Synthesis of 5a,5a′-dicarba-D-glucobioses from conformationally restricted carbaglucosyl triflates using SN2-type inversion with carbaglucosyl nucleophiles

B i o o r g an i c &M e d i c i n a l C h e m i s tr y x x x (x xxx )x xx–xxx

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Bioorganic & Medicinal Chemistry

journal homepage: www.elsevier.com/locate/bmc

Synthesis of 5a,5a′-dicarba-D-glucobioses from conformationally restricted

carbaglucosyl triﬂates using S_N2-type inversion with carbaglucosyl

nucleophiles

Naoya Tateda, Katsumi Ajisaka, Masaji Ishiguro^⁎, Tatsuo Miyazaki^⁎

Department of Applied Life Sciences, Graduate School of Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan

A R T I C L E I N F O

A B S T R A C T

Keywords:

Novel carbohydrate mimics were designed which contain two 5a-carba-D-glucose residues, one each at reducing

and nonreducing end, and thus these mimics are 5a,5a′-dicarba-^D-glucobioses. Dicarbadisaccharides have at-

tractive features such as stability against endogenous degradative enzymes and being resistant to glycation

reactions such as the Maillard reaction. For the synthesis of dicarba-β-^D-isomaltose derivatives, the carbaglucosyl

triﬂate locked in ⁴C₁conformation was synthesized by protecting with butane-2,3-diacetal group or benzylidene

group. Then, 5a,5a′-dicarba-β-^D-maltose and 5a,5a′-dicarba-α,β-D-trehalose were synthesized by the S_N2-type

inversion reaction using 4,6-O-benzylidene carbaglucosyl triﬂate with 4-OH and 1-OH carba-β-^D-glucose deri-

vatives, respectively, and similarly 5a,5a′-dicarba-α-^D-isomaltose with 6-OH carba-α-D-glucose derivative.

Carbohydrate mimics

Carbasugar

Dicarbadisaccharides

S_N2-type inversion

Conformationally restricted carbaglucosyl

triﬂates

1. Introduction

synthesis of various carbasugars using an optically active Diels-Alder

adduct.²³In addition, Yu and Chung synthesized the entire D-series of

Carbohydrates play important roles as glycoconjugates in a variety

of biological processes such as cell-cell recognition, fertilization, cell

growth, viral and bacterial infection, and tumor cell metastasis.^1–4

Glycoconjugates are poly- or oligosaccharides linked to proteins, lipids,

and other molecules. Oligosaccharides and their analogues are potential

therapeutic agents^5–10because they can act as regulators of biological

processes.

16 carbasugar stereoisomers by systematically altering the hydroxyl

stereochemistry of a carba-β-^D-altropyranose derivative.²⁴However,

carbasugar synthesis on the preparative scale remains challenging due

to the multiple steps required.

The synthesis of disaccharide mimics with a carbasugar at the

nonreducing or reducing end has recently been reported.²⁵The 5a-

carbadisaccharides should be stable against glycation in vivo. The 5a-

carbadisaccharides are easily synthesized in excellent yield using either

conventional glycosylation or enzyme-catalyzed glycosylation^26,27but

are easily hydrolyzed chemically or enzymatically. On the other hand,

carbadisaccharides with a carbasugar at the nonreducing end (5a′-car-

badisaccharides) are resistant against enzymatic cleavage by glycosi-

dases. 5a′-Carbadisaccharides have been synthesized by two ap-

proaches: (i) S_N2-type inversion between 5a-carbasugar C-1 alcohols

and carbohydrate triﬂates, and (ii) epoxide opening under basic con-

ditions. However, these synthetic methods aﬀorded the 5a′-carbadi-

saccharides in poor yield, except for the S_N2-type inversion using the C-

4 triﬂate of the 1,6-anhydrogalactose derivative²⁸or the epoxide

opening of 1,2-anhydro-5a-carbasugar derivatives.^29,30There are

therefore no general methods available for the preparation of 5a′-car-

badisaccharides.

Much research has focused on developing carbohydrate mimics such

as azasugars, thiosugars, carbasugars, and phosphasugars, where the

ring oxygen has been replaced by nitrogen, sulfur, carbon, and phos-

phorus, respectively. In particular, azasugars have been reported to be

potent inhibitors of several glycosidases.^11,12Also, nucleotide analo-

gues containing thiosugar or carbasugar have been reported to be gly-

cosyltransferase inhibitors.^13–16Carbasugars with a cyclohexane ring

are expected to be the most stable of carbohydrate mimics towards

endogenous degradative enzymes. In addition, carbasugars do not un-

dergo glycation in vivo. For example, carbasugars do not undergo the

Maillard reaction¹⁷due to the absence of an acetal moiety. Carbasugars

are useful as carbohydrate mimics in glycobiology because they are

recognized by the corresponding enzymes or lectins.^18–20

A number of synthetic strategies for carbasugars have been re-

ported²¹since the ﬁrst synthesis of 5a-carba-α-DL-talopyranose by

McCasland.²²For example, Ogawa and co-workers reported the

The purpose of the present study was to establish the process to

synthesize 5a,5a′-dicarba-^D-glucobioses (1–4) containing a 5a-carba-D-

^⁎Corresponding authors.

E-mail addresses: ishiguro@nupals.ac.jp (M. Ishiguro), tmiyazaki@nupals.ac.jp (T. Miyazaki).

https://doi.org/10.1016/j.bmc.2018.12.027

Received 2 November 2018; Received in revised form 15 December 2018; Accepted 18 December 2018

0968 -0 896 /©201 8 E l s e v i e r L t d .A l l r i g h t s r e s e r v ed.

Pleasecitethisarticleas:Tateda,N.,Bioorganic&MedicinalChemistry,https://doi.org/10.1016/j.bmc.2018.12.027

N. Tateda et al.

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Scheme 1. Retrosynthetic analysis of four kinds of 5a,5a′-dicarba-D-glucobioses.

glucose residue linked at both the reducing and the nonreducing end

(Scheme 1). As a starting material, 2-deoxy-scyllo-inosose (DOI) was

prepared from the culture medium of metabolically engineered Es-

cherichia coli.³¹Then the obtained DOI was changed to 5a-carba-β-D-

glucose according to the literature³²in large scale. A benzyl protected

or conformationally restricted 5a-carba-β-^D-glucose derivative bearing

a leaving group at the 1-position and carbaglucosyl derivatives having

an OH group are provided from the 5a-carba-β-^D-glucose. The optimum

conditions for the synthesis of 5a,5a′-dicarba-^D-glucobioses of various

linkage by the S_N2-type inversion were examined using the upper car-

baglucosyl derivatives. Thus, obtained 5a,5a′-dicarba-^D-glucobioses are

expected to be used as the new sources in the medicinal screening.

reaction on the 6-oxo moiety aﬀorded the exo methylene derivative 6 in

72% yield in three steps. Hydroboration of the exocyclic oleﬁn 6 with 9-

BBN under reﬂux in THF gave a mixture of two diastereomeric alcohols

(gluco:ido = 2.7:1). After acetylation of the diastereomeric mixture, the

desired carba-β-^D-glucose derivative 7 was isolated by recrystallization

from diisopropyl ether in 60% yield. Additionally, the two isomers in

the ﬁltrate were separated by silica gel column chromatography to

provide a 6% yield of carba-β-^D-glucose derivative 7 and a 20% yield of

carba-α-^L-idose. Saponiﬁcation of the acetyl group to provide com-

pound 8 and subsequent removal of the benzyl groups provided the 5a-

carba-β-^D-glucose 9 as a key synthetic intermediate. 5a-Carba-β-D-glu-

cose 9 was converted to compound 11 via compound 10 by the re-

ported method.³³The hydroxyl group of compound 11 was protected as

a p-methoxybenzyl group, then the acetal groups were removed using

60% aqueous acetic acid. Subsequent benzylation provided compound

12 in 78% yield from compound 11. The p-methoxybenzyl group of 12

was oxidatively removed using CAN in a solution of aqueous acetoni-

trile to give compound 13 in 82% yield. Treatment of compound 13

with triﬂuoromethanesulfonic anhydride (Tf₂O) and utilization of the

less nucleophilic base di-tert-butyl-4-methylpyridine (DTBMP) led to

the desired carbaglucosyl triﬂate 14 in 92% yield. Compound 13 was

converted to mesylate 15 and chloromesylate 16 in 94% and 87% yield

by treatment with methanesulfonyl chloride and chlor-

omethanesulfonyl chloride, respectively. Compound 13 was reacted

with p-toluenesulfonyl chloride at 50 °C to give tosylate 17 in 96%

yield. Brosylate 18 and nosylate 19 were obtained in 87% and 88%

yield, respectively, at this raised temperature.

2. Results and discussion

2.1. Synthesis of dicarba-β-^D-isomaltose derivative via S_N2-type inversion

reaction by use of carbaglucosyl sulfonates.

2.1.1. Synthesis of the reducing-end moiety 8 and 5a-carba-β-^D-glucose

derivatives having various leaving groups at the 1-position 14–19

The carbaglucosyl derivatives bearing a leaving group at the 1-po-

sition were synthesized by preparing 5a-carba-β-^D-glucose from 2-

deoxy-scyllo-inosose (DOI), which in turn was derived from ^D-glucose

through bioconversion (Scheme 2). We established a facile puriﬁcation

method for DOI from the culture solution. Culture solution containing

DOI was ﬁltered through a membrane ﬁlter to provide the cell-free

solution. DOI is unstable under basic conditions and thus the ﬁltrate

was desalted using strong cation–exchange column chromatography

(H⁺form) and weak anion–exchange column chromatography (AcO^–

form). DOI was isolated by crystallization from methanol and ethanol in

67% yield based on the amount of ^D-glucose used in the fermentation.

DOI was converted to 5a-carba-β-^D-glucose 9 using the methods

described by Kakinuma and co-workers,³²with modiﬁcations. Wittig

2.1.2. Optimization of reaction condition in S_N2-type reaction by use of

carbaglucosyl sulfonates 14–19

The results of S_N2-type inversion between the carbaglucosyl sulfo-

nates 14–19 and 1,2,3,4-O-Bn-carba-β-^D-glucoside 8 are summarized in

Table 1. Treatment of compound 8 (2.5 equiv. based on triﬂate 14) with

2

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Scheme 2. Synthesis of the reducing-end moiety 8 and the carbaglucosyl sulfonates 14–19. Reagents and conditions: (a) 1. 9-BBN, THF, reﬂux, 2 h then 30% H₂O₂,

3 N NaOH, 0 °C, 3 h, (gluco:ido = 2.7:1); 2. Ac₂O, pyridine, rt, 2 h, 65%, two steps; (b) NaOMe, MeOH, rt, quant; (c) H₂, 10% Pd/C, MeOH, AcOH, quant; (d)

benzaldehyde dimethylacetal, CSA, DMF, 60 °C, 3 h, 80%; (e) 2,2-dimethoxypropane, CSA, DMF, 60 °C, 20 min, 53%; (f) 1. 4-methoxybenzyl chloride, NaH, DMF,

0 °C, 1 h; 2. 60% AcOH, 60 °C, 1.5 h; 3. BnBr, NaH, DMF, 0 °C, 10 min, 78%, three steps; (g) CAN, MeCN, H₂O, rt, 82%; (h) Tf₂O, DTBMP, CH₂Cl₂, −10 °C, 15 min,

92% (i) methanesulfonyl chloride, pyridine, 0 °C, overnight, 94%; (j) chloromethanesulfonyl chloride, pyridine, 0 °C, 10 min, 87%; (k) p-toluenesulfonyl chloride,

DMAP, pyridine, 50 °C, overnight, 96%; (l) 4-bromobenzenesulfonyl chloride, DMAP, pyridine, 40 °C, 5 h, 87%; (m) 4-nitorobenzenesulfonyl chloride, DMAP, 50 °C,

4 h, 88%. 9-BBN = 9-borabicyclo[3.3.1]nonane, CAN = cerium ammonium nitrate, DTBMP = di-tert-butyl-4-methylpyridine, CMs = chloromethanesulfonyl,

Bs = 4-bromobenzensulfonyl, Ns = 4-nitrobenzensulfonyl.

Table 1

Optimization of S_N2-type inversion between the carbaglucosyl sulfonates 14–19 and 1,2,3,4-tetra-O-Bn-carba-β-D-glucopyranoside 8.

Entry Sulfonate

X

Conc. (M) 14–19 Conc. (M) 8 Solvent NaH (equiv.) 15-Crown-5 (equiv.) Temp. (°C) Product (%) 20 Oleﬁn (%) 21 Recovered (%) 8

1

14

15

16

17

18

19

14

Tf

Ms

0.08

0.34

0.68

1.36

0.68

0.20

0.85

1.70

3.40

1.68

THF

2.5

7.3

2.5

14.8

7.4

3.7

–

rt

50

rt

0

6

79

40

47

49

52

41

16

10

–

86

66

67

73

68

73

92

77

91

59

88

84

76

85

95

74

2

Neat

THF

10

21

22

11

–

3

4

5

6^a

7^b

8

Neat

THF

7.5

7.4

7.3

3.7

CMs 0.68

–

Ts

Bs

Ns

Tf

0.68

–

9^c

10^d

11

12

13

14

15

16

–

37

24

47

33

28

46

26

70

33

37

28

50

0

MeCN

HMPA

DMI

0

a

b

c

Compound 13 was obtained in 29%.

Mesylate 15 was obtained in 18%.

Compound 22 was obtained in 24%.

Compound 22 was obtained in 19%.

d

3

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experiment on compound 22 showed a correlation between C-4^″of the

phenyl group and H-6. Unfortunately, no dicarbadisaccharide 20 was

formed under these reaction conditions utilizing the sulfonates 15–19.

The yields of compound 20 and oleﬁn 21 at 50 °C were 24% and

70%, respectively, and the yield of compound 20 improved to up to

37% and that of oleﬁn 21 was suppressed to 26% when the reaction was

conducted at 0 °C (entries 11 and 12). The eﬀect of solvent (THF,

acetonitrile, hexamethylphosphoramide (HMPA) and 1,3-dimethyl-2-

imidazolidine (DMI) on the reaction was investigated at 0 °C. As shown

in entries 13–16, THF and DMI improved the yields of desired com-

pound 20, up to 47% and 46%, respectively, whereas acetonitrile and

HMPA did not improve the yield. The improved yield might be due to

the sodium alkoxide generated from compound 8 dissolving well in THF

and DMI. The structure of the obtained dicarbadisaccharide 20 was

conﬁrmed from its NMR spectra: 1) the ¹H NMR spectrum showed the

coupling constants for J_{1′, 2′}, J_{1′, 5′aax}and J_{1′, 5′aeq}as 2.7, 1.3 and 3.7 Hz,

respectively; and 2) the chemical shift of C-6 (δ 70.23) was shifted

downﬁeld in comparison to that of the C-6 signal in 8 (δ 64.60); 3) in

the HMBC spectrum, indicating the correlation between C-1′ and H-6.

These results conﬁrmed that compound 20 has the α1 → 6 linkage.

Fig. 1. Structure of compound 22.

sodium hydride in THF in the presence of 15-crown-5 ether, and then

reaction with triﬂate 14 (0.08 M) at room temperature (entry 1), gave

the desired 5a,5a′-dicarba-β-^D-isomaltose 20 in low yield (6%). This

reaction preferred β-elimination of triﬂate 14, to give oleﬁn 21 in 79%

yield. Conducting the reaction at higher substrate concentration

(0.34 M, 0.68 M and 1.38 M) under neat reaction conditions increased

the yield of coupling product 20 to 10%, 21% and 22% yield, respec-

tively (entries 2–4). The reaction without 15-crown-5 ether provided

compound 20 in 11% yield, showing that 15-crown-5 ether is an ef-

fective additive to improve the yield (entry 5).

The reaction of mesylate 15 under the same conditions as entry 3

gave only the recovered material 15. Reaction at a higher temperature

(50 °C) gave the oleﬁn 21 in 41% yield and the hydrolyzed compound

13 in 29% yield (entry 6). The reaction of chloromesylate 16 and

compound 8 gave the oleﬁn 21 and the mesylate 15, which may be

derived from reductive nucleophilic attack on the chloromesylate group

(entry 7). Although the reaction of tosylate 17 at room temperature led

only to oleﬁn 21 (entry 8), the reaction of brosylate 18 or nosylate 19

with compound 8 unexpectedly yielded the coupled product 22 in 24%

and 19% yield, respectively (entries 9 and 10), (Fig. 1). The HMBC

2.2. Synthesis of dicarbaglucobioses derivatives via S_N2-type inversion

reaction by use of conformationally restricted carbaglucosyl triﬂates 27, 30,

33, 40 and 42

2.2.1. Synthesis of the conformationally restricted carbaglucosyl triﬂates

27, 30, 33, 40 and 42

In the synthesis of 5a,5a′-dicarba-β-^D-isomaltose derivative 20, we

selected the synthetic strategy using 1-O-Tf-carba-β-^D-glucose deriva-

tive as electrophile. Although we also tried another synthetic strategy

using

a 1-OH-carba-α-^D-glucosyl derivative as a nucleophile, the

Scheme 3. Synthesis of conformationally restricted carbaglucosyl triﬂates 27, 30, 33, 40 and 42. Reagents and conditions: (a) 4-methoxybenzyl chloride, NaH, DMF,

0 °C, 1 h, 90%; (b) 2-(Bromomethyl)naphthalene, NaH, DMF, 0 °C, 1 h, 92%; (c) 60% AcOH, MeOH, 60 °C, 1.5 h, 77%; (d) BnBr, NaH, DMF, rt, 30 min, 93%; (e) DDQ,

CH₂Cl₂, H₂O, rt, 1 h, 85%; (f) Tf₂O, DTBMP, CH₂Cl₂, −15 °C, 15 min, 80%; (g) α,α′-dibromo-o-xylene, NaH, DMF, rt, overnight, 56%; (h) DDQ, CH₂Cl₂, H₂O, rt,

40 min, 97%; (i) Tf₂O, pyridine, CH₂Cl₂, −10 °C, 2 h, 85%; (j) 1. 60% AcOH, 60 °C, 10 h; 2. BnBr, NaH, DMF, 0 °C, 30 min, 80%; (k) DDQ, CH₂Cl₂, H₂O, rt, 1.5 h, 91%;

(l) Tf₂O, pyridine, CH₂Cl₂, −10 °C, 2 h, 83%; (m) 60% AcOH, MeOH, 60 °C, 2 h, 85%; (n) BH₃·THF, CoCl₂, rt, 5 h, 89%; (o) 2,3-butanedione, trimethyl orthoformate,

CSA, MeOH, 60 °C, 4.5 h, 95%; (p) BnBr, NaH, DMF, rt, 2 h, 96%; (q) DDQ, CH₂Cl₂, H₂O, rt, 1 h, 81%; (r) Tf₂O, pyridine, CH₂Cl₂, −10 °C, 2.5 h, 87%; (s) 1. H₂, 10%

Pd/C, MeOH, AcOH, rt, overnight; 2. benzaldehyde dimethylacetal, CSA, DMF, 60 °C, 15 min, 78%, two steps; (t) Tf₂O, pyridine, CH₂Cl₂, −10 °C, 2 h, 92%. Nap = 2-

naphthylmethyl.

4

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required 6-O-Tf-carba-β-D-glucose derivative could not be synthesized

in typical triﬂation conditions due to the instability of 6-O-Tf-product.

Furthermore, a low reactivity of the 1-OH carba-α-^D-glucose derivative

led us to select the carba-β-^D-glucose derivative bearing a triﬂate at the

1-position for the electrophile in the following experiments. Since β-

elimination of the triﬂate 14 should occur in the axial form, the triﬂates

were synthesized in the conformationally ﬁxed form locked in the ⁴C₁

conformation (Scheme 3). Compound 11 was protected as a p-meth-

oxybenzyl ether, followed by chemoselective removal of the iso-

propylidene group using acetic acid at 60 °C to give the 2,3-diol 24.

Benzylation of 24 followed by removal of the p-methoxybenzyl group

using DDQ and subsequent triﬂation provided triﬂate 27 in 63% yield

over three steps.

desired dicarba-β-^D-isomaltose derivatives and synthesis of the un-

desired oleﬁns is suppressed. Finally, deprotection of compounds 20,

43, 45, 47, 48, and 50 gave the desired 5a,5a′-dicarba-β-^D-isomaltose 1

in quantitative yield (Scheme 4).

2.2.3. Synthesis of 5a,5a′-dicarba-β-^D-maltose 2 and 5a,5a′-dicarba-α,β-D-

trehalose 3

We evaluated substrate speciﬁcity under the optimized reaction

conditions using the carbaglucosyl derivatives 52 and 13, which have a

secondary alcohol (Scheme 5). The carbaglucosyl derivative 52 with a

hydroxyl group at the 4-position was prepared from compound 10.

Benzylation of the hydroxyl group, followed by selective ring-opening

of the benzylidene group using trimethylamine borane and AlCl₃in

THF, provided compound 52 in 79% yield in two steps. The S_N2-type

inversion reaction of the per-O-Bn-triﬂate 14 and compound 52 gave

dicarba-β-^D-maltose 53 in only 3% yield. On the other hand, the use of

triﬂate 27 bearing the benzyliden group increased the yield of com-

pound 54 up to 20%. Deprotection of both 53 and 54 gave the desired

5a,5a′-dicarba-β-^D-maltose 2 in quantitative yield.

Triﬂate with the o-xylylene group at the 2,3-positions was prepared

from compound 11. Compound 11 was treated with α,α′-dibromo-o-

xylene and NaH in DMF to provide compound 28 in 56% yield. The p-

methoxybenzyl group was removed and the resulting hydroxyl group

was converted into the Tf group to give triﬂate 30. Then, acidic clea-

vage of the benzylidene of compound 28, followed by benzylation,

provided compound 31 in 80% yield. After DDQ oxidation of the ob-

tained compound 31, triﬂation gave the desired triﬂate 33 in 83%

yield.

Next, we reacted carbaglucosyl derivative 13 bearing a hydroxyl

group at the 1-position with the per-O-Bn-triﬂate 14 to aﬀord dicarba-

α,β-^D-trehalose derivative 55 in 37% yield. In contrast, the use of tri-

ﬂate 27 increased the yield of compound 56 up to 64%. Deprotection of

compounds 55 and 56 gave the desired 5a,5a′-dicarba-α,β-^D-trehalose 3

in quantitative yield. Application of the optimized reaction conditions

to the two carbaglucosyl derivatives with a secondary alcohol resulted

in moderate yields. The higher reactivity of compound 13 is likely due

to less steric hindrance between the hydroxy group and the adjacent

deoxy moiety at the 5a-position.

Triﬂate with butane-2,3-diacetal (BDA) group at the 2,3-positions

was prepared from compound 11. Compound 11 was treated with 2-

(bromomethyl)naphthalene and NaH in DMF to aﬀord compound 34.

Removal of the isopropylidene group with acetic acid at 60 °C gave the

2,3-diol 35 in 85% yield. Installation of a BDA group was attempted

using 1,1,2,2-tetramethoxydiacetal, generated in situ from 2,3-butane-

dione and trimethoxy orthoformate.³⁴However, the desired compound

was obtained only in 23% yield because the benzylidene group was

deprotected under this condition. Therefore, selective ring-opening re-

duction of compound 35 was attempted by the use of BH₃·THF and

CoCl₂to give compound 36 in 89% yield, followed by installation of the

BDA group, yielding compound 37 in 95% yield. Benzylation of 37 and

subsequent oxidative cleavage of the 2-methylnaphtyl group, then tri-

ﬂation, gave the desired triﬂate 40. Hydrogenolysis of compound 37

over Pd/C removed the 2-methylnaphtyl and benzyl groups simulta-

neously. Introduction of the benzylidene group yielded compound 41 in

78% yield in two steps. Finally, triﬂation of compound 41 gave the

triﬂate 42 in 92% yield. Large coupling constants in ¹H NMR,

2.2.4. Synthesis of 5a,5a′-dicarba-α-^D-isomaltose 4

An α-form of 5a,5a′-dicarba-α-^D-isomaltose 4 was also synthesized

to compare the isomaltose and the corresponding dicarbadisaccharide

(Scheme 6). Triﬂation of compound 26, followed by the inversion re-

action with CsOAc, aﬀorded the carba-α-glucose derivative 57 in 94%

yield. After deacetylation, the resulting product was protected with the

benzyl group, and subsequent selective ring-opening reduction pro-

vided the compound 59. In a similar manner, the S_N2-type inversion

reaction of triﬂate 14 by compound 59 proceeded to furnish dicarba-α-

D-isomaltose 60 in 17% yield. As expected, the use of triﬂate 27 in-

creased desired compound 61 to up to 37% yield. Deprotection of

compounds 60 and 61 gave 5a,5a′-dicarba-α-^D-isomaltose 4 in quanti-

tative yield.

J_1,2= 8.7 Hz,

J_1,5aax= 11.8 Hz,

J_2,3= 8.8 Hz,

J_3,4= 9.0 Hz,

J

_4,5= 9.3 Hz, and J_5,5aax= 11.8 Hz, indicate a ⁴C₁conformation for the

triﬂate 27. Triﬂates 30, 33, 40 and 42 also show similar large coupling

constants, indicating the ⁴C₁conformation for these compounds.

