Effective and one-step stereo-controlled synthesis of benzyloxylated- diiodopentanes for the synthesis of five-membered imino-sugars

Article abstract of DOI:10.1016/j.tetlet.2013.02.115

An effective and stereo-controlled synthesis of 1,3,4-tris(benzyloxy)-2,5- diiodopentane starting from 2,3,5-tris(benzyloxy)pentane-1,4-diol was reported. Synthesis was improved to get the diiodide compound instead of forming the ring-closure product (ben

Full text of DOI:10.1016/j.tetlet.2013.02.115

Tetrahedron Letters 54 (2013) 2579–2582
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effective and one-step stereo-controlled synthesis of
benzyloxylated-diiodopentanes for the synthesis of five-membered
imino-sugars
Lina Guo a, Yonghui Liu a, Yue Wan a, Peng George Wang a,b, Wei Zhao a,
⇑
a College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China
b The Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective and stereo-controlled synthesis of 1,3,4-tris(benzyloxy)-2,5-diiodopentane starting from
2,3,5-tris(benzyloxy)pentane-1,4-diol was reported. Synthesis was improved to get the diiodide com-
pound instead of forming the ring-closure product (benzyloxylated tetrahydrofuran). From the diiodide
intermediate, the five-membered aza-sugar was synthesized with high yield.
Received 25 November 2012
Revised 2 February 2013
Accepted 22 February 2013
Available online 21 March 2013
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrate mimetics
Benzyloxylated-diiodopentanes
Stereo-controlled synthesis
Ring-closure
Remote group participation
Carbohydrate mimetics in which the endocyclic oxygen is re-
placed by sulfur, nitrogen, and other heteroatoms (Fig. 1a) have
been found to possess a range of biological activities against HIV,
Gaucher’s disease, hepatitis, cancer, diabetes, and other diseases.1
The five-membered sugar mimetics (1 and 3), core structures of
many azasugar- and thiosugar-nucleosides, have emerged as
promising synthetic drugs as inhibitors of DNA- or RNA-related en-
zymes2 and glycosidases (Fig. 1).3 The C-nucleoside hydrochloride
nucleophile reactant (Scheme 1a). For example, Fleet has demon-
strated the efficient assembly of azetidines with poly-hydroxyl
and poly-chiral centers via a ring closure reaction from sugar ditri-
flate.9 Satoh has investigated the synthesis of thiosugar via ring
open sugar by the reduction reaction.10 However, these methods
suffered from the drawback of the carbon chiral centers of C5
which were reversed by the SN2 nucleophilic reaction. Recently,
Kumar et al.11 and Zhang et al.12 synthesized a series of imino-su-
gar derivatives by inversion of the configuration of C5 by the Mits-
unobu reaction followed by the second SN2 substitution reaction
D
-ImmH (2), now ‘Fodosine™’, is in phase II clinical trials as an
anti-T-cell leukemia agent.4 A new class of naturally occurring gly-
cosidase inhibitors (4) was isolated by Yoshikawa et al.5 from Sal-
acia reticulata Wight (known as ‘kothala himbutu’ in Singhalese),
used in Ayurveda medicine for the treatment of Type II diabetes
mellitus, and the core structure was thiosugar (3). In this regard,
the development of reaction methodologies, which provides a sim-
ple and economically favorable synthesis of such carbohydrate
mimetics, is very necessary.
To date, a number of synthetic strategies for the total synthesis
of these challenging imino-, thio-, and seleno-sugar mimetics have
been demonstrated, starting from amino acids6 or carbohydrates as
well as by asymmetric7 or enzymatic synthesis.8 Previous studies
show that a simple and convenient strategy was to introduce
two leaving groups via one step and close the sugar ring by a
⇑
Corresponding author. Tel./fax: +86 022 2350 7760.
E-mail address: wzhao@nankai.edu.cn (W. Zhao).
Figure 1. Carbohydrate derivatives with O atom substituted by other heteroatoms
(S, N, and Se).
0040-4039/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.115

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L. Guo et al. / Tetrahedron Letters 54 (2013) 2579–2582
Scheme 1. Reported strategies for the ring-closure reaction.
