Efficient synthesis of 2,6,7,8-tetrahydroxyindolizidines (castanospermine analogues) via the dipolar cycloadditions of N-benzyl-C-(tetrofuranos-4-yl)nitrones to methyl acrylate

Tetrahedron: Asymmetry 18 (2007) 1809–1827

Eﬃcient synthesis of 2,6,7,8-tetrahydroxyindolizidines

(castanospermine analogues) via the dipolar cycloadditions of

N-benzyl-C-(tetrofuranos-4-yl)nitrones to methyl acrylate

a

´

M Isabel Torres-Sanchez, Pastora Borrachero, Francisca Cabrera-Escribano,

a,

b

c

´

*

´

Manuel Gomez-Guillen, Manuel Angulo-Alvarez, Eleuterio Alvarez,

Sylvain Favre^dand Pierre Vogel^d

^aDepartamento de Quı´mica Orga´nica ‘Profesor Garcı´a Gonza´lez’, Facultad de Quı´mica, Universidad de Sevilla,

Apartado de Correos No. 1203, E-41071 Sevilla, Spain

^bServicio de RMN, Centro de Investigacio´n, Tecnologı´a e Innovacio´n de la Universidad de Sevilla (C.I.T.I.U.S.),

Avda. Reina Mercedes, s/n, E-41012 Sevilla, Spain

^cInstituto de Investigaciones Quı´micas, C.S.I.C.-Universidad de Sevilla, Centro de Investigaciones Cientı´ﬁcas ‘Isla de La Cartuja’,

Avda. Ame´rico Vespucio, 49, E-41092 Sevilla, Spain

d

`

´

Laboratoire de Glycochimie et de synthese asymetrique, Swiss Federal Institute of Technology (EPFL),

BCH, CH-1014 Lausanne-Dorigny, Switzerland

Received 6 June 2007; accepted 1 August 2007

Abstract—The dipolar cycloaddition of (Z)-N-benzyl-(3-O-benzyl-1,2-O-isopropylidene-a-D-ribofuranos-5-ylidene)amine N-oxide to

methyl acrylate gives a 53:16:26:5 diastereomeric mixture of isoxazolidine derivatives. The dipolar cycloaddition of the xylo analogue

to methyl acrylate is more diastereoselective, producing a 44:13:43 mixture of only three diastereomers. The ribo-conﬁgured adducts have

been converted (4 steps only) into the new (2R,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aS)- and (2R,6S,7S,8R,8aS)-2,6,7,8-

tetrahydroxyindolizidines. Similarly, the two xylo-conﬁgured major isoxazolidine derivatives were converted into the known derivatives

(2R,6S,7R,8R,8aS)- and (2S,6S,7R,8R,8aR)-2,6,7,8-tetrahydroxyindolizidines. The six isomeric indolizidine derivatives obtained have

been evaluated for their inhibiting activities towards 15 glycosidases. Only the (2R,6S,7S,8R,8aR)-conﬁgured isomer is a selective inhib-

itor of amyloglucosidases from Aspergillus niger (IC₅₀= 350 lM) and from Rhizopus mold (IC₅₀= 90 lM, K_i= 195 lM, non-compet-

itive), the other indolizidines show very little inhibitory activity at 1 mM concentration.

1. Introduction

HO

OH

H

N

H

N

H

N

HO

Polyhydroxylated indolizidines are compounds of high

interest as their most prominent natural derivatives, cast-

anospermine 1, swainsonine 2 and lentiginosine 3¹are

potent glycosidase inhibitors²and potential therapeutic

agents against HIV,^3,4hepatitis C,⁵HSV 1,⁶multiple scle-

rosis,⁷cancer⁸or diabetes.⁹This has resulted in much eﬀort

from synthetic chemists to develop synthetic routes

towards 1–3^10–13and analogues.^14–19

OH

1: (+)-castanospermine 2: (-)-swainsonine

3: (+)-lentiginosine

As we had shown that 1,2,6,7,8-pentahydroxyindolizidines

with cis,cis-6,7,8-trihydroxy moieties can be potent and

selective inhibitors of a-mannosidases,²⁰we have embarked

on a project to generate more polyhydroxyindolizidines

with cis,cis-6,7,8-trihydroxy substituents.

*

A very useful general method for the synthesis of polyfunc-

tional higher-chain products is the 1,3-cycloaddition of

Corresponding author. Tel.: +34 954 557151; fax: +34 954 624960;

e-mail: mguillen@us.es

doi:10.1016/j.tetasy.2007.08.001

1810

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

Bn

N

HO

H

O

HO

O

OH

OBn

OH

N

O

4

5

6

HO

H

HO

N

7

8

Scheme 1. Dhavale’s synthesis of 2-hydroxy-1-deoxycastanospermine analogues.

sugar-derived nitrones to oleﬁns. An early review on the

stereoselectivity of the reaction for a number of examples

was published by Fisˇera et al. in 1992.²¹Several research

groups have applied this methodology for diﬀerent pur-

poses, including the preparation of higher-chain amino

sugars and/or other derivatives. For instance, the 1,3-di-

polar cycloaddition of tetrose-derived nitrones to styrene

has been used as a model for studying its stereoselectivity,²²

while a cyclic nitrone has been made to react with a glycal

to aﬀord imino-C-disaccharides,²³or with an a,b-unsatu-

rated d-lactone,²⁴or with open-chain a,b-unsaturated

esters²⁵to give polyhydroxyindolizidines. We have applied

this approach to the synthesis of C₇and C₈aminodialdos-

es²⁶and to the synthesis of polyhydroxyperhydroazaazu-

lenes²⁷(homologues of 1) starting from a C-glycosyl

nitrone derived from ^D-galactose and methyl acrylate as

the dipolarophile. The same method is now applied to nit-

rones derived from pentoses and generates 2,6,7,8-tetra-

hydroxyindolizidines. While this work was underway,

Dhavale et al.^18breported a similar approach based on

the 1,3-dipolar cycloaddition of ^D-xylose-derived nitrone

4 with allyl alcohol, which led to the preparation of

2-hydroxy-1-deoxycastanospermine stereomers 5 and 6

and 2-hydroxy-1-deoxy-8a-epi-castanospermine stereomers

7 and 8 (Scheme 1).

a ﬁrst fraction containing a 1:0.41 mixture of lactams 11

and 12 and a second fraction (21%) containing pure 13.

The major compound 11 could be isolated by crystalliza-

tion from absolute EtOH. Its structure was established

unambiguously by X-ray diﬀraction studies (Fig. 1).

Similarly, the mixture of 10c and 10d was converted into

a 10:3.5 mixture of lactams 14 and 15 (69%) and the

debenzylated derivative 16 (8%). Pure 14 was obtained by

crystallization from absolute EtOH with its structure

established by X-ray diﬀraction studies (Fig. 2).

This allowed us to propose the structures shown in Scheme

2 for diastereomers 12 and 15. The 3,5-cis relative conﬁgu-

ration of 11 and 14 was conﬁrmed by the observation of the

1

NOE’s in the 2D-NOESY H NMR spectra of these com-

pounds. Such NOE’s were not observed for 12 and 15. The

structures of the debenzylated derivatives 13 and 16 were

deduced from their 2D NOESY ¹H NMR spectra and fur-

ther conﬁrmed by their conversion into tetrahydroxyindol-

izidines (see below).

The reduction of pyrrolidinone mixtures 11 and 12, and 14

and 15 with LiAlH₄in Et₂O aﬀorded the expected mixtures

of hydroxypyrrolidines 17 and 18 (81%) and 19 and 20

(75%), respectively. Column chromatography on silica gel

of these mixtures gave pure 17 (39%), 18 (19%), 19 (47%)

and 20 (8.5%). When pure 11 and 14 were reduced by

LiAlH₄in Et₂O, pure 17 and pure 19 were both isolated

in 96% yield. Applying the method we developed for the

synthesis of pentahydroxyperhydroazaazulene,²⁷com-

pounds 17–20 were converted into the four stereoisomeric

(2,6S,7S,8R)-tetrahydroxyindolizidines 25–28. The reac-

tion sequences start with the hydrolysis of the acetonide

moieties in 80% aqueous CF₃COOH, to give the corre-

sponding furanoses 21 (98%), 22 (96%), 23 (98%) and 24

(98%). Subsequent hydrogenolysis of the benzyl ether and

benzyl amine moieties (H₂/Pd–C) led to the corresponding

5-aminoaldehydes, which equilibrated with the correspond-

ing bicyclic imines that were reduced^18b,19ainto the indol-

izidines 25 (97%), 26 (96%), 27 (97%) and 28 (97%),

respectively.

2. Results and discussion

We have previously studied the 1,3-dipolar cycloaddition

of methyl acrylate to the ^D-ribose-derived nitrone 9.²⁸

The reaction of 9 with methyl acrylate in toluene at 35 ꢁC

gives a 53:16:26:5 mixture of the four possible adducts

10a, 10b, 10c and 10d in 90% yield (Scheme 2). This lack

of diastereoselectivity is in contrast with the good diastere-

oselectivity we observed for the 1,3-dipolar cycloaddition

of methyl acrylate to a ^D-galactose-derived nitrone.²⁷Col-

umn chromatography on silica gel provided two fractions,

the ﬁrst one containing a 10:3 mixture of 10a and 10b

(62%) while the second one was made up of a 10:1.9 mix-

ture of 10c and 10d (28%). Treatment of these two mixtures

with Mo(CO)₆in boiling CH₃CN/H₂O^29–31provided the

corresponding mixtures of lactams, along with variable

amounts of debenzylated derivatives. Thus, from the 10:3

mixture of 10a and 10b, a mixture of 11 and 12 was

obtained. Column chromatography on silica gel provided

The N-debenzylated pyrrolidinone derivative 13 could also

be converted into tetrahydroxyindolizidine 25, thus con-

tributing to the overall yield of this compound. Reduction

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1811

Bn

N

O

E

NBn

R

NBn

R

NBn

R

NBn

R

E

toluene

35°C

+

O

BnO

O

9

10a

10b

10c

10d

O

E = COOMe

R =

O

BnO

O

3

HO

Mo(CO)₆

MeCN/H₂O

NR'

R

NBn

R

+

10a + 10b

5

11 R' = Bn (X-ray)

13 R' = H

12

O

HO

₈H

HO

7

HO

Mo(CO)₆

MeCN/H₂O

NR'

R

NBn

R

+

10c + 10d

OH

6

2

N

5

Ha³

Ha

Hb

14 R' = Bn (X-ray)

16 R' = H

15

25

HO

H

HO

OH

N

HO

CF₃COOH

H₂O, 20°C

LiAlH₄

Et₂O

NBn

R

NBn

4

26

O

2

OH

HO

H

HO

BnO OH

N

CHO

(2R,4R): 17

(2R,4S): 18

(2S,4S): 19

(2S,4R): 20

21

22

23

24

27

H

HO

N

28

Scheme 2. Synthesis of the four stereoisomeric (2,6S,7S,8R)-tetrahydroxyindolizidines 25–28.

1

of 13 with LiAlH₄in Et₂O aﬀorded 29 (96%). When treated

with CF₃COOH/H₂O, this compound did not produce the

desired furanose 30, but a mixture of bicyclic compounds.

We thus protected the pyrrolidine moiety of 29 as a benzyl

carbamate under standard conditions (Scheme 3). This

produced 31 in 97% yield. Subsequent acidic hydrolysis

(CF₃COOH/H₂O) and hydrogenation (H₂/Pd–C) provided

25 in 88% yield.

C(5)/H_a-3 correlations. The H NMR spectra of 25 and

26 show relatively large H,H coupling constants ³J(H-

8,H-8a) and J(H_b-5,H-6) as expected for trans diaxial vic-

3

8

inal proton pairs. This suggests C₅conformations for the

piperidine moieties with an (8aR)-conﬁguration. The 2D

and 1D-NOESY ¹H NMR spectra of 25 show NOE

between the proton pair H-2 (d_H= 4.33 ppm)/H-8a

(d_H= 2.33 ppm), thus establishing the (2R)-conﬁguration.

Furthermore, NOE’s were observed between the proton

pairs H-6 (d_H= 3.80 ppm)/H-8 (d_H= 3.42 ppm) and H-

8a (d_H= 2.33 ppm)/H_b-5 (d_H= 2.28 ppm). The 2D

The structures of the new tetrahydroxyindolizidines 25–28

were deduced from those of 11, 12, 14 and 15, respectively,

while those of 11 and 14 were established by X-ray diﬀrac-

tion studies (Figs. 1 and 2). No epimerization was expected

to occur under the conditions applied for the conversion of

11, 12, 14 and 15 into 25–28. The spectral data of 25–28

were all in agreement with the proposed structures. The

bicyclic structures were corroborated by the heteronuclear

bond correlation HMBC experiments showing typical

1

NOESY H NMR spectrum of 26 shows NOE’s between

proton pairs H_b-1 (d_H= 1.45 ppm)/H-8 (d_H= 3.42 ppm)

and H_b-1 (d_H=1.45 ppm)/H-2 (d_H= 4.47 ppm) conﬁrming

the cis relative conﬁguration between these protons and

deﬁning the (2S) conﬁguration. This spectrum also shows

NOE’s between proton pairs H-6 (d_H= 3.82 ppm)/H-8

(d_H= 3.42 ppm)

and

H_b-5

(d_H= 2.75 ppm)/H-8a

1812

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

Figure 2. ORTEP drawing of the molecule 14 showing thermal ellipsoids

at the 30% probability level. Hydrogen atoms have been omitted for

clarity, except for those directly attached to the stereogenic carbon atoms.

Figure 1. ORTEP drawing of the molecule 11 showing thermal ellipsoids

at the 30% probability level. Hydrogen atoms have been omitted for

clarity, except for those directly attached to the stereogenic carbon atoms.

8

spectra of 25 and 28 showed that H-6 and H-8 are more

deshielded in 25 than in 28 whereas H-7 is more shielded

in 25 than in 28. Similar eﬀects were seen when comparing

the H NMR spectra of 26 and 27. This is consistent with

the exchange of protons from the axial to equatorial posi-

tion and vice versa.

(d_H= 3.14 ppm). This conﬁrms the C₅conformation of

the piperidine ring of 26 (Fig. 3).

1

5

The NMR data for 27 and 28 were consistent with C₈

rather than C₅conformations for their piperidine rings

(Fig. 3). The 2D NOESY H NMR spectrum of 27 shows

8

1

NOE’s between proton pairs H-7 (d_H= 3.61 ppm)/H-8a

(d_H= 2.78 ppm) and H-2 (d_H= 4.50 ppm)/H-8a (d_H=

2.78 ppm), conﬁrming the (2S,8aS) conﬁguration, which

was also deduced from the X-ray diﬀraction data of 14

(Fig. 2) assuming no epimerization during its conversion

As mentioned above, Dhavale et al. have prepared the four

stereoisomeric (2,6S,7R,8)-tetrahydroxyindolizidines 5–8

via the dipolar cycloaddition of the ^D-xylose-derived nit-

rone 4 to allylic alcohol.^18bWe have explored the reaction

of 4 towards methyl acrylate and have found that it pro-

duces a 44:13:43:ꢀ0 mixture of the four possible diastereo-

meric cycloadducts 33, from which 33a, 33b and 33c were

isolated in 33%, 10% and 31% yield after column chroma-

tography on silica gel (Scheme 4). As for the chemistry

presented above (Scheme 2), these isoxazolidines were

converted into the corresponding 3-hydroxypyrrolidinones

1

into 27. The 2D NOESY H NMR spectrum of 28 shows

NOE’s between proton pairs H_b-1 (d_H= 1.97 ppm)/H-8a

(d_H= 3.66 ppm), H-8a (d_H= 3.66 ppm)/H_b-3 (d_H=

2.93 ppm), H_a-1 (d_H= 2.36 ppm)/H-2 (d_H= 4.58 ppm),

H-2 (d_H= 4.58 ppm)/H_a-3 (d_H= 3.95 ppm). This conﬁrms

the (2R,8aS)-conﬁguration of this indolizidine. Moreover,

1

comparison of the proton chemical shifts in the H NMR

HO

R'

O

N

HO

R'

H₂, Pd-C

EtOH (98%)

N

13

25

OH

H

R

BnO OH

29 R' = H

ClCOOBn, NaHCO₃

1:1 EtOH/H₂O

20 °C (97%)

H₂, Pd-C

EtOH

[30 R' = H]

32 R' = COOBn

4:1 CF₃COOH

H₂O, 20°C

(95%)

31 R' = COOBn

Scheme 3. Conversion of 13 into 25.