3. Conclusion

2.2.2. Optimization of reaction condition for the 5a,5a′-dicarba-β-^D-

isomaltose

In the present study, a novel approach was investigated for the

synthesis of 5a,5a′-dicarba-^D-glucobioses having α1 → 6, α1 → 4, and

α1 → β1 linkages by S_N2-type inversion reaction. The 5a-carba-D-glu-

cose residue was introduced with α-linkage by the S_N2 inversion using

of 5a-carba-β-^D-glucosyl triﬂate 14 and 6-OH carbaglucose derivatives

8, the 5a,5a′-dicarba-β-^D-isomaltose derivative 20 was obtained in the

yield of 47% at 0 °C under high concentration. As a next step, the

carbaglucosyl triﬂate 14 was changed to a conformationally restricted

carbaglucosyl triﬂate bearing with 4,6-O-benzylidene 27 or 2,3-O-BDA

groups 40, the yield of 5a,5a′-dicarba-β-^D-isomaltose derivative 43 and

48 increased to 55% and 57%. By the similar reactions using con-

formationally restricted carbaglucosyl triﬂate 27, 5a,5a′-dicarba-β-^D-

maltose derivative 54, 5a,5a′-dicarba-α,β-^D-trehalose derivative 56,

and 5a,5a′-dicarba-α-^D-isomaltose derivative 61 were obtained in yield

of 20%, 64%, and 37%, respectively. The conformationally restricted

structure of carbaglucosyl triﬂate was revealed to be critical in this S_N2-

type inversion reaction. The present approach is expected as a new tool

for the synthesis of 5a,5a′-dicarba-^D-glucobioses of various linkages or

pseudo-oligosaccharides as new chemical sources for medical uses. The

dicarbadisaccharide are expected to be stable against glucosidases and

The ﬁve conformationally restricted triﬂates 27, 30, 33, 40, and 42

were reacted with carbaglucosyl derivative 8 under optimized reaction

conditions in the presence of NaH and 15-crown-5 ether at 0 °C in THF

(0.68 M). The results are summarized in Table 2. The S_N2-type inver-

sion of triﬂate 27 bearing only the benzylidene group and compound 8

gave the desired dicarbadisaccharide 43 in 55% yield (entry 2). The

restricted triﬂate gave better yield than per-O-Bn-triﬂate, and the yield

of the oleﬁn was decreased to 19%. In a similar manner, triﬂate 33

bearing only the o-xylylene group was reacted with carbaglucosyl de-

rivative 8 to aﬀord the corresponding dicarbadisaccharide 45 in 32%

yield (entry 3). The use of triﬂate 30 having both the benzylidene and o-

xylylene groups gave dicarbadisaccharide 47 in 35% yield (entry 4). On

the other hand, S_N2-type inversion of the triﬂate 40 bearing the BDA

group by the carbaglucosyl derivative 8 gave the dicarbadisaccharide

48 in 57% yield and reduced the degree of β-elimination, giving the

oleﬁn 49 in 9% yield (entry 5). The use of triﬂate 42 bearing the

benzylidene and BDA groups resulted in the dicarbadisaccharide 50 in

53% yield (entry 6). These results suggested that using a triﬂate with

either 4,6-O-benzylidene or 2,3-O-BDA groups eﬃciently provides the

5

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Table 2

S_N2-type inversion by use of the conformationally restricted carbaglucosyl triﬂates 27, 30, 33, 40 and 42.

Entry

Triﬂates

Dicarbadisaccharide product (%)

Yield of oleﬁn (%)

1

2

3

4

–

5

6

–

the Maillard reaction. Thus, a preliminary test against hydrolases such

as α-glucosidases showed a good stability of these carba-analogs of the

disaccharides with little inhibitory activity. A further investigation on

their biological properties is in due course.

4. Experimental section

Scheme 4. Synthesis of 5a,5a′-dicarba-β-D-isomaltose 1. Reagents and condi-

tions: (a) H₂, Pd Black, MeOH, AcOH, rt, quant; (b) 1. 60% AcOH, 60 °C; 2. H₂,

Pd Black, MeOH, AcOH, rt, quant, two steps.

4.1. General methods

All reagents and anhydrous solvents were obtained from

6

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Scheme 5. Synthesis of 5a,5a′-dicarba-β-D-maltose

2

and 5a,5a′-dicarba-α,β-^D-trehalose 3. Reagents

and conditions: (a) BnBr, NaH, DMF, rt, overnight,

94%; (b) trimethylamine borane, AlCl₃, THF, rt,

overnight, 84%; (c) NaH, 15-crown-5, THF, 0 °C, 53:

5%, 54 : 20%, 55 : 37%, 56: 64%; (d) H₂, Pd Black,

MeOH, AcOH, rt, quant.

commercial suppliers and were used as supplied without further pur-

iﬁcation. Non-aqueous reactions were performed under an atmosphere

of argon. Thin layer chromatography (TLC) was carried out on plates

precoated with silica gel 60 F-254 (E. Merck). Compounds ware vi-

sualized by UV-light at 254 nm and by dipping the plates in a cerium

sulfate ammonium molybdate solution followed by heating. Column

chromatography was carried out on Silica gel 60N (63–210 μm, sphe-

rical, neutral, Kanto Chemical Co.) and Silica gel 60N (40–50 μm,

spherical, neutral, Kanto Chemical Co.). Proton nuclear magnetic re-

sonance spectra (¹H NMR) were obtained on a Bruker AVANCE II 400

(400 MHz) and are reported in parts per million (δ) relative to the re-

sonance of the solvent. Dates are represented as follows: chemical shift,

integration, multiplicity (s, singlet; d, doublet; m, multiplet; br, broad),

coupling constant in hertz (Hz), and assignment. Carbon nuclear mag-

netic resonance spectra (¹³C NMR) were obtained on a Bruker AVANCE

II 400 (100 MHz) and are reported in parts per million (δ) relative to the

resonance of the solvent. Infrared spectra were measured on a Perkin-

Elmer Ultra II FT-IR spectrometer and are reported in terms of frequency

of absorption (cm⁻¹). Optical rotations were measured on a JASCO P-

2300 Polarimeter with a path length of 1 dm; concentrations are given

in g/100 mL. Melting points (mp) were recorded using an apparatus

and not corrected. High-resolution mass spectra (HRMS) were recorded

with a Bruker micrOTOF II.

membrane ﬁlter (Mixed cellulose ester, pore size 0.45, 2.0, 5.0 μm,

diameter 293 mm, ADVANTEC Co. Ltd.) under pressure to give the cell-

free solution. The ﬁltrate was subsequently desalted by strong cation-

exchange column chromatography (Amberlite 200CT, H⁺form, 5 L,

ϕ14 cm × 32 cm, ORGANO Co. Ltd.) and the weak anion-exchange

column chromatography (Amberlite IRA96SB, AcO⁻form, 7.5 L,

ϕ13 cm × 56 cm, ORGANO Co. Ltd.). Then, the eluted solution in-

cluding DOI was evaporated. After the residue (422 g) was dissolved in

MeOH (505 mL), then EtOH (3.5 L) was added with dropwise to crys-

talize the DOI. The obtained DOI was dried in desiccator with P₂O₅. The

yield was 67% (283 g) based on utilizing the ^D-glucose (473 g) in fer-

mentation. The physical data were identical to the reported data.³²

Keto form: ¹H NMR (400 MHz, D₂O) δ 4.37(d, 1H, J_3,4= 10.2 Hz, H-

4), 3.82(dd, 1H, J_1,2= 9.6 Hz, J_2,3= 9.3 Hz, H-2), 3.75(ddd, 1H, H-1),

3.47(dd, 1H, H-3), 2.83–2.74(m, 2H, H-5aeq, H-5aax); ¹³C NMR

(100 MHz, D₂O) δ 206.92(C-5), 77.84(C-4), 76.06(C-2), 73.87(C-3),

68.20(C-1), 44.16(C-5a).

Hydrate form: ¹H NMR (400 MHz, D₂O)

δ 3.67(ddd, 1H,

J

_1,2= 9.0 Hz, J_1,5aeq= 5.0 Hz, J_1,5aax= 11.9 Hz, H-1), 3.49(d, 1H,

_3,4= 9.1 Hz, H-4), 3.43(dd, 1H, J_2,3= 9.1 Hz, H-3), 3.38(dd, 1H, H-2),

2.25(dd, 1H, J_gem= 13.3 Hz, H-5aeq), 1.73(dd, 1H, H-5aax); ¹³C NMR

(100 MHz, D₂O) δ 93.27(C-5), 77.01(C-2), 76.27(C-4), 73.54(C-3),

68.47(C-1), 40.68(C-5a).

4.1.1. Puriﬁcation of DOI 5 from the culture solution

4.1.2. 2,4/3,5–2,3,4,5-Tetrabenzyloxy-1-methylenecyclohexane (6)

The culture solution³¹10.5 L (DOI 39.2 g / L) was ﬁltered through a

To a stirred suspension of methyltriphenylphosphonium bromide

Scheme 6. Synthesis of 5a,5a′-dicarba-α-D-iso-

maltose 4. Reagents and conditions: (a) 1. Tf₂O,

DTBMP, CH₂Cl₂, −10 °C, 10 min; 2. CsOAc, 18-

crown-6, Toluene, rt, 1 h, 96%, two steps; (b) 1.

NaOMe, MeOH, rt, 7 h; 2. BnBr, NaH, DMF, 0 °C,

30 min, 90%, two steps; (c) THF·BH₃, CoCl₂, THF, rt,

2 h, 93%; (d) NaH, 15-crown-5, THF, 0 °C, 60: 17%,

61: 37%; (e) H₂, Pd Black, MeOH, AcOH, rt, quant.

7

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(69.0 g, 192.9 mmol) in THF (200 mL) was added dropwise a solution of

n-BuLi (55 mL, 2.64 M in hexane, 144.6 mmol) at −60 °C. After the

addition, the suspension was stirred at room temperature. The sus-

pension was added a solution of 3,4,5,6-O-benzyl-2-deoxy-scyllo-in-

osose (25.20 g, 48.2 mmol) in THF (50 mL) dropwise at −60 °C. After

being stirred at room temperature for 40 min, the solution was diluted

with EtOAc and washed subsequently with 1 M HCl, saturated NaHCO₃,

and brine. The organic layer was dried (MgSO₄) and concentrated in

vacuo. The residue was puriﬁed by column chromatography (hexane/

EtOAc, 9:1) to give compound 6 (24.4820 g, 98%) as a white amor-

phous solid. R_f= 0.36 (Hex/EtOAc, 10:1); [α] = −25.8° (c 1.00,

CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.25(m, 20H), 5.24(m, 1H,

H-6a), 4.97(m, 1H, H-6b), 4.92(d, 1H, J = 10.7 Hz), 4.91(d, 1H,

J = 10.8 Hz), 4.86(d, 1H, J = 10.8 Hz), 4.82(d, 1H, J = 10.7 Hz),

4.74(d, 1H, J = 11.4 Hz), 4.68(s, 2H), 4.68(d, 1H, J = 11.4 Hz), 3.92(d,

1H, J_3,4= 9.2 Hz, H-4), 3.62(dd, 1H, J_1,2= 9.0 Hz, J_2,3= 9.1 Hz, H-2),

3.43(ddd, 1H, J_1,5aeq= 5.1 Hz, J_1,5aax= 11.9 Hz, H-1), 3.39(dd, 1H, H-

3), 2.72(dd, 1H, J_gem= 12.9 Hz, H-5aeq), 2.04(dd, 1H, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 140.16(C-5), 138.87, 138.83, 138.53, 138.35,

128.38, 128.30, 128.29, 127.97, 127.96, 127.75, 127.69, 127.61,

127.48, 110.34(C-6), 85.81(C-3), 85.09(C-2), 83.10(C-4), 80.44(C-1),

75.86, 75.84, 73.54, 72.56, 36.39(C-5a); HRMS(ESI) m/z: [M+Na]⁺

calcd for C₃₅H₃₆O₄Na 543.2506, found 543.2508.

3:1); [α] = +29.7° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.35–7.25(m, 20H), 4.96(d, 1H, J = 10.8 Hz), 4.95(d, 2H, J = 10.8 Hz),

4.83(d, 2H, J = 10.8 Hz), 4.68(d, 1H, J = 11.5 Hz), 4.65(d, 1H,

J = 10.8 Hz), 4.64(d, 1H, J = 11.5 Hz), 3.66–3.55(m, 2H, H-6a, H-6b),

3.57(dd, 1H, J_2,3= 8.8 Hz, J_3,4= 8.8 Hz, H-3), 3.54(m, 1H, H-1),

3.51(dd, 1H, J_1,2= 8.7 Hz, H-2), 3.42(dd, 1H, J_4,5= 10.4 Hz, H-4),

2.03(ddd, 1H, J_1,5aeq= 3.8 Hz, J_5,5aeq= 3.8 Hz, J_gem= 13.1 Hz, H-

5aeq), 1.81(br, 1H, OH), 1.62(m, 1H, H-5), 1.26(ddd, 1H,

J

_1,5aax= 11.0 Hz, J_5,5aax= 11.0 Hz, H-5aax); ¹³C NMR (100 MHz,

CDCl₃) δ 138.77, 138.64, 138.54, 138.12, 128.58, 128.39, 128.37,

128.33, 128.24, 127.96, 127.76, 127.68, 127.59, 127.56, 127.53,

86.28(C-3), 85.93(C-2), 82.09(C-4), 80.10(C-1), 75.79, 75.75, 75.10,

72.36, 64.60(C-6), 40.16(C-5), 29.89(C-5a); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₃₅H₃₈O₅Na 561.2611, found561.2613.

4.1.5. 5a-Carba-β-^D-glucopyranose (9)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (41.71 g, 77.43 mmol) in MeOH (300 mL), THF (50 mL), and AcOH

(20 mL) was added 10% Pd/C (4.12 g, 3.87 mmol). The resulting sus-

pension was hydrogenated at 1 atm. After 10.5 h, further portion of

10% Pd/C (4.12 g, 3.87 mmol) was added to the mixture. After being

stirred for total 36.5 h, the solution was ﬁltered through of Celite, and

the solvent was evaporated. The residue was chromatographed on a

column of Amberlite 200CT ion-exchange resin (H⁺form) and IRA

96SB ion-exchange resin (OH^–) to give compound 9 (14.3957 g, quant)

4.1.3. 6-O-Acetyl-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose (7)

A

solution of 2,4/3,5–2,3,4,5-tetrabenzyloxy-1-methylenecyclo-

as

a

colorless syrup. R_f= 0.30 (CHCl₃/MeOH/H₂O, 10:5:1);

hexane 6 (25.00 g, 48.2 mmol) in 9-BBN (193 mL, 0.5 M in THF,

96.4 mmol) was stirred for 2 h at reﬂux. To the solution cooled to 0 °C

was added H₂O (35 mL), 3 N NaOH (30 mL), and 30% H₂O₂(30 mL).

After being stirred for 3 h at room temperature, the solution was diluted

with EtOAc and washed subsequently with 1 M HCl, saturated NaHCO₃,

and brine. The organic layer was dried (MgSO₄) and concentrated in

vacuo. The residue was puriﬁed by column chromatography (hexane/

[α] = +16.1° (c 1.00, H₂O); ¹H NMR (400 MHz, D₂O) δ 3.81(dd, 1H,

J

_5,6a= 3.6 Hz, J_gem= 11.2 Hz, H-6a), 3.68(dd, 1H, J_5,6b= 6.1 Hz, H-

6b), 3.61(ddd, 1H, J_1,2= 8.9 Hz, J_1,5aeq= 4.7 Hz, J_1,5aax= 11.6 Hz, H-

1), 3.34(m, 1H, H-4), 3.32(m, 1H, H-3), 3.28(dd, 1H, J_2,3= 9.8 Hz, H-

2), 2.05(ddd, 1H, J_5,5aeq= 3.8 Hz, J_gem= 12.9 Hz, H-5aeq), 1.68(m,

1H, H-5), 1.31(ddd, 1H,

J

_5,5aax= 11.8 Hz, H-5aax); ¹³C NMR

(100 MHz, D₂O) δ 76.93(C-2), 76.77(C-3), 72.59(C-4), 71.06(C-1),

62.14(C-6), 40.06(C-5), 31.64(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd

for C₇H₁₄O₅Na 201.0733, found 201.0735.

EtOAc, 2:1) to give

a mixture of two diastereomeric alcohols

(25.6130 g, 99%) as a colorless syrup. To a solution of the mixture

(47.13 g, 87.5 mmol) in pyridine (40 mL) was added Ac₂O (21 mL,

219 mmol). After being stirred for overnight, MeOH was added, and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed subsequently with 1 M HCl, saturated NaHCO₃, and

brine. The organic layer was dried (MgSO₄) and concentrated in vacuo.

The residue was crystallized from diisopropyl ether to give compound 7

(30.5998 g, 60%) as a white solid. The residue was puriﬁed by column

chromatography (toluene/EtOAc, 20:1) to give compound 7 (3.0154 g,

6%) as a white amorphous solid and isomer (10.3459 g, 20%) as a

colorless syrup. R_f= 0.40 (Hex/EtOAc, 2:1); [α] = +32.3° (c 1.00,

CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.26(m, 20H), 4.95(d, 2H,

J = 10.8 Hz), 4.90(d, 1H, J = 10.8 Hz), 4.85(d, 1H, J = 10.8 Hz),

4.84(d, 1H, J = 10.8 Hz), 4.68(s, 2H), 4.55(d, 1H, J = 10.8 Hz),

4.1.6. 4,6-O-Benzylidene-5a-carba-β-^D-glucopyranose (10)

To a solution of 5a-carba-β-^D-glucopyranose 9 (7.43 g, 41.7 mmol)

in DMF (100 mL) at 60 °C was added benzaldehyde dimethyl acetal

(9.3 mL, 62.5 mmol) and CSA (4.8 g, 20.9 mmol). After being stirred for

3 h, the solution was cooled to 0 °C and neutralized with Et₃N. The

solution was concentrated in vacuo, and the residue was crystallized

from EtOH–H₂O to give compound 10 (7.00 g, 63%) as a white solid.

The residue was puriﬁed by column chromatography (CHCl₃/MeOH,

10:1) to give compound 10 (1.8731 g, 17%) as a white amorphous

solid. R_f= 0.21 (CHCl₃/MeOH, 10:1); [α] = −50.0° (c 1.00, MeOH);

¹H NMR (400 MHz, MeOD) δ 7.52–7.32(m, 5H), 5.56(s, 1H, PhCH),

4.13(dd, 1H,

J

_5,6a= 4.4 Hz, J_gem= 10.9 Hz, H-6a), 3.66(dd, 1H,

4.19(dd, 1H,

_5,6b= 4.8 Hz, H-6b), 3.55–3.51(m, 3H, H-1, H-2, H-3), 3.40(dd, 1H,

J_3,4= 8.5 Hz, J_4,5= 10.6 Hz, H-4), 2.06(ddd, 1H, J_1,5aeq= 3.6 Hz,

J_5,6a= 3.1 Hz, J_gem= 10.9 Hz, H-6a), 4.15(dd, 1H,

J

_5,6b= 10.9, H-6b), 3.52(ddd, 1H, J_1,5aeq= 4.8 Hz, J_1,2= 9.0 Hz,

J

_1,5aax= 11.4 Hz, H-1), 3.47(dd, 1H, J_2,3= 8.9 Hz, J_3,4= 9.4 Hz, H-3),

3.43(dd, 1H, J_4,5= 9.4 Hz, H-4), 3.24(dd, 1H, H-2), 1.79(m, 1H, H-5),

1.74(ddd, 1H, J_5,5aeq= 3.3 Hz, J_gem= 12.6 Hz, H-5aeq), 1.11(ddd, 1H,

J_5,5aax= 11.4 Hz, H-5aax); ¹³C NMR (100 MHz, MeOD) δ 139.88,

129.77, 129.00, 127.51, 102.88(PhCH), 84.07(C-4), 79.61(C-2),

75.85(C-3), 72.87(C-1), 71.97(C-6), 35.53(C-5), 31.77(C-5a); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₁₄H₁₈O₅Na 266.1046, found 266.1046.

J

_5,5aeq= 3.6 Hz, J_gem= 13.3 Hz, H-5aeq), 2.00(s, 3H), 1.74(m, 1H, H-

5), 1.34(ddd, 1H, J_1,5aax= 11.0 Hz, J_5,5aax= 11.0 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 170.88, 138.71, 138.63, 138.47, 138.14,

128.44, 128.39, 128.34, 128.11, 127.98, 127.80, 127.76, 127.68,

127.62, 127.56, 86.20(C-3), 85.83(C-2), 80.14(C-4), 79.90(C-1), 75.83,

75.23, 72.55, 64.18(C-6), 37.71(C-5), 30.13(C-5a), 20.80(CH₃); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₃₇H₄₀O₆Na 603.2717, found 603.2717.

4.1.7. 4,6-O-Benzylidene-2,3-O-isopropylidene-5a-carba-β-^D-

glucopyranose (11)

4.1.4. 1,2,3,4-Tetra-O-benzyl-5a-carba-β-^D-glucopyranose (8)

To a solution of 4,6-O-benzylidene-5a-carba-β-^D-glucopyranose 10

(8.00 g, 30.04 mmol) in DMF (150 mL) at 60 °C was added 2,2-di-

methoxypropane (18.6 mL, 150.2 mmol) and CSA (698 mg, 3.00 mmol).

After being stirred for 20 min, the solution was cooled to 0 °C and

neutralized with Et₃N. The solution was concentrated in vacuo. The

residue was puriﬁed by column chromatography (hexane/acetone, 4:1)

To a solution of 6-O-acetyl-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glu-

copyranose 7 (44.90 g, 77.43 mmol) in MeOH (250 mL) was added

NaOMe (4.18 g, 77.43 mmol). After being stirred for overnight, the

solution was neutralized with Amberlite 200CT (H⁺), and the resin was

ﬁltered oﬀ. The ﬁltrate was concentrated in vacuo to give compound 8

(43.78 g, quant) as a white amorphous solid. R_f= 0.24 (Hex/EtOAc,

to

give

4,6-O-benzylidene-2,3-O-isopropylidene-5a-carba-β-^D-

8

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glucopyranose 11 (4.8818 g, 53%) as a white amorphous solid and 4,6-

O-benzylidene-1,2-O-isopropylidene-5a-carba-β-^D-glucopyranose

(4.1501 g, 45%) as a white amorphous solid. R_f= 0.24 (hexane/

acetone, 3:1); [α] = −33.3° (c 1.00, CHCl₃); ¹H NMR (400 MHz,

J = 10.8 Hz), 4.45(s, 2H), 3.61(dd, 1H, J_5,6a= 5.0 Hz, J_gem= 8.9 Hz,

H-6a), 3.56(ddd, 1H, J_1,5aeq= 4.2 Hz, J_1,2= 9.2 Hz, J_1,5aax= 11.9 Hz ,

H-1), 3.56–3.52(m, 2H, H-3, H-4), 3.49(dd, 1H, J_5,6b= 2.7 Hz, H-6b),

3.31(dd, 1H, J_2,3= 9.2 Hz, H-2), 2.28(br, 1H, OH), 2.02(ddd, 1H,

CDCl₃)

δ

7.51–7.30(m, 5H), 5.58(s, 1H, PhCH), 4.19(dd, 1H,

J_5,5aeq= 4.2 Hz, J_gem= 13.0 Hz, H-5aeq), 1.75(m, 1H, H-5), 1.52(ddd,

J_5,6a= 4.1 Hz, J_gem= 11.0 Hz, H-6a), 3.99(ddd, 1H, J_1,5aeq= 4.5 Hz,

1H, J_5,5aax= 11.9 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 138.58,

138.52, 138.48, 138.37, 128.64, 128.42, 128.39, 128.33, 127.921,

27.90, 127.70, 127.65, 127.58, 127.52, 127.51, 86.42(C-3), 86.38(C-2),

81.12(C-4), 75.52, 75.48, 75.29, 73.06, 71.28(C-1), 69.79(C-6),

39.29(C-5), 31.85(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

J

_1,2= 9.5 Hz, J_1,5aax= 9.9 Hz, H-1), 3.81(dd, 1H, J_3,4= 9.4 Hz,

_4,5= 9.5 Hz, H-4), 3.74(dd, 1H, J_5,6b= 11.0 Hz, H-6b), 3.65(dd, 1H,

_2,3= 9.3 Hz, H-3), 3.44(dd, 1H, H-2), 2.46(br, 1H, OH), 1.94(m, 1H,

H-5), 1.88(ddd, 1H, J_5,5aeq= 4.3 Hz, J_gem= 13.0 Hz, H-5aeq), 1.48(s,

3H, CH₃), 1.46(s, 3H, CH₃), 1.16(ddd, 1H, J_5,5aax= 10.3 Hz, H-5aax);

¹³C NMR (100 MHz, CDCl₃) δ 137.55, 129.01, 128.16, 126.40, 111.79,

101.67(PhCH), 82.71(C-2), 80.54(C-4), 77.80(C-3), 70.85(C-6),

69.61(C-1), 36.55(C-5), 31.90(C-5a), 26.78(CH₃), 26.77(CH₃); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₁₄H₁₈O₅Na 329.1359, found 329.1360.

C₃₅H₃₈O₅Na 561.2611, found 561.2618.

4.1.10. 2,3,4,6-Tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-5a-carba-β-

D-glucopyranose (14)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (464 mg, 0.861 mmol) in CH₂Cl₂(15 mL) at −10 °C was added 2,6-

di-t-butyl-4-methylpyridine (248 mg, 1.20 mmol) and Tf₂O (435 μL,

2.58 mmol). After being stirred for 15 min, the solution was diluted

with CH₂Cl₂and washed saturated NaHCO₃and brine. The organic

layer was dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (Toluene) to give compound 14

(532 mg, 92%) as a white amorphous solid. R_f= 0.51 (Toluene);

4.1.8. 2,3,4,6-Tetra-O-Benzyl-1-O-(p-methoxybenzyl)-5a-carba-β-^D-

glucopyranose (12)

To a solution of 4,6-O-benzylidene-2,3-O-isopropylidene-5a-carba-

β-^D-glucopyranose 11 (183 mg, 0.597 mmol) in DMF (3 mL) and NaH

(60 mg, 1.49 mmol), and the mixture was stirred for 30 min under Ar.