(Scheme 1b). Although this strategy can synthesize target products
in a good yield, the synthetic routes are time-consuming because
of the protection and deprotection steps. Protection group-free
synthesis of aza-sugars from carbohydrates was also reported,13
but only 2,3-cis-pyrrolidine products could be obtained. In contin-
uation of our studies on glycosidase inhibitors,14 we herein report a
more concise and practical synthesis of imino-sugar derivatives
from stereo-controlled benzyloxylated-diiodopentane intermedi-
ate via stereochemistry.
compound 6. As shown in Scheme 4, the ratio and the yield of com-
pounds 6 and 7 varied, as the reaction time was prolonged at the
same temperature. After stirring at À30 °C for 48 h and a subse-
quent reaction time of 2 h in refluxing toluene, diiodide compound
6 was obtained in 90% yield.
With the key diiodide compound 6 in hand, azido-iodide com-
pound 8,16 instead of diazido compound, was synthesized selec-
tively and conveniently using sodium azide in DMF under 50 °C
for 3 h. After reduction and ring-closure simultaneously, the sec-
ondary amine was protected by Boc for purification. Deprotection
of Boc by AcCl/MeOH and subsequent debenzylation using Pd/C
under hydrogen atmosphere afforded compound 120 in nearly
quantitative yield.
Skrydstrup and co-workers17 reported the transformation of
two hydroxyl groups into iodic groups simultaneously from methyl
2,4-di-O-benzyl-D-mannopyranoside. The alkene product, but not
the C3-nitrile compound was isolated due to the trans-b-elimina-
tion reaction of the C4-proton. Also, only the 3,6-anhydro product
was observed from corresponding ditriflate sugars. In our ap-
Afterward, the diiodide product 1221 (P/E = 10:1, Rf = 0.8) was
synthesized from arabinose with high yield and simple operation
to further demonstrate the efficiency of this general application
(Scheme 5). As an important intermediate for the synthesis of sal-
asinol, the corresponding thiosugar 1322 was prepared with an
overall yield of 92%.
To test the feasibility of this approach, the developed protocol
was further applied to the six-membered aza-sugars’ synthesis.
However, a complex mixture of elimination products was obtained
with no trace of the corresponding diiodide and the major product
14 was separated and characterized. The spectroscopic data were
consistent with the compound reported in the literature.23 The re-
mote group participation of methyloxyl and benzyloxyl groups has
been disclosed in previous synthesis.24 It was hypothesized that
intramolecular participation of the 4-O-benzyl group led to the for-
mation of oxonium ion intermediate (Scheme 6), which was at-
tacked by the iodide ion to form 14 and benzyl iodide. The
spectroscopic data of the benzyl iodide product supported this
hypothesis.
In summary, we have developed a novel and efficient synthesis
of stereo-controlled benzyloxylated-diiopentane which was the
key intermediate of carbohydrate mimetics’ synthesis. The most
important feature of this system was to simultaneously convert
two hydroxyl groups into iodic groups as leaving ligands and re-
verse the stereochemistry of the 4-OH with high yield. This method
is practical for the large scale synthesis of poly-benzylated-dii-
opentanes and imino-sugar derivatives available to the carbohy-
drate mimetics research.
proach, diol compound 5, easily prepared from D-ribose through
four steps,10 was treated with PPh3/I2 to afford the key intermedi-
ate 615 as depicted in Scheme 2. Subjection of the diiodide deriva-
tive 6 to excess sodium azide in DMF led to the mono-substituted
compound 816 selectively. Subsequent treatment of 8 with PPh3/
THF/H2O and ring-closure simultaneously, afforded the protected
1,4-imino D-ribitol. After deprotection using Pd/C, the final com-
pound (+)-1,4-dideoxy-1,4-imino D
-ribitol 1,7 which is consistent
with that reported in literatures,7 was obtained.
Unfortunately, at room temperature or at higher temperature,
the yield of diiodide compound 6 from diol compound 5 was very
low (only 5%). It was assumed that this was due to the lower reac-
tivity of the secondary hydroxyl group18and the mono-substituted
intermediate (Scheme 3a) was produced predominantly. With the
nucleophilic group and the leaving group existing in one linear
structure, the intramolecular nucleophilic reaction happened eas-
ily to obtain the 2,5-anhydro products 719 (Scheme 3a). To avoid
the intramolecular nucleophilic reaction and the formation of
2,5-anhydro products, lower temperature was applied for the syn-
thesis of the di-phosphide intermediate (Scheme 3b). The lower
temperature reaction was conducted using diethyl ether–acetoni-
trile (1:1, v/v) or DCM as solvent which, among many other sol-
vents screened, such as THF and toluene, was found to be best in
terms of suspension and reaction yield. An effort to prevent the for-
mation of 2,5-anhydro product 7 by lowering the temperature and
prolonging the reaction time led to maximized yield of diiodide
Scheme 2. Reagents and conditions: (a) PPh3/I2, 90% for 6 and 7 (Scheme 4); (b) NaN3, 90%; (c) (i) PPh3/H2O, THF, (ii) Boc2O/NaOH, 82%, (d) AcCl/MeOH (100%); (e) Pd/C, H2
(97%).

