Synthesis and glycosidase inhibitory activities of 5-(1′,4′-dideoxy-1′,4′-imino-d-erythrosyl)-2- methyl-3-furoic acid (=5-[(3s,4r)-3,4-dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylic acid) derivatives: New leads as selective α-l-fucosidase and β-galactosidase inhibitors

Article abstract of DOI:10.1002/hlca.200390152

The Garcia-Gonzalez reaction of D-glucose and ethyl acetoacetate generated ethyl 5-[(1′S)-D-erythrosyl]-2-methyl-3-furoate (5), which was converted to ethyl 5-[(1′R)-1′,4′-dideoxy-1′,4′-imino-D- erythrosyl]-2-methyl-3-furoate (3c) and to ethyl 5-[(1′S)-1′,4′-dideoxy-1′,4′-imino-D- erythrosyl]-2-methyl-3-furoate (4c). Similar methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl (see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl-(see 3k and 4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1′,4′-dideoxy-1′,4′-imino-D-erythrosyl)-3-furoic acid (=5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group is a good and selective α-L-fucosidase inhibitor (K_i = 2-4 μM), whereas 4b (with a N-benzylcarboxamide group) is a good β-galactosidase inhibitor.

Full text of DOI:10.1002/hlca.200390152

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis and Glycosidase Inhibitory Activities of 5-(1',4'-Dideoxy-1',4'-
imino-d-erythrosyl)-2-methyl-3-furoic Acid (ˆ 5-[(3S,4R)-3,4-
Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylic Acid) Derivatives:
New Leads as Selective a-l-Fucosidase and b-Galactosidase Inhibitors
by Antonio J. Moreno-Vargasa), Inmaculada Robina*a), Raynald Demangeb), and Pierre Vogel*b)
a
¬
) Departamento de QuÌmica Organica, Facultad de QuÌmica, Universidad de Sevilla, E-41071 Sevilla
(fax: ‡34954624960; e-mail: robina@us.es)
b
¬
¬ ¬
) Institut de Chimie Moleculaire et Biologique, Ecole Polytechnique Federale de Lausanne (EPFL), BCH,
CH-1015 Lausanne (fax: ‡41216939375; e-mail: Pierre.Vogel@epfl.ch)
¬
The GarcÌa-Gonzalez reaction of d-glucose and ethyl acetoacetate generated ethyl 5-[(1'S)-d-erythrosyl]-
2-methyl-3-furoate (5), which was converted to ethyl 5-[(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-
3-furoate (3c) and to ethyl 5-[(1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (4c). Similar
methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl
(see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b
and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl- (see 3k and
4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1',4'-dideoxy-1',4'-imino-d-erythrosyl)-3-furoic acid
(ˆ 5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for
inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group
is a good and selective a-l-fucosidase inhibitor (Ki ˆ 2 4 mm), whereas 4b (with a N-benzylcarboxamide group)
is a good b-galactosidase inhibitor.
Introduction. Derivatives of pyrrolidine-3,4-diols (ˆ1,4-dideoxy-1,4-iminoaldi-
tols) constitute an important class of glycosidase inhibitors [1] although, in some cases,
there is a lack of selectivity due to the higher conformational flexibility compared to
1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple
meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents
activity towards several glycosidases.
COZR
RZOC
3
H
N
2
4
HO
HO
OH
OH
Me
Me
H
H
HO
OH
N
O
O
4'
1'
N
5
3'
2'
1
OH
HO
H
N
3a ZR = SPh
b ZR = NHBn
4c ZR = OEt
b ZR = NHBn
N
CH2Ar
H
2
Approaches have been developed to increase selectivity in enzyme inhibition that
consist of providing the dideoxy-iminosugar with some information about the shape
and charge of the glycosyl moiety cleaved in the enzymatic hydrolysis and also that of