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1813

OH

H

2

OH

Ha

Hb

HO

Ha

Hb

H

³Hb

H

Hb

2

Hb

Ha

³Hb

Ha

2

1

2

3

Hb¹

N

H

Ha

N

H

8a

H

Hb

5

Ha

1

Ha

OH

H

5

8a

Ha

HO⁸

8a

HO ⁸

H^8a

6

N

H

6

N

H

⁵Ha

H

Hb

6

Hb

8

6

8

H

7

OH

HO

7

H

HO

H

HO

OH

HO

OH

25

26

27

28

1

Figure 3. NOE’s observed in the 2D NOESY H NMR spectra of 25–28.

O

E

Hb

E

NBn

X

NBn

X

E

toluene

35°C

4

+

Hb

Ha

X

Ha

X

33a (major)

Mo(CO)₆

O

33b (minor)

33c

33d (not seen)

O

OBn

X =

Mo(CO)₆

O

Mo(CO)₆

O

HO

N

R'

X

34 R' = Bn

37 R' = H

35 R' = Bn

38 R' = H

36 R' = Bn

39 R' = H

LiAlH₄/Et₂O, 20 °C

HO

N

R'

X

40 R' = Bn

42 R' = H

41 R' = Bn

43 R' = H

40

41

CF₃COOH/H₂O, 20 °C

HO

N

O

OBn

N

O

OBn

Bn

H

OH

44

45

OH

N

HO

OH

5

6

Scheme 4. Synthesis of 5 and 6.

34, 35 and 36 in 37, 64 and 36% yield, respectively. Various

amounts of the N-debenzylated derivatives 37 (34%), 38

(16%) and 39 (22%) were also isolated. Reduction of 34,

36, 37 and 39 provided the corresponding pyrrolidines 40

(76%), 41 (95%), 42 (83%) and 43 (97%). The N-benzylpyrr-

olidines 40 and 41 were treated with CF₃COOH/H₂O to

give the corresponding furanoses 44 and 45 both in 98%

yield. Subsequent catalytic hydrogenation provided the

known tetrahydroxyindolizidines 5 (94%) and 6 (97%),

respectively.

1814

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

O

H H

Ph

H

^aH

5

H

CO₂Me

O

5

b

4

_bH

_aH

Ph

⁵O

N

H

N

H

O

H

Ph

3

4

O

⁴H

_bH

3

N

a

3

H

O

4'

H

4'

H

Ph

H_4'

H

O

H

O

H

O

33a

33b

33c

Figure 4. Favoured conformations of 33a, 33b and 33c as suggested by NOE’s.

The structures of products 35–45 were deduced from their

chemical correlation with the known compounds 5 and 6

and by their spectral data. The 2D NOESY ¹H NMR spec-

tra of the major cycloadduct 33a show NOE’s for the pro-

ton pairs H_a-4 (d_H= 2.96 ppm)/H-5 (d_H= 4.65 ppm) and

H_b-4 (d_H= 2,77 ppm)/H-3 (d_H= 3.95 ppm), thus conﬁrm-

ing the trans relative conﬁguration between H-3 and H-5.

NOE’s were also observed between the proton pairs

belonging to the two diﬀerent rings of 33a, for instance

between proton pairs H_a-4 (d_H= 2.96 ppm)/H-4⁰(d_H=

relationship as corroborated by the observation of NOE

between proton pair H-5/H_a-4 that is more pronounced

than for H-5/H_b-4, and by the contact H-5/H-3. Similar

to the facial diastereomeric 33a/33b pair, molecular models

show for the 33c and 33d the same diﬀerence in the possi-

bility of stacking of the phenyl rings of the N-benzyl and O-

benzyl groups for both structures in the preferred 3,4⁰-anti

conformation, so that the (3R)-conﬁgured diastereomers

33a and 33c are capable of showing stacking, whilst the

(3S) 33b and 33d are not. These absolute conﬁguration

assignments for 33a–33c agree with those carried out by

other authors³³on the basis of other arguments. The p-

stacking invoked for the cycloaddition of 4 to methyl acryl-

ate does not intervene in the case of the cycloaddition of

ribosyl analogue 9 to methyl acrylate, because of that less

diastereoselectivity is observed in the latter than in the for-

mer cycloaddition.

1

4.13 ppm) (Fig. 4). The 2D NOESY H NMR spectrum

of the minor cycloadduct 33b show NOE’s between proton

pairs H_a-4 (d_H= 2.38 ppm)/MeOOC (d_H= 3.72 ppm),

H_a-4 (d_H= 2.38 ppm)/H-3 (d_H= 3.43 ppm) and H_b-4

(d_H= 2.20 ppm)/H-4⁰(d_H= 4.21 ppm), thus suggesting a

trans relationship between H-3 and H-5 as in 33b, but with

an opposite conﬁguration at these centres. It is possible

that p-stacking between two benzyl groups of 33a stabilizes

the conformation shown in Figure 4. This p-stacking could

already intervene in the transition state of the dipolar

cycloaddition of 4 to methyl acrylate and thus could

explain why 33a is the major adduct.³²With regard to

the second main diastereomer 33c, the correlations between

H-5 and the N-benzyl aromatic and methylene protons

3. Glycosidase inhibition studies

The known tetrahydroxyindolizidines 5 and 6 and the new

derivatives 25–28 were assayed for their inhibitory activity

towards 16 commercially available glycosidases applying

standard protocols.³⁴At 1 mM concentration and under

optimal pH for the enzymes, these compounds did not

inhibit a-galactosidases from coﬀee beans and from

Escherichia coli, b-galactosidase from E. coli and from

Aspergillus orizae, a-glucosidase (maltase) from yeast and

from rice, a-mannosidase from jack beans, b-mannosidase

from Helix pomatia, b-xylosidase from Aspergillus niger

1

observed in the 2D-NOESY H NMR spectrum indicated

the same orientation of them in relation to the isoxazoli-

dine ring, also applicable to H_a-4, which was correlated

with the same methylene protons (Fig. 4). The H_b-4 was

the only of the proton pair H_a-4/H_b-4 showing a strong

NOE with the sugar moiety proton, H-4⁰, and with the es-

ter methyl proton. Hence, H-5 and H-3 should have the cis

Table 1. Inhibitory activity of 2,6,7,8-tetrahydroxyindolizidines 5, 6 and 25–28 towards glycosidases^a

Enzyme compd

a-Fucosidase from

bovine epididymis

b-Galactosidase

from bovine liver

Amylosidase from

Aspergillus niger

Amylosidase from

Rhizopus mold

b-Glucosidase

from almonds

5

22%

NI

36%

58%

84%

IC₅₀= 168

K_i= 137 (M)

NI

6

25

NI

73%

NI

86%

NI

IC₅₀= 350

IC₅₀= 90

K_i= 195 (NC)

26

27

28

NI

27%

NI

27%

NI

^aPercentage of inhibition at 1 mM concentration, IC₅₀and K_iin lM when measured (M = mixed type of inhibition, NC = non-competitive inhibition,

NI = no inhibition).

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

Table 2. Tentative activity/structure relationship

1815

HO

OH

H

N

H

N

H

N

HO

46

47

48

HO

OH

H

N

H

N

H

N

HO

OH

25

inhibits

26

49^a

weak inhibitor of

poor inhibitor

amyloglucosidases

of amyloglucosidase

β-glucosidase (almond)

and β-galactosidase

(

Aspergillus niger)

HO

OH

H

HO

OH

H

HO

H

HO

OH

N

HO

(-)-50

(-)-51

(+)-52

potent and selective

inhibitor of

inhibits α-fucosidase

α-mannosidases

^aThe three other 1,2-stereoisomers of 49 are not known.

and b-N-acetylglucosaminidase from jack beans and from

bovine kidney. For ﬁve other glycosidases the results are

shown in Table 1.

reported for amyloglucosidases. Compound 48, the 1-epi-

mer of 47, has been prepared as a racemic mixture and

shown to inhibit a-fucosyltransferase-1,6 moderately with

IC₅₀ꢀ 2.4 mM;^16cno data are given for the inhibition of

glycosidases. Thus, it appears that the ^D-allopyranoside

conﬁguration of 25, 47 and 26 does not prohibit some

a-glucosidases from recognizing these tetrahydroxyindo-

lizidines that are in fact 7-epimer of castanospermine ana-

logues. It should be noted that only amyloglucosidase and

not a-glucosidase from brewer’s yeast and from rice are

inhibited by 25. As expected, some enzymes are more

permissive than others for inhibitors with ‘stereochemical

errors’ (^D-allo instead of D-gluco conﬁguration). Contrary

to the pentahydroxyindolizidine (ꢁ)-50, which is a potent

and selective inhibitor of a-mannosidases from jack bean

(IC₅₀= 2 lM) and from almonds (IC₅₀= 10 lM),²⁰our

new tetrahydroxyindolizidines 25–28 ignore these enzymes.

This was also the case with (ꢁ)-51²⁰and (+)-52. The latter

trihydroxyindolizidine has been reported to be a good a-

fucosidase inhibitor³⁵(Table 2).

Dhavale et al.^18bhave reported weak inhibitory activities

for 5 and 6 (IC₅₀> 10 mM) towards an a-galactosidase, a

b-galactosidase and an a-mannosidase. They found IC₅₀

values about 10 times as large as our value for the inhibi-

tion of b-glucosidase from almonds by

5

and

IC₅₀= 3.7 mM for the inhibition of this enzyme by 6. In

our assays, 6 did not show any inhibitory activity at

1 mM concentration. Inversion of the C(7) centre in 5

and 6 gave our indolizidines 25 and 26. The latter did

not inhibit b-glucosidase from almond, nor a-fucosidase

and b-galactosidase. Indolizidine 25 is the most active

inhibitor in our assays as it inhibits both amyloglucosidase

from A. niger and from Rhizopus mold with IC₅₀values of

350 and 90 lM, respectively. Towards these enzymes, 25 is

more active than its 7-epimer 5, a surprise as the latter com-

pound shares the conﬁguration of ^D-glucopyranosides

whereas 25 imitates ^D-allopyranosides. The (8aR)-conﬁgu-

ration of 25 is essential for its inhibitory activity towards

the amyloglucosidases, as its 8a-epimer 28 ignores all the

glycosidases assayed. The 2-epimer of 28, indolizidine 27,

also ignores all glycosidases, except for a weak inhibitory

activity of b-galactosidase from bovine liver. Our work

shows that (2S,6S,7S,8R,8aR)-tetrahydroxyindolizidine

25 is able to recognize the amyloglucosidase and not the

other glucosidases. The 2-deoxy-analogue 46 have been

prepared^14cbut no inhibition data has been reported for

this compound. Analogue 47^15cwith a (1S)-hydroxy group

instead of a (2S)-hydroxy group, inhibits a-^D-glucosidase

from human liver (92% at 1 mM). Data have not been

4. Conclusion

The dipolar cycloaddition of (Z)-N-benzyl-(3-O-benzyl-

1,2-O-isopropylidene-a-^D-ribofuranos-5-ylidene)amine N-

oxide

9 (^D-ribofuranosyl-derived nitrone) to methyl

acrylate is less stereoselective than that of its xylo

stereomer 4. This might be due to the p-stacking

interaction intervening in 4 that limits the number of con-

formations reacting with the dipolarophile. These p-stack-

ing interactions would not bias the dipolar cycloaddition of

9 to methyl acrylate. Applying the method developed

1816

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

earlier by us for the conversion of 5-(methoxycarbon-

yl)isoxazolidines into polyhydroxyperhydroazaazulenes²⁷

to the cycloadducts obtained with 9 and 4, the four new

2,6,7,8-tetrahydroxyindolizidines 25 [(2R,6S,7S,8R,8aR)-],

26 [(2S,6S,7S,8R,8aR)-], 27 [(2S,6S,7S,8R,8aS)-] and 28

[(2R,6S,7S,8R,8aS)-], as well as the known stereomers 5

[(2R,6S,7R,8R,8aR)-] and 6 [(2S,6S,7R,8R,8aR)-], have

been prepared. These indolizidines have been evaluated

for their inhibitory activities towards 15 glycosidases.

Apart from 25, which is a selective, but moderate inhibitor

of amyloglucosidase from A. niger (IC₅₀= 350 lM) and

from Rhizopus mold (IC₅₀= 90 lM, non-competitive), the

other indolizidines 26 and 27 were not recognized by any

of the glycosidases assayed. The (2R,8aR)-conﬁguration

is required for activity for tetrahydroxyindolizidines, shar-

ing the conﬁguration of ^D-allopyranosides for their tri-

hydroxypiperidine moiety. Structural assignments of 25–

28 are based on NMR studies and chemical correlation

with intermediates 11 and 14, for which the molecular

structures have been established by X-ray diﬀraction

studies.

AutoSpecQ instrument with a resolution of 10,000 (5% val-

ley deﬁnition).

5.2. 53:16:26:5 Mixture of (3R,5R-, 3R,5S-, 3S,5S- and

3S,5R-)-2-benzyl-3-(3-O-benzyl-1,2-O-isopropylidene-a-^D-

ribo-tetrofuranos-4-yl)-5-(methoxycarbonyl)isoxazolidines

10a, 10b, 10c and 10d

A solution of nitrone 9²⁸(3.15 g, 8.26 mmol) and methyl

acrylate

2 (1.73 mL, 1.64 g, 19.1 mmol) in toluene

(37 mL) was stirred under an argon atmosphere at 35 ꢁC.

Monitoring of the reaction (TLC, 4:1 hexane/ethyl acetate)

indicated complete conversion after 2 h. The solution was

then concentrated to give a crude residue (0.640 g), which

was subjected to column chromatography. First eluted a

1

fraction that proved to be a 10:3 mixture (by H NMR)

of 10a and 10b (oil, 2.39 g, 62%), and a second eluted

another fraction, composed of a 10:1.9 mixture of 10c

and 10d (oil, 1.09 g, 28%).

The 10:3 10a/10b mixture had R_f0.45 (3:1 hexane/ethyl

acetate); IR (NaCl) m_max1744 (ester C@O), 1375 (CMe₂),

1084 and 1020 cm^ꢁ1(C–O–C); HRCIMS m/z: 470.2190

(calcd for C₂₆H₃₁NO₇+ H: 470.2178).

5. Experimental

5.1. General

5.2.1. Diastereomer 10a. ¹H NMR (300 MHz, CDCl₃) d

7.43–7.25 (m, 10H, 2Ph), 5.70 (d, 1H, J_{1 ;2}¼ 3:6, H-1⁰),

4.76, 4.52 (each d, each 1H, J_gem= 11.7, OCH₂Ph), 4.62–

4.52 (m, 2H, H-2⁰+ H-5), 4.20, 4.02 (each d, each 1H,

0

Hexane and ether were distilled from sodium prior to use.

TLC was performed on silica gel plates (DC-Alufolien

F₂₅₄, E. Merck, or Alugram Sil G/UV₂₅₄, Macherey-Na-

gel), and preparative TLC on Kieselgel 60 F₂₅₄DC-Platten

105715 HR; detection of the compounds was accomplished

with UV light (254 nm) and by charring with H₂SO₄and

phosphomolybdic reagent. Silica Gel 60 (E. Merck, 230–

400 mesh) was used for column chromatography. Solutions

were concentrated under a diminished pressure at <40 ꢁC.

