Total synthesis and identification of two diastereoisomers of 1-methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl β-L-fucopyranoside

Article abstract of DOI:10.1016/j.carres.2004.11.016

The reaction of a racemic mixture of (2R,2′S)- and (2S,2′R)-N-(p-tolylsulfonyl)-2-pyrrolidinyl-2-propanol, prepared from (S)-proline, with 2,3,4-tri-O-acetyl-α-l-fucopyranosyl trichloroacetimidate led to both diastereoisomers of the title compound after O-deacetylation.

Full text of DOI:10.1016/j.carres.2004.11.016

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 309–314
Note
Total synthesis and identification of two diastereoisomers
of 1-methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl
b-L-fucopyranoside
Maria Joselice e Silva,a,b Louis Cottier,b Rajendra M. Srivastava,a,*
Denis Sinoub and Alain Thozetc
a
´
´
Departamento de Quımica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, 50.740-540 Recife, PE, Brazil
b
`
´
´
Laboratoire de Synthese Asymetrique, UMR 5181 CNRS, C.P.E. Lyon,Universite Claude Bernard Lyon 1,
43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France
c
´
Laboratoire de Cristallographie, UMR 5078 CNRS, Universite Claude Bernard Lyon 1,
43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France
Received 12 July 2004; received in revised form 22 November 2004; accepted 25 November 2004
Abstract—The reaction of a racemic mixture of (2R,20S)- and (2S,20R)-N-(p-tolylsulfonyl)-2-pyrrolidinyl-2-propanol, prepared from
(S)-proline, with 2,3,4-tri-O-acetyl-a-L-fucopyranosyl trichloroacetimidate led to both diastereoisomers of the title compound after
O-deacetylation.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: L-Proline; b-Aminoalcohols; b-L-Fucopyranosides
Pyrrolidine alkaloids,1–3 such as hygroline and pseudo-
hygroline, [(2S,20S)- and (2S,20R)-N-methyl-2-(20-
hydroxypropyl)pyrrolidines, respectively] possess inter-
esting biological activities.4,5 These compounds have
been isolated from plants.1,6–9 All four stereoisomers
have previously been synthesized.3 One of them has been
found as an aglycone in 1-methyl-2-(1-methyl-2-pyrro-
lidinyl)ethyl 6-deoxy-3-O-[(Z)-2-methyl-2-buten-oyl)-a-
galactopyranoside isolated from Schizanthus integrifo-
lius Phil. (Solanaceae), the absolute configuration of
fucose and hygroline moieties has not yet been deter-
mined.10 In our ongoing research work on the synthesis
of glycoheterocyclic compounds, we were interested in
the preparation of diastereomerically pure b-L-fucopyr-
anosides 1a and 1b, having only a fucosyl and a
pyrrolidinyl moiety, for biological activity tests, the
starting alcohols being a racemic mixture of (2R,20S)-
and (2S,20R)-N-(p-tolylsulfonyl)-2-pyrrolidinyl-2-propa-
nol 2a and 2b.
CH3
CH3
2R
N
Ts
R
O
OH
HO
HO
N
O
S
2'S
Ts
HO
OH
2a
1a
CH3
CH3
2S
N
Ts
S
O
OH
N
O
R
2'R
Ts
HO
OH
2b
1b
We have first synthesized a mixture of all four stereo-
isomers 2a–d in seven steps starting from (S)-proline 3
(Scheme 1). Compounds 4–7 were prepared as described
in the literature.11,12 Treatment of 7 with (COCl)2, fol-
lowed by reaction with the sodium salt of diethyl malon-
ate afforded diester 8 in 78% yield. Decarboxylation of 8
under acidic conditions at 100 ꢁC gave ketone 9 in 79%
yield, unfortunately as a racemic mixture. Reduction of
9a,b gave alcohols 2a–d.
