Thiosugars VI: A simple stereoselective approach to (1→3)-3-S-thiodisaccharides from levoglucosenone

Article abstract of DOI:10.1007/s007060200025

A new stereoselective synthesis of (1→3)-3-S-thiodisaccharides is described. Levoglucosenone-derived chiral building blocks produced by the selenium-mediated iodination at C-3 afforded 3-iodoketones in moderate yield. Iodine displacement with sulfur nucleophiles (1-thiols) resulted in 3-thiodisaccharides. Following reduction of the C-2 keto function constituted a new two-step general approach to these biologically important thiosugars.

Full text of DOI:10.1007/s007060200025

Monatshefte fuÈr Chemie 133, 521±530 ꢀ2002)
Thiosugars VI: A Simple Stereoselective
Approach to ꢀ1!3)-3-S-Thiodisaccharides
from Levoglucosenone
Zbigniew J. Witczak1;Ã, Peter Kaplon2, and Mark Kolodziej2
1
Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University,
Wilkes-Barre, PA 18766, USA
2
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut,
Storrs, CT 06269-2092, USA
Summary. A new stereoselective synthesis of ꢀ1!3)-3-S-thiodisaccharides is described.
Levoglucosenone-derived chiral building blocks produced by the selenium-mediated iodination at
C-3 afforded 3-iodoketones in moderate yield. Iodine displacement with sulfur nucleophiles ꢀ1-
thiols) resulted in 3-thiodisaccharides. Following reduction of the C-2 keto function constituted a
new two-step general approach to these biologically important thiosugars.
Keywords. Thiosugars; Levoglucosenone; SN2 Displacement; ꢀ1 ! 3†-3-S-Thiodisaccharides.
Introduction
In continuation of our program on C-glycosyl compounds [1] and C-disaccharides
[2] as non-hydrolyzable epitopes, we focused our attention on the development of
new strategies for the synthesis of ꢀ1!4), ꢀ1!2), and ꢀ1!3)-S-thiodisaccharides
[3, 4]. Thiodisaccharides [5] containing sulfur in the glycosidic linkage have been
synthesized previously by a variety of methods [6±14], including SN2-type reac-
tions involving the action of a thiolate anion and a glycosyl halide, i.e. the dis-
placement of a leaving group by 1-thio-glucopyranose.
Taking into account that existing synthetic methods of thiodisaccharide syn-
thesis are multistep [6±17] and overall low-yield approaches, an urgent need for
shorter and more convergent syntheses exists. Moreover, the biological relevance
and therapeutic potential of thiosugars [5], including antitumor activity of ꢀ1!2)-
S-linked thiodisaccharides on selected cell culture systems [9], make them attrac-
tive new biological targets and constitutes the rationale for their synthesis.
In our efforts towards preparing thiodisaccharides [3, 4], we employed the new
chiral building blocks 1±6 derived from levoglucosenone [19±21] ꢀ1,6-anhydro-
3,4-dideoxy-ꢀ-D-glycero-hex-3-enopyranos-2-ulose). These new `synthons' are
Ã
Corresponding author. E-mail: witczak@wilkes.edu

