2-(Hydroxycarbonyl)benzyl glycosides: A novel type of glycosyl donors for highly efficient β-mannopyranosylation and oligosaccharide synthesis by latent-active glycosylation

Article abstract of DOI:10.1021/ja015842s

2-(Benzyloxycarbonyl)benzyl (BCB) glycosides were prepared by coupling of the corresponding tetraacetylglycosyl bromides and benzyl 2-(hydroxymethyl)benzoate. The BCB glycosides were converted almost quantitatively into the corresponding 2-(hydroxycarbony

Full text of DOI:10.1021/ja015842s

J. Am. Chem. Soc. 2001, 123, 8477-8481
8477
2-(Hydroxycarbonyl)benzyl Glycosides: A Novel Type of Glycosyl
Donors for Highly Efficient â-Mannopyranosylation and
Oligosaccharide Synthesis by Latent-Active Glycosylation
Kwan Soo Kim,* Jin Hwan Kim, Yong Joo Lee, Yong Jun Lee, and Jin Park
Contribution from the Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea
ReceiVed March 18, 2001. ReVised Manuscript ReceiVed July 19, 2001
Abstract: 2-(Benzyloxycarbonyl)benzyl (BCB) glycosides were prepared by coupling of the corresponding
tetraacetylglycosyl bromides and benzyl 2-(hydroxymethyl)benzoate. The BCB glycosides were converted almost
quantitatively into the corresponding 2-(hydroxycarbonyl)benzyl (HCB) glycosides by selective hydrogenolysis
of the benzyl ester functionality without affecting the benzylidene acetal and the benzyl ether. Treatment of
the HCB 4,6-O-benzylidenemannopyranoside 4 with triflic anhydride in the presence of di-tert-butylmeth-
ylpyridine and subsequent addition of the glycosyl acceptor having a primary hydroxyl group afforded exclusively
the disaccharide of the â-mannopyranosyl linkage. Glycosylation of the compound 4 with secondary and tertiary
alcohols also provided â-mannopyranosides as the major products. Glycosylation of the HCB 4,6-O-
cyclohexylidenemannoside 5 with primary alcohols was also highly â-selective, and the HCB 2,3-O-
cyclohexylidenemannoside 6 exhibited the moderate â-selectivity. On the other hand, unlike the HCB
mannosides, the HCB 4,6-O-benzylideneglucoside 7 gave exclusively the disaccharides of the R-glycopyranosyl
linkage in the glycosylation with primary alcohols. The latent BCB-disaccharide 23, which was obtained
from the HCB mannoside 4 as the donor and the BCB glucoside 12 as the acceptor by the present glycosylation
method, was converted into the active HCB-disaccharide 39 by selective hydrogenolysis. Repetitive
glycosylation of the donor 39 with the same acceptor 12 afforded the BCB-trisaccharide 40. Other BCB-
trisaccharides 42 and 46 were also efficiently synthesized by employing the present methodology.
Introduction
displacement of the intermediate R-triflates11 generated from
glycosyl sulfoxides or thioglycosides.12 Another recent focus
in this field has been the development of sequential glycosylation
strategies for the efficient construction of oligosaccharides.13
The success of sequential glycosylation depends on the fine-
tuning of the reactivity of the anomeric leaving group by
employing either different anomeric leaving groups or identical
leaving groups having different protective groups in glycosyl
donors.14 Another known strategy for the rapid assembly of
oligosaccharides is the latent-active glycosylation method in
which a stable anomeric group is converted into a good leaving
group by a simple transformation.15 In fact, the latent-active
glycosylation strategy has certain advantages over the other
strategies since it does not require the tuning of the anomeric
leaving group so that the glycosyl donor and the acceptor could
A great deal of effort has been devoted to the development
of efficient and stereoselective glycosylation methodologies1 in
recent years due to the biological significance of glycoconju-
gates.2 Devising new glycosyl donors and developing new
activating systems for existing donors have led to major
advances in this field. Thioglycosides,3 glycosyl sulfoxides,4
glycals,5 glycosyl trichloroacetimidates,6 n-pentenyl glycosides,7
and glycosyl fluorides8 have been the most widely used glycosyl
donors for the synthesis of various important oligosaccharides.
