Synthesis of a novel C-branched polyhydroxylated cyclic nitrone

Article abstract of DOI:10.1016/j.cclet.2016.12.033

A novel C-branched polyhydroxylated cyclic nitrone 25, which could be a valuable intermediate for the synthesis of C-branched pyrrolidine iminosugars, was synthesized starting from the commercially available L-arabinose in 29.0% total yield.

Full text of DOI:10.1016/j.cclet.2016.12.033

Accepted Manuscript
Title: Synthesis of a novel C-branched polyhydroxylated
cyclic nitrone
Author: <ce:author id="aut0005"
author-id="S1001841717300177-
b902ca1e6d8fd3c6dcc156790552b043"> Qing-Kun
Wu<ce:author id="aut0010"
author-id="S1001841717300177-
7dfeb846d6d1dc2cadcd536bd51affc0"> Yi-Xian Li<ce:author
id="aut0015" author-id="S1001841717300177-
bb6e0b7be649c18f3823b9ae7cbf3dd4"> Yue-Mei
Jia<ce:author id="aut0020" author-id="S1001841717300177-
db42c6a53877fc309656edac67a0405d"> Chu-Yi
Yu
PII:
S1001-8417(17)30017-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2016.12.033
CCLET 3944
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Chinese Chemical Letters
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14-11-2016
6-12-2016
8-12-2016
Please cite this article as: Qing-Kun Wu, Yi-Xian Li, Yue-Mei Jia, Chu-Yi Yu, Synthesis
of a novel C-branched polyhydroxylated cyclic nitrone, Chinese Chemical Letters
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Original article
Synthesis of a novel C-branched polyhydroxylated cyclic nitrone
Qing-Kun Wua,b, Yi-Xian Lia, Yue-Mei Jiaa, Chu-Yi Yua,c

a Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China
b University of Chinese Academy of Sciences, Beijing 100049, China
c National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China
 Corresponding author.
E-mail address: yucy@iccas.ac.cn
ARTICLE INFO
Article history:
Received 14 November 2016
Received in revised form 6 December 2016
Accepted 8 December 2016
Available online
Graphical abstract
A novel C-branched polyhydroxylated cyclic nitrone 25, which could be a valuable intermediate for the synthesis of C-branched pyrrolidine
iminosugars, was synthesized starting from the commercially available L-arabinose in 29.0% total yield.
ABSTRACT
A novel C-branched polyhydroxylated cyclic nitrone 25, which could be a valuable intermediate for the synthesis of C-branched pyrrolidine
iminosugars, was synthesized starting from the commercially available L-arabinose in 29.0% total yield.
Keywords:
Cyclic nitrone
Branched chain
Iminosugars
Azasugars
Polyhydroxylated pyrrolidine
1. Introduction
“Nitrogen-in-the-ring” analogues of pyranoses and furanoses, namely iminosugars, azasugars or polyhydroxylated alkaloids, are
potent inhibitors of glycosidases and other glycosyl processing enzymes [1, 2]. Therefore, these compounds have great potential in the
treatment of type II diabetes, cancers and viral infections, and some of them have already been used as drugs, such as NHE-DNJ
(Miglitol) and NB-DNJ (Miglustat) [3-6]. Until now, numerous methods have been developed for the synthesis of natural iminosugars
and their non-natural analogs from either carbohydrates or non-sugar chiral-pool compounds [7-12]. Among these approaches to
iminosugars, polyhydroxylated or sugar-derived cyclic nitrones (1-7, Fig. 1) have been proven to be one of the most useful
———

