Simple and efficient synthesis of steroidal hybrids of estrogen and vitamin D3

Article abstract of DOI:10.1080/00397910802369620

A simple and efficient synthesis of steroidal hybrids of estrogen and vitamin D3 through modification of estrone (5) at position 16 of the steroid nucleus is described. Copyright Taylor & Francis Group, LLC.

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Simple and Efficient Synthesis
of Steroidal Hybrids of Estrogen
and Vitamin D3
Atul Gupta a , Rachid Gueddah a & Gervais Bérubé a
a Groupe de Recherche en Biopathologies Cellulaires
et Moléculaires, Département de Chimie-Biologie,
Université du Québec à Trois-Rivières, Trois-Rivières,
Québec, Canada
Published online: 15 Feb 2011.
To cite this article: Atul Gupta , Rachid Gueddah & Gervais Brub (2008) Simple
and Efficient Synthesis of Steroidal Hybrids of Estrogen and Vitamin D3 , Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:1, 61-69, DOI: 10.1080/00397910802369620
To link to this article: http://dx.doi.org/10.1080/00397910802369620
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Synthetic Communications1, 39: 61–69, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369620
Simple and Efficient Synthesis of Steroidal
Hybrids of Estrogen and Vitamin D3
´
´
Atul Gupta, Rachid Gueddah, and Gervais Berube
´
Groupe de Recherche en Biopathologies Cellulaires et Moleculaires,
´
´
´
`
`
Departement de ChimieꢀBiologie, Universite du Quebec a Trois-Rivieres,
`
Trois-Rivieres, Quebec, Canada
´
Abstract: A simple and efficient synthesis of steroidal hybrids of estrogen and
vitamin D3 through modification of estrone (5) at position 16 of the steroid
nucleus is described.
Estrogens, mainly estradiol (1) and vitamin-D3 (2), are the hormones
involved in the maintenance of bones (Fig. 1).[1] In the body, both of
these hormones are synthesized from the same starting material, choles-
terol (3), in a multistep synthesis. Structurally, estradiol (1) has a tetra-
cyclic rigid system with two hydroxyl groups placed at definite
distance, required for its biological activity, whereas vitamin D3 (2) has
a highly flexible triene system (9,10-seco-steroid or b-ring seco-steroid).[2]
In addition to this, vitamin D3 has a flexible side chain with
1,25a-hydroxy groups required for its calcemic and antiproliferative
activity.[3–7] In our search for bone-selective, antiproliferative agents for
treatment of osteoporosis and breast cancer, we designed and synthesized
steroidal hybrids of estrogen and vitamin D3 of type 4 (Fig. 1). The target
compounds (see structure 4, R ¼ CH3 or R ¼ CH2CH3) were made
through modifications of estrone (5) at position 16 to which a side chain
Received May 5, 2008.
Address correspondence to Gervais Berube, Groupe de Recherche en
´
Biopathologies Cellulaires et Moleculaires, Departement de Chimie-Biologie,
´
´
Universite du Quebec a Trois-Rivieres, C. P. 500, Trois-Rivieres, Quebec, Canada
´
´
G9A 5H7. E-mail: Gervais.Berube@uqtr.ca
´
`
`
`
61

´ ´
A. Gupta, R. Gueddah, and G. Berube
62
Figure 1. Biologically active steroidal molecules.
was incorporated as present in the vitamin D3 (2) and its synthetic
analogs as well as the tetracyclic core of estradiol (1) itself.
This communication presents a simple and efficient synthesis of
steroidal hybrids of estrogen and vitamin-D3 (4). The synthesis of the final
compound (4) started from estrone (5) (Scheme 1). Estrone (5) was pro-
tected using dihydropyran in dichloromethane at room temperature (Rt),
yielding 3-tetrahydropyranyloxy estrone (6) in 100% yield. Compound 6
was activated at position 16 through formation of b-ketoester (7).
Compound 7 was obtained by reaction of 6 with dimethyl carbonate in
the presence of potassium hydride (KH) in dry THF at reflux tempera-
ture in 90% yield. Alkylation of compound 7 with ethyl 4-iodobutyrate,
prepared from ethyl 4-bromobutyrate, in biphasic medium using 10%
aqueous solution of sodium hydroxide and dichloromethane and in the
presence of benzyltriethylammonium chloride [Bn(Et)3NþClꢀ, phase-
transfer catalyst (PTC)] gave compound 8 in 64% yield. It is noteworthy
that the alkylation of compound 7 with ethyl 4-bromobutyrate to pro-
duce 8 under PTC reaction conditions was inefficient, so the correspond-
ing ethyl 4-iodobutyrate ester was used instead. Decarboalkoxylation of
compound 8 with lithium chloride in N,N-dimethylformamide at reflux
temperature for 22 h gave compound 9 in 75% yield. Esterification of
compound 9 with thionyl chloride in methanol at reflux temperature gave
10 in 95% yield. Grignard reaction was done on compound 10
using methyl and ethyl magnesium bromide in a dry diethyl ether–THF