One of the challenges in the glycoside synthesis has been the
stereospecific formation of the 1,2-cis-â-D-mannopyranosyl
linkage. Several diverse and innovative strategies for the
â-mannopyranosylation9 have been developed including the
recent indirect intramolecular aglycone delivery approach.10
More recently, Crich et al. have developed a direct approach
for the formation of â-mannopyranosides by the SN2-like
(9) For reviews of â-mannopyranosylation, see: (a) Barresi, F.; Hinds-
gaul, O. In Modern Methods in Carbohydrate Synthesis; Khan, S. H.,
O’Neil, R. A., Eds.; Harwood Academic Publishers: Amsterdam, 1996;
pp 251-276. (b) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin
Trans. 1 2000, 1471-1491.
(10) For selected references of the intramolecular aglycon delivery
approach for â-mannosylation, see: (a) Barresi, F.; Hindsgaul, O. J. Am.
Chem. Soc. 1991, 113, 9376-9377. (b) Stork, G.; Kim, G. J. Am. Chem.
Soc. 1992, 114, 1087-1088. (c) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1765-1767. (d) Ziegler, T.; Lemanski, G. Angew. Chem.,
Int. Ed. 1998, 37, 3129-3132.
(11) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(12) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507. (b) Crich,
D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199. (c) Crich, D.; Sun, S. J.
Am. Chem. Soc. 1998, 120, 435-436. (d) Crich, D.; Sun, S. Tetrahedron
1998, 54, 8321-8348. (e) Crich, D.; Smith, M. Org. Lett. 2000, 2, 4067-
4069.
* To whom correspondence should be addressed. E-mail: kwan@
yonsei.ac.kr.
(1) For a review on the glycosylation, see: Toshima K.; Tatsuta, K.
Chem. ReV. 1993, 93, 1503-1531.
(2) Varki, A. Glycobiology 1993, 3, 97-130.
(3) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205.
(4) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc.
1989, 111, 6881-6882. (b) Gildersleeve, J.; Pascal, R. A., Jr.; Kahne, D.
J. Am. Chem. Soc. 1998, 120, 5961-5969.
(5) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380-1419.
(6) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21-123.
(7) Fraser-Reid, B.; Madsen, R. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 339-356.
(8) Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998, 799-822.
(13) For a review on strategies in oligosaccharide synthesis, see: Boons,
G.-J. Tetrahedron 1996, 52, 1095-1121.
10.1021/ja015842s CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/09/2001

8478 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Kim et al.
Scheme 1
readily achieved by just addition of 3.5 equiv of ammonium
acetate to provide the desired HCB mannoside 4 in 95% yield.16
The amount of ammonium acetate does not have to be accurate
and thus hydrogenolysis of other BCB glycosides with 1-4
equiv of ammonium acetate also gave the HCB glycosides in
almost quantitative yields. The HCB glycosides 5-8 were also
prepared in an analogous fashion and could be stored at room
temperature for a few months without any change.
Scheme 2a
Glycosylation was carried out by the following sequence: (i)
stirring the solution of 1 equiv of the HCB glycoside and 2
equiv of DTBMP in the presence of 4 Å molecular sieves (MS)
for 30 min at room temperature in CH2Cl2, (ii) addition of 1
equiv of Tf2O to this solution at -78 °C and stirring the solution
for 10 min, (iii) addition of 2 equiv of the glycosyl acceptor
and stirring the reaction mixture for further 1 h at -78 °C and
allowing to warm over 2 h to 0 °C, and (iv) quenching the
reaction by addition of aqueous NaHCO3. Glycosylation of 4
with primary alcohols 9-13 was so efficient that the reaction
virtually completed in 1 h at -78 °C to afford only â-manno-
sides in high yields (Scheme 2 and entries 1-5 in Table 1).
