Convergent total syntheses of oligosaccharides by one-pot sequential stereoselective glycosylations

ꢀ 2003 The Chemical Society of Japan

Bull. Chem. Soc. Jpn., 76, 1829–1848 (2003) 1829

Convergent Total Syntheses of Oligosaccharides by One-Pot Sequential

Stereoselective Glycosylations

#

ꢀ;

Takashi Hashihayata, Kazuhiro Ikegai, Kazuya Takeuchi, Hideki Jona, and Teruaki Mukaiyama

Center for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003

Received April 11, 2003; E-mail: mukaiyam@abeam.ocn.ne.jp

A convergent total synthesis of F1ꢀ antigen, a member of the tumor-associated O-linked mucin glycosyl amino

acid, was tried by one-pot sequential glycosylation. Highly ꢀ-selective glycosylation of amino acid 7 with thioglycoside

6 was successfully carried out by combining trityl triﬂuoromethanesulfonate (TrOTf) and N-iodosuccimide (NIS) which

gave glycosyl amino acid 21 in high yield (97%, ꢀ=ꢁ ¼ 83=17). Next, the glycosylation of thioglycoside 4 with ga-

lactosyl phenyl carbonate 2 or ﬂuoride 3 was tried by the promotion of trityl tetrakis(pentaﬂuorophenyl)borate

[TrB(C₆F₅)₄] or triﬂuoromethanesulfonic acid (TfOH); protected F1ꢀ 25 was aﬀorded in 80 or 89% overall yield, re-

spectively, by the further addition of glycosyl amino acid 5 and NIS. The desired trisaccharide was obtained in high

yield after removal of the protecting groups. Next, a convergent total synthesis of branched hepta-ꢁ-glucoside 30 having

phytoalexin-elicitor activity was eﬃciently performed by way of two one-pot sequential glycosylation reactions: that is,

trisaccharide 34 was synthesized in high yield by TfOH-catalyzed one-pot glycosylation using three given monosaccha-

rides (31, 35, and 36) as shown in Scheme 12 and by subsequent selective deprotection of 6⁰-O-TBDPS group. The

second one-pot glycosylation of trisaccharide 34 with three monosaccharides (31, 32, and 33d) also proceeded smoothly

to aﬀord heptaglucoside 43 stereoselectively in 48% total yield based on monosaccharide 32. Phytoalexin-elicitor active

branched hepta-ꢁ-glucoside 30 was aﬀorded by the sequential deprotection.

Development of a stereoselective glycosylation reaction is

one of the most fundamental and important topics in carbohy-

drate chemistry. In the last two decades, various types of su-

perb glycosyl donors combined with suitable activators have

been developed¹since classical Koenigs–Knorr-type reactions²

were reported. Nowadays, glycosyl ﬂuoride, which was ﬁrst

reported from our laboratory in 1981, is recognized as one

of the most excellent glycosyl donors (Scheme 1).³Actually,

ꢀ-glucosides were obtained with good stereoselectivities when

the glycosylation reaction of various glycosyl acceptors with

glucosyl ﬂuoride was carried out by using stoichiometric

amounts of activator formed from tin(b) chloride (SnCl₂)

and silver perchlorate (AgClO₄). After the above-mentioned

combined-catalyst system was introduced, the glycosyl ﬂuo-

rides as donors attracted much attention from many research

groups. Preparative methods for glycosides using glycosyl ﬂu-

orides with various activators such as SiF₄,⁴Me₃SiOTf,⁴

saccharides. In developing an one-pot sequential glycosyla-

tion method, it is very important to choose the most suitable

combinations of glycosyl donors and related activating

agents. Kahne reported¹⁸the one-pot glycosylation method

ﬁrst; the synthesis of Ciclamycin trisaccharide moiety was car-

ried out by tuning the reactivity of leaving group, a sulfoxide.

Takahashi and Chenault described independently the sequen-

tial one-pot glycosylation using two diﬀerent glycosyl donors

such as glycosyl bromide and thioglycoside¹⁹or isopropenyl

glycoside and 4-pentenyl glycoside,²⁰respectively. Also,

Ley reported²¹the one-pot multistep glycosylation by utilizing

his own protecting group strategy. In addition, programmable

one-pot oligosaccharide synthesis was developed by Wong.²²

In our previous papers,^23,24two types of one-pot sequential

glycosylation for the synthesis of trisaccharides were reported.

In the ﬁrst step, the corresponding disaccharide was formed

from glycosyl phenyl carbonate or ﬂuoride and thioglycoside

by the promotion of a catalytic amount of trityl tetrakis(penta-

ﬂuorophenyl)borate [TrB(C₆F₅)₄] or triﬂuoromethanesulfonic

acid (TfOH), and trisaccharide was aﬀorded in high yield by

the subsequent glycosylation of methylglycoside with the

above disaccharide and further addition of N-iodosuccimide

(NIS) (Scheme 2).¹⁹The results prompted us to search for a

rapid total synthesis of biologically active oligosaccharide.

In this paper, we would like to report on a convergent and con-

venient total synthesis of linear- or branched-type oligosac-

charide by one-pot sequential glycosylation.

Et₂O BF₃,⁵TiF₄,⁶SnF₄,⁶Cp₂MCl₂–AgClO₄(M = Ti, Zr,

ꢁ

Hf),⁷

Me₂GaCl,⁸

Tf₂O,⁹

LiClO₄,¹⁰

Yb(OTf)₃,¹¹

La(ClO₄)₃nH₂O,¹¹SO₄/ZrO₂,¹²TrB(C₆F₅)₄,¹³TfOH,¹⁴

ꢁ

HClO₄,¹⁵and HB(C₆F₅)₄¹⁵have been developed since then.¹⁶

Further development of new strategies and tactics in oligo-

saccharide synthesis is still of growing importance and many

studies have recently been reported; for example, armed-dis-

armed, two-stage activation, active-latent, orthogonal, one-

pot multistep, and solid-phase glycosylation reactions.¹The

one-pot procedure¹⁷certainly reduced the steps of laborious

and time-consuming puriﬁcation processes of intermediate

Results and Discussion

A Convergent Total Synthesis of Mucin Related F1ꢀ

Antigen. During the last decade, mucins have been regarded

# The Kitasato Institute for Life Sciences, Kitasato University, 5-

9-1 Shirokane, Minato-ku, Tokyo 108-8641

Published on the web September 15, 2003; DOI 10.1246/bcsj.76.1829

1830 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

Scheme 1.

Scheme 2.

as important substances in antitumor immunological studies

because of their high expression on epithelial cell surfaces

and their high content of clustered ꢀ-O-linked carbohydrates.

Recently, F1ꢀ antigens, Galꢁ-(1!4)GlcNAcꢁ-(1!6)-

GalNAcꢀ-(1!3)Ser and -(1!3)Thr, were found; these repre-

sented good examples of aberrant carbohydrate epitopes found

on mucins associated with gastric adenocarcinomas.²⁵There-

fore, total synthesis of F1ꢀ antigens²⁶continues to be an inter-

esting topic because of their structures and biological proper-

ties, and their total synthesis has already been reported by R.

R. Koganty et al.²⁷in 1997 and S. J. Danishefsky et al.²⁸in

1998.

The retro synthetic analysis of F1ꢀ (1) is shown in

Scheme 3. The results of our reported procedure indicated that

the fully protected F1ꢀ could be synthesized by one-pot se-

quential glycosylation using galactosyl donor 2 or 3, thiogly-

coside 4, and glycosyl amino acid 5. Galactosyl donor 2 or

3 having 2-O-para-methylbenzoyl (p-MeBz) and 3,4,6-O-tri-

benzyl groups was prepared according to a procedure similar

to that of glucosyl donors.^23,29By changing benzoyl protect-

ing groups at 3, 4, and 6 positions to benzyl ones, our research

group has shown that the reactivity of donor 2 or 3 was im-

proved dramatically compared with that of fully benzoylated

one.^14,23aThioglycoside

4

having 4,5-dichlorophthaloyl

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1831

Scheme 3.

Scheme 4.

with thioglycoside 6.²³

(DCPhth) protected amino function was chosen due to ease in

removing the amino protecting group; it was prepared by

standard protecting group manipulations.³⁰It was thought that

two ꢁ-glycoside linkages would be perfectly controlled by

neighboring group participation, and that ꢀ-5 would be pre-

pared by ꢀ-selective glycosylation of the protected serine 7

The starting galactosyl donors 2, 3, and thioglycoside 4

were successfully prepared from 8 via 9–15 and 16 via 17–

19, respectively, as shown in Schemes 4 and 5. The hydrolysis

of thioglycoside 14 was carried out by using a combination of

TfOH and nBu₄NIO₄according to our reported procedure.³¹

1832 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

Scheme 5.

tation, ꢀ-selectivity was not observed when the reaction was

tried in Et₂O (Entries 1, 4, 5). When the above glycosylation

was carried out in toluene using TfOH or perchloric acid

(HClO₄),³⁴on the other hand, signiﬁcant ꢀ-selectivity was ob-

served (Entries 3, 7). However, the yield of saccharide was not

suﬃcient because partial deprotection of the benzylidene ace-

tal took place during this glycosylation.

Next, the glycosylation of 7 with 6 was tried by using a

combination of trityl salt and NIS (Table 2). It was reported

from our laboratory that trityl salts, such as trityl perchlorate

(TrClO₄) and TrB(C₆F₅)₄, could eﬀectively be employed as

Lewis acid catalysts^35,36for aldol, Michael, and glycosylation

reactions. Furthermore, glycosylation reaction with thioglyco-

side using a combination of TrB(C₆F₅)₄and NIS²³was recent-

ly reported to proceed smoothly to aﬀord the disaccharide in

high yield as previously noted in Scheme 2. When TrB(C₆F₅)₄

was used together with NIS, the glycosyl amino acid 21 was

obtained in high yield; however, the undesired ꢁ-glycoside

was also formed (Entries 1, 2, 3). It was thought that a protic

acid would activate an oxygen atom in a benzylidene protect-

ing group, while a Lewis acid having trityl cation would aﬀord

the desired 21 in high yield without giving damage to 1,3-ben-

zylidene group. Actually, the TrOTf (generated in situ from

trityl chloride and AgOTf)-catalyzed glycosylation aﬀorded

21 in good yield (Entries 4, 5, 6). The highest ꢀ-selectivity

and chemical yield were observed when the reaction was car-

ried out in toluene (Entry 5), while the TrClO₄-catalyzed gly-

cosylation did not proceed at all (Entries 7, 8). It is interesting

to note that the stereoselectivity could be reversed only by

changing the counter anion of the catalyst, as reported previ-

ously from our laboratory. Additionally, the glycosylation

of hindered ^L-threonine derivative 22 with 6 also proceeded

smoothly to aﬀord the corresponding ꢀ-glycoside 23 in high

yield (Scheme 7). It was already noted that the stereoselectiv-

ity was strongly inﬂuenced by the combined use of counter

anion of catalyst and solvent by studying the glycosylation

with glycosyl ﬂuoride in detail. In addition, ꢀ-selective glyco-

sylation proceeded eﬀectively when HClO₄or TfOH was

used³⁴(Table 3). It was thought that the high ꢀ-selectivity

in glycosylation of 7 or 22 with 6 in toluene, a nonpolar sol-

Scheme 6.

Next, stereoselective synthesis of 6 was examined (Scheme 6):

that is, the corresponding thioglycoside 6 was obtained in good

yield by treating 1-O-hydroxy sugar 20 which was prepared by

a known procedure,³²with SOCl₂in DMF, and by the subse-

quent anomeric substitution with NaSPh.

In the ﬁrst place, ꢀ-selective glycosylation of 7 with 6 was

examined using a combination of protic acid such as TfOH and

NIS³³(Table 1), which was already shown as a strong catalyst

system for the activation of thioglycoside. Against our expec-

Table 1. Glycosylation of L-Serine Derivative 7 with Thio-

glycoside 6

Entry Protic acid

Solvent

Et₂O

TfOH Toluene–Dioxane^c)

Time/h Yield/% (ꢀ=ꢁ)^b)

1

2

3

TfOH

4.5

2.5

29 (69/31)

73 (85/15)

78 (94/6)

TfOH

Toluene

a)

4

5

6

7

HClO₄

Et₂O

2.5

4.5

0.5

45 (69/31)^d)

61 (65/35)

81 (66/34)

36 (>99/1)

HClO₄Toluene–Dioxane^c)

HClO₄

Toluene

18

t

a) HClO₄was generated from AgClO₄and BuCl in toluene,

and the supernatant was used. b) The ꢀ=ꢁ ratios were deter-

mined by isolated yields of both isomers. c) Toluene–1,4-Di-

oxane (v/v = 2/1). d) The reaction was carried out at ꢂ20

^ꢃC.

vent, was due to the eﬀect of counter anion (TfO^ꢂor ClO₄

)

ꢂ

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1833

Table 2. Glycosylation Using the Combination of Trityl Salts and NIS

Entry

Trityl salt

Solvent

Time/h

Yield/% (ꢀ=ꢁ)^a)

1

2

3

TrB(C₆F₅)₄

Et₂O

Toluene

Toluene–^tBuCN (v/v = 3/1)

1.5

89 (51/49)

90 (36/64)

68 (10/90)

4

5

6

TrCl + AgOTf

Et₂O

Toluene

Toluene–^tBuCN (v/v = 3/1)

4

1.5

4

78 (79/21)

97 (83/17)

79 (81/19)

7

8

TrClO₄

Toluene

Et₂O

4

trace

a) The ꢀ=ꢁ ratios were determined by isolations of both isomers.

Scheme 7.

Table 3. Eﬀect of Counter Anion of Catalyst and Solvent

Yield/% (ꢀ=ꢁ)

(Et₂O, rt, 4 h)

Yield/% (ꢀ=ꢁ)

Entry

Catalyst

ꢃ

(BTF–^tBuCN, 0 C, 2 h)

1

2

HOTf

HClO₄

98 (88/12)

98 (92/8)

>99 (47/53)

>99 (60/40)

3

4

5

HB(C₆F₅)₄

TrB(C₆F₅)₄

SnCl₂–AgB(C₆F₅)₄

95 (55/45)

85 (47/53)

90 (43/57)

99 (7/93)

88 (4/96)

95 (8/92)

as shown in Tables 1 and 2. After separation of these isomers,

a regioselective benzylidene ring opening³⁷of 21ꢀ was tried

by using a combination of Et₃N BH₃and Et₂O BF₃to give

alcohol 5 in moderate yield (Scheme 8). This method proved

to be eﬀective for the synthesis of mucin basic unit,

GalNAcꢀ(1!3)Ser/Thr, and to be applicable for the prepara-

tion of related derivatives.

Then, stereo- and chemo-selective glycosylation of thiogly-

coside 4 with galactosyl donor 2 or 3 were examined in detail

according to our previously reported one-pot glycosylation

procedure so as to optimize the reaction conditions (Tables 4

and 5). In Table 4, the TrB(C₆F₅)₄-catalyzed glycosylation

of 4 with phenyl carbonate donor 2 proceeded more smoothly

in (triﬂuoromethyl)benzene (BTF) (Entries 4, 6, 7) than in

ꢁ

1834 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

Scheme 8.

