R. G. Soengas / Tetrahedron Letters 51 (2010) 105–108
107
Supplementary data
R4
O
O
R4
O
CO2Et
OH
OR1
In
Supplementary data (specific experimental procedures and 1H
and 13C NMR spectra for 16a, 19a and 20a + 20b) associated with
this article can be found, in the online version, at doi:10.1016/
+
R3O
n OR1
THF
n
Br CO2Et
R3O
OR2
OR2
9-14
15-20
Scheme 2. Reaction of aldonolactones and ethyl a-bromoisobutyrate.
References and notes
bonyl group while other functional groups such as alkenes (entry
8) and acid-sensitive protecting groups like isopropylidene (entries
5–8 and 10), benzylidene ketals (entry 9) and silyl esters (entry 9)
remained unaltered.
1. Watterson, M. P.; Edwards, A. A.; Leach, J. A.; Smith, M. D.; Ichihara, O.; Fleet, G.
W. J. Tetrahedron Lett. 2003, 44, 5853–5857.
2. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680.
3. Long, D. D.; Smith, M. D.; Martin, A.; Wheatley, J. R.; Watkin, D. G.; Muller, M.;
Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2002, 1982–1998.
As far as the selectivity is concerned, excellent results were
achieved for lactones 10 and 13 (entries 6 and 9), which gave their
respective adducts 16a and 19a only, as established by NMR exper-
iments.17 Lactone 14 (entry 10) gave the anomeric mixture
20a + 20b, in which the major component was the thermodynam-
ically favoured anomer 20a, as determined by NMR experiments.18
Lactones 9, 11 and 12 (entries 5, 7 and 8) provided the anomeric
mixtures 15a + 15b, 17a + 17b and 18a + 19b, respectively. We as-
sumed that in these cases the major anomers were also the ther-
modynamically favoured anomers 15a, 17a and 18a. These
results are consistent with previous studies on the mechanism of
Reformatsky reactions on aldonolactones, which showed that the
predominant anomer is always the thermodynamically more sta-
ble anomer.4a,c,e,f This finding is due either to the substituents at
position C-2 acting as directing groups during the addition or to
subsequent anomerization to the thermodynamically more stable
anomer.
4. (a) Csuk, R.; Glänzer, B. I. J. Carbohydr. Chem. 1990, 9, 797–807; (b) Grassberger,
V.; Berger, A.; Dax, K.; Fechter, M.; Gradnig, G.; Stütz, A. E. Liebigs Ann. Chem.
1993, 379–390; (c) Hanessian, S.; Giraud, C. Synlett 1994, 865–867; (d) Orsini,
F.; di Teodoro, E. Tetrahedron: Asymmetry 2003, 14, 2521–2528; (e) Csuk, R.;
Franke, U.; Hu, Z.; Krieger, C. Tetrahedron 2003, 59, 7887–7895; (f) Cuenca, A.
B.; D’Hooge, F.; Gouge, V.; Castelot-Deliencourt, G.; Oulyadi, H.; Leclerc, E.;
Jubault, P.; Pannecoucke, X.; Quirion, J.-C. Synlett 2005, 17, 2627–2630.
5. Araki, S.; Ito, H.; Katsumura, N.; Butsugan, Y. J. Organomet. Chem. 1989, 369,
291–296.
6. (a) Cintas, P. Synlett 1995, 1087–1096; (b) Podlech, J.; Maier, T. C. Synthesis
2003, 633; (c) Nair, V.; Ros, R.; Jayan, C. N.; Pillai, B. Tetrahedron 2004, 60, 1959–
1982; (d) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org. Chem. 2005, 70,
10408–10419.
7. (a) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. J. Org. Chem. 1993, 58,
5500–5507; (b) Chan, T. H.; Isaac, M. B. Pure Appl. Chem. 1996, 68, 919–924; (c)
Canac, Y.; Levoirier, E.; Lubineau, A. J. Org. Chem. 2001, 66, 3206–3210; (d)
Levoirier, E.; Canac, Y.; Norsikian, S.; Lubineau, A. Carbohydr. Res. 2004, 339,
2737–2747; (e) Balla, E.; Zamyatina, A.; Hofinger, A.; Kosma, P. Carbohydr. Res.
2007, 342, 2537–2545; (f) Alcaide, B.; Almendros, P.; Rodríguez-Acebes, R. J.
Org. Chem. 2002, 67, 1925–1928; (g) Chan, t.; Hang, L.; Chao, J. J. Chem. Soc.,
Chem. Commun. 1992, 747–748.
In summary, we have developed a new method for the homol-
ogation of lactones. This approach consists of an indium-mediated
Reformatsky reaction of aldonolactones with a-bromoisobutyrate.
8. Typical procedure: To a suspension of indium powder (0.5 mmol) and ethyl a-
bromobutyrate (0.75 mmol) in THF (1 mL) was added the corresponding lactone
(0.5 mmol) and the mixture was sonicated for 6 h. The reaction mixture was
quenched with saturated aqueous sodium hydrogen carbonate (10 mL) and
extracted with ether (3 ꢀ 25 mL). The combined organic layers were dried over
magnesium sulphate, filtered and evaporated in vacuo. The residue was purified
by flash column chromatography in mixtures of ethyl acetate/hexane to obtain
the compounds shown in Tables 1 and 2. All the compounds were fully
characterized and gave correct high resolution mass spectra. Representative
example: ethyl 5,8-anhydro-2-deoxy-4,5:7,8-di-O-isopropyliden-2,2-dimethyl-
The preliminary results reported here suggest that the process is
simpler than previous procedures, which require special reagents,
inert conditions and high temperatures. In fact, the milder chemo-
selective conditions reported here allowed several 2-deoxy-2,20-di-
methyl-3-ulosonates to be obtained with remarkably high levels of
stereoselectivity.