Helvetica Chimica Acta Vol. 86 (2003)
1895
the aglycon itself. Dideoxy-imino-C-disaccharide mimetics fulfill these requirements,
and several syntheses of this type of compounds have been reported [3]. Nevertheless,
the use of these inhibitors present some inconveniences, such as critical reaction
conditions and multiple-step sequences needed for their preparation. Furthermore,
their preparation does not allow for the required molecular and configurational
diversity needed for drug development.
To design more-active and more-specific enzyme inhibitors, we envisaged other
alternatives like attaching to the pyrrolidine ring several moieties through hydrolyti-
cally stable CÀC bonds, using easy and high-yielding reactions. We have found that
pyrrolidinediols of type 2 with (benzylamino)methyl side chains [2] can be highly
selective and competitive inhibitors of a-mannosidases, and we have presented a quick
combinatorial approach for their preparation [4].
In a preliminary communication [5], we have reported that 5-[(1'R)-1',4'-dideoxy-
1',4'-imino-d-erythrosyl]-2-methyl-3-furoic acid ester and amide derivatives1) (ˆ 5-
[(2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylic acid esters and -
3-carboxamides) of type 3 are selective and competitive inhibitors of a-l-fucosidase
from bovine epididymis and from human placenta. We have also found [6] that
stereoisomeric derivatives of type 4 are specific inhibitors of various b-galactosidases.
We describe here the details of the synthesis of these inhibitors that can be viewed as a
new type of dideoxy-iminosugar-derived C-nucleoside analogue. We also prepared
further derivatives and tested them for inhibitory activity towards 25 commercially
available glycosidases. It appears that thioester 3a and N-benzylcarboxamide 3b are the
most-potent a-l-fucosidase inhibitors found for this series (Ki ˆ 2 3 mm) and 4b and 4c
the most-potent b-galactosidase inhibitors (Ki ˆ 6 7 mm). These compounds are leads
in the search for better a-l-fucosidase and b-galactosidase inhibitors, a search that must
probably involve changes of the furan-ring substitution and the introduction of a Me
group at C(4') of 3 generating (4'S) configuration and hydroxylated side chains at C(4')
of 4 if inhibitors as potent as deoxyfuconojirimycin and 1-deoxygalactonojirimycin
(low nm range) are to be found [7].
Synthesis of the New Inhibitors. For the synthesis of dideoxy-iminosugar-derived
C-glycosides of heterocylces, we applied a methodology that implies a double
functionalization of (polyhydroxyalkyl)-substituted heterocycles with appropriate
leaving groups, followed by nucleophilic internal displacements. Thus, starting from
the known furan derivative 5 obtained in a single step from d-glucose [8], selective
tosylation of the primary-alcohol function (TsCl/pyridine, À158, 2 h) provided tosyloxy
derivative 6 in 57% yield (Scheme 1). Treatment of 6 with N-chlorosuccinimide (NCS)
and dimethyl sulfide [9] (CH2Cl2, À208) gave a mixture of chloro compounds 7 and 8 in
a ratio of 1:1 that reacted with butylamine or benzylamine to give 9 or 10, with the
(1'R) (ˆ b-d) configuration at the pseudoanomeric center, in 47% and 44% yield
respectively. This result can be explained by the formation of an oxirane intermediate 11
1
)
For convenience, C-glycoside names are used in the General Part and for the characterization of NMR
spectra; for systematic names, see Exper. Part.

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Helvetica Chimica Acta Vol. 86 (2003)
by 1,3-elimination of HCl. Debenzylation (H2, Pd/C, EtOH) of 10 gave 3c in 98% yield.
Its structure was established by spectral data and confirmed by NOE experiments.
Scheme 1
COOEt
Me
COOEt
Me
OH
OH
NCS, SMe2
TsO
O
RO
O
-20° to 0°
CH2Cl2
OH
Cl
OH OH
quant.
7 (1'S) + 8(1'R), 1:1
5 R = H
6 R = Ts
TsCl, Py
-15°
(57%)
RNH2
(44-47%)
(R = Bu, Bn)
COOEt
Me
R
COOEt
Me
O
N
O
(1'R)
TsO
O
OH
HO
(1'S)
OH
9 R = Bu
10 R = Bn
11
H2, Pd/C, EtOH
97%
3c R = H
When azide anion was used as the nucleophile, a mixture 12/13 was obtained in 64%
overall yield with a product ratio of 2 :1 (Scheme 2). This result can be interpreted in
terms of competing SN1 and SN2 azidolyses together with the intermediacy of oxirane
11. Hydrogenation (H2, Pd/C, EtOH, 208) of 12/13 gave the corresponding primary-
amine derivatives. The latter underwent displacement of the tosyloxy group furnishing
a 2 :1 mixture of (1'R)- and (1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl derivatives (b-d
and a-d configuration, resp.) that could be separated by chromatography on silica gel
after protection of the amino group as benzyl carbamate (Cbz ˆ (benzyloxy)carbonyl)
and the OH groups as acetates. This provided 14 and 15 in 40 and 20% yield,
respectively. Their structures were established by analytical and spectral data (see
1
Exper. Part) and were confirmed by NOE experiments in their H-NMR spectra.
Compound 15 showed a strong NOE (10%) between proton pairs HÀC(1') (d 5.14)/HÀC(2') (d 5.44) that
was not observed for 14, indicating (1'R) and (1'S) configuration in 14 and 15, respectively. Noteworthy is the
observation of coupling constants 3J(1',2') for both N-protected compounds that are markedly different:
3J(1',2') ˆ 3.3 H for 14 and 3J(1',2') ˆ 7.2 Hz for 15. In the case of the corresponding N-unprotected targets 3c and
4c, 3J(1',2') ˆ 7.5 and 4.3 Hz, respectively, were found. This is in accordance with the data reported for derivatives
of dideoxy-imino-d-ribitols [10] and dideoxy-imino-l-lyxitols [11]. A modification in the average conformation
of the pyrrolidine moiety explains this change.
Alkaline methanolysis of 14 and 15 followed by hydrogenolysis gave 3c and 4c in
100 and 92% yields, respectively (Scheme 2). Reduction of 3c with LiAlH4 afforded
alcohol 16 in 90% yield. Saponification of 14 and 15 gave 17 and 18, respectively, that,
after hydrogenolysis on Pd/C, provided the corresponding N-unprotected furoic acids
3d and 4d, respectively, in good yields (Scheme 2).