The highly â-selective mannosylation of 4 was also achieved
with the secondary alcohols 14-16 and with the hindered
tertiary alcohol 17 (entries 6-9). These results indicate that the
present HCB glycoside method for the â-mannopyranosylation
is comparable to the Crich-Kahne sulfoxide method in terms
of the yield and the stereoselectivity. For comparison, the
glycosylation results by the sulfoxide method were also listed
in Table 1 [(d) of entries 2, 6, and 8]. Unlike the sulfoxide
method for â-mannopyranosylation,12a toluene was also found
to be a good solvent in the present method [(b) of entry 1]. The
presence of the cyclic 4,6-acetal in mannosyl donors has been
recognized as one of the necessary factors for the improvement
of the â-selectivity in mannosylation: Crich et al. have
suggested that the 4,6-benzylidene group stabilizes the inter-
mediate R-triflate to give selectively the â-mannopyranosides
via the SN2-like displacement,11 while Ito et al. reported the
4,6-cyclohexylidene group was the better protecting group than
the benzylidene group.17 The present result indicates that the
glycosylation with the HCB 4,6-O-cyclohexylidenemannoside
5 was also highly â-selective but â-selectivity was somewhat
reduced compared to its benzylidene counterpart 4 when the
secondary alcohol 14 and the tertiary alcohol 17 were employed
as glycosyl acceptors (entries 12-16). It is notable that the
glycosylation of the HCB 2,3-O-cyclohexylidenemannoside 6,
which does not contain the cyclic 4,6-acetal group, with glycosyl
acceptors afforded also â-mannosyl disaccharides as the major
products (entries17 and 18).18 The present HCB glycoside
protocol could be applied to not only the mannosylation but
also the glucosylation. Thus, glycosylation of 7 with acceptors
9 and 11 provided R-glucosides as the major products (entries
19 and 20).19
a (a) (i) benzyl 2-(hydroxymethyl)benzoate (1), HgBr2, Hg(CN)2,
CH3CN (86%); (ii) NaOMe, MeOH (93%); (b) (i) PhCH(OMe)2, CSA,
DMF (70%); (ii) BnBr, NaH, DMF (80%); (c) H2 (balloon), Pd/C, 3.5
equiv NH4OAc, MeOH (95%); (d) Tf2O, DTBMP, 4 Å MS, CH2Cl2,
-78 °C, then 9, -78 to 0 °C (91%).
be prepared from a common building block and the sequential
glycosylation could be carried out employing a single glyco-
sylation method. Herein we introduce 2-(hydroxycarbonyl)-
benzyl (HCB) glycosides as a novel type of glycosyl donors
that is useful for the â-mannopyranosylation but also very
effective for the efficient construction of oligosaccharides by
the latent-active glycosylation strategy. We envisioned that
treatment of the HCB mannoside A with Tf2O in the presence
of di-tert-butlymethylpyridine (DTBMP) would induce the
lactonization of A via the mixed anhydride B to generate
phthalide and the oxocarbenium ion C, which might be in
equilibrium with the R-triflate D as shown in Scheme 1.
Subsequent reaction of C or D with the glycosyl acceptor would
provide the â-mannopyranoside E.
Results and Discussion
Differentially protected HCB manno- and glucopyranosides
4-8 were efficiently prepared starting from the corresponding
acetylated glycosyl bromides and crystalline benzyl 2-(hydroxy-
methyl)benzoate (1), which was readily obtained in large
quantities from inexpensive phthalide. For example, the synthetic
sequence for the HCB mannoside 4 is shown in Scheme 2.
Coupling of the tetraacetylmannosyl bromide and 1 followed
by deacetylation of the resulting tetraacetylmannoside afforded
the 2-(benzyloxycarbonyl)benzyl (BCB) mannoside 2, of which
benzylidenation and subsequent benzylation afforded the pro-
tected BCB mannoside 3. Selective hydrogenolysis of the benzyl
ester functionality in the compound 3 in the presence of the
benzylidene acetal and the benzyl ether, which was the crucial
step for the efficient preparation of the HCB glycosides, was
(14) For selected references on the sequential glycosylation, see: (a)
Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. An. Chem.
Soc. 1988, 110, 5583-5584. (b) Mehta, S.; Pinto, B. M. Tetrahedron Lett.
