyl (Quin) group substituted furanose ethyl thioglycosides as glycosyl donors. The method permits a wide range of phenol acceptors to b

Full text of DOI:10.1016/j.tetlet.2017.02.079

Accepted Manuscript
Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the
synthesis of the carbohydrate portion of antibiotic hygromycin A
Yuan Xu, Hua-Chao Bin, Fu Su, Jin-Song Yang
PII:
S0040-4039(17)30267-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.079
TETL 48690
Reference:
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Tetrahedron Letters
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21 February 2017
25 February 2017
Please cite this article as: Xu, Y., Bin, H-C., Su, F., Yang, J-S., Stereoselective synthesis of aryl 1,2-cis-furanosides
and its application to the synthesis of the carbohydrate portion of antibiotic hygromycin A, Tetrahedron Letters
(
2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.079
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Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the synthesis of the carbohydrate
portion of antibiotic hygromycin A
Yuan Xu, Hua-Chao Bin, Fu Su, Jin-Song Yang*
1

Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the synthesis of the carbohydrate
portion of antibiotic hygromycin A
Yuan Xu, Hua-Chao Bin, Fu Su, Jin-Song Yang*
Department of Chemistry of Medicinal Natural Products, and Key Laboratory of Drug Targeting, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Corresponding author. Tel. & Fax: +86 28 85503723. E-mail address: yjs@scu.edu.cn (J.-S. Yang).
Abstract: An efficient methodology for the synthesis of aryl 1,2-cis-furanosidic linkages has been developed
with 2-quinolinecarbonyl (Quin) group substituted furanose ethyl thioglycosides as glycosyl donors. The method
permits a wide range of phenol acceptors to be used, thus resulting in the formation of structurally diverse phenol
furanosides in good to excellent chemical yields with complete 1,2-cis anomeric selectivity. The synthetic utility
of the approach has been demonstrated by concise preparation of the carbohydrate portion of antibiotic
hygromycin A.
Keywords: furanoside; hygromycin A; glycosylation; synthesis; thioglycoside; stereoselectivity
Introduction
1
Hygromycin A is an antibiotic produced by several strains of Streptomyces and was first isolated in 1953. It
has been revealed that hygromycin A has a relatively broad spectrum of activity against Gram-positive and
1
a,b
Gram-negative bacteria.
In recent years, hygromycin A has held renewed appeal as it was found to be an
effective agent for the control of swine dysentery, a mucohemorrhagic disease of economic importance to swine
2
producers. On the other hand, originally separated from a strain of Streptomyces capreolus in 1976, A201A is
3
another structurally unique nucleoside antibiotic. This compound was also found to be highly active against
4
Gram-positive bacteria and most Gram-negative anaerobic bacteria. The common structural feature of both
natural products is that they possess the unique 1,2-cis glycosidic linkage between the furanose residue and the
centeral phenol moiety. It is known that construction of 1,2-cis glycosides in a highly stereoselective manner is a
5
significantly challenging task in synthetic carbohydrate chemistry.
Fig. 1. Structures of hygromycin A and A201A.
6
In 1991, Ogawa and co-workers reported the first total synthesis of hygromycin A. For the construction of the
core phenol 1,2-cis-β-furanoside framework, they adopted 2,3-di-O-benzyl (Bn) protected furanose hemiacetal
sugar as glycosyl donor to glycosylate with a suitable phenol derivative under standard Mistunobu reaction
2

3
conditions (Ph P, diethyl azodicarboxylate, THF). However, this coupling method provided the phenol furanoside
product as an inseparable mixture of isomers with disappointing degree of stereocontrol (α:β = 4:5). In addition,
Donohoe et al., by taking advantage of the same Mistunobu-type glycosylation but a 2,3-di-O-triisopropylsilyl
(TIPS) ether protected furanose hemiacetal as donor instead, greatly elevated the stereoselectivity of the
glycosylation to α:β = 1:9. Then, using this reaction as the key step, they accomplished the second total synthesis
7
of hygromycin A. More recently, this means was also employed by Yu et al. for the construction of the silimar
8
aryl 1,2-cis-furanoside structure, thus leading to the first total synthesis of A201A.
