The exo-deoxoanomeric effect in the conformational preferences of C-glycosides

Tetrahedron: Asymmetry 18 (2007) 931–948

The exo-deoxoanomeric eﬀect in the conformational

preferences of C-glycosides

*

´

Carlos Mayato, Rosa L. Dorta and Jesu´s T. Vazquez

Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Departamento de Quı´mica Orga´nica,

Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain

Received 7 February 2007; accepted 12 April 2007

Abstract—Rotational studies of a series of b-D-C-glycopyranosides were carried out by CD and NMR spectroscopy. The populations

around the C-glycosidic bond were strongly dependent on the structure of the C-aglycon, the exo–syn rotamer population increasing

with the degree of substitution on the C-aglycon. The hydroxymethyl group populations also showed dependence on the aglycon,

although to a lesser degree; its gt rotamer smoothly increases with the substitution on the aglycon. These rotational preferences, together

with the experimentally observed correlations between ¹H and ¹³C NMR chemical shifts and the structural nature of the C-aglycon, point

to a stereoelectronic r_CH–r^ꢀ_COeﬀect (hyperconjugation) directly involved in the rotation around the pseudo-glycosidic bond and indi-

rectly around the C5–C6 bond (hydroxymethyl group).

1. Introduction

sides,^5a,b,eand that conformational diﬀerences between

them do exist, both in solution and in the protein-bound

state.^5b–gHowever, both research groups agree that the

predominant conformer adopts the ‘exo-anomeric’ confor-

mation around the C-glycosidic bond, the C1–C2 bond

being antiperiplanar to the C1⁰–C2⁰bond (exo–syn con-

former) (Figs. 1 and 2).

Carbohydrates play a central role in a variety of important

physiological events, including inﬂammation, metastasis,

immune response, and bacterial and viral infection.¹This

has recently stimulated the development of eﬀective thera-

peutic strategies based upon the recognition of these carbo-

hydrates. One approach lies in the replacement of the

exocyclic oxygen with a carbon to provide C-glycosidic

analogues, which have a high resistance to degradation

by glycosidases. This has led to a wealth of synthetic

approaches²and consequently biological data on C-glyco-

sides have started to emerge.³To understand these events

from a molecular point of view, not only their three-dimen-

sional structure but also their conformational preferences

in solution must be known. Numerous studies have there-

fore been performed on the conformational properties of

C-glycosides. Kishi et al.⁴concluded from their NMR data

that glycosides and their C-glycosyl analogues share the

same conformational properties in solution as in the pro-

The similar conformational properties observed by Kishi

et al.⁴between C-glycosides and the corresponding O-gly-

cosides led them to conclude that steric eﬀects determine

the preferences of these two types of compounds. In addi-

tion, after their conformational study with 2-deoxy

H

H_S

R

H

H_R

R

H

O

1'

>>

>

H_R

R

2

H_S

H_R

1

H_S

glc, gal

exo-syn

exo-anti

non-exo

tein-bound state.^4d,eUsing NMR and molecular mechanics

5

´

calculations, Jimenez-Barbero et al. demonstrated that the

glycosidic linkages of C-glycosyl analogues present a high-

er degree of ﬂexibility than those of the natural O-glyco-

H_R

1'

H_S

R

O

H

O

R

H_R

H_S

H_R

2

H¹

exo-syn

H_S

H

man

non-exo

exo-anti

*

Corresponding author. Tel.: +34 922 318581; fax: +34 922 318571;

e-mail: jtruvaz@ull.es

Figure 1. Conformational preferences around the b-C-glycosidic bond.

doi:10.1016/j.tetasy.2007.04.007

932

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

determine whether this group follows the same behavior

6

ω

H

O

1

1'

as O-glycosides. The absence of the exocyclic oxygen with

its non-bonding electron pairs in the C-glycosides suggests,

a priori, that its hydroxymethyl group would behave diﬀer-

ently than in O-glycosides, since the exo-anomeric eﬀect

cannot be involved.

5

R

Φ

H

H_6R

H_6S

O₅

OH

O₅

C₄

HO

H_6S

H_6R

OH

H_6R

H_6S

H₅

In this article, we report an experimental study of the rota-

tional dependence of the C-glycosidic bond and the

hydroxymethyl group on the structure of C-aglycon. While

non-bonded interactions can explain the former depen-

dence, these cannot account for the rotational behavior

of the hydroxymethyl group. On the basis of the experi-

mental data obtained, we propose that the exo-deoxoano-

meric eﬀect,⁶as a stereoelectronic r_CH–r_C^ꢀ_Oeﬀect, is also

involved in the rotation around the pseudo-glycosidic bond

and indirectly around the C5–C6 bond (hydroxymethyl

group).

gg

gt

tg

H_1'R

O₅

H_1'S

R

O₅

C₂

R

O₅

H_1'R

H_1'S

H_1'R

R

H_1'S

H₁

exo-syn

exo-anti

non-exo

Figure 2. Torsion angle U, around the C-glucosidic C1⁰–C1 bond, and x

around the C5–C6 bond (top). Newman projections of the idealized

staggered rotamers around the C5–C6 bond (central) and the C1⁰–C1

bond (bottom).

analogues, they exclude the 1,3-diaxial-like interaction

from being the factor controlling this behavior and attri-

bute the preference for the ‘exo-anomeric’ conformation

in C-glycosides to gauche interactions.^4aThese results even

led them to question the existence of an electronic stabiliza-

tion (the exo-anomeric eﬀect) for O-glycosides.⁴The origin

of the observation by Kishi et al. that C-glycosides have a

gauche O–C1–C1⁰–C2⁰torsional arrangement was investi-

gated by Houk et al.⁶by ab initio quantum mechanic cal-

culations with acyclic and cyclic models. This study

concluded that this preference, which they call exo-deoxo-

anomeric eﬀect, arises from static and induced electrostatic

interactions, along with steric ones. The importance of 1,3-

type interactions was shown in 2-ethyltetrahydropyran

when a hydroxyl group was located at the 3-position,

explaining the higher stability of the exo–syn versus non-

2. Results and discussion

2.1. Synthesis

Among the diﬀerent methodologies for the preparation of

C-glycosides,²the addition of carbon nucleophiles to

activated glycal epoxides has been widely used.¹⁰In

accordance with this practice, the model C-gluco- and

C-mannosides were prepared from tri-O-benzyl ^D-glucal,

while the C-galactosides were prepared from tri-O-benzyl

D-galactal. Thus, epoxidation of the glycal using di-

methyldioxirane (DMDO) in acetone/CH₂Cl₂, according

to Danishefsky’s protocol,¹¹and the addition of Grignard

reagents to the resulting 1,2-anhydrosugar¹²led to a mix-

ture of a- and b-C-glycoside derivatives. Although the a/

b ratio was variable, under our solvent and temperature

conditions the b-isomer was favored (Scheme 1), the b-^D-

C-glucosides 1a–1h and b-^D-C-galactosides 2c and 2f were

obtained in moderate to good yields. Deprotection of the

benzyl groups with hydrogen, and subsequent acetylation

or 4-bromobenzoylation led to the tetra-O-acetyl C-gluco-

sides 3b, 3c, 3f, and 3h, the tetra-O-(4-bromobenzoyl)

C-glucosides 4a–4h, or the tetra-O-(4-bromobenzoyl) C-

galactosides 5c and 5f. The model b-^D-C-mannosides 7c

and 7f were synthesized from the b-^D-C-glucosides 1c and

1f, as follows:¹³(i) oxidation with DMSO–Ac₂O, (ii) subse-

quent reduction with NaBH₄in CH₂Cl₂/MeOH (1:1) to

give C-mannosides 6c and 6f, (iii) hydrogenation and (iv)

4-bromobenzoylation in pyridine.

´

exo conformers, by 0.7–2.2 kcal/mol. Recently, Jimenez-

Barbero et al.^5dhave conﬁrmed the existence of an impor-

tant stereoelectronic stabilization for the exo–syn con-

former of O-glycosides and conclude that the exo-

anomeric eﬀect⁷is indeed a key factor in determining the

conformational behavior of U angles in O-glycosides

(>2.3 kcal/mol). Moreover, the unique existence of the

exo-anomeric conformation around the U angle in O-gly-

cosides with an equatorial hydroxyl group at the 2-position

(b-gluco and b-galacto series) is explained by adding the

1,3-type interactions (>3.3 kcal/mol) to the exo-anomeric

eﬀect.

In addition to the torsion angle U, the torsion angle x

around the C5–C6 bond (Fig. 2) needs to be considered

in determining the structure of oligosaccharides, especially

when the hydroxymethyl group is involved in a linkage.

This angle is also used to describe the conformation of

unsubstituted hydroxymethyl groups. The conformation

of the hydroxymethyl group around the C5–C6 bond is

generally described by means of the populations of the

gauche–gauche (gg), gauche–trans (gt), and trans–gauche

(tg) rotamers.⁸Since the torsion angle x in O-glycosides

has been proved to be conformationally dependent on the

structure of the aglycon,⁹which fact is attributable to

the exo-anomeric eﬀect, this conformational study of the

hydroxymethyl group in C-glycosides was undertaken to

Vinyl C-glucopyranoside 8 (Scheme 2) was obtained by

epoxidation of the tri-O-benzyl D-glucal, using dimethyldi-

oxirane (DMDO) in acetone/CH₂Cl₂, and subsequent

addition of divinylcuprate¹⁴to the resulting oxacyclopro-

pane. Ozonolysis and then reduction with NaBH₄in

CH₂Cl₂/MeOH (1:1) led to diol 9. This compound was

acetylated with Ac₂O/Py to give 10, which was treated with

hydrogen in Pd–C to remove the benzyl groups and then

again with Ac₂O/Py to obtain the penta-acetyl C-glucopyr-

anoside 11. Acetonide 12, obtained by protecting diol 9

with 2,2-dimethoxypropane and p-toluenesulfonic acid,

was treated ﬁrst with hydrogen and then with Ac₂O/Py

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

933

O

R

and reductive workup led to mono-alcohol 16. Acetylation

of its primary hydroxyl group led to 17, which was sub-

jected to catalytic hydrogenolysis to remove the benzyl

groups, and then via a per-4-bromobenzoylation to give

mainly the expected compound 18, as well as a small

amount of the transesteriﬁed meso derivative 19.

BnO

1

a

b

O

2

OH

OBn

glc, gal

glc: 1a−1h

gal: 2c, 2f

β

R

O

BnO

HO

R'O

c

d

or e

2.2. Characterization and spectroscopic analysis

OH

OR'

OBn

OH

OR'

All these compounds¹⁵were characterized on the basis of

their one- (¹H and ¹³C) and two-dimensional (COSY-G,

HMQC, and T-ROESY) NMR spectra. These model com-

pounds contain acetates or p-bromobenzoate esters, to

facilitate analyses by CD and, in addition, because these

groups aﬀect the proton and carbon resonances where they

are located leading to less crowded NMR spectra, allowing

the coupling constants under study to be measured

accurately by means of a ﬁrst order NMR analysis. The

stereochemistry at C1 (b equatorial) of the synthesized C-

glycosides 3–5 (Scheme 1) was established by analyzing

glc: 1a−1h

gal: 2c, 2f

glc: 3b, 3c, 3f, 3h, R' = Ac

glc: 4a−4h, R' = 4-BrBz

gal: 5c, 5f, R' = 4-BrBz

β

R

O

f

c,e

BnO

R'O

OH

OR'

OBn

OR'

glc: 1c and 1f

man: 6c and 6f

man: 7c and 7f,

R' = 4-BrBz

1

the H NMR J_1,2value (around 9.5 Hz) and conﬁrmed

H

H_R

H_S

H_R

by means of the T-ROESY experiments, by observing the

intense clear cross peaks involving the pseudo-anomeric

proton H1, that is, between H1 and H3, H5, and H1⁰S as

well as between H2 and H1⁰R. Since for C-mannopyrano-

sides 7 the C1 (b equatorial) conﬁguration was in their pre-

cursor glucopyranosides, there was no need to establish

this; however it was conﬁrmed by T-ROESY experiments.

CH₃

H

CH₃

H_S

CH₃

H_S

1'

H

a

b

c

d

H_R

CH₃

H_S

CH₃

e

f

g

h

The ¹H NMR signals of the prochiral protons at C6, H6R,

and H6S were diﬀerentiated on the basis of their chemical

shifts and coupling constants (accuracy 0.2 Hz);¹⁶that is,

in general, for the 4-bromobenzoyl series of gluco- and

mannopyranosides, H6R proton signals appear at a higher

ﬁeld than H6S signals (d_H6S> d_H6R),^16a,bthe reverse

behavior being observed for the galactopyranosides and

the acetyl glucopyranosides (d_H6S< d_H6R).^16a,cOn the

Scheme 1. Synthesis of model b-D-C-glycosides. Reagents and conditions:

(a) DMDO, acetone/CH₂Cl₂, 0 ꢁC; (b) RMgX, Et₂O, ꢁ40 ꢁC; (c) H₂, 5%

Pd–C, EtOH; (d) Ac₂O/Py, rt; (e) p-BrBzCl, DMAP, Py, 60 ꢁC; (f) (1)

DMSO, Ac₂O (2:1); (2) NaBH₄, CH₂Cl₂/MeOH (1:1).

to give acetonide 13 or with 4-bromobenzoyl chloride/Py

to provide acetonide 14. Alternatively, the hydroxyl group

of vinyl C-glucoside 8 was protected with benzyl bromide

to give the tetra-benzyl derivative 15, which by ozonolysis

other hand, as a general rule, J_H5,H6Rcoupling constants

16a,b

have higher values than J_H5,H6S

.

O

OAc

AcO

BnO

c, b

AcO

OAc

O

b

d

OH

BnO

OAc

O

OBn

O

BnO

10

11

a

OH

BnO

RO

O

OBn

c

OBn

b or e

8

9

O

RO

OBn

OR

f

12

13, R = Ac

14, R = 4-BrBz

O

BnO

OAc

OBzBr

R

BrBzO

a

BnO

c, e

+

OBn

BrBzO

OBzBr

OBn

OBzBr

OBn

18

19

15

16, R = OH

17, R = OAc

b

Scheme 2. Synthesis of model b-D-C-glucosides. Reagents and conditions: (a) (1) O₃, CH₂Cl₂/MeOH (1:1), ꢁ78 ꢁC; (2) NaBH₄, CH₂Cl₂/MeOH (1:1),

from ꢁ78 ꢁC to rt; (b) Ac₂O/Py, rt; (c) H₂, 5% Pd–C, EtOH; (d) 2,2-dimethoxypropane, p-TsOH, THF; (e) p-BrBzCl, DMAP, Py, 60 ꢁC; (f) BnBr, NaH,

DMF.

934

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

The assignment of H1⁰R and H1⁰S was in agreement with

gg

OR

H_S

OR

H_S

0

the values of the coupling constants J_{H1,H1 R}and J_{H1,H1 S}

,

H_S

O

H_R

R

H_S

R

O

as determined by Kishi et al. using speciﬁcally deuterated

C-glycosides,⁴and with the above mentioned ROE eﬀects.

For some compounds, such as 3c, 4c, 4d, and 4e, H1⁰R and

H1⁰S exhibited identical chemical shifts, so their coupling

constants with the pseudo-anomeric proton H1 were

obtained by analyzing H1 signals.