1991, 32, 4435-4438. (c) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993,
115, 1580-1581. (d) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem.
Soc. 1994, 116, 7919-7920. (e) Ley, S. V.; Priepke, H. W. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2292-2294. (f) Kanie, O.; Ito, Y.; Ogawa,
T. J. Am. Chem. Soc. 1994, 116, 12073-12074. (g) Zhang, Z.; Ollmann, I.
R.; Ye, X.-S.; Wischnat, R.; Bassov, T.; Wong, C.-H. J. Am. Chem. Soc.
1999, 121, 734-753. (h) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew.
Chem., Int. Ed. 2001, 40, 414-417.
(15) (a) Roy, R.; Andersson, F. O.; Letellier, M. Tetrahedron Lett. 1992,
33, 6053-6056. (b) Boons, G.-J.; Isles, S. Tetrahedron Lett. 1994, 35,
3593-3596. (c) Boons, G.-J.; Isles, S. J. Org. Chem. 1996, 61, 4262-
4271. (d) Boons, G.-J.; Heskamp, B.; Hout, F. Angew. Chem., Int. Ed. Engl.
1996, 33, 2845-2847.
When the mannosylation was performed with the reversal of
the order of addition of the reactants, for example, when Tf2O
(16) For suppression effect of NH4OAc on the hydrogenolysis of benzyl
ethers, see: Sajiki, H. Tetrahedron Lett. 1995, 36, 3465-3468.
(17) Ito, Y.; Ohnishi, Y.; Ogawa, T.; Nakahara, Y. Synlett 1998, 1102-
1104.
(18) On the other hand, glycosylation of HCB 2,3,4,6-tetra-O-benzyl-
R-D-mannopyranoside, which neither contains the 2,3-acetal nor the 4,6-
acetal, with the acceptor 10 gave the R-disaccharide as the major product
(â/R ) 1:1.3).

2-(Hydroxycarbonyl)benzyl Glycosides
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8479
Scheme 3a
Table 1. Glycosylation with HCB Glycosides 4, 5, 6, and 7 in
CH2Cl2
a (a) H2 (balloon), Pd/C, 1 equiv NH4OAc, MeOH (92%); (b) Tf2O,
DTBMP, 4 Å MS, CH2Cl2, -45 °C, then 12, -45 to 0 °C (72%); (c)
H2 (balloon), Pd/C, 3.5 equiv NH4OAc, MeOH (94%); (d) Tf2O,
DTBMP, 4 Å MS, CH2Cl2, -78 °C, then 13, -78 to 0 °C (73%).
glycosylation to produce a substantial amount of an ester (entry
11). In the case of the HCB glucoside 7, the stereoselectivity
of both anomers was almost same, but the â-anomer 7 was also
less reactive than its R-anomer although the glycosylation of
both anomers proceeded smoothly without formation of the ester
(entry 21).20 We also observed the generation of phthalide with
the disappearance of the starting HCB glycoside as soon as Tf2O
was added to the HCB glycoside at -78 °C in the absence of
the acceptor. On the basis of the aforementioned results, we
think that the reaction mechanism of the present glycosylation
would be as shown in Scheme 1. Yet, it is difficult to say
whether â-mannosylation would occur only through SN2-like
displacement of the R-triflate D by the acceptor11 or by direct
attack of the acceptor to the oxocarbenium ion C.21
The successful glycosylation of the HCB glycoside 4 with
the BCB glycosides 12 and 13 indicated that the sequential
glycosylation for oligosaccharide synthesis would be possible
employing this methodology since the resulting BCB disaccha-
ride could be used for another glycosylation after selective
removal of the benzyl ester linkage. In fact, the stable (“latent”)
BCB disaccharide 23,22 obtained from 4 and 12, was readily
converted into the “active” HCB glycoside 39 in 92% yield by
the selective hydrogenolysis. Repetitive glycosylation of 39 with
the same glycosyl acceptor 12 provided the BCB trisaccharide
40 in 72% yield as shown in Scheme 3. Similarly, the BCB
trisaccharide 42 was also efficiently prepared from 4 and 13
via the latent BCB disaccharide 24 and the active HCB
disaccharide 41. Finally, we also prepared the trisaccharide 46
from the HCB glycoside 8 and the methyl glycoside 43 via
disaccharides 44 and 45 in 74% overall yield in three steps by
the conventional protection-deprotection method as shown in
Scheme 4.