Melting points were determined on a Gallenkamp MFB-

595 apparatus and are uncorrected. A Perkin–Elmer 241

MC polarimeter was used for measurement of optical rota-

tions. IR spectra (neat on an NaCl plate or on a KBr disc)

were obtained on a FTIR Bomem Michelson MB-120 spec-

trophotometer. NMR experiments were recorded on a Bru-

ker AMX-300 (or 500) or a Bruker Avance-300 (or 500)

spectrometer; chemical shifts (d) are given in ppm, using

the residual protonated solvent signal as reference. Assign-

ments were conﬁrmed by selective homonuclear decou-

pling, homonuclear 2D COSY, NOESY (1D or 2D), 1D

TOCSY, heteronuclear multiple (or single) quantum corre-

lation (HMQC or HSQC) and heteronuclear multiple bond

correlation (2D-HMBC) spectra. Selective inversion in 1D

experiments were performed by using the Double Pulsed

Field Gradient Spin Echo (DPFGSE) module. For the

NOESY experiments, the mixing time was 400 ms in all

cases. EI mass spectra (70 eV) were measured with a Kra-

tos MS-80RFA instrument, with an ionising current of

100 lA, an accelerating voltage of 4 kV, and a resolution

of 10,000 (10% valley deﬁnition). Fast-atom bombardment

mass spectrometry (FABMS) was performed on the same

instrument; ions were produced by a beam of xenon atoms

(6–7 keV) using a matrix consisting of m-nitrobenzyl alco-

hol or thioglycerol and NaI as salt. HRCIMS (150 eV) and

HRLSIMS experiments were performed with a Micromass

0

J_gem= 13.5, NCH₂Ph), 4.14 (dd, 1H, J_{4 ;3}¼ 2:7,

J_{4 ;3}¼ 7:2, H-4⁰), 3.98 (dd, 1H, J_{3 ;2}¼ 4:5, J_{3 ;4}¼ 7:2, H-

0

3⁰), 3.77 (s, 3H, MeOCO), 3.53 (ddd, 1H, J_3;4¼ 2:4,

0

J_3,4a= 5.4, J_3,4b= 8.1, H-3), 2.68 (ddd, 1H, J_4a,3= 5.7,

J_4a,4b= 12.6, J_4a,5= 8.7, H-4a), 2.54 (ddd, 1H,

J_4b,3= 8.4, J_4b,4a= 12.9, J_4b,5= 6.3, H-4b), 1.58 and 1.36

(each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃)

d 172.7 (COOMe), 137.6, 137.5 (2 ipso-C of Ph), 129.4–

127.2 (Ph), 113.0 (CMe₂), 103.8 (C-1⁰), 78.8 (C-4⁰), 78.6

(C-3⁰), 77.5 (C-2⁰), 76.2 (C-5), 72.2 (OCH₂Ph), 64.5 (C-3),

62.7 (NCH₂Ph), 52.3 (COOMe), 34.3 (C-4), 26.9 and 26.6

(CMe₂).

5.2.2. Diastereomer 10b. ¹H NMR (300 MHz, CDCl₃) d

7.43–7.25 (m, 10H, 2Ph), 5.64 (d, 1H, J_{1 ;2}¼ 3:6, H-1⁰),

4.74, 4.53 (each d, each 1H, J_gem= 11.4, OCH₂Ph), 4.62–

4.52 (m, 2H, H-2⁰+ H-5), 4.20, 4.00 (each d, each 1H,

0

J_gem= 13.5, NCH₂Ph), 4.26 (dd, 1H, J_{4 ;3}¼ 2:4,

J_{4 ;3}¼ 8:7, H-4⁰), 4.00 (overlapped signal, H-3⁰), 3.65 (s,

0

3H, MeOCO), 3.35 (ddd, 1H, J_3;4¼ 2:4, J_3,4a= 8.7,

J_3,4b= 8.7, H-3), 2.68 (overlapped signal,1H, H-4a), 2.54

(overlapped signal, 1H, H-4b), 1.58 and 1.36 (each s, each

3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 172.7

(COOMe), 137.6, 137.5 (2 ipso-C of Ph), 129.4–127.2

(Ph), 113.0 (CMe₂), 103.8 (C-1⁰), 78.6 (C-3⁰), 78.2 (C-4⁰),

77.5 (C-2⁰), 74.4 (C-5), 71.9 (OCH₂Ph), 64.2 (C-3), 60.4

(NCH₂Ph), 52.1 (COOMe), 34.3 (C-4), 26.6 and 26.5

(CMe₂).

The 10:1.9 10c/10d mixture had R_f0.35 (3:1 hexane/ethyl-

acetate); IR (NaCl) m_max1753 (ester C@O), 1377 (CMe₂),

1209 and 1173 cm^ꢁ1(C–O–C); HRCIMS m/z: 470.2130

(calcd for C₂₆H₃₁NO₇+ H: 470.2178).

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1817

5.2.3. Diastereomer 10c. ¹H NMR (300 MHz, CDCl₃) d

J_gem= 11.6, OCH₂Ph), 4.61 (d, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:9,

H-2⁰), 4.44 (dd, 1H, J_4a,5= 4.5, J_4b,5= 9.0, H-5), 4.41,

4.03 (each d, each 1H, J_gem= 14.1, NCH₂Ph), 4.21 (dd,

0

7.40–7.25 (m, 10H, 2Ph), 5.79 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰),

0

4.65 (dd, 1H, J_4a,5= J_4b,5= 7.8, H-5), 4.54 (dd, 1H,

J_{2 ;3}¼ J_{2 ;1}¼ 4:2, H-2⁰), 4.49, 4.22 (each d, each 1H,

J_gem= 10.8, OCH₂Ph), 4.16, 4.94 (each d, each

1H, J_{4 ;3}¼ 8:5, J_{4 ;3}¼ 2:0, H-4⁰), 3.88 (d, 1H, J_{3 ;4}¼ 3:5,

0

H-3⁰), 3.72 (s, 3H, MeOCO), 3.43 (ddd, 1H, J_4a,3= 7.5,

0

1H, J_gem= 13.2, NCH₂Ph), 4.01 (dd, 1H, J_{4 ;3}¼ 4:2,

J_{4 ;3}¼ J_4b;3¼ 8:5, H-3), 2.38 (ddd, 1H, J_4a,3= 7.3, J_4a,4b

=

J_{4 ;3}¼ 8:7, H-4⁰), 3.78 (s, 3H, MeOCO), 3.76 (overlapped

12.5, J_4a,5= 4.8, H-4a), 2.20 (ddd, 1H, J_4b,3= J_4b,5= 8.8,

J_4b,4a= 12.5, H-4b), 1.48 and 1.32 (each s, each 3H,

CMe₂); ¹³C NMR (127.5 MHz, CDCl₃) d 172.1 (COOMe),

138.2, 136.9 (2 ipso-C of Ph), 129.7–127.0 (Ph), 111.9

(CMe₂), 105.5 (C-1⁰), 83.0 (C-3⁰), 81.7 (C-4⁰), 81.3 (C-2⁰),

74.9 (C-5), 71.8 (OCH₂Ph), 63.8 (C-3), 62.4 (NCH₂Ph),

52.2 (COOMe), 36.1 (C-4), 26.8 and 26.4 (CMe₂); HRC-

IMS m/z: 470.2171 (calcd for C₂₆H₃₁NO₇+ H: 470.2178).

0

signal, 1H, H-3⁰), 3.40 (ddd, 1H, J_4a,3= J_4b,3= 5.7,

0

J_{4 ;3}¼ 4:5, H-3), 2.68 (dd, 2H, J_{4a or 4b,3}= 5.0,

J_{4a or 4b,5}= 7.8, H-4a + H-4b), 1.58 and 1.45 (each s, each

3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 172.9

(COOMe), 137.3 (2 ipso-C of Ph), 129.4–127.2 (Ph), 112.7

(CMe₂), 104.2 (C-1⁰), 80.5 (C-2⁰), 78.9 (C-3⁰), 77.0 (C-

2⁰+ C-5), 71.8 (OCH₂Ph), 63.9 (C-3), 63.2 (NCH₂Ph),

52.1 (COOMe), 35.4 (C-4), 26.6 and 26.5 (CMe₂).

5.3.3. Compound 33c. Oil; R_f0.20 (4:1 hexane/ethyl ace-

26

25

5.2.4. Diastereomer 10d. The signals of the minor diaste-

reomer were overlapped with those of the major one 10c.

tate); ½aꢂ_D¼ ꢁ24 (c 0.6, CH₂Cl₂), {lit.³³½aꢂ_D¼ ꢁ4 (c

0.75, CHCl₃)}; IR (NaCl) m_max1741 (ester C@O), 1377

(CMe₂), 1074 and 1034 cm^ꢁ1(C–O–C); ¹H NMR

(500 MHz, CDCl₃) d 7.38–7.20 (m, 10H, 2Ph), 5.88 (d,

5.3. 44:13:43 Mixture of (3R,5R-, 3S,5S- and 3R,5S-)-2-

benzyl-3-(3-O-benzyl-1,2-O-isopropylidene-a-^D-xylo-tetro-

furanos-4-yl)-5-(methoxycarbonyl)isoxazolidines 33a, 33b

and 33c

1H, J_{1 ;2}¼ 3:8, H-1⁰), 4.75 (dd, 1H, J_4a,5= 9.9,

0

J_4b,5= 5.4, H-5), 4.58 (d, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:8, H-2⁰),

0

4.54, 4.34 (each d, each 1H, J_gem= 12.0, OCH₂Ph), 4.29

(dd, 1H, J_{4 ;3}¼ 9:8, J_{4 ;3}¼ 3:1, H-4⁰), 4.14 (d, 1H,

0

A solution of nitrone 4²⁸(0.535 g, 1.40 mmol) and methyl

acrylate (264 lL, 0.253 g, 2.93 mmol) in toluene (4.6 mL)

was stirred under an argon atmosphere at 35 ꢁC. Monitor-

ing of the reaction (TLC, 4:1 hexane/ethyl acetate) indi-

cated a complete conversion after 14 h. The solution was

then concentrated to give a crude residue (0.640 g), which

was subjected to column chromatography (6:1 hexane/

ethyl acetate); ﬁrst eluted diastereomer 33a (0.214 g,

33%), second eluted 33c (0.207 g, 31%) and third, diaste-

reomer 33b (0.064 g, 10%).

J_{3 ;4}¼ 3:1, H-3⁰), 3.94, 3.83 (each d, each 1H, J_gem= 13.5,

0

NCH₂Ph), 3.82 (ddd, 1H, J_4a,3= 7.9, J_{4 ;3}¼ 9:8,

J_4b,3= 2.5, H-3), 3.76 (s, 3H, MeOCO), 2.82 (ddd, 1H,

J_4a,3= 7.9, J_4a,4b= 13.3, J_4a,5= 9.9, H-4a), 2.71 (ddd,

1H, J_4b,3= 2.4, J_4b,4a= 13.3, J_4b,5= 5.4, H-4b), 1.51 and

1.32 (each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz,

CDCl₃) d 171.5 (COOMe), 137.6, 136.9 (2 ipso-C of Ph),

129.4–127.5 (Ph), 111.9 (CMe₂), 104.8 (C-1⁰), 82.4 (C-2⁰),

81.7 (C-3⁰), 80.6 (C-4⁰), 75.3 (C-5), 71.9 (OCH₂Ph), 62.2

(C-3), 61.1 (NCH₂Ph), 52.3 (COOMe), 35.4 (C-4), 26.8

and 26.5 (CMe₂); HRCIMS m/z: 470.2130 (calcd for

C₂₆H₃₁NO₇+ H: 470.2178).

5.3.1. Compound 33a. Oil; R_f0.30 (4:1 hexane/ethyl ace-

26

25

tate); ½aꢂ_D¼ ꢁ11:2 (c 1.25, CH₂Cl₂), {lit.³³½aꢂ_D¼ ꢁ21 (c

1.25, CHCl₃)}; IR (NaCl) m_max1744 (ester C@O), 1375

(CMe₂), 1084 and 1020 cm^ꢁ1(C–O–C); ¹H NMR

(500 MHz, CDCl₃) d 7.28–7.22 (m, 10H, 2Ph), 5.91 (d,

5.4. General procedure for reductive ring cleavage of the

isoxazolidine derivatives 10a–d and 33a–c

1H, J_{1 ;2}¼ 3:8, H-1⁰), 4.65 (dd, 1H, J_5,4a= J_5,4b= 8.5, H-

To a solution of the respective isoxazolidine derivative (or

mixture of isoxazolidine derivatives) in a mixture of aceto-

nitrile and water, hexacarbonylmolybdenum was added,

and the mixture heated at reﬂux (85 ꢁC), monitoring the

reaction by TLC (15:1 dichloromethane/methanol). Silica

gel was then added, and the suspension stirred for 12 h, ﬁl-

tered through Celite and the solid thoroughly washed with

ethyl acetate. The combined ﬁltrate and washings were

concentrated, and the crude residue was subjected to col-

umn chromatography (40:1 dichloromethane/methanol)

to obtain the product (or products) of the reaction.

0

5), 4.58 (d, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:5, H-2⁰), 4.52, 4.33 (each

0

d, each 1H, J_gem= 11.5, OCH₂Ph), 4.23, 3.77 (each d, each

0

1H, J_gem= 13.0, NCH₂Ph), 4.13 (dd, 1H, J_{4 ;3}¼ 9:3,

J_{4 ;3}¼ 3:0, H-4⁰), 4.10 (d, 1H, J_{3 ;4}¼ 3:0, H-3⁰), 3.95 (m,

1H, H-3), 3.79 (s, 3H, MeOCO), 2.96 (ddd, 1H,

J_4a,3= 1.7, J_4a,4b= 13.0, J_4a,5= 8.5, H-4a), 2.77 (ddd,

1H, J_4b,3= 7.5, J_4b,4a= 13.0, J_4b,5= 8.2, H-4b) and 1.48,

1.31 (each s, each 3H, CMe₂); ¹³C NMR (125.7 MHz,

CDCl₃) d 173.2 (COOMe), 137.6, 137.5 (2ipso-C of Ph),

129.2–127.3 (Ph), 111.7 (CMe₂), 104.9 (C-1⁰), 82.3 (C-2⁰),

81.7 (C-3⁰), 79.8 (C-4⁰), 77.2 (C-5), 71.9 (OCH₂Ph), 63.0

(C-3), 62.3 (NCH₂Ph), 52.4 (COOMe), 34.8 (C-4), 26.8

and 26.2 (CMe₂); HRCIMS m/z: 470.2190 (calcd for

C₂₆H₃₁NO₇+ H: 470.2178).

0

5.4.1. (3R,5R- and 3S,5R-)-1-Benzyl-5-(3-O-benzyl-1,2-O-

isopropylidene-a-^D-ribo-tetrofuranos-4-yl)-3-hydroxy-2-oxo-

pyrrolidines 11 and 12, respectively, and (3R,5R)-5-(3-O-

benzyl-1,2-O-isopropylidene-a-^D-ribo-tetrofuranos-4-yl)-3-

hydroxy-2-oxopyrrolidine 13. Starting from the 10:3 10a/

10b mixture (1.2 g, 2.56 mmol) in acetonitrile (36.8 mL)/

water (2.54 mL), and hexacarbonylmolybdenum (0.46 g),

monitoring of the reaction indicated that the reaction had

ended after 2 h. After using silica gel (0.478 g) to facilitate

the extraction of the products, two fractions were obtained;

5.3.2. Compound 33b. Oil; R_f0.18 (4:1 hexane/ethyl ace-

26

25

tate); ½aꢂ_D¼ ꢁ112 (c 0.9, CH₂Cl₂), {lit.³³½aꢂ_D¼ ꢁ67 (c

0.95, CHCl₃)}; IR (NaCl) m_max1742 (ester C@O), 1375

(CMe₂), 1092 and 1022 cm^ꢁ1(C–O–C); ¹H NMR

(500 MHz, CDCl₃) d 7.42–7.19 (m, 10H, 2Ph), 5.96 (d,

1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.69, 4.42 (each d, each 1H,

0

1818

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

ﬁrst eluted a 1:0.41 11/12 mixture (by NMR; oil; 0.550 g,

50.0%), and second the N-deprotected compound 13

(0.184 g, 21%), isolated as an amorphous, white solid.

Crystallization (absolute ethanol) of a small amount of

the major diastereomer 11 present in the ﬁrst fraction

was achieved.

ﬁxed to 0.47 and 0.52. An identical model of disorder was

detected for the two methyl groups of dimethyl acetal pro-

tecting group with the occupancy factors reﬁned and ﬁxed

to 0.40 and 0.60. Since a large standard uncertainty (su) on

the Flack parameter ꢁ0.4(17), the Friedel pairs were aver-

aging in the reﬁnement (MERG 4 command). Thereby, the

absolute conﬁguration of the new stereogenic centres C(3)-

(R) and C(5)-(R) have been assigned by reference to other

unchanging stereogenic centres in the synthetic procedure

of known absolute conﬁguration. All the non-hydrogen

atoms were reﬁned with anisotropic displacement parame-

ters. Some few reﬂections to low angle that present values

very below their calculated values, possibly partially cov-

ered for ‘beam stopper’ were eliminated at the end of the

reﬁnement (OMIT command). The hydrogen atoms were

included from calculated positions and reﬁned riding on

their respective carbon atoms with isotropic displacement

parameters. The ﬁnal diﬀerence map displayed no electron

The 1:0.41 11/12 fraction had R_f0.50 (15:1 CH₂Cl₂/

MeOH);

HRCIMS

m/z:

440.2075

(calcd

for

C₂₅H₂₉NO₆+ H: 440.2073).