intermediates due to their capability of undergoing a variety of important transformations, such as 1,3-dipolar cycloaddition,
nucleophilic addition, and pinacol-type coupling reaction [13-15]. Based on our general interests in the synthesis and bioactivity study
of iminosugars, we became interested in synthesis of a novel C-branched polyhydroxylated cyclic nitrone, which is likely to be of
significant value as a diverse intermediate for the construction of some C-branched pyrrolidine iminosugars with functionalized
quaternary centers on the pyrrolidine ring [16-20].
Introduction of C-branched chain is a useful method for structural modification of iminosugars in the study of structure-activity
relationship, and some of these alkaloids have already been reported (8-16, Fig. 2). For example, isoDAB (8) was a potent but more
selective α-glucosidase inhibitor comparing to its parent iminosugar DAB [21]. 4-C-Me-DAB (9) is a competitive, specific and potent
α-glucosidase inhibitior [22]. Compound 10 shows potent inhibition to α-glucosidase from rice (IC50 = 5 μmol/L), while L-isoDMDP
(11) is potent specific competitive inhibitor of gut disaccharidases (Ki = 81 mmol/L for rat intestinal maltase) and is more effective in
the suppression of hyperglycaemia in a maltose loading test than Miglitol [23, 24]. Both compound 12 and 13 display moderate
inhibitory activity against Mycobacterium smegmatis galactan biosynthesis [25]. Compound 14 was a specific potent α-glucosidase
inhibitor (IC50 = 52 nmol/L, rice α-glucosidase), while DNJ and castanospermine are also inhibitors of β-glucosidase [15]. Azepane 15
displays selective and moderate competitive L-fucosidase inhibition [26]. Early in this year, a new iminosugar 16 [27] had been
synthesized from D-glucose by Zhang and coworkers, whose enantiomer could be synthesied from the title cyclic nitrone in one step.
2. Results and discussion
The synthetic route of the title nitrone was shown in Scheme 1. (2S, 3S)-2-Hydroxymethyl-2,3-O-isopropylidene-L-erythrose (19)
was prepared in 74% yield from commercially available L-arabinose according to the literature reported method [28]. The detail is
deposited in Supporting information. Initially, we attempted to obtain the triol 22 by the Grignard addition between compound 19 and
vinyl magnesium bromide without supplementing more protecting groups (Scheme 2). Unfortunately, the resulting two diastereomers
22 and 4-epi-22 are a pair of inseparable isomers and failed to be separated by flash column chromatography.
Thus, compound 19 was first transformed to silyl ether 20 and then underwent Grignard addition to produce diol 21 (d.r. = 74:26),
the C4 configuration of which was confirmed as R by the crystal structure of compound 25. The TBS protecting group of diol 21 was
removed by TBAF, and then the C1 and C5 hydroxyl groups were protected by acetonide to give alcohol 23. The free hydroxyl group
in 23 was activated by mesyl chloride to afford methanesulfonate 24. Compound 24 was then ozonized to give the intermediate
aldehyde, which was used directly due to its instability. The aldehyde was then put under routine procedure to give the title nitrone,
(2S, 3R, 4R)-1-amino-1,4-anhydro-1,N-didehydro-3-(1,2-dihydroxyl)ethyl-2,6:3,5-di-O-isopropylidene-L-threose N-oxide (25).
Compound 25 is unstable and would decompose while purified by silica gel column chromatography. However, it was found stable
when purified by alkaline aluminum oxide column chromatography [29]. The structure of compound 25 was confirmed unambiguously
by spectroscopic data and X-ray crystal structure (Fig. 3). The crystal data is deposited in Supporting information and at the Cambridge
Crystallographic Data Centre with number of CCDC 1515829.
3. Conclusion
In summary, a novel C-branched polyhydroxylated cyclic nitrone 25 with a quaternary chiral center has been synthesized starting
from commercially available L-arabinose in 29.0% total yield, with Grignard addition, ozonization and cyclization as the key steps.
4. Experimental
4.1 General Methods.
NMR spectra was recorded at 300 MHz or 400 MHz (1H NMR) and 75 MHz, 100 MHz (13C NMR) in CDCl3 (with TMS as
internal standard). High-resolution mass spectra (HRMS) were performed with a LTQ/FT linear ion trap mass spectrometer. All
reagents were used as received from commercial sources without further purification or prepared as described in the literature.
Tetrahydrofuran was distilled from sodium and benzophenone. TLC plates were visualized by treatment with a spray of Pancaldi
reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, H2O). Polarimetry was determined using a polarimeter with concentrations (c) given in gram
per 100 mL.
4.2 Synthesis of (2S, 3S)-2-((tert-butyldimethylsilyl)oxy)methyl-2,3-O-isopropylidene-L-erythrose (20)
TBSCl (10.1 g, 67.1 mmol) and imidazole (6.1 g, 89.4 mmol) were added into a solution of compound 16 (8.5 g, 44.7 mmol) in
dichloromethane (150 mL) and the reaction mixture was stirred at room temperature for 6 h. Then water (100 mL) was added, the
aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane (100 mL×3). The organic
phases were combined, dried with MgSO4, concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (petroleum ether/EtOAc = 5/1) to give compound 17 as a light yellow syrup (13.4 g, 99%). Data for 17:

[α]D20 +11 (c 1.05 in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 5.33-5.31 (d, 0.5H, J = 6.6 Hz), 4.98 – 4.94 (d, 0.5H, J = 12 Hz), 4.67 –
4.66 (d, 1H, J = 3 Hz), 4.67 – 4.66 (d, 1H, J = 3 Hz), 4.38 – 4.36 (d, 0.5H, J = 6.6 Hz), 4.08 – 3.94 (m, 2H), 3.86 – 3.74 (m, 2H), 3.56 –
3.51 (m, 0.5H), 1.55 (s, 1.5H), 1.48 (s, 1.5H), 1.43 (s, 1.5H), 1.39 (s, 1.5H), 0.92 (s, 4.5H), 0.90 (s, 4.5H), 0.13 (s, 3H), 0.09 (s, 3H);
13C NMR (75 MHz, CDCl3): δ 113.50, 113.42, 104.75, 97.72, 92.19, 88.30, 83.34, 82.77, 72.09, 68.03, 64.16, 63.09, 27.48, 27.45,
27.05, 26.77, 25.76, 25.74, 18.14, -5.59, -5.64, -5.68; HRMS(ESI) calcd. for C14H28O5SiNa+ [M+Na]+ 327.1598, found 327.1593.
4.3 Synthesis of (2S, 3R, 4R)-2-((tert-butyldimethylsilyl)oxy)methyl-2,3-O-isopropylidene-5-ene-1,4-diol (21)
Compound 20 (100.0 mg, 0.3 mmol) was dissolved in anhydrous THF (10 mL), and vinyl magnesium bromide (1 mol/L, 0.3 mL)
was added dropwise at 0 oC under Ar atmosphere. The reaction mixture was stirred for 1 h, and then saturated aqueous NH4Cl solution
was added dropwise to quench the reaction. Water (10 mL) was added, the organic and the aqueous phases were separated and the
aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried with MgSO4, concentrated under
reduced pressure and the crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 3/1) to give
compound 21 as a light yellow syrup (21, 73.1 mg: 4-epi-21, 25.7 mg; 90% total yeild). Data for 21: [α]D20 +52 (c 2.15 in CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ 6.17 – 6.10 (m, 1H), 5.56 – 5.28 (m, 2H), 4.41 – 4.37 (m, 1H), 4.30 – 4.27 (m, 1H), 4.09 – 3.94 (m, 3H),
3.77 – 3.75 (m, 1H), 3.63 – 3.60 (m, 1H), 3.34 – 3.30 (m, 1H) 1.45 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ 136.88, 115.87, 108.40, 82.40, 81.42, 73.24, 65.57, 61.06, 28.46, 26.76, 25.78, 18.13, -5.67, -5.83; HRMS(ESI) calcd. for
C16H32O5SiNa+ [M+Na]+ 355.1911, found 355.1906.
4.4 Synthesis of (2S, 3R, 4R)-2-hydroxymethyl-1,4:2,3-di-O-isopropylidene-5-hexene (23)
Compound 21 (1.0 g, 3.0 mmol) and TBAF (950.0 mg, 3.0 mmol) were dissolved in THF (25 mL), and the reaction mixture was
stirred at room temperature for 2 h. Water (10 mL) was added and the aqueous phase was extracted with ethyl acetate (40 mL×7). The
organic phases were combined, dried with MgSO4, concentrated under reduced pressure and the crude product was used in the next
step without further purification. The crude product, 2,2-dimethyoxypropane (376.4 mg 3.6 mmol) and p-TSA (51.6 mg, 0.3 mmol)
were dissolved in DMF (10 mL), and the reaction mixture was stirred at r.t. for 10 hours. H2O (30 mL) was added and the aqueous
phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried with MgSO4, the solvent was removed
under reduced pressure and the crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4/1) to
give compound 23 as a yellow syrup (684.2 mg, 88% for 2 steps). Data for 23: [α]D20 +79 (c 1.75 in CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ 6.07 – 5.97 (m, 1H), 5.39 – 5.23 (m, 2H), 4.55 (dd, 1H, J = 3.5, 1.9 Hz), 4.14 (s, 1H), 4.00 (d, 2H, J = 1.5 Hz), 3.78 – 3.60
(m, 2H), 2.13 – 2.08 (m, 1H), 1.55 (s, 3H), 1.40 (s, 6H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 133.84, 116.07, 108.01, 101.86,
83.43, 77.45, 77.38, 77.03, 76.60, 71.30, 61.36, 58.95, 28.55, 26.13, 24.27, 23.51; HRMS(ESI) calcd. for C13H22O5Na+ [M+Na]+
281.1359, found 281.1360.
4.5 Synthesis of (2S, 3R, 4R)-2-((mesyloxy)methyl)-1,4:2,3-di-O-isopropylidene-5-hexene (24)