a Determined after isolation. b In toluene as a solvent. c Tf2O was
added to the mixture of the glycosyl donor and the acceptor. d The result
by the Crich-Kahne sulfoxide method, see ref 12d. e After isolation
of most of â-anomer, the ratio of the remaining â/R mixture was
1
determined by H NMR.
Conclusions
was added to the mixture of 4 and 9, the â-mannoside 20 was
still the major product (91%, â/R ) 16:1, [(c) of entry 1] and
addition of Tf2O to the mixture of 4 and 14 afforded also
â-mannoside 25 as the major product (88%, â/R ) 8:1, [(c) of
entry 6]. We also examined the relative reactivity and stereo-
selectivity in the glycosylation of the R-anomer 4 and its
â-anomer and of the â-anomer 7 and its R-anomer. The
â-anomer of the HCB mannoside 4 exhibited almost same
stereoselectivity but much lower reactivity compared to its
R-anomer 4 so that the esterification between a portion of the
â-anomer and the acceptor alcohol 9 occurred faster than the
In conclusion, we described the synthesis of novel HCB
glycosides and the highly efficient and stereoselective procedure
for the â-mannopyranosylation employing the HCB manno-
pyranoside with triflic anhydride. The present HCB glycoside
method for â-mannopyranosylation was found to be comparable
(20) The higher reactivity of the R-anomer could be attributed to the
higher nucleophilicity of the anomeric oxygen or the weaker anomeric C-O
bond due to the anomeric effect, see: Deslongchamps, P. Stereoelectronic
Effects in Organic Chemistry; Pergamon Press: Oxford, 1983; pp 4-53.
(21) For a recent suggestion of direct attack on the oxocarbenium by
the glycosyl acceptor in â-mannopyranosylation, see: Weingart, R.;
Schimidt, R. R. Tetrahedron Lett. 2000, 41, 8753-8758.
(22) The BCB glycosides are inert not only under the present glycosy-
lation conditions but also toward various Lewis acids and glycosylation
promoters except toward TMSOTf above room temperature.
(19) For the R-glucopyranosylation employing glycosyl sulfoxides and
thioglycosides, see: Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926-
4930.

8480 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Kim et al.
Scheme 4a
NaOMe (94 mg, 1.74 mmol). After stirring at room temperature for
further 20 min, the reaction mixture was neutralized with DOWEX
CCR-3 (H+ mode) and concentrated to give the title compound 2 (3.28
g, 8.11 mmol, 93%), which was used for the next step without
purification.
2-(Benzyloxycarbonyl)benzyl 2,3-Di-O-benzyl-4,6-O-benzylidene-
r-D-mannopyranoside (3). A solution of the compound 2 and
benzaldehyde dimethylacetal (1.34 mL, 8.93 mmol, 1.1 equiv) in the
presence of camphor sulfonic acid (56 mg, 0.24 mmol, 0.03 equiv) in
DMF (30 mL) was stirred at 50 °C for 4 h. After being quenched with
saturated aqueous NaHCO3 (100 mL), the reaction mixture was
extracted with EtOAc (3 × 70 mL). The combined organic layer was
washed with saturated aqueous NH4Cl (2 × 50 mL) and brine (50 mL),
dried (MgSO4), and concentrated in vacuo. The residue was purified
by silica gel flash column chromatography (50% ethyl acetate in hexane)
to afford 2-(benzyloxycarbonyl)benzyl 4,6-O-benzylidene-R-D-man-
nopyranoside (2.80 g, 70%): white solid, mp 129-131 °C; Rf ) 0.28
a (a) 8, Tf2O, DTBMP, 4 Å MS, CH2Cl2, -78 °C, then 43, -78 to
0 °C (90%); (b) NaOMe, MeOH, reflux (99%); (c) 8, Tf2O, DTBMP,
4 Å MS, CH2Cl2, -78 °C, then 45, -78 to 0 °C (83%).
to the thioglycoside and the glycosyl sulfoxide methods in terms
of stereoselectivity. We also found that not only 4,6-acetals but
also the 2,3-O-cyclohexylidene-protecting group in the HCB
mannopyranoside facilitated the formation of â-mannopyrano-
sides. R-Glucopyranosides were produced as the major product
in the glycosylation of the HCB 4,6-O-benzylideneglucoside.
