Combinatorial synthesis of deoxyhexasaccharides related to the landomycin a sugar moiety, based on an orthogonal deprotection strategy

DOI: 10.1002/asia.200900640

Combinatorial Synthesis of Deoxyhexasaccharides Related to the

Landomycin A Sugar Moiety, Based on an Orthogonal Deprotection Strategy

Hiroshi Tanaka,*^[a]Sho Yamaguchi,^[a]Atsushi Yoshizawa,^[a]Motoki Takagi,^[b]

Kazuo Shin-ya,^[b]and Takashi Takahashi*^[a]

Abstract: In this report, we describe

the stereoselective synthesis of a com-

binatorial library comprised of 16 de-

oxyhexasaccharides that are related to

a landomycin A sugar moiety, based on

an orthogonal deprotection strategy.

The use of an olivosyl donor containing

a benzyl ether at the C3 position and

benzoyl ester at the C4 position, and

the olivosyl donor, a naphthylmethyl

tion and deprotection procedure. Using

a phenylthio 2,3,6-trideoxyglycoside, a-

selective glycosidation proceeded with-

out anomerization of the 2,6-dideoxy-

b-glycosides. In addition, alkylhydro-

quinone and levulinoyl groups were

found to be an effective set of orthogo-

nal protecting groups for the anomeric

position and a hydroxyl group. The

coupling of all combinations of trisac-

charide units in a b-selective manner

was accomplished by activation of the

glycosyl imidate with I₂and Et₃SiH. No

cleavage of the acid-labile 2,3,6-tri-

deoxyglycoside was observed under the

conditions used for the reactions. Final-

ly, all of the protected hexasaccharides

were deprotected by hydrolysis of the

esters, microwave (MW) assisted cleav-

age of the 2-trimethylsilylethoxyme-

thoxy (SEM) ether, and a Birch reduc-

tion.

ether, and

a p-nitrobenzylethyl or

Keywords: combinatorial chemis-

try · 2-deoxyglycoside · glycosyl

imidates · glycosylation · saccha-

rides

benzyl sulfonyl ester enabled the syn-

thesis of a set of four diolivosyl units

containing a hydroxyl group at the C3

or C4 position by a simple glycosyla-

Introduction

ing group participation for stereoselective glycosidation is

not possible and the absence of electron-withdrawing sub-

stituents on saccharide units permits the interconversion of

thermodynamically unstable b-glycosides to a-glycosides by

anomerization and cleavage of the b-glycosidic linkage

during the glycosidation. In addition, the stereoselectivity of

glycosidation of 2-deoxyglycosides is strongly dependent on

the nature of the protecting groups used for the reaction.

We recently reported our development of direct a- and b-se-

lective glycosidation methods using glycosyl imidates, which

are key reactions for the synthesis of combinatorial libraries

of anomeric stereoisomers of deoxyoligosaccharides.^[3,4]

Therein, protection of a C4 hydroxyl group with a strongly

electron-withdrawing protecting group such as benzylsulfon-

yl and 2-(p-nitrobenzyl)ethylsulfonyl (Npes) esters, im-

proved the desired stereoselectivity. Our next challenge is to

develop a method for the assembly of their regioisomers.

An orthogonal deprotection strategy is known to be an ef-

fective method for the synthesis of regioisomers of oligosac-

charides and for minimizing the number of building blocks

and/or synthetic intermediates required.^[5]However, stereo-

selective glycosidation and orthogonal deprotection of 2-de-

oxyglycosides requires further careful selection of these pro-

2-Deoxysaccharides are key components of biologically

active natural products. The application of combinatorial

synthesis for preparing 2-deoxyoligosaccharides is an attrac-

tive way to provide effective resources for the preparation

of new biologically active compounds.^[1]However, they rep-

resent difficult and challenging synthetic targets:^[2]neighbor-

[a] Prof. Dr. H. Tanaka, S. Yamaguchi, Dr. A. Yoshizawa,

Prof. Dr. T. Takahashi

Department of Applied Chemistry

Graduate School of Science and Engineering

Tokyo Institute of Technology

2-12-1-S1-35 Ookayama, Meguro, Tokyo 152-8552 (Japan)

Fax : (+81)3-5734-2471

E-mail: thiroshi@apc.titech.ac.jp

[b] Dr. M. Takagi, Dr. K. Shin-ya

Biological Systems Control Team

Biomedicinal Information Research Center

National Institute of Advanced Industrial Science and Technology

2-42 Aomi, Koto-ku, Tokyo 135-0064 (Japan)

Fax : (+81)3-3599-8494

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/asia.200900640.

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1407

FULL PAPERS

tecting groups. In this report, we describe the combinatorial

synthesis of deoxyhexasaccharides related to the landomycin

A sugar moiety, based on an orthogonal deprotection strat-

egy.

Landomycin A (1) (Figure 1), an angucylic-type antitumor

antibiotic, exhibits potent antitumor and antibacterial activi-

ty, and inhibits G1/S cell cycle progression, which results in

syl phosphites and tetrazoles.^[7]The direct dimerization was

difficult to achieve in a stereoselective manner and resulted

in a moderate coupling yield and stereoselectivity. Indirect

approaches using olivosides, in which stereodirecting sub-

stituents were attached to the C2 position, have been report-

ed as alternative methods for the synthesis of the deoxyhex-

asaccharide.^[8,9,10]However, in all of these methods it was

difficult to completely prevent anomerization and cleavage

of the 2,3,6-trideoxyglycoside. In addition, these methods

are based on target oriented synthetic strategy. Therefore,

an effective method for the systematic synthesis of deoxyoli-

gosaccharides related to the landomycin A hexasaccharide

moiety continues to be a subject of attention in terms of

both chemical and biological interests.

Results and Discussion

Figure 1. The structure of landomycin A (1).

The hydroquinone substituted landomycin A hexasaccharide

2aa and their 15 regioisomers 2ab–dd constitute the target

library of compounds (Scheme 1). The hydroquinone moiety

the induction of apoptosis.^[6]It

is composed of

aglycon and

a

tetracyclic

structurally

a

unique, complex deoxyhexasac-

charide. The deoxyhexasacchar-

ide is made up of a head-to-tail

dimer of a repeating trisacchar-

ide subunit (l-rhodinoside-b-

ACHTUNGTRENNUNG(1,3)-d-olivoside-bACHTUNGTRENNUNG(1,4)-d-olivo-

side). This structure appears to

be required for the biological

activity of the molecule, since

that of naturally occurring land-

omycin derivatives that contain

shorter glycan chains is signifi-

cantly lower.^[6f]However, the

number of naturally occurring

landomycin A derivatives are

limited and mainly vary in the

number of saccharide units.

Scheme 1. Strategy for the synthesis of a combinatorial library of a landomycin sugar moiety.

Therefore, a chemical synthesis of the deoxyoligosaccharide

and derivatives thereof would facilitate identification of

their biological roles.

Sulikowski and Guo reported the first chemical synthesis

of the landomycin deoxyhexasaccharide by a direct head-to-

tail coupling of the repeating trisaccharide units using glyco-

serves not only as a partial structure of the landomycin agly-

con, but also as a protecting group at the anomeric position

for further coupling with various aglycons. The strategy for

the synthesis of the hexasaccharide library 2aa–dd involves

direct and stereoselective head-to-tail coupling of the trisac-

charide glycosyl acceptors 3a–d and donors 4a–d. These

building blocks 3a–d and 4a–d could be prepared from the

hydroquinone derivative 6, three olivosides 7, 8a, and 8b,

and rhodinoside 9 based on an orthogonal deprotection

strategy. The first glycosyl donor 7 contained two orthogonal

protecting groups; a benzyl ether at the C3 position and a

benzoate at the C4 position. A combination of an electron-

withdrawing protecting group at the C4 hydroxyl that partic-

ipates in the reaction and an electron-donating protecting

group at the C3 hydroxyl could be effective for achieving se-

lective, direct b glycosylation.^[11]The second glycosyl donor

Abstract in Japanese:

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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

8a was protected by a 2-naphthylmethyl (NAP) ether and

an Npes ester at the C3 and C4 positions, respectively. An

alternative olivoside 8b, with a benzylsulfonyl ester protect-

ing group in place of the Npes ester at C4, was also used.

The protecting groups of 8a and 8b are orthogonally depro-

tectable without affecting the benzyl ether and benzoate

protecting groups of 7. Introduction of the a-rhodinoside

should be possible without decomposition of the b-linked

disaccharides. We selected the thiorhodinoside 9 containing

a levulinoyl (Lev) ester at the C4 position as a glycosyl

donor because it is a chemically stable compound and could

undergo glycosidation under oxidative activation conditions.

The trisaccharides 5a–d were converted to the correspond-

ing glycosyl acceptors 3a–d and donors 4a–d by removing

the Lev protecting groups and the p-(trimethylethoxyme-

thoxy)phenyl group.

imidates were used for the next reactions without purifica-

tion by chromatography on silica gel.

Preparation of phenylthio d-rhodinoside 9 is outlined in

Scheme 3. Treatment of diacetylglycal 19 with FeCl₃in the

presence of MeOH provided the a-methyl glycoside.^[12]Sub-

Preparation of olivosyl donors 7, 8a, and 8b is outlined in

Scheme 2. Hydrolysis of the acetyl groups of the diacetyl

glycal 10, followed by regioselective O-alkylation with

benzyl and 2-naphthylmethyl bromides, via a tin acetal, pro-

Scheme 3. Reagents and conditions: (a) FeCl₃, MeOH, CH₃CN, 08C to

RT, 3 h; (b) K₂CO₃, MeOH, 50% from 19; (c) p-nitrobenzoic acid, PPh₃,

DEAD, THF, 08C to RT, 2 h; (d) NaOMe, THF/MeOH (1:1), RT, 2 h,

70% from 20; (e) Ac₂O, NEt₃, DMAP, CH₂Cl₂, RT, 6 h, 55%; (f) H₂

(1 atm), Pd/C, EtOAc; (g) PhSH, ScACHTNUGTREN(UNG OTf)₃, CH₂Cl₂, 50% from 22;

(h) NaOMe, MeOH, RT, 3 h; (i) LevOH, EDCI, DMAP, DIEA, CH₂Cl₂,

80% from 24.

sequently, hydrolysis of the remaining acetyl group provided

alcohol 20 in 50% yield. Inversion of the stereochemistry of

the hydroxyl group was achieved by Mitsunobu reaction,

and was followed by hydrolysis of the generated ester to

provide secondary alcohol 21 in 70% yield. The resulting al-

cohol 21 was protected with acetic anhydride to afford the

allylic acetate 22 in 55% yield. Hydrogenation of the

double bond of 22, followed by treatment of the methyl gly-

coside 23 with thiophenol in the presence of ScACTHNUGTRENUNG(OTf)₃pro-

vided the phenylthio a-glycoside 24 in 50% yield from 22.

Hydrolysis of the acetate, followed by acylation with levulic

acid provided the d-rhodinosyl donor 9 in 80% yield.

Scheme 2. Reagents and conditions: (a) K₂CO₃, MeOH, RT; (b) Bu₂SnO,

toluene, 1408C, then TBAI, BnBr; (c) Bu₂SnO, toluene, 1408C, then

TBAI, NAPBr, 75% from 10; (d) BzCl, DMAP, TMEDA, RT;

(e) BnSO₂Cl, DMAP, Py, RT, 95%; (f) NpesCl, DMAP, Py, RT; (g) LiBr,

Dowex, CH₃CN, H₂O, 85% from 10 for 16, 99% from 12 for 17, 70%

from 12 for 18; (h) CCl₃CN, Cs₂CO₃, CH₂Cl₂, RT.

Scheme 4 shows the synthesis of four trisaccharides 5a–d

from imidate 7. Treatment of the olivosyl imidate 7 and 1.5

equivalents of phenol 6 with I₂and a catalytic amount of

Et₃SiH at ꢀ788C provided the phenyl glycoside 25 in 79%

yield with b/a>90:10. Treatment of benzoate 25 with

NaOMe in MeOH provided 26, with an unprotected C4 hy-

droxyl, in quantitative yield. Alternatively, hydrogenation of

the benzyl ether of glycoside 25 using a Pd catalyst led to

27, with an unprotected C3 hydroxyl, in 80% yield. Glycosy-

lation of the C4 and C3 hydroxyls 26 and 27 with olivoside

8a was then examined. Treatment of acceptor 27 with 1.5

equivalents of the Npes protected olivoside 8a, I₂and a cat-

alytic amount of Et₃SiH at ꢀ94 to ꢀ788C gave the disac-

charide 29 in 79% yield with b/a=90:10. However, the

Npes protected olivoside 8a did not undergo glycosidation

at the C4 hydroxyl of 26 under the same glycosidation con-

ditions and resulted in decomposition of the donor 8a and

vided alcohols 11 and 12. The remaining hydroxyl group of

11 was protected with benzoyl chloride to afford glycal 13.

The remaining hydroxyl group of 12 was protected with 2-

(p-nitrophenyl)ethylsulfonyl and benzylsulfonyl chlorides

providing sulfonyl esters 14 and 15. Hydration of the glycols

13, 14, and 15 provided the hemiacetals 16-18, respectively.

The hemiacetals 16, 17, and 18 were converted to the corre-

sponding glycosyl imidates 7, 8a, and 8b under conventional

conditions for the synthesis of trichloroacetimidates. The

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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H. Tanaka, T. Takahashi et al.

FULL PAPERS

Scheme 4. Synthesis of the four trisaccharides 5a–d. Reagents and conditions: (a) 6, I₂, cat Et₃SiH, MS 4ꢁ, toluene, ꢀ788C, 2.0 h, 79% b/a=>90:10;

(b) NaOMe, MeOH, RT, 3 h, quant.; (c) H₂(1 atm), Pd/C, MeOH/THF=1:1, RT, 12 h, 80%; (d) I₂, cat Et₃SiH, MS 4ꢁ, toluene, ꢀ94 to ꢀ788C, 0% for

28a, 75% b/a=93:7 for 28b, 79% b/a=90:10 for 29; (e) DDQ, NaHCO₃aq., CH₂Cl₂, 3 h, 71% for 15, 71% for 17; (f) NH₂Na, DMF, 24 h, 99%;

(g) DBU, CH₂Cl₂, 71%; (h) 9, Bu₄NOTf, NBS, CH₂Cl₂, MS 4ꢁ, ꢀ78 to ꢀ408C, 95%, b/a=>95:5 for 5a, 76%, b/a=>90:10 for 5b, 76%, b/a=>95:5

for 5c, 90%, b/a=>90:10 for 5d.

recovery of the acceptor 26. In a subsequent experiment, we

used olivoside 8b, which has a benzylsulfonyl ester at the

C4 position, as the glycosyl donor. Treatment of acceptor 26

and 1.5 equivalents of olivoside 8b with I₂and a catalytic

amount of Et₃SiH at ꢀ94 to ꢀ788C provided the disacchar-

ide 28b in 75% yield with b/a=93:7. Reasons for the differ-

ence in the glycosidation reactions of the Npes and benzyl-

sulfonyl protected donors 8a and 8b are not clear. Oxidative

removal of the NAP group of disaccharides 28b and 29 was

accomplished by treatment with DDQ to provide the corre-

sponding alcohols 30 and 32, each in 71% yield and without

any detectable cleavage of the dialkylhydroquinone moiety.

Additionally, the benzylsulfonyl ester of 28b and the Npes

group of 29 were removed by treatment with NaNH₂and

DBU, respectively, to provide the corresponding disacchar-

ides 31 and 33, with free hydroxyl groups at C4 in 99% yield

for 31and 71% yieldfor 33.

ꢀ78 to ꢀ408C provided the trisaccharides 5a in 95% yield

(a/b>95:5). Bu₄NOTf enhanced the rate of activation of

the thioglycoside without reducing a-selectivity (Table 1).^[13]

Use of IBr as an activator resulted in the decomposition of

the product. By the same method, the remaining disacchar-

ide acceptors 31–33 were converted to the corresponding tri-

saccharides 5b–d in 76% (a/b>90:10), 76% (a/b>95:5)

and 90% (a/b>90:10) yields, respectively. No evidence of

anomerization or cleavage of glycosidic linkages was ob-

served in the a-glycosidation.

The synthesis of the landomycin A hexasaccharide 2aa

from trisaccharide 5a was then carried out as shown in

Scheme 5. Treatment of trisaccharide 5a with NH₂NH₂and

AcOH provided glycosyl acceptor 3a in 80% yield. For the

synthesis of the glycosyl donor 4a, oxidative cleavage of the

dialkylhydroquinone moiety of 5a by treatment with CAN

afforded the hemiacetal 34a, which when treated with

CCl₃CN under basic conditions provided the glycosyl imi-

date 4a. The imidate 4a was used for the subsequent glyco-

sylation without purification by column chromatography on

silica gel. Hexasaccharide formation was achieved by treat-

ing the acceptor 3a and the imidate 4a, prepared from 2.0

equivalents of 5a, with I₂and a catalytic amount of Et₃SiH

in toluene at ꢀ948C for 1 h to provide a mixture of the hex-

asaccharides b- and a-35aa in 93% yield based on 3a. The

ratio of the anomeric isomers b- and a-35aa was determined

by HPLC analysis based on IR detection to be b/a=82:18.

Anomerization of the b-2,6-dideoxyglycosides and/or cleav-

The glycosylation of disaccharide 30 with d-rhodinoside 9

was then examined (Table 1). Treatment of disaccharides 30

with 2.0 equivalents of rhodinoside 9, NBS and Bu₄NOTf at

Table 1. Glycosylation of diolivoside 30 with thiorhodinoside 9.

Entry

Conditions

T [8C]

Yield [%]

a/b

1

2

3

4

NBS, Bu₄NOTf

NBS

I₂, Bu₄NOTf

IBr, Bu₄NOTf

ꢀ78 to ꢀ40

ꢀ78 to ꢀ25

ꢀ78 to 0

ꢀ78

95

72

35

–

>95:5

–

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Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

donors 4a and 4b, which con-

tain a benzyl ether at the C3

position, underwent only mod-

erately b-selective glycosylation

(b/a=65:35 to 77:23). Depro-

tection of the protected oligo-

saccharides 35ab–35dd provid-

ed a set of regioisomers of the

landomycin hexasaccharide iso-

mers 2ab–2dd in moderate

total yields.^[15]

Scheme 5. Synthesis of the hexasaccharide 2aa. Reagents and conditions: (a) NH₂NH₂, AcOH, H₂O, Py., RT,

80%; (b) CAN, H₂O, CH₃CN, RT, 10 min; (c) CCl₃CN, Cs₂CO₃, CH₂Cl₂, RT, 3 h; (d) I₂, cat Et₃SiH, MS 4ꢁ,

toluene, ꢀ948C, 1.0 h, 93%, b/a=82:18; (e) (i)NaOMe, MeOH/THF=1:1, 508C, 6 h; (ii)TBAF in THF, DMF,

MW (300W), 1008C, 15 min; (iii)Na, NH₃(l), THF, ꢀ788C, 30 min, then MeOH, 70% overall yield from b-

35aa.

Conclusions

In conclusion, we report herein

an efficient combinatorial syn-

age of 2,3,6-trideoxyglycosides were not observed. The b-

and a-isomers of 35aa were separated by HPLC. Deprotec-

tion of the purified b-35aa was achieved as follows: (1) re-

moval of the ester and sulfonyl

ester protecting groups under

basic conditions; (2) cleavage of

the SEM ether with TBAF

under MW irradiation; and

(3) deprotection of the benzyl

ether protecting group by Birch

reduction to afford the fully de-

protected hexasaccharide b-2aa

in 70% yield based on b-35aa.

Removal of the SEM group

prior to the Birch reduction

was important to prevent re-

duction of the hydroquinone

moiety.^[14]In addition, MW irra-

diation was effective in terms of

minimizing the reaction time

required for removal of the

SEM group.

thesis of deoxyhexasaccharides related to the landomycin

sugar moiety, based on an orthogonal deprotection strategy.

The orthogonal deprotection approach is effective for as-

The synthesis of regioisomers

2ab–dd (Figure 2 was then car-

ried

out

(entries 2–16

in

Tables 2 and 3). The acceptors

3b–d and donors 4b–d were

prepared from 5b–d using es-

tablished procedures. Coupling

of all remaining combinations

of the glycosyl acceptors 3a–d

and donors 4a–d provided all

of the desired hexasaccharides

35ab–35dd in good yields. The

use of the glycosyl donors 4c

and 4d, containing a benzoate

at the C4 position of the olivo-

side, resulted in good b-selectiv-

ity (b/a=83:17 to >90:10). On

the other hand, the glycosyl Figure 2. The hexasaccharide library 2 based on the strucutre of the landomycin sugar part.

Chem. Asian J. 2010, 5, 1407 – 1424

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H. Tanaka, T. Takahashi et al.

FULL PAPERS

Table 2. Coupling of two deoxytrisaccharide units via direct b-selective

glycosylation.

strongest and/or structurally important absorbances are reported as the

IR data given in cm^ꢀ1. Optical rotations were measured on a JASCO

model P-1020 polarimeter. The reactions were monitored by thin layer

chromatography carried out on Merck precoated TLC plates (60F-254)

using UV light and p-anisaldehyde/H₂SO₄/ethanol solution. Flash column

chromatography separations were performed using silica gel (KANTO,

silica gel 60 N, spherical, neutral, 40–100 um). NH column chromatogra-

phy separations were performed using silica gel (FUJI SILYSIA, NH-

functionalized silica gel, 100–200 mesh). Gel permeation chromatography

(GPC) for qualitative analysis was performed on Japan Analytical Indus-

try Model LC908 (recycling preparative HPLC) using a polystyrene gel

Entry

Donor^[a]

Acceptor

Product

Yield [%]

b/a^[b]

1

2

3

4

5

6

7

8

3a

3b

3c

3d

4a

4b

4c

4d

4a

4b

4c

4d

4a

4b

4c

4d

4a

4b

4c

4d

35aa

35ab

35ac

35ad

35ba

35bb

35bc

35bd

35ca

35cb

35cc

35cd

35da

35db

35dc

35dd

95

72

90

67

93

76

88

86

80

71

72

90

82

79

93

82:18

77:23

69:31

77:23

70:30

65:35

90:10

>90:10

90:10

85:15

>90:10

73:17

column (JAIGEL-1H, 20 mm

ꢂ 600 mm). Detection of products was

9

made by UV detector (Japan Analytical Industry Model 310) and refrac-

tive index detector (Japan Analytical Industry Model RI-5). ESI-TOF

Mass spectra were measured with P. E. Biosystems TK-3500 Biospectr-

ometry Workstation. Dry THF, dry toluene, and dry ether were distilled

from sodium wire in the presence of a catalytic amount of benzophenone.

