Robust perfluorophenylboronic acid-catalyzed stereoselective synthesis of 2,3-unsaturated O-, C-, N- And S-linked glycosides

Article abstract of DOI:10.3762/bjoc.15.125

A convenient protocol was developed for the synthesis of 2,3-unsaturated C-, O-, N- and S-linked glycosides (enosides) using 20 mol % perflurophenylboronic acid catalyst via Ferrier rearrangement. Using this protocol, D-glucals and L-rhamnals reacted with various C-, O-, N- and S-nucleophiles to give a wide range of glycosides in up to 98% yields with mainly α-anomeric selectivity. The perflurophenylboronic acid successfully catalyzed a wide range of substrates (both glucals and nucleophiles) under very mild reaction conditions.

Full text of DOI:10.3762/bjoc.15.125

Robust perfluorophenylboronic acid-catalyzed
stereoselective synthesis of 2,3-unsaturated
O-, C-, N- and S-linked glycosides
Madhu Babu Tatina, Xia Mengxin, Rao Peilin and Zaher M. A. Judeh*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1275–1280.
School of Chemical and Biomedical Engineering, Nanyang
Technological University, Singapore, 62 Nanyang Drive, N1.2–B1-14,
Singapore 637459, Tel.: +65-6790-6738; Fax: +65-6794-7553
doi:10.3762/bjoc.15.125
Received: 06 March 2019
Accepted: 22 May 2019
Published: 11 June 2019
Email:
Zaher M. A. Judeh* - zaher@ntu.edu.sg
Associate Editor: S. Flitsch
* Corresponding author
© 2019 Tatina et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
C-; O-; N- and S-linked glycosides; enosides; Ferrier-rearrangement;
organocatalyst; pseudo-glycosides
Abstract
A convenient protocol was developed for the synthesis of 2,3-unsaturated C-, O-, N- and S-linked glycosides (enosides) using
20 mol % perflurophenylboronic acid catalyst via Ferrier rearrangement. Using this protocol, D-glucals and L-rhamnals reacted
with various C-, O-, N- and S-nucleophiles to give a wide range of glycosides in up to 98% yields with mainly α-anomeric selec-
tivity. The perflurophenylboronic acid successfully catalyzed a wide range of substrates (both glucals and nucleophiles) under very
mild reaction conditions.
Introduction
2,3-Unsaturated glycosides, also known as pseudo-glycosides or fashion. Several classes of catalysts have been successfully
enosides, are an important class of natural products with many applied in the Ferrier rearrangement including Brønsted acids
biological activities and capacity to serve as substrates for [7-13], Lewis acids [14-19], redox reagents [20] and metal cata-
further reactions [1-3]. They are involved in biochemical pro- lysts [21-23]. However, many of these catalysts have limited
cesses such as molecular recognition, cell–cell interaction, substrate scope, give variable selectivities and yields, require
immunological recognition and transmission of biological infor- harsh reaction conditions and an excess amount of catalysts that
mation [4-6]. They are easily transformed into important bioac- are typically expensive, toxic and moisture/air sensitive. The
tive compounds such as oligosaccharides, glycopeptides, majority of the reported catalysts are metal-based, and in phar-
nucleosides, antibiotics, uronic acids and other natural products maceutical manufacturing, traces of metals pose a major chal-
[1-3].
lenge for their removal to acceptable limits. Therefore, the
discovery of efficient, metal-free and mild catalysts for the
The Ferrier rearrangement is one of the most useful processes to Ferrier rearrangement is still challenging and desirable espe-
synthesize pseudo-glycosides in a direct and stereoselective cially if such catalysts work well with a wide range of C-, O-,
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Beilstein J. Org. Chem. 2019, 15, 1275–1280.
N- and S-nucleophiles under mild conditions. We also noted unsaturated glucoside 3a in CH3CN or CH3NO2 solvents
that the use of organocatalysts to catalyze the Ferrier rearrange- (Table 1, entries 3 and 4). It gave better 92% yield of glucoside
ment is scarcely reported.