R

H_S

H_R

H_S

exo-syn

exo-anti

non-exo

gt

H_R

OR

H_R

OR

O

OR

O

H_S

H_R

R

H_S

O

R

H_S

H_R

exo-anti

H_R

R

non-exo

Among the diﬀerent types of Karplus equations, we have

chosen those of Serianni et al.¹⁷to calculate the rotamer

populations of the hydroxymethyl group, since they con-

tain new limiting values for J_H5,H6Rand J_H5,H6S, based

on J-couplings computed from density functional theory

(DFT). This set of equations yields a more accurate repre-

sentation of the rotameric populations in solution and

positive values for the tg rotamer population in all cases.

Although these equations were optimized for the analysis

of the C5–C6 rotamer populations, as a good approxima-

tion they were similarly used to calculate the C1–C1⁰rot-

amer populations of the C-glycosidic bond. Errors on the

percent rotamer population smaller than 5% can be esti-

mated from coupling constant values (accuracy 0.2 Hz).

H_S

exo-syn

tg

H_S

H_R

H_S

H_R

O

H_R

O

RO

H_R

R

H_S

O

R

H_S

exo-syn

H_S

H_R

exo-anti

H_R

R

non-exo

Figure 3. Diﬀerent orientations around the / and x torsion angles of

C-glycosyl compounds.

ideal staggered conformers, as shown in Fig. 3. The glyco-

sidic and hydroxymethyl populations were calculated from

The IUPAC system of nomenclature (R–S system) was

used to designate the prochiral protons at C1⁰and C6.

The R/S descriptors for the protons at C6 remain invari-

able throughout this paper, whereas they alter for those

at C1⁰as a consequence of the changes of priority, carbon

versus oxygen.¹⁸Therefore, care must be taken in the assig-

nation of these protons when applying coupling constants

in the Karplus equations.

0

the experimental J_{H1,H1 R}and J_{H1,H1 S}and J_H5,H6Rand

J_H5,H6Scoupling constants, respectively, by using the Kar-

plus equations recently published by Serianni et al.¹⁷

Analysis of the coupling constants of the prochiral protons

at C1⁰and C6, or their calculated rotamer populations,

reveals a relationship with the structure of the C-aglycon.

Thus, a strong dependence of the glycosidic populations

(exo–syn, exo–anti, and non-exo rotamers) and a slight

dependence of the hydroxymethyl populations (gg, gt,

and tg rotamers) on the structure of the C-aglycon were

observed. The rotational study around the C1–C1⁰of the

C-glucopyranosides showed the exo–syn rotamer to be

the most stable for both the acetyl series 3b–3h (Table 1)

and the 4-bromobenzoyl series 4b–4h (Table 2), as also

observed in the T-ROESY experiments. Furthermore, its

population increases with the degree of substitution on

the C-aglycon, that is, in the benzoyl series, from around

60% in unbranched C-alkyls 4b–4e, to 90% for secondaries

4f and 4g, and 100% for a tertiary branched C-aglycon

4h.²⁰This increase in the exo–syn population is at the ex-

pense of the other two rotamers, as seen in Graph 1 and

Table 2. Further analysis of the populations around the

pseudo-glucosidic bond (Tables 1 and 2) revealed a vari-

able degree of ﬂexibility, which was possible to correlate

with the substitution of the C-aglycon. Thus, unbranched

The CD exciton chirality method¹⁹oﬀers a versatile sensi-

tive approach for determining the absolute conﬁguration

and conformation of a variety of molecules in solution;

as a result, we have applied it in this study. C-Glycosides

4a–4h, 5c, 5f, 7c, and 7f were analyzed by CD, exhibiting

the intramolecular charge-transfer band of the 4-bro-

mobenzoate chromophore around 245 nm in UV, and exci-

ton Cotton eﬀects around 252 and 234 nm in the CD

spectra.

2.3. Conformational analysis

In b-C-glycosides, rotation around the glycosidic bond (an-

gle U, O5–C1–C1⁰–C2⁰) led to the exo–syn, exo–anti, and

non-exo rotamers, while the rotation around the C5–C6

bond (angle x, O5–C5–C6–O6) led to the gg, gt, and tg

rotamers (Fig. 2). Thus, these rotations gave rise to nine

0

Table 1. J_H1,H1and J_H5,H6Coupling constants (CDCl₃) and calculated rotameric populations (%) for the model acetyl b-D-C-glucopyranosides 3b–3h, 11,

and 13

0

J_{H1,H1 S}

0

J_{H1,H1 R}

Compd.

exo–syn

exo–anti

non-exo

J_H5,H6S

J_H5,H6R

gg

gt

tg

3b

3c

3f

2.9

4.3

2.3

ND

4.9

5.3

8.3

7.0

9.9

8.9

2.1

72

53

91

100

39

0

21

25

9

0

61

0

7

22

0

2.3

2.1

2.0

5.0

5.1

5.3

6.2

4.9

4.8

58

57

55

47

61

60

42

43

45

53

39

40

0

3h

11

13

10.5

100

ND: Not detected.²⁰

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

935

0

Table 2. J_H1,H1and J_H5,H6coupling constants (CDCl₃) and calculated rotameric populations (%) for the model p-bromobenzoyl b-D-C-glucopyranosides

4a–4h, 14, 18, and 19

0

J_{H1,H1 S}

0

J_{H1,H1 R}

Compd.

exo–syn

exo–anti

non-exo

J_H5,H6S

J_H5,H6R

gg

gt

tg

4a

4b

4c

4d

4e

4f

—

69

57

64

56

91

89

100

0

—

24

27

25

26

9

11

0

—

7

16

11

18

0

100

4

6

3.1

3.2

3.1

3.2

3.1

3.0

2.9

2.7

3.1

3.0

4.8

5.1

5.3

5.4

5.7

6.1

6.6

4.8

4.9

5.2

57

54

51

50

47

44

39

60

56

53

37

40

41

43

42

46

50

56

39

38

41

6

8

7

8

7

6

5

1

6

3.0

3.8

3.3

4.0

2.2

2.3

ND

5.2

5.0

5.2

8.0

7.1

7.7

7.1

9.9

9.7

8.8

10.5

2.9

3.0

4g

4h

14

18

19

40

41

56

53

ND: Not detected.²⁰

in the mannose one. Thus, while a small increase in the

non-exo population was observed by comparing either

compound 4c (16%) or 5c (13%) with 7c (23%), a greater

change was observed for those stereoisomers having a more

voluminous C-aglycon, 4f (0%), 5f (0%), and 7f (20%).

100

75

50

25

0

Furthermore, there is an alternation in the exo–syn and

non-exo populations as the length of the chain increases:

compounds having an unbranched alkyl chain with an even

number of carbon atoms showed higher exo–syn and lower

non-exo populations than their homologs with an odd

number of carbon atoms. This observation establishes a

dependency of the glycosidic linkage on the structure of

the C-aglycon, in both the degree of substitution and the

length of the aglyconic chain. This last result is striking

in solution, a diﬀerent polarization along the even/odd

chain may account for this behavior.

4b

4c

4d

4e

4f

4g

4h

Graph 1. Rotational populations (%) around the C1–C1⁰bond, calculated

0

from the J_H1,H1coupling constants of compounds 4b–4h (CDCl₃); exo–

syn/exo–anti/non-exo rotamers (red/blue/yellow).

or secondary C2⁰aglycons are highly ﬂexible around the

0

´

C1–C1 bond, in agreement with Jimenez-Barbero’s results,

while branched tertiary C2⁰or quaternary C2⁰aglycons

have slight or no ﬂexibility at all, respectively, which sup-

ports Kishi’s observations.

With respect to the populations around the C5–C6 bond

(hydroxymethyl group), an increase in the J_H5,H6Rcoupling

constant around the C5–C6 bond (x) in C-gluco-, C-gal-

acto-, and C-mannopyranosides was also observed as the

substitution in the aglycon increased. For the acetyl C-glu-

cosides series, this coupling constant increased from 5.0 up

to 6.2 Hz, passing from compounds 3b to 3h. Similarly, a

gradual increase from 4.8 to 6.6 Hz was observed for the

p-bromobenzoyl series from 4a to 4h. Namely, from 4a

(4.8) to compounds with an unbranched aglycon: 4b

(5.1), 4c (5.3), 4d (5.4), and 4e (5.4 Hz), to compounds with

a branched aglycon: 4f (5.7), 4g (6.1), and 4h (6.6 Hz).

Moreover, the unbranched alkyl chain of the C-galacto-

and C-mannosides 5c and 7c exhibited a smaller J_H5,H6R

coupling constant than their respective compounds with a

branched alkyl chain: compounds 5f and 7f. On the other

hand, the J_H5,H6Svalue remained more or less constant

Analysis of the C-galacto- and C-mannopyranoside deriv-

atives (Table 3) revealed the same conformational behavior

as C-glucopyranosides.²¹Thus, compounds 5f and 7f with

branched aglycons showed higher J_{H1,H1 R}and smaller

J_{H1,H1 S}coupling constants than compounds 5c and 7c

with an unbranched aglycon, and therefore the former pair

possesses higher exo–syn populations. Additional features

can be observed by comparing these mannopyranosides

with their corresponding glucopyranosides (4c and 4f) or

galactopyranosides (5c and 5f). The populations of the

non-exo rotamers are higher in the C-mannopyranosides

than in the C-gluco- or C-galactopyranosides. The b axial

conﬁguration at C-2 in mannopyranosides permits an in-

crease in its non-exo populations, since the 1,3-type inter-

action for this rotamer in the glucose series disappeared

0

Table 3. J_H1,H1and J_H5,H6coupling constants (CDCl₃) and calculated rotameric populations (%) for the model p-bromobenzoyl b-D-C-galacto- (5c and

5f) and mannopyranosides (7c and 7f)

0

J_{H1,H1 S}

0

J_{H1,H1 R}

Compd.

exo–syn

exo–anti

non-exo

J_H5,H6S

J_H5,H6R

gg

gt

tg

5c

5f

7c

7f

3.5^a

2.2

4.3

4.0

8.0^a

9.9

7.8

8.7

67

91

61

71

20

9

16

9

13

0

23

20

6.5

6.1

2.9

2.8

6.7

7.0

4.9

5.1

12

57

55

40

45

39

41

48

43

4

^aCoupling constants obtained from the doublet of doublets observed for H-1 when H-2 was irradiated.

936

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

(around 2.3 Hz for the acetyl series and around 3.1 Hz for

the benzoyl series). These experimental NMR data corre-

late with the increased gt population of the hydroxymethyl

group at the expense of gg, with the tg population remain-

ing constant, as seen in Graph 2 for the benzoyl C-gluco-

sides series. Although the same rotamer behavior was

observed for the two structural series analyzed, slightly

higher tg populations were obtained for the series contain-

ing benzoates than for the tetra-acetyl series (Tables 1 and

2). These increases in the rotational population of the tg

rotamer in the former series may be explained by favorable

p–p interactions between the two aromatic rings in this

array.

the 4-bromobenzoyl C-glucopyranosides series are shown

in Table 4. It is striking that only the prochiral hydrogen

H1⁰S shows a clear displacement toward higher ﬁelds

throughout both series. For instance, for the 4-bro-

mobenzoyl series, from compounds with an unbranched

aglycon: 4b (1.69), 4c (1.57), 4d (1.56), and 4e (1.58 ppm),

to compounds with a ramiﬁed aglycon: 4f (1.30), 4g

(1.35), and 4h (1.38 ppm); whereas H1⁰R remains almost

constant (at approximately 1.57 ppm), as shown in Graph

3. In addition, the chemical shift of C1⁰and C1 is de-

shielded and shielded, respectively, as the structure of the

C-aglycon is enlarged or ramiﬁed. Figure 4 summarizes

these results.

Analyses of the ¹H NMR coupling constants of com-

pounds 4b, 4f, and 4h in non-polar (benzene and chloro-

form) and polar aprotic (acetonitrile and dimethyl

sulfoxide) solvents revealed that while rotation around

the glycosidic bond is relatively independent of the solvent,

that around the C5–C6 bond is somewhat solvent depen-

dent. In general, ranging from non-polar to aprotic-polar

solvents, the population of the gt rotamer decreased while

that of the gg rotamer increased. In any case, the overall

observed rotational trends are independent of the solvents.

The interpretation of the chemical shifts for protons in

alkyl groups larger than methyl is unfortunately not as sim-

ple as one would hope, since inductive and steric eﬀects,

hydrogen bonding, and shielding by magnetically aniso-

1.8

1.6

H1'R

1.4

H1'S

The ¹H and ¹³C NMR chemical shifts of the anomeric and

prostereogenic carbons C1⁰and C6 for both the acetyl and

1.2

4b

4c

4d

4e

4f

4g

4h

1

Graph 3. H NMR chemical shifts of the H1⁰R (blue) and H1⁰S (red)

60

40

20

0

protons of compounds 4b–4h (CDCl₃).

ROE

constant

H₂

O⁵

C¹

H₁

H_1'

deshielded

R

R'O

C^1'

H_1'

R

S

shielded

4a 4b 4c 4d 4e

4f

4g 4h

shielded

ROE

Graph 2. Rotational populations (%) around the C5–C6 bond (hydroxy-

methyl group) calculated from the J_H5,H6coupling constants of com-

pounds 4a–4h (CDCl₃); gg/gt/tg rotamers (blue/red/yellow).

Figure 4. ¹H and ¹³C NMR chemical shift characteristics of C-glycosides

as the substituent R increases in size.

Table 4. ¹H and ¹³C NMR chemical shifts (CDCl₃) for the model C-glycosides 3–5, and 7

R

H1

C1

C1⁰

H1⁰S

H1⁰R

C6

H6S

H6R

3b

3c

3f

3.34

3.39

3.45

3.48

78.8

77.6

76.3

75.9

24.3

33.3

40.1

44.2

1.60

1.44

1.18

1.25

1.45

1.44

1.46

1.44

62.4

62.7

4.10

4.09

4.07

4.06

4.25

4.24

4.19

3h

4a

4b

4c

4d

4e

4f

3.87

3.66

3.72

3.70

3.77

3.80

3.81

74.7

79.2

78.0

78.2

78.1

76.7

76.2

76.3

17.7

24.5

33.3

31.0

31.4

40.1

38.8

44.3

—

63.5

63.6

63.7

63.9

4.56

4.57

4.56

4.55

4.54

4.53

4.52

4.43

4.44

4.43

4.44

4.43

4.40

1.69

1.57

1.56

1.58

1.30

1.35

1.38

1.57

1.56

1.58

1.61

1.55

1.58

4g

4h

5c

5f

3.72

3.78

78.3

77.0

33.6

40.4

1.64

1.37

1.64

1.71

62.5

62.6

4.32

4.34

4.59

4.58

7c

7f

3.87

3.94

77.1

75.7

32.6

39.4

1.47

1.28

1.70

1.63

63.5

63.6

4.68

4.67

4.44

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

937

30

tropic groups may be involved. The same behavior in both

series (acetate and 4-bromobenzoate) rules out the possibil-

ity of an anisotropic eﬀect toward H1⁰S from the

4-bromobenzoyl group at C2. Furthermore, since similar

C-glycosidic populations were obtained in both series, no

signiﬁcant steric diﬀerences should exist to account for

the observed rotational behavior. Among the diﬀerent

possible explanations for the observed proton chemical

shifts, the anisotropic shielding by carbon–carbon (and

possibly carbon–hydrogen) single bonds is the most plausi-

ble. The observed shielding for H1⁰S and C1 can be attrib-

uted to greater electron densities around such nuclei.

