Metal-free oxidative lactonization of carbohydrates using molecular iodine

Article abstract of DOI:10.1016/j.tet.2013.05.021

We describe herein the oxidative lactonization of fully or partially protected carbohydrates using molecular iodine. Oxidation of aldose hemiacetals is generally carried out by classical procedures, which are rarely chemo or regioselective. We recently re

Full text of DOI:10.1016/j.tet.2013.05.021

Tetrahedron xxx (2013) 1e4
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Metal-free oxidative lactonization of carbohydrates using molecular
iodine
,
,
b
,
a
,
,b
Maxime B. Fusaro a b, Vincent Chagnault a , Solen Josse b, Denis Postel a
*
a Laboratoire des Glucides, CNRS e FRE 3517, 10 rue Baudelocque, 80000 Amiens, France
b Institut de Chimie de Picardie, FR-3085, UFR des Sciences e UPJV, 33 rue Saint Leu, 80039 Amiens Cedex 1, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the oxidative lactonization of fully or partially protected carbohydrates using mo-
lecular iodine. Oxidation of aldose hemiacetals is generally carried out by classical procedures, which are
rarely chemo or regioselective. We recently reported an optimized methodology for the oxidative ami-
dation of aldose with functionalized amines and we found molecular iodine as a good selective oxidant.
This property has been already observed by other research groups but the scope of this reactivity has
never been studied for carbohydrates. The main advantage of this approach relies on the operational
simplicity, elimination of use of complicated reagents and procedures.
Received 25 March 2013
Received in revised form 7 May 2013
Accepted 9 May 2013
Available online xxx
Keywords:
Oxidative lactonization
Iodine chemistry
Metal-free oxidation
Carbohydrates chemistry
Lactone
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
not affected. Those molecules being often key reaction in-
termediates, this emphasizes the need to find softer and selec-
Diversely protected carbohydrate lactones are useful precursors
for the synthesis of natural products, in particular for an easy access
to compounds involving a C-glycosidic junction.1e6 The preparation
of these lactones can be obtained by classical oxidation reaction and
numerous procedures have already been employed.1e5,7e18 How-
ever, as carbohydrates contain a large number of hydroxyl groups,
control of both chemo- and regio-selectivity is difficult, therefore
specific protecting groups are required. Concerning the oxidation of
a hemiacetalic function to produce lactones, only few methodolo-
gies are well described, and they are rarely chemoselective. Oxi-
dative lactonization of reducing sugars can then be obtained using
bromine water and a BaCO3 buffer to form in situ the hypobromite/
bromate oxidative agents.19 Under these conditions, oxidation is
selective for the anomeric position but restricted to water soluble
derivatives. Moreover, this methodology generally provides a mix-
tive methodologies.
We recently reported an optimized procedure for the direct
oxidative amidation of benzylated carbohydrates using molecular
iodine.25 This process allows a large variety of functional groups
and implies the lactonization, which results in the oxidation of the
hemiacetal group. The reaction of this lactone with primary amines
led to glyconamides in high yields. The free primary or secondary
hydroxyls of these compounds being not affected during the re-
action, we decided to investigate the potential of molecular iodine
on the direct oxidative lactonization of carbohydrates.
This oxidation process has already been observed by other re-
search teams but, to our knowledge, the scope of this methodology
has never been studied for carbohydrates.26e28
2. Results
ture of d- and g-lactones. A similar procedure with molecular iodine
has been developed and has the same disadvantages.20e23
Another procedure has been used by Cordova and co-workers
on deoxycarbohydrates but implies large amounts of MnO2
(15 equiv).24 Under these conditions, the hemiacetalic functional
group was selectively oxidized and secondary hydroxyls were
Lactol 129 (easily available at multi-gram scale) was chosen as
starting material for optimization of the reaction conditions de-
fined during our previous investigations on the oxidative
amidation.25
Thus, compound 1 was treated with iodine (2 equiv) and K2CO3
(2 equiv) in methanol (0.1 M) at room temperature. The reaction
was monitored by TLC on silica gel, which showed complete con-
version after 24 h (Scheme 1). Under these conditions, NMR anal-
yses and mass spectroscopy indicated the presence of the desired
* Corresponding author. Tel.: þ33 322828812; fax: þ33 322827568; e-mail ad-
dresses: vincent.chagnault@u-picardie.fr, chagnault@gmail.com (V. Chagnault).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.021
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2
M.B. Fusaro et al. / Tetrahedron xxx (2013) 1e4
Scheme 1. Oxidative lactonization by molecular iodine in methanol.
