Glycal-mediated synthesis of enantiomerically pure 5-substituted isoxazoles containing a differentially O-benzylated glycerol moiety

Article abstract of DOI:10.1016/S0040-4039(02)00872-9

A short, glycal-mediated synthesis of new chiral 5-substituted isoxazoles bearing a differentially O-protected glycerol moiety in the side chain has been accomplished. An X-ray crystallographic structural analysis confirmed the structural assignment of th

Full text of DOI:10.1016/S0040-4039(02)00872-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4613–4615
Glycal-mediated synthesis of enantiomerically pure 5-substituted
isoxazoles containing a differentially O-benzylated
glycerol moiety
Hans-Georg Weinig, Pietro Passacantilli,* Marcello Colapietro† and Giovanni Piancatelli*
Dipartimento di Chimica Universita` ‘La Sapienza’ and Istituto di Chimica Biomolecolare, Sezione di Roma,
Piazzale Aldo Moro 5, 00185 Roma, Italy
Received 22 April 2002; accepted 7 May 2002
Abstract—A short, glycal-mediated synthesis of new chiral 5-substituted isoxazoles bearing a differentially O-protected glycerol
moiety in the side chain has been accomplished. An X-ray crystallographic structural analysis confirmed the structural assignment
of the new products. © 2002 Elsevier Science Ltd. All rights reserved.
Isoxazole containing natural and non natural com-
pounds are interesting because of their biological
activities1 e.g. as fungicides,2 herbicides,3 or as nicotinic
acetylcholine receptor ligands.4 Typical procedures1a
include the cycloaddition of nitrile oxides with alkynes,
or the condensation of 1,3-dicarbonyl compounds or
heteroanalogues5 with hydroxylamine. Taking into
account the plethora of realized isoxazole syntheses,
there are only few cyclocondensation reactions
described leading to enantiomerically pure 5-substituted
isoxazoles containing a more complex, stereocenter-
bearing side chain.6 Furthermore, these reactions were
carried out with only low to moderate yields, and/or
gave isomeric mixtures of 5- and 3-substituted isoxa-
zoles, respectively. A high yielding cyclocondensation
of an enaminone with hydroxylamine during the syn-
thesis of isoxazole C-nucleosides has been published by
Maeba and co-workers.7
Herein we report on a short, glycal-mediated synthesis
of the enantiomerically pure, 5-substituted isoxazoles
4–7 with differentially O-benzylated alcohol functional-
ities in the glycerol8 side chain. Tri-O-benzylgalactal
(1a) and tri-O-benyzlglucal (1b), quantitatively
obtained by perbenzylation of the starting glucals with
sodium hydride/benzyl bromide, have been selectively
Scheme 1. Syntheses of the isoxazoles 4 and 5.
Keywords: glycals; isoxazoles; glycerol; hypervalent iodine; carbohydrates.
* Corresponding authors. E-mail: pietro.passacantilli@uniroma1.it; giovanni.piancatelli@uniroma1.it
† Author for X-ray analysis.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00872-9

4614
H.-G. Weinig et al. / Tetrahedron Letters 43 (2002) 4613–4615
biological activities of all the new compounds will be
tested in the near future.
OH
CrCl2/LiI
4a
BnO
N
EtOAc
3 h, 65 °C
23 %
O
HO
6
Acknowledgements
Scheme 2. Synthesis of 6.
We gratefully acknowledge financial support from
I.C.B. and from the Deutsche Forschungsgemeinschaft
(DFG) (postdoctoral fellowship to H.-G. W.). Prof. Dr.
