Glycosylation reactions with a (4-alkoxypentadienyl)oxy leaving group linking the glycosyl donor and the acceptor moiety

Full text of DOI:10.1021/jo971778e

J . Org. Chem. 1999, 64, 1319-1325
1319
Notes
Sch em e 1
Glycosyla tion Rea ction s w ith a
(4-Alk oxyp en ta d ien yl)oxy Lea vin g Gr ou p
Lin k in g th e Glycosyl Don or a n d th e
Accep tor Moiety
Go¨tz Scheffler and Richard R. Schmidt*
Fakulta¨t Chemie, Universita¨t Konstanz, Fach M 725,
D-78457 Konstanz, Germany
Received September 24, 1997
modification of the known 4-pentenyloxy leaving group.15
As shown in Scheme 2, selection of a cis-configured 2,4-
pentadienyloxy group and attachment of the acceptor
moiety at C-4 via an enol ether linkage (f A) would not
only facilitate activation of the C-4-C-5 double bond by
an electrophilic reagent (E+X-) but also generate close
proximity of the anomeric carbon with the acceptor
moiety in intermediate B. Thus, ensuing bond reorgani-
zation in a cage, i.e., cleavage of the bond between the
anomeric carbon and the oxonium oxygen (f C and D)
and then immediate attack of the electrophilic carbon of
C at the nucleophilic oxygen of D will readily generate
glycoside F and, due to the presence of the benzene ring,
resonance-stabilized species E. A face-selective 1,3-shift
in this cage should favor retention of configuration in this
process (f F R in Scheme 2). However, solvent separation
of intermediates C and D or, alternatively, direct disin-
tegration of B into independent fragments C and D could
result in an intermolecular reaction course and then
ultimately to loss of anomeric diastereocontrol (F R + F â).
On the basis of previous findings in O-glycosyl ortho ester
rearrangement11 success in this internal reorganization
of O-glycosyl acetal B leading to glycoside bond formation
was envisaged.
In tr od u ction
Glycosyl transfer within the active site of an enzyme
can be regarded as an intramolecular process in which
the anomeric center of the glycosyl donor and the
accepting moiety are held in close proximity to ensure
regio- and diastereoselective glycoside bond formation.1,2
To enforce a related reaction course, various approaches
to intramolecular glycoside bond formation have been
recently proposed;3-14 they are based on attachment of
the acceptor to the donor moiety via the 2-hydroxy group
at the donor or, alternatively, as exhibited in Scheme 1,
attachment through the spacer Y via the leaving group
L.3-14 Varying results have been obtained, and for some
cases even an intermolecular reaction course could be
verified, though model considerations favored intramo-
lecularity of the process.13
Particularly suitable for connecting the acceptor moiety
to the leaving group at the glycosyl donor seems to be
(1) Schmidt, R. R.; Dietrich, H. Angew. Chem. 1991, 109, 1348;
Angew. Chem., Int. Ed. Engl. 1991, 30, 1328. Dietrich, H.; Schmidt,
R. R. Carbohydr. Res. 1993, 250, 161. Schmidt, R. R.; Frische, K.
Bioorg. Med. Chem. Lett. 1993, 3, 1747.
(2) Sinnott, L. M. Chem. Rev. 1990, 90, 1171. Legler, G. Adv.
Carbohydr. Chem. Biochem. 1990, 48, 319.
Resu lts a n d Discu ssion
(3) Barresi, F.; Hindsgaul, O. J . Am. Chem. Soc. 1991, 113, 9376;
Synlett 1992, 759; Can. J . Chem. 1994, 72, 1447.
(4) Preuss, R.; J ung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992,
377.
(5) Stork, G.; Kim, G. J . Am. Chem. Soc. 1992, 114, 1087.
(6) Bols, M. J . Chem. Soc., Chem. Commun. 1992, 913; Acta Chem.
Scand. 1996, 50, 931.
(7) Ito, Y.; Ogawa, T. Angew. Chem. 1994, 106, 1843; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1765.
(8) Ziegler, T.; Lau, R. Tetrahedron Lett. 1995, 36, 1417. Lau, R.;
Schu¨le, G.; Schwaneberg, U.; Ziegler, T. Liebigs Ann. Chem. 1995,
1745.
(9) Valverde, S.; Gomez, A. M.; Hernandez, A.; Herradon, B.; Lopez,
J . C. J . Chem. Soc., Chem. Commun. 1995, 2005. Valverde, S.; Gomez,
A. M.; Lopez, J . C.; Herradon, B. Tetrahedron Lett. 1996, 37, 1105.
(10) Yamada, H.; Imamura, K.; Takahashi, T. Tetrahedron Lett.
1997, 38, 391.
To test the concept detailed in the Introduction, man-
nopyranoside and glucopyranoside formation were in-
vestigated. Toward this aim, 2-bromobenzyl alcohol was
mannosylated with known glycosyl donor 116 (Scheme 3);
ensuing removal of O-acetyl groups with NaOMe/MeOH
(Zemple´n conditions)17 and O-benzylation with BnBr/
NaH in DMF afforded R-mannopyranoside 2. Bromo/
lithium exchange with n-butyllithium in THF at -100
°C and then CO2 addition furnished after workup benzoic
acid derivative 3. As glycosyl acceptors the known 6-O-
unprotected and 4-O-unprotected methyl glucopyrano-
sides 418 and 519 were employed. Ester formation with 3
(11) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249.
Schmidt, R. R. In Carbohydrates-Synthetic Methods and Applications
in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami, T., Eds.;
Kodanasha: Tokyo, 1992; p 68. Behrendt, M. E.; Schmidt, R. R.
Tetrahedron Lett. 1993, 34, 6733.
(12) Iimori, T.; Shibazaki, T.; Ikegami, S. Tetrahedron Lett. 1996,
37, 2267.