Dry CH₂Cl₂was distilled from P₂O₅. Dry DMF and dry triethylamine

were distilled from CaH₂. Dry methanol and dry ethanol were distilled

from magnesium in the presence of a catalytic amount of iodine.

10

11

12

13

14

15

16

[a] The donors, prepared from 2.0 equivalents of the corresponding 5a–d,

were used. [b] The ratio was determined by HPLC based on RI.

Synthesis

16: To a solution of 10 (1.42 g, 6.65 mmol) in methanol (20.0 mL) was

added K₂CO₃(9.00 mg, 0.0665 mmol) at room temperature. After stirring

at room temperature for 1 h, the reaction mixture was concentrated in

vacuo. The residue was used for the next reaction without further purifi-

cation. To a stirred solution of the residue in toluene (66.5 mL) was

added Bu₂SnO (4.58 g, 18.4 mmol) at room temperature. The reaction

mixture was stirred at 1408C for 6 h, then cooled to room temperature.

Bu₄NI (6.84 g, 18.4 mmol) and benzyl bromide (2.98 mL, 25.1 mmol)

were added to the reaction mixture at room temperature. After stirring

at 1008C for 18 h, the reaction mixture was poured into saturated aq.

NaHCO₃. The aqueous layer was extracted with two portions of ethyl

acetate. The combined extract was washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo. The residue was used for the next re-

action without further purification. To a stirred solution of the residue in

CH₂Cl₂(33.3 mL) was added benzoyl chloride (0.926 mL, 7.98 mmol),

TMEDA (6.65 mL), and a catalytic amount of DMAP at 08C under

argon. After stirring at room temperature for 2 h, the reaction mixture

was poured into saturated aq. NaHCO₃. The aqueous layer was extracted

with two portions of ethyl acetate. The combined extract was washed

with 3m HCl, saturated aq. NaHCO₃, brine, dried over MgSO₄, filtered,

and concentrated in vacuo. The residue was used for the next reaction

without further purification. To a stirred solution of the residue in aceto-

nitrile (33.3 mL) and water (6.65 mL) was added lithium bromide (1.74 g,

20.0 mmol) and a catalytic amount of Dowex at room temperature. After

stirring at room temperature for 1 h, the reaction mixture was poured

into saturated aq. NaHCO₃. The aqueous layer was extracted with two

portions of ethyl acetate. The combined extract was washed with brine,

dried over MgSO₄, filtered, and concentrated in vacuo. The residue was

chromatographed on silica gel with 70:30 hexane/ethyl acetate to give 16

(1.91 g, 5.59 mmol, 4 steps 84%, a/b=72:28). The a/b ratio was deter-

mined by ¹H NMR analysis. ¹H NMR (400 MHz, CDCl₃): d=8.05–7.15

(m, 20H), 5.40 (brs, 1H), 5.04 (t, 1H, J=9.2 Hz), 5.03 (t, 1H, J=9.2 Hz),

4.85 (brd, 1H, J=9.7 Hz), 4.62–4.46 (m, 4H), 4.21–4.04 (m, 2H), 3.73–

3.54 (m, 2H), 3.03 (brs, 1H), 2.46 (m, 1H), 2.34 (dd, 1H, J=13.0 Hz, J=

4.8 Hz), 2.04 (brs, 1H), 1.82 (t, 1H, J=13.0 Hz), 1.71 (ddd, 1H, J=

11.6 Hz, J=9.7 Hz), 1.26 (d, 3H, J=7.2 Hz), 1.21 ppm (d, 3H, J=

Table 3. Deprotection of the protected oligosaccharides 35aa–dd.

Entry

Substrates

Products

Overall yield [%]

1

2

3

4

5

6

7

8

35aa

35ab

35ac

35ad

35ba

35bb

35bc

35bd

35ca

35cb

35cc

35cd

35da

35db

35dc

35dd

2aa

2ab

2ac

2ad

2ba

2bb

2bc

2bd

2ca

2cb

2cc

2cd

2da

2db

2dc

2dd

70

55

45

34

65

71

39

68

55

72

71

57

49

80

44

77

9

10

11

12

13

14

15

16

sembling the various regioisomers of deoxyoligosaccharides

and involves the use of a small set of building blocks. Fur-

ther biological evaluation of the hexasaccharide library, and

the total synthesis of landomycin A are currently in prog-

ress.

Experimental Section

General

6.3 Hz); IR (neat): n˜ =1723, 1272, 1126, 772 cm^ꢀ1

.

NMR spectra were recorded on a JEOL Model EX-270 (270 MHz for

¹H, 67.8 MHz for ¹³C) or a JEOL Model ECP-400 (400 MHz for ¹H,

100 MHz for ¹³C) in the specified solvent. Chemical shifts are reported in

parts per million (ppm) relative to the signal (0.00 ppm) for internal tet-

ramethylsilane in CDCl₃. ¹H NMR spectral data are reported as follows:

CDCl₃(7.26 ppm) or CD₂Cl₂(5.30 ppm). ¹³C NMR spectral data are re-

ported as follows: CDCl₃(77.1 ppm). NMR multiplicities are reported

using the following abbreviations. (s: singlet, d: doublet, t: triplet, q:

quartet m: multiplet, br: broad, J: coupling constants in Hertz.). Infrared

spectra (IR) were recorded on a Perkin–Elmer Spectrum 1. Only the

7: To a stirred solution of 16 (50.0 mg, 0.150 mmol) in CH₂Cl₂(1.50 mL)

was added trichloroacetonitrile (44.0 mL, 0.440 mmol) and a catalytic

amount of Cs₂CO₃at room temperature under argon. After stirring at

room temperature for 3 h, the reaction mixture was filtered through

celite, and concentrated in vacuo. After ion exchange chromatography on

NH-functionalized silica gel with CH₂Cl₂, the residue was used for the

next reaction without further purification.

12: To a solution of 10 (3.30 g, 15.4 mol) in methanol (50.0 mL) was

added K₂CO₃(21.3 mg, 0.154 mmol) at room temperature. After stirring

1412

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

at room temperature for 1 h, the reaction mixture was concentrated in

vacuo. The residue was used for the next reaction without further purifi-

cation. To a stirred solution of the residue in toluene (50.0 mL) was

added Bu₂SnO (4.22 g, 16.9 mmol) at room temperature under argon.

The reaction mixture was stirred under 1408C for 5 h, then cooled to

room temperature. Then Bu₄NI (6.30 g, 16.9 mmol) and naphthyl bro-

mide (5.11 g, 23.1 mmol) were added to the reaction mixture at room

temperature. After stirring at 1008C for 18 h, the reaction mixture was

poured into saturated aq. NaHCO₃. The aqueous layer was extracted

with two portions of ethyl acetate. The combined extract was washed

with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The

residue was chromatographed on silica gel with 80:20 hexane/ethyl ace-

tate to give 12 (3.12 g, 11.5 mmol, 2 steps 75%). ½aꢁ²_D⁶=ꢀ83.6 (c=1.05,

13.1 Hz, J=4.8 Hz), 1.76–1.61 (m, 2H), 1.33 (d, 3H, J=6.3 Hz), 1.29 ppm

(d, 3H, J=6.3 Hz); IR (neat): n˜ =3020, 1730, 1351, 1217, 998, 759 cm^ꢀ1

.

8b: To a stirred solution of 28 (2.42 g, 5.47 mmol) in CH₂Cl₂(54.7 mL)

was added trichloroacetonitrile (1.65 mL, 16.4 mmol) and a catalytic

amount of Cs₂CO₃at room temperature under argon. After stirring at

room temperature for 3 h, the reaction mixture was filtered through

celite and concentrated in vacuo. After ion exchange chromatography on

NH-functionalized silica gel with CH₂Cl₂, the residue was used for the

next reaction without further purification.

20: To

a stirred solution of 19 (11.2 g, 52.2 mmol) in acetonitrile

(261 mL) was added methanol (21.1 mL, 52.2 mmol) and a catalytic

amount of FeCl₃at 08C. After stirring at room temperature for 3 h, the

reaction mixture was poured into saturated aq. NaHCO₃. The aqueous

layer was extracted with two portions of ethyl acetate. The combined ex-

tract was washed with brine, dried over MgSO_4,filtered, and concentrat-

ed in vacuo. The residue was used for the next reaction without further

purification. To a stirred solution of the residue in methanol (261 mL)

was added a catalytic amount of sodium methoxide at room temperature

under argon. After stirring at room temperature for 12 h, the reaction

mixture was poured into saturated aq. NaHCO₃. The aqueous layer was

extracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO₄, filtered, and concentrated in

vacuo. The residue was chromatographed on silica gel with 80:20 hexane/

ethyl acetate to give 20 (4.06 g, 26.1 mmol, 2 steps 50%, a/b=>99:1) as

a colorless oil. The a/b ratio was determined by ¹H NMR analysis.

¹H NMR (400 MHz, CDCl₃): d=5.88 (brd, 1H, J=10.6 Hz), 5.68 (ddd,

1H, J=10.2 Hz, J=2.4 Hz), 4.78 (brs, 1H), 3.87–3.54 (m, 2H), 3.39 (s,

3H), 2.55 (m, 1H), 1.29 ppm (d, 3H, J=5.8 Hz); IR (neat): n˜ =3018,

1

CHCl₃); H NMR (400 MHz, CDCl₃): d=7.84–7.46 (m, 7H), 6.34 (d, 1H,

J=6.3 Hz), 4.87–4.83 (m, 2H), 4.69 (brd, 1H, J=11.6 Hz), 4.08 (brd,

1H, J=7.3 Hz), 3.87 (m, 1H), 3.64 (t, 1H, J=8.2 Hz), 2.43 (brs, 1H,

OH), 1.37 ppm (d, 3H, J=6.3 Hz); ¹³C NMR (100 MHz, CDCl₃): d=

145.0, 135.7, 133.2, 132.9, 128.3, 127.8, 12.7, 126.5, 126.2, 125.9, 125.7,

99.7, 76.8, 74.4, 72.7, 70.6, 17.1 ppm; IR (neat): n˜ =3406, 2974, 1646, 1509,

1451, 1387, 1230, 1056, 856, 817, 743, 476 cm^ꢀ1

17: To stirred solution of 12 (47.0 mg, 0.174 mmol) in pyridine

.

a

(0.870 mL) was added (p-nitrobenzyl)ethylsulfonyl chloride (49.9 mg,

0.261 mmol) and a catalytic amount of DMAP at 08C under argon. After

stirring at room temperature for 2 h, the reaction mixture was poured

into saturated aq. NaHCO₃. The aqueous layer was extracted with two

portions of ethyl acetate. The combined extract was washed with 3m

HCl, saturated aq. NaHCO₃, brine, dried over MgSO₄, filtered, and con-

centrated in vacuo. The residue was used for the next reaction without

further purification. To a stirred solution of the residue in acetonitrile

(0.870 mL) and water (0.174 mL) was added lithium bromide (45.0 mg,

0.524 mmol) and a catalytic amount of Dowex at room temperature.

After stirring at 508C for 3 h, the reaction mixture was poured into satu-

rated aq. NaHCO₃. The aqueous layer was extracted with two portions of

ethyl acetate. The combined extract was washed with brine, dried over

MgSO₄, filtered, and concentrated in vacuo. The residue was chromato-

graphed on silica gel with 70:30 hexane/ethyl acetate to give 17 (84.4 mg,

0.173 mmol, 2 steps 99%, a/b=79:21). The a/b ratio was determined by

1584, 1478, 1439, 1375, 1219, 1105, 1014, 969, 771 cm^ꢀ1

.

22: To a stirred solution of 20 (0.510 g, 3.54 mmol) in THF (8.85 mL) was

added 4-nitrobenzoic acid (0.887 g, 5.31 mmol) and PPh₃(1.36 g,

7.79 mmol) at 08C. After stirring at room temperature for 30 min, the re-

action mixture was added dropwise a 2.20m toluene solution of DEAD

(3.54 mL, 7.79 mmol) in THF (8.85 mL) at 08C. After stirring at room

temperature for 2 h, the reaction mixture was concentrated in vacuo. The

residue was used for the next reaction without further purification. To a

stirred solution of the residue in THF (17.7 mL) and methanol (17.7 mL)

was added a catalytic amount of sodium methoxide at room temperature

under argon. After stirring at room temperature for 12 h, the reaction

mixture was poured into saturated aq. NaHCO₃. The aqueous layer was

extracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO_4,filtered, and concentrated in

vacuo. The residue was used for the next reaction without further purifi-

cation. To a stirred solution of the residue in CH₂Cl₂(17.7 mL) was

added acetic anhydride (0.401 mL, 4.25 mmol), triethylamine (3.54 mL),

and a catalytic amount of DMAP at room temperature. After stirring at

room temperature for 6 h, the reaction mixture was poured into saturated

aq. NaHCO₃. The aqueous layer was extracted with two portions of ethyl

acetate. The combined extract was washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo. The residue was chromatographed

on silica gel with 80:20 hexane/ethyl acetate to give 22 (0.253 g,

1.36 mmol, 3 steps 39%, a/b=>99:1). The a/b ratio was determined by

¹H NMR analysis. ¹H NMR (400 MHz, CDCl₃): d=6.10–5.99 (m, 2H),

4.92 (brs, 2H), 4.28 (m, 1H), 3.43 (s, 3H), 2.10 (s, 3H), 1.22 ppm (d, 3H,

J=6.8 Hz); IR (neat): n˜ =3018, 1735, 1584, 1478, 1439, 1375, 1219, 1105,

1

¹H NMR. H NMR (400 MHz, CDCl₃): d=7.75–6.65 (m, 22H), 5.42 (brs,

1H), 4.92–4.83 (m, 3H), 4.47 (d, 1H, J=10.6 Hz), 4.45 (d, 1H, J=

10.6 Hz), 4.36 (t, 1H, J=9.2 Hz), 4.36 (t, 1H, J=9.2 Hz), 4.20–4.13 (m,

2H), 3.81 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.59 (m, 1H),

3.40–2.95 (m, 8H), 2.68–2.63 (m, 2H), 2.55 (dd, 1H, J=13.0 Hz, J=

4.8 Hz), 1.77 (m, 1H), 1.69 (ddd, 1H, J=11.6 Hz, J=13.0 Hz, J=9.7 Hz),

1.44 (d, 3H, J=5.8 Hz), 1.39 ppm (d, 3H, J=6.3 Hz); IR (neat): n˜ =3020,

1730, 1523, 1349, 1218, 771 cm^ꢀ1

.

18: To a stirred solution of 12 (770 mg, 2.85 mmol) in pyridine (14.2 mL)

was added benzylsulfonyl chloride (815 mg, 4.28 mmol) and a catalytic

amount of DMAP at 08C under argon. After stirring at room tempera-

ture for 2 h, the reaction mixture was poured into saturated aq. NaHCO₃.

The aqueous layer was extracted with two portions of ethyl acetate. The

combined extract was washed with 3m HCl, saturated aq. NaHCO₃, and

brine, dried over MgSO₄, filtered, and concentrated in vacuo. The residue

was used for the next reaction without further purification. To a stirred

solution of the residue in acetonitrile (14.2 mL) and water (2.85 mL) was

added lithium bromide (735 mg, 8.55 mmol) and a catalytic amount of

Dowex at room temperature. After stirring at room temperature for 1 h,

the reaction mixture was poured into saturated aq. NaHCO₃. The aque-

ous layer was extracted with two portions of ethyl acetate. The combined

extract was washed with brine, dried over MgSO₄, filtered, and concen-

trated in vacuo. The residue was chromatographed on silica gel with

70:30 hexane/ethyl acetate to give 18 (900 mg, 2.00 mmol, 2 steps 70%,

a/b=73:27). The a/b ratio was determined by ¹H NMR analysis.

¹H NMR (400 MHz, CDCl₃): d=7.78–7.16 (m, 24H), 5.33 (brs, 1H),

4.83–4.62 (m, 4H), 4.77 (brd, 1H, J=9.2 Hz), 4.45–4.36 (m, 4H), 4.27 (d,

1H, J=14.2 Hz), 4.27 (d, 1H, J=14.2 Hz), 4.16 (ddd, 1H, J=11.1 Hz, J=

4.8 Hz, J=9.7 Hz), 4.11 (m, 1H), 3.76 (ddd, 1H, J=11.6 Hz, J=4.8 Hz,

J=9.2 Hz), 3.68 (m, 1H), 3.49 (dq, 1H, J=6.3 Hz, J=9.2 Hz), 3.00 (brs,

1H), 2.50 (ddd, 1H, J=1.5 Hz, J=12.6 Hz, J=4.8 Hz), 2.43 (dd, 1H, J=

1014, 969, 771 cm^ꢀ1

.

24: To a stirred solution of 22 (0.739 g, 3.97 mmol) in ethyl acetate

(19.9 mL) was added Pd/C (100 mg/mmol) at room temperature. After

stirring at room temperature for 75 min, the reaction mixture was con-

centrated in vacuo. The residue was used for the next reaction without

further purification. To a stirred solution of the residue in CH₂Cl₂

(19.9 mL) was added thiophenol (0.814 mL, 7.94 mmol) and a catalytic

amount of ScACHTNUTRGNENG(U OTf)₃at 08C. After stirring at room temperature for 3 h,

the reaction mixture was poured into saturated aq. NaHCO₃. The aque-

ous layer was extracted with two portions of ethyl acetate. The combined

extract was washed with brine, dried over MgSO₄, filtered and concen-

trated in vacuo. The residue was chromatographed on silica gel with

80:20 hexane/ethyl acetate to give 24 (0.528 g, 1.99 mmol, 2 steps 50%,

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

1413

H. Tanaka, T. Takahashi et al.

FULL PAPERS

a/b=>99:1). The a/b ratio was determined by ¹H NMR analysis.

¹H NMR (400 MHz, CDCl₃): d=7.47–7.19 (m, 5H), 5.66 (brs, 1H, J=

5.3 Hz), 4.88 (brs, 1H), 4.49 (q, 1H, J=6.8 Hz), 2.35 (m, 1H), 2.13 (s,

3H), 2.06 (tt, 1H, J=14.5 Hz, J=3.4 Hz), 1.92 (m, 1H), 1.81 (brd, 1H,

J=14.0 Hz), 1.12 ppm (d, 3H, J=6.8 Hz); IR (neat): n˜ =3016, 1729,

ꢀ1.47 ppm; IR (neat): n˜ =3018, 1719, 1507, 1451, 1365, 1270, 1219, 1035,

1000, 861, 772, 528 cm^ꢀ1

478.2625, found: 478.2625.

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

27: To a stirred solution of 25 (100 mg, 0.177 mmol) in THF (0.885 mL)

and methanol (0.855 mL) was added Pd/C (17.7 mg). After stirring at

room temperature for 12 h under H₂, the reaction mixture was filtered

and concentrated in vacuo. The residue was chromatographed on silica

gel with 70:30 hexane/ethyl acetate to give 27 (66.7 mg, 0.142 mmol,

80%). ½aꢁ²_D⁶=ꢀ0.95 (c=0.575, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

8.04–7.41 (m, 5H), 6.98 (brs, 4H), 5.16 (s, 2H), 5.07 (dd, 1H, J=9.7 Hz,

J=1.9 Hz), 4.82 (t, 1H, J=9.2 Hz), 3.93 (ddd, 1H, J=9.2 Hz, J=5.3 Hz,

J=11.6 Hz), 3.75 (t, 2H, J=8.2 Hz), 3.68 (m, 1H), 3.15 (brs, 1H), 2.45

(ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=5.3 Hz), 2.01 (ddd, 1H, J=11.6 Hz,

J=12.6 Hz, J=9.7 Hz), 1.32 (d, 3H, J=5.8 Hz), 0.96 (t, 2H, J=8.2 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=166.8, 152.8, 151.8,

133.4, 129.7, 129.4, 128.4, 117.8, 117.2, 98.1, 93.4, 78.7, 77.3, 70.1, 69.8,

65.9, 39.3, 17.9, 17.8, ꢀ1.52 ppm; IR (neat): n˜ =3019, 1710, 1506, 1364,

1218, 1070, 1001, 772, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

492.2418, found: 492.2416.

1447, 1367, 1247, 1065, 770, 669 cm^ꢀ1

.

9: To a stirred solution of 24 (386 mg, 1.72 mmol) in methanol (8.60 mL)

was added a catalytic amount of NaOMe at room temperature. After stir-

ring at room temperature for 3 h, the reaction mixture was poured into

saturated aq. NaHCO₃. The aqueous layer was extracted with two por-

tions of ethyl acetate. The combined extract was washed with brine, dried

over MgSO₄, filtered, and concentrated in vacuo. The residue was used

for the next reaction without further purification. To a stirred solution of

the residue in CH₂Cl₂(8.60 mL) was added EDCI (490 mg, 2.58 mmol),

LevOH (264 mL, 2.58 mmol), and DIEA (591 mL, 3.44 mmol) at 08C.

After stirring at room temperature for 3 h, the reaction mixture was

poured into saturated aq. NaHCO₃. The aqueous layer was extracted

with two portions of ethyl acetate. The combined extract was washed

with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The

residue was chromatographed on silica gel with 80:20 hexane/ethyl ace-

tate to give 9 (665 mg, 2.06 mmol, 2 steps 80%, a/b=>99:1). The a/b

ratio was determined by ¹H NMR analysis. ¹H NMR (400 MHz, CDCl₃):

d=7.47–7.20 (m, 5H), 5.65 (brd, 1H), 4.87 (brs, 1H), 4.48 (q, 1H), 2.79–

2.63 (m, 4H), 2.34 (m, 1H), 2.19 (s, 3H), 2.04 (m, 1H), 1.92 (m, 1H),

1.81 (brd, 1H, J=14.0 Hz), 1.12 ppm (d, 3H, J=6.8 Hz); IR (neat): n˜ =

28b: To a stirred solution of 7 in toluene (109 mL) was added 26 (1.73 g,

3.76 mmol), and pulverized activated MS 4ꢁ (1.00 gmmol^ꢀ1). After stir-

ring at room temperature for 30 min under argon to remove a trace

amount of water, the reaction mixture was cooled to ꢀ948C. After

10 min, I₂(2.00 g, 8.21 mmol) and a catalytic amount of triethylsilane

were added to the reaction mixture at the same temperature. After stir-

ring for 3 h, the reaction mixture was neutralized with triethylamine, fil-

tered through celite, and poured into a mixture of aq. NaHCO₃and aq.