After being cooled to 0 °C, to the solution was added 4-methoxybenzyl

chloride (202 μL, 1.49 mmol). After being stirred for 45 min, MeOH was

added, and the solution was concentrated in vacuo. The residue was

diluted with Et₂O, and washed brine. The organic layer was dried

(MgSO₄), and concentrated in vacuo. To a solution of the residue was

dissolved in AcOH (1.5 mL) and H₂O (1 mL) at 60 °C, and the mixture

was stirred for 1.5 h. The solvent was concentrated in vacuo. To a so-

lution of the residue was dissolved in DMF (3 mL) was added NaH

(191 mg, 4.78 mmol), and the mixture was stirred for 30 min. After

being cooled to 0 °C, to the solution was added BnBr (568 μL,

4.78 mmol). After being stirred for 10 min, MeOH was added, and the

solution was concentrated in vacuo. The residue was diluted with Et₂O,

and washed brine. The organic layer was dried (MgSO₄), and con-

centrated in vacuo. The residue was puriﬁed by column chromato-

graphy (hexane/EtOAc, 5:1) to give compound 12 (308 mg, 78%) as a

white amorphous solid. R_f= 0.33 (hexane/EtOAc, 5:1); [α] = +16.0°

(c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.18(m, 22H),

6.86–6.83(m, 2H), 4.94(d, 1H, J = 10.7 Hz), 4.92(d, 1H, J = 10.7 Hz),

4.86(d, 1H, J = 11.0 Hz), 4.82(d, 1H, J = 10.7 Hz), 4.82(d, 1H,

J = 10.7 Hz), 4.62(d, 1H, J = 11.0 Hz), 4.57(d, 1H, J = 11.0 Hz),

4.50(d, 1H, J = 11.0 Hz), 4.45(s, 2H), 3.79(s, 3H), 3.56(dd, 1H,

[α] = +0.51° (c 0.955, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.36–7.16(m, 20H), 4.86(s, 2H), 4.85(d, 1H, J = 10.7 Hz), 4.83(m, 1H,

H-1), 4.82(s, 2H), 4.52(d, 1H, J = 10.7 Hz), 4.46(d, 1H, J = 12.0 Hz),

4.42(d, 1H, J = 12.0 Hz), 3.67(dd, 1H, J_5,6a= 4.4 Hz, J_gem= 9.0 Hz, H-

6a), 3.61(dd, 1H, J_2,3= 9.1 Hz, J_1,2= 9.3 Hz, H-2), 3.57(dd, 1H,

J

_4,5= 6.3 Hz, J_3,4= 8.8 Hz, H-4), 3.54(dd, 1H, H-3), 3.45(dd, 1H,

_5,6b= 2.5 Hz, H-6b), 2.23(ddd, 1H, J_1,5aeq= 3.8 Hz, J_5,5aeq= 5.1 Hz,

_gem= 12.9 Hz,

H-5aeq),

1.93(ddd,

1H,

J_1,5aax= 12.4 Hz,

_5,5aax= 12.4 Hz, H-5aax), 1.72(m, 1H, H-5); ¹³C NMR (100 MHz,

CDC_l3) δ 138.18, 138.12, 127.97, 127.39, 128.44, 128.35, 128.10,

127.91, 127.82, 127.80, 127.79, 127.67, 127.55, 88.14(C-1), 85.83(C-

3), 82.45(C-2), 79.59(C-4), 75.91, 75.88, 75.42, 73.22, 68.76(C-6),

38.48(C-5), 30.73(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C₃₆H₃₇O₇NaSF₃693.2104 found 693.2098.

4.1.11. 2,3,4,6-Tetra-O-Benzyl-1-O-methanesulfonyl-5a-carba-β-^D-

glucopyranose (15)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (21 mg, 0.039 mmol) in pyridine (500 μL) was added methane-

sulfonyl chloride (15 μL, 0.195 mmol) at 0 °C, and the solution was

stirred overnight. To the solution was added MeOH, and the solvents

were evaporated. The residue was diluted with EtOAc, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (hexane/EtOAc,

4:1) to give compound 15 (23 mg, 94%) as a white amorphous solid.

R_f= 0.44 (Toluene/EtOAc, 10:1); [α] = +23.6° (c 1.00, CHCl₃); ¹H

NMR (400 MHz, CDCl₃) δ 7.36–7.18(m, 20H), 4.93(d, 1H, J = 11.0 Hz),

4.90(d, 1H, J = 10.7 Hz), 4.87(d, 1H, J = 10.7 Hz), 4.85(dd, 1H,

J = 10.8 Hz), 4.73(d, 1H, J = 11.0 Hz), 4.54(d, 1H, J = 10.8 Hz),

4.47(ddd, 1H, J_1,5aeq= 5.1 Hz, J_1,2= 8.4 Hz, J_1,5aax= 12.0 Hz, H-1),

4.44(s, 2H), 3.69(dd, 1H, J_5,6a= 4.1 Hz, J_gem= 9.0 Hz, H-6a),

3.58–3.55(m, 3H, H-2, H-3, H-4), 3.44(dd, 1H, J_5,6b= 2.4 Hz, H-6b),

2.82(s, 3H, CH₃), 2.25(ddd, 1H, J_5,5aeq= 3.3 Hz, J_gem= 13.0 Hz, H-

5aeq), 1.86(ddd, 1H, J_5,5aax= 11.9 Hz, H-5aax), 1.74(m, 1H, H-5); ¹³C

NMR (100 MHz, CDCl₃) δ 138.27, 138.26, 138.12, 137.94, 128.45,

128.42, 128.38, 127.91, 127.81, 127.74, 127.65, 127.63, 127.60,

86.19(C-3), 83.21(C-2), 81.87(C-1), 79.97(C-4), 75.83, 75.80, 75.38,

73.17, 68.94(C-6), 38.71(C-5), 38.11(CH₃), 31.56(C-5a); HRMS(ESI)

m/z: [M+Na]⁺calcd for C₃₆H₄₀O₇NaS 639.2387, found 639.2388.

J

_5,6a= 5.3 Hz, J_gem= 8.9 Hz, H-6a), 3.54–3.47(m, 2H, H-2, H-3),

3.53(dd, 1H, J_5,6b= 3.1 Hz, H-6b), 3.50(m, 1H, H-1), 3.46(dd, 1H,

J

_3,4= 8.9 Hz, J_4,5= 8.9 Hz, H-4), 2.16(ddd, 1H, J_1,5aeq= 3.7 Hz,

_5,5aeq= 3.7 Hz, J_gem= 13.2 Hz, H-5aeq), 1.69(m, 1H, H-5), 1.45(ddd,

1H, J_1,5aax= 11.0 Hz, J_5,5aax= 11.0 Hz, H-5aax); ¹³C NMR (100 MHz,

CDCl₃) δ 159.13, 138.93, 138.83, 138.58, 138.41, 130.85, 129.28,

128.36, 128.35, 128.31, 128.00, 127.96, 127.80, 127.60, 127.53,

127.51, 127.47, 113.78, 86.34(C-3), 85.96(C-2), 80.87(C-4), 80.03(C-

1), 75.80, 75.76, 75.24, 73.11, 72.05, 70.19(C-6), 55.26(OCH₃),

39.03(C-5), 30.59(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C₄₃H₄₆O₆Na 681.3187, found 681.3187.

4.1.9. 2,3,4,6-Tetra-O-benzyl-5a-carba-β-^D-glucopyranose (13)

To a solution of 2,3,4,6-tetra-O-benzyl-1-O-(p-methoxybenzyl)-5a-

carba-β-^D-glucopyranose 12 (4.70 g, 7.13 mmol) in MeCN–H₂O (9:1,

100 mL) was added CAN (7.8 g, 14.27 mmol). After being stirred for

2.5 h, the solution was diluted with CH₂Cl₂and washed saturated

NaHCO₃and brine. The organic layer was dried (MgSO₄) and con-

centrated in vacuo. The residue was puriﬁed by column chromato-

graphy (hexane/EtOAc, 4:1) to give compound 13 (3.1556 g, 82%) as a

white amorphous solid. R_f= 0.16 (hexane/EtOAc, 4:1); [α] = +9.2° (c

1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.20(m, 20H), 4.99(d,

1H, J = 11.3 Hz), 4.92(d, 1H, J = 11.1 Hz), 4.88(d, 1H, J = 11.1 Hz),

4.87(d, 1H, J = 11.1 Hz), 4.69(d, 1H, J = 11.3 Hz), 4.54(d, 1H,

4.1.12. 2,3,4,6-Tetra-O-benzyl-1-O-chloromethanesulfonyl-5a-carba-β-^D-

glucopyranose (16)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (22 mg, 0.041 mmol) in pyridine (500 μL) was added

9

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

chloromethanesulfonyl chloride (19 μL, 0.200 mmol) at 0 °C, and the

solution was stirred 10 min. To the solution was added MeOH, and the

solvents were evaporated. The residue was diluted with EtOAc, and

washed brine. The organic layer was dried (MgSO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(Toluene/EtOAc, 20:1) to give compound 16 (23 mg, 87%) as a color-

less syrup. R_f= 0.59 (Toluene/EtOAc, 10:1); [α] = +22.1° (c 1.00,

CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.17(m, 20H), 4.93(d, 1H,

J = 10.8 Hz), 4.90(d, 1H, J = 11.0 Hz), 4.85(d, 1H, J = 11.0 Hz),

4.85(d, 1H, J = 10.8 Hz), 4.79(d, 1H, J = 10.8 Hz), 4.64(ddd, 1H,

4.44(d, 1H, J = 12.0 Hz), 4.41(d, 1H, J = 12.0 Hz), 3.65(dd, 1H,

J_5,6a= 4.2 Hz, J_gem= 9.0 Hz, H-6a), 3.52(dd, 1H, J_3,4= 9.5 Hz,

J

_4,5= 9.5 Hz, H-4), 3.51(dd, 1H, J_2,3= 8.0 Hz, H-2), 3.47(dd, 1H, H-3),

3.43(dd, 1H, J_5,6b= 2.4 Hz, H-6b), 2.25(ddd, 1H, J_5,5aeq= 3.4 Hz,

J

_gem= 13.0 Hz, H-5aeq), 1.83(ddd, 1H, J_5,5aax= 12.0 Hz, H-5aax),

1.73–1.65(m, 1H, H-5); ¹³C NMR (100 MHz, CDCl₃) δ 138.30, 138.26,

138.13, 137.91, 136.02, 132.36, 129.13, 128.70, 128.40, 128.37,

128.29, 127.89, 127.71, 127.70, 127.67, 127.62, 127.59, 127.56,

127.31, 85.98(C-3), 82.98(C-2), 82.67(C-1), 79.87(C-4), 75.89, 75.40,

75.34, 73.16, 69.02(C-6), 38.67(C-5), 31.41(C-5a); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₄₁H₄₁O₇NaBr 779.1649, found 779.1650.

J

_1,5aeq= 5.1 Hz, J_1,2= 8.8 Hz, J_1,5aax= 11.9 Hz, H-1), 4.53(d, 1H,

J = 10.8 Hz), 4.44(s, 2H), 4.43(d, 1H, J = 12.4 Hz), 4.38(d, 1H,

J = 12.4 Hz), 3.68(dd, 1H, J_5,6a= 4.2 Hz, J_gem= 9.0 Hz, H-6a),

3.59(m, 1H, H-2), 3.57(m, 2H, H-3, H-4), 3.45(dd, 1H, J_5,6b= 2.4 Hz,

4.1.15. 2,3,4,6-Tetra-O-benzyl-1-O-(4-nitrobenzenesulfonyl)-5a-carba-β-

D-glucopyranose (19)

H-6b), 2.27(ddd, 1H,

J

_5,5aeq= 3.6 Hz, J_gem= 13.0 Hz, H-5aeq),

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (150 mg, 0.278 mmol) in pyridine (5 mL) was added 4-ni-

trobenzenesulfonyl chloride (370 mg, 1.67 mmol) and DMAP (3.0 mg,

0.028 mmol). After being stirred at 50 °C for 4 h, the solution was

cooled to 0 °C and MeOH was added to the solution. The solution was

concentrated in vacuo. The residue was diluted with EtOAc, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (hexane/EtOAc,

7:1) to give compound 19 (177 mg, 88%) as a white amorphous solid.

R_f= 0.48 (hexane/EtOAc, 7:1); [α] = +2.9° (c 1.00, CHCl₃); ¹H NMR

1.89(ddd, 1H, J_5,5aax= 12.1 Hz, H-5aax), 1.74(m, 1H, H-5); ¹³C NMR

(100 MHz, CDCl₃) δ 138.18, 138.06, 137.81, 128.43, 128.41, 127.91,

127.84, 127.77, 127.70, 127.67, 127.62, 86.14(C-3), 83.98(C-1),

82.90(C-2), 79.87(C-4), 75.84, 75.78, 75.39, 73.17, 68.87(C-6), 54.12,

38.60(C-5), 31.39(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C

₃₆H₃₉O₇NaSCl 673.1997, found 673.1999.

4.1.13. 2,3,4,6-Tetra-O-benzyl-1-O-(4-toluenesulfonyl)-5a-carba-β-^D-

glucopyranose (17)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (164 mg, 0.304 mmol) in pyridine (2 mL) was added 4-toluene-

sulfonyl chloride (580 mg, 3.04 mmol) and DMAP (4 mg, 0.030 mmol)

at 50 °C, and the solution was stirred overnight. To the solution was

added MeOH, and the solvents were evaporated. The residue was di-

luted with EtOAc, and washed brine. The organic layer was dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

column chromatography (Toluene → Toluene/EtOAc, 20:1) to give

compound 17 (203 mg, 96%) as a white amorphous solid. R_f= 0.31

(Toluene/EtOAc, 20:1); [α] = +14.5° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.75–7.73(m, 2H), 7.35–7.09(m, 22H), 4.83(d, 1H,

J = 10.8 Hz), 4.80(d, 1H, J = 10.7 Hz), 4.77(d, 1H, J = 10.7 Hz),

4.68(d, 1H, J = 10.7 Hz), 4.63(d, 1H, J = 10.7 Hz), 4.52(ddd, 1H,

(400 MHz, CDCl₃)

δ

7.98–7.92(m, 4H), 7.36–7.14(m, 18H),

7.02–6.99(m, 2H), 4.84(d, 1H, J = 10.8 Hz), 4.82(d, 1H, J = 10.7 Hz),

4.80(d, 1H, J = 11.8 Hz), 4.77(d, 1H, J = 10.7 Hz), 4.53(ddd, 1H,

J

_1,5aeq= 5.0 Hz, J_1,2= 9.1 Hz, J_1,5aax= 11.9 Hz, H-1), 4.51(d, 1H,

J = 10.8 Hz), 4.44(s, 2H), 4.42(d, 1H, J = 11.8 Hz), 3.67(dd, 1H,

J

_5,6a= 4.2 Hz, J_gem= 8.9 Hz, H-6a), 3.55(dd, 1H, J_3,4= 9.5 Hz,

_4,5= 9.5 Hz, H-4), 3.50(m, 2H, H-2, H-3), 3.45(dd, 1H, J_5,6b= 2.5 Hz,

H-6b), 2.29(ddd, 1H,

J_5,5aeq= 3.5 Hz, J_gem= 13.0 Hz, H-5aeq),

1.89(ddd, 1H, J_5,5aax= 12.1 Hz, H-5aax), 1.73(m, 1H, H-5); ¹³C NMR

(100 MHz, CDCl₃) δ 150.24, 142.33, 138.22, 138.06, 138.02, 137.74,

128.82, 128.43, 128.42, 128.40, 128.19, 127.87, 127.77, 127.68,

127.62, 126.62, 124.08, 86.05(C-3), 83.56(C-1), 82.69(C-2), 79.82(C-

4), 75.95, 75.37, 75.04, 73.21, 68.93(C-6), 38.69(C-5), 31.60(C-5a);

HRMS(ESI) m/z: [M+Na]⁺calcd for C₄₁H₄₁O₉NNa 746.2394, found

746.2399.

J

_1,5aeq= 5.1 Hz, J_1,2= 8.3 Hz, J_1,5aeq= 12.0 Hz, H-1), 4.50(d, 1H,

J = 10.8 Hz), 4.43(d, 1H, J = 12.0 Hz), 4.40(d, 1H, J = 12.0 Hz),

3.64(dd, 1H, J_5,6a= 4.3 Hz, J_gem= 8.9 Hz, H-6a), 3.53–3.47(m, 3H, H-

2, H-3, H-4), 3.42(dd, 1H, J_5,6b= 2.5 Hz, H-6b), 2.34(s, 3H, CH₃),

2.22(ddd, 1H, J_5,5aeq= 3.2 Hz, J_gem= 12.8 Hz, H-5aeq), 1.80(ddd, 1H,

4.1.16. Experimental for Table 2

4.1.16.1. Entry 1. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (60 mg, 0.112 mmol) in 15-crown-5 ether (132 μL,

0.667 mmol) was added NaH (4 mg, 0.112 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

O-triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose 14 (30 mg,

0.045 mmol). After being stirred for 5 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give compound 20 (3 mg,

6%) as a colorless syrup and oleﬁn 21 (18 mg, 79%) as a colorless syrup

and recovered 8 (52 mg, 86%). Date for 2,3,4,6-tetra-O-benzyl-5a-

carba-α-^D-glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O- benzyl-5a-carba-β-D-

glucopyranoside (20): R_f= 0.20 (hexane/EtOAc, 6:1); [α] = +46.3° (c

1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.23(m, 40H), 4.95(d,

1H, J = 10.9 Hz), 4.95(d, 1H, J = 10.9 Hz), 4.94(d, 1H, J = 10.8 Hz),

4.92(d, 1H, J = 10.7 Hz), 4.90(d, 1H, J = 10.8 Hz), 4.83(d, 1H,

J = 10.8 Hz), 4.82(d, 1H, J = 10.9 Hz), 4.82(d, 1H, J = 10.9 Hz),

4.67(s, 2H), 4.66(d, 1H, J = 11.2 Hz), 4.61(d, 1H, J = 11.2 Hz),

4.54(d, 1H, J = 10.7 Hz), 4.52(d, 1H, J = 10.8 Hz), 4.38(s, 2H),

J

_1,5aax= 12.0 Hz, H-5aax), 1.68(m, 1H, H-5); ¹³C NMR (100 MHz,

CDCl₃) δ 144.44, 138.37, 138.20, 138.10, 134.18, 129.68, 128.38,

128.36, 128.33, 128.10, 127.88, 127.69, 127.66, 127.60, 127.54,

127.53, 127.35, 85.93(C-3), 83.14(C-2), 82.13(C-1), 79.92(C-4), 75.85,

75.37, 75.30, 73.11, 69.12(C-6), 38.66(C-5), 31.36(C-5a), 21.60(CH₃);

HRMS(ESI) m/z: [M+Na]⁺calcd for C₄₂H₄₄O₇NaS 715.2700, found

715.2705.

4.1.14. 2,3,4,6-Tetra-O-benzyl-1-O-(p-bromobenzenesulfonyl)-5a-carba-β-

D-glucopyranose (18)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (14 mg, 0.026 mmol) in pyridine (500 μL) was added 4-bromo-

benzenesulfonyl chloride (66 mg, 0.26 mmol) and DMAP (1.0 mg,

0.008 mmol). After being stirred at 40 °C for 5 h, the solution was

cooled to 0 °C and MeOH was added to the solution. The solution was

concentrated in vacuo. The residue was diluted with EtOAc, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (hexane/EtOAc,

7:1) to give compound 18 (17 mg, 87%) as a white amorphous solid.

R_f= 0.54 (hexane/EtOAc, 3:1); [α] = +11.4° (c 1.00, CHCl₃); ¹H NMR

3.92(dd, 1H,

J_2′,3′= 9.6 Hz, J_3′,4′= 9.4 Hz, H-3′), 3.72(ddd, 1H,

(400 MHz, CDCl₃)

δ

7.69–7.66(m, 2H), 7.43–7.40(m, 2H),

J

_1′,2′= 2.7 Hz, J_1′,5a′ax= 1.3 Hz, J_1′,5a′eq= 3.7 Hz, H-1′), 3.70–3.67(m,

7.36–7.06(m, 20H), 4.83(d, 1H, J = 10.8 Hz), 4.80(s, 2H), 4.76(d, 1H,

J = 10.9 Hz), 4.58(d, 1H, J = 10.9 Hz), 4.51(d, 1H, J = 10.8 Hz),

4.50(ddd, 1H, J_1,5aeq= 5.2 Hz, J_1,2= 8.4 Hz, J_1,5aax= 11.8 Hz, H-1),

2H, H-6), 3.64(dd, 1H,

J_5′,6′a= 4.3 Hz, J_gem= 8.9 Hz, H-6′a),

3.55–3.50(m, 3H, H-1, H-2, H-3), 3.47(dd, 1H, J_4′,5′= 9.0 Hz, H-4′),

3.46(dd, 1H, J_3,4= 9.0 Hz, J_4,5= 9.0 Hz, H-4), 3.38(dd, 1H, H-2′),

10

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3.34(dd, 1H, J_5′,6′b= 2.5 Hz, H-6′b), 2.16(ddd, 1H, J_1,5aeq= 3.5 Hz,

4.1.16.5. Entry 5. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (40 mg, 0.074 mmol) in THF (44 μL) was added NaH

(3 mg, 0.074 mmol). After being stirred for 30 min under Ar, to the

solution was added 2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-

5a-carba-β-^D-glucopyranose 14 (20 mg, 0.030 mmol). After being stirred

for 10 h, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic layer

was dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed

by column chromatography (Hexane/EtOAc, 6:1) to give compound 20

(3 mg, 11%) as a colorless syrup and oleﬁn 21 (8 mg, 52%) as a colorless

syrup and recovered 8 (27 mg, 68%).

J

_5,5aeq= 3.5 Hz, J_gem= 13.0 Hz, H-5aeq), 2.07(m, 1H, H-5′), 1.85(ddd,

1H, J_5′,5a′eq= 3.7 Hz, J_gem= 14.3 Hz, H-5a′eq), 1.67(m, 1H, H-5),

1.52(ddd, 1H, J_1,5aax= 10.9 Hz, J_5,5aax= 10.9 Hz, H-5aax), 1.39(ddd,

1H, J_5′,5a′ax= 13.1 Hz, H-5a′ax); ¹³C NMR (100 MHz, CDCl₃) δ 139.12,

138.94, 138.91, 138.83, 138.78, 138.76, 138.57, 128.36, 128.33,

128.31, 128.30, 128.27, 128.04, 128.01, 127.87, 127.79, 127.65,

127.64, 127.59, 127.52, 127.44, 127.42, 127.36, 86.40(C-3),

86.01(C-2), 83.88(C-3′), 83.83(C-2′), 80.96(C-4′), 80.71(C-4),

80.34(C-1), 75.79, 75.68, 75.22, 75.13, 74.87(C-1′), 72.93, 72.46,

72.26, 70.23(C-6), 69.95(C-6′), 39.19(C-5), 37.35(C-5′), 30.48(C-5a),

29.28(C-5′a); HRMS(ESI) m/z: [M+Na]⁺calcd for C₇₀H₇₄O₉Na

1081.5225, found 1081.5225.

4.1.16.6. Entry 6. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (37 mg, 0.069 mmol) in 15-crown-5 ether (41 μL,

0.207 mmol) was added NaH (3 mg, 0.069 mmol), and the mixture

was stirred for 30 min under Ar. After being stirred for 30 min, to the

solution was added 2,3,4,6-tetra-O-benzyl-1-O-methanesulfonyl-5a-

carba-β-^D-glucopyranose 15 (17 mg, 0.028 mmol). After being stirred

for 6 h, to the solution was added, MeOH was added and the solution

was concentrated in vacuo. The residue was diluted with EtOAc, and

washed brine. The organic layer was dried (MgSO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(Hexane/EtOAc, 10:1) to give oleﬁn 21 (6 mg, 41%) as a colorless

syrup and compound 13 (4 mg, 29%) and recovered 8 (27 mg, 73%).

Date for oleﬁn 21: R_f= 0.50 (hexane/EtOAc, 6:1); [α] = +105.1°

(c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.18(m, 20H),

5.72(ddd, 1H,

5.67(ddd, 1H,

J

_1,2= 2.2 Hz, J_1,5= 2.2 Hz, J_1,5a= 10.2 Hz, H-1),

4

J

_5,5a= 1.6 Hz, J_2,5a= 1.6 Hz, H-5a), 4.91(s, 2H),

4.91(d, 1H, J = 10.9 Hz), 4.69(s, 2H), 4.46(d, 1H, J = 12.2 Hz), 4.45(d,

1H, J = 10.9 Hz), 4.40(d, 1H, J = 12.2 Hz), 4.25(m, 1H, H-2), 3.81(dd,

1H, J_2,3= 7.7 Hz, J_3,4= 10.0 Hz, H-3), 3.67(dd, 1H, J_4,5= 9.8 Hz, H-

4), 3.54(dd, 1H, J_5,6a= 3.5 Hz, J_gem= 9.0 Hz, H-6a), 3.51(dd, 1H,

J

_5,6b= 4.7 Hz, H-6b), 1.26(m, 1H, H-5); ¹³C NMR (100 MHz, CDCl₃) δ

138.92, 138.60, 138.53, 138.24, 129.19(C-5a), 128.38, 128.35, 128.33,

128.06, 127.89, 127.85, 127.76, 127.62, 127.59, 127.49, 126.84(C-1),

85.35(C-3), 80.89(C-2), 78.42(C-4), 75.28, 75.27, 73.10, 72.05,

69.20(C-6), 44.39(C-5); HRMS(ESI) m/z: [M+Na]⁺calcd for

4.1.16.7. Entry 7. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (62 mg, 0.115 mmol) in 15-crown-5 ether (68 μL,

0.345 mmol) was added NaH (4 mg, 0.115 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

C

₃₅H₃₆O₄Na 543.2506, found 543.2502.

4.1.16.2. Entry 2. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (60 mg, 0.112 mmol) in 15-crown-5 ether (132 μL,

0.667 mmol) was added NaH (4 mg, 0.112 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

O-triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose 14 (30 mg,

0.045 mmol). After being stirred for 7 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give compound 20 (5 mg,

10%) as a colorless syrup and oleﬁn 21 (9 mg, 40%) as a colorless syrup

and recovered 8 (40 mg, 66%).

O-chloromethanesulfonyl-5a-carba-β-^D-glucopyranose

16

(30 mg,

0.046 mmol). After being stirred for 8 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Toluene/EtOAc, 20:1) to give oleﬁn 21 (4 mg, 16%)

as a colorless syrup and recovered mesylate 15 (5 mg, 18%) and

recovered 8 (57 mg, 92%).

4.1.16.8. Entry 8. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (58 mg, 0.108 mmol) in 15-crown-5 ether (63 μL,

0.319 mmol) was added NaH (4 mg, 0.108 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

4.1.16.3. Entry 3. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (60 mg, 0.112 mmol) in 15-crown-5 ether (66 μL,

0.335 mmol) was added NaH (4 mg, 0.112 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

O-triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose 14 (30 mg,

0.045 mmol). After being stirred for 11 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give compound 20 (10 mg,

21%) as a colorless syrup and oleﬁn 21 (11 mg, 47%) as a colorless

syrup and recovered 8 (40 mg, 67%).

O-(4-toluenesulfonyl)-5a-carba-β-^D-glucopyranose

17

(30 mg,

0.043 mmol). After being stirred for overnight, MeOH was added and

the solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give oleﬁn 21 (2 mg, 10%)

as a colorless syrup and recovered tosylate 17 (17 mg, 56%) and

recovered 8 (44 mg, 77%).

