New N-alkylsulfonamides and alkyl sulfonates derived from 6-C-sulfosugars

Article abstract of DOI:10.1016/S0040-4020(02)00874-8

Protected 6-C-sulfosugars have been transformed into alkyl sulfonates and N-alkylsulfonamides, including a pseudo-disaccharide with a 6 to 6′-sulfonamide linkage. The method involves the oxidation of 6-thioacetate sugar derivatives to 6-C-sulfosugars, and their transformation into sulfonyl chlorides using SO₂Cl₂ in anhydrous CH₂Cl₂ followed by in situ coupling with nucleophiles in the presence of an excess of base. Sulfonylation through phase-transfer conditions has proved to be suitable for the synthesis of the pseudo-disaccharide.

Full text of DOI:10.1016/S0040-4020(02)00874-8

Tetrahedron 58 (2002) 7967–7973
New N-alkylsulfonamides and alkyl sulfonates derived
from 6-C-sulfosugars
*
´ ´ ´ ´ ´
Vıctor Ulgar, Ines Maya, Jose Fuentes and Jose G. Fernandez-Bolan˜os
´ ´ ´
Departamento Quımica Organica, Facultad Quımica, Universidad Sevilla, Apartado 553, E-41071 Seville, Spain
Received 7 May 2002; revised 25 June 2002; accepted 15 July 2002
Abstract—Protected 6-C-sulfosugars have been transformed into alkyl sulfonates and N-alkylsulfonamides, including a pseudo-
disaccharide with a 6 to 60-sulfonamide linkage. The method involves the oxidation of 6-thioacetate sugar derivatives to 6-C-sulfosugars, and
their transformation into sulfonyl chlorides using SO2Cl2 in anhydrous CH2Cl2 followed by in situ coupling with nucleophiles in the presence
of an excess of base. Sulfonylation through phase-transfer conditions has proved to be suitable for the synthesis of the pseudo-
disaccharide. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
peroxy acids.20–23 We now carry out the transformation of
differently protected 6-C-sulfosugar derivatives into alkyl
sulfonate esters and N-alkylsulfonamides.
Sulfonamides have been shown to possess a wide spectrum
of therapeutic applications.1 Thus, their potential use as
antihypertensive,2 antiglaucoma,3 antibacterial,4 antiviral,5
antiprotozoal,6 antifungal,7 and antitumoral8 agents as well
as therapeutic drugs for the treatment of rheumatoid
arthritis,9 male erectile dysfunction,10 and obesity11 has
been reported. Furthermore, some of them have proved to be
useful as herbicides12 and plaguicides.13 Alkyl sulfonates
have been found to be inhibitors of cell proliferation, thus
being potentially useful for the treatment of cancer.14 These
activities have increased the interest in the synthesis of
complex sulfonates and sulfonamides.
2. Results and discussion
In this paper we describe the preparation of the sulfonyl
chlorides 3 and 12 starting from the known 6-thioacetates
122 and 10,24 which by oxidation with 33% (w/v) hydrogen
peroxide in glacial acetic acid in the presence of 1 equiv. of
tetrabutylammonium acetate led to 2 and 11, in 85 and 90%
yield, respectively, after purification by column chroma-
tography (Schemes 1 and 2). The preparation of the
tetrabutylammonium salts 2 and 11 was a good choice in
order to increase the commonly low solubility of potassium
or sodium salts in organic solvents.
Few reports deal with the synthesis of carbohydrate-derived
sultones,15,16 sulfonates17,18 and sulfonamides.17d–19 These
syntheses have been focused mainly on the preparation of
antisense and antiviral oligonucleotides, in which the
phosphate linkage has been replaced by a methylene-
sulfonyloxy or methylenesulfonamido internucleoside link-
age. The described methodology exploits the reactivity of
nucleophilic a-lithio mesylates or sulfonate-stabilized
Horner–Emmons reagents on primary iodides or carbonyl
compounds, and involves the sugar homologation with a
methylene group. To our knowledge, there is no report on
the synthesis of non-homologated sugar sulfonate esters or
sulfonamides.
A wide variety of methods have been reported for the
preparation of sulfonyl chlorides. The most common
synthetic procedure involves the reaction of a sulfonic
acid or its salts with PCl5, POCl3 and SOCl2.25 The use of
triphosgene18 or Ph3P/SO2Cl2 has been reported for the
26
preparation of carbohydrate sulfonyl chlorides, in which the
carbohydrate ring and the chlorosulfonyl group are linked
by an ethylidene bridge. A recent transformation of arene
and alkane sodium sulfonates into sulfonyl chlorides and
bromides using Ph3P·Cl2 and Ph3P·Br2 has been described.27
In our hands, treatment of the sodium salt of 2 with
triphenylphosphine dichloride or dibromide in dry aceto-
nitrile was unsuccessful. This sodium salt was prepared by
oxidation of thioacetate 1 in the presence of sodium acetate.