Scheme 1. 2-Quinolinecarbonyl-assisted 1,2-cis-furanosylation reaction.
Recently, an efficient hydrogen-bond-mediated aglycone delivery (HAD) method was disclosed by
9
Demchenko’s group to stereoselectively synthesize a variety of 1,2-cis-pyranosides. Based on such a concept,
our group developed a novel 2-quinolinecarbonyl (Quin)-assisted 1,2-cis-furanosylation strategy for facile
10
assembly of β-arabinofuranosides and α-galactofuranosides (Scheme 1). The Quin group acting as a hydrogen
bond acceptor displays a strong stereocontrolling capability in the glycosylation of both arabino- and
galactofuranose thioglycoside donors with a wide scope of carbohydrate and non-carbohydrate acceptors. So, we
sought to adopt this Quin-assisted 1,2-cis-furanosylation approach to the preparation of the relevant phenol
1,2-cis-furanosidic bond possessed by antibiotic hygromycin A and A201A. On the basis of these considerations,
a set of Quin-containing furanose derivatives including 2,3-di-O-Bn-5-O-Quin substituted D- and
1
0a
10a
10c
L-thioarabinofuranoses 1a and 1b, and 2,3-di-O-Bn-5- or 6-O-Quin substituted D-thiogalactofuranoses 1c
10b
and 1d (Table 1) were prepared and used to condense with various phenol compounds. These thioglycosides
have been proved by us to be excellent glycosylating reagents in the glycosylation with alcohol nucleophiles.
Herein, we describe the development of a novel stereoselective glycosylation method for construction of phenol
1,2-cis furanosyl glycosides by use of thioglycosides 1a-d and its application to the efficient preparation of the
sugar fragment of hygromycin A.
Results and discussion
Initially, the glycosylation of thiofuranose donors 1a-d with a variety of phenol acceptors was investigated.
The results of these glycosylation reactions are summarized in Table 1. In the first instance, upon activation by
the N-iodosuccinimide (NIS, 1.2 equiv)/trifluoromethanesulfonic acid (TfOH, 0.1 equiv) promoter system in
2 2
dichloroethane (ClCH CH Cl) at −30 → 0 °C for 2 h, the coupling reaction between the D-arabinose donor 1a
and the simple phenol 2a afforded the phenol glycoside 3a in 86% yield as a only β product (Table 1, entry 1).
1
11
The product stereochemistry was deduced by H NMR spectroscopy in CDCl
3
.
For the α-arabinofuranoside,
3
3
J
H1,H2 is ~2.0 Hz, while for the β-arabinofuranoside, JH1,H2 is ~5.0 Hz. Then, the influence of the substituent
pattern of the phenol substrates on the reaction outcome was examined. As shown in Table 1, entries 2-5, the
glycosylations of the diversely para-substituted phenol nucleophiles 2b-e with donor 1a gave the corresponding
products 3b-e in good to excellent yield and with exclusive β-stereocontrol. Furthermore, the couplings between
1a and the ortho- or meta-substituted phenols 2f and 2g also led to high chemical yield and only
β-stereoselectivity (Table 1, entries 6 and 7, respectively). However, in the case of the NIS/TfOH (cat.)-mediated
3

coupling of trisubstituted 2,4,6-tribromophenol 2h to 1a, only 45% yield of the desired glycoside 3h was
obtained. After screening several glycosylation conditions, we found that the reaction worked well under the
12
2 2
promotion of diphenyl sulfoxide (Ph SO, 2.8 eq)/trifluoromethanesulfonic anhydride (Tf O, 1.4 eq) at −60 °C in
dichloromethane (CH
2
Cl
2
) for 2 h, furnishing the required aryl O-glycoside 3h in an improved 66% yield as a
8
single β-isomer. For the reactions of 1a with the structurally more complex phenol derivatives 2i and 2j (see
Supporting Information), good to excellent yields were obtained as well, giving rise to the corresponding
D-arabinofuranosides 3i and 3j as exclusive β-isomers in 90% and 85% yield, respectively. Importantly, these
glycosides represent the characteristic carbohydrate subunits of hygromycin A and A201A, which would be
benefit to the synthesis of these natural products and their analogues.