Na₂S₂O₃. The aqueous layer was extracted with two portions of ethyl ace-

tate. The combined extract was washed with brine, dried over MgSO₄, fil-

tered, and concentrated in vacuo. The residue was chromatographed on

silica gel with 80:20 hexane/ethyl acetate and GPC to give 28b (2.48 g,

2.82 mmol, 75%, a/b=7:93). The a/b ratio was determined by ¹H NMR

analysis. ½aꢁ²_D¹=ꢀ29.3 (c=1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

7.83–7.19 (m, 17H), 7.00–6.94 (m, 4H), 5.18 (s, 2H), 4.98 (dd, 1H, J=

9.7 Hz, J=1.5 Hz), 4.85 (d, 1H, J=11.6 Hz), 4.77 (dd, 1H, J=9.7 Hz, J=

1.5 Hz), 4.70 (brs, 2H), 4.67 (d, 1H, J=11.6 Hz), 4.44 (t, 1H, J=9.2 Hz),

4.41 (d, 1H, J=13.5 Hz), 4.29 (d, 1H, J=13.5 Hz), 3.78 (m, 1H), 3.77 (t,

2H, J=8.2 Hz), 3.67 (ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=8.7 Hz), 3.51–

3.36 (m, 3H), 2.52–2.47 (m, 2H), 1.90 (ddd, 1H, J=12.1 Hz, J=12.6 Hz,

J=9.7 Hz), 1.73 (ddd, 1H, J=12.1 Hz, J=12.6 Hz, J=9.7 Hz), 1.34 (d,

3H, J=5.8 Hz), 1.33 (d, 3H, J=5.8 Hz), 0.98 (t, 2H, J=8.2 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=152.8, 151.9, 138.4,

134.7, 133.2, 133.0, 130.4, 128.7, 128.6, 128.4, 128.3, 127.8, 127.7, 127.6,

127.5, 126.7, 126.3, 126.1, 125.6, 117.7, 117.2, 99.8, 98.1, 93.4, 83.8, 82.6,

77.2, 76.0, 71.7, 71.1, 70.7, 70.2, 66.0, 57.4, 36.9, 36.8, 18.3, 18.0, 17.9,

ꢀ1.47 ppm; IR (neat): n˜ =3020, 1732, 1506, 1359, 1216, 1085, 980, 758,

3016, 1729, 1447, 1367, 1247, 1065, 770, 669 cm^ꢀ1

.

25: To a stirred solution of 7 in toluene (3.00 mL) was added p-(2-(trime-

thylsilyl)ethoxymethoxy)phenol 6 (35.0 mg, 0.150 mmol), and pulverized

activated 4ꢁ molecular sieves (MS 4ꢁ) (150 mg). After stirring at room

temperature for 30 min under argon to remove a trace amount of water,

the reaction mixture was cooled to ꢀ948C. After 10 min, I₂(56.0 mg,

0.220 mmol) and a catalytic amount of triethylsilane were added to the

reaction mixture at the same temperature. After stirring for 3 h, the reac-

tion mixture was neutralized with triethylamine, filtered through Celite,

and poured into aq. NaHCO₃and aq. Na₂S₂O₃. The aqueous layer was

extracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO₄, filtered, and concentrated in

vacuo. The residue was chromatographed on silica gel with 80:20 hexane/

ethyl acetate and GPC to give 25 (64.0 mg, 0.115 mmol, 79%, a/b=10:

>90). The a/b ratio was determined by ¹H NMR analysis. ½aꢁ_D²¹=ꢀ42.3

1

(c=0.260, CHCl₃) ; H NMR (400 MHz, CDCl₃): d=8.07–7.20 (m, 10H),

6.99 (brs, 4H), 5.18 (s, 2H), 5.13 (t, 1H, J=9.2 Hz), 5.07 (dd, 1H, J=

9.7 Hz, J=1.9 Hz), 4.66 (d, 1H, J=12.1 Hz), 4.52 (d, 1H, J=12.6 Hz),

3.82–3.75 (m, 3H), 3.66 (m, 1H), 2.57 (ddd, 1H, J=1.9 Hz, J=12.6 Hz,

J=4.8 Hz), 2.04 (ddd, 1H, J=12.6 Hz, J=9.7 Hz), 1.33 (d, 3H, J=

6.8 Hz), 0.98 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H,); ¹³C NMR (100 MHz,

CDCl₃): d=165.6, 152.9, 151.8, 137.8, 133.1, 129.9, 129.7, 128.4, 128.2,

127.5, 117.8, 117.2, 98.3, 93.4, 77.2, 76.0, 75.4, 70.8, 70.4, 66.0, 36.5, 18.0,

17.8, ꢀ1.49 ppm; IR (neat): n˜ =3019, 1711, 1506, 1364, 1218, 1119, 1090,

1056, 923, 771, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 582.2887,

found: 582.2897.

668 cm^ꢀ1

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 902.3969, found:

902.3975.

29: To a stirred solution of 8b in toluene (49.2 mL) was added 27 (1.14 g,

2.40 mmol) and pulverized activated MS 4ꢁ (246 mg). After stirring at

room temperature for 30 min under argon to remove a trace amount of

water, the reaction mixture was cooled to ꢀ948C. After 10 min, I₂

(938 mg, 3.70 mmol) and a catalytic amount of triethylsilane was added

to the reaction mixture at the same temperature. After stirring for 3 h,

the reaction mixture was neutralized with triethylamine, filtered through

celite, and poured into a mixture of aq. NaHCO₃and aq. Na₂S₂O₃. The

aqueous layer was extracted with two portions of ethyl acetate. The com-

bined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was chromatographed on silica gel

with 80:20 hexane/ethyl acetate and GPC to give 29 (1.07 g, 1.95 mmol,

79%, a/b=10:90). The a/b ratio was determined by ¹H NMR analysis.

26: To

a stirred solution of 25 (100 mg, 0.177 mmol) in methanol

(1.77 mL) was added a catalytic amount of sodium methoxide at 08C

under argon. After stirring at room temperature for 2 h, the reaction mix-

ture was poured into saturated aq. NaHCO₃. The aqueous layer was ex-

tracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO₄, filtered, and concentrated in

vacuo. The residue was chromatographed on silica gel with 70:30 hexane/

ethyl acetate to give 26 (81.6 mg, 0.177 mmol, quant.). ½aꢁ²_D¹=ꢀ39.9 (c=

0.150, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.39–7.31 (m, 5H), 6.97–

6.93 (brs, 4H), 5.16 (s, 2H), 5.00 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.73 (d,

1H, J=11.6 Hz), 4.52 (d, 1H, J=11.6 Hz), 3.76 (t, 2H, J=8.2 Hz), 3.48

(ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=8.7 Hz), 3.41 (m, 1H), 3.30 (t, 1H,

J=9.2 Hz), 2.61 (s, 1H), 2.50 (ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=

4.8 Hz), 1.84 (ddd, 1H, J=11.6 Hz, J=12.6 Hz, J=9.7 Hz), 1.38 (d, 3H,

J=6.3 Hz), 0.97 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=152.8, 151.9, 137.9, 128.6, 127.9, 127.8, 117.7,

117.2, 98.2, 93.5, 78.7, 77.2, 75.4, 71.8, 70.9, 66.0, 35.9, 18.0, 17.9,

½aꢁ²_D¹=ꢀ28.3 (c=1.33, CHCl₃); H NMR (400 MHz, CDCl₃): d=8.09–6.61

1

(m, 16H), 6.98 (brs, 4H), 5.17 (s, 2H), 5.10 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 5.00 (t, 1H, J=9.2 Hz), 4.75 (d, 1H, J=10.6 Hz), 4.65 (dd, 1H,

J=9.7 Hz, J=1.9 Hz), 4.34 (d, 1H, J=10.6 Hz), 4.18 (m, 1H), 4.16 (t,

1H, J=9.2 Hz), 3.76 (t, 2H, J=8.2 Hz), 3.76–3.68 (m, 2H), 3.43 (m, 1H),

3.34–2.94 (m, 4H), 2.52 (ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=5.3 Hz), 2.47

(ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=4.8 Hz), 2.03 (ddd, 1H, J=12.6 Hz,

1414

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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

J=12.1 Hz, J=9.7 Hz), 1.64 (ddd, 1H, J=12.6 Hz, J=12.1 Hz, J=

9.7 Hz), 1.34 (d, 3H, J=6.3 Hz), 1.22 (d, 3H, J=6.3 Hz), 0.96 (t, 2H, J=

8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=165.9, 153.0,

151.8, 146.5, 144.3, 134.2, 133.1, 132.9, 130.2, 129.8, 128.3, 127.6, 126.6,

126.5, 126.4, 125.4, 123.4, 117.9, 117.3, 98.2, 96.1, 93.5, 84.3, 76.3, 74.9,

74.0, 70.5, 70.1, 66.1, 51.5, 36.6, 36.4, 28.9, 18.0, 17.9, 17.6, ꢀ1.46 ppm; IR

(neat): n˜ =3020, 1729, 1506, 1349, 1217, 771, 669 cm^ꢀ1; HRMS (ESI-TOF)

[M+NH₄]⁺calcd.: 975.3769, found: 975.3788.

9.7 Hz), 1.57 (ddd, 1H, J=12.1 Hz, J=12.6 Hz, J=9.7 Hz), 1.31 (d, 3H,

J=5.8 Hz), 1.12 (d, 3H, J=5.8 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.00 ppm (s,

9H); ¹³C NMR (100 MHz, CDCl₃): d=166.1, 153.0, 151.7, 147.0, 145.0,

133.2, 130.0, 129.7, 129.4, 128.3, 123.9, 117.8, 117.3, 98.1, 96.0, 93.5, 86.0,

77.2, 75.0, 74.2, 70.4, 69.5, 69.2, 66.0, 51.7, 40.0, 36.6, 29.6, 18.0, 17.9, 17.4,

ꢀ1.48 ppm; IR (neat): n˜ =3020, 1726, 1506, 1349, 1216, 1064, 838, 772,

669 cm^ꢀ1

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 835.3143, found:

835.3143.

30: To

a

stirred solution of 28b (633 mg, 0.715 mmol) in CH₂Cl₂

33: To a stirred solution of 29 (315 mg, 0.329 mmol) in CH₂Cl₂(1.65 mL)

was added a large excess of DBU at 08C under argon. After stirring at

room temperature for 6 h, the reaction mixture was poured into H₂O.

The aqueous layer was extracted with two portions of ethyl acetate. The

combined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was chromatographed on silica gel

with 70:30 hexane/ethyl acetate to give 33 (223 mg, 0.296 mmol, 90%).

½aꢁ²_D¹=ꢀ48.6 (c=0.360, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=8.12–

7.39 (m, 12H), 7.00 (brs, 4H), 5.09 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 5.01

(t, 1H, J=9.2 Hz, J=9.2 Hz), 4.74 (d, 1H, J=11.6 Hz), 4.57–4.52 (m,

2H), 4.16 (ddd, 1H, J=12.6 Hz, J=5.3 Hz, J=9.2 Hz), 3.78 (t, 2H, J=

8.2 Hz), 3.70 (m, 1H), 3.37 (ddd, 1H, J=13.0 Hz, J=4.8 Hz, J=8.7 Hz),

3.16 (m, 1H), 3.06 (t, 1H, J=8.5 Hz, J=8.7 Hz), 2.63 (s, 1H), 2.50 (ddd,

1H, J=1.5 Hz, J=11.1 Hz, J=4.8 Hz), 2.26 (ddd, 1H, J=1.5 Hz, J=

11.1 Hz, J=4.8 Hz), 2.03 (ddd, 1H, J=13.0 Hz, J=11.1 Hz, J=9.7 Hz),

1.50 (ddd, 1H, J=13.0 Hz, J=11.1 Hz, J=9.7 Hz), 1.35 (d, 3H, J=

5.8 Hz), 1.12 (d, 3H, J=5.8 Hz), 0.99 (t, 2H, J=8.2 Hz), 0.00 ppm (s,

9H); ¹³C NMR (100 MHz, CDCl₃): d=165.8, 152.9, 151.8, 135.3, 133.1,

132.9, 132.8, 130.3, 129.8, 128.3, 128.1, 127.8, 127.6, 126.4, 126.1, 125.9,

125.5, 117.8, 117.2, 98.2, 96.5, 93.4, 78.5, 77.2, 75.4, 75.1, 73.5, 71.5, 70.5,

70.4, 65.9, 36.7, 36.0, 18.0, 17.9, 17.6, ꢀ1.50 ppm; IR (neat): n˜ =3018,

(3.58 mL) and NaHCO₃aq. (0.715 mL) was added DDQ (324 mg,

1.43 mmol) at 08C under argon. After stirring at room temperature for

3 h, the reaction mixture was poured into saturated aq. NaHCO₃. The

aqueous layer was extracted with two portions of ethyl acetate. The com-

bined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was chromatographed on silica gel

with 70:30 hexane/ethyl acetate to give 30 (378 mg, 0.508 mmol, 71%).

½aꢁ²_D⁰=ꢀ25.3 (c=0.770, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.42–

7.28 (m, 10H), 6.96 (brs, 4H), 5.15 (s, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 4.73 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.68 (brs, 2H), 4.49 (brs,

2H), 4.20 (t, 1H, J=9.2 Hz), 3.76–3.71 (m, 3H), 3.63 (ddd, 1H, J=

12.1 Hz, J=5.3 Hz, J=9.2 Hz), 3.44 (m, 1H), 3.34 (t, 1H, J= J=9.2 Hz),

3.27 (m, 1H), 2.68 (d, 1H, J=3.9 Hz), 2.45 (ddd, 1H, J=1.9 Hz, J=

12.5 Hz, J=5.3 Hz), 2.31 (ddd, 1H, J=1.9 Hz, J=12.5 Hz, J=5.3 Hz),

1.86 (ddd, 1H, J=12.1 Hz, J=12.5 Hz, J=9.7 Hz), 1.67 (ddd, 1H, J=

12.1 Hz, J=12.5 Hz, J=9.7 Hz), 1.34 (d, 3H, J=5.8 Hz), 1.10 (d, 3H, J=

6.3 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz,

CDCl₃): d=152.9, 151.9, 138.5, 130.7, 129.2, 128.9, 128.3, 127.7, 127.6,

127.5, 117.7, 117.2, 100.0, 98.2, 93.5, 85.2, 82.9, 71.8, 71.2, 69.6, 69.1, 66.0,

57.2, 39.3, 36.9, 18.3, 18.0, 17.5 ppm; IR (neat): n˜ =3020, 1732, 1506, 1359,

1216, 1085, 980, 758, 668 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

762.3343, found: 762.3345.

1725, 1506, 1219, 1070, 1001, 772, 670 cm^ꢀ1

; HRMS (ESI-TOF)

[M+NH₄]⁺calcd.: 762.3674, found: 762.3688.

31: To a stirred solution of 28b (547 mg, 0.620 mmol) in DMF (6.20 mL)

was added a large excess of sodium amide at 0 8C under argon. After stir-

ring at room temperature for 12 h, the reaction mixture was poured into

H₂O. The aqueous layer was extracted with two portions of ethyl acetate.

The combined extract was washed with brine, dried over MgSO₄, filtered,

and concentrated in vacuo. The residue was chromatographed on silica

gel with 70:30 hexane/ethyl acetate to give 31 (446 mg, 0.611 mmol,

99%). ½aꢁ²_D¹=ꢀ20.9 (c=1.12, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

7.86–7.27 (m, 12H), 6.98 (brs, 4H), 5.16 (s, 2H), 4.96 (dd, 1H, J=9.7 Hz,

J=1.9 Hz), 4.77 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.86–4.64 (m, 4H), 3.76

(t, 2H, J=8.2 Hz), 3.67 (ddd, 1H, J=11.6 Hz, J=5.3 Hz, J=9.2 Hz),

3.50–3.42 (m, 2H), 3.37 (t, 1H, J=9.2 Hz, J=9.2 Hz), 3.27–3.22 (m, 2H),

2.48–2.44 (m, 2H), 2.38 (ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=4.8 Hz), 1.88

(ddd, 1H, J=11.6 Hz, J=12.6 Hz, J=9.7 Hz), 1.60 (ddd, 1H, J=11.6 Hz,

J=12.6 Hz, J=9.7 Hz), 1.34 (d, 3H, J=6.3 Hz), 1.30 (d, 3H, J=5.3 Hz),

0.97 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃):

d=153.0, 152.1, 138.7, 135.6, 133.4, 133.2, 128.4, 128.0, 127.8, 127.7, 126.7,

126.4, 125.7, 117.9, 117.4, 100.3, 98.3, 93.6, 82.3, 79.0, 77.7, 77.3, 75.8, 72.0,

71.9, 71.4, 71.2, 66.1, 37.0, 36.6, 18.5, 18.2, 18.1, ꢀ1.32 ppm; IR (neat): n˜ =

3018, 1505, 1370, 1218, 1060, 929, 771, 670 cm^ꢀ1; HRMS (ESI-TOF)

[M+NH₄]⁺calcd.: 748.3881, found: 748.3879.

5a: A mixture of 9 (13.8 mg, 0.0420 mmol), 30 (12.5 mg, 0.0168 mmol)

and pulverized activated MS 4ꢁ in dry CH₂Cl₂(1.00 mL) was stirred at

room temperature for 30 min under argon to remove a trace amount of

water. Bu₄NOTf (8.23 mg, 0.0210 mmol) and NBS (11.2 mg, 0.0630 mg)

were added to the reaction mixture at ꢀ788C. The reaction mixture was

warmed to ꢀ408C, neutralized with triethylamine, then filtered through

celite, and poured into a mixture of aq. NaHCO₃and aq. Na₂S₂O₃. The

aqueous layer was extracted with two portions of ethyl acetate. The com-

bined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was purified by chromatography on

silica gel with 60:40 hexane/ethyl acetate, and gel permeation chromatog-

raphy (GPC) to give 5a (16.1 mg, 0.0169 mmol, 95%, a/b=>95:5). The

a/b ratio was determined by ¹H NMR analysis. ½aꢁ²_D²=ꢀ29.3 (c=1.00,

CHCl₃) ; ¹H NMR (400 MHz, CDCl₃): d=7.38–7.27 (m, 10H), 6.98–6.90

(m, 4H), 5.15 (brs, 2H), 5.04 (brs, 1H), 4.95 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 4.77–4.73 (m, 2H), 4.68 (brs, 2H), 4.41–4.30 (d, 2H, J=13.5 Hz),

4.38 (t, 1H, J=9.7 Hz, J=9.7 Hz), 4.03 (q, 1H, J=6.3 Hz), 3.81 (ddd,

1H, J=11.6 Hz, J=4.8 Hz, J=9.7 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.63 (ddd,

1H, J=11.6 Hz, J=4.8 Hz, J=9.7 Hz), 3.43 (m, 1H), 3.38–3.30 (m, 2H),

2.81–2.61 (m, 4H), 2.47 (ddd, 1H, J=1.9 Hz, J=12.1 Hz, J=4.8 Hz), 2.45

(ddd, 1H, J=1.9 Hz, J=12.1 Hz, J=4.8 Hz), 2.19 (s, 3H), 2.20–1.49 (m,

6H), 1.33 (d, 3H, J=5.8 Hz), 1.16 (d, 3H, J=5.8 Hz), 1.03 (d, 3H, J=

6.3 Hz), 0.97 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz,

CDCl₃): d=206.4, 172.3, 152.9, 151.9, 138.6, 130.7, 129.1, 128.9, 128.3,

127.7, 127.5, 127.4, 117.7, 117.2, 99.9, 98.2, 93.5, 91.7, 82.8, 82.4, 71.8, 71.2,

70.2, 69.8, 69.7, 66.0, 65.1, 57.9, 38.0, 36.9, 35.6, 29.8, 28.1, 23.8, 22.2, 18.4,

18.0, 17.9, 16.9, ꢀ1.46 ppm; IR (neat): n˜ =3019, 1720, 1506, 1362, 1216,

1084, 769, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 974.4392,

found: 974.4402.

32: To a stirred solution of 29 (777 mg, 0.810 mmol) in CH₂Cl₂(4.05 mL)

and NaHCO₃aq. (0.810 mL) was added DDQ (184 mg, 1.62 mmol) at

08C under argon. After stirring at room temperature for 3 h, the reaction

mixture was poured into saturated aq. NaHCO₃. The aqueous layer was

extracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO₄, filtered, and concentrated in

vacuo. The residue was chromatographed on silica gel with 70:30 hexane/

ethyl acetate to give 32 (471 mg, 0.575 mmol, 71%). ½aꢁ²_D¹=ꢀ24.7 (c=

1.49, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=8.14–7.35 (m, 9H), 6.96

(brs, 4H), 5.16 (s, 2H), 5.08 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.95 (t, 1H,

J=9.2 Hz, J=9.2 Hz), 4.60 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.13 (ddd,

1H, J=12.1 Hz, J=5.3 Hz, J=9.2 Hz), 4.00 (t, 1H, J=9.2 Hz, J=

9.2 Hz), 3.81–3.68 (m, 2H), 3.75 (t, 2H, J=8.2 Hz), 3.61 (m, 1H), 3.46

(m, 1H), 3.32 (m, 1H), 3.27–3.22 (m, 2H), 2.68 (d, 1H, J=4.8 Hz), 2.50

(ddd, 1H, J=1.5 Hz, J=12.6 Hz, J=5.3 Hz), 2.21 (ddd, 1H, J=1.5 Hz,

J=12.6 Hz, J=5.3 Hz), 1.99 (ddd, 1H, J=12.1 Hz, J=12.6 Hz, J=

5b: According to the method for the synthesis of 5a, a mixture of 9

(137 mg, 0.425 mmol), 31 (212 mg, 0.289 mmol), and pulverized activated

MS 4ꢁ in dry CH₂Cl₂(4.30 mL) was treated with Bu₄NOTf (83.3 mg,

0.213 mmol) and NBS (113 mg, 0.638 mg) to provide 5b (243 mg,

0.323 mmol, 76%, a/b=>90:10). ½aꢁ²_D¹=ꢀ31.2 (c=0.500, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=7.82–7.24 (m, 12H), 6.97–6.90 (m, 4H),

5.15 (brs, 2H), 5.02 (brs, 1H), 4.94 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.79–

4.60 (m, 5H), 4.59 (brs, 1H), 4.30 (q, 1H, J=6.8 Hz), 3.74 (t, 2H, J=

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

1415

H. Tanaka, T. Takahashi et al.

FULL PAPERS

8.2 Hz), 3.63 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=8.2 Hz), 3.53 (ddd, 1H,

J=11.6 Hz, J=4.8 Hz, J=8.7 Hz), 3.47–3.23 (m, 3H), 3.25 (m, 1H), 2.72–

2.58 (m, 4H), 2.48–2.37 (m, 1H), 2.16 (s, 3H), 2.03–1.52 (m, 6H), 1.31 (d,

3H, J=5.8 Hz), 1.26 (d, 3H, J=6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.67 (d,

3H, J=6.8 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=

206.5, 172.3, 152.9, 151.9, 138.7, 135.6, 133.2, 133.0, 128.3, 128.1, 127.8,

127.7, 127.5, 126.7, 126.2, 126.0, 125.9, 117.8, 117.2, 100.2, 98.2, 97.1, 93.5,

82.4, 79.7, 77.5, 72.3, 72.0, 71.3, 71.2, 69.9, 66.0, 65.2, 38.0, 37.0, 29.8, 28.2,

24.0, 18.6, 18.3, 18.1, 16.6, ꢀ1.45 ppm; IR (neat): n˜ =3020, 1731, 1506,

1374, 1249, 1216, 1161, 1059, 910, 758, 669 cm^ꢀ1; HRMS (ESI-TOF)

[M+NH₄]⁺calcd.: 960.4929, found: 960.4940.