*
Corresponding author. Tel.: +55 81 2126 8440; fax: +55 81 2126
8442; e-mail: rms@ufpe.br
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.11.016

310
M. J. e Silva et al. / Carbohydrate Research 340 (2005) 309–314
ii
i
OTs
CH2OH
COOH
N
H
4
N
H
3
N
Ts
5
iii
4
3
O
O
v, vi
iv
COCH2CH3
CH
COCH2CH3
C
2'
5
COOH
CN
2
N
N
N
1'
3'
Ts
Ts
Ts
O
8
7
6
vii
4
3
SO2
6
O
OH
viii
7
8
11
10
5
2
Ts =
CH3
2'
CH3
N
N
1'
3'
Ts
Ts
9
2a-d
9a,b
CH3
12
Scheme 1. Reagents and conditions: (i) Zn(BH4)2, THF, D, 10 h, 61%;
(ii) TsCl, Py, rt, 12 h, 89%; (iii) NaCN, Me2SO, rt, 72 h, 90%; (iv)
AcOH, 37% HCl, 100 ꢁC, 4 h, 66%; (v) (COCl)2, DMF, CH2Cl2, rt,
4 h; (vi) NaH, CH2(CO2CH2CH3)2, THF, D, 3 h, 78%; (vii) 4 M
H2SO4, 100 ꢁC, 12 h, 79%; (viii) (1) 2 equiv NaBH4, MeOH, 0 ꢁC, 1 h;
(2) 2 M HCl, 0 ꢁC, 96% (2a,b:2c,d––2.1:1).
Figure 1. Structure of compound 2a,b.
TLC [1.5:1.0 petroleum ether–EtOAc] of the mixture
2a,d showed two spots of Rf values 0.4 and 0.5 under
ultraviolet light. Each spot constituted racemic mixtures
of 2R,20S–2S,20R and 2S,20S–2R,20R. Each enantio-
meric pair was separated by liquid chromatography over
silica gel in the ratio of 2:1 (2a,b:2c,d). The one having
Rf value of 0.4 (2a,b) produced crystals from which a
suitable crystal was picked up and subjected to X-ray
analysis (Fig. 1, Table 1). It showed the relative configu-
ration at positions 2 and 20, which could either be 2R,20S
or 2S,20R. Compound 2b was synthesized enantiomeri-
cally pure starting from compound 6 as shown in
Scheme 2 and gave similar 1H NMR spectra as the race-
mic mixture (2a,b).
Table 1. Crystal data and structure refinement of 2a,b
Empirical formula
Formula weight
Temperature (K)
C14H21NO3S
283.38
293 (2)
0.71073
Monoclinic
P21/n
˚
Radiation wavelength (A)
Crystal system
Space group
Unit cell dimensions
˚
a (A)
˚
13.188(3), a = 90ꢁ
7.7314(15), b = 100.85(3)ꢁ
14.682(3), c = 90ꢁ
1470.2(5)
b (A)
˚
c (A)
3
˚
Volume (A )
Z
1
1.280
Calculated density (Mg mÀ3
)
These N-tosyl alcohols 2a,b and 2c,d have not been re-
ported in the literature and the 1H NMR spectra of 2a–d
are consistent with the proposed structures. Compounds
2b and 9a were found to be enantiomerically pure by 1H
NMR spectroscopy as verified by the chiral shift reagent
europium tris[3-heptafluoropropylhydroxymethylene)-
(+)-camphorate.
The next step was the glycosidation process, which
was performed using the trichloroacetimidate method.13
Acetylation of L-fucose followed by hydrolysis gave the
known 2,3,4-tri-O-acetyl-a/b-L-fucopyranose.14,15 This
compound was treated with trichloroacetonitrile in
dichloromethane with DBU as the catalyst to give
2,3,4-tri-O-acetyl-a-L-fucopyranosyl trichloroacetimi-
date 11.16 Reaction of optically pure 2b with 11 in the
presence of BF3ÆEt2O in CH2Cl2 gave a single com-
pound 12b in 78% yield, having the configuration
200S,20R, Rf value of 0.45 on TLC in 1.5:1.0 petroleum
ether–EtOAc. On the other hand, the reaction of the
racemic mixture 2a,b with 11 in the presence of
Absorption coefficient (mmÀ1
F(000)
Crystal size (mm)
)
0.224
608
1.0 · 0.2 · 0.2
1.91–27.53
H Range for data collection (ꢁ)
Limiting indices
À17 6 h 6 16,
0 6 k 6 10, 0 6 l 6 19
3339/3339 [Rint = 0.0000]
98.9
Reflections collected/unique
Completeness to h (%)
Absorption correction
None
Max and min transmission
Refinement method
0.9566 and 0.8071
Full-matrix least-squares on F2
3339/0/193
Data/restraints/parameters
Goodness-of-fit on F2
1.449
Final R indices [I > 2r(I)]
R indices (all data)
Largest diff. peak and hole (e AÀ3
R1 = 0.0782, wR2 = 0.1799
R1 = 0.1649, wR2 = 0.2500
1.048 and À0.959
)
TMSOTf in CH2Cl2 gave a mixture of diastereoisomers
showing two spots on the TLC plate: one with Rf value
of 0.45 corresponding to 12b, the other one with Rf
value of 0.52 and so corresponding to 12a. With careful

M. J. e Silva et al. / Carbohydrate Research 340 (2005) 309–314
311
O
gel 60 (230–400 mesh) has been employed for liquid
chromatography. Petroleum ether used in the experi-
ments had a boiling range of 40–65 ꢁC.