Δε

4c

4f

4h

0

−10

200

250

300

350 nm

2.4. Circular dichroism analysis

Figure 5. CD spectra comparison of compounds 4c, 4f, and 4h (CH₃CN).

The high sensitivity and simple spectral interpretation of

the circular dichroic exciton chirality method¹⁹provides

further conformational data. The exciton-coupled chro-

mophores in our molecules, namely p-bromobenzoates,

permit analysis by this method, applying the additivity

principle in multichromophoric systems,^22,23the interchro-

mophoric distance, and the dihedral angle of the chro-

mophores involved in each pairwise interaction.¹⁹

According to this method, the CD spectrum of a 2,3,4,6-

tetra chromophorically substituted glycopyranosyl system

is composed of six pairwise interactions.^22,23Three have

constant intensity and sign: the 2/3, 3/4, and 2/4 interac-

tions; and the other three have variable intensity and sign:

the 2/6, 3/6, and 4/6, which involve the chromophore at the

6-position. Furthermore, the amplitude of the split Cotton

eﬀects (A value)²⁴depends on the interchromophoric dis-

tance and the dihedral angle;¹⁹therefore, the sign and

intensity of the pairwise interactions depend on the glyco-

pyranosyl system conﬁgurations under study: glucose,^9a

galactose,^9bor mannose^9ctype. Since no ring distortion

has been observed for our model compounds, the 2/3, 3/

4, and 2/4 interactions are constant and therefore the CD

spectral diﬀerences between the model compounds arise

from the pairwise interactions involving the chromophore

at the 6-position.

nil

6

4

O

2

nil

3

gg

gt

tg

Figure 6. 2/6, 3/6, and 4/6 pairwise interactions involving the chromo-

phore at the 6-position in each of the three stable rotamers (gg, gt, and tg)

for the glucopyranosyl system.

nil

6

nil

4

O

2

3

gg

gt

tg

Figure 7. 2/6, 3/6, and 4/6 pairwise interactions involving the chromo-

phore at the 6-position in each of the three stable rotamers (gg, gt, and tg)

for the galactopyranosyl system.

of the 4/6 pairwise interaction in the tg rotamer and/or a

lesser positive contribution from this pairwise interaction

in the gt. Therefore, these CD spectra are totally in agree-

ment with their corresponding NMR results.

The tetrachromophoric compounds 4a–4h exhibited exci-

ton Cotton eﬀects around 252 and 234 nm in the CD spec-

tra in CH₃CN. The amplitude of the split CD curve (A

value) gradually decreased from compounds 4a (28.9), 4b

(27.0), 4c (25.1), 4d (23.5), 4e (23.4), 4f (21.9), and 4g

(15.9) to 4h (14.2). Figure 5 shows the CD spectra of some

representative compounds: with an unbranched aglycon or

a secondary C2⁰(4c), with a tertiary C2⁰(4f), and with a

quaternary C2⁰(4h). These intensities are only consistent

with reduced positive contributions from the pairwise inter-

actions between the chromophore at the 6-position (gg rot-

amer) and those at positions 3 and 4 (Fig. 6)^9aand

therefore to a reduction in the population of this gg rot-

amer throughout the series from compounds 4a to 4h,

which is in agreement with the above NMR results.

Data comparison of C-mannopyranosides 7c and 7f (Table

3) shows that as in the C-glucopyranosides, the exo–syn

population is higher for the compound with the ramiﬁed

C-aglycon 7f, the increase of which also correlates with a

slightly higher gt population. These NMR results correlate

very well with those by CD. The amplitude of the split CD

curve (A value) for compound 7c (A = ꢁ90.2) was smaller

than that of 7f (A = ꢁ94.1), as expected from the CD anal-

ysis of their pairwise interactions,^9cespecially 4/6 (Fig. 8).

2.5. The exo-deoxoanomeric eﬀect

As for the C-galactopyranosides, the amplitude of the split

CD curve (A value) of compound 5c (A = 90.4) was less

than that of 5f (A = 96.1), as expected from the CD analy-

sis of their pairwise interactions,^9bespecially 4/6 (Fig. 7).

This is in accordance with a greater negative contribution

For the most stable conformer around the C1–C1⁰bond,

the exo–syn or ‘exo-anomeric’ conformer, the H1⁰S is

in an anti disposition to the endocyclic oxygen (O5)

(Fig. 9). Therefore, a stereoelectronic interaction between

938

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

that the non-exo rotamer (interaction r_CH–r^ꢀ_CO) does not

favor the gt rotamer of the hydroxymethyl group.

nil

O

nil

6

3

4

O

OR

2

nil

H_R

H_S

O

RO

R'

gg

gt

tg

H_S

O

OR H_R

Figure 8. 2/6, 3/6, and 4/6 pairwise interactions involving the chromo-

phore at the 6-position in each of the three stable rotamers (gg, gt, and tg)

for the mannopyranosyl system.

13, R = Ac

14, R = 4-BrBz

11, R = R' = Ac

18, R = 4-BrBz, R' = Ac

19, R = R' = 4-BrBz

For 18 and the meso compounds 11 and 19, the presence of

an electron-withdrawing group at C1⁰, acetyloxys 11 and

18 or 4-bromobenzoyloxy 19, would debilitate or even an-

C₂

O₅

C₂

O₅

C₂

O₅

*

CO H₁

CO

H₁

H_1'S

H_1'

H₁

R

0

nul this stereoelectronic eﬀect. Analysis of the J_H1,H1cou-

CH

H_1'

PH₂

R

H_1'S

^CCR

H

1'R

1'S

pling constants of compound 18 led to the highest exo–anti

and lowest exo–syn populations (Table 2) of the alkyl

C-glucopyranosides, in both the acetyl 3b–3h and 4-bro-

mobenzoyl 4b–4h series. This result supports the existence

of hyperconjugation in alkyl C-glycosides. In meso com-

pounds 11 and 19, the populations around C1–C1⁰and

C5–C6 bonds at either side of the molecule were the same,

exo syn

exo anti

non exo

Figure 9. Molecular orbitals involved in the exo-deoxoanomeric eﬀect.

the C1⁰–H1⁰S bonding orbital and the C1–O5 antibonding

orbital can be established,²⁵since r_CHis a moderate donor

and r^ꢀ_COa good acceptor. This interaction can also occur in

the exo–anti conformation, by means of the molecular

bonding orbital C1⁰–H1⁰R; although as the C-aglycon

becomes bulkier, the population of this rotamer decreases

0

because J_{H1,H1 S}= J_H5,H6Rand J_{H1,H1 R}= J_H5,H6S. Thus,

for compound 19, the exo–anti = gg = 53; exo–

syn = gt = 41; and non-exo = tg = 6. While these are obvi-

ously normal values for a hydroxymethyl group, when con-

sidering one of the two as if it was a C-aglycon, high exo–

anti and low exo–syn populations were obtained, since an

electron-withdrawing group at C1⁰weakens or annuls the

hyperconjugation.

due to the steric eﬀects. In addition, it is known that r_CC

26

bonds are worse donors than r_CH

;

therefore the

r

_CC–r^ꢀ_COinteraction (non-exo conformer) must be much

weaker than the former or nil.

As the series 3b to 3h, or 4b to 4h progresses (the degree of

substitution at C2⁰increasing from Me to R = ^tBu), the

population of the exo–syn rotamer increases (Tables 1

and 2) along with the electron density on the pseudo-ano-

meric carbon C1 (Table 4). Therefore, the donor capacity

of the C1⁰–H1⁰S bonding orbital toward the C1–O5 anti-

bonding orbital increases as the substitution at C2⁰in-

creases along with the population of the exo–syn

rotamer. This hyperconjugation phenomenon could in-

volve the contraction of the C1–C1⁰bond and the conse-

quent enlargement of the C1–O5 bond, as observed in

O-glycosides,⁹altering the surroundings of the hydroxy-

methyl group, and therefore its populations (Graph 2).

When comparing Graphs 1 and 2, the rise in the gt rotamer

population of the hydroxymethyl group (Graph 2) corre-

lates with that in the exo–syn population (Graph 1).

3. Conclusions

On the basis of the ¹H NMR coupling constant values and

CD spectral diﬀerences, the present conformational analy-

sis of C-glycoside shows that the rotamer populations

around the pseudo-glycosidic linkage (torsion angle U)

and those of the hydroxymethyl group (torsion angle x)

depend on the structural nature of the C-aglycon, the pop-

ulation of the exo–syn rotamer (‘exo-anomeric’ conforma-

tion), and that of the gt rotamer, increasing with the degree

of substitution of the C-aglycon. When an electron-with-

drawing group is located at C1⁰in the C-aglycon, the

exo–anti rotamer becomes the most stable and the gt rot-

amer population decreases. All these observations, together

1

with the correlations between H and ¹³C NMR chemical

shifts and the size or degree of substitution of the C-agly-

con, point to hyperconjugation as another factor involved

in the conformational preferences around the glycosidic

bond of C-glycosides, in addition to the 1,3-type interac-

tions. We can explain this hyperconjugation as a stereoelec-

tronic eﬀect of type r_CH–r^ꢀ_CO, which inﬂuences the

conformation around the C-glycosidic bond; the term

exo-deoxoanomeric eﬀect being proposed for this hyper-

conjugation by analogy with the exo-anomeric eﬀect in

O-glycosides. The stability of the exo–syn rotamer can be

explained in terms of steric and stereoelectronic interac-

tions, which occurs in O-glycosides. The observed rota-

tional dependence of the hydroxymethyl group on the

structure of the C-aglycon, increasing as it does the popu-

lation of the gt rotamer as that of the exo–syn rotamer in-

To test this theory further, acetonides 13 and 14, acetyls 11

and 18, and 4-bromobenzoyl 19 were synthesized, since a

nil or low exo-deoxoanomeric eﬀect would be expected

for them. For acetonides 13 and 14, the conformation is

totally restricted to the non-exo rotamer, so the interaction

r

_CH–r^ꢀ_COis not possible. These compounds exhibited high

0

J_{H1,H1 R}(10.5 Hz) and low J_{H1,H1 S}(5.3 Hz) values (Tables

1 and 2) in agreement with the spatial disposition of the

H1⁰protons and also conﬁrming the correct NMR assign-

ment for these protons. Besides this, their J_H5,H6values

gave high gg and low gt hydroxymethyl populations. This

result conﬁrms the correlation between the rotamer popu-

lation around the pseudo-glycosidic bond and that around

the C5–C6 bond (hydroxymethyl group). It also conﬁrms

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

939

creases, could be explained by the exo-deoxoanomeric

eﬀect. The similar but not identical conformational behav-

ior of C- and O-glycosides in solution is probably due

to stereoelectronic eﬀects caused by the r–r^*and n–r^*

interactions, respectively, along their 1,3-type steric

interactions.

after which it was concentrated to dryness, dissolved in

CH₂Cl₂, and washed with water and brine. The organic ex-

tract was dried over anhydrous MgSO₄, ﬁltered, and evap-

orated in a vacuum. Then, 2 equiv of sodium borohydride

was added to a solution of the crude reaction mixture in

dry 1:1 CH₂Cl₂/MeOH (10 mL/mmol) at 0 ꢁC in a nitrogen

atmosphere and then the ice bath removed. When the reac-

tion was complete, it was diluted with CH₂Cl₂and washed

with water, 1% citric acid solution, NaHCO₃saturated

solution, and brine. The combined organic layers were

dried over anhydrous MgSO₄, ﬁltered, and evaporated in

a vacuum. The product was puriﬁed by silica gel column

chromatography.

4. Experimental

4.1. General

¹H NMR spectra were recorded at 400 or 500 MHz, and

¹³C NMR at 100 MHz, VTU 300.0 K. Chemical shifts

are reported in parts per million. The residual solvent peak

(CDCl₃) was used as an internal reference, 7.26 for proton

and 77.0 ppm for the central peak for carbon NMR. Opti-

cal rotations were measured on a digital polarimeter in a

1 dm cell. UV and CD spectra were recorded in the range

400–200 nm using 10 mm cells. The concentrations of the

CD samples were ascertained from the UV spectra, using

the experimentally determined e values at 245 nm: tetra-

(4-bromobenzoate) e 76,400. For analytical thin-layer chro-

matography, silica gel ready-foils were used, developed

with 254 nm UV light and/or spraying with AcOH/H₂O/

H₂SO₄(80:16:4) and heating at 150 ꢁC. Flash column chro-

4.4. General procedure for debenzylation and acetylation or

p-bromobenzoylation

To a solution of the substrate in dry ethanol (10 mL/mmol)

was added 100 mg/mmol of palladium at 5% on activated

carbon with suﬃcient hydrogen. After the reaction was

complete, the mixture was diluted in ethanol, ﬁltered

through a bed of Celite, and evaporated under reduced

pressure. (a) Acetylation: The crude reaction mixture was

dissolved in 20 mL/mmol of a 1:1 solution of dry pyri-

dine/acetic anhydride at room temperature and stirred

overnight. The solvent was removed under reduced pres-

sure in the presence of toluene and the residue chromato-

graphed. (b) p-Bromobenzoylation: The crude reaction

mixture was dissolved in dry pyridine (10 mL/mmol), and

then treated with 6 equiv of p-bromobenzoyl chloride

and DMAP as catalyst. The solution was heated at 60 ꢁC

and stirred overnight. The solvent was removed under

reduced pressure in the presence of toluene and the residue

chromatographed.

˚

matography was performed using silica gel (60 A). All

reagents were from commercial sources, and used without

further puriﬁcation; and solvents were dried and distilled

before use. All reactions were performed under a dry

nitrogen atmosphere. The compounds prepared were

characterized on the basis of their one- (¹H and ¹³C) and

two-dimensional (COSY, HMQC, and TROESY) NMR

spectra, as well as by elemental analysis, HRMS, UV,

and CD spectroscopy.

4.2. General procedure for the preparation of b-C-glucosides

or b-C-galactosides

4.5. General procedure for reductive ozonolysis and

acetylation or ketal formation

A solution of dimethyldioxirane in acetone (2 equiv, ca.

0.075 M) was added to a stirred solution of the correspond-

ing tri-O-benzyl-^D-glycal (glucal or galactal) in dry CH₂Cl₂

(5 mL/mmol) at 0 ꢁC under a nitrogen atmosphere, and the

reaction stirred at 0 ꢁC for 30 min. The 1,2-anhydrosugar

thus obtained was concentrated under reduced pressure

and left under vacuum for 2 h. It was then dissolved in

dry Et₂O (10 mL/mmol) under dry nitrogen, cooled to

ꢁ40 ꢁC and the corresponding Grignard reagent was

added. When the reaction was completed, it was diluted

with Et₂O, quenched with NH₄Cl saturated solution, and

extracted with Et₂O three times. The combined organic lay-

ers were washed with NaHCO₃saturated solution and

brine, dried over anhydrous MgSO₄, ﬁltered, and evapo-

rated in a vacuum. The product was puriﬁed by silica gel

column chromatography.

A solution of sugar in dry 1:1 CH₂Cl₂/MeOH (65 mL/

mmol) under a nitrogen atmosphere was cooled to

ꢁ78 ꢁC, and ozone was bubbled in until it became blue (ap-

prox. 5 min). Then nitrogen was bubbled through to expel

excess ozone, and the mixture allowed to warm to 0 ꢁC.