Table 4. Glycosylation of 4 with 2 Using TrB(C₆F₅)₄

Table 5. Glycosylation of 4 with Galactosyl Fluoride 3

Using TfOH

Entry Additive Conditions Time/h Yield/%

Entry

Conditions

ꢃ

Time/h

Yield/%

1

2

3

4

Drierite

CH₂Cl₂

Et₂O

Toluene

BTF

6

14

24

7

1

2

3

4^a)

5

CH₂Cl₂, 0 C

ꢃ

0.75

1

1.5

1

4.5

77

88

94

91

82

91

CH₂Cl₂, ꢂ10 C

ꢃ

CH₂Cl₂, ꢂ20 C

61

CH₂Cl₂, ꢂ20 C

ꢃ

5

6

7^a)

MS 5A

CH₂Cl₂

BTF

6

4

5

12

69

84

BTF, ꢂ10 C

6

Et₂O, rt

a) 3ꢀ was used in stead of 3ꢁ.

a) 1.8 mol. amt. of the donor 2 was used.

thio group even when only 1.2 molar amount of glycosyl donor

3 was employed (Table 5, Entry 3). A similar result was also

obtained when ꢀ-glycosyl ﬂuoride 3ꢀ, a less reactive donor

compared with 3ꢁ, was used under the same conditions (Entry

4).

The above results led us to attempt one-pot sequential gly-

cosylations by using glycosyl phenyl carbonate or ﬂuoride, as

shown in Scheme 9. In the ﬁrst step, glycosyl ﬂuoride 3 or

phenyl carbonate 2 was treated with thioglycoside 4 in the

presence of a catalyst such as TfOH or TrB(C₆F₅)₄; 4 was al-

CH₂Cl₂, Et₂O, or toluene (Entries 1, 2, 3, 5). The former sol-

vent was used as a substitute of the above three solvents; it was

successively employed in the trityl salt-promoted

glycosylation. Further, the yield was improved when the gly-

cosylation was carried out by using MS 5A and 1.8 molar

amount of 2 (Entry 7). Next, the glycosylation of 4 with gly-

cosyl ﬂuoride 3 was further examined by using 0.20 molar

amount TfOH in CH₂Cl₂at ꢂ20 ^ꢃC. The desired disaccharide

24 was obtained in excellent yield without giving damage to

ꢃ

Scheme 9. Condition A: 2 (1.8 mol. amt.), 4 (1.0 mol. amt.), TrB(C₆F₅)₄(0.30 mol. amt.), MS 5A, BTF, ꢂ15 C, 5 h, then 5 (5.0

mol. amt.), NIS (2.0 mol. amt.), BTF–CH₂Cl₂, ꢂ30 ^ꢃC, 2 h, 80% (based on 4). Condition B: 3 (1.2 mol. amt.), 4 (1.0 mol. amt.),

ꢃ

TfOH (0.20 mol. amt.), MS 5A, CH₂Cl₂, ꢂ20 C, 1 h, then 5 (1.5 mol. amt.), NIS (2.0 mol. amt.), CH₂Cl₂, ꢂ20 C, 1 h, 89%

(based on 4).

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1835

Scheme 10.

Scheme 11.

most completely consumed within 1 h or 5 h, respectively, as

was conﬁrmed by TLC monitoring. Next, the second glycosyl-

ation of glycosyl amino acid 5 with thus formed disaccharide

24 was carried out by successively adding NIS in one-pot op-

eration; fully protected F1ꢀ 25 was stereoselectively obtained

in high yield (89% or 80%, respectively). Thus, the one-pot

sequential glycosylation using glycosyl ﬂuoride 3 was eﬀec-

tively performed in higher yield even when the amount of thio-

glycoside acceptor 4 was less than that shown in the case of

using glycosyl phenyl carbonate 2.

Transformation of 25 into F1ꢀ is shown in Scheme 10. In

the ﬁrst place, the azido group of 25 was reduced with thioace-

tic acid to give 26 in 85% yield. Successive deprotection of

DCPhth group of 26 proceeded smoothly to aﬀord the desired

diacetamido glycosyl amino acid 27 in high yield after acety-

lation (2 steps, 82%) when hydrazine acetate³⁸was used in eth-

anol at 70 ^ꢃC, while complicated mixtures resulted under

standard conditions (hydrazine acetate, ethylenediamine, and

NaBH₄-reduction followed by AcOH). Finally, removal of

benzyl and benzyloxycarbonyl group of compound 27 by hy-

drogenolysis and careful saponiﬁcation of p-MeBz group af-

forded the desired product, F1ꢀ (1), in 84% yield.

sperma f. sp. Glycinea, induced antibiotic phytoalexin accu-

mulation in soybeans.³⁹Since then, chemical synthesis of phy-

toalexin elicitor related ꢁ-glucans such as 29 have been draw-

ing much attention because of their complex branched-struc-

tures (Scheme 11).^19,40

Recently, it was reported from our laboratory^23,24that sever-

al one-pot sequential glycosylation reactions¹⁹for convenient

synthesis of linear trisaccharides were accomplished by utiliz-

ing orthogonal properties⁴¹of donor and acceptor glycosides

as had already been described in the above section: that is,

the combination of glycosyl ﬂuorides (or glycosyl phenyl car-

bonates) and thioglycosides. It is signiﬁcant to demonstrate

extended utility of the above one-pot sequential glycosylations

by applying the above-mentioned methods to the synthesis of

complex branched-oligosaccharides. In this section, a conver-

gent and convenient total synthesis of methyl heptaglucoside

30 having phytoalexin elicitor activity by one-pot sequential

glycosylation is described.⁴²

Synthetic strategy for hepta-ꢁ-glucoside 30 involved two

one-pot glycosylation reactions (Scheme 12). According to

our previously reported procedure, it was considered that

methyl triglucoside 34 should rapidly be constructed by

TfOH-catalyzed one-pot glycosylation using three compo-

nents: monosaccharides 31, 35, and 36. Next, three independ-

ent glycosylation reactions, the armed-disarmed glycosylation

using a pair of reactivity-tuned thioglucosides⁴³(32 and 33) as

A Convergent Total Synthesis of the Phytoalexin-Elicitor

Active Heptasaccharide. P. Albersheim et al. reported in

1984 that elicitor-active hexa-ꢁ-D-glucopyranosyl-D-glucitol

28, isolated from the mycelial walls of Phytophthora mega-

1836 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

Scheme 12.

well as orthogonal glycosylation⁴¹using the combination of

glucosyl ﬂuoride 31 and thioglucoside 32, and sequential gly-

cosylation of triglucoside 34 were employed in one-pot for the

formation of fully protected heptasaccharide. The assistance

of 2-O-benzoyl protecting group must have controlled stereo-

chemistries of those glycosylation reactions.

Glucosyl ﬂuoride 31 having 2-O-para-methylbenzoyl group

(p-MeBz) was prepared easily by treating the corresponding 1-

O-hydroxy sugar²³with (diethylamino)sulfur triﬂuoride

(DAST)²⁹in CH₂Cl₂. ꢀ-Ethylthio glucosides 32 and 35 corre-

sponding to 3,6-branching positions were synthesized from

methyl glucoside 36 using NIS–TfOH promoter system³³that

gave the corresponding silylated trisaccharide 40 in high yield

(86% based on 35). The desired trisaccharide unit 34 was ob-

tained in 93% yield after selective deprotection of the t-butyl-

diphenylsilyl (TBDPS) group on treatment with tetrabutylam-

monium ﬂuoride (TBAF) in the presence of acetic acid.

Next, the second one-pot glycosylation of ‘‘4-units’’ was

studied in detail. In the ﬁrst step, double glycosylation of diol

32 having thioglycosidic linkage with 2.1 molar amounts of 31

was attempted in the presence of 0.30 molar amount of TfOH

and molecular sieves 5A (MS 5A); terminal branched-trisac-

charide 41 was aﬀorded directly in excellent yield, as shown

in Scheme 15. Subsequent armed-disarmed glycosylation of

several disarmed thioglycoside acceptors with thus formed_ꢃtri-

saccharide 41 was tried at low temperature (ꢂ60 to ꢂ50 C)

using NIS–TfOH. However, the desired tetrasaccharide 42a

was not obtained when ꢁ-phenylthio glycoside 33a was used

as an acceptor; instead, self-coupling of 33a exclusively took

place and trisaccharide 41 was recovered (Scheme 16). Tetra-

saccharide 42b was obtained in 51% yield only by changing

the leaving group from ꢁ-phenylthio to ꢀ-ethylthio (Table 6,

Entries 2, 3, 4). It should be noted that the reactivity of ꢀ-eth-

ylthio group stabilized by the anomeric eﬀect⁴⁵is lower than

that of corresponding ꢁ-phenylthio group. After screening

ethyl

2-O-benzoyl-4,6-O-benzylidene-3-O-chloroacetyl-1-

thio-ꢀ-D-glucopyranoside⁴⁴by standard protecting group ma-

nipulations (Scheme 13). In the above procedure, regioselec-

tive introduction of benzoyl group to 2-O-hydroxy substituent

in glucoside with 2 and 3-O-free hydroxy groups was carried

out by using 4,6-O-benzylidene protected glucoside having

ꢀ-ethylthio moiety.

In the ﬁrst place, synthesis of trisaccharide unit 34 was car-

ried out according to our previously reported one-pot proce-

dure (Scheme 14):^23,24that is, TfOH-catalyzed glycosylation¹⁴

of thioglucoside 35 having a free hydroxy group at C-3 posi-

tion with glucosyl ﬂuoride 31 aﬀorded the corresponding

disaccharide, which in turn was followed by glycosylation of

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1837

Scheme 13.

Scheme 14.

Scheme 15.

Scheme 16.

1838 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

Table 6. The Second One-Pot Glycosylation of Four Units

pling with p-CF₃Bz-protected 33d aﬀorded tetraglucoside

42d as a major product, as was conﬁrmed by TLC

monitoring. Next, the glycosylation of the above-mentioned

trisaccharide unit 34 with 42d was tried by adding NIS

successively. As a result, four glycosidic linkages were

formed sequentially in one-pot manners and fully protected

heptaglucoside 43 was obtained stereoselectively in 48% yield

(based on 32). Finally, the protected 43 was converted to the

ﬁnal product 30 in 95% yield by saponiﬁcation of benzoyl

groups and subsequent hydrogenolysis (Scheme 18).

Conclusion

Thus, convergent and convenient total syntheses of linear

and branched types of oligosaccharides were accomplished

by one-pot sequential glycosylations. In the ﬁrst section,

one-pot sequential glycosylation proceeded smoothly by the

promotion of TrB(C₆F₅)₄or TfOH using three components

and addition of NIS to the reaction mixture aﬀord protected

F1ꢀ 28 in high yield. It is noted that the high ꢀ-selectivity

in glycosylation of amino acid 7 with thioglycoside 6 was

strongly inﬂuenced by the kind of counter anion of the

catalyst. In the second section, fully protected heptasaccharide

47 was rapidly assembled in only three steps from the compo-

nent monosaccharides by two one-pot reactions. It is also not-

ed that a signiﬁcant reactivity diﬀerence was observed be-

tween ꢀ-ethylthio- and ꢁ-phenylthio-glucosides, which indi-

cated that the reactivity tuning of thioglycoside donors is con-

trolled by their anomeric conﬁgurations. In summary, it is

noted that these methodologies proved to be applicable for

the rapid assembly of various types of oligosaccharides.

Entry

Thioglycoside

33a: R = SPh (ꢁ), R⁰= Bz

Yield/%

1

2

Not Detected

51

33b: R = SEt (ꢀ), R⁰= Bz

3

4

33c: R = SEt (ꢀ), R⁰= p-ClBz

33d: R = SEt (ꢀ), R⁰= p-CF₃Bz

71

76

several protective groups, the desired tetraglucoside 42d was

synthesized in high yield (total 76% yield based on 32) when

p-CF₃Bz-protected ꢀ-ethylthio glucoside 33d was used (Entry

4).

Based on the above results, one-pot sequential heptasac-

charide synthesis using four building blocks was attempted,

as shown in Scheme 17. First, TfOH-catalyzed double glyco-

sylation of 36 with 35, followed by the armed-disarmed cou-

Scheme 17.

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1839

Scheme 18.

ꢃ

CHCl₃(225 mL) was added AlCl₃(10.3 g, 76.9 mmol) at 0 C.

After stirring for 4 h at the same temperature, 2,6-lutidine (63

mL) was slowly added. To the mixture was successively added

EtOH (250 mL) and the reaction mixture was stirred for an addi-

tional 16 h at rt. The reaction mixture was diluted with sat. aq.

NaHCO₃(250 mL), 2.5 M aq. NaOH (250 mL), and CHCl₃

(325 mL). The aqueous layer was extracted with CHCl₃and

the combined organic layer was dried over Na₂SO₄. After ﬁltra-

tion and evaporation, the residue was dried in vacuo. The crude

product was used without further puriﬁcation. To a solution of

the crude product in MeOH (375 mL) was added 28% NaOMe

(3 mL) in MeOH at rt. After stirring for 3 h, the solvent was re-

moved by evaporation. The residue was dried in vacuo. To a so-

lution of the crude product in DMF (375 mL) was added portion-

wise 55% NaH (16.8 g, 385 mmol) oil dispersion during 20 min at

0 ^ꢃC. After stirring for 30 min at the same temperature, a solution

of benzyl bromide (39 mL, 328 mmol) in DMF (50 mL) was add-

ed dropwise during 1.5 h. After stirring for 5 h at rt, the reaction

mixture was quenched by adding H₂O. The aqueous layer was ex-

tracted with Et₂O. The combined organic layer was washed with

H₂O and brine, and dried over Na₂SO₄. After ﬁltration and evap-

oration, the residue was dried in vacuo. To a solution of the crude

product and silica gel (25 g, which was washed with 3 M aq. HCl)

in CH₂Cl₂(500 mL) was added 3 M aq. HCl (50 mL) at rt. After

stirring for 3 h at the same temperature, the reaction mixture was

diluted with H₂O. The aqueous layer was extracted with CH₂Cl₂

and the combined organic layer was washed with sat. aq. NaHCO₃

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was dried in vacuo. To a solution of the crude

product in MeOH (250 mL) and CH₂Cl₂(50 mL) was added

28% NaOMe (2 mL) in MeOH at rt. After stirring for 3 h, the re-

action mixture was acidiﬁed with Amberlite¹IR-120 cation ex-

change resin (until ca. pH 6). After ﬁltration and evaporation,

the residue was puriﬁed by silica gel column chromatography to

aﬀord 12 (13.75 g, 48%) as oil. ꢀ, ꢁ-mixture; R_f0.19 (hex-

ane/ethyl acetate = 1/1, v/v); ¹H NMR (500 MHz, CDCl₃): ꢂ

3.36 (dd, J ¼ 2:7, 9.8 Hz), 3.38–3.45 (m), 3.46–3.59 (m), 3.70

(dd, J ¼ 2:7, 10.1 Hz), 3.80–3.91 (m), 4.07–4.14 (m), 4.32–4.57

(m), 4.60–4.71 (m), 4.83 (dd, J ¼ 4:0, 11.6 Hz), 5.26 (d,

J ¼ 3:7 Hz), 7.15–7.40 (m, Ar-H); ¹³C NMR (125 MHz, CDCl₃):

ꢂ 68.74, 69.08, 69.52, 72.53, 72.57, 73.28, 73.47, 73.56, 74.20,

74.55, 74.62, 79.20, 82.01, 92.69, 97.33, 127.69–128.53, 137.71,

137.75, 138.12, 138.31, 138.38, 138.49; IR (neat): 741, 1065,

Experimental

General. All melting points were measured on a Yanaco MP-

S3 micro melting point apparatus. Infrared spectra were recorded

on a Horiba FT-300 infrared spectrometer. ¹H NMR spectra were

recorded on a JEOL JNM-EX270 (270 MHz), JNM-EX300 (300

MHz), JNM-LA400 (400 MHz), JEOL JNM-LA500 (500 MHz),

or Varian INOVA600 (600 MHz) spectrometer; chemical shifts

(ꢂ) are reported in parts per million relative to tetramethylsilane.

