A novel approach to the stereocontrolled synthesis of C-vinyl β-D-galactopyranosides

Article abstract of DOI:10.1016/S0008-6215(03)00275-1

Reaction of a lithiated dithiinyl reagent with a O-perbenzylated D-glycono-δ-lactone readily generates the corresponding masked C-vinyl galactosides in high yields and full β-selectivity. Removal of the sulfur mask renders the free vinyl aglycone with the vinyl group in either the Z or E configuration, depending on the desulfurization conditions chosen.

Full text of DOI:10.1016/S0008-6215(03)00275-1

Carbohydrate Research 338 (2003) 1877ꢀ1880
/
www.elsevier.com/locate/carres
Note
A novel approach to the stereocontrolled synthesis of C-vinyl
b- -galactopyranosides
D
Romualdo Caputo, Pasquale Festa, Annalisa Guaragna, Giovanni Palumbo,
Silvana Pedatella*
Dipartimento di Chimica Organica e Biochimica, Universita` di Napoli Federico II, Via Cynthia, 4, 80126 Napoli, Italy
Received 6 May 2003; accepted 13 June 2003
Abstract
Reaction of a lithiated dithiinyl reagent with a O-perbenzylated
D-glycono-d-lactone readily generates the corresponding masked
C-vinyl galactosides in high yields and full b-selectivity. Removal of the sulfur mask renders the free vinyl aglycone with the vinyl
group in either the Z or E configuration, depending on the desulfurization conditions chosen.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: C-Glycosides; Glycosylation; Dithiinyl reagents; Sialyl Lewis X mimics
C-Glycosylic compounds, often termed C-glycosides,
are regarded as mimics of biologically relevant O-
Dithiinyl reagents like 2 can be conveniently prepared
containing a number of different side chains.5
The hemiacetal 3 was then treated6 with Et3SiH and
glycosides. The replacement of the exocyclic carbonꢀ
/
oxygen bond at the anomeric center with a carbonꢀ
/
BF3×
/
Et2O at ꢁ40 8C and thus converted into the
/
carbon bond confers resistance to acid and enzymatic
hydrolysis, resulting in hydrolytically stable carbohy-
drate mimics with many possible biological applica-
tions.1 C-Vinyl, C-allyl, and C-alkynyl glycosides2
constitute a group of synthetically useful compounds
that allows a wide range of transformations based on the
expected C-glycoside 4. It is noteworthy that the O-
allyl group was essential to the conversion. When 4-
methoxybenzyl protection was used, under the same
conditions, spirocyclization at the anomeric carbon took
place leading to 1,6-dioxaspiro[4,5]dec-3-enes.7
Compound 4, which actually is the key intermediate
we were working on for the synthesis of our target sialyl
Lewis X mimics, was further elaborated for the purpose
of getting to a C-vinyl glycoside with the fully depro-
tected aglycone moiety. It was, therefore, deallylated by
elaboration of the CꢀC unsaturated bond.
/
We report here a novel approach toward the prepara-
tion of a new class of sialyl Lewis X mimics.3 These
mimics are characterized by two modified sugar units
linked through variously substituted three-carbon
spacers (Fig. 1).
tert-butyllithium in hexaneꢀ
ture, and desulfurized8 by Raney Ni in THF, to obtain
the final C-vinyl b- -glycoside 6, the S configuration of
which was ascertained by H NMR analysis [500 MHz,
/toluene at room tempera-
O-Perbenzylated-
D-galactono-d-lactone 1 (Scheme 1)
D
was coupled with C-3 lithiated 5,6-dihydrodithiinyl
reagent 2 to give the hemiacetal derivative 3. Reagent
2, already devised in our laboratory,4 represents an allyl
anion equivalent that accomplishes three-carbon elon-
gations of suitable electrophiles, introducing both a fully
protected double bond and a primary hydroxyl group.