522
Z. J. Witczak et al.
Scheme 1
extremely attractive and versatile building blocks because of their high func-
tionality and conformational rigidity ꢀScheme 1).
The 1,6-anhydro bridge in 1±6 eliminates the need for protecting groups at the
anomeric carbon and the C-6-OH. Moreover, the bridge ®xes the conformation of
the system and sterically hinders the ꢀ-D-face of the molecules. Therefore, these
`synthons' have already been used in the synthesis of various natural products and
their intermediates [22±24].
Results and Discussion
The new approach presented here features ongoing studies on the utility of the new,
convenient chiral `synthons' 5 and 6 produced from levoglucosenone [19±21].
Michael addition of methanol to levoglucosenone under basic conditions proceeds
easily with the direct formation of adduct 2 [25]. Analogous addition of water
afforded adduct 3 [19] which by conventional in situ acetylation furnished the
acetyl derivative 4. Direct ꢁ-iodination of 2 and 4 using iodine=selenium dioxide
[26] led to the isolation of a diastereoisomeric mixture ꢀ1:1) of the 3-iodoketones 5
and 6 in 72% yield.
Taking into account that 3-iodoketone 5 will require additional deprotection of
the C-4 methyl group after coupling reaction with thiols, the 3-iodoketone 6 was
chosen as a more versatile and reactive substrate in the stereoselective displace-
ment reaction with glycosyl thiols 7 [27] and 8 [28±30].
The reaction of 6 with thiols 7 [27] and 8 [28±30] proceeded smoothly with the
formation of ꢀ-ꢀ1!3)-3-S-thiodisaccharides 9 and 10 in 60±72% yield. Proton±
1
proton couplings in the H NMR spectra of 9 and 10 con®rmed that only the
3-equatorial products was obtained as the single product in both cases. This ste-
reospeci®city has been observed previously in levoglucosenone conjugate addition
[3, 4] and proceeds by the attack of incoming nucleophile at the iodine face
opposite the 1,6-anhydro ring.
The advantage of the stereoselective iodide displacement is the exclusive
formation of an S-linkage from the less hindered face of the molecule with in-
version of the con®guration at C-3. The shielding effect of the 1,6-anhydro bridge
in 6 effectively prevents the formation of the 3-axial ꢀa) product, thus yielding only

A Simple Approach to Thiodisaccharides
523
the 3-equatorial ꢀe) product. This equatorial attack of the sulfur nucleophiles was
expected [12±14], but a new chiral center at C-3 surprisingly stabilizes the
molecule, as no epimerization [11, 13] or ꢀ-elimination was observed during the
coupling reaction. Also, the 4-acetyl protecting group of 6 is suf®ciently stable
under the above reaction conditions, and no deacetylation or epoxide formation has
been observed. This important observation additionally indicates the preferential
stereochemistry at C-3 of 6. The sterically hindered 1,6-anhydro bridge is therefore
assumed to effectively prevent an attack from the upper side of the molecule,
which could give an access to the alternative formation of the 3-axial product.
1
Indeed, the proton±proton couplings in the H NMR spectra of 9 and 10
con®rmed the D-allo stereochemistry with coupling constants of J3a,4 ˆ 7.6 Hz,
indicating an equatorial orientation of the substituent at C-3. The 1H NMR spectra
of the products did not show signals corresponding to the D-gluco isomer, clearly
demonstrating that the stereochemistry of the reaction of thiols 7 and 8 with 3-
ketone 6 is completely controlled by the steric bulk of the 1,6-anhydro bridge. The
13C NMR spectra of both 9 and 10 showed no ±CH2± group signal, and the C-3
signal appeared at ca. 23.0±23.4 ppm.
The reduction of the C-2 keto function of ketones 9 and 10 with L-Selectride1,
followed by conventional in situ acetylation, proceeded stereoselectively under
formation of the D-altro isomers 12 and 13 in 79% yield. Only a trace amount of
1
the corresponding D-altro isomers 11a and 12a were detected by H NMR spec-
troscopy. Additionally, the absence of a coupling between H-4 and H-5 and cou-
pling constants of J1,2 ˆ 8.2 and J2,3 ˆ 5.2 Hz for 11 and 12 indicate an equatorial
orientation of the new substituent at C-2.
Unlike levoglucosenone, where the C-2 keto group reduction was predictably
controlled [31] by the 1,6-anhydro bridge, the analogous reduction of 9 and 10 was
expected to be dominated by the relative steric contribution of the bulky equatorial
substituent at C-3 as well as by the 1,6-anhydro bridge. This is in full agreement
with earlier observations [14, 15] of high stereoselectivity and another classical
example of the preferential attack of the reducing agent from the bottom face on
this bicyclic molecule. Moreover, the 1H and 13C NMR spectra of 11 and 12 ®rmly
support their assignments to the D-allo con®guration. Particularly, the coupling
constants between the equatorially disposed H-2 and the axially oriented H-3 are of
great diagnostic value ꢀJ2,3 ˆ 5 Hz).
The cleavage of the 1,6-anhydro ring in 11 and 12 was examined under various
reaction conditions. Acetolysis using tri¯uoroacetic acid and acetic anhydride
Scheme 2

524
Z. J. Witczak et al.
Scheme 3
Fig. 1. 3-S-ꢀ-D-Galactopyranosyl-3-thio-D-allopyranose
afforded an anomeric mixture of octaacetates 13 and 14 in good yield ꢀ62%).
Employing acetic anhydride and a catalytic amount of borontri¯uoride etherate
also gave acceptable results ꢀ68%). However, chromatographic puri®cation of the
crude material was required.