The power of the present methodology was demonstrated by
the efficient synthesis of trisaccharides employing the pair of
the latent BCB glycoside and the active HCB glycoside.
(50% ethyl acetate in hexane); [R]20 ) +55 (c ) 1.4, CHCl3); IR
D
(CHCl3 film) 3378, 3244, 2911, 1715, 1256, 1064, 742 cm-1; 1H NMR
(250 MHz, CDCl3) δ 2.68 (brs, 2 H), 3.77-3.98 (m, 3 H), 4.08-4.16
(m, 2 H), 4.25 (dd, J ) 3.0, 8.7 Hz, 1 H), 4.95 (d, J ) 13.5 Hz, 1 H),
4.97 (d, J ) 1.5 Hz, 1 H), 5.14 (d, J ) 13.5 Hz, 1 H), 5.34 (s, 2 H),
5.52 (s, 1 H), 7.34-7.60 (m, 13 H), 8.01 (dd, J ) 1.0, 7.7 Hz, 1 H);
13C NMR (63 MHz, CDCl3) δ 63.4, 66.8, 67.6, 68.7, 68.8, 70.9, 78.9,
100.1, 102.2, 126.3, 127.4, 127.9, 128.3, 128.6, 129.2, 130.8, 132.5,
135.8, 137.2, 139.5, 166.7. Anal. Calcd for C28H28O8: C, 68.28; H,
5.73. Found: C, 68.28; H, 5.74.
Experimental Section
Benzyl 2-(Hydroxymethyl)benzoate (1). A suspension of phthalide
(10 g, 74.6 mmol) on an aqueous 1 N NaOH (75 mL) was stirred at
100 °C for 1 h. The reaction mixture was concentrated in vacuo,
coevaporated with toluene, and dried under high vacuum to give a white
solid. The solution of the resulting solid sodium salt and benzyl bromide
(8.87 mL, 74.6 mmol) in DMF (50 mL) was stirred at room temperature
for 1 h. After being quenched with water (100 mL), the reaction mixture
was extracted with EtOAc (2 × 200 mL). The combined organic layer
was washed with saturated aqueous NH4Cl (100 mL) and brine (100
mL), dried (MgSO4), and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography (25% ethyl acetate
in hexane) to afford the pure 1 (16.8 g, 93%): white solid, mp 62-64
°C; Rf ) 0.33 (25% ethyl acetate in hexane); IR (CHCl3 film) 3270,
1710, 1262, 736 cm-1; 1H NMR (250 MHz, CDCl3) δ 3.83 (t, J ) 7.3
Hz, 1 H), 4.79 (d, J ) 7.3 Hz, 2 H), 5.37 (s, 2 H), 7.36-7.53 (m, 8 H),
8.05 (dd, J ) 1.2, 6.6 Hz, 1 H); 13C NMR (63 MHz, CDCl3) δ 64.9,
67.3, 128.0, 128.4, 128.6, 128.8, 128.9, 130.5, 131.4, 133.3, 135.7,
143.3, 167.9. Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C,
74.35; H, 5.84.