Splitting patterns are designated as s, singlet; d, doublet; t, triplet;

q, quartet; m, multiplet; br, broad. ¹³C NMR spectra were record-

ed on a JEOL JNM-EX270L (68 MHz), a JEOL JNM-LA400 (100

MHz), or a JEOL JNM-LA500 (125 MHz) spectrometer with

complete proton decoupling. Chemical shifts are reported in parts

per million relative to tetramethylsilane with the solvent reso-

nance as the internal standard (CDCl₃; ꢂ 77.0 ppm). High-resolu-

tion mass spectra were recorded on a Micromass Q-TOF2 instru-

ment [ESI positive, 0.01 M (1 M = 1 mol dm^ꢂ3) AcONH₄in

H₂O/MeCN]. Optical rotations were recorded on a Jasco-P-

1020 polarimeter. Analytical TLC was done on precoated (0.25

mm) silica gel 60 F₂₅₄plates (E. Merck). Thin-layer chromatog-

raphy was performed on Wakogel B-5F. Column chromatography

was performed on Silica gel 60 (Merck). Reversed-phase column

chromatography was performed on YMC-Gel ODS-AQ 120-S50.

Ion-exchange column chromatography was performed on Dowex

50WX-8.

All reactions were carried out under argon atmosphere in dried

glassware, unless otherwise noted. All reagents were purchased

from Tokyo Kasei Kogyo, Kanto Chemical, or Aldrich and used

without further puriﬁcation, unless otherwise noted. Triﬂuoro-

methanesulfonic acid (TfOH: donated by Central Glass Co. Lim-

ited) was simply distilled and used for glycosylation. CH₂Cl₂and

pivalonitrile were distilled from P₂O₅and then from CaH₂and

were stored over molecular sieves 4A. Toluene and (triﬂuoro-

methyl)benzene (BTF) were distilled from P₂O₅and stored over

molecular sieves 4A. Dry THF and Et₂O were purchased from

ꢃ

Kanto Chemical. Powdered and pre-dried (at 260 C/133 Pa, 6

h) molecular sieves 4A and 5A were used in gl_ꢃycosylation

reactions. Suﬃciently crushed and pre-dried (at 260 C/133 Pa,

6 h) Drierite from W. A. Hammond Drierite Company was used

in the glycosylations.

3,4,6-Tri-O-benzyl-^D-galactopyranose (12). To a solution of

pentaacetyl-ꢁ-D-galactopyranoside 8 (25.0 g, 128 mmol) in

1840 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

1111, 2870, 2939, 3055, 3089, 3186, 3271, 3356 cm^ꢂ1; HRMS:

(15H, m, Ar-H), 7.94 (2H, d, J ¼ 8:2 Hz, Ar-H); ¹³C NMR (125

MHz, CDCl₃) ꢂ 21.66, 67.89, 70.40, 71.89, 72.17, 73.55, 74.60,

74.63, 79.52, 96.66 (C-1), 120.81-129.97, 137.35, 137.64,

138.20, 143.93, 150.73, 152.31, 165.06; IR (KBr) 741, 1103,

m=z calcd for C₂₇H₃₀O₆Na [M + Na]^þ473.1940, found

473.1941.

ꢁ

3,4,6-Tri-O-benzyl-2-O-p-toluoyl-^D-galactopyranose (15).

To a solution of 12 (9.00 g, 20.0 mmol) and 4-dimethylaminopyr-

idine (224 mg, 2.00 mmol) in pyridine (40 mL) was added p-

methylbenzoyl chloride (7.90 mL, 60.0 mmol) at 0 ^ꢃC. After stir-

ring for 4 h at the same temperature, 2,6-lutidine (63 mL) was

slowly added. After additional stirring for 2 h at rt, the reaction

mixture was quenched by adding sat. aq. NaHCO₃. The aqueous

layer was extracted with AcOEt and the combined organic layer

was washed with sat. aq. NH₄Cl, H₂O and brine, and dried over

Na₂SO₄. After ﬁltration and evaporation, the residue was dried

1273, 1728, 1774 cm^ꢂ1; HRMS m=z calcd for C₄₂H₄₀O₉NH₄

ꢁ

[M + NH₄]^þ706.3016, found 706.3011.

3,4,6-Tri-O-benzyl-2-O-p-toluoyl-^D-galactopyranosyl Fluo-

ride (3). To a solution of 15 (100 mg, 0.176 mmol) in CH₂Cl₂

(1.76 mL) was dropwise added (diethylamino)sulfur triﬂuoride

(0.0350 mL, 0.264 mmol) at ꢂ35 ^ꢃC. After stirring for 1 h at

the same temperature, the reaction mixture was quenched by add-

ing MeOH and sat. aq. NaHCO₃. The aqueous layer was extracted

with CH₂Cl₂. The combined organic layer was washed with H₂O

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was puriﬁed by preparative TLC (silica gel) to af-

ford 3 (95.4 mg, 95%, ꢀ=ꢁ ¼ 60=40), and both anomers were also

isolated by preparative TLC (silica gel).

in vacuo.

The crude product was used without further

puriﬁcation. To a solution of the crude product and dodecane-

1-thiol (5.7 mL, 24.0 mmol) in CH_ꢃ₂Cl₂(50 mL) was added

Et₂O BF₃(2.76 mL, 22.0 mmol) at 0 C; the mixture was stirred

ꢁ

for 30 min at the same temperature. After additional stirring for

30 min at rt, the mixture was quenched by adding sat. aq.

NaHCO₃. The aqueous layer was extracted with CH₂Cl₂. The

combined organic layer was washed with 1 M aq. NaOH, H₂O

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was dried in vacuo. To a solution of the crude

product and tetrabutylammonium periodate (2.63 g, 6.08 mmol)

in CH₃CN (700 mL) was added 70% aq. TfOH (0.7 mL, 4.94

mmol) at 0 ^ꢃC. After stirring for 3 h at the same temperature,

the reaction mixture was quenched by adding triethylamine (2.0

mL). After evaporation, the mixture was diluted with 10% aq.

Na₂S₂O₃. The aqueous layer was extracted with CH₂Cl₂and

the combined organic layer was washed with H₂O and brine,

and dried over Na₂SO₄. After ﬁltration and evaporation, the res-

idue was puriﬁed by silica gel column chromatography to aﬀord

15 (7.72 g, 68% from 12) as colorless amorphous. ꢀ, ꢁ-mixture;

3ꢀ: colorless oil; R_f0.54 (hexane/ethyl acetate, 3/1, v/v);

26

½ꢀꢄ_D+107.7 (c 1.00, CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ

2.41 (3H, s), 3.57–3.66 (2H, m), 4.05–4.12 (2H, m), 4.13–4.20

(1H, m), 4.40 (1H, d, J ¼ 11:6 Hz), 4.50 (1H, d, J ¼ 11:6 Hz),

4.59 (1H, d, J ¼ 11:3 Hz), 4.66 (1H, d, J ¼ 12:2 Hz), 4.70 (1H,

d, J ¼ 12:2 Hz), 4.97 (1H, d, J ¼ 11:3 Hz), 5.61 (1H, brdd,

J ¼ 10:1, 24.4 Hz), 5.86 (1H, brd, J ¼ 54:3 Hz), 7.20–7.37

(17H, m, Ar-H), 7.94 (2H, d, J ¼ 8:2 Hz, Ar-H); ¹³C NMR (125

MHz, CDCl₃) ꢂ 21.67, 68.13, 70.61 (d, J ¼ 23:8, C-2), 71.90,

72.44, 73.54, 73.66, 74.84, 75.81, 105.19 (d, J ¼ 225:5 Hz, C-

1), (126.78–129.90, 137.62, 137.73, 138.12, 144.02) (C-Ar),

165.89; IR (neat) 748, 1119, 1272, 1728, 2869, 2923 cm^ꢂ1

;

HRMS m=z calcd for C₃₅H₃₅FO₆NH₄[M + NH₄]^þ588.2761,

found 588.2745.

ꢁ

3ꢁ: colorless solid; R_f0.37 (hexane/ethyl acetate, 3/1, v/v);

26

Mp 84–85 ^ꢃC; ½ꢀꢄ_D+53.3 (c 1.05, CHCl₃); ¹H NMR (500

1

R_f0.16 (hexane/ethyl acetate = 3/1, v/v); H NMR (500 MHz,

MHz, CDCl₃) ꢂ 2.41 (3H, s), 3.65–3.81 (4H, m), 4.01 (1H, brs),

4.44 (1H, d, J ¼ 11:7 Hz), 4.50 (1H, d, J ¼ 11:7 Hz), 4.53 (1H,

d, J ¼ 12:9 Hz), 4.61 (1H, d, J ¼ 11:5 Hz), 4.64 (1H, d,

J ¼ 12:9 Hz), 4.94 (1H, d, J ¼ 11:5 Hz), 5.27 (1H, dd, J ¼ 6:6,

52.9 Hz, H-1), 5.66–5.76 (1H, m), 7.15–7.36 (17H, m, Ar-H),

7.91 (2H, d, J ¼ 6:8 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ

21.69, 68.42, 71.40 (d, J ¼ 24:8 Hz, C-2), 71:97 ꢅ 2, 73.63,

74.08 (d, J ¼ 5:0 Hz), 74.33, 78.27 (d, J ¼ 8:3 Hz, C-3),

107.58 (d, J ¼ 217:5 Hz, C-1), 126.85–129.92, 137.39, 137.66,

CDCl₃): ꢂ 2.38 (s, CH₃Bz), 2.40 (s, CH₃Bz), 3.43 (dd, J ¼ 5:8,

9.5 Hz), 3.50–3.74 (m), 3.89–4.22 (m), 4.31–4.70 (m), 4.86–

4.97 (m), 5.45 (dd, J ¼ 7:9, 10.1 Hz), 5.55 (bd), 7.16–7.35 (m,

Ar-H), 7.89 (d, J ¼ 7:9 Hz, Ar-H), 7.94 (d, J ¼ 8:2 Hz, Ar-H);

¹³C NMR (125 MHz, CDCl₃): ꢂ 21.60, 68.34, 69.28, 71.54,

72.02, 72.63, 72.79, 73.44, 73.50, 73.63, 74.45, 74.48, 74.52,

74.63, 76.28, 79.30, 90.88, 96.36, 127.23–129.89, 137.57,

138.10, 138.28, 143.61, 165.99; IR (neat): 694, 1018, 1435,

1481, 1731, 1843, 2006, 2368, 3494 cm^ꢂ1; HRMS: m=z calcd

138.07, 143.99, 165.20; IR (KBr) 741, 1126, 1257, 1728 cm^ꢂ1

;

for C₃₅H₃₆O₇NH₄[M + NH₄]^þ586.2805, found 586.2785.

HRMS m=z calcd for C₃₅H₃₅FO₆NH₄[M + NH₄]^þ588.2761,

found 588.2751.

ꢁ

Phenyl 3,4,6-Tri-O-benzyl-2-O-p-toluoyl-ꢁ-D-galactopyra-

nosyl Carbonate (2). To a solution of 15 (7.72 g, 13.6 mmol)

and triethylamine (12.7 mL, 91.1 mmol) in CH₂Cl₂(136 mL)

was added dropwise phenyl chloroformate (1.81 mL, 14.3 mmol)

during 1 h at rt. After stirring for 1 h at the same temperature, the

reaction mixture was quenched by adding sat. aq. NaHCO₃. The

aqueous layer was extracted with CH₂Cl₂. The combined organic

layer was washed with H₂O and brine, and dried over Na₂SO₄.

After ﬁltration and evaporation, the residue was puriﬁed by silica

gel column chromatography and recrystallization to aﬀord 2 (7.87

g, 84%) as colorless solid. R_f0.42 (hexane/CHCl₃/acetone, 10/

Ethyl 3,4,6-Tri-O-acetyl-2-deoxy-2-(4,5-dichlorophthalimi-

To a solution of

do)-1-thio-ꢁ-D-glucopyranoside (18).

1,3,4,6-tetra-O-acetyl-2-deoxy-2-(4,5-dichlorophthalimido)-ꢁ-D-

glucopyranoside 17³⁰(10.0 g, 18.3 mmol) and ethanethiol (5.6

mL, 75.3 mmol) in CH₂Cl₂(50 mL) was added Et₂O BF₃(2.76

ꢁ

ꢃ

mL, 22.0 mmol) at 0 C. The reaction mixture was additionally

stirred for 3 days at rt, and then the mixture was quenched by add-

ing sat. aq. NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂and the combined organic layer was washed with H₂O

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was puriﬁed by silica gel column chromatography

and recrystallization to aﬀord 18 (8.40 g, 84%) as colorless solid.

20

10/1, v/v/v); Mp 111–114 ^ꢃC; ½ꢀꢄ_D+25.6 (c 1.06, CHCl₃);

¹H NMR (500 MHz, CDCl₃) ꢂ 2.43 (3H, s), 3.62–3.76 (3H, m),

3.81 (1H, dd, J ¼ 6:1, 6.1 Hz), 4.07 (1H, brd), 4.44 (1H, d,

J ¼ 11:6 Hz), 4.48 (1H, d, J ¼ 11:6 Hz), 4.51 (1H, d, J ¼ 12:2

Hz), 4.64 (1H, d, J ¼ 11:3 Hz), 4.65 (1H, d, J ¼ 12:2 Hz), 5.00

(1H, d, J ¼ 11:3 Hz), 5.69 (1H, d, J ¼ 8:3 Hz, H-1), 5.84 (1H,

dd, J ¼ 8:3, 9.8 Hz), 7.00 (2H, d, J ¼ 7:6 Hz, Ar-H), 7.10–7.38

R_f0.30 (hexane/ethyl acetate, 2/1, v/v); Mp 118–121 ^ꢃC; ½ꢀꢄ_D

20

+44.2 (c 1.04, CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ 1.22 (3H, t,

J ¼ 7:3 Hz), 1.88 (3H, s), 2.05 (3H, s), 2.11 (3H, s), 2.60–2.75

(2H, m), 3.89 (1H, ddd, J ¼ 2:1, 4.9, 10.1 Hz), 4.18 (1H, dd,

J ¼ 2:1, 12.2 Hz), 4.31 (1H, dd, J ¼ 4:9, 12.2 Hz), 4.35 (1H,

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1841

dd, J ¼ 10:1, 10.4 Hz), 5.18 (1H, dd, J ¼ 9:5, 10.1 Hz), 5.45 (1H,

d, J ¼ 10:4 Hz, H-1), 5.77 (1H, dd, J ¼ 9:5, 10.1 Hz), 7.94 (1H,

s), 7.96 (1H, s); ¹³C NMR (125 MHz, CDCl₃) ꢂ 14.84, 20.42,

20.57, 20.72, 24.38, 54.03, 62.20, 68.62, 71.49, 75.91, 80.93 (C-

1), 125.78-131.79, 139.35, 139.54, 165.20, 165.80, 169.42,

+38.0 (c 1.01, CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ 1.15

(3H, t, J ¼ 7:3 Hz), 2.52–2.68 (2H, m), 3.60–3.89 (4H, m),

4.11–4.23 (2H, m), 4.50 (1H, d, J ¼ 12:2 Hz), 4.58 (1H, d,

J ¼ 11:9 Hz), 4.63 (1H, d, J ¼ 11:9 Hz), 4.78 (1H, d, J ¼ 12:2

Hz), 5.21 (1H, d, J ¼ 10:1 Hz, H-1), 6.90–7.06 (5H, m, Ar-H),

7.25–7.41 (5H, m, Ar-H), 7.68 (1H, s), 7.84 (1H, s); ¹³C NMR

(125 MHz, CDCl₃); ꢂ 14.84, 23.96, 54.71, 70.79, 73.78,

74.59 ꢅ 2, 77.54, 79.53, 80.89 (C-1), 125.34–138.72, 165.47,

165.91; IR (KBr) 741, 1056, 1095, 1134, 1373, 1712, 2861,

2923 cm^ꢂ1; HRMS m=z calcd for C₃₀H₂₉Cl₂NO₆S NH₄[M +

170.25, 170.72; IR (KBr) 1034, 1227, 1381, 1712, 1743 cm^ꢂ1

;

HRMS m=z calcd for C₂₂H₂₃Cl₂NO₉S NH₄[M + NH₄]^þ

565.0814, found 565.0822.