i
ii
CN
COOCH2CH3
N
N
N
CH3
Ts
6
Ts
10
Ts
9a
1.1. Diethyl (À)-(S)-{[N-(p-tolylsulfonyl)-2-pyrrolidin-
iii
yl]acetyl}malonate (8)
OH
OH
+
N
N
CH3
CH3
To (À)-(S)-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]acetic acid
7 (1.0 g, 3.53 mmol) in CH2Cl2 (10.0 mL) was added
two drops of DMF and oxalyl chloride (0.5 mL,
ꢀ1.5 equiv) at 0 ꢁC. The mixture was stirred for 4 h at
room temperature and concentrated to dryness. Diethyl
malonate (2.7 mL, 17.66 mmol) and 60% NaH (0.70 g,
17.66 mmol) in dry THF (10.0 mL) were stirred for
30 min at room temperature. Addition of the generated
acid chloride in dry THF (15.0 mL) to this malonate
suspension followed by stirring for 4 h at 70 ꢁC com-
pleted the reaction. Addition of water, extraction with
CH2Cl2, drying the soln over Na2SO4 and solvent
removal provided the crude product. Purification by col-
umn chromatography over silica gel using 4:1 petroleum
ether–EtOAc gave 1.17 g (78%) of an oil characterized
Ts
Ts
2b
2c
Scheme 2. Reagents and conditions: (i) EtOH, HCl(gas), rt, 24 h, 60%;
(ii) (1) 1 equiv Tebbeꢀs reagent 0.5 M in toluene, THF, 0 ꢁC, 30 min; (2)
Et2O, 0.1 M NaOH; (3) 1 M HCl, CHCl3, rt, 1.5 h, 79% from 10; (iii)
(1) 2 equiv NaBH4, MeOH, 0 ꢁC, 1 h; (2) 2 M HCl, 0 ꢁC, 96% (2b:2c––
2.1:1).
handling, these two compounds were separated and
their specific rotations and spectroscopic data obtained
(Scheme 3).
Deacetylation of 12a and 12b was performed individ-
ually using 9:6:1 methanol–water–triethylamine,17 which
gave 1a and 1b in excellent yields (Scheme 3).
Compounds 1a and 1b were evaluated for their cyto-
toxic activity with tumor cells HEp2 (larynx carcinoma)
and NCI-H292 (lung carcinoma). The methodology used
for this test was in accordance with the protocol for
Screening Chemical Agents and Natural Products.18
Unfortunately the results of the cytotoxic evaluation in
vitro showed that compounds 1a and 1b were inactive
up to a concentration of 10 lg/mL.
as a 1:1 keto-enolic mixture of 8: TLC (4:1 petroleum
25
ether–EtOAc): Rf 0.54; ½aꢁ À101.8 (c 1.05, CH2Cl2);
D
1H NMR (300 MHz, CDCl3): d 13.25 (s, 0.5H, OH),
7.76 (d, 2H, J 8.2 Hz, H-7, H-11), 7.33 (d, 2H, J
7.9 Hz, H-8, H-10), 4.50 (s, 0.5H, H-30), 4.29 (q, 4H, J
7.1 Hz, –OCH2–), 4.01–3.94 (m, 1H, H-2), 3.49–3.41
(m, 1H, H-5), 3.39 (dd, 0.5H, J 3.1 Hz, J 18.2 Hz, H-
10), 3.18 (dd, 0.5H, J 4.5 Hz, J 13.7 Hz, H-10), 3.10–
3.03 (m, 1H, H-5), 3.01 (dd, 0.5H, J 9.8 Hz, J 18.2 Hz,
H-10), 2.66 (dd, 0.5H, J 10.0 Hz, J 13.7 Hz, H-10), 2.44
(s, 1.5H, H-12), 2.43 (s, 1.5H, H-12), 1.83–1.45 (m,
4H, H-3, H-4), 1.34–1.28 (4t overlapping, 6H, J
6.9 Hz, aliph.–CH3). Anal. Calcd for C20H27NO5SÆ
1/4H2O: C, 55.86; H, 6.44. Found: C, 55.91; H, 6.41.