4.1.16.9. Entry 9. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (89 mg, 0.165 mmol) in 15-crown-5 ether (97 μL,

0.488 mmol) was added NaH (7 mg, 0.165 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

O-(p-bromobenzenesulfonyl)-5a-carba-β-^D-glucopyranose 18 (50 mg,

0.066 mmol). After being stirred for 26 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Toluene/EtOAc, 20:1) to give compound 22 (15 mg,

19%) as a colorless syrup and recovered 18 (17 mg, 34%) and recovered

8 (62 mg, 70%). Date for compound 22: R_f= 0.31 (hexane/EtOAc, 3:1);

[α] = +30.4° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.75(m,

2H), 7.35–7.12(m, 40H), 6.65(m, 2H), 4.98(d, 1H, J = 10.9 Hz),

4.98(d, 1H, J = 11.1 Hz), 4.89(d, 1H, J = 11.6 Hz), 4.88(d, 1H,

4.1.16.4. Entry 4. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

glucopyranose 8 (60 mg, 0.112 mmol) in 15-crown-5 ether (33 μL,

0.167 mmol) was added NaH (4 mg, 0.112 mmol). After being stirred

for 30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-

O-triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose 14 (30 mg,

0.045 mmol). After being stirred for 9 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give compound 20 (10 mg,

22%) as a colorless syrup and oleﬁn 21 (11 mg, 49%) as a colorless

syrup and recovered 8 (44 mg, 73%).

11

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

J = 10.9 Hz), 4.86(d, 1H, J = 11.1 Hz), 4.83(d, 1H, J = 11.3 Hz),

4.80(d, 1H, J = 11.9 Hz), 4.76(d, 1H, J = 11.9 Hz), 4.71(d, 1H,

J = 10.0 Hz), 4.70(s, 2H), 4.66(d, 1H, J = 10.0 Hz), 4.50(m, 1H, H-

1′), 4.50(d, 1H, J = 11.6 Hz), 4.47(d, 1H, J = 11.3 Hz), 4.44(d, 1H,

J = 13.0 Hz), 4.39(d, 1H, J = 13.0 Hz), 3.86–3.80(m, 2H, H-6a, H-6b),

3.64(dd, 1H, J_5′,6′a= 4.1 Hz, J_gem= 9.0 Hz, H-6′a), 3.62–3.54(m, 2H,

H-2, H-3), 3.58(m, 1H, H-1), 3.52(m, 1H, H-4), 3.51(dd, 1H,

solution was added 2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-

5a-carba-β-^D-glucopyranose 14 (40 mg, 0.060 mmol). After being stirred

for 6.5 h, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic layer

was dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed

by column chromatography (hexane/EtOAc, 6:1) to give compound 20

(29 mg, 47%) as a white amorphous solid and oleﬁn 21 (10 mg, 33%) as

a colorless syrup and recovered 8 (61 mg, 76%).

J

_3′,4′= 9.9 Hz, J_4′,5′= 10.3 Hz, H-4′), 3.51(dd, 1H, J_1′,2′= 10.0 Hz,

_2′,3′= 9.6 Hz, H-2′), 3.46(dd, 1H, H-3′), 3.42(dd, 1H, J_5′,6′b= 2.2 Hz,

H-6′b),

2.26(ddd,

1H,

J

_1′,5a′eq= 4.7 Hz,

J_5′,5a′eq= 3.4 Hz,

J_1,5aeq= 3.5 Hz,

4.1.16.14. Entry 14. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-

D-glucopyranose 8 (80 mg, 0.149 mmol) in MeCN (44 μL) was added

NaH (6 mg, 0.149 mmol) and 15-crown-5 ether (44 μL, 0.222 mmol),

and the mixture was stirred for 30 min under Ar. After being cooled to

0 °C, to the solution was added 2,3,4,6-tetra-O-benzyl-1-O-

J

_gem= 12.8 Hz, H-5a′eq),

2.18(ddd, 1H,

J_5,5aeq= 3.5 Hz, J_gem= 13.1 Hz, H-5aeq), 1.82(m, 1H, H-5),

1.81(ddd, J_1′,5a′ax= 12.3 Hz, J_5′,5a′ax= 12.3 Hz, H-5a′ax), 1.69(m, 1H,

H-5′), 1.50(ddd, 1H, J_1,5aax= 11.1 Hz, J_5,5aax= 11.1 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 162.68, 138.71, 138.56, 138.48, 138.35,

138.18, 138.15, 138.06, 129.84, 128.64, 128.46, 128.41, 128.36,

128.33, 128.15, 128.13, 127.99, 127.87, 127.83, 127.81, 127.68,

127.67, 127.65, 127.62, 127.60, 127.57, 127.51, 127.39, 114.56,

86.28(C-3), 85.93(C-2), 85.85(C-3′), 83.16(C-2′), 81.84(C-1′),

79.95(C-1, C-4), 79.92(C-4′), 75.90, 75.86, 75.84, 75.39, 75.33,

75.28, 73.10, 72.55, 69.11(C-6′), 68.09(C-6), 38.68(C-5′), 38.15(C-5),

31.32(C-5a′), 30.21(C-5a); HRMS(ESI) m/z: calcd for [M+Na]⁺

C₇₆H₇₈O₁₂NaS 1237.5106, found 1237.5102.

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

21

(40 mg,

0.060 mmol). After being stirred for 10 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column

chromatography (hexane/EtOAc, 6:1) to give compound 20 (21 mg,

33%) as a white amorphous solid and oleﬁn 21 (10 mg, 33%) as a

colorless syrup and recovered 8 (68 mg, 85%).

4.1.16.15. Entry 15. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-

D-glucopyranose 8 (60 mg, 0.112 mmol) in HMPA (33 μL) was added

NaH (4 mg, 0.112 mmol) and 15-crown-5 ether (33 μL, 0.167 mmol),

and the mixture was stirred for 30 min under Ar. After being cooled to

0 °C, to the solution was added 2,3,4,6-tetra-O-benzyl-1-O-

4.1.16.10. Entry 10. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-

D-glucopyranose 8 (40 mg, 0.075 mmol) in 15-crown-5 ether (44 μL,

0.22 mmol) was added NaH (3 mg, 0.075 mmol). After being stirred for

30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-O-

(4-nitrobenzenesulfonyl)-5a-carba-β-^D-glucopyranose

19

(22 mg,

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

14

(30 mg,

0.030 mmol). After being stirred for 4 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Toluene/EtOAc, 20:1) to give compound 22 (7 mg,

19%) as a colorless syrup and recovered 8 (23 mg, 59%).

0.045 mmol). After being stirred for 5 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column

chromatography (hexane/EtOAc, 6:1) to give compound 20 (13 mg,

28%) as a white amorphous solid and oleﬁn 21 (8 mg, 37%) as colorless

syrup and recovered 8 (57 mg, 95%).

4.1.16.11. Entry 11. To a solution of 1,2,3,4-tetra-O-Benzyl-5a-carba-

β-^D-glucopyranose 8 (20 mg, 0.037 mmol) in 15-crown-5 ether (22 μL,

0.109 mmol) was added NaH (4 mg, 0.110 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-5a-

carba-β-^D-glucopyranose 14 (10 mg, 0.015 mmol). After being stirred

for 5 h, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic

layer was dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane/EtOAc, 6:1) to give

compound 20 (5.8 mg, 37%) as a colorless syrup and oleﬁn 21

(2.0 mg, 26%) as a colorless syrup and recovered 8 (17 mg, 88%).

4.1.16.16. Entry 16. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-

D-glucopyranose

8

(60 mg, 0.112 mmol) in 1,3-dimethyl-2-

imidazolidinone (33 μL) was added NaH (4 mg, 0.112 mmol) and 15-

crown-5 ether (33 μL, 0.167 mmol), and the mixture was stirred for

30 min under Ar. After being cooled to 0 °C, to the solution was added

2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-5a-carba-β-^D-

glucopyranose 14 (30 mg, 0.045 mmol). After being stirred for 17 h,

MeOH was added and the solution was concentrated in vacuo. The

residue was diluted with EtOAc, and washed brine. The organic layer

was dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed

by column chromatography (hexane/EtOAc, 6:1) to give compound 20

(21 mg, 46%) as a white amorphous solid and oleﬁn 21 (7 mg, 28%) as

a colorless syrup and recovered 8 (44 mg, 74%).

4.1.16.12. Entry 12. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-

ββ-^D-glucopyranose 8 (20 mg, 0.037 mmol) in 15-crown-5 ether (22 μL,

0.11 mmol) was added NaH (1 mg, 0.037 mmol). After being stirred for

30 min under Ar, to the solution was added 2,3,4,6-tetra-O-benzyl-1-O-

4.1.17. 4,6-O-Benzylidene-2,3-O-isopropylidene-1-O-(p-methoxybenzyl)-

5a-carba-β-^D-glucopyranose (23)

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

14

(10 mg,

To a solution of 4,6-O-benzylidene-2,3-O-isopropylidene-5a-carba-

β-^D-glucopyranose 11 (2.89 g, 9.43 mmol) in DMF (25 mL) and NaH

(1.13 g, 28.3 mmol), and the mixture was stirred for 30 min under Ar.

After being cooled to 0 °C, to the solution was added 4-methoxybenzyl

chloride (3.84 mL, 28.3 mmol). After being stirred for 1 h, MeOH was

added, and the solution was concentrated in vacuo. The residue was

diluted with EtOAc, and washed brine. The organic layer was dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 5:1) to give compound 23

(3.63 g, 90%) as a white amorphous solid. R_f= 0.22 (hexane/EtOAc,

5:1); [α] = +4.2° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.50–7.28(m, 7H), 6.90–6.86(m, 2H), 5.56(s, 1H, PhCH), 4.75(d, 1H,

J = 11.5 Hz), 4.59(d, 1H, J = 11.5 Hz), 4.15(dd, 1H, J_5,6a= 4.0 Hz,

0.015 mmol). After being stirred at 50 °C for 23 h, MeOH was added

and the solution was concentrated in vacuo. The residue was diluted

with EtOAc, and washed brine. The organic layer was dried (MgSO₄),

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (Hexane/EtOAc, 6:1) to give 20 (4 mg, 24%) as a

colorless syrup and oleﬁn 21 (5 mg, 70%) as a colorless syrup and

recovered 8 (17 mg, 84%).

4.1.16.13. Entry 13. To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-

D-glucopyranose 8 (80 mg, 0.149 mmol) in THF (44 μL) was added NaH

(6 mg, 0.149 mmol) and 15-crown-5 ether (44 μL, 0.222 mmol), and the

mixture was stirred for 30 min under Ar. After being cooled to 0 °C, to the

12

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

J_gem= 10.9 Hz, H-6a), 3.80(s, 3H, OCH₃), 3.77(dd, 1H, J_3,4= 9.4 Hz,

CH₂Cl₂–H₂O (18:1, 13.3 mL) was added DDQ (388 mg, 1.71 mmol).

After being stirred for 1 h, the solution was diluted with CH₂Cl₂and

washed saturated NaHCO₃and brine. The organic layer was dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 2:1) to give compound 26

(431 mg, 85%) as a white amorphous solid. R_f= 0.10 (hexane/EtOAc,

4:1); [α] = −63.9° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.52–7.25(m, 15H), 5.59(s, 1H, PhCH), 5.05(d, 1H, J = 11.3 Hz),

5.01(d, 1H, J = 10.9 Hz), 4.77(d, 1H, J = 10.9 Hz), 4.68(d, 1H,

J

_4,5= 9.6 Hz, H-4), 3.74(ddd, 1H, J_1,5aeq= 4.3 Hz, J_1,2= 9.1 Hz,

_1,5aax= 10.2 Hz, H-1), 3.71(dd, 1H, J_5,6b= 10.9 Hz, H-6b), 3.63(dd,

1H,

J_2,3= 9.4 Hz, H-3), 3.56(dd, 1H, H-2), 1.89(ddd, 1H,

J

_5,5aeq= 4.3 Hz, J_gem= 14.3 Hz, H-5aeq), 1.88(m, 1H, H-5), 1.49(s, 3H,

CH₃), 1.47(s, 3H, CH₃), 1.14(ddd, 1H, J_5,5aax= 10.2 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 159.21. 137.61, 130.43, 129.36, 128.96,

128.13, 126.42, 113.79, 111.52, 101.65(PhCH), 82.48(C-2), 80.49(C-

4), 78.10(C-3), 75.57(C-1), 71.36, 70.91, 55.26(OCH₃), 36.40(C-5),

30.20(C-5a), 26.88(CH₃), 26.87(CH₃); HRMS(ESI) m/z: [M+Na]⁺

calcd for C₂₅H₃₀O₆Na 449.1935, found 449.1935.

J = 11.3 Hz), 4.20(dd, 1H,

3.70(dd, 1H, _2,3= 8.9 Hz,

J_5,6a= 4.4 Hz, J_gem= 11.0 Hz, H-6a),

J

= 9.3 Hz, H-3), 3.66(dd, 1H,

= 11.0 Hz, H-6b), 3.63(m, 1H, H-

3,4

5,6b

J_4,5= 9.4 Hz, H-4), 3.64(dd, 1H, J

4.1.18. 4,6-O-Benzylidene-1-O-(p-methoxybenzyl)-5a-carba-β-^D-

glucopyranose (24)

1), 3.35(dd, 1H, J_1,2= 8.8 Hz, H-2), 2.40(d, 1H, J_1,OH= 1.9 Hz, OH),

1.87(m, 1H, H-5), 1.79(ddd, 1H, J_5,5aeq= 3.5 Hz, J_1,5aeq= 4.7 Hz,

To a solution of 4,6-O-benzylidene-2,3-O-isopropylidene-1-O-(p-

methoxybenzyl)-5a-carba-β-^D-glucopyranose 23 (506 mg, 1.19 mmol)

in MeOH (20 mL) was added AcOH (2 mL). After being stirred at 60 °C

for 1.5 h, the solvent was concentrated in vacuo. The residue was pur-

iﬁed by column chromatography (hexane/EtOAc, 1:1) to give com-

pound 24 (351 mg, 77%) as a white amorphous solid. R_f= 0.20

(hexane/EtOAc, 1:2); [α] = −38.5° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.50–7.23(m, 7H), 6.91–6.86(m, 2H), 5.52(s, 1H,

PhCH), 4.62(d, 1H, J = 11.2 Hz), 4.53(d, 1H, J = 11.2 Hz), 4.16(dd,

1H, J_5,6a= 4.5 Hz, J_gem= 11.0 Hz, H-6a), 3.80(s, 3H, OCH₃), 3.64(dd,

1H, J_2,3= 9.0 Hz, J_3,4= 9.3 Hz, H-3), 3.61(dd, 1H, J_5,6b= 11.0 Hz, H-

6b), 3.55(dd, 1H, J_1,2= 9.0 Hz, H-2), 3.44(dd, 1H, J_4,5= 9.7 Hz, H-4),

3.42(ddd, 1H, J_1,5aeq= 4.3 Hz, J_1,5aax= 11.1 Hz, H-1), 1.89(ddd, 1H,

J

_gem= 12.7 Hz,

H-5aeq),

1.09(ddd,

1H,

J_1,5aax= 11.6 Hz,

_5,5aax= 11.6 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 138.53,

138.13, 138.13, 128.76, 128.65, 128.37, 128.21, 127.98, 127.97,

127.69, 125.92, 101.7(PhCH), 85.78(C-2), 84.15(C-4), 83.07(C-3),

75.62, 75.36, 71.19(C-1), 71.02(C-6), 34.16(C-5), 29.49(C-5a); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₂₈H₃₀O₅Na 469.1985, found 469.1983.

4.1.21. 2,3-Di-O-benzyl-4,6-O-Benzylidene-1-O-triﬂuoromethanesulfonyl-

5a-carba-β-^D-glucopyranose (27)

To a solution of 2,3-di-O-benzyl-4,6-O-benzylidene-5a-carba-β-^D-

glucopyranose 26 (300 mg, 0.672 mmol) in CH₂Cl₂(8 mL) at −15 °C

was added 2,6-di-t-butyl-4-methylpyridine (138 mg, 0.672 mmol) and

Tf₂O (226 μL, 1.34 mmol). After being stirred for 15 min, the solution

was diluted with CH₂Cl₂and washed saturated NaHCO₃and brine. The

organic layer was dried (MgSO₄), and concentrated in vacuo. The re-

sidue was puriﬁed by column chromatography (Toluene) to give com-

pound 27 (311 mg, 80%) as a white amorphous solid. R_f= 0.12

(Toluene); [α] = −23.5° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.49–7.25(m, 15H), 5.58(s, 1H, PhCH), 4.96(d, 1H, J = 10.8 Hz),

4.88(d, 1H, J = 10.2 Hz), 4.88(ddd, 1H, J_1,5aeq= 5.2 Hz, J_1,2= 8.7 Hz,

J_1,5aax= 11.8 Hz, H-1), 4.80(d, 1H, J = 10.2 Hz), 4.74(d, 1H,

J

_5,5aeq= 3.6 Hz, J_gem= 12.7 Hz, H-5aeq), 1.79(m, 1H, H-5), 1.05(ddd,

1H, J_5,5aax= 11.3 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 159.38,

137.75, 130.11, 129.40, 129.08, 128.28, 126.24, 113.95,

101.81(PhCH), 82.26(C-4). 78.72(C-1), 76.91(C-2), 74.29(C-3), 71.65,

70.87(C-6), 55.27(OCH₃), 33.76(C-5), 27.75(C-5a); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₂₂H₂₆O₆Na 409.1622, found 409.1622.

4.1.19. 2,3-Di-O-benzyl-4,6-O-benzylidene-1-O-(p-methoxybenzyl)-5a-

carba-β-^D-glucopyranose (25)

J = 10.8 Hz), 4.24(dd, 1H,

3.73(dd, 1H, _2,3= 8.8 Hz, J_3,4= 9.0 Hz, H-3), 3.67(dd, 1H,

_5,6b= 11.0 Hz, H-6b), 3.66(dd, 1H, H-2), 3.65(dd, 1H, J_4,5= 9.3 Hz,

J_5,6a= 4.4 Hz, J_gem= 11.0 Hz, H-6a),

To

a

solution of 4,6-O-benzylidene-1-O-(p-methoxybenzyl)-5a-

J

carba-β-^D-glucopyranose 24 (400 mg, 1.04 mmol) in DMF (3 mL) and

NaH (207 mg, 5.18 mmol), and the mixture was stirred for 30 min

under Ar. After being cooled to 0 °C, to the solution was added BnBr

(615 μL, 5.18 mmol). After being stirred for overnight, MeOH was

added, and the solution was concentrated in vacuo. The residue was

diluted with EtOAc, and washed brine. The organic layer was dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 5:1) to give compound 25

(543 mg, 93%) as a white amorphous solid. R_f= 0.20 (hexane/EtOAc,

1:2); [α] = −22.4° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.51–7.22(m, 17H), 6.87–6.83(m, 2H), 5.57(s, 1H, PhCH), 4.94(d, 1H,

J = 11.0 Hz), 4.89(s, 2H), 4.78(d, 1H, J = 11.0 Hz), 4.62(d, 1H,

J = 11.3 Hz), 4.59(d, 1H, J = 11.3 Hz), 4.18(dd, 1H, J_5,6a= 4.5 Hz,

J_gem= 11.0 Hz, H-6a), 3.80(s, 3H, OCH₃), 3.67(dd, 1H, J_2,3= 8.9 Hz,

J

H-4), 2.08(ddd, 1H, J_5,5aeq= 3.2 Hz, J_gem= 12.5 Hz, H-5aeq), 1.87(m,

1H, H-5), 1.48(ddd, 1H,

J

_5,5aax= 11.8 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 138.06, 137.62, 137.33, 128.97, 128.40, 128.34,

128.27, 128.21, 128.18, 127.88, 127.84, 125.90, 101.28(PhCH),

87.07(C-1), 82.91(C-3), 82.70(C-4), 81.81(C-2), 76.14, 75.82, 70.36(C-

6), 33.11(C-5), 29.01(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C

₂₉H₂₉O₇NaSF₃601.1478, found 601.1475.

4.1.22. 4,6-O-Benzylidene-1-O-(p-methoxybenzyl)-2,3-O-(o-xylylene)-5a-

carba-β-^D-glucopyranose (28)

To

a solution of 4,6-O-benzylidene-1-O-(p-methoxybenzyl)-5a-

carba-β-^D-glucopyranose 24 (366 mg, 0.947 mmol) in DMF(60 mL) and

NaH (189 mg, 4.73 mmol), and the mixture was stirred for 30 min

under Ar. To the solution was added α,α′-dibromo-o-xylene (500 mg,

1.89 mmol). After being stirred for overnight, MeOH was added, and

the solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (Toluene → Toluene/EtOAc, 7:1) to give compound 28 (256 mg,

56%) as a white amorphous solid. R_f= 0.43 (Toluene/EtOAc, 7:1);

J

_3,4= 9.0 Hz, H-3), 3.62(dd, 1H, J_5,6b= 10.9 Hz, H-6b), 3.61(dd, 1H,

J_4,5= 9.1 Hz, H-4), 3.56(ddd, 1H, J_1,2= 8.9 Hz, J_1,5aeq= 3.4 Hz,

J

_1,5aax= 11.0 Hz, H-1), 3.54(dd, 1H, H-2), 1.86(ddd, 1H,

_5,5aeq= 3.4 Hz, J_gem= 12.6 Hz, H-5aeq), 1.78(m, 1H, H-5), 1.07(ddd,

1H, J_5,5aax= 11.0 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 159.22,

138.86, 138.77, 138.18, 130.57, 129.32, 128.71, 128.31, 128.28,

128.17, 128.16, 128.02, 127.55, 127.53, 125.93, 113.83, 101.03,

85.53(C-2), 83.50(C-4), 83.20(C-3), 79.72(C-1), 76.05, 75.61, 72.39,

71.02(C-6), 55.27(OCH₃), 33.83(C-5), 28.57(C-5a); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₃₆H₃₈O₆Na 589.2561, found 589.2558.

[α] = +48.2° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.53–7.50(m, 2H), 7.39–7.13(m, 9H), 6.92–6.89(m, 2H), 5.52(s, 1H,

PhCH), 5.20(d, 1H, J = 14.2 Hz), 5.17(d, 1H, J = 13.8 Hz), 5.07(d, 1H,

J = 14.2 Hz), 4.98(d, 1H, J = 13.8 Hz), 4.72(d, 1H, J = 11.4 Hz),

4.62(d, 1H, J = 11.4 Hz), 4.12(dd, 1H, J_5,6a= 4.4 Hz, J_gem= 11.2 Hz,

H-6a), 3.82(s, 3H, OCH₃), 3.62(dd, 1H, J_2,3= 8.5 Hz, J_3,4= 8.9 Hz, H-

3), 3.53(dd, 1H, J_1,2= 8.3 Hz, H-2), 3.53(dd, 1H, J_5,6b= 11.6 Hz, H-

6b), 3.49(ddd, 1H, J_1,5aeq= 4.6 Hz, J_1,5aax= 11.1 Hz, H-1), 3.46(dd,

4.1.20. 2,3-Di-O-benzyl-4,6-O-benzylidene-5a-carba-β-^D-glucopyranose

(26)

To a solution of 2,3-di-O-benzyl-4,6-O-benzylidene-1-O-(p-methox-

ybenzyl)-5a-carba-β-^D-glucopyranose 25 (645 mg, 1.14 mmol) in

13

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

1H, J_4,5= 9.3 Hz, H-4), 1.78(ddd, 1H, J_5,5aeq= 3.2 Hz, J_gem= 12.7 Hz,

H-5aeq), 1.77(m, 1H, H-5), 1.03(ddd, 1H, J_5,5aax= 11.1 Hz, H-5aax);

¹³C NMR (100 MHz, CDCl₃) δ 159.21, 138.12, 137.18, 137.09, 130.83,

130.12, 129.42, 129.20, 129.02, 128.84, 128.20, 127.79, 127.70,

126.25, 113.83, 101.50(PhCH), 85.69(C-2), 82.30(C-3), 81.74(C-4),

78.62(C-1), 73.67, 73.24, 72.48, 70.95(C-6), 55.29(OCH₃), 33.77(C-5),

28.51(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for C₃₀H₃₂O₆Na

511.2091, found 511.2095.

3.47 mmol), and the mixture was stirred for 30 min. After being cooled

to 0 °C, to the solution was added BnBr (412 μL, 3.47 mmol). After being

stirred for overnight, MeOH was added, and the solution was con-

centrated in vacuo. The residue was diluted with EtOAc, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (hexane/EtOAc,

5:1) to give compound 31 (323 mg, 80%) as a colorless syrup. R_f= 0.28

(Hexane/EtOAc, 5:1); [α] = +69.8° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃)

δ

7.36–7.22(m, 14H), 7.14–7.12(m, 2H),

4.1.23. 4,6-O-Benzylidene-2,3-O-(o-xylylene)-5a-carba-β-^D-glucopyranose

(29)

6.91–6.87(m, 2H), 5.18(d, 1H, J = 13.8 Hz), 5.16(d, 1H, J = 14.3 Hz),

5.08(d, 1H, J = 14.3 Hz), 4.98(d, 1H, J = 13.8 Hz), 4.94(d, 1H,

J = 11.0 Hz), 4.69(d, 1H, J = 11.4 Hz), 4.62(d, 1H, J = 11.4 Hz),

4.53(d, 1H, J = 11.0 Hz), 4.44(d, 1H, J = 12.2 Hz), 4.41(d, 1H,

J = 12.2 Hz), 3.81(s, 3H. OCH₃), 3.54–3.51(m, 2H, H-6), 3.49(dd, 1H,

To a solution of 4,6-O-benzylidene-1-O-(p-methoxybenzyl)-2,3-O-(o-

xylylene)-5a-carba-β-D-glucopyranose 28 (28 mg, 0.057 mmol) in

CH₂Cl₂-H₂O (18:1, 570 μL) was added DDQ (14 mg, 0.063 mmol). After

being stirred for 40 min, the solution was diluted with CH₂Cl₂and

washed saturated NaHCO₃and brine. The organic layer was dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 2:1) to give compound 29

(20 mg, 97%) as a colorless syrup. R_f= 0.15 (Toluene/EtOAc, 5:1);

J

_2,3= 8.6 Hz, J_3,4= 9.0 Hz, H-3), 3.43(dd, 1H, J_1,2= 8.4 Hz, H-2),

3.38(m, 1H, H-1), 3.37(dd, 1H, J_4,5= 10.5 Hz, H-4), 2.09(ddd, 1H,

J

_1,5aeq= 3.7 Hz, J_5,5aeq= 3.7 Hz, J_gem= 13.2 Hz, H-5aeq), 1.64(m, 1H,

H-5), 1.40(ddd, 1H, J_1,5aax= 11.3 Hz, J_5,5aax= 11.3 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 159.09, 138.96, 138.43, 137.46, 137.19,

131.15, 129.67, 129.13, 129.10, 128.35, 128.31, 128.00, 127.67,

127.54, 127.51, 127.50, 113.77, 87.18(C-3), 86.57(C-2), 79.96(C-4),

78.46(C-1), 75.11, 74.09, 73.93, 73.10, 72.22, 70.24(C-6), 55.28(CH₃),

38.69(C-5), 30.69(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

[α] = +111.8° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.54–7.52(m, 12H), 7.42–7.21(m, 6H), 7.09–7.07(m, 1H), 5.57(s, 1H,

PhCH), 5.36(d, 1H, J = 12.6 Hz), 5.23(d, 1H, J = 15.2 Hz), 4.99(d, 1H,

J = 15.2 Hz), 4.81(d, 1H, J = 12.6 Hz), 4.17(dd, 1H, J_5,6a= 4.3 Hz,

J

_gem= 10.9 Hz, H-6a), 3.63(dd, 1H, J_5,6b= 10.9 Hz, J_gem= 10.9 Hz, H-

C₃₇H₄₀O₆Na 603.2717, found 603.2717.