We have previously reported the preparation of a number of
sugar 6-sulfonic acids by oxidation of 6-thiosugars with
Keywords: sulfonyl chlorides; sulfonates; sulfonamides; pseudo-
disaccharide; phase-transfer catalysis.
Chlorination of 2 with an excess of 1:1 Ph3P/SO2Cl2
(5 equiv.) in dry CH2Cl2, followed by portionwise addition
*
Corresponding author. Tel.: þ34-95-455-7151; fax: þ34-95-462-4960;
e-mail: bolanos@us.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00874-8

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V. Ulgar et al. / Tetrahedron 58 (2002) 7967–7973
Scheme 1. Reagents and conditions: (a) H2O2, Bu4NOAc, AcOH, 408C, 12 h; (b) SO2Cl2, CH2Cl2, rt, 4 h; (c) BuNH2; (d) 0.5 M NaOMe, MeOH; Amberlite
IR-120 (Hþ); (e) 1:1 ROH/Et3N; (f) Bu4NHSO4, sat. aq. NaHCO3, 8 (3 equiv.), CH2Cl2.
of butylamine at 2158C up to pH 6–7 led to the O-protected
N-butylsulfonamide 4 (47%). The attempt at chromato-
graphic isolation of the sulfonyl chloride 3 resulted in the
formation of the methyl sulfonate 6 (32%) using CH2Cl2–
MeOH as eluent, and extensive decomposition was
observed using EtOAc–hexane.
The synthesis of the sulfonamide-linked pseudo-disacchar-
ide 9 (Scheme 1), attempted by coupling 3 with the
6-amino-D-galactopyranose derivative 8 (2 equiv.) followed
by portionwise addition of Et3N up to pH 6–7, was
unsuccessful. So we tried the coupling step under phase-
transfer conditions28,29 in CH2Cl2 and aqueous saturated
NaHCO3 as a source of base, using tetrabutylammonium
hydrogenosulfate as catalyst. This gave 9 in 40% yield.
These phase-transfer conditions have also been applied to
the preparation of the N-butyl sulfonamide 4 and the
isopropyl sulfonate 7 from 2 in 51 and 20% yields,
respectively.
Chlorination of 2 with SO2Cl2 (5 equiv.) in the absence of
Ph3P, followed by addition of butylamine gave 4 in a better
yield (70%), with the additional advantage of avoiding the
´
tedious elimination of the formed Ph3PO. Zemplen de-O-
acetylation of 4 gave 5 (95%). Preparation of the alkyl
sulfonates 6 and 7 was carried out by reaction of 2 with
sulfuryl chloride and in situ addition of a 1:1 mixture of the
corresponding alcohol and Et3N up to pH 6–7. The lower
yield of 6 (41%) is presumably due to the lability of the
methyl sulfonate ester to SN2 reactions during the isolation
and purification steps, compared with the more sterically
hindered isopropyl sulfonate 7 (54%).
Activation of the furanosic 6-C-sulfosugar 11 with SO2Cl2
(Scheme 2) followed by careful addition of butylamine up to
pH 6–7, led to an irresolvable 1:2 mixture of the protected
N-butylsulfonamide 13 and the a,b-unsaturated N-butyl-
sulfonamide 14, in 43% yield. The 1H NMR spectrum of the
mixture showed signals in the olephinic region for protons

V. Ulgar et al. / Tetrahedron 58 (2002) 7967–7973
7969
Scheme 2. Reagents and conditions: (a) H2O2, Bu4NOAc, AcOH, 408C, 12 h; (b) SO2Cl2, CH2Cl2, rt, 4 h; (c) BuNH2; (d) 1:1 i-PrOH/Et3N.
H-5 and H-6, with a J5,6 of 15.0 Hz, indicating a trans
relationship for these protons. The cis isomer was not
detected. Similarly, chlorination of 11, followed by reaction
with 1:1 i-PrOH–Et3N afforded a chromatographically
irresolvable 1:1 mixture of the isopropyl sulfonate 15 and
the a,b-unsaturated isopropyl sulfonate 16 in 36% yield, as
deduced from the 1H NMR spectrum of the mixture
(Scheme 2). No traces of the cis isomer of 16 were detected.
When the furanosic sulfonyl chloride 12 was reacted with
butylamine in phase-transfer conditions, a non-resolved 2:7
mixture of compounds 13 and 14 was obtained in 28% yield.
The higher proportion of the elimination compound 14,
compared with that obtained when the reaction is carried out
in CH2Cl2 quenching with butylamine (13/14 in 1:2 ratio),
may be associated to the longer reaction times in phase-
transfer conditions.
elimination process would result in the opening of the
tetrahydropyrane ring.