Helvetica Chimica Acta Vol. 86 (2003)
1897
Scheme 2
COOEt
1. NCS, SMe2, -20°
OH
CH2Cl2, 30min
6
Me
TsO
O
2. NaN3, DMF, r.t.
30 min
OH
N3
12 (1'R) + 13 (1'S) 2:1
64%
1.H2, 10% Pd/C
2.CbzCl, NaHCO3
EtOH, H2O, 20 °
3. Ac2O, Py
4. Chromatography
COOEt
Cbz
N
Me
(1'S)
+
Cbz
N
(1'R)
OAc
14 (40%)
O
COOEt
AcO
92%
OAc
O
AcO
15 (20%)
Me
1. MeOH, MeONa
2. H2, Pd/C, EtOH
1. MeOH, MeONa
2. H2, Pd/C, EtOH
100%
R
Me
H
N
(1'S)
H
O
N
COOEt
HO
OH
(1'R)
O
HO
OH
4c
Me
3c R = COOEt
16 R =CH2OH
LiAlH4
THF
90%
COOH
Me
R'
N
R'
N
O
(1' S)
NaOH, EtOH
60°, 2h
NaOH, EtOH
60°, 2h
15
14
(1'R)
COOH
HO
OH
69%
O
72%
HO
OH
Me
18 R' =Cbz
4d R '=H
H2, Pd/C
EtOH
92%
H2, Pd/C
EtOH
94%
17 R' =Cbz
3d R' =H
Acid 17 was transformed into a small library of esters and amides (Scheme 3).
i
Esterification with MeOH, PrOH, or BuOH was achieved in the presence of 2,6-
dichlorobenzoyl chloride as the activating agent that, after hydrogenolysis in MeOH or

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Helvetica Chimica Acta Vol. 86 (2003)
THF, gave esters 3e g in moderate yields. The formation of amides by reaction of 17
with glycine ethyl ester, aniline, isopropylamine, diethylamine, and l-phenylalanine
methyl ester was performed by means of PyBOP and H¸nig×s base (iPr2EtN) as
activating agents. Subsequent removal of the protecting N-[(benzyloxy)carbonyl]
group was carried out in MeOH or THF. Hydrogenolysis in MeOH gave poor yields,
except for compound 3h, which was obtained in 84% overall yield under these
conditions. Compound 3i was obtained in 17% yield. The success of the hydrogenolysis
in THF is strongly dependent on the nature of the substrate. While esters gave
reasonable yields, in the case of amides, the pyrrolidine amino group, probably assisted
by Pd, provoked the opening of the THF ring, and compounds 19 21 were obtained.
There is only one recent precedent of this type of reaction in the literature reported by
Nicolaou and co-workers [12] in the course of their total synthesis of balanol. As in the
case of the latter synthesis, the presence of an amide moiety is required for this
aminohydrogenolysis of tetrahydrofuran. Under similar conditions, pyrrolidinediol and
pyrrolidine refused to react with THF.
With the goal in mind to avoid this side reaction during the deprotection step,
another synthetic route was explored (Scheme 4). Saponification of mixture 3c/4c,
followed by silylation of the diol moieties with Me3SiCl/pyridine, followed by treatment
with FmocCl (9H-fluoren-9-ylmethyl carbonochloridate) and H2O [13], provided a 2 :1
mixture of carboxylic acids 22 and 23, respectively, after aqueous workup. This mixture
was directly submitted to the amidification conditions (PyBOP, iPr2EtN) with
isopropylamine, benzylamine, and diethylamine to give the corresponding amide
mixtures, which were separated by chromatography (silica gel). Alkaline methanolysis
and Fmoc deprotection with Et2NH in DMF liberated pure N-deprotected furyol
amides 3b, 3j, and 3k derived from furoic acid 22 and 4b, 4j, and 4k derived from furoic
acid 23. The same treatment (without acetylation) applied to 22 and ethylamine gave 3l
after Fmoc deprotection.
Finally the reaction of 22 and 23 with thiophenol in the presence of dicyclohex-
ylcarbodiimide (DCC) and N,N-dimethylpyridin-4-amine (DMAP), followed by
acetylation gave a mixture of thioesters 24 and 25 that were separated by
chromatography and, independently, deprotected upon basic methanolysis and treat-
ment with Et2NH, to give pure N-unprotected furancarbathioic acid S-ester 3a
(Scheme 5). The products 3e and 4e resulting from a transesterification during the
deprotection of 24 and 25 were also isolated (in the latter case, the S-ester 4a (ˆ(1'S)-
epimer of 3a) was not observed. Pure 3m was obtained by a similar treatment applied
to 22 and ethanethiol.
Inhibitory Studies Towards Glycosidases. We assayed [14] all the new compounds
3, 4, and 19 21 as well as derivatives 9 and 1 towards two a-l-fucosidases (from bovine
epididymis, human placenta), three a-galactosidases (from coffee beans, Aspergillus
niger, E. coli), five b-galactosidases (from E. coli, bovine liver, Aspergillus niger,
Aspergillus oryzae, jack beans), two a-glucosidases (from yeast, rice), one isomaltase
(from bakers yeast), two amyloglucosidases (from Aspergillus niger, Rhizopus mold),
two b-glucosidases (from almonds, Caldocellum saccharolyticum), two a-mannosidases
(from jack beans, almonds), one b-mannosidase (from Helix pomatia), one b-
xylosidase (from Aspergillus niger), one a-N-acetylgalactosaminidase (from chicken