J=9.2 Hz), 3.53 (brs, 1H), 3.46–3.33 (m, 3H), 2.50 (ddd, 1H, J=1.9 Hz,

J=12.1 Hz, J=4.8 Hz), 2.46 (ddd, 1H, J=1.9 Hz, J=12.1 Hz, J=4.8 Hz),

2.12–1.49 (m, 6H), 1.35 (d, 3H, J=5.8 Hz), 1.18 (d, 3H, J=6.3 Hz), 1.13

(d, 3H, J=6.6 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=152.8, 151.9, 138.5, 130.6, 129.1, 128.9, 128.3,

127.6, 127.5, 127.4, 117.7, 117.2, 99.9, 98.1, 93.5, 91.8, 82.7, 82.6, 71.8, 71.2,

70.2, 69.7, 67.2, 66.3, 66.0, 57.8, 36.9, 35.6, 25.2, 23.1, 18.4, 18.0, 17.0 ppm;

IR (neat): n˜ =3020, 1732, 1506, 1359, 1216, 1085, 980, 758, 668 cm^ꢀ1

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4024, found: 876.4033.

;

3b: According to the method for the synthesis of 3a, a solution of 5b

(54.2 mg, 0.0520 mmol) in pyridine (0.263 mL) and AcOH (0.390 mL)

was treated with H₂NNH₂·H₂O (12.6 mL, 0.260 mmol) to provide 3b

(36.0 mg, 0.0426 mmol, 82%) ½aꢁ²_D¹=ꢀ33.5 (c=0.740, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=7.84–7.26 (m, 12H), 6.96–6.90 (m, 4H), 5.15 (brs,

2H), 4.98 (brs, 1H), 4.95 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.73 (dd, 1H,

J=9.7 Hz, J=1.9 Hz), 4.80–4.63 (m, 4H), 4.24 (q, 1H, J=6.3 Hz), 3.74 (t,

2H, J=8.2 Hz), 3.63 (ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=8.7 Hz), 3.55

(ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=8.7 Hz), 3.47–3.23 (m, 4H), 3.35

(brs, 1H), 2.46–2.38 (m, 1H), 1.99–1.52 (m, 6H), 1.32–1.26 (m, 6H), 0.95

(t, 2H, J=8.2 Hz), 0.75 (d, 3H, J=6.3 Hz), 0.00 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=152.8, 151.9, 138.7, 135.7, 133.3, 133.0, 128.3,

128.1, 127.7, 127.6, 127.5, 126.8, 126.2, 126.1, 126.0, 117.8, 100.2, 98.2,

97.2, 93.5, 82.4, 79.7, 77.7, 77.5, 77.2, 72.3, 72.0, 71.4, 71.3, 67.4, 66.5, 66.0,

37.1, 25.6, 23.4, 18.6, 18.3, 18.1, 16.7, ꢀ1.44 ppm; IR (neat): n˜ =3018,

1505, 1370, 1218, 1060, 929, 771, 670 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd.: 862.4530, found: 862.4567.

5c: According to the method for the synthesis of 5a, a mixture of 9

(221 mg, 0.685 mmol), 32 (422 mg, 0.515 mmol), and pulverized activated

MS 4ꢁ in dry CH₂Cl₂(6.85 mL) was treated with Bu₄NOTf (134 mg,

0.343 mmol) and NBS (182 mg, 1.03 mmol) to provide 5c (402 mg,

0.390 mmol, 76%, a/b=>95:5). ½aꢁ²_D³=ꢀ35.9 (c=0.550, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=8.19–7.35 (m, 9H), 6.98 (brs, 4H), 5.16

(s, 2H), 5.07 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.95 (t, 1H, J=9.2 Hz, J=

9.2 Hz), 4.91 (brs, 1H), 4.67 (brs, 1H), 4.59 (dd, 1H, J=9.7 Hz, J=

1.5 Hz), 4.17 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.15 (ddd, 1H, J=11.6 Hz,

J=4.8 Hz, J=9.6 Hz), 4.00 (q, 1H, J=6.8 Hz), 3.78–3.65 (m, 4H), 3.48–

3.23 (m, 5H), 2.75–2.60 (m, 4H), 2.47 (ddd, 1H, J=1.5 Hz, J=12.6 Hz,

J=4.8 Hz), 2.30 (ddd, 1H, J=1.5 Hz, J=12.0 Hz, J=4.8 Hz), 2.18 (s,

3H), 2.00 (ddd, 1H, J=4.8 Hz, J=12.6 Hz, J=9.7 Hz), 1.93–1.37 (m,

5H), 1.31 (d, 3H, J=6.3 Hz), 1.11 (d, 3H, J=5.3 Hz), 1.05 (d, 3H, J=

6.8 Hz), 0.97 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz,

CDCl₃): d=206.5, 172.2, 165.7, 153.0, 151.8, 147.2, 144.7, 133.1, 130.2,

129.8, 129.3, 128.3, 124.1, 117.9, 117.3, 98.1, 96.3, 93.5, 91.9, 83.4, 77.2,

75.0, 74.1, 70.5, 70.0, 69.8, 69.3, 66.0, 65.4, 52.5, 37.9, 36.7, 35.5, 29.8, 29.4,

28.1, 23.9, 22.2, 18.0, 17.9, 16.8, ꢀ1.46 ppm; IR (neat): n˜ =3020, 1728,

1506, 1349, 1216, 1087, 770, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd.: 1047.4192, found: 1047.4200.

3c: According to the method for the synthesis of 3a, a solution of 5c

(54.2 mg, 0.0520 mmol) in pyridine (0.263 mL) and AcOH (0.390 mL)

was treated with H₂NNH₂·H₂O (12.6 mL, 0.260 mmol) to provide 3c

(34.4 mg, 0.0442 mmol, 85%). ½aꢁ²_D³=ꢀ49.1 (c=1.01, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=8.18–7.35 (m, 9H), 6.96 (brs, 4H), 5.16 (s, 2H),

5.07 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.95 (t, 1H, J=9.2 Hz, J=9.2 Hz),

4.87 (brs, 1H), 4.60 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.14 (t, 1H, J=

9.2 Hz, J=9.2 Hz), 4.10 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.92

(q, 1H, J=6.3 Hz), 3.78–3.67 (m, 4H), 3.49–3.20 (m, 6H), 2.46 (ddd, 1H,

J=1.5 Hz, J=12.6 Hz, J=4.8 Hz), 2.33 (ddd, 1H, J=1.5 Hz, J=12.6 Hz,

J=4.8 Hz), 2.00 (ddd, 1H, J=11.6 Hz, J=12.6 Hz, J=9.7 Hz), 1.90–1.36

(m, 5H), 1.31 (d, 3H, J=5.8 Hz), 1.13–1.11 (m, 6H), 0.95 (t, 2H, J=

8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=165.7, 153.0,

151.7, 147.2, 144.8, 133.0, 130.2, 129.8, 129.3, 128.3, 124.0, 117.9, 117.2,

98.1, 96.4, 93.5, 92.0, 83.6, 77.2, 75.0, 74.1, 70.5, 70.0, 69.8, 66.9, 66.6, 66.0,

52.4, 36.7, 35.4, 29.4, 25.2, 23.0, 18.0, 17.9, 17.8, 16.9, ꢀ1.47 ppm; IR

(neat): n˜ =3020, 1729, 1506, 1349, 1216, 1087, 770, 669 cm^ꢀ1; HRMS

(ESI-TOF) [M+NH₄]⁺calcd.: 949.3824, found: 949.3858.

5d: According to the method for the synthesis of 5a, a mixture of 9

(109 mg, 0.330 mmol), 33 (223 mg, 0.299 mmol) and pulverized activated

MS 4ꢁ in dry CH₂Cl₂(6.85 mL) was treated Bu₄NOTf (65.0 mg,

0.165 mmol) and NBS (88.0 mg, 0.495 mmol) to provide 5d (287 mg,

0.297 mmol, 90%, a/b=>90:10). ½aꢁ²_D¹=ꢀ44.7(c 0.650, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=8.08–7.37 (m, 12H), 6.97 (brs, 4H), 5.17 (s, 2H,

a), 5.08 (dd, 1H, J=9.6 Hz, J=1.9 Hz), 4.97 (t, 1H, J=9.2 Hz), 4.91 (brs,

1H), 4.70 (d, 1H, J=11.1 Hz), 4.56 (brs, 1H), 4.55 (dd, 1H, J=9.7 Hz,

J=1.5 Hz), 4.50 (d, 1H, J=11.1 Hz), 4.26 (q, 1H, J=6.8 Hz), 4.14 (ddd,

1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.75 (m,

1H), 3.49 (ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=8.2 Hz), 3.22–3.18 (m,

2H), 2.72–2.55 (m, 4H), 2.48 (ddd, 1H, J=1.9 Hz, J=12.6 Hz, J=

4.8 Hz), 2.30 (ddd, 1H, J=1.5 Hz, J=12.0 Hz, J=5.3 Hz), 2.15 (s, 3H),

2.00 (ddd, 1H, J=12.1 Hz, J=12.6 Hz, J=9.6 Hz), 2.00–1.47 (m, 5H),

1.33 (d, 3H, J=5.8 Hz), 1.07 (d, 3H, J=5.3 Hz), 0.97 (t, 2H, J=8.2 Hz),

0.62 (d, 3H, J=6.8 Hz), 0.00 ppm (s, 9H, TMS); ¹³C NMR (100 MHz,

CDCl₃): d=206.5, 172.4, 165.9, 152.9, 151.8, 135.4, 133.2, 133.0, 130.4,

129.9, 128.2, 128.1, 127.8, 127.7, 126.8, 126.2, 126.1, 126.0, 117.9, 117.3,

98.3, 96.9, 96.5, 93.5, 79.5, 77.2, 75.1, 73.5, 72.0, 70.8, 70.6, 70.0, 66.1, 65.2,

38.0, 36.8, 36.5, 29.8, 28.2, 23.9, 22.6, 18.3, 18.1, 18.0, 16.6, ꢀ1.45 ppm; IR

(neat): n˜ =2933, 1702, 1506, 1366, 1016, 857, 756, 522 cm^ꢀ1; HRMS (ESI-

TOF) [M+NH₄]⁺calcd.: 974.4722, found: 974.4731.

3d: According to the method for the synthesis of 3a, a solution of 5d

(54.2 mg, 0.0520 mmol) in pyridine (0.263 mL) and AcOH (0.390 mL)

was treated with H₂NNH₂·H₂O (12.6 mL, 0.260 mmol) to provide 3d

(34.6 mg, 0.0442 mmol, 85%). ½aꢁ²_D³=ꢀ55.3 (c=0.810, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=8.08–7.38 (m, 12H), 6.97 (brs, 4H), 5.17 (s, 2H),

5.08 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.98 (t, 1H, J=9.2 Hz, J=9.2 Hz),

4.87 (brs, 1H), 4.70 (d, 1H, J=11.1 Hz), 4.55 (dd, 1H, J=9.7 Hz, J=

1.5 Hz), 4.53 (d, 1H, J=11.1 Hz), 4.20 (q, 1H, J=6.3 Hz), 4.15 (ddd, 1H,

J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.75 (t, 2H, J=8.2 Hz), 3.70 (m, 1H),

3.50 (ddd, 1H, J=12.1 Hz, J=4.8 Hz, J=8.2 Hz), 3.32 (brs, 1H), 3.20–

3.17 (m, 2H), 2.49 (ddd, 1H, J=1.9 Hz, J=12.5 Hz, J=4.8 Hz), 2.30

(ddd, 1H, J=1.5 Hz, J=12.5 Hz, J=4.8 Hz), 2.05–1.47 (m, 6H), 1.33 (d,

3H, J=6.3 Hz), 1.08 (d, 3H, J=5.3 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.69 (d,

3H, J=6.3 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=

165.8, 152.9, 151.8, 135.5, 133.2, 132.9, 130.3, 129.8, 128.2, 128.0, 127.7,

127.6, 126.8, 126.1, 125.9, 117.8, 98.2, 97.0, 96.4, 93.5, 79.4, 77.2, 75.1, 73.4,

72.0, 70.9, 70.5, 67.3, 66.4, 66.0, 36.8, 36.5, 25.3, 23.3, 18.3, 18.0, 17.9, 16.6,

ꢀ1.46 ppm; IR (neat): n˜ =3019, 1713, 1506, 1217, 1064, 979, 771,

3a: To

a stirred solution of 5a (100 mg, 0.119 mmol) in pyridine

(0.595 mL) and AcOH (0.893 mL) was added H₂NNH₂·H₂O (28.8 mL,

0.595 mmol) at 08C under argon. After stirring at the same temperature

for 3 h, the reaction mixture was poured into saturated aq. NaHCO₃. The

aqueous layer was extracted with two portions of ethyl acetate. The com-

bined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was chromatographed on silica gel

with 70:30 hexane/ethyl acetate to give 3a (74.4 mg, 0.0952 mmol, 80%).

669 cm^ꢀ1

876.4365

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4354, found:

1

½aꢁ²_D²=ꢀ22.2 (c=1.00, CHCl₃); H NMR (400 MHz, CDCl₃): d=7.39–7.27

(m, 10H), 6.97–6.91 (m, 4H), 5.15 (brs, 2H), 5.00 (brs, 1H), 4.95 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.76 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.69 (brs,

2H), 4.41–4.30 (d, 2H, J=13.5 Hz), 4.36 (t, 1H, J=9.2 Hz, J=9.2 Hz),

4.01 (q, 1H, J=6.6 Hz), 3.83 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=

9.2 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.63 (ddd, 1H, J=11.6 Hz, J=4.8 Hz,

35aa: To a stirred solution of 5a (77.5 mg, 0.0920 mmol) in CH₃CN

(1.00 mL) and water (1.00 mL) was added CAN (75.5 mg, 0.138 mmol) at

08C under argon. After stirring at room temperature for 1 h, the reaction

mixture was poured into saturated aq. NaHCO₃. The aqueous layer was

1416

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

extracted with two portions of ethyl acetate. The combined extract was

washed with brine, dried over MgSO₄, filtered and concentrated in vacuo.

After short pass chromatography, the residue was used for the next reac-

tion without further purification. To a stirred solution of the residue in

CH₂Cl₂(0.920 mL) were added trichloroacetonitrile (27.5 mL,

0.276 mmol, 3.00 equiv) and a catalytic amount of Cs₂CO₃at room tem-

perature under argon. After stirring at room temperature for 3 h, the re-

action mixture was filtered through celite and concentrated in vacuo.

After ion exchange chromatography on NH-functionalized silica gel with

CH₂Cl₂as eluent, the residue was used for the next reaction without fur-

ther purification. To a stirred solution of the residue in toluene (1.84 mL)

was added 3a (65.0 mg, 0.0750 mmol), and pulverized activated MS 4ꢁ

(1.00 gmmol^ꢀ1). After stirring at room temperature for 30 min under

argon to remove a trace amount of water, the reaction mixture was

cooled to ꢀ948C. After 10 min, I₂and a catalytic amount of triethylsilane

were added to the reaction mixture at the same temperature. After stir-

ring for 3 h, the reaction mixture was neutralized with triethylamine, fil-

tered through celite, and poured into aq. NaHCO₃and aq. Na₂S₂O₃. The

aqueous layer was extracted with two portions of ethyl acetate. The com-

bined extract was washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo. The residue was purified by silica gel chromatog-

raphy with 70:30 hexane/ethyl acetate and GPC to give 35aa (87.3 mg,

0.0553 mmol, 93%, b/a=82:18). The b/a ratio was determined by HPLC

analysis (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

4.38 (d, 1H, J=14.0 Hz), 4.34 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.33 (d, 1H,

J=14.0 Hz), 4.22 (brd, 1H, J=9.6 Hz), 4.13 (q, 1H, J=6.3 Hz), 4.02 (q,

1H, J=5.8 Hz), 3.78 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.74 (t,

2H, J=8.2 Hz), 3.63 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.55–

3.20 (m, 9H), 3.17 (brs, 1H), 2.77–2.62 (m, 4H), 2.48–2.37 (m, 3H), 2.29

(m, 1H), 2.19 (s, 3H), 2.04–1.48 (m, 12H), 1.32–1.14 (m, 12H), 1.02 (d,

3H, J=5.8 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.71 (d, 3H, J=6.3 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=206.5, 172.3, 152.8,

151.9, 138.7, 135.8, 133.2, 132.9, 130.0, 129.1, 128.9, 128.4, 128.3, 128.0,

127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 126.6, 126.5, 126.3, 126.1, 126.0,

125.9, 125.6, 117.7, 117.2, 101.3, 100.2, 99.9, 98.2, 97.1, 93.5, 91.7, 82.8,

82.5, 82.3, 82.2, 79.2, 78.9, 77.7, 77.6, 77.4, 77.2, 76.2, 75.7, 72.4, 72.0, 71.8,

71.4, 71.1, 70.8, 70.1, 69.8, 69.7, 66.2, 66.0, 65.1, 57.8, 38.0, 37.1, 37.0, 36.9,

36.4, 35.6, 29.8, 28.1, 24.6, 24.2, 23.8, 22.2, 18.6, 18.3, 18.0, 17.9, 16.9, 16.8,

ꢀ1.46 ppm; IR (neat): n˜ =2935, 1729, 1506, 1364, 1213, 1064, 1019, 987,

835, 754, 698 cm^ꢀ1HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1578.7428,

;

found 1578.7479. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=7.84–7.26

(m, 22H), 6.96–6.90 (m, 4H), 5.15 (s, 2H), 5.01 (brs, 2H), 4.95 (dd, 1H,

J=9.7 Hz, J=1.5 Hz), 4.92 (brs, 1H), 4.81–4.54 (m, 9H), 4.40–4.29 (m,

3H), 4.24 (q, 1H, J=6.3 Hz), 4.03 (q, 1H, J=6.3 Hz), 3.85 (ddd, 1H, J=

10.6 Hz, J=5.3 Hz, J=8.2 Hz), 3.79 (m, 1H), 3.74 (t, 2H, J=8.2 Hz),

3.64 (ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=8.2 Hz), 3.57 (m, 2H), 3.47–3.33

(m, 2H), 3.29–3.20 (m, 5H), 2.77–2.62 (m, 4H), 2.46–2.42 (m, 3H), 2.25–

2.19 (s, 4H), 1.90–1.44 (m, 12H),1.31 (d, 3H, J=5.8 Hz), 1.26 (d, 3H, J=

5.3 Hz), 1.11 (d, 3H, J=6.3 Hz), 1.09 (d, 3H, J=6.3 Hz), 1.03 (d, 3H, J=

6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.73 (d, 3H, J=6.3 Hz), 0.00 ppm (s,

9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.3, 152.8, 151.9, 138.9,

138.7, 135.7, 133.2, 132.9, 130.7, 129.1, 128.9, 128.3, 128.2, 128.1, 127.7,

127.6ꢂ2, 127.5, 127.4, 126.8, 126.2, 126.1, 126.0, 117.7, 117.2, 100.2, 99.8,

98.2, 96.9, 93.5, 92.6, 91.7, 83.4, 82.6, 82.3, 79.2, 77.2, 75.7, 72.4, 72.1, 72.0,

71.4, 71.3, 70.2, 69.8, 69.7, 68.7, 66.0, 65.1, 57.9, 38.0, 29.8, 28.2, 19.8, 18.6,

18.4, 18.1, 18.0, 17.9, 17.1, 17.0, ꢀ1.44 ppm; IR (neat): n˜ =2935, 1729,

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=20.5 min, a-isomer=

1

22.0 min). b-isomer: ½aꢁ²_D²=ꢀ27.3 (c=0.875, CHCl₃); H NMR (400 MHz,

CDCl₃): d=7.40–7.15 (m, 20H), 6.96–6.90 (m, 4H), 5.15 (brs, 2H), 5.03

(brs, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.77–4.72 (m, 3H), 4.68

(brs, 2H), 4.64 (brs, 2H), 4.45–4.29 (m, 7H), 4.02 (q, 1H, J=6.8 Hz),

3.96 (q, 1H, J=6.8 Hz), 3.87–3.78 (m, 2H), 3.74 (t, 2H, J=8.2 Hz), 3.64

(ddd, 1H, J=11.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.55 (ddd, 1H, J=11.6 Hz,

J=4.8 Hz, J=9.2 Hz), 3.43–3.24 (m, 7H), 2.77–2.62 (m, 4H), 2.51–2.43

(m, 3H), 2.35 (m, 1H), 2.18 (s, 3H), 2.04–1.46 (m, 12H), 1.34–1.14 (m,

12H), 1.10 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz), 0.95 (t, 2H, J=

8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CD₂Cl₂): d=206.7, 172.5,

153.2, 152.3, 139.5, 139.4, 131.1, 129.4, 129.2, 128.6, 128.5, 128.4, 127.9,

127.8, 127.7, 118.0, 117.7, 101.6, 100.1, 98.4, 94.0, 92.4, 92.2, 83.8, 83.3,

83.2, 83.0, 77.9, 77.8, 77.4, 76.4, 72.1, 71.8ꢂ2, 71.4, 70.5, 70.2, 70.0, 66.7,

66.4, 65.5, 58.2, 38.3, 37.6, 37.4, 36.3, 36.2, 30.1, 29.9, 28.6, 24.6, 24.3, 22.7,

18.4, 18.3, 17.1, ꢀ1.41 ppm; IR (neat): n˜ =3019, 1720, 1506, 1362, 1216,

1084, 769, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1592.6891,

found 1592.6887. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=7.39–7.15

(m, 20H), 6.96–6.90 (m, 4H), 5.15 (brs, 2H), 5.04 (brs, 2H), 4.97–4.94

(m, 2H), 4.77–4.69 (m, 6H), 4.60 (d, 1H, J=11.1 Hz), 4.44–4.29 (m, 6H),

4.06–3.99 (m, 2H), 3.92 (ddd, 1H, J=10.1 Hz, J=3.9 Hz, J=8.2 Hz),

3.89–3.77 (m, 2H), 3.74 (t, 2H, J=8.2 Hz), 3.74 (m, 1H), 3.63 (m, 1H),

3.49 (brs, 1H), 3.43–3.26 (m, 5H), 2.78–2.62 (m, 4H), 2.51–2.44 (m, 3H),

2.26 (m, 1H), 2.19 (s, 3H), 1.96–1.43 (m, 12H), 1.33 (d, 3H, J=5.8 Hz),

1.22 (d, 3H, J=6.3 Hz), 1.22–1.02 (m, 12H), 0.95 (t, 2H, J=8.2 Hz),

0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.3, 152.8,

151.9, 138.9, 138.5, 130.7, 129.1, 128.9, 128.3, 128.2, 127.7, 127.6, 127.5,

127.4, 127.3, 117.7, 117.2, 100.0ꢂ2, 98.2, 93.5, 92.7, 91.7, 83.5, 82.9, 82.8,

82.5, 77.3, 77.2, 72.1, 71.8, 71.2, 70.2, 69.8, 69.7, 69.6, 68.9, 67.1, 66.6, 66.0,

65.1, 57.9, 38.0, 36.9, 35.9, 35.6, 35.5, 29.8, 28.1, 23.8, 23.5, 22.2, 19.4, 18.4,

18.2, 18.0, 17.9, 17.5, 17.0, ꢀ1.45 ppm; IR (neat): n˜ =3020, 1731, 1374,

1506, 1364, 1213, 1064, 1019, 987, 835, 754, 698 cm^ꢀ1

.