5.4.1.1. Compound 11. Mp 190–191 ꢁC; crystallo-

graphic analysis proved its (3R,5R) absolute conﬁgura-

26

tion; ½aꢂ_D¼ þ52:9 (c 0.5, CH₂Cl₂); IR (NaCl) m_max3385

(OH), 1680 (amide C@O), 1377 (CMe₂), 1022 (C–OH),

1

872, 743 and 702 cm^ꢁ1(arom C–H); H NMR (300 MHz,

CDCl₃)

d 7.35–7.22 (m, 10H, 2Ph), 5.69 (d, 1H,

J_{1 ;2}¼ 3:6, H-1⁰), 4.92, 4.15 (each d, each 1H, J_gem= 15.0,

0

ꢁ3

˚

density higher than 0.363 e A

.

NCH₂Ph), 4.75, 4.43 (each d, each 1H, J_gem

=

12.3, OCH₂Ph), 4.54 (dd, 1H, J_{2 ;3}¼ J_{2 ;1}¼ 3:9, H-2⁰),

0

5.4.1.2. Compound 12. ¹H NMR (300 MHz, CDCl₃) d

4.30 (dd, 1H, J_{4 ;3}¼ 9:3, J_{4 ;5}¼ 1:5, H-4⁰), 4.21 (ddd,

0

7.36–7.22 (m, 10H, 2Ph), 5.63 (d, 1H, J_{1 ;2}¼ 3:6, H-1⁰),

4.84, 4.15 (each d, each 1H, J_gem= 14.7, NCH₂Ph), 4.75,

4.43 (each d, each 1H, J_gem= 12.3, OCH₂Ph), 4.56 (dd,

0

1H, J_3,OH=5.7, J_3,4a= 8.4, J_3,4b= 6.3, H-3), 3.63 (ddd,

0

1H, J_5;4¼ 1:5, J_5,4a= J_5,4b= 7.5, H-5), 3.47 (dd, 1H,

J_{3 ;2}¼ 4:2, J_{3 ;4}¼ 9:3, H-3⁰), 3.04 (d, 1H, J_OH,3= 5.7,

OH), 2.44 (ddd, 1H, J_4a,5= 7.8, J_4a,3= 8.1, J_4a,4b= 13.2,

H-4a), 1.78 (ddd, J_4b,3= 6.0, J_4b,5= 6.6, 1H, H-4b), 1.56

and 1.38 (each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz,

CDCl₃) d 174.9 (C@O), 136.7, 136.0 (2 ipso-C of Ph),

128.6–127.5 (Ph), 113.4 (CMe₂), 103.8 (C-1⁰), 77.03 (C-

2⁰+ C-3⁰), 74.8 (C-4⁰), 71.9 (OCH₂Ph), 69.1 (C-3), 54.2

(C-5), 44.9 (NCH₂Ph), 27.5 (C-4), 26.7 and 26.4 (CMe₂);

HRCIMS m/z: 440.2079 (calcd for C₂₅H₂₉NO₆+ H:

440.2073). Crystallographic analysis : The sample used

was a colourless needle of size 0.31 · 0.13 · 0.13 mm³,

crystallized from ethanol in the monoclinic system, space

group P2₁(no. 4); unit-cell dimensions, a = 12.3539(6),

0

1H, J_{2 ;3}¼ J_{2 ;1}¼ 4:2, H-2⁰), 4.23 (overlapped signal, 2H,

H-3 + H-4⁰), 3.54 (overlapped signal, 1H, H-5), 3.48 (over-

lapped signal, 1H, H-3⁰), 2.10 (ddd, 1H, J_4a,5= J_4a,3= 7.8,

J_4a,4b= 13.2, H-4a), 1.64 (overlapped signal, 1H, H-4b),

1.53 and 1.36 (each s, each 3H, CMe₂). ¹³C NMR

(75.4 MHz, CDCl₃) d 175.4 (C@O), 136.8, 135.9 (2ipso-C

of Ph), 128.7–127.7 (Ph), 113.4 (CMe₂), 103.9 (C-1⁰), 77.4

(C-4⁰), 77.2 (C-2⁰+ C-3⁰), 72.2 (OCH₂Ph), 68.9 (C-3), 54.5

(C-5), 45.6 (NCH₂Ph), 29.2 (C-4), 26.8 and 26.3 (CMe₂).

0

5.4.1.3. Compound 13. Oil; R_f0.33 (15:1 dichlorometh-

26

ane/methanol); ½aꢂ_D¼ þ16 (c 1.0, CH₂Cl₂); IR (NaCl) m_max

˚

3362 (NH and OH), 1712 (amide C@O), 1379 (CMe₂) and

b = 5.2555(3), c = 17.0731(9) A, b = 92.263(2)ꢁ; unit-cell

1052 cm^ꢁ1(C–OH); H NMR (300 MHz, CDCl₃) d 7.40–

3

1

˚

volume, V = 1107.62(10) A ; formula units per unit-cell,

Z = 2; q_calcd= 1.318 Mg m^ꢁ3; k(Mo K_a1) = 0.71073 A;

˚

7.28 (m, 5H, Ph), 6.84 (s, 1H, NH), 5.65 (d, 1H,

F(000) = 468; absorption coeﬃcient, l = 0.094 mm^ꢁ1

;

J_{1 ;2}¼ 3:6, H-1⁰), 4.67, 4.45 (each d, each 1H, J_gem= 11.4,

0

OCH₂Ph), 4.52 (dd, 1H, J_{2 ;3}¼ J_{2 ;1}¼ 3:9, H-2⁰), 4.19 (dd,

0

T = 100(2) K. Reﬂections were collected from a Bruker-

AXS X8Kappa APEX II CCD diﬀractometer in the range

5.92 < 2h < 61.00ꢁ, and 6531 independent reﬂections

[R_int= 0.0197] were used in the structural analysis. Reﬂec-

tions were corrected for Lorentz polarization eﬀects and

absorption applied by (^SADABS).³⁶The structure was solved

by direct methods (^SIR-2002)³⁷and reﬁned against all F²

data by full-matrix least-squares techniques (SHELXTL-

6.12)³⁸to R₁= 0.0473, wR₂= 0.1138 [I > 2r(I₀)], and to

R₁= 0.0539, wR₂= 0.1285 for all data, with a goodness-

of-ﬁt on F²= 1.068 and 345 parameters. The asymmetric

unit of the structure is formed by one molecule of 11. In

the ﬁrst stage of the reﬁnement we observed a static disor-

der of the phenyl ring of one benzyl group in two diﬀerent

positions with the occupancy factors ﬁrst reﬁned and later

0

1H, J_3,4a= J_3,4b= 8.7, H-3), 4.01 (dd, 1H, J_{4 ;3}¼ 9:0,

J_{4 ;5}¼ 4:2, H-4⁰), 3.65 (ddd, 1H, J_5;4¼ 4:8, J_5,4a= 6.9,

0

J_5,4b= 8.7, H-5), 3.60 (dd, 1H, J_{3 ;2}¼ 4:2, J_3,4b= 8.7, H-

3⁰), 3.15 (br s, 1H, OH), 2.32 (ddd, 1H, J_4a,3= 8.4,

J_4a,4b= 13.2, J_4a,5= 6.9, H-4a), 1.98 (ddd, 1H,

J_4b,3= J_4b,5= 8.7, J_4b,4a= 12.9, H-4b), 1.58 and 1.36 (each

s, each, 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 177.9

(C@O), 136.9 (ipso-C of Ph), 128.6–127.9 (Ph), 113.3

(CMe₂), 103.9 (C-1⁰), 78.6 (C-4⁰), 77.6 (C-3⁰), 77.3 (C-2⁰),

71.9 (O-CH₂Ph), 69.1 (C-3), 51.2 (C-5), 30.9 (C-4), 26.8

and 26.6 (CMe₂); HRCIMS m/z: 350.1607 (calcd for

C₁₈H₂₃NO₆+ H: 350.1603).

5.4.2. (3S,5S)- and (3R,5S)-1-Benzyl-5-(3-O-benzyl-1,2-O-

isopropylidene-a-^D-ribo-tetrofuranos-4-yl)-3-hydroxy-2-oxo-

pyrrolidines 14 and 15, respectively, and (3S,5S)-5-(3-O-

benzyl-1,2-O-isopropylidene-a-^D-ribo-tetrofuranos-4-yl)-3-

hydroxy-2-oxopyrrolidine 16. Starting from the 10:1.9

10c/10d mixture (1.1 g, 2.32 mmol) in a mixture of aceto-

nitrile (33 mL) and water (2.3 mL), and hexacarbonylmo-

lybdenum (0.414 g), monitoring of the reaction indicated

Crystallographic data (excluding structure factors) for this structure have

been deposited with the Cambridge Crystallographic Centre as Supple-

mentary Publication Number CCDC 648583. Copies of the data can be

obtained, free of charge, on application to CCDC, 12 Union Road,

Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:

deposit@ccdc.cam.ac.uk].

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1819

a complete conversion after 3 h. After using silica gel

(0.478 g) to facilitate the extraction of products, and col-

umn chromatography, two fractions were obtained. First

eluted was a 10:3.5 14/15 mixture (0.700 g; 69%); second

eluted was the N-deprotected product 16 (0.083 g; 8%),

which was isolated as a colourless oil. From the ﬁrst

fraction, crystallization of compound 14 (from absolute

ethanol) was achieved.

C5-(S) have been assigned by reference to other unchang-

ing chiral centres of known, unchanging absolute conﬁgu-

ration. All the non-hydrogen atoms were reﬁned with

anisotropic displacement parameters. Some few reﬂections

to low angle gave values, which were very below their cal-

culated values, possibly partially covered for ‘beam stop-

per’, were eliminated at the end of the reﬁnement (OMIT

command). The hydrogen atoms were included from calcu-

lated positions and reﬁned riding on their respective carbon

atoms with isotropic displacement parameters. The ﬁnal

The 10:3.5 14/15 mixture had R_f0.63 (15:1 dichlorometh-

ane/methanol); HRCIMS m/z: 440.2061 (calcd for

C₂₅H₂₉NO₆+ H: 440.2073).

diﬀerence_ꢁm₃ap displayed no electron density higher than

˚

0.344 e A

.

5.4.2.2. Compound 15. ¹H NMR (300 MHz, CDCl₃) d

5.4.2.1. Compound 14. Mp 137–138 ꢁC; crystallo-

7.38–7.22 (m, 10H, 2Ph), 5.75 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰),

5.05, 4.25 (each d, each 1H, J_gem= 14.7, NCH₂Ph), 4.77,

4.48 (each d, each 1H, J_gem= 11.4, OCH₂Ph), 4.52 (over-

lapped signal, 1H, H-2⁰), 4.50 (overlapped signal, 1H, H-

0

graphic analysis evidenced its (3S,5S) absolute conﬁgura-

26

tion; ½aꢂ_D¼ þ34:8 (c 0.325, CH₂Cl₂); IR (KBr) m_max3412

(OH), 1636 (amide C@O), 1383 (CMe₂), 1123 (C–OH),

1

896, 724 and 696 cm^ꢁ1(arom C–H); H NMR (300 MHz,

3), 4.03 (dd, 1H, J_{4 ;5}¼ 8:1, J_{3 ;4}¼ 8:4, H-4⁰), 3.86 (br s,

0

CDCl₃)

d 7.38–7.22 (m, 10H, 2Ph), 5.73 (d, 1H,

J_{1 ;2}¼ 3:9, H-1⁰), 4.94, 4.42 (each d, each 1H, J_gem= 15.0,

0

1H, OH), 3.49 (overlapped signal, 1H, H-5), 3.45 (dd,

1H, J_{3 ;2}¼ 4:5, J_{3 ,4}= 9.0, H-3⁰), 2.69 (ddd, 1H,

J_4a,3= 1.0, J_4a,5= 8.4, J_4a,4b= 13.2, H-4a), 1.86 (ddd,

1H, J_4b,3= 9.0, J_4a,5= 4.2, J_4a,4b= 13.2, H-4b), 1.59 and

1.38 (each s, each 3H, CMe₂). ¹³C NMR (75.4 MHz,

CDCl₃) d 175.8 (C@O), 136.3, 135.9 (ipso-C of Ph),

128.6–127.4 (Ph), 113.2 (CMe₂), 104.0 (C-1⁰), 80.8 (C-4⁰),

79.4 (C-3⁰), 76.8 (C-2⁰), 71.9 (OCH₂Ph), 68.7 (C-3), 56.3

(C-5), 46.2 (NCH₂Ph), 30.1 (C-4), 26.6 and 26.3 (CMe₂).

0

NCH₂Ph), 4.75, 4.51 (each d, each 1H, J_gem= 11.7,

OCH₂Ph), 4.54 (dd, 1H, J_{2 ;3}¼ 4:2, J_{2 ;1}¼ 3:9, H-2⁰),

4.31 (ddd, 1H, J_3,OH= 2.7, J_3,4a= J_3,4b= 8.1, H-3), 4.11

0

(dd, 1H, J_{4 ;3}¼ 8:7, J_{4 ;5}¼ 7:5, H-4⁰), 3.58 (dd, 1H,

0

J_{3 ;2}¼ 4:5,

J_{3 ;4}¼ 8:7,

H-3⁰),

3.51

(ddd,

1H,

0

J_5;4¼ J_5;4a¼ 7:5, J_5,4b= 7.2, H-5), 3.17 (d,1H, J_OH,3

=

3.0, OH), 2.30 (ddd, 1H, J_4a,5= J_4a,3= 7.2, J_4a,4b= 13.5,

H-4a), 2.00 (ddd, J_4b,3= J_4b,5= 7.5, 1H, H-4b), 1.51 and

1.37 (each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz,

CDCl₃) d 174.7 (C@O), 136.9, 136.8 (2 ipso-C of Ph),

128.6–127.4 (Ph), 113.3 (CMe₂), 104.0 (C-1⁰), 76.8 (C-4⁰),

78.8 (C-3⁰), 76.8 (C-2⁰), 71.9 (OCH₂Ph), 69.4 (C-3), 56.7

(C-5), 45.6 (NCH₂Ph), 29.4 (C-4), 26.8 and 26.7 (CMe₂).

Crystallographic analysis^à: The crystal used was a colour-

less needle of size 0.28 · 0.07 · 0.06 mm³, crystallized from

ethanol in the monoclinic system, space group P2₁

5.4.2.3. Compound 16. R_f0.53 (15:1 dichloromethane/

26

methanol); ½aꢂ_D¼ þ36 (c 1.0, CH₂Cl₂); IR (KBr) m_max

3364 (NH and OH), 1717 (amide C@O), 1377 (CMe₂)

1

and 1067 cm^ꢁ1(C–OH); H NMR (300 MHz, CDCl₃) d

7.39–7.25 (m, 5H, Ph), 6.49 (s, 1H, NH), 5.74 (d, 1H,

J_{1 ;2}¼ 3:6, H-1⁰), 4.78, 4.53 (each d, each 1H, J_gem= 11.7,

0

OCH₂Ph), 4.63 (dd, 1H, J_{2 ;3}¼ J_{2 ;1}¼ 3:9, H-2⁰), 4.26 (dd,

0

˚

0

1H, J_3,4a= J_3,4b= 8.4, H-3), 3.95 (dd, 1H, J_{4 ;3}¼ 8:7,

(no. 4); a = 12.769(4), b = 5.5568(17), c = 15.941(6) A, b =

3

J_{4 ;5}¼ 6:6, H-4⁰), 3.61 (dd, 1H, J_{3 ;4}¼ 8:7, J_{2 ;3}¼ 4:2, H-

3⁰), 3.52 (overlapping signal, 1H, H-5), 2.50 (ddd, 1H,

J_4a,3= J_4a,5= 8.1, J_4a,4b= 13.5, H-4a), 1.98 (ddd, 1H,

J_4b,3= J_4b,5= 7.8, J_4b,4a= 13.5, H-4b), 1.60 and 1.36 (each

s, each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 177.2

(C@O), 137.0 (ipso-C of Ph), 128.6–127.4 (Ph), 104.1 (C-

1⁰), 80.4 (C-4⁰), 78.9 (C-3⁰), 77.3 (C-2⁰), 72.0 (OCH₂Ph),

69.1 (C-3), 52.7 (C-5), 32.4 (C-4), 26.8 and 26.6 (CMe₂);

HRCIMS m/z: 350.1601 (calcd for C₁₈H₂₃NO₆+ H:

350.1603).