Helvetica Chimica Acta Vol. 86 (2003)
1899
Scheme 3
COOR
Me
H
N
O
1. ROH, 2,6-Cl2C6H4COCl
Py, DMF
17
(1'R)
2. H2, Pd/C, MeOH
HO
OH
3e R = Me (37% overall)
f R = i Pr (19% overall)
g R = Bu (37% overall)
CONR1R2
Me
H
N
O
1. PyBOP, iPr2EtN, R1R2NH, DMF
2. H2, Pd/C, MeOH
17
(1'R)
HO
OH
3h R1 = H, R2 = CH2COOEt (84% overall)
i R1 = H, R2 = Ph (17% overall)
OH
CONR1R2
Me
O
1. PyBOP, iPr2EtN, R1R2NH, DMF
2. H2, Pd/C, THF
N
17
(1'R)
HO
OH
19 R1 = H, R2 = iPr(46% overall)
20 R1 = R2 = Et (22% overall)
21 R1 = H, R2 = CH(Bn)COOMe (40% overall)
liver), and three b-N-acetylglucosaminidases (from jack beans, bovine epididymis A
and B). At 1 mm concentration, no inhibition was observed by all these 1',4'-dideoxy-
1',4'-imino-d-erythrosyl or dihydroxypyrrolidine derivatives for a-galactosidases from
Aspergillus niger and from E. coli, for a-glucosidases from yeast and from rice, for b-
mannosidases from Helix pomatia, for b-xylosidase from Aspergillus niger, and for b-N-
acetylglucosaminidases from jack beans, and from bovine epididymis A and B. At
1 mm, the simple meso-pyrrolidine-2,3-diol (1) was also assayed and proved to be a
weak inhibitor of the following enzymes: a-galactosidase from coffee beans (50%,
IC50 ˆ 1 mm), b-galactosidase from E. coli (41%), from bovine liver (25%), from
Aspergillus niger (39%), from Aspergillus oryzae (53%, IC50 ˆ 790 mm), and from jack

1900
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 4
COOH
Fmoc
N
1. NaOH, EtOH, 60 °
3c / 4c
Me
2. Me3SiCl, Py
3. FmocCl
4. H2O
O
HO
OH
(82%)
22(1'R) + 23(1'S) 2:1
1. PyBOP, iPr2EtN
DMF, R1R2NH
(55-81%)
2. Ac2O, Py
3. Chromatography
1. MeOH, MeONa
2. Et2NH, DMF
(71-83%)
H
N
CONR1R2
Me
H
N
CONR1R2
O
+
HO
OH
O
Me
HO
OH
3b R1 = H, R2 = Bn
3j R1 = H, R2 = iPr
3k R1 = Et, R2 = Et
4b R1 = H, R2 = Bn
4j R1 = H, R2 = iPr
4k R1 = Et, R2 = Et
CONHEt
Me
1. PyBOP, iPr2EtN
DMF, EtNH2
H
N
O
22
2. Et2NH, DMF
56%
HO
OH
3l
beans (55%, IC50 ˆ 700 mm), a-glucosidase (isomaltase) from bakers yeast (32%),
amyloglucosidase from Aspergillus niger (24%), and from Rhizopus mold (47%), b-
glucosidase from almonds (60%, IC50 ˆ 600 mm), a-mannosidase from jack beans (70%,
IC50 ˆ 400 mm), and from almonds (44%), and a-N-acetylgalactosaminidase from
chicken liver (63%, IC50 ˆ 500 mm).
Coupling the pyrrolidine-2,3-diol moiety at C(5) of a 2-methyl-3-furoic acid moiety
as in 3 and 4 generated more selective and more-potent glycosidase inhibitors. Most
interesting is the observation that the [(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-
furoic acid derivatives 3 are selective a-l-fucosidase inhibitors (see Table 1), whereas
the corresponding (1'S)-epimers 4 are selective b-galactosidase inhibitors (see Table 2).