35ac: According to the method for the synthesis of 35aa, a solution of

5a (60.5 mg, 0.0725 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (59.9 mg, 0.110 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (22.0 mL, 0.219 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3c

(51.2 mg, 0.0540 mmol) with the imidate in toluene (1.46 mL) by activa-

tion with I₂(28.0 mg, 0.110 mmol) provided the hexasaccharide 35ac

(65.3 mg, 0.0540 mmol, 72%, b/a=73:27). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=26.5 min, a-isomer=

37.5 min). b-isomer: ½aꢁ_D¹⁷=ꢀ43.6 (c=1.14, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=8.16–7.24 (m, 19H), 6.94 (brs, 4H), 5.14 (s, 2H), 5.07 (brd,

1H, J=9.7 Hz), 5.01 (brs, 1H), 4.89 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.84

(brs, 1H), 4.72–4.59 (m, 5H), 4.42 (d, 1H, J=14.0 Hz), 4.35–4.28 (m,

3H), 4.15–4.06 (m, 2H), 4.02 (q, 1H, J=6.3 Hz), 3.86–3.63 (m, 4H), 3.73

(t, 2H, J=8.2 Hz), 3.50–3.21 (m, 10H), 2.74–2.55 (m, 4H), 2.50–2.46 (m,

2H), 2.35–2.28 (m, 2H), 2.13 (s, 3H), 2.09–1.35 (m, 12H), 1.26 (d, 3H,

J=6.3 Hz), 1.23 (d, 3H, J=5.8 Hz), 1.15–1.09 (m, 6H), 1.03 (d, 3H, J=

6.3 Hz), 0.90 (d, 3H, J=6.3 Hz), 0.93 (t, 2H, J=8.2 Hz), 0.00 ppm (s,

9H); ¹³C NMR (68.7 MHz, CD₂Cl₂): d=206.8, 172.5, 166.0, 153.3, 152.1,

147.5, 145.6, 139.4, 133.4, 131.1, 130.6, 130.1, 129.8, 129.4, 129.2, 128.6,

128.5, 128.3, 127.7, 127.6, 124.2, 118.0, 117.6, 101.5, 100.1, 98.3, 96.9, 93.8,

92.4, 92.1, 84.2, 83.2, 83.1, 77.6, 76.0, 75.3, 74.5, 71.8, 71.4, 70.7, 70.4, 70.2,

70.1, 69.9, 66.9, 66.4, 65.4, 58.1, 54.4, 54.0, 53.6, 52.7, 38.3, 37.5, 37.1, 36.1,

36.0, 30.0, 29.9, 29.8, 28.5, 24.5, 24.4, 24.2, 22.6, 18.5, 18.3, 18.2, 18.1, 18.0,

17.1, 16.9, ꢀ1.45 ppm; IR (neat): n˜ =3020, 1723, 1506, 1349, 1216, 1087,

1019, 756, 668 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1665.6691,

found 1665.6721. a-isomer: ¹H NMR (400 MHz, CD₂Cl₂): d=8.16–7.25

(m, 19H), 6.94 (brs, 4H), 5.14 (s, 2H), 5.08 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 5.01 (brs, 1H), 4.88 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.86 (brs,

2H), 4.73–4.68 (m, 3H), 4.62–4.57 (m, 2H), 4.42 (d, 1H, J=14.0 Hz),

4.34 (d, 1H, J=14.0 Hz), 4.30 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.15–4.08

(m, 2H), 4.02 (q, 1H, J=6.3 Hz), 3.93 (q, 1H, J=6.8 Hz), 3.86–3.79 (m,

3H), 3.73 (t, 2H, J=8.2 Hz), 3.69–3.64 (m, 2H), 3.53–3.22 (m, 8H), 2.74–

2.55 (m, 4H), 2.50–2.46 (m, 2H), 2.34 (ddd, 1H, J=4.8 Hz, J=12.1 Hz,

J=1.9 Hz), 2.19–2.05 (m, 4H), 1.97–1.34 (m, 12H), 1.26 (d, 3H, J=

1216, 1000, 772, 668 cm^ꢀ1

.

35ab: According to the method for the synthesis of 35aa, a solution of

5a (61.1 mg, 0.0725 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (12.6 mg, 0.260 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (21.8 mL, 0.218 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3b

(40.2 mg, 0.0470 mmol) with the imidate in toluene (1.45 mL) by activa-

tion with I₂(27.6 mg, 0.109 mmol) provided the hexasaccharide 35ab

(82.2 mg, 0.0520 mmol, 95%, b/a=73:27). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=18.0 min, a-isomer=

19.5 min). b-isomer: ½aꢁ_D²¹=ꢀ36.9 (c=1.17, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=7.84–7.26 (m, 22H), 6.97–6.90 (m, 4H), 5.15 (s, 2H), 5.03–

5.00 (m, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.81–4.55 (m, 9H),

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

1417

H. Tanaka, T. Takahashi et al.

FULL PAPERS

6.3 Hz), 1.18 (d, 3H, J=5.8 Hz), 1.15–1.09 (m, 9H), 0.99 (d, 3H, J=

6.3 Hz), 0.93 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz,

CD₂Cl₂): d=206.8, 176.8, 172.5, 166.0, 153.3, 152.1, 147.5, 145.5, 139.2,

133.4, 131.1, 130.7, 130.1, 129.7, 129.4, 129.2, 128.6, 128.5, 128.3, 127.7,

127.6, 124.3, 118.0, 117.6, 100.1, 98.3, 96.9, 93.9, 93.4, 92.2, 92.1, 84.0, 83.7,

83.2, 75.8, 75.3, 74.6, 72.2, 70.8, 70.4, 70.3, 70.2, 70.1, 69.9, 69.4, 67.6, 67.3,

66.4, 65.4, 58.1, 53.6, 52.7, 38.3, 37.0, 36.1, 29.9, 29.8, 28.5, 24.2, 22.6, 18.3,

18.2, 18.1, 18.0, 17.2, 17.1, ꢀ1.45 ppm; IR (neat): n˜ =3020, 1723, 1506,

J=11.6 Hz, J=5.3 Hz, J=8.2 Hz), 3.60–3.50 (m, 2H), 3.49–3.21 (m, 8H),

2.72–2.56 (m, 4H), 2.52–2.43 (m, 2H), 2.42–2.31 (m, 2H), 2.16 (s, 3H),

2.04–1.47 (m, 12H), 1.33 (d, 3H, J=5.8 Hz), 1.28–1.19 (m, 9H), 1.10 (d,

3H, J=6.8 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.66 (d, 3H, J=6.8 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=206.4, 172.3, 152.8,

151.9, 138.8, 138.5, 135.5, 133.2, 132.9, 130.7, 129.2, 129.0, 128.9, 128.3,

128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 126.7, 126.2, 126.0, 125.9, 117.7,

117.2, 101.4, 100.1, 100.0, 98.2, 97.0, 93.5, 91.9, 85.2, 83.2, 82.9, 82.8, 82.4,

79.7, 77.8, 77.4, 77.2, 76.0, 72.2, 71.8, 71.6, 71.2, 71.0, 70.2, 69.9, 69.7, 69.6,

69.1, 66.3, 66.0, 65.2, 60.3, 57.8, 57.2, 39.3, 37.9, 37.2, 36.9, 35.7, 29.8, 28.2,

24.2, 24.0, 23.9, 22.6, 21.0, 18.5, 18.3, 18.2, 18.1, 18.0, 17.5, 17.0, 16.6, 14.1,

ꢀ1.47 ppm; IR (neat): n˜ =2935, 1729, 1506, 1364, 1213, 1064, 1019, 987,

1349, 1216, 1087, 1019, 756, 668 cm^ꢀ1

.

35ad: According to the method for the synthesis of 35aa, a solution of

5a (66.5 mg, 0.0790 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (64.8 mg, 0.119 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (23.9 mL, 0.237 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3d

(28.8 mg, 0.0330 mmol) with the imidate in toluene (1.20 mL) by activa-

tion with I₂(27.0 mg, 0.119 mmol) provided the hexasaccharide 35ad

(46.0 mg, 0.0297 mmol, 90%, b/a=69:31). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

835, 754, 698 cm^ꢀ1HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1578.7428,

;

found 1578.7428. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=7.83–7.24

(m, 22H), 6.97–6.90 (m, 4H), 5.15 (s, 2H), 5.03–5.01 (m, 2H), 4.96–4.94

(m, 2H), 4.80–4.58 (m, 9H), 4.44–4.29 (m, 4H), 4.01 (q, 1H, J=6.8 Hz),

3.93 (ddd, 1H, J=10.6 Hz, J=4.8 Hz, J=8.7 Hz), 3.83 (ddd, 1H, J=

11.1 Hz, J=4.8 Hz, J=8.7 Hz), 3.76–3.71 (m, 3H), 3.63 (ddd, 1H, J=

12.1 Hz, J=5.3 Hz, J=8.2 Hz), 3.52 (m, 1H), 3.49 (brs, 1H), 3.43–3.33

(m, 4H), 3.30–3.21 (m, 2H), 2.72–2.56 (m, 4H), 2.52–2.40 (m, 3H), 2.24

(m, 1H), 2.16 (s, 3H), 2.04–1.42 (m, 12H), 1.33 (d, 3H, J=5.8 Hz), 1.26–

1.14 (m, 12H), 0.95 (t, 2H, J=8.2 Hz), 0.66 (d, 3H, J=6.3 Hz), 0.00 ppm

(s, 9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.4, 152.9, 151.9,

139.0, 138.6, 135.6, 133.2, 132.9, 130.7, 129.1, 128.9, 128.3, 128.2, 128.1,

127.8, 127.7, 127.6, 127.5, 127.3, 126.7, 126.2, 126.0, 125.9, 117.8, 117.2,

(100.2, 100.0, 98.2, 97.1, 93.5, 92.8, 91.7, 83.1, 82.9, 79.7, 77.3, 77.2, 76.0,

72.2, 71.8, 71.2, 70.2, 70.0, 69.7, 68.8, 67.3, 66.6, 66.0, 65.2, 57.9, 38.0, 36.9,

35.6, 29.8, 28.2, 24.0, 23.5, 22.7, 18.5, 18.4, 18.1, 18.0, 17.4, 16.6,

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=19.0 min, a-isomer=

1

17.0 min). b-isomer: ½aꢁ²_D²=ꢀ43.8 (c=0.825, CHCl₃); H NMR (400 MHz,

CDCl₃): d=8.07–7.31 (m, 22H), 6.96 (brs, 4H), 5.16 (s, 2H), 5.08 (dd,

1H, J=9.7 Hz, J=1.5 Hz), 5.02 (brs, 1H), 4.96 (t, 1H, J=9.2 Hz, J=

9.2 Hz), 4.90 (brs, 1H), 4.75–4.50 (m, 7H), 4.40–4.29 (m, 3H), 4.20 (m,

1H), 4.13 (m, 1H), 4.10 (m, 1H), 4.02 (q, 1H, J=6.3 Hz), 3.81–3.66 (m,

4H), 3.48 (ddd, 1H, J=12.1 Hz, J=4.4 Hz, J=8.2 Hz), 3.48 (ddd, 1H,

J=12.1 Hz, J=4.4 Hz, J=8.2 Hz), 3.29 (m, 1H), 3.25–3.19 (m, 4H), 3.14

(brs, 1H), 2.78–2.62 (m, 4H), 2.50–2.43 (m, 2H), 2.30–2.25 (m, 2H), 2.19

(s, 3H), 2.04–1.41 (m, 12H), 1.32 (d, 3H, J=6.3 Hz), 1.24 (d, 3H, J=

6.8 Hz), 1.14 (d, 3H, J=6.3 Hz), 1.07 (d, 3H, J=5.3 Hz), 1.02 (d, 3H, J=

6.3 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.65 (d, 3H, J=6.3 Hz), 0.00 ppm (s,

9H); ¹³C NMR (100 MHz, CDCl₃): d=206.5, 172.3, 165.9, 152.9, 151.7,

138.6 135.7, 133.2, 132.9, 130.6, 130.4, 129.9, 129.1, 128.9, 128.2, 128.0,

127.8ꢂ2, 127.7, 127.6, 127.5, 127.3, 126.6, 126.1, 126.0, 125.8, 117.9, 117.3,

101.3, 99.9, 98.3, 96.9, 96.4, 93.5, 91.7, 82.8, 82.5, 79.0, 78.6, 77.7, 77.2,

76.7, 76.1, 75.5, 75.1, 73.6, 73.4, 72.1, 71.4, 70.9, 70.8, 70.6, 70.1, 69.8, 69.7,

66.0, 65.1, 60.3, 57.9, 38.0, 36.9, 36.8, 36.7, 36.6, 35.6, 29.8, 28.1, 24.1, 23.8,

22.2, 18.3, 18.1, 18.0, 17.9, 16.9, 16.7, 14.2, ꢀ1.45 ppm; IR (neat): n˜ =3436,

1643, 1219, 772 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1592.7221,

found 1592.7222. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=8.08–7.26

(m, 22H), 6.97 (brs, 4H), 5.17 (s, 2H), 5.08 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 5.01 (brs, 1H), 4.97 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.90 (brs,

2H), 4.75 (brs, 1H), 4.72–4.49 (m, 6H), 4.38 (d, 1H, J=14.0 Hz), 4.32 (t,

1H, J=9.2 Hz, J=9.2 Hz), 4.29 (d, 1H, J=14.0 Hz), 4.20 (q, 1H, J=

5.8 Hz), 4.14 (m, 1H), 4.03 (q, 1H, J=6.8 Hz), 3.86–3.67 (m, 5H), 3.57–

3.46 (m, 2H), 3.31–3.19 (m, 5H), 2.78–2.62 (m, 4H), 2.51–2.41 (m, 2H),

2.29 (m, 1H), 2.23–2.13 (s, 4H), 2.04–1.39 (m, 12H), 1.33 (d, 3H, J=

5.8 Hz), 1.11–1.04 (m, 12H), 0.96 (t, 2H, J=8.2 Hz), 0.67 (d, 3H, J=

5.8 Hz), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.3,

165.9, 152.9, 151.8, 139.0, 135.5, 133.2, 132.9, 130.7, 130.3, 129.9, 129.1,

128.9, 128.2, 128.0, 127.7, 127.6, 127.4, 126.9, 126.2, 125.9, 117.8, 117.2,

99.8, 98.3, 96.7, 96.4, 93.5, 92.6, 91.7, 83.4, 82.6, 79.0, 77.2, 75.7, 75.1, 73.4,

72.1, 71.0, 70.6, 70.1, 69.8, 69.7, 68.6, 66.9, 66.4, 66.1, 65.1, 57.9, 38.0, 36.8,

36.6, 36.0, 35.5, 29.8, 29.7, 28.2, 23.8, 23.5, 22.2, 19.8, 18.4, 18.1, 17.9, 17.1,

ꢀ1.45 ppm; IR (neat): n˜ =3020, 1731, 1216, 1047, 758, 669 cm^ꢀ1

.

35bb: According to the method for the synthesis of 35aa, a solution of

5b (54.7 mg, 0.0660 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (54.1 mg, 0.138 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (20.0 mL, 0.198 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3b

(39.1 mg, 0.0462 mmol) with the imidate in toluene (1.32 mL) by activa-

tion with I₂(25.0 mg, 0.0990 mmol) provided the hexasaccharide 22ad

(66.5 mg, 0.0420 mmol, 93%, b/a=70:30). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=18.0 min, a-isomer=

19.5 min). b-isomer: ½aꢁ_D²¹=ꢀ37.3 (c=1.48, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=7.83–7.26 (m, 22H), 6.97–6.90 (m, 4H), 5.15 (s, 2H), 5.01

(brs, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.81–4.59 (m, 11H), 4.30

(q, 1H, J=6.8 Hz), 4.22 (brd, 1H, J=9.7 Hz), 4.13 (m, 1H), 3.74 (t, 2H,

J=8.2 Hz), 3.64 (ddd, 1H, J=11.6 Hz, J=5.3 Hz, J=8.2 Hz), 3.56–3.17

(m, 12H), 2.72–2.56 (m, 4H), 2.46–2.38 (m, 3H), 2.27 (m, 1H), 2.16 (s,

3H), 2.04–1.46 (m, 12H), 1.32–1.24 (m, 12H), 0.95 (t, 2H, J=8.2 Hz),

0.72 (d, 3H, J=6.8 Hz), 0.67 (d, 3H, J=6.8 Hz), 0.00 ppm (s, 9H);

¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.3, 152.8, 151.9, 138.7, 138.6,

138.5, 135.8, 135.5, 135.4, 133.2, 133.0, 132.9, 128.4, 128.3, 128.2, 128.1,

128.0, 127.8, 127.7, 127.6ꢂ2, 127.5, 127.4, 126.7, 126.6, 126.5, 126.3, 126.2,

126.1, 126.0ꢂ2, 125.9ꢂ2, 125.8, 125.6, 117.7, 117.2, 101.4, 100.2, 100.1,

98.2, 97.0, 93.5, 82.3, 82.2, 79.7, 79.2, 78.9, 77.9, 77.7, 77.2, 76.1, 75.6, 72.4,

72.3, 72.0, 71.8, 71.7, 71.6, 71.4, 71.3ꢂ2, 71.2, 71.1, 70.9, 69.9, 66.2, 66.0,

65.2, 60.3, 37.9, 37.0, 36.4, 29.8, 28.2, 24.6, 24.2, 24.0, 22.6, 18.6, 18.5, 18.4,

18.3, 18.2, 18.0, 17.9, 16.8, 16.6, 14.2, ꢀ1.46 ppm; IR (neat): n˜ =3019,

17.0, ꢀ1.45 ppm; IR (neat): n˜ =3019, 1714, 1216, 756 cm^ꢀ1

.

35ba: According to the method for the synthesis of 35aa, a solution of

5b (82.8 mg, 0.100 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (82.1 mg, 0.150 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (30.0 mL, 0.300 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3a

(56.7 mg, 0.0650 mmol) with the imidate in toluene (2.00 mL) by activa-

tion with I₂(38.1 mg, 0.150 mmol) provided the hexasaccharide 35ad

(69.0 mg, 0.0442 mmol, 67%, b/a=77:23). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

1721, 1506, 1366, 1216, 1063, 771, 669 cm^ꢀ1

; HRMS (ESI-TOF)

[M+NH₄]⁺calcd. 1546.7622, found 1546.7622. a-isomer: ¹H NMR

(400 MHz, CDCl₃): d=7.83–7.24 (m, 24H), 6.96–6.90 (m, 4H), 5.15 (s,

2H), 5.01 (brs, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.92 (brs, 1H),

4.81–4.54 (m, 11H), 4.29 (q, 1H, J=6.3 Hz), 4.25 (q, 1H, J=6.8 Hz), 3.86

(ddd, 1H, J=11.1 Hz, J=5.3 Hz, J=9.2 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.63

(ddd, 1H, J=11.6 Hz, J=3.4 Hz, J=8.2 Hz), 3.30 (brs, 1H), 3.58–3.20

(m, 10H), 2.74–2.56 (m, 4H), 2.46–2.38 (m, 3H), 2.21 (ddd, 1H, J=

5.3 Hz, J=12.6 Hz, J=1.5 Hz), 2.16 (s, 3H), 2.01–1.44 (m, 12H), 1.31 (d,

3H, J=6.3 Hz), 1.26 (d, 3H, J=5.8 Hz), 1.20 (d, 3H, J=5.8 Hz), 1.09 (d,

3H, J=6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.75 (d, 3H, J=6.8 Hz), 0.65 (d,

3H, J=6.3 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=

206.5, 172.4, 152.8, 151.9, 139.1, 138.7, 135.7, 135.6, 133.2, 132.9, 128.3,

128.2, 128.1, 128.0, 127.8, 127.7ꢂ2, 127.5ꢂ2, 127.3, 126.8, 126.7, 126.2ꢂ2,

60/40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=18.0 min, a-isomer=

19.0 min). b-isomer: ½aꢁ¹_D⁵=ꢀ37.2 (c=0.725, CHCl₃); H NMR (400 MHz,

CDCl₃): d=7.82–7.26 (m, 22), 6.97–6.90 (m, 4H), 5.15 (s, 2H), 5.04–5.01

(m, 2H), 4.95 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.77–4.62 (m, 8H), 4.59

(brs, 1H), 4.46–4.27 (m, 5H), 3.96 (q, 1H, J=6.8 Hz), 3.83 (ddd, 1H, J=

12.1 Hz, J=5.3 Hz, J=10.2 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.64 (ddd, 1H,

1

1418

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

126.0, 125.9, 117.8, 117.2, 100.2, 100.0, 98.2, 97.0, 96.9, 93.5, 92.6, 83.0,

82.3, 79.7, 79.3, 77.6, 77.2, 75.8, 72.4, 72.3, 72.0, 71.4, 71.3, 71.1, 70.0, 68.6,

67.1, 66.6, 66.0, 65.2, 38.0, 37.1, 37.0, 36.9, 36.0, 29.8, 24.0, 23.6, 22.7, 19.8,