1
4
CDCl3: dꢂ
We consider of interest to have devised a path to
prepare C-vinyl
-galactosides with full b-D-selectivity
/
4.19 (t, 1 H, J 8.8 Hz, H-2)].
D
and in high overall yield: it is also remarkable that the
aglycone moiety may present various substituents at the
double bond (alkyl and formyl, besides hydroxymethyl
group),5 whereas the double bond itself may be depro-
tected into either Z configuration (as described by this
* Corresponding author. Tel.: ꢃ
674102.
E-mail address: pedatell@unina.it (S. Pedatella).
/
39-81-674118; fax: ꢃ39-81-
/
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00275-1

1878
R. Caputo et al. / Carbohydrate Research 338 (2003) 1877ꢀ1880
/
tography: E. Merck Kieselgel 60 (70ꢀ230 mesh). Dry
/
solvents were distilled immediately before use.
1.2. (2R,3R,4S,5S,6R)-2-{3?-[(Allyloxy)methyl]-5?,6?-
dihydro-1?,4?-dithiin-2?-yl}-3,4,5-tri(benzyloxy)-6-
[(benzyloxy)methyl]tetrahydro-2H-2-pyranol (3)
Fig. 1. General structure of new C-glycosyl sialyl Lewis X
analogues.
1.6 M BuLi in hexane (1.0 mL, 1.6 mmol) was added
dropwise over 5 min to a stirred solution of 5-
[(allyloxy)methyl]-2,3-dihydro-1,4-dithiin (2) (0.3 g, 1.5
˚
mmol) over 4 A molecular sieves in anhyd THF (1.5
mL), at ꢁ78 8C and under an N2 atmosphere. After 20
/
min, 2,3,4,6-tetra-O-benzyl-D-galactono-d-lactone (0.5
g, 1.0 mmol), dissolved in the same solvent (1.5 mL),
was added dropwise via cannula. The reaction mixture
was kept at ꢁ
aq NH4Cl (5 mL) and extracted with AcOEt (3ꢄ
/
78 8C for 1.5 h, then quenched with 10%
15
/
mL). The combined organic layers were dried (Na2SO4),
and the solvents were evaporated under reduced pres-
sure. Chromatography on silica gel (7:3 petroleum
etherꢀ
pure hemiacetal 3 (0.6 g, 80%) as an oil: [a]D25
1.3, CHCl3); 1H NMR (500 MHz): d 2.26ꢀ
2.38 (m, 2 H,
2.67 (m, 1 H,
/EtOAc) of the crude residue finally afforded the
ꢃ
/
12.18 (c
/
SCH2), 2.41ꢀ
/
2.48 (m, 1 H, SCHaH), 2.59ꢀ
/
SCHbH), 3.61 (dd, 1 H, 3J 8.8 Hz, 4J 5.2 Hz, Ha-7), 3.67
(ddt, 1 H, 3J 13.2 Hz, 4J 5.4 Hz, 5J 1.5 Hz,
Scheme 1. Reagents and conditions: (i) THF, ꢁ
Et3SiH, BF3×Et2O, 1:1 CH2Cl2ꢀCH3CN, 40 8C, 1.5 h; (iii) t-
BuLi, 5:1 hexaneꢀtoluene, r.t., 4 h; (iv) Raney Ni, THF, r.t.,
15 min.