Helvetica Chimica Acta Vol. 86 (2003)
1901
Scheme 5
22 (1'R) + 23(1'S) 2:1
1.PhSH, DCC
DMAP, THF
2. Ac2O/Py
66%
COSPh
Fmoc
N
Me
Fmoc
N
O
COSPh
AcO
OAc
O
25
AcO
OAc
Me
24
1. NaOMe / MeOH
2. Et2NH / DMF
1. NaOMe / MeOH
2. Et2NH / DMF
56%
COR
Me
H
N
O
H
N
COOMe
HO
OH
O
HO
OH
4e
Me
3a R = SPh (23%)
3e R = OMe (28%)
COSEt
O
Me
R
N
EtSH, DCC
22
DMAP, THF
30%
HO
OH
26 R = Fmoc
3m R = H
Et2NH, DMF, 90%
The enzyme selectivity depends on the nature of the carboxylic acid derivative
(COZR). In the case of compounds 3, all COZR are recognized by b-galactosidases
from bovine liver, but not by the other b-galactosidases, except for 3c with the COOEt
group (see Table 3). A general trend is that esters, i.e., 3c, 3e, 3f, and 3g, are less
selective than the other derivatives as they all inhibit amyloglucosidases and a-
mannosidases to some extent. The S-ethyl thioester 3m has a behavior similar to that of

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Helvetica Chimica Acta Vol. 86 (2003)
O-alkyl esters. Interestingly, the S-phenyl thioester 3a is not only one of the most-
potent a-l-fucosidase inhibitors (see Ki values in Table 1) but appears to be also the
most selective. Amides 3b, 3j, 3k, and 3l are weak inhibitors of amyloglucosidase and a-
mannosidases. The ethyl glycinate derivative 3h is more selective than other amides but
not as potent as a-l-fucosidase inhibitor.
Table 1. Inhibitory Activities of [(1'R)-1',4'-Dideoxy-1',4'-imino-d-erythrosyl]furancarboxylic Acid Derivatives
3 and of 16 towards Two a-l-Fucosidases. Percentage of inhibition at 1 mm, IC50 (in parenthesis), and Ki (bold
and italic) in mm if measured. Optimal pH, 358a)b)c).
COZR
a-l-Fucosidase
from human placenta
from bovine epididymis
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
16
COSPh
CONHBn
COOEt
89% (38)
94% (28)
84% (200)
n.i.
80% (100)
91% (50)
91% (35)
2.9
2.2
9
90% (60)
95% (43)
76% (300) 15
n.i.
88% (150) 13.8
92% (160)
93% (75)
73% (360) 26
51% (1000)
93% (80)
86% (220) 20
3.8
3.4
COOH
COOMe
COO-iPr
COOBu
CONHCH2COOEt
CONHPh
CONHiPr
CONEt2
6.5
4.9
4.1
8.6
4.2
72% (360) 13
10%
94% (40)
85% (110)
91% (40)
92% (44)
n.i.
3
5.3
9.1
3.2
3.1
CONHEt
COSEt
92% (80)
94% (120)
n.i.
4.8
5.7
a) For conditions of measurements, see [14]. b) All inhibitors showed competitive inhibition from Line-
weaverÀBurk plots. c) n.i. ˆ no inhibition at 1 mm.
Table 2. Inhibitory Activities of [(1'S)-1',4'-Dideoxy-1',4'-imino-d-erythrosyl]furancarboxylic Acid Derivatives
4 and of 1 towards b-Galactosidases. Percentage of inhibition at 1 mm, IC50 (in parenthesis), and Ki (bold and
italic) in mm if measured. Optimal pH, 358a)b)c).
COZR
b-Galactosidase from
E. coli
Bovine liver
Aspergillus
niger
Aspergillus
oryzae
Jack bean
66% (420)
4b
4c
CONHBn
COOEt
81% (150)
7 (m.)
83% (90)
74 (c.)
88% (120)
20 (c.)
78% (250)
35 (m.)
n.i.
94% (50)
60 (non-c.)
99% (7.5)
9.8 (non-c.)
n.i.
89% (20)
20 (c.)
98% (12)
6.6 (m.)
n.i.
94% (12)
6.4 (m.)
n.i.
4d
4e
COOH
COOMe
n.i.
55% (750)
80% (200)
94% (50)
47 (non-c.)
79% (250)
96% (28)
30 (non-c.)
39%
87% (90)
27 (c.)
68% (500)
93% (65)
13 (m.)
53% (790)
81% (240)
4j
4k
CONHiPr
CONEt2
n.i.
33%
49% (1000)
90% (42)
13 (c.)
22%
52% (1000)
1
41%
25%
55% (720)
a) For conditions of measurements, see [14]. b) c. ˆ competitive, non-c. ˆ non-competitive, m. ˆ mixed type of
inhibition, from LineweaverÀBurk plots. c) n.i. ˆ no inhibition at 1 mm.

