Indium-mediated Reformatsky reaction on lactones: preparation of 2-deoxy-2,2′-dimethyl-3-ulosonic acids

Article abstract of DOI:10.1016/j.tetlet.2009.10.092

Indium-mediated Reformatsky reactions of simple lactones and aldonolactones with ethyl α-bromoisobutyrate allow the synthesis of the corresponding ketals and ulosonic acid esters, respectively, in good yields.

Full text of DOI:10.1016/j.tetlet.2009.10.092

Tetrahedron Letters 51 (2010) 105–108
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium-mediated Reformatsky reaction on lactones: preparation
of 2-deoxy-2,20-dimethyl-3-ulosonic acids
*
Raquel G. Soengas
Departamento de Química Fundamental, Universidade de A Coruña, 15031 A Coruña, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Indium-mediated Reformatsky reactions of simple lactones and aldonolactones with ethyl
sobutyrate allow the synthesis of the corresponding ketals and ulosonic acid esters, respectively, in good
yields.
a-bromoi-
Received 15 September 2009
Revised 16 October 2009
Accepted 19 October 2009
Available online 23 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium
Reformatsky reaction
Sugar lactones
Ulosonic acids
Carbohydrates have been widely used as starting materials for
the synthesis of important small biological molecules and for
new biopolymeric materials. In particular, sugar lactones provide
short syntheses of novel nucleosides,1 imino sugars2 and sugar-de-
rived amino acids.3 All these targets have unbranched carbon
chains, but recent results have indicated that all three classes of
such carbon-branched materials give rise to promising biologically
active compounds and novel biopolymers. In particular, alkyl-
branched sugars could be of great biological interest because the
presence of a highly lipophilic region in their sugar skeleton could
modify the binding to certain enzymes and thus alter their biolog-
ical activity.
Some previous work on the Reformatsky reaction of simple and
sugar lactones has been reported.4 However, these reactions
proved to be experimentally complex, were subjected to functional
group incompatibilites and in some cases only low yields and low
regio- and/or stereoselectivity levels were achieved. On the other
hand, it has been reported that indium5 efficiently promotes Refor-
matsky reactions on aldehydes and ketones.6 Moreover, it is well
known that indium can promote C–C formation reactions in sub-
strates with free hydroxyl groups aqueous media and is therefore
a suitable reagent in synthetic carbohydrate chemistry because it
avoids the tedious processes required for protection of hydroxy
groups in classical carbohydrate chemistry, thus simplifying syn-
thetic applications of carbohydrates that involve organometallic
reagents.7
As a contribution to this field, we report here preliminary re-
sults on a highly efficient indium-mediated Reformatsky reaction
between aldonolactones and ethyl
a-bromoisobutyrate. This re-
agent was selected with the aim to open novel opportunities for
the access to branched-chain sugars, a class of carbohydrates of
great current interest.
We first studied the case of commercially available five-mem-
bered lactone 2. Sonication of mixtures of this compound, indium
powder8 and ethyl
a-bromoisobutyrate in DMF and in THF (Ta-
ble 1) at room temperature for 6 h allowed the racemic mixture
of compound 6 to be obtained in 90% and 95% yield, respectively.9
But when MeOH/H2O 1:4 and THF/H2O 1:1 were the solvents, the
starting material remained practically unaltered after 12 h
(Scheme 1).
Further similar studies with commercially available four-, six-
and seven-membered lactones 1, 3 and 4 (Table 1) carried out in
THF for experimental simplicity provided the expected racemic ad-
ducts 5 (88% yield), 7 (82% yield) and 8 (92% yield), respectively.
Good to excellent results were achieved and of particular inter-
est is the 88% yield obtained for compound 1 (entry 1), because to
date only cuprates10 and samarium enolates4c have allowed four-
membered lactone 1 to be transformed into adduct 5 and even
then only in moderate and low yields, respectively.
Encouraged by these excellent results we decided to extend the
study to the five- and six-membered sugar lactones 911, 1012, 11,
1213, 1314 and 1415, which provided the expected adducts 15–20,
respectively, in moderate to good yield (see Table 2) (Scheme 2).
* Tel.: +34 981167000x2207.
E-mail address: rsoengas@udc.es
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.092