˚

0

90.422(16)ꢁ; V = 1131.0(7) A ; Z = 2;

q_calcd= 1.291

k(Mo K_a1) = 0.71073 A; F(000) = 468; l =

T = 173(2) K. 4673 Reﬂections were

Mg m^ꢁ3

0.092 mm^ꢁ1

;

˚

;

collected from a Bruker-AXS X8Kappa APEX II CCD

diﬀractometer in the range 3.02 < 2h < 25.56ꢁ, and 2287

independent reﬂections [R_int= 0.0931] were used in the

structural analysis. Reﬂections were corrected for Lorentz

polarization eﬀects and absorption applied by (^SADABS).³⁶

The structure was solved by direct methods (SIR-2002)³⁷

and reﬁned against all F²data by full-matrix least-squares

techniques (^SHELXTL-6.12)³⁸to R₁= 0.0556, wR₂= 0.1332

[I > 2r(I₀)], and to R₁= 0.0775, wR₂= 0.1457 for all data,

with a goodness-of-ﬁt on F²= 1.041 and 289 parameters.

The asymmetric unit of the structure is formed by one mol-

ecule of 14. Because a large standard uncertainty (su) on

the Flack parameter 0.0(10), the Friedel pairs were averag-

ing in the reﬁnement (MERG 4 command). Thereby, the

absolute conﬁguration of new chiral centres C3-(S) and

5.4.3. (3R,5R-, 3S,5S- and 3S,5R-)-1-Benzyl-5-(3-O-benzyl-

1,2-O-isopropylidene-a-^D-xylo-tetrofuranos-4-yl)-3-hydroxy-

2-oxopyrrolidine 34, 35 and 36, respectively, and (3R,5R-,

3S,5S- and 3S,5R-)-5-(3-O-benzyl-1,2-O-isopropylidene-a-

D-xylo-tetrofuranos-4-yl)-3-hydroxy-2-oxopyrrolidine 37, 38

and 39, respectively. Starting from 33a (1.30 g, 2.77

mmol) in acetonitrile (40 mL)/water (2.5 mL) and 0.50 g

of hexacarbonylmolybdenum (time of reaction, 6 h), the

amount of silica gel used was 1.0 g. After workup, com-

pounds 34 (0.450 g, 37%) and 37 (0.324 g, 34%) were

isolated.

^àCrystallographic data (excluding structure factors) for this structure have

been deposited with the Cambridge Crystallographic Centre as Supple-

mentary Publication Number CCDC 648584. Copies of the data can be

obtained, free of charge, on application to CCDC, 12 Union Road,

Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:

deposit@ccdc.cam.ac.uk].

5.4.3.1. Compound 34. Amorphous white material; R_f

26

0.60 (15:1 dichloromethane/methanol); ½aꢂ_D¼ ꢁ36:8 (c

1820

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

25

0.25, CH₂Cl₂), {lit.³³½aꢂ_D¼ ꢁ22 (c 0.88, CHCl₃)}; IR

(NaCl) m_max3372 (OH), 1684 (amide C@O), 1379

(CMe₂), 1074 (C–OH), 737 and 700 cm^ꢁ1(arom C–H);

¹H NMR (300 MHz, CDCl₃) d 7.32–7.13 (m, 10H, 2Ph),

each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 175.5

(C@O), 136.5 (2 ipso-C of Ph), 128.6–127.4 (Ph), 111.8

(CMe₂), 105.6 (C-1⁰), 83.9 (C-4⁰), 82.1 (C-3⁰), 80.9 (C-2⁰),

71.7 (O–CH₂Ph), 68.7 (C-3), 53.3 (C-5), 46.1 (N–CH₂Ph),

31.4 (C-4), 26.7 and 26.1 (CMe₂); HRCIMS m/z:

440.2058 (calcd for C₂₅H₂₉NO₆+ H: 440.2073).

5.94 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.82, 4.20 (each d, each

0

1H, J_gem= 15.3, N–CH₂Ph), 4.62, 4.35 (each d, each 1H,

0

J_gem= 11.7, O–CH₂Ph), 4.58 (dd, 1H, J_{2 ;3}ꢃ 0,

J_{2 ;1}¼ 3:9, H-2⁰), 4.33 (overlapped signal, 1H, H-4⁰), 4.26

0

5.4.3.4. Compound 38. Colourless oil; R_f0.46 (15:1

dichloromethane/methanol); IR (NaCl) m_max3362 (NH

and OH), 1707 (amide C@O), 1379 (CMe₂), 1067 (C–

OH), 870, 743 and 700 cm^ꢁ1(arom C–H); HRCIMS

m/z: 350.1612 (calcd for C₁₈H₂₃NO₆+ H: 350.1603).

0

(m, overlapped signal, H-3), 3.82 (d, 1H, J_{4 ;3}¼ 3:6, H-

3⁰), 3.75 (ddd, 1H, J_5,4= 2.4, J_5,4a= 7.8, J_5,4b= 4.8, H-

0

3), 3.31 (d,1H, J_OH,3= 6.3, OH), 2.44 (ddd, 1H,

J_4a,3= J_4a,5=7.8, J_4a,4b= 14.1, H-4a), 2.27 (ddd,

J_4b,3= J_4b,5= 4.8, 1H, H-4b), 1.49 and 1.35 (each s, each

3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 174.7

(C@O), 136.9 (ipso-C of OBn), 136.1 (ipso-C of NBn),

128.8–127.5 (Ph), 112.1 (CMe₂), 104.7 (C-1⁰), 82.5 (C-3⁰),

81.9 (C-2⁰), 77.3 (C-4⁰), 71.7 (O–CH₂Ph), 69.5 (C-3), 55.0

(C-5), 44.6 (N–CH₂Ph), 30.7 (C-4), 26.8 and 26.3 (CMe₂);

HRCIMS: m/z 440.2057 (calcd for C₂₅H₂₉NO₆+ H:

440.2073).

Starting from 33c (1.20 g, 2.52 mmol) in acetonitrile

(38.2 mL)/water (2.34 mL) and 0.467 g hexacarbonyl-

molybdenum (time of reaction, 5 h), the amount of silica

gel used was 0.8 g. After workup, compounds 36 (0.533 g,

36%) and 39 (0.189 g, 22%) were isolated.

5.4.3.5. Compound 36. Oil; R_f0.46 (15:1 dichlorometh-

26

ane/methanol); ½aꢂ_D¼ ꢁ58 (c 0.5, CH₂Cl₂), {lit.³³

25

5.4.3.2. Compound 37. Amorphous white material; R_f

½aꢂ_D¼ ꢁ86 (c 0.64, CHCl₃)}; IR (NaCl) m_max3364 (OH),

26

0.34 (15:1 dichloromethane/methanol); ½aꢂ_D¼ ꢁ40:5 (c

1684 (amide C@O), 1379 (CMe₂), 1074 (C–OH), 858, 739

1

and 700 cm^ꢁ1(arom C–H); H NMR (300 MHz, CDCl₃)

0.6, CH₂Cl₂); IR (NaCl) m_max3428 (NH and OH), 1703

(amide C@O), 1379 (CMe₂), 1074 (C–OH), 856, 739 and

698 cm^ꢁ1(arom C–H); ¹H NMR (500 MHz, CDCl₃) d

7.43–7.24 (m, 5H, Ph), 6.27 (s, 1H, NH), 5.95 (d, 1H,

d 7.37–7.17 (m, 10H, 2Ph), 5.94 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰),

4.84, 4.12 (each d, each 1H, J_gem= 15.0, N–CH₂Ph),

4.66, 4.40 (each d, each 1H, J_gem= 12.0, O–CH₂Ph),4.61

0

J_{1 ;2}¼ 3:8, H-1⁰), 4.73, 4.52 (each d, each 1H, J_gem= 12.0,

0

(dd, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:9, H-2⁰), 4.60 (m, overlapped

0

O–CH₂Ph), 4.68 (dd, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:8, H-2⁰), 4.27

0

signal, H-3), 4.24 (dd, 1H, J_{3 ;4}¼ J_5;4¼ 3:3, H-4⁰), 3.83

0

(d, 1H, J_{4 ;3}¼ 3:3, H-3⁰), 3.50 (m, 1H, H-5), 2.99 (br s,

1H, OH), 2.87 (dd, 1H, J_4a,3ꢃ 0, J_4a,5= 8.1,

J_4a,4b= 12.9, H-4a), 1.96 (ddd, J_4b,3= J_4b,5= 9.0, 1H, H-

4b), 1.47 and 1.35 (each s, each 3H, CMe₂); ¹³C NMR

(75.4 MHz, CDCl₃) d 175.7 (C@O), 136.8, 135.8 (2 ipso-C

of Ph), 128.8–127.4 (Ph), 111.8 (CMe₂), 104.9 (C-1⁰), 82.7

(C-3⁰), 81.9 (C-2⁰), 78.4 (C-4⁰), 71.7 (O–CH₂Ph), 69.1 (C-

3), 54.5 (C-5), 45.2 (N–CH₂Ph), 31.2 (C-4), 26.8 and 26.2

(dd, J_3,4a= J_3,4b= 8.2, 1H, H-3), 4.06 (dd, 1H, J_{4 ;3}¼ 3:4,

0

J_{4 ;5}¼ 8:1, H-4⁰), 4.02 (d, 1H, J_{3 ;4}¼ 3:4, H-3⁰), 3.83 (ddd,

1H, J_5,4a= 6.8, J_5,4b= 7.4, H-5), 3.45 (br s, 1H, OH), 2.69

(ddd, 1H, J_4a,5= 6.8, J_4a,4b= 13.5, J_4a,3= 8.0, H-4a), 1.98

(ddd, 1H, J_4b,5= 7.4, J_4b,4a= 13.5, J_4b,3= 8.2, H-4b), 1.51

and 1.35 (each s, each 3H, CMe₂); ¹³C NMR (127.5 MHz,

CDCl₃) d 177.6 (C@O), 136.9 (ipso-C of Ph), 128.8–127.9

(Ph), 105.2 (C-1⁰), 83.4 (C-4⁰), 81.9 (C-2⁰), 81.1 (C-3⁰),

71.6 (O–CH₂Ph), 69.2 (C-3), 49.3 (C-5), 34.2 (C-4), 26.8

and 26.3 (CMe₂); HRCIMS m/z: 350.1601 (calcd for

C₁₈H₂₃NO₆+ H: 350.1603).

0

(CMe₂);

HRCIMS

m/z:

440.2042

(calcd

for

C₂₅H₂₉NO₆+ H: 440.2073).

Starting from 33b (0.134 g, 0.286 mmol) in acetonitrile

(4.2 mL)/water (2.58 lL), and 0.0515 g hexacarbonylmo-

lybdenum (time of reaction, 5 h), the amount of silica gel

used was 0.060 g. After workup, compounds 35 (0.080 g,

64%) and 38 (0.019 g, 16%) were isolated.

5.4.3.6. Compound 39. Amorphous white material; R_f

26

0.33 (15:1 dichloromethane/methanol); ½aꢂ_D¼ ꢁ109 (c

0.875, CH₂Cl₂); IR (NaCl) m_max3391 (NH and OH), 1703

(amide C@O), 1379 (CMe₂), 1074 (C–OH), 856, 737 and

700 cm^ꢁ1(arom C–H); ¹H NMR (300 MHz, CDCl₃) d

7.38–7.28 (m, 5H, Ph), 5.95 (s, 1H, NH), 5.94 (d, 1H,

J_{1 ;2}¼ 3:9, H-1⁰), 4.74, 4.47 (each d, each 1H, J_gem= 12.0,

0

O–CH₂Ph), 4.68 (dd, 1H, J_{2 ;3}ꢃ 0, J_{2 ;1}¼ 3:9, H-2⁰), 4.39

0

5.4.3.3. Compound 35. Amorphous white material; R_f

26

0.65 (15:1 dichloromethane/methanol); ½aꢂ_D¼ þ14:3 (c

25

(dd, J_3,4a= 8.4, J_3,4b= 8.7, 1H, H-3), 3.97 (dd, 1H,

1.75, CH₂Cl₂), {lit.³³½aꢂ_D¼ ꢁ29 (c 0.81, CHCl₃)}; IR

J_{4 ;3}¼ 3:3, J_{4 ;5}¼ 8:4, H-4⁰), 3.93 (d, 1H, J_{3 ;4}¼ 3:3, H-

3⁰), 3.88 (dd, 1H, J_5,4a= 1.2, J_5,4b= 8.4, H-5), 3.29 (br s,

1H, OH), 2.65 (ddd, 1H, J_4a,5= 1.2, J_4a,4b= 13.5,

0

(NaCl) m_max3399 (OH), 1678 (amide C@O), 1377

(CMe₂), 1071 (C–OH), 855, 739 and 699 cm^ꢁ1(arom C–

H); ¹H NMR (300 MHz, CDCl₃) d 7.37–7.18 (m, 10H,

J_4a,3= 8.4, H-4a), 2.19 (ddd, 1H,

J_4b,5= 8.4,

2Ph), 5.98 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰), 5.05, 4.35 (each d, each

J_4b,4a= 13.5, J_4b,3= 8.7, H-4b), 1.51 and 1.35 (each s, each

3H, CMe₂); ¹³C NMR (74.5 MHz, CDCl₃) d 177.8 (C@O),

136.9 (ipso-C of Ph), 128.9–127.9 (Ph), 111.9 (CMe₂) 105.4

(C-1⁰), 82.0 (C-4⁰), 81.9 (C-2⁰), 81.1 (C-3⁰), 71.5 (O-

CH₂Ph), 67.9 (C-3), 49.4 (C-5), 32.7 (C-4), 26.8 and 26.2

0

1H, J_gem= 14.4, N–CH₂Ph), 4.61, 4.34 (each d, each 1H,

0

J_gem= 11.7, O–CH₂Ph), 4.57 (dd, 1H, J_{2 ;3}ꢃ 0,

J_{2 ;1}¼ 3:9, H-2⁰), 4.44 (dd, 1H, J_4a,3= J_4b,3= 8.4, H-3),

0

4.06 (dd, 1H, J_{3 ;4}¼ 3:3, J_3;4¼ 9:6, H-4⁰), 3.89 (d, 1H,

0

J_{4 ;3}¼ 3:3, H-3⁰), 3.82 (ddd, 1H, J_4a,5= 3.3, J_4b,5= 7.5,

(CMe₂);

HRCIMS

m/z:

350.1588

(calcd

for

0

H-5), 1.93 (m, 2H, H-4a + H-4b), 1.45 and 1.31 (each s,

C₁₈H₂₃NO₆+ H: 350.1603).

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1821

5.5. General procedure for the reduction of the 5-(glycosyl)-

3-hydroxy-2-oxopyrrolidine derivatives 11, 12, 14, 15, 13,

34, 36, 37 and 39 with lithium aluminium hydride to the

respective 2-(3-O-benzyl-1,2-O-isopropylidene-tetrofuranos-

4-yl)-4-hydroxypyrrolidine derivatives 17–20, 29 and 40–43

5.5.2.1. Compound 18. R_f0.26 (15:1dichloromethane/

26

methanol); ½aꢂ_D¼ þ13:1 (c 1.5, CH₂Cl₂); IR (KBr) m_max

1

3352 (OH), 1642 (Ph) and 1074 cm^ꢁ1(C–OH); H NMR

(300 MHz, CDCl₃) d 7.40–7.23 (m, 10H, 2Ph), 5.66 (d,

1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.82, 4.54 (each d, each 1H,

0

J_gem= 12.0, OCH₂Ph), 4.59 (dd, 1H, J_{2 ;1}¼ J_{2 ;3}¼ 4:2,

H-2⁰), 4.29 (dd, 1H, J_{4 ;3}¼ 9:0, J_{4 ;2}¼ 1:5, H-4⁰), 4.23

0

To a solution of the respective lactam in ether, cooled in an

ice bath, a 1 M solution of lithium aluminium hydride in

ether was added slowly, and the mixture then heated at

reﬂux under stirring for 3 h (monitoring by TLC, 15:1

dichloromethane/methanol). After destroying the excess

of hydride by adding saturated aqueous sodium sulfate,

the mixture was ﬁltered through Celite, and the solid thor-

oughly washed with ethyl acetate and ether. The ﬁltrate

and washings were concentrated and the residue was sub-

jected to column chromatography (30:1 dichloromethane/

methanol) to aﬀord the reduced product.