Table 3. Inhibitory Activities of Compounds 3 towards Other Glycosidases than a-l-Fucosidases. Percentage of inhibition at 1 mm and IC50 (in parenthesis, mm) if
measured. Optimal pH, 358a)b)c).
3
a
3
b
3
c
3
e
3
f
3
g
3
h
(COZRˆ (COZRˆ (COZRˆ
(COZRˆ (COZRˆ
(COZRˆ
(COZRˆCONHÀ (COZRˆ (COZRˆ (COZRˆ (COZRˆ
COSPh)
CONHBn) COOEt)
COOMe) COOiPr)
COOBu)
GlyÀOEt)
CONHiPr CONEt2) CONHEt) COSEt)
a-Galactosidase:
coffee bean
Isomaltase:
bakers yeast
Amyloglucosidase:
Asp. niger
48%
n.i.
n.i.
n.i.
n.i.
n.i.
42%
n.i.
29%
n.i.
43%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
57% (650)
n.i.
n.i.
n.i.
n.i.
52%
71% (310) 25%
23%
33%
27%
44%
38%
52%
n.i.
n.i.
23%
33%
n.i.
25%
n.i.
26%
n.i.
33%
Rhiz. mold
b-Glucosidase:
almonds
Caldoc. sacch.
a-Mannosidase:
jack bean
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
32%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
38%
n.i.
23%
36%
78% (250)d) 71% (320)c) n.i.
57%
n.i.
29%
27%
31%
29%
32%
69% (390)
53%
almonds
52%
n.i.
a-N-Acetyl-
galactosaminidase
chicken liver
b-Galactosidase:
bovine liver
Asp. niger
n.i.
n.i.
n.i.
48%
54%
n.i.
27%
n.i.
n.i.
n.i.
n.i.
57% (690)
67% (450) 43%
57%
57%
n.i.
n.i.
76%
n.i.
n.i.
21%
n.i.
n.i.
38%
n.i.
n.i.
58%
n.i.
n.i.
52%
n.i.
n.i.
58%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.c)
n.i.
n.i.
80% (370)c) n.i.
Asp. oryzae
jack bean
45%
42%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
a) For conditions of measurements, see [14]. b) n.i. ˆ no inhibition at 1 mm. c) Ki ˆ 340 mm (m.). d) Ki ˆ 85 mm (c.). e) Ki ˆ 116 mm (c.).

1904
Helvetica Chimica Acta Vol. 86 (2003)
N-Substitution at the imino moiety suppresses all inhibitory activity toward all the
enzymes assayed as found for derivatives 19 21 and 9.
The most-potent b-galactosidase inhibitor of (1'S)-series 4 is the N-benzylcarbox-
amide 4b, which shows competitive inhibition of b-galactosidases from bovine liver and
from Aspergillus oryzae, noncompetitive inhibition towards b-galactosidase from
Aspergillus niger, and mixed-type inhibition towards b-galactosidase from E. coli (see
Table 2). As in the case of carboxylic acid 3d, the (1'S)-epimer 4d is inactive towards all
enzymes assayed. Except for N-isopropylcarboxamide 4j, which is a moderate inhibitor
of some of the b-galactosidases assayed, the other compounds 4b, 4c, 4e, and 4h are
weak inhibitors of a-mannosidases. None of the (1'S)-epimers 4 that were tested is a
specific inhibitor of other glycosidases than b-galactosidases (see Table 4).
Table 4. Inhibition of Other Glycosidases than b-Galactosidases by 4. Percentage of inhibition at 1 mm and IC50
(in parenthesis, mm) if measured. Optimal pH, 358a)b).
4b
4c
4e
4j
4k
(COZRˆ
(COZRˆ
(COZRˆ
(COZRˆ
(COZRˆ
CONHBn)
COOEt)
COOMe)
CONHiPr)
CONEt2)
a-l-Fucosidase:
from bovine epididymis
from human placenta
a-Glucosidase (isomaltase).
from baker yeast
a-Mannosidase:
37%
56% (640)
n.i.
n.i.
36%
48%
22%
39%
n.i.
n.i.
43%
n.i.
n.i.
n.i.
n.i.
from jack beans
from almonds
37%
40%
49%
37%
22%
34%
n.i.
n.i.
37%
38%
b-Glucosidase:
from almonds
Caldoc. sacch.
n.i.
n.i.
38%
36%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
a) For conditions of measurements, see [14]. b) n.i. ˆ no inhibition at 1 mm.
Conclusions. Efficient syntheses of [(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-
furoic acid derivatives 3 and their (1'S)-epimers 4 were developed starting from d-
glucose and ethyl acetoacetate. Whereas 3 are selective inhibitors of a-l-fucosidases,
derivatives 4 are selective inhibitors of b-galactosidases. This work demonstrates that
meso-pyrrolidine-3,4-diol (1), which is a weak inhibitor of a larger number of
glycosidases, can be converted to potent and selective a-l-fucosidase or b-galactosidase
inhibitors by linking its C(2) position to C(5) of a 2-methyl-3-furoic acid moiety.
Whereas the 3-furoic acids do not inhibit any of the glycosidases assayed, their esters,
thioesters, and amides are interesting inhibitors. They constitute new leads for the
search of a-l-fucosidase and b-galactosidase inhibitors that possess not only polar (OH,
NH) functions but also lipophilic moieties, which might be required for the develop-
ment of orally active drugs. The inhibitory activities observed are still three orders of
magnitude lower than those reported for 1-deoxy-l-fuconojirimycin and 1-deoxy-d-
galactonojirimycin [1], but introduction of additional substituents at C(4') of the 1',4'-
dideoxy-1',4'-imino-d-erythrosyl moiety as well as modification of the furan ring by
substituents (nature and position) leave the possibility to find better leads. It is possible