3a in CH3NO2 over a shorter reaction time (Table 1, entries 4
vs 3). Under the same conditions, the reaction did not proceed
Recently, organoboron-catalysis emerged as a mild and effec- in THF or DCM due to the lower polarity of these solvents in
tive strategy for activation of alcohols [24], epoxide opening comparison to CH3CN and CH3NO2 (Table 1, entry 2 vs 3 and
[25,26], Friedel–Crafts alkylations [27], dehydrative glycosyla- 4). Attempts to reduce the amount of perfluorophenylboronic
tion [28] and many other reactions [29-31]. The robustness and acid to 5 mol % resulted in a reduction of the yield of glucoside
mildness of organoboronic acid catalysts in comparison to tradi- 3a despite various attempts to promote the reaction by increas-
tional strong Lewis and Brønsted acid catalysts inspired us to ing the temperature and time (Table 1, entries 5 and 6). In all
investigate them as promoters for the Ferrier rearrangement. We the cases, the α:β ratio of glucoside 3a was 90:10. Conditions in
envisioned that organoboronic acids can activate the allylic Table 1, entry 4 were considered as optimum. The structure of
acetate of glycals making them susceptible to nucleophilic glucoside 3a was confirmed by the 1H NMR spectra where the
attacks under conditions favoring a strong polarization of the anomeric proton (H1) appeared at δ 5.16 ppm (for glucal 1a it
allylic acetate moiety (see Figure 4).
appears at δ 6.47 ppm) and the protons of the new double bond
(H2, H3) appeared at δ 5.90–5.88 ppm [19]. The corresponding
Herein, we report a phenylboronic acid-catalyzed synthesis of protons in the β-isomer appeared at δ 5.22 (H1) and δ 6.01 (H2,
2,3-unsaturated C-, O-, N- and S-glycosides via Ferrier rear- H3) [19,21].
rangement under very mild conditions. We also demonstrate the
scope of the reaction using a wide range of glycals and C-, O-, Using the optimized conditions in Table 1, entry 4, we then ex-
N- and S-nucleophiles.
amined the substrate scope. Therefore, glucal 1a was reacted
with various O-nucleophiles (using primary, secondary, tertiary,
allyl, propargyl alcohols and sugars), C-nucleophiles (using tri-
Results and Discussion
We began our study by investigating the reaction of 3,4,6-tri-O- methylsilyl cyanide and trimethyl(propargyl)silane), S-nucleo-
acetyl-D-glucal (1a) with benzyl alcohol (2) in the presence of philes (using thiophenol and p-toluenethiol) and N-nucleo-
20 mol % of arylboronic acids in different solvents (Table 1, philes (methane sulfonamide and p-toluene sulfonamide)
entries 1–6). Phenylboronic acid failed to promote the reaction (Figure 1). In all the cases, the reactions successfully gave the
in several solvents and the starting glucal 1a was recovered un- respective 2,3-unsaturated glycosides 3a–u in up to 92% yield
changed (Table 1, entry 1). This is attributed to its low acidity. with mainly α-anomeric selectivity (Table 1). Noteworthy, the
Gratifyingly, the more acidic perflurophenylboronic acid suc- reaction also gave disaccharide 3n and 3o smoothly with com-
cessfully promoted the reaction to give 4,6-di-O-acetyl-2,3- plete α-anomeric selectivity albeit in a moderate yield. Like-
Table 1: Optimization of the arylboronic acid-catalyzed reaction of 3,4,6-tri-O-acetyl-D-glucal (1a) with benzyl alcohol (2).
Entry
1
Arylboronic acid (mol %)
phenylboronic acid (20)
Solvent
Time (h) / T (°C)
3a Yield (%) (α:β)b
CH3CN or DCM or THF or 10/40
CH3NO2
NDc
2
3
4
5
6
perfluorophenylboronic acid (20)
perfluorophenylboronic acid (20)
perfluorophenylboronic acid (20)
perfluorophenylboronic acid (10)
perfluorophenylboronic acid (5)
DCM or THF
CH3CN
10/40
10/40
6/40
ND
70 (90:10)
92 (90:10)
88 (90:10)
60 (90:10)
CH3NO2
CH3NO2
CH3NO2
6/60
12/60
a3,4,6-Tri-O-acetyl-D-glucal (1a, 1 equiv) reacted with benzyl alcohol (2, 1.1 equiv). bIsolated yields. α:β ratio calculated from NMR after column chro-
matography purification. cND: not detected.