2-(Benzyloxycarbonyl)benzyl r-D-Mannopyranoside (2). To a
stirred solution of 2,3,4,6-tetra-O-acetyl-R-D-mannopyranosyl bromide
(5.0 g, 12.2 mmol) in the presence of 4 Å MS in acetonitrile (25 mL)
at 0 °C were added mercury (II) bromide (5.28 g, 14.7 mmol, 1.2 equiv),
mercury (II) cyanide (3.70 g, 14.7 mmol, 1.2 equiv), and finally the
compound 1 (3.25 g, 13.4 mmol, 1.1 equiv). After stirring at 0 °C for
further 20 min, the reaction mixture was filtered, and the filtrate was
concentrated. The resulting oil was dissolved in CH2Cl2 (50 mL), and
the solution was washed with saturated aqueous NaHCO3 (2 × 50 mL)
and brine (50 mL). The organic phase was dried (MgSO4) and
concentrated in vacuo, and the residue was purified by silica gel flash
column chromatography (33% ethyl acetate in petroleum ether) to afford
2-(benzyloxycarbonyl)benzyl 2,3,4,6-tetra-O-acetyl-R-D-mannopyrano-
side (6.0 g, 86%): Rf ) 0.25 (33% ethyl acetate in petroleum ether);
[R]20D ) +52.4 (c ) 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 2.01
(s, 3 H), 2.04 (s, 3 H), 2.09 (s, 3 H), 2.16 (s, 3 H), 4.03-4.14 (m, 2
H), 4.31 (dd, J ) 5.1, 12.3 Hz, 1 H), 4.96 (d, J ) 1.5 Hz, 1 H), 4.98
(d, J ) 13.8 Hz, 1 H), 5.18 (d, J ) 13.8 Hz, 1 H), 5.33 (s, 2 H), 5.33
(t, J ) 9.9 Hz, 1 H), 5.38 (dd, J ) 1.5, 3.3 Hz, 1 H), 5.44 (dd, J ) 3.3,
9.9 Hz, 1 H), 7.30-7.46 (m, 6 H), 7.56 (td, J ) 8.1, 1.5 Hz, 1 H), 7.63
(dd, J ) 0.6, 8.1 Hz, 1 H), 8.01 (dd, J ) 1.5, 8.1 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 20.7 (3), 20.9, 62.3, 66.1, 66.8, 67.8, 68.7, 69.3,
69.5, 97.5, 127.6, 127.8, 128.1, 128.2, 128.3, 128.6, 130.8, 132.7, 135.9,
139.0, 166.4, 169.7, 169.9, 170.0, 170.6. Anal. Calcd for C29H32O12:
C, 60.83; H, 5.63. Found: C, 60.88; H, 5.68.
To a solution of 2-(benzyloxycarbonyl)benzyl 4,6-O-benzylidene-
R-D-mannopyranoside (2.50 g, 5.08 mmol, 1 equiv) and benzyl bromide
(1.45 mL, 12.2 mmol, 2.4 equiv) in DMF (15 mL) was added NaH
(0.49 g, 12.2 mmol, 2.4 equiv) at 0 °C, and then the ice bath was
removed. After stirring at room temperature for 1 h, the reaction mixture
was quenched with water (50 mL) and extracted with EtOAc (2 × 100
mL). The combined organic layer was washed with saturated aqueous
NH4Cl (50 mL) and brine (50 mL), dried (MgSO4), and concentrated
in vacuo. The residue was purified by silica gel flash column
chromatography (20% ethyl acetate in hexane) to afford the compound
3 (2.73 g, 80%): Rf ) 0.40 (20% ethyl acetate in hexane); [R]20
)
D
1
+50.8 (c ) 4.4, CHCl3); H NMR (300 MHz, CDCl3) δ 3.83-3.91
(m, 3 H), 4.03 (dd, J ) 3.3, 10.2 Hz, 1 H), 4.21-4.32 (m, 2 H), 4.66
(d, J ) 12.0 Hz, 1 H), 4.74 (d, J ) 12.3 Hz, 1 H), 4.81 (d, J ) 12.0
Hz, 1 H), 4.85 (d, J ) 12.3 Hz, 1 H), 4.91 (d, J ) 14.1 Hz, 1 H), 4.94
(d, J ) 1.5 Hz, 1 H), 5.07 (d, J ) 14.1 Hz, 1 H), 5.28 (s, 2 H), 5.64
(s, 1 H), 7.26-7.51 (m, 23 H), 7.98 (dd, J ) 1.2, 7.8 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 64.5, 66.7, 67.4, 68.8, 73.2, 73.4, 76.3, 76.4,
79.2, 99.1, 101.4, 126.0, 127.3, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3,
128.4, 128.6, 128.8, 130.7, 132.5, 135.8, 137.7, 138.5, 138.6, 139.6,
166.6. Anal. Calcd for C42H40O8: C, 74.98; H, 5.99. Found: C, 74.87;
H, 5.92.