NaBH₄(8 equiv) was added and the solution stirred for

1 h at room temperature, then poured into an aqueous

solution of 10% HCl, and extracted with CH₂Cl₂. The

organic layer was washed with a saturated NaHCO₃solu-

tion and brine, dried over Na₂SO₄anhydrous, and concen-

trated under reduced pressure. (a) Acetylation: The mixture

was dissolved in 20 mL/mmol of a 1:1 solution of dry pyr-

idine/acetic anhydride at room temperature and stirred

overnight. The solvent was removed under reduced pres-

sure in the presence of toluene and the residue chromato-

graphed. (b) Ketal formation: The mixture was dissolved

in 5 mL/mmol of dry THF at room temperature, and then

treated with 20 equiv of 2,2-dimethoxypropane and

0.25 equiv of p-toluenesulfonic acid, and stirred overnight.

The reaction was quenched with the addition of 0.5 mL of

Et₃N. The solvent was removed under reduced pressure

and the residue chromatographed.

4.3. General procedure for the preparation of b-C-

mannosides

The sugar was treated with 1:2 acetic anhydride/dimethyl

sulfoxide (8 mL/mmol) mixture. The reaction was left for

24 h at room temperature under a nitrogen atmosphere,

940

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

4.6. 2,6-Anhydro-4,5,7-tri-O-benzyl-1-deoxy-D-glycero-D-

gulo-heptitol 1a

Flash column chromatography (n-hexane/EtOAc, 8.5:1.5)

of the residue yielded 1c (608 mg, 1.28 mmol, 76%) as an

epimer mixture b/a = 1.5: TLC R_f= 0.4 (n-hexane/EtOAc,

8:2); [a]_D= +30.2 (c 1.1, CHCl₃); HRMS (FAB) Calcd for

C₃₀H₃₅O₅(Mꢁ1)⁺: 475.2484. Found: 475.2474; IR

Following the general procedure for the preparation of

b-C-glucosides, 35 mL (2.63 mmol) of a solution of

DMDO in acetone was added to a solution of glucal

(550 mg, 1.32 mmol) in 6.5 mL of dry CH₂Cl₂at 0 ꢁC.

Later, the product was directly dissolved in Et₂O (13 mL)

and methylmagnesium iodide (4.0 mL, 4.00 mmol) was

added. Flash column chromatography (n-hexane/EtOAc,

7:3) of the residue yielded 1a (356 mg, 0.79 mmol, 60%)

as an epimer mixture b/a = 12: TLC R_f= 0.4 (n-hexane/

EtOAc, 6:4); [a]_D= +42.9 (c 1.1, CHCl₃); HRMS (FAB)

Calcd for C₂₈H₃₁O₅(Mꢁ1)⁺: 447.2171. Found: 447.2171;

1

ꢁ1

~

m ¼ 3336 cm (OH); H NMR (CDCl₃): d 7.37–7.20 (m,

15H), 4.96 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 10.8 Hz,

1H), 4.75 (d, J = 11.6 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H),

4.60 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H),

3.75–3.69 (m, 2H), 3.62 (t, J = 9.3 Hz, 1H), 3.47 (t,

J = 8.9 Hz, 1H), 3.42 (m, 1H), 3.31 (t, J = 9.0 Hz, 1H),

3.16 (ddd, J = 2.3, 8.6, and 9.0 Hz, 1H), 2.37 (br s, 1H),

1.77 (m, 1H), 1.59 (m, 1H), 1.53 (m, 2H), 1.03 (d,

J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃): d 138.5, 138.1,

138.0, 128.5–127.4, 86.9, 79.1, 78.9, 78.4, 75.0, 74.6, 73.9,

73.3, 68.9, 33.8, 18.5, 14.0. Anal. Calcd for C₃₀H₃₆O₅: C,

75.60; H, 7.61. Found: C, 75.57; H, 7.58.

1

ꢁ1

~

IR m ¼ 3308 cm (OH); H NMR (CDCl₃): d 7.42–7.18

(m, 15H), 4.96 (d, J = 11.6 Hz, 1H), 4.81 (d, J = 10.8 Hz,

1H), 4.77 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 12.2 Hz, 1H),

4.57 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H),

3.76–3.68 (m, 2H), 3.62 (t, J = 9.2 Hz, 1H), 3.51–3.45 (m,

2H), 3.32 (dddd, J = 5.6, 5.6, 5.6, and 9.0 Hz, 1H), 3.26

(t, J = 8.9 Hz, 1H), 2.44 (br s, 1H), 1.33 (d, J = 5.6 Hz,

3H); ¹³C NMR (CDCl₃): d 138.5, 137.9 (·2), 128.5–127.5,

86.6, 78.7, 78.4, 75.5, 75.4, 74.9, 74.6, 73.3, 68.9, 17.9. Anal.

Calcd for C₂₈H₃₂O₅: C, 74.97; H, 7.19. Found: C, 74.98; H,

7.07.

4.9. 5,9-Anhydro-7,8,10-tri-O-benzyl-1,2,3,4-tetradeoxy-^D-

glycero-^D-gulo-decitol 1d

Following the general procedure for the preparation of

b-C-glucosides, 13 mL (0.98 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (199 mg,

0.48 mmol) in 2.4 mL of dry CH₂Cl₂at 0 ꢁC. Later, the

product was directly dissolved in Et₂O (5.0 mL) before

adding n-butylmagnesium bromide (1.5 mL, 1.50 mmol).

Flash column chromatography (n-hexane/EtOAc, 8.5:1.5)

of the residue yielded 1d (148 mg, 0.30 mmol, 63%) as an

epimer mixture b/a = 2: TLC R_f= 0.4 (n-hexane/EtOAc,

8:2); [a]_D= +29.0 (c 1.0, CHCl₃); HRMS (FAB) Calcd

for C₃₁H₃₈O₅(M)⁺: 490.2719. Found: 490.2742; IR

4.7. 3,7-Anhydro-5,6,8-tri-O-benzyl-1,2-dideoxy-^D-glycero-

D-gulo-octitol 1b

Following the general procedure for the preparation of

b-C-glucosides, 40 mL (3.00 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (620 mg,

1.49 mmol) in 7.5 mL of dry CH₂Cl₂at 0 ꢁC. Later, the

product was directly dissolved in Et₂O (15 mL) and ethyl-

magnesium bromide (4.5 mL, 4.50 mmol) was added. Flash

column chromatography (n-hexane/EtOAc, 8.5:1.5) of the

residue yielded 1b (549 mg, 1.19 mmol, 80%) as an epimer

mixture b/a = 10: TLC R_f= 0.4 (n-hexane/EtOAc,

7.5:2.5); [a]_D= +35.8 (c 1.1, CHCl₃); HRMS (FAB) Calcd

for C₂₉H₃₃O₅(Mꢁ1)⁺: 461.2328. Found: 461.2308; IR

1

ꢁ1

~

m ¼ 3440 cm (OH); H NMR (CDCl₃): d 7.37–7.22 (m,

15H), 4.97 (d, J = 11.6 Hz, 1H), 4.83 (d, J = 11.0 Hz,

1H), 4.79 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 12.3 Hz, 1H),

4.62 (d, J = 11.0 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 3.75

(m, 2H), 3.64 (t, J = 9.2 Hz, 1H), 3.50 (t, J = 8.7 Hz,

1H), 3.45 (m, 1H), 3.33 (t, J = 8.9 Hz, 1H), 3.17 (br t,

J = 8.2 Hz, 1H), 2.53 (br s, 1H), 1.85 (m, 1H), 1.70–1.47

(m, 5H), 1.05 (d, J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃): d

138.5, 138.1, 138.0, 128.4–127.3, 86.9, 79.1, 78.9, 78.4,

74.9, 74.5, 73.9, 73.2, 68.9, 33.3, 27.4, 22.6, 14.0. Anal.

Calcd for C₃₁H₃₈O₅: C, 75.89; H, 7.81. Found: C, 75.91;

H, 7.77.

1

ꢁ1

~

m ¼ 3311 cm (OH); H NMR (CDCl₃): d 7.38–7.21 (m,

15H), 4.97 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 10.8 Hz,

1H), 4.73 (d, J = 11.6 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H),

4.61 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H),

3.76–3.72 (m, 2H), 3.62 (t, J = 9.3 Hz, 1H), 3.47 (t,

J = 8.9 Hz, 1H), 3.42 (m, 1H), 3.32 (t, J = 9.0 Hz, 1H),

3.10 (ddd, J = 2.6, 8.5, and 8.5 Hz, 1H), 2.03 (br s, 1H),

1.86 (m, 1H), 1.51 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H); ¹³C

NMR (CDCl₃): d 138.6, 138.2, 138.0, 128.7–127.5, 86.9,

80.4, 79.0, 78.6, 75.1, 74.7, 73.5, 73.5, 69.0, 24.7, 9.6. Anal.

Calcd for C₂₉H₃₄O₅: C, 75.30; H, 7.41. Found: C, 75.29; H,

7.66.

4.10. 6,10-Anhydro-8,9,11-tri-O-benzyl-1,2,3,4,5-pentade-

oxy-^D-glycero-D-gulo-undecitol 1e

Following the general procedure for the preparation of

b-C-glucosides, 32 mL (2.40 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (500 mg,

1.20 mmol) in 6.0 mL of dry CH₂Cl₂at 0 ꢁC. Then, the

product was directly dissolved in Et₂O (12 mL) before add-

ing a 1.0 M solution of n-pentylmagnesium bromide in

Et₂O (3.6 mL, 3.60 mmol). Flash column chromatography

(n-hexane/EtOAc, 9:1) of the residue yielded 1e (438 mg,

0.87 mmol, 72%) as an epimer mixture b/a = 2: TLC

R_f= 0.4 (n-hexane/EtOAc, 8:2); [a]_D= +24.8 (c 1.0,

CHCl₃); HRMS (FAB) Calcd for C₃₂H₄₀O₅(M)⁺:

4.8. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-^D-

glycero-^D-gulo-nonitol 1c

Following the general procedure for the preparation of

b-C-glucosides, 45 mL (3.38 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (697 mg,

1.67 mmol) in 8.5 mL of dry CH₂Cl₂at 0 ꢁC. Later, the

product was directly dissolved in Et₂O (17 mL) before add-

ing n-propylmagnesium chloride (5.0 mL, 5.00 mmol).

1

ꢁ1

~

504.2876. Found: 504.2862; IR m ¼ 3354 cm (OH); H

NMR (CDCl₃):

d

7.40–7.24 (m, 15H), 4.97 (d,

J = 11.6 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.72 (d,

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

941

J = 11.6 Hz, 1H), 4.65 (d, J = 12.3 Hz, 1H), 4.60 (d, J =

10.8 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 3.74 (dd, J = 2.2

and 10.9 Hz, 1H), 3.69 (dd, J = 4.1 and 10.9 Hz, 1H),

3.61 (t, J = 9.3 Hz, 1H), 3.46 (t, J = 8.9 Hz, 1H), 3.41

(ddd, J = 2.2, 4.1, and 9.7 Hz, 1H), 3.31 (t, J = 9.0 Hz,

1H), 3.15 (ddd, J = 2.5, 8.9, and 8.9 Hz, 1H), 2.06 (br s,

1H,), 1.78 (m, 1H), 1.55 (m, 2H), 1.45 (m, 1H), 1.34–1.24

(m, 4H), 0.88 (t, J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃): d

138.6, 138.3, 138.1, 128.7–127.5, 87.0, 79.4, 79.1, 78.6,

75.1, 74.7, 73.9, 73.4, 69.0, 31.9, 31.7, 25.0, 22.6, 14.0. Anal.

Calcd for C₃₂H₄₀O₅: C, 76.16; H, 7.99. Found: C, 76.41; H,

7.89.

2.03 (br s, 1 H), 1.79–1.56 (m, 7H), 1.41 (m, 1H), 1.29–

1.16 (m, 3H), 0.99–0.85 (m, 2H); ¹³C NMR (CDCl₃): d

138.5, 138.2, 138.0, 128.5–127.4, 86.9, 78.9, 78.4, 77.2,

75.0, 74.5, 74.4, 73.2, 68.9, 39.3, 34.3, 33.8, 32.4, 26.5,

26.3, 26.1. Anal. Calcd for C₃₄H₄₂O₅: C, 76.95; H, 7.98.

Found: C, 76.94; H, 7.90.

4.13. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-2,2-

dimethyl-^D-glycero-D-gulo-nonitol 1h

Following the general procedure for the preparation of

b-C-glucosides, 31 mL (2.33 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (478 mg,

1.15 mmol) in 5.8 mL of dry CH₂Cl₂at 0 ꢁC. Then, the

product was directly dissolved in Et₂O (11.5 mL) before

adding 2,2-dimethylpropylmagnesium bromide (3.5 mL,

3.50 mmol). Flash column chromatography (n-hexane/

EtOAc, 9:1) of the residue yielded 1h (397 mg, 0.79 mmol,

69%) as an epimer mixture a/b = 5: TLC R_f= 0.5 (n-hex-

ane/EtOAc, 8:2); [a]_D= +18.1 (c 1.1, CHCl₃); HRMS

(FAB) Calcd for C₃₂H₃₉O₅(Mꢁ1)⁺: 503.2797. Found:

4.11. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-2-

methyl-^D-glycero-D-gulo-nonitol 1f

Following the general procedure for the preparation of

b-C-glucosides, 32 mL (2.40 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (505 mg,

1.21 mmol) in 6.0 mL of dry CH₂Cl₂at 0 ꢁC. Then, the

product was directly dissolved in Et₂O (12 mL) before

adding iso-butylmagnesium bromide (3.6 mL, 3.60 mmol).

Flash column chromatography (n-hexane/EtOAc, 9:1) of

the residue yielded 1f (525 mg, 1.07 mmol, 88%) as an epi-

mer mixture a/b = 2: TLC R_f= 0.4 (n-hexane/EtOAc, 8:2);

[a]_D= +18.2 (c 1.1, CHCl₃); HRMS (FAB) Calcd for

C₃₁H₃₉O₅(M+1)⁺: 491.2797. Found: 491.2799; IR

1

ꢁ1

~

503.2782; IR m ¼ 3512 cm (OH); H NMR (CDCl₃): d

7.38–7.25 (m, 15H), 5.00 (d, J = 11.6 Hz, 1H), 4.84 (d,

J = 10.9 Hz, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.68- 4.64

(m, 2H), 4.58 (d, J = 12.3 Hz, 1H), 3.72 (m, 2H), 3.67 (t,

J = 9.3 Hz, 1H), 3.51 (t, J = 8.5 Hz, 1H), 3.42 (m, 1H),

3.30–3.27 (m, 2H), 2.16 (br s, 1H), 1.74 (br d,

J = 14.5 Hz, 1H), 1.42 (dd, J = 8.5 and 14.5 Hz, 1H),

1.00 (s, 9H); ¹³C NMR (CDCl₃): d 138.6, 138.3, 138.2,

128.6–127.5, 86.9, 78.9, 78.4, 77.2, 75.2, 74.6, 74.4, 73.4,

68.9, 44.5, 30.2 (·3), 30.1. Anal. Calcd for C₃₂H₄₀O₅: C,

76.16; H, 7.99. Found: C, 76.17; H, 8.30.