A Simple Approach to Thiodisaccharides
525
The method of choice was acetolysis using acetic anhydride solution and a
catalytic amount of tri¯uoromethanesulfonate and proceeding according to the
convenient protocol of Fraser-Reid [32]. This resulted in the formation of an
anomeric mixture of octaacetates 13 and 14 ꢀꢁ:ꢀ ˆ 1:5) in 89% yield. The presence
of the sulfur bridge at C-3 clearly indicates the strong in¯uence of the 1,6-anhydro
ring on the cleavage; a prolonged reaction time ꢀup to the 12 h) as compared with
the literature data reported [32] is required. Separation of the anomers proved
1
impossible because of their almost identical Rf values. However, the H and
13C NMR spectra and mass spectroscopic data for the mixture ®rmly established
their identity.
Final deprotection of octaacetates 13 and 14 was performed with an aqueous
methanolic solution of triethylamine ꢀMeOH:Et3N:H2O ˆ 4:1:5) at room tempera-
ture for 8 h, resulting in the new thiodisacharides 3-S-ꢀꢀ-D-glucopyranosyl)-3-thio-
D-allopyranose ꢀ15) and 3-S-ꢀꢀ-D-galactopyranosyl)-3-thio-D-allopyranose 16 in
89% yield.
A molecular model of 16 ꢀFig. 1; generated by ACD Chemsketch 4.0, 3D
software program) clearly con®rms the structure as determined by NMR spectros-
Ê
copy. The length of the C-1±S bond amounts to 1.8132 A, whereas the C-3±S
Ê
distance is 1.8086 A; the dihedral and torsional angles for the C±S±C bridge are
107.887 and 61.305ꢀ, respectively. Calculations for the sulfur bridge of other
thiodisaccharides give similar results and differ substantially from those of their
oxygen counterparts as previously postulated in the literature [33, 34].
Conclusions
The SN2 nucleophilic displacement reaction of 3-iodoketone 6 with protected 1-
thiosugars, followed by C-2 keto group reduction and deprotection, constitutes a
new short and stereoselective approach to ꢀ1!3)-3-S-thiodisacharides. All new
functionalized thiodisaccharides are stable glycomimetics of potential biological
interest.
Experimental
General
Unless otherwise noted, starting materials were obtained from commercial suppliers and used
without puri®cation. All melting points are uncorrected and were measured in open capillary tubes.
Optical rotations were determined on a Jasco Model DIP-370 polarimeter in CHCl3. Thin-layer
chromatography ꢀTLC) was performed on precoated Silica gel 60F254 plates from E. Merck; spots
were visualized by spraying with 10% ethanolic H2SO4 and subsequent heating. Column
chromatography was performed on Silica Gel 60 ꢀ70±230 mesh, Merck No. 34). NMR samples
were prepared in CDCl3 ꢀ99.8 at.% D), ®ltered, freeze-thawed, and sealed in a 5 mm tube. TMS was
used as an internal chemical shift reference. High-resolution NMR spectra were obtained on a
Bruker DMX-500 spectrometer. Mass spectra were obtained either in the EI mode at 70 eV or
using CI ꢀNH3). Levoglucosenone was produced according to the published methodology [19±21].
1,6-Anhydro-4-O-methyl-ꢀ-D-erythro-hexopyranos-2-ulose ꢀ2) [25] and 1,6-anhydro-4-hydroxy-
ꢀ-D-erythro-hexopyranos-2-ulose ꢀ3) [14] were prepared according to literature methods. 2,3,
4,6-Tetra-O-acetyl-1-thio-ꢀ-D-glucopyranose ꢀ7) [27] and 2,3,4,6-tetra-O-acetyl-1-thio-ꢀ-D-galac-
topyranose ꢀ8) [28, 29] were prepared by reacting the corresponding ꢁ- or ꢀ-glycosyl halides with