Compound 23 (54.0 mg, 0.21 mmol) and Et3N (31.7 mg, 0.31 mmol) were dissolved in dichloromethane (25 mL), and mesyl
chloride (28.8 mg, 0.25 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 8 h, water (20 mL) was added. The
organic and the aqueous were separated and the aqueous phase was extracted with dichloromethane (20 mL×3). The organic phases
were combined, dried with MgSO4, concentrated under reduced pressure and the crude product was purified by column
chromatography on silica gel (petroleum ether/EtOAc = 4/1) to give compound 24 as a colorless syrup (64.0 mg, 91%). Data for 24:
[α]D20 79 (c 6.60 in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 6.07 – 5.97 (m, 1H), 5.42 – 5.25 (m, 2H), 4.52 – 4.51 (m, 1H), 4.40 – 4.25
(m, 2H), 4.13 (s, 1H), 3.98 (s, 2H), 3.02 (s, 3H), 1.55 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
132.86, 116.76, 108.31, 101.92, 82.74, 75.53, 70.38, 66.99, 58.18, 37.41, 28.42, 25.83, 24.26, 23.51; HRMS(ESI) calcd. for
C14H24O7SNa+ [M+Na]+ 359.1135, found 359.1131.
4.6 Synthesis of (2S, 3R, 4R)-1-amino-1,4-anhydro-1,N-didehydro-3-(1,2-dihydroxyl)ethyl-2,6:3,5-di-O-isopropylidene-L-threose N-
oxide (25)
The solution of compound 24 (44.0 g, 0.13 mmol) in CH3OH (20 mL) was cooled to -60 °C and purged with oxygen, then
submitted to the ozonization procedure until TLC showed completion of the reaction. The reaction mixture was purged with Ar and
quenched by dimethyl sulfide. The resulting mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. Water
(20 mL) was added and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried with
MgSO4, concentrated under reduced pressure and the residue was used without further purification. The crude product was dissolved in
ethanol (8 mL) and H2O (2 mL), NH2OH·HCl (27 mg, 0.39 mmol) and NaHCO3 (44 mg, 0.52mmol) were added, and the reaction
mixture was stirred at r.t. for 8 h. Then H2O (20 mL) was added and the aqueous phase was extracted with ethyl acetate (20 mL×3).
The organic phases were combined, dried with MgSO4, the solvent was removed under reduced pressure and the crude product was
purified by column chromatography on alkaline aluminum oxide (petroleum ether/EtOAc = 1/1) to give compound 25 as a white solid
(25 mg, 75.0% for 2 steps). Data for 25: mp: 56-57 °C; [α]D20 +56 (c 1.80 in CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H),
4,794 – 4.790 (d, 1H, J = 1.6 Hz), 4.33 – 4.29 (m, 1H), 4.14 (s, 1H), 4.07 – 4.03 (m, 1H), 3.93 – 3.81 (m, 2H), 1.46 (s, 3H), 1.39 (s,
3H), 1.38 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 132.25, 109.29, 102.26, 83.94, 78.28, 77.59, 69.94, 57.99, 27.60,
+
25.28, 24.37, 24.00; HRMS(ESI) calcd. for C12H20O5 [M+H]+ 258.1336, found 258.1334.

Acknowledgment
Financial support from National Basic Research Program of China (No. 2012CB822101), the National Natural Science Foundation
of China (No. 21272240), National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (No.
2013ZX09508104) and National Engineering Research Center for Carbohydrate Synthesis of Jiangxi Normal University are gratefully
acknowledged.
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Fig. 1. Examples of some polyhydroxylated cyclic nitrones.
Fig. 2. Structures of some branched iminosugars.
Fig. 3. Crystal structure of compound 25.

Scheme 1. Synthesis of (2S, 3R, 4R)-1-amino-1,4-anhydro-1,N-didehydro-3-(1,2-dihydroxyl)ethyl-2,6:3,5-di-O-isopropylidene-l-threose N-
oxide (25).
Scheme 2. Attempt of the synthesis of triol 22.