1. Experimental
Melting points were determined on a Electrothermal
digital melting point apparatus (model IA9100) and
are uncorrected. Specific rotations were measured with
a Perkin–Elmer polarimeter model 241. 1H and 13C
NMR spectra were recorded on a Bruker AM 300 spec-
¨
trophotometer using TMSas internal standard. Silica
1.2. N-(p-Tolylsulfonyl)-2-pyrrolidinylacetone (9a,b)
Diethyl (À)-(S){[N-(p-tolylsulfonyl)-2-pyrrolidinyl]acet-
yl}malonate 8 (1.10 g, 2.59 mmol) in 4 M H2SO4
(55.0 mL) was stirred for 12 h at 100 ꢁC. The mixture
was neutralized with satd aq NaHCO3 and extracted
with CH2Cl2. The extract was washed with water
(3 · 100 mL), dried (Na2SO4) and concentrated to yield
the crude product. Purification by column chromatogra-
phy over silica gel using 7:3 petroleum ether–EtOAc
gave 9a,b, which after crystallization from petroleum
ether–CH2Cl2 yielded colourless crystals (575 mg,
CH3
CCl3
*
O
N
*
O
2a,b, TMSOTf, CH2Cl2
O
NH
OAc
Ts
AcO
OAc
O
-30˚C, 1.5h, 91%
(12a + 12b, 1:1)
OAc
AcO
OAc
12a: 2''R,2'S + 12b: 2''S,2'R
11
MeOH: H2O: Et3N (9:6:1)
12h, rt
2b, BF3.Et2O
CH2Cl2, -5˚C, 2h, 78%
4''
3''
2''
3'
CH3
5''
1
5
CH3
6
4
O
OH
2'
N
O
3
1'
S
1
O
OAc
HO
OH
SO2
N
2
R
79%): mp 101–102 ꢁC; H NMR (300 MHz, CDCl3): d
O
6''
Ts
11''
10''
AcO
OAc
7''
8''
7.72 (d, 2H, J 8.2 Hz, H-7, H-11), 7.33 (d, 2H, J
7.9 Hz, H-8, H-10), 3.94–3.89 (m, 1H, H-2), 3.47–3.40
(m, 1H, H-5), 3.25 (dd, 1H, J 3.2 Hz, J 17.8 Hz, H-10),
3.12–3.04 (m, 1H, H-5), 2.65 (dd, 1H, J 9.7 Hz, J
17.8 Hz, H-10), 2.43 (s, 3H, H-12), 2.17 (s, 3H, H-30),
1.82–1.72 (m, 2H, H-3), 1.61–1.43 (m, 2H, H-4); 13C
12b
1a: 91%
1b: 88%
9''
MeOH: H2O: Et3N (9:6:1)
12h, rt
CH3
12''
1b
Scheme 3.

312
M. J. e Silva et al. / Carbohydrate Research 340 (2005) 309–314
NMR (75.5 MHz, CDCl3): d 207.57 (C-20), 143.94 (C-6),
134.03 (C-9), 130.15 (C-7, C-11), 128.00 (C-8, C-10),
56.26 (C-2), 51.04 (C-10), 49.55 (C-5), 32.47 (C-3),
30.94 (C-30), 24.18 (C-4), 21.91 (C-12). The NMR spec-
tra agreed with the literature data.19
from petroleum ether–CH2Cl2 yielded colourless crys-
25
D
tals (0.22 g, 79%): mp 94–96 ꢁC; ½aꢁ À116.9 (c 1,
CH2Cl2). The NMR spectra agreed with those of com-
pounds 9a,b given above.
1.5. N-(p-Tolylsulfonyl)-2-pyrrolidinyl-2-propanol (2a,b
and 2c,d)
1.3. Ethyl (À)-(S)-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ace-
tate (10)
Sodium borohydride (148 mg, 3.91 mmol) was added at
0 ꢁC to racemic 9a,b (550 mg, 1.96 mmol) dissolved in
MeOH (40.0 mL), and the reaction mixture was stirred
for 1 h at this temperature. To the soln, 2.0 M HCl
was added followed by stirring for an additional
10 min. Neutralization of this soln with aq NaHCO3,
extraction with CH2Cl2 and work-up yielded two diaste-
reoisomers, which were separated by column chroma-
tography over silica gel using 1.5:1.0 petroleum ether–
EtOAc of 2a,b (359 mg) and 2c,d (171 mg) (2.1:1). The
combined yield was 96%. These compounds were recrys-
tallized in 5:1 hexane–EtOAc.