1

ꢁ1

~

m ¼ 3511 cm (OH); H NMR (CDCl₃): d 7.36–7.22 (m,

15H), 4.97 (d, J = 11.6 Hz, 1H), 4.82 (d, J = 10.9 Hz,

1H), 4.77 (d, J = 11.6 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H),

4.62 (d, J = 10.9 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H),

3.76–3.69 (m, 2H), 3.64 (t, J = 9.3 Hz, 1H), 3.49 (t,

J = 8.7 Hz, 1H), 3.42 (m, 1H), 3.29 (t, J = 9.2 Hz, 1H),

3.23 (br t, J = 9.2 Hz, 1H), 2.36 (br s, 1H), 1.93 (m, 1H),

1.60 (m, 1H), 1.45 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H),

0.92 (d, J = 6.5 Hz, 3H); ¹³C NMR (CDCl₃): d 138.6,

138.2, 138.1, 128.5–127.4, 86.7, 79.0, 78.4, 77.7, 75.0,

74.6, 74.4, 73.3, 68.9, 40.7, 24.3, 23.7, 21.7. Anal. Calcd

for C₃₁H₃₈O₅: C, 75.89; H, 7.81. Found: C, 75.81; H,

7.85.

4.14. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-^D-

glycero-^L-manno-nonitol 2c

Following the general procedure for the preparation of

b-C-galactosides, 14 mL (1.12 mmol) of a solution of

DMDO in acetone was added to a solution of galactal

(210 mg, 0.50 mmol) in 2.5 mL of dry CH₂Cl₂at 0 ꢁC.

Then, the product was directly dissolved in Et₂O

(5.0 mL) before adding a 2.0 M solution of n-propylmagne-

sium chloride in Et₂O (750 lL, 1.50 mmol). Flash column

chromatography (n-hexane/EtOAc, 8.5:1.5) of the residue

yielded 2c (175 mg, 0.37 mmol, 73%) as an epimer mixture

b/a = 1: TLC R_f= 0.6 (n-hexane/EtOAc, 7:3); [a]_D=

+152.7 (c 1.1, CHCl₃); HRMS (EI) Calcd for C₂₃H₂₉O₅

(MꢁC₇H₇)⁺: 385.2015. Found: 385.1998; ¹H NMR

(CDCl₃): d 7.39–7.33 (m, 15H), 4.88 (d, J = 11.6 Hz, 1H),

4.75 (d, J = 11.7 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.55

(d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.49 (d,

J = 11.7 Hz, 1H), 3.69–3.59 (m, 3H), 4.06 (d, J = 2.4 Hz,

1H), 3.80 (t, J = 9.3 Hz, 1H), 3.67–3.59 (m, 3H), 3.40

(dd, J = 2.8 and 9.4 Hz, 1H), 3.21 (ddd, J = 2.4, 9.1, and

9.1 Hz, 1H), 2.44 (br s, 1H), 1.85 (m, 1H), 1.63–1.46 (m,

2H), 1.41 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); ¹³C NMR

(CDCl₃): d 138.5, 137.9, 137.8, 128.5–127.5, 84.3, 79.7,

77.1, 74.3, 73.5, 72.6, 71.5, 70.7, 68.9, 33.9, 18.7, 14.0. Anal.

Calcd for C₃₀H₃₆O₅: C, 75.60; H, 7.61. Found: C, 75.58; H,

7.45.

4.12. 2,6-Anhydro-4,5,7-tri-O-benzyl-1-cyclohexyl-1-deoxy-

D-glycero-D-gulo-heptitol 1g

Following the general procedure for the preparation of

b-C-glucosides, 15 mL (1.13 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (230 mg,

0.55 mmol) in 2.8 mL of dry CH₂Cl₂at 0 ꢁC. The product

was then directly dissolved in Et₂O (5.5 mL) before

adding bromomagnesium methylcyclohexane (1.7 mL,

1.70 mmol). Flash column chromatography (n-hexane/

EtOAc, 9:1) of the residue yielded 1g (140 mg, 0.26 mmol,

48%) as an epimer mixture b/a = 2: TLC R_f= 0.4 (n-hex-

ane/EtOAc, 8.5:1.5); [a]_D= +22.3 (c 1.1, CHCl₃); HRMS

(FAB) Calcd for C₃₄H₄₂O₅(M+1)⁺: 530.3032. Found:

1

ꢁ1

~

530.3060; IR m ¼ 3516 cm (OH); H NMR (CDCl₃): d

7.35–7.22 (m, 15H), 4.97 (d, J = 11.6 Hz, 1H), 4.81 (d,

J = 10.8 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.65 (d,

J = 12.1 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 4.58 (d, J =

12.1 Hz, 1H), 3.75 (dd, J = 2.1 and 11.0 Hz, 1H), 3.69

(dd, J = 4.2 and 11.0 Hz, 1H), 3.62 (t, J = 9.3 Hz, 1H),

3.47 (t, J = 8.6 Hz, 1H), 3.40 (m, 1H), 3.32–3.22 (m, 2H),

942

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

4.15. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-2-

methyl-^D-glycero-L-manno-nonitol 2f

2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H), 1.55

(m, 1H), 1.49–1.41 (m, 2H), 1.32 (m, 1H), 0.89 (t,

J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃): d 170.7, 170.4,

169.7, 169.5, 77.6, 75.6, 74.5, 72.0, 68.8, 62.4, 33.3, 20.7

(·2), 20.6 (·2), 18.3, 13.8. Anal. Calcd for C₁₇H₂₆O₉: C,

54.54; H, 7.00. Found: C, 54.62; H, 7.12.

Following the general procedure for the preparation of

b-C-glucosides, 13 mL (0.98 mmol) of a solution of DMDO

in acetone was added to a solution of galactal (203 mg,

0.49 mmol) in 2.4 mL of dry CH₂Cl₂at 0 ꢁC. Then, the

product was directly dissolved in Et₂O (4.9 mL) before

adding a 2.0 M solution of iso-butylmagnesium bromide

in Et₂O (730 lL, 1.46 mmol). Flash column chromatogra-

phy (n-hexane/EtOAc, 8.5:1.5) of the residue yielded 2f

(115 mg, 0.23 mmol, 48%) as an epimer mixture a/b = 3:

TLC R_f= 0.7 (n-hexane/EtOAc, 7:3); [a]_D= +155.1 (c

1.0, CHCl₃); HRMS (EI) Calcd for C₂₄H₃₁O₅(MꢁC₇H₇)⁺:

399.2171. Found: 399.2162; ¹H NMR (CDCl₃): d 7.37–7.28

(m, 15H), 4.85 (d, J = 11.7 Hz, 1H), 4.72 (d, J = 11.7 Hz,

1H), 4.64 (d, J = 11.7 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H),

4.48 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.03

(d, J = 2.6 Hz, 1H), 3.74 (t, J = 9.2 Hz, 1H), 3.65–3.55

(m, 3H), 3.38 (dd, J = 2.7 and 9.3 Hz, 1H), 3.24 (ddd,

J = 2.3, 9.5, and 9.5 Hz, 1H), 2.30 (br s, 1H), 1.89 (m,

1H), 1.62 (ddd, J = 2.3, 9.6, and 14.2 Hz, 1H), 1.50 (ddd,

J = 4.5, 9.9, and 14.2 Hz, 1H), 0.92 (d, J = 6.7 Hz, 3H),

0.89 (d, J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃): d 138.6,

138.0, 137.8, 128.6–127.6, 84.4, 78.2, 77.2, 74.3, 73.5,

72.5, 71.6, 71.0, 69.0, 40.7, 24.2, 23.7, 21.6. Anal. Calcd

for C₃₁H₃₈O₅: C, 75.89; H, 7.81. Found: C, 75.88; H, 7.99.

4.18. 5,6,7,9-Tetra-O-acetyl-4,8-anhydro-2-methyl-^D-

glycero-^D-gulo-nonitol 3f

Compound 3f (16 mg, 0.041 mmol, 80%) was obtained

from compound 1f (50 mg, 0.053 mmol), as for 3b: TLC

R_f= 0.4 (n-hexane/EtOAc, 6:4); [a]_D= ꢁ14.5 (c 0.5,

CHCl₃); HRMS (FAB) Calcd for C₁₈H₂₉O₉(M+1)⁺:

1

389.1812. Found: 389.1799; H NMR (CDCl₃): d 5.17 (t,

J = 9.4 Hz, 1H), 5.03 (t, J = 9.7 Hz, 1H), 4.84 (t,

J = 9.5 Hz, 1H), 4.24 (dd, J = 5.3 and 12.2 Hz, 1H), 4.07

(dd, J = 2.3 and 12.2 Hz, 1H), 3.61 (ddd, J = 2.3, 5.3,

and 9.9 Hz, 1H), 3.45 (ddd, J = 2.3, 9.9, and 9.9 Hz, 1H),

2.06 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.81

(m, 1H), 1.46 (ddd, J = 4.5, 9.9, and 14.2 Hz, 1H), 1.18

(ddd, J = 2.3, 9.5, and 14.2 Hz, 1H), 0.91 (d, J = 6.7 Hz,

3H), 0.86 (d, J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃): d

170.7, 170.4, 170.0, 169.5, 76.3, 75.7, 74.5, 72.4, 68.8,

62.4, 40.1, 24.3, 23.4, 21.5, 20.7 (·2), 20.6 (·2). Anal. Calcd

for C₁₈H₂₈O₉: C, 55.66; H, 7.27. Found: C, 55.49; H,

7.37.

4.16. 4,5,6,8-Tetra-O-acetyl-3,7-anhydro-1,2-dideoxy-^D-

glycero-^D-gulo-octitol 3b

4.19. 5,6,7,9-Tetra-O-acetyl-4,8-anhydro-1,2,3-trideoxy-2,2-

dimethyl-D-glycero-D-gulo-nonitol 3h

Compound 3b (15 mg, 0.042 mmol, 77%) was obtained

from compound 1b (50 mg, 0.054 mmol), following the

procedure for debenzylation and acetylation, after column

chromatography (n-hexane/EtOAc, 7.5:2.5): TLC R_f= 0.3

(n-hexane/EtOAc, 6:4); [a]_D= ꢁ8.7 (c 0.5, CHCl₃); HRMS

(FAB) Calcd for C₁₆H₂₅O₉(M+1)⁺: 361.1499. Found:

Compound 3h (10 mg, 0.025 mmol, 69%) was obtained

from compound 1h (35 mg, 0.036 mmol), following the

procedure for debenzylation and acetylation, after column

chromatography (n-hexane/EtOAc, 8:2): TLC R_f= 0.4 (n-

hexane/EtOAc, 6:4); [a]_D= ꢁ7.8 (c 0.4, CHCl₃); HRMS

(FAB) Calcd for C₁₉H₃₁O₉(M+1)⁺: 403.1968. Found:

1

361.1505; H NMR (CDCl₃): d 5.17 (t, J = 9.4 Hz, 1H),

403.1962; H NMR (CDCl₃): d 5.17 (t, J = 9.3 Hz, 1H),

5.05 (t, J = 9.7 Hz, 1H), 4.90 (t, J = 9.6 Hz, 1H), 4.25

(dd, J = 5.0 and 12.2 Hz, 1H), 4.10 (dd, J = 2.3 and

12.2 Hz, 1H), 3.62 (ddd, J = 2.3, 5.0, and 9.9 Hz, 1H),

3.34 (ddd, J = 2.9, 8.3, and 9.9 Hz, 1H), 2.07 (s, 3H),

2.03 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.60 (ddddd,

J = 2.9, 7.4, 7.4, 7.4, and 14.8 Hz, 1H), 1.45 (ddddd,

J = 7.4, 7.4, 7.4, 8.3, and 14.8 Hz, 1H), 0.96 (t,

J = 7.4 Hz, 3H); ¹³C NMR (CDCl₃): d 170.7, 170.4,

169.7, 169.5, 78.8, 75.6, 74.5, 71.7, 68.8, 62.4, 24.3, 20.7

(·2), 20.6 (·2), 9.3. Anal. Calcd for C₁₆H₂₄O₉: C, 53.33;

H, 6.71. Found: C, 53.32; H, 6.54.

4.99 (t, J = 9.7 Hz, 1H), 4.82 (t, J = 9.5 Hz, 1H), 4.19

(dd, J = 6.2 and 12.1 Hz, 1H), 4.06 (dd, J = 2.3 and

12.1 Hz, 1H), 3.62 (ddd, J = 2.3, 6.2, and 9.9 Hz, 1H),

3.48 (t, J = 8.9 Hz, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 2.01

(s, 3H), 1.99 (s, 3H), 1.44 (dd, J = 8.9 and 14.7 Hz, 1H),

1.25 (d, J = 14.7 Hz, 1H), 0.91 (s, 9H); ¹³C NMR (CDCl₃):

d 170.6, 170.4, 169.8, 169.6, 75.9, 75.4, 74.5, 72.2, 69.0,

62.7, 44.2, 30.0, 29.8 (·3), 20.7 (·2), 20.6 (·2). Anal. Calcd

for C₁₉H₃₀O₉: C, 56.71; H, 7.51. Found: C, 56.84; H,

7.57.

4.20. 2,6-Anhydro-3,4,5,7-tetra-O-(p-bromobenzoyl)-1-

deoxy-^D-glycero-D-gulo-heptitol 4a

4.17. 5,6,7,9-Tetra-O-acetyl-4,8-anhydro-1,2,3-trideoxy-^D-

glycero-^D-gulo-nonitol 3c

Debenzylation of compound 1a (208 mg, 0.46 mmol) and

then p-bromobenzoylation were performed as in the gen-

eral procedure, giving compound 4a (384 mg, 0.42 mmol,

91%) after column chromatography (n-hexane/EtOAc,

Compound 3c (15 mg, 0.040 mmol, 80%) was obtained

from compound 1c (48 mg, 0.051 mmol), as for 3b: TLC

R_f= 0.4 (n-hexane/EtOAc, 6:4); [a]_D= ꢁ13.0 (c 0.7,

CHCl₃); HRMS (FAB) Calcd for C₁₇H₂₇O₉(M+1)⁺:

8:2):

TLC

R_f= 0.5

(n-hexane/EtOAc,

7.5:2.5);

1

375.1655. Found: 375.1651; H NMR (CDCl₃): d 5.16 (t,

[a]_D= +50.0 (c 1.1, CHCl₃); ¹H NMR (CDCl₃): d 7.86

(d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.6 Hz, 2H), 7.72

(d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.55 (d,

J = 8.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.48 (d,

J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 5.77 (t,

J = 9.4 Hz, 1H), 5.04 (t, J = 9.7 Hz, 1H), 4.87 (t,

J = 9.6 Hz, 1H), 4.24 (dd, J = 5.1 and 12.2 Hz, 1H), 4.09

(dd, J = 2.3 and 12.2 Hz, 1H), 3.61 (ddd, J = 2.3, 5.1,

and 9.9 Hz, 1H), 3.39 (ddd, J = 4.3, 7.0, and 9.9 Hz, 1H),

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

943

J = 9.6 Hz, 1H), 5.60 (t, J = 9.7 Hz, 1H), 5.30 (t,

4.23. 5,9-Anhydro-6,7,8,10-tetra-O-(p-bromobenzoyl)-

1,2,3,4-tetradeoxy-^D-glycero-D-gulo-decitol 4d

J = 9.6 Hz, 1H), 4.56 (dd, J = 3.1 and 12.2 Hz, 1H), 4.43

(dd, J = 4.8 and 12.2 Hz, 1H), 4.07 (ddd, J = 3.1, 4.8,

and 9.7 Hz, 1H), 3.87 (dddd, J = 6.1, 6.1, 6.1, and

9.6 Hz, 1H), 1.34 (d, J = 6.1 Hz, 3H); ¹³C NMR (CDCl₃):

d 165.4, 165.2, 164.7, 164.5, 131.8–131.2, 128.8 (·2), 128.7,

128.4, 128.3, 127.7, 127.5 (·2), 75.6, 74.7, 74.6, 74.0, 70.0,

63.5, 17.7; UV (CH₃CN) k_max245 nm; CD (CH₃CN) k_ext

(De) 251 nm (22.4), 234 nm (ꢁ6.5). Anal. Calcd for

C₃₅H₂₆Br₄O₉: C, 46.19; H, 2.88. Found: C, 46.12; H,

2.92.