a
Table 1. Glycosylation of Furanose Thioglycosides 1a-d with Phenol Compounds
a
Glycosylations were carried out with donor 1a-d (1.3 equiv, 5 mM), acceptor (1 equiv), NIS (2.6 equiv)/TfOH
b
(
0.26 equiv), 4 Å molecular sieves (MS) in dichloroethane at −30 → 0 °C for 2 h unless otherwise noted. Yield
c
1
of isolated product based on the acceptor unless otherwise noted. Determined by H NMR analysis of the
d
corresponding reaction mixtures. Glycosylation was performed with donor 1a (1.0 equiv), acceptor 2h (1.5
equiv), diphenyl sulfoxide (Ph
2 2
SO, 2.8 equiv), trifluoromethanesulfonic anhydride (Tf O, 1.4 equiv),
e
2
,4,6-tri-tert-butylpyrimidine (TTBP, 3 equiv) at −60 °C in dichloromethane for 2 h. Yield was calculated based
f
on the donor. Combined yield of the α- and β-isomers.
To extend this methodology to the stereoselective synthesis of β-L-arabinofuranosyl phenol glycoside, we
further studied the glycosylation of L-arabinofuranose donor 1b with different phenol acceptors. It is found that
1b exhibits similar reaction properties as that of its enantiomer 1a. As shown by entries 11-14 in Table 1, each
4

condensation between 1b and the phenol substrates 2b, 2d, 2e, and 2k was high yielding (55-93%) and
β-selective (β only).
Finally, the reaction behaviour of the D-galactofuranose donors 1c-d was tested. As displayed by entries 15-18
(Table 1), high yields and complete α-selectivity were also obtained in the glycosylation of the 5-O-Quin
substituted donor 1c with para-substituted phenol substrates. In contrast, the reaction between the 6-O-Quin
substituted thioglycoside 1d and 4-ethylphenol 2b exhibited no stereoselectivity, resulting in the glycoside
product 3s as a separable mixture of isomers (α:β = 1:1) in an 88% combined yield. This is similar to the results
that, in the galactofuranosylation of a variety of alcohol acceptors, the 5-O-substituted thiogalactofuranose donor
generally provided higher stereoselectivity than the corresponding 6-O-substituted thiogalactofuranose donor
10b
counterpart. The difference in stereochemical outcome between both galactose donors is due to the probability
that the hydrogen bond formed between the 6-O-Quin equipped donor 1d and the acceptor is more flexible than
that formed between the 5-O-Quin donor 1c and the acceptor, thus leading to lower anomeric selectivity. The
1
anomeric configuration of the formed D-galactofuranosidic bonds was also verified based on H NMR
3
spectroscopy in CDCl
3
. For the α-galactofuranoside anomer, the JH1,H2 is 4.0~4.5 Hz, while, for the β-anomer,
3
13
J
H1,H2 is 0~2.0 Hz.
Having realized a practical approach to the synthesis of aryl 1,2-cis furanosyl glycoside, we planned to apply it
as a key step for synthesizing the sugar portion of hygromycin A. Carboxylic acid 11 (Scheme 3), containing a
core phenol 1,2-cis furanoside skeleton, was chosen as the target molecule.
Scheme 2. Preparation of aglycon 5.
The aglycon part of 11 was first synthesized. As illustrated in Scheme 2, the readily available carboxylic ester
4
2j was reduced with lithium aluminium hydride (LiAlH ) in tetrahydrofuran (THF) for 6 h, affording alcohol 4 in
67% yield. Then, selective protection of the primary alcohol hydroxyl group of 4 with tert-butyldimethylsilyl
(TBS) ether gave the desired phenol 5 (78% yield).