ꢁ

Ethyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-(4,5-dichlo-

rophthalimido)-1-thio-ꢁ-D-glucopyranoside (19). To a solution

of 18 (9.20 g, 16.8 mmol) in MeOH/CH₂Cl₂(90 _ꢃmL, 2/1, v/v)

was added 28% NaOMe (0.75 mL) in MeOH at 0 C. After stir-

ring for 1.5 h at the same temperature, the mixture was acidiﬁed

with p-toluenesulfonic acid monohydrate (until ca. pH 5–6). Af-

ter evaporation, the residue was dried in vacuo. The crude product

was used without further puriﬁcation. To a solution of p-toluene-

sulfonic acid monohydrate (813 mg, 4.27 mmol) in MeCN (200

mL) was added benzaldehyde dimethyl acetal (2.0 mL, 13.3

mmol) at rt. After stirring at the same temperature for 3 h, benz-

aldehyde dimethyl acetal (2.0 mL, 13.3 mmol) was added. After

additional stirring for 5 h, the mixture was quenched by adding

triethylamine (2.0 mL). The mixture was concentrated, diluted

with CH₂Cl₂, and ﬂiltrated to remove insoluble substrate. After

evaporation, the crude product (6.60 g) was obtained by crystalli-

zation; it was used without further puriﬁcation. To a solution of

the crude product (4.12 g) and molecular sieves 4A (4.04 g, acti-

vated) in DMF (20 mL) was added dropwise benzyl bromide (9.66

ꢁ

NH₄]^þ619.1436, found 619.1445.

Phenyl 2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-

thio-ꢁ-D-galactopyranoside (6). To a solution of 2-azido-3-O-

benzyl-4,6-O-benzylidene-2-deoxy-ꢁ-D-glucopyranose 20³¹(793

mg, 2.07 mmol) in CH₂Cl₂/DMF (21 mL, 20/1, v/v) was added

thionyl chloride (0.230 mL, 3.12 mmol) at 0 ^ꢃC. After stirring for

12 h at rt, the mixture was quenched by adding sat. aq. NaHCO₃.

The aqueous layer was extracted with CH₂Cl₂and the combined

organic layer was washed with H₂O and brine, and dried over

Na₂SO₄. After ﬁltration and evaporation, the residue was roughly

puriﬁed by silica gel column chromatography (R_f0.38, hexane/

ethyl acetate, 3/1, v/v) and crystallization (hexane/ethyl

acetate). The crude product (572 mg) was used without further

puriﬁcation. To a solution of 55% NaH (84.7 mg, 1.94 mmol)

oil dispersion in THF (13 mL) was added dropwise benzenethiol

ꢃ

(0.200 mL, 1.94 mmol) at 0 C. After stirring for 30 min at rt,

the crude product (520 mg) was added at 0 ^ꢃC. After stirring

for 3 h at rt, the mixture was ﬁltered through a pad of celite. After

evaporation, the residue was puriﬁed by silica gel column chroma-

tography to aﬀord 6 (611 mg, 71%) as colorless solid. R_f0.20

ꢃ

mL, 80.8 mmol) at 0 C. After stirring for 30 min at the same

temperature, 55% NaH (707 mg, 17.6 mmol) oil dispersion was

added and the reaction mixture was stirred for 30 min. After addi-

tional stirring for 1 h at rt, the reaction mixture was quenched by

adding H₂O. The aqueous layer was extracted with Et₂O. The

combined organic layer was washed with H₂O and brine, and

dried over Na₂SO₄. After ﬁltration and evaporation, the residue

was puriﬁed by silica gel column chromatography and recrystalli-

zation (hexane/ethyl acetate) to aﬀord 19 (3.45 g, 55% from 18)

as white solid. R_f0.50 (hexane/ethyl acetate, 4/1, v/v); Mp 179–

ꢃ

23

(hexane/ethyl acetate, 3/1, v/v); Mp 122–124 C; ½ꢀꢄ_Dꢂ32:0

(c 0.98, CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ 3.38 (1H, brs),

3.44 (1H, dd, J ¼ 3:4, 9.8 Hz), 3.79 (1H, dd, J ¼ 9:8, 9.8 Hz),

3.97 (1H, brd, J ¼ 12:2 Hz), 4.08 (1H, brd, J ¼ 3:4 Hz), 4.33–

4.40 (2H, m, include H-1), 4.70 (2H, s), 5.44 (1H, s), 7.20–7.75

(15H, m, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 59.80, 69.34,

69.86, 71.62, 72.14, 79.57, 85.22 (C-1), 101.16, 126.45–137.61;

IR (KBr); 694, 748, 995, 1095, 1280, 2114 cm^ꢂ1; HRMS m=z

20

181 ^ꢃC; ½ꢀꢄ_D+55.5 (c 1.07, CHCl₃); ¹H NMR (500 MHz,

CDCl₃) ꢂ 1.16 (3H, t, J ¼ 7:3 Hz), 2.60–2.73 (2H, m), 3.65–

3.72 (1H, m), 3.77–3.86 (2H, m), 4.24 (1H, dd, J ¼ 9:8, 10.7

Hz), 4.38–4.44 (2H, m), 4.48 (1H, d, J ¼ 12:5 Hz), 4.80 (1H, d,

J ¼ 12:5 Hz), 5.28 (1H, d, J ¼ 10:7 Hz, H-1), 5.63 (1H, s),

6.90–7.05 (5H, m, Ar-H), 7.35–7.44 (3H, m), 7.52 (2H, dd,

J ¼ 1:2, 7.6 Hz, Ar-H), 7.67 (1H, s, Ar-H), 7.89 (1H, s, Ar-H);

¹³C NMR (125 MHz, CDCl₃) ꢂ 14.84, 24.13, 55.04, 68.07,

70.51, 74.30, 75.43, 81.57 (C-1), 82.93, 101.36, 125.43, 125.54,

126.04, 127.45, 128.12, 128.30, 129.07, 130.61, 137.22, 137.85,

138.75, 138.85, 165.68, 165.68; IR (KBr) 748, 1095, 1373, 1720

calcd for C₂₆H₂₅N₃O₄S H [M + H]^þ476.1644, found 476.1658.

ꢁ

O-(2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-^D-galac-

topyranosyl)-N-(benzyloxycarbonyl)-^L-serine Benzyl Ester

(21). To a stirred suspension of trityl chloride (1.70 mg, 6.00

mmol) and MS 5A (90.0 mg, activated) in toluene (1.00 mL)

was added AgOTf (1.50 mg, 6.00 mmol) at rt. After stirring for

30 min at the same temperature, thioglycoside 6 (14.3 mg, 30.0

mmol), ^L-serine 7 (14.8 mg, 45.0 mmol) and NIS (10.1 mg, 45.0

ꢃ

mmol) were added at ꢂ35 C. After additional stirring for 1.5 h

at the same temperature, the reaction mixture was quenched by

adding sat. aq. NaHCO₃and 10% aq. Na₂S₂O₃. The mixture

was ﬁltered through a pad of celite. The aqueous layer was ex-

tracted with CH₂Cl₂and the combined organic layer was washed

with H₂O and brine, and dried over Na₂SO₄. After ﬁltration and

evaporation, the residue was puriﬁed by preparative TLC (silica

gel) to aﬀord 21ꢀ (16.9 mg, 81%) as colorless solid and 21ꢁ

(3.40 mg, 16%) as colorless solid. The ꢀ=ꢁ ratios were deter-

mined by isolations of both stereoisomers.

cm^ꢂ1; HRMS m=z calcd for C₃₀H₂₇Cl₂NO₆S H [M + H]^þ

ꢁ

600.1014, found 600.1006.

Ethyl 3,6-Di-O-benzyl-2-deoxy-2-(4,5-dichlorophthalimido)-

1-thio-ꢁ-D-glucopyranoside (4). To a solution of 19 (3.62 g,

4.36 mmol) and triethylsilane (3.48 mL, 21.8 mmol) in CH₂Cl₂

(45 mL) was added dropwise triﬂuoroacetic acid (1.68 mL, 21.8

ꢃ

mmol) during 15 min at 0 C. After stirring for 4.5 h at rt, the

mixture was quenched by adding sat. aq. NaHCO₃. The aqueous

layer was extracted with CH₂Cl₂and the combined organic layer

was washed with H₂O and brine, and dried over Na₂SO₄. After

ﬁltration and evaporation, the residue was puriﬁed by silica gel

column chromatography and recrystallization (hexane/ethyl ace-

tate) to aﬀord 4 (2.15 g, 82%) as colorless solid. R_f0.11 (hex-

21ꢀ: R_f0.32 (hexane/ethyl acetate, 2/1, v/v); Mp 123–125

24

1

^ꢃC; ½ꢀꢄ_D+101.5 (c 0.99, CHCl₃); H NMR (400 MHz, CDCl₃)

ꢂ 3.44 (1H, brs), 3.78–4.00 (4H, m), 4.06–4.21 (3H, m), 4.57 (1H,

brd), 4.67 (1H, d, J ¼ 12:2 Hz), 4.71 (1H, d, J ¼ 12:2 Hz), 4.88

(1H, brs, H-1), 5.10 (1H, d, J ¼ 12:2 Hz), 5.13 (1H, d, J ¼ 12:2

Hz), 5.17 (1H, d, J ¼ 12:5 Hz), 5.21 (1H, d, J ¼ 12:5 Hz), 5.40

22

ane/CHCl₃/acetone, 10/10/1, v/v/v); Mp 98–99.5 ^ꢃC; ½ꢀꢄ_D

1842 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

(1H, s), 5.86 (1H, d, J ¼ 8:1 Hz), 7.20–7.55 (20H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃) ꢂ 54.66, 58.54, 63.28, 67.14,

67.72, 69.12, 69.98, 71.18, 72.70, 74.09, 99.95 (C-1), 100.78,

126.11–128.99, 135.08, 136.11, 137.47, 137.76, 155.90, 169.73;

4.68 (1H, d, J ¼ 11:2 Hz), 4.72 (1H, d, J ¼ 11:2 Hz), 4.84 (1H,

d, J ¼ 3:2 Hz, H-1), 4.87 (1H, d, J ¼ 11:5 Hz), 5.11 (2H, s),

5.18 (1H, d, J ¼ 12:0 Hz), 5.22 (1H, d, J ¼ 12:0 Hz), 5.99 (1H,

d, J ¼ 8:1 Hz), 7.25–7.50 (20H, m, Ar-H); ¹³C NMR (125 MHz,

CDCl₃); ꢂ 54.72, 59.62, 62.18, 67.12, 67:67 ꢅ 2, 70.09, 71.60,

72.40, 72.94, 74.52, 77.07, 99.72 (C-1), 127.82–137.35, 155.90,

169.87; IR (KBr) 733, 1072, 1134, 1242, 1281, 1535, 1689,

IR (KBr) 694, 741, 1057, 1281, 1543, 1689, 1736, 2106 cm^ꢂ1

;

HRMS m=z calcd for C₃₈H₃₈N₄O₉H [M + H]^þ695.2717, found

695.2733.

ꢁ

21ꢁ: R_f0.12 (hexane/ethyl acetate, 2/1, v/v); Mp 119–121

1736, 2106 cm^ꢂ1; HRMS m=z calcd for C₃₈H₄₀N₄O₉Na [M +

ꢁ

23

1

^ꢃC; ½ꢀꢄ_D+13.8 (c 0.72, CHCl₃); H NMR (500 MHz, CDCl₃)

ꢂ 3.13 (1H, brs), 3.30 (1H, dd, J ¼ 2:8, 10.1 Hz), 3.80 (1H, dd,

J ¼ 8:4, 9.2 Hz), 3.89 (1H, dd, J ¼ 2:4, 10.1 Hz), 3.94 (1H,

brd), 4.03 (1H, brd), 4.18 (1H, d, J ¼ 8:4 Hz, H-1), 4.23 (1H,

brd), 4.40 (1H, brd), 4.58 (1H, brd), 4.72 (2H, s), 5.11 (1H, d, J ¼

11:9 Hz), 5.14 (1H, d, J ¼ 11:9 Hz), 5.18 (1H, d, J ¼ 12:2 Hz),

5.22 (1H, d, J ¼ 12:2 Hz), 5.46 (1H, s), 5.89 (1H, d, J ¼ 7:9

Hz), 7.20–7.56 (20H, m, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ

54.42, 61.86, 66.52, 66.92, 67.48, 68.87, 69.49, 71.45, 72.20,

77.53, 101.02, 102.38 (C-1), 126.26–128.99, 135.24, 136.33,

137.55, 137.57, 156.01, 169.49; IR (KBr) 694, 741, 1065, 1697,

Na]^þ719.2693, found 719.2710.

Ethyl 3,6-Di-O-benzyl-4-O-(3⁰,4⁰,6⁰-tri-O-benzyl-2⁰-O-p-tol-

uoyl-ꢁ-D-galactopyranosyl)-2-deoxy-2-(4,5-dichlorophthalimi-

do)-1-thio-ꢁ-D-glucopyranoside (24). This compound was syn-

thesized from glycosyl donor 2 and glycosyl acceptor 4 as color-

less solid (see experimental: compound 25). R_f0.32 (hexane/

21

CHCl₃/acetone, 10/10/1, v/v/v); ½ꢀꢄ_D+26.1 (c 0.91, CHCl₃);

¹H NMR (500 MHz, CDCl₃) ꢂ 1.10 (3H, t, J ¼ 7:4 Hz), 2.44 (3H,

s), 2.46–2.61 (2H, m), 3.37 (1H, dd, J ¼ 1:8, 9.8 Hz), 3.45–3.55

(5H, m), 3.64 (1H, dd, J ¼ 3:7, 11.0 Hz), 3.97–4.02 (2H, m),

4.11–4.24 (2H, m), 4.28–4.49 (5H, m), 4.53 (1H, d, J ¼ 11:6

Hz), 4.59–4.65 (3H, m, include H-1⁰), 4.88 (1H, d, J ¼ 12:5

Hz), 4.96 (1H, d, J ¼ 11:6 Hz), 5.06 (1H, d, J ¼ 10:1 Hz, H-1),

5.62 (1H, dd, J ¼ 7:9, 10.4 Hz), 6.83–6.90 (3H, m, Ar-H), 6.97

(2H, dd, J ¼ 1:7, 7.6 Hz, Ar-H), 7.14–7.37 (22H, m, Ar-H),

7.66 (1H, s), 7.81 (1H, s), 7.87 (2H, d, J ¼ 8:2, Ar-H); ¹³C NMR

(125 MHz, CDCl₃) ꢂ 14.85, 21.68, 23.93, 55.15, 67.92, 68.19,

71.05, 72.25, 72.58, 73.25, 73.34, 73.46, 74.39, 74.90, 77.54,

78.12, 78.93, 79.70, 80.76 (C-1), 100.83 (C-1⁰), 125.34–143.80,

165.10, 165.51, 165.74; IR (KBr) 741, 1095, 1265, 1373, 1720

1728, 2114 cm^ꢂ1; HRMS m=z calcd for C₃₈H₃₈N₄O₉H [M +

ꢁ

H]^þ695.2717, found 695.2711.