A. Kirschning (Hannover) and Dr. M. Pa¨tzel (Berlin)
are thanked for helpful discussions.
oxidized to enones 2 with bis-acetoxyiodobenzene
(BAIB) and para-toluenesulfonic acid (Koser’s
reagent9) following a modified10 procedure formerly
described by Kirschning11 (Scheme 1). Thus, we were
able to raise the yields respectively up to 86% for 2a
(lit.:11 57%) and 59% for 2b (lit.:11 49%). The fact that
the yield of 2b could not be significantly altered is in
accordance with a favored formation of side products
in this reaction.12
References
1. (a) Gru¨nanger, P.; Vita-Finzi, P. In The Chemistry of
Heterocyclic Compounds, Isoxazoles, Part 1; Weissberger,
A.; Taylor, E. C., Eds.; Wiley-Interscience: New York,
1991; (b) Johansen, T. N.; Ebert, B.; Bra¨uner-Osborne,
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Elliott, J. D. Chem. Abstr. 1997, 127, 205581.
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Sinhorin, A.; Bonacorso, H. G.; Zanatta, N. Tetrahedron
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Ziegler, H.; Trah, S.; Zurfluh, R.; O’Sullivan, A. C.
Chem. Abstr. 1997, 126, 186095.
Reaction of enones 2 with one equivalent hydroxyl-
amine, prepared from hydroxylamine hydrochloride
and sodium hydroxide as ethanolic solution,13 afforded
the isoxazolines 3 as inseparable epimeric mixtures in
good yield. The latter were dehydrated in high yield
with para-toluenesulfonic acid7 in dichloromethane at
room temperature to give isoxazoles 4 with a free
hydroxyl at C-2% as target compounds. Deprotection of
the primary benzyl ether leading to the diols 5 was
achieved in a selective manner with boron trifluoride
etherate (1.2 equiv.) and tetrabutyl ammonium iodide
in dichloromethane.14 In alternative, debenzylation of
4a with chromium(II) chloride/lithium iodide15,16 led
regioselectively to diol 6 (Scheme 2). The yield of 23%
is rather poor, but this reaction sequence has not been
optimized.
3. Newton, T. W. Chem. Abstr. 1998, 129, 119078.
4. Silva, N. M.; Tributino, J. L. M.; Miranda, A. L. P.;
Barreiro, E. J.; Fraga, C. A. M. Eur. J. Med. Chem. 2002,
37, 163–170.
5. For a review see: Pa¨tzel, M.; Liebscher, J. Synthesis 1995,
879–894.
Alcohol 4a was then converted into mesylate 7 which
could be recrystallized from ethyl acetate to give single
crystals suitable for X-ray analysis. The formation and
the X-ray crystal structure17 of 7 is shown in Scheme 3.
6. (a) Klein, U.; Steglich, W. Liebigs Ann. Chem. 1989,
247–254; (b) Falorni, M.; Giacomelli, G.; Spanedda, A.
M. Tetrahedron: Asymmetry 1998, 9, 3039–3046; (c)
Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans.
1 2000, 2311–2316.
In summary, a short and efficient synthesis of new,
enantiomerically pure 5-substituted isoxazoles with dif-
ferent O-benzyl protection in the glycerol side chain has
7. Maeba, I.; Ito, Y.; Wakimura, M.; Ito, C. Heterocycles
been accomplished starting from
D-galactal and D-glu-
1993, 36, 1617–1623.
cal, respectively. This opens firm ground for further
functionalization of the hydroxy groups which should
lead to a variety of related derivatives. An X-ray crys-
tallographic structural analysis of mesylate 7 confirmed
the structural assignment of the new products, and the
8. For synthetic studies towards chiral glycerols, see: (a)
Giannis, A.; Mu¨nster, P.; Sandhoff, K.; Steglich, W.
Tetrahedron 1988, 44, 7177–7180; (b) Prasad, K.; Ester-
mann, H.; Chen, C.-P.; Repic, O.; Hardtmann, G. E.
Tetrahedron: Asymmetry 1990, 1, 421–424.
Scheme 3. Synthesis and X-ray structure of 7. Thermal ellipsoids are shown with 30% probability.

H.-G. Weinig et al. / Tetrahedron Letters 43 (2002) 4613–4615
4615
9. For a recent review, see: Koser, G. F. Aldrichim. Acta
2001, 34, 89–102.