526
Z. J. Witczak et al.
thiourea and the reduction of the isothiouronium salts with potassium pyrosul®te according to the
published procedure [30].
4-O-Acetyl-1,6-anhydro-2,3-dideoxy-ꢀ-D-erythro-hexopyranos-2-ulose ꢀ4; C8H10O5)
Compound 3 ꢀ0.1 mmol) was conventionally acetylated at room temperature for 24 h with acetic
anhydride ꢀ5 cm3) in pyridine ꢀ4 cm3). The reaction mixture was poured into ice water and extracted
with ethyl acetate. The extract was washed and dried. Removal of the solvent on a rotary evaporator
ꢀcoevaporation with toluene:EtOH ˆ 1:1; 5  30 cm3) afforded an oily residue that was subjected to
column chromatography on silica gel. The fraction eluted with 20% ethyl acetate in hexane ꢀv=v)
gave a syrupy product which crystallized from ether=hexane.
Yield: 205 mg ꢀ83%); m.p.: 108±110.2ꢀC; Rf ˆ 0.45 ꢀEtOAc); [ꢁ]D ˆ ‡ 231ꢀ ꢀc ˆ 1.0, CHCl3);
1
for H and 13C NMR data, see Tables 1 and 2.
General method for the preparation of 3-iodoketones 5 and 6
Compounds 5 and 6 were produced by the Bekaert [26] methodology as described below. To a
solution of 4 ꢀ0.1 mol) in 50 cm3 of CH3CN, 6.1 g powdered selenium dioxide ꢀ55 mmol) and 13.97 g
iodine ꢀ55 mmol) were added. The mixture was heated at 80ꢀC for 8 h. The red selenium precipitate
was removed by ®ltration through a short silica gel column. The dark-red solution was diluted with
200 cm3 of H2O and extracted with CH2Cl2. The organic layer was extracted with 100 cm3 of a 10%
solution of Na2S2O3 and washed with H2O. After drying with anhydrous magnesium sulfate, the
solvent was removed on a rotary evaporator, and the residue was puri®ed by column chromatography
on silica gel. The fraction eluted with 20% ethyl acetate in hexane ꢀv=v) gave pure syrupy products
which crystallized from ether=hexane.
1,6-Anhydro-2,3-dideoxy-3-iodo-4-methoxy-ꢀ-D-erythro-hexopyranos-2-ulose
ꢀ5; C7H9IO4)
Yield: 205 mg ꢀ73%); m.p.: 80±82.5ꢀC; Rf ˆ 0.51 ꢀEtOAc); [ꢁ]D ˆ ‡ 301ꢀ ꢀc ˆ 1.0, CHCl3); for 1H
and 13C NMR data, see Tables 1 and 2.
1,6-Anhydro-2,3-dideoxy-3-iodo-4-O-acetyl-ꢀ-D-erythro-hexopyranos-2-ulose
ꢀ6; C8H9IO5)
Yield: 235 mg ꢀ73%); m.p.: 60±61.5ꢀC; Rf ˆ 0.59 ꢀEtOAc); [ꢁ]D ˆ ‡ 318ꢀ ꢀc ˆ 1.0, CHCl3); for 1H
and 13C NMR data, see Tables 1 and 2.
General method for the preparation of )1!3)-3-S-thiodisacharides 9 and 10
To a solution of 126 mg 3-iodoketone 6 ꢀ0.1 mmol) in 10 cm3 CH3CN, a solution of 125 mg 7 [26]
3
or 8 [27, 28] ꢀ0.34 mmol) in 5 cm3 of CH3CNand 2 cm of thiethylamine was added dropwise.
The reaction mixture was stirred at room temperature for 24 h; then, pyridine ꢀ4 cm3) and acetic
anhydride ꢀ5 cm3) were added, and the mixture was stirred at room temperature overnight, poured
into ice water, and extracted with ethyl acetate. The extract was washed and dried. Removal of
the solvent in vacuo after coevaporation with 5  30 cm3 toluene:EtOH ˆ 1:1 afforded an oily resi-
due that was subjected to column chromatography on silica gel. The fraction eluted with 20%
ethyl acetate in hexane ꢀv=v) gave syrupy products 9 and 10 which crystallized from ether=
hexane.