/
78 8C, 2 h; (ii)
3
CH2), 3.71 (ddt, 1 H, J 13.2 Hz, J 5.4
4
OCHaHCHÄ
/
/
/
5
3
CH2), 3.77 (d, 1 H, J 11.6
Hz, J 1.5 Hz, OCHbHCHÄ
/
/
Hz, CHaHOAll), 3.84 (t, 1 H, 3Jꢂ4
(dd, 1 H, J 9.5 Hz, J 2.9 Hz, H-4), 3.99 (dd, 1 H, J
/
J 8.8 Hz, Hb-7), 3.97
4
4
4
4
3
2.9, J 1.5 Hz, H-5), 4.20 (d, 1 H, J 11.7 Hz, HaÃ
4.26 (d, 1 H, 3J 11.7 Hz, HbÃ
Bni), 4.38ꢀ4.42 (m, 1 H, H-
6), 4.42 (d, 1 H, J 11.7 Hz, HaÃBnii), 4.52 (d, 1 H, J
/
Bni),
paper) or E configuration [by LiAlH4/Ti(i-PrO)4], as
already reported.9
/
/
3
3
/
In our opinion the present C-glycosylation reaction
can be regarded as one paralleling the C-vinyl glycoside
preparation via reduction of C-alkynyl glycosides.
However, such a procedure is characterized by the
near absence of selectivity of the coupling reaction,
leading to mixtures of a and b epimeric glycosides.6,10
3
11.7 Hz, HbÃ
/
Bnii), 4.62 (d, 1 H, J 11.2 Hz, HaÃ
/
Bniii),
4.63 (d, 1 H, J 9.5 Hz, H-3), 4.74 (d, 1 H, J 10.5 Hz,
Haà Bniv), 4.91 (ddd,
Bniv), 4.90 (d, 1 H, 3J 10.5 Hz, HbÃ
1 H, 3J 3.4 Hz, 4J 10.3 Hz, 5J 1.5 Hz, CHÄ
CHaH), 5.04
(d, 1 H, 3J 11.2 Hz, HbÃBniii), 5.12 (ddd, 1 H, 3J 3.4 Hz,
4J 17.5 Hz, 5J 1.5 Hz, CHÄCHbH), 5.26 (d, 1 H, 3J 11.6
Hz, CHbHOAll), 5.63ꢀ5.75 (m, 1 H, CH ÄCH2), 7.02ꢀ
7.45 (m, 20 H, HAr); 13C NMR (125 MHz): d 26.8, 28.0
(2ꢄ SCH2), 68.8, 70.9, 71.9, 72.7, 73.4, 75.1, 76.0 (C-7,
OCH2CHÄCH2, CH2OAll, 4ꢄ OCH2Ph), 70.7, 75.6,
80.4, 80.9 (C-3, C-4, C-5 and C-6), 100.1 (C-2), 116.5
(CHÄCH2), 127.4ꢀ128.9 (20ꢄ CHAr, SC ÄCS), 134.0
(CHÄCH2), 138.4ꢀ139.3 (4ꢄ PhÃC4). Anal. Calcd for
4
3
/
/
/
/
/
/
/
/
/
1. Experimental
/
/
1.1. General
/
/
/
/
/
/
/
/
1H and 13C NMR spectra: Varian Inova 500, Bruker
DRX-400, Varian Gemini 200 spectrometers, in C6D6
unless otherwise specified; assignments were aided by
C42H46O7S2: C, 69.39; H, 6.38. Found: C, 69.11; H,
6.32.
1Hꢀ1
Molecular sieves (4 A, 8ꢀ
activated at 160 8C under vacuum for Â
rotations (in CHCl3): JASCO P-1010 (1.0 dm cell).
Combustion analyses: PerkinꢀElmer Series II 2400,
/
H COSY correlation spectroscopy and DEPT.