2-(Hydroxycarbonyl)benzyl 2,3-Di-O-benzyl-4,6-O-benzylidene-
r-D-mannopyranoside (4). Compound 3 (2.0 g, 2.97 mmol, 1 equiv)
was stirred under hydrogen atmosphere using a balloon in the presence
of Pd/C (10%, 221 mg, 0.07 equiv) and ammonium acetate (801 mg,
10.39 mmol, 3.5 equiv) in MeOH (100 mL) at room temperature for 1
h. The reaction mixture was filtered through Celite, and the filtrate
was concentrated in vacuo. The residue was purified by silica gel flash
column chromatography (50% ethyl acetate in hexane) to afford the
title compound 4 (1.66 g, 96%): white solid, mp 81-82 °C; Rf ) 0.40
(50% ethyl acetate in hexane); [R]20 ) +62.6 (c ) 2.5, CHCl3); IR
D
(CHCl3 film) 3070, 3034, 2915, 1695, 1101, 746 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.86-3.88 (m, 2 H), 3.91 (dd, J ) 1.8, 3.3 Hz, 1 H),
4.06 (dd, J ) 3.3, 10.2 Hz, 1 H), 4.25-4.30 (m, 2 H), 4.67 (d, J )
12.0 Hz, 1 H), 4.74 (d, J ) 12.3 Hz, 1 H), 4.81 (d, J ) 12.3 Hz, 1 H),
4.86 (d, J ) 12.0 Hz, 1 H), 4.92 (d, J ) 14.4 Hz, 1 H), 4.99 (d, J )
1.8 Hz, 1 H), 5.12 (d, J ) 14.4 Hz, 1 H), 5.64 (s, 1 H), 7.24-7.56 (m,
18 H), 8.07 (dd, J ) 1.2, 7.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
64.7, 67.6, 68.9, 73.3, 73.6, 76.4, 76.5, 79.2, 99.3, 101.6, 126.2, 127.5,
127.6, 127.8, 127.9, 128.2, 128.3, 128.4, 128.5, 128.9, 131.7, 133.4,
137.8, 138.2, 138.7, 140.5, 172.1. Anal. Calcd for C35H34O8: C, 72.15;
H, 5.88. Found: C, 72.15; H, 5.84.
To a solution of 2-(benzyloxycarbonyl)benzyl 2,3,4,6-tetra-O-acetyl-
R-D-mannopyranoside (5.0 g, 8.73 mmol) in MeOH (50 mL) was added

2-(Hydroxycarbonyl)benzyl Glycosides
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8481
General Procedure for the Glycosylation Employing HCB
Glycosides. A solution of the HCB glycoside (0.10 mmol, 1 equiv)
and 2,6-di-tert-butyl-4-methylpyridine (0.20 mmol, 2 equiv) in CH2-
Cl2 (6 mL) in the presence of 4 Å MS was stirred for 30 min at room
temperature and cooled to -78 °C. After addition of Tf2O (0.10 mmol,
1 equiv), the solution was stirred at -78 °C for 10 min, and then the
glycosyl acceptor (0.20 mmol, 2 equiv) was added. The reaction mixture
was stirred at -78 °C for further 1 h and allowed to warm over 2 h to
0 °C. The reaction mixture was quenched with saturated aqueous
NaHCO3, and the organic phase was washed with brine, dried (MgSO4),
concentrated, and purified by silica gel flash column chromatography.
Acknowledgment. This research was supported by a grant
from KOSEF-CMDS (Center for Molecular Design and Syn-
thesis). We thank Yong Sung Seo and Sung-Soo Kang for
experimental assistance.
Supporting Information Available: Synthetic procedure for
5-8 and for 39-46 and spectral data for 12, 13, and 20-38.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA015842S