(13) Scheffler, G.; Schmidt, R. R. Tetrahedron Lett. 1997, 38, 2943.
(14) Mukai, C.; Itoh, T.; Hanaoka, M. Tetrahedron Lett. 1997, 38,
4595.
(15) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Mettit,
J . R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927. Madsen,
R.; Fraser-Reid, B. In Modern Methods in Carbohydrate Synthesis;
Khan, S. H., O’Neill, R. A., Eds.; Harwood: Amsterdam, 1996; p 150.
(16) Masato, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1990, 195, 199.
Kereckgyarto, J .; Kamerling, J . P.; Bouwstra, J . B.; Vliegenthart, J .
F. G.; Liptak, A. Carbohydr. Res. 1989, 186, 51.
(17) Zemple´n, G. Ber. Dtsch. Chem. Ges. 1927, 60, 1555.
(18) Liptak, A.; J odal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1.
10.1021/jo971778e CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/22/1999

1320 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 2
in the presence of DCC/DMAP as condensing agents and
then methylenation with Tebbe’s reagent20 in THF at 0
°C afforded the desired enol ethers 6 and 7, respectively,
in high overall yields. Among the various promoter
systems investigated for glycoside bond formation with
6 and 7, phenylselenyl trifluoromethanesulfonate (Ph-
SeOTf was generated in situ from PhSeCl/AgOTf) in
toluene at 0 °C proved to be particularly successful. Thus,
6 and 7 afforded the desired disaccharides 821 and 9,21
respectively, in high yields and, in this case where kinetic
and thermodynamic effects favor R-product formation,
expectedly only R-products were obtained.
For the glucosylation studies, the required glucopyra-
nosyl precursors 13R and 13â were readily obtained via
the same route; thus, from 2-bromobenzyl alcohol and
known glucosyl donor 1022 glycoside 11â13 was obtained
(Scheme 4). Anomeric O-alkylation of 2,3,4,6-tetra-O-
benzyl-D-glucose23 (12) with 2-bromobenzyl bromide as
alkylating agent and NaH as base in DMF at room
temperature afforded a separable 1:1 mixture of 11R and
11â in practically quantitative yield. Transformation of
11R,â into benzoic acid derivatives 13R,â and then into
enol ethers 14R, 14â, and 15â, respectively, was per-
formed as described above. For the generation of disac-
charides, PhSeOTf and TMSOTf were employed as
promoter systems; thus, 14R and 14â gave disaccharides
1627 in high yield. Surprisingly, however, at 0 °C the
anomer ratio of the product 16 was practically indepen-
dent of the configuration of the starting material 14 and
independent of the two promotor systems selected; pref-
erentially the â-isomer 16â was obtained (Table 1). At
lower temperatures (-40 °C) the â-anomer 16â predomi-
nated with a ratio between 1:5 and 1:20. This result could
be due to competing reaction of glycosyl cation intermedi-
ate C with counterion X- (Scheme 2, X- ) trifluo-
romethanesulfonate) from the R-side,11,24-26 thus provid-
ing in an ensuing slow SN2-type reaction with D the
â-glycoside. A similar result was obtained for the trans-
formation of 15â; though (1-4)-linkage between two
glucose residues is frequently less efficient, disaccharide
1727 was obtained in good yield, yet also some R-anomer
17R was generated (R:â ) 1:2).
This result prompted us to perform competition studies
in order to further elucidate the reaction course. Toward
this aim, a 1:1 mixture of 14â and 20R,â (R:â ) 1:1;
Scheme 5), prepared via anomeric O-alkylation as de-
scribed above, was treated with different promoter
systems (see Table 2). Obviously, intramolecular reaction
in a cage (C + D in Scheme 2) should exclusively result
in formation of disaccharides 16 and 18.13 However,
under all reaction conditions (see entries 1-5) scrambling
of donors and acceptors is observed, thus leading also to
crossover products 21R,â13 and 11R,â, respectively, in
practically equal amounts. Yet, as found above, at low
temperatures (-40 °C) the â-selectivity observed in the
direct product 16 from 14â is increased, whereas for the
1:1 ratio of 20R,â the same ratio is also found in the
products 11 and 18. From these results it can be reasoned
that intermediate B disintegrates even in toluene as
(19) Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97.
(20) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J . Am. Chem. Soc.
1978, 100, 3611.
(21) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U. J .
Chem. Soc., Chem. Commun. 1988, 823.
(22) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249.
(23) Perrine, T. D.; Glaudemans, C. P. J .; Ness, R. K.; Kyle, J .;
Fletcher, J r., H. G. J . Org. Chem. 1967, 32, 664.
(24) Schmidt, R. R. In Carbohydrates-Synthetic Methods and
Applications in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami,
T., Eds.; Khodanasho: Tokyo, 1992; pp 68-88. Schmidt, R. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Winter-
feldt, E., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 6, pp 33-64.
(25) Whitfield, D. M.; Douglas, S. P. Glycoconjugate J . 1996, 13, 5.
(26) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198.
(27) Pougny, J .-R.; J acquinet, J .-C.; Nassr, M.; Duchet, D.; Milat,
M.-L.; Sinay¨, P. J . Am. Chem. Soc. 1977, 99, 6762.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1321
Sch em e 3
essentially an intermolecular reaction course could be
verified. However, it can be presumed that extension of
this concept to systems with less translational and
rotational freedom will eventually lead to a highly
efficient methodology for glycoside bond formation.
Exp er im en ta l Section
Materials were obtained from Aldrich Chemical Co. All
reactions were conducted under a positive pressure of dry argon.