Steroidal Hybrids of Estrogen and Vitamin D3
63
Scheme 1. (a) Dihydropyran, pyridinium p-toluenesulphonate, DCM, 22 ꢁC;
(b) dimethyl carbonate, KH, dry THF, reflux; (c) ethyl 4-iodobutyrate,
Bn(Et)3NþClꢀ, 10% NaOH, DCM, reflux; (d) LiCl, DMF, reflux; (e) thionyl
chloride, CH3OH, reflux; (f) CH3MgBr or CH3CH2MgBr, dry Et2O-THF, 22 ꢁC.
mixture, which gave the target compounds 11a–c in 48–70% yields. The
Grignard reaction with methyl magnesium bromide on compound 10
gave a separable mixture of 16-a and b-alkyl substituted compounds
(11a and 11b) with b-orientation of the 17-hydroxy group. On a thin-
layer chromatogram, the retention factors for 16-a and 16-b isomer in
30% acetone–hexane solvent system are 0.16 and 0.11 respectively. The
16-b isomer (compound 11b) was the major product in this case, whereas
the Grignard reaction with ethyl magnesium bromide yielded mainly the
16-b isomer (compound 11c), which was the sole isolated product and has
1
a 0.19 retention factor in 30% acetone–hexane solvent system. In H
NMR spectra, the 16-a (11a) and 16-b isomers (11b) showed singlets at

´ ´
A. Gupta, R. Gueddah, and G. Berube
64
0.94 ppm and 0.84 ppm respectively for the 18-CH3 group, whereas in 13
C
NMR, these isomers showed signals at 13.8 ppm and 14.9 ppm for 18-
CH3 in 16-a and 16-b isomers, respectively. It is reported in the literature
that 16a-alkyl substituted estradiol derivatives showed signals for 18-CH3
group at higher ppm values in 1H NMR spectra and at lowers ppm values
in 13C NMR spectra as compared to the corresponding 16-b isomer.[11]
We assigned the stereochemistry of these novel compounds on the basis
of observed similarities between our results and the reported data.
EXPERIMENTAL
Anhydrous reactions were performed under an inert atmosphere, with
the setup assembled and cooled under dry nitrogen. Unless otherwise
noted, starting material, reactant, and solvents were obtained commer-
cially and were used as such or purified and dried by standard means.[8]
Organic solutions were dried over magnesium sulfate (MgSO4) and
evaporated on a rotatory evaporator under reduced pressure. All reac-
tions were monitored by UV fluorescence or stained with iodine. Com-
mercial thin-layer chromatography (TLC) plates were Sigma T 6145
˚
(polyester silica gel 60 A, 0.25 mm). Flash chromatography was per-
formed according to the method of Still and coworkers on Merck
grade 60 silica gel, 230–400 mesh.[9] All solvents used in chromatogra-
phy had been distilled. Melting points (MP) were recorded in open
capillaries on an Electrothermal apparatus and are uncorrected. The
infrared spectra (IR) were taken on a Nicolet model 205 FT-IR spec-
trophotometer. Nuclear magnetic resonance (NMR) spectra were
obtained in a CDCl3 solution (unless otherwise noted), on a Varian
200-MHz instrument: chemical shifts were measured relative to the
internal standard, tetramethylsilane (TMS, d 0 ppm), for 1H NMR.
Chemical shifts (d) are expressed in parts per million (ppm); the cou-
pling constants (J) are expressed in hertz (Hz). Multiplicities are
described by the following abbreviations: s for singlet, d for doublet,
dd for double of doublet, t for triplet, q for quartet, m for multiplet,
#m for several multiplets, and bs for broad singlet.
Synthesis of 3-Tetrahydropyranyloxy-1,3,5(10)-estratrien-17-one (6)[10]
To a solution of estrone 5 (5.00 g, 18.62 mmol) in dichloromethane
(50 mL), dihydropyran (5.1 mL, 55.85 mmol) and pyridinium
p-toluenesulfonate (100 mg) were added. The reaction mixture was stirred
at 23 ꢁC for 18 h. Afterward, sodium bicarbonate (NaHCO3, 500 mg) and