(ddd, J=7/4/4 Hz, 1H, 2%-H); 4.42 (d, J=11 Hz, 1H,
Bn-H); 4.61 (d, J=11 Hz, 1H, Bn-H); 4.73 (d, J=7 Hz,
1H, 1%-H); 6.36 (d, J=2 Hz, 1H, 4-H); 7.26–7.39 (m, 5H,
aromat.-H); 8.26 (d, J=2 Hz, 1H, 3-H). 13C NMR (50.3
MHz, CDCl3): l 62.6 (C-3%); 72.1 (C-Bn); 73.1, 73.8
(C-1%,2%); 102.8 (C-4); 128.2, 128.3, 128.6, 136.6 (C-aro-
mat.); 150.2 (C-3); 168.9 (C-5).
Compound 5b: Yellow crystals. Mp 75°C (CHCl3).
[h]2D0=+100 (c 3.1, CHCl3). 1H NMR (200 MHz, CDCl3):
l 2.57 (bs, 1H, OH); 3.18 (bs, 1H, OH); 3.66 (dd, J=10/4
Hz, 1H, 3%-H); 3.70 (dd, J=10/4 Hz, 1H, 3%-H); 4.01 (dt,
J=6/4 Hz, 1H, 2%-H); 4.39 (d, J=11 Hz, 1H, Bn-H); 4.56
(d, J=11 Hz, 1H, Bn-H); 4.67 (d, J=6 Hz, 1H, 1%-H);
6.31 (d, J=2 Hz, 1H, 4-H); 7.24–7.38 (m, 5H, aromat.-
H); 8.22 (d, J=2 Hz, 1H, 3-H). 13C NMR (50.3 MHz,
CDCl3): l 62.9 (C-3%); 72.1 (C-Bn); 72.6, 74.5 (C-1%,2%);
102.8 (C-4); 128.0, 128.2, 128.6, 136.7 (C-aromat.); 150.2
(C-3); 169.5 (C-5).
10. The oxidation was performed following the procedure
described in Ref. 11 without aqueous work-up. Instead,
the solvent was evaporated at room temperature and the
crude product was immediately subjected to flash column
chromatography on silica gel. Analytical data of the
obtained products were in full accordance with that
reported.
11. Kirschning, A. J. Org. Chem. 1995, 60, 1228–1232.
12. Kirschning, A. Eur. J. Org. Chem. 1998, 2267–2274.
13. Greven, R.; Ju¨tten, P.; Scharf, H.-D. J. Org. Chem. 1993,
58, 3742–3747.
14. Mandal, A. K.; Soni, N. R.; Ratnam, K. R. Synthesis
1985, 274–275.
15. (a) Falck, J. R.; Barma, D. K.; Venkataraman, S. K.;
Baati, R.; Mioskowski, C. Tetrahedron Lett. 2002, 43,
963–966; (b) Falck, J. R.; Barma, D. K.; Baati, R.;
Mioskowski, C. Angew. Chem., Int. Ed. 2001, 40, 1281–
1283.
Compound 6: Colorless oil. [h]2D0=+10 (c 0.4, CHCl3). 1H
NMR (200 MHz, CDCl3): l 2.04 (bs, 2H, OH); 3.63 (dd,
J=10/5 Hz, 1H, 3%-H); 3.69 (dd, J=10/4 Hz, 1H, 3%-H);
4.10 (ddd, J=5/4/4 Hz, 1H, 2%-H); 4.57 (s, 2H, Bn-H);
4.97 (d, J=4 Hz, 1H, 1%-H); 6.31 (d, J=2 Hz, 1H, 4-H);
7.29–7.38 (m, 5H, aromat.-H); 8.20 (d, J=2 Hz, 1H,
3-H). 13C NMR (50.3 MHz, CDCl3): l 68.2 (C-3%); 71.2,
71.5 (C-1%,2%); 73.8 (C-Bn); 101.5 (C-4); 127.9, 128.1,
128.6, 137.2 (C-aromat.); 150.2 (C-3); 166.8 (C-5).