O-(2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-ꢀ-D-galac-

topyranosyl)-N-(benzyloxycarbonyl)-^L-threonine Benzyl Ester

(23). To a stirred suspension of trityl chloride (1.70 mg, 6.00

mmol) and MS 5A (90.0 mg, activated) in toluene (1.00 mL) was

added AgOTf (1.50 mg, 6.00 mmol) at rt. After stirring for 30 min

at the same temperature, thioglycoside 6 (14.3 mg, 30.0 mmol), ^L-

threonine 22 (15.5 mg, 45.0 mmol) and NIS (10.1 mg, 45.0 mmol)

ꢃ

were added at ꢂ35 C. After stirring for 5 h at the same temper-

cm^ꢂ1; HRMS m=z calcd for C₆₅H₆₃Cl₂NO₁₂S NH₄[M + NH₄]^þ

ꢁ

ature and for 30 min at ꢂ20 ^ꢃC, the reaction mixture was

quenched by adding sat. aq. NaHCO₃and 10% aq. Na₂S₂O₃.

The mixture was ﬁltered through a pad of celite. The aqueous lay-

er was extracted with CH₂Cl₂and the combined organic layer was

washed with H₂O and brine, and dried over Na₂SO₄. After ﬁltra-

tion and evaporation, the residue was puriﬁed by preparative TLC

(silica gel) to aﬀord a single ꢀ-isomer 23 (17.5 mg, 82%) as col-

1169.3792, found 1169.3815.

O-[2-Azido-3,4-di-O-benzyl-6-O-{3⁰,6⁰-di-O-benzyl-2⁰-de-

oxy-2⁰-(4,5-dichlorophthalimido)-4⁰-O-(3⁰⁰,4⁰⁰,6⁰⁰-tri-O-benzyl-

2⁰⁰-O-p-toluoyl-ꢁ-D-galactopyranosyl)-ꢁ-D-glucopyranosyl}-2-

deoxy-ꢀ-D-galactopyranosyl]-N-(benzyloxycarbonyl)-L-serine

Benzyl Ester (25). Condition A: To a stirred suspension of MS

5A (150 mg, activated), 2 (37.2 mg, 54.0 mmol), and glycosyl ac-

ceptor 4 (18.1 mg, 30.0 mmol) in BTF (2.5 mL) was added

25

orless amorphous material. ½ꢀꢄ_D+106.0 (c 1.11, CHCl₃);

¹H NMR (500 MHz, CDCl₃) ꢂ 1.27 (3H, d, J ¼ 6:4 Hz), 3.52

(1H, brs), 3.80–3.89 (2H, m), 3.96 (1H, brd), 4.13 (1H, brs),

4.17 (1H, brd), 4.38–4.45 (2H, m), 4.68 (1H, d, J ¼ 11:9 Hz),

4.73 (1H, d, J ¼ 11:9 Hz), 4.90 (1H, d, J ¼ 3:1 Hz, H-1), 5.10–

5.25 (4H, m), 5.42 (1H, s), 5.64 (1H, d, J ¼ 9:5 Hz), 7.20–7.52

(20H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 18.57, 58.82,

59.02, 63.20, 67.24, 67.69, 69.21, 71.29, 72.76, 74.63, 76.47,

99.27 (C-1), 100.86, 126.13–137.79, 156.77, 170.01; IR (KBr)

TrB(C₆F₅)₄(8.30 mg, 9.0 mmol) at ꢂ15 C. After stirring for 5

ꢃ

h at the same temperature, the completion of the ﬁrst glycosyla-

tion reaction was monitored by TLC, CH₂Cl₂(0.6 mL), 5 (105

mg, 0.150 mmol), and NIS (13.5 mg, 60.0 mmol) were successive-

ly added at ꢂ35 ^ꢃC. The reaction mixture was stirred for an addi-

tional 2 h at the same temperature; then the reaction mixture was

quenched by adding sat. aq. NaHCO₃and 10% aq. Na₂S₂O₃. The

mixture was ﬁltered through a pad of celite. The aqueous layer

was extracted with CH₂Cl₂and the combined organic layer was

washed with H₂O and brine, and dried over Na₂SO₄. After ﬁltra-

tion and evaporation, the residue was puriﬁed by preparative TLC

(silica gel) to aﬀord 25 (42.9 mg, 80%) as colorless solid.

Condition B: To a stirred suspension of MS 5A (90 mg, activat-

ed), 3 (20.5 mg, 36.0 mmol), and glycosyl acceptor 4 (18.1 mg,

30.0 mmol) in CH₂Cl₂(1.0 mL) was added a solution of TfOH

(0.90 mg, 6.0 mmol) in toluene (0.100 mL) at ꢂ20 ^ꢃC. After stir-

ring for 1 h at the same temperature, the completion of the ﬁrst

glycosylation reaction was monitored by TLC, CH₂Cl₂(0.6

mL), 5 (31.4 mg, 45.0 mmol_ꢃ), and NIS (13.5 mg, 60.0 mmol) were

successively added at ꢂ35 C. The reaction mixture was stirred

for an additional 1 h at the same temperature; then the reaction

mixture was quenched by adding sat. aq. NaHCO₃and 10% aq.

Na₂S₂O₃. The mixture was ﬁltered through a pad of celite.

The aqueous layer was extracted with CH₂Cl₂and the combined

organic layer was washed with H₂O and brine, and dried over

1728, 2114 cm^ꢂ1; HRMS m=z calcd for C₃₉H₄₀N₄O₉H [M +

ꢁ

H]^þ709.2874, found 709.2853.

O-(2-Azido-3,4-di-O-benzyl-2-deoxy-ꢀ-D-galactopyranosyl)-

N-(benzyloxycarbonyl)-^L-serine Benzyl Ester (5). To a solu-

tion of 21ꢀ (1.01 g, 1.45 mmol) and triethylamine–borane (1/1)

(4.29 mL, 29.0 mmol) in CH₂Cl₂(14.5 mL) was added dropwise

ꢃ

Et₂O BF₃(0.460 mL, 3.63 mmol) during 10 min at 0 C. After

ꢁ

stirring for 1 h at rt, the reaction mixture was quenched by adding

sat. aq. NaHCO₃. The aqueous layer was extracted with CH₂Cl₂

and the combined organic layer was washed with H₂O and brine,

and dried over Na₂SO₄. After ﬁltration and evaporation, the res-

idue was puriﬁed by silica-gel column chromatography to aﬀord 5

(612 mg, 61%) as colorless solid. R_f0.13 (hexane/ethyl acetate,

2/1, v/v); Mp 97–97.5 ^ꢃC; ½ꢀꢄ_D+79.1 (c 1.11, CHCl₃);

24

¹H NMR (500 MHz, CDCl₃) ꢂ 3.46 (1H, dd, J ¼ 4:6, 11.0 Hz),

3.60–3.90 (5H, m), 3.94 (1H, dd, J ¼ 2:4, 10.7 Hz), 4.16 (1H,

dd, J ¼ 2:9, 10.7 Hz), 4.54 (1H, d, J ¼ 11:5 Hz), 4.58 (1H, m),

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1843

Na₂SO₄. After ﬁltration and evaporation, the residue was puriﬁed

by preparative TLC (silica gel) to aﬀord 25 (47.6 mg, 89%) as col-

orless solid. R_f0.34 (hexane/ethyl acetate, 2/1, v/v); ½ꢀꢄ_D

MHz, CDCl₃) ꢂ 1.84 (3H, s), 1.93 (3H, s), 2.37 (3H, s), 3.97

(1H, brs), 3.31–4.09 (17H, m), 4.15–4.80 (18H, m), 4.97 (1H, d,

J ¼ 11:5 Hz), 5.00–5.20 (4H, m), 5.26 (1H, d, J ¼ 8:3 Hz),

5.59 (1H, dd, J ¼ 8:3, 9.8 Hz), 6.06 (2H, brd), 7.10–7.45 (47H,

m, Ar-H), 7.84 (2H, d, J ¼ 8:3 Hz, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) ꢂ 21.70, 23.24, 23.34, 48.85, 52.66, 54.41, 67.14, 67.35,

67.99, 69.08, 70.13, 71.36, 71:69 ꢅ 2, 72.12, 72.53, 72.64,

73.22, 73:51 ꢅ 2, 73:55 ꢅ 2, 73.64, 74.08, 74.71, 74.99, 76.73,

78.74, 79.20, (98.72, 99.45, 100.87) (anomeric positions),

126.89–138.62, 144.39, 155.99, 166.02, 169.87, 170.15; IR

24

+37.7 (c 1.01, CHCl₃); ¹H NMR (500 MHz, CDCl₃); ꢂ 2.44

(3H, s), 3.23 (1H, brd), 3.35–3.69 (12H, m), 3.71–3.80 (2H, m),

3.97 (1H, brd), 4.02 (1H, dd, J ¼ 8:5, 9.8 Hz), 4.05–4.20 (3H,

m), 4.30 (1H, d, J ¼ 11:9 Hz), 4.33–4.64 (12H, m), 4.66 (1H, d,

J ¼ 11:3 Hz), 4.86 (1H, d, J ¼ 12:5 Hz), 4.92–5.15 (6H, m, in-

cluding H-1⁰), 5.62 (1H, dd, J ¼ 8:0, 10.1 Hz), 5.83 (1H, d,

J ¼ 8:6 Hz), 6.82–6.94 (5H, m, Ar-H), 7.14–7.40 (42H, m, Ar-

H), 7.66 (1H, s), 7.76 (1H, s), 7.84 (2H, d, J ¼ 8:3 Hz); ¹³C NMR

(125 MHz, CDCl₃); ꢂ 21.68, 54.29, 55.98, 59.20, 66.86, 66.96,

67:28 ꢅ 2, 67.50, 68.03, 69.30, 69.53, 71.19, 71.71, 72.08,

72.39, 73.17, 73.22, 73.40, 74:35 ꢅ 2, 74.54, 74.74, 76.52,

76.88, 77.32, 79.47, (97.75, 99.22, 100.62) (anomeric positions),

125.07–130.65, 135.01–138.84, 143.82, 155.89, 164.99, 165.59,

165.88, 169.52; IR (KBr) 702, 741, 1057, 1095, 1265, 1381,

(KBr) 694, 741, 1057, 1095, 1265, 1535, 1666, 1728 cm^ꢂ1

;

HRMS m=z calcd for C₉₇H₁₀₃N₃O₂₁H [M + H]^þ1646.7162,

ꢁ

found 1646.7141.

O-[2-Acetamido-6-O-{2⁰-acetamido-2⁰-deoxy-4⁰-O-(ꢁ-D-ga-

lactopyranosyl)-ꢁ-D-glucopyranosyl}-2-deoxy-ꢀ-D-galactopy-

ranosyl]-^L-serine (1). To a solution of 27 (51.2 mg, 31.1 mmol)

in THF/CH₂Cl₂/H₂O (4 mL, 4/2/1, v/v/v) was added palladium

(b) hydroxide (76.7 mg, 20 wt % on carbon). After purging with

H₂(1:01 ꢅ 10⁵Pa) and stirring for 42 h, H₂was removed. Then

the catalyst was ﬁltered oﬀ and the mixture was evaporated in

vacuo. The crude residue was used without further puriﬁcation.

To a solution of the crude product in MeOH (0.8 mL) was added

1720, 2106 cm^ꢂ1; HRMS m=z calcd for C₁₀₁H₉₇Cl₂N₅O₂₁NH₄

ꢁ

[M + NH₄]^þ1803.6397, found 1803.6447.

O-[2-Acetamido-3,4-di-O-benzyl-6-O-{3⁰,6⁰-di-O-benzyl-2⁰-

deoxy-2⁰-(4,5-dichlorophthalimido)-4⁰-O-(3⁰⁰,4⁰⁰,6⁰⁰-tri-O-ben-

zyl-2⁰⁰-O-p-toluoyl-ꢁ-D-galactopyranosyl)-ꢁ-D-glucopyrano-

syl}-2-deoxy-ꢀ-D-galactopyranosyl]-N-(benzyloxycarbonyl)-L-

serine Benzyl Ester (26). To a solution of 25 (335 mg, 187

mmol) in pyridine (1.5 mL) was added thioacetic acid (1.5 mL,

distilled) at 0 ^ꢃC. After stirring for 7 h at rt, the reaction mixture

was diluted with ethyl acetate and 1 M aq. HCl. The aqueous lay-

er was extracted with ethyl acetate and the combined organic layer

was washed with 1 M aq. HCl, sat. aq. NaHCO₃, H₂O and brine,

and dried over Na₂SO₄. After ﬁltration and evaporation, the res-

idue was puriﬁed by preparative TLC (silica gel) to aﬀord 26 (285

mg, 85%) as yellow solid. R_f0.44 (hexane/ethyl acetate, 1/2, v/

ꢃ

0.1 M aq. NaOH (1.6 mL, 0.16 mmol) at 0 C. After stirring for

2.5 h at the same temperature, an excess amount of Dowex

50WX-8 was added; then the mixture was puriﬁed by ion-ex-

change column chromatography (MeOH, then aq. NH₃) and re-

versed-phase column chromatography (H₂O) to aﬀord 1 (17.7

mg, 84% from 27) as colorless solid. R_f0.06 (CH₃CN/AcOH/

20

H₂O, 3/1/1, v/v/v); ½ꢀꢄ_D¼ þ54:0 (c 0.1, H₂O); ¹H NMR

(500 MHz, CDCl₃) ꢂ 1.82 (3H, s, Ac), 1.83 (3H, s, Ac), 3.33

(1H, dd, J ¼ 7:9, 9.8, H-2⁰⁰), 3.38–3.42 (1H, m, H-5⁰), 3.45 (1H,

dd, J ¼ 3:4, 10.1 Hz, H-3⁰⁰), 3.47–3.59 (7H, m, H-2⁰, H-3⁰, H-

4⁰, H-5⁰⁰, H-6, H-6⁰, H-6⁰⁰), 3.63 (1H, dd, J ¼ 4:9, 12.2 Hz, H-

6⁰), 3.66–3.73 (3H, m, H-3, H-4⁰⁰, Ser), 3.74–3.84 (5H, m, H-4,

H-5, H-6⁰), 3.86 (1H, dd, J ¼ 3:4, 10.4 Hz, H-6), 3.96 (1H, dd,

J ¼ 3:7, 11.0 Hz, H-2), 4.26 (1H, d, J ¼ 7:9 Hz, H-1⁰⁰), 4.36

(1H, d, J ¼ 7:6 Hz, H-1⁰), 4.67 (1H, d, J ¼ 3:7 Hz, H-1);

¹³C NMR (125 MHz, CDCl₃) ꢂ 21.7 (CH₃CO), 21.9 (CH₃CO),

49.2 (C-2), 54.1 (Ser C(NH₂)COOH), 54.7 (C-2⁰), 59.7 (C-6⁰),

60.7 (C-6⁰⁰), 66.3 (Ser OCH₂), 67.0 (C-3), 68.1 (C-4), 68.2 (C-

4⁰⁰), 69.4 (C-6), 69.6 (C-5), 70.6 (C-2⁰⁰), 72.0 (C-3⁰), 72.2 (C-

3⁰⁰), 74.4 (C-5⁰), 75.0 (C-5⁰⁰), 78.2 (C-4⁰), 97.7 (C-1), 101.1 (C-

1⁰), 102.5 (C-1⁰⁰), 171.4 (COOH), 174.2 (C=O), 174.4 (C=O);

FT-IR (KBr) 1049, 1072, 1643 cm^ꢂ1; HRMS m=z calcd for

v); ½ꢀꢄ_D+35.3 (c 0.71, CHCl₃); ¹H NMR (500 MHz, CDCl₃); ꢂ

24

1.80 (3H, s), 2.44 (3H, s), 3.20–3.74 (14H, m), 3.96–4.09 (3H, m),

4.13–4.27 (3H, m), 4.31 (1H, d, J ¼ 11:6 Hz), 4.34–4.64 (12H,

m), 4.75 (1H, d, J ¼ 11:6 Hz), 4.87 (1H, d, J ¼ 12:8 Hz), 4.93

(1H, d, J ¼ 8:5 Hz, H-1⁰), 4.96 (1H, d, J ¼ 11:9 Hz), 4.99–5.16

(4H, m), 5.18 (1H, d, J ¼ 7:6 Hz), 5.62 (1H, dd, J ¼ 8:5, 9.5

Hz), 5.69 (1H, d, J ¼ 8:5 Hz), 6.82–6.96 (5H, m, Ar-H), 7.10–

7.42 (42H, m, Ar-H), 7.63 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J ¼

7:9 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃); ꢂ 21.64, 23.21,

48.60, 54.71, 56.14, 67.11, 67.26, 67.57, 67:80 ꢅ 2, 68.09,

68.40, 69.93, 71.30, 71:34 ꢅ 2, 72.04, 72.13, 72.51, 73.24,

73.39, 74.07, 74.34, 74.71, 76.85, 76.92, 77.00, 79.58, (97.77,

98.75, 100.65) (anomeric positions), 125.41–129.83, 134.84,

136.00, 137.69–138.88, 143.78, 165.00, 165.67, 165.80, 169.66,

169.92; IR (KBr) 694, 741, 1057, 1095, 1265, 1381, 1720

C₂₅H₄₃N₃O₁₈H [M + H]^þ674.2620, found 674.2626; Anal.