Debenzylation of compound 1d (340 mg, 0.69 mmol) and

then p-bromobenzoylation were performed as in the gen-

eral procedure, to give compound 4d (630 mg, 0.66 mmol,

95%) after column chromatography (n-hexane/EtOAc,

9:1): TLC R_f= 0.3 (n-hexane/EtOAc, 9:1); [a]_D= +33.2

1

(c 1.0, CHCl₃); H NMR (CDCl₃): d 7.86 (d, J = 8.5 Hz,

2H), 7.76 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H),

7.65 (d, J = 8.5 Hz, 2H), 7.56–7.52 (m, 4H), 7.49 (d,

J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 5.77 (t,

J = 9.5 Hz, 1H), 5.55 (t, J = 9.7 Hz, 1H), 5.34 (t, J =

9.6 Hz, 1H), 4.55 (dd, J = 3.1 and 12.1 Hz, 1H), 4.43 (dd,

J = 5.4 and 12.1 Hz, 1H), 4.04 (ddd, J = 3.1, 5.4, and

9.7 Hz, 1H), 3.70 (ddd, J = 3.3, 7.7, and 9.6 Hz, 1H),

1.60–1.53 (m, 3H), 1.35–1.25 (m, 3H), 0.84 (t, J = 7.1 Hz,

3H); ¹³C NMR (CDCl₃): d 165.4, 165.2, 164.7, 164.5,

131.8–131.1, 128.8, 128.7, 128.6, 128.5, 128.3, 127.8,

127.6 (·2), 78.2, 75.7, 74.8, 72.7, 70.2, 63.6, 31.0, 27.2,

22.4, 13.9; UV (CH₃CN) k_max245 nm; CD (CH₃CN) k_ext

(De) 251 nm (17.6), 234 nm (ꢁ5.9). Anal. Calcd for

C₃₈H₃₂Br₄O₉: C, 47.93; H, 3.39. Found: C, 47.77; H, 3.51.

4.21. 3,7-Anhydro-4,5,6,8-tetra-O-(p-bromobenzoyl)-1,2-

dideoxy-D-glycero-D-gulo-octitol 4b

Debenzylation of compound 1b (409 mg, 0.88 mmol) and

then p-bromobenzoylation were performed as in the gen-

eral procedure, giving compound 4b (796 mg, 0.86 mmol,

97%) after column chromatography (n-hexane/EtOAc,

8:2): TLC R_f= 0.5 (n-hexane/EtOAc, 8:2); [a]_D= +42.8

1

(c 1.4, CHCl₃); H NMR (CDCl₃): d 7.86 (d, J = 8.5 Hz,

2H), 7.78 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H),

7.65 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.51

(d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.43 (d,

J = 8.5 Hz, 2H), 5.78 (t, J = 9.5 Hz, 1H), 5.57 (t, J =

9.7 Hz, 1H), 5.36 (t, J = 9.6 Hz, 1H), 4.57 (dd, J = 3.1

and 12.1 Hz, 1H), 4.44 (dd, J = 5.1 and 12.1 Hz, 1H),

4.05 (ddd, J = 3.1, 5.1, and 9.7 Hz, 1H), 3.66 (ddd,

J = 3.0, 8.0, and 9.6 Hz, 1H), 1.69 (m, 1H), 1.57 (m, 1H),

1.01 (t, J = 7.4 Hz, 3H); ¹³C NMR (CDCl₃): d 165.4,

165.2, 164.7, 164.5, 131.8–131.1, 128.8, 128.7, 128.6,

128.5, 128.3, 127.8, 127.6 (·2), 79.2, 75.6, 74.8, 72.4, 70.2,

63.5, 24.5, 9.3; UV (CH₃CN) k_max245 nm; CD (CH₃CN)

k_ext(De) 251 nm (21.0), 234 nm (ꢁ6.0). Anal. Calcd for

C₃₆H₂₈Br₄O₉: C, 46.78; H, 3.05. Found: C, 46.87; H,

3.00.

4.24. 6,10-Anhydro-7,8,9,11-tetra-O-(p-bromobenzoyl)-

1,2,3,4,5-pentadeoxy-^D-glycero-D-gulo-undecitol 4e

Debenzylation of compound 1e (148 mg, 0.29 mmol) and

then p-bromobenzoylation were performed as in the gen-

eral procedure, to give compound 4e (276 mg, 0.29 mmol,

98%) after column chromatography (n-hexane/EtOAc,

9:1): TLC R_f= 0.4 (n-hexane /EtOAc, 8.5:1.5);

[a]_D= +34.2 (c 1.2, CHCl₃); ¹H NMR (CDCl₃): d 7.86

(d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.72 (d,

J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.55–7.53 (m,

4H), 7.49 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H),

5.77 (t, J = 9.5 Hz, 1H), 5.55 (t, J = 9.7 Hz, 1H), 5.34 (t,

J = 9.6 Hz, 1H), 4.55 (dd, J = 3.2 and 12.1 Hz, 1H), 4.44

(dd, J = 5.4 and 12.1 Hz, 1H), 4.04 (ddd, J = 3.2, 5.4,

and 9.7 Hz, 1H), 3.70 (ddd, J = 4.0, 7.1, and 9.6 Hz, 1H),

1.58 (m, 3H), 1.35 (m, 1H), 1.24 (m, 4H), 0.83 (t,

J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃): d 165.2, 165.1,

164.6, 164.4, 131.7–131.1, 128.7 (·2), 128.6, 128.4, 128.2,

127.7, 127.5 (·2), 78.1, 75.7, 74.8, 72.7, 70.2, 63.6, 31.4,

31.3, 24.6, 22.4, 13.8; UV (CH₃CN) k_max245 nm; CD

(CH₃CN) k_ext(De) 251 nm (17.4), 234 nm (ꢁ6.0). Anal.

Calcd for C₃₉H₃₄Br₄O₉: C, 48.48; H, 3.55. Found: C,

48.46; H, 3.42.

4.22. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-1,2,3-

trideoxy-^D-glycero-D-gulo-nonitol 4c

Debenzylation of compound 1c (171 mg, 0.36 mmol) and

then p-bromobenzoylation were performed as in the gen-

eral procedure, to give compound 4c (300 mg, 0.32 mmol,

89%) after column chromatography (n-hexane/EtOAc,

9:1): TLC R_f= 0.5 (n-hexane/EtOAc, 8:2); [a]_D= +37.7

1

(c 1.0, CHCl₃); H NMR (CDCl₃): d 7.85 (d, J = 8.6 Hz,

2H), 7.78 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H),

7.65 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.53

(d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.43 (d,

J = 8.6 Hz, 2H), 5.78 (t, J = 9.5 Hz, 1H), 5.56 (t, J =

9.7 Hz, 1H), 5.34 (t, J = 9.6 Hz, 1H), 4.56 (dd, J = 3.2

and 12.1 Hz, 1H), 4.43 (dd, J = 5.3 and 12.1 Hz, 1H),

4.04 (ddd, J = 3.2, 5.3, and 9.7 Hz, 1H), 3.72 (ddd,

J = 3.8, 7.1, and 9.6 Hz, 1H), 1.61–1.54 (m, 3H), 1.40 (m,

1H), 0.89 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃): d

165.3, 165.1, 164.6, 164.4, 131.8–131.1, 128.8, 128.7,

128.6, 128.4, 128.3, 127.7, 127.5 (·2), 78.0, 75.6, 74.8,

72.7, 70.1, 63.5, 33.3, 18.2, 13.8; UV (CH₃CN) k_max

245 nm; CD (CH₃CN) k_ext(De) 251 nm (18.8), 234 nm

(ꢁ6.3). Anal. Calcd for C₃₇H₃₀Br₄O₉: C, 47.36; H, 3.22.

Found: C, 47.56; H, 3.18.

4.25. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-2-

methyl-^D-glycero-D-gulo-nonitol 4f

Debenzylation of compound 1f (235 mg, 0.48 mmol) and

then p-bromobenzoylation as in the general procedure gave

compound 4f (331 mg, 0.35 mmol, 73%) after column chro-

matography (n-hexane/EtOAc, 9:1): TLC R_f= 0.3 (n-hex-

1

ane/EtOAc, 9:1); [a]_D= +28.9 (c 1.1, CHCl₃); H NMR

(CDCl₃): d 7.85 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz,

2H), 7.72 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H),

7.56–7.52 (m, 4H), 7.49 (d, J = 8.5 Hz, 2H), 7.43 (d,

J = 8.5 Hz, 2H), 5.78 (t, J = 9.5 Hz, 1H), 5.54 (t,

J = 9.7 Hz, 1H), 5.32 (t, J = 9.6 Hz, 1H), 4.54 (dd,

944

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

J = 3.1 and 12.1 Hz, 1H), 4.43 (dd, J = 5.7 and 12.1 Hz,

1H), 4.05 (ddd, J = 3.1, 5.7, and 9.7 Hz, 1H), 3.77 (ddd,

J = 2.2, 9.6, and 9.9 Hz, 1H), 1.87 (m, 1H), 1.61 (ddd,

J = 4.4, 9.9, and 14.2 Hz, 1H), 1.30 (ddd, J = 2.2, 9.5,

and 14.2 Hz, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.87 (d,

J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃): d 165.4, 165.2,

164.7, 164.5, 131.9–131.1, 128.9, 128.8, 128.7, 128.5,

128.3, 127.8, 127.6 (·2), 76.7, 75.8, 74.8, 73.1, 70.2, 63.7,

40.1, 24.4, 23.4, 21.5; UV (CH₃CN) k_max245 nm; CD

(CH₃CN) k_ext(De) 251 nm (16.7), 234 nm (ꢁ5.2). Anal.

Calcd for C₃₈H₃₂Br₄O₉: C, 47.93; H, 3.39. Found: C,

48.03; H, 3.63.

4.28. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-1,2,3-

trideoxy-^D-glycero-L-manno-nonitol 5c

Debenzylation of compound 2c (69 mg, 0.14 mmol) and

then p-bromobenzoylation as in the general procedure led

to 5c (125 mg, 0.13 mmol, 92%) after column chromatogra-

phy (n-hexane/EtOAc, 9:1): TLC R_f= 0.5 (n-hexane/

1

EtOAc, 7.5:2.5); [a]_D= +152.7 (c 1.1, CHCl₃); H NMR

(CDCl₃): d 7.90 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz,

2H), 7.78 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H),

7.59 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.53

(d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 5.93 (d,

J = 2.8 Hz, 1H), 5.60 (t, J = 9.7 Hz, 1H), 5.53 (dd,

J = 3.3 and 10.1 Hz, 1H), 4.59 (dd, J = 6.7 and 11.2 Hz,

1H), 4.32 (dd, J = 6.5 and 11.2 Hz, 1H), 4.23 (t,

J = 6.5 Hz, 1H), 3.72 (ddd, J = 3.5, 8.0, and 9.7 Hz, 1H),

1.69–1.58 (m, 3H), 1.42 (m, 1H), 0.93 (t, J = 6.8 Hz, 3H);

¹³C NMR (CDCl₃): d 165.3, 164.9 (·3), 132.1–131.1,

129.0, 128.8, 128.7, 128.5, 128.4, 128.2, 128.0, 127.7, 78.3,

74.1, 73.3, 70.6, 69.1, 62.5, 33.6, 18.3, 13.9; UV (CH₃CN)

k_max245 nm; CD (CH₃CN) k_ext(De) 251 nm (66.9),

234 nm (ꢁ23.5). Anal. Calcd for C₃₇H₃₀Br₄O₉: C, 47.36;

H, 3.22. Found: C, 47.36; H, 3.30.

4.26. 2,6-Anhydro-3,4,5,7-tetra-O-(p-bromobenzoyl)-1-

cyclohexyl-1-deoxy-^D-glycero-D-gulo-heptitol 4g

Debenzylation of compound 1g (205 mg, 0.39 mmol) and

then p-bromobenzoylation as in the general procedure gave

4g (353 mg, 0.36 mmol, 92%) after column chromatogra-

phy (n-hexane/EtOAc, 9:1): TLC R_f= 0.3 (n-hexane/

EtOAc, 9:1); [a]_D= +22.1 (c 1.1, CHCl₃); ¹H NMR

(CDCl₃): d 7.86 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz,

2H), 7.73 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H),

7.55 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.49

(d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 5.77 (t,

J = 9.5 Hz, 1H), 5.52 (t, J = 9.7 Hz, 1H), 5.30 (t,

J = 9.6 Hz, 1H), 4.53 (dd, J = 3.0 and 12.0 Hz, 1H), 4.43

(dd, J = 6.1 and 12.0 Hz, 1H), 4.04 (ddd, J = 3.0, 6.1,

and 9.7 Hz, 1H), 3.80 (ddd, J = 2.3, 9.7, and 9.7 Hz, 1H),

1.76–1.50 (m, 7H), 1.38–1.02 (m, 4H), 0.96–0.78 (m, 2H);

¹³C NMR (CDCl₃): d 165.3, 165.2, 164.7, 164.5, 131.8–

131.1, 128.8, 128.7, 128.6, 128.5, 128.3, 127.8, 127.5 (·2),

76.2, 75.8, 74.8, 73.1, 70.3, 63.7, 38.8, 34.0, 33.9, 32.3,

26.3, 26.2, 26.0; UV (CH₃CN) k_max245 nm; CD (CH₃CN)

k_ext(De) 251 nm (12.2), 234 nm (ꢁ3.8). Anal. Calcd for

C₄₁H₂₆Br₄O₉: C, 49.62; H, 3.66. Found: C, 49.46; H, 3.90.

4.29. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-2-

methyl-^D-glycero-L-manno-nonitol 5f

Debenzylation of compound 2f (50 mg, 0.10 mmol) and

then p-bromobenzoylation as in the general procedure led

to 5f (62 mg, 0.065 mmol, 64%) after column chromatogra-

phy (n-hexane/EtOAc, 9:1): TLC R_f= 0.5 (n-hexane/

1

EtOAc, 7.5:2.5); [a]_D= +155.1 (c 1.0, CHCl₃); H NMR

(CDCl₃): d 7.91 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz,

2H), 7.78 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H),

7.59 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.53

(d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.94 (d,

J = 2.7 Hz, 1H), 5.57 (t, J = 10.0 Hz, 1H), 5.53 (dd,

J = 3.2 and 10.0 Hz, 1H), 4.58 (dd, J = 7.0 and 11.3 Hz,

1H), 4.34 (dd, J = 6.1 and 11.3 Hz, 1H), 4.23 (t,

J = 6.6 Hz, 1H), 3.78 (ddd, J = 2.2, 9.9, and 9.9 Hz, 1H),

1.92 (m, 1H), 1.71 (ddd, J = 4.6, 9.9, and 14.1 Hz, 1H),

1.37 (ddd, J = 2.2, 9.5, and 14.1 Hz, 1H), 0.94 (d,

J = 6.7 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); ¹³C NMR

(CDCl₃): d 165.3, 165.0 (·2), 164.9, 132.1–131.1, 129.0,

128.8, 128.7, 128.5, 128.4, 127.9 (·2), 127.7, 77.0, 74.6,

73.2, 70.9, 69.1, 62.6, 40.4, 24.4, 23.5, 21.5; UV (CH₃CN)

k_max245 nm; CD (CH₃CN) k_ext(De) 251 nm (70.4),

234 nm (ꢁ25.7). Anal. Calcd for C₃₈H₃₂Br₄O₉: C, 47.93;

H, 3.39. Found: C, 47.93; H, 3.49.