Steroidal Hybrids of Estrogen and Vitamin D3
65
MgSO4 (5.0 g) were added to the reaction mixture and stirred 15 min
before being filtered on a short pad of Celite1 silica gel (1 cm=4 cm) using
dichloromethane (DCM) as the eluent. The filtrate was evaporated to a
viscous oil (100% yield), which was used without further purification in
the next step.
1
IR (KBr, nmax, cmꢀ1): 1742. H NMR (200 MHz, CDCl3, d ppm):
7.19 (d, J ¼ 8.50 Hz, 1H, ArH), 6.90–6.76 (2H, m, ArH), 5.39 (t,
J ¼ 3.50 Hz, 1H, CH2), 3.90–3.58 (m, 2H, CH), 2.88 (m, 2H, CH2),
2.60–1.30 (#m, 19H, 3 ꢂ CH and 8 ꢂ CH2), 0.90 (3H, s, CH3). 13C
NMR (50 MHz, CDCl3, d ppm): 220.9, 155.3, 137.9, 133.2, 126.4,
116.8, 114.4, 96.6, 62.2, 50.7 48.2, 44.3, 38.6, 36.1, 31.8, 30.7, 29.8,
26.8, 26.1, 25.5, 21.8, 19.0, 14.1.
Synthesis of 3-Tetrahydropyranyloxy-16a,b-methoxycarbonyl-1,3,5(10)-
estratrien-17-one (7)[10]
A solution of 3-tetrahydropyranyloxy-1,3,5(10)-estratrien-17-one (6)
(6.58 g, 18.20 mmol) in dry THF (50 mL) was added over a period of
20 min to a solution of dimethylcarbonate (3.98 mL, 47.2 mmol) and
potassium hydride [2.27 g (3.6 g, 70% in oil), 56.68 mmol] in dry THF
(40 mL). The mixture was heated to reflux for a period of 3 h. Most of
the solvent was then evaporated, and the residue was diluted with ethyl
acetate (100 mL) and treated with a saturated ammonium chloride solu-
tion (50 mL). The organic phase was washed with water (6 ꢂ 40 mL),
dried, and evaporated to give a yellowish solid. Trituration of the residue
with a mixture of acetone–hexanes (1:1) yielded the title compound in
90% yield as a white solid.
1
IR (NaCl, nmax, cmꢀ1): 1755, 1728; H NMR (200 MHz, CDCl3,
d ppm): 7.19 (d, J ¼ 8.5 Hz, 1H, ArH), 6.90–6.76 (m, 2H, ArH), 5.39 (t,
J ¼ 3.50 Hz, 1H, CH), 3.90–3.58 (m, 2H, CH2), 3.76 (s, 3H, CH3), 3.21
(t, J ¼ 8.6 Hz, 1H, CH), 2.88 (m, 2H, CH2), 2.50–1.20 (#m, 19H,
3 ꢂ CH and 8 ꢂ CH2), 0.98 (s, 3H, CH3). 13C-NMR (50 MHz, CDCl3,
d ppm): 212.4, 170.1, 155.3, 137.8, 132.9, 126.5, 116.7, 114.3, 96.5, 62.2,
54.3, 52.8, 49.2, 48.1, 44.3, 38.1, 32.2, 30.6, 29.8, 26.8, 26.6, 26.0, 25.5,
19.0, 14.6.
Synthesis of Ethyl 4-Iodobutyrate
Sodium iodide (0.58 g, 3.85 mmol) was added to a solution of ethyl
4-bromobutanoate (0.50 g, 2.56 mmol) in dry acetone (7 mL). The reac-
tion mixture was stirred at an ambient temperature of 22 ꢁC for 19 h in
an inert atmosphere of nitrogen. Then, acetone was evaporated, and