ꢁ

calcd for C₂₅H₄₃N₃O₁₈3H₂O: C, 41.26, H, 6.79; N, 5.77%,

found: C, 41.46; H, 7.17; N, 5.97%.

ꢁ

cm^ꢂ1; HRMS m=z calcd for C₁₀₃H₁₀₁Cl₂N₃O₂₂H [M + H]^þ

3,4,6-Tri-O-benzyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl Fluo-

ride (31). To a solution of 3,4,6-tri-O-benzyl-2-O-p-toluoyl-ꢁ-

D-glucopyranose²³(13.8 g, 24.2 mmol) in CH₂Cl₂(100 mL)

was added dropwise (diethylamino)sulfur triﬂuoride (3.84 mL,

29.1 mmol) at ꢂ35 ^ꢃC. After stirring for 1 h at the same temper-

ature, the reaction mixture was quenched by adding MeOH and

sat. aq. NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂. The combined organic layer was washed with H₂O

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was puriﬁed by silica gel column chromatography

and crystallization to aﬀord 31 (6.04 g, 44%, 1st crop) as colorless

solid. R_f0.45 (hexane/ethyl acetate, 3/1, v/v), Mp 84–85 ^ꢃC;

ꢁ

1802.6332, found 1802.6310.

O-[2-Acetamido-3,4-di-O-benzyl-6-O-{2⁰-acetamido-3⁰,6⁰-di-

O-benzyl-4⁰-O-(3⁰⁰,4⁰⁰,6⁰⁰-tri-O-benzyl-2⁰⁰-O-p-toluoyl-ꢁ-D-galac-

topyranosyl)-2⁰-deoxy-ꢁ-D-glucopyranosyl}-2-deoxy-ꢀ-D-galac-

topyranosyl]-N-(benzyloxycarbonyl)-^L-serine Benzyl Ester

(27). To a solution of 26 (268 mg, 0.148 mmol) in EtOH (7.4

mL) was added hydrazine acetate (137 mg, 1.48 mmol) at rt. Af-

ter stirring for 2 h at 70 ^ꢃC, the reaction mixture was diluted with

CHCl₃and water. The aqueous layer was extracted with CHCl₃

and the combined organic layer was washed with brine, and dried

over Na₂SO₄. After ﬁltration and evaporation, the residue was pu-

riﬁed by silica gel column chromatography to aﬀord 27 (199 mg,

82%) as colorless solid. R_f0.13 (hexane/ethyl acetate, 1/2, v/v);

15

½ꢀꢄ_D+68.0 (c 0.71, CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ

2.41 (3H, s), 3.71–3.86 (4H, m), 3.94 (1H, dd, J ¼ 8:5, 8.5 Hz),

17

Mp 169–171 ^ꢃC; ½ꢀꢄ_D+35.3 (c 1.00, CHCl₃); ¹H NMR (400

4.52–4.81 (6H, m), 5.33–5.52 (2H, m, including anomeric posi-

1844 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

tion), 7.10–7.38 (17H, m, Ar-H), 7.91 (2H, d, J ¼ 8:1 Hz, Ar-H);

¹³C NMR (125 MHz, CDCl₃) ꢂ 21.67, 68.47, 72.77 (d, J ¼ 28:9

Hz), 73.52, 74.18, 74.80, 74.92, 76.47, 81.39 (d, J ¼ 7:4 Hz),

106.74 (d, J ¼ 218:33 Hz, anomeric position), 126.42–129.85,

137.42, 137.63, 137.77, 144.22, 165.04; IR (KBr) 748, 1111,

J ¼ 5:6, 9.8 Hz), 5.62 (1H, dd, J ¼ 9:8, 10.0 Hz), 5.96 (1H, d,

J ¼ 5:6 Hz, anomeric position), 6.11 (1H, dd, J ¼ 9:8, 9.8 Hz),

7.55–7.71 (6H, m, Ar-H), 8.00 (2H, d, J ¼ 8:0 Hz, Ar-H), 8.06–

8.14 (4H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃, major signals)

ꢂ 14.67, 24.51, 60.97, 69.71, 70.00, 71.42, 71.85, 81.92 (anomeric

position), 119.10–135.46, 164.16, 164.55, 164.95; IR (KBr) 694,

771, 856, 1118, 1265, 1327, 1736, 2954 cm^ꢂ1; HRMS m=z calcd

1712 cm^ꢂ1; HRMS m=z calcd for C₃₅H₃₅FO₆Na [M + Na]^þ

ꢁ

593.2315, found 593.2339.

Ethyl

2,3,4-Tri-O-benzoyl-1-thio-ꢀ-D-glucopyranoside

for C₃₂H₂₅F₉O₈S Na [M + Na]^þ763.1024, found 763.1008.

ꢁ

(33b). To a solution of ethyl 1-thio-ꢀ-D-glucopyranoside (2.00

g, 8.92 mmol) and 4-dimethylaminopyridine (327 mg, 2.68 mmol)

in pyridine/DMF (25 mL, 5/1, v/v) was added t-butyldiphenylsi-

lyl chloride (2.55 mL, 9.81 mmol) at rt; the reaction mixture was

stirred for 1.5 h at the same temperature. After additional stirring

for 1 h at 60 ^ꢃC, the completion of the ﬁrst reaction was monitored

by TLC; benzoyl chloride (3.60 mL, 31.2 mmol) was successively

added at 0 ^ꢃC. After stirring for 3 h at rt, the reaction mixture was

quenched by adding sat. aq. NaHCO₃. The aqueous layer was ex-

tracted with Et₂O. The combined organic layer was washed with

0.1 M aq. NaOH, 0.1 M aq. HCl, H₂O, and brine, and dried over

Na₂SO₄. After ﬁltration and evaporation, the residue was dried in

vacuo. The crude product was used without further puriﬁcation.

To a solution of the crude product in THF (12.5 mL) were added

acetic acid (1.43 mL) and tetrabutylammonium ﬂuoride (12.5 mL,

1 M in THF) at rt. After stirring for 38 h at the same temperature,

the reaction mixture was diluted with Et₂O. The organic layer

was washed with H₂O and brine, and dried over Na₂SO₄. After

ﬁltration and evaporation, the residue was puriﬁed by silica gel

column chromatography to aﬀord 33b (3.30 g, 69%, 3 steps) as

colorless solid. R_f0.12 (hexane/ethyl acetate, 3/1, v/v); Mp

Ethyl 2-O-Benzoyl-4-O-benzyl-3-O-chloroacetyl-1-thio-ꢀ-D-

glucopyranoside (39). To a solution of ethyl 2-O-benzoyl-4,6-

O-benzylidene-3-O-chloroacetyl-1-thio-ꢀ-D-glucopyranoside

38⁴⁴(3.63 g, 7.36 mmol) and triethylamine–borane (1/1) (11.6

mL, 73.6 mmol) in CH₂Cl₂(14.5 mL) was added dropwise a solu-

46

tion of AlCl₃(1.96 g, 14.7 mmol) in Et₂O at 0 ^ꢃC. After stirring

for 30 min at rt, the reaction mixture was quenched by adding sat.

aq. NaHCO₃. The mixture was ﬁltered with a pad of celite. The

aqueous layer was extracted with CH₂Cl₂. The combined organic

layer was washed with H₂O and brine, and dried over Na₂SO₄.

After ﬁltration and evaporation, the residue was puriﬁed by silica

gel column chromatography and recrystallization (hexane/ethyl

acetate) to aﬀord 39 (2.07 g, 57%, 1st crop) as colorless solid.

R_f0.16 (hexane/ethyl acetate, 3/1, v/v); Mp 102–104 ^ꢃC;

16

½ꢀꢄ_D+158.8 (c 0.38, CHCl₃); ¹H NMR (400 MHz, CDCl₃) ꢂ

1.21 (3H, t, J ¼ 7:3 Hz), 2.45–2.61 (2H, m), 3.67 (1H, d,

J ¼ 14:6 Hz), 3.76 (1H, d, J ¼ 14:6 Hz), 3.85 (1H, dd, J ¼ 9:8,

9.8 Hz), 3.89 (2H, brs), 4.24 (1H, ddd, J ¼ 2:4, 2.7, 9.8 Hz),

4.64 (1H, d, J ¼ 11:5 Hz), 4.74 (1H, dd, J ¼ 11:5 Hz), 5.15

(1H, dd, J ¼ 5:7, 10.0 Hz), 5.66 (1H, dd, J ¼ 9:8, 10.0 Hz),

5.78 (1H, d, J ¼ 5:7 Hz, anomeric position), 7.25–7.61 (8H, m,

Ar-H), 7.99 (2H, d, J ¼ 7:6 Hz, Ar-H); ¹³C NMR (100 MHz,

CDCl₃) ꢂ 14.61, 24.26, 40.41, 61.18, 71.12, 71.65, 74.15, 74.69,

75.18, 81.78 (anomeric position), 128.04–137.60, 165.46,

14

114–115 ^ꢃC; ½ꢀꢄ_D+87.5 (c 1.00, CHCl₃); ¹H NMR (500

MHz, CDCl₃) ꢂ 1.27 (3H, t, J ¼ 7:3 Hz), 2.55–2.67 (2H, m),

3.77 (1H, dd, J ¼ 3:3, 12.8 Hz), 3.83 (1H, dd, J ¼ 2:1, 12.8

Hz), 4.49 (1H, ddd, J ¼ 2:1, 3.3, 10.1 Hz), 5.48–5.56 (2H, m),

5.97 (1H, d, J ¼ 5:8 Hz, anomeric position), 6.13 (1H, dd,

J ¼ 9:8, 9.8 Hz), 7.25–7.55 (9H, m, Ar-H), 7.86–8.01 (6H, m,

Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 14.59, 24.30, 60.99,

69.49, 70.20, 70.62, 71.62, 82.09 (anomeric position), 128.23–

129.92, 133.12, 133.37, 133.65, 165.33, 165.58, 166.35; IR

(KBr) 702, 1018, 1126, 1157, 1311, 1736 cm^ꢂ1; HRMS m=z calcd

166.37; IR (KBr) 755, 1095, 1273, 1728, 2815, 2985 cm^ꢂ1

;

HRMS m=z calcd for C₂₄H₂₇ClO₇S H [M + H]^þ495.1244, found

495.1239.

ꢁ

Ethyl 2-O-Benzoyl-4-O-benzyl-1-thio-ꢀ-D-glucopyranoside

(32). To a solution of 39 (30.0 mg, 60.6 mmol) in DMF (0.6

mL) was added thiourea (9.20 mg, 0.12 mmol). After stirring

for 3 h at 70 ^ꢃC, the reaction mixture was diluted with Et₂O

and H₂O. The aqueous layer was extracted with Et₂O and the

combined organic layer was washed with H₂O and brine, and

dried over Na₂SO₄. After ﬁltration and evaporation, the residue

was puriﬁed by silica gel column chromatography and crystalliza-

tion (hexane/ethyl acetate) to aﬀord 32 (10.8 mg, 43%) as color-

less solid. R_f0.28 (hexane/ethyl acetate, 2/1, v/v); Mp 117–119

for C₂₉H₂₈O₈S H [M + H]^þ537.1583, found 537.1573.

ꢁ

Ethyl 2,3,4-Tri-O-p-chlorobenzoyl-1-thio-ꢀ-D-glucopyrano-

side (33c). This compound was synthesized as colorless solid ac-

cording to the above-mentioned procedure (see experimental:

compound 33b). R_f0.38 (hexane/ethyl acetate, 2/1, v/v), Mp

15

135–136 ^ꢃC; ½ꢀꢄ_D+66.1 (c 1.00, CHCl₃); ¹H NMR (400

16

1

MHz, CDCl₃) ꢂ 1.28 (3H, t, J ¼ 7:3 Hz), 2.43–2.70 (2H, m),

3.75 (1H, dd, J ¼ 2:9, 12.9 Hz), 3.83 (1H, brd), 4.47 (1H, brd),

5.44–5.54 (2H, m), 5.92 (1H, d, J ¼ 5:9 Hz, anomeric position),

6.04 (1H, dd, J ¼ 9:8, 10.0 Hz), 7.26–7.41 (6H, m, Ar-H),

7.78–7.94 (6H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) ꢂ 14.62,

24.38, 60.92, 69.50, 70.01, 70.92, 71.56, 81.96 (anomeric posi-

tion), 126.74–131.31, 139.95, 140.13, 140.43, 164.45, 164.78,

^ꢃC; ½ꢀꢄ_D+164.1 (c 1.00, CHCl₃); H NMR (500 MHz, CDCl₃)

ꢂ 1.22 (3H, t, J ¼ 7:3 Hz), 2.47–2.59 (2H, m), 3.63 (1H, dd,

J ¼ 9:5, 9.8 Hz), 3.84 (1H, dd, J ¼ 3:4, 11.9 Hz), 3.87 (1H, dd,

J ¼ 2:8, 11.9 Hz), 4.15 (1H, ddd, J ¼ 2:8, 3.4, 9.8 Hz), 4.19

(1H, dd, J ¼ 9:5, 9.5 Hz), 4.79 (1H, d, J ¼ 11:6 Hz), 4.88 (1H,

d, J ¼ 11:6 Hz), 5.11 (1H, dd, J ¼ 5:8, 9.5 Hz), 5.70 (1H, d, J ¼

5:8 Hz, anomeric position), 7.26–7.60 (8H, m, Ar-H), 8.07 (2H, d,

J ¼ 8:5 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 14.70, 24.29,

61.64, 70.86, 72.60, 73.60, 74.80, 77.44, 81.86 (anomeric posi-

tion), 127.99–138.01, 165.96; IR (KBr) 702, 1103, 1265, 1728,

165.39; IR (KBr) 764, 1095, 1273, 1713, 1728, 2947 cm^ꢂ1

;

HRMS m=z calcd for C₂₉H₂₅Cl₃O₈S H [M + H]^þ639.0414,

found 639.0395.

ꢁ

Ethyl

1-Thio-2,3,4-tri-O-p-(triﬂuoromethyl)benzoyl-ꢀ-D-

3294 cm^ꢂ1; HRMS m=z calcd for C₂₂H₂₆O₆S Na [M + Na]^þ

ꢁ

glucopyranoside (33d). This compound was synthesized as col-

orless solid according to the above-mentioned procedure (see ex-

perimental: compound 33b). R_f0.40 (hexane/ethyl acetate, 2/1,

441.1348, found 441.1349.