(overlapped signal, 1H, H-4), 4.12, 3.54 (each d, each 1H,

0

J_gem= 13.8, NCH₂Ph), 3.86 (dd, 1H, J_{3 ;4}¼ 9:0,

J_{3 ;2}¼ 4:5, H-3⁰), 3.32 (ddd, J_2;4¼ 1:5, J_2,3a

=

0

J_2,3b= 8.1, H-2), 3.14 (dd, 1H, J_5a,5b= 9.9, J_5a,4= 5.4,

H-5a), 2.30 (dd, 1H, J_5b,4= 5.1, J_5a,5b= 10.2, H-5b), 2.14

(ddd, 1H, J_3a,2= J_3a,4= 7.5, J_3a,3b= 14.7, H-3a), 1.60

(ddd, 1H, J_3b,2= 8.7, J_3b,4= 4.2, J_3a,3b= 14.7, H-3b),

1.60 and 1.38 (each s, each 3H, CMe₂); ¹³C NMR

(75.4 MHz, CDCl₃) d 139.5, 137.6 (2 ipso-C of Ph),

128.8–126.7 (Ph), 112.9 (CMe₂), 103.9 (C-1⁰), 78.8 (C-4⁰),

78.0 (C-3⁰), 77.0 (C-2⁰), 71.9 (OCH₂Ph), 70.1 (C-4), 62.3

(C-5), 61.3 (C-2), 59.4 (NCH₂Ph), 35.4 (C-3), 26.9 and

26.7 (CMe₂); HRCIMS m/z: 426.2284 (calcd for

C₂₅H₃₁NO₅+ H: 426.2280).

5.5.1. (2R,4R)-1-Benzyl-2-(3-O-benzyl-1,2-O-isopropylidene-

a-^D-ribo-tetrofuranos-4-yl)-4-hydroxypyrrolidine 17. From

11 (0.217 g, 0.482 mmol) in ether (4.0 mL) and a 1 M solu-

tion of lithium aluminium hydride in ether (1.80 mL;

1.80 mmol), after destroying the excess of hydride by adding

saturated aqueous sodium sulfate (700 lL), and general

workup, column chromatography provided pure product

5.5.3. (2S,4S)-1-Benzyl-2-(3-O-benzyl-1,2-O-isopropylidene-

a-^D-ribo-tetrofuranos-4-yl)-4-hydroxypyrrolidine 19 and

(2S,4R)-1-benzyl-2-(3-O-benzyl-1,2-O-isopropylidene-a-^D-

ribo-tetrofuranos-4-yl)-4-hydroxypyrrolidine 20. From the

10:3.5 14/15 mixture (0.441 g, 1.005 mmol) in ether (10 mL)

and a 1 M solution of lithium aluminium hydride in THF

(1.58 mL, 1.58 mmol), after destroying the excess of

hydride by adding saturated aqueous sodium sulfate

(340 lL) and workup, a crude product was obtained

(0.320 g, 0.753 mmol; 75%), which, after column chroma-

tography, aﬀorded two pure products: compound 19

(0.200 g; 0.471 mmol; 47%), isolated as a white foam, and

compound 20 (0.036 g, 0.085 mmol; 8.5%), obtained as

an oil.

17 as an oil (0.198 g; 96%); R_f0.44 (15:1 dichlorometh-

26

ane/methanol); ½aꢂ_D¼ þ73 (c 1.0, CH₂Cl₂); IR (KBr) m_max

3443 (OH), 1642 (C–N) and 1130 cm^ꢁ1(C–OH); ¹H

NMR (300 MHz, CDCl₃) d 7.39–7.23 (m, 10H, 2Ph), 5.76

(d, 1H, J_{1 ;2}¼ 3:6, H-1⁰), 4.83, 4.54 (each d, each 1H,

0

,

J_gem= 12.0, OCH₂Ph), 4.62 (dd, 1H, J_{2 ;1}¼ 3:9 ¼ J_{2 ;3}

H-2⁰), 4.23 (br d 1H, J_{4 ;3}¼ 9:0, H-4⁰), 4.06, 3.54 (each d,

0

each 1H, J_gem= 13.8, NCH₂Ph), 4.05 (overlapped signal,

1H, H-4), 3.60 (dd, 1H, J_{3 ;4}¼ 9:3, J_{3 ;2}¼ 4:2, H-3⁰), 3.00

0

(ddd, J_2;4ꢃ 0, J_2,3a= 10.8, J_2,3b= 3.0, H-2), 2.95 (dd,

1H, J_5a,5b= 9.6, J_5a,4= 1.5, H-5a), 2.36 (dd, 1H,

J_5b,4= 3.3, J_5a,5b= 9.6, H-5b), 1.94 (ddd, 1H, J_3a,2= 10.8,

J_3a,3b= 13.8, J_3a,4= 5.4, H-3a), 1.59 (overlapped signal,

1H, H-3b) 1.59 and 1.39 (each s, each 3H, CMe₂); ¹³C

NMR (75.4 MHz, CDCl₃) d 138.8, 137.3 (2 ipso-C of Ph),

128.8–126.9 (Ph), 113.3 (CMe₂), 103.9 (C-1⁰), 78.7 (C-3⁰),

78.3 (C-4⁰), 77.3 (C-2⁰), 71.9 (OCH₂Ph), 70.0 (C-4), 62.3

(C-5), 60.9 (C-2), 57.9 (NCH₂Ph), 34.4 (C-3), 26.9 and

26.7 (CMe₂); HRCIMS m/z: 426.2288 (calcd for

C₂₅H₃₁NO₅+ H: 426.2280).

5.5.3.1. Compound 19. R_f0.62 (30:1 dichloromethane/

26

methanol; 1.5 running); ½aꢂ_D¼ þ13 (c 0.3, CH₂Cl₂); IR

(KBr) m_max3372 (OH), 1642 (Ph) and 1123 cm^ꢁ1(C–

1

OH); H NMR (300 MHz, CDCl₃) d 7.35–7.23 (m, 10H,

2Ph), 5.86 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.77, 4.45 (each d, each

0

1H, J_gem= 11.4, OCH₂Ph), 4.70 (dd, 1H, J_{2 ;1}

¼

J_{2 ;3}¼ 3:9, H-2⁰), 4.15 (overlapped signal, 1H, H-4), 4.13

0

(dd, 1H, J_{4 ;3}¼ 8:7, J_{4 ;2}¼ 3:0, H-4⁰), 4.00, 3.45 (each d,

0

each 1H, J_gem= 14.1, NCH₂Ph), 3.92 (dd, 1H,

J_{3 ;4}¼ 9:0, J_{3 ;2}¼ 4:2, H-3⁰), 3.69 (d, 1H, J_OH,4= 10.8),

0

3.18 (ddd, J_2;4¼ J_2;3b¼ 3:0, J_2,3a= 11.1, H-2), 2.96 (br

5.5.2. Compound 17 and (2R,4S)-1-benzyl-2-(3-O-benzyl-

1,2-O-isopropylidene-a-^D-ribo-tetrofuranos-4-yl)-4-hydroxy-

pyrrolidine 18. From the 1:0.41 11/12 mixture (0.424 g,

0.965 mmol) in ether (8 mL) and lithium aluminium

hydride in THF (1.50 mL; 1.50 mmol), after destroying

the excess of hydride by adding saturated aqueous sodium

sulfate (600 lL) and workup, a crude product was obtained

(0.334 g, 0.786 mmol; 81%), which was subjected to column

chromatography to aﬀord two fractions. First eluted 17,

d, 1H, J_5a,5b= 10.2, H-5a), 2.39 (ddd, 1H, J_5b,4= 3.9,

J_5a,5b= 10.2, H-5b), 2.29 (ddd, 1H, J_3a,2= 11.1,

J_3a,4= 5.7, J_3a,3b= 14.4, H-3a), 1.91 (br d, 1H,

J_3a,3b= 14.4, H-3b), 1.62 and 1.40 (each s, each 3H,

CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 137.1, 136.6 (2

ipso-C of Ph), 128.4–126.8 (Ph), 113.2 (CMe₂), 103.7 (C-

1⁰), 81.2 (C-4⁰), 77.7 (C-3⁰), 77.2 (C-2⁰), 71.8 (OCH₂Ph),

71.1 (C-4), 63.4 (C-5), 61.1 (C-2), 60.5 (NCH₂Ph), 37.0

(C-3), 26.8 and 26.7 (CMe₂); HRCIMS m/z: 426.2282

(calcd for C₂₅H₃₁NO₅+ H: 426.2280).

1

isolated as an oil (0.158 g; 0.372 mmol; 39%); H and ¹³C

NMR spectra were, respectively, identical with those of

the product obtained from pure 11. The fraction eluted sec-

ond provided compound 18 (0.078 g, 0.184 mmol; 19%),

isolated as a colourless oil.

5.5.3.2. Compound 20. R_f0.27 (30:1 dichloromethane/

26

methanol; 1.5 running); ½aꢂ_D¼ þ4 (c 0.25, CH₂Cl); IR

(KBr) m_max3426 (OH), 1683 (Ph) and 1119 cm^ꢁ1(C–

1822

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1

0

OH); H NMR (300 MHz, CDCl₃) d 7.39–7.23 (m, 10H,

3.19 (br s, 1H, OH), 3.07 (ddd, J_2,4= 2.4, J_2,3a= 4.2,

2Ph), 5.79 (d, 1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.76, 4.49 (each d, each

J_2,4b= 8.1, H-2), 2.97 (d, 1H, J_5a,5b= 9.9, H-5a), 2.39

(dd, 1H, J_5b,4= 3.3, J_5a,5b= 9.9, H-5b), 2.19 (m, 2H, H-

3a + H-3b), 1.45 and 1.34 (each s, each 3H, CMe₂); ¹³C

NMR (75.4 MHz, CDCl₃) d 139.2, 137.5 (2 ipso-C of

Ph), 128.7–126.9 (Ph), 111.8 (CMe₂), 104.8 (C-1⁰), 82.6

(C-3⁰), 82.4 (C-2⁰), 81.6 (C-4⁰), 71.6 (OCH₂Ph), 70.8 (C-

4), 61.9 (C-5), 61.1 (C-2), 58.9 (NCH₂Ph), 36.4 (C-3),

27.0 and 26.5 (CMe₂); HRCIMS m/z: 426.2275 (calcd for

C₂₅H₃₁NO₅+ H: 426.2280).

0

1H, J_gem= 11.7, OCH₂Ph), 4.60 (dd, 1H, J_{2 ;1}¼ J_{2 ;3}

¼

4:2, H-2⁰), 4.37 (m, overlapped signal, 1H, H-4), 4.23,

3.55 (each d, each 1H, J_gem= 13.2, NCH₂Ph), 4.08 (dd,

1H, J_{4 ;3}¼ 8:7, J_{4 ;2}¼ 5:7, H-4⁰), 3.67 (dd, 1H, J_{3 ;4}

¼

0

8:7, J_{3 ;2}¼ 4:5, H-3⁰), 3.16 (dd., 1H, J_5a,5b= 10.8,

J_5a,4= 5.1, H-5a), 3.14 (m, J_2,3a= 7.8, H-2), 2.32 (dd,

1H, J_5b,4= 4.5, J_5a,5b=10.5, H-5b), 2.16 (ddd, 1H,

J_3a,2= J_3a,4= 7.2, J_3a,3b= 13.8, H-3a), 1.81 (ddd., 1H,

J_3b,2= 8.1, J_3b,4= 3.9, J_3a,3b= 13.8, H-3b), 1.62 and 1.38

(each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃)

d 139.7, 137.5 (2 ipso-C of Ph), 128.9–126.7 (Ph), 112.7

(CMe₂), 104.0 (C-1⁰), 82.0 (C-4⁰), 79.4 (C-3⁰), 77.1 (C-2⁰),

71.9 (OCH₂Ph), 70.9 (C-4), 63.6 (C-2), 61.9 (C-5), 60.5

(NCH₂Ph), 37.2 (C-3), 26.9 and 26.8 (CMe₂); HRCIMS

m/z: 426.2277 (calcd for C₂₅H₃₁NO₅+ H: 426.2280).

0

5.5.6. (2R,4S)-1-Benzyl-2-(3-O-benzyl-1,2-O-isopropylidene-

41.

a-^D-xylo-tetrofuranos-4-yl)-4-hydroxypyrrolidine

From 36 (0.337 g, 0.767 mmol) in ether (6.2 mL) and a

1 M solution of lithium aluminium hydride in ether

(2.80 mL; 2.80 mmol), after reﬂuxing for 3 h and using

981 lL of saturated aqueous sodium sulfate (981 lL) to de-

stroy the excess hydride, pure product 41 was obtained as

5.5.4. (2R,4R)-2-(3-O-Benzyl-1,2-O-isopropylidene-a-^D-ribo-

tetrofuranos-4-yl)-4-hydroxypyrrolidine 29. From 13

(0.145 g, 0.415 mmol) in ether (3.5 mL) and a 1 M solution

of lithium aluminium hydride in ether (1.57 mL,

1.57 mmol), after destroying the excess of hydride by add-

ing saturated aqueous sodium sulfate (340 lL) and work-

an oil (0.296 g; 91%); R_f0.29 (15:1 dichloromethane/meth-

20

anol); ½aꢂ_D¼ ꢁ39 (c 0.3, CH₂Cl₂); {lit.^18b[a]_D= ꢁ17.8 (c

0.41, CHCl₃)}; IR (KBr) m_max3321 (OH), 1083 (C–OH),

1032 (C–N), 737 and 704 cm^ꢁ1(arom C–H); ¹H NMR

(300 MHz, CDCl₃) d 7.33–7.24 (m, 10H, Ph), 5.93 (d,

1H, J_{1 ;2}¼ 3:6, H-1⁰), 4.66, 4.43 (each d, each 1H,

0

J_gem= 11.4, OCH₂Ph), 4.63 (d, 1H, J_{2 ;1}¼ 3:6, H-2⁰),

0

up, compound 29 was obtained (0.134 g; 96%) as an oil;

26

R_f0.25 (15:1 dichloromethane/methanol); ½aꢂ_D¼ þ82:3 (c

4.38 (m, overlapped signal, H-4), 4.11 (dd, 1H,

0

0.875, CH₂Cl₂); IR (KBr) m_max3414 (NH and OH), 1643

(Ph), 1379 (CMe₂) and 1074 cm^ꢁ1(C–OH); ¹H NMR

(300 MHz, CDCl₃) d 7.30–7.19 (m, 5H, Ph), 5.67 (d, 1H,

J_{4 ;3}¼ 3:0, J_{4 ;2}¼ 6:6, H-4), 4.02, 3.61 (each d, each 1H,

J_gem= 13.8, NCH₂Ph), 3.98 (d, 1H, J_{3 ;4}¼ 3:0, H-3⁰),

0 0

0

3.47 (br s, 1H, OH), 3.46 (ddd, J_2;4¼ J_2;3a¼ 6:6,

J_{1 ;2}¼ 3:6, H-1⁰), 4.72, 4.43 (each d, each 1H, J_gem= 11.7,

J_2,4b= 7.5, H-2), 3.12 (dd, 1H, J_5a,4= 4.8, J_5a,5b= 10.2,

H-5a), 2.39 (dd, 1H, J_5b,4= 4.5, J_5a,5b= 9.9, H-5b), 2.27

(ddd, 1H, J_3a,2= J_3a,4= 6.3, J_3a,3b= 13.2, H-3a), 2.01

(ddd, 1H, J_3b,2= 7.8, J_3b,4= 5.1, J_3a,3b= 13.2, H-3a),

1.52 and 1.36 (each s, each 3H, CMe₂); ¹³C NMR

(75.4MHz, CDCl₃) d 139.8, 137.3 (2 ipso-C of Ph), 128.9–

126.9 (Ph), 111.5 (CMe₂), 104.6 (C-1⁰), 82.9 (C-4⁰), 82.3

(C-3⁰), 81.8 (C-2⁰), 71.4 (OCH₂Ph), 71.1 (C-4), 61.5 (C-5),

60.3 (NCH₂Ph), 60.1 (C-2), 38.4 (C-3), 26.8 and 26.3

0

OCH₂Ph), 4.54 (dd, 1H, J_{2 ;1}¼ 3:9, J_{2 ;3}¼ 4:2, H-2⁰), 4.13

0

(dd, 1H, J_{4 ;3}¼ 9:0, J_{4 ;2}¼ 3:0, H-4⁰), 4.13 (overlapped sig-

0

nal, 1H, H-4), 3.52 (dd, 1H, J_{3 ;4}¼ 9:0, J_{3 ;2}¼ 4:5, H-3⁰),

0

3.32 (ddd, 1H, J_2;4¼ 3:3, J_2,3a= 9.0, J_2,3b= 4.8, H-2),

2.88 (br d, 1H, J_5a,5b= 11.4, H-5a), 2.71 (dd, J_5b,4= 3.9,

J_5b,5a= 11.4, H-5b), 1.78 (ddd, 1H, J_3a,3b= 14.7,

J_3a,2= 9.0, J_3a,4= 5.7, H-3a), 1.45 (ddd, 1H, J_3b,2= 3.3,

J_3b,3a= 14.1, J_3b,4= 2.1, H-3b), 1.53 and 1.29 (each s, each

3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃) d 137.3, (ipso-C

of Ph), 128.7–128.1 (Ph), 113.3 (CMe₂), 104.0 (C-1⁰), 79.6

(C-4⁰), 79.1 (C-3⁰), 77.7 (C-2⁰), 72.0 (OCH₂Ph), 71.7 (C-

4), 57.5 (C-2), 55.9 (C-5), 35.1 (C-3), 26.8 and 26.7

(CMe₂);

HRCIMS

m/z:

426.2257

(calcd

for

C₂₅H₃₁NO₅+ H: 426.2280).