4.27. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-1,2,3-

trideoxy-2,2-dimethyl-^D-glycero-D-gulo-nonitol 4h

Debenzylation of compound 1h (66 mg, 0.13 mmol) and

then p-bromobenzoylation as in the general procedure gave

compound 4h (96 mg, 0.099 mmol, 76%) after column

chromatography (n-hexane/EtOAc, 9:1): TLC R_f= 0.4

(n-hexane/EtOAc, 9:1); [a]_D= +14.7 (c 1.1, CHCl₃); ¹H

NMR (CDCl₃): d 7.85 (d, J = 8.5 Hz, 2H), 7.77 (d,

J = 8.5 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.64 (d,

J = 8.5 Hz, 2H), 7.56–7.52 (m, 4H), 7.50 (d, J = 8.5 Hz,

2H), 7.43 (d, J = 8.5 Hz, 2H), 5.78 (t, J = 9.5 Hz, 1H),

5.49 (t, J = 9.7 Hz, 1H), 5.30 (t, J = 9.6 Hz, 1H), 4.52

(dd, J = 2.9 and 12.0 Hz, 1H), 4.40 (dd, J = 6.6 and

12.0 Hz, 1H), 4.07 (ddd, J = 2.9, 6.6, and 9.7 Hz, 1H),

3.81 (dd, J = 8.8 and 9.6 Hz, 1H), 1.58 (dd, J = 8.8 and

14.7 Hz, 1H), 1.38 (d, J = 14.7 Hz, 1H), 0.91 (s, 9H); ¹³C

NMR (CDCl₃): d 165.3, 165.2, 164.7, 164.6, 131.8–131.1,

128.9, 128.8, 128.6, 128.4, 128.3, 127.8, 127.5 (·2), 76.3,

75.6, 74.9, 72.7, 70.3, 63.9, 44.3, 30.1, 29.8 (·3); UV

(CH₃CN) k_max245 nm; CD (CH₃CN) k_ext(De) 251 nm

(10.6), 234 nm (ꢁ3.7). Anal. Calcd for C₃₉H₃₄Br₄O₉: C,

48.48; H, 3.55. Found: C, 48.49; H, 3.67.

4.30. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-^D-

glycero-^D-galacto-nonitol 6c

Following the general procedure for the preparation of

b-C-mannosides, 370 mg (0.78 mmol) of b-C-glucoside 1c

led to 6c (200 mg, 0.42 mmol, 54%), after ﬂash column

chromatography (n-hexane/EtOAc, 8:2): TLC R_f= 0.5

(n-hexane/EtOAc, 7.5:2.5); [a]_D= ꢁ165.3 (c 1.0, CHCl₃);

HRMS (EI) Calcd for C₂₃H₂₉O₅(MꢁC₇H₇)⁺: 385.2015.

Found: 385.1990; ¹H NMR (CDCl₃): d 7.37–7.20 (m,

15H), 4.86 (d, J = 10.8 Hz, 1H), 4.76 (d, J = 11.6 Hz,

1H), 4.68 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H),

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

945

4.57 (d, J = 12.2 Hz, 1H), 4.53 (d, J = 10.8 Hz, 1H), 3.91

(d, J = 2.6 Hz, 1H), 3.79–3.73 (m, 2H), 3.68 (dd, J = 5.1

and 10.8 Hz, 1H), 3.59 (dd, J = 3.3 and 9.1 Hz, 1H), 3.40

(ddd, J = 1.9, 5.1, and 9.8 Hz, 1H), 3.32 (t, J = 6.8 Hz,

1H), 2.18 (br s, 1H), 1.80 (m, 1H), 1.59 (m, 1H), 1.48–

1.39 (m, 2H), 0.95 (d, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃):

d 138.6, 138.5, 138.2, 128.6–126.2, 83.8, 79.4, 78.0, 75.2,

75.0, 73.8, 71.6, 69.7, 68.5, 33.0, 19.3, 14.3. Anal. Calcd

for C₃₀H₃₆O₅: C, 75.60; H, 7.61. Found: C, 75.58; H, 7.64.

to compound 7f (75 mg, 0.078 mmol, 95%) after column

chromatography (n-hexane/EtOAc, 9:1): TLC R_f= 0.4

(n-hexane/EtOAc, 7.5:2.5); [a]_D= ꢁ170.6 (c 1.1, CHCl₃);

¹H NMR (CDCl₃): d 7.90 (d, J = 8.5 Hz, 2H), 7.86 (d,

J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.61 (d, J =

8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz,

2H), 7.49 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H),

5.84 (t, J = 10.0 Hz, 1H), 5.71 (d, J = 3.1 Hz, 1H), 5.57

(dd, J = 3.2 and 10.1 Hz, 1H), 4.67 (dd, J = 2.9 and

12.0 Hz, 1H), 4.44 (dd, J = 5.1 and 12.0 Hz, 1H), 4.06

(ddd, J = 2.8, 5.1, and 9.8 Hz, 1H), 3.94 (dd, J = 4.0 and

8.7 Hz, 1H), 1.78 (m, 1H), 1.63 (ddd, J = 6.2, 8.7, and

14.3 Hz, 1H), 1.28 (ddd, J = 4.0, 7.9, and 14.3 Hz, 1H),

0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H); ¹³C

NMR (CDCl₃): d 165.3, 165.0, 164.9, 164.7, 132.0–131.1,

128.9, 128.8 (·2), 128.7, 128.3, 128.1, 127.7, 127.6, 76.0,

75.7, 73.5, 71.3, 67.5, 63.6, 39.4, 24.5, 22.9, 22.1; UV

(CH₃CN) k_max245 nm; CD (CH₃CN) k_ext(De) 251 nm

(ꢁ71.3), 234 nm (22.9). Anal. Calcd for C₃₈H₃₂Br₄O₉: C,

47.93; H, 3.39. Found: C, 47.77; H, 3.43.

4.31. 4,8-Anhydro-6,7,9-tri-O-benzyl-1,2,3-trideoxy-2-

methyl-^D-glycero-D-galacto-nonitol 6f

Following the general procedure for the preparation of

b-C-mannosides, 135 mg (0.28 mmol) of b-C-glucoside 1f

gave compound 6f (74 mg, 0.15 mmol, 55%), after ﬂash

column chromatography (n-hexane/EtOAc, 8:2): TLC

R_f= 0.5 (n-hexane/EtOAc, 7.5:2.5); [a]_D= ꢁ170.6 (c 1.1,

CHCl₃); HRMS (EI) Calcd for C₂₄H₃₁O₅(MꢁC₇H₇)⁺:

399.2171. Found: 399.2155; ¹H NMR (CDCl₃): d 7.36–

7.20 (m, 15H), 4.86 (d, J = 10.8 Hz, 1H), 4.75 (d,

J = 11.5 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.62 (d, J =

12.2 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.54 (d,

J = 10.8 Hz, 1H), 3.87 (d, J = 3.0 Hz, 1H), 3.78–3.72 (m,

2H), 3.68 (dd, J = 5.1 and 10.9 Hz, 1H), 3.60 (dd, J = 3.2

and 9.1 Hz, 1H), 3.41–3.37 (m, 2H), 1.95 (br s, 1H),

1.82–1.77 (m, 2H), 1.38 (m, 1H), 0.93 (d, J = 6.4 Hz,

3H), 0.91 (d, J = 6.5 Hz, 3H); ¹³C NMR (CDCl₃): d

138.3, 138.3, 137.8, 128.6–127.4, 83.7, 79.3, 76.2, 75.0,

74.8, 73.4, 71.5, 69.5, 68.7, 39.6, 24.6, 23.0, 22.4. Anal.

Calcd for C₃₁H₃₈O₅: C, 75.89; H, 7.81. Found: C, 75.87;

H, 7.86.

4.34. 3,7-Anhydro-5,6,8-tri-O-benzyl-1,2-dideoxy-^D-glycero-

D-gulo-oct-1-enitol 8

Following the general procedure for the preparation of b-

C-glucosides, 39 mL (2.93 mmol) of a solution of DMDO

in acetone was added to a solution of glucal (610 mg,

1.47 mmol) in 7.5 mL of dry CH₂Cl₂at 0 ꢁC. Then, the

product was directly dissolved in Et₂O (30 mL, 20 mL/

mmol) and 2.5 equiv of a solution of bromomagnesium

divinylcuprate in diethyl ether (42.5 mL, 3.67 mmol) was

added. Flash column chromatography (n-hexane/EtOAc,

7.5:2.5) of the residue yielded 8 (407 mg, 0.88 mmol, 60%)

as an epimer mixture b/a = 4.

4.32. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-1,2,3-

trideoxy-^D-glycero-D-galacto-nonitol 7c

4.35. 1,3-Di-O-acetyl-2,6-anhydro-4,5,7-tri-O-benzyl-^D-

glycero-^D-gulo-heptitol 10

Debenzylation of compound 6c (165 mg, 0.35 mmol) and

then p-bromobenzoylation as in the general procedure led

to 7c (310 mg, 0.33 mmol, 95%) after column chromatogra-

phy (n-hexane/EtOAc, 9:1): TLC R_f= 0.4 (n-hexane/

Compound 10 (33 mg, 0.059 mmol, 91%) was obtained

from compound 8 (30 mg, 0.061 mmol), following the

procedure for reductive ozonolysis and acetylation, after

column chromatography (n-hexane/EtOAc, 7.5:2.5): TLC

R_f= 0.4 (n-hexane/EtOAc, 6:4); [a]_D= +19.9 (c 1.1,

CHCl₃); HRMS (FAB) Calcd for C₃₂H₃₇O₈(M+1)⁺:

549.2488. Found: 549.2502; ¹H NMR (CDCl₃): d 7.35–

7.26 (m, 13H), 7.17 (m, 2H), 5.06 (ddd, J = 2.5, 6.8, and

9.6 Hz, 1H), 4.83 (d, J = 11.4 Hz, 1H), 4.79 (d,

J = 10.8 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.62 (d,

J = 12.1 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.56 (d, J =

10.8 Hz, 1H), 4.21 (dd, J = 5.2 and 12.2 Hz, 1H), 4.11

(dd, J = 2.3 and 12.2 Hz, 1H), 3.76 (dd, J = 1.6 and

11.1 Hz, 1H), 3.72–3.65 (m, 3H), 3.56–3.49 (m, 2H), 2.07

(s, 3H), 1.93 (s, 3H); ¹³C NMR (CDCl₃): d 170.8, 169.6,

138.2, 138.1, 137.8, 128.4-127.6, 84.4, 79.3, 78.1, 76.0,

75.2, 75.0, 73.4, 70.3, 68.8, 62.8, 20.8 (·2). Anal. Calcd

for C₃₂H₃₆O₈: C, 70.06; H, 6.61. Found: C, 70.01; H, 7.00.

1

EtOAc, 7.5:2.5); [a]_D= ꢁ165.3 (c 1.0, CHCl₃); H NMR

(CDCl₃): d 7.91 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz,

2H), 7.74 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H),

7.57 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.49

(d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 5.86 (t,

J = 10.0 Hz, 1H), 5.74 (d, J = 3.1 Hz, 1H), 5.55 (dd,

J = 3.2 and 10.1 Hz, 1H), 4.68 (dd, J = 2.9 and 12.1 Hz,

1H), 4.44 (dd, J = 4.9 and 12.1 Hz, 1H), 4.05 (ddd,

J = 2.9, 4.9, and 9.9 Hz, 1H), 3.87 (dd, J = 4.3 and

7.8 Hz, 1H), 1.70–1.47 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H);

¹³C NMR (CDCl₃): d 165.2, 165.0, 164.9, 164.7, 132.0–

131.0, 128.8 (·2), 128.6 (·2), 128.3, 128.0, 127.6 (·2),

77.1, 75.9, 73.5, 70.8, 67.9, 63.5, 32.6, 18.7, 13.8; UV

(CH₃CN) k_max245 nm; CD (CH₃CN) k_ext(De) 251 nm

(ꢁ70.2), 234 nm (20.0). Anal. Calcd for C₃₇H₃₀Br₄O₉: C,

47.36; H, 3.22. Found: C, 47.34; H, 3.48.

4.33. 4,8-Anhydro-5,6,7,9-tetra-O-(p-bromobenzoyl)-2-

methyl-^D-glycero-D-galalcto-nonitol 7f

4.36. 1,3,4,5,7-Penta-O-acetyl-2,6-anhydro-^D-glycero-D-

gulo-heptitol 11

Debenzylation of compound 6f (41 mg, 0.084 mmol) and

then p-bromobenzoylation as in the general procedure led

Debenzylation of compound 10 (22 mg, 40.1 lmol) and

then acetylation were performed as in the general

946

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

procedure leading to 11 (15 mg, 36.8 lmol, 92%) after

column chromatography (n-hexane/EtOAc, 5:5): TLC

R_f= 0.3 (n-hexane/EtOAc, 5:5); HRMS (FAB) Calcd for

C₁₇H₂₅O₁₁(M+1)⁺: 405.1397. Found: 405.1389; ¹H

NMR (CDCl₃): d 5.21 (t, J = 9.3 Hz, 1H), 5.10 (t,

J = 9.7 Hz, 2H), 4.26 (dd, J = 4.9 and 12.4 Hz, 2H), 4.12

(dd, J = 2.1 and 12.4 Hz, 2H), 3.69 (ddd, J = 2.1, 4.9,

and 9.7 Hz, 2H), 2.09 (s, 6H), 2.03 (s, 6H), 2.01 (s, 3H);

¹³C NMR (CDCl₃): d 170.6 (·2), 170.3, 169.4 (·2), 75.9

(·2), 74.2, 68.2 (·2), 62.1 (·2), 20.7 (·2), 20.6 (·3). Anal.

Calcd for C₁₇H₂₄O₁₁: C, 50.49; H, 5.98. Found: C, 50.45;

H, 6.20.

EtOAc, 6:4); [a]_D= ꢁ33.0 (c 1.2, CHCl₃); HRMS (FAB)

Calcd for C₃₁H₂₇Br₃O₉(M)⁺: 785.9144. Found: 785.9149;

¹H NMR (CDCl₃): d 7.84 (d, J = 8.4 Hz, 2H), 7.77 (d,

J = 8.4 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.53–7.44 (m,

6H), 5.61 (t, J = 9.3 Hz, 1H), 5.52 (t, J = 9.5 Hz, 1H),

4.53 (dd, J = 2.7 and 12.2 Hz, 1H), 4.38 (dd, J = 4.8 and

12.2 Hz, 1H), 4.06 (ddd, J = 2.7, 4.8, and 9.5 Hz, 1H),

4.02 (dd, J = 5.2 and 10.5 Hz, 1H), 3.94 (t, J = 9.5 Hz,

1H), 3.81 (t, J = 10.5 Hz, 1H), 3.56 (ddd, J = 5.2, 9.8,

and 9.8 Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H); ¹³C NMR

(CDCl₃): d 165.3, 165.1, 164.6, 131.8–131.2, 128.8, 128.4,

128.3 (·3), 127.5, 99.8, 76.4, 74.0, 72.2, 71.7, 70.3, 63.4,

62.0, 28.8, 19.0; UV (CH₃CN) k_max245 nm; CD (CH₃CN)

k_ext(De) 254 nm (ꢁ18.4), 237 nm (10.5). Anal. Calcd for

C₃₁H₂₇Br₃O₉: C, 47.54; H, 3.47. Found: C, 47.51; H, 3.60.