Analysis of the vecinal coupling constants J1,2, J2,3, J3,4 for
13–16 (3.6–3.7, 0.0, 3.0–3.3 Hz, respectively), indicates
the preference of these compounds for an E4 conformation
in solution. The sequence C-3–S of 13 and 15 adopts
preferentially a ziz-zag planar arrangement (Fig. 1) as
The formation of the a,b-unsaturated C-sulfo derivatives 14
and 16 can be explained as a result of base-catalysed acetic
acid elimination, due to the acidity of a hydrogen in a
position to a sulfonyl group. The absence of elimination
products in the pyranosic derivatives is not surprising, as the
Figure 1. Major conformation of 13 and 15.

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V. Ulgar et al. / Tetrahedron 58 (2002) 7967–7973
deduced from the J3,4, J4,5, J5,6a and J5,6b values (3.0, 8.1–
8.5, 2.3 and 8.8–8.9 Hz, respectively).
J¼7.3 Hz, 4Me butyl); 13C NMR (75.5 MHz, CD3OD): d
172.18, 171.73, 170.37 (CO), 135.22, 132.92, 129.56,
128.47 (Ph), 99.27 (C-1), 73.12 (C-4), 72.72 (C-3), 67.45
(C-5), 59.50 (C-1 butyl), 56.31 (OMe), 53.84 (C-2, C-6),
24.78 (C-2 butyl), 20.70 (C-3 butyl and 2COMe ), 13.94
(C-4 butyl); IR: nmax 3452 (NH), 1752 (CvO acetate), 1664
(Amide I), 1239 (AcO, SO23 ) cm21; FAB-MS, m/z 490
[100%, (M2Bu4Nþ2Na)þ]. Anal. calcd for C34H60N2O11S:
C, 57.93; H, 8.58; N, 3.97. Found: C, 57.74; H, 8.28; N,
3.95.
3. Conclusion
We have described a method for the synthesis of N-alkyl
sugar sulfonamides and alkyl sugar sulfonates from
6-thiosugar derivatives by oxidation to 6-C-sulfosugars,
chlorination with SO2Cl2, and coupling of the sulfonyl
chloride with amines and alcohols in the presence of a base.
A novel procedure based on the coupling of sugar sulfonyl
chlorides with nucleophiles in phase-transfer conditions is
presented.
4.1.2. Tetrabutylammonium 3,5-di-O-acetyl-6-deoxy-
1,2-O-isopropylidene-a-D-glucofuranose-6-sulfonate
(11). To a solution of 1024 (684 mg, 1.89 mmol) in glacial
acetic acid (8 mL) were added tetrabutylammonium acetate
(569 mg, 1.89 mmol) and 33% (w/v) hydrogen peroxide
(2.3 mL, 22.6 mmol). The solution was stirred at 408C for
12 h, concentrated, and then co-concentrated with H2O
(3£10 mL). The residue was purified by column chroma-
tography (20:1!5:1 CH2Cl2–MeOH) to give 11 (1.04 g,
90%) as a colourless oil. Rf¼0.31 (10:1 CH2Cl2–MeOH);
[a ]D¼þ58 (c 1.3, CHCl3); 1H NMR (300 MHz, CD3OD): d
5.90 (d, 1H, J1,2¼3.7 Hz, H-1), 5.55 (m, 1H, J4,5¼8.1 Hz,
J5,6a¼2.3 Hz, J5,6b¼8.9 Hz, H-5), 5.22 (d, 1H, J3,4¼3.0 Hz,
H-3), 4.52 (d, 1H, H-2), 4.36 (dd, 1H, H-4), 3.24 (dd, 1H,
J6a,b¼14.6 Hz, H-6a), 3.24 (m, 8H, 4CH2 butyl), 3.06 (dd,
1H, H-6b), 2.05, 1.98 (2s, 3H each, Ac), 1.66 (m, 8H, 4CH2
butyl), 1.47, 1.29 (2s, 3H each, Me2C), 1.41 (m, 8H, 4CH2
butyl), 1.02 (m, 12H, J¼7.3 Hz, 4Me butyl); 13C NMR
(75.5 MHz, CD3OD): d 171.48, 171.24 (CO), 113.44
(Me2C ), 106.40 (C-1), 84.65 (C-2), 80.51 (C-4), 75.90
(C-3), 67.73 (C-5), 59.50 (C-1 butyl), 53.13 (C-6), 26.97,
26.40 (Me2C), 24.78 (C-2 butyl), 21.07, 20.90 (COMe),
20.69 (C-3 butyl), 13.93 (C-4 butyl); IR: nmax 1752 (CvO),
1244 (AcO, SO23 ) cm21; HRFAB-MS, m/z calcd for
[MþBu4N]þ C45H91N2O10S 851.6394, found 851.6398.