A Simple Approach to Thiodisaccharides
527

528
Z. J. Witczak et al.
1,6-Anhydro-3-S-)2,3,4,6-tetra-O-acetyl-ꢀ-glucopyranosyl)-ꢀ-D-glycero-
hexopyranos-4-ulose ꢀ9; C20H26O12S)
Yield: 436 mg ꢀ89%); m.p.: 157±158.5ꢀC; Rf ˆ 0.59 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À120.21ꢀ ꢀc ˆ
0.84, CHCl3); HRMS: m=z ˆ 490.11 ꢀcalcd.: 490.47); for 1H and 13C NMR data: see Tables 1 and 2.
1,6-Anhydro-3-S-)2,3,4,6-tetra-O-acetyl-ꢀ-galactopyranosyl)-ꢀ-D-glycero-
hexopyranos-4-ulose ꢀ10; C20H26O12S)
Yield: 385 mg ꢀ78.5%); m.p.: 151±152.5ꢀC; Rf ˆ 0.41 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À122.2ꢀ
1
ꢀc ˆ 0.8, CHCl3); HRMS: m=z ˆ 490.11 ꢀcalcd.: 490.47); for H and 13C NMR data, see Tables 1
and 2.
General method for the reduction of )1!3)-3-S-thiodisacharides 9 and 10
To a cooled and stirred solution of 210 mg thiodisaccharides 9 or 10 ꢀ0.428 mmol) in THF, 1.0 cm3 L-
Selectride1 ꢀ1 M in THF) was added at À78ꢀC under an Ar atmosphere. The reaction mixture was
stirred for 3 h; then, pyridine ꢀ4 cm3) and acetic anhydride ꢀ5 cm3) were added, and stirring at room
temperature was continued overnight. The reaction mixture was poured into ice water and extracted
with ethyl acetate. The extract was washed and dried. Removal of the solvent in vacuo after
coevaporation with 5  30 cm3 toluene:EtOH ˆ 1:1 afforded an oily residue that was subjected to
column chromatography on silica gel. The fraction eluted with 20% ethyl acetate in hexane ꢀv=v)
gave syrupy products 11 and 12.
4-O-Acetyl-1,6-anhydro-3-S-)2,3,4,6-tetra-O-acetyl-3-thio-ꢀ-glucopyranosyl)-
ꢀ-D-allo-hexo-pyranose ꢀ11; C24H32O15S)
Yield: 190 mg ꢀ79%); Rf ˆ 0.42 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À34.2ꢀ ꢀc ˆ 0.84, CHCl3); HRMS:
1
m=z ˆ 592.14 ꢀcalcd.: 592.57); for H and 13C NMR data, see Tables 1 and 2.
4-O-Acetyl-1,6-anhydro-3-S-)2,3,4,6-tetra-O-acetyl-3-thio-ꢀ-galactopyranosyl)-
ꢀ-D-allo-hexo-pyranose ꢀ12, C24H33O15S)
Yield: 170 mg ꢀ81.5%); Rf ˆ 0.33 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À30.4ꢀ ꢀc ˆ 0.68, CHCl3); HRMS:
1
m=z ˆ 592.17 ꢀcalcd.: 592.57); for H and 13C NMR data, see Tables 1 and 2.
General method for the hydrolysis of )1!3)-S-thiodisaccharides 11 and 12
a) 0.2 g Thiodisaccharide 11 or 12 ꢀ0.375 mmol) were dissolved in Ac2O ꢀ8.5 cm3) and
CF3COOH ꢀ6.2 cm3), and the mixture was stirred at room temperature for 10 h. After the sol-
vent was evaporated, the resulting brown syrup was chromatographed ꢀhexane:Et2OAc ˆ 2:1)
to afford an anomeric mixture of 160 mg ꢀ62%) heptaacetates 13 and 14 as colorless syrup
ꢀꢁ:ꢀ-ratio: 1:5).
b) 0.4 g Thiodisaccharide 11 or 12 ꢀ0.75 mmol) were dissolved in Ac2O ꢀ8.5 cm3). Boron tri-
¯uoride etherate ꢀBF3 Á Et2O, 0.1 cm3) was added, and the mixture was stirred at room tempera-
ture for 10 h. After the solvent was evaporated, the resulting brown syrup was chromatographed
ꢀhexane:Et2OAc ˆ 2:1) to afford 0.30 g ꢀ68%) of an anomeric mixture of heptaacetates 13 and
14 as a colorless syrup ꢀꢁ:ꢀ-ratio ˆ 1:5).
c) To a cooled solution ꢀ0ꢀC) of 0.5 g of 11 or 12 ꢀ0.93 mmol) in acetic anhydride ꢀ10 cm3) stirred
under argon, two drops ꢀ3 mm3) of trimethylsilyl tri¯uoromethanesulfonate were added. TLC