1.3. (2R,3R,4S,5S,6R)-2-{3?-[(Allyloxy)methyl]-5?,6?-
dihydro-1?,4?-dithiin-2?-yl}-3,4,5-tri(benzyloxy)-6-
[(benzyloxy)methyl]tetrahydro-2H-2-pyran (4)
˚
/
12 mesh, Aldrich) were
16 h. Optical
/
/
Et3SiH (0.4 mL, 2.5 mmol) was added to a magnetically
stirred solution of hemiacetal 3 (0.4 g, 0.5 mmol) in 1:1
CHNS analyzer. TLC analyses: E. Merck Silica Gel 60
F254 plates (0.2 mm layer thickness). Column chroma-
CH2Cl2ꢀ
/
CH3CN (2 mL) at ꢁ40 8C. After 1 h, a
/

R. Caputo et al. / Carbohydrate Research 338 (2003) 1877ꢀ
/
1880
1879
solution (3% v/v in CH2Cl2) of BF3×
/
Et2O (0.2 mL) was
H, 4J 9.3 Hz, H-2), 4.40 (s, 2 H, CÄ
/
CÃ
/
CH2OH), 4.41 (d,
1 H, 3J 10.3 Hz, CHbHPh), 4.48 (t, 1 H, 4J 9.3 Hz, H-3),
4.59 (d, 1 H, 3J 11.7 Hz, CHaHPh), 4.72 (d, 1 H, 3J 10.7
carefully added, and after 20 min the reaction was
quenched with Et3N (0.03 mL, 0.2 mmol). The organic
layer was washed with brine and dried (Na2SO4), and
the solvents were evaporated under reduced pressure to
afford a crude residue, the chromatography of which on
Hz, CHaHPh), 4.78 (d, 1 H, 3J 10.7 Hz, CHbHPh), 5.00
3
(d, 1 H, J 11.7 Hz, CHbHPh), 6.95ꢀ
/
7.45 (m, 20 H,
SCH2),
64.1, 68.9, 73.4, 74.4, 74.7, 77.6 (C-7, CH2OH, 4ꢄ
OCH2Ph), 72.3, 76.0, 77.4, 79.4, 84.5 (C-2, C-3, C-4,
C-5 and C-6), 125.7, 130.2 (SC ÄCS), 127.5ꢀ129.1 (20ꢄ
CHAr), 138.1ꢀ139.5 (4ꢄ PhÃC4). Anal. Calcd for
H
Ar); 13C NMR (125 MHz): d 26.4, 29.5 (2ꢄ
/
silica gel column (8:2 petroleum etherꢀ
the pure product 4 (0.3 g, 85%) as an oil: [a]D25
3.0, CHCl3); 1H NMR (500 MHz): d 2.50ꢀ
2.62 (m, 3 H,
2.83 (m, 1 H, SCH2CHbHS), 3.40
/EtOAc) afforded
/
ꢃ
/
12.98 (c
/
/
/
/
SCH2CHaHS), 2.76ꢀ
/
/
/
/
(dd, 1 H, 4J 9.2 Hz, 4J 2.4 Hz, H-4), 3.51 (dd, 1 H, 4J 5.3
Hz, 4J 8.8 Hz, H-6), 3.58 (dd, 1 H, 3J 8.8 Hz, 4J 5.3 Hz,
C42H46O6S2: C, 70.96; H, 6.52. Found: C, 71.22; H,
6.56.
Ha-7), 3.72 (t, 1 H, 3Jꢂ4
2 H, OCH2CHÄ
3.98 (d, 1 H, J 12.3 Hz, CHaHOAll), 4.17 (d, 1 H, J
/
J 8.8 Hz, Hb-7), 3.86ꢀ
/
3.88 (m,
4
/
CH2), 3.90 (br d, 1 H, J 2.4 Hz, H-5),
1.5. (Z)-1-{(2S,3R,4S,5S,6R)-3,4,5-Tri(benzyloxy)-6-
[(benzyloxy)methyl]tetrahydro-2H-2-pyranyl}-1-propen-
3-ol (6)
3
3
3
11.7 Hz, HaÃ
4.44 (d, 1 H, 3J 12.1 Hz, HaÃ
Hz, HbÃBnii), 4.50ꢀ4.54 (m, 2 H, H-2 and H-3), 4.61 (d,
1 H, J 11.7 Hz, HaÃ
HaÃ
Bniv and CHbHOAll), 4.87 (d, 1 H, 3J 11.7 Hz, HbÃ
Bniii), 4.98 (ddd, 1 H, J 3.4 Hz, J 10.5 Hz, J 1.5 Hz,