4. Experimental
4.1. General methods
Melting points were determined on an Electrothermal
apparatus and are uncorrected. Optical rotations were
measured at 208C with a Perkin–Elmer 241 polarimeter,
and IR spectra (KBr disks) were obtained with an FT-IR
Bomem MB-120 spectrophotometer. 1H (300 and
500 MHz) and 13C (75.5 and 125.7 MHz) NMR spectra
were recorded on Bruker AMX-300 and AMX-500
spectrometers for solutions in CDCl3 and CD3OD, using
tetramethylsilane as internal standard. The assignments of
1H and 13C signals were confirmed by homonuclear COSY
and heteronuclear 2D correlated spectra, respectively. Mass
spectra were recorded on Kratos MS 80 RFA and
Micromass AutoSpeQ mass spectrometers. All reactions
were monitored by TLC, which was carried out on
aluminium sheets coated with silica gel 60 F254 (Merck);
spots were visualized by UV light and by charring with
10% H2SO4 in EtOH. Column chromatography was
performed using Merck silica gel 60 (40–63 mm), and
preparative TLC was carried out using Merck silica
gel 60 HF254 (5–40 mm). Microanalyses were performed
4.2. General methods for the synthesis of alkyl sulfonates
and N-alkylsulfonamides
´
at the ‘Instituto de Investigaciones Quımicas’, Sevilla,
Spain.
To a solution of 2 or 11 (0.17 mmol) in dry CH2Cl2 (2 mL)
at 08C was slowly added sulfuryl chloride (68 mL,
˚
0.85 mmol) under Ar in the presence of activated 4 A
4.1.1. Tetrabutylammonium methyl 3,4-di-O-acetyl-2-
benzamido-2,6-dideoxy-a-D-glucopyranoside-6-sul-
fonate (2). To a solution of 3,4-di-O-acetyl-6-S-acetyl-2-
benzamido-2-deoxy-6-thio-a-D-glucopyranoside122 (500 mg,
0.73 mmol) in glacial acetic acid (6 mL) were added
tetrabutylammonium acetate (220 mg, 0.73 mmol) and
33% (w/v) hydrogen peroxide (2.3 mL, 14.6 mmol). The
solution was stirred at 408C for 12 h, concentrated, and then
co-concentrated with H2O (3£10 mL). The resulting residue
was purified by column chromatography using 10:1
CH2Cl2–MeOH as eluent to give 2 (781 mg, 85%) as a
colourless oil. Rf¼0.25 (10:1 CH2Cl2–MeOH); [a ]D¼þ568
molecular sieves. The reaction was left at room temperature
for 4 h. Then one or various of the following methods was
used.
Method A: the reaction mixture was cooled at 2158C and
butylamine was slowly added up to pH 6–7. The solution
was concentrated to dryness and the product was purified as
indicated.
Method B: the reaction mixture was cooled at 2158C and
1:1 ROH–Et3N mixture was slowly added up to pH 6–7.
The solution was concentrated to dryness and the product
was purified as indicated.
1
(c 1.1, CHCl3); H NMR (300 MHz, CD3OD): d 8.05 (d,
1H, J2,NH¼9.4 Hz, NHBz), 7.76–7.42 (m, 5H, Ph), 5.41
(dd, 1H, J2,3¼10.8 Hz, J3,4¼9.2 Hz, H-3), 4.90 (dd, 1H,
J4,5¼10.1 Hz, H-4), 4.80 (d, 1H, J1,2¼3.6 Hz, H-1), 4.48
(ddd, 1H, H-2), 4.41 (dt, 1H, 1/2(J5,6aþJ5,6b)¼5.4 Hz, H-5),
3.52 (s, 3H, OMe), 3.24 (m, 8H, 4CH2 butyl), 3.00 (d, 2H,
H-6a, H-6b), 2.04, 1.92 (2s, 3H each, Ac), 1.66 (m, 8H,
4CH2 butyl), 1.41 (m, 8H, 4CH2 butyl), 1.02 (t, 12H,
Method C: the reaction mixture was slowly added at 08C to a
stirred mixture of saturated aq. NaHCO3 (10 mL) containing
Bu4NHSO4 (25 mg, 0.07 mmol) and a solution of butyl-
amine (1.70 mmol) in CH2Cl2 (4 mL). The mixture was
stirred at rt for 1 h. The organic phase was separated, dried
(MgSO4), concentrated and chromatographed.

V. Ulgar et al. / Tetrahedron 58 (2002) 7967–7973
7971
Method D: the reaction mixture was slowly added at 08C to a
stirred mixture of saturated aq. NaHCO3 (10 mL) containing
Bu4NHSO4 (25 mg, 0.07 mmol) and a solution of ROH
(1.70 mmol) in CH2Cl2 (4 mL). The mixture was stirred at rt
for 1 h. The organic phase was separated, dried (MgSO4),
concentrated and chromatographed.