4.37. 2,6-Anhydro-4,5,7-tri-O-benzyl-1,3-O-iso-propylidene-

D-glycero-D-gulo-heptitol 12

Compound 12 (338 mg, 0.67 mmol, 93%) was obtained

from compound 8 (333 mg, 0.72 mmol), following the pro-

cedure for reductive ozonolysis and ketal formation, after

column chromatography (n-hexane/EtOAc, 7.5:2.5): TLC

R_f= 0.6 (n-hexane/EtOAc, 6:4); [a]_D= +18.7 (c 1.4,

CHCl₃); HRMS (FAB) Calcd for C₃₁H₃₇O₆(M+1)⁺:

505.2590. Found: 505.2589; ¹H NMR (CDCl₃): d 7.39–

7.28 (m, 13H), 7.16 (m, 2H), 4.93 (d, J = 11.3 Hz, 1H),

4.88 (d, J = 10.8 Hz, 1H), 4.77 (d, J = 11.3 Hz, 1H), 4.61

(d, J = 12.3 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.50 (d,

J = 10.8 Hz, 1H), 3.97 (dd, J = 5.3 and 10.8 Hz, 1H),

3.79 (t, J = 10.5 Hz, 1H), 3.74–3.66 (m, 4H), 3.62 (t,

J = 9.4 Hz, 1H), 3.54 (ddd, J = 1.7, 3.7, and 9.3 Hz, 1H),

3.29 (ddd, J = 5.3, 9.6, and 9.6 Hz, 1H), 1.52 (s, 3H),

1.45 (s, 3H); ¹³C NMR (CDCl₃): d 138.9, 138.2, 137.9,

128.6-127.5, 99.1, 83.6, 79.5, 77.5, 75.2, 74.9, 74.6, 73.5,

71.4, 69.0, 62.4, 29.2, 19.2. Anal. Calcd for C₃₁H₃₆O₆: C,

73.79; H, 7.19. Found: C, 73.64; H, 7.11.

4.40. 1-O-Acetyl-2,6-anhydro-3,4,5,7-tetra-O-benzyl-^D-

glycero-^D-gulo-heptitol 17

Two equivalents (25 mg, 0.99 mmol) of sodium hydride

was added to a solution of substrate 8 in dry DMF

(5 mL/mmol) under a nitrogen atmosphere. After 15 min,

2 equiv of benzyl bromide (120 ll, 0.99 mmol) was added

dropwise. When the reaction was complete, it was

quenched with water and the mixture extracted with

CH₂Cl₂. The combined organic layers were washed with

saturated NH₄Cl solution, saturated NaHCO₃solution,

and brine, dried over anhydrous Na₂SO₄, ﬁltered, and con-

centrated. Then the residue was submitted to the reductive

ozonolysis and acetylation procedure to give compound 17

(255 mg, 0.43 mmol, 87%), after column chromatography

(n-hexane/EtOAc, 7.5:2.5): TLC R_f= 0.5 (n-hexane/

EtOAc, 6:4); [a]_D= ꢁ6.0 (c 0.5, CHCl₃); HRMS (FAB)

Calcd for C₃₇H₄₁O₇(M+1)⁺: 597.2852. Found: 597.2846;

¹H NMR (CDCl₃): d 7.34–7.26 (m, 18H), 7.16 (m, 2H),

4.95–4.88 (m, 2H), 4.87 (d, J = 11.0 Hz, 1H), 4.82 (d,

J = 10.8 Hz, 1H), 4.63-4.57 (m, 3H), 4.55 (d, J = 12.2 Hz,

1H), 4.38 (dd, J = 1.8 and 11.9 Hz, 1H), 4.21 (dd, J = 4.6

and 11.9 Hz, 1H), 3.76–3.68 (m, 3H), 3.63 (t, J = 9.3 Hz,

1H), 3.55–3.51 (m, 2H), 3.47 (ddd, J = 2.1, 4.1, and

9.6 Hz, 1H), 2.04 (s, 3H); ¹³C NMR (CDCl₃): d 170.8,

138.5, 138.2, 138.0, 137.7, 128.5–127.6, 87.2, 79.2, 78.3,

78.1, 77.0, 75.6, 75.1, 75.0, 73.5, 68.9, 63.5, 20.9. Anal.

Calcd for C₃₇H₄₀O₇: C, 74.47; H, 6.76. Found: C, 74.41;

H, 6.89.

4.38. 4,5,7-Tri-O-acetyl-2,6-anhydro-1,3-O-iso-propylidene-

D-glycero-D-gulo-heptitol 13

Debenzylation of compound 12 (89 mg, 0.18 mmol) and

then acetylation were performed as in the general proce-

dure leading to compound 13 (49 mg, 0.14 mmol, 77%)

after column chromatography (n-hexane/EtOAc, 6:4):

TLC R_f= 0.3 (n-hexane/EtOAc, 6:4); [a]_D= +42.3 (c 1.0,

CHCl₃); HRMS (FAB) Calcd for C₁₆H₂₅O₉(M+1)⁺:

1

361.1499. Found: 361.1498; H NMR (CDCl₃): d 5.11 (t,

J = 9.3 Hz, 1H), 5.00 (t, J = 9.5 Hz), 4.19 (dd, J = 4.8

and 12.4 Hz), 4.04 (dd, J = 2.0 and 12.4 Hz), 3.92 (dd,

J = 5.3 and 10.8 Hz), 3.71 (t, J = 10.5 Hz), 3.69 (m, 2H),

3.33 (ddd, J = 5.3, 9.9, and 9.9 Hz, 1H), 2.09 (s, 3H),

2.05 (s, 3H), 2.03 (s, 3H), 1.47 (s, 3H), 1.39 (s, 3H); ¹³C

NMR (CDCl₃): d 170.6, 170.3, 169.7, 99.7, 76.4, 73.4,

71.8, 71.3, 69.0, 62.2, 61.9, 28.8, 20.8, 20.7, 20.6, 18.9. Anal.

Calcd for C₁₆H₂₄O₉: C, 53.33; H, 6.71. Found: C, 53.29; H,

6.76.

4.41. 1-O-Acetyl-2,6-anhydro-3,4,5,7-tetra-O-(p-bromo-

benzoyl)-^D-glycero-D-gulo-heptitol 18 and 2,6-anhydro-

1,3,4,5,7-penta-O-(p-bromobenzoyl)-^D-glycero-D-gulo-hepti-

tol 19

Debenzylation of compound 17 (234 mg, 0.39 mmol) and

then p-bromobenzoylation as in the general procedure led

to 18 (240 mg, 0.25 mmol, 63%) and 19 (102 mg,

0.092 mmol, 23%) after column chromatography (n-hex-

ane/EtOAc, 7.5:2.5).

4.39. 2,6-Anhydro-4,5,7-penta-O-(p-bromobenzoyl)-1,3-O-

iso-propylidene-^D-glycero-D-gulo-heptitol 14

Compound 18: TLC R_f= 0.6 (n-hexane/EtOAc, 6:4);

[a]_D= +32.9 (c 1.1, CHCl₃); ¹H NMR (CDCl₃): d 7.85

(d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.72 (d,

J = 8.6 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.56–7.52 (m,

4H), 7.49 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H),

Debenzylation of compound 12 (112 mg, 0.22 mmol) and

then p-bromobenzoylation as in the general procedure led

to 14 (140 mg, 0.18 mmol, 80%) after column chromatogra-

phy (n-hexane/EtOAc, 7.5:2.5): TLC R_f= 0.6 (n-hexane/

C. Mayato et al. / Tetrahedron: Asymmetry 18 (2007) 931–948

947

Surolia, A.; Vijayan, M.; Lim, S.; Kishi, Y. J. Am. Chem. Soc.

1998, 120, 11297–11303; (f) Kishi, Y. Tetrahedron 2002, 58,

6239–6258, and references cited therein.

5.82 (t, J = 9.6 Hz, 1H), 5.61 (t, J = 9.7 Hz, 1H), 5.54 (t,

J = 9.7 Hz, 1H), 4.58 (dd, J = 3.1 and 12.2 Hz, 1H), 4.46

(dd, J = 4.9 and 12.2 Hz, 1H), 4.29 (dd, J = 5.0 and

12.3 Hz, 1H), 4.24 (dd, J = 2.9 and 12.3 Hz, 1H), 4.11

(ddd, J = 3.1, 4.9, and 9.8 Hz, 1H), 4.01 (ddd, J = 2.9,

5.0, and 9.7 Hz, 1H), 2.02 (s, 3H); ¹³C NMR (CDCl₃): d

170.4, 165.2, 165.0, 164.4 (·2), 131.8–131.1, 128.9 (·2),

128.7, 128.3, 128.2, 127.4, 127.3 (·2), 76.0, 75.8, 74.4,

69.6, 69.3, 63.2, 62.4, 20.6; UV (CH₃CN) k_max245 nm;

CD (CH₃CN) k_ext(De) 251 nm (20.9), 234 nm (ꢁ6.6). Anal.

Calcd for C₃₇H₂₈Br₄O₁₁: C, 45.90; H, 2.91. Found: C,

45.91; H, 2.88.

´

5. (a) Espinosa, J. F.; Martın-Pastor, M.; Asensio, J. L.;

´

Dietrich, H.; Martın-Lomas, M.; Schmidt, R. R.; Jimenez-

Barbero, J. Tetrahedron Lett. 1995, 36, 6329–6332; (b)

´

Espinosa, J. F.; Canada, F. J.; Asensio, J. L.; Martın-Pastor,

˜

´

M.; Dietrich, H.; Martın-Lomas, M.; Schmidt, R. R.;

´

Jimenez-Barbero, J. J. Am. Chem. Soc. 1996, 118, 10862–

10871; (c) Espinosa, J. F.; Montero, E.; Vian, A.; Garcia, J.

´

L.; Dietrich, H.; Schmidt, R. R.; Martın-Lomas, M.; Imberty,

´

A.; Canada, F. J.; Jimenez-Barbero, J. J. Am. Chem. Soc.

˜

1998, 120, 1309–1318; (d) Asensio, J. L.; Canada, F. J.;

˜

´

Garcia-Herrero, A.; Murillo, M. T.; Fernandez-Mayoralas,

´

A.; Johns, B. A.; Kozak, J.; Zhu, Z.; Johnson, C. R.; Jimenez-

Compound 19: TLC R_f= 0.6 (n-hexane/EtOAc, 6:4);

Barbero, J. J. Am. Chem. Soc. 1999, 121, 11318–11329; (e)

Asensio, J. L.; Canada, F. J.; Cheng, X.; Khan, N.; Mootoo,

D. R.; Jimenez-Barbero, J. Chem. Eur. J. 2000, 6, 1035–1041;

HRMS (FAB) Calcd for C₄₂H₂₉Br₅O₁₁(M)⁺: 1113.7524.

˜

Found: 1113.7495; ¹H NMR (CDCl₃):

d 7.80 (d,

´

J = 8.6 Hz, 4H), 7.73 (d, J = 8.6 Hz, 4H), 7.65 (d,

J = 8.6 Hz, 2H), 7.51–7.48 (m, 8H), 7.43 (d, J = 8.6 Hz,

2H), 5.86 (t, J = 9.6 Hz, 1H), 5.61 (t, J = 9.8 Hz, 2H),

4.60 (dd, J = 3.0 and 12.2 Hz, 2H), 4.44 (dd, J = 5.2 and

12.2 Hz, 2H), 4.15 (ddd, J = 3.0, 5.2, and 9.8 Hz, 2H);

¹³C NMR (CDCl₃): d 165.2 (·2), 165.1, 164.4 (·2),

131.8–131.1, 129.0 (·2), 128.8, 128.4 (·2), 128.3 (·2),

127.3 (·3), 75.9 (·2), 74.4, 69.6 (·2), 63.2 (·2); UV

(CH₃CN) k_max245 nm. Anal. Calcd for C₄₂H₂₉Br₅O₁₁: C,

45.48; H, 2.64. Found: C, 45.48; H, 2.59.

´

(f) Jimenez-Barbero, J.; Espinosa, J. F.; Asensio, J. L.;

Canada, F. J.; Poveda, A. Adv. Carbohydr. Chem. Biochem.

2001, 56, 235–284; (g) Garcia-Herrero, A.; Montero, E.;

Munoz, J. L.; Espinosa, J. F.; Vian, A.; Garcıa, J. L.;

Asensio, J. L.; Canada, F. J.; Jimenez-Barbero, J. J. Am.

˜

´

˜

´

˜

Chem. Soc. 2002, 124, 4804–4810.

6. Houk, K. N.; Eksterowicz, J. E.; Wu, Y.-D.; Fuglesang, C.

D.; Mitchell, D. B. J. Am. Chem. Soc. 1993, 115, 4170–4177.

7. (a) Juaristi, E.; Cuevas, G. In The Anomeric Eﬀect in New

Directions in Organic and Biological Chemistry; Juaristi Rees,

´

C. W., Ed.; CRC: Boca Raton, FL, 1995; (b) Tvaroska, I.;

Carver, J. P. J. Phys. Chem. 1995, 99, 6234–6241; (c) Cramer,

C.; Truhlar, D. G.; French, A. D. Carbohydr. Res. 1997, 298,

1–14.

Acknowledgments

8. The ﬁrst descriptor indicates the torsional relationship

between O6 and O5, and the second that between O6 and C4.

Support of this work by the Universidad de La Laguna

(Spain) is gratefully acknowledged. C.M. thanks the Con-

´

9. (a) Morales, E. Q.; Padron, J. I.; Trujillo, M.; Vazquez, J. T. J.

´

Org. Chem. 1995, 60, 2537–2548; (b) Padron, J. I.; Morales, E.

´

sejerıa de Educacion, Cultura y Deportes (Gobierno de

´

Q.; Vazquez, J. T. J. Org. Chem. 1998, 63, 8247–8258; (c)

Canarias) for a fellowship.

´

Nobrega, C.; Vazquez, J. T. Tetrahedron: Asymmetry 2003, 14,

´

2793–2801; (d) Mayato, C.; Dorta, R. L.; Vazquez, J. T.

Tetrahedron: Asymmetry 2004, 15, 2385–2397; (e) Roe¨n, A.;

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3

0

20. Since no J_{H1,H1 S}was detectable and J_{H1,H1 R}had a high

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3

conformer, H1–C1–C1⁰–H1⁰S ꢂ 90ꢁ, J_{H1,H1 S}= 0) was

0

assumed.

21. The axial conﬁguration at C4 in alkyl galactopyranosides

makes the gt and tg more stable rotamers.

Article Doi

The exo-deoxoanomeric effect in the conformational preferences of C-glycosides

DOI: 10.1016/j.tetasy.2007.04.007

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Full text of DOI:10.1016/j.tetasy.2007.04.007

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