Helvetica Chimica Acta Vol. 86 (2003)
1905
also that other heterocycles than furan attached at C(1') of the 1',4'-dideoxy-1',4'-imino-
d-erythrosyl moiety might generate new and better leads as glycosidase inhibitors.
¬
¬
¬
We are grateful to the Direccion General de Investigacion CientÌfica y Tecnica of Spain (Grant No. BQU-
2001-3779, BP 97-0730), the European Program SOCRATES (EPFL/Seville), the Swiss National Science
¬
¬
Fondation (Grant No. 20.63667.00), and the −Office Federal de l×Education et de la Science× (Bern, COST D13/
0001/99) for generous support. We thank also the University of Seville for a fellowship to A.J.M.-V.
Experimental Part
General. Anh. solvents and reagents were freshly distilled under N2 prior to use: THF from sodium and
i
benzophenone, CH2Cl2 and Pr2NEt from CaH2. TLC: silica gel HF254 (Merck); detection by UV light and
charring with H2SO4. Prep. chromatography (CC): silica gel 60 (Merck; 230 mesh). Optical rotations: at 258;
Perkin-Elmer 241-MC and Jasco DIP-370 spectropolarimeters. IR Spectra: FT-IR Bomem MB-120 instrument;
.
nÄ in cmÀ1 1H- and 13C-NMR Spectra1): Bruker AMX-300, Bruker ARX-400, and Bruker AMX-500
spectrometers; CDCl3, (D6)DMSO, CD3OD, and D2O solns.; J values in Hz and d in ppm. FAB-MS, EI-MS,
and CI-MS: Kratos MS-80-RFA instrument; for HR-MS, Micromass AutoSpeQ instrument; in m/z (rel. %).
Ethyl 2-Methyl-5-[(1S,2R,3R)-1,2,3,4-trihydroxybutyl]furan-3-carboxylate (6). To a stirred soln. of 5 (4g,
14.6 mmol) in dry pyridine (20 ml) at À158, a soln. of TsCl (7 g, 36.7 mmol) in dry pyridine (10 ml) was added.
The mixture was stirred for 2 h at À158, then H2O (2 ml) was added and the soln. stirred for 15 min at r.t. The
solvent was evaporated, the residue dissolved in CH2Cl2, and the soln. washed with 1m HCl, sat. aq. NaHCO3
soln., and brine, dried (Na2SO4), and evaporated, and the residue purified by CC (SiO2, ether/petroleum ether
1:2 ! 3 :1): 6 (3.56 g, 57%). Hygroscopic solid. [a]2D5 ˆ À15 (c ˆ 3.3, MeOH). IR: 3468 (OH), 2982, 2922, 1709
(CO), 1589, 1408, 1099, 980, 833. 1H-NMR (500 MHz, CDCl3): 7.77 (d, 3J(2'',3'') ˆ 3J(5'',6'') ˆ 8.3, HÀC(2'') and
HÀC(6'') of Ph); 7.33 (d, HÀC(3'') and HÀC(5'') of Ph); 6.59 (s, HÀC(4)); 4.91 (m,HÀC(1')); 4.25
(q, 3J(H,H) ˆ 7.1, MeCH2); 4.29 4.20 (m, HaÀC(4')); 4.17 (dd, 3J(3',4'b) ˆ 5.8, 3J(4'a,4'b) ˆ 10.5, HbÀC(4'));
3.98 3.93 (m, HÀC(3')); 3.85 (dd, 3J(1',2') ˆ 2.4, 3J(2',3') ˆ 7.7, H ÀC(2')); 3.10 (s, Me of Ts); 2.51 (s, Me); 1.32
(t, 3J(H,H) ˆ 7.1, MeCH2). 13C-NMR (125.7 MHz, CDCl3): 163.9 (COOEt); 158.9, 151.6 (C(2), C(5)); 145.1
(C(1'') of Ph), 132.2 (C(4'') of Ph); 129.9, 127.9 (2 C each, Ph); 114.1 (C(3)); 108.4 (C(4)); 72.0, 71.5 (C(2'),
C(3')); 69.6 (C(4')); 66.3 (C(1')); 60.2 (MeCH2); 21.5 (Me of Ts), 14.2 (MeCH2), 13.7 (Me). FAB-MS: 451 (100,
‡
‡
