Novel polyhydroxylated cyclic nitrones and N-hydroxypyrrolidines through BCl3-mediated deprotection

Article abstract of DOI:10.1021/ol8007759

(Chemical Equation Presented) A general method to prepare a new class of carbohydrate-derived, enantiomerically pure polyhydroxypyrroline N-oxides from their alkoxy (protected) derivatives is presented. Boron trichloride is shown to cleave efficiently benzyl ethers and ketals without affecting the imine N-oxide functionality of nitrones. The same reagent (BCl₃) also allowed the efficient synthesis of a polyhydroxylated N-hydroxypyrrolidine, giving access to a novel class of N-hydroxyiminosugars.

Full text of DOI:10.1021/ol8007759

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2967-2970
Novel Polyhydroxylated Cyclic Nitrones
and N-Hydroxypyrrolidines through
BCl3-Mediated Deprotection
Ste´phanie Desvergnes,† Yannick Valle´e, and Sandrine Py*
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-2607, CNRS -
UniVersite´ Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France
sandrine.py@ujf-grenoble.fr
Received April 4, 2008
ABSTRACT
A general method to prepare a new class of carbohydrate-derived, enantiomerically pure polyhydroxypyrroline N-oxides from their alkoxy
(protected) derivatives is presented. Boron trichloride is shown to cleave efficiently benzyl ethers and ketals without affecting the imine
N-oxide functionality of nitrones. The same reagent (BCl3) also allowed the efficient synthesis of a polyhydroxylated N-hydroxypyrrolidine,
giving access to a novel class of N-hydroxyiminosugars.
Polyhydroxylated heterocycles containing an endocyclic
nitrogen atom are coined by the general term of iminosug-
ars.1 Iminosugars have demonstrated outstanding biological
activities as glycosidase inhibitors and, more generally, as
glycoprocessing enzyme modulators.2 Since the inhibition
of glycoprocessing enzymes has potential applications in the
development of antiviral,3 anticancer,4 and metabolic dis-
order5 therapies, iminosugars have attracted much attention.
In particular, polyhydroxylated pyrrolidines and pyrrolines
(five-membered ring iminosugars) are among the most potent
inhibitors of individual glycoprocessing enzymes (Figure 1).6
In contrast to the intense research devoted to iminosugars
and to their structure-function relationship, little or no
attention has been given to their N-oxygenated analogues.
Very few polyhydroxylated pyrrolidine N-oxides7 (I) and
(5) (a) Butter, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100,
4683. (b) Fan, J.-Q. Trends Pharmacol. Sci. 2003, 24, 355.
(6) For recent references on preparation and bioactivity of five-membered
ring iminosugars, see inter alia: (a) Cren, S.; Wilson, C.; Thomas, N. R.
Org. Lett. 2005, 7, 3521. (b) Hay, P. A.; Courtney, S. M.; McNeil, L. A.;
Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005, 127, 506. (c) Fiaux,
H.; Popowycz, F.; Favre, S.; Schu¨tz, C.; Vogel, P.; Gerber-Lemaire, S.;
Juillerat-Jeanneret, L. J. Med. Chem. 2005, 48, 4237. (d) Clinch, K.; Evans,
G. B.; Fleet, G. W. J.; Furneaux, R. H.; Johnson, S. W.; Lenz, D. H.; Mee,
S. P. H.; Rands, P. R.; Schramm, V. L.; Taylor Ringia, E. A.; Tyler, P. C.
Org. Biomol. Chem. 2006, 4, 1131. (e) Moriarty, R. M.; Mitan, C. I.; Branza-
Nichita, N.; Phares, K. R.; Parrish, D. Org. Lett. 2006, 8, 3465. (f) Liang,
P.-H.; Cheng, W.-C.; Lee, Y.-L.; Yu, H.-P.; Wu, Y.-T.; Lin, Y.-L.; Wong,
C.-H. ChemBioChem 2006, 7, 165. (g) Chevrier, C.; Defoin, A.; Tarnus,
C. Bioorg. Med. Chem. 2007, 15, 4125. (h) Otero, J. M.; Soengas, R. G.;
Este´vez, J. C.; Este´vez, R. J.; Watkin, D. J.; Evinson, E. L.; Nash, R. J.;
Fleet, G. W. J. Org. Lett. 2007, 9, 623. (i) Caines, M. E. C.; Hancock,
S. M.; Tarling, C. A.; Wrodnigg, T. M.; Stick, R. V.; Stuetz, A. E.; Vasella,
A.; Withers, S. G.; Strynadka, N. C. J. Angew. Chem., Int. Ed. 2007, 46,
4474. See also ref 2.
† Current address: Wolfson Laboratory of Medicinal Chemistry, Depart-
ment of Pharmacy and Pharmacology, University of Bath, Claverton Down,
Bath BA2 7AY, United Kingdom
(1) For comments on this naming convention, see ref 8 in: Garcia-
Moreno, M. I.; Diaz-Perez, P.; Ortiz Mellet, C.; Garcia Fernandez, J. M. J.
Org. Chem. 2003, 68, 8890.
(2) (a) Compain, P.; Martin, O. R. Iminosugars: From Synthesis to
Therapeutic Applications; Wiley: Chichester, 2007. (b) Stu¨tz, A. E.
Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-
VCH: Weinheim, 1999.
(3) (a) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P.
Curr. Drug Metab. 2004, 5, 329. (b) Greimel, P.; Spreitz, J.; Stu¨tz, A. E.;
Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513.
(4) (a) Wrodnigg, T. M.; Steiner, A. J.; Ueberbacher, B. J. Anti-Cancer
Agents Med. Chem. 2008, 8, 77. (b) Gerber-Lemaire, S.; Juillerat-Jeanneret,
L. Mini-ReV. Med. Chem. 2006, 6, 1043.
10.1021/ol8007759 CCC: $40.75
Published on Web 06/21/2008
2008 American Chemical Society