These novel branched-chain sugars constitute a new family of
ulosonic acids, which are important carbohydrate constituents of
cellular and bacterial membranes and are involved in several bio-
logical functions.19 Hence, the 3-ulosonic acid analogues reported
should be of interest not only as synthetic intermediates for the
preparation of a wide range of branched carbohydrate derivatives
but also as potential inhibitors in the biosynthesis of membrane
lipopolysaccharides in bacteria.
a
,b-D-gluco-3,6-furanoso-3-octulosonate: purification of the crude material by
flash column chromatography (ethyl acetate/hexane 1:2) afforded a single
anomer (16a) (0.10 g, 62%) as a clear oil. ½a D29
ꢁ
ꢂ6.2 (c 1.2 in CHCl3). 1H NMR
(CDCl3, ppm): 1.26 (t, 3H, J = 4.3 Hz, –OCH2CH3); 1.25, 1.29, 1.31 (3 ꢀ s, 12H,
4 ꢀ CH3); 3.33 (d, 1H, –OH); 4.17 (dd, 2H, J = 4.3 Hz, –OCH2CH3); 4.51 (d, 1H,
J = 2.9 Hz, H-5); 4.65 (d, 1H, J = 2.1 Hz, H-7); 4.79–4.81 (m, 1H, H-6); 5.38 (s, 1H,
H-4); 6.03 (d, 1H, J = 2.1 Hz, H-8). 13C NMR (CDCl3, ppm): 14.11 (–OCH2CH3);
20.05, 22.03, 27.22, 27.69 (4 ꢀ CH3); 48.55, 49.65 (C-2); 61.71 (–OCH2CH3);
72.49, 81.80, 83.22, 86.70 (C-4, C-5, C-6, C-7); 105.36 (C-3), 107.37 (C-8), 113.19
(–C(CH3)2); 177.84 (C@O). MS (ESI, m/z %): 239.13 (24, [M+Na]+); 199.13 (54,
[MꢂH2O+H]+). HRMS for C11H20O4Na ([M+Na]+) calculated 239.1253. Found:
239.1250.
9. Similarly to previous studies on indium-mediated Reformatsky reactions, it is
reasonable to postulate that the ulosonic acids are formed by nucleophilic
addition of indium sesquihalide (EtO2C(CH3)2C)3In2Br3 to the lactone. Tussa, L.;
Lebreton, C.; Mosset, P. Chem Eur. J. 1997, 3, 1064–1070.
Evaluation of the biological activity of the unprotected adducts
15–20 is currently in progress.
Work is also in progress aimed at extending this promising in-
dium-mediated Reformatsky reaction to other bromoesters. The
aim of these studies is to gain access to a pannel of lactone-adducts
to be converted into biologically active branched-chain imino sug-
ars and novel biopolymers based on branched-chain heterocyclic
amino acids.
10. Pommier, A.; Pons, J.-M. Synthesis 1993, 441–459.
11. Luzzio, F. A.. In The Oxidation of Alcohols by Modified Oxochromium(IV)-Amine
Reagents, Organic Reactions; Hoboken: N.J., United States, 1998; Vol. 53.
12. Bayshal, B. P.; Hak Fun, C.; Fellows, L. E.; Fleet, G. W. J. Tetrahedron 1987, 43,
415–422.
13. Banda, G.; Chakravarthy, I. E. Tetrahedron: Asymm. 2006, 17, 1684–1687.
14. Lefeber, D. J.; Steunenberg, P.; Vliengenthart, J. F. G.; Kamerling, J. P.
Tetrahedron: Asymmetry 2005, 16, 507–511.
15. Obtained from selective deprotection of the primary hydroxyl group by
treatment with PPTS in EtOH at 50 °C of the corresponding 5-O-(1-methoxy-1-
methyl-ethoxymetyl) derivative, prepared as described in the literature:
Hanessian, S.; Stephane, M.; Machaalani, R.; Huang, G.; Pierron, J.; Loiseleur,
O. Tetrahedron 2006, 62, 5201–5214.
16. (a) Chiara, J. L.; Cabri, W.; Hanessian, S. Tetrahedron. Lett. 1991, 32, 1125–1128;
(b) Hanessian, S.; Girard, C.; Chiara, J. L. Tetrahedron. Lett. 1992, 33, 573–576;
(c) Girard, C.; Hanessian, S. Synlett 1994, 861–862; (d) Girard, C.; Hanessian, S.
Synlett 1994, 863–864.
Acknowledgments
Financial support from the Spanish Ministry of Science and
Innovation (CTQ2008-06493) and the Xunta de Galicia (Isidro Par-
ga Pondal program) is gratefully acknowledged. I would like to
thank Professors R. J. Estévez, J. C. Estévez and L. Sarandeses for
helpful discussions.