L. Guo et al. / Tetrahedron Letters 54 (2013) 2579–2582
2581
Scheme 3. (a) The pathway of ring closure; (b) the pathway of diiodide reaction.
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D
-ribitol hydrochloride 1H NMR (MeOD, 400 MHz) d 4.23 (m, C2H), 4.09 (dd,
C3H, J = 8, 4 Hz), 3.88 (dd, C5H, J = 12, 3.2 Hz), 3.73 (dd, C5H, J = 12, 5.8 Hz), 3.52
(m, C4H), 3.35 (dd, C1H, J = 12.4, 3.6 Hz), 3.23 (d, C1H, J = 12.4 Hz); 13C NMR
(MeOD, 100 MHz) d 73.00, 71.16, 63.97, 59.46, 51.14.
8. (a) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z. Y.; Ichikawa, Y.; John, A.;
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Scheme 6. Proposed mechanism for remote group participation reaction.
Acknowledgments
10. Satoh, H.; Yoshimura, Y.; Sakata, S.; Miura, S.; Machida, H.; Matsuda, A. Bioorg.
Med. Chem. Lett. 1998, 8, 989–992.
We thank the National High Technology Research and Develop-
ment Program of China (863 Program 2012AA021505) and the Nat-
ural Science Foundation of Tianjin (Grant No. 12JCYBJC18600) for
financial support.
11. Kumar, N. S.; Pinto, B. M. Carbohydr. Res. 2005, 340, 2612–2619.
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15. Spectroscopic data for 6: (2S,3S,4R)-1,3,4-tribenzyloxy-2,5-diiodopentane 1H
NMR (CDCl3, 400 MHz) d 7.44–7.26 (m, 15H), 4.85 (d, J = 12.6 Hz, 1H), 4.79 (dd,
J = 7.2, 8.8 Hz, 1H), 4.75–4.69 (m, 2H), 4.56 (t, J = 12.6 Hz, 1H), 4.48 (t,
J = 10.8 Hz, 2H), 3.87–3.78 (m, 2H), 3.60–3.54 (m, 2H), 3.32 (d, J = 8.4 Hz, 1H),
3.22 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 137.98, 137.52, 137.21,
128.47, 128.44, 128.20, 128.04, 127.89, 127.86, 127.77, 127.58, 79.36, 78.06,
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tet-
let.2013.02.115. These data include MOL files and InChiKeys of
the most important compounds described in this article.
74.96, 72.73, 72.67,71.78, 35.82, 9.06. HRMS Calcd for
C26H32I2NO3 m/z:
660.0472 (M+NH4)+. Found: 660.0446.
16. Spectroscopic data for 8: (2S,3S,4S)-5-azido-1,3,4-tri (benzyloxy)-2-iodopentane
1H NMR (CDCl3, 400 MHz) d 7.38–7.25 (m, 15H), 4.76–4.73 (m, 2H), 4.69–4.61
(m, 3H), 4.52 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 3.86–3.78 (m, 2H),
3.72 (dd, J = 2.8, 5.6 Hz, 1H), 3.65 (dd, J = 2.4, 13.2 Hz, 1H), 3.36 (d, J = 8.4 Hz,
1H), 3.29 (dd, J = 2.4, 9.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 138.05, 137.62,
137.54, 128.69, 128.65, 128.60, 128.54, 128.47, 128.30, 128.22, 128.13, 128.05,
127.91, 127.77, 81.73, 75.78, 74.64, 73.02, 72.95, 72.76, 49.78, 35.54. HRMS
Calcd for C26H32IN4O3 m/z: 575.1519 (M+NH4)+, Found: 575.1511.
17. Mikkelsen, L. M.; Krintel, S. L.; Jiménez-Barbero, J.; Skrydstrup, T. J. Org. Chem.
2002, 67, 6297–6308.