Figure 2. PBN: spin-trapping activity and hydrophilic derivatives.
Figure 1. Pyrrolidine iminosugars and N-oxy analogues.
N-hydroxy-pyrrolidines6g,8 (II) have been reported. Remark-
ably, only a single letter describes the obtention of a
polyhydroxylated endocyclic nitrone, in the course of
structural studies on the enediyne antibiotic esperamycin A1.9
Nitrones share with imines10,11 the sp2 character at the
pseudoanomeric position (beneficial to mimic oxocarbenium-
like transition states) and with tertiary amine N-oxides the
zwitterionic character.12 Notwithstanding these potentially
advantageous properties, the biological activity of polyhy-
droxylated nitrones related to iminosugars has never been
evaluated, although numerous polyalkoxylated nitrones have
been used by chemists as synthetic intermediates.13
In addition, nitrones have been recognized as protective
agents against oxidative stress in biological systems.14 While
R-phenyl-N-tert-butylnitrone (PBN) is the most studied
nitrone with respect to spin-trapping properties,15 several
hydrophilic derivatives, such as NXY-05916 and LPBNAH,17
have been designed for better distribution (Figure 2).
Interestingly, the activity of nitrones as antioxidants is
dependent on their lipophilicity/hydrophilicity balance as
recently demonstrated by the group of Pucci.18 Highly water-
soluble nitrones are still scarce in the literature, and their
physicochemical properties have not been investigated in
detail.
In this paper, we disclose a method to prepare polyhy-
droxylated cyclic nitrones from polyalkoxy precursors that
are themselves readily prepared from commercially available
carbohydrates.13 Such cyclic nitrones are generally prepared
by (i) introduction of ethers or isopropylidene ketals to
protect hydroxyl groups in carbohydrates and (ii) cyclization
by intramolecular N-alkylation of an oxime function placed
at the anomeric center. Benzyl ethers have proved particularly
convenient in such sequences, as benzyl groups are stable
to a large variety of chemical treatments but can be removed
by hydrogenolysis.19 Consequently, benzyl protection of
hydroxyl groups has been commonly used for the synthesis
of carbohydrate-derived nitrones.13,20
(7) (a) Humphrey, A. J.; Parsons, S. F.; Smith, M. E. B.; Turner, N. J.
Tetrahedron Lett. 2000, 41, 4481. (b) Palmer, A. M.; Ja¨ger, V. Synlett 2000,
1405. (c) O’Neil, I. A.; Cleator, E.; Hone, N.; Southern, J. M.; Tapolczay,
D. J. Synlett 2000, 1408. (d) Laventine, D. M.; Davies, M.; Evinson, E. L.;
Jenkins, P. R.; Cullis, P. M.; Fawcett, J. Tetrahedron Lett. 2005, 46, 307.
(8) (a) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z.; Ishikawa,
Y.; Porco, J. A., Jr; Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6187. (b)
Palmer, A. M.; Ja¨ger, V. Eur. J. Org. Chem. 2001, 66, 1293. (c) Palmer,
A. M.; Ja¨ger, V. Eur. J. Org. Chem. 2001, 66, 2547.
The deprotection of benzyloxy-substituted nitrones could
not be effected by hydrogenolysis as the nitrone functionality
does not resist such conditions.21 We thus considered another
method for benzyl ether cleavage, previously used in
carbohydrate chemistry, that involves treatment of benzyl
ethers with boron trichloride.22 It should be noted that