Scheme 3. Preparation of carboxylic acid 11.
5

With the required aglycon building block in hand, we next turned our attention to the synthesis of 11. As
14
2 2 2 2
depicted in Scheme 3, upon activation by Tf O/Ph SO at –68 °C in CH Cl for 2 h, the D-arabinofuranose
donor 1a was condensed with the phenol derivative 5 to give solely the β-monosaccharide glycoside 6 in 78%
yield. The β-configuration of the newly formed arabinofuranosidic bond was clearly determined by the doublet
11
for the anomeric signal of the Araf unit (δH1 = 5.633 ppm, d, JH1/H2 = 4.8 Hz). Removal of the 5-O-Quin group
of 6 by treatment with sodium methoxide in methanol followed by Swern oxidation of the resulting alcohol
afforded the corresponding aldehyde 7 in 70% yield over the two steps. Then, after reaction with Grignard
reagent methylmagnesium bromide (MeMgBr) in THF at –78 °C and followed by oxidation with the Dess-Martin
reagent, compound 7 was readily converted into methyl ketone 8 (65% yield, two steps from 7). Selective
cleavage of the TBS group of 8 by treatment with tetrabutylammonium fluoride (TBAF) buffered with HOAc in
THF yielded free alcohol 9 in a good 85% yield. Finally, the stage was set to oxide this material to the target
1
5
carboxylic acid product 11. However, subjection of 9 to the well-studied TEMPO oxidation protocol failed to
generate the desired acid 11. Instead, only a trace amount of aldehyde 10 was obtained. Pleasingly, successful
conversion of 9 to 11 was achieved by a two-step procedure. Firstly, the hydroxyl group of 9 was oxided to
aldehyde group by treatment of 9 under Dess-Martin conditions, giving rise to aldehyde 10 in 88% yield.
16
Secondly, oxidation of 10 under Pinnick oxidation conditions (NaClO
expected acid 11 in 75% yield.
2 2 4
, NaH PO ) led to the formation of the
In conclusion, we have developed an efficient approach to the construction of the difficult-to-obtain phenol
1,2-cis furanosyl glycosidic linkages using a HAD strategy. The methodology was applied successfully to the
short synthesis of the sugar fragment of hygromycin A. Further application of the method to the preparation of
carbohydrates bearing an aryl 1,2-cis furanoside structure is currently underway.
Acknowledgements
We appreciate NSFC (21572145, 21372166, 21321061) of China for financial support.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http:// .
References and notes
1.
(a) Pittenger, R. C.; Wolfe, R. N.; Hohen, M. M.; Marks, P. N.; Daily, W. A.; McGuire, M. Antibiot.
Chemother. 1953, 3, 1268; (b) Mann, R. L.; Gale, R. M.; Van Abeele, F. R. Antibiot. Chemother. 1953, 3,
1
279; (c) Sumiki, Y.; Nakamura, G.; Kawasaki, M.; Yamashita, S.; Anzai, K.; Isono, K.; Serizawa, Y.;
Tomiyama, Y.; Suzuki, S. J. Antibiot. 1955, 8, 170; (d) Isono, K.; Yamashita, S.; Tomiyama, Y.; Suzuki, S. J.
Antibiot. 1957, 10, 21; (e) Wakisaka, Y.; Koizumi, K.; Nishimoto, Y.; Kobayashi, M.; Tsuji, N. J. Antibiot.
1
980, 33, 695.
2.
(a) Hecker, S. J.; Minich, M. L.; Werner, K. M. Bioorg. Med. Chem. Lett. 1992, 2, 533; (b) Hecker, S. J.;
Lilley, S. C.; Minich, M. L.; Werner, K. M. Bioorg. Med. Chem. Lett. 1992, 2, 1015; (c) Hecker, S. J.; Lilley,
S. C.; Werner, K. M. Bioorg. Med. Chem. Lett. 1992, 2, 1043; (d) Hecker, S. J.; Cooper, C. B.; Blair, K. T.;
Lilley, S. C.; Minich, M. L.; Werner, K. M. Bioorg. Med. Chem. Lett. 1993, 3, 289; (e) Cooper, C. B.; Blair,
K. T.; Jones, C. S.; Minich, M. L. Bioorg. Med. Chem. Lett. 1997, 7, 1747.
3.