/
Bni), 4.22 (d, 1 H, J 11.7 Hz, HbÃ
/Bni),
/
Bnii), 4.49 (d, 1 H, 3J 12.1
/
/
A solution of product 5 (0.2 g, 0.3 mmol) in THF (3 mL)
was added in one portion to a stirred suspension of
Raney Ni (W2) (2.7 g, wet) in the same solvent (2 mL) at
r.t. The suspension was stirred for 15 min (TLC
monitoring), and the solid was then filtered off and
washed with EtOAc. The filtrate was neutralized with
3
3
/Bniii), 4.78 (br d, 2 H, J 11.7 Hz,
/
/
3
4
5
3
CHÄ
(ddd, 1 H, 3J 3.7 Hz, 4J 17.1 Hz, 5J 1.9 Hz, CHÄ
CHbH), 5.76ꢀ5.85 (m, 1 H, CH ÄCH2), 7.25ꢀ7.65 (m,
20 H, HAr); 13C NMR (125 MHz): d 21.7, 29.2 (2ꢄ
SCH2), 67.6, 69.1, 69.2, 71.1, 72.1, 73.5, 74.2 (C-7,
OCH2CHÄCH2, CH2OAll, 4ꢄ OCH2Ph), 73.3, 76.0,
76.2, 77.1, 83.3 (C-2, C-3, C-4, C-5 and C-6), 114.9
(CHÄCH2), 126.0ꢀ127.1 (20ꢄ CHAr, SC ÄCS), 134.1
(CHÄCH2), 137.2ꢀ138.3 (4ꢄ PhÃC4). Anal. Calcd for
/
CHaH), 5.03 (d, 1 H, J 11.7 Hz, HbÃ
/Bniv), 5.23
/
/
/
/
saturated aq Na2CO3 and extracted with EtOAc (3ꢄ15
/
/
mL). The combined organic layers were washed with
brine until neutral and dried (Na2SO4), and the solvents
were evaporated under reduced pressure to afford a
crude residue. Chromatography of the latter on silica gel
/
/
/
/
/
/
column (8:2 petroleum etherꢀEtOAc) gave the pure
/
/
/
/
/
sulfur-free product 6 (0.1 g, 80%) as an oil: [a]D25
ꢃ25.18
/
1
(c 0.41, CHCl3); H NMR (500 MHz): d 3.35 (dd, 1 H,
C39H42O6S2: C, 69.82; H, 6.31. Found: C, 70.01; H,
6.28.
4J 9.4 Hz, 4J 2.9 Hz, H-4), 3.42ꢀ
3.47 (m, 1 H, H-6), 3.61
(dd, 1 H, J 8.9 Hz, J 5.4 Hz, Ha-7), 3.69 (dd, 1H, J
/
3
4
3
4
8.9 Hz, J 7.7 Hz, Hb-7), 3.86 (m, 2 H, H-3 and H-5),
1.4. (2R,3R,4S,5S,6R)(3-{3,4,5-Tri(benzyloxy)-6-
[(benzyloxy)methyl]tetrahydro-2H-2-pyranyl}-5,6-
dihydro-1,4-dithiin-2-yl)methanol (5)
3
4.05 (dd, 1 H, J 13.3 Hz, J 4.3 Hz, CHaHOH), 4.09
4
3
4
(dd, 1 H, J 13.3 Hz, J 4.3 Hz, CHbHOH), 4.18ꢀ
(m, 3 H, 2ꢄ HÃBni and H-2), 4.37ꢀ4.44 (m, 3 H, HaÃ
Bnii and 2ꢄ HÃ
Bniv), 4.77 (d, 1 H, 3J 10.7 Hz, HbÃ
11.3 Hz, HbÃBniv), 5.57ꢀ5.69 (m, 2 H, HCÄ
7.40 (m, 20 H, HAr); 13C NMR (125 MHz): d 59.6, 69.2,
72.3, 73.5, 75.1, 75.6 (4ꢄ OCH2Ph, C-7 and CH2OH),
74.7, 76.2, 76.9, 79.2, 84.7 (C-2, C-3, C-4, C-5 and C-6),
127.7ꢀ128.5 (20ꢄ CHAr), 129.5, 133.5 (HC ÄCH),
138.6, 138.9, 139.0, 139.4 (4ꢄ PhÃC4). Anal. Calcd
/4.26
/
/
/
/
3
2.0 M t-BuLi in hexane (0.22 mL, 0.44 mmol) was added