6b), 3.59(m, 1H, H-1), 3.59–3.52(m, 2H, H-3, H-4), 3.40(dd, 1H,

J_1,2= 8.8 Hz, J_2,3= 8.8 Hz, H-2), 2.66(d, 1H, J_1,OH= 1.7 Hz, OH),

1.78(ddd, 1H, J_1,5aeq= 4.9 Hz, J_5,5aeq= 3.0 Hz, J_gem= 13.2 Hz, H-

5aeq), 1.13(ddd, 1H, J_1,5aax= 11.5 Hz, J_5,5aax= 11.5 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 138.15, 137.46, 136.39, 131.76, 128.83,

128.32, 128.21, 127.90, 127.55, 126.11, 101.42(PhCH), 84.97(C-2),

82.40(C-4), 82.34(C-3), 73.96, 72.83, 71.04(C-1), 70.92(C-6), 34.16(C-

5), 29.28(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for C₂₂H₂₄O₅Na

391.1516, found 391.1519.

4.1.26. 4,6-Di-O-benzyl-2,3-O-(o-xylylene)-5a-carba-β-^D-glucopyranose

(32)

To a solution of 4,6-di-O-benzyl-1-O-(p-methoxybenzyl)-2,3-O-(o-

xylylene)-5a-carba-β-^D-glucopyranose 31 (150 mg, 0.258 mmol) in

CH₂Cl₂-H₂O (18:1, 2.52 mL) was added DDQ (64 mg, 0.284 mmol).

After being stirred for 2 h, the solution was diluted with CH₂Cl₂and

washed saturated NaHCO₃and brine. The organic layer was dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 2:1) to give compound 32

(107 mg, 91%) as a colorless syrup. R_f= 0.10 (Toluene/EtOAc, 3:1);

4.1.24. 4,6-O-Benzylidene-1-O-triﬂuoromethanesulfonyl-2,3-O-(o-

xylylene)-5a-carba-β-^D-glucopyranose (30)

[α] = +158.8° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

To a solution of 4,6-O-benzylidene-2,3-O-(o-xylylene)-5a-carba-β-^D-

glucopyranose 29 (52 mg, 0.141 mmol) in CH₂Cl₂(500 μL) and pyridine

(500 μL) at −10 °C was added Tf₂O (36 μL, 0.212 mmol). After being

stirred for 2 h, MeOH was added, and the solution was concentrated in

vacuo. The residue was diluted with EtOAc, and washed brine. The

organic layer was dried (MgSO₄), and concentrated in vacuo. The re-

sidue was puriﬁed by column chromatography (hexane/EtOAc, 8:1) to

give compound 30 (59 mg, 85%) as a white amorphous solid. R_f= 0.19

(Hexane/EtOAc, 8:1); [α] = +43.4° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.52–7.14(m, 9H), 5.53(s, 1H, PhCH), 5.13(d, 1H,

J = 13.9 Hz), 5.12(d, 1H, J = 14.2 Hz), 5.04(d, 1H, J = 14.2 Hz),

7.38–7.04(m, 14H), 5.29(d, 1H, J = 13.0 Hz), 5.21(d, 1H, J = 15.2 Hz),

5.01(d, 1H, J = 15.2 Hz), 4.93(d, 1H, J = 11.0 Hz), 4.83(d, 1H,

J = 13.0 Hz), 4.59(d, 1H, J = 11.0 Hz), 4.44(s, 2H), 3.58(dd, 1H,

J

_5,6a= 5.0 Hz, J_gem= 8.8 Hz, H-6a), 3.48(ddd, 1H, J_1,2= 8.9 Hz,

J_1,5aeq= 4.6 Hz, J_1,5aax= 11.8 Hz, H-1), 3.48(dd, 1H, J_3,4= 8.9 Hz,

J

_4,5= 8.8 Hz, H-4), 3.47(dd, 1H, J_5,6b= 2.9 Hz, H-6b), 3.41(dd, 1H,

_2,3= 8.9 Hz, H-3), 3.29(dd, 1H, H-2), 2.62(br, 1H, 1-OH), 2.01(ddd,

1H,

J_5,5aeq= 3.4 Hz, J_gem= 12.9 Hz, H-5aeq), 1.67(m, 1H, H-5),

1.53(ddd, 1H, J_5,5aax= 11.8 Hz, J_gem= 12.9 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 138.74, 138.39, 137.43, 136.60, 131.16, 128.41,

128.32, 128.10, 128.01, 127.74, 127.66, 127.51, 127.40, 87.04(C-3),

85.44(C-2), 80.51(C-4), 75.36, 74.26, 73.24, 73.06, 70.77(C-1),

69.84(C-6), 39.00(C-5), 31.60(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd

for C₂₉H₃₂O₅Na 483.2142, found483.2142.

5.03(d,

1H,

_1,5aeq= 5.3 Hz, J_1,5aax= 11.8 Hz, H-1), 4.20(dd, 1H, J_5,6a= 4.4 Hz,

_gem= 11.1 Hz, H-6a), 3.70–3.64(m, 2H, H-2, H-3), 3.62(dd, 1H,

J = 13.9 Hz),

4.81(brddd,

1H,

J_1,2= 9.1 Hz,

J

J_5,6b= 11.0 Hz), 3.51(brdd, 1H, J_3,4= 9.9 Hz, J_4,5= 9.9 Hz, H-4),

2.04(ddd, 1H, J_5,5aeq= 3.2 Hz, J_gem= 12.5 Hz, H-5aeq), 1.85(m, 1H,

H-5), 1.46(ddd, 1H, J_5,5aax= 12.3 Hz, H-5aax); ¹³C NMR (100 MHz,

CDCl₃) δ 137.60, 136.52, 136.18, 129.97, 129.86, 129.07, 128.29,

128.12, 126.20, 101.68(PhCH), 86.87(C-1), 82.25(C-2), 81.50(C-3),

80.79(C-4), 73.57, 73.47, 70.31(C-6), 33.18(C-5), 28.92(C-5a); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₂₃H₂₃O₇NaF₃S 523.1009,

found523.1007.

4.1.27. 4,6-Di-O-benzyl-2,3-O-(o-xylylene)-1-O-triﬂuoromethanesulfonyl-

5a-carba-β-^D-glucopyranose (33)

To a solution of 4,6-di-O-benzyl-2,3-O-(o-xylylene)-5a-carba-β-^D-

glucopyranose 32 (55 mg, 0.119 mmol) in CH₂Cl₂(500 μL) and pyridine

(500 μL) at −10 °C was added Tf₂O (30 μL, 0.179 mmol). After being

stirred for 2 h, MeOH was added, and the solution was concentrated in

vacuo. The residue was diluted with EtOAc, and washed brine. The

organic layer was dried (MgSO₄), and concentrated in vacuo. The re-

sidue was puriﬁed by column chromatography (hexane/EtOAc, 8:1) to

give compound 33 (58 mg, 83%) as a white amorphous solid. R_f= 0.33

(hexane/EtOAc, 8:1); [α] = +67.5° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.38–7.12(m, 14H), 5.15(d, 1H, J = 13.7 Hz),

5.10(d, 1H, J = 14.5 Hz), 5.05(d, 1H, J = 14.5 Hz), 4.98(d, 1H,

J = 13.7 Hz), 4.93(d, 1H, J = 11.0 Hz), 4.74(ddd, 1H, J_1,5aeq= 5.2 Hz,

4.1.25. 4,6-Di-O-benzyl-1-O-(p-methoxybenzyl)-2,3-O-(o-xylylene)-5a-

carba-β-^D-glucopyranose (31)

To a solution of 4,6-O-benzylidene-1-O-(p-methoxybenzyl)-2,3-O-(o-

xylylene)-5a-carba-β-^D-glucopyranose 28 (339 mg, 0.694 mmol) was

dissolved in AcOH (6 mL) and H₂O (4 mL) at 60 °C, and the mixture was

stirred for 1 h. The solvent was concentrated in vacuo. To a solution of

the residue was dissolved in DMF (3 mL) was added NaH (139 mg,

J

_1,2= 8.8 Hz, J_1,5aax= 12.2 Hz, H-1), 4.53(d, 1H, J = 11.0 Hz), 4.44(d,

14

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

1H, J = 12.0 Hz), 4.39(d, 1H, J = 12.0 Hz), 3.48(dd, 1H,

3.97 mmol). After being stirred for 5 h, the solution was diluted with

EtOAc, and was ﬁltered through Celite. The ﬁltrate was added aq

NaBH₄(30 mg, 0.794 mmol), and was ﬁltered through Celite. The ﬁl-

trate was washed saturated NaHCO₃and brine. The organic layer was

dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (hexane/EtOAc, 1:4) to give compound

36 (361 mg, 89%) as a white amorphous solid. R_f= 0.26 (hexane/

EtOAc, 1:2); [α] = +12.7° (c 1.00, MeOH); ¹H NMR (400 MHz, CDCl₃)

δ 7.83–7.76(m, 4H), 7.49–7.25(m, 8H), 4.95(d, 1H, J = 11.3 Hz),

4.83(d, 1H, J = 11.7 Hz), 4.71(d, 1H, J = 11.3 Hz), 4.67(d, 1H,

J

_5,6a= 4.5 Hz, J_gem= 9.1 Hz, H-6a), 3.55(dd, 1H, J_2,3= 8.8 Hz, H-2),

3.51(dd, 1H, J_3,4= 8.8 Hz, H-3), 3.45(dd, 1H, J_4,5= 9.0 Hz, H-4),

3.44(dd, 1H, J_5,6b= 2.6 Hz, H-6b), 2.18(ddd, 1H, J_5,5aeq= 3.6 Hz,

J

_gem= 12.8 Hz, H-5aeq), 1.88(ddd, 1H, J_5,5aax= 12.4 Hz, H-5aax),

1.69(m, 1H, H-5); ¹³C NMR (100 MHz, CDCl₃) δ 138.54, 138.00,

136.56, 129.85, 129.17, 129.03, 128.42, 128.41, 128.22, 128.02,

127.81, 127.74, 127.66, 87.67(C-1), 85.84(C-3), 83.21(C-2), 78.55(C-

4), 75.32, 74.08, 73.97, 73.20, 68.88(C-6), 38.22(C-5), 30.64(C-5a);

HRMS(ESI) m/z: [M+Na]⁺calcd for C₃₀H₃₁O₇NaF₃S 615.1635, found

615.1635.

J = 11.7 Hz), 3.66–3.59(m, 2H, H-6), 3.58(dd, 1H,

J_3,4= 9.0 Hz, H-3), 3.44(dd, 1H, J_1,2= 9.0 Hz, H-2), 3.38(ddd, 1H,

_1,5aeq= 4.0 Hz, J_1,5aax= 11.0 Hz, H-1), 3.34(dd, 1H, J_4,5= 10.4 Hz,

H-4), 2.94(br, 1H, 2-OH), 2.81(br, 1H, 3-OH), 2.08(ddd, 1H,

J_2,3= 8.9 Hz,

4.1.28. 4,6-O-Benzylidene-2,3-O-isopropylidene-1-O-(2-naphthyl)-5a-

carba-β-^D-glucopyranose (34)

J

To a solution of 4,6-O-benzylidene-2,3-O-isopropylidene-5a-carba-

β-^D-glucopyranose 11 (1.50 g, 4.90 mmol) in DMF (12 mL) and NaH

(392 mg, 9.8 mmol), and the mixture was stirred for 30 min under Ar.

After being cooled to 0 °C, to the solution was added 2-(bromomethyl)

naphthalene (216 mg, 9.8 mmol). After being stirred for 1 h, MeOH was

added, and the solution was concentrated in vacuo. The residue was

diluted with EtOAc, and washed brine. The organic layer was dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

column chromatography (hexane/EtOAc, 6:1) to give compound 34

(2.01 g, 92%) as a white amorphous solid. R_f= 0.28 (hexane/EtOAc,

5:1); [α] = +5.5° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.84–7.80(m, 4H), 7.50–7.27(m, 8H), 5.55(s, 1H, PhCH), 4.98(d, 1H,

J = 12.3 Hz), 4.81(d, 1H, J = 12.3 Hz), 4.13(dd, 1H, J_5,6a= 4.1 Hz,

J_5,5aeq= 4.0 Hz, J_gem= 13.0 Hz, H-5aeq), 1.94(br, 1H, 6-OH), 1.63(m,

1H, H-5), 1.26(ddd, 1H,

J

_5,5aax= 11.0 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 138.26, 135.56, 133.24, 133.02, 128.60, 128.34,

128.29, 127.99, 127.86, 127.70, 126.52, 126.21, 126.01, 125.68,

81.37(C-4), 78.89(C-1), 77.47(C-3), 76.80(C-2), 74.48, 71.63, 64.53(C-

6), 39.91(C-5), 29.12(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C₂₅H₂₈O₅Na 431.1829, found431.1830.

4.1.31. 4-O-Benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-(2-

naphthyl)-5a-carba-β-^D-glucopyranose (37)

To a solution of 4-O-benzyl-1-O-(2-naphthyl)-5a-carba-β-^D-gluco-

pyranose 36 (302 mg, 0.739 mmol) in MeOH (7.4 mL) at 60 °C was

added trimethyl orthoformate (808 μL, 7,39 mmol), 2,3-butanedione

(257 μL, 2.96 mmol) and CSA (21 mg, 0.148 mmol). After being stirred

for 4.5 h, the solution was neutralized with NaHCO₃, and the resin was

ﬁltered oﬀ. The ﬁltrate was concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane/EtOAc, 3:1) to give

compound 37 (366 mg, 95%) as a white amorphous solid. R_f= 0.51

(hexane/EtOAc, 1:1); [α] = −48.1° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.82–7.79(m, 4H), 7.48(m, 8H), 5.07(d, 1H,

J = 11.2 Hz), 4.99(d, 1H, J = 12.2 Hz), 4.84(d, 1H, J = 12.2 Hz),

4.66(d, 1H, J = 11.2 Hz), 3.77(dd, 1H, J_2,3= 9.3 Hz, J_3,4= 9.4 Hz, H-

J

_gem= 10.9 Hz, H-6a), 3.80(ddd, 1H, J_1,5aeq= 4.3 Hz, J_1,2= 8.9 Hz,

_1,5aax= 10.2 Hz, H-1), 3.77(dd, 1H, J_3,4= 9.2 Hz, J_4,5= 9.3 Hz, H-4),

3.69(dd, 1H, J_5,6b= 10.9 Hz, H-6b), 3.63(dd, 1H, J_2,3= 9.0 Hz, H-3),

3.60(dd, 1H, H-2), 1.92(ddd, 1H, J_5,5aeq= 4.3 Hz, J_gem= 13.0 Hz, H-

5aeq), 1.86(m, 1H, H-5), 1.51(s, 3H, CH₃), 1.48(s, 3H, CH₃), 1.18(ddd,

1H, J_5,5aax= 10.2 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 137.59,

135.84, 133.26, 132.94, 128.95, 128.11, 127.84, 127.66, 126.41,

126.39, 126.06, 125.83, 125.72, 111.57, 101.62(PhCH), 82.45(C-2),

80.44(C-4), 78.09(C-3), 75.93(C-1), 71.74, 70.86(C-6), 36.37(C-5),

30.18(C-5a), 26.89(CH₃); HRMS(ESI) m/z: [M+Na]⁺calcd for

3), 3.72(dd, 1H,

J_1,2= 9.3 Hz, H-2), 3.63(dd, 1H, J_5,6a= 5.7 Hz,

C

₂₈H₃₀O₅Na 469.1985, found469.1987.

J_gem= 10.8 Hz, H-6a), 3.61(m, 1H, H-1), 3.58(dd, 1H, J_5,6b= 4.2 Hz,

H-6b), 3.51(dd, 1H, J_4,5= 9.5 Hz, H-4), 3.35(s, 3H, OCH₃), 3.32(s, 3H,

OCH₃), 1.99(ddd, 1H, J_5,5aeq= 4.0 Hz, J_1,5aeq= 4.5 Hz, J_gem= 13.3 Hz,

H-5aeq), 1.70(m, 1H, H-5), 1.40(s, 3H, CH₃), 1.38(s, 3H, CH₃),

1.31(ddd, 1H, J_1,5aax= 11.2 Hz, J_5,5aax= 11.2 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 138.29, 136.54, 133.27, 132.88, 128.54, 128.28,

127.96, 127.94, 127.82, 127.64, 125.97, 125.92, 125.68, 125,58,

99.23, 99.17, 79.69(C-4), 76.09(C-1), 75.09, 74.55(C-3), 74.02(C-2),

73.05, 65.14(C-6), 47.90(OCH₃), 47.85(OCH₃), 40.39(C-5), 31.01(C-

5a), 17.85(CH₃), 17.84(CH₃); HRMS(ESI) m/z: [M+Na]⁺calcd for

4.1.29. 4,6-O-Benzylidene-1-O-(2-naphthyl)-5a-carba-β-^D-glucopyranose

(35)

To a solution of 4,6-O-benzylidene-2,3-O-isopropylidene-1-O-(2-

naphthyl)-5a-carba-β-^D-glucopyranose 34 (828 mg, 1.85 mmol) in

MeOH (50 mL) was added AcOH (4 mL). After being stirred at 60 °C for

2 h, the solvent was concentrated in vacuo. The residue was puriﬁed by

column chromatography (EtOAc) to give compound 35 (639 mg, 85%)

as

a white amorphous solid. R_f= 0.63 (CHCl₃/MeOH, 10:1);

[α] = −28.5° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

C₃₁H₃₈O₇Na 545.2510, found 545.2508.

7.85–7.79(m, 4H), 7.51–7.45(m, 5H), 7.38–7.33(m, 3H), 5.51(s, 1H,

PhCH), 4.84(d, 1H, J = 11.8 Hz), 4.78(d, 1H, J = 11.8 Hz), 4.14(dd,

1H, J_5,6a= 4.4 Hz, J_gem= 11.4 Hz, H-6a), 3.64(dd, 1H, J_2,3= 9.0 Hz,

4.1.32. 4,6-Di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-(2-

naphthyl)-5a-carba-β-^D-glucopyranose (38)

J

_3,4= 9.0 Hz, H-3), 3.59(dd, 1H, J_1,2= 8.5 Hz, H-2), 3.59(dd, 1H,

To a solution of 4-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-

1-O-(2-naphthyl)-5a-carba-β-^D-glucopyranose 37 (366 mg, 0.700 mmol)

in DMF (2 mL) and NaH (70 mg, 1.75 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added BnBr (208 μL, 1.75 mmol). After being stirred for overnight,

MeOH was added, and the solution was concentrated in vacuo. The

residue was diluted with EtOAc, and washed brine. The organic layer

was dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed

by column chromatography (hexane/EtOAc, 6:1) to give compound 38

(411 mg, 96%) as a colorless syrup. R_f= 0.42 (hexane/EtOAc, 6:1);

J_5,6b= 10.6 Hz,

H-6b),

3.48(ddd,

1H,

J_5,5aeq= 4.6 Hz,

J

_5,5aax= 11.1 Hz, H-1), 3.43(dd, 1H, J_4,5= 9.0 Hz, H-4), 2.98(br, 1H),

2.89(br, 1H), 1.92(ddd, 1H, J_5,5aeq= 3.5, J_gem= 12.9 Hz, H-5aeq),

1.83(m, 1H, H-5), 1.09(ddd, 1H, J_5,5aax= 11.1 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 137.74, 135.58, 133.24, 133.02, 129.09, 128.35,

128.28, 127.86, 127.71, 126.49, 126.24, 126.21, 126.01, 125.67,

101.80(PhCH), 82.22(C-4). 79.01(C-1), 77.00(C-2), 74.33(C-3), 72.13,

70.84(C-6), 33.72(C-5), 27.85(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd

for C₂₅H₂₆O₅Na 429.1672, found 429.1673.

[α] = −51.5° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

4.1.30. 4-O-Benzyl-1-O-(2-naphthyl)-5a-carba-β-^D-glucopyranose (36)

To a solution of 4,6-O-benzylidene-1-O-(2-naphthyl)-5a-carba-β-^D-

glucopyranose 35 (403 mg, 0.99 mmol) in THF (5.9 mL) was added

THF·BH₃(4.0 mL, 1.0 M in THF, 3.97 mmol) and CoCl₂(515 mg,

7.81–7.79(m, 4H), 7.49–7.24(m, 13H), 5.00(d, 1H, J = 11.8 Hz),

4.97(d, 1H, J = 10.7 Hz), 4.84(d, 1H, J = 11.8 Hz), 4.52(d, 1H,

J = 10.7 Hz), 4.45(d, 1H, J = 12.1 Hz), 4.41(d, 1H, J = 12.1 Hz),

3.77–3.71(m, 2H, H-2, H-3), 3.60(ddd, 1H,

J_1,5aeq= 4.6 Hz,

15

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

J_1,2= 9.3 Hz, J_1,5aax= 11.1 Hz, H-1), 3.56(m, 1H, H-4), 3.50(dd, 1H,

4.1.35. 4,6-O-Benzylidene-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-5a-

J

_5,6a= 4.8 Hz, J_gem= 8.8 Hz, H-6a), 3.49(dd, 1H, J_5,6b= 2.6 Hz, H-

carba-β-^D-glucopyranose (41)

6b), 3.35(s, 3H, OCH₃), 3.31(s, 3H, OCH₃), 2.15(ddd, 1H,

To a solution of 4-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-

5a-carba-β-^D-glucopyranose 37 (508 mg, 0.972 mmol) in MeOH

(30 mL) and AcOH (500 μL) was added 10% Pd/C (103 mg,

0.097 mmol). The resulting suspension was hydrogenated at 1 atm for

overnight. The solution was ﬁltered through of Celite, and the solvent

was evaporated. The residue in DMF (4 mL) at 60 °C was added ben-

zaldehyde dimethyl acetal (218 μL, 1.46 mmol) and CSA (22 mg,

0.097 mmol). After being stirred for 15 min, the solution was cooled to

0 °C and neutralized with Et₃N. The solution was concentrated in vacuo,

and the residue was puriﬁed by ﬂash column chromatography (hexane/

EtOAc, 1:1) to give compound 41 (288 mg, 78%) as a white amorphous

solid. R_f= 0.17 (hexane/EtOAc, 1:1); [α] = −171.9° (c 1.00, CHCl₃);

¹H NMR (400 MHz, CDCl₃) δ 7.49–7.30(m, 5H), 5.54(s, 1H, PhCH),

J

_5,5aeq= 3.6 Hz, J_gem= 13.1 Hz, H-5aeq), 1.71(m, 1H, H-5), 1.58(ddd,

1H, J_5,5aax= 11.2 Hz, H-5aax), 1.39(s, 3H. CH₃), 1.38(s, 3H, CH₃); ¹³C

NMR (100 MHz, CDCl₃) δ 138.85, 138.49, 136.74, 133.31, 132.88,

128.31, 128.30, 128.14, 127.92, 127.84, 127.64, 127.58, 127.46,

125.93, 125.89, 125.63, 99.20, 99.15, 77.45(C-4), 76.40(C-1), 75.27,

74.65(C-3), 74.16(C-2), 73.09, 73.04, 70.02(C-6), 47.90(OCH₃),

47.83(OCH₃), 39.32(C-5), 31.70(C-5a), 17.87(CH₃); HRMS(ESI) m/z:

[M+Na]⁺calcd for C₃₈H₄₄O₇Na 635.2979, found 635.2974.

4.1.33. 4,6-Di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-5a-carba-

β-^D-glucopyranose (39)

To a solution of 4,6-di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-

diyl)-1-O-(p-methoxybenzyl)-5a-carba-β-^D-glucopyranose 38 (50 mg,

0.082 mmol) in CH₂Cl₂–H₂O (18:1, 1.9 mL) was added DDQ (28 mg,

0.122 mmol). After being stirred for 1 h, the solution was diluted with

CH₂Cl₂and washed saturated NaHCO₃and brine. The organic layer was

dried (MgSO₄) and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (hexane/EtOAc, 2:1) to give compound

39 (31 mg, 81%) as a colorless syrup. R_f= 0.20 (hexane/EtOAc, 2:1);

4.16(dd, 1H, J_5,6a= 4.2 Hz, J_gem= 11.0 Hz, H-6a), 3.81(ddd, 1H,

J

_1,5aeq= 4.7 Hz, J_1,2= 9.5 Hz, J_1,5aax= 11.0 Hz, H-1), 3.79(dd, 1H,

J_2,3= 9.6 Hz, J_3,4= 9.7 Hz, H-3), 3.68(dd, 1H, J_5,6b= 11.0 Hz, H-6b),

3.66(dd, 1H, J_4,5= 9.7 Hz, H-4), 3.55(dd, 1H, H-2), 3.29(s, 6H, OCH₃),

2.47(br, 1H), 1.88(m, 1H, H-5), 1.84(ddd, 1H, J_5,5aeq= 3.6 Hz,

J

_gem= 13.3 Hz, H-5aeq), 1.34(s, 6H, CH₃), 1.15(ddd, 1H,

_5,5aax= 11.0 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 138.12,

128.69, 128.08, 126.06, 101.03(PhCH), 99.50, 99.28, 79.54(C-4),

74.19(C-2), 70.97(C-6), 69.89(C-3), 69.01(C-1), 48.01(OCH₃),

47.90(OCH₃), 34.99(C-5), 30.01(C-5a), 17.65(CH₃), 17.60(CH₃); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₂₀H₂₈O₇Na 403.1727, found 407.1727.