lactone as well as the corresponding methyl ester (singlet at
3.62 ppm), which was identified as the major product (35:65,
respectively).
The mechanism of the reaction is believed to go through O-io-
dinated species, which allow an elimination of an HI molecule. The
need of a base has been previously demonstrated.25 When the re-
action is carried out without potassium carbonate, the oxidation
could not be obtained (Scheme 2).
Scheme 3. Role of methanol on the oxidation process.
It is important to note that, using methanol as solvent, we were
not able to avoid the formation of ester 3, which is rapidly formed,
even after 30 min of stirring (data not shown). Best yields were
obtained with dichloromethane and t-butanol (81 and 72%,
respectively).
The use of a more important excess of iodine was necessary to
reduce the reaction time. Thus, we performed the reaction in dif-
ferent solvents using 5 equiv of molecular iodine and potassium
carbonate. As before, reactions were monitored by TLC on silica gel
and by NMR spectroscopy. Results are summarized in Table 2.
Scheme 2. Mechanism of the oxidation process.
As reactions implying molecular iodine are affected by solvent
effects,30 we studied the influence of different solvents on the ox-
idative lactonization. After 24 h, reactions were directly neutralized
by a saturated solution of sodium thiosulfate and the aqueous
phase extracted with dichloromethane, dried and evaporated.
Evaluation of crude reaction mixtures was carried out by NMR
spectroscopy. As shown in Table 1, in contrast with the reaction
carried out in methanol, other solvents led to a slow formation of
the desired lactone 2 (doublet at 4.15 ppm).
Table 2
Solvent effect using 5 equiv of iodine
Table 1
Solvent effect using 2 equiv of iodine
Entry
Solvent
1 (%)
2 (%)
3 (%)
1
2
3
4
5
CH2Cl2
CH3CN
THF
t-BuOH
MeOH
d
100
>98
70
d
d
d
d
Traces
30
d
100
Complex mixture
Reaction conditions: I2 (5 equiv), K2CO3 (5 equiv), 5 h at room temperature. When
dichloromethane was replaced by t-BuOH, the temperature was raised to 30 ꢀC.
Entry
Solvent
1 (%)
2 (%)
3 (%)
In dichloromethane and t-butanol the reaction is quantitative
and the crude reaction mixture was very clean. Using anhydrous or
analytical grade THF, 30% of compound 1 were recovered. Aceto-
nitrile seems to be a better solvent than THF, but after 5 h, traces of
starting material were detected by 1H NMR (<5%). These reaction
conditions are thus well adapted for the oxidative lactonization if
dichloromethane or t-butanol is used as solvent. We demonstrated
that THF can be used but will induce longer reaction times. In the
case of methanol (entry 5), a complex mixture has been obtained.
Compound 3 was detected by mass spectrometry and NMR spec-
troscopic analysis. We were also able to detect by 13C NMR the
1
2
3
4
5
CH2Cl2
CH3CN
THF
t-BuOH
MeOH
19
41
47
28
d
81
59
53
72
35
d
d
d
d
65
Reaction conditions: I2 (2 equiv), K2CO3 (2 equiv), 24 h at room temperature. When
dichloromethane was replaced by t-BuOH, the temperature was raised to 30 ꢀC.