18.6, 18.5, 18.3, 18.1, 18.0, 17.2, 16.6, ꢀ1.45 ppm; IR (neat): n˜ =3019,

1721, 1506, 1366, 1216, 1063, 771, 669 cm^ꢀ1

J=8.2 Hz), 3.70 (m, 1H), 3.53–3.43 (m, 3H), 3.36 (t, 1H, J=9.2 Hz, J=

9.2 Hz), 3.25–3.15 (m, 5H), 3.14 (brs, 1H), 2.72–2.57 (m, 4H), 2.47 (ddd,

1H, J=4.4 Hz, J=11.6 Hz, J=1.5 Hz), 2.39 (ddd, 1H, J=4.8 Hz, J=

12.6 Hz, J=1.5 Hz), 2.30–2.22 (m, 2H), 2.16 (s, 3H), 2.02–1.41 (m, 12H),

1.32 (d, 3H, J=6.3 Hz), 1.25–1.06 (m, 9H), 0.96 (t, 2H, J=8.2 Hz), 0.67–

0.64 (m, 6H), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.6,

172.4, 165.9, 152.9, 151.8, 138.7, 135.7, 135.5, 133.2, 132.9, 132.9, 130.3,

129.9, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4, 126.7, 126.6, 126.2,

126.1ꢂ2, 126.0ꢂ2, 125.9, 117.8, 117.2, 101.4, 100.1, 98.2, 97.1, 96.9, 96.4,

93.5, 82.2, 79.7, 78.9, 77.9, 77.2, 76.1, 75.1, 73.3, 72.2, 72.1, 71.5, 71.1, 70.9,

70.5, 69.9, 66.1, 65.2, 37.9, 36.9, 36.8, 29.8, 28.2, 24.0, 22.6, 18.5, 18.3ꢂ2,

18.1, 17.9, 16.7, 16.6, ꢀ1.44 ppm; IR (neat): n˜ =2933, 1720, 1506, 1366,

1016, 857, 756, 522 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1578.7758,

found 1578.7816. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=8.08–7.22

(m, 24H), 6.97 (brs, 4H), 5.17 (s, 2H), 5.08 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 5.00 (brs, 1H), 4.97 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.90 (m, 2H),

4.77–4.50 (m, 6H), 4.63 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.59 (brs, 1H),

4.55 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.29 (q, 1H, J=6.3 Hz), 4.20 (q, 1H,

J=6.3 Hz), 4.14 (m, 1H), 3.83 (ddd, 1H, J=11.1 Hz, J=5.3 Hz, J=

8.7 Hz), 3.75 (t, 2H, J=8.2 Hz), 3.70 (m, 1H), 3.57–3.46 (m, 3H), 3.35 (t,

1H, J=9.2 Hz, J=9.2 Hz), 3.27 (brs, 1H), 3.25–3.17 (m, 4H), 2.73–2.57

(m, 4H), 2.48 (ddd, 1H, J=4.8 Hz, J=12.6 Hz, J=1.9 Hz), 2.38 (ddd,

1H, J=4.8 Hz, J=12.6 Hz, J=1.5 Hz), 2.28 (ddd, 1H, J=4.8 Hz, J=

12.6 Hz, J=1.5 Hz), 2.22–2.16 (m, 4H), 2.04–1.39 (m, 12H), 1.33 (d, 3H,

J=6.3 Hz), 1.20–1.06 (m, 9H), 0.96 (t, 2H, J=8.2 Hz), 0.69 (d, 3H, J=

6.3 Hz), 0.65 (d, 3H, J=6.3 Hz), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz,

CD₂Cl₂): d=206.8, 172.6, 166.2, 153.3, 152.2, 139.8, 136.4, 136.3, 133.6,

133.3, 130.8, 130.1, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.5,

127.1, 127.0, 126.7, 126.6, 126.5, 126.4, 126.2, 118.0, 117.6, 100.1, 98.4,

97.5, 97.4, 96.9, 93.9, 92.9, 83.6, 80.4, 79.8, 77.9, 77.6, 75.8, 75.5, 73.8, 72.5,

72.4, 71.3, 71.2, 70.8, 70.2, 69.8, 69.2, 67.5, 66.8, 66.4, 65.5, 54.4, 53.6, 38.2,

37.4, 37.1, 37.0, 36.4, 29.9, 28.5, 24.4, 24.0, 23.0, 20.2, 18.6, 18.5, 18.3, 18.2,

18.1, 17.3, 16.8, ꢀ1.43 ppm; IR (neat): n˜ =2933, 1720, 1506, 1366, 1016,

35bc: According to the method for the synthesis of 35aa, a solution of

5b (61.3 mg, 0.0740 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (60.7 mg, 0.111 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (22.5 mL, 0.222 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3c

(32.3 mg, 0.0340 mmol) with the imidate in toluene (1.50 mL) by activa-

tion with I₂(28.2 mg, 0.111 mmol) provided the hexasaccharide 35bc

(42.3 mg, 0.0259 mmol, 76%, b/a=70:30). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=20.0 min, a-isomer=

23.5 min). b-isomer: ½aꢁ¹_D⁷=ꢀ45.8 (c=0.625, CHCl₃); H NMR (400 MHz,

CDCl₃): d=8.19–7.26 (m, 21H), 6.97 (m, 4H), 5.16 (s, 2H), 5.07 (dd, 1H,

J=9.7 Hz, J=1.5 Hz), 5.00 (brs, 1H), 4.95 (t, 1H, J=9.2 Hz, J=9.2 Hz),

4.88 (brs, 1H), 4.78–4.59 (m, 7H), 4.31 (m, 1H), 4.29 (q, 1H, J=6.8 Hz),

4.15–4.07 (m, 2H), 3.85 (q, 1H, J=6.8 Hz), 3.77–3.66 (m, 4H), 3.56–3.21

(m, 12H), 2.72–2.57 (m, 4H), 2.48 (ddd, 1H, J=5.3 Hz, J=12.1 Hz, J=

1.5 Hz), 2.40 (ddd, 1H, J=4.4 Hz, J=12.6 Hz, J=1.9 Hz), 2.33–2.30 (m,

2H), 2.16 (s, 3H), 2.04–1.41 (m, 12H), 1.31 (d, 3H, J=6.3 Hz), 1.27–1.12

(m, 9H), 1.07 (d, 3H, J=6.8 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.66 (d, 3H,

J=6.8 Hz), 0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=206.5,

172.4, 165.8, 153.0, 151.8, 147.2, 144.9, 138.8, 135.6, 133.2, 133.1, 133.0,

130.2, 129.8, 129.3, 128.3, 128.2, 128.1, 127.8, 127.7, 127.5, 126.8, 126.2,

126.1, 126.0, 124.0, 117.9, 117.3, 101.2, 100.1, 98.2, 97.1, 96.4, 93.5, 92.3,

85.9, 84.0, 82.4, 79.7, 77.6, 77.5, 77.2, 75.6, 75.0, 74.2, 72.3, 71.7, 71.2, 70.5,

70.2, 70.0, 69.9, 66.7, 66.1, 65.2, 52.4, 38.0, 37.2, 37.0, 36.7, 35.7, 29.8, 29.7,

29.6, 29.5, 28.2, 24.2, 24.0, 22.7, 18.6, 18.2, 18.1, 17.9, 17.8, 16.8, 16.6, 14.2,

ꢀ1.44 ppm; IR (neat): n˜ =3019, 1720, 1506, 1349, 1217, 1066, 772,

1

669 cm^ꢀ1

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1651.7228, found

857, 756, 522 cm^ꢀ1

.

1651.7229. a-isomer: ¹H NMR (400 MHz, CDCl₃): d=8.20–7.23 (m,

21H), 6.97 (brs, 4H), 5.17 (s, 2H), 5.07 (dd, 1H, J=9.7 Hz, J=1.5 Hz),

5.00 (brs, 1H), 4.96 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.89 (brs, 2H), 4.69

(dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.79–4.58 (m, 5H), 4.61 (brs, 1H), 4.30

(q, 1H, J=6.3 Hz), 4.16–4.07 (m, 2H), 3.96 (q, 1H, J=6.8 Hz), 3.96 (ddd,

1H, J=11.1 Hz, J=5.3 Hz, J=8.7 Hz), 3.81–3.65 (m, 3H), 3.75 (t, 2H,

J=8.2 Hz), 3.55–3.43 (m, 2H), 3.40 (brs, 1H), 3.40–3.21 (m, 7H), 2.73–

2.57 (m, 4H), 2.48 (ddd, 1H, J=4.8 Hz, J=11.1 Hz, J=1.5 Hz), 2.42

(ddd, 1H, J=4.3 Hz, J=12.1 Hz, J=1.5 Hz), 2.34 (ddd, 1H, J=4.8 Hz,

J=12.1 Hz, J=1.5 Hz), 2.21 (ddd, 1H, J=5.3 Hz, J=13.1 Hz, J=1.5 Hz),

2.16 (s, 3H), 2.04–1.38 (m, 12H), 1.32 (d, 3H, J=6.3 Hz), 1.25 (d, 3H,

J=5.8 Hz), 1.18 (d, 3H, J=6.3 Hz), 1.14 (d, 3H, J=6.8 Hz), 1.12 (d, 3H,

J=6.3 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.66 (d, 3H, J=6.3 Hz), 0.00 ppm (s,

9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.6, 172.4, 165.8, 153.0, 151.8,

147.2, 144.8, 139.0, 135.5, 133.2, 133.1, 132.9, 130.2, 129.8, 129.3, 128.3,

128.2, 128.1, 127.8, 127.7, 127.4, 127.3, 126.7, 126.2, 126.0, 125.9, 124.1,

117.9, 117.3, 100.3, 98.1, 97.1, 96.4, 93.5, 93.0, 91.9, 83.7, 82.9, 79.7, 77.2,

76.0, 75.0, 74.2, 72.3, 72.2, 71.2, 70.5, 70.0, 69.9, 69.8, 68.9, 67.3, 67.0, 66.1,

65.2, 60.4, 52.4, 37.9, 36.9, 36.7, 35.8, 35.6, 29.8, 29.7, 29.4, 28.2, 24.0, 22.6,

19.7, 18.5, 18.1, 18.0, 17.9, 17.8, 17.1, 16.6, 14.2, ꢀ1.44 ppm; IR (neat): n˜ =

35ca: According to the method for the synthesis of 35aa, a solution of 5c

(44.2 mg, 0.0483 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (39.6 mg, 0.0725 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (14.5 mL, 0.145 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3a

(39.8 mg, 0.0462 mmol) with the imidate in toluene (1.30 mL) by activa-

tion with I₂(18.4 mg, 0.0725 mmol) provided the hexasaccharide 35ca

(66.2 mg, 0.0401 mmol, 86%, b/a=90:10). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=21.0 min, a-isomer=

23.5 min). ½aꢁ¹_D⁶=ꢀ58.5 (c=1.56, CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=8.20–7.29 (m, 19H), 6.96 (brs, 4H), 5.15 (s, 2H), 5.05 (brs, 1H), 4.95

(dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.91 (brs, 1H), 4.86 (t, 1H, J=9.2 Hz,

J=9.2 Hz), 4.76 (dd, 1H, J=9.2 Hz, J=1.5 Hz), 4.69 (brs, 2H), 4.67 (brs,

1H), 4.55 (brd, 1H, J=8.7 Hz), 4.50 (brd, 1H, J=9.2 Hz), 4.44 (d, 1H,

J=13.5 Hz), 4.36 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.33 (d, 1H, J=13.5 Hz),

4.14 (t, 1H, H-E4, J_4,3=9.2 Hz, J=9.2 Hz), 4.04–3.95 (m, 3H), 3.84 (ddd,

1H, J=11.1 Hz, J=4.8 Hz, J=9.2 Hz), 3.77–3.71 (m, 3H), 3.63 (ddd, 1H,

J=12.1 Hz, J=5.3 Hz, J=8.7 Hz), 3.51–3.23 (m, 11H), 2.72–2.56 (m,

4H), 2.53–2.43 (m, 2H), 2.37–2.28 (dd, 2H), 2.19 (s, 3H), 2.07–1.37 (m,

12H), 1.33 (d, 3H, J=5.8 Hz), 1.21 (d, 3H, J=6.3 Hz), 1.20 (d, 3H, J=

6.3 Hz), 1.13 (d, 3H, J=6.8 Hz), 1.10 (d, 3H, J=6.3 Hz), 1.05 (d, 3H, J=

6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz,

CDCl₃): d=206.5, 172.2, 165.8, 152.8, 151.9, 147.2, 144.7, 138.5, 133.0,

130.7, 130.3, 129.7, 129.3, 129.1, 128.9, 128.3, 128.2, 127.7, 127.6, 127.4,

124.1, 117.7, 117.2, 101.2, 100.0, 98.2, 96.3, 93.5, 91.9, 91.8, 83.5, 83.2, 82.8,

77.3, 77.2, 76.3, 75.2, 74.6, 71.8, 71.2, 70.1, 70.0, 69.7, 69.3, 66.2, 66.0ꢂ2,

65.4, 57.9, 52.5, 37.9, 36.9, 35.7, 35.5, 29.8, 29.6, 29.4, 28.1, 24.1, 24.0, 23.9,

22.2, 18.4, 18.0, 17.9, 17.8, 17.0, 16.8, ꢀ1.46 ppm; IR (neat): n˜ =3020,

1723, 1506, 1349, 1216, 1087, 1019, 756, 668 cm^ꢀ1; HRMS (ESI-TOF)

[M+NH₄]⁺calcd.: 1665.6691, found: 1665.6711.

3019, 1720, 1506, 1349, 1217, 1066, 772, 669 cm^ꢀ1

.

35bd: According to the method for the synthesis of 35aa, a solution of

5b (41.4 mg, 0.0500 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (41.0 mg, 0.0750 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (15.5 mL, 0.150 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3d

(29.8 mg, 0.0340 mmol) with the imidate in toluene (1.30 mL) by activa-

tion with I₂(20.0 mg, 0.0750 mmol) provided the hexasaccharide 35bd

(47.7 mg, 0.0300 mmol, 88%, b/a=65:35). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=19.0 min, a-isomer=

17.5 min). b-isomer: ½aꢁ¹_D⁶=ꢀ55.9 (c=0.420, CHCl₃); H NMR (400 MHz,

CDCl₃): d=8.07–7.22 (m, 24H), 6.96 (brs, 4H), 5.17 (s, 2H), 5.07 (dd,

1H, J=9.7 Hz, J=1.5 Hz), 5.00 (brs, 1H), 4.96 (t, 1H, J=9.2 Hz, J=

9.2 Hz), 4.89 (brs, 1H), 4.77–4.50 (m, 9H), 4.29 (q, 1H, J=6.8 Hz), 4.19

(brd, 1H, J=9.7 Hz), 4.14 (m, 1H), 4.08 (q, 1H, J=6.8 Hz), 3.75 (t, 2H,

1

35cb: According to the method for the synthesis of 35aa, a solution of

5c (43.0 mg, 0.0470 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (38.6 mg, 0.0705 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (14.5 mL, 0.145 mmol) in

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

1419

H. Tanaka, T. Takahashi et al.

FULL PAPERS

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3b

(36.2 mg, 0.0420 mmol) with the imidate in toluene (1.30 mL) by activa-

tion with I₂(17.9 mg, 0.0705 mmol) provided the hexasaccharide 35cb

(54.6 mg, 0.0330 mmol, 80%, b/a=>90:10). The b,a isomers were sepa-

4.33 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.17–4.09 (m, 3H), 3.99 (q, 1H, J=

6.3 Hz), 3.92 (ddd, 1H, J=12.6 Hz, J=5.8 Hz, J=9.2 Hz), 3.77–3.67 (m,

4H), 3.52–3.19 (m, 10H), 2.77–2.58 (m, 4H), 2.48 (m, 1H), 2.30–2.23 (m,

3H), 2.19 (s, 3H), 2.04–1.46 (m, 12H), 1.33–1.03 (m, 15H), 0.96 (t, 2H,

J=8.2 Hz), 0.67 (d, 3H, J=6.3 Hz), 0.00 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=206.5, 172.2, 165.9, 153.0, 151.9, 147.3, 144.7,

135.8, 135.3, 133.2, 132.9, 130.3, 129.9, 129.8, 129.3, 128.4, 128.2, 128.0,

127.8, 127.6, 126.6, 126.5, 126.2, 126.1, 126.0, 125.8, 125.6, 124.1, 117.9,

117.3, 101.2, 98.3, 96.9, 96.5, 96.2, 93.5, 91.9, 83.5, 79.0, 78.6, 77.2, 76.3,

75.5, 75.3, 75.2, 74.4, 73.6, 73.4, 72.1, 71.5, 70.9, 70.6, 70.1, 69.8, 69.4, 66.0,

65.4, 60.3, 52.5, 37.9, 36.7, 36.0, 35.6, 29.8, 29.4, 28.1, 24.7, 24.1, 23.9, 22.2,

18.1, 17.9, 17.8, 16.8, 14.2, ꢀ1.45 ppm; IR (neat): n˜ =3020, 1725, 1506,

1350, 1216, 1064, 1017, 771, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd.: 1665.7021, found: 1665.7079.

rated by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl ace-

21

tate=60:40, 2.0 mLmin^ꢀ1; Retention time: b-isomer=17.0 min). ½aꢁ_D

=

ꢀ51.5 (c=0.560, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=8.20–7.24 (m,

21H), 6.94 (brs, 4H), 5.15 (s, 2H), 5.02 (brs, 1H), 4.95 (dd, 1H, J=

9.7 Hz, J=1.9 Hz), 4.90 (brs, 1H), 4.88–4.62 (m, 6H), 4.65 (brs, 1H),

4.51 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.35 (brd, 1H, J=9.2 Hz), 4.17–4.09

(m, 2H), 3.99 (q, 1H, J=6.3 Hz), 3.94 (ddd, 1H, J=12.1 Hz, J=5.3 Hz,

J=9.2 Hz), 3.74 (t, 2H, J=8.2 Hz), 3.71 (m, 1H), 3.64 (ddd, 1H, J=

11.6 Hz, J=5.3 Hz, J=8.7 Hz), 3.54 (ddd, 1H, J=11.1 Hz, J=4.4 Hz, J=

8.7 Hz), 3.43–3.23 (m, 11H), 2.77–2.58 (m, 4H), 2.46–2.41 (m, 2H), 2.40–

2.19 (m, 2H), 2.18 (s, 3H), 2.04–1.30 (m, 12H), 1.31 (d, 3H, J=5.8 Hz),

1.26 (d, 3H, J=7.3 Hz), 1.23 (d, 3H, J=6.3 Hz), 1.10 (d, 3H, J=6.3 Hz),

1.04 (d, 3H, J=6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.74 (d, 3H, J=6.3 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=206.5, 172.2, 165.8,

152.8, 151.9, 147.2, 144.7, 138.0, 135.8, 133.2, 133.0, 132.9, 130.3, 129.7,

129.2, 128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 126.6, 126.1, 125.9, 124.1,

117.7, 117.2, 101.2, 100.2, 98.2, 97.1, 96.2, 93.5, 91.8, 83.5, 82.3, 79.2, 77.6,

77.2, 76.3, 75.2, 74.4, 72.4, 71.9, 71.3, 70.0, 69.7, 69.3, 66.1, 66.0, 65.4, 60.3,

52.5, 37.9, 37.1, 37.0, 36.7, 35.5, 29.8, 29.6, 29.4, 28.1, 24.7, 24.1, 23.9, 22.2,

18.6, 18.3, 18.0, 17.9, 16.8, 16.7, 14.2, ꢀ1.46 ppm; IR (neat): n˜ =3019,

35da: According to the method for the synthesis of 35aa, a solution of

5d (61.1 mg, 0.0725 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (59.5 mg, 0.109 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (22.0 mL, 0.218 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3a

(43.4 mg, 0.0500 mmol) with the imidate in toluene (1.46 mL) by activa-

tion with I₂(27.8 mg, 0.109 mmol) provided the hexasaccharide 35da

(71.1 mg, 0.0451 mmol, 90%, b/a=90:10). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=18.0 min, a-isomer=

1720, 1506, 1349, 1216, 1062, 759, 668 cm^ꢀ1

; HRMS (ESI-TOF)

19.0 min). ½aꢁ²_D²=ꢀ51.9 (c=0.825, CHCl₃) ; ¹H NMR (400 MHz, CDCl₃)

8.05–7.26 (m, 22H), 6.97–6.91 (m, 4H), 5.15 (s, 2H), 5.05 (brs, 1H), 4.96

(dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.90 (brs, 1H), 4.87 (t, 1H, J=9.2 Hz,

J=9.2 Hz), 4.76 (brd, 1H, J=9.2 Hz), 4.56 (brs, 1H), 4.71–4.49 (m, 4H),

4.51 (m, 1H), 4.50 (m, 1H), 4.44 (d, 1H, J=13.5 Hz), 4.36 (t, 1H, J=

9.2 Hz, J=9.2 Hz), 4.34 (d, 1H, J=13.5 Hz), 4.26 (q, 1H, J=6.3 Hz),

4.05–3.97 (m, 2H), 3.84 (ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=9.2 Hz), 3.74

(t, 2H, J=8.2 Hz), 3.63 (ddd, 1H, J=12.6 Hz, J=5.3 Hz, J=8.2 Hz),

3.52–3.34 (m, 6H), 3.20–3.12 (m, 2H), 2.72–2.56 (m, 4H), 2.53–2.44 (m,

2H), 2.35 (dd, 1H, J=5.3 Hz, J=12.6 Hz, J=1.9 Hz), 2.27 (dd, 1H, J=

5.3 Hz, J=12.1 Hz, J=1.9 Hz), 2.15 (s, 3H), 2.07–1.47 (m, 12H), 1.34–

1.20 (m, 9H), 1.13 (d, 3H, J=6.3 Hz), 1.06 (d, 3H, J=6.3 Hz), 0.95 (t,

2H, J=8.2 Hz), 0.61 (d, 3H, J=6.3 Hz), 0.00 (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=206.4, 172.3, 165.9, 152.9, 151.9, 138.6, 135.4,

133.2, 132.9, 132.8, 130.7, 130.5, 129.8, 129.2, 129.1, 128.9, 128.3, 128.1,

127.8, 127.6, 127.5, 127.4, 126.8, 126.1, 125.9, 117.8, 117.2, 101.3, 100.0,

98.2, 96.9, 96.4, 93.5, 92.0, 83.2, 82.8, 79.5, 77.2, 76.2, 75.3, 73.9, 71.9, 71.8,

71.2, 70.7, 70.2, 69.9, 69.8, 66.3, 66.0, 65.1, 57.9, 57.2, 37.9, 37.0, 36.9, 36.5,

35.7, 29.8, 28.2, 24.2, 24.0, 23.9, 22.6, 18.4, 18.3, 18.0, 17.8, 17.1, 16.5,

ꢀ1.46; IR (neat): n˜ =3019, 1720, 1506, 1364, 1217, 1066, 1018, 770,

[M+NH₄]⁺calcd.: 1651.7228, found: 1651.7247.