THF was distilled from sodium benzophenone ketyl. All reactions
were monitored by TLC (Merck Kieselgel 60 F254 plates); flash
chromatography was performed over silica 40 (Baker). Petroleum
ether was used in the boiling range of 35-65 °C; EtOAc and
toluene were distilled. Melting points were uncorrected. 1H NMR
spectra were recorded with TMS as internal standard; NMR
peak assignments are derived from 2-D NMR techniques (600
MHz). FAB mass spectra were recorded using a m-nitrobenzyl
alcohol matrix with NaI.
2-Br om oben zyl 2,3,4,6-Tetr a -O-ben zyl-r-D-m a n n op yr a -
n osid e (2). To a slurry of 116 (9.80 g, 19.7 mmol) and 2-bro-
mobenzyl alcohol (5.80 g, 31 mmol) in dry CH2Cl2 (30 mL) at 0
°C was added distilled BF3‚OEt2 (0.23 mL, 1.9 mmol). After the
mixture was stirred for 20 min, saturated aqueous NaHCO3 (50
mL) and water (50 mL) were added and the mixture was
extracted with EtOAc (2 × 200 mL). The combined organic
phases were washed with water (100 mL) and brine (100 mL),
dried over MgSO4, and concentrated in vacuo. Flash chroma-
tography (petroleum ether/EtOAc 2:1) was done twice and
yielded a white solid (6.85 g, 13.3 mmol, 67%). The solid was
dissolved in dry MeOH (70 mL), NaOMe (1 M in MeOH, 3 mL,
3 mmol) was added, and the reaction mixture was stirred for 1
h at room temperature. The reaction mixture was then neutral-
ized with Amberlite IR120 (H+ mode) and concentrated in vacuo.
After it was dried under high vacuum, the residue was dissolved
in DMF (30 mL) and benzyl bromide (7.7 mL, 66 mmol) was
added. NaH (1.58 g, 66 mmol) was added at 0 °C in portions.
After addition of tetra-n-butylammonium iodide (200 mg, 0.54
mmol), ice-cooling was removed. The reaction mixture was
stirred for 16 h at room temperature with exclusion of light.
Addition of MeOH (2 mL), followed after some minutes by
saturated aqueous NaHCO3 (80 mL) and water (80 mL),
quenched the reaction. The mixture was extracted with Et2O (2
× 200 mL). The combined organic layers were washed with
water (80 mL) and brine (200 mL), dried over MgSO4, and
concentrated in vacuo. Flash chromatography (petroleum ether/
EtOAc 8:1) yielded 2 (7.41 g, 79%) as a colorless syrup: Rf 0.67
(toluene/EtOAc 10:1); [R]D 48.3 (c 1.0, CHCl3); 1H NMR (250
MHz, CDCl3) δ 3.72-4.08 (m, 6 H), 4.50-4.80 (m, 9 H), 4.89 (d,
J ) 10.7 Hz, 1 H), 5.03 (d, J ) 1.6 Hz, 1 H), 7.11-7.37 (m, 23
H), 7.52 (dd, 1 H). Anal. Calcd for C41H41BrO6: C, 69.39; H, 5.82.
Found: C, 69.41; H, 5.87.
2-{[(2,3,4,6-Tet r a -O-b en zyl-r-D-m a n n op yr a n osyl)oxy]-
m eth yl}ben zoic Acid (3). To 2 (3.00 g, 4.23 mmol) in a mixture
of dry THF (60 mL) and dry n-hexane (16 mL) at -100 °C was
added n-butyllithium (1.6 M in hexane, 2.9 mL, 4.6 mmol). After
the mixture was stirred for 20 min, dry CO2 (developed from
dry ice) was bubbled through the solution for 30 min at -100
°C. The reaction mixture was warmed to room temperature and
poured on a Et2O (200 mL)/ice (75 mL)/concentrated hydrochloric
acid (30 mL) mixture. After separation, the aqueous layer was
extracted with Et2O (3 × 75 mL). The combined organic layers
were washed with water (30 mL) and brine (3 × 100 mL), dried
over MgSO4, and concentrated in vacuo. Flash chromatography
(petroleum ether/EtOAc 2:1) yielded 3 (2.68 g, 94%) as a
colorless, viscous syrup: Rf 0.0-0.2 (petroleum ether/EtOAc 3:1);
[R]D 52.6 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.71-
3.86 (m, 4 H), 3.96-4.09 (m, 2 H), 4.52 (d, J ) 10.7 Hz, 1 H),
4.54 (d, J ) 12.1 Hz, 1 H), 4.65 (s, 2 H), 4.68 (d, J ) 12.1 Hz, 1
H), 4.74 (s, 2 H), 4.88 (d, J ) 10.7 Hz, 1 H), 4.91 (d, J ) 14.3 Hz,
1 H), 5.06 (d, J ) 1.8 Hz, 1 H), 5.13 (d, J ) 14.3 Hz, 1 H), 7.14-
7.39 (m, 21 H), 7.46-7.56 (m, 2 H), 8.03 (dd, 1 H). Anal. Calcd
for C42H42O8: C, 74.76; H, 6.27. Found: C, 74.85; H, 6.38.
Meth yl 6-{1-[2-(((2,3,4,6-Tetr a -O-ben zyl-r-D-m a n n op yr a -
n osyl)oxy)m eth yl)p h en -1-yl]vin yl}-2,3,4-tr i-O-ben zyl-r-D-
glu cop yr a n osid e (6). To 3 (709 mg, 1.05 mmol), 418 (488 mg,
solvent, either by direct means or via a cage, into donor
and acceptor species C and D, which leads to practically
complete scrambling in the product formation.
Con clu sion
In conclusion, activated pentadienyloxy systems offer
high glycosyl donor properties. Their combination with
an appropriately attached glycosyl acceptor leads in the
R-mannopyranosyl donor case to complete R-selectivity.