54.23 (C-6), 43.84 (C-1 butyl), 33.33 (C-2 butyl), 20.85
(C-3 butyl), 14.01 (C-4 butyl); IR: nmax 3309 (NH, OH),
1649 (Amide I), 1331, 1187 (SO2) cm21; HRFAB-MS, m/z
calcd for [MþNa]þ C18H28N2O7SNa 439.1515, found
439.1510.
4.2.3. Methyl 3,4-di-O-acetyl-2-benzamido-2,6-dideoxy-
a-D-glucopyranoside-6-(methyl sulfonate) (6). Purifi-
cation by column chromatography (1:1 EtOAc–hexane).
Method B: 33 mg, 41%. Rf¼0.10 (1:2 EtOAc–hexane);
[a ]D¼þ808 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.74–7.42 (m, 5H, Ph), 6.39 (d, 1H, J2,NH¼9.2 Hz, NH),
5.38 (dd, 1H, J2,3¼10.8 Hz, J3,4¼9.4 Hz, H-3), 4.99 (t, 1H,
J4,5¼9.5 Hz, H-4), 4.86 (d, 1H, J1,2¼3.6 Hz, H-1), 4.51
(ddd, 1H, H-2), 4.38 (td, 1H, J5,6a¼9.3 Hz, J5,6b¼2.1 Hz,
H-5), 3.93 (s, 3H, SO3Me), 3.48 (s, 3H, OMe), 3.42 (dd, 1H,
J6a,b¼15.0 Hz, H-6a), 3.25 (dd, 1H, H-6b), 2.09, 1.98 (2s,
3H each, Ac); 13C NMR (75.5 MHz, CDCl3): d 171.25,
169.72, 166.99 (CO), 133.38, 131.81, 128.58, 126.88 (Ph),
98.01 (C-1), 70.54 (C-3), 70.37 (C-4), 64.99 (C-5), 55.94
(SO3Me), 55.79 (OMe), 52.29 (C-2), 50.80 (C-6), 20.54
(2COMe ); IR: nmax 3333 (NH), 1752 (CvO), 1664 (Amide
I), 1363, 1170 (SO2), 1243 (AcO) cm21; HRFAB-MS, m/z
calcd for [MþNa]þ C19H25NO10SNa 482.1097, found
482.1103.
4.2.1. Methyl 3,4-di-O-acetyl-2-benzamido-2,6-dideoxy-
a-D-glucopyranoside-6-N-butylsulfonamide (4). Purifi-
cation by column chromatography (40:1 CH2Cl2–MeOH).
Method A: 59 mg, 70%. Method C: 43 mg, 51%. Rf¼0.72
(10:1 CH2Cl2–MeOH); [a ]D¼þ808 (c 1.7, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.74–7.43 (m, 5H, Ph), 6.43 (d,
1H, J2,NH¼9.2 Hz, NHBz), 5.00 (t, 1H, J3,4¼9.5 Hz,
J4,5¼10.0 Hz, H-4), 4.88 (dd, 1H, J2,3¼10.9 Hz, H-3),
4.87 (d, 1H, J1,2¼3.5 Hz, H-1), 4.49 (ddd, 1H, H-2), 4.39
(td, 1H, J5,6a¼10.2 Hz, J5,6b¼2.5 Hz, H-5), 4.20 (m, 1H,
SO2NH), 3.49 (s, 3H, OMe), 3.31 (dd, 1H, J6a,b¼14.8 Hz,
H-6a), 3.14 (dd, 1H, H-6b), 3.13 (m, 2H, CH2 butyl), 2.09,
1.99 (2s, 3H each, Ac), 1.56 (m, 2H, CH2 butyl), 1.39 (m,
2H, CH2 butyl), 0.95 (t, 3H, J¼7.3 Hz, Me butyl); 13C
NMR: (75.5 MHz, CDCl3): d 171.35, 169.60, 167.04 (CO),
133.28, 131.86, 128.58, 126.88 (Ph), 98.20 (C-1), 70.42,
70.35 (C-3, C-4), 65.69 (C-5), 55.99 (OMe), 52.45 (C-2),
51.74 (C-6), 43.18 (C-1 butyl), 31.83 (C-2 butyl), 20.53,
20.50 (COMe ), 19.59 (C-3 butyl), 13.42 (C-4 butyl); IR:
nmax 3304 (NH), 1745 (CvO), 1657 (Amide I), 1244
(AcO), 1333, 1147 (SO2) cm21; HRFAB-MS, m/z calcd for
[MþNa]þ C22H32N2O9SNa 523.1723, found 523.1736.
Anal. calcd for C22H32N2O9S: C, 52.79; H, 6.44; N, 5.60.
Found: C, 52.82; H, 6.31; N, 5.82.
4.2.4. Methyl 3,4-di-O-acetyl-2-benzamido-2,6-dideoxy-
a-D-glucopyranoside-6-(isopropyl sulfonate) (7). Purifi-
cation by column chromatography (1:1 EtOAc–hexane).