(a) Isono, K. Pharmacol. Ther. 1991, 52, 269; (b) Knapp, S. Chem. Rev. 1995, 95, 1859.
4.
(a) Kirst, H. A.; Dorman, D. E.; Occolowitz, J. L.; Jones, N. D.; Paschal, J. W.; Hamill, R. L.; Szymanski, E.
F. J. Antibiot. 1985, 38, 575; (b) Barrasa, M. I.; Tercero, J. A.; Lacalle, R. A.; Jimenez, A. Eur. J. Biochem.
6

1
995, 228, 562; (c) Barrasa, M. I.; Tercero, J. A.; Jimenez, A. Eur. J. Biochem. 1997, 245, 54.
5.
For reviews on stereoselective synthesis of 1,2-cis glycosides, see: (a) Nigudkar, S. S.; Demchenko, A. V.
Chem. Sci. 2015, 6, 2687; (b) Demchenko, A. V. Synlett 2003, 1225.
6.
(a) Chida, N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J. Chem. Soc., Chem. Commun. 1989, 436; (b) Chida,
N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J. Org. Chem. 1991, 56, 2976.
7.
Donohoe, T. J.; Flores, A.; Bataille, C. J. R.; Churruca, F. Angew. Chem., Int. Ed. 2009, 48, 6507.
8. Nie, S.-Y.; Li, W.; Yu, B. J. Am. Chem. Soc. 2014, 136, 4157.
9.
(a) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012, 134, 20097; (b) Yasomanee, J. P.;
Demchenko, A. V. Angew. Chem., Int. Ed. 2014, 53, 10453; (c) Pistorio, S. G.; Yasomanee, J. P.;
Demchenko, A. V. Org. Lett. 2014, 16, 716; (d) Yasomanee, J. P.; Demchenko, A. V. Chem. -Eur. J. 2015,
2
1, 6572; (e) Kayastha, A. K.; Jia, X.-G.; Yasomanee, J. P.; Demchenko, A. V. Org. Lett. 2015, 17, 4448.
10. (a) Liu, Q.-W.; Bin, H.-C.; Yang, J.-S. Org. Lett. 2013, 15, 3974; (b) Gao, P.-C.; Zhu, S.-Y.; Cao, H.; Yang,
J.-S. J. Am. Chem. Soc. 2016, 138, 1684; (c) Zhu, K.; Yang, J.-S. Tetrahedron 2016, 72, 3113.
1. Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.; Matsuura, H. Carbohydr. Res. 1989, 185, 27.
2. Codée, J. D. C.; Litjens, Remy E. J. N.; den Heeten, R.; Overkleeft, H. S.; van Boom, J. H.; van der Marel, G.
A. Org. Lett. 2003, 5, 1519.
1
1
1
3. Gola, G.; Tilve, M. J.; Gallo-Rodriguez, C. Carbohydr. Res. 2011, 346, 1495.
4. Only trace amounts of the desired product 6 was obtained when the glycosylation was activated with NIS (2
equiv) and TfOH (cat.) in dichloroethane.
1
1
5. (a) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153; (b) Baisch, G.; Ohrlein, R.
Carbohydr. Res. 1998, 312, 61; (c) Li, K. C.; Helm, R. F. Carbohydr. Res. 1995, 273, 249.
6. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
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1. A approach to the construction of aryl 1,2-cis-furanosidic bonds is developed.
2. Aryl 1,2-cis-furanosides are synthesized using Quin-substituted thiofuranosides.
3. The method is demonstrated by preparation of the sugar portion of hygromycin A.
8