35cc: According to the method for the synthesis of 35aa, a solution of 5c

(45.7 mg, 0.0500 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (41.0 mg, 0.0750 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (15.0 mL, 0.150 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3c

(32.5 mg, 0.0340 mmol) with the imidate in toluene (1.20 mL) by activa-

tion with I₂(19.0 mg, 0.0750 mmol) provided the hexasaccharide 35cc

(41.6 mg, 0.0241 mmol, 71%, b/a=>90:10). The b,a isomers were sepa-

rated by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl ace-

17

tate=60:40, 2.0 mLmin^ꢀ1; Retention time: b-isomer=24.5 min). ½aꢁ_D

=

ꢀ56.8 (c=1.20, CHCl₃); ¹H NMR (400 MHz, CD₂Cl₂); 8.16–7.31 (m,

18H), 6.94 (brs, 4H), 5.14 (brs, 2H), 5.07 (dd, 1H, J=9.7 Hz, J=

1.9 Hz), 4.91–4.85 (m, 3H), 4.77 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.62–4.55

(m, 3H), 4.43 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.12 (m, 1H), 4.10 (t, 1H,

J=9.2 Hz, J=9.2 Hz), 4.10 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.02–3.93 (m,

2H), 3.85 (q, 1H, J=6.3 Hz), 3.80–3.62 (m, 3H), 3.73 (t, 2H, J=8.2 Hz),

3.55–3.21 (m, 12H), 2.71–2.53 (m, 4H), 2.48 (ddd, 1H, J=5.3 Hz, J=

12.5 Hz, J=1.9 Hz), 2.35–2.28 (m, 3H), 2.13 (s, 3H), 2.00–1.34 (m, 12H),

1.26 (d, 3H, J=6.3 Hz), 1.17 (d, 3H, J=6.3 Hz), 1.12–1.08 (m, 6H), 1.05

(d, 3H, J=6.3 Hz), 1.00 (d, 3H, J=6.3 Hz), 0.93 (t, 2H, J=8.2 Hz),

0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz, CD₂Cl₂): d=206.8, 172.5, 166.1,

166.0, 153.3, 152.1, 147.5, 147.4, 145.6, 145.5, 133.4, 133.3, 130.8, 130.7,

130.1, 129.8, 129.7, 128.7, 128.6, 124.3, 124.2, 118.1, 117.7, 101.4, 98.3,

96.9ꢂ2, 93.9, 92.6, 92.2, 84.2, 83.8, 77.9, 76.4, 75.6, 75.3, 74.9, 74.5, 70.8,

70.5ꢂ2, 70.4, 70.3, 70.2, 69.6, 67.0, 66.4, 65.7, 54.6, 54.4, 54.2, 54.0, 53.8,

53.6, 53.4, 53.0, 52.8, 52.7, 38.2, 37.3, 37.1, 36.1, 35.9, 29.9, 29.8, 28.5, 24.6,

24.5, 24.2, 22.6, 18.3, 18.1, 18.0ꢂ2, 16.9, 16.9, ꢀ1.43 ppm; IR (neat): n˜ =

3020.2, 1728.7, 1505.9, 1349.2, 1216.0, 1086.7, 770.2, 669.3 cm^ꢀ1; HRMS

(ESI-TOF) [M+NH₄]⁺calcd.: 1738.6491, found: 1738.6481

669 cm^ꢀ1

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd. 1592.7221, found

1592.7217.

35 db: According to the method for the synthesis of 35aa, a solution of

5d (81.2 mg, 0.149 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (81.2 mg, 0.149 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (24.0 mL, 0.297 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3a

(44.4 mg, 0.0520 mmol) with the imidate in toluene (2.00 mL) by activa-

tion with I₂(37.7 mg, 0.0149 mmol) provided the hexasaccharide 35 db

(66.4 mg, 0.0425 mmol, 82%, b/a=85:15). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

35 cd: According to the method for the synthesis of 35aa, a solution of

5c (33.8 mg, 0.0370 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (30.4 mg, 0.0555 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (11.0 mL, 0.111 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3d

(26.0 mg, 0.0300 mmol) with the imidate in toluene (1.20 mL) by activa-

tion with I₂(14.0 mg, 0.0555 mmol) provided the hexasaccharide 35 cd

(35.5 mg, 0.0215 mmol, 72%, b/a=>90:10). The b,a isomers were sepa-

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=20.0 min, a-isomer=

23.5 min). b-isomer: ½aꢁ_D²¹=ꢀ63.1 (c=1.65, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=8.05–7.26 (m, 24H), 6.97–6.90 (m, 4H), 5.15 (brs, 2H), 5.03

(brs, 1H), 4.95 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.90 (brs, 1H), 4.89–4.63

(m, 8H), 4.56 (brs, 1H), 4.51–4.46 (m, 2H), 4.36 (brd, 1H, J=8.7 Hz),

4.26 (q, 1H, J=6.8 Hz), 4.16 (q, 1H, J=6.3 Hz), 3.97 (ddd, 1H, J=

12.6 Hz, J=5.3 Hz, J=10.1 Hz), 3.75 (t, 2H, J=8.2 Hz), 3.64 (ddd, 1H,

J=11.6 Hz, J=5.3 Hz, J=8.2 Hz), 3.55 (ddd, 1H, J=11.6 Hz, J=4.4 Hz,

J=8.7 Hz), 3.48–3.33 (m, 4H), 3.29–3.24 (m, 2H), 3.18–3.14 (m, 2H),

2.71–2.56 (m, 4H), 2.47–2.38 (m, 2H), 2.31–2.26 (m, 2H), 2.15 (s, 3H),

2.04–1.47 (m, 12H), 1.33–1.23 (m, 9H), 1.05 (d, 3H, J=5.3 Hz), 0.96 (t,

2H, J=8.2 Hz), 0.75 (d, 3H, J=6.3 Hz), 0.60 (d, 3H, J=6.8 Hz),

0.00 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=206.5, 172.3, 165.9,

152.8, 151.9, 138.6, 135.9, 135.4, 133.3, 133.2, 132.9, 132.8, 130.5, 129.8,

rated by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl ace-

20

tate=60:40, 2.0 mLmin^ꢀ1; Retention time: b-isomer=20.0 min). ½aꢁ_D

=

ꢀ69.7 (c=0.230, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=8.20–7.35 (m,

21H), 6.96 (brs, 4H), 5.16 (s, 2H), 5.08 (dd, 1H, J=9.7 Hz, J=1.5 Hz),

4.96 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.90 (brs, 2H), 4.82 (t, 1H, J=9.2 Hz,

J=9.2 Hz), 4.71 (d, 1H, J=11.6 Hz), 4.66 (brs, 1H), 4.56–4.50 (m, 3H),

1420

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 126.8, 126.6, 126.3,

126.1, 125.9, 117.4, 117.2, 101.3, 100.2, 98.2, 97.1, 96.9, 96.3, 93.5, 82.3,

79.5, 79.2, 77.7, 77.4, 77.2, 76.2, 75.4, 73.8, 72.4, 71.9, 71.8, 70.7, 70.1, 69.9,

66.2, 66.0, 65.1, 60.3, 37.9, 37.1, 37.0, 36.8, 36.5, 29.8, 28.2, 24.7, 24.2, 23.9,

22.6, 21.0, 18.6, 18.3, 18.0, 17.9, 16.8, 16.5, 14.2, ꢀ1.46 ppm; IR (neat): n˜ =

2933, 1720, 1506, 1366, 1016, 857, 756, 522 cm^ꢀ1; HRMS (ESI-TOF)

[M+NH₄]⁺calcd. 1578.7758, found 1578.7816. a-isomer: ¹H NMR

(400 MHz, CDCl₃): d=8.03–7.26 (m, 24H), 6.97–6.91 (m, 4H), 5.15 (brs,

2H), 5.03 (brs, 1H), 4.97 (brs, 1H), 4.96 (dd, 1H, J=9.7 Hz, J=1.9 Hz),

4.85 (brs, 1H), 4.55 (brs, 1H), 4.44 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.87–

4.50 (m, 8H), 4.29 (q, 1H, J=6.3 Hz), 4.27–4.18 (m, 2H), 3.74 (t, 2H, J=

8.2 Hz), 3.74 (m, 1H), 3.67 (ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=8.2 Hz),

3.56 (ddd, 1H, J=11.1 Hz, J=4.9 Hz, J=8.7 Hz), 3.47–3.26 (m, 6H),

3.15–3.09 (m, 2H), 2.70–2.55 (m, 4H), 2.48–2.40 (m, 2H), 2.24 (ddd, 1H,

J=4.8 Hz, J=11.1 Hz, J=1.5 Hz), 2.19–2.14 (m, 4H), 1.95–1.48 (m,

12H), 1.32 (d, 3H, J=5.8 Hz), 1.27 (d, 3H, J=5.8 Hz), 1.06 (d, 3H, J=

6.3 Hz), 0.95 (t, 2H, J=8.2 Hz), 0.91 (d, 3H, J=6.3 Hz), 0.78 (d, 3H, J=

6.3 Hz), 0.58 (d, 3H, J=6.8 Hz), 0.00 ppm (s, 9H); ¹³C NMR (68.7 MHz,

CDCl₃): d=206.5, 172.4, 152.8, 151.9, 138.6, 135.6, 135.5, 133.2, 133.1,

132.9, 132.8, 132.7, 130.5, 129.9, 128.3, 128.1, 127.8, 127.7, 127.6, 127.5,

126.9, 126.7, 126.2, 126.1, 126.1, 126.0, 125.9, 117.7, 117.2, 100.2, 98.2,

97.3, 96.9ꢂ2, 93.5, 93.0, 82.3, 79.5, 79.2, 77.2, 72.9, 72.4, 72.0, 71.7, 71.5,

71.3, 70.8, 70.7, 70.0, 69.3, 66.4, 66.3, 66.0, 65.1, 37.9, 37.1, 37.0, 36.9, 36.3,

29.8, 23.9, 22.6, 18.7, 18.4, 18.1, 18.0, 17.5, 17.1, 16.5, ꢀ1.45 ppm; IR

2H), 4.84 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.73–4.44 (m, 7H), 4.33 (dd, 1H,

J=9.7 Hz, J=1.5 Hz), 4.25 (q, 1H, J=6.8 Hz), 4.18–4.09 (m, 2H), 3.95

(ddd, 1H, J=12.1 Hz, J=5.3 Hz, J=9.2 Hz), 3.75 (t, 2H, J=8.2 Hz), 3.70

(m, 1H), 3.53–3.42 (m, 3H), 3.23–3.10 (m, 5H), 2.72–2.56 (m, 4H), 2.48

(ddd, 1H, J=5.8 Hz, J=12.6 Hz, J=1.5 Hz), 2.30–2.21 (m, 3H), 2.15 (s,

3H), 2.04–1.44 (m, 12H), 1.33 (d, 3H, J=5.8 Hz), 1.23 (d, 3H, J=

6.3 Hz), 1.08 (d, 3H, J=5.3 Hz), 1.04 (d, 3H, J=5.3 Hz), 0.96 (t, 2H, J=

8.2 Hz), 0.67 (d, 3H, J=6.8 Hz), 0.59 (d, 3H, J=6.8 Hz), 0.00 ppm (s,

9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.5, 172.3, 165.9, 152.9, 151.8,

135.7, 135.4, 133.2, 133.1, 132.9ꢂ2, 132.8, 130.4, 130.3, 129.8, 129.8, 128.2,

128.1ꢂ2, 128.0, 127.8, 127.7, 126.8, 126.6, 126.1ꢂ2, 126.0, 125.9, 125.8,

117.8, 117.2, 101.3, 98.2, 97.0, 96.9, 96.4, 96.3, 93.5, 79.5, 79.0, 77.2, 76.2,

75.4, 75.1, 73.8, 73.4, 72.1, 71.9, 70.9, 70.7, 70.5, 70.1, 69.9, 66.1, 66.0, 65.1,

60.3, 37.9, 36.8, 36.7, 36.6, 36.5, 29.8, 28.2, 24.7, 24.1, 23.9, 22.6, 18.3, 18.2,

18.0, 17.9, 17.8, 16.8, 16.5, 14.2, ꢀ1.46 ppm; IR (neat): n˜ =2933, 1702,

1506, 1366, 1016, 857, 756, 522 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd. 1572.7415, found 1572.7415.

2aa: To

a stirred solution of the hexasaccharides 35aa (8.13 mg,

5.16 mmol) in THF/MeOH (1:1 2 mL) was added a catalytic amount of

sodium methoxide at room temperature under argon. After stirring at

508C for 24 h, the reaction mixture was poured into water. The aqueous

layer was extracted with two portions of ethyl acetate. The combined ex-

tract was washed with brine, dried over MgSO₄, filtered, and concentrat-

ed in vacuo. After short pass chromatography, the residue was used for

the next reaction without further purification. To a stirred solution of the

residue in HMPA (103 mL) was added a 1.00m THF solution of tetrabutyl-

ammonium fluoride (15.5 mL, 15.5 mm) at room temperature. After micro-

wave irradiation (300 W, 1008C, 30 min) reaction, the reaction mixture

was poured into saturated aq. NaHCO₃. The aqueous layer was extracted

with two portions of ethyl acetate. The combined extract was washed

with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The

residue was used for the next reaction without further purification. To a

stirred solution of the residue in THF (1.00 mL) was added a large

amount of liq. NH₃(5.00 mL) and Na (50.0 mg) at ꢀ788C. After stirring

at the same temperature for 1 h, the reaction mixture was quenched by

methanol, and poured into brine. The aqueous layer was extracted with

two portions of ethyl acetate. The combined extract was washed with

brine, dried over MgSO₄, filtered, and concentrated in vacuo. The residue

was chromatographed on silica gel with 95:5 chloroform/methanol to give

hexasaccharide 2aa (3.10 mg, 3.61 mmol, 3 steps 70%). ½aꢁ²_D⁷=ꢀ54.5 (c=

(neat): n˜ =3020, 1728, 1375, 1216, 1064, 756, 669 cm^ꢀ1

.

35dc: According to the method for the synthesis of 35aa, a solution of

5d (65.7 mg, 0.0780 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (64.0 mg, 0.117 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (23.5 mL, 0.234 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3c

(33.0 mg, 0.0350 mmol) with the imidate in toluene (1.56 mL) by activa-

tion with I₂(30.0 mg, 0.117 mmol) provided the hexasaccharide 35dc

(46.0 mg, 0.0270 mmol, 79%, b/a=>90:10). The b,a isomers were sepa-

rated by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl ace-

21

tate=60:40, 2.0 mLmin^ꢀ1; Retention time: b-isomer=18.5 min). ½aꢁ_D

=

ꢀ61.7 (c=1.39, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=8.19–7.37 (m,

21H), 6.97 (brs, 4H), 5.16 (brs, 2H), 5.07 (dd, 1H, J=9.7 Hz, J=

1.5 Hz), 4.96 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.89 (brs, 2H), 4.86 (t, 1H,

J=9.2 Hz, J=9.2 Hz), 4.69 (d, 1H, J=11.6 Hz), 4.60 (brd, 1H, J=

9.7 Hz), 4.56 (brs, 1H), 4.50 (d, 1H, J=11.6 Hz), 4.49 (dd, 1H, J=

9.7 Hz, J=1.5 Hz), 4.45 (brd, 1H, J=9.7 Hz), 4.26 (q, 1H, J=6.3 Hz),

4.14 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.12 (m, 1H), 4.00 (ddd, 1H, J=

12.6 Hz, J=4.8 Hz, J=9.2 Hz), 3.88 (q, 1H, J=4.8 Hz), 3.75 (t, 2H, J=

8.2 Hz), 3.77–3.65 (m, 2H), 3.54–3.46 (m, 3H), 3.40–3.33 (m, 2H), 3.29–

3.16 (m, 5H), 2.71–2.56 (m, 4H), 2.47 (m, 1H), 2.33–2.25 (m, 3H), 2.15

(s, 3H), 2.03–1.42 (m, 12H), 1.32 (d, 3H, J=6.3 Hz), 1.22 (d, 3H, J=

6.3 Hz), 1.13 (d, 3H, J=6.3 Hz), 1.09 (d, 3H, J=6.8 Hz), 1.05 (d, 3H, J=

4.8 Hz), 0.96 (t, 2H, J=8.2 Hz), 0.61 (d, 3H, J=6.3 Hz), 0.00 ppm (s,

9H); ¹³C NMR (68.7 MHz, CDCl₃): d=206.6, 172.3, 165.9, 165.7, 153.0,

151.7, 147.1, 144.9, 135.4, 133.2, 133.1, 133.0, 132.9, 132.8, 130.4, 130.1,

129.8, 129.7, 129.3, 128.3, 128.2, 128.1, 127.8, 127.7, 126.8, 126.1, 126.0,

125.9, 124.0, 117.8, 117.2, 101.2, 98.1, 96.9, 96.4, 93.4, 92.4, 83.9, 79.5, 77.2,

52.4, 37.9, 37.0, 36.7, 36.5, 35.7, 29.8, 29.6, 29.4, 28.1, 24.2, 24.1, 23.9, 22.6,

18.2, 18.0, 17.9, 17.8, 16.8, 16.5, ꢀ1.46 ppm; IR (neat): n˜ =3020, 1722,

1349, 1216, 1018, 757, 668 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.

1665.7021, found 1665.7061.

1

0.155, CHCl₃); H NMR (400 MHz, CD₂Cl₂): d=6.89 (d, 2H, J=8.7 Hz),

6.74 (d, 2H, J=8.7 Hz), 5.03–4.94 (m, 4H), 4.55–4.48 (m. 5H), 4.38 (brs,

1H), 4.26 (brs, 1H), 4.12 (q, 1H, J=6.8 Hz), 4.07 (q, 1H, J=6.8 Hz),

3.68–3.34 (m, 7H), 3.62 (brs, 1H), 3.54 (brs, 1H), 3.30 (m, 1H), 3.13–

3.03 (m, 3H), 2.97 (dd, 1H, J=9.7 Hz, J=9.7 Hz), 2.37 (ddd, 1H, J=

5.3 Hz, J=12.5 Hz, J=1.9 Hz), 2.28–2.24 (m, 3H), 2.08–1.52 (m, 12H),

1.37–1.15 ppm (m, 18H); ¹³C NMR (100 MHz, CD₂Cl₂): d=151.2, 151.1,

118.0, 115.8, (101.4, 100.9ꢂ2, 98.3, 97.8, 97.5, 88.5, 88.1, 80.5, 80.3, 75.9,

75.3, 72.3, 72.2, 70.6, 70.4, 69.6, 69.4, 67.7, 67.1, 38.5, 38.4, 37.1, 37.0, 29.7,

25.6, 25.1, 24.5, 17.7, 16.8, 16.7 ppm; IR (neat): n˜ =3417, 3020, 2400, 1510,

1216, 770, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593,

found: 876.4596.

2ab: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35ab (8.61 mg, 5.51 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (16.5 mL, 16.5 mmol) in HMPA

35dd: According to the method for the synthesis of 35aa, a solution of

5d (53.1 mg, 0.0630 mmol) in H₂O (0.100 mL) and CH₃CN (1.00 mL) was

treated with CAN (51.7 mg, 0.0945 mmol) to provide a hemiacetal. The

hemiacetal was treated with trichloroacetonitrile (20.0 mL, 0.189 mmol) in

CH₂Cl₂(1.00 mL) to provide imidate. Glycosylation of acceptor 3d

(33.2 mg, 0.0380 mmol) with the imidate in toluene (1.20 mL) by activa-

tion with I₂(24.0 mg, 0.0945 mmol) provided the hexasaccharide 35dd

(56.2 mg, 0.0352 mmol, 93%, b/a=83:17). The b,a isomers were separat-

ed by HPLC (Senshu Pak Silica-3301-N, Eluent: Hexane/Ethyl acetate=

(110 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2ab (2.60 mg, 3.03 mmol,

3 steps 55%). ½aꢁ²_D³=ꢀ48.1 (c=0.130, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 5.00–4.80

(m, 5H), 4.52–4.45 (m. 5H), 4.22 (brs, 1H), 4.12–4.04 (m, 2H), 3.66–3.23

(m, 8H), 3.59 (brs, 1H), 3.51 (brs, 1H), 3.09–2.92 (m, 4H), 2.34 (m, 1H),

2.27–2.20 (m, 3H), 2.05–1.52 (m, 12H), 1.33–1.13 ppm (m, 18H);

¹³C NMR (100 MHz, CD₂Cl₂): d=152.3, 151.1, 118.3, 116.2, 101.7, 101.5,

101.3, 100.2, 98.7, 97.9, 88.8, 88.5, 88.3, 80.6, 76.1, 75.7, 72.6, 71.2, 70.9,

70.8, 70.3, 69.9, 69.8, 68.4, 68.1, 67.4, 38.9, 38.7, 38.6, 37.3, 37.0, 36.9, 30.1,

25.9, 25.5, 24.7, 18.1, 17.9, 17.1, 17.0 ppm; IR (neat): n˜ =3400, 3019, 2400,

60:40, 2.0 mLmin^ꢀ1

; Retention time: b-isomer=18.0 min, a-isomer=

19.0 min). ½aꢁ²_D²=ꢀ71.5 (c=1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=8.08–7.35 (m, 24H), 6.97 (brs, 4H), 5.17 (s, 2H), 5.08 (dd, 1H, J=

9.7 Hz, J=1.5 Hz), 4.97 (t, 1H, J=9.2 Hz, J=9.2 Hz), 4.91–4.89 (brs,

1509, 1218, 772, 669 cm^ꢀ1

876.4593, found: 876.4591.