[α] = −48.4° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.35–7.24(m, 10H), 4.96(d, 1H, J = 10.8 Hz), 4.52(d, 1H, J = 10.8 Hz),

4.46(d, 1H, J = 11.9 Hz), 4.41(d, 1H, J = 11.9 Hz), 3.70(ddd, 1H,

J_1,5aeq= 4.6 Hz, J_1,2= 9.6 Hz, J_1,5aax= 11.2 Hz, H-1), 3.67(dd, 1H,

J

_2,3= 9.6 Hz, J_3,4= 9.6 Hz, H-3), 3.61(dd, 1H, J_5,6a= 4.4 Hz,

_gem= 8.9 Hz, H-6a), 3.60(dd, 1H, J_4,5= 9.6 Hz, H-4), 3.48(dd, 1H,

_5,6b= 2.6 Hz, H-6b), 3.46(dd, 1H, H-2), 3.30(s, 3H, OCH₃), 3.29(s, 3H,

4.1.36. 4,6-O-Benzylidene-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose (42)

To a solution of 4,6-O-benzylidene-2,3-O-(2,3-dimethoxybutane-

2,3-diyl)-5a-carba-β-^D-glucopyranose 41 (100 mg, 0.263 mmol) in

CH₂Cl₂(1.0 mL) and pyridine(1.0 mL) at −10 °C was added Tf₂O

(66 μL, 0.394 mmol). After being stirred for 2 h, MeOH was added, and

the solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (hexane/EtOAc, 8:1) to give compound 42 (122 mg, 92%) as a

white amorphous solid. R_f= 0.29 (hexane/EtOAc, 8:1); [α] = −124.2°

(c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.33(m, 5H), 5.53(s,

1H), 4.91(ddd, 1H, J_1,2= 10.7 Hz, J_1,5aeq= 5.3 Hz, J_1,5aax= 11.0 Hz,

H-1), 4.19(dd, 1H, J_5,6a= 4.3 Hz, J_gem= 11.0 Hz, H-6a), 3.87(m, 1H,

H-2), 3.85(m, 1H, H-3), 3.69(dd, 1H, J_5,6b= 10.9 Hz, H-6b), 3.66(dd,

1H, J_3,4= 9.8 Hz, J_4,5= 9.8 Hz, H-4), 3.28(s, 3H, OCH₃), 3.26(s, 3H,

OCH₃), 2.10(ddd, 1H, J_5,5aeq= 3.4 Hz, J_gem= 12.8 Hz, H-5aeq),

1.90(m, 1H, H-5), 1.52(ddd, J_5,5aax= 11.4 Hz, H-5aax), 1.33(s, 3H,

CH₃), 1.32(s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 137.67, 128.90,

128.16, 126.03, 101.17(PhCH), 99.89, 99.63, 84.51(C-1), 78.28(C-4),

70.56(C-2), 70.34(C-6), 69.90(C-3), 48.02(OCH₃), 47.94(OCH₃),

34.27(C-5), 29.64(C-5a), 17.52(CH₃), 17.24(CH₃); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₂₁H₂₇O₉NaF₃S 535.1220, found 535.1226.

OCH₃), 2.05(ddd, 1H, J_5,5aeq= 4.4 Hz, J_gem= 13.0 Hz. H-5aeq),

1.74(m, 1H, H-5), 1.57(ddd, 1H, J_5,5aax= 11.4 Hz, H-5aax), 1.36(s, 3H,

CH₃), 1.34(s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 138.82, 138.49,

128.29, 128.28, 128.09, 127.57, 127.45, 99.20, 77.49(C-4), 75.22,

74.11(C-3), 73.70(C-2), 73.03, 69.78(C-6), 68.94(C-1), 47.89(OCH₃),

47.86(OCH₃), 39.37(C-5), 32.27(C-5a), 17.84(CH₃), 17.66(CH₃); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₂₇H₃₆O₇Na 495.2353, found 495.2349.

4.1.34. 4,6-Di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose (40)

To a solution of 4,6-di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-

diyl)-5a-carba-β-^D-glucopyranose 39 (96 mg, 0.203 mmol) in CH₂Cl₂

(1.0 mL) and pyridine(1.0 mL) at −10 °C was added Tf₂O (51 μL,

0.304 mmol). After being stirred for 2.5 h, MeOH was added, and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (hexane/EtOAc, 10:1) to give compound 40 (106 mg, 87%) as a

colorless syrup. R_f= 0.36 (hexane/EtOAc, 10:1); [α] = −51.6° (c 1.00,

CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.23(m, 10H), 4.94(d, 1H,

J = 10.9 Hz),

4.83(ddd,

1H,

J

_1,5aeq= 5.2 Hz,

J_1,2= 9.5 Hz,

4.1.37. 2,3-Di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-glucopyranosyl-

(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (43)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (233 mg, 0.173 mmol) in THF (130 μL) was added 15-crown-5 ether

(125 μL, 0.634 mmol) and NaH (17 mg, 0.432 mmol), and the mixture

was stirred for 30 min under Ar. After being cooled to 0 °C, to the so-

J_1,5aax= 11.6 Hz, H-1), 4.50(d, 1H, J = 10.9 Hz), 4.45(d, 1H,

J = 10.9 Hz), 4.39(d, 1H, J = 10.9 Hz), 3.77(dd, 1H, J_2,3= 9.5 Hz, H-

2), 3.70(dd, 1H,

J_3,4= 9.5 Hz, H-3), 3.66(dd, 1H, J_5,6a= 4.3 Hz,

J

_gem= 9.0 Hz, H-6a), 3.62(dd, 1H, J_4,5= 9.5 Hz, H-4), 3.42(dd, 1H,

_5,6b= 2.5 Hz, H-6b), 3.27(s, 6H, OCH₃), 2.22(ddd, 1H,

_5,5aeq= 4.0 Hz,

J_gem= 13.1 Hz,

H-5aeq),

1.96(ddd,

1H,

lution

was

added

2,3-di-O-benzyl-4,6-O-benzylidene-1-O-tri-

27 (100 mg,

J_5,5aax= 11.8 Hz, H-5aax), 1.73(m, 1H, H-5), 1.35(s, 3H, CH₃), 1.30(s,

3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 138.43, 138.07, 128.40,

128.38, 128.13, 127.76, 127.71, 127.61, 99.52, 99.50, 85.53(C-1),

76.68(C-4), 75.32, 73.72(C-3), 73.18, 70.13(C-2), 68.70(C-6),

47.92(OCH₃), 47.89(OCH₃), 38.92(C-5), 31.34(C-5a), 17.71(CH₃),

17.28(CH₃); HRMS(ESI) m/z: [M+Na]⁺calcd for C₂₈H₃₅O₉NaF₃S

627.1846, found627.1850.

ﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

0.173 mmol). After being stirred for 19 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (Toluene/EtOAc, 40:1) to give compound 43 (91 mg, 55%) as a

white amorphous solid and oleﬁn 44 (14 mg, 19%) as a colorless syrup

and recovered

8 (172 mg, 74%). Date for 2,3-di-O-benzyl-4,6-O-

16

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

benzylidene-5a-carba-α-D-glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O-

benzyl-5a-carba-β-^D-glucopyranoside (43): R_f= 0.26 (Toluene/EtOAc,

20:1); [α] = +25.0° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ

7.54–7.22(m, 35H), 5.56(s, 1H, PhCH), 4.97(d, 1H, J = 10.5 Hz),

4.95(d, 1H, J = 10.3 Hz), 4.95(d, 1H, J = 11.2 Hz), 4.92(d, 1H,

J = 10.6 Hz), 4.84(d, 1H, J = 10.5 Hz), 4.82(d, 1H, J = 10.3 Hz),

4.82(d, 1H, J = 10.6 Hz), 4.75(d, 1H, J = 11.9 Hz), 4.68(d, 1H,

J = 11.9 Hz), 4.67(d, 1H, J = 11.5 Hz), 4.62(d, 1H, J = 11.5 Hz),

4.55(d, 1H, J = 11.2 Hz), 4.08(dd, 1H, J_5′,6′a= 4.4 Hz, J_gem= 11.0 Hz,

H-6′a), 3.98(dd, 1H, J_2′,3′= 9.4 Hz, J_3′,4′= 9.2 Hz, H-3′), 3.74(dd, 1H,

J_5,6a= 2.5 Hz, J_gem= 9.0 Hz, H-6a), 3.76(m, 1H, H-1′), 3.64(dd, 1H,

J

_5,6b= 5.0 Hz, H-6b), 3.53(dd, 1H, J_5′,6′b= 11.0 Hz, H-6′b),

3.49–3.41(m, 2H, H-2, H-3), 3.46(dd, 1H, J

= 2.7 Hz, J_2′,3′= 9.2 Hz,

1′,2′

H-2′), 3.44–3.34(m, 1H, H-4), 3.43(dd, 1H, J_4′,5′= 10.2 Hz, H-4′),

3.39(ddd, 1H, J_1,2= 9.1 Hz, J_1,5aeq= 3.9 Hz, J_1,5aax= 11.4 Hz, H-1),

2.22(m, 1H, H-5′), 1.90(ddd, 1H, J_5,5aeq= 3.9 Hz, J_gem= 13.1 Hz, H-

5aeq),

1.56(ddd,

1H,

J

_1′,5a′eq= 2.5 Hz,

J

= 3.5 Hz,

5′,5a′eq

J

_gem= 13.5 Hz, H-5a′eq), 1.55(m, 1H, H-5), 1.30(ddd, 1H,

_5,5aax= 11.4 Ha, H-5aax), 1.00(ddd, 1H, J_1′,5a′ax= 1.8 Hz,

_5′,5a′ax= 13.4 Hz, H-5a′ax); ¹³C NMR (100 MHz, CDCl₃) δ 138.88,

J

_5,6a= 2.6 Hz, J_gem= 8.9 Hz, H-6a), 3.73(m, 1H, H-1′), 3.68(dd, 1H,

138.80, 138.78, 138.27, 137.35, 136.99, 130.53, 128.74, 128.56,

128.36, 128.31, 128.27, 128.14, 128.04, 127.81, 127.77, 127.63,

127.56, 127.54, 127.47, 127.43, 127.39, 126.31, 101.61(PhCH),

86.29(C-3), 85.88(C-2), 83.14(C-2′), 82.91(C-4′), 80.59(C-4), 80.58(C-

3′), 80.21(C-1), 76.30(C-1′), 75.73, 75.05, 73.98, 72.60, 71.98,

71.30(C-6′), 70.85(C-6), 39.07(C-5), 32.51(C-5′), 29.98(C-5a), 28.05(C-

5a′); HRMS(ESI) m/z: [M+Na]⁺calcd for C₅₇H₆₀O₉Na 911.4130,

found 911.4130.

J_5,6b= 5.1 Hz, H-6b), 3.54(dd, 1H, J_5′,6′b= 11.2 Hz, H-6′b), 3.53(m,

1H, H-2), 3.53(m, 1H, H-3), 3.51(dd, 1H, J_3′,4′= 9.2 Hz, J_4′,5′= 9.2 Hz,

H-4′), 3.50(m, 1H, H-1), 3.47(dd, 1H, J_3,4= 9.5 Hz, J_4,5= 9.5 Hz, H-4),

3.38(dd, 1H, J_1′,2′= 2.8 Hz, J_2′,3′= 9.4 Hz, H-2′), 2.26(m, 1H, H-5′),

2.16(ddd, 1H, J_1,5aeq= 3.7 Hz, J_5,5aeq= 3.7 Hz, J_gem= 13.1 Hz, H-

5aeq), 1.68(m, 1H, H-5), 1.60(ddd, 1H,

J

_1′,5a′eq= 3.5 Hz,

J_5′,5a′eq= 3.5 Hz,

_1,5aax= 12.4 Hz,

J_gem= 13.9 Hz,

H-5a′eq),

H-5aax),

1.52(ddd,

0.92(ddd,

1H,

J

J_5,5aax= 12.4 Hz,

J_1′,5a′ax= 1.8 Hz, J_5′,5a′ax= 12.2 Hz, H-5a′ax); ¹³C NMR (100 MHz,

CDCl₃) δ 139.04, 138.88, 138.79, 138.73, 138.34, 128.63, 128.40,

128.34, 128.31, 128.20, 128.17, 128.12, 128.05, 127.78, 127.64,

127.57, 127.56, 127.49, 127.47, 127.44, 127.43, 126.06,

101.23(PhCH), 86.39(C-3), 85.99(C-2), 84.25(C-4′), 82.90(C-2′),

80.68(C-4), 80.51(C-3′), 80.28(C-1), 75.80, 75.78, 75.60, 75.22(C-1′),

75.10, 72.93, 72.27, 71.29(C-6′), 70.66(C-6), 39.13(C-5), 32.60(C-5′),

30.43(C-5a), 27.53(C-5a′); HRMS(ESI) m/z: [M+Na]⁺calcd for

4.1.39. 4,6-Di-O-benzyl-2,3-O-(o-xylylene)-5a-carba-α-^D-glucopyranosyl-

(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (45)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (90 mg, 0.168 mmol) in THF (49 μL) was added 15-crown-5 ether

(49 μL, 0.248 mmol) and NaH (7 mg, 0.168 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 4,6-di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

33

(40 mg,

C

₆₃H₆₆O₉Na 989.4599, found 989.4596.

0.067 mmol). After being stirred for 14 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column chro-

matography (Hexane/EtOAc, 6:1) to give compound 45 (21 mg, 32%)

as a colorless syrup and oleﬁn 46 (4.9 mg, 16%) as a colorless syrup and

recovered 8 (66 mg, 74%). Date for 4,6-di-O-benzyl-2,3-O-(o-xylylene)-

5a-carba-α-^D-glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-

Date for oleﬁn 44: R_f= 0.46(Toluene/EtOAc, 20:1); [αα] = +38.4°

(c 0.97, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.24(m, 15H),

5.75(ddd, 1H, J_1,2= 2.9, J_1,5= 2.9, J_1,5a= 9.9 Hz, H-1), 5.63(s, 1H,

PhCH), 5.39(ddd, 1H, J_5,5a= 1.7 Hz, ⁴J_2,5a= 1.7 Hz, H-5a), 5.02(d, 1H,

J = 11.4 Hz), 4.80(d, 1H, J = 11.4 Hz), 4.74(d, 1H, J = 11.6 Hz),

4.67(d, 1H, J = 11.6 Hz), 4.29 (dd, 1H, J_5,6a= 4.6 Hz, J_gem= 11.0 Hz,

H-6a), 4.29(m, 1H, H-2), 4.00(dd, 1H, J_2,3= 7.0 Hz, J_3,4= 10.1 Hz, H-

3), 3.81(dd, 1H, J_4,5= 9.9 Hz, H-4), 3.64(dd, 1H, J_5,6b= 11.2 Hz, H-

6b), 2.70(m, 1H, H-5); ¹³C NMR (100 MHz, CDCl₃) δ 138.72, 138.41,

138.16, 128.93(C-5a), 128.76, 128.37, 128.30, 128.18, 128.13, 128.11,

127.82, 127.64, 127.56, 125.96, 125.06(C-1), 101.51(PhCH), 82.15(C-

4), 81.94(C-3), 80.65(C-2), 74.68, 72.26, 70.00(C-6), 38.57(C-5);

HRMS(ESI) m/z: [M+Na]⁺calcd for C₂₈H₂₈O₄Na 451.1880, found

451.1880.

β-^D-glucopyranoside

(45):

R_f= 0.34(Hexane/EtOAc,

6:1);

[α] = +82.7° (c 0.96, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.36–7.04(m, 34H), 5.12(d, 1H, J = 14.3 Hz), 5.12(d, 1H, J = 14.0 Hz),

5.05(d, 1H, J = 14.3 Hz), 4.96(d, 1H, J = 11.0 Hz), 4.91(d, 1H,

J = 10.7 Hz), 4.89(d, 1H, J = 10.8 Hz), 4.86(d, 1H, J = 14.0 Hz),

4.84(d, 1H, J = 10.6 Hz), 4.79(d, 1H, J = 10.7 Hz), 4.78(d, 1H,

J = 10.8 Hz), 4.58(d, 1H, J = 11.0 Hz), 4.55(d, 1H, J = 11.6 Hz),

4.49(d, 1H, J = 10.6 Hz), 4.48(d, 1H, J = 11.6 Hz), 4.39(s, 2H),

3.87(dd, 1H, J_2′,3′= 9.4 Hz, J_3′,4′= 9.0 Hz, H-3′), 3.74(m, 1H, H-1′),

4.1.38. 4,6-O-Benzylidene-2,3-O-(o-xylylene)-5a-carba-α-^D-

glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-

3.73(dd, 1H, J_5,6a= 2.3 Hz, J_gem= 9.0 Hz, H-6a), 3.65(dd, 1H,

glucopyranoside (47)

J_5′,6′a= 4.4 Hz, J_gem= 8.9 Hz, H-6′a), 3.61(dd, 1H, J_5,6b= 5.0 Hz, H-

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (108 mg, 0.200 mmol) in THF (59 μL) was added 15-crown-5 ether

(59 μL, 0.296 mmol) and NaH (8 mg, 0.200 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 4,6-O-benzylidene-1-O-triﬂuoromethanesulfonyl-2,3-O-(o-

xylylene)-5a-carba-β-^D-glucopyranose 30 (40 mg, 0.080 mmol). After

being stirred for 17.5 h, MeOH was added and the solution was con-

centrated in vacuo. The residue was diluted with EtOAc, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography (Hexane/

EtOAc, 4:1) to give compound 47 (24 mg, 35%) as a colorless syrup and

6b), 3.44(dd, 1H, J_2,3= 8.6 Hz, J_3,4= 9.2 Hz, H-3), 3.43(dd, 1H,

J

_4′,5′= 8.6 Hz, H-4′), 3.42(dd, 1H, J_1,2= 8.3 Hz, H-2), 3.40(dd, 1H,

_1′,2′= 2.3 Hz, H-2′), 3.36(m, 1H, H-1), 3.36(dd, 1H, J_4,5= 9.5 Hz, H-

4), 3.35(dd, 1H, J_5′,6′b= 2.1 Hz, H-6′b), 2.03(m, 1H, H-5′), 1.90(ddd,

1H, J_1,5aeq= 3.8 Hz, J_5,5aeq= 3.8 Hz, J_gem= 13.2 Hz, H-5aeq),

1.81(ddd, 1H, J_1′,5a′eq= 3.7 Hz, J_5′,5a′eq= 3.7 Hz, J_gem= 14.3 Hz, H-

5a′eq), 1.53(m, 1H, H-5), 1.48(ddd, 1H, J_1′,5a′ax= 1.6 Hz,

J

_5′,5a′ax= 12.8 Hz, H-5a′ax), 1.28(ddd, 1H, J_1,5aax= 11.4 Hz,

_5,5aax= 11.4 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 139.13,

138.93, 138.87, 138.83, 138.80, 138.59, 137.50, 137.33, 130.09,

128.34, 128.31, 128.28, 128.25, 128.05, 127.98, 127.81, 127.72,

127.66, 127.58, 127.50, 127.47, 127.44, 127.43, 127.37, 127.35,

86.31(C-3), 85.91(C-2), 85.55(C-3′), 84.19(C-2′), 80.66(C-4), 80.62(C-

4′), 80.27(C-1), 76.68(C-1′), 75.74, 75.24, 75.08, 74.66, 73.35, 72.98,

71.94, 70.39(C-6), 69.99(C-6′), 39.09(C-5), 37.19(C-5′), 30.03(C-5a),

29.91(C-5a′); HRMS(ESI) m/z: [M+Na]⁺calcd for C₆₄H₆₈O₉Na

1003.4756, found 1003.4757.

recovered

8

(77 mg, 72%). R_f= 0.27(Hexane/EtOAc, 3:1);

[α] = +87.0° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.58–7.05(m, 29H), 5.55(s, 1H, PhCH), 5.18(d, 1H, J = 13.3 Hz),

5.12(d, 1H, J = 14.6 Hz), 5.04(d, 1H, J = 14.6 Hz), 4.93(d, 1H,

J = 10.6 Hz), 4.91(d, 1H, J = 10.8 Hz), 4.88(d, 1H, J = 10.9 Hz),

4.82(d, 1H, J = 13.3 Hz), 4.81(d, 1H, J = 10.6 Hz), 4.79(d, 1H,

J = 10.8 Hz), 4.58(d, 1H, J = 11.7 Hz), 4.52(d, 1H, J = 11.7 Hz),

4.50(d, 1H, J = 10.9 Hz), 4.08(dd, 1H, J_5′,6′a= 4.4 Hz, J_gem= 10.9 Hz,

H-6′a), 3.91(dd, 1H, J_2′,3′= 9.2 Hz, J_3′,4′= 9.2 Hz, H-3′), 3.78(dd, 1H,

Date for oleﬁn 46: R_f= 0.37(Hexane/EtOAc, 6:1); [α] = +235.2°

(c 0.21, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.08(m, 14H),

5.64–5.59(m, 2H), 5.27(d, 1H, J = 12.8 Hz), 5.24(d, 1H, J = 14.7 Hz),

17

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

5.06(d, 1H, J = 14.7 Hz), 4.99(d, 1H, J = 11.0 Hz), 4.76(d, 1H,

J = 12.8 Hz), 4.53(d, 1H, J = 11.0 Hz), 4.45(d, 1H, J = 12.3 Hz),

4.39(d, 1H, J = 12.3 Hz), 4.24(dd, 1H, J_1,2= 3.6 Hz, J_2,3= 7.2 Hz, H-

2), 3.71(dd, 1H, J_3,4= 10.5 Hz, H-3), 3.65(dd, J_4,5= 9.6 Hz, H-4),

3.51–3.47(m, 2H, H-6), 2.40(m, 1H, H-5); ¹³C NMR (100 MHz, CDCl₃) δ

138.75, 138.25, 137.24, 136.78, 132.05, 129.18(C-5a), 128.41, 128.38,

128.35, 128.23, 128.16, 127.75, 127.74, 127.67, 127.62, 127.25(C-1),

84.84(C-3), 79.76(C-2), 77.96(C-4), 75.41, 73.31, 73.08, 71.91,

69.17(C-6), 44.06(C-5); HRMS(ESI) m/z: [M+Na]⁺calcd for

4.1.41. 4,6-O-Benzylidene-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-5a-

carba-α-^D-glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-D-

glucopyranoside (50)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (53 mg, 0.098 mmol) in THF (29 μL) was added 15-crown-5 ether

(28 μL, 0.144 mmol) and NaH (4 mg, 0.098 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C to the solution

was added 4,6-O-benzylidene-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-

O-triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose 42 (20 mg,

0.039 mmol). After being stirred for 16.5 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by preparative thin-

layer chromatography (Toluene/EtOAc, 10:1) to give compound 50

(18 mg, 53%) as a colorless syrup and recovered 8 (38 mg, 71%).

R_f= 0.20 (Toluene/EtOAc, 10:1); [α] = −19.3° (c 1.65, CHCl₃); ¹H

NMR (400 MHz, CDCl₃) δ 7.53–7.26(m, 25H), 5.53(s, 1H, PhCH),

4.97(d, 1H, J = 10.7 Hz), 4.95(d, 1H, J = 10.9 Hz), 4.90(d, 1H,

J = 10.9 Hz), 4.85(d, 1H, J = 10.7 Hz), 4.84(d, 1H, J = 10.9 Hz),

4.75(d, 1H, J = 11.6 Hz), 4.66(d, 1H, J = 11.6 Hz), 4.58(d, 1H,

C

₂₉H₃₀O₄Na 465.2036, found 465.2031.

4.1.40. 4,6-Di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-5a-carba-

α-^D-glucopyranosyl-(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-D-

glucopyranoside (48)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

8 (53 mg, 0.099 mmol) in THF (56 μL) was added 15-crown-5 ether

(24 μL, 0.120 mmol) and NaH (2 mg, 0.099 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 4,6-di-O-benzyl-2,3-O-(2,3-dimethoxybutane-2,3-diyl)-1-O-

triﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

40

(16 mg,

J = 10.9 Hz), 4.19(dd, 1H,

4.09(dd, 1H, _5′,6′a= 4.2 Hz, J_gem= 10.9 Hz, H-6′a), 3.94(d, 1H,

_gem= 8.9 Hz, H-6a), 3.78(dd, 1H, J_5,6b= 2.9 Hz, H-6b), 3.66(m, 1H,

H-1′), 3.61–3.48(m, 5H, H-1, H-2, H-3, H-4, H-4′), 3.59(dd, 1H,

_1′,2′= 3.1 Hz, H-2′), 3.59(dd, 1H, J_5,6b= 10.9 Hz, H-6′b), 3.24(s, 6H),

2.30(m, 1H, H-5′), 2.21(m, 1H, H-5aeq), 1.64(m, 1H, H-5), 1.63(m, 1H,

J_2′,3′= 9.8 Hz, J_3′,4′= 9.8 Hz, H-3′),

0.026 mmol). After being stirred for 18.5 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column chro-

matography (hexane/EtOAc, 6:1) to give compound 48 (15 mg, 57%) as

a colorless syrup and oleﬁn 49 (2 mg, 9%) as a colorless syrup and

recovered 8 (38 mg, 71%). Date for 4,6-di-O-benzyl-2,3-O-(2,3-di-

methoxybutane-2,3-diyl)-5a-carba-α-^D-glucopyranosyl-(1 → 6)-1,2,3,4-

tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (48): R_f= 0.19 (Toluene/

EtOAc, 20:1); [α] = −5.21° (c 0.48, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

J

H-5aax),

1.57(ddd,

1H,

J_1′,5a′eq= 3.3 Hz,

J_5′,5a′eq= 3.3 Hz,

J

_gem= 13.5 Hz, H-5a′eq), 1.30(s, 6H), 1.10(ddd, 1H, J_1′,5a′ax= 1.9 Hz,

_5′,5a′ax= 13.4 Hz, H-5a′ax); ¹³C NMR (100 MHz, CDCl₃) δ 138.97,

138.93, 138.89, 138.38, 128.59, 128.36, 128.31, 128.28, 128.26,

128.10, 128.03, 127.81, 127.68, 127.57, 127.44, 127.38, 127.36,

126.23, 101.17, 99.43, 98.90, 86.39(C-3), 86.11(C-2), 80.62(C-4),

80.49(C-1), 80.47(C-4′), 75.83, 75.68, 75.23, 74.74(C-1′), 72.54(C-2′),

72.01, 71.40(C-6′), 70.72(C-6), 67.98(C-3′), 47.84, 47.78, 39.22(C-5),

33.52(C-5′), 30.36(C-5a), 29.24(C-5a′), 17.77, 17.75; HRMS(ESI) m/z:

[M+Na]⁺calcd for C₅₅H₆₄O₁₁Na 923.4341, found 923.4339.