As shown in Scheme 3, we assume that methanol could par-
ticipate either in the formation of the O-iodinated species (Route A)
and/or in the elimination of HI (Route B) through an acidic in-
teraction. Moreover, the presence of iodine probably facilitates the
opening of the lactone to form the non desired ester 3.
presence of a mixture of
a- and b-methyl-D-xylopyranosides. We
assume that using a large excess of iodine, its Lewis acid property
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M.B. Fusaro et al. / Tetrahedron xxx (2013) 1e4
3
Table 4
allows the formation of acetals. In comparison with methanol, the
same reactivity was observed using 2,2,2-trifluoroethanol despite
Oxidative lactonization of aldose hemiacetalsa
its weakest nucleophilicity.
Entry
Substrate
Product
Time
3 h
Yieldc
80%
The structure of the 2,3,4-tri-O-benzyl-
D
-xylono-1,5-lactone 2 is
in accordance with the literature.14 The presence of a 4JH,H coupling
O
O
OH
O
O
HO
HO
1
constant indicates clearly
a
predominantly 2S4 conformation
(4J3,5eq¼1.5 Hz).
O
O
O
O
Finally, to extend the scope of this methodology and to avoid the
use of too large excess of iodine, which could interact with pro-
tecting groups like acetonides,30 we attempted the oxidative lac-
tonization using 3 equiv of iodine and potassium carbonate.
The reaction was carried out in dichloromethane, which has
been selected regarding to the results previously obtained (Tables 1
and 2). Different benzylated carbohydrates were tested and results
are summarized in Table 3.
1134
1635
O
O
OH
N3
N3
2
3
4
3 h
5 h
5 hb
2 h
100%
100%
70%
d
O
O
O
O
1236
1736
O
O
Table 3
O
O
O
O
O
OH
Oxidation of benzylated aldose hemiacetals to d
-lactonesa
Entry
Substrate
Product
Time
16 h
Yield
100%
O
O
O
O
1337
1837
1
5
O
4
1
2
O
O
OH
BnO
7
BnO
1
4
5
6
714
3
8
O
OH
O
OH
6
1437
19
2
3
24 h
16 h
16 h
100%
100%
100%
OAc
83
O
OH
5
d
AcO
OAc
OAc
1539
915
a
Reaction conditions: Carbohydrate (0.238 mmol), K2CO3 (0.713 mmol), I2
(0.713 mmol), CH2Cl2 (2.4 mL) at room temperature for 16e24 h.
b
Dichloromethane was replaced by t-BuOH and temperature raised to 30 ꢀC.
Yields after purification by column chromatography on silica gel.
4
c
1032
towards lactonization depending on the solvent used. When the
reaction was performed in dichloromethane, the different products
formed during the oxidation process were not soluble in organic
solvents. This is probably due to the deprotection of the allyl group.
Nevertheless, the use of t-BuOH to replace dichloromethane did not
induce this deprotection and lactone 19 was obtained in 70% yield
after 5 h. One limitation of this procedure was reached when using
a
Reaction conditions: Carbohydrate (0.238 mmol), K2CO3 (0.713 mmol), I2
(0.713 mmol), CH2Cl2 (2.4 mL) at room temperature for 16e24 h.
Using 3 equiv of iodine and potassium carbonate, benzylated
derivatives 1, 5 and 6 were quantitatively oxidized after 16 h.31
In the case of compound 4, 24 h were required, which is in
agreement with the difference of reactivity of the anomeric posi-
tion described during our previous researches with glucose de-
rivatives.25 Similar observations have been reported upon
palladium-catalysed oxidation of benzylated aldose hemiacetals.33
We then examined the scope of this process using various car-
bohydrates bearing different functional groups (Table 4).
2,3,4,6-tetra-O-acetyl- -glucopyranose 15. Whatever the applied
conditions, the deprotection of acetates could not be avoided.