106
R. G. Soengas / Tetrahedron Letters 51 (2010) 105–108
Table 1
O
Indium-mediated Reformatsky-type reaction between simple lactones and ethyl
bromoisobutyrate
a-
CO2Et
n OH
In
THF
O
O
+
n
Br CO2Et
R
Entry
Lactone
Reaction with BrC(CH)2CO2Eta
Yieldb (%)
R
1: n=1, R=CH3
2: n=2, R=H
3: n=3, R=H
4: n=4, R=H
5: n=1, R=CH3
6: n=2, R=H
7: n=3, R=H
8: n=4, R=H
O
O
CO2Et
OH
1
88
O
1
5
Scheme 1. Reaction of simple lactones and ethyl a-bromoisobutyrate.
O
O
O
O
O
O
CO2Et
2
3
95
82
OH
2
The indium-mediated procedure described here has some clear
advantages over previous Reformatsky additions to sugar lactones.
For example, as shown in entries 6 and 10, the reaction can be car-
ried out on lactones bearing free hydroxyl groups. Moreover, prob-
ably due to the ability of SmI2 to promote deoxygenation at the C-2
position of sugar lactones,16 the previously reported SmI2-medi-
ated Reformatsky reactions on aldonolactones were mostly carried
out on 2-deoxygenated substrates. However, our indium procedure
overcomes this limitation as it is compatible with the presence of
hydroxy and alkoxy substituents at position C-2 of sugar lactones.
Another interesting feature of the indium-mediated procedure
is the remarkable chemoselectivity and the mild conditions re-
quired. In fact, ethyl isobutyrate readily added to the lactone car-
6
CO2Et
OH
3
7
O
O
CO2Et
OH
O
4
92
4
8
a
All reactions conducted according to Ref. 9.
Yields of isolated products.
b
Table 2
Indium-mediated Reformatsky-type reaction between sugar lactones and ethyl
a
-bromoisoburyrate
Entry
Lactone
Reaction with BrC(CH)2CO2Eta
Yieldb (%)
Ratio a
:bc
O
O
O
O
O
O
O
O
CO2Et
O
CO2Et
O
+
OH
OH
5
87
80:20
O
O
O
O
O
O
O
15a
15b
9
O
O
O
O
O
O
CO2Et
OH
OH
+
6
7
62
78
100:0
60:40
O
O
OH
10
16b
O
O
O
O
CO2Et
CO2Et
OH
OH
+
O
O
O
O
O
O
O
O
11
17a
17b
O
O
O
CO2Et
CO2Et
OH
OH
+
8
62
52
72
85:15
100:0
85:15
O
O
O
O
O
18a
18b
12
O
O
O
CO2Et
OH
OTBS
+
O
OTBS
9
O
O
O
Ph
13
Ph
19b
O
O
O
HO
CO2Et
HO
OH
+
O
O
10
O
O
14
20b
a
b
c
All reactions conducted according to Ref. 9.
Yields of isolated products.
Determined by NMR.

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/
j.tetlet.2009.10.092.
+
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.

108
R. G. Soengas / Tetrahedron Letters 51 (2010) 105–108
17. Compound 16a: NOE between H-4 and the CH3 in C-2 and between H-4 and the
ethyl group. Compound 19a: NOE between H-4/H-5 and the CH3 in C-2 and
between H-4/H-5 and the ethyl group.
OH
CO2Et
OH
O
CO2Et
O
O
H
O
16a
O
H
OTBS
O
HO
O
19. (a) Ogura, H.; Hosegawa, A.; Suami, T. Carbohydrates, Synthetic Methods and
Applications in Medicinal Chemistry; VCH: Cambridge, Basel, 1992; (b) Unger, F.
M. Adv. Carbohydr. Chem. Biochem. 1981, 38, 323–388; (c) Schauer, R. Adv.
Carbohydr. Chem. Biochem. 1982, 40, 131–234.
19a
Ph
18. Compound 20a: NOE between H-4 and the CH3 in C-2 and between H-4 and the
ethyl group.