In the glucopyranosyl donor series of experiments, inde-
pendent of the configuration of the starting material,
similar R:â-ratios in the products were obtained and at
low temperatures preferentially the â-linked disaccha-
rides were formed. On the basis of crossover experiments

1322 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 4
2
Ta ble 1. Disa cch a r id e F or m a tion fr om Com p ou n d s 14r
a n d 14â
(m, 11 H, 8 PhCH, styrene-CH2, 1b-H), 4.85 (d, J ) 10.9 Hz, 1
2
H, PhCH), 4.88 (d, J ) 10.8 Hz, 1 H, PhCH), 4.94 (d, 1 H, 1a-
2
H), 4.95 (d, J ) 11.2 Hz, 1 H, PhCH), 7.17 (m, 2 H), 7.24-7.33
reaction conditions
(m, 37 H); 13C NMR (150.9 MHz, CDCl3 + 1 vol % d6-pyridine,
extract of data) δ 55.17 (OMe), 66.63 (6b-C), 68.87 (5b-C), 69.21
(6a-C), 72.08 (5a-C), 74.72 (2a-C), 74.91 (4a-C), 77.73 (4b-C),
80.06 (3a-C), 80.09 (2b-C), 82.00 (3b-C), 86.67 (vinyl-CH2), 97.33
product 16R,â
temp
educt solvent
promoter (amt, equiv)
(°C) yield (%) R:â
14r
14r
14r
14r
14â
14â
14â
14â
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
PhSeCl (1.5), AgOTf (1.5)
PhSeCl (1.5), AgOTf (1.5) -40
TMSOTf (1.0)
TMSOTf (1.0)
PhSeCl (1.5), AgOTf (1.5)
PhSeCl (1.5), AgOTf (1.5) -40
TMSOTf (1.0)
TMSOTf (1.0)
0
82
41
77
75
70
75
81
70
1:2
1:5
2:3
1:8
1:3
1:20
1:2
1
1
(1a-C), 97.88 (1b-C); INEPT J 1a-H,1a-C ) 169 Hz, J 1b-H,1b-C
)
168 Hz; MS (FAB, 3-NBOH, NaI) m/e 1293 (3%, [M + NaI]Na+),
0
-40
0
1158 (7%, MK+), 1142 (100%, MNa+).
Meth yl 4-{1-[2-(((2,3,4,6-Tetr a -O-ben zyl-r-D-m a n n op yr a -
n osyl)oxy)m eth yl)p h en -1-yl]vin yl}-2,3,6-tr i-O-ben zyl-r-D-
glu cop yr a n osid e (7). To 3 (715 mg, 1.06 mmol), 519 (492 mg,
1.06 mmol), and DMAP (26 mg, 0.21 mmol) in dry CH2Cl2 (3
mL) at 0 °C was added DCC (437 mg, 2.12 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(toluene/EtOAc 12:1) was done twice and yielded a colorless
syrup (916 mg, 77%). To the syrup (500 mg, 0.446 mmol) in dry
THF (5 mL) at 0 °C was added Tebbe’s reagent (0.5 M in toluene,
1.3 mL, 0.65 mmol). Ice-cooling was removed after 30 min, and
stirring at room temperature was continued for 3 h. Workup
was carried out as described for 6. Flash chromatography
(petroleum ether/EtOAc 6:1, 1 vol % triethylamine) yielded 7
(400 mg, 80%) as a colorless oil: Rf 0.43 (petroleum ether/EtOAc
3:1); [R]D 39.9 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.38
(s, 3 H), 3.58-4.10 (m, 12 H), 4.36-4.85 (m, 19 H), 4.90 (d, J )
1.9 Hz, 1 H), 7.13-7.37 (m, 39 H); MS (FAB, 3-NBOH, NaI) m/e
1293 (3%, [M + NaI]Na+), 1158 (6%, MK+), 1142 (100%, MNa+).
Meth yl O-(2,3,4,6-Tetr a -O-ben zyl-r-D-m a n n op yr a n osyl)-
(1f6)-2,3,4-tr i-O-ben zyl-r-D-glu cop yr a n osid e (8). Gen er a l
P r oced u r e for th e Glycosid e Syn th eses. To dry toluene (1.5
mL) and activated molecular sieves 4 Å (0.3 g) at 0 °C were
added phenylselenyl chloride (28 mg, 0.15 mmol) and dried AgI-
OTf (38 mg, 0.15 mmol). After the reaction mixture was stirred
for 10 min at 0 °C under exclusion of light, a solution of 6 (110
mg, 0.098 mmol) in dry toluene (1.0 mL) was added dropwise
over 2 min. The reaction mixture was stirred for 40 min at 0 °C
0
-40
1:12
1.05 mmol), and DMAP (26 mg, 0.21 mmol) in dry CH2Cl2 (3
mL) at 0 °C was added DCC (433 mg, 2.10 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(toluene/EtOAc 12:1) was done twice and yielded a colorless
syrup (1.05 g, 0.937 mmol, 89%). To the syrup (500 mg, 0.446
mmol) in dry THF (5 mL) at 0 °C was added commercially
available Tebbe’s reagent (0.5 M in toluene, 1.3 mL, 0.65 mmol).