Method B: 46 mg, 54%. Method D: 17 mg, 20%. Rf¼0.21
(1:2 EtOAc–hexane); [a]D¼þ968 (c 0.9, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.73–7.40 (m, 5H, Ph), 6.40 (d, 1H,
J2,NH¼9.4 Hz, NH), 5.36 (dd, 1H, J3,4¼10.8 Hz,
J4,5¼9.4 Hz, H-4), 4.98 (t, 1H, J2,3¼10.8 Hz, H-3), 4.94
(m, 1H, J¼6.2 Hz, CHMe2), 4.84 (d, 1H, J1,2¼3.6 Hz, H-1),
4.50 (ddd, 1H, H-2), 4.38 (td, 1H, J5,6a¼9.2 Hz,
J5,6b¼2.1 Hz, H-5), 3.47 (s, 3H, OMe), 3.35 (dd, 1H,
J6a,b¼14.8 Hz, H-6a), 3.21 (dd, 1H, H-6b), 2.08, 1.97 (2 s,
3H each, Ac), 1.41 (d, 6H, CHMe2); 13C NMR (75.5 MHz,
CDCl3): d 171.23, 169.71, 166.99 (CO), 133.43, 131.77,
128.56, 126.87 (Ph), 97.91 (C-1), 77.55 (CHMe2), 70.63
(C-3), 70.43 (C-4), 65.05 (C-5), 55.76 (OMe), 52.51, 52.30
(C-2, C-6), 22.99, 22.82 (CHMe2), 20.51 (2COMe ); IR:
Compound 4 was also prepared using 1:1 Ph3P/SO2Cl2 in
the chlorination step: to a stirred solution of Ph3P (223 mg,
0.85 mmol) in dry CH2Cl2 (2 mL) and cooled at 08C sulfuryl
chloride (70 mL, 0.85 mmol) was slowly added under Ar in
˚
the presence of activated 4 A molecular sieves. After 4 h at
rt a solution 2 (117 mg, 0.17 mmol) in dry CH2Cl2 (2 mL)
was added, and stirred for 2 h. The reaction mixture was
cooled to 2158C and butylamine portionwise added up to
pH 6–7. The solution was concentrated and 4 (49 mg, 47%)
isolated by preparative TLC (40:1 CH2Cl2–MeOH).
4.2.2. Methyl 2-benzamido-2,6-dideoxy-a-D-gluco-
pyranoside-6-N-butylsulfonamide (5). To a solution of 4
(45 mg, 0.09 mmol) in dry MeOH (2 mL) 0.5 M methanolic
NaOMe was added up to pH 9–10. After 4 h at rt Amberlite
IR-120 (Hþ) cation exchange resin was added up to pH 7,
removed by filtration and washed with MeOH. The
combined methanolic solutions were concentrated and the
residue was purified by preparative TLC (10:1 CH2Cl2–
MeOH) to give 5 (35 mg, 95%). Rf¼0.37 (10:1 CH2Cl2–
n
max 3340 (NH), 1748 (CvO), 1658 (Amide I), 1383, 1167
(SO2), 1238 (AcO) cm21; CI-MS, m/z 456 (41%,
[M2OMe]þ), 488 (100%, [MþH]þ); HRCI-MS, m/z
calcd for [MþH]þ C21H30NO10S 488.1590, found
488.1580.
4.2.5. Methyl 3,4-di-O-acetyl-2-benzamido-2,6-dideoxy-
a-D-glucopyranoside-6-N-(6-deoxy-1,2:3,4-di-O-isopro-
pylidene-a-D-galactopyranos-6-yl)sulfonamide (9). Puri-
fication by column chromatography (1:2!1:1 EtOAc–
hexane). Prepared following Method C but using 3 equiv. of
6-amino-6-deoxy-1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose (8): 45 mg, 40%. Rf¼0.26 (1:1 EtOAc–hexane);
1
MeOH); [a]D¼þ528 (c 1.3, CHCl3); H NMR (300 MHz,
CD3OD): d 7.86–7.43 (m, 5H, Ph), 4.80 (d, 1H,
J1,2¼3.6 Hz, H-1), 4.14 (dd, 1H, J2,3¼10.8 Hz, H-2), 4.09
(td, 1H, J4,5¼9.8 Hz, J5,6a¼1.8 Hz, J5,6b¼9.7 Hz, H-5), 3.84
(dd, 1H, J3,4¼8.9 Hz, H-3), 3.57 (dd, 1H, J6a,b¼14.7 Hz,
H-6a), 3.45 (s, 3H, OMe), 3.26 (dd, 1H, H-6b), 3.25 (dd, 1H,
H-4), 3.07 (t, 2H, J¼7.0 Hz, CH2 butyl), 1.55 (m, 2H, CH2