(À)-(S)-[N-(p-Tolylsulfonyl)-2-pyrrolidinyl]acetonitrile
6 (1.0 g, 3.79 mmol) in absolute EtOH (40.0 mL)
saturated with HCl gas was stirred for 24 h at room tem-
perature. Solvent removal under diminished pressure,
dissolution of the residue in ice-cold water followed by
treatment with NaHCO3 furnished an alkaline soln with
a pH value of ꢀ9.0. Extraction with CH2Cl2, drying
(Na2SO4), filtration and solvent removal left an oil. Li-
quid chromatography of the above material over silica
gel using a mixture of 1:1 petroleum ether–diethyl ether
gave 0.71 g (60%) of chromatographically pure product
having the Rf value of 0.5 (1:1 petroleum ether–diethyl
Compound 2a,b: TLC (1.5:1 petroleum ether–
EtOAc): Rf 0.4; mp 76–78 ꢁC; 1H NMR (300 MHz,
CDCl3): d 7.73 (d, 2H, J 8.2 Hz, H-7, H-11), 7.33 (d,
2H, J 8.1 Hz, H-8, H-10), 3.93–3.85 (m, 2H, H-2, H-
20), 3.45–3.37 (m, 1H, H-5), 3.22–3.14 (m, 1H, H-5),
2.42 (s, 3H, H-12), 2.03–1.44 (m, 6H, H-10, H-3, H-4),
1.26 (d, 3H, J 6.2 Hz, H-12); 13C NMR (75.5 MHz,
CDCl3): d 143.84 (C-6), 134.80 (C-9), 130.09 (C-7, C-
11), 128.04 (C-8, C-10), 66.64 (C-20), 58.59 (C-2), 49.24
(C-5), 46.43 (C-10), 31.67 (C-3), 24.79 (C-30), 24.38 (C-
4), 21.91 (C-12).
Compound 2c,d: TLC (1.5:1 petroleum ether–
EtOAc): Rf 0.5; mp 87–89 ꢁC; 1H NMR (300 MHz,
CDCl3): d 7.73 (d, 2H, J 8.2 Hz, H-7, H-11), 7.33 (d,
2H, J 8.1 Hz, H-8, H-10), 4.20–4.16 (m, 1H, H-20),
4.10–4.02 (m, 1H, H-2), 3.46 (br s, 1H, OH), 3.42–3.34
(m, 1H, H-5), 3.22–3.13 (m, 1H, H-5), 2.43 (s, 3H, H-
12), 1.88–1.31 (m, 6H, H-10, H-3, H-4), 1.23 (d, 3H, J
6.4 Hz, H-12); 13C NMR (75.5 MHz, CDCl3): 144.12
(C-6), 134.70 (C-9), 130.19 (C-7, C-11), 127.98 (C-8,
C-10), 64.10 (C-20), 58.10 (C-2), 48.80 (C-5), 45.84
(C-10), 31.70 (C-3), 24.46 (C-4), 23.26 (C-30), 21.93
(C-12).
25
ether): ½aꢁ À103.2 (c 1.04, CH2Cl2); IR (cmÀ1): 1735
D
(m C@O), 1250 and 1050 (m C–O); 1H NMR
(300 MHz, CDCl3): d 7.76 (d, 2H, J 8.2 Hz, H-7, H-
11), 7.32 (d, 2H, J 8.2 Hz, H-8, H-10), 4.14 (2q overlap-
ping, 2H, J 7.1 Hz, –OCH2–), 3.99–3.93 (m, 1H, H-2),
3.48–3.41 (m, 1H, H-5), 3.17–3.11 (m, 1H, H-5), 3.10
(dd, 1H, J 3.9 Hz, J 16.0 Hz, H-10), 2.53 (dd, 1H, J
10.1 Hz, J 16.0 Hz, H-10), 2.44 (s, 3H, H-12), 1.90–
1.51 (m, 4H, H-3, H-4), 1,27 (t, 3H, J 7.1 Hz, aliph.