D
3. Conclusion
To conclude, this methodology allows quick access in one-step
to lactones starting from variously substituted lactols. Dichloro-
methane and t-BuOH seem to be the most indicated solvents.
Dichloromethane allows the oxidation at room temperature but the
use of t-BuOH involves heating the reaction mixture to 30 ꢀC.
However, this alcohol is surely more eco-friendly and should be
favoured for environmental reasons. The advantages of this method
are the operational simplicity, elimination of use of complicated
reagents and procedures, and chemoselectivity of the reaction.
Under these conditions, reaction times were shorter than those
observed with benzylated derivatives (2e5 h). 2,3-O-Iso-
propylidene- -ribofuranose 11 was chemoselectively oxidized with
D
80% yield (entry 1). Primary and secondary hydroxyl groups were
not affected by iodine (entry 1 and 4).
It is also important to note that acetonides 11,12 and 13 were not
deprotected (entry 1, 2 and 3), which highlights the mild reaction
conditions despite the Lewis acid nature of molecular iodine.
Allyl ether protecting groups are known to be reactive with
electrophiles like bromine or iodine. Deprotection of unsaturated
ethers can be observed depending on the solvent used. In the case
of dichloromethane, the addition of iodine to the double bond of
the allyl group can be observed as well as the deprotection. How-
ever, acetonitrile or t-BuOH do not seem to affect these unsaturated
groups.30 As shown in Table 4, compound 14 behaves differently
4. Experimental section
4.1. General
All reagent-grade chemicals were obtained from commercial
suppliers and were used as received. Characterizations of known
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4
M.B. Fusaro et al. / Tetrahedron xxx (2013) 1e4
compounds were in accordance with literature. Optical rotations
were recorded in CH2Cl2 solution. FTIR spectra were obtained using
(C-3), 77.3 (C-4), 73.7 (CH2-Ph), 72.3 (C-2), 71.7 (C-6), 67.1 (C-5);
HRMS calcd for C15H18O5Na 301.1052, found m/z 301.1047 [MþNa]þ.
ATR and are reported in cmꢁ1 1H NMR (300 MHz) and 13C NMR
.
(75 MHz) spectra were recorded in CDCl3. The proton and carbon
signal assignments were determined from decoupling experiments,
COSY spectra and HSQC spectra. TLC were performed on Silica F254
and detection by UV light at 254 nm or by charring with cerium
molybdate reagent. Column chromatography was performed on
Silica Gel 60 (230 mesh). High-resolution electrospray mass spectra
in the positive ion mode were obtained on a Q-TOF Ultima Global
hybrid quadrupole/time-of-flight instrument, equipped with
a pneumatically assisted electrospray (Z-spray) ion source and an
additional sprayer (Lock Spray) for the reference compound. The
source and desolvation temperatures were kept at 80 and 150 ꢀC,
respectively. Nitrogen was used as the drying and nebulizing gas at
flow rates of 350 and 50 L/h, respectively. The capillary voltage was
3.5 kV, the cone voltage 100 V and the RF lens1 energy was opti-
mised for each sample (40 V). For collision-induced dissociation
(CID) experiments, argon was used as collision gas at an indicated
analyser pressure of 5ꢂ10ꢁ5 Torr and the collision energy was
optimised for each parent ion (50e110 V). Lock mass correction,
using appropriate cluster ions of sodium iodide (NaI)nNaþ, was ap-
plied for accurate mass measurements. The mass rangewas typically
50e2050 Da and spectra were recorded at 2 s/scan in the profile
mode at a resolution of 10,000 (FWMH).
Acknowledgements
We thank CNRS (France) for financial support and the Region
Picardie and Europe (FEDER) for a grant (to M.B.F.).
References and notes
1. Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739e5752.
2. Li, L.-T.; Zhou, L.-F.; Li, Y.-J.; Huang, J.; Liu, R.-H.; Wang, B.; Wang, P. Bioorg. Med.
Chem. Lett. 2012, 22, 642e644.