butyl), 1.39 (m, 2H, CH2 butyl), 0.94 (t, 3H, J¼7.2 Hz, Me
butyl); 13C NMR (75.5 MHz, CD3OD): d 170.72 (CO),
135.56, 132.74, 129.48, 128.54 (Ph), 99.82 (C-1), 75.02
(C-4), 72.31 (C-3), 69.06 (C-5), 56.27 (OMe), 55.94 (C-2),
1
[a ]D¼þ338 (c 1.8, CHCl3); H NMR (500 MHz, CDCl3)
glucose unit: d 7.73–7.43 (m, 5H, Ph), 6.40 (d, 1H,
J2,NH¼9.3 Hz, NHBz), 5.36 (dd, 1H, J2,3¼10.8 Hz,
J3,4¼9.4 Hz, H-3), 5.03 (t, 1H, J4,5¼10.2 Hz, H-4), 4.88
(d, 1H, J1,2¼3.6 Hz, H-1), 4.51 (ddd, 1H, H-2), 4.38 (td,
J5,6a¼10.2 Hz, J5,6b¼2.3 Hz, H-5), 3.50 (dd, 1H, J6a,b
¼
14.6 Hz, H-6a), 3.49 (s, 3H, OMe), 3.21 (dd, 1H, H-6b),

7972
V. Ulgar et al. / Tetrahedron 58 (2002) 7967–7973
2.07, 1.97 (2s, 3H each, Ac); galactose unit: d 5.56 (d, 1H,
J1,2¼5.1 Hz, H-1), 4.90 (br s, 1H, SO2NH), 4.61 (dd, 1H,
J2,3¼2.4 Hz, J3,4¼7.9 Hz, H-3), 4.34 (dd, 1H, H-2), 4.21
(dd, 1H, J4,5¼1.9 Hz, H-4), 3.96 (ddd, 1H, J5,6a¼5.2 Hz,
J5,6b¼8.0 Hz, H-5), 3.39 (m, 1H, J6a,b¼13.7 Hz, H-6a), 3.34
(m, 1H, H-6b), 1.54, 1.46, 1.35, 1.33 (4s, 3H each, Me2C);
13C NMR (125.5 MHz, CDCl3) glucose unit: d 171.33,
169.51, 167.02 (CO), 133.55, 131.81, 128.61, 127.14, (Ph),
98.21 (C-1), 70.73 (C-3), 70.52 (C-4), 65.83 (C-5), 56.01
(OMe), 53.76 (C-6), 52.41 (C-2), 20.54 (2COMe ); galactose
unit: d 109.48, 108.85 (Me2C), 96.29 (C-1), 71.21 (C-4),
70.80 (C-3), 70.26 (C-2), 65.83 (C-5), 43.48 (C-6), 25.90,
25.78, 24.74, 24.29 (Me2C); IR: nmax 3297 (NH), 1752
(CvO), 1650 (Amide I), 1379, 1149 (SO2), 1237 (AcO)
cm21; CI-MS, m/z 629 [50%, (M2Me2COþH)þ], 655
[39%, (M2MeOHþH)þ], 687 (100%, [MþH]þ); HRCI-
MS, m/z calcd for [MþH]þ C30H43N2O14S 687.2435, found
687.2434.
CDCl3) compound 15: d 5.91 (d, 1H, J1,2¼3.6 Hz, H-1),
5.57 (td, 1H, J4,5¼8.1 Hz, J5,6a¼2.3 Hz, J5,6b¼8.8 Hz, H-5),
5.33 (d, 1H, J3,4¼3.0 Hz, H-3), 4.97 (m, 1H, J¼6.3 Hz,
CHMe2), 4.49 (d, 1H, H-2), 4.40 (dd, 1H, H-4), 3.65 (dd,
1H, J6a,b¼15.0 Hz, H-6a), 3.38 (dd, 1H, H-6b), 2.09, 2.05
(2s, 3H each, Ac), 1.31, 1.25 (2s, 3H each, Me2C), 1.41, (d,
6H, CHMe2); compound 16: 6.76 (dd, 1H, J4,5¼3.5 Hz,
J5,6¼15.1 Hz, H-5), 6.62 (dd, 1H, J4,6¼1.8 Hz, H-6), 5.99
(d, 1H, J1,2¼3.7 Hz, H-1), 5.32 (d, 1H, J3,4¼3.3 Hz, H-3),
4.99 (td, 1H, H-4), 4.78 (m, 1H, J¼6.2 Hz, CHMe2), 4.62
(d, 1H, H-2), 2.05 (s, 3H, Ac), 1.53, 1.34 (2 s, 3H each,
Me2C), 1.41, (d, 6H, CHMe2); 13C NMR: (75.5 MHz,
CDCl3) compound 15: d 170.53, 169.38 (CO), 112.55
(Me2C ), 104.81 (C-1), 83.24 (C-2), 78.47 (C-4), 77.39
(C HMe2), 74.13 (C-3), 64.24 (C-5), 52.17 (C-6), 29.52,
25.99 (Me2C), 23.03, 22.81 (CHMe2), 20.58, 20.35
(COMe ); compound 16: d 169.38 (CO), 138.81 (C-5),
128.31 (C-6), 112.55 (Me2C ), 104.50 (C-1), 83.14 (C-2),
77.39 (C-4, CHMe2), 77.14 (C-3), 26.54, 25.99 (Me2C),
23.03, 22.81 (CHMe2), 20.58 (COMe ); IR: nmax 1728
(CvO), 1240 (SO2) cm21; FAB-MS, compound 15 m/z 411
(5%, [MþH]þ); compound 16 m/z 351 (15%, [MþH]þ).