A Simple Approach to Thiodisaccharides
529
ꢀEtOAc:hexane ˆ 1:1) indicated the completion of the reaction after 12 h. A solution of saturated
sodium bicarbonate was added, and the mixture was stirred for 30 min and was extracted with
3 Â 20 cm3 ethyl acetate. The combined extracts were washed with 20 cm3 saturated NaHCO3 and
20 cm3 brine and dried over Na2SO4. Evaporation of the solvent under reduced pressure yielded
0.35 g ꢀ89%) of an inseparable anomeric mixture ꢀꢁ:ꢀ-ratio ꢁ 1:6).
1,2,4,6-Tetra-O-acetyl-3-S-)2,3,4,6-tetra-O-acetyl-ꢀ-glucopyranosyl)-3-thio-
ꢁ,ꢀ-D-allo-pyranose ꢀ13; C28H38O18S)
Yield: 0.648 g ꢀ91%); colorless syrup; Rf ˆ 0.34, 0.31 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À12.4ꢀ ꢀc ˆ
1
0.82, CHCI3); HRMS: m=z ˆ 636.17 ꢀcalcd.: 636.62); for H and 13C NMR data ꢀmainly the ꢀ-
anomer), see Tables 1 and 2.
1,2,6-Tri-O-acetyl-3-S-)2,3,4,6-tetra-O-acetyl-ꢀ-galactopyranosyl)-3-thio-
ꢁ,ꢀ-D-allopyranose ꢀ14; C26H38O18S)
Yield: 0.641 g ꢀ86%); colorless syrup; Rf ˆ 0.42, 0.41 ꢀhexane:EtOAc ˆ 1:4); [ꢁ]30 ˆ À12.4ꢀ ꢀc ˆ
1
0.82, CHCl3); HRMS: m=z ˆ 636.17 ꢀcalcd.: 636.62); for H and 13C NMR data ꢀmainly the ꢀ-
anomer), see Tables 1 and 2.
General method for the deprotection of )1!3)-3-S-thiodisacharides 13 and 14
0.250 mg of thiodisaccharides 13 or 14 ꢀ0.15 mmol) were dissolved in 15 cm3 of a MeOH:
Et3N:H2O ˆ 4:1:5 mixture and stirred at room temperature. TLC indicated the completion of the
reaction after 6 h. Evaporation of the solvent produced an inseparable anomeric mixture ꢀꢁ:ꢀ-
ratio ˆ 1:6).
3-S-)ꢀ-D-Glucopyranosyl)-3-thio-D-allopyranose ꢀ15; C12H22O10S)
Yield: 119 mg ꢀ89%); colorless syrup; [ꢁ]30 ˆ À10.2ꢀ!À16.2ꢀ ꢀc ˆ 0.82, H2O); HRMS:
1
m=z ˆ 342.09 ꢀcalcd.: 342.36); for H and 13C NMR data ꢀmainly the ꢀ-anomer), see Tables 1
and 2.
3-S-)ꢀ-D-Galactopyranosyl)-3-thio-D-allopyranose ꢀ16; C12H22O10S)
Yield: 88 mg ꢀ66%); colorless syrup; [ꢁ]30 ˆ À12.6ꢀ!À14ꢀ ꢀc ˆ 0.8, H2O); HRMS: m=z ˆ 342.12
1
ꢀcalcd.: 342.36); for H and 13C NMR data ꢀmainly the ꢀ-anomer), see Tables 1 and 2.
Acknowledgments
Financial support from the American Cancer Society ꢀInstitutional Grant to University of
Connecticut Health Center, ACSIN152L-132 grant program) is gratefully acknowledged.
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Received November 11, 2001. Accepted November 22, 2001