5.5.7.

(2R,4R)-2-(3-O-Benzyl-1,2-O-isopropylidene-a-^D-

(CMe₂);

C₁₈H₂₅NO₅+ H: 336.1811).

HRCIMS

m/z:

336.1815

(calcd

for

xylo-tetrofuranos-4-yl)-4-hydroxypyrrolidine 42. From 37

(0.324 g, 0.928 mmol) in ether (7.5 mL) and a 1 M solution

of lithium aluminium hydride in ether (3.38 mL;

3.38 mmol), after reﬂuxing for 3 h and using 1.07 mL of

saturated aqueous sodium sulfate to destroy the excess of

hydride, compound 42 was isolated as an oil (0.258 g;

5.5.5. (2R,4R)-2-(3-O-Benzyl-1,2-O-isopropylidene-a-^D-xylo-

tetrofuranos-4-yl)-4-hydroxypyrrolidine 40. From 34

(0.211 g, 0.480 mmol) in ether (3.9 mL) and a 1 M solution

of lithium aluminium hydride in ether (1.75 mL;

1.75 mmol), after reﬂuxing for 3 h and using 614 lL of sat-

urated aqueous sodium sulfate to destroy the excess of

hydride, pure compound 40 was obtained as an oil

83%); R_f0.15 (15:1 dichloromethane/methanol);

26

½aꢂ_D¼ ꢁ40 (c 0.2, CH₂Cl₂); IR (NaCl) m_max3408 (NH

and OH), 1368 (CMe₂) and 1074 cm^ꢁ1(C–OH); ¹H

NMR (300 MHz, CDCl₃) d 7.39–7.27 (m, 5H, Ph), 5.95

(d, 1H, J_{1 ;2}¼ 3:9, H-1⁰), 4.72, 4.49 (each d, each 1H,

0

(0.154 g; 76%); R_f0.38 (15:1 dichloromethane/methanol);

26

½aꢂ_D¼ ꢁ1:56 (c 0.3, CH₂Cl₂); {lit.^18b[a]_D= ꢁ40.0 (c

J_gem= 12.0, OCH₂Ph), 4.64 (dd, 1H, J_{2 ;1}¼ 4:2,

0

J_{2 ;3}ꢃ 0, H-2⁰), 4.30 (m, 1H, H-4), 4.17 (dd, 1H,

0

0.25, CHCl₃)}; IR (NaCl) m_max3136 (OH), 1400 (C–N),

1069 (C–OH), 846, 730 and 700 cm^ꢁ1(arom C–H); ¹H

NMR (300 MHz, CDCl₃) d 7.40–7.23 (m, 10H, 2Ph),

J_{4 ;3}¼ 3:3, J_{4 ;2}¼ 6:6, H-4⁰), 4.00 (d, 1H, J_{3 ;4}¼ 3:6, H-

3⁰), 3.44 (m, 1H, H-2), 2.92 (br d, 1H, H-5a), 2.82 (ddd,

J_5b,5a= 12.0, J_5b,4= 4.2, J_5b,NH= 7.8, H-5b), 2.23 (ddd,

1H, J_3a,3b= 14.4, J_3a,2= 9.0, J_3a,4= 5.7, H-3a), 1.88

(ddd, 1H, J_3b,2= 5.4, J_3b,3a= 14.1, J_3b,4= 1.8, H-3b),

1.50 and 1.33 (each s, each 3H, CMe₂); ¹³C NMR

(75.4 MHz, CDCl₃) d 137.5, (ipso-C of Ph), 128.5–127.7

0

5.98 (d, 1H, J_{1 ,2}= 3.6, H-1⁰), 4.67, 4.44 (each d, each

0

1H, J_gem= 12.0, OCH₂Ph), 4.60 (dd, 1H, J_{2 ;1}¼ 3:96,

J_{2 ;3}ꢃ 0, H-2⁰), 4.24 (dd, 1H, J_{4 ;3}¼ J_{4 ;2}¼ 3:06, H-4⁰),

0

4.14 (br s, 1H, H-4), 3.93, 3.57 (each d, each 1H,

J_gem= 13.5, NCH₂Ph), 3.85 (d, 1H, J_{3 ;4}¼ 3:6, H-3⁰),

0

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1823

(Ph), 111.8 (CMe₂), 105.2 (C-1⁰), 84.1 (C-4⁰), 82.3 (C-2⁰),

82.1 (C-3⁰), 72.4 (C-4), 71.8 (OCH₂Ph), 55.5 (C-2), 55.3

(C-5), 38.5 (C-3), 26.8 and 26.3 (CMe₂); HRCIMS m/z:

336.1813 (calcd for C₁₈H₂₅NO₅+ H: 336.1811).

(OCH₂Ph), 69.6 (C-4⁰), 66.9 (CH₂Ph of Cbz), 65.3 (C-4),

57.2 (C-2), 56.6 (C-5), 33.8 (C-3) and 26.6 (CMe₂);

HRFABMS m/z: 470.2172 (calcd for C₂₆H₃₁NO₇+ H:

470.2179).

5.5.8. (2R,4S)-2-(3-O-Benzyl-1,2-O-isopropylidene-a-^D-xylo-

tetrofuranos-4-yl)-4-hydroxypyrrolidine 43. From 39

(0.150 g, 0.430 mmol) in ether (3.5 mL) and a 1 M solution

of lithium aluminium hydride in ether (1.57 mL;

1.57 mmol), after reﬂuxing for 4 h, and using 550 lL of

saturated aqueous sodium sulfate to destroy the excess hy-

5.7. General procedure for the 1⁰,2⁰-O-deprotection of N-

protected 2-(3-O-benzyl-1,2-O-isopropylidene-a-^D-ribo(or

xylo)-tetrofuranos-4-yl)-4-hydroxypyrrolidine derivatives 17,

18, 19, 20, 31, 40 and 41. Synthesis of the respective N-

protected 2-(3-O-benzyl-^D-ribo(or xylo)-tetros-4-yl)-4-

hydroxypyrrolidine derivatives 21, 22, 23, 24, 32, 44 and 45

dride, compound 43 was isolated as an oil (0.139 g; 97%);

26

R_f0.12 (15:1 dichloromethane/methanol); ½aꢂ ¼ ꢁ31:7 (c

0.45, CH₂Cl₂); IR (NaCl) m_max3183 (NH an^Dd OH), 1377

(CMe₂) and 1067 cm^ꢁ1(C–OH); ¹H NMR (300 MHz,

An aqueous 80% solution of triﬂuoroacetic acid was added

dropwise to the corresponding N-protected 2-(3-O-benzyl-

1,2-O-isopropylidene-tetrofuranos-4-yl)-4-hydroxypyrroli-

dine derivative, and the mixture stirred at room tempera-

ture until the starting material was totally consumed (12–

20 h, monitoring by TLC, 8:1 dichloromethane/methanol).

The solution was then concentrated under diminished pres-

sure and the residue dissolved in dichloromethane and

washed with aqueous 10% sodium hydrogen carbonate

until pH ꢀ7.5. After drying over sodium sulfate, the

solvent was evaporated at reduced pressure to aﬀord, in

some cases after column chromatography, the respective

N-deprotected compound.

0

CDCl₃) d 7.34–7.28 (m, 5H, Ph), 5.93 (d, 1H, J_{1 ;2}¼ 3:9,

H-1⁰), 4.73, 4.52 (each d, each 1H, J_gem= 11.7, OCH₂Ph),

4.62 (dd, 1H, J_{2 ;1}¼ 3:6, J_{2 ;3}ꢃ 0, H-2⁰), 4.41 (m, 1H, H-

0

4), 4.03 (d, 1H, J_{3 ;4}¼ 3:3, H-3⁰), 3.94 (dd, 1H,

0

J_{4 ;3}¼ 3:3, J_{4 ;2}¼ 9:0, H-4⁰), 3.75 (m, 1H, H-2), 3.46 (s,

1H, OH), 2.94 (dd, 1H, J_4,5a= 3.9, J_5a,5b= 12.0, H-5a),

2.83 (br d, J_5b,5a= 12.0, H-5b), 2.03 (br dd, 1H,

J_3a,3b= 14.1, J_3a,2= 7.2, H-3a), 1.84 (ddd, 1H,

J_3b,2= 8.7, J_3b,3a= 13.8, J_3b,4= 5.1, H-3b), 1.48 and 1.31

(each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃)

d 137.6, (ipso-C of Ph), 128.8–126.9 (Ph), 111.6 (CMe₂),

105.2 (C-1⁰), 84.5 (C-4⁰), 82.2 (C-2⁰), 82.1 (C-3⁰), 72.8 (C-

4), 71.8 (OCH₂Ph), 54.8 (C-5), 54.1 (C-2), 39.8 (C-3),

26.8 and 26.2 (CMe₂); HRCIMS m/z: 336.1815 (calcd for

C₁₈H₂₅NO₅+ H: 336.1811).

0

5.7.1. (2R,4R)-1-Benzyl-2-(3-O-benzyl-^D-ribo-tetros-4-yl)-4-

hydroxypyrrolidine 21. From 17 (0.198 g, 0.465 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(14 mL), compound 21 was obtained, after workup (with-

out neutralizing with aqueous 10% sodium hydrogen car-

bonate), as an oil (0.175 g, 0.456 mmol; 98%); R_f0.57

(8:1 dichloromethane/methanol); IR (KBr) m_max3345 (O–

H), 1632 (Ph) and 1094 cm^ꢁ1(C–OH); HRFABMS m/z:

386.1934 (calcd for C₂₂H₂₇NO₅+ H: 386.1967).

5.6. N-Protection of compound 29. Synthesis of (2R,4R)-2-

(3-O-benzyl-1,2-O-isopropylidene-a-^D-ribo-tetrofuranos-4-

yl)-1-benzyloxycarbonyl-4-hydroxypyrrolidine 31

Sodium hydrogen carbonate (0.162 g, 1.93 mmol) and

benzyl chloroformate (176.6 lL, 1.25 mmol) were added

to a solution of 29 (0.198 g, 0.59 mmol) in 1:1 ethanol/

water (7.4 mL). The mixture was shaken at room tempera-

ture for 1–2 h (monitoring by TLC, 15:1 dichloromethane/

methanol), then poured into saturated aqueous sodium

hydrogen carbonate (21 mL) and extracted with

3 · 20 mL of ethyl acetate. The combined organic layers

were dried over sodium sulfate and concentrated, and the

residue was subjected to column chromatography (40:1

dichloromethane/methanol) to aﬀord pure compound 31

5.7.2. (2R,4S)-1-Benzyl-2-(3-O-benzyl-^D-ribo-tetros-4-yl)-4-

hydroxypyrrolidine 22. From 18 (0.078 g, 0.183 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(5.4 mL), after workup (without neutralizing with aqueous

10% sodium hydrogen carbonate), compound 22 was

obtained as a coloured oil (0.068 g, 0.176 mmol; 96%); R_f

0.41 (8:1 dichloromethane/methanol); IR (KBr) m_max3412

(O–H), 1632 (Ph) and 1096 cm^ꢁ1(C–OH); HRFABMS

m/z 386.1956 (calcd for C₂₂H₂₇NO₅+ H: 386.1967).

as an oil (0.213 g; 0.454 mmol, 97%); R_f0.75 (15:1 dichlo-

5.7.3. (2S,4S)-1-Benzyl-2-(3-O-benzyl-^D-ribo-tetros-4-yl)-4-

hydroxypyrrolidine 23. From 19 (0.200 g, 0.465 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(14 mL), after workup (without neutralizing with aqueous

10% sodium hydrogen carbonate), compound 23 was

obtained as a coloured oil (0.175 g, 0.456 mmol; 98%); R_f

0.60 (8:1 dichloromethane/methanol); IR (KBr) m_max3412

(O–H), 1614 (Ph) and 1096 cm^ꢁ1(C–OH); HRFABMS

m/z: 386.1963 (calcd for C₂₂H₂₇NO₅+ H: 386.1967).

26

romethane/methanol); ½aꢂ_D¼ þ44:7 (c 0.45, CH₂Cl₂); IR

(KBr) m_max3426 (OH), 1645 (C@O), 1410 (C–O), 1356

(CMe₂) and 1074 cm^ꢁ1(C–OH); ¹H NMR (300 MHz,

CDCl₃)

d 7.40–7.22 (m, 10H, 2Ph), 5.79 (d, 1H,

J_{1 ;2}¼ 3:6, H-1⁰), 5.18 (br s, 1H, CH₂Ph of Cbz), 4.83,

0

4.52 (each d, each 1H, J_gem= 12.0, OCH₂Ph), 4.72 (d,

1H, J = 5.7, H-4), 4.64 (dd, 1H, J_{2 ;3}ꢃ J_{2 ;1}¼ 3:8, H-2⁰),

0

4.22 (m, 1H, J_{4 ;3}¼ 5:7, J_{4 ;2}¼ 10:0, H-4⁰), 4.11 (m, over-

lapped signal, 1H, H-2), 3.58 (m, overlapped signal, 1H,

H-3⁰), 3.52(m, overlapped signal, 1H, H-5a), 3.51 (d, 1H,

J_5a,5b= 12.0, J_4,5aꢃ 0, H-5b), 2.02 (br s, 1H, H-3a), 1.71

(ddd, 1H, J_3b,4= 6.0, J_3b,3a= 11.4, H-3b), 1.62 and 1.38

(each s, each 3H, CMe₂); ¹³C NMR (75.4 MHz, CDCl₃)

d 156.0 (C@O), 137.0 (ipso-C of Ph), 128.6–127.0 (Ph),

105.0 (CMe₂), 103.9 (C-1⁰), 78.7 (C-3⁰), 77.0 (C-2⁰), 71.8

0

5.7.4. (2S,4R)-1-Benzyl-2-(3-O-benzyl-^D-ribo-tetros-4-yl)-4-

hydroxypyrrolidine 24. From 20 (0.025 g, 0.059 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(5.0 mL), after workup (without neutralizing with aqueous

10% sodium hydrogen carbonate), compound 24 was ob-

tained as a coloured oil (0.022 g, 0.057 mmol; 98%); R_f

1824

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

0

0.46 (8:1 dichloromethane/methanol); IR (KBr) m_max3406

(O–H), 1642 (Ph) and 1102 cm^ꢁ1(C–OH); HRFABMS

m/z: 386.1976 (calcd for C₂₂H₂₇NO₅+ H: 386.1967).