´ ´
A. Gupta, R. Gueddah, and G. Berube
66
the residue was taken in the diethyl ether (50 mL) and washed with a
solution of thiosulfate (5% w=v, 2 ꢂ 20 mL) and 3 ꢂ 20 mL of water.
The organic phase was separated dried over anhydrous MgSO4 and
concentrated to give desired compound as brown oil (0.60 g) in 100% yield.
The product has been used without any purification in the next step.
IR (nmax, cmꢀ1): 1731, 1200, 1164; 1NMR (200 MHz, CDCl3, d ppm):
4.15 (q, J ¼ 7.20 Hz, 2H, CH2), 3.20 (t, J ¼ 6.60 Hz, 2H, CH2), 2.40 (t,
J ¼ 7.00 Hz, 2H, CH2), 2.08 (q, J ¼ 7.10 Hz, 2H, CH2), 1.19 (t, J ¼ 7.20 Hz,
Hz, 3H, CH3). 13C-NMR (50 MHz, CDCl3, d ppm): 172.4, 60.7, 35.0, 28.7,
14.4, 5.80.
Synthesis of 3-Tetrahydropyranyloxy-16b-(methoxycarbonyl)-16a-
(4-ethoxycarbonylbutyl)-1,3,5(10)-estratrien-17-one (8)
A solution containing compound 7 (0.28 g, 0.67 mmol), the 4-ethyl iodo-
butyrate (0.65 g, 1.67 mmol), benzyltriethylammonium chloride (100 mg)
and sodium hydroxide to 10% w=v (4 mL), 6 mL of dichloromethane was
stirred vigorously and heated at reflux for 20 h. The reaction mixture was
diluted with ether (10 mL) and extracted with a saturated solution of
ammonium chloride (2 ꢂ 20 mL), and with water (4 ꢂ 10 mL). The
organic phase was filtered, evaporated, and dried. The crude was purified
by flash column chromatography with a mixture of hexane–acetone
(8.5:1.5) to give the desired product 8 in 64% yield.
IR (nmax, cmꢀ1): 1727, 1717, 1600, 1031; 1H NMR (200 Hz, CDCl3, d
ppm): 7.16 (d, J ¼ 8.60 Hz, 1H, ArH), 6.86–6.78 (m, 2H, ArH), 5.39–5.37
(bs, 1H, CH), 4.14 (q, 2H, CH2), 3.96–3.84 (m, 1H, CH), 3.71 (s, 3H,
OCH3), 3.65–3.52 (m, 1H, CH), 2.89–2.85 (m, 2H, CH2), 2.33–2.6 (m,
4H, CH2), 2.08–1.79 (#m, 9H, 3CH and 3CH2), 1.79–1.36 (#m, 13H,
CH and numbers of CH2), 0.92 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3,
d ppm): 213.9, 173.2, 171.7, 155.3, 137.8, 132.9, 126.4, 116.7, 114.3, 96.5,
62.1, 60.6, 60.2, 52.9, 49.7, 46.3, 44.3, 38.1, 34.9, 34.4, 32.3, 30.7, 30.6,
29.8, 26.7, 25.9, 25.5, 21.1, 19.0, 14.5.
Synthesis of 3-Hydroxy-16a,b-(4-carboxylbutyl)-1,3,5(10)-estratrien-
17-one (9)
Estrone derivative 8 (0.20 g, 0.33 mmol), lithium chloride (0.31 g,
7.37 mmol), and water (0.4 mL) were dissolved in N,N-dimethylforma-
mide (2 mL) and refluxed for 22 h. On the completion of reaction,
the mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with a solution of hydrochloric