Ethyl 2-O-Benzoyl-4-O-benzyl-6-O-t-butyldiphenylsilyl-1-

thio-ꢀ-D-glucopyranoside (35). To a solution of 32 (1.50 g,

3.58 mmol) and imidazole (730 mg, 10.7 mmol) in DMF (7.2

mL) was added t-butyldiphenylsilyl chloride (2.55 mL, 9.81

mmol) at rt. After stirring for 3 h at the same temperature, the re-

14

v/v); ½ꢀꢄ_D+67.5 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

ꢂ 1.30 (3H, t, J ¼ 7:3 Hz), 2.57–2.72 (2H, m), 3.78 (1H, dd,

J ¼ 3:4, 12.9 Hz), 3.87 (1H, brd), 4.54 (1H, brd), 5.55 (1H, dd,

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1845

action mixture was diluted with Et₂O and H₂O. The aqueous lay-

er was extracted with Et₂O and the combined organic layer was

washed with H₂O and brine, and dried over Na₂SO₄. After ﬁltra-

tion and evaporation, the residue was puriﬁed by silica gel column

chromatography to aﬀord 35 (2.35 g, quant.) as colorless oil. R_f

was washed with H₂O and brine, and dried over Na₂SO₄. After

ﬁltration and evaporation, the residue was puriﬁed by silica gel

column chromatography to aﬀord 34 (56.0 mg, 93%) as colorless

15

solid. R_f0.50 (hexane/ethyl acetate, 1/1, v/v); ½ꢀꢄ_D+56.6 (c

1

1.00, CHCl₃); H NMR (500 MHz, CDCl₃) ꢂ 2.44 (3H, s), 3.10

16

0.55 (hexane/ethyl acetate, 3/1, v/v); ½ꢀꢄ_D+86.1 (c 1.00,

(3H, s), 3.36 (2H, brd), 3.46–3.64 (5H, m), 3.67 (1H, dd,

J ¼ 8:6, 8.9 Hz), 3.75–3.86 (2H, m), 3.94 (1H, d, J ¼ 10:6 Hz),

4.04–4.13 (1H, m), 4.24–4.31 (1H, m), 4.43–4.62 (7H, m), 4.74

(1H, d, J ¼ 10:7 Hz), 4.81 (1H, d, J ¼ 7:6 Hz, anomeric position),

4.92 (1H, brs, anomeric position), 4.99–5.10 (3H, m), 5.24 (1H,

dd, J ¼ 7:6, 8.2 Hz), 5.34 (1H, dd, J ¼ 9:8, 9.8 Hz), 6.01 (1H,

dd, J ¼ 9:5, 10.1 Hz), 6.99–7.70 (34H, m, Ar-H), 7.74 (2H, d, J ¼

6:7 Hz, Ar-H), 7.78 (2H, d, J ¼ 7:6 Hz, Ar-H), 7.86 (2H, d, J ¼

7:6 Hz, Ar-H), 7.92 (2H, d, J ¼ 7:6 Hz, Ar-H), 8.05 (2H, d, J ¼

7:6 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 21.66, 55.07,

61.92, 67.86, 68.08, 69.02, 70.01, 70.22, 71.90, 73.41, 73.72,

73.78, 74.79, 74.97, 75.00, 75.03, 75.28, 75.49, 75.54, 77.95,

78.76, (96.41, 100.07, 100.57) (anomeric positions), 126.93–

143.51, 164.22, 165.28, 165.57, 165.61, 165.66; IR (KBr) 756,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) ꢂ 1.09 (9H, s), 1.18 (3H,

t, J ¼ 7:3 Hz), 2.42–2.58 (2H, m), 3.71 (1H, dd, J ¼ 9:2, 9.8

Hz), 3.92 (1H, brd), 3.98 (1H, dd, J ¼ 4:0, 11.3 Hz), 4.15–4.24

(2H, m), 4.73 (1H, d, J ¼ 11:3 Hz), 4.85 (1H, d, J ¼ 11:3 Hz),

5.16 (1H, dd, J ¼ 5:8, 9.8 Hz), 5.74 (1H, d, J ¼ 5:8 Hz, anomeric

position), 7.45–7.76 (18H, m, Ar-H), 8.07 (2H, d, J ¼ 8:2 Hz, Ar-

H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 14.58, 19.27, 23.92, 26.52,

26:78 ꢅ 2, 62.79, 71.53, 72.89, 73.79, 74.90, 78.13, 81.29

(anomeric position), 127.55–138.18, 165.97; IR (KBr) 501, 609,

702, 818, 1103, 1265, 1458, 1712, 2931, 3054, 3509 cm^ꢂ1; HRMS

m=z calcd for C₃₈H₄₄O₆SSi Na [M + Na]^þ679.2526, found

ꢁ

679.2521.

Methyl 2,3,4-Tri-O-benzoyl-6-O-[2-O-benzoyl-4-O-benzyl-

3-O-(3,4,6-tri-O-benzyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl)-6-

O-t-butyldiphenylsilyl-ꢁ-D-glucopyranosyl]-ꢀ-D-glucopyrano-

side (40). To a stirred suspension of MS 5A (150 mg, activated),

glucosyl ﬂuoride 31 (31.4 mg, 55.0 mmol), and thioglucoside 35

(32.8 mg, 50.0 mmol) in CH₂Cl₂(1.5 mL) was added the solution

of TfOH (1.50 mg, 10.0 mmol) in toluene (0.100 mL) at 0 ^ꢃC. Af-

ter stirring for 30 min at the same temperature, the completion of

the ﬁrst glycosylation reaction was monitored by TLC; methyl

glucoside 36 (30.4 mg, 60.0 mmol) and NIS (13.5 mg, 60.0 mmol)

re successively added at ꢂ20 ^ꢃC. The reaction mixture was stirred

for an additional 30 min at the same temperature. Then the reac-

tion mixture was quenched by adding sat. aq. NaHCO₃and 10%

aq. Na₂S₂O₃. The mixture was ﬁltered through a pad of celite.

The aqueous layer was extracted with CH₂Cl₂and the combined

organic layer was washed with H₂O and brine, and dried over

Na₂SO₄. After ﬁltration and evaporation, the residue was puriﬁed

by preparative TLC (silica gel) to aﬀord 40 (70.7 mg, 86%) as col-

orless solid. R_f0.46 (hexane/CHCl₃/acetone, 10/10/1, v/v/v);

1095, 1265, 1728, 2993 cm^ꢂ1

; HRMS m=z calcd for

C₈₃H₈₀O₂₁NH₄[M + NH₄]^þ1430.5536, found 1430.5504.

ꢁ

Ethyl 2-O-Benzoyl-4-O-benzyl-3,6-bis-O-(3,4,6-tri-O-ben-

zyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl)-1-thio-ꢀ-D-glucopyran-

oside (41). To a stirred suspension of MS 5A (150 mg, activat-

ed), glucosyl ﬂuoride 31 (59.9 mg, 0.105 mmol), and thiogluco-

side 32 (20.9 mg, 50.0 mmol) in CH₂Cl₂(1.5 mL) was added

the solution _ꢃof TfOH (2.25 mg, 15.0 mmol) in toluene (0.100

mL) at ꢂ20 C. After stirring for 1.5 h at the same temperature,

the reaction mixture was quenched by adding sat. aq. NaHCO₃.

The mixture was ﬁltered through a pad of celite. The aqueous lay-

er was extracted with CH₂Cl₂and the combined organic layer was

washed with H₂O and brine, and dried over Na₂SO₄. After ﬁltra-

tion and evaporation, the residue was puriﬁed by preparative TLC

(silica gel) to aﬀord 41 (73.4 mg, 97%) as colorless solid. R_f0.35

16

(hexane/CHCl₃/acetone, 10/10/1, v/v/v); ½ꢀꢄ_D+79.0 (c 1.00,

1

CHCl₃); H NMR (500 MHz, CDCl₃) ꢂ 0.98 (3H, t, J ¼ 7:3 Hz),

2.17–2.31 (2H, m), 2.23 (3H, s), 2.25 (3H, s), 3.40 (1H, dd,

J ¼ 8:5, 10.1 Hz), 3.49–3.64 (5H, m), 3.67–3.81 (6H, m), 4.13

(1H, brd), 4.22 (1H, brdd), 4.29–4.61 (11H, m), 4.64 (1H, d, J ¼

11:0 Hz), 4.69 (1H, d, J ¼ 11:0 Hz), 4.75 (1H, d, J ¼ 10:7 Hz),

4.79 (1H, d, J ¼ 11:0 Hz), 4.88–4.93 (3H, m), 5.21 (1H, dd,

J ¼ 8:2, 9.2 Hz), 5.29 (1H, dd, J ¼ 8:2, 9.2 Hz), 5.49 (1H, d, J ¼

5:8 Hz, anomeric position), 6.99–7.66 (44H, m, Ar-H), 7.85 (2H,

d, J ¼ 8:2 Hz, Ar-H), 7.99 (2H, d, J ¼ 7:3 Hz, Ar-H); ¹³C NMR

(125 MHz, CDCl₃) ꢂ 14.29, 21.59, 21.66, 23.46, 68.31, 68.81,

69.94, 69.96, 73.43, 73.48, 73.53, 73.78, 74.50, 74.54, 74.92,

74.99, 75:05 ꢅ 2, 75.37, 75.59, 75.96, 77.89, 78.00, 78.05, 80.60

(anomeric position), 82.91, 83.04, (100.99, 101.15) (anomeric po-

sitions), 126.78–138.68, 143.41, 143.64, 164.72, 165.10, 165.17;

IR (KBr) 702, 741, 1095, 1265, 1728, 2985 cm^ꢂ1; HRMS m=z

17

½ꢀꢄ_D+55.5 (c 1.23, CHCl₃); ¹H NMR (400 MHz, CDCl₃) ꢂ

0.96 (9H, s), 2.44 (3H, s), 2.98 (3H, s), 3.37 (1H, brd), 3.46–

3.60 (4H, m), 3.67 (1H, brd), 3.72 (1H, brd), 3.78–3.89 (3H,

m), 4.02 (1H, d, J ¼ 11:5 Hz), 4.08–4.16 (1H, m), 4.31 (1H, dd,

J ¼ 9:0, 9.0 Hz), 4.37–4.62 (7H, m), 4.74 (1H, d, J ¼ 10:7 Hz),

4.83–4.89 (2H, m, anomeric positions), 5.01 (1H, dd, J ¼ 2:4,

10.0 Hz), 5.10–5.30 (4H, m), 6.02 (1H, dd, J ¼ 7:6, 9.8 Hz),

6.99–7.66 (44H, m, Ar-H), 7.72 (2H, d, J ¼ 8:1 Hz, Ar-H), 7.76

(2H, d, J ¼ 7:1 Hz, Ar-H), 7.84 (2H, d, J ¼ 7:1 Hz, Ar-H),

7.93 (2H, d, J ¼ 7:1 Hz, Ar-H), 8.06 (2H, d, J ¼ 7:3 Hz, Ar-

H); ¹³C NMR (100 MHz, CDCl₃) ꢂ 19.07, 21.71, 26:64 ꢅ 2,

54.81, 62.63, 68.24, 68.52, 69.14, 69.46, 70.39, 71.97,

73:48 ꢅ 2, 73.79, 74.33, 75.01, 75:14 ꢅ 2, 75.58, 75.83, 76.03,

78.07, 79.19, 83.06, (96.22, 100.23, 101.50) (anomeric positions),

126.97–143.46, 164.38, 165.17, 165.49, 165.61, 165.64; IR (KBr)

702, 756, 1100, 1265, 1728 cm^ꢂ1; HRMS m=z calcd for

calcd for C₉₂H₉₄O₁₈NH₄[M + NH₄]^þ1536.6505, found

ꢁ

1536.6555.

Ethyl

2,3,4-Tri-O-benzoyl-6-O-[2-O-benzoyl-4-O-benzyl-

C₉₉H₉₈O₂₁Si NH₄[M + NH₄]^þ1668.6714, found 1668.6680.

3,6-bis-O-(3,4,6-tri-O-benzyl-2-O-p-toluoyl-ꢁ-D-glucopyrano-

syl)-ꢁ-D-glucopyranosyl]-1-thio-ꢀ-D-glucopyranoside (42b).

To a stirred suspension of MS 5A (180 mg, activated), glucosyl

ﬂuoride 31 (59.9 mg, 105 mmol), and thioglucoside 32 (20.9

mg, 50.0 mmol) in CH₂Cl₂(1.5 mL) was added the solution of

TfOH (2.25 mg, 15.0 mmol) in toluene (0.100 mL) at 0 ^ꢃC. After

stirring for 30 min at the same temperature, the completion of the

ﬁrst glycosylation reaction was monitored by TLC; thioglucoside

33b (40.2 mg, 75.0 mmol) and NIS (13.5 mg, 60.0 mmol) were

ꢁ

Methyl 2,3,4-Tri-O-benzoyl-6-O-[2-O-benzoyl-4-O-benzyl-

3-O-(3,4,6-tri-O-benzyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl)-ꢁ-

D-glucopyranosyl]-ꢀ-D-glucopyranoside (34). To a solution of

the trisaccharide 40 (70.7 mg, 42.8 mmol) in THF (1.0 mL) were

added acetic acid (0.049 mL) and tetrabutylammonium ﬂuoride

(0.43 mL, 1 M in THF) at rt; the reaction mixture was stirred

for 59 h at the same temperature. After stirring for 9 h at 50

^ꢃC, the reaction mixture was diluted with Et₂O. The organic layer

1846 Bull. Chem. Soc. Jpn., 76, No. 9 (2003)

One-Pot Sequential Glycosylations

successively added at ꢂ60 ^ꢃC. The reaction mixture was allowed

to warm to ꢂ50 ^ꢃC over 1 h and quenched by adding sat. aq.

NaHCO₃and 10% aq. Na₂S₂O₃. The mixture was ﬁltered through

a pad of celite. The aqueous layer was extracted with CH₂Cl₂and

the combined organic layer was washed with H₂O and brine, and

dried over Na₂SO₄. After ﬁltration and evaporation, the residue

was puriﬁed by preparative TLC (silica gel) to aﬀord 42b (50.7

mg, 51%) as colorless solid. R_f0.24 (hexane/CHCl₃/acetone,

4.94 (1H, d, J ¼ 11:3 Hz), 5.04 (1H, dd, J ¼ 8:2, 8.5 Hz),

5.18–5.30 (4H, m), 5.71 (1H, d, J ¼ 5:5 Hz), 5.87 (1H, dd,

J ¼ 9:8, 9.8 Hz), 7.00–8.08 (60H, m, Ar-H); ¹³C NMR (125

MHz, CDCl₃, major signals) ꢂ 14.29, 21.59, 21.67, 23.75,

66.50, 68.18, 68.59, 69.12, 69.75, 71.63, 71.68, 73.44, 73.69,

73.83, 73.92, 74.55, 74.91, 74.94, 75.00, 75.06, 75.11, 75.35,

75.54, 75.91, 77.87, 78.05, 78.85, 81.00, 82.82, 82.96, 99.99,

100.26, 101.25, 122.32–143.64, 163.85, 163.88, 164.18, 164.34,

164.91, 165.31; IR (KBr) 756, 1088, 1265, 1736 cm^ꢂ1; HRMS

16

10/10/1, v/v/v); ½ꢀꢄ_D+52.5 (c 0.10, CHCl₃); ¹H NMR (500

MHz, CDCl₃) ꢂ 1.03 (3H, t, J ¼ 7:3 Hz), 2.25–2.38 (2H, m),

2.37 (3H, s), 2.44 (3H, s), 3.16–3.23 (2H, m), 3.38–3.58 (6H,

m), 3.62 (1H, dd, J ¼ 9:1, 9.9 Hz), 3.68–3.82 (5H, m), 3.86

(1H, dd, J ¼ 9:2, 9.2 Hz), 4.05 (1H, brd), 4.16 (1H, dd,

J ¼ 8:9, 8.9 Hz), 4.24 (1H, d, J ¼ 7:6 Hz, anomeric position),

4.29 (1H, ddd, J ¼ 3:1, 4.0, 10.1 Hz), 4.37–4.82 (15H, m), 4.93

(1H, d, J ¼ 11:3 Hz), 5.00 (1H, dd, J ¼ 7:9, 8.9 Hz), 5.14–5.26

(4H, m), 5.71 (1H, d, J ¼ 5:5 Hz, anomeric position), 5.88 (1H,

dd, J ¼ 9:8, 10.1 Hz), 6.99–7.61 (51H, m, Ar-H), 7.71–7.75

(4H, m, Ar-H), 7.80 (2H, d, J ¼ 7:3 Hz, Ar-H), 7.85 (2H, d, J ¼

8:2 Hz, Ar-H), 7.94 (2H, d, J ¼ 7:0 Hz, Ar-H), 8.08 (2H, d, J ¼

7:3 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃) ꢂ 14.33, 21.63,

21.70, 23.68, 67.08, 68.25, 68.63, 68.69, 69.05, 69.61, 69.78,

70.87, 71.59, 73.43, 73.46, 73.69, 73.88, 74.04, 74.50, 74.86,

74.91, 74.99, 75.10, 75.42, 75.57, 75.94, 77.94, 78.07, 78.67,

81.26 (anomeric position), 82.82, 82.97, (99.92, 100.36, 101.29)

(anomeric positions), 127.00–138.36, 143.51, 143.62, 164.19,

164.98, 165.02, 165.19, 165.38, 165.50; IR (KBr) 702, 748,

m=z calcd for C₁₁₂H₁₁₃F₉O₂₆S NH₄[M + NH₄]^þ2214.7441,

ꢁ

found 2214.738.