[M ‡ Na] ). HR-FAB-MS: 451.1022 ([C19H24O9S ‡ Na] ; calc. 451.1039). Anal. calc. for C19H24O9S: C 57.27,
H 6.07; found: C 57.10, H 5.90.
Ethyl 5-[(2R,3S,4R)-1-Butyl-3,4-dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (9) and Ethyl 5-
[(2R,3S,4R)-3,4-Dihydroxy-1-(phenylmethyl)pyrrolidin-2-yl]-2-methylfuran-3-carboxylate (10). To a stirred
soln. of N-chlorosuccinimide (NCS; 167 mg, 1.25 mmol) in dry CH2Cl2 (3 ml) cooled to 08, Me2S (97 ml,
1.25 mmol) was added under N2. After 5 min, a soln. of 6 (0.41 g, 0.94 mmol) in dry CH2Cl2 (4ml) at À208 was
added under N2. The mixture was allowed to warm to 58 and the solvent evaporated. The crude product
containing ethyl 5-((1S,2R,3R)- and (1R,2R,3R)-1-chloro-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}bu-
tyl)-2-methylfuran-3-carboxylate (7 and 8, resp.) ((1S)/(1R) 1:1) was used without purification in the next step.
1H-NMR (500 MHz, CDCl3); epimer a: 7.75 (d, 3J(2'',3'') ˆ 3J(5'',6'') ˆ 8.3, HÀC(2'') and HÀC(6'') of Ph); 7.33
(d, HÀC(3'') and HÀC(5'') of Ph); 6.68 (s, HÀC(4)); 5.36 (d, 3J(1',2') ˆ 2.2, HÀC(1')); 4.28 4.14 (m, MeCH2,
HaÀC(4'), HbÀC(4')); 3.97 (dd, 3J(2',3') ˆ 8.4, HÀC(2')); 3.90 3.87 (m,HÀC(3')); 2.70 (s, Me of Ts); 2.41
(s, Me); 1.31 1.27 (m, MeCH2); epimer b: 7.75 (d, 3J(2'',3'') ˆ 3J(5'',6'') ˆ 8.3, HÀC(2'') and HÀC(6'') of Ph);
7.33 (d, HÀC(3'') and HÀC(5'') of Ph); 6.69 (s, HÀC(4)); 5.20 (d, 3J(1',2') ˆ 4.1, HÀC(1')); 4.28 4.14
(m, MeCH2, CH2(4')); 4.04 (dd, 3J(2',3') ˆ 8.4, HÀC(2')); 3.75 3.72 (m, HÀC(3')); 2.72 (s, Me of Ts); 2.51
(s, Me); 1.31 1.27 (m, MeCH2). 13C-NMR (125.7 MHz, CDCl3; mixture of epimers): 163.5, 163.4( COOEt(a),
COOEt(b)); 159.5, 159.3, 149.1, 147.4 (C(2)(a), C(5)(a), C(2)(b), C(5)(b)); 144.9 (C(1'') of Ph(a), C(1'') of
Ph(b)); 132.2 (C(4'') of Ph(a), C(4'') of Ph(b)); 129.7, 127.8 (4C each, C(2 ''), C(3''), C(5''), C(6'') of Ph(a) and
Ph(b)); 114.3 (2 C, C(3)(a), C(3)(b)); 111.0, 110.0 (C(4)(a), C(4)(b)); 73.9, 72.0, 71.3, 71.3 (4C, C(2 ')(a),
C(3')(a), C(2')(b), C(3')(b)); 69.7 (C(4')(b)); 69.5 (C(4')(a)); 60.1 (2 C, MeCH2(a), MeCH2(b)); 56.0
(C(1')(a)); 55.5 (C(1')(b)); 21.4(2 C, Me of Ts( a) and Ts(b)); 14.1 (2 C, MeCH2(a), MeCH2(b)); 13.7, 13.6
(Me(a), Me(b)).
The mixture 7/8 was dissolved in butylamine (6.5 ml; for 9) or benzylamine (10 ml; for 10) cooled at 08. The
soln. was allowed to warm to r.t. and stirred for 4h (for 9) or 12 h (for 10). Then the solvent was evaporated and
the residue purified by CC (SiO2, Et2O/petroleum ether, 1:1 ! 3 :1 (for 9) or 1:3 ! 1:1 (for 10).

1906
Helvetica Chimica Acta Vol. 86 (2003)
Data of 9: 134.7 mg (47% overall from 6). Syrup. [a]3D0 ˆ ‡26 (c ˆ 2, CH2Cl2). 1H-NMR (300 MHz,
CDCl3): 6.53 (s, HÀC(4)); 4.31 4.25 (m, HÀC(3')); 4.25 (q, 3J(H,H) ˆ 7.1, MeCH2); 4.16 (t, 3J(1',2') ˆ
3J(2',3') ˆ 6.5,HÀC(2')); 3.53 (dd, 3J(3',4'a) ˆ 6.2, 3J(4'a,4'b) ˆ 10.4, HaÀC(4')); 3.39 (d