–CH3); 13C NMR (75.5 MHz, CDCl3): d 171.62 (CO),
143.92 (C-6), 134.48 (C-9), 130.10 (C-7, C-11), 127.94
(C-8, C-10), 60.83 (–OCH2–), 56.95 (C-2), 49.56 (C-10),
41.77 (C-5), 32.00 (C-3), 24.12 (C-4), 21.88 (C-12),
14.57 (aliph.–CH3). The IR and NMR spectra agreed
with the literature data.19
1.4. (À)-(S)-[N-(p-Tolylsulfonyl)-2-pyrrolidinyl]acetone
(9a)
Tebbeꢀs reagent (2.0 mL, 0.5 M in toluene) was added to
ester 10 (0.31 g, 1.0 mmol) dissolved in THF (3.0 mL) at
0 ꢁC, and the mixture was stirred for 30 min at room
temperature. Soon after, ether (15.0 mL) and seven
drops of 0.1 M NaOH were added, and the soln was stir-
red for an additional 30 min. Drying (Na2SO4), filtra-
tion over celite and solvent removal left the crude
product. This was then dissolved in CHCl3 (15.0 mL)
and six drops of 2.0 M HCl were added to it followed
by stirring for 1.5 h at room temperature. Water
(30.0 mL) was added to the soln followed by neutral-
ization with NaHCO3. Extraction with CH2Cl2
(3 · 30 mL), drying (Na2SO4), filtration and solvent re-
moval provided the crude product (0.28 g). Column
chromatography over silica gel using 1.5:1.0 petroleum
ether–EtOAc gave pure 9a, which after crystallization
1.6. (À)-(2S,20R)- and (À)-(2S,20S)-N-(p-Tolylsulfonyl)-
2-pyrrolidinyl]-2-propanol (2b and 2c)
Starting from enantiomerically pure ketone 9a and fol-
lowing the procedure described above, 2b and 2c were
obtained in a (2.1:1) ratio and separated on column
chromatography. Yield 96%.
25
D
Compound 2b: Rf 0.4; mp 84–85 ꢁC; ½aꢁ À98.0 (c
1.04, CH2Cl2). Anal. Calcd for C14H21NO3S: C, 59.33;
H, 7.47. Found: C, 59.26; H, 7.31.
25
D
Compound 2c: Rf 0.5; mp 92.5–94 ꢁC; ½aꢁ À20.5 (c
0.83, CH2Cl2). Anal. Calcd for C14H21NO3S: C, 59.33;

M. J. e Silva et al. / Carbohydrate Research 340 (2005) 309–314
313
H, 7.47. Found: C, 59.69; H, 7.72. The NMR spectra for
2b and 2c agreed with those of compounds 2a,b and 2c,d
above.
135.02 (C-900), 130.15 (C-700, C-1100), 127.95 (C-800, C-
1000), 101.71 (C-1), 76.51 (C-20), 71.98 (C-3), 70.72 (C-
4), 69.73 (C-2), 69.45 (C-5), 57.65 (C-200), 49.15 (C-500),
43.84 (C-10), 31.71 (C-300), 24.45 (C-400), 22.06 (C-30),
21.91(C-1200), 21.16 (COCH3), 21.07 (COCH3), 21.05
(COCH3), 16.59 (C-6). Anal. Calcd for C26H37NO10S:
C, 56.20; H, 6.71; N, 2.52; S, 5.77. Found: C, 56.20;
H, 7.01; N, 2.78; S, 5.85.
1.7. 1-Methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl
2,3,4-tri-O-acetyl-b-L-fucopyranoside (12a and 12b)
To a cold (À30 ꢁC) suspension of 2a,b (150 mg,
0.53 mmol) and trichloroacetimidate 11 (345 mg,
0.79 mmol) in dry CH2Cl2 (5.0 mL) containing a small
1.8. 1-Methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl
2,3,4-tri-O-acetyl-b-L-fucopyranoside (12b)
˚
amount of 4 A molecular sieves under argon atmosphere
was added TMSOTf (20 lL). After stirring for 1.5 h, the
reaction mixture was treated with 1.5 g of NaHCO3 and
filtered. Water was then added and the mixture was ex-
tracted with CH2Cl2 (3 · 20.0 mL). Drying (Na2SO4)
and solvent removal provided crude diastereoisomers
12a and 12b, which were separated by column chroma-
tography over silica gel using 1.5:1 petroleum ether–
EtOAc. The ratio of 12a (126.8 mg) and 12b (139 mg)
was ꢀ1:1. The combined yield was 91%.
To a cold (À5 ꢁC) suspension of 2b (20 mg, 0.07 mmol),
˚
trichloroacetimidate 11 (61 mg, 0.14 mmol) and 4 A
molecular sieves in dry CH2Cl2 (2.0 mL) under argon,
was added BF3ÆEt2O (20 lL). After stirring for 2 h, the
reaction mixture was treated with a satd aq NaHCO3
(4 mL) and filtered. Extraction of the mixture with
CH2Cl2 (3 · 20 mL), drying (Na2SO4) and solvent re-
moval provided the crude product of 12b, which was
purified by preparative TLC over silica gel using
9.7:0.3 toluene–MeOH to yield 30 mg (78%) of pure
12b. The NMR spectra agreed with those of compound
12b above.