Methyl 2,3,4-Tri-O-benzoyl-6-O-{2-O-benzoyl-4-O-benzyl-

6-O-[2-O-benzoyl-4-O-benzyl-3,6-bis-O-(3,4,6-tri-O-benzyl-2-

O-p-toluoyl-ꢁ-D-glucopyranosyl)-ꢁ-D-glucopyranosyl]-2,3,4-

tri-O-p-(triﬂuoromethyl)benzoyl-ꢁ-D-glucopyranosyl-ꢁ-D-glu-

copyranosyl}-ꢀ-D-glucopyranoside (43). To a stirred suspen-

sion of MS 5A (180 mg, activated), glucosyl ﬂuoride 31 (59.9

mg, 105 mmol), and thioglucoside 32 (20.9 mg, 50.0 mmol) in

CH₂Cl₂(1.5 mL) was added the solu_ꢃtion of TfOH (2.25 mg,

15.0 mmol) in toluene (0.100 mL) at 0 C. After stirring for 1.5

h at the same temperature, the completion of the ﬁrst glycosyla-

tion reaction was monitored by TLC; thioglucoside 33d (55.5

mg, 75.0 mmol) and NIS (13.5 mg, 60.0 mmol) were successively

ꢃ

added at ꢂ60 C. The reaction mixture was allowed to warm to

ꢃ

ꢂ50 C over 1 h. After the completion of the second glycosyla-

tion reaction was monitored by TLC; trisaccharide 44 (212 mg,

150 mmol) and NIS (22.5 mg, 100 mmol) were successively added

at the same temperature. The reaction mixture was allowed to

warm to ꢂ20 ^ꢃC and stirred for 1 h and then quenched by adding

sat. aq. NaHCO₃and 10% aq. Na₂S₂O₃. The mixture was ﬁltered

through a pad of celite. The aqueous layer was extracted with

CH₂Cl₂and the combined organic layer was washed with H₂O

and brine, and dried over Na₂SO₄. After ﬁltration and evapora-

tion, the residue was puriﬁed by preparative TLC (silica gel) to af-

ford 43 (84.7 mg, 48%) as colorless solid. R_f0.50 (hexane/

1095, 1265, 1728 cm^ꢂ1; HRMS m=z calcd for C₁₁₉H₁₁₆O₂₆S NH₄

ꢁ

[M + NH₄]^þ2010.7819, found 2010.7762.

Ethyl 6-O-[2-O-Benzoyl-4-O-benzyl-3,6-bis-O-(3,4,6-tri-O-

benzyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl)-ꢁ-D-glucopyrano-

syl]-2,3,4-tri-O-p-chlorobenzoyl-1-thio-ꢀ-D-glucopyranoside

(42c). This compound was synthesized as colorless solid (74.7

mg, 71%) according to the above-mentioned procedure (see ex-

perimental: compound 42b). R_f0.23 (hexane/CHCl₃/acetone,

10/10/1, v/v/v); ½ꢀꢄ_D+51.1 (c 0.10, CHCl₃); ¹H NMR (400

CHCl₃/acetone, 10/10/2, v/v/v); ½ꢀꢄ_D+26.5 (c 0.56, CHCl₃);

16

17

MHz, CDCl₃) ꢂ 1.02 (3H, t, J ¼ 7:3 Hz), 2.25–2.37 (2H, m),

2.38 (3H, s), 2.44 (3H, s), 3.18–3.30 (2H, m), 3.39–3.82 (12H,

m), 3.86 (1H, dd, J ¼ 9:0, 9.3 Hz), 4.06 (1H, brd), 4.17 (1H,

dd, J ¼ 8:8, 8.8 Hz), 4.22–4.83 (17H, m), 4.94 (1H, d, J ¼ 11:2

Hz), 5.02 (1H, dd, J ¼ 8:1, 9.0 Hz), 5.21–5.37 (4H, m), 5.67

(1H, d, J ¼ 5:6 Hz, anomeric), 5.80 (1H, dd, J ¼ 9:8, 10.0 Hz),

6.98–8.08 (60H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) ꢂ

14.28, 21.62, 21.71, 23.64, 66.72, 68.15, 68:57 ꢅ 2, 69.04,

69.52, 71.18, 71.47, 73:41 ꢅ 2, 73.64, 73.80, 73.89, 74.54,

74:91 ꢅ 2, 74.98, 75.00, 75.12, 75.36, 75.50, 75.88, 77.85,

78.02, 78.77, 81.05, 82.75, 82.92, 99.96, 100.29, 101.21,

126.91–143.63, 164:13 ꢅ 2, 164.24, 164.63, 164.92, 165.34; IR

(KBr) 702, 748, 1088, 1265, 1728 cm^ꢂ1; HRMS m=z calcd for

¹H NMR (500 MHz, CDCl₃) ꢂ 2.33 (3H, s), 2.39 (3H, s), 2.42 (3H,

s), 2.87 (3H, s), 2.94 (1H, dd, J ¼ 8:9, 9.2 Hz), 3.08–3.28 (3H, m),

3.30–3.91 (22H, m), 3.94–4.05 (4H, m), 4.11 (1H, dd, J ¼ 8:5, 9.2

Hz), 4.20–4.26 (3H, m), 4.32–4.60 (15H, m), 4.69–4.98 (13H, m),

5.16–5.26 (4H, m), 5.29 (1H, dd, J ¼ 9:8, 10.1 Hz), 5.34 (1H, dd,

J ¼ 8:5, 9.5 Hz), 5.47 (1H, dd, J ¼ 9:5, 10.1 Hz), 5.94 (1H, dd,

J ¼ 9:8, 9.8 Hz), 6.07 (1H, dd, J ¼ 9:5, 10.1 Hz), 6.95–8.03

(104H, m, Ar-H); ¹³C NMR (125 MHz, CDCl₃, major signals) ꢂ

21.67, 21.72, 21.73, 54.69, 67.74, 67.87, 67.93, 68.83, 68.96,

69.11, 70.10, 70.21, 71.95, 72.52, 73.36, 73.55, 73.69, 73.83,

74.02, 74.24, 74.29, 74.54, 74.64, 75.02, 75.05, 75.13, 75.17,

75.50, 75.54, 75.70, 75.98, 76.09, 78.02, 78.08. 78.12, 78.19,

78.88, 79.56, 82.87, 82.96, 83.00, (96.49, 100.20, 100.23,

100.40, 100.47, 100.62, 101.25) (anomeric positions), 122.22–

143.88, 163.92, 164.02, 164.21, 164.27, 164.58, 165.13, 165.32,

165.41, 165.61, 165.69, 165.86; IR (KBr) 701, 1095, 1265, 1736

C

₁₁₉H₁₁₃Cl₃O₂₆S NH₄[M + NH₄]^þ2112.6650, found 2112.668.

ꢁ

Ethyl 6-O-[2-O-Benzoyl-4-O-benzyl-3,6-bis-O-(3,4,6-tri-O-

benzyl-2-O-p-toluoyl-ꢁ-D-glucopyranosyl)-ꢁ-D-glucopyrano-

syl]-1-thio-2,3,4-tri-O-p-(triﬂuoromethyl)benzoyl-ꢀ-D-gluco-

pyranoside (42d). This compound was synthesized as colorless

solid (84.0 mg, 76%) according to the above-mentioned procedure

(see experimental: compound 42b). R_f0.28 (hexane/CHCl₃/ace-

cm^ꢂ1; HRMS m=z calcd for C₂₀₃H₁₈₇F₉O₄₇NH₄[M + 2(NH₄)]^2þ

ꢁ

1791.6393, found 1791.6423.

Methyl

6-O-[6-O-{6-O-[3,6-Di-(ꢁ-D-glucopyranosyl)-ꢁ-D-

glucopyranosyl]-ꢁ-D-glucopyranosyl}-3-O-(ꢁ-D-glucopyrano-

syl)-ꢁ-D-glucopyranosyl]-ꢀ-D-glucopyranoside (30). To a solu-

tion of heptasaccharide 43 (40.9 mg, 12.2 mmol) in THF/MeOH

(6 mL, 2/1, v/v) was added 2 M aq. NaOH (1 mL) at rt. After

stirring for 12 h at the same temperature, the reaction mixture

was neutralized with Amberlite¹IR-120 cation exchange resin

(until ca. pH 7). After ﬁltration and evaporation, the residue

tone, 10/10/1, v/v/v); ½ꢀꢄ_D+61.7 (c 0.10, CHCl₃); ¹H NMR

16

(500 MHz, CDCl₃) ꢂ 1.05 (3H, t, J ¼ 7:3 Hz), 2.26–2.41 (2H,

m), 2.37 (3H, s), 2.44 (3H, s), 3.24–3.33 (2H, m), 3.41–3.64

(7H, m), 3.68–3.84 (5H, m), 3.86 (1H, dd, J ¼ 9:2, 9.2 Hz),

4.06 (1H, d, J ¼ 10:4 Hz), 4.18 (1H, dd, J ¼ 8:5, 8.6 Hz), 4.30

(1H, d, J ¼ 7:6 Hz), 4.31–4.62 (11H, m), 4.65–4.82 (5H, m),

T. Hashihayata et al.

Bull. Chem. Soc. Jpn., 76, No. 9 (2003) 1847

was simply puriﬁed by preparative TLC (silica gel). To a solution

of the crude product in THF/CH₂Cl₂/H₂O (7 mL, 4/2/1, v/v/v)

was added palladium(b) hydroxide (40.7 mg, 20 wt % on carbon).

After purging with H₂(1:01 ꢅ 10⁵Pa) and stirring for 83 h, H₂

was removed. After ﬁltration and evaporation, the residue was pu-

riﬁed by reversed-phase column chromatography to aﬀord 3 (13.5

31, 2435 (1990).

a) H. P. Wessel, Tetrahedron Lett., 31, 6863 (1990). b) H.

P. Wessel and N. Ruiz, J. Carbohydr. Chem., 10, 901 (1991).

9

10 a) G. Bohm and H. Waldmann, Tetrahedron Lett., 36, 3843

¨

(1995). b) G. Bohm and H. Waldmann, Liebigs Ann. Chem., 1996,

¨

613. c) G. Bohm and H. Waldmann, Liebigs Ann. Chem., 1996,

621.

¨

20

mg, 95%) as colorless solid. ½ꢀꢄ_D¼ ꢂ3:98 (c 1.0, H₂O),

¹H NMR (600 MHz, D₂O, 285 K); ꢂ 3.12–3.76 (41H, m), 4.01–

4.06 (4H, m), [4.34 (1H, d, J ¼ 8:4 Hz), 4.37 (3H, t, J ¼ 8:4

Hz), 4.58 (1H, d, J ¼ 7:8 Hz), 4.59 (1H, d, J ¼ 7:8 Hz), 4.63

(1H, d, J ¼ 3:6 Hz) anomeric positions]; ¹³C NMR (125 MHz,

D₂O); ꢂ 54.98, 60:39 ꢅ 2, 60.43, 67.72, 67.74, 68:34 ꢅ 2, 68.48,

68.58, 69.04, 69.14, 69:26 ꢅ 2, 69.31, 70.22, 70.82, 72.48,

72.50, 72.67, 72.76, 72.78, 73.12, 73.16, 74.25, 74.32, 74.55,

75:23 ꢅ 2, 75.27, 75.35, 75.59, 75.66, 75.68, 83.96, 84.05,

(99.01, 102.19, 102.41, 102.45, 102.52, 102.62, 102.65) (anomeric

positions); IR (KBr): 764, 1033, 3410 cm^ꢂ1; HRMS m=z calcd for

11 a) S. Hosono, W. S. Kim, H. Sasai, and M. Shibasaki, J.

Org. Chem., 60, 4 (1995). b) W. S. Kim, S. Hosono, H. Sasai,

and M. Shibasaki, Tetrahedron Lett., 36, 4443 (1995). c) W.-S.

Kim, S. Hosono, H. Sasai, and M. Shibasaki, Heterocycles, 42,

795 (1996).

12 K. Toshima, K. Kasumi, and S. Matsumura, Synlett, 1998,

643.

13 K. Takeuchi and T. Mukaiyama, Chem. Lett., 1998, 555.

14 T. Mukaiyama, H. Jona, and K. Takeuchi, Chem. Lett.,

2000, 696.

C₄₃H₇₄O₃₆NH₄[M + NH₄]^þ1184.4304, found 1184.4308.

15 H. Jona, H. Mandai, and T. Mukaiyama, Chem. Lett., 2001,

426.

ꢁ

16 Reviews on glycosyl ﬂuoride; a) M. Shimizu, H. Togo, and

M. Yokoyama, Synthesis, 1998, 799. b) M. Yokoyama, Carbo-

hydr. Res., 327, 5 (2000). c) K. Toshima, Carbohydr. Res., 327,

15 (2000). d) T. Mukaiyama and H. Jona, Proc. Jpn. Acad. Ser.

B, 78, 73 (2002).

17 Review on one-pot glycosylation; K. M. Koeller and C.-H.

Wong, Chem. Rev., 100, 4465 (2000).

18 S. Raghavan and D. Kahne, J. Am. Chem. Soc., 115, 1580

(1993).

19 a) H. Yamada, T. Harada, H. Miyazaki, and T. Takahashi,

Tetrahedron Lett., 35, 3979 (1994). b) H. Yamada, T. Harada, and

T. Takahashi, J. Am. Chem. Soc., 116, 7919 (1994).

20 H. K. Chenault and A. Castro, Tetrahedron Lett., 35, 9145

(1994).

This study was supported in part by a Grant of the 21st Cen-

tury COE Program from the Ministry of Education, Culture,

Sports, Science and Technology (MEXT). We thank Asahi

Glass Engineering Co., Ltd. for providing TrB(C₆F₅)₄, and

Central Glass Co. Limited for providing TfOH. We thank

Ms. Chihiro Suzuki-Sato, Ms. Aya Mitsuya, Mr. Hirokazu

Ohsawa, and Dr. Shigeru Nakajima, Banyu Pharmaceutical

Company, for their kind help concerning optical rotation anal-

yses, elementary analysis, High Resolution Mass Spectrometry

analyses, and NMR spectral analyses.

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Article Doi

Convergent total syntheses of oligosaccharides by one-pot sequential stereoselective glycosylations

DOI: 10.1246/bcsj.76.1829

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