substrates containing nitrone or hydroxylamine functions
have never been subjected to such treatment. At first, this
(9) Golik, J.; Wong, H.; Krishnan, B.; Vyas, D. M.; Doyle, T. W.
Tetrahedron Lett. 1991, 32, 1851.
(10) Sugar imines have shown enhanced inhibitory properties over their
fully reduced counterparts: (a) Wong, C.-H.; Provencher, L.; Porco, J. A.;
Jung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J. Org.
Chem. 1995, 60, 1492. (b) Takayama, S.; Martin, R.; Wu, J. Y.; Laslo, K.;
(16) Nitrone NXY-059 (Astra Zeneca) has been in phase III clinical trials
as a neuroprotective agents for the treatment of cerebral ischemias: (a) Lapchak,
P. A.; Song, D.; Wei, J.; Zivin, J. A. Exp. Neurol. 2004, 188, 279.
(17) Poeggeler, B.; Durand, G.; Polidori, A.; Pappolla, M. A.; Vega-
Naredo, I.; Coto-Montes, A.; Bo¨cker, J.; Hardeland, R.; Pucci, B. J. Neu-
rochem. 2005, 95, 962.
Siuzdak, G.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146
.
(11) Nectrisine (FR-900484) is an example of potent R-mannosidase
and glucosidase inhibitor, exhibiting immunomodulator activity: (a) Hibata,
T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.; Terano; H.; Ohsaka, M. J.
Antibiot. 1988, 41, 296. (b) Kim, Y. J.; Takatsuki, A.; Kogoshi, N.; Kitahara,
(18) Durand, G.; Poeggeler, B.; Bo¨ker, J.; Raynal, S.; Polidori, A.;
Pappolla, M. A.; Hardeland, R.; Pucci, B. J. Med. Chem. 2007, 50, 3976.
(19) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis; Wiley Interscience: New York, 2007.
T. Tetrahedron 1999, 55, 8353
.
(12) Such zwitterionic character was proposed to allow better interaction
with the putative carboxylate and carboxylic acid residues in active sites
of glycosidases due to stronger electrostatic interactions. However, this
hypothesis has yet to be validated as the previously prepared polyhydroxy-
lated piperidine and pyrrolidine N-oxides exhibited weak or unsignificant
activity against glycosidases: (a) Dong, W.; Jespersen, T.; Bols, M.;
Skrydstrup, T.; Sierk, M. R. Biochemistry 1996, 35, 2788. See also ref 8a,
c.
(20) For examples from our laboratory, see: (a) Desvergnes, S.; Py, S.;
Valle´e, Y. J. Org. Chem. 2005, 70, 1459. (b) Desvergnes, S.; Desvergnes,
V.; Martin, O. R.; Itoh, K.; Liu, H-w.; Py, S. Bioorg. Med. Chem. 2007,
15, 6443. (c) Pillard, C.; Desvergnes, V.; Py, S. Tetrahedron Lett. 2007,
48, 6209
.
(21) (a) Oppolzer, W.; Merifield, E. HelV. Chim. Acta 1993, 76, 957.
(b) Murahashi, S.-I.; Tsuji, T.; Ito, S. Chem. Commun. 2000, 409. (c) Baillie,
L. C.; Bearder, J. R.; Sherringham, J. A.; Whiting, D. A. J. Chem. Soc.,
Perkin Trans. 1 1997, 2687. (d) Broggini, G.; Zecchi, G. Tetrahedron:
Asymmetry 1997, 8, 1431. (e) Broggini, G.; Zecchi, G. Synthesis 1996, 1280.
(f) Ali, S. A.; Wazeer, M. I. M. Tetrahedron 1993, 49, 4339. (g) Duvall,
J. R.; Wu, F.; Snider, B. B. J. Org. Chem. 2006, 71, 8579.
(13) For a recent review on enantiopure, carbohydrate-derived cyclic
nitrones, see: (a) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis
2007, 485.
(14) For a review, see: (a) Floyd, R. A. AdV. Pharm. 1997, 38, 361.
(15) Janzen, E. G.; Kotake, Y.; Hinton, R. D. Free Radical Biol. Med.
1992, 12, 169, and references therein.
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Org. Lett., Vol. 10, No. 14, 2008