4.2.6. 3,5-Di-O-acetyl-6-deoxy-1,2-O-isopropylidene-a-
D-glucofuranose-6-N-butylsulfonamide (13) and (E )-3-
O-acetyl-5,6-dideoxy-1,2-O-isopropylidene-a-D-xylo-
hex-5-enofuranose-6-N-butylsulfonamide (14). Purifi-
cation by column chromatography (1:2 EtOAc–hexane).
Method A: 28 mg, 43% (13/14 in 1:2 ratio). Method C:
18 mg, 28% (13/14 in 2:7 ratio). Rf¼0.28 for both
compounds (1:2 EtOAc–hexane); 1H NMR (300 MHz,
CDCl3) compound 13: d 5.91 (d, 1H, J1,2¼3.7 Hz, H-1),
5.47 (td, 1H, J4,5¼9.1 Hz, J5,6a¼2.1 Hz, J5,6b¼9.6 Hz, H-5),
5.35 (d, 1H, J3,4¼3.0 Hz, H-3), 4.49 (d, 1H, H-2), 4.63 (t,
1H, J¼6.5 Hz, NH), 4.35 (dd, 1H, H-4), 3.54 (dd, 1H,
J6a,b¼14.9 Hz, H-6a), 3.28 (dd, 1H, H-6b), 3.12 (q, 2H,
J¼6.8 Hz, CH2 butyl), 2.07, 2.04 (2s, 3H each, COMe), 1.53
(m, 2H, CH2 butyl), 1.38 (m, 2H, CH2 butyl), 1.31, 1.25 (2s,
3H each, Me2C), 0.94 (t, 3H, Me butyl); compound 14: d
6.62 (dd, 1H, J4,5¼3.5 Hz, J5,6¼15.0 Hz, H-5), 6.57 (d, 1H,
H-6), 5.98 (d, 1H, J1,2¼3.7 Hz, H-1), 5.30 (d, 1H,
J3,4¼3.1 Hz, H-3), 4.97 (dd, 1H, J4,5¼2.8 Hz, H-4), 4.61
(d, 1H, H-2), 4.28 (br t, 1H, J¼6.5 Hz, NH), 3.00 (m, 2H,
J¼6.8 Hz, CH2 butyl), 2.05 (s, 3H, Ac), 1.53, 1.33 (2s, 3H
each, Me2C), 1.53 (m, 2H, CH2 butyl), 1.38 (m, 2H, CH2
butyl), 0.92 (t, 3H, Me butyl); 13C NMR (75.5 MHz, CDCl3)
compound 13: d 170.53, 169.38 (CO), 112.56 (Me2C ),
104.90 (C-1), 83.19 (C-2), 78.71 (C-4), 74.07 (C-3), 64.83
(C-5), 52.89 (C-6), 42.81 (C-1 butyl), 31.98 (C-2 butyl),
29.52, 26.00 (Me2C), 20.69, 20.54, (COMe ), 19.55 (C-3
butyl), 13.41 (C-4 butyl); compound 14: d 169.38 (COMe),
136.19 (C-5), 130.72 (C-6), 112.44 (Me2C ), 104.48 (C-1),
83.19 (C-2), 77.35 (C-4), 76.85 (C-3), 42.62 (C-1 butyl),
31.81 (C-2 butyl), 26.57, 26.00 (Me2C), 20.42 (COMe ),
19.58 (C-3 butyl), 13.41 (C-4 butyl). IR: nmax 3301 (NH),
1752 (CvO), 1236 (AcO) cm21; FAB-MS, compound 13
m/z 446 (100%, [MþNa]þ); compound 14 m/z 386 (97%,
[MþNa]þ); HRFAB-MS, m/z calcd for 13 [MþNa]þ
C17H29NO9SNa 446.1461, found 446.1456.
Acknowledgments
´
We thank the Direccion General de Ensen˜anza Superior e
Investigacion Cientıfica (Grant No. BQU 2001-3740) and
´
´
the Junta de Andalucia (FQM134) for financial support.
´
V. U. thanks the Ministerio de Educacion y Cultura for the
award of a fellowship. This work is part of the European
Programme COSTD13, action number D13/0001/98.
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