3. Kang, S. Y.; Song, K.-S.; Lee, J.; Lee, S.-H.; Lee, J. Bioorg. Med. Chem. 2010, 18,
6069e6079.
4. Plet, J. R. H.; Porter, M. J. Chem. Commun. 2006, 1197e1199.
5. Bowen, E. G.; Wardrop, D. J. Org. Lett. 2010, 12, 5330e5333.
6. Xavier, N. M.; Rauter, A.; Queneau, Y. In Carbohydrates in Sustainable De-
velopment II; Rauter, A. P., Vogel, P., Queneau, Y., Eds.; Springer: Berlin Heidel-
berg, 2010; Vol. 295, pp 19e62.
7. Thiem, J.; Thimm, J.; Louchami, K.; Waschke, D.; Leshch, Y.; Malaisse, W.
WO2012016935A1, 2012.
8. Zhang, F.; Vasella, A. Carbohydr. Res. 2007, 342, 2546e2556.
9. Himmelsbach, F.; Eckhardt, M.; Eickelmann, P.; Thomas, L. WO2007000445A1, 2007.
10. El-Badri, M. H.; Willenbring, D.; Tantillo, D. J.; Gervay-Hague, J. J. Org. Chem.
2007, 72, 4663e4672.
11. Devita, R. J.; Morriello, G. J.; Ogawa, A. K.; Ujjainwalla, F. WO2006138163A2, 2006.
12. Jung, M.; Paik, Y. -K. WO2005075491A1, 2005.
13. Wang, W.; Zhang, Y.; Zhou, H.; Bleriot, Y.; Sinay, P. Eur. J. Org. Chem. 2001, 2001,
1053e1059.
14. Lopez, R.; Fernandez-Mayoralas, A. J. Org. Chem. 1994, 59, 737e745.
15. Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59, 6404e6412.
16. Benhaddou, R.; Czernecki, S.; Farid, W.; Ville, G.; Xie, J.; Zegar, A. Carbohydr. Res.
1994, 260, 243e250.
17. Rajanikanth, B.; Seshadri, R. Tetrahedron Lett. 1989, 30, 755e758.
18. Kuzuhara, H.; Fletcher, H. G. J. Org. Chem. 1967, 32, 2531e2534.
19. Mantell, S. J.; Ford, P. S.; Watkin, D. J.; Fleet, G. W. J.; Brown, D. Tetrahedron Lett.
1992, 33, 4503e4506.
ꢀ
€
4.2. General procedure A for oxidative lactonization reactions
Aldose (0.476 mmol) was dissolved in dichloromethane (ana-
lytical grade; 0.1 M) and K2CO3 (3 equiv) and iodine (3 equiv) were
added. The solution was stirred at room temperature and moni-
tored by TLC on silica gel. Then a saturated aqueous solution of
Na2S2O3 (1 mL) was added with vigorous stirring until complete
disappearance of the dark brown colour. The organic phase was
isolated and the aqueous phase extracted with ethyl acetate
(3ꢂ20 mL). All the organic phases were combined, dried over
MgSO4 and evaporated under reduced pressure. When needed, the
residue was purified by chromatography on silica gel (cyclohexane/
EtOAc) to give the desired lactone.
20. Jeong, Y.-I.; Seo, S.-J.; Park, I.-K.; Lee, H.-C.; Kang, I.-C.; Akaike, T.; Cho, C.-S. Int. J.
Pharm. 2005, 296, 151e161.
~
ꢀ
ꢀ
ꢀ
21. Munoz-Bonilla, A.; Bordege, V.; Leon, O.; Cuervo-Rodríguez, R.; Sanchez-
ꢀ
Chaves, M.; Fernandez-García, M. Eur. Polym. J. 2012, 48, 963e973.
22. Hayashida, O.; Hamachi, I. J. Org. Chem. 2004, 69, 3509e3516.
23. Morimoto, N.; Ogino, N.; Narita, T.; Kitamura, S.; Akiyoshi, K. J. Am. Chem. Soc.
2006, 129, 458e459.