method was tested on nitrone 1, prepared from 3-(benzy-
loxy)-2,2-dimethylpropanal23 (Scheme 1). When 1 was
Table 1. BCl3-Mediated O-Dealkylation of Polyalkoxy
Carbohydrate-Derived Endocyclic Nitronesa
Scheme 1. Nitrone Debenzylation in the Presence of BCl3
treated with 1 equiv of BCl3, incomplete reaction was
observed, but when the reagent was used in excess (3 equiv)
the O-benzyl-deprotected nitrone 2 was isolated as the sole
product; both the nitrone functionality and the N-benzyl
substituent remained unaffected under these conditions.
The method was then applied to polyalkoxy-substituted
nitrones 3,20a,24 4,25 5,20c and 626 readily obtained from
l-xylose, d-arabinose, d-ribose, and d-glucose, respectively
(Table 1). Using excess BCl3, O-debenzylation of nitrones
3-5 was performed to yield the corresponding polyhydroxyl
nitrones 9–11 in good yields (entries 1-3). The branched
nitrone exhibiting the galacto configuration (6) was also
deprotected in good yield (entry 4).
In a similar fashion, isopropylidene protected nitrones 727
and 8,28 prepared respectively from d-mannose and l-
erythrose, were smoothly transformed to nitrones 13 and 14,
respectively (entries 5 and 6).
Encouraged by the success of this method for preparing
polyhydroxylated nitrones, we next examined the possibility
of deprotecting N-hydroxypyrrolidines. Such compounds can
be obtained from nitrones by nucleophilic additions29 or
reductive coupling with electrophiles.30
Secondary hydroxylamines are sensitive compounds, prone
to dehydration in acidic conditions. However, when the cyclic
N-hydroxypyrrolidine 1520b was treated in the above-
(22) (a) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes,
A. B.; Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett 1993, 663. (b)
Meade, E. A.; Woring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
1997, 40, 794. (c) Bosco, M.; Bisseret, P.; Bouix-Peter, C.; Eustache, J.
Tetrahedron Lett. 2001, 42, 7949. (d) Xie, J.; Me´nand, M.; Valery, J. M.
Carbohydr. Res. 2005, 340, 481–487. (e) Magdolen, P.; Vasella, A. HelV.
Chim. Acta 2005, 88, 2454. (f) Behr, J.-B.; Kalla, A.; Harakat, D.; Plantier-
Royon, R. J. Org. Chem. 2008, 73, 3612.
a Conditions: BCl3 (1 M in hexanes), CH2Cl2, 0 °C, 17 h. See the
Supporting Information. b Isolated yields.
described conditions to deprotect benzyl ethers, the corre-
sponding polyhydroxylated N-hydroxypyrrolidine 16 was
isolated in 92% yield (Scheme 2).
(23) (a) Stumpp, M. C.; Schmidt, R. R. Tetrahedron 1986, 42, 5941.
(b) Upadhya, T. T.; Gurunath, S.; Sudalai, A. Tetrahedron:Asymmetry 1999,
10, 2899.
(24) (a) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A.
Tetrahedron Lett. 2003, 44, 2315. (b) Carmona, A. T.; Wightman, R. H.;
Robina, I.; Vogel, P. HelV. Chim. Acta 2003, 86, 3066
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71, 1614.
(26) Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R. J.
Org. Chem. 2006, 71, 7337.
Scheme 2. N-Hydroxypyrrolidine Debenzylation using BCl3
(27) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344.
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Trombini, C. Synthesis 2000, 759.
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Int. Ed. 2003, 42, 2265. (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5,
229. (c) Johannesen, S. A.; Albu, S.; Hazell, R. G.; Skrydstrup, T. Chem.
Commun. 2004, 1962. (d) Cividino, P.; Delair, P.; Py, S.; Greene, A. E. J.
Org. Chem. 2007, 72, 485.
Org. Lett., Vol. 10, No. 14, 2008
2969

In conclusion, the use of BCl3 as a Lewis acid promotes
efficient cleavage of benzyl ethers and isopropylidene ketals
in nitrones and in a N-hydroxypyrrolidine.31 The described
method thus opens a route to two new classes of enantio-
pure polyhydroxylated cyclic nitrones and polyhydroxylated
N-hydroxypyrrolidines. Such products could find useful
applications as novel glycomimetics and/or as water-soluble
radical-trapping agents (in the case of nitrones). Biological
evaluations in both these directions are now possible as a
consequence of the easy access to these compounds.
Acknowledgment. This work was financially supported
by the Centre National de la Recherche Scientifique (CNRS)
and the Universite´ Joseph Fourier. S.D. is grateful to the
DCM (De´partement de Chimie Mole´culaire) for a doctoral
fellowship. Ms. Pascale Cividino (DCM) is thanked for
technical assistance.
Supporting Information Available: Experimental pro-
cedures, compounds characterization data, and copies of 1H
NMR and 13C NMR for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(31) Some of the work described herein has been patented: Py, S.;
Desvergnes, S.; Valle´e, Y. (Universite´ Joseph Fourier-CNRS), FR2902097,
2007; Chem. Abstr. 2007, 148, 54460.
OL8007759
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