Steroidal Hybrids of Estrogen and Vitamin D3
67
acid 10% v=v and water. After filtration, the organic phase was dried
and evaporated. The resulting product was purified by flash chromato-
graphy with a mixture of hexane solvents–acetone (85: 15), which gave
compound 9 in 75% yield.
Mp 206–08 ꢁC; IR (NaCl, nmax, cmꢀ1): 3200–3600, 1711, 1604, 1231,
1
1021; H NMR (200 Hz, CDCl3, d ppm): 11.20 (s, 1H, OH). 7.20 (d,
J ¼ 8.70 Hz, 1H, ArH), 6.89 (dd, J ¼ 2.60 Hz and J ¼ 8.70 Hz, 1H,
ArH), 6.69 (d, J ¼ 2.00 Hz, 1H, ArH), 5.20 (s, 1H, OH), 2.88–2.83 (m,
2H, CH2), 2.40–1.20 (#m, 23H, 1 ꢂ CH3, 4 ꢂ CH and 8 ꢂ CH2), 0.98
(s, 3H, 18-CH3). 13C-NMR (50 MHz, CDCl3 and DMSO-d6, d ppm):
222.8, 222.3, 176.3, 176.2, 155.0, 137.9, 131.0, 126.4, 115.6, 113.3, 49.3,
49.1, 48.8, 48.6, 48.4, 44.9, 44.3, 44.1, 38.5, 38.2, 34.2, 32.1, 30.6, 29.7,
28.7, 27.5, 26.9, 26.7, 26.0, 23.7, 14.8, 14.2.
Synthesis of 3-Hydroxy-16a,b-(4-methyloxycarbonylbutyl)-1,3,5(10)-
estratrien-17-one (10)
Thionyl chloride (0.23 mL) was added drop by drop to a solution of acid
9 (0.20 g 0.56 mmol) in dry methanol at 0 ꢁC. The ice bath was removed
after complete addition, and the mixture was refluxed for 4 h. The solvent
was evaporated, and residue was taken in the ether (15 mL) and washed
with water (3 ꢂ 5 mL). The organic layer was separated, dried over anhy-
drous MgSO4, and concentrated. The crude was purified by flash
chromatography using a mixture of hexane–acetone (95:5), yielding
compound 10 in 95% yield.
MP 144–46 ꢁC; IR (NaCl, nmax, cmꢀ1): 3200–3600, 1711, 1604, 1231,
1021; 1H NMR (200 Hz, CDCl3, d ppm): 7.18 (d, J ¼ 8.70 Hz, 1H, ArH),
6.91 (dd, J ¼ 2.60 Hz and J ¼ 8.70 Hz, 1H, ArH), 6.69 (d, J ¼ 2.00 Hz, 1H,
ArH), 5.10 (s, 1H, OH), 3.67 (s, 3H, CH3), 2.88–2.83 (m, 2H, CH2), 2.40–
1.20 (#m, 23H, 4 ꢂ CH and 8 ꢂ CH2), 0.98 (s, 3H, CH3). 13C-NMR
(50 MHz, CDCl3, d ppm): 223.5, 222.9, 174.6, 174.5, 154.3, 138.1, 131.8,
126.5, 115.6, 113.2, 52.0, 49.4, 49.1, 50.0, 48.8, 48.5, 44.9, 44.3, 44.1,
38.5, 38.2, 34.2, 34.1, 32.1, 31.9, 31.2, 30.7, 29.7, 28.7, 27.5, 26.9, 26.7,
26.1, 23.7, 14.9, 14.2.
Synthesis of 16a-(4-Hydroxy-4-methylpentyl)-17a-methyl-1,3,5(10)-
estratrien-3,17b-diol (11a) and 16b-(4-Hydroxy-4-methylpentyl)-
17a-methyl-1,3,5(10)-estratrien-3,17b-diol (11b)
To a solution of methyl magnesium bromide (3.00 molar solution in
Et2O, 5.61 mL, 15.14 mmol), a solution of methyl ester (10) (0.18 g,