δ

7.37–7.22(m, 30H), 5.00(d, 1H, J = 11.0 Hz), 4.94(d, 1H,

J = 10.8 Hz), 4.92(d, 1H, J = 10.8 Hz), 4.86(d, 1H, J = 11.4 Hz),

4.83(d, 1H, J = 10.8 Hz), 4.82(d, 1H, J = 10.8 Hz), 4.73(d, 1H,

J = 11.6 Hz), 4.63(d, 1H, J = 11.6 Hz), 4.57(d, 1H, J = 11.4 Hz),

4.53(d, 1H, J = 11.0 Hz), 4.43(d, 1H, J = 11.9 Hz), 4.38(d, 1H,

J = 11.9 Hz), 4.14(dd, 1H, J_2′,3′= 9.8 Hz, J_3′,4′= 9.7 Hz, H-3′), 3.90(d,

1H, J_gem= 8.7 Hz, H-6a), 3.76(dd, 1H, J_5,6b= 3.0 Hz, H-6b), 3.70(dd,

1H, J_5′,6′a= 4.3 Hz, J_gem= 9.0 Hz, H-6′a), 3.62(m, 1H, H-1′), 3.58(dd,

1H, J_4′,5′= 10.3 Hz, H-4′), 3.56–3.46(m, 4H, H-1, H-2, H-3, H-4),

3.54(dd, 1H, J_1′,2′= 2.2 Hz, H-2′), 3.38(dd, 1H, J_5′,6′b= 2.4 Hz, H-6′b),

3.26(s, 6H), 2.18(m, 1H, H-5aeq), 2.10(m, 1H, H-5′), 1.80(ddd, 1H,

4.1.42. 5a,5a′-Dicarba-β-^D-isomaltose (1)

To

a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-α-^D-glucopyr-

anosyl-(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside 20

(63 mg, 0.059 mmol) in MeOH (5 mL) and AcOH (100 μL) was added Pd

Black (2 mg, 0.019 mmol). The resulting suspension was hydrogenated

at 1 atm for 2.5 h. The solution was ﬁltered through of Celite, and the

solvent was evaporated. The residue was chromatographed on a column

of Amberlite 200CT ion-exchange resin (H⁺form) and IRA 96SB ion-

exchange resin (OH^–form) to give compound 1 (18.9 mg, 95%) as a

colorless syrup. R_f= 0.16 (CHCl₃/MeOH/H₂O, 10:5:1); [α] = +69.7°

(c 0.50, H₂O); ¹H NMR (400 MHz, D₂O) δ 3.84(ddd, 1H, J_1′,2′= 3.2 Hz,

J

_1′,5a′eq= 3.8 Hz,

J_5′,5a′eq= 3.8 Hz,

J_gem= 14.1 Hz,

H-5a′eq),

1.64–1.54(m, 2H, H-5aax, H-5a′ax), 1.61(m, 1H, H-5), 1.33(s, 3H),

1.30(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 139.22, 139.01, 138.97,

138.90, 138.71, 128.34, 128.30, 128.27, 128.24, 128.11, 128.07,

127.88, 127.73, 127.57, 127.52, 127.41, 127.40, 127.37, 127.32,

99.23, 98.86, 86.35(C-3), 86.11(C-2), 80.67(C-4), 80.54(C-1), 78.13(C-

4′), 75.82, 75.70, 75.82, 75.70, 75.28, 75.26, 74.89(C-1′), 72.94,

72.31(C-2′, C-3′), 71.91, 70.41(C-6), 69.99(C-6′), 47.83, 47.59,

39.27(C-5), 37.78(C-5′), 31.14(C-5a′), 30.35(C-5a), 17.99, 17.83;

HRMS(ESI) m/z: [M+Na]⁺calcd for C₆₂H₇₂O₁₁Na 1015.4967, found

1015.4960.

J

_1′,5a′eq= 3.6 Hz, J_1′,5a′ax= 1.4 Hz, H-1′), 3.79(dd, 1H, J_5′,6′a= 3.6 Hz,

_gem= 11.2 Hz, H-6′a), 3.71(dd, 1H, J_5′,6′b= 5.9 Hz, H-6′b),

3.68–3.61(m, 2H, H-6), 3.65(dd, 1H, J_2′,3′= 9.6 Hz, J_3′,4′= 9.1 Hz, H-

3′), 3.61(ddd, 1H, J_1,2= 9.1 Hz, J_1,5aeq= 4.3 Hz, J_1,5aax= 11.9 Hz, H-

1), 3.52(dd, 1H, H-2′), 3.39(dd, 1H, J_3,4= 8.7 Hz, J_4,5= 8.8 Hz, H-4),

3.33(dd, 1H, J_4′,5′= 11.2 Hz, H-4′), 3.33(dd, 1H, J_2,3= 8.9 Hz, H-3),

3.28(dd, 1H, H-2), 2,18(ddd, 1H, J_5′,5a′eq= 3.6 Hz, J_gem= 14.6 Hz, H-

Date for oleﬁn 49: R_f= 0.23 (Toluene/EtOAc, 20:1); [α] = +13.9°

(c 0.38, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.23(m, 10H),

5.61(m, 2H, H-1, H-5a), 5.00(d, 1H, J = 11.0 Hz), 4.50(d, 1H,

J = 12.2 Hz), 4.46(d, 1H, J = 11.0 Hz), 4.39(d, 1H, J = 12.2 Hz),

4.39(m, 1H, H-2), 3.93(dd, 1H, J_2,3= 9.1 Hz, J_3,4= 10.4 Hz, H-3),

3.78(dd, 1H, J_4,5= 8.6 Hz, H-4), 3.53–3.48(m, 2H, H-6), 3.30(s, 3H),

3.29(s. 3H), 2.52(m, 1H, H-5), 1.37(s, 3H, 1.34(s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 138.97, 138.30, 128.88(C-5a), 128.34, 128.27,

128.10, 127.76, 127.61, 127.52, 126.52(C-1), 99.93, 99.67, 75.61(C-4),

74.98, 74.37(C-3), 73.04, 69.39(C-6), 68.27(C-2), 47.91, 47.76,

45.60(C-5), 17.99, 17.82; HRMS(ESI) m/z: [M+Na]⁺calcd for

5a′eq), 2.11(ddd, 1H,

J_5,5aeq= 4.2 Hz, J_gem= 13.0 Hz, H-5aeq),

1.91–1.79(m, 2H, H-5, H-5′), 1.35(ddd, 1H,

J_5,5aax= 12.0 Hz,

J

_gem= 13.0 Hz, H-5aax), 1.30(ddd, 1H, H-5a′ax); ¹³C NMR (100 MHz,

D₂O) δ 76.91(C-2), 76.80(C-1′), 76.76(C-3), 75.05(C-3′), 73.78(C-2′),

73.37(C-4), 73.10(C-4′), 71.05(C-1), 69.59(C-6′), 62.32(C-6), 38.39(C-

5), 38.17(C-5′), 32.08(C-5a), 26.29(C-5a′); HRMS(ESI) m/z: [M+Na]⁺

calcd for C₁₄H₂₆O₉Na 361.1469, found 361.1471.

4.1.43. 1,2,3-Tri-O-benzyl-4,6-O-benzylidene-5a-carba-β-^D-glucopyranose

(51)

C

₂₇H₃₄O₆Na 477.2248, found 477.2245.

To a solution of 4,6-O-benzylidene-5a-carba-β-^D-glucopyranose 10

18

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

(520 mg, 1.95 mmol) in DMF (10 mL) and NaH (585 mg, 14.6 mmol),

and the mixture was stirred for 30 min under Ar. After being cooled to

0 °C, to the solution was added BnBr (1.7 mL, 14.6 mmol). After being

stirred for overnight, MeOH was added, and the solution was con-

centrated in vacuo. The residue was diluted with Et₂O, and washed

brine. The organic layer was dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (hexane/EtOAc,

7:1) to give compound 51 (977 mg, 94%) as a white amorphous solid.

R_f= 0.48 (hexane/EtOAc, 4:1); [α] = −29.3° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.51–7.24(m, 20H), 5.58(s, 1H, PhCH), 4.95(d, 1H,

J = 11.0 Hz), 4.90(s, 2H), 4.79(d, 1H, J = 11.0 Hz), 4.70(d, 1H,

J = 11.5 Hz), 4.67(d, 1H, J = 11.5 Hz), 4.18(dd, 1H, J_5,6a= 4.5 Hz,

[α] = +34.1° (c 0.27, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ

7.36–7.13(m, 40H), 5.00(d, 1H, J = 11.9 Hz), 4.91(d, 1H, J = 10.6 Hz),

4.87(d, 1H, J = 11.0 Hz), 4.84(d, 1H, J = 10.8 Hz), 4.75(d, 1H,

J = 11.9 Hz), 4.70(d, 1H, J = 11.6 Hz), 4.69(d, 1H, J = 10.6 Hz),

4.65(d, 1H, J = 10.8 Hz), 4.64(d, 1H, J = 12.4 Hz), 4.64(d, 1H,

J = 11.6 Hz), 4.61(m, 1H, H-1′), 4.57(d, 1H, J = 12.4 Hz), 4.48(d, 1H,

J = 12.1 Hz), 4.47(d, 1H, J = 11.0 Hz), 4.38(d, 1H, J = 12.1 Hz),

4.30(d, 1H, J = 12.1 Hz), 4.25(d, 1H, J = 12.1 Hz), 3.94(dd, 1H,

J

_2′,3′= 9.5 Hz, J_3′,4′= 9.1 Hz, H-3′), 3.74(dd, 1H, J_5,6a= 4.6 Hz,

_gem= 8.6 Hz, H-6a), 3.73(dd, 1H, J_3,4= 8.1 Hz, J_4,5= 10.0 Hz, H-4),

3.61–3.51(m, 2H, H-2, H-3), 3.53(m, 1H, H-1), 3.51(dd, 1H,

J_5′,6′a= 3.7 Hz, J_gem= 9.0 Hz, H-6′a), 3.45(dd, 1H, J_3′,4′= 9.1 Hz,

J

_gem= 11.0 Hz, H-6a), 3.67(dd, 1H, J_2,3= 8.9 Hz, J_3,4= 9.1 Hz, H-3),

J

_4′,5′= 10.7 Hz, H-4′), 3.42(dd, 1H, J_5,6b= 2.7 Hz, H-6b), 3.29(dd, 1H,

_1′,2′= 2.9 Hz, J_2′,3′= 9.5 Hz, H-2′), 3.14(dd, 1H, J_5′,6′b= 3.7 Hz, H-

3.63(dd, 1H, J_5,6b= 11.1 Hz, H-6b), 3.62(dd, 1H, J_4,5= 9.2 Hz, H-4),

3.58(ddd, 1H, J_1,2= 8.9 Hz, J_1,5aeq= 4.3 Hz, J_1,5aax= 10.9 Hz, H-1),

3.56(dd, 1H, H-2), 1.89(ddd, 1H, J_5,5aeq= 3.3 Hz, J_gem= 12.8 Hz, H-

5aeq), 1.78(m, 1H, H-5), 1.10(ddd, 1H, J_5,5aax= 10.9 Hz, H-5aax); ¹³C

NMR (100 MHz, CDCl₃) δ 138.80, 138.76, 138.47, 138.17, 128.72,

128.41, 128.32, 128.29, 128.18, 128.16, 128.05, 127.69, 127.66,

127.55, 125.93, 101.04(PhCH), 85.53(C-2), 83.51(C-4), 83.20(C-3),

80.04(C-1), 76.09, 75.62, 72.71, 71.01(C-6), 33.82(C-5), 28.55(C-5a);

HRMS(ESI): [M+Na]⁺calcd for C₃₅H₃₆O₅Na 559.2455, found

559.2458.

6′b), 2.15(ddd, 1H, J_1′,5a′eq= 3.5 Hz, J_5′,5a′eq= 3.5 Hz, J_gem= 14.8 Hz,

H-5a′eq),

2.08(ddd,

1H,

J

_1,5aeq= 3.2 Hz,

J_5,5aeq= 3.2 Hz,

J

_gem= 13.0 Hz, H-5aeq), 1.95(m, 1H, H-5′), 1.76(m, 1H, H-5),

1.58(ddd, 1H, J_1,5aax= 11.3 Hz, J_5,5aax= 11.3 Hz, H-5aax), 1.31(ddd,

1H, J_1′,5a′ax= 1.7 Hz, J_5′,5a′ax= 13.2 Hz, H-5a′ax); ¹³C NMR (100 MHz,

CDCl₃) δ 139.28, 139.23, 139.08, 138.74, 138.67, 138.60, 138.58,

138.54, 128.35, 128.27, 128.20, 128.18, 128.09, 127.82, 127.78,

128.66, 127.63, 127.56, 127.51, 127.48, 127.43, 127.31, 127.26,

127.24, 127.14, 126.98, 126.49, 86.70(C-3), 86.61(C-2), 83.84(C-3′),

82.79(C-2′), 80.98(C-4′), 80.25(C-1), 75.71, 75.28, 75.09, 74.00,

73.27(C-4), 72.96, 72.78(C-1′), 72.66, 72.60, 72.21, 70.35(C-6),

69.77(C-6′), 38.79(C-5), 36.73(C-5′), 30.50(C-5a), 27.13(C-5a′); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₇₀H₇₄O₉Na 1081.5225, found

1081.5225.

4.1.44. 1,2,3,6-Tetra-O-benzyl-5a-carba-β-^D-glucopyranose (52)

To a solution of 1,2,3-tri-O-benzyl-4,6-O-benzylidene-5a-carba-β-^D-

glucopyranose 51 (1.127 g, 2.10 mmol) and trimethylamine borane

(1.0 g, 14.7 mmol) in THF (42 mL) was added powdered MS4A (5.0 g),

and the mixture was stirred for 1 h under Ar. To the solution was added

AlCl₃(1.9 g, 14.7 mmol), and the solution was stirred overnight. The

solution was ﬁltered through of Celite, and the solvent was evaporated.

The residue was diluted with EtOAc, and washed saturated NaHCO₃

and brine. The organic layer was dried (MgSO₄) and concentrated in

vacuo. The residue was puriﬁed by column chromatography (hexane/

EtOAc, 4:1) to give compound 52 (953 mg, 84%) as a colorless syrup.

R_f= 0.38 (hexane/EtOAc, 4:1); [α] = −14.6° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.36–7.24(m, 20H), 4.97(d, 1H, J = 11.4 Hz),

4.96(d, 1H, J = 10.5 Hz), 4.82(d, 1H, J = 10.5 Hz), 4.74(d, 1H,

J = 11.4 Hz), 4.69(d, 1H, J = 11.6 Hz), 4.64(d, 1H, J = 11.6 Hz),

4.51(s, 2H), 3.62(dd, 1H, J_5,6a= 5.1 Hz, J_gem= 9.1 Hz, H-6a), 3.54(m,

1H, H-1), 3.53(dd, 1H, J_5,6b= 5.7 Hz, H-6b), 3.50(dd, 1H,

4.1.46. 2,3-Di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-glucopyranosyl-

(1 → 4)-1,2,3,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (54)

To a solution of 1,2,3,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

52 (85 mg, 0.158 mmol) in THF (47 μL) was added 15-crown-5

ether (46 μL, 0.233 mmol) and NaH (6 mg, 0.158 mmol), and the

mixture was stirred for 30 min under Ar. After being cooled to 0 °C, to

the solution was added 2,3-di-O-benzyl-4,6-O-benzylidene-1-O-tri-

ﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

27

(36 mg,

0.063 mmol). After being stirred for 15 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by preparative thin-

layer chromatography (Toluene/EtOAc, 10:1) to give compound 54

(12 mg, 20%) as a colorless syrup and oleﬁn 44 (9 mg, 36%) as a col-

orless syrup and recovered 52 (68 mg, 80%). R_f= 0.13 (Toluene/

EtOAc, 20:1); [α] = −11.4° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ 7.52–7.13(m, 35H), 5.45(s, 1H, PhCH), 4.99(d, 1H, J = 11.7 Hz),

4.92(d, 1H, J = 10.6 Hz), 4.81(d, 1H, J = 11.0 Hz), 4.78(d, 1H,

J = 11.7 Hz), 4.73(d, 1H, J = 12.1 Hz), 4.70(d, 1H, J = 11.7 Hz),

4.68(d, 1H, J = 10.6 Hz), 4.68(d, 1H, J = 11.0 Hz), 4.68(m, 1H, H-1′),

4.65(d, 1H, J = 11.7 Hz), 4.65(d, 1H, J = 12.1 Hz), 4.59(d, 1H,

J = 11.0 Hz), 4.42(d, 1H, J = 12.1 Hz), 4.01(dd, 1H, J_2′,3′= 9.3 Hz,

J

_1,2= 9.0 Hz, J_2,3= 9.0 Hz, H-2), 3.36(dd, 1H, J_3,4= 9.0 Hz,

_4,5= 9.8 Hz, H-4), 3.34(dd, 1H, H-3), 2.14(ddd, 1H, J_1,5aeq= 3.8 Hz,

_5,5aeq= 3.8 Hz, J_gem= 13.1 Hz, H-5aeq), 1.71(m, 1H, H-5), 1.28(ddd,

1H, J_1,5aax= 11.2 Hz, J_5,5aax= 11.2 Hz, H-5aax); ¹³C NMR (100 MHz,

CDCl₃) δ 138.74, 138.57, 138.08, 128.53, 128.39, 128.36, 128.34,

128.02, 127.90, 127.75, 127.66, 127.65, 127.56, 85.78(C-3), 85.38(C-

2), 80.28(C-1), 75.61, 75.57, 74.05(C-4), 73.38, 72.32, 72.06(C-6),

38.38(C-5), 30.14(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for

C

₃₅H₃₈O₅Na 561.2611, found 561.2611.

4.1.45. 2,3,4,6-Tetra-O-benzyl-5a-carba-α-^D-glucopyranosyl-(1 → 4)-

1,2,3,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (53)

J

_3′,4′= 9.6 Hz, H-3′), 3.99(dd, 1H, J_5′,6′a= 4.4 Hz, J_gem= 11.0 Hz, H-

6′a), 3.81(dd, 1H, J_5,6a= 4.4 Hz, J_gem= 11.0 Hz, H-6a), 3.75(dd, 1H,

J_3,4= 8.9 Hz, J_4,5= 9.1 Hz, H-4), 3.60(dd, 1H, J_2,3= 8.7 Hz, H-3),

To a solution of 1,2,3,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

52 (80 mg, 0.149 mmol) in THF (44 μL) was added NaH (6 mg,

0.149 mmol) and 15-crown-5 ether (44 μL, 0.222 mmol), and the mix-

ture was stirred for 30 min under Ar. After being cooled to 0 °C to the

3.58–3.50(m, 2H, H-1, H-2), 3.50(dd, 1H,

J

= 10.1 Hz, H-4′),

4′,5′

3.48(dd, 1H, J_5′,6′b= 11.0 Hz, H-6′b), 3.41(dd, 1H, J_5,6b= 2.3 Hz, H-

6b), 3.31(dd, 1H, J_1′,2′= 2.9 Hz, H-2′), 2.19(m, 1H, H-5′), 2.06(ddd,

solution

was

added

2,3,4,6-tetra-O-benzyl-1-O-tri-

14 (40 mg,

1H,

J_1,5aeq= 3.2 Hz, J_5,5aeq= 3.2 Hz, J_gem= 13.0 Hz, H-5aeq),

ﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

1.98(ddd, 1H, J_1′,5a′eq= 3.3 Hz, J_5′,5a′eq= 3.3 Hz, J_gem= 14.4 Hz, H-

5a′eq), 1.76(m, 1H, H-5), 1.64(ddd, 1H, _1,5aax= 11.3 Hz,

J_1′,5a′ax= 1.5 Hz,

0.060 mmol). After being stirred for overnight, MeOH was added and

the solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (hexane/EtOAc, 6:1) to give compound 53 (3 mg, 5%) as a

colorless syrup and oleﬁn 21 (24 mg, 80%) as a colorless syrup and

recovered 52 (71 mg, 89%). R_f= 0.16 (Toluene/EtOAc, 20:1);

J

_5,5aax= 11.3 Hz,

H-5aax),

0.79(ddd,

1H,

J_5′,5a′ax= 12.9 Hz, H-5a′ax); ¹³C NMR (100 MHz, CDCl₃) δ 139.11,

138.67, 138.61, 138.58, 138.53, 128.57, 128.36, 128.27, 128.20,

128.17, 128.16, 128.09, 127.68, 127.64, 127.54, 127.49, 127.39,

127.36, 127.00, 126.47, 126.04, 101.12(PhCH), 86.61(C-2, C-3),

84.55(C-4′), 81.83(C-2′), 80.58(C-3′), 80.17(C-1), 75.72, 75.36, 73.90,

19

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

73.47(C-4), 73.25, 73.23(C-1′), 72.88, 72.24, 71.26(C-6′), 70.18(C-6),

38.72(C-5), 32.29(C-5′), 30.56(C-5a), 25.27(C-5a′); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₆₃H₆₆O₉Na 989.4599, found 989.4599.

127.39, 127.27, 127.18, 126.96, 86.29(C-3), 85.79(C-2), 84.00(C-3′),

83.76(C-2′), 81.06(C-4′), 80.73(C-4), 79.38(C-1), 75.82, 75.40, 75.26,

75.17, 73.10, 72.99, 72.74, 72.62(C-1′), 70.23(C-6), 70.16(C-6′),

38.86(C-5), 37.48(C-5′), 30.98(C-5a), 30.86(C-5a′); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₇₀H₇₄O₉Na 1081.5225, found 1081.5225.

4.1.47. 5a,5a′-Dicarba-β-^D-maltose (2)

To a solution of 2,3-di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-

glucopyranosyl-(1 → 4)-1,2,3,6-tetra-O-benzyl-5a-carba-β-^D-glucopyr-

anoside 54 (18 mg, 0.018 mmol) in MeOH (1.5 mL), THF (0.5 mL) and

AcOH (0.3 mL) was added Pd Black (2 mg, 0.019 mmol). The resulting

suspension was hydrogenated at 1 atm for overnight. The solution was

ﬁltered through of Celite, and the solvent was evaporated. The residue

was chromatographed on a column of Amberlite 200CT ion-exchange

resin (H⁺form) and IRA 96SB ion-exchange resin (OH^–form) to give

compound 2 (4.8 mg, 80%) as a colorless syrup. R_f= 0.16 (CHCl₃/

MeOH/H₂O, 10:5:1); [α] = +70.0° (c 0.15, H₂O); ¹H NMR (400 MHz,

D₂O) δ 4.17(ddd, 1H, J_1′,2′= 3.3 Hz, J_1′,5a′eq= 3.7 Hz, J_1′,5a′ax= 2.2 Hz,

H-1′), 3.80(dd, 1H, J_5,6a= 3.3 Hz, J_gem= 11.0 Hz, H-6a), 3.80(dd, 1H,

J_5′,6′a= 3.3 Hz, J_gem= 11.1 Hz, H-6′a), 3.73(dd, 1H, J_5′,6′b= 2.8 Hz, H-

6′b), 3.71(dd, 1H, J_5,6b= 2.8 Hz, H-6b), 3.66(dd, 1H, J_2′,3′= 10.0 Hz,

J_3′,4′= 9.2 Hz, H-3′), 3.61(ddd, 1H, J_1,2= 9.1 Hz, J_1,5aeq= 4.8 Hz,

4.1.49. 2,3-Di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-glucopyranosyl-

(1 → 1)-2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (56)

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (90 mg, 0.168 mmol) in THF (50 μL) was added 15-crown-5

ether (49 μL, 0.248 mmol) and NaH (7 mg, 0.168 mmol), and the

mixture was stirred for 30 min under Ar. After being cooled to 0 °C, to

the solution was added 2,3-di-O-benzyl-4,6-O-benzylidene-1-O-tri-

ﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

27

(39 mg,

0.067 mmol). After being stirred for 20 h, MeOH was added, and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by preparative thin-

layer chromatography (Toluene/EtOAc, 20:1) to give compound 56

(42 mg, 64%) as a white amorphous solid and oleﬁn 44 (3 mg, 1%) as a

colorless syrup and recovered 13 (57 mg, 64%). R_f= 0.35 (Toluene/

EtOAc, 20:1); [α] = +11.1° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ 7.53–7.13(m, 35H), 5.57(s, 1H, PhCH), 5.16(d, 1H, J = 10.8 Hz),

4.91(d, 1H, J = 10.7 Hz), 4.87(d, 1H, J = 11.0 Hz), 4.81(d, 1H,

J = 10.8 Hz), 4.79(d, 1H, J = 10.7 Hz), 4.76(d, 1H, J = 12.1 Hz),

4.69(d, 1H, J = 11.0 Hz), 4.64(d, 1H, J = 12.1 Hz), 4.54(d, 1H,

J = 11.0 Hz), 4.50(d, 1H, J = 11.0 Hz), 4.45(s, 2H), 4.18(dd, 1H,

J

_1,5aax= 11.7 Hz, H-1), 3.56(dd, 1H, H-2′), 3.55(dd, 1H, J_2,3= 9.3 Hz,

_3,4= 9.2 Hz, H-3), 3.41(dd, 1H, J_4,5= 10.6 Hz, H-4), 3.34(dd, 1H, H-

2), 3.32(dd, 1H, J_4′,5′= 9.3 Hz, H-4′), 2.08(ddd, 1H, J_5′,5a′eq= 3.7 Hz,

J

_gem= 14.2 Hz, H-5a′eq), 2.06(ddd, 1H, J_5,5aeq= 3.7 Hz, H-5aeq),

1.91(m, 1H, H-5′), 1.72(m, 1H, H-5), 1.41(ddd, 1H, J_5′,5a′ax= 12.7 Hz,

H-5a′ax), 1.37(ddd, 1H, J_5,5aax= 11.9 Hz, H-5aax); ¹³C NMR (100 MHz,

D₂O) δ 82.03(C-4), 79.77(C-1′), 77.48(C-3), 76.76(C-2), 75.07(C-3′),

74.22(C-2′), 72.83(C-4′), 70.95(C-1), 62.19(C-6′), 61.72(C-6), 39.58(C-

5), 38.66(C-5′), 31.63(C-5a), 28.70(C-5a′); HRMS(ESI) m/z: [M+Na]⁺

calcd for C₁₄H₂₆O₉Na 361.1469, found 361.1470.