Ice-cooling was removed after 40 min, and stirring at room
temperature was continued for 2 h. The black reaction mixture
was diluted with Et2O (10 mL), and aqueous NaOH (2.5 M, 1
mL) was added cautiously over 25 min in portions. After it was
stirred for 2 h at room temperature, the deep orange reaction-
mixture was filtered with a 1:1 mixture of Celite and MgSO4
and concentrated in vacuo (bath temperature below 30 °C). Flash
chromatography (petroleum ether/EtOAc 4:1, 1 vol % triethy-
lamine) yielded 6 (388 mg, 78%) as a colorless oil: Rf 0.41
1
(petroleum ether/EtOAc 3:1); [R]D 50.2 (c 1.0, CHCl3); H NMR
(600 MHz, CDCl3 + 1 vol % d6-pyridine) δ 3.33 (s, 3 H, OMe),
3.50 (2b-H), 3.54 (4b-H-H), 3.68 (6a-H), 3.77 (2a-H), 3.77 (6′a-
H), 3.80 (5a-H), 3.88 (5b-H), 3.89 (m, 2 H, 6b-, 6′b-H), 3.94 (3a-
H), 3.99 (3b-H), 4.03 (4a-H), 4.20 (d, 1 H, vinyl-H), 4.21 (d, 1 H,
vinyl-H), 4.48 (d, 2J ) 12.1 Hz, 1 H, PhCH), 4.51 (d, 2J ) 10.9
2
Hz, 1 H, PhCH), 4.55 (d, J ) 11.2 Hz, 1 H, PhCH), 4.56-4.82

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1323
Sch em e 5
Ta ble 2. Com p etition Exp er im en ts w ith Com p ou n d s 14â a n d 20r,â
reaction conditions
yield (%) (R:â)
entry
no.
temp
(°C)
concn
solvent
promoter (amt, equiv)
(10-2 M)
16r,â
21r,â
11r,â
18r,â
1
2
3
4
5
Tol
Tol
Tol
Tol
Tol
BF3.OEt2 (0.8)
TMSOTf (1)
TMSOTf (1.1)
PhSeCl (1.5), AgOTf (1.5)
PhSeCl (1.5), AgOTf (1.5)
0
0
-40
-40
0
2
2
2
1
5
11 (1:1)
38 (1:2)
17 (1:4)
36 (1:5)
41 (1:2)
11 (1:1)
38 (1:2)
17 (1:4)
28 (1:4)
41 (1:2)
33 (1:1)
26 (1:1)
6 (1:1)
27 (1:1)
41 (1:1)
29 (1:1)
26 (1:1)
6 (1:1)
27 (1:1)
41 (1:1)
and then diluted with EtOAc (4 mL) and, after addition of
saturated aqueous Na2S2O3 (3 mL), was again stirred for 2 h at
room temperature. Water (10 mL) and EtOAc (50 mL) were
added, and the layers were separated. The organic layer was
washed with water (20 mL) and brine (30 mL), dried over
MgSO4, and concentrated in vacuo. Flash chromatography
(toluene/EtOAc 12:1) yielded the known 821 (77 mg, 80%).
Via the same route the known 9,21 the known 16R/â27 and
the known 17R/â27 were prepared.
added. After it was stirred for 1 h at room temperature, the
reaction mixture was neutralized by addition of Amberlite IR120
(H+-mode), concentrated in vacuo, and dried under high vacuum.
The residue was dissolved in DMF (16 mL); at 0 °C benzyl
bromide (2.8 mL, 24.0 mmol), NaH (576 mg, 24.0 mmol), and a
catalytic amount of tetra-n-butylammonium iodide (100 mg, 0.27
mmol) were added, and the reaction was carried out and the
mixture worked up as described for 2. Flash chromatography
(petroleum ether/EtOAc 8:1) yielded 11â (2.41 g, 69%) as a white
solid: mp 92 °C; Rf 0.65 (toluene/EtOAc 10:1); [R]D -7.2 (c 1.0,
CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.47-3.81 (m, 6 H), 4.53-
5.05 (m, 9 H), 7.12-7.37 (m, 22 H), 7.53-7.57 (m, 2 H). Anal.
Calcd for C41H41BrO6: C, 69.39; H, 5.82. Found: C, 69.77; H
5.88.
2-Br om oben zyl 2,3,4,6-Tetr a -O-ben zyl-r/â-D-glu cop yr a -
n osid e (11r/â). (a ) F r om 12. To 1223 (1.05 g, 1.94 mmol) in 5
mL of DMF at 0 °C was added 2-bromobenzyl bromide (0.73 g,
2.96 mmol) and then NaH (67 mg, 2.8 mmol). Ice-cooling was
removed after 10 min, and stirring under exclusion of light was
continued for 2 h at room temperature. The reaction mixture
was diluted with Et2O (50 mL) and quenched with saturated
aqueous NaHCO3 (20 mL) and water (20 mL). The layers were
separated, and the aqueous phase was extracted with Et2O (2
× 75 mL). The combined organic layers were washed with water
(2 × 50 mL) and brine (100 mL), dried over MgSO4, and
concentrated in vacuo. Flash chromatography (petroleum ether/
EtOAc 6:1) yielded 11R,â13 (1.32 g, 96%, R:â ) 1:1) as a colorless
solid. Separation was performed by column chromatography
(CHCl3/Et2O 60:1). 11R/â: Rf 0.65 (toluene/EtOAc 10:1). 11R: Rf
0.60 (CHCl3/Et2O 30:1). 11â: Rf 0.57 (CHCl3/Et2O 30:1).
(b) F r om 10. To a slurry of 1022 (3.20 g, 6.48 mmol) and
2-bromobenzyl alcohol (1.82 g, 9.72 mmol) in dry CH2Cl2 (10 mL)
at 0 °C was added distilled BF3‚ OEt2 (80 µL, 0.65 mmol). After
20 min, the reaction mixture was quenched with saturated
aqueous NaHCO3 (10 mL). Water (40 mL) and EtOAc (100 mL)
were added, and the separated aqueous layer was extracted with
EtOAc (2 × 50 mL). The resulting organic layers were combined
and washed with water (100 mL) and brine (100 mL), dried over
MgSO4, and concentrated in vacuo. The residue was purified via
flash chromatography (petroleum ether/EtOAc 1.3:1). The eluted
white solid (2.54 g, 4.92 mmol, 76%) was dissolved in dry MeOH
(32 mL), and NaOMe (1 M in MeOH, 0.48 mL, 0.48 mmol) was
2-{[(2,3,4,6-Te t r a -O-b e n zyl-r-D-glu cop yr a n osyl)oxy]-
m eth yl}ben zoic Acid (13r). To 11R (0.25 g, 0.37 mmol) in a
mixture of dry THF (5 mL) and dry n-hexane (1.5 mL) at -100
°C was added n-butyllithium (1.6 M in hexane, 0.24 mL, 0.38
mmol). The reaction was carried out and the mixture worked
up as described for 3. Concentration in vacuo gave a solid, which
was crystallized in Et2O/petroleum ether at 4 °C (13R, 122 mg,
51%). Crystallization of the concentrated mother liquor from
Et2O/petroleum ether at 4 °C gave again 13â (105 mg, 42%):
mp 104 °C; Rf 0.45-0.65 (toluene/EtOAc 1:1); [R]D 57.3 (c 1.0,
1
CHCl3); H NMR (250 MHz, CDCl3) δ 3.60-3.76 (m, 4 H), 3.85
(m, 1 H), 4.07 (dd, 1 H), 4.44 (d, J ) 12.1 Hz, 1 H), 4.47 (d, J )
10.8 Hz, 1 H), 4.60 (d, J ) 12.1 Hz, 1 H), 4.63 (d, J ) 11.9 Hz,
1 H), 4.75 (d, J ) 11.9 Hz, 1 H), 4.82 (d, J ) 10.8 Hz, 1 H), 4.84
(d, J ) 10.8 Hz, 1 H), 4.91-5.01 (m, 3 H), 5.10 (d, J ) 14.7 Hz,
1 H), 6.97-7.13 (m, 2 H), 7.20-7.40 (m, 19 H), 7.51 (ddd, 1 H),
7.77 (d, 1 H), 8.03 (dd, 1 H).
2-{[(2,3,4,6-Te t r a -O-b e n zyl-â-D-glu cop yr a n osyl)oxy]-
m eth yl}ben zoic Acid (13â). To 11â (1.96 g, 2.75 mmol) in a
mixture of dry THF (40 mL) and dry n-hexane (12 mL) at -100
°C was added n-butyllithium (1.6 M in hexane, 1.9 mL, 3.0
mmol). The reaction was carried out and the mixture worked
up as described for 3. Concentration in vacuo gave a solid, which

1324 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
was dissolved in EtOAc (6 mL) at 70 °C. Crystallization with
addition of petroleum ether yielded 13â (1.28 g, 69%) as white
crystals. Crystallization of the concentrated mother liquor from
Et2O/petroleum ether at room temperature gave again 13â (0.48
g, 26%): mp 144 °C (EtOAc/petroleum ether); Rf 0.45-0.65
(toluene/EtOAc 1:1); [R]D - 2.6 (c 1.0, CHCl3); 1H NMR (250
MHz, CDCl3) δ 3.50 (m, 1 H), 3.56-3.80 (m, 5 H), 4.51-4.56
(m, 2 H), 4.58 (d, J ≈ 8 Hz, 1 H), 4.63 (d, J ) 12.2 Hz, 1 H), 4.80
(d, J ) 10.9 Hz, 1 H), 4.81 (d, J ) 11.0 Hz, 1 H), 4.83 (d, J )
10.7 Hz, 1 H), 4.94 (d, J ) 10.9 Hz, 1 H), 5.00 (d, J ) 11.0 Hz,
1 H), 5.18 (d, J ) 14.9 Hz, 1 H), 5.37 (d, J ) 14.9 Hz, 1 H),
7.14-7.38 (m, 21 H), 7.50 (ddd, 1 H), 7.80 (dd, 1 H), 8.06 (dd, 1
H). Anal. Calcd for C42H42O8: C, 74.46; H, 6.27. Found: C, 74.77;
H, 6.28.
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(toluene/EtOAc 10:1) was done twice and yielded a white solid
(1.30 g, 85%). To the solid (720 mg, 0.642 mmol) in dry THF (8
mL) at 0 °C was added Tebbe’s reagent (0.5 M in toluene, 1.6
mL, 0.80 mmol). The reaction was carried out and the mixture
worked up as described for 7. Flash chromatography (petroleum
ether/EtOAc 3.5:1, 1 vol % triethylamine) yielded 15â (689 mg,
96%) as a colorless oil: Rf 0.27 (petroleum ether/EtOAc 3:1); [R]D
11.7 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.27 (m, 1 H),
3.37 (s, 3 H), 3.43-3.73 (m, 7 H), 3.82 (m, 1 H), 4.02 (dd, 1 H),
4.35-4.93 (m, 21 H), 5.08 (d, J ) 12.5 Hz, 1 H), 7.12-7.30 (m,
38 H), 7.59 (dd, 1 H); MS (FAB, 3-NBOH, NaI) m/e 1158 (5%,
MK+), 1142 (100%, MNa+).
Meth yl 6-{1-[2-(((2,3,4,6-Tetr a -O-ben zyl-r-D-glu cop yr a -
n osyl)oxy)m eth yl)p h en -1-yl]vin yl}-2,3,4-tr i-O-ben zyl-r-D-
glu cop yr a n osid e (14r). To 13R (340 mg, 0.50 mmol), 418 (234
mg, 0.50 mmol), and DMAP (12 mg, 0.010 mmol) in dry CH2Cl2
(2 mL) at 0 °C was added DCC (268 mg, 1.01 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(petroleum ether/EtOAc 4:1) eluted a residue that was purified
via a second flash chromatography (toluene/EtOAc 10:1), which
gave a white solid (465 mg, 0.41 mmol, 82%; Rf 0.14 (CHCl3/
Et2O 30:1), Rf 0.42 (petroleum ether/EtOAc 3:1)). To the solid
(403 mg, 0.359 mmol) in dry THF (2.8 mL) at 0 °C was added
Tebbe’s reagent (0.5 M in toluene, 0.95 mL, 0.48 mmol). The
reaction was carried out and the mixture worked up as described
for 6. Flash chromatography (petroleum ether/EtOAc 4.5:1, 1
vol % triethylamine) yielded 14R (380 mg, 95%) as a colorless
syrup: Rf 0.51 (petroleum ether/EtOAc 3:1); [R]D 56.9 (c 1.0,
2-[2,3,4,6-Tet r a -O-(3-m et h ylb en zyl)-r/â-D-glu cop yr a n o-
syloxym eth yl]ben zoic Acid (19r/â). To an anomeric mixture
of 18R/â13 (2.80 g, 3.66 mmol, R:â ) 1:1) in a mixture of dry THF
(60 mL) and dry n-hexane (18 mL) at -100 °C was added
n-butyllithium (1.6 M in hexane, 2.5 mL, 4.0 mmol). The reaction
was carried out and the mixture worked up as described for 3.
Concentration in vacuo gave a syrup, which was purified by flash
chromatography (petroleum ether/EtOAc 2:1). 19R/â (2.30 g,
86%, R:â ) 1:1) was obtained as a colorless, waxy solid: Rf 0.05-
0.19 (petroleum ether/EtOAc 3:1); 1H NMR (250 MHz, CDCl3) δ
2.25-2.32 (m, 12 H), 3.50 (m, 0.5 H), 3.57-3.87 (m, 5 H), 4.08
(dd, 0.5 H), 4.39-5.14 (m, 10 H), 5.19 (d, J ) 15.0 Hz, 0.5 H),
5.38 (d, J ) 15.0 Hz, 0.5 H), 6.96 (m, 2 H), 7.06-7.24 (m, 14 H),
7.36 (m, 1 H), 7.52 (m, 1 H), 7.82 (m, 1 H), 8.06 (m, 1 H). Anal.
Calcd for C46H50O8: C, 75.59; H, 6.90. Found: C, 75.37; H, 6.89.
{1-[2-(((2,3,4,6-Tetr a -O-(3-m eth ylben zyl)-r/â-D-glu cop y-
r an osyl)oxy)m eth yl)ph en -1-yl]vin yl}-2-br om oben zyl Eth er
(20r/â). To an anomeric mixture of 19R/â (1.20 g, 1.64 mmol,
R:â ) 1:1), 2-bromobenzyl alcohol (0.38 g, 2.03 mmol), and
4-(dimethylamino)pyridine (33 mg, 0.27 mmol) in dry CH2Cl2
(4 mL) at 0 °C was added DCC (0.56 g, 2.7 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(petroleum ether/EtOAc 7:1) was done twice and yielded a
colorless, waxy solid (1.41 g, 96%, R:â ) 1:1; Rf 0.63 (toluene/
EtOAc 10:1)). To the solid (440 mg, 0.489 mmol, R:â ) 1:1) in
dry THF (4 mL) at 0 °C was added Tebbe’s reagent (0.5 M in
toluene, 1.4 mL, 0.70 mmol). The reaction mixture was stirred
at 0 °C for 90 min. Workup was carried out as described for 6.
Flash chromatography (petroleum/EtOAc 10:1, 1 vol % triethy-
lamine) yielded 20R/â (435 mg, 99%, R:â ) 1:1) as a colorless
oil: Rf 0.66 (toluene/EtOAc 10:1); 1H NMR (250 MHz, CDCl3) δ
2.25-2.30 (m, 12 H), 3.44 (m, 0.5 H), 3.49-3.73 (m, 4.5 H), 3.81
(m, 0.5 H), 4.04 (dd, 0.5 H), 4.36-4.98 (m, 14.5 H), 5.13 (d, J )
12.9 Hz, 0.5 H), 6.94-6.98 (m, 2 H), 7.05-7.67 (m, 22 H); MS
(FAB, 3-NBOH, NaI): m/e 921 (17%, MNa+), 303 (11%), 209
(93%), 169 (100%, [BrPhCH2]+).
Com p etition Exp er im en ts. (a ) P h SeOTf Activa tion . To
dry toluene (2.0 mL) and activated molecular sieves 4A (0.5 g)
at 0 °C were added phenylselenyl chloride (63 mg, 0.33 mmol)
and dried AgIOTf (85 mg, 0.33 mmol). After the mixture was
stirred for 10 min at 0 °C with exclusion of light, a solution of
14â (110 mg, 0.098 mmol) and 20R,â (99 mg, 0.110 mmol, R:â )
1:1) in dry toluene (2.6 mL), cooled to 0 °C, was added by syringe
dropwise over 2 min. The reaction mixture was stirred for 90
min at 0 °C and then diluted with EtOAc (8 mL) and after
addition of saturated aqueous Na2S2O3 (6 mL) again stirred for
2 h at room temperature. Water (20 mL) and EtOAc (80 mL)
were added, and the layers were separated. The organic layer
was washed with water (40 mL) and brine (60 mL), dried over
MgSO4, concentrated in vacuo, and coevaporated twice with
toluene. Flash chromatography (22 g of SiO2) was started with
toluene/EtOAc (60:1, 450 mL). The fractions, which contained
18R,â and 11R,â, partially separated, were combined. The second
solvent system (toluene/EtOAc 15:1, 450 mL) eluted 21R,â
followed by 16R,â, which were again partially separated. These
fractions were also combined. The total anomeric ratio could be
determined with the help of the 1H NMR signals by employing
the following equations for the 16R/â + 21R/â mixture: (i) 16R
+ 16â + 21R + 21â ) 1; (ii) (16R + 16â)/(21R + 21â) ) x, which
was determined from the integration of 3-methylbenzyl signals
at δ ∼2.3; (iii) (16R + 21R)/(16â + 21â) ) y, which was
1
CHCl3); H NMR (600 MHz, CDCl3) δ 3.34 (s, 3 H, OMe), 3.50
(2b-H), 3.52 (6b-H), 3.54 (2a-H), 3.56 (4b-H), 3.67 (4a-H), 3.68
(6′b-H), 3.80 (5a-H), 3.89 (5b-H), 3.90 (6a-H), 3.94 (6′a-H), 4.00
(3b-H), 4.04 (3a-H), 4.27 (d, 1 H, vinyl-H), 4.36 (d, 1 H, vinyl-
H), 4.40 (d, 2J ) 12.1 Hz, 1 H), 4.48 (d, 2J ) 10.8 Hz, 1 H), 4.55-
4.59 (m, 3 H), 4.62 (d, 1 H, 1b-H), 4.64-4.67 (m, 3 H), 4.74 (d,
2J ) 12.1 Hz, 1 H), 4.78-4.87 (m, 5 H), 4.88 (d, 3J ) 3.4 Hz, 1
H, 1a-H), 4.97 (m, 2 H), 7.14 (m, 2 H), 7.23-7.34 (m, 36 H), 7.59
(d, 1 H); 13C NMR (150.9 MHz, CDCl3, extract of data) δ 55.2
(OMe), 66.7 (6a-C), 68.4 (6b-C), 68.9 (5b-C), 70.4 (5a-C), 77.7 (4a-
C), 77.8 (2a-C), 80.0 (2b-C), 80.2 (4b-C), 82.0 (3b-C), 82.0 (3a-
C), 87.1 (vinyl-CH2), 96.3 (1a-C), 97.9 (1b-C); MS (FAB, 3-NBOH,
NaI) m/e 1293 (5%, [M + NaI]Na+), 1158 (9%, MK+), 1142 (100%,
MNa+).
Meth yl 6-{1-[2-(((2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a -
n osyl)oxy)m eth yl)p h en -1-yl]vin yl}-2,3,4-tr i-O-ben zyl-r-D-
glu cop yr a n osid e (14â). To 13â (800 mg, 1.19 mmol), 418 (553
mg, 1.19 mmol), and DMAP (29 mg, 0.24 mmol) in dry CH2Cl2
(3 mL) at 0 °C was added DCC (490 mg, 2.38 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred
for 16 h at room temperature. Concentration in vacuo was
followed by coevaporation with toluene. Flash chromatography
(toluene/EtOAc 10:1) eluted a residue that was purified via a
second flash chromatography (petroleum ether/EtOAc 3.5:1),
which gave a white solid (1.05 g, 0.857 mmol, 72%; Rf 0.09
(CHCl3/Et2O 30:1), Rf 0.42 (petroleum ether/EtOAc 3:1)). To the
solid (555 mg, 0.495 mmol) in dry THF (5 mL) at 0 °C was added
Tebbe’s reagent (0.5 M in toluene, 1.3 mL, 0.65 mmol). The
reaction was carried out and the mixture worked up as described
for 6. Flash chromatography (petroleum ether/EtOAc 5:1, 1 vol
% triethylamine) yielded 14â (535 mg, 97%) as a white solid,
which crystallized from EtOAc/petroleum ether at room tem-
perature: mp 110 °C (EtOAc/petroleum ether); Rf 0.51 (petro-
leum ether/EtOAc 3:1); [R]D 19.3 (c 1.0, CHCl3); 1H NMR (250
MHz, CDCl3) δ 3.34 (s, 3 H), 3.41 (m, 1 H), 3.49-3.68 (m, 7 H),
3.87-3.93 (m, 3 H), 4.00 (dd, 1 H), 4.26 (d, J ) 2.4 Hz, 1 H),
4.33 (d, J ) 2.4 Hz, 1 H), 4.47 (d, J ) 7.5 Hz, 1 H), 4.47-5.00
(m, 17 H), 7.14-7.38 (m, 38 H), 7.58 (dd, 1 H). Anal. Calcd for
C
71H74O12: C, 76.18; H, 6.66. Found: C, 76.14; H, 6.67.
Meth yl 4-{1-[2-(((2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a -
n osyl)oxy)m eth yl)p h en -1-yl]vin yl}-2,3,6-tr i-O-ben zyl-r-D-
glu cop yr a n osid e (15â). To 13â (915 mg, 1.36 mmol), 519 (630
mg, 1.36 mmol), and DMAP (33 mg, 0.27 mmol) in dry CH2Cl2
(4 mL) at 0 °C was added DCC (536 mg, 2.60 mmol). Ice-cooling
was removed after 10 min, and the reaction mixture was stirred

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1325
determined from the integration of the R-OMe signal at δ 3.35
and the â-OMe signal at δ 3.32; (iv) 16â/21â ) z, which was
determined from the integration of 16â 1-H at δ 4.33 and 21â
1-H at δ 4.34. Similar equations were employed for the 11R/â +
18R/â mixture: (i) 11R + 11â + 18R + 18â ) 1; (ii) (11R + 11â)/
(18R + 18â) ) x, taken from the 3-methylbenzyl signal at δ ∼2.3;
(iii) (11R + 18R)/(11â + 18â) ) y, taken from the 3R-H signal of
the R-anomers at δ 4.06, 4.07; (iv) 11R/18R ) z, taken from 3R-H
of 11R at δ 4.07 and 18R at δ 4.06. In the described experiment,
the resulting yields were as follows: 18R,â,13 37 mg, 44%, R:â )
1:1; 11R,â,13 34 mg, 44%, R:â ) 1:1; 21R,â,13 47 mg, 41%; 16R,â,27
45 mg, 41%; ∑R:â ) 1:2.
(b) TMSOTf Activa tion . The activating reagent was added
to a solution of 14â and 20R,â at the corresponding temperature.
The reaction was quenched with saturated aqueous NaHCO3
instead of saturated aqueous Na2S2O3.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. G.S. is grateful for a stipend
from the Fonds der Chemischen Industrie.
J O971778E