´ ´
A. Gupta, R. Gueddah, and G. Berube
68
0.50 mmol) dissolved in anhydrous THF was added drop by drop at
room temperature (Rt). The reaction mixture was stirred for 3 h. On
the completion of reaction, the mixture was quenched with a saturated
solution of ammonium chloride and extracted with ethyl acetate. The
organic phase was dried and concentrated to crude product. The purifica-
tion of the crude product was carried out on a silica-gel column using
a mixture of hexane–acetone (75:25) as the eluent, which gave pure
compound 11a (22% yield) and 11b (48% yield) as white solids.
Spectral data for 11a: MP 122–24 ꢁC; IR (nmax, cmꢀ1): 3350, 1507,
1
1456, 1240, 1157, 1089, 758; H NMR (200 Hz, acetone, d ppm): 7.93
(bs, 1H, OH), 7.08 (d, J ¼ 8.00 Hz, 1H, ArH), 6.61–6.51 (m, 2H, ArH),
3.12 (bs, 1H, OH), 2.90 (bs, 1H, OH), 2.74 (bs, 2H, CH2), 2.31–2.23
(m, 1H, CH), 2.07–2.02 (m, 2H, CH2), 1.90–1.81 (m, 1H, CH), 1.61–
1.21 (m, 12H, CH and CH2), 1.15 (s, 6H, 2 ꢂ CH3), 0.94 (s, 3H, CH3);
13C NMR (50 MHz, acetone, d ppm): 155.3, 137.8, 131.6, 126.3, 115.3,
112.9, 81.9, 69.5, 48.2, 47.3, 46.8, 44.6, 44.3, 40.1, 32.2, 31.9, 29.7, 29.0,
27.7, 26.6, 24.03, 18.9, 13.8.
Spectral data for 11b: MP 149–151 ꢁC; IR (nmax, cmꢀ1): 3365, 1513,
1
1456, 1291, 1254, 1220, 1154, 755; H NMR (200 Hz, acetone, d ppm):
7.92 (bs, 1H, OH), 7.09 (d, J ¼ 8.20 Hz, 1H, ArH), 6.61–6.51 (m, 2H,
ArH), 3.15 (bs, 1H, OH), 2.92 (bs, 1H, OH), 2.76 (bs, 2H, CH2), 2.31–
1.80 (m, 4H, CH and CH2), 1.73–1.23 (m, 14H, CH and CH2), 1.20 (s,
3H, CH3), 1.15 (s, 6H, 2 ꢂ CH3), 0.84 (s, 3H, CH3); 13C NMR
(50 MHz, acetone, d ppm): 155.3, 137.8, 131.6, 126.3, 115.3, 112.9,
80.2, 69.6, 49.7, 48.5, 46.8, 44.6, 44.1, 39.6, 34.0, 33.1, 32.9, 29.8, 28.4,
28.0, 27.9, 26.6, 23.9, 14.9.
Synthesis of 16b-(4-Hydroxy-4-ethylhexyl)-17a-methyl-1,3,5(10)-
estratrien-3,17b-diol (11c)
Compound 11c was synthesized in 50% yield with the same experimental
procedure used for the synthesis of compound 11a, substituting methyl-
magnesium bromide by ethylmagnesium bromide.
Mp 91–93 ꢁC; IR (nmax, cmꢀ1): 3350, 1613, 1502, 1456, 1291, 1257,
1
1074, 755; H NMR (200 Hz, acetone, d ppm): 7.92 (bs, 1H, OH), 7.09
(d, J ¼ 10.00 Hz, 1H, ArH), 6.61–6.51 (m, 2H, ArH), 3.76–3.69 (dd, 1H,
CH), 3.53–3.49 (dd, 1H, CH), 3.47–3.39 (m, 1H, CH), 3.31 (d, J ¼ 6.00 Hz,
Hz, 1H, CH), 2.84–2.73 (m, 2H, CH2), 2.31–1.61 (m, 2H, CH2), 1.54–0.97
(m, 16H, 3 ꢂ CH3 and #CH2), 0.95 (t, J ¼ 7.40 Hz, 2 ꢂ CH2), 0.78 (s, 3H,
CH3); 13C NMR (50 MHz, acetone, d ppm): 155.3, 137.8, 131.5, 126.4,
115.3, 112.9, 81.7, 72.2, 48.9, 44.3, 40.8, 38.9, 38.1, 37.8, 32.8, 32.2, 30.4,
29.7, 27.7, 26.6, 25.2, 25.1, 12.5, 9.79.

Steroidal Hybrids of Estrogen and Vitamin D3
CONCLUSIONS
69
In conclusion, this communication presents a simple and efficient
synthesis of biologically important steroid based hybrids of estradiol
and vitamin D3 (4) through simple modifications of estrone 5 at position
16 of the steroid nucleus.
ACKNOWLEDGMENT
We are grateful to the Fonds de Recherche sur la Nature et les Technol-
´
ogies du Quebec (FQRNT) for generous financial support.
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