References and notes
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Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–2191; (e)
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Asymmetry 2000, 11, 1645–1680.
18. Minakawa, N.; Kaga, D.; Kato, Y.; Endo, K.; Tanak, M.; Sasaki, T.; Matsuda, A. J.
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L. Guo et al. / Tetrahedron Letters 54 (2013) 2579–2582
19. Yamazaki, O.; Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1 1999, 2891–
2896.
73.03, 72.69,72.58, 31.97, 5.92. HRMS Calcd for C26H32I2NO3 m/z: 660.0472
(M+NH4)+. Found: 660.0459.
20. Spectroscopic data for 10: (2R,3R,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)
pyrrolidine hydrochloride 1H NMR (CDCl3, 400 MHz) d 9.32 (br, 2H), 7.34–7.21
(m, 15H), 4.66 (dd, J = 6.4, 12 Hz, 2H), 4.52 (d, J = 12 Hz, 1H), 4.46 (d, J = 11.2 Hz,
1H), 4.42 (t, J = 12.4 Hz, 2H), 4.00 (br, 1H), 3.95–3.92 (m, 2H), 3.77 (d, J = 9.6 Hz,
1H), 3.73(dd, J = 4, 10.8 Hz, 1H), 3.50 (d, J = 11.2 Hz, 1H), 3.32 (dd, J = 3.2, 12 Hz,
1H); 13C NMR (CDCl3, 100 MHz) d 137.57, 137.21, 137.09, 128.51, 128.42,
128.12, 128.00, 127.95, 127.80, 77.97, 74.07, 73.30, 72.30, 71.63, 66.55, 59.84,
47.06. HRMS Calcd for C26H30NO3 m/z: 404.5213 (M+H)+, Found: 404.5211.
21. Spectroscopic data for 12: (2S,3S,4S)-1,3,4-tribenzyloxy-2,5-diiodopentane 1H
NMR (CDCl3, 400 MHz) d 7.35–7.30(m, 15H), 4.88 (d, J = 11.2 Hz, 1H), 4.70 (d,
J = 11.6 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.61 (d, J = 11.2 Hz, 1H), 4.51 (d,
J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.29 (ddd, J = 2.8, 5.6, 8.4 Hz, 1H), 3.81
(dd, J = 8.4, 10.4 Hz, 1H), 3.70 (dd, J = 5.6, 10.4 Hz, 1H), 3.58 (dd, J = 4.6, 10.6 Hz,
1H), 3.50 (dd, J = 2.8, 6.4 Hz, 1H), 3.40 (dd, J = 4, 11.2 Hz,1H), 3.26 (dd, J = 4.8,
10.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 138.27, 137.65, 137.64, 128.41,
128.32, 128.11, 127.87, 127.77, 127.72, 127.68, 127.61, 82.06, 79.18, 74.73,
22. Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001, 66, 2312.
23. Jiang, Y.-H.; Fang, Z.-J.; Zheng, B.-H.; Feng, W.-W. Hecheng Huaxue 2011, 19, 24–
27. The structure of this compound was characterized in this Letter by 1H NMR,
13C NMR, HSQC and NOESY. Spectroscopic data for 14: (R)-2-(benzyloxy)-1-
((2R,3R,4S)-3,4-bis(benzyloxy)tetrahydrofuran-2-yl)ethanol 1H NMR (CDCl3,
400 MHz) d 7.34–7.27 (m, 15H), 4.59 (dd, J = 3.6, 12 Hz, 2H), 4.57 (dd, J = 3.6,
12 Hz, 2H), 4.48 (d, J = 12 Hz, 1H), 4.45 (d, J = 12 Hz, 1H), 4.17–4.08 (m, 3H),
4.06 (d, J = 4.0 Hz, 1H), 3.97 (dd, J = 4.0, 8.4 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 3.74
(dd, J = 2.8, 10.0 Hz, 1H), 3.61 (dd, J = 6.4, 9.6 Hz, 1H), 2.73 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) d 138.21, 137.76, 128.66, 128.62, 128.52, 128.10, 128.01,
127.96, 127.82, 127.74, 82.15, 82.02, 80.43, 73.62, 72.41,72.38, 71.98, 71.50,
68.70. HRMS Calcd for C27H31O5 m/z: 435.2171 (M+H)+, Found: 435.2173.
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