Compound 7: Colorless crystals. Mp 82°C (Et2O). [h]2D0=
16. Compound 4a: Colorless oil. [h]2D0=−66 (c 4.7, CHCl3).
1H NMR (200 MHz, CDCl3): l 2.55 (bs, 1H, OH); 3.40
(dd, J=10/5 Hz, 1H, 3%-H); 3.55 (dd, J=10/5 Hz, 1H,
3%-H); 4.08 (q, J=5 Hz, 1H, 2%-H); 4.42 (d, J=11 Hz, 1H,
Bn-H); 4.46–4.49 (m, 2H, Bn-H); 4.60 (d, J=11 Hz, 1H,
Bn-H); 4.80 (d, J=5 Hz, 1H, 1%-H); 6.29 (d, J=2 Hz, 1H,
4-H); 7.22–7.40 (m, 10H, aromat.-H); 8.22 (d, J=2 Hz,
1H, 3-H). 13C NMR (50.3 MHz, CDCl3): l 69.8 (C-3%);
72.0 (C-2%); 72.2, 73.4 (C-Bn); 73.6 (C-1%); 102.5 (C-4);
127.7, 128.1, 128.3, 128.4, 136.8, 137.6 (C-aromat.); 150.0
(C-3); 169.4 (C-5).
1
−7 (c 0.3, CHCl3). H NMR (200 MHz, CDCl3): l 2.92
(s, 3H, CH3); 3.54 (dd, J=11/5 Hz, 1H, 3%-H); 3.74 (dd,
J=11/3 Hz, 1H, 3%-H); 4.40 (d, J=12 Hz, 1H, Bn-H);
4.42 (d, J=12 Hz, 1H, Bn-H); 4.51 (d, J=12 Hz, 1H,
Bn-H); 4.58 (d, J=12 Hz, 1H, Bn-H); 4.97 (d, J=4 Hz,
1H, 1%-H); 5.00 (ddd, J=5/4/3 Hz, 1H, 2%-H); 6.36 (d,
J=2 Hz, 1H, 4-H); 7.22–7.37 (m, 10H, aromat.-H); 8.25
(d, J=2 Hz, 1H, 3-H). 13C NMR (50.3 MHz, CDCl3): l
38.4 (CH3); 68.5 (C-3%); 72.3 (C-1%); 72.4, 73.6 (C-Bn);
80.9 (C-2%); 103.7 (C-4); 127.8, 128.0, 128.1, 128.3, 128.5,
136.3, 137.1 (C-aromat.); 150.3 (C-3); 167.3 (C-5).
Compound 4b: Colorless oil. [h]2D0=+55 (c 4.6, CHCl3).
1H NMR (200 MHz, CDCl3): l 2.53 (bs, 1H, OH); 3.55
(dd, J=10/4 Hz, 1H, 3%-H); 3.63 (dd, J=10/5 Hz, 1H,
3%-H); 4.15 (ddd, J=7/5/4 Hz, 1H, 2%-H); 4.36 (d, J=12
Hz, 1H, Bn-H); 4.47–4.50 (m, 2H, Bn-H); 4.53 (d, J=12
Hz, 1H, Bn-H); 4.70 (d, J=7 Hz, 1H, 1%-H); 6.30 (d, J=2
Hz, 1H, 4-H); 7.20–7.36 (m, 10H, aromat.-H); 8.22 (d,
J=2 Hz, 1H, 3-H). 13C NMR (50.3 MHz, CDCl3): l 70.0
(C-3%); 71.6 (C-2%); 71.9, 73.4 (C-Bn); 73.6 (C-1%); 102.6
(C-4); 127.8, 128.0, 128.4, 136.9, 137.6 (C-aromat.); 150.1
(C-3); 169.6 (C-5).
17. Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 184268. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Compound 5a: Colorless waxy solid. [h]2D0=−119 (c 2.2,
CHCl3). 1H NMR (200 MHz, CDCl3): l 2.04 (t, J=6 Hz,
1H, 3%-OH); 2.91 (bs, 1H, 2%-OH); 3.49 (ddd, J=12/6/4
Hz, 1H, 3%-H); 3.66 (ddd, J=12/6/4 Hz, 1H, 3%-H); 3.97