J

_5′,6′a= 4.3 Hz, J_gem= 11.9 Hz, H-6′a), 4.08(m, 1H, H-1′), 4.04(dd, 1H,

_2′,3′= 9.4 Hz, J_3′,4′= 9.3 Hz, H-3′) 3.88(ddd, 1H, J_1,2= 8.4 Hz,

_1,5aeq= 4.2 Hz, J_1,5aax= 11.8 Hz, H-1), 3.58(dd, 1H, J_5,6b= 11.0 Hz,

_2,3= 8.6 Hz,

,

H-6′b), 3.57–3.48(m, 2H, H-6), 3.52(dd, 1H,

J

4.1.48. 2,3,4,6-Tetra-O-benzyl-5a-carba-α-^D-glucopyranosyl-(1 → 1)-

2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside (55)

J_3,4= 9.0 Hz, H-3), 3.52(dd, 1H, H-4′), 3.48(dd, 1H, H-2), 3.44(dd, 1H,

J_4,5= 9.1 Hz, H-4′), 3.36(dd, 1H, J_1′,2′= 2.8 Hz, H-2′), 2.38(m, 1H, H-

5′), 2.08(ddd, 1H, J_5,5aeq= 4.0 Hz, J_gem= 13.0 Hz, H-5aeq), 1.66(m,

1H, H-5), 1.65(ddd, 1H, J_1′,5a′eq= 3.4 Hz, J_5′,5a′eq= 3.4 Hz,

To a solution of 2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranose

13 (80 mg, 0.149 mmol) in THF (44 μL) was added 15-crown-5 ether

(44 μL, 0.222 mmol) and NaH (6 mg, 0.149 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-5a-

carba-β-^D-glucopyranose 14 (40 mg, 0.060 mmol). After being stirred

for 7.5 h, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic

layer was dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane/EtOAc, 6:1) to give

compound 55 (23 mg, 37%) as a colorless syrup and oleﬁn 21 (10 mg,

34%) as a colorless syrup and recovered 13 (62 mg, 77%). R_f= 0.28

(hexane/EtOAc, 6:1); [α] = +33.1° (c 1.00, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.37–7.12(m, 40H), 5.18(d, 1H, J = 11.1 Hz),

4.90(d, 1H, J = 10.6 Hz), 4.87(d, 1H, J = 10.7 Hz), 4.86(d, 1H,

J = 10.8 Hz), 4.79(d, 1H, J = 11.1 Hz), 4.78(d, 1H, J = 10.6 Hz),

4.73(d, 1H, J = 10.8 Hz), 4.66(d, 1H, J = 12.1 Hz), 4.62(d, 1H,

J = 12.1 Hz), 4.54(d, 1H, J = 10.8 Hz), 4.50(d, 1H, J = 10.7 Hz),

4.49(d, 1H, J = 10.8 Hz), 4.44(s, 2H), 4.43(s, 2H), 4.06(m, 1H,

J

_gem= 13.6 Hz, H-5a′eq), 1.52(ddd, 1H, J_5,5aax= 12.0 Hz, H-5aax),

1.01(ddd, 1H, J_1′,5a′ax= 1.6 Hz, J_5′,5a′ax= 13.1 Hz, H-5a′ax); ¹³C NMR

(100 MHz, CDCl₃) δ 139.24, 139.11, 138.78, 138.57, 138.41, 138.35,

128.60, 128.34, 128.27, 128.17, 128.10, 128.08, 128.03, 127.96,

127.89, 127.58, 127.52, 127.41, 127.30, 127.27, 127.03, 125.99,

101.13(PhCH), 86.26(C-3), 85.65(C-2), 84.40(C-4′), 82.76(C-2′),

80.87(C-3), 80.67(C-4), 79.44(C-1), 75.83, 75.49, 75.30, 75.17, 73.20,

73.12, 72.86(C-1′), 71.36(C-6′), 70.21(C-6), 38.85(C-5), 32.74(C-5′),

30.90(C-5a), 28.98(C-5a′); HRMS(ESI) m/z: [M+Na]⁺calcd for

C

₆₃H₆₆O₉Na 989.4599, found 989.4597.

4.1.50. 5a,5a′-Dicarba-α,β-^D-trehalose (3)

To solution of 2,3,4,6-tetra-O-benzyl-5a-carba-α-^D-glucopyr-

a

anosyl-(1 → 1)-2,3,4,6-tetra-O-benzyl-5a-carba-β-^D-glucopyranoside 55

(19 mg, 0.018 mmol) in MeOH (1 mL), THF (100 μL) and AcOH

(200 μL) was added Pd Black (2 mg, 0.020 mmol). The resulting sus-

pension was hydrogenated at 1 atm for 5 h. The solution was ﬁltered

through of Celite, and the solvent was evaporated. The residue was

chromatographed on a column of Amberlite 200CT ion-exchange resin

(H⁺form) and IRA 96SB ion-exchange resin (OH^–form) to give com-

pound 3 (6.1 mg, 100%) as a colorless syrup. R_f= 0.17 (CHCl₃/MeOH/

H₂O, 10:5:1); [α] = +41.3° (c 0.30, H₂O); ¹H NMR (400 MHz, D₂O) δ

4.10(ddd, 1H, J_1′,2′= 3.2 Hz, J_1′,5a′eq= 3.7 Hz, J_1′,5a′ax= 2.0 Hz, H-1′),

J

_1′,5a′eq= 3.6 Hz, J_1′,5a′ax= 1.3 Hz, H-1′), 3.98(dd, 1H, J_2′,3′= 9.6 Hz,

_3′,4′= 9.4 Hz, H-3′), 3.84(ddd, 1H, J_1′,2′= 8.7 Hz, J_1′,5a′eq= 4.2 Hz,

_gem= 11.6 Hz, H-1), 3.69(dd, 1H, J_5′,6′a= 4.4 Hz, J_gem= 8.8 Hz, H-

6′a), 3.54(dd, 1H, J_5,6a= 5.4 Hz, J_gem= 8.6 Hz, H-6a), 3.52(dd, 1H,

J

_2,3= 8.5 Hz, H-3), 3.49(dd, 1H, J_5,6b= 8.6 Hz, H-6b), 3.46(m, 1H, H-

4′), 3.46(dd, 1H, J_5′,6′b= 5.5 Hz, H-6′b), 3.45(dd, 1H, H-2), 3.43(m, 1H,

H-4), 3.34(dd, 1H, J_1′,2′= 2.6 Hz, H-2′), 2.18(m, 1H, H-5′), 2.08(ddd,

3.80(dd, 1H, J_5,6a= 4.9 Hz,

J

= 11.0 Hz, H-6a), 3.79(dd, 1H,

gem

1H,

J

_5,5aeq= 3.9 Hz, J_gem= 13.1 Hz, H-5aeq), 1.87(ddd, 1H,

J

_5′,6′a= 4.9 Hz, J_gem= 11.0 Hz, H-6′a), 3.70(dd, 1H, J_5′,6′b= 10.8 Hz,

J

_1′,5a′eq= 3.6 Hz, J_5′,5a′eq= 3.6 Hz, J_gem= 14.3 Hz, H-5a′eq), 1.64(m,

H-6′b), 3.69 (dd, 1H,

J_5,6b= 10.9 Hz, H-6b), 3.65(dd, 1H,

1H, H-5), 1.47(ddd, 1H, J_1′,5a′eq= 1.3 Hz, J_5′,5a′eq= 13.1 Hz, H-5a′ax),

1.36(ddd, 1H, J_1,5aax= 11.6 Hz, J_5,5aax= 11.9 Hz, H-5aax); ¹³C NMR

(100 MHz, CDCl₃) δ 139.37, 139.24, 139.01, 138.85, 138.80, 138.64,

138.62, 138.43, 128.34, 128.30, 128.26, 128.18, 128.16, 128.04,

127.96, 127.90, 127.89, 127.79, 127.56, 127.52, 127.48, 127.46,

J_2′,3′= 9.7 Hz, J_3′,4′= 9.2 Hz, H-3′), 3.55 (ddd, 1H, J_1,2= 9.2 Hz,

J

_1,5aeq= 4.4 Hz, J_1,5aax= 11.4 Hz, H-1), 3.51(dd, 1H, H-2′), 3.45(dd,

1H, J_2,3= 9.1 Hz, H-2), 3.37(dd, 1H, J_3,4= 9.2 Hz, H-3), 3.33(dd, 1H,

J

_4.5= 9.5 Hz, H-4), 3.32(dd, 1H, J_4′,5′= 10.7 Hz, H-4′), 2.12(ddd, 1H,

_5,5aeq= 4.1 Hz, J_gem= 13.0 Hz, H-5aeq), 2,08(ddd, 1H,

20

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

J_5′,5a′eq= 3.7 Hz, J_gem= 14.8 Hz, H-5a′eq), 1.91(m, 1H, H-5′), 1.67(m,

1H, H-5), 1.44(ddd, 1H, J_5′,5a′ax= 12.9 Hz, H-5a′ax), 1.34(ddd, 1H,

72.94, 71.76, 71.34(C-6), 32.37(C-5), 26.92(C-5a); HRMS(ESI) m/z: [M

+Na]⁺calcd for C₃₅H₃₆O₅Na 559.2455 found 559.2452.

J

_5,5aax= 11.6 Hz, H-5aax); ¹³C NMR (100 MHz, D₂O) δ 80.82(C-1),

78.98(C-1′), 76.73(C-3), 76.67(C-2), 75.15(C-3′), 74.32(C-2′), 72.90(C-

4′), 72.41(C-4), 62.26(C-6′), 62.14(C-6), 40.01(C-5), 38.43(C-5′),

30.95(C-5a), 29.30(C-5a′); HRMS(ESI) m/z: [M+Na]⁺calcd for

4.1.53. 1,2,3,4-Tetra-O-benzyl-5a-carba-α-^D-glucopyranose (59)

To a solution of 1,2,3-tri-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-

glucopyranose 58 (176 mg, 0.328 mmol) in THF (0.9 mL) was added

THF·BH₃(1.3 mL, 1.0 M in THF, 1.31 mmol) and CoCl₂(170 mg,

1.31 mmol). After being stirred for 2 h, the solution was diluted with

EtOAc, and was ﬁltered through Celite. The ﬁltrate was added aq

NaBH₄(9.9 mg, 0.262 mmol), and was ﬁltered through Celite. The ﬁl-

trate was washed saturated NaHCO₃and brine. The organic layer was

dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (hexane/EtOAc, 3:1) to give compound

59 (163 mg, 93%) as a white amorphous solid. R_f= 0.11 (hexane/

EtOAc, 4:1); [α] = +52.6° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

C

₁₄H₂₆O₉Na 361.1469, found 361.1469.

4.1.51. 1-O-Acetyl-2,3-di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-

glucopyranose (57)

To a solution of 2,3-di-O-benzyl-4,6-O-benzylidene-5a-carba-β-^D-

glucopyranose 26 (230 mg, 0.515 mmol) in CH₂Cl₂(7 mL) at −10 °C

was added 2,6-di-t-butyl-4-methylpyridine (106 mg, 0.515 mmol) and

Tf₂O (173 μL, 1.03 mmol). After being stirred for 10 min, the solution

was diluted with CH₂Cl₂and washed saturated NaHCO₃and brine. The

organic layer was dried (MgSO₄), and concentrated in vacuo. To a so-

lution of the residue in Toluene (7 mL) was added CsOAc (642 mg,

3.34 mmol) and 18-Crown-6 ether (272 mg, 1.03 mmol). After being

stirred for 1 h, the solution was diluted with EtOAc_.The solution wa-

shed with brine, and the organic layer was dried (MgSO₄) and con-

centrated in vacuo. The residue was puriﬁed by ﬂash column chroma-

tography (hexane/EtOAc, 4:1) to give compound 57 (241 mg, 96%) as a

white amorphous solid. R_f= 0.22 (hexane/EtOAc, 4:1); [α] = −5.3° (c

1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.24(m, 15H), 5.60(s,

1H), 5.49(ddd, 1H, J_1,2= 3.2 Hz, J_1,5aeq= 3.6 Hz, J_1,5aax= 2.2 Hz, H-

1), 4.92(d, 1H, J = 11.0 Hz), 4.82(d, 1H, J = 11.0 Hz), 4.74(d, 1H,

J = 11.7 Hz), 4.62(d, 1H, J = 11.7 Hz), 4.17(dd, 1H, J_5,6a= 4.3 Hz,

δ

7.39–7.26(m, 20H), 5.03(d, 1H, J = 10.8 Hz), 4.98(d, 1H,

J = 11.1 Hz), 4.83(d, 1H, J = 10.8 Hz), 4.70(d, 1H, J = 12.1 Hz),

4.67(d, 1H, J = 11.1 Hz), 4.65(s, 2H), 4.64(d, 1H, J = 12.1 Hz),

4.08(dd, 1H, J_2,3= 9.5 Hz, J_3,4= 9.1 Hz, H-3), 3.88(ddd, m, 1H, H-1),

2

3.62(ddd, 1H, J_5,6a= 3.6 Hz, J_6a,OH= 7.4 Hz, J_gem= 10.8 Hz, H-6a),

2

3.53(ddd, 1H, J_5,6b= 5.1 Hz, J_6b,OH= 3.8 Hz, H-6b), 3.38(dd, 1H,

J

_1,2= 2.9 Hz, H-2), 3.38(dd, 1H, J_4,5= 10.8 Hz, H-4), 2.11(m, 1H, H-

5), 1.85(ddd. 1H, J_1,5aeq= 3.7 Hz, J_5,5aeq= 3.7 Hz, J_gem= 14.5 Hz, H-

5aeq), 1.66(dd, 1H, OH), 1.11(ddd, 1H,

J_1,5aax= 1.9 Hz,

J

_5,5aax= 12.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 139.01, 138.74,

138.58, 138.41, 128.55, 128.33, 128.27, 127.98, 127.88, 127.70,

127.64, 127.53, 127.47, 127.45, 83.87(C-3), 83.60(C-2), 82.32(C-4),

75.64, 74.93, 72.86(C-1), 72.43, 71.30, 64.74(C-6), 38.23(C-5),

28.01(C-5a); HRMS(ESI) m/z: [M+Na]⁺calcd for C₃₅H₃₈O₅Na

561.2611, found 561.2613.

J

_gem= 10.9 Hz, H-6a), 3.94(dd, 1H, J_2,3= 9.3 Hz, J_3,4= 9.3 Hz, H-3),

3.59(dd, 1H, J_4,5= 9.3 Hz, H-4), 3.59(dd, 1H, J_5,6b= 10.9 Hz, H-6b),

3.48(dd, 1H, H-2), 2.26(m, 1H, H-5), 2.13(s, 3H), 1.73(ddd, 1H,

J

_5,5aeq= 3.6 Hz,

J_gem= 14.5 Hz,

H-5aeq),

1.15(ddd,

1H,

_5,5aax= 13.1 Hz, H-5aax); ¹³C NMR (100 MHz, CDCl₃) δ 170.36,

4.1.54. 2,3,4,6-Tetra-O-benzyl-5a-carba-α-^D-glucopyranosyl-(1 → 6)-

1,2,3,4-tetra-O-benzyl-5a-carba-α-^D-glucopyranoside (60)

138.91, 138.15, 138.01, 128.73, 128.35, 128.24, 128.18, 128.11,

127.98, 127.71, 127.52, 125.93, 101.18(PhCH), 83.73(C-4), 80.40(C-

2), 80.37(C-3), 75.71, 72.51, 71.02(C-6), 68.08(C-1), 32.83(C-5),

27.20(C-5a), 21.24; HRMS(ESI) m/z: [M+Na]⁺calcd for C₃₀H₃₂O₆Na

511.2091, found 511.2087.

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-α-^D-glucopyranose

59 (40 mg, 0.075 mmol) in THF (22 μL) was added 15-crown-5 ether

(22 μL, 0.111 mmol) and NaH (3 mg, 0.075 mmol), and the mixture was

stirred for 30 min under Ar. After being cooled to 0 °C, to the solution

was added 2,3,4,6-tetra-O-benzyl-1-O-triﬂuoromethanesulfonyl-5a-

carba-β-^D-glucopyranose 14 (20 mg, 0.030 mmol). After being stirred

for 19 h, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic

layer was dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by preparative thin-layer chromatography (hexane/EtOAc,

6:1) to give compound 60 (3.8 mg, 12%) as a colorless syrup and oleﬁn

21 (10.2 mg, 66%) as a colorless syrup and recovered 8 (35 mg, 87%).

R_f= 0.17 (hexane/EtOAc, 6:1); [α] = +47.6° (c 0.29, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 7.37–7.21(m, 40H), 5.00(d, 1H, J = 10.7 Hz),

4.96(d, 1H, J = 11.1 Hz), 4.92(d, 1H, J = 10.8 Hz), 4.88(d, 1H,

J = 11.0 Hz), 4.81(d, 1H, J = 10.7 Hz), 4.79(d, 1H, J = 10.8 Hz),

4.64(s, 6H), 4.56(d, 1H, J = 11.1 Hz), 4.51(d, 1H, J = 11.0 Hz), 4.36(s,

2H), 4.03(dd, 1H, J_2,3= 9.3 Hz, J_3,4= 9.2 Hz, H-3), 3.86(dd, 1H,

4.1.52. 1,2,3-Tri-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-glucopyranose

(58)

To a solution of 1-O-acetyl-2,3-di-O-benzyl-4,6-O-benzylidene-5a-

carba-α-^D-glucopyranose 57 (205 mg, 0.420 mmol) in MeOH (4 mL)

was added NaOMe (45 mg, 0.839 mmol). After being stirred for 7 h, the

solution was neutralized with Amberlite 200CT (H⁺), and the resin was

ﬁltered oﬀ_.The ﬁltrate was concentrated in vacuo. To a solution of the

residue in DMF (1.5 mL) and NaH (47 mg, 1.16 mmol), and the mixture

was stirred for 30 min under Ar. After being cooled to 0 °C, to the so-

lution was added BnBr (138 μL, 0.256 mmol). After being stirred for

30 min, MeOH was added and the solution was concentrated in vacuo.

The residue was diluted with EtOAc, and washed brine. The organic

layer was dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane/EtOAc, 4:1) to give

compound 58 (224 mg, 90%) as a white amorphous solid. R_f= 0.34

(hexane/EtOAc, 4:1); [α] = −8.8° (c 1.00, CHCl₃); ¹H NMR (400 MHz,

CDCl₃) δ 7.53–7.24(m, 20H), 5.57(s, 1H), 4.94(d, 1H, J = 10.9 Hz),

4.84(d, 1H, J = 10.9 Hz), 4.75(d, 1H, J = 12.0 Hz), 4.74(d, 1H,

J = 12.2 Hz), 4.67(d, 1H, J = 12.0 Hz), 4.65(d, 1H, J = 12.2 Hz),

J

_2′,3′= 9.6 Hz, J_3′,4′= 9.3 Hz, H-3′), 3.84(dd, 1H, J_5,6a= 5.2 Hz,

J_gem= 9.0 Hz, H-6a), 3.84(m, 1H, H-1), 3.71(m, 1H, H-1′), 3.62(dd,

1H, J_5′,6′a= 4.2 Hz, J_gem= 8.9 Hz, H-6′a), 3.58(dd, 1H, J_5,6b= 2.2 Hz,

H-6b), 3.48(dd, 1H, J_4,5= 9.2 Hz, H-4), 3.46(dd, 1H, J_4′,5′= 9.2 Hz, H-

4′), 3.39(dd, 1H, J_1,2= 2.8 Hz, H-2), 3.36(dd, 1H, J_1′,2′= 2.7 Hz, H-2′),

3.30(dd, 1H, J_5′,6′b= 2.4 Hz, H-6′b), 2.14–1.98(m, 2H, H-5, H-5′),

1.89(ddd, 1H, J_1,5aeq= 3.7 Hz, J_5,5aeq= 3.7 Hz, J_gem= 14.6 Hz, H-

4.13(dd, 1H,

J_5,6a= 4.5 Hz, J_gem= 11.0 Hz, H-6a), 4.11(dd, 1H,

J_2,3= 9.4 Hz, J_3,4= 9.3 Hz, H-3), 3.90(ddd, m, 1H, H-1), 3.56(dd, 1H,

5aeq),

1.83(ddd,

1H,

J_1′,5a′eq= 3.7 Hz,

J_5′,5a′eq= 3.7 Hz,

J_1,5aax= 1.7 Hz,

J_1′,5a′ax= 1.4 Hz,

J

_5,6b= 11.0 Hz, H-6b), 3.54(dd, 1H, J_4,5= 10.2 Hz, H-4), 3.41(dd, 1H,

_1,2= 3.0 Hz, H-2), 2.38(m, 1H, H-5), 1.71(ddd, 1H, J_1,5aeq= 3.6 Hz,

J

_gem= 14.4 Hz,

H-5a′eq),

H-5aax),

1.44(ddd,

1.39(ddd,

1H,

_5,5aax= 14.6 Hz,

J_5,5aeq= 3.6 Hz,

J_gem= 14.0 Hz,

H-5aeq),

0.91(ddd,

1H,

J_5′,5a′ax= 12.8 Hz, H-5a′ax); ¹³C NMR (100 MHz, CDCl₃) δ 139.14,

139.13, 138.99, 138.84, 138.75, 138.74, 138.33, 128.62, 128.36,

128.29, 128.22, 128.19, 128.15, 128.13, 128.00, 127.69, 127.66,

127.54, 127.49, 127.45, 127.40, 127.36, 126.01, 101.16, 84.30(C-4′),

84.04(C-3), 83.69(C-2), 83.03(C-2′), 80.80(C-4), 80.22(C-3′), 75.70,

J

_1,5aax= 1.9 Hz, J_5,5aax= 13.9 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ

139.12, 138.70, 138.64, 138.39, 128.62, 128.29, 128.20, 128.17,

128.13, 127.66, 127.65, 127.51, 127.49, 127.41, 125.99,

101.16(PhCH), 84.34(C-4), 82.64(C-2), 80.73(C-3), 75.67, 73.67(C-1),

21

N. Tateda et al.

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx

75.42, 75.11, 74.85(C-1′), 73.03(C-1), 72.78, 72.44, 71.30(C-6′), 71.05,

70.41(C-6), 37.35(C-5), 32.68(C-5′), 28.30(C-5a), 27.69(C-5a′); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₇₀H₇₄O₉Na 1081.5225, found

1081.5221.

H-5aeq), 1.93–1.81(m, 1H, H-5′), 1.55(ddd, 1H, J_5,5aax= 12.7 Hz,

J

_gem= 14.6 Hz, H-5aax), 1.30(ddd, 1H, J_5′,5a′ax= 13.2 Hz, H-5a′ax);

¹³C NMR (100 MHz, D₂O) δ 76.70(C-1′), 75.06(C-3′), 74.45(C-3),

73.88(C-4), 73.85(C-2, C-2′), 73.10(C-4′), 69.67(C-6), 68.83(C-1),

62.33(C-6′), 38.15(C-5′), 36.43(C-5), 30.55(C-5a), 26.28(C-5a′); HRMS

(ESI) m/z: [M+Na]⁺calcd for C₁₄H₂₆O₉Na 361.1469, found 361.1466.

4.1.55. 2,3-Di-O-benzyl-4,6-O-benzylidene-5a-carba-α-^D-glucopyranosyl-

(1 → 6)-1,2,3,4-tetra-O-benzyl-5a-carba-α-^D-glucopyranoside (61)

To a solution of 1,2,3,4-tetra-O-benzyl-5a-carba-α-^D-glucopyranose

59 (93 mg, 0.173 mmol) in THF (52 μL) was added 15-crown-5

ether (50 μL, 0.256 mmol) and NaH (7 mg, 0.173 mmol), and the

mixture was stirred for 30 min under Ar. After being cooled to 0 °C, to

the solution was added 2,3-di-O-benzyl-4,6-O-benzylidene-1-O-tri-

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number

JP23750199, JP15K05571. The authors are grateful to Prof. Hiroaki

Takaku (Niigata Univ. of Pharmacy and Applied Life Sciences) for

generously providing the culture solution containing DeOxyInosose

(DOI).

ﬂuoromethanesulfonyl-5a-carba-β-^D-glucopyranose

27

(40 mg,

0.691 mmol). After being stirred for 14 h, MeOH was added and the

solution was concentrated in vacuo. The residue was diluted with

EtOAc, and washed brine. The organic layer was dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by preparative thin-

layer chromatography (hexane/EtOAc, 4:1) to give compound 61

(25 mg, 37%) as a colorless syrup and oleﬁn 44 (10 mg, 34%) as a

colorless syrup and recovered 59 (73 mg, 79%). R_f= 0.13 (hexane/

EtOAc, 6:1); [α] = +38.1° (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃)

δ 7.53–7.20(m, 35H), 5.55(s, 1H, PhCH), 5.01(d, 1H, J = 10.8 Hz),

5.00(d, 1H, J = 11.3 Hz), 4.90(d, 1H, J = 11.0 Hz), 4.81(d, 1H,

J = 10.8 Hz), 4.81(d, 1H, J = 11.0 Hz), 4.73(d, 1H, J = 11.8 Hz),

4.66(d, 1H, J = 11.8 Hz), 4.66(d, 1H, J = 12.2 Hz), 4.65(s, 2H), 4.62(d,

1H, J = 12.2 Hz), 4.57(d, 1H, J = 11.3 Hz), 4.04(dd, 1H,

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://

doi.org/10.1016/j.bmc.2018.12.027.

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23

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Synthesis of 5a,5a′-dicarba-D-glucobioses from conformationally restricted carbaglucosyl triflates using SN2-type inversion with carbaglucosyl nucleophiles

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