dropwise over 10 min to a stirred solution of 4 (0.3 g, 0.4
/
/
Bniii), 4.58 (d, 1 H, J 11.3 Hz, HaÃ
Bnii), 4.98 (d, 1 H, 3J
CH), 6.98ꢀ
/
/
mmol) in anhyd 5:1 hexaneꢀ
/
toluene (4 mL), at room
/
/
/
/
temperature (r.t.) and under N2 atmosphere. After 4 h
(TLC monitoring), the reaction mixture was quenched
with 10% aq NH4Cl (5 mL) and extracted with AcOEt
/
(2ꢄ/10 mL). The combined organic layers were dried
/
/
/
(Na2SO4), and the solvents were evaporated under
reduced pressure. Chromatography on silica gel (8:2
/
/
for C37H40O6: C, 76.53; H, 6.94. Found: C, 76.38; H,
petroleum etherꢀEtOAc) of the crude residue finally
/
6.91.
afforded the pure product 5 (0.2 g, 75%) as an oil: [a]D25
1
ꢁ
/
2.58 (c 3.02, CHCl3); H NMR (500 MHz): d 2.26ꢀ
/
2.45 (m, 3 H, SCH2CHaHS), 2.62ꢀ
/
2.69 (m, 1 H,
4
SCH2CHbHS), 3.11 (bs, 1 H, OH), 3.31 (dd, 1 H, J
Acknowledgements
4
9.3 Hz, J 2.9 Hz, H-4), 3.36ꢀ
/3.41 (m, 1 H, H-6), 3.56
This work represents a partial fulfilment of the master
1
(dd, 1 H, 3J 9.0 Hz, 4J 5.3 Hz, Ha-7), 3.65 (t, 1 H, 3J 9.0
Hz, 4J 7.8 Hz, Hb-7), 3.82 (bd, 1 H, 4J 2.9 Hz, H-5), 4.15
(d, 1 H, 3J 11.7 Hz, CHaHPh), 4.20 (d, 1 H, 3J 11.7 Hz,
CHbHPh), 4.22 (d, 1 H, 3J 10.3 Hz, CHaHPh), 4.37 (d, 1
thesis by Dr Nunzia Carusio. H and 13C NMR spectra
were performed at Centro Interdipartimentale di Meto-
dologie Chimico-Fisiche, Universita` di Napoli Federico
II, and Lab. of Consorzio Interuniversitario Nazionale

1880
R. Caputo et al. / Carbohydrate Research 338 (2003) 1877ꢀ1880
/
3. Kaila, N.; Thomas IV, B.-E. Med. Res. Rev. 2002, 22,
566ꢀ601.
4. Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J.
Org. Chem. 1997, 62, 9369ꢀ9371.
La Chimica per l’Ambiente (INCA). The Inova 500
Varian instrument was used in the frame of a project by
INCA (M.I.U.R., L. 488/92, Cluster 11-A).
/
/
5. Caputo, R.; Ferreri, C.; Isita, P.; Longobardo, L.;
Mastroianni, D.; Palumbo, G. Synth. Commun. 1992,
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1350.
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(Eds.), Glycochemistry Principles, Synthesis and Applica-
/
/
tions, Marcel Dekker, New York, 2000; pp. 77ꢀ
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131;
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(c) Postema, M.H.D. C-Glycoside Synthesis, CRC Press,
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/