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

Chem. Asian J. 2010, 5, 1407 – 1424

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

1421

H. Tanaka, T. Takahashi et al.

FULL PAPERS

2ac: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35ac (16.0 mg, 9.82 mmol) in THF-MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

17.9, 17.1, 17.0 ppm; IR (neat): n˜ =3401, 3019, 2401, 1509, 1219, 1038,

772, 668 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593, found:

876.4593.

with

a 1m THF solution of TBAF (16.5 mL, 16.5 mmol) in HMPA

2bc: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35bc (8.30 mg, 5.08 mmol) in THF-MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

(196 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2ac (3.80 mg, 4.42 mmol,

3 steps 45%). ½aꢁ²_D⁶=ꢀ31.2 (c=0.180, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.94 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.91–4.90 (m, 2H), 4.55–4.43 (m. 3H), 4.12–

4.01 (m, 2H), 3.58–3.25 (m, 10H), 3.09–2.92 (m, 4H), 2.29–2.19 (m, 4H,),

2.05–1.46 (m, 12H), 1.33–1.03 ppm (m, 18H); ¹³C NMR (68.7 MHz,

CD₂Cl₂): d=151.5, 118.4, 116.2, (101.8, 101.3, 100.1, 98.5, 98.1, 97.9

(anomeric)), 88.8, 82.2, 80.8, 80.7, 76.3, 75.7, 75.6, 75.3, 72.6, 72.5, 72.4,

70.8, 70.0, 69.9, 68.1, 68.0, 67.4, 46.5, 38.8, 37.7, 37.6, 37.4, 36.1, 30.1, 25.9,

24.5, 18.2, 18.0, 17.9, 17.1, 17.0 ppm; IR (neat): n˜ =3408, 3019, 1218, 1063,

771, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593, found:

876.4594.

with

a 1m THF solution of TBAF (15.2 mL, 15.2 mmol) in HMPA

(102 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2bc (1.70 mg, 1.98 mmol,

3 steps 39%). ½aꢁ²_D²=ꢀ60.3 (c=0.105, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=9.2 Hz), 4.94 (dd,

1H, J=9.7 Hz, J=1.5 Hz), 4.91–4.88 (m, 2H), 4.75 (brs, 1H), 4.55–4.45

(m. 3H), 4.40 (brs, 1H), 4.37 (brs, 1H), 4.33 (brs, 1H), 4.11 (q, 1H, J=

6.8 Hz), 4.04 (q, 1H, J=6.8 Hz), 3.62–3.24 (m, 10H), 3.08–2.91 (m, 4H),

2.29–2.19 (m, 4H), 2.10–1.45 (m, 12H), 1.33–1.12 ppm (m, 18H);

¹³C NMR (100 MHz, CD₂Cl₂): d=151.5, 118.4, 116.2, 101.8, 101.5, 100.2,

100.1, 98.6, 98.1, 88.8, 88.5, 82.2, 80.8, 76.3, 75.7, 75.3, 72.6, 72.5, 71.2,

70.8, 70.3, 69.9, 68.5, 68.0, 67.4, 60.6, 46.4, 38.9, 38.6, 37.7, 37.6, 30.1, 25.8,

25.4, 24.8, 24.6, 18.2, 18.1, 18.0, 17.9, 17.1 ppm; IR (neat): n˜ =3401, 2933,

1509, 1370, 1219, 1067, 772 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.

876.4593, found 876.4594.

2ad: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35ad (10.3 mg, 6.51 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (19.5 mL, 19.5 mmol) in HMPA

(130 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2ad (1.90 mg, 2.21 mmol,

3 steps 34%). ½aꢁ²_D⁸=ꢀ39.8 (c=0.100, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.94 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.92–4.86 (m, 2H), 4.75 (brs, 1H), 4.55–4.44

(m. 4H), 4.12–4.04 (m, 2H), 3.58–3.23 (m, 10H), 3.09–2.92 (m, 4H),

2.32–2.19 (m, 4H), 2.10–1.48 (m, 12H), 1.33–1.00 ppm (m, 18H);

¹³C NMR (68.7 MHz, CD₂Cl₂): d=151.6, 118.4, 116.2, 101.7, 101.3, 100.2,

100.1, 98.6, 97.9, 88.8, 88.4, 82.2, 80.6, 76.1, 75.7, 75.3, 72.6, 72.5, 71.7,

71.2, 70.9, 70.8, 70.3, 69.9, 68.4, 68.1, 67.4, 46.6, 38.9, 38.8, 37.7, 37.4, 30.1,

25.9, 25.6, 25.0, 24.7, 18.2, 18.0, 17.1, 17.0, 11.5 ppm; IR (neat): n˜ =3409,

3019, 2400, 1217, 1063, 771, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd.: 876.4593, found: 876.4592.

2bd: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35bd (12.8 mg, 8.22 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (24.7 mL, 24.7 mmol) in HMPA

(164 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2bd (4.80 mg, 5.59 mmol,

3 steps 68%). ½aꢁ¹_D⁶=ꢀ55.9 (c=0.420, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.94 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.89–4.85 (m, 2H), 4.77–4.75 (m, 2H), 4.55–

4.33 (m. 5H), 4.11 (q, 1H, J=6.8 Hz), 4.06 (q, 1H, J=6.8 Hz), 3.60–3.24

(m, 10H), 3.09–2.91 (m, 4H), 2.30–2.21 (m, 3H), 2.10–1.39 (m, 12H),

1.32–1.13 ppm (m, 18H); ¹³C NMR (100 MHz, CD₂Cl₂): d=151.5, 118.4,

116.2, 101.7, 101.5, 100.2ꢂ3, 98.6, 88.8, 88.4, 88.2, 76.1, 75.3, 72.6, 72.5,

71.2, 70.8, 70.3, 69.9, 68.5, 68.4, 67.4, 38.9, 38.8, 38.7, 38.6, 37.7, 30.1, 26.0,

25.8, 24.7, 24.6, 23.3, 18.2, 18.1, 18.0, 17.1, 17.0, 15.0ppm; IR (neat): n˜ =

3392, 2931, 1724, 1509, 1371, 1217, 1064, 769, 667 cm^ꢀ1; HRMS (ESI-

TOF) [M+NH₄]⁺calcd.: 876.4593, found: 876.4595.

2ba: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35ba (11.8 mg, 7.52 mmol) in THF-MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (22.6 mL, 22.6 mmol) in HMPA

(150 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2ba (4.20 mg, 4.89 mmol, 3

steps 65%). ½aꢁ²_D⁵=ꢀ19.4 (c=0.210, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.98 (dd,

1H, J=10.2 Hz, J=1.5 Hz), 4.91–4.85 (m, 3H), 4.75 (brs, 1H), 4.51–4.45

(m. 5H), 4.39 (brs, 1H), 4.34 (brs, 1H), 4.11 (q, 1H, J=6.8 Hz), 4.04 (q,

1H, J=6.3 Hz), 3.62–3.32 (m, 7H), 3.58 (brs, 1H), 3.51 (brs, 1H), 3.28

(m, 1H), 3.08–2.91 (m, 4H), 2.34 (ddd, 1H, J=5.8 Hz, J=12.6 Hz, J=

1.5 Hz), 2.25–2.21 (m, 3H), 2.03–1.45 (m, 12H), 1.34–1.13 ppm (m, 18H);

¹³C NMR (100 MHz, CD₂Cl₂): d=151.5, 151.3, 118.3, 116.1, 101.7, 101.4,

101.3, 100.1, 98.6, 98.1, 88.8, 88.4, 80.8, 76.2, 75.6, 72.6, 71.1, 70.9, 70.7,

70.3, 69.8, 69.7, 68.5, 68.0, 67.3, 38.8, 38.7, 38.6, 37.4, 30.1, 25.8, 25.4, 24.8,

24.5, 18.1, 18.0, 17.9ꢂ2, 17.1ꢂ2 ppm; IR (neat): n˜ =3412, 3020, 2401,

2ca: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35ca (14.9 mg, 9.05 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (27.2 mL, 27.2 mmol) in HMPA

(181 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2ca (3.50 mg, 4.07 mmol,

3 steps 45%). ½aꢁ²_D⁷=ꢀ45.1 (c=0.225, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.98 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.91–4.90 (m, 2H), 4.53–4.49 (m, 3H), 4.43

(dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.12–4.02 (m, 2H), 3.65–3.29 (m, 9H),

3.17 (m, 1H), 3.09–2.96 (m, 4H), 2.34 (ddd, 1H, J=5.3 Hz, J=12.5 Hz,

J=1.9 Hz), 2.25–2.14 (m, 3H), 2.09–1.48 (m, 12H), 1.34–1.03 ppm (m,

18H); ¹³C NMR (100 MHz, CD₂Cl₂): d=151.5, 118.4, 116.2, 101.6, 101.3,

100.1, 98.7, 98.2, 97.9, 88.5, 82.4, 80.9, 80.7, 76.2, 75.7, 75.5, 72.7, 72.6,

72.4, 71.0, 69.8, 68.1, 68.0, 67.4, 46.5, 38.7, 37.9, 37.5, 30.1, 25.9, 25.5, 24.9,

24.5, 18.2, 18.0ꢂ2, 17.9, 17.1, 17.0 ppm; IR (neat): n˜ =3330, 3019, 1216,

1062, 757, 669 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593,

found: 876.4596.

1509, 1217, 771, 669 cm^ꢀ1

876.4593, found: 876.4598.

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

2bb: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35bb (17.5 mg, 11.3 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (33.9 mL, 33.9 mmol) in HMPA

2cb: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35cb (19.0 mg, 11.6 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

(226 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2bb (6.90 mg, 8.03 mmol,

3 steps 71%). ½aꢁ²_D⁴=ꢀ50.4 (c=0.350, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.85 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=9.2 Hz), 4.98 (dd,

1H, J=9.7 Hz, J=1.5 Hz), 4.88–4.77 (m, 4H), 4.52–4.41 (m. 5H), 4.11 (q,

1H, J=6.8 Hz), 4.06 (q, 1H, J=6.3 Hz), 3.66–3.38 (m, 9H 4), 3.28 (m,

1H), 3.04–2.91 (m, 4H), 2.34 (ddd, 1H, J=5.3 Hz, J=12.5 Hz, J=

1.5 Hz), 2.26–2.21 (m, 3H), 2.10–1.39 (m, 12H), 1.29–1.13 ppm (m, 18H);

¹³C NMR (100 MHz, CD₂Cl₂): d=151.5, 151.4, 118.3, 116.2, 101.7, 101.4ꢂ

2, 100.2ꢂ2, 98.6, 88.8, 88.5, 88.3, 76.1, 71.2, 71.1, 71.0, 70.8, 70.3, 70.2,

69.9, 69.7, 68.5, 68.4, 67.3, 38.8, 38.7, 38.6, 30.1, 25.8, 25.5, 24.7, 24.5, 18.1,

with

a 1m THF solution of TBAF (34.8 mL, 34.8 mmol) in HMPA

(232 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2cb (7.20 mg, 8.38 mmol,

3 steps 72%). ½aꢁ²_D⁴=ꢀ64.5 (c=0.325, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.8 Hz), 4.98 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.91–4.81 (m, 3H), 4.52–4.47 (m. 2H), 4.43

(dd, 1H, J=10.2 Hz, J=1.9 Hz), 4.29 (brs, 1H), 4.24 (brs, 1H), 4.18–4.03

(m, 2H), 3.66–3.28 (m, 9H), 3.17 (m, 1H), 3.09–2.93 (m, 4H), 2.34 (ddd,

1H, J=5.3 Hz, J=12.6 Hz, J=1.9 Hz), 2.26–2.13 (m, 3H), 2.08–1.52 (m,

1422

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Combinatorial Synthesis of Deoxyhexasaccharides

12H), 1.32–1.13 ppm (m, 18H); ¹³C NMR (100 MHz, CD₂Cl₂): d=151.5,

118.3, 116.2, 101.5, 101.4, 100.2, 100.0, 98.6, 97.9, 88.5, 88.3, 82.4, 80.7,

76.0, 75.7, 75.4, 72.5, 72.3, 71.2, 70.9, 70.3, 69.7, 68.4, 68.0, 67.4, 38.7, 38.6,

37.9, 37.5, 30.1, 25.9, 25.5, 24.7, 24.5, 18.2, 18.1, 18.0, 17.9, 17.1, 17.0 ppm;

IR (neat): n˜ =3400, 2934, 1731, 1510, 1217, 1064, 760, 627 cm^ꢀ1; HRMS

(ESI-TOF) [M+NH₄]⁺calcd. 876.4593, found 876.4594.

CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.98 (brd,

1H, J=9.7 Hz), 4.88–4.83 (m, 3H), 4.74 (brs, 1H), 4.53–4.49 (m, 3H),

4.43 (brd, 1H, J=9.2 Hz), 4.11 (q, 1H, J=6.3 Hz), 4.06 (q, 1H, J=

6.3 Hz), 3.66–3.35 (m, 9H), 3.17 (m, 1H), 3.04–2.93 (m, 4H), 2.34 (m,

1H), 2.27–2.14 (m, 3H), 2.10–1.53 (m, 12H), 1.29–1.13 ppm (m, 18H);

¹³C NMR (100 MHz, CD₂Cl₂): d=151.6, 118.3, 116.2, 101.5, 101.4, 100.2ꢂ

2, 100.1, 98.6, 89.2, 88.5, 88.3, 82.4, 76.0, 75.4, 72.3, 71.2, 71.1, 70.9, 70.3,

69.7, 68.5, 68.4, 67.3, 38.8, 38.7, 38.6, 37.8, 30.1, 25.8, 25.5, 24.7, 24.5, 24.3,

18.2, 18.1, 18.0, 17.9, 17.1, 17.0 ppm; IR (neat): n˜ =3394, 3018, 1505, 1220,

1012, 772, 670 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593,

found: 876.4590.

2cc: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35cc (21.7 mg, 12.6 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (37.8 mL, 37.8 mmol) in HMPA

(252 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2cc (7.70 mg, 8.96 mmol,

3 steps 71%). ½aꢁ²_D³=ꢀ47.6 (c=0.385, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 4.94 (brd,

1H, J=9.7 Hz), 4.90 (brs, 1H), 4.90 (brs, 1H), 4.55–4.50 (m. 2H), 4.43

(brd, 1H, J=9.7 Hz), 4.38 (brs, 1H), 4.36 (brs, 1H), 4.29 (brs, 1H,), 4.23

(bs, 1H), 4.09 (q, 1H, J=6.3 Hz), 4.04 (q, 1H, J=6.3 Hz), 3.59–3.27 (m,

9H), 3.17 (m, 1H), 3.09–2.96 (m, 4H), 2.29–2.14 (m, 4H), 2.10–1.49 (m,

12H), 1.33–1.12 ppm (m, 18H); ¹³C NMR (100 MHz CD₂Cl₂): d=151.5,

151.4, 118.3, 116.2, 101.6, 100.1, 100.0, 98.5, 98.1, 97.8, 82.4, 82.2, 80.9,

80.7, 76.2, 75.7, 75.5, 75.3, 72.6, 72.5, 72.3, 68.1, 68.0, 67.4, 37.9, 37.7, 37.6,

37.5, 30.1, 25.9, 25.4, 24.8, 24.5, 18.2, 18.0, 17.1 ppm; IR (neat): n˜ =3369,

2934, 1510, 1366, 1220, 1065, 772 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺

calcd.: 876.4593, found: 876.4592.

2dc: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35dc (23.1 mg, 14.0 mmol) in THF-MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (42.0 mL, 42.0 mmol) in HMPA

(280 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2dc (5.30 mg, 6.17 mmol,

3 steps 44%). ½aꢁ²_D¹=ꢀ61.5 (c=0.265, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=9.2 Hz), 4.94 (dd,

1H, J=9.7 Hz, J=1.9 Hz), 4.90–4.85 (m, 3H), 4.72 (brs, 1H), 4.55–4.50

(m, 2H), 4.42 (dd, 1H, J=9.7 Hz, J=1.9 Hz), 4.38 (brs, 1H), 4.36 (brs,

1H), 4.25 (brs, 1H), 4.11 (q, 1H, J=6.8 Hz), 4.04 (q, 1H, J=6.8 Hz),

3.60–3.27 (m, 9H), 3.17 (m, 1H), 3.08–2.93 (m, 4H), 2.29–2.14 (m, 4H),

2.06–1.48 (m, 12H), 1.32–1.12 ppm (m, 18H); ¹³C NMR (100 MHz

CD₂Cl₂): d=151.6, 151.4, 118.3, 116.2, 101.6, 100.1ꢂ3, 98.5, 98.2, 88.5,

82.5, 82.2, 80.9, 76.2, 75.7, 75.5, 75.3, 72.6, 72.5, 72.3, 71.1, 70.4, 68.5, 68.0,

67.3, 38.8, 37.9, 37.7, 37.6, 30.1, 25.8, 25.4, 24.8, 24.5, 18.2, 18.1, 18.0,

17.1 ppm; IR (neat): n˜ =3393, 3019, 2400, 1415, 1219, 1096, 1019, 772,

2 cd: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35 cd (7.06 mg, 4.28 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (85.6 mL, 85.6 mmol) in HMPA

669 cm^ꢀ1

;

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593, found:

(85.6 mL) under microwave irradiation, and reduction of the benzyl

ethers under Birch reduction conditions provided 2 cd (2.10 mg,

876.4589.

steps 57%). ½aꢁ²_D²=ꢀ63.3 (c=0.0500, CHCl₃); ¹H NMR

2dd: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35dd (17.1 mg, 10.7 mmol) in THF/MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

2.44 mmol,

3

(400 MHz, CD₂Cl₂): d=6.88 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=8.7 Hz),

4.94 (brd, 1H, J=9.7 Hz, J=1.9 Hz), 4.90–4.86 (m, 3H), 4.75 (brs, 1H),

4.55–4.49 (m, 2H), 4.42 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.32 (brs, 1H),

4.28 (brs, 1H), 4.23 (brs, 1H), 4.12–4.04 (m, 2H), 3.58–3.13 (m, 10H),

3.09–2.93 (m, 4H), 2.30 (m, 1H), 2.27–2.13 (m, 3H), 2.10–1.52 (m, 12H),

1.32–1.24 (m, 12H), 1.16–1.13 ppm (m, 6H); ¹³C NMR (100 MHz,

CD₂Cl₂): d=151.5, 118.4, 116.2, 101.5, 100.2, 100.1, 100.0, 98.6, 97.9, 88.4,

82.4, 82.2, 80.7, 76.0, 75.7, 75.5, 75.3, 72.6, 72.3, 72.0, 70.9, 70.3, 68.4, 68.0,

67.4, 38.8, 37.9, 37.7, 37.5, 32.3, 30.1, 25.9, 25.5, 24.8, 24.5, 18.2, 18.1, 18.0,

with

a 1m THF solution of TBAF (32.1 mL, 32.1 mmol) in HMPA

(214 mL) under microwave irradiation, and reduction of the benzyl ethers

under Birch reduction conditions provided 2dd (7.10 mg, 8.27 mmol,

3 steps 77%). ½aꢁ²_D⁴=ꢀ51.5 (c=0.355, CHCl₃); ¹H NMR (400 MHz,

CD₂Cl₂): d=6.86 (d, 2H, J=8.7 Hz), 6.72 (d, 2H, J=8.7 Hz), 4.94 (brd,

1H, J=9.7 Hz), 4.87–4.72 (m, 4H), 4.55–4.50 (m. 2H), 4.43 (brd, 1H, J=

9.7 Hz), 4.34 (brs, 1H), 4.26 (brs, 1H), 4.14–4.03 (m, 2H), 3.60–3.13 (m,

10H), 3.10–2.93 (m, 4H), 2.30–2.15 (m, 4H), 2.10–1.50 (m, 12H), 1.32–

1.13 ppm (m, 18H); ¹³C NMR (100 MHz CD₂Cl₂): d=151.5, 118.4, 116.2,

101.5, 100.2ꢂ2, 100.1ꢂ2, 98.5, 88.5, 88.3, 82.4, 82.2, 75.9, 75.4, 75.3, 72.5,

72.3, 71.2, 71.1, 70.4, 68.5, 68.4, 67.3, 38.8, 37.9, 37.7, 30.1, 25.8, 25.5, 24.7,

24.5, 18.2, 18.1, 18.0, 17.1, 17.0 ppm; IR (neat): n˜ =3401, 2934, 1670, 1509,

1369, 1218, 1067, 771, 667 cm^ꢀ1; HRMS (ESI-TOF) [M+NH₄]⁺calcd.:

876.4593, found: 876.4590.

17.1, 17.0 ppm; IR (neat): n˜ =3401, 3018, 2399, 1509, 1219, 772, 670 cm^ꢀ1

HRMS (ESI-TOF) [M+NH₄]⁺calcd.: 876.4593, found: 876.4595.

;

2da: According to the method for the synthesis of 2aa, hydrolysis of the

ester group of 35da (7.85 mg, 4.98 mmol) in THF-MeOH (1:1 2.00 mL)

with a catalytic amount of sodium methoxide, removal of the SEM ether

with

a 1m THF solution of TBAF (14.9 mL, 14.9 mmol) in HMPA

(99.6 mL) under microwave irradiation, and reduction of the benzyl

ethers under Birch reduction conditions provided 2da (2.10 mg,

2.44 mmol,

3

steps 49%). ½aꢁ²_D⁴=ꢀ48.2 (c=0.105, CHCl₃); ¹H NMR

(400 MHz, CD₂Cl₂): d=6.85 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz),

4.98 (dd, 1H, J=10.2 Hz, J=1.5 Hz), 4.90–4.88 (m, 2H), 4.70 (brs, 1H),

4.53–4.49 (m. 3H), 4.42 (dd, 1H, J=9.7 Hz, J=1.5 Hz), 4.36 (brs, 1H),

4.25 (brs, 1H), 4.11 (q, 1H, J=6.3 Hz), 4.04 (q, 1H, J=6.3 Hz), 3.65–

3.32 (m, 7H), 3.58 (brs, 1H), 3.51 (brs, 1H), 3.17 (m, 1H), 3.08–2.93 (m,

4H), 2.34 (ddd, 1H, J=5.3 Hz, J=13.1 Hz, J=1.5 Hz), 2.25–2.15 (m,

3H), 2.10–1.48 (m, 12H), 1.34–1.13 ppm (m, 18H); ¹³C NMR (100 MHz

CD₂Cl₂): d=151.6, 151.4, 118.3, 116.2, 101.6, 100.3, 100.2, 100.1, 98.7,

98.2, 88.5, 82.5, 80.9, 76.2, 75.7, 72.7, 71.1, 70.9, 70.4, 69.8, 68.5, 68.0, 67.4,

38.8, 38.7, 37.9, 37.5, 30.1, 25.8, 25.4, 24.8, 24.6, 18.2, 18.1, 18.0, 17.9,

Acknowledgements

This work was financially supported by NEDO (New Energy and Indus-

trial Technology Development Organization) and was partially supported

by JSPS research fellowships for young scientists (DC2). We thank EI-

WEISS Chemical Corporation for supplying EDCI.

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2db: According to the method for the synthesis of 2aa, hydrolysis of the

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Chem. Asian J. 2010, 5, 1407 – 1424

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Received: November 13, 2009

Revised: January 7, 2010

Published online: May 17, 2010

1424

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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 1407 – 1424

Article Doi

Combinatorial synthesis of deoxyhexasaccharides related to the landomycin a sugar moiety, based on an orthogonal deprotection strategy

DOI: 10.1002/asia.200900640.

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Article abstract of DOI:10.1002/asia.200900640.

Full text of DOI:10.1002/asia.200900640.

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