Glycosylation via Cp2ZrCl2/AgClO4-mediated activation of anomeric sulfoxides

Full text of DOI:10.1021/jo015952h

7910
J . Org. Chem. 2001, 66, 7910-7914
Sch em e 1
Glycosyla tion via Cp 2Zr Cl2/
AgClO4-Med ia ted Activa tion of An om er ic
Su lfoxid es
Peter Wipf* and J onathan T. Reeves
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
pwipf+@pitt.edu
Received J uly 19, 2001
Sch em e 2
In tr od u ction
The presence of saccharide moieties in biologically
active molecules has provided major impetus for recent
advances in the state of the art of carbohydrate synthe-
sis.1 Of central importance is the construction of the
glycosidic bond. A multitude of glycosyl donors and
activating systems have been developed for this purpose,
producing varying levels of stereoselectivity.1,2 Neverthe-
less, the field as a whole still lags behind the state of the
analogous areas of peptide and nucleotide coupling
chemistry.3,4 Additional efficient and stereoselective meth-
ods for formation of O-glycosidic bonds are therefore
desirable.
Kahne and co-workers introduced the use of anomeric
sulfoxides as glycosyl donors in 1989.5 Activation of the
glycosyl sulfoxide is generally accomplished with triflic
anhydride in the presence of stoichiometric 2,6-di-tert-
butyl-4-methyl pyridine (DTBMP) as a triflic acid scav-
enger.6 In our recent work on the development of a
fluorous THP protecting group,7 we initially employed the
Tf2O/DTBMP conditions to activate sulfoxide 1 but
obtained primarily elimination product 2 instead of the
desired acetal 3 (Scheme 1). In contrast, in the presence
of a 1:2 ratio of Cp2ZrCl2/AgClO4 to activate the sul-
foxide, good yields of acetals 3 were obtained with no
elimination product. In an extension of pioneering studies
by Mukaiyama on the activation of glycosyl fluorides
with SnCl2/AgClO4,8 Suzuki and co-workers were first
in exploring the combination of zirconocene dichloride
and silver perchlorate for glycosyl fluoride transfer.9
Herein,we report the application of this reagent combina-
tion to coupling of carbohydrate-derived sulfoxide donors
(Scheme 2).
Resu lts a n d Discu ssion
The glycosylation under cationic zirconocene conditions
was first investigated using the peracetylated donor 4,
prepared in four steps from D-glucose (Figure 1).10 Ad-
dition of 4 to a -20 °C solution of a 1:2:2 molar ratio of
Cp2ZrCl2/AgClO4/benzyl alcohol in CH2Cl2, however,
yielded no O-glycoside product after 8 h. Variation of
temperature, reagent stoichiometry, and solvent also
failed to lead to any product. The corresponding axial
sulfoxide 5 was prepared11 but also found to be unreac-
tive. The lack of reactivity of tetraacetates 4 and 5 can
be attributed to deactivation of the sulfoxide oxygen by
the electron withdrawing inductive effect of the acetyl
groups. This is a well-known property of ester-bearing
(disarmed) versus ether-bearing (armed) glycosyl donors
and has been exploited in polysaccharide synthesis, first
by Fraser-Reid and co-workers with n-pentenyl glyco-
sides12 and later for other donor systems.13
Given the unreactive nature of the peracylated donors
under our reaction conditions and the known increase of
reactivity with peralkylated donors, we prepared the
glycosyl sulfoxide 614 in six steps from D-glucose (Table
1). Under otherwise identical reaction conditions, this
donor afforded benzyl glycoside 8 as a 4.4:1 R/â mixture
of anomers in 80% combined yield. Secondary and
tertiary alcohols also afforded good yields of products,
with a shift toward â-selectivity as the steric bulk of the
acceptor alcohol increased. Changing the solvent from
CH2Cl2 to benzene gave decreased selectivity (R/â )
(1) (a) Davis, B. G. J . Chem. Soc., Perkin Trans. 1 2000, 2137. (b)
Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 45, 8385. (c)
Bashkin, J . K., Ed. Frontiers in Carbohydrate Research. Chem. Rev.
2000, 100, 4265-4711.
(2) (a) Boons, G.-J . Carbohydrate Chemistry; Thomson Science:
London, 1998. (b) Boons, G.-J . Tetrahedron 1996, 52, 1095. (c)
Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380. (d) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
(3) Seitz, O. Angew. Chem., Int. Ed. Engl. 1998, 37, 3109.
(4) (a) Humphrey, J . M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100, 4349.
(5) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J . Am. Chem.
Soc. 1989, 111, 6881.
(10) Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.;
Sofia, M. J . J . Org. Chem. 1996, 61, 8347.
(6) For mechanistic discussions, see: (a) Crich, D.; Sun, S. J . Am.
Chem. Soc. 1997, 119, 11217. (b) Gildersleeve, J .; Pascal, R. A.; Kahne,
D. J . Am. Chem. Soc. 1998, 120, 5961. (c) Crich, D.; Cai, W. J . Org.
Chem. 1999, 64, 4926.
(7) Wipf, P.; Reeves, J . T. Tetrahedron Lett. 1999, 40, 4649.
(8) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431.
(9) (a) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G.
Tetrahedron Lett. 1988, 29, 3567. (b) Matsumoto, T.; Katsuki, M.; J ona,
H.; Suzuki, K. J . Am. Chem. Soc. 1991, 113, 6982. (c) Matsumoto, T.;
Hosoya, T.; Suzuki, K. J . Am. Chem. Soc. 1992, 114, 3568. (d) Suzuki,
K. Pure Appl. Chem. 1994, 66, 1557.
(11) Ramkumar, D.; Sankararaman, S. Synthesis 1993, 1057.