J_2;3¼ 6:4, H-2), 3.93 (dd, 1H, J_7,8= 2.5, J_7,6= 3.0, H-7),

0

3.80 (ddd, 1H, J_6,5= 5.5, J_6;5¼ 11:0, J_6,7= 3.0, H-6),

3.42 (dd, 1H, J_8,7= 2.5, J_8,8a= 9.5, H-8), 2.93 (d, 1H,

0

J_3;3¼ 10:5, H-3), 2.81 (dd, 1H, J_5,6= 5.0, J_5;5¼ 10:0, H-

0

5.7.5. (2R,4R)-2-(3-O-Benzyl-^D-ribo-tetros-4-yl)-1-benzyl-

oxycarbonyl-4-hydroxypyrrolidine 32. From 31 (0.090 g,

0.191 mmol) and an aqueous 80% solution of triﬂuoroace-

tic acid (7.0 mL), after workup (without neutralizing with

aqueous 10% sodium hydrogen carbonate), and column

chromatography, compound 32 was obtained as a coloured

oil (0.074 g; 0.172 mmol; 90%); R_f0.22 (8:1 dichlorometh-

ane/methanol); IR (KBr) m_max3336 (O–H), 1632 (Ph) and

1172 cm^ꢁ1(C–OH); HRFABMS m/z: 452.1688 (calcd for

C₂₃H₂₇NO₇+ Na: 452.1685).

5), 2.46 (ddd, 1H, J_1,8a= 6.5, J_1;1¼ 13:5, J_1,2= 8.0, H-

1), 2.45 (dd, 1H, J_{3 ;2}¼ 6:0, J_3;3¼ 10:0, H-3⁰), 2.33 (ddd,

0

1H, J_8a;8ꢃ J_8a;1¼ 10:0, J_8a,1= 6.5, H-8a), 2.28 (dd, 1H,

J_{5 ;5}ꢃ J_{5 ;6}¼ 10:5, H-5⁰) and 1.45 (ddd, 1H, J_{1 ;2}¼ 4:5,

0

J_{1 ;8a}¼ 10:5, J_{1 ;1}¼ 13:0, H-1⁰); ¹³C NMR (125.7 MHz,

CD₃OD) d 73.0 (C-8), 71.7 (C-7), 68.9 (C-2), 68.2 (C-6),

62.4 (C-3), 61.3 (C-8a), 51.4 (C-5) and 38.6 (C-1); HRC-

IMS m/z: 190.1082 (calcd for C₈H₁₅NO₄+ H: 190.1079).

0

(b) From 32 (0.074 g, 0.172 mmol) in ethanol (7.0 mL),

using an excess of catalyst (0.062 g) and hydrogenation

for 24 h (TLC, 3:1:0.1 dichloromethane/methanol/10%

ammonia), general workup, without column chromatogra-

phy, yielded a colourless oil (0.032 g, 0.169 mmol, 98%),

identiﬁed as 25 (NMR and MS data, respectively,

identical).

5.7.6. (2R,4R)-1-Benzyl-2-(3-O-benzyl-^D-xylo-tetros-4-yl)-

4-hydroxypyrrolidine 44. From 40 (0.228 g; 0.536 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(16.5 mL), after workup, 44 was obtained as an oil

(0.202 g; 0.525 mmol; 98%); R_f0.33 (8:1 dichlorometh-

ane/methanol); IR (KBr) m_max3380 (HO), 1380 (C–N)

and 1089 cm^ꢁ1(C–OH); HRFABMS m/z: 386.1923 (calcd

for C₂₂H₂₇NO₅+ H: 386.1967).

5.8.2. (2S,6S,7S,8R,8aR)-2,6,7,8-Tetrahydroxyindolizidine

26. From 22 (0.068 g, 0.176 mmol) in ethanol (10 mL),

using an excess of catalyst (0.054 g) and hydrogenation

for 24 h (TLC, 3:1:0.1 dichloromethane/methanol/10%

ammonia), general workup (eluent for column chromatog-

raphy, the same as for TLC) gave 26 (0.032 g, 0.169 mmol,

5.7.7. (2R,4S)-1-Benzyl-2-(3-O-benzyl-^D-xylo-tetros-4-yl)-4-

hydroxypyrrolidine 45. From 41 (0.228 g; 0.536 mmol)

and an aqueous 80% solution of triﬂuoroacetic acid

(16.5 mL), after workup, compound 45 was obtained as

an oil (0.202 g; 0.525 mmol; 98%); R_f0.32 (8:1 dichloro-

methane/methanol); IR (KBr) m_max3400 (O–H), 1392 (C–

N) and 1074 cm^ꢁ1(C–OH); HRFABMS m/z: 386.1942

(calcd for C₂₂H₂₇NO₅+ H: 386.1967).

96%) as a colourless oil; R_f0.36 (5:1:0.1!3:1:0.1 dichloro-

26

methane/methanol/10% ammonia); ½aꢂ_D¼ þ0:2 (c 1.35,

MeOH); IR (KBr) m_max3396 (OH) and 1172 cm^ꢁ1(C–

1

OH); H NMR (500 MHz, CD₃OD) d 4.47 (m, 1H, H-2),

3.98 (dd, 1H, J_7,8ꢃ J_7,6= 2.5, H-7), 3.82 (ddd, 1H,

0

J_6,5= 5.0, J_6;5¼ 11:0, J_6,7= 3.0, H-6), 3.59 (dd, 1H,

0

5.8. General procedure for the catalytic hydrogenation of the

N-protected 2-(3-O-benzyl-^D-ribo(or xylo)-tetros-4-yl)-4-

hydroxypyrrolidine derivatives 21, 22, 23, 24, 32, 44 and 45.

Synthesis of the respective 2,6,7,8-tetrahydroxyindolizidines

25, 26, 27, 28, 5 and 6

J_3,2= 6.5, J_3;3¼ 11:0, H-3), 3.42 (dd, 1H, J_8,7= 2.0,

J_8,8a= 10.0, H-8), 3.14 (m, 1H, H-8a), 3.04 (dd, 1H,

0

J_5,6= 4.5, J_5;5¼ 10:5, H-5), 2.75 (dd, 1H, J_{5 ;5}

ꢃ

J_{5 ;6}¼ 11:0, H-5⁰), 2.59 (dd, 1H, J_{3 ;2}¼ 4:0, J_3;3¼ 10:5,

0

H-3⁰), 2.05 (ddd, 1H, J_1,8a= 6.0, J_1;1¼ 14:0, J_1,2= 1.5,

0

H-1) and 1.45 (ddd, 1H, J_{1 ;2}¼ 7:5, J_{1 ;8a}¼ 10:0, J_{1 ;1}

¼

To a solution of the corresponding N-protected 2-(3-

O-benzyl-^D-ribo(or xylo)-tetros-4-yl)-4-hydroxypyrrolidine

derivative in ethanol, 10% Pd/C catalyst was added. The

mixture was shaken at room temperature under hydrogen

for a period of time (monitoring by TLC), and then ﬁltered

through Celite, which was washed with ethanol and meth-

anol. The combined ﬁltrate and washing were concen-

trated, and the residue was puriﬁed by column

chromatography (3:1:0.3 dichloromethane/methanol/10%

ammonia or other eluent indicated in each case) to aﬀord

the respective 2,6,7,8-tetrahydroxyindolizidine.

13:5, H-1⁰); ¹³C NMR (125.7 MHz, CD₃OD) d 71.1 (C-

8), 71.0 (C-7), 67.7 (C-2), 67.0 (C-6), 61.3 (C-3), 60.3 (C-

8a), 50.1 (C-5) and 37.7 (C-1); HRCIMS m/z: 190.1076

(calcd for C₈H₁₅NO₄+ H: 190.1079).

5.8.3. (2S,6S,7S,8R,8aS)-2,6,7,8-Tetrahydroxyindolizidine

27. From 23 (0.175 g, 0.456 mmol) in ethanol (20 mL),

using an excess of catalyst (0.138 g) and hydrogenation

for 24 h (TLC, 3:1:0.1 dichloromethane/methanol/10%

ammonia), general workup (eluent for column chromato-

graphy, 5:1:0.1!3:1:0.1 dichloromethane/methanol/10%

ammonia) aﬀorded 27 (0.083 g, 0.442 mmol 97%) as a col-

5.8.1. (2R,6S,7S,8R,8aR)-2,6,7,8-Tetrahydroxyindolizidine

25. (a) From 21 (0.082 g, 0.213 mmol) in ethanol

(10 mL), using an excess of catalyst (0.074 g) and hydroge-

nation for 24 h (eluent for TLC, 3:1:0.1, dichloromethane/

methanol/10% ammonia), general workup (eluent for col-

umn chromatography, the same as for TLC) provided 25

(0.039 g, 0.207 mmol; 97%) as a colourless oil; R_f0.64

ourless oil; R_f0.24 (2:1:0.5 dichloromethane/methanol/

26

10% ammonia); ½aꢂ_D¼ þ0:2 (c 0.5, MeOH); IR (KBr) m_max

1

3374 (OH) and 1107 cm^ꢁ1(C–OH); H NMR (500 MHz,

0

CD₃OD) d 4.50 (dddd, 1H, J_2,3= 1.5, J_2;1ꢃ J_2;3¼ 6:5,

0

J_2;1¼ 11:0, H-2), 4.00 (br s, 1H, H-6), 3.94 (br s, 1H, H-

8), 3.61 (dd, 1H, J_7,6ꢃ J_7,8= 3.5, H-7), 3.40 (dd, 1H,

0

J_5,6= 2.5, J_5;5¼ 12:0, H-5), 3.22 (d, 1H, J_3;3¼ 11:0, H-

3), 2.85 (dd, 1H, J_3,2= 6.5, J_3;3¼ 10:5, H-3⁰), 2.78 (m,

0

(3:1:0.1,

dichloromethane/methanol/10%

ammonia);

26

1H, H-8a), 2.70 (br d, 1H, J_{5 ;5}¼ 12:0, H-5⁰), 2.37 (ddd,

0

½aꢂ_D¼ ꢁ0:4 (c 0.75, MeOH); IR (KBr) m_max3399 (OH)

and 1107 cm^ꢁ1(C–OH); H NMR (500 MHz, CD₃OD) d

1H, J_1,2ꢃ J_1,8a= 7.5, J_{1 ;1}¼ 13:5, H-1) and 2.03 (ddd,

1

0

4.33 (dddd, 1H, J_2,1= 7.8, J_2;1¼ 4:4, J_2,3= 1.3,

1H, J_{1 ;2}¼ 11:0, J_{1 ;8a}¼ 4:0, J_{1 ;1}¼ 13:5, H-1⁰); ¹³C NMR

0

M. I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 18 (2007) 1809–1827

1825

(125.7 MHz, CD₃OD) d 69.3 (C-7), 68.4 (C-8), 68.1 (C-6),

68.0 (C-2), 67.3 (C-8a), 61.5 (C-3), 55.3 (C-5) and 34.6 (C-

1); HRCIMS m/z: 190.1074 (calcd for C₈H₁₅NO₄+ H:

190.1079).

0.21, MeOH)}; IR (KBr) m_max3397 (OH) and 1097 cm^ꢁ1

1

(C–OH); H NMR (500 MHz, D₂O) d 4.45 (m, 1H, H-2),

0

3.58 (ddd, 1H, J_6,5= 5.5, J_6;5¼ 10:2, J_6,7= 9.5, H-6),

0

3.41 (dd, 1H, J_3;3¼ 10:5, J_2,3= 7.0, H-3), 3.29 (dd, 1H,

J_7,8= J_7,6= 9.5, H-7), 3.18 (dd, 1H, J_8,7= J_8,8a= 9.0, H-

0

5.8.4. (2R,6S,7S,8R,8aS)-2,6,7,8-Tetrahydroxyindolizidine

28. From 24 (0.022 g, 0.058 mmol) in ethanol (5.0 mL),

using an excess of catalyst (0.038 g) and hydrogenation

for 24 h (TLC, 6:1:0.1 dichloromethane/methanol/10%

ammonia), general workup (eluent for column chromatog-

raphy, 5:1:0.1!3:1:0.1 dichloromethane/methanol/10%

ammonia) gave pure 28 (0.011 g, 0.056 mmol; 97%) as a

8), 3.13 (dd, 1H, J_5,6= 5.0, J_5;5¼ 11:0, H-5), 2.40 (ddd,

0

1H, J_1,8a= 6.0, J_8a;1¼ J_8;8a¼ 10:0, H-8a), 2.22 (dd, 1H,

0

J_{3 ;2}¼ 5:5,

J_3;3¼ 10:0,

H-3⁰),

2.18

(dd,

1H,

J_{5 ;5}¼ J_{5 ;6}¼ 11:0, H-5⁰), 1.94 (ddd, 1H, J_1,2= 1.5,

0

J_1,8a= 6.0, J_{1 ;1}¼ 13:5, H-1) and 1.85 (ddd, 1H,

J_{1 ;2}¼ 8:0, J_{1 ;8a}¼ 10:5, J_{1 ;1}¼ 13:8, H-1⁰); ¹³C NMR

(125.7 MHz, D₂O) d 78.4 (C-7), 74.2 (C-8), 70.2 (C-6),

68.9 (C-2), 65.3 (C-8a), 61.1 (C-3), 54.7 (C-5) and 38.2

(C-1); HRCIMS m/z: 190.1085 (calcd for C₈H₁₅NO₄+ H:

190.1079).

0

colourless oil; R_f0.14 (6:1:0.1 dichloromethane/methanol/

26

10% ammonia); ½aꢂ_D¼ ꢁ1:2 (c 1.0, MeOH); IR (KBr) m_max

1

3456 (OH) and 1092 cm^ꢁ1(C–OH); H NMR (500 MHz,

CD₃OD) d 4.58 (m,1H, H-2), 4.17 (br s, 1H, H-8), 4.14

0

(br s, 1H, H-6), 3.95 (dd, 1H, J_3,2= 6.5, J_3;3¼ 12:0, H-

3), 3.84 (br s, 1H, H-7), 3.66 (dd, 1H, J_1,8a= 6.0,

Acknowledgements

0

J_8a;1¼ 5:5, H-8a), 3.62 (d, 1H, J_5;5¼ 11:5, H-5), 3.32

(dd, 1H, J_{5 ;5}¼ 11:5, J_{5 ;6}¼ 11:5, H-5⁰), 2.93 (dd, 1H,

0

´

We thank the ‘Direccion General de Investigacion, Minis-

0

J_{3 ;2}¼ 4:0,

J_{3 ;3}¼ 12:0,

H-3⁰),

2.36

(ddd,

1H,

´

terio de Ciencia y Tecnologıa’ of Spain (Grant No.

0

J_1,2ꢃ J_1,8a= 6.5, J_{1 ;1}¼ 13:5, H-1) and 1.97 (dd, 1H,

´

BQU2000-1155), the ‘Direccion General de Universidades

13

J_{1 ;8a}¼ 5:5, J_{1 ;1}¼ 14:0, H-1⁰); C NMR (125.7 MHz,

CD₃OD) d 68.2 (C-7), 67.7 (C-8), 67.3 (C-6), 66.9 (C-2),

60.6 (C-3), 60.6 (C-8a), 55.9 (C-5) and 34.3 (C-1); HRC-

IMS m/z: 190.1069 (calcd for C₈H₁₅NO₄+ H: 190.1079).

0

´

e Investigacion, Consejerıa de Educacion y Ciencia’ of

Andalusia (FQM 142) and the Swiss Federal Science Foun-

dation for ﬁnancial support. We also thank Miss Catherine

Schuetz for her technical assistance.

5.8.5. (2R,6S,7R,8R,8aR)-2,6,7,8-Tetrahydroxyindolizidine

5. From 44 (0.100 g, 0.259 mmol) in ethanol (5.0 mL),

using an excess of catalyst (0.045 g) and adding acetic acid

(5 drops), after hydrogenation for 24 h (eluent for TLC,

6:1:0.25 dichloromethane/methanol/10% ammonia), the

general workup was followed, except for the elimination

of the acetic acid, which was co-evaporated with ethanol

and water. Column chromatography aﬀorded 5 (0.046 g;

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26

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´

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26

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Article Doi

Efficient synthesis of 2,6,7,8-tetrahydroxyindolizidines (castanospermine analogues) via the dipolar cycloadditions of N-benzyl-C-(tetrofuranos-4-yl)nitrones to methyl acrylate

DOI: 10.1016/j.tetasy.2007.08.001

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Full text of DOI:10.1016/j.tetasy.2007.08.001

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