ꢀ
ꢀ
24. Cordova, A.; Ibrahem, I.; Casas, J.; Sunden, H.; Engqvist, M.; Reyes, E. Chem.
dEur. J. 2005, 11, 4772e4784.
25. Fusaro, M. B.; Chagnault, V.; Postel, D. Tetrahedron 2013, 69, 542e550.
26. Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915e5925.
27. Cho, C.-C.; Liu, J.-N.; Chien, C.-H.; Shie, J.-J.; Chen, Y.-C.; Fang, J.-M. J. Org. Chem.
2009, 74, 1549e1556.
28. Colombeau, L.; Traore, T.; Compain, P.; Martin, O. R. J. Org. Chem. 2008, 73,
8647e8650.
29. Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831e834.
30. Das, S.; Borah, R.; Devi, R. R.; Thakur, A. J. Synlett 2008, 2741e2762.
31. Isolated yields after purification over silica gel chromatography.
32. Gervay, J.; Flaherty, T. M.; Holmes, D. Tetrahedron 1997, 53, 16355e16364.
33. Bessmertnykh, A.; Henin, F.; Muzart, J. Carbohydr. Res. 2004, 339, 1377e1380.
34. Thiyagarajan, A.; Salim, M. T. A.; Balaraju, T.; Bal, C.; Baba, M.; Sharon, A. Bioorg.
Med. Chem. Lett. 2012, 22, 7742e7747.
35. Fan, A.; Jaenicke, S.; Chuah, G.-K. Org. Biomol. Chem. 2011, 9, 7720e7726.
36. Simone, M. I.; Edwards, A. A.; Tranter, G. E.; Fleet, G. W. J. Tetrahedron: Asym-
metry 2008, 19, 2887e2894.
4.3. 3-O-Allyl-6-O-benzyl-D-xylono-1,4-lactone (19)
Lactol 1438 (200 mg, 0.714 mmol) was treated as described in the
general procedure using K2CO3 (296 mg, 2.14 mmol) and I2
(543 mg, 2.14 mmol). The resulting crude product was purified by
silica gel chromatography (cyclohexane/EtOAc gradient) to provide
20
19 (139 mg, 70%) as a colourless oil: [
a
]
D
þ65.0 (c 0.2, CH2Cl2); IR
(ATR) 1786 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d 7.49e7.12 (m, 5H,
Ph), 6.00e5.80 (m, 1H, H-7), 5.40e5.14 (m, 2H, H-8), 4.75 (d,
J¼8.0 Hz, 1H, H-2), 4.64 (dt, J¼7.8, 2.7 Hz, 1H, H-4), 4.58 (d,
J¼12.2 Hz, 1H, CH2-Ph), 4.53 (d, J¼12.1 Hz, 1H, CH2-Ph), 4.31 (t,
J¼7.9 Hz, 1H, H-3), 4.30e4.23 (m, 1H, H-6), 4.18e4.07 (m, 1H, H-6),
3.77 (dd, J¼11.1, 2.8 Hz, 1H, H-5), 3.73 (dd, J¼11.0, 2.9 Hz, 1H, H-5),
37. Oddo, A.; Holl, R. Carbohydr. Res. 2012, 359, 59e64.
38. Shuto, S.; Tatani, K.; Ueno, Y.; Matsuda, A. J. Org. Chem. 1998, 63, 8815e8824.
39. Gorityala, B. K.; Lu, Z.; Leow, M. L.; Ma, J.; Liu, X.-W. J. Am. Chem. Soc. 2012, 134,
15229e15232.
3.28 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3)
d 175.5 (C-1), 137.7
(Ph), 133.9 (C-7), 128.5 (Ph), 127.8 (Ph), 127.6 (Ph), 117.8 (C-8), 80.4
Please cite this article in press as: Fusaro, M. B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.021