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Beilstein J. Org. Chem. 2019, 15, 1275–1280.
Figure 1: Perfluorophenylboronic acid-catalyzed reaction between 3,4,6-tri-O-acetyl-D-glucal 1a and O-, C-, S-, N-nucleophiles.
wise, reaction using Et3SiH gave the desired 2,3-unsaturated lyzed rearrangements of 2-substituted sugars such as 2,3,4,6-
sugar 3i in 74% yield. These results testify to the robustness of tetra-O-acetyl-D-glucal (4a) to enosides are limited in the litera-
the perflurophenylboronic acid as a versatile organocatalyst for ture and pose special challenges including low product yields
the Ferrier rearrangement reaction. We noted that the yields of and selectivities, the need for a large excess of the catalyst and
the disaccharides 3n and 3o and sulfonamides 3t and 3u can be formation of by-products such as furaldehydes and enones
increased with increase in the temperature (60 °C) and exten- [1,33-35]. Enosides are important building blocks especially for
sion of the reaction time. The results in Table 1 are superior to natural product synthesis [36-40]. Therefore, we used the
the results obtained using boron trifluoride diethyl etherate [32]. perfluorophenyl boronic acid catalyst in the reaction between
2,3,4,6-tetra-O-acetyl-D-glucal (1a) and benzyl alcohol, n-butyl
We then applied the perfluorophenylboronic acid catalyst to alcohol, cyclohexyl alcohol and p-toluenethiol (Figure 2). Grati-
promote the reaction between 2,3,4,6-tetra-O-acetyl-D-glucal fyingly, the reaction proceeded smoothly under mild and cata-
(4a) and O- and S-nucleophiles (Figure 2). The Ferrier-cata- lytic conditions to give the respective 2-acetoxy-2,3-unsatu-
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Beilstein J. Org. Chem. 2019, 15, 1275–1280.
Figure 2: Perfluorophenylboronic acid-catalyzed reaction between 2,3,4,6-tetra-O-acetyl-D-glucal 4a and O- and S-nucleophiles.
rated glycosides (enosides) 5a–d in 62–78% yields albeit with with complete α-anomeric selectivity (except for 7a). Disaccha-
moderate α-selectivity. No byproducts were detected and no ride 7g was also obtained smoothly with complete α-anomeric
further attempts were made to optimize the yield and selectivity selectivity. The reactions using rhamnal 6a was completed at a
of this reaction. The yields and selectivities are similar to those much faster rate within 2 h at room temperature in comparison
reported using HClO4·SiO2 [33].
to glucals 1a and 4a which required ≈6 h at 40 °C to give the
products.
Based on the excellent results obtained with the reactions of
glucals 1a and 4a with O-, C-, N-, S-nucleophiles, we further A plausible pathway of the reaction is proposed in Figure 4.
extended the scope of this reaction to 3,4-di-O-acetyl-L- Coordination of perflurophenylboronic acid to the allylic
rhamnal (6a, Figure 3). As a demonstration, the reaction be- acetate moiety of glucal 1a induces polarization (structure I)
tween 3,4-di-O-acetyl-L-rhamnal (6a) and selected alcohols and and leads to the formation of an allyloxycarbenium ion (struc-
p-toluenethiol proceed smoothly and afforded the desired 2,3- ture II) in the preferred 4H3 conformation. Addition of the
unsaturated L-rhamnosides (enosides) 7a–h in up to 89% yield nucleophiles to C1 from the α-face gives the lower energy half-
Figure 3: Perfluorophenylboronic-acid-catalyzed reaction between 3,4-di-O-acetyl-L-rhamnal (6a) and O- and S-nucleophiles.
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Figure 4: Plausible perfluorophenylboronic acid-catalyzed activation of glycal 1a.
chair conformer and results in the observed α-selectivity of the Acknowledgements
2,3-unsaturated glycosides III (Figure 4) [22]. However, the ad- We thank Nanyang Technological University, Singapore for
dition of the nucleophiles from the β-face gives the higher financial help (RG 13/18).
energy twist-boat conformer.
ORCID® iDs
Madhu Babu Tatina - https://orcid.org/0000-0003-3495-1800
Conclusion
We developed a robust perfluorophenylboronic-acid-catalyzed
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