Compound 12a: TLC (1.5:1.0 petroleum ether–
25
D
EtOAc): Rf 0.52; ½aꢁ +64.7 (c 1, CH2Cl2); mp 146–
1
147 ꢁC (petroleum ether–EtOAc); H NMR (300 MHz,
CDCl3): d 7.75 (d, 2H, J 8.2 Hz, H-700, H-1100), 7.34 (d,
2H, J 7.9 Hz, H-800, H-1000), 5.22 (d, 1H, J4,3 3.4 Hz,
H-4), 5.15 (dd, 1H, J2,1 7.7 Hz, J2,3 10.5 Hz, H-2), 5.04
(dd, 1H, J3,2 10.5 Hz, J3,4 3.4 Hz, H-3), 4.50 (d, 1H,
J1,2 7.7 Hz, H-1), 4.02–3.91 (m, 1H, H-20), 3.80–3.71
(m, 2H, H-200, H-5), 3.44–3.36 (m, 1H, H-500), 3.23–
3.15 (m, 1H, H-500), 2.43 (s, 3H, H-1200), 2.18 (s, 3H,
COCH3), 2.05 (s, 3H, COCH3), 1.99 (s, 3H, COCH3),
1.84–1.37 (m, 6H, H-300, H-400, H-10), 1.21 (d, 3H, J
6.0 Hz, H-30), 1.17 (d, 3H, J6,5 6.4 Hz, H-6); 13C NMR
(75.5 MHz, CDCl3): d 170.31 (CO), 169.87 (CO),
169.19 (CO), 142.78 (C-600), 134.20 (C-900), 129.21 (C-
700, C-1100), 127.37 (C-800, C-1000), 98.60 (C-1), 72.13 (C-
20), 71.06 (C-3), 70.05 (C-4), 68.71 (C-2), 68.60 (C-5),
56.94 (C-200), 48.66 (C-500), 42.76 (C-10), 30.72 (C-300),
23.50 (C-400), 21.16 (C-1200), 20.46 (COCH3), 20.39
1.9. 1-Methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl
b-L-fucopyranoside (1)
A 1% soln of 12 in 9:6:1 MeOH–water–triethylamine
was stirred overnight at room temperature. Water was
added and extraction with CH2Cl2 (3 · 20 mL), drying
(Na2SO4), filtration and solvent removal provided the
crude product 1. Column chromatography over silica
gel using 9.5:0.5 CH2Cl2–MeOH as eluent, gave pure
1, which after crystallization from 9:1 cyclohexane–
CH2Cl2, yielded colourless crystals.
25
D
Compound 1a: Starting from 12a, 91%; ½aꢁ +87.3 (c
0.48, MeOH); mp 196–198 ꢁC (C6H12–CH2Cl2); 1H
NMR (300 MHz, CD3OD): d 7.76 (d, 2H, J 8.1 Hz,
H-700, H-1100), 7.46 (d, 2H, J 7.8 Hz, H-800, H-1000), 4.22
(d, 1H, J1,2 7.8 Hz, H-1), 4.02–3.93 (m, 1H, H-20),
3.84–3.73 (m, 1H, H-200), 3.61–3.48 (m, 4H, H-2, H-3,
H-4, H-5), 3.38–3.07 (m, 2H, H-500), 2.43 (s, 3H, H-
1200), 2.21–2.12 (m, 1H, H-10), 1.78–1.32 (m, 5H, H-300,
H-400, H-10), 1.22 (d, 3H, J 6.0 Hz, H-30), 1.18 (d, 3H,
J6,5 6.6 Hz, H-6); 13C NMR (75.5 MHz, CD3OD): d
144.92 (C-600), 135.45 (C-900), 130.90 (C-700, C-1100),
128.94 (C-800, C-1000), 102.63 (C-1), 75.12 (C-20), 73.05
(C-3, C-4), 72.28 (C-2), 71.65 (C-5), 58.87 (C-200), 50.36
(C-500), 45.24 (C-10), 31.83 (C-300), 24.83 (C-400), 21.46
(C-1200), 20.79 (C-30), 16.85 (C-6). Anal. Calcd for
C20H31NO7S: C, 55.92; H, 7.27; N, 3.26; S, 7.46. Found:
(COCH3), 20.29 (COCH3), 19.23 (C-30), 15.17 (C-6);
+
HRFABMS[M+H] calcd for C26H38NO10S:
556.2217. Found = 556.2222.
Compound 12b: TLC (1.5:1 petroleum ether–EtOAc):
25
Rf 0.44; ½aꢁ À50 (c 1, CH2Cl2); mp 181–182 ꢁC (petro-
D
leum ether–EtOAc); 1H NMR (300 MHz, CDCl3): d
7.74 (d, 2H, J 8.2 Hz, H-700, H-1100), 7.36 (d, 2H, J
8.1 Hz, H-800, H-1000), 5.22 (d, 1H, J4,3 3.5 Hz, H-4),
5.18 (dd, 1H, J2,1 7.9, J2,3 10.3 Hz, H-2), 5.02 (dd, 1H,
J3,2 10.3, J3,4 3.5 Hz, H-3), 4.50 (d, 1H, J1,2 7.9 Hz, H-
1), 3.89 (m, 1H, H-20), 3.80 (m, 1H, H-5), 3.69 (m, 1H,
H-200), 3.41–3.33 (m, 1H, H-500), 3.26–3.18 (m, 1H, H-
500), 2.43 (s, 3H, H-1200), 2.17 (s, 3H, COCH3), 1.98 (s,
3H, COCH3), 1.91 (s, 3H, COCH3), 1.79–1.39 (m, 6H,
H-300, H-400, H-10), 1.36 (d, 3H, J 6.2 Hz, H-30), 1.23
(d, 3H, J6,5 6.2 Hz, H-6); 13C NMR (75.5 MHz, CDCl3):
d 171.20 (CO), 170.65 (CO), 169.65 (CO), 143.71 (C-600),
C, 55.99; H, 7.30; N, 3.29; S, 7.43.
25
D
Compound 1b: Starting from 12b, 88%; ½aꢁ À68.3 (c
0.36, MeOH); mp 171–172 ꢁC (C6H12–CH2Cl2); 1H
NMR (300 MHz, CDCl3): d 7.75 (d, 2H, J 8.4 Hz,

314
M. J. e Silva et al. / Carbohydrate Research 340 (2005) 309–314
H-700, H-1100), 7.31 (d, 2H, J 8.4 Hz, H-800, H-1000), 4.26 (d,
1H, J1,2 7.2 Hz, H-1), 3.97–3.91 (m, 1H, H-20), 3.80–3.61
(m, 5H, H-2, H-3, H-4, H-5, H-200), 3.39–3.32 (m, 1H, H-
500), 3.15–3.07 (m, 1H, H-500), 2.41 (s, 3H, H-1200), 2.16–
2.07 (m, 1H, H-10), 1.82–1.77 (m, 1H, H-10), 1.58–1.44
(m, 4H, H-300, H-400), 1.36 (d, 3H, J 6.6 Hz, H-30), 1.33
(d, 3H, J6,5 6.3 Hz, H-6); 13C NMR (75.5 MHz, CDCl3):
d 143.33 (C-600), 134.56 (C-900), 129.69 (C-700, C-1100),
127.53 (C-800, C-1000), 103.85 (C-1), 75.36 (C-20), 73.89
(C-3), 71.48 (C-4), 70.40 (C-2), 66.08 (C-5), 58.12 (C-
200), 48.77 (C-500), 45.85 (C-10), 31.11 (C-300), 24.28 (C-
400), 22.53 (C-1200), 21.45(C-30), 16.39 (C-6). Anal. Calcd
for C20H31NO7S: C, 55.92; H, 7.27; N, 3.26; S, 7.46.
Found: C, 56.26; H, 7.05; N, 2.77; S, 7.99.
Bernard Lyon 1, Villeurbanne, France, for obtaining
the crystallographic data.
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Supplementary materials
The crystallographic data were deposited at Cambridge
structural database (accession number CCDC 252734).
These data can be obtained free of charge from the
director, CCDC, 12 Union road, Cambridge CB21EZ,
UK (fax: +44 1223 336033; e-mail: deposit@ccdc.
cam.ac.uk or http://www.ccdc.cam.ac.uk).
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The authors express their gratitude to CAPES(Brazil),
CNPq (Brazil) and CNRS(France) for financial help.
One of us (M. J. e Silva) is thankful to CAPES/COFE-
CUB for
a
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Doboszewski for his participation in group meetings
and his nice suggestions at the initial stage of this work,
and to Dr. Silene C. do Nascimento for evaluating the
cytotoxic activity. We also thank Miss Monique Perrin,
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´
Laboratoire de Cristallographie, Universite Claude