(12) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B. J . Am. Chem. Soc. 1988, 110, 5583. (b) Fraser-Reid, B.; Wu, Z.;
Udodong, U. E.; Ottosson, H. J . Org. Chem. 1990, 55, 6068. (c)
Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-Reid, B. J .
Chem. Soc., Chem. Commun. 1990, 270.
(13) (a) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron
Lett. 1990, 31, 4313. (b) Veeneman, G. H.; van Boom, J . H. Tetrahedron
Lett. 1990, 31, 275. (c) Veeneman, G. H.; van Leeuwen, S. H.; van
Boom, J . H. Tetrahedron Lett. 1990, 31, 1331. (d) Nicolaou, K. C.;
Caulfield, T. J .; Groneberg, R. D. Pure Appl. Chem. 1991, 63, 555.
10.1021/jo015952h CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7911
Sch em e 3
F igu r e 1. Unreactive anomeric sulfoxide donors.
Ta ble 1. Glycosyla tion w ith Glu cose-Der ived
P er m eth yla ted Don or Su lfoxid es
Ta ble 2. Glycosyla tion w ith Ma n n ose-Der ived Don or s
a
b
Combined yield of R- and â-anomers. Determined after
isolation of individual anomers by chromatography on SiO2.
a
b
Combined yield of R- and â-anomers. Determined after
c Determined by 1H NMR analysis of anomeric mixture.
isolation of individual anomers by chromatography on SiO2.
c Determined by 1H NMR analysis of anomeric mixture.
1.3:1, 70% combined yield) in the glycosylation of benzyl
alcohol, and no reaction occurred in Et2O. Lower initial
temperature (-78 °C) inhibited the reaction; however,
upon warming to room temperature, a similar yield and
selectivity were obtained (R/â ) 3.8:1, 77% combined
yield). The process was found to require stoichiometric
quantities of Cp2ZrCl2/AgClO4 reagent, giving only a trace
of product when 10 mol % of Cp2ZrCl2 and 20 mol % of
AgClO4 were used. The corresponding axial sulfoxide 714
was also prepared in five steps from D-glucose and tested
in the glycosylation procedure. This donor was slightly
â-selective in the coupling with benzyl alcohol and
cyclohexanol.
To examine the effect of an axial C-2 substituent on
the stereoselectivity of the reaction the mannose-derived
donors 15 and 16 were prepared from the known tet-
raacetates 1115 and 1216 (Scheme 3). Zemple`n deacety-
lation17 followed by exhaustive methylation gave the
tetra-methylated sulfides 13 and 14, which were oxidized
with m-chloroperoxybenzoic acid at low temperature to
give sulfoxides 15 and 16.
The possibility of epimerization of the kinetically
formed product ratio of anomers to a thermodynamic
distribution by either the zirconium complex or traces of
HClO4 formed under the reaction conditions was exam-
ined next. A pure sample of â-17 was subjected to a 1:2:1
ratio of Cp2ZrCl2/AgClO4/BnOH in CH2Cl2 for 6 h at room
temperature. 1H NMR of the crude product after workup
revealed only the starting â-anomer, with no trace of
R-anomer. Similarly, pure R-17 was subjected to the
reaction conditions, and no epimerization to the â-anomer
was detected by 1H NMR. Thus, it appears that the
isolated product distributions are obtained in a kineti-
cally controlled fashion, and that the Cp2ZrCl2/AgClO4
reagent system is unable to activate the product O-
glycosides toward transacetalization. This result also
suggests that HClO4 is not produced under the reaction
conditions. However, to verify that initial activation of
the sulfoxide occurs by a zirconium species rather than
by HClO4, the reaction of sulfoxide 16 with BnOH was
conducted in the presence of 1.0 equiv of 2,6-di-tert-butyl-
4-methyl pyridine. Under these conditions, glycoside 17
was obtained in similar yield and anomeric selectivity
(70%, R/â ) 6:1) as in the absence of the proton scavenger.
It can be concluded, therefore, that sulfoxide activation
is indeed accomplished by a cationic zirconium complex
rather than by in situ produced protic acid.
Under the optimized conditions developed with glucose-
derived donors, 15 gave excellent yields and high R-se-
lectivity for primary, secondary and tertiary alcohols.
R-Sulfoxide 16 gave decreased R-selectivity in the glyco-
sylation of primary and secondary alcohols (Table 2).
(14) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217.
(15) Kametani, T.; Kawamura, K.; Honda, T. J . Am. Chem. Soc.
1987, 109, 3010.
Importantly, this new methodology for anomeric sul-
foxide activation is not limited to the coupling of methyl
(16) Katsunori, K.; Toshio, K.; Hiroshi, M. Tetrahedron Lett. 1980,
21, 3771.
(17) Zemple`n, G. Ber. Dtsch. Chem. Ges. 1927, 60, 1555.

7912 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 4
much less air- and moisture-sensitive than the triflate
derivatives that have traditionally been used for ano-
meric sulfoxide activation.21 In particular, AgClO4 ad-
sorbed onto Celite is prepared from an aqueous slurry
and can be stored for years without loss in activity.18e
With electron-rich (i.e., methyl-, benzyl-, or allyl ether-
protected) donors, the reaction gives good yields of
glycosides with primary, secondary and tertiary alcohols,
and the process readily lends itself to the preparation of
differentially protected disaccharide building blocks. The
mechanism of the glycosylation reaction likely involves
sulfoxide activation by a cationic zirconium-acceptor
alcohol complex. After ionization of the donor, the coor-
dinated acceptor alcohol can trap the resultant oxonium
ion from either the R- or â-face. The facial selectivity
seems to rely heavily on the geometry of the sulfoxide;
e.g., â-sulfoxide donors favor R-attack, whereas R-sulfox-
ides favor â-attack. These considerations, in combination
with the inherent steric effects of the donor-carbohy-
drate interaction, determine the ultimate anomeric ratio
of products. The high R-selectivity found for the mannose-
derived â-sulfoxides can be explained not only by a
delivery of the acceptor alcohol to the oxonium ion from
the opposite (R) face of the starting sulfoxide, but also
by the gauche interaction of a â-mannosidic substituent
and the stronger anomeric effect present in C-2 axial
sugars.22 Work is currently underway to apply the Cp2-
ZrCl2/AgClO4 reagent system to other glycosidic bond
formation chemistry.
Sch em e 5
ether-protected substrates, which are difficult to depro-
tect. More commonly, benzyl and allyl ethers are em-
ployed as carbohydrate protective groups. Scheme 4
demonstrates the convenient preparation of a fully
protected glucosylglucose derivative by the Cp2ZrCl2/
AgClO4 reagent. Disaccharide 22 is obtained in 72% yield
as a 2.9:1 mixture of R- to â-anomers. Alternatively, the
use of AgClO4 adsorbed on Celite18e provides 22 in
comparable yield and stereoselectivity.
We have previously studied the Ag(I)-catalyzed opening
of oxiranes with alkenylzirconocenes, which also follows
a cationic reaction pathway.18 Accordingly, we were
interested to test the potential of glycosyl sulfoxides to
serve as acceptors in C-glycosylation reactions with
organozirconocenes. However, addition of 5 mol % AgClO4
to a mixture of sulfoxide 6 and in situ prepared19
zirconocene 23 only led to vinyl sulfide 25, possibly via
an intramolecular displacement of the S-O bond in
complex 24 (Scheme 5). Nonetheless, the conversion of
1-octyne to vinyl sulfide 25 represents a new method for
aryl vinyl thioether synthesis that complements the
method of Huang et al.20
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under an
atmosphere of N2 and all glassware was dried in an oven at 140
°C prior to use. Et2O was dried by distillation over Na/ben-
zophenone. Dry CH2Cl2 was obtained by distillation from CaH2.
Unless otherwise stated, solvents or reagents were used without
further purification. NMR spectra were recorded at 300 MHz/
75 MHz (1H/13C NMR) in CDCl3. Elemental analyses were ob-
tained from Atlantic Microlabs, Inc., Norcross, GA. Commercially
available anhydrous AgClO4 was used without special precau-
tions. CAUTION: Anhydrous AgClO4, especially solvated crys-
tals containing organic compounds, can explode when struck.
AgClO4 is also hygroscopic and light sensitive, decomposes at
or above 450 °C, and explodes readily at 800 °C. Several com-
panies, including Aldrich and Strem, offer anhydrous AgClO4;
most suppliers of fine chemicals offer silver perchlorate mono-
hydrate which can be dried by azeotropic distillation. AgAsF6
has been suggested as a safe, but ca. 10× more expensive,
alternative to AgClO4.23 Alternatively, AgClO4 monohydrate can
also be used but reactions proceed more slowly. AgClO4 adsorbed
onto Celite is a viable alternative for the use of anhydrous
AgClO4.18e
Gen er a l P r oced u r e A for Glycosyla tion . Ben zyl 2,3,4,6-
Tet r a -O-m et h yl-D-glu cop yr a n osid e (8). A suspension of
Cp2ZrCl2 (1.20 g, 4.11 mmol, 1.0 equiv), AgClO4 (1.70 g, 8.21
mmol, 2.0 equiv), and 4 Å molecular sieves (500 mg) in CH2Cl2
(50 mL) was stirred at room temperature for 15 min. Benzyl
alcohol (0.85 mL, 8.2 mmol, 2.0 equiv) was added, and the
temperature was lowered to -20 °C. A solution of sulfoxide 6
(1.43 g, 4.16 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added
dropwise, and the reaction mixture was allowed to warm
gradually to room temperature. After 6 h, saturated aqueous
NaHCO3 was added, and the aqueous layer was extracted with
Con clu sion s
We have developed a new method for activating gly-
cosyl sulfoxides for the construction of O-glycosidic link-
ages using the easy to handle Cp2ZrCl2/AgClO4 reagent
combination. Both Cp2ZrCl2 and AgClO4 are readily
available solids that are more convenient to weigh and
(18) (a) Wipf, P.; Xu, W. J . Org. Chem. 1993, 58, 825. (b) Wipf, P.;
Xu, W. J . J . Org. Chem. 1993, 58, 5880. (c) Wipf, P.; Xu, W.; Kim, H.;
Takahashi, H. Tetrahedron 1997, 53, 16575. (d) Wipf, P.; Tsuchimoto,
T.; Takahashi, H. Pure Appl. Chem. 1999, 71, 415. (e) Wipf, P.; Methot,
J .-L. Org. Lett. 1999, 1, 1253.
(19) Wipf, P.; J ahn, H. Tetrahedron 1996, 52, 12853.
(20) Huang, X.; Zhong, P.; Guo, W. Org. Prep. Proc. Int. 1999, 31,
201.
(21) For a recent report on the use of solid acid and sulfated zirconia
as activators of mannopyranosyl sulfoxides, see: Nagai, H.; Kawahara,
K.; Matsumura, S.; Toshima, K. Tetrahedron Lett. 2001, 42, 4159.
(22) Steinlin, H.; Camarda, L.; Vasella, A. Helv. Chim. Acta 1979,
62, 378.
(23) Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba, S.
Tetrahedron 1995, 51, 4483.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7913
CH2Cl2. The combined organic layers were dried (MgSO4) and
concentrated. Chromatography on SiO2 (hexanes/EtOAc, 85:15
f 70:30) gave R-8 (884 mg, 2.71 mmol, 65%) and â-8 (201 mg,
0.617 mmol, 15%) as viscous oils. r-8: [R]D +47.3 (c 0.13, CHCl3);
(hexanes/EtOAc, 75:25) gave 13 (3.89 g, 11.9 mmol, 77%) as a
viscous oil: [R]D -95.6 (c 0.59, CHCl3); IR (neat) 2907, 1584,
1485, 1069 cm-1; 1H NMR δ 7.52-7.48 (m, 2 H), 7.32-7.20 (m,
3 H), 4.71 (s, 1 H), 3.89 (d, 1 H, J ) 2.8 Hz), 3.72-3.68 (m, 1 H),
3.70 (s, 3 H), 3.60 (dd, 2 H, J ) 10.8, 5.8 Hz), 3.53 (s, 3 H), 3.48-
3.41 (m, 1 H), 3.39 (s, 3 H), 3.31 (ddd, 1 H, J ) 9.5, 5.8, 1.8 Hz),
3.23 (dd, 1 H, J ) 9.2, 3.1 Hz); 13C NMR δ 135.5, 130.7, 128.9,
127.1, 87.5, 86.1, 79.7, 79.1, 76.4, 71.9, 62.1, 60.9, 59.4, 58.1.
Anal. Calcd for C16H24O5S: C, 58.51; H, 7.37. Found: C, 58.62;
H, 7.41.
1
IR (neat) 2927, 1450, 1156, 1101, 1046 cm-1; H NMR δ 7.35-
7.27 (m, 5 H), 4.97 (d, 1 H, J ) 3.7 Hz), 4.70 (d, 1 H, J ) 12.2
Hz), 4.57 (d, 1 H, J ) 12.2 Hz), 3.61 (s, 3 H), 3.60-3.43 (m, 4
H), 3.52 (s, 3 H), 3.38 (s, 6 H), 3.24-3.14 (m, 2 H); 13C NMR δ
137.0, 128.2, 128.1, 127.6, 95.0, 83.1, 81.4, 79.2, 70.7, 70.0, 69.0,
60.7, 60.3, 59.0, 58.3. Anal. Calcd for C17H26O6: C, 62.56; H, 8.03.
Found: C, 62.67; H, 8.05. â-8: [R]D -68.0 (c 0.10, CHCl3); IR
(neat) 2932, 1452, 1369, 1096 cm-1; 1H NMR δ 7.36-7.26 (m, 5
H), 4.94 (d, 1 H, J ) 12.1 Hz), 4.62 (d, 1 H, J ) 12.1 Hz), 4.34
(d, 1 H, J ) 7.5 Hz), 3.69-3.54 (m, 2 H), 3.62 (s, 3 H), 3.59 (s,
3 H), 3.53 (s, 3 H), 3.42 (s, 3 H), 3.30-3.04 (m, 4 H); 13C NMR
δ 137.6, 128.4, 127.7, 102.4, 86.4, 83.8, 79.4, 74.6, 71.4, 70.9,
60.9, 60.6, 60.5, 59.4. Anal. Calcd for C17H26O6: C, 62.56; H, 8.03.
Found: C, 62.76; H, 7.98. F r om Su lfoxid e 7. According to the
general procedure A, Cp2ZrCl2 (112 mg, 0.384 mmol), AgClO4
(158 mg, 0.763 mmol), benzyl alcohol (80 µL, 0.76 mmol), and
sulfoxide 7 (130 mg, 0.378 mmol) gave 8 (98 mg, 0.30 mmol,
79%, R/â ) 1:1.15).
P h en yl 2,3,4,6-Tetr a -O-m eth yl-1-d eoxy-1-th io-r-D-m a n -
n op yr a n osid e (14). According to the protocol used for the
conversion of 11 to 13, thioether 14 (6.19 g, 90%) was obtained
as a viscous oil from tetraacetate 12 (9.2 g): [R]D +128.6 (c 4.6,
1
CHCl3); IR (neat) 3061, 2931, 1580, 1481, 1109 cm-1; H NMR
δ 7.54-7.51 (m, 2 H), 7.35-7.20 (m, 3 H), 5.68 (d, 1 H, J ) 1.5
Hz), 4.15-4.09 (m, 1 H), 3.86 (dd, 1 H, J ) 3.1, 1.7 Hz), 3.71-
3.49 (m, 4 H), 3.57 (s, 3 H), 3.55 (s, 3 H), 3.48 (s, 3 H), 3.41 (s,
3 H); 13C NMR δ 134.6, 131.0, 129.0, 127.2, 84.6, 81.5, 78.7, 76.2,
72.1, 71.2, 60.7, 59.1, 58.1, 57.7. Anal. Calcd for C16H24O5S: C,
58.51; H, 7.37. Found: C, 58.52; H, 7.39.
P h en yl 2,3,4,6-Tetr a -O-m eth yl-1-d eoxy-1-th io-â-D-m a n -
n op yr a n osid e S-Oxid e (15). A solution of 13 (1.60 g, 4.89
mmol) in CH2Cl2 (50 mL) was treated at -50 °C with 50-60%
m-CPBA (1.40 g, 4.88 mmol based on 60% peroxide content).
After 30 min, a few drops of dimethyl sulfide were added, and
the reaction mixture was allowed to warm to room temperature.
Saturated NaHCO3 solution was added and the aqueous layer
was extracted with CH2Cl2, dried (MgSO4), and concentrated.
Chromatography on SiO2 (hexanes/EtOAc, 30:70) gave 15 (1.34
g, 3.90 mmol, 80%) as a viscous oil: [R]D +98.7 (c 0.31, CHCl3);
Cycloh exyl 2,3,4,6-Tetr a-O-m eth yl-D-glu copyr an oside (9).
According to the general procedure A, Cp2ZrCl2 (108 mg, 0.369
mmol), AgClO4 (152 mg, 0.734 mmol), cyclohexanol (74 mg, 0.74
mmol), and sulfoxide 6 (127 mg, 0.369 mmol) gave R-9 (43 mg,
0.14 mmol, 38%) and â-9 (52 mg, 0.16 mmol, 43%) as viscous
oils. r-9: [R]D +138.4 (c 0.25, CHCl3); IR (neat) 2931, 1442, 1362,
1
1097 cm-1; H NMR δ 5.08 (d, 1 H, J ) 3.6 Hz), 3.72-3.48 (m,
5 H), 3.62 (s, 3 H), 3.53 (s, 3 H), 3.45 (s, 3 H), 3.40 (s, 3 H),
3.23-3.17 (m, 2 H), 2.00-1.67 (m, 4 H), 1.55-1.15 (m, 6 H); 13
C
NMR δ 93.8, 83.2, 81.5, 79.6, 75.1, 71.0, 69.8, 60.9, 60.5, 59.2,
58.2, 33.3, 31.4, 25.6, 24.6, 24.2. Anal. Calcd for C16H30O6: C,
60.36; H, 9.50. Found: C, 60.43; H, 9.48. â-9: [R]D -26.2 (c 0.20,
IR (neat) 2935, 1442, 1097, 1038 cm-1 1H NMR δ 7.76-7.72
;
(m, 2 H), 7.54-7.48 (m, 3 H), 4.29 (d, 1 H, J ) 2.3 Hz), 3.91 (d,
1 H, J ) 0.6 Hz), 3.79 (s, 3 H), 3.60-3.35 (m, 3 H), 3.54 (s, 3 H),
3.52 (s, 3 H), 3.30 (s, 3 H), 3.20 (dd, 1 H, J ) 9.3, 2.8 Hz), 3.08
(ddd, 1 H, J ) 12.6, 4.2, 2.8 Hz); 13C NMR δ 142.3, 131.3, 128.8,
124.8, 96.0, 85.7, 80.3, 76.0, 72.8, 71.3, 61.8, 61.0, 59.1, 57.9.
Anal. Calcd for C16H24O6S: C, 55.80; H, 7.02. Found: C, 55.87;
H, 6.87.
1
CHCl3); IR (neat) 2931, 1453, 1358, 1156, 1030 cm-1; H NMR
δ 4.31 (d, 1 H, J ) 7.7 Hz), 3.65-3.53 (m, 3 H), 3.61 (s, 3 H),
3.58 (s, 3 H), 3.51 (s, 3 H), 3.39 (s, 3 H), 3.28-3.21 (m, 1 H),
3.17-3.05 (m, 2 H), 3.00-2.93 (m, 1 H), 2.00-1.75 (m, 2 H),
1.75-1.60 (m, 2 H), 1.55-1.20 (m, 6 H); 13C NMR δ 101.5, 86.5,
83.8, 79.5, 77.2, 74.6, 71.6, 60.8, 60.6, 60.4, 59.4, 33.6, 31.7, 25.7,
24.0, 23.8. Anal. Calcd for C16H30O6: C, 60.36; H, 9.50. Found:
C, 60.49; H, 9.49. F r om Su lfoxid e 7. According to the general
procedure A, Cp2ZrCl2 (101 mg, 0.346 mmol), AgClO4 (144 mg,
0.696 mmol), cyclohexanol (74 µL, 0.70 mmol), and sulfoxide 7
(120 mg, 0.348 mmol) gave 9 (84 mg, 0.26 mmol, 76%, R/â )
1:1.3).
P h en yl 2,3,4,6-Tetr a -O-m eth yl-1-d eoxy-1-th io-r-D-m a n -
n op yr a n osid e S-Oxid e (16). According to the protocol used for
the conversion of 13 to 15, sulfide 14 (6.02 g) was converted to
viscous, oily sulfoxide 16 (3.92 g, 62%): [R]D -53.9 (c 0.43,
1
CHCl3); IR (neat) 2931, 2820, 1446, 1117, 1038 cm-1; H NMR
δ 7.62-7.59 (m, 2 H), 7.49-7.45 (m, 3 H), 4.48 (d, 1 H, J ) 1.7
Hz), 4.12 (dd, 1 H, J ) 3.4, 1.9 Hz), 3.86 (ddd, 1 H, J ) 10.0,
5.1, 2.0 Hz), 3.76 (dd, 1 H, J ) 9.3, 3.4 Hz), 3.56-3.44 (m, 3 H),
3.50 (s, 3 H), 3.48 (s, 3 H), 3.28 (s, 6 H); 13C NMR δ 141.6, 131.2,
129.0, 124.2, 94.8, 80.8, 77.2, 75.2, 73.4, 71.3, 60.5, 59.1, 58.1,
57.7. Anal. Calcd for C16H24O6S: C, 55.80; H, 7.02. Found: C,
55.93; H, 6.88.
ter t-Bu tyl 2,3,4,6-Tetr a-O-m eth yl-D-glu copyr an oside (10).
According to general procedure A, Cp2ZrCl2 (91 mg, 0.31 mmol),
AgClO4 (129 mg, 0.62 mmol), tert-butyl alcohol (46 mg, 0.62
mmol), and sulfoxide 6 (106 mg, 0.311 mmol) gave R-10 (14 mg,
0.048 mmol, 15%) and â-10 (39 mg, 0.13 mmol, 42%) as viscous
oils. r-10: [R]D +8.2 (c 0.17, CHCl3); IR (neat) 2978, 2827, 1461,
Ben zyl 2,3,4,6-Tetr a -O-m eth yl-D-m a n n op yr a n osid e (17).
According to the general procedure A, Cp2ZrCl2 (333 mg, 1.14
mmol), AgClO4 (472 mg, 2.28 mmol), benzyl alcohol (0.24 mL,
2.28 mmol), and sulfoxide 15 (391 mg, 1.14 mmol) gave R-17
(291 mg, 0.893 mmol, 78%) and â-17 (14 mg, 0.043 mmol, 4%)
as viscous oils. r-17: [R]D +75.3 (c 0.58, CHCl3); IR (neat) 2907,
1453, 1113 cm-1; 1H NMR δ 7.25-7.18 (m, 5 H), 4.90 (d, 1 H, J
) 1.5 Hz), 4.64 (d, 1 H, J ) 11.8 Hz), 4.38 (d, 1 H, J ) 11.8 Hz),
3.58-3.44 (m, 5 H), 3.42 (s, 3 H), 3.40-3.36 (m, 1 H), 3.38 (s, 3
H), 3.34 (s, 3 H), 3.30 (s, 3 H); 13C NMR δ 137.2, 128.3, 127.8,
127.7, 96.2, 81.2, 77.1, 76.4, 71.6, 71.4, 69.0, 60.4, 59.0, 58.8,
57.6. Anal. Calcd for C17H26O6: C, 62.56; H, 8.03. Found: C,
62.58; H, 8.08. â-17: [R]D -79.1 (c 1.5, CHCl3); IR (neat) 2895,
1366, 1156, 1105 cm-1 1H NMR δ 5.19 (d, 1 H, J ) 3.7 Hz),
;
3.78 (dt, 1 H, J ) 10.0, 2.6 Hz), 3.63 (s, 3 H), 3.62-3.45 (m, 3
H), 3.55 (s, 3 H), 3.46 (s, 3 H), 3.40 (s, 3 H), 3.24 (dd, 1 H, J )
9.8, 9.0 Hz), 3.15 (dd, 1 H, J ) 9.7, 3.7 Hz), 1.26 (s, 9 H); 13C
NMR δ 90.7, 83.1, 81.9, 79.6, 75.2, 71.0, 69.3, 60.8, 60.5, 59.2,
58.4, 28.6. Anal. Calcd for C14H28O6: C, 57.51; H, 9.65. Found:
C, 57.45; H, 9.60. â-10: [R]D -8.3 (c 0.23, CHCl3); IR (neat) 2978,
1469, 1358, 1093 cm-1 1H NMR δ 4.37 (d, 1 H, J ) 7.8 Hz),
;
3.62 (s, 3 H), 3.61-3.52 (m, 2 H), 3.56 (s, 3 H), 3.51 (s, 3 H),
3.37 (s, 3 H), 3.24 (ddd, 1 H, J ) 9.4, 4.9, 2.0 Hz), 3.17-2.91 (m,
3 H), 1.26 (s, 9 H); 13C NMR δ 97.6, 86.7, 84.0, 79.7, 74.4, 71.8,
60.8, 60.6, 60.4, 59.4, 28.7. Anal. Calcd for C14H28O6: C, 57.51;
H, 9.65. Found: C, 57.59; H, 9.58.
1453, 1362, 1105, 1042 cm-1 1H NMR δ 7.35-7.26 (m, 5 H),
;
P h en yl 2,3,4,6-Tetr a -O-m eth yl-1-d eoxy-1-th io-â-D-m a n -
n op yr a n osid e (13). A solution of tetraacetate 11 (6.77 g, 15.4
mmol) in MeOH (75 mL) was treated with NaOMe (810 mg, 15.0
mmol). After 1 h, the reaction mixture was neutralized with
Amberlite H+ resin, filtered, and concentrated. The residue was
dried under high vacuum at 65 °C for 1 h, dissolved in DMF
(100 mL), cooled to 0 °C, and treated portionwise with 60% NaH
(4.70 g, 0.118 mol, 7.7 equiv). After 45 min, MeI (5.75 mL, 0.0923
mol, 6.0 equiv) was added dropwise, and the reaction mixture
was allowed to warm to room temperature. After 3 h, the solution
was quenched with H2O, diluted with Et2O, washed with H2O,
dried (MgSO4), and concentrated. Chromatography on SiO2
4.97 (d, 1 H, J ) 12.1 Hz), 4.58 (d, 1 H, J ) 12.1 Hz), 4.41 (s, 1
H), 3.72-3.58 (m, 3 H), 3.66 (s, 3 H), 3.51 (s, 3 H), 3.47 (s, 3 H),
3.42 (s, 3 H), 3.39-3.24 (m, 2 H), 3.15 (dd, 1 H, J ) 9.0, 3.2 Hz);
13C NMR δ 137.4, 128.3, 127.8, 127.7, 100.0, 84.0, 77.0, 76.5,
75.6, 71.9, 70.6, 61.7, 60.7, 59.3, 57.3. Anal. Calcd for C17H26O6:
C, 62.56; H, 8.03. Found: C, 62.50; H, 8.05. F r om Su lfoxid e
16. According to the general procedure A, Cp2ZrCl2 (192 mg,
0.658 mmol), AgClO4 (271 mg, 1.31 mmol), benzyl alcohol (0.13
mL, 1.31 mmol), and sulfoxide 16 (225 mg, 0.654 mmol) gave
17 (143 mg, 0.439 mmol, 67%, R/â ) 5.8:1).
Cycloh exyl 2,3,4,6-Tetr a -O-m eth yl-D-m a n n op yr a n osid e
(18). According to the general procedure A, Cp2ZrCl2 (383 mg,

7914 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
1.31 mmol), AgClO4 (542 mg, 2.62 mmol), cyclohexanol (0.280
mL, 2.62 mmol), and sulfoxide 15 (451 mg, 1.31 mmol) gave R-18
(305 mg, 0.959 mmol, 73%) and â-18 (16 mg, 0.050 mmol, 4%)
as viscous oils. r-18: [R]D +63.1 (c 0.49, CHCl3); IR (neat) 2931,
and the reaction mixture was allowed to warm gradually to
room-temperature overnight. Saturated aqueous NaHCO3 was
added, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and concentrated.
Chromatography on SiO2 (hexanes/EtOAc, 85:15) gave 22 (197
mg, 0.222 mmol, 72%, R/â ) 2.9:1) as a viscous oil: [R]D +62.2
(c 4.95, CHCl3); IR (neat) 3064, 1491, 1453, 1358 cm-1; 1H NMR
1453, 1109, 1053 cm-1 1H NMR δ 4.94 (d, 1 H, J ) 1.4 Hz),
;
3.60-3.30 (m, 7 H), 3.42 (s, 3 H), 3.40 (s, 3 H), 3.37 (s, 3 H),
3.29 (s, 3 H), 1.80-1.70 (m, 2 H), 1.65-1.55 (m, 2 H), 1.50-1.35
(m, 1 H), 1.35-1.00 (m, 5 H); 13C NMR δ 94.5, 81.1, 77.6, 76.4,
74.5, 71.5, 71.0, 60.3, 58.9, 58.6, 57.4, 33.0, 31.2, 25.4, 23.9, 23.6.
Anal. Calcd for C16H30O6: C, 60.36; H, 9.50. Found: C, 60.45;
H, 9.49. â-18: [R]D -73.2 (c 0.25, CHCl3); IR (neat) 2931, 1446,
(600 MHz) δ 7.50-7.20 (m, 25 H), 6.15-5.95 (m,
2 H),
5.42-5.26 (m, 4 H), 5.16-5.04 (m, 3 H), 4.97-4.87 (m, 3 H),
4.85-4.80 (m, 2 H), 4.77-4.64 (m, 3 H), 4.60-4.48 (m, 3 H),
4.42-4.08 (m, 4 H), 3.97-3.75 (m, 6 H), 3.73-3.68 (m, 2 H),
3.67-3.52 (m, 1 H), 3.49, 3.47 (2 s, 3 H), 3.46-3.44 (m, 1 H);
13C NMR (151 MHz) δ 138.81, 138.51, 138.47, 138.46, 138.42,
138.35, 138.23, 138.09, 137.97, 135.34, 135.32, 134.90, 134.87,
128.42, 128.39, 128.35, 128.30, 128.04, 127.93, 127.92, 127.90,
127.83, 127.80, 127.74, 127.68, 127.67, 127.65, 127.63, 127.61,
127.57, 117.71, 117.53, 116.58, 116.46, 103.84, 98.09, 98.03,
97.30, 84.80, 82.10, 81.75, 81.74, 81.56, 80.06, 79.73, 79.50, 77.95,
77.89, 77.70, 77.60, 75.75, 75.54, 75.04, 75.03, 74.99, 74.92, 74.90,
74.31, 74.30, 73.44, 73.42, 72.61, 72.57, 72.44, 70.23, 69.82, 69.00,
68.63, 68.43, 66.16, 55.12, 55.06.
1370, 1109, 1069 cm-1 1H NMR δ 4.48 (d, 1 H, J ) 0.5 Hz),
;
3.70-3.53 (m, 4 H), 3.64 (s, 3 H), 3.50 (s, 3 H), 3.47 (s, 3 H),
3.38 (s, 3 H), 3.32-3.20 (m, 2 H), 3.16 (dd, 1 H, J ) 9.1, 3.2 Hz),
2.00-1.60 (m, 4 H), 1.50-1.10 (m, 6 H); 13C NMR δ 99.0, 84.1,
77.6, 76.6, 76.1, 75.6, 72.1, 61.7, 60.7, 59.2, 57.3, 33.2, 31.3, 25.7,
23.7, 23.6. Anal. Calcd for C16H30O6: C, 60.36; H, 9.50. Found:
C, 60.43; H, 9.54. F r om Su lfoxid e 16. According to the general
procedure A, Cp2ZrCl2 (217 mg, 0.743 mmol), AgClO4 (306 mg,
1.48 mmol), cyclohexanol (0.16 mL, 1.5 mmol), and sulfoxide 16
(256 mg, 0.745 mmol) gave 18 (161 mg, 0.506 mmol, 68%, R/â )
4.1:1).
Glycosyla tion Usin g 10 w t % AgClO4 on Celite. A suspen-
sion of Cp2ZrCl2 (57.0 mg, 0.195 mmol), AgClO4 on Celite (∼10
wt %, 810 mg, 0.390 mmol),18e and 4 Å molecular sieves (100
mg) in CH2Cl2 (5 mL) was stirred at room temperature for 15
min. Alcohol 21 (142 mg, 0.390 mmol) in CH2Cl2 (0.5 mL) was
added, and the temperature was lowered to -20 °C. A solution
of sulfoxide 20 (126 mg, 0.195 mmol) in CH2Cl2 (0.5 mL) was
added dropwise, and the reaction mixture was allowed to warm
gradually to room-temperature overnight. Saturated aqueous
NaHCO3 was added, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried (MgSO4) and
concentrated. Chromatography on SiO2 (hexanes/EtOAc, 85:15)
gave 22 (112 mg, 0.127 mmol, 65%, R/â ) 3.0:1).
ter t-Bu t yl 2,3,4,6-Tet r a -O-m et h yl-D-m a n n op yr a n osid e
(19). According to the general procedure A, Cp2ZrCl2 (1.18 g,
4.04 mmol), AgClO4 (1.67 g, 8.07 mmol), tert-butyl alcohol (0.78
mL, 8.16 mmol), and sulfoxide 15 (1.41 g, 4.10 mmol) gave R-19
(655 mg, 2.24 mmol, 55%) and â-19 (39 mg, 0.13 mmol, 3%) as
viscous oils. r-19: [R]D +48.1 (c 2.5, CHCl3); IR (neat) 2978, 2820,
1457, 1366, 1109 cm-1 1H NMR δ 5.17 (d, 1 H, J ) 1.8 Hz),
;
3.71 (ddd, 1 H, J ) 9.3, 4.1, 2.1 Hz), 3.58-3.33 (m, 5 H), 3.50 (s,
3 H), 3.47 (s, 3 H), 3.44 (s, 3 H), 3.35 (s, 3 H), 1.22 (s, 9 H); 13
C
NMR δ 91.2, 81.0, 78.6, 76.5, 75.2, 71.6, 70.7, 60.5, 59.1, 58.6,
57.6, 28.4. Anal. Calcd for C14H28O6: C, 57.51; H, 9.65. Found:
C, 57.35; H, 9.50. â-19: [R]D -64.4 (c 1.3, CHCl3); IR (neat) 2977,
2831, 1464, 1363, 1112, 1072 cm-1; 1H NMR δ 4.51 (d, 1 H, J )
0.6 Hz), 3.65-3.49 (m, 3 H), 3.64 (s, 3 H), 3.49 (s, 3 H), 3.47 (s,
3 H), 3.36 (s, 3 H), 3.30-3.14 (m, 3 H), 1.25 (s, 9 H); 13C NMR
δ 95.5, 83.7, 78.1, 76.2, 75.2, 74.7, 71.7, 61.5, 60.3, 58.7, 56.9,
28.1. Anal. Calcd for C14H28O6: C, 57.51; H, 9.65. Found: C,
57.45; H, 9.65.
Glycosyla tion in th e P r esen ce of 2,6-Di-ter t-bu tyl-4-
m eth ylp yr id in e. A mixture of Cp2ZrCl2 (245 mg, 0.839 mmol),
AgClO4 (351 mg, 1.70 mmol), 4 Å molecular sieves (100 mg),
and CH2Cl2 (8 mL) was stirred at room temperature for 10 min.
Benzyl alcohol (0.17 mL, 1.65 mmol) was added, followed by 2,6-
di-tert-butyl-4-methylpyridine (172 mg, 0.839 mmol). The reac-
tion mixture was cooled to -20 °C, and a solution of sulfoxide
16 (289 mg, 0.840 mmol) in CH2Cl2 (2 mL) was added dropwise.
The reaction mixture was allowed to warm to room temperature.
After 8.5 h, saturated aqueous NaHCO3 solution was added, and
the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and concentrated. Chroma-
tography on SiO2 (hexanes/EtOAc, 70:30) gave 17 (192 mg, 0.589
mmol, 70%, R/â ) 6:1).
(E)-1-(P h en ylth io)-1-octen e (25). A solution of 1-octyne
(86.0 µL, 0.582 mmol) in CH2Cl2 (2.5 mL) was treated with
Cp2Zr(H)Cl (150 mg, 0.582 mmol). The reaction mixture was
stirred at room temperature for 15 min, cooled to 0 °C, and
treated with a solution of â-sulfoxide 6 (100 mg, 0.291 mmol) in
CH2Cl2 (0.5 mL), followed by AgClO4 (6.0 mg, 0.029 mmol). The
reaction mixture was stirred at room temperature for 1 h,
quenched with saturated NaHCO3 solution, and extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4),
concentrated, and chromatographed on SiO2 (hexanes/EtOAc,
19:1) to give 25 (43.6 mg, 0.198 mmol, 68%) as an oil that
1
provided H NMR and HRMS data in agreement with literature
values.26
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE-0078944) and Merck
& Co.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Met h yl 2,3-Di-O-a llyl-4-O-b en zyl-6-O-(2,3,4,6-t et r a -O-
ben zyl-D-glu cop yr a n osyl)-r-D-glu cop yr a n osid e (22). A su-
spension of Cp2ZrCl2 (90.0 mg, 0.309 mmol), AgClO4 (128 mg,
0.618 mmol), and 4 Å molecular sieves (100 mg) in CH2Cl2 (4
mL) was stirred at room temperature for 15 min. Alcohol 2124
(225 mg, 0.618 mmol) in CH2Cl2 (0.5 mL) was added, and the
temperature was lowered to -20 °C. A solution of sulfoxide 2025
(200 mg, 0.309 mmol) in CH2Cl2 (0.5 mL) was added dropwise,
J O015952H
(24) Kuester, D. Liebigs Ann. Chem. 1975, 2179.
(25) Zhang, H.; Wang, Y.; Voelter, W. Tetrahedron Lett. 1995, 36,
1243.
(26) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J . Am. Chem. Soc.
1999, 121, 5108.