5a-Carba-β-D-, 5a-carba-β-L- and 5-thio-β-L-xylopyranosides as new orally active venous antithrombotic agents

Article abstract of DOI:10.1002/(SICI)1522-2675(19981111)81:11<2043::AID-HLCA2043>3.0.CO;2-6

Mitsunobu displacement of (-)-(1S,4R,5S,6S)-4,5,6-tris{[(tert- butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((-)-12; a (-)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one (16) provided a 5a- carba-β-D-pyranoside (+)-17 that was convert

Full text of DOI:10.1002/(SICI)1522-2675(19981111)81:11<2043::AID-HLCA2043>3.0.CO;2-6

Helvetica Chimica Acta ± Vol. 81 (1998)
2043
5a-Carba-b-d-, 5a-Carba-b-l- and 5-Thio-b-l-xylopyranosides
as New Orally Active Venous Antithrombotic Agents
by Patrice Renaut, Jean Millet, Christiane Sepulchre, Jocelyne Theveniaux, and VeÂronique Barberousse
Laboratoires Fournier, S. A., Centre de Recherche, 50 rue de Dijon, F-21121 Daix
1
and Vincent Jeanneret ) and Pierre Vogel*
Â
Institut de chimie organique de lꢀUniversite de Lausanne, BCH, CH-1015 Lausanne-Dorigny
Mitsunobu displacement of ( )-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol
(( )-12; a ( )-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one (16) provided a 5a-
carba-b-d-pyranoside (‡)-17 that was converted into (‡)-4-ethyl-7-[(1'R,4'R,5'S,6'R)-4',5',6'-trihydroxycyclo-
hex-2'-en-1'-yloxy]-2H-1-benzopyran-2-one ((‡)-5) and (‡)-4-ethyl-7-[(1'R,2'R,3'S,4'R)-2',3',4'-trihydroxycy-
clohexyloxy]-2H-1-benzopyran-2-one ((‡)-6). The 5a-carba-b-d-xyloside (‡)-6 was an orally active anti-
thrombotic agent in the rat (venous Wesslerꢀs test), but less active than racemic carba-b-xylosides (Æ)-5 and (Æ)-6.
The 5a-carba-b-l-xyloside ( )-6 was derived from the enantiomer (‡)-12 and found to be at least 4 times as
active as (‡)-6. (‡)-4-Cyanophenyl 5-thio-b-l-xylopyranoside ((‡)-3) was synthesized from l-xylose and found
to maintain ca. 50% of the antithrombotic activity of its d-enantiomer. Compounds (Æ)-5, (Æ)-6, and ( )-6 are
in vitro substrates for galactosyltransferase 1.
Introduction. ± Thromboembolic disorders are a major cause of morbidity and
mortality. Dermatan sulfate, the chondroitin sulfates, and heparan sulfate have in vivo
antithrombotic activities [1][2]. Since the demonstration that 4-nitrophenyl b-d-
xylopyranoside [3][4] can be a primer for the biosynthesis of glycosaminoglycan
(GAG), it has been shown that b-d-xylopyranosides of aglycones making these
compounds able to penetrate the plasmic membranes are antithrombotic agents that
can be taken orally [5]. Among the various xylosides and analogues tested (more than
700) [6], naroparcil (1), beciparcil (( )-2), and iliparcil (4) have the most interesting
activities [7]. Naroparcil (1) was shown to be a primer for the free GAG chain synthesis
after oral administration in the rabbit [8]. The GAGꢀs extracted from the plasma were
found to enhance inhibition of thrombin by heparin cofactor II and contained
dermatan-sulfate-like compounds that can be responsible for the antithrombotic effect
[8].
The observed plasma level of inactive aglycone following oral administration of
xyloside 4 suggests that hydrolysis may reduce the antithrombotic potency of such
systems. In order to increase their bioavailability, we have envisioned to replace the b-
d-xylopyranoside by carba-pyranoside analogues such as the conduritol-B derivative
(‡)-5 and its dihydro analogue (‡)-6.
In a preliminary communication [9], we have shown that (‡)-6 has a weak activity
as oral antithrombotic agent in the rat (modified Wesslerꢀs model). Surprisingly, its
1
)
Present address: Scribbs Research Institute, La Jolla, CA, USA.

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Helvetica Chimica Acta ± Vol. 81 (1998)
enantiomer ( )-6 which has the configuration of l-xylose was found to have an activity
close to that of iliparcil (4). We report here the details of these studies and answer the
question whether thio-l-xylopyranosides should also be antithrombotic agents. As we
shall see, (‡)-4-cyanophenyl 5-thio-b-l-xylopyranoside ((‡)-3) derived from l-xylose
maintains ca. 50% of the antithrombotic activity of ( )-3.
Syntheses. ± Since the ethereal link between the conduritol-B moiety and the
aglycone (4-ethyl-7-hydroxy-2H-1-benzopyran-2-one) will be generated through a SN2
displacement, a suitably semi-protected conduritol-F intermediate was required.
Among the numerous synthesis of conduritol-F that have been proposed [10], the
one by Le Drian [11] has demonstrated that racemic (Æ)-12 can be derived from the
Diels-Alder adduct (Æ)-7 of furan to 1-cyanovinyl acetate via (Æ)-8 ± 11, whereas
enantiomerically pure (‡)-12 and ( )-12 can be derived with the same ease from the
Diels-Alder adducts of furan to enantiomerically pure 1-cyanovinyl esters [12]. The
synthesis of (Æ)-12 [11] involves the base-induced isomerization of the 7-oxabicy-
clo[2.2.1]heptan-2-one derivative (Æ)-10 into cyclohex-2-enone (Æ)-11 (91%). The
reduction of (Æ)-11 under Lucheꢀs conditions [13] provided a 2.5 : 1 mixture of
conduritol derivatives (Æ)-12 and (Æ)-13 in 84% yield. Compound (Æ)-10 was obtained
in 8 steps and 50% yield following Le Drianꢀs method [11]. Applying Allemannꢀs
modification [14], (Æ)-10 was derived from (Æ)-7 in 4 steps and 37% overall yield
(Scheme 1).

Helvetica Chimica Acta ± Vol. 81 (1998)
2045
Scheme 1
Enantiomerically pure ( )-10 was prepared according to the Le Drianꢀs method
[11]. Alternatively, it was obtained by the Johnson-Zeller [15] resolution of (Æ)-10: The
products of addition of the lithium conjugate base of (‡)-(S)-N,S-dimethyl-S-phenyl-
sulfoximide to (Æ)-10 were separated by flash chromatography (silica gel) yielding (‡)-
14 (42%) and ( )-15 (39%). Pyrolysis of ( )-15 (100 ± 2008/0.2 Torr) gave ( )-10 in
94% yield. The latter was transformed to ( )-12 as described in the racemic series.
The Mitsunobu [16] displacement of ( )-12 with hydroxycoumarine 16 [17]
provided (‡)-17. The reaction produced a low yield using Ph3P and diethyl
azodicarboxylate (< 30%). With 1,1'-(azodicarbonyl)bispiperidine and (Bu)3P in
anh. THF (0 ± 258), (‡)-17 was isolated in 63% yield when starting with a 5 : 2 mixture
of ( )-12 and ( )-13. Probably for steric reasons, ( )-13 did not react under the
Mitsunobu conditions and was recovered after chromatographic purification. Treat-
ment of (‡)-17 with 40% aqueous HF solution (PhMe, MeCN, 208, 24 h) provided
crude (‡)-5. Acetylation (Ac2O, pyridine, cat. 4-(dimethylamino)pyridine (DMAP),
208, 24 h) gave the triacetate (‡)-18 (79%), the ammonolysis of which with NH3/
MeOH (208, 48 h) produced pure (‡)-5. Hydrogenation of (‡)-17 (AcOEt, 20% Pd/C,
H2, 1 atm) gave (‡)-19 (92%), and desilylation (HF/PhMe, MeCN) produced crude
(‡)-6. Acetylation (Ac2O/pyridine, cat. DMAP) led to ( )-20 (71%), the ammonol-
ysis (NH3/MeOH) of which furnished pure (‡)-6 (86%). The racemic (Æ)-5 and (Æ)-6
were prepared in the same way using a 5 : 2 mixture of (Æ)-12 and (Æ)-13.

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Helvetica Chimica Acta ± Vol. 81 (1998)
The carba-xylopyranoside analogues (‡)-5, (Æ)-5, (‡)-6, and (Æ)-6 were submitted
to in vivo and in vitro tests (see below) and found to be active as antithrombotic agents.
Strikingly, the racemic carba-xyloside (Æ)-6 appeared to be more active than the
enantiomerically pure (‡)-6 with the d-xylo configuration. We thus prepared the carba-
b-l-pyranoside ( )-6 starting from diastereoisomeric sulfoximide (‡)-14 (from (Æ)-10)
and confirmed that the carba-b-l-xylopyranoside ( )-6 is more potent than its b-d-
enantiomer (‡)-6 as oral antithrombotic agent in the rat. This led us to prepare 4-
cyanophenyl 5-thio-b-l-xylopyranoside ((‡)-3) starting from (‡)-26 (via (‡)-27).
Glycosyl bromide (‡)-26 was obtained from l-xylose which was protected ( !(‡)-21)
and then tosylated [18a] ( !(‡)-22; Scheme 2). Subsequently, the 5-O-tosyl derivative
(‡)-22 was transformed according to a procedure similar to that reported by Ingles and
Whistler [18b] for the thio-d-xyloside ( !(‡)-23 !(‡)-24 !( )-25 !(‡)-26; see
Scheme 2 and Exper. Part), the main modification consisting in using AcSK instead
of BnSNa. In the thio-xylopyranoside series, the b-l-enantiomer (‡)-3 is less active
than the b-d-enantiomer ( )-3, in contrast to the carba-b-xyloside enantiomers (‡)-
and ( )-6.
Scheme 2
Biological Assays. ± The carba-xylosides (Æ)-5, (Æ)-6, (‡)-6, and ( )-6 and the thio-
xylosides (‡)-3 and ( )-3 [19] were tested for their oral venous antithrombotic activity
in the rat [6a][20] (modified Wesslerꢀs test [21]). Oral administration of these
compounds 4 h before the injection of the thrombogenic stimulus Xa factor reduced
thrombus weight in a dose-related manner as shown in the Table. In parallel (see
Table), we examined the in vitro ability of these compounds to be substrates for
galactosyltransferase 1 (GT-1), the second enzyme involved in the biosynthesis of the
glycosaminoglycan-linkage region. The enzyme was extracted from the epiphyses of
femurs and tibias of chick embryos [22]. It is worth noting that the oral antithrombotic
activity parallels the Km values.
Conclusion. ± For the first time, we demonstrate that carba analogues of coumarine
b-xylopyranosides have a significant potential as oral antithrombotic agents. Because
these compounds are expected to be hydrolyzed more slowly than the corresponding
O- and S-xylosides, studies should be pursued to define their therapeutic index and

Helvetica Chimica Acta ± Vol. 81 (1998)
2047
Table. In vivo (rat) Antithrombotic Activity and in vitro Association Constant (Km) for Galactosyltransferase 1
(GT-1) of Carba-xylosides 5 and 6 and Thio-xylosides 3
Configuration of
the xyloside
in vivo Activity
in vitro Activity
Km (GT-1)
Dose
Activitya)
(Æ)-5
(Æ)-6
(‡)-6
dl
dl
d
l
d
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
10 mg/kg
10 mg/kg
28 Æ 10%
55 Æ 10%
21 Æ 10%
96 Æ 3%
98 Æ 2%
45 Æ 10%
3.6 mm
0.94 mm
b
)
(
(
)-6
)-3
0.61 mm
0.041 mm
b
(‡)-3
l
)
a) Inhibition of thrombus formation, see text. b) Cannot be evaluated at 5 mm.
cumulative dose/activity ratio in order to establish whether they can be alternative
drugs for the treatment of thromboembolic disorders. Our work demonstrates also that
thio-b-l- and carba-b-l-xylopyranosides are potential oral antithrombotic agents.
Although the thio-b-l-pyranoside (‡)-3 is found to be less active than its enantiomer
( )-3, it is striking to observe for the carba-xylosides that the l-xylo-configurated
derivative ( )-6 is significantly more active than its d-xylo-enantiomer (‡)-6.
Furthermore, it is found that the carba-xylosides with the configuration of l-xylose
can be substrates for the galactosyltransferase 1.
Experimental Part
General. See [23]. FC ˆ flash chromatography.
4-Cyanophenyl 5-Thio-b-l-xylopyranoside ((‡)-3). A suspension of (‡)-27 (260 mg, 0.66 mmol) and 18.8%
MeONa in MeOH (60 ml) in MeOH (15 ml) was stirred under N2 for 90 min. The mixture was then neutralized
‡
with resin Amberlite ꢁ 120 IRH and filtered. The filtrate was evaporated and the residue crystallized from
MeOH/Et2O: 90 mg (51%) of (‡)-3. White crystals. M.p. 1808. [a]2D9 ˆ 70 (c ˆ 0.43, MeOH). 1H-NMR
(300 MHz, (D6)DMSO): 7.80 (d, J ˆ 9, 2 H); 7.26 (d, J ˆ 9, 2 H); 5.32 (d, J ˆ 8.7, 1 H); 3.60 (m, 1 H); 3.51
(m, 1 H); 3.15 (m, 1 H); 2.62 (m, 2 H). 13C-NMR, IR, UV, MS: similar to those reported for the d-xylo series.
Anal. calc. for C12H13NO4S (267.31): C 53.91, H 4.90; found: C 53.47, H 5.00.
(‡)-4-Ethyl-7-[(1'R,4'R,5'S,6'R)-4',5',6'-trihydroxycyclohex-2'-en-1'-yloxy]-2H-1-benzopyran-2-one ((‡)-
5). A mixture of (‡)-18 (0.5 g, 1.13 mmol) and MeOH sat. with NH3 (30 ml) was stirred at 208 for 48 h. The
solvent was evaporated and the residue purified by FC (silica gel, AcOEt/light petroleum ether/MeOH 8 :2 :1;
25
25
25
Rf 0.4): 300 mg (84%) of (‡)-5. Colorless solid. M.p. 197 ± 1988. [a] ˆ‡ 165, [a] ˆ‡ 175, [a] ˆ‡ 201,
589
577
546
25
25
[a] ˆ‡ 376, [a] ˆ‡ 479 (c ˆ 0.7, CH2Cl2/MeOH 1 : 1). UV (MeCN): 214 (14000), 255 (2700). IR (KBr):
435
405
3450, 3400, 3340, 3890, 1670, 1610, 1540, 1510, 1425, 1400, 1375, 1290, 1200, 1150, 1110, 1080, 1050, 1020, 1000,
960, 890, 850, 815, 800, 780, 750. 1H-NMR (400 MHz, (D6)DMSO): 7.71 (d, 3J ˆ 8.9, H C(5)); 7.03 (d, 4J ˆ 2.4,
H
C(8)); 6.99 (dd, 3J ˆ 8.9, 4J ˆ 2.4, H C(6)); 6.15 (s, H C(3)); 5.65 (ddd, J(2',3') ˆ 10.3, J(1',2') ˆ 2.4,
J(2',4') ˆ 1.7, H C(2')); 5.55 (ddd, J(2',3') ˆ 10.3, J(3',4') ˆ 2.3, J(1',3') ˆ 1.9, H C(3')); 5.40 ± 4.80 (br. s,
3 OH); 4.96 (ddd, J(1',6') ˆ 7.7, J(1',2') ˆ 2.4, J(1',3') ˆ 1.9, H C(1')); 3.97 (ddd, J(4',5') ˆ 7.6, J(3',4') ˆ 2.3,
J(2',4') ˆ 1.7, H C(4')); 3.54 (dd, J(5',6') ˆ 10.2, J(1',6') ˆ 7.7, H C(6')); 3.34 (dd, J(5',6') ˆ 10.2, J(4',5') ˆ 7.6,
H
C(5')); 2.79 (q, J ˆ 7.4, MeCH2); 1.22 (t, J ˆ 7.4, MeCH2). 13C-NMR (100.6 MHz, (D6)DMSO): 161.2
(s, C(2)); 160.4 (s, C(7)); 158.2, 154.8 (2s, C(4a), C(8a)); 133.5 (d, J ˆ 161, C(3)); 126.0, 123.7 (2d, J ˆ 162, 163,
C(2'), C(3')); 112.3 (s, C(4)); 113.1, 109.2, 102.6 (3d, C(5), C(6), C(8)); 79.3, 75.8, 73.7, 71.2 (4d, J ˆ 147, 138,
139, 140, C(1'), C(6'), C(5'), C(4')); 24.0 (t, J ˆ 128, MeCH2); 12.3 (q, J ˆ 127, MeCH2). CI-MS (NH3): 318 (60,
‡
M ), 281(4), 246(10), 255(2), 181(2), 147(100), 96(6). Anal. calc. for C17H18O16 (318.33): C 63.64, H 5.74,
O 30.62 (with 0.14 H2O, as titrated by the Karl-Fisher technique); found: C 63.19, H 5.78.
Racemate (Æ)-5 was prepared from (Æ)-18 as above. M.p. 149 ± 1518.
(‡)-4-Ethyl-7-[(1'R,2'R,3'S,4'R)-2',3',4'-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((‡)-6). A soln.
of 40% aq. HF soln. (0.53 ml) in MeCN (11 ml) was added dropwise to a soln. of (‡)-19 (1.1 g, 1.66 mmol) in

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Helvetica Chimica Acta ± Vol. 81 (1998)
toluene (6 ml) at 208. After stirring at 208 for 24 h, the solvent was evaporated and the residue purified by FC
(silica gel, AcOEt/light petroleum ether/MeOH 8 :1:1; Rf 0.4): 498 mg (93%) of (‡)-6. White solid. M.p. 140 ±
25
25
25
25
25
1508. [a] ˆ‡ 8, [a] ˆ ‡ 9, [a] ˆ ‡ 15, [a] ˆ‡ 21, [a] ˆ‡ 12 (c ˆ 0.9, CH2Cl2/MeOH 1 : 1). UV
589
577
546
435
405
(MeCN): 214 (11000), 223 (8300). IR (KBr): 3400 (br.), 3060, 2960, 2940, 2900, 1720, 1610, 1550, 1530, 1500,
1450, 1430, 1370, 1340, 1270, 1200, 1160, 1135, 1080, 1070, 1030, 1000, 940, 880, 850, 820, 800. 1H-NMR
(400 MHz, (D6)DMSO): 7.68 (d, J(5,6) ˆ 8.9, H C(5)); 7.04 (d, J(6,8) ˆ 2.4, H C(8)); 6.97 (dd, J(5,6) ˆ 8.9,
J(6,8) ˆ 2.4, H C(6)); 6.13 (s, H C(3)); 4.27 (ddd, J(1',6') ˆ 10.1, J(1',2') ˆ 8.8, J(1',6') ˆ 4.5, H C(1')); 3.29
(dd, J(2',3') ˆ 8.9, J(1',2') ˆ 8.8, H C(2')); 3.25 (ddd, J(4',5') ˆ 10.9, J(3',4') ˆ 8.8, J(4',5') ˆ 4.7, H C(4')); 3.06
(dd, J(2',3') ˆ 8.9, J(3',4') ˆ 8.8, H C(3')); 2.78 (q, J ˆ 7.4, MeCH2); 1.95 (dm, J(1',6') ˆ 4.5, H C(6')); 1.73
(dm, J(4',5') ˆ 4.7,
H
C(5')); 1.43 ± 1.27 (m, H C(5'),
H
C(6')); 1.22 (t, J ˆ 7.4, MeCH2). 13C-NMR
(100.6 MHz, (D6)DMSO): 161.6 (s, C(2)); 160.5 (s, C(7)); 158.3, 154.8 (2s, C(4a), C(8a)); 125.8 (d, J ˆ 162,
C(3)); 113.4, 109.0, 102.4 (3d, J ˆ 164, 170, 163, C(5), C(6), C(8)); 112.0 (s, C(4)); 79.3, 77.7, 75.5, 71.5 (4d, J ˆ
155, 146, 134, C(1'), C(2'), C(3'), C(4')); 28.4, 25.6 (2t, J ˆ 130, 131, C(5'), C(6')); 24.1 (t, J ˆ 128, MeCH2); 12.4
‡
(q, J ˆ 127, MeCH2). CI-MS (NH3): 320 (33, M ), 190(100), 162(29), 147(14), 112(15), 83(21). Anal. calc.
for C17H20O6 (320.34): C 62.78, H 6.37, O 30.85 (with 0.27 H2O, as titrated by the Karl-Fisher technique); found:
C 62.58, H 6.19.
Enantiomer ( )-6 was prepared from ( )-19 (derived from (‡)-14) as above. White solid. M.p. 142 ± 1498.
[a]2D5
ˆ
8 (c ˆ 1.0, CH2Cl2/MeOH 1 : 1).
Racemate (Æ)-6 was prepared from (Æ)-19 as above. M.p. 157 ± 1588.
(
)-(1R,4R,5R,6R)-5-exo,6-endo-Bis{[(tert-butyl)dimethylsilyl]oxy}-7-oxabicyclo[2.2.1]heptan-2-one (( )-
10). In a Büchi bulb oven, ( )-15 (2.55 g, 4.60 mmol) was heated to 508/5 min, 1008/5 min, 1508/4 min, 1808/
2 min, 1908/5 min, and 2008/6 min under 0.2 Torr. The crude oil obtained was filtered through a pad of silica gel
(AcOEt/light petroleum ether 1 :9). 1.6 g (94%) of ( )-10. Colorless oil. [a]D25
spectral data: see [11].
ˆ
30 (c ˆ 2.8, CHCl3). Other
(‡)-(1S,4S,5S,6S)-5-exo,6-endo-Bis{[(tert-butyl)dimethylsilyl]oxy}-7-oxabicyclo[2.2.1]heptan-2-one ((‡)-
10). As described for ( )-10, starting with (‡)-14. [a]2D5 ˆ‡ 32 (c ˆ 2.3, CHCl3).
(1S,2S,4S,5S,6S)-2-exo-{[(S)-N-Methyl-S-phenylsulfonimidoyl]methyl}-5,6-bis{[(tert-butyl)dimethylsilyl]-
oxy}-7-oxabicyclo[2.2.1]heptan-2-ol ((‡)-14) and (1R,2R,4R,5R,6R)-2-exo-{[(S)-N-Methyl-S-phenylsulfon-
imidoyl]methyl}-5,6-bis{[(tert-butyl)dimethylsilyl]oxy}-7-oxabicyclo[2.2.1]heptan-2-ol (( )-15). At 258, 1.6m
BuLi in hexane (6.5 ml, 10.4 mmol) was added dropwise to a stirred soln. of (‡)-(S)-N,S-dimethyl-S-
phenylsulfoximide (1.7 g, 10.04 mmol) in anh. THF (88 ml). After stirring at 08 for 10 min, the soln. was cooled
to 788, and ketone (Æ)-10 [11] (3.5 g, 9.39 mmol) in anh. THF (18 ml) was added dropwise under stirring.
After stirring at 788 for 1 h, the soln. was poured into a sat. aq. NH4Cl soln. (100 ml). The mixture was
extracted with Et2O (300 ml, 4 Â ), the combined extract dried (MgSO4) and evaporated, and the residue
separated and purified by FC (silica gel (5 Â 26 cm), AcOEt/light petroleum ether 1 : 4 (5 l), AcOEt/light
petroleum ether 2 : 3 (1 l), AcOEt/light petroleum ether 1 : 1 (1 l)): 2.2 g (42%) of (‡)-14 and 2.0 g (39%) of
(
)-15.
25
25
25
25
25
Data for (‡)-14: Oil. [a] ˆ‡ 58, [a] ˆ‡ 59, [a] ˆ‡ 68, [a] ˆ‡ 117, [a] ˆ‡ 144 (c ˆ 1.18,
589
577
546
435
405
CHCl3). UV (MeCN): 224(2300), 259(1200), 265(1200), 271(1000). IR (KBr): 3400 (br.), 3250 (br.), 2950,
2930, 2880, 2855, 2800, 1740, 1470, 1460, 1440, 1390, 1250, 1150, 1110, 1080, 1000, 990, 870, 840, 780, 740.
1H-NMR (400 MHz, CDCl3): 7.90 ± 7.88, 7.60 ± 7.26 (m, 5 arom. H); 5.67 (s, OH); 4.59 (dd, J(5,6) ˆ 5.1,
J(1,6) ˆ 2.1, H C(6)); 4.27 (dd, J(5,6) ˆ 5.1, J(4,5) ˆ 1.7, H C(5)); 4.16 (dd, J(3exo,4) ˆ 6.0, J(4,5) ˆ 1.7,
H
C(4)); 3.51, 3.46 (2d, 2J ˆ 14.2, ArCH2); 3.83 (d, J(1,6) ˆ 2.1, H C(1)); 2.99 (dd, 2J ˆ 13.4, J(3exo,4) ˆ 6.0,
Hexo C(3)); 2.67 (s, MeN); 1.68 (d, 2J ˆ 13.4, Hendo C(3)); 0.91, 0.89 (2s, t-BuSi); 0.19, 0.16, 0.08, 0.07
(4s, 2 Me2Si). 13C-NMR (100.6 MHz, CDCl3): 139.7 (s, arom. C); 132.6, 129.1, 129.0 (3d, J ˆ 162, 170, 170,
arom. C); 86.0, 84.8, 81.8, 76.8 (4d, J ˆ 149, 160, 146, 146, C(1), C(4), C(5), C(6)); 80.5 (s, C(2)); 64.7 (t, J ˆ
143, ArCH2); 43.6 (t, J ˆ 133, C(3)); 29.3 (q, J ˆ 137, MeN); 25.7, 25.6 (2q, J ˆ 125, Me3CSi); 17.9, 18.0
‡
(2s, 2 Me3CSi); 4.4, 4.8, 4.9, 5.1 (4q, J ˆ 125, 2 Me2Si). CI-MS (NH3): 542 (1, M ), 484 (2, [M (t-
‡
Bu)] ), 315(1), 231(7), 154(10), 125(28), 73(100). Anal. calc. for C26H47NO5SSi2 (541.89): C 57.63, H 8.74;
found: C 57.68, H 8.65.
25
25
25
25
25
Data for ( )-15: Oil. [a]
CHCl3). UV (MeCN): 224(2500), 259(1200), 265(1200), 271(1000). IR (KBr): 3430 (br.), 2930, 2880, 2855,
2800, 1740, 1470, 1460, 1440, 1390, 1370, 1360, 1260, 1150, 1010, 940, 910, 770, 740. 1H-NMR (400 MHz, CDCl3):
ˆ
16, [a]
ˆ
17, [a]
ˆ
19, [a]
ˆ
26, [a]
ˆ
26 (c ˆ 1.40,
589
577
546
435
405
7.86 ± 7.83, 7.58 ± 7.26 (m, 5 arom. H); 5.40 (s, OH); 4.84 (dd, J(5,6) ˆ 5.2, J(1,6) ˆ 1.9,
H C(6)); 4.31
(dd, J(5,6) ˆ 5.2, J(4,5) ˆ 2.1, H C(5)); 4.14 (dd, J(3exo,4) ˆ 6.6, J(4,5) ˆ 2.1, H C(4)); 3.76 (d, J(1,6) ˆ 1.9,
H
C(1)); 3.73, 3.54 (2d, 2J ˆ 14.9, ArCH2); 2.02 (dd, 2J ˆ 13.4, J(3exo,4) ˆ 6.6, Hexo C(3)); 2.62 (s, MeN); 1.59

Helvetica Chimica Acta ± Vol. 81 (1998)
2049
(d, 2J ˆ 13.4, Hendo C(3)); 0.92, 0.89 (2s, t-BuSi); 0.25, 0.17, 0.06, 0.05 (4s, 2 Me2Si). 13C-NMR (100.6 MHz,
CDCl3): 139.4 (s, arom. C); 132.3, 129.3, 128.8 (3d, J ˆ 161, 165, 165 arom. C); 86.1, 84.2, 82.0, 77.3 (4d, J ˆ 150,
148, C(1), C(4), C(5), C(6)); 80.8 (s, C(2)); 63.4 (t, J ˆ 138, ArCH2); 44.3 (t, J ˆ 140, C(3)); 29.3 (q, J ˆ 143,
MeN); 25.7, 25.6 (2q, J ˆ 125, 2 Me3CSi); 17.9, 17.8 (2s, 2 Me3CSi); 4.4, 4.8, 5.0, 5.1 (4q, J ˆ 125,
‡
‡
2 Me2Si). CI-MS (NH3): 542 (1, M ), 484 (5, [M (t-Bu)] ), 329(2), 247(8), 169(4), 125(17), 73(100). Anal.
calc. for C26H47NO5SSi2 (541.89): C 57.63, H 8.74; found: C 57.74, H 8.67.
(‡)-4-Ethyl-7-{(1'R,4'R,5'S,6'S)-4',5',6'-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2'-en-1'-yloxy}-2H-1-
benzopyran-2-one ((‡)-17). A soln. of 1,1'-(azodicarbonyl)bispiperidine (516 mg, 2.05 mmol) and (Bu)3P
(85%; 500 ml, 1.73 mmol) in anh. THF (15 ml) was added dropwise to a stirred soln. of 4-ethyl-7-hydroxy-2H-1-
benzopyran-2-one (16; 312 mg, 1.64 mmol) [17] in anh. THF (15 ml) at 258. After stirring at 258 for 15 min, the
mixture was cooled to 08 and a 5 :2 mixture of alcohols ( )-12 and ( )-13 [11] (1.0 g, 2.05 mmol) in anh. THF
(8 ml) was added and the mixture stirred at 08 for 3 h, then at 208 for 18 h. The solvent was evaporated and the
residue purified by FC (silica gel, Et2O/light petroleum ether 1:15; Rf 0.2): 850 mg (63%) of (‡)-17 and 267 mg
of ( )-13.
25
25
25
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25
Data for (‡)-17: Colorless oil. [a] ˆ‡ 400, [a] ˆ‡ 420, [a] ˆ‡ 483, [a] ˆ‡ 882, [a] ˆ‡ 1107
589
577
546
435
405
(c ˆ 2.18, CHCl3). UV (hexane): 317 (7200), 244(5400). IR (KBr): 2430, 2350, 1720, 1705, 1605, 1500, 1460,
1
1380, 1300, 1150, 1130, 1060, 870, 830, 770. H-NMR (400 MHz, CDCl3): 7.53 (d, J(5,6) ˆ 8,6, H C(5)); 6.81
(dm, J(5,6) ˆ 8.6, H C(6), H C(8)); 6.16 (s, H C(3)); 5.90 (ddd, J(2',3') ˆ 10.2, J(1',2') ˆ 1.7, J(2',4') ˆ 2.0,
H
C(2')); 5.76 (ddd, J(2',3') ˆ 10.2, J(3',4') ˆ 1.5, J(1',3') ˆ 2.0, H C(3')); 4.79 (ddd, J(4',5') ˆ 5.8, J(3',4') ˆ
1.5, J(2',4') ˆ 2.0, H C(4')); 4.18 (dd, J(5',6') ˆ 5.5, J(1',6') ˆ 4.7, H C(6')); 3.96 (dd, J(4',5') ˆ 5.8, J(5',6') ˆ
5.5, H C(5')); 3.79 (ddd, J(1',6') ˆ 4.7, J(1',2') ˆ 1.7, J(1',3') ˆ 2.0, H C(1')); 2.78 (q, J ˆ 7.4, MeCH2); 1.32
(t, J ˆ 7.4, MeCH2); 0.93 ± 0.83 (m, 3 Me2Si); 0.15 ± 0.10 (m, 3 t-BuSi). 13C-NMR (100.6 MHz, CDCl3): 161.6
(s, C(2)); 160.4 (s, C(7)); 157.5, 155.4, (2s, C(8a), C(4a)); 132.9 (d, J ˆ 164, C(3)); 125.2, 124.5 (2d, J ˆ 161, 164,
C(2'), C(3')); 114.2 (s, C(4)); 112.8, 110.0, 102.6 (3d, J ˆ 161, 169, 163, C(5), C(6), C(8)); 77.7, 76.5, 75.3, 71.7
(4d, J ˆ 143, 145, 145, 139, C(1'), C(6'), C(5'), C(4')); 24.7 (t, J ˆ 125, MeCH2); 12.1 (q, J ˆ 128, MeCH2); 26.2,
26.1, 26.0 (3q, J ˆ 125, Me3CSi); 18.2, 18.0 (2s, Me3CSi); 4.3, 4.2, 3.9, 3.8, 3.5, 3.2 (6q, 1J(C,H) ˆ 120, MeSi). CI-
‡
MS (NH3): 660 (1, M ), 603(100), 417(17), 397(11), 339(11), 288(26), 209(4), 147(7), 73(14). Anal. calc.
for C35H60O6Si3 (661.11): C 63.59, H 9.15, O 14.52, Si 12.74; found: C 63.62, H 9.15, O 14.43, Si 12.78.
Racemate (Æ)-17 was prepared following the same procedure starting with a 5 : 2 mixture of (Æ)-12 and
(Æ)-13. (Æ)-17. Colorless solid, m.p. 129 ± 1308.
(‡)-4-Ethyl-7-[(1'R,4'R,5'S,6'S)-4',5',6'-triacetoxycyclohex-2'-en-1'-yloxy]-2H-1-benzopyran-2-one ((‡)-18).
An aq. HF soln. (40%; 240 ml, 5.45 mmol) and MeCN (2 ml) were added to a soln. of (‡)-17 (200 mg,
0.30 mmol) in toluene (1.2 ml). Afer stirring at 208 for 24 h, the solvent was evaporated and the residue dried
under high vacuum (4 h). Ac2O (4 ml), anh. pyridine (440 ml, 5.46 mmol), and 4-(dimethylamino)pyridine
(DMAP, 37 mg, 0.30 mmol) were added. After stirring at 208 for 24 h, the solvent was evaporated and the
residue purified by FC (silica gel, AcOEt/light petroleum ether 1:1; Rf 0.5): 106 mg (79%) of (‡)-18. White
25
25
25
25
25
solid. M.p. 158 ± 1618. [a] ˆ‡ 73, [a] ˆ‡ 76, [a] ˆ‡ 87, [a] ˆ‡ 147, [a] ˆ ‡ 173 (c ˆ 1.10, CHCl3).
589
577
546
435
405
UV (MeCN): 315(3100), 259(1060), 202(9700). IR (KBr): 3070, 2960, 2940, 2920, 1750, 1710, 1600, 1500,
1420, 1400, 1370, 1340, 1250, 1230, 1160, 1130, 1060, 1040, 1010, 960, 910, 870, 850, 820, 780. 1H-NMR (400 MHz,
CDCl3): 7.54 (d, J(5,6) ˆ 9.5, H C(5)); 7.06 (dm, J(5,6) ˆ 9.5, H C(6), H C(8)); 6.18 (d, J(MeCH2,3) ˆ 1.1,
H
C(3)); 5.90 (ddd, J(2',3') ˆ 10.4, J(1',2') ˆ 1.9, J(2',4') ˆ 2.0, H C(2')); 5.79 (ddd, J(2',3') ˆ 10.4, J(3',4') ˆ
2.2, J(1',3') ˆ 2.0, H C(3')); 5.65 (ddd, J(4',5') ˆ 7.9, J(3',4') ˆ 2.2, J(2',4') ˆ 2.0, H C(4')); 5.52 (dd, J(5',6') ˆ
11.1, J(1',6') ˆ 7.9, C(6')); 5.40 (dd, J(5',6') ˆ 11.1, J(4',5') ˆ 7.9, C(5')); 5.11 (ddd, J(1',6') ˆ 7.9,
J(1',2') ˆ 1.9, J(1',3') ˆ 2.0,
H
H
H
C(1')); 2.77 (dq, J ˆ 7.4, J(MeCH2,3) ˆ 1.1, MeCH2); 2.08, 2.07, 1.96
(3s, AcO); 1.32 (t, J ˆ 7.4, MeCH2). 13C-NMR (100.6 MHz, CDCl3): 170.2, 169.9, 169.5, (3s, 3 AcO); 161.2
(s, C(2)); 160.1 (s, C(7)); 157.3, 155.2 (2s, C(8a), C(4a)); 127.9 (d, J ˆ 168, C(3)); 126.7, 125.4 (2d, J ˆ 167,
C(3'), C(2')); 113.8 (s, C(4)); 113.3, 110.6, 102.9 (3d, J ˆ 164, 169, 163, C(5), C(6), C(8)); 76.0, 71.8, 71.6, 71.3
(4d, J ˆ 153, 148, 150, 152, C(1'), C(6'), C(5'), C(4')); 24.7 (t, J ˆ 128, MeCH2); 20.8, 20.6 (2q, J ˆ 130, 3 AcO);
‡
12.1 (q, J ˆ 128, MeCH2). CI-MS (NH3): 440 (3, M ), 340(4), 300(3), 255(100), 223(8), 191(12), 153(70),
94(26). Anal. calc. for C23H24O9 (444.44): C 62.16, H 5.44; found: C 62.23, H 5.53.
Racemate (Æ)-18. As described for (‡)-18, starting with (Æ)-17. Colorless solid, m.p. 193 ± 1958.
(‡)-4-Ethyl-7-{(1'R,2'S,3'S,4'R)-2',3',4'-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohexyloxy}-2H-1-benzopyr-
an-2-one ((‡)-19). A degassed mixture of (‡)-17 (0.5 g, 0.76 mmol), AcOEt (20 ml), and 20% Pd(OH)2/C
(120 mg) was shaken under H2 (1 atm) at 208 for 40 min. After consumption of 1 equiv. of H2, the mixture was
degassed, purged with N2, and filtered. The solvent was evaporated and the residue purified by FC (silica gel,
25
25
Et2O/light petroleum ether 1:9; Rf 0.3): 462 mg (92%) of (‡)-19. Colorless oil. [a] ˆ‡ 88, [a] ˆ‡ 91,
589
577

2050
Helvetica Chimica Acta ± Vol. 81 (1998)
25
25
25
[a] ˆ‡ 105, [a] ˆ‡ 116. [a] ˆ‡ 81 (c ˆ 1.00, CHCl3). UV (MeCN): 317 (15300), 221 (12500). IR (KBr):
546
435
405
2940, 2920, 2880, 2840, 1720, 1610, 1550, 1500, 1460, 1380, 1250, 1190, 1140, 1080, 1020, 1000, 930, 900, 830, 760,
1
730, 660. H-NMR (400 MHz, CDCl3): 7.62 (d, J(5,6) ˆ 8.8, H C(5)); 6.78 ± 6.83 (dm, J(5,6) ˆ 8.8, H C(6),
H
C(8)); 6.12 (s, H C(3)); 4.48 (ddd, J(1',6') ˆ 6.0, J(1',2') ˆ 4.0, J(1',6') ˆ 2.0, H C(1')); 3.82 (dd, J(1',2') ˆ
4.0, J(2',3') ˆ 2.5, H C(2')); 3.79 (dm, J(3',4') ˆ 3.5, H C(4')); 3.67 (dd, J(3',4') ˆ 3.5, J(2',3') ˆ 2.5, H C(3'));
2.76 (q, J ˆ 7.2, MeCH2); 2.19 ± 2.10 (m, H C(5')); 1.29 ± 1.45 (ddm, J(1',6') ˆ 6.0, J(1',5') ˆ 2.0, 2 H C(6'));
1.20 (t, J ˆ 7.2, MeCH2); 0.93 ± 0.88 (m, 3 Me2Si); 0.09 ± 0.02 (m, 3 t-BuSi). 13C-NMR (100.6 MHz, CDCl3):
161.8 (s, C(2)); 160.9 (s, C(7)); 157.6, 155.4 (2s, C(4a), C(8a)); 125.0 (d, J ˆ 160, C(3)); 112.4 (s, C(4)); 113.1,
109.6, 102.3 (3d, J ˆ 162, 169, 162, C(5), C(6), C(8)); 77.7, 75.6, 74.1, 71.0 (4d, J ˆ 155, 146, 145, 142 C(1'),
C(2'), C(3'), C(4')); 25.9, 25.7 (2t, J ˆ 125, C(5'), C(6')); 24.6 (t, J ˆ 127, MeCH2); 12.4 (q, J ˆ 128, MeCH2);
24.2, 24.6 (2q, J ˆ 125, 3 Me3CSi); 19.4, 19.0, 18.1 (3s, 3 Me3CSi); 4.2, 4.4, 4.6, 4.7, 4.9, 5.0 (6q,
3 Me2Si). CI-MS (NH3): 647(3), 605(10), 535(2), 473(30), 399(5), 341(6), 267(4), 209(2). Anal. calc. for
C35H63O6Si3 (663.13): C 63.39, H 9.42; found: C 63.30, H 9.32.
Racemate (Æ)-19 was prepared from (Æ)-17. Colorless oil.
(
)-4-Ethyl-7-[(1'R,2'S,3'S,4'R)-2',3',4'-triacetoxycyclohexyloxy]-2H-benzopyran-2-one (( )-20). As de-
scribed for (‡)-17 !(‡)-18, starting with (‡)-19 (1.2 g, 1.81 mmol): 573 mg (71%) of
(
)-20 after
25
25
recrystallization from AcOEt/light petroleum ether. Colorless crystals. M.p. 168 ± 1708. [a]
ˆ
50, [a]
ˆ
589
577
25
25
25
64, [a]
ˆ
64, [a]
ˆ
137, [a]
ˆ
184 (c ˆ 1.00, CHCl3). UV (MeCN): 315(13800), 220(12400). IR
546
435
405
(KBr): 2960, 2940, 1760, 1740, 1710, 1600, 1500, 1420, 1370, 1240, 1210, 1190, 1150, 1130, 1060, 1030, 1000, 940,
900, 850, 840, 820, 800, 740. 1H-NMR (400 MHz, CDCl3): 7.53 (d, J(5,6) ˆ 7.7, H C(5)); 6.85 (dm, J(5,6) ˆ 7.7,
H
C(6), H C(8)); 6.17 (d, J(MeCH2,3) ˆ 1.1, H C(3)); 5.27 (dd, J(1',2') ˆ 9.2, J(2',3') ˆ 2.0, H C(2')); 5.17
(dd, J(3',4') ˆ 9.7, J(2',3') ˆ 2.0, H C(3')); 4.95 (ddd, J(4',5') ˆ 11.3, J(3',4') ˆ 9.7, J(4',5') ˆ 4.8, H C(4')); 4.38
(ddd, J(1',6') ˆ 11.4, J(1',2') ˆ 9.2, J(1',6') ˆ 4.6, H C(1')); 2.77 (qd, J ˆ 7.4, J(MeCH2,3) ˆ 1.1, MeCH2); 2.28 ±
2.19 (ddm, J(5',6') ˆ 11.2, J(1',6') ˆ 4.6, 2 H C(6')); 2.1, 2.0, 1.9 (3s, 3 AcO); 1.73 ± 1.48 (ddm, J(5',6') ˆ 11.2,
J(4',5') ˆ 4.8, 2 H C(5')); 1.32 (t, 3 H, J ˆ 7.4, MeCH2). 13C-NMR (100.6 MHz, CDCl3): 170.1, 170.0, 169.7 (3s,
3 MeCO2); 161.4 (s, C(2)); 160.4 (s, C(7)); 157.3, 155.2 (2s, C(4a), C(8a)); 125.3 (d, J ˆ 161, C(3)); 113.6
(s, C(4)); 113.5, 110.5, 102.9 (3d, J ˆ 164, 169, 163, C(5), C(6), C(8)); 76.9, 73.9, 72.9, 71.6 (4d, J ˆ 148, 157, 137,
136 C(1'), C(2'), C(3'), C(4')); 25.4, 25.3 (2t, J ˆ 124, 127, C(5'), C(6')); 24.8 (t, J ˆ 129, MeCH2); 20.9, 20.6
‡
(2q, J ˆ 130, 3 MeCO2); 12.1 (q, J ˆ 128, MeCH2). CI-MS (NH3): 446 (21, M ), 383(3), 354(10), 273(12),
233(3), 136(32), 96(100). Anal. calc. for C23H26O9 (446.45): C 61.88, 5.87; found: C 61.90, H 5.84.
Racemate (Æ)-20 was prepared from (Æ)-19 as above. M.p. 202 ± 2038.
(‡)-1,2-O-Isopropylidene-a-l-xylofuranose ((‡)-21). A soln. of H2SO4 (0.5 ml, d 1.83) was added to a
suspension of l-xylose (2 g, 13.3 mmol) and molecular sieves 13X in anh. acetone (30 ml) under N2. After
heating for 4 h at 358, the mixture was neutralized by successive addition of K2CO3 (4.3 g) and H2O (3 ml). After
filtration and solvent evaporation, the residue was dissolved in 1,2-dimethoxyethane under N2 and heated to 508.
Then 0.25m HCl (0.8 ml) was added and the mixture stirred for 1 h at 508. It was neutralized with NaHCO3 and
concentrated. The residue was dissolved in AcOEt, dried (Na2SO4), and purified by FC (silica gel, CH2Cl2/
MeOH 19 :1): 1.39 g (55%) of (‡)-21. Colorless crystals. M.p. 37 ± 398. [a]2D4 ˆ‡ 20.4 (c ˆ 1.05, MeOH).
1H-NMR (300 MHz, (D6)DMSO): 5.80 (d, J(1,2) ˆ 3.9, H C(1)); 4.36 (d, H C(2)); 3.95 (m, H C(3),
H
C(4)); 3.60 (t, 2J ˆ J(4,5) ˆ 5.7, H C(5)); 3.50 (dd, 2J ˆ 5.7, J(4,5') ˆ 11, H' C(5)); 1.37 (s, Me); 1.22
(s, Me). Anal. calc. for C8H14O5 ´ 0.12 H2O (192.35): C 49.95, H 7.46; found: C 49.97, H 7.40.
(‡)-1,2-O-Isopropylidene-5-O-(p-tolylsulfonyl)-a-l-xylofuranose ((‡)-22). A soln. of p-toluenesulfonyl
chloride (52 g, 0.27 mol) in CHCl3 (120 ml) was added dropwise at 38 to a soln. of (‡)-21 (49 g, 0.26 mol) in
pyridine (60 ml) and CHCl3 (250 ml) in 90 min under N2. After stirring at 208 for 2.5 h, the mixture was poured
into ice-water and left overnight. The org. layer was washed successively with 1n HCl, H2O, aq. NaHCO3 soln.,
and H2O and dried (Na2SO4). After evaporation, (‡)-22 was obtained by precipitation in CHCl3/(i-Pr)2O as
white crystals (54 g, 61%). The filtrate was purified by FC (silica gel, toluene/AcOEt 4 :1): 12 g of (‡)-22. M.p.
1388. [a]2D3 ˆ‡ 10 (c ˆ 0.35, CHCl3). 1H-NMR ((D6)DMSO, 300 MHz): 7.80, 7.50 (2d, 3J ˆ 8.2, C6H4); 5.80
(d, J(1,2) ˆ 3.6, H C(1)); 4.35 (d, 3J ˆ 3.6, H C(2)); 4.23 (dd, 3J ˆ 10.5, 3, H C(5)); 4.10, 3.97 (2m); 2.42, 1.33,
1.21 (3s, 3 Me). Anal. calc. for C15H20O7S (344.39): C 52.31, H 5.85; found: C 52.33, H 5.49.
3-O,5-S-Diacetyl-1,2-O-isopropylidene-5-thio-a-l-xylofuranose ((‡)-23). AcSK (44 g, 0.39 mol) was added
under N2 to a boiling soln. of (‡)-22 (66 g, 0.20 mol) in 1,2-dimethoxyethane (800 ml). The mixture was heated
under reflux for 6 h, then filtered, concentrated, diluted with AcOEt, washed, dried (Na2SO4), and evaporated.
The residue was purified by FC (silica gel, 4 :1 toluene/AcOEt) yielding (‡)-23 (38 g, 63%). Colorless oil.
[a]2D3 ˆ‡ 13 (c ˆ 0.75, CHCl3). 1H-NMR (300 MHz, CDCl3): 5.90 (d, J(1,2) ˆ 3.6, H C(1)); 5.18 (d, 3J ˆ 3.6,

Helvetica Chimica Acta ± Vol. 81 (1998)
2051
H
C(2)); 4.50 (d, 3J ˆ 3.6, H C(3)); 4.35 (m, H C(4)); 3.14 (dd, 2J ˆ 4.5, J(3,4) ˆ 6.9, CH2(5)); 2.34, 2.12 (2s,
2 MeCOO); 1.50, 1.30 (2s, 2 Me). Anal. calc. for C12H18O6S (290.34): C 49.64, H 6.25; found: C 49.76, H 6.25.
1,2-O-Isopropylidene-5-thio-a-l-xylofuranose ((‡)-24). A 18.8% soln. of MeONa in MeOH (43 ml) was
added to a cooled soln. of (‡)-23 (37 g, 0.127 mol) in MeOH (350 ml) under N2. The mixture was stirred for
90 min, then neutralized with cooled AcOH and evaporated. The residue was suspended in (i-Pr)2O, the mixture
filtered, and the filtrate evaporated: 26 g (100%) of (‡)-24. White solid. M.p. 768. [a]2D3 ˆ‡ 46 (c ˆ 0.345,
CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 5.30 (d, 3J ˆ 2.1, H C(1)); 4.40 (d, 3J ˆ 2.1, H C(2)); 4.03
(m, H C(3), H C(4)); 2.63 (m, CH2(5)); 1.38, 1.23 (2s, 2 Me). Anal. calc. for C8H14O4S (206.26): C 46.59,
H 6.84; found: C 47.02, H 6.45.
1,2,3,4-Tetra-O-acetyl-5-thio-l-xylopyranose (( )-25). A soln. of (‡)-24 (13 g, 63 mmol) in AcOH (26 ml)
and H2O (78 ml) was heated to 608 for 48 h under N2. After evaporation, the residue was dissolved in H2O. The
by-products were eliminated by extraction with CHCl3. The aq. layer was evaporated to give 5-thio-l-
xylopyranose (10.4 g, 100%) which was dissolved in Ac2O (50 ml) and pyridine (50 ml). The soln. was stirred at
208 overnight under N2. The mixture was then concentrated and extracted with AcOEt. The org. layer was
washed successively with 1n HCl, aq. NaHCO3 soln., and H2O, dried (Na2SO4), and evaporated: 19.9 g (95%) of
1
(
)-25. Colorless oil that crystallized. M.p. 928. [a]D23
ˆ
176 (c ˆ 0.45, CHCl3). H-NMR (300 MHz, CDCl3):
6.08 (d, J(1,2) ˆ 9.9, H C(1) of a-l-anomer); 5.83 (d, J(1,2) ˆ 9, H C(1) of b-l-anomer); 5.44 (dd, J(2,3) ˆ
10.2, J(3,4) ˆ 9.9, H C(3) of a-l-anomer); 5.33 (t, 3J ˆ 9.9, H C(3) of b-l-anomer); 5.21 (dd, J(2,3) ˆ 10.2,
H
C(2) of a-l-anomer); 5.10 (m, H C(4) of a-l-anomer, H C(2) and H C(4) of b-l-anomer); 3.00
(m, H C(5) of both anomers); 2.78 (m, H' C(5) of both anomers); 2.18 ± 2.00 (m, 4 MeCOO). Anal. calc. for
C13H18O8S (334.35): C 46.70, H 5.43; found: C 46.74, H 5.35.
2,3,4-Tri-O-acetyl-5-thio-a-l-xylopyranosyl Bromide ((‡)-26). A soln. of ( )-25 (19.9 g, 60 mmol) in
CHCl3 (100 ml) and 30% HBr in AcOH (40 ml) was stirred at 08 for 1 h. The mixture was then extracted with
CHCl3 and ice-cold H2O. The org. layer was washed with a cooled sat. NaHCO3 soln. and then with iced H2O,
dried (MgSO4), and evaporated. The residue was crystallized from Et2O: 8.6 g (41%) of white crystals. The
filtrate was purified by FC (silica gel, toluene/AcOEt 5 :1): 4.3 g of (‡)-26. Total yield 61%. M.p. 1478. [a]D24
ˆ
‡ 37 (c ˆ 0.4, CHCl3). 1H-NMR (300 MHz, CDCl3): 5.32 (t, 3J ˆ 9, H C(2)); 5.12 (m, H C(4)); 5.03 (t, 3J ˆ 9,
H
C(3)); 4.70 (d, 3J ˆ 9.9, H C(1)); 2.89 (dd, 2J ˆ 13.5, 3J ˆ 4.2, H C(5)); 2.74 (dd, 2J ˆ 13.5, 3J ˆ 10.2,
H' C(5)); 2.09 ± 2.04 (m, 3 MeCOO). No elemental analysis for instability reasons.
4-Cyanophenyl 2,3,4-Tri-O-acetyl-5-thio-b-l-xylopyranoside ((‡)-27). A suspension of (‡)-26 (3.6 g,
10 mmol), 4-cyanothiophenol (1 g, 8.3 mol), ZnO (2.5 g, 30.7 mmol), molecular sieves 13X in toluene (25 ml),
and MeCN (25 ml) was heated to 508 overnight under N2. The mixture was then filtered and extracted with
AcOEt. The org. layer was washed successively with 1n HCl, 1n NaOH, and H2O, dried (Na2SO4), and
evaporated. The residue was purified by FC (silica gel, toluene/AcOEt 6 :1) and then precipitated in Et2O:
103 mg (2.5%) of (‡)-27. Colorless crystals. M.p. 1408. [a]2D4 ˆ‡ 22 (c ˆ 0.25, CHCl3). 1H-NMR (300 MHz,
CDCl3): 7.62, 7.10 (2d, 3J ˆ 7.5, 4 arom. H); 5.51 (t, 3J ˆ 8.4, H C(2)); 5.25 (d, 3J ˆ 8.7, H C(1)); 5.14
(m, H C(4), H C(3)); 3.01 (dd, 3J ˆ 3.9, 2J ˆ 13.5, H C(5)); 2.71 (dd, 3J ˆ 9.9, 2J ˆ 13.5, H' C(5)); 2.06 ±
2.00 (m, 3 MeCOO). Anal. calc. for C18H19NO7S ´ 0.19 H2O (396.83): C 54.48, H 4.92, N 3.53; found: C 54.10,
H 5.06, N 3.54.
We thank the Swiss National Science Foundation and the Fonds Herbette, Lausanne, for partial financial
support.
REFERENCES
[1] A. N. Teien, U. Abildgaard, M. Höök, Thromb. Res. 1976, 8, 859.
[2] W. F. Long, F. B. Williamson, G. Kindness, M. Edward, Thromb. Res. 1980, 18, 493.
[3] M. Okayama, K. Kimata, S. Suzuki, J. Biochem. (Tokyo) 1973, 74, 1069.
[4] N. B. Schwartz, L. Galligani, P. L. Ho, A. Dorfman, Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 4047;
N. B. Schwartz, J. Biol. Chem. 1977, 252, 6316; K. Mani, B. Havsmark, S. Persson, Y. Kaneda, H. Yama-
moto, K. Sakurai, S. Ashikari, H. Habuchi, S. Suzuki, K. Kimata, A. Malmström, G. Westergren-Thorsson,
L.-A. Fransson, Cancer Res. 1998, 58, 1099.
[5] F. Bellamy, V. Barberousse, N. Martin, P. J. Masson, J. Millet, S. Samreth, C. Sepulchre, J. Theveniaux,
D. Horton, Eur. J. Med. Chem. 1995, Suppl. to Vol. 30, 101s.
[6] a) F. Bellamy, D. Horton, F. Millet, F. Picart, S. Samreth, J. B. Chazan, J. Med. Chem. 1993, 36, 898; b) see
also: T. A. Fritz, F. N. Lugemwa, A. K. Sarkar, J. D. Esko, J. Biol. Chem. 1994, 269, 300; F. N. Lugemwa,
A. K. Sarkar, ibid. 1996, 271, 19159; S. Samreth, V. Barberousse, F. Bellamy, D. Horton, P. Masson,

2052
Helvetica Chimica Acta ± Vol. 81 (1998)
J. Millet, P. Renaut, C. Sepulchre, J. Theveniaux, ꢂPharmacochemistry Library, Trends in Receptor
Â
Researchꢀ, Ed. v. Claassen, Elsevier Science Publ. B. V., Amsterdam, 1993, Vol. 20, p. 41; E. Bozo,
S. Borasa, J. Kuszmann, Carbohydr. Res. 1997, 299, 59; ibid. 1997, 301, 23.
[7] N. B. Martin, P. J. Masson, C. Sepulchre, J. Theveniaux, J. Millet, F. Bellamy, Semin. Thromb. Hemost.
1996, 22, 247.
[8] P. J. Masson, D. Coup, J. Millet, N. L. Brown, J. Biol. Chem. 1995, 270, 2662.
[9] V. Jeanneret, P. Vogel, P. Renaut, J. Millet, J. Theveniaux, V. Barberousse, Bioorg. Med. Chem. Lett. 1998,
8, 1687.
[10] See, e.g., M. Nakajima, I. Tomida, S. Takei, Chem. Ber. 1959, 92, 163; H. Paulsen, W. Röben, F. R. Heiker,
ibid. 1981, 114, 3242; S. V. Ley, M. Parra, A. J. Redgrave, F. Sternfeld, Tetrahedron 1990, 46, 4995;
H. Seçen, Y. Sütbeyaz, M. Balci, Tetrahedron Lett. 1990, 31, 1323; Y. Sütbeyaz, H. Seçen, M. Balci, J.
Chem. Soc., Chem. Commun. 1988, 1330; H. A. J. Carless, K. Busia, Tetrahedron Lett. 1990, 31, 16170;
T. Hudlicky, J. D. Price, F. Rulin, T. Tsunoda, J. Am. Chem. Soc. 1990, 112, 9439; T. Hudlicky, H. Luna,
H. F. Olivo, C. Andersen, T. Nugent, J. D. Price, J. Chem. Soc., Perkin Trans. 1 1991, 2907; T. Hudlicky,
M. Mandel, J. Rouden, R. S. Lee, B. Bachmann, T. Dudding, K. J. Yost, S. Merola, ibid. 1994, 1553;
T. Hudlicky, J. D. Price, H. F. Olivo, Synlett 1991, 645; C. Jaramillo, R. Fernandez de la Pradilla, M. Martin-
Lomas, Carbohydr. Res. 1991, 209, 296; K.-I. Stao, S. Sakuma, S. Muramatsu, M. Bokura, Chem. Lett. 1991,
1473; T. K. Park, S. J. Danishefsky, Tetrahedron Lett. 1994, 35, 2667; N. Chida, M. Ohtsuka, K. Nakazawa,
S. Ogawa, J. Chem. Soc., Chem. Commun. 1989, 436; N. Chida, M. Ohtsuka, K. Nakazawa, S. Ogawa, J.
Org. Chem. 1991, 56, 2976; D. H. Barton, S. Bath, D. C. Billington, S. D. Gero, B. Quiclet-Sire, M. Samadi,
J. Chem. Soc., Perkin Trans. 1 1995, 1551; T. Akiyama, H. Shima, M. Ohnari, T. Okazaki, Ozaki, Bull.
Chem. Soc. Jpn. 1993, 66, 3760; K. Kishta, J. R. Falck, J. Capdevila, Tetrahedron Lett. 1993, 34, 7869;
T. Yoshimitsu, K. Ogasawara, Synlett 1995, 257.
[11] C. Le Drian, J.-P. Vionnet, P. Vogel, Helv. Chim. Acta 1990, 73, 161.
[12] E. Vieira, P. Vogel, Helv. Chim. Acta 1983, 66, 1865; J.-L. Reymond, P. Vogel, Tetrahedron: Asymmetry
1990, 1, 729.
[13] J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226; J. L. Luche, A. L. Gemal, ibid. 1979, 101, 5848.
[14] S. Allemann, P. Vogel, Tetrahedron 1994, 50, 2469.
[15] C. R. Johnson, J. R. Zeller, J. Am. Chem. Soc. 1982, 104, 4021.
[16] O. Mitsunobu, Synthesis 1981, 1; T. Tsunoda, Y. Yamamiya, S. Ito, Tetrahedron Lett. 1993, 34, 1639.
[17] V. K. Akluwalia, Sunita, Indian J. Chem., Sect. B 1977, 15B3, 240.
[18] a) P. A. Levene, A. L. Raymond, J. Biol. Chem. 1933, 102, 317; b) D. L. Ingles, R. L. Whistler, J. Org.
Chem. 1962, 27, 3896.
[19] S. Samreth, J. Millet, F. Bellamy, J. Bajgrowicz, V. Barberousse, P. Renaut, Eur. Pat. 365, 397, 1990.
[20] J. Millet, J. Theveniaux, M. Pascal, Thromb. Res. 1987, 45, 123; J. Millet, J. Theveniaux, N. L. Brown,
Thromb. Haemost. 1992, 67, 176.
[21] S. Wessler, M. Reimer, M. Shap, J. Appl. Physiol. 1957, 14, 943.
Â
[22] N. B. Schwartz, L. Roden, J. Biol. Chem. 1975, 250, 5200.
[23] K. Kraehenbuehl, S. Picasso, P. Vogel, Helv. Chim. Acta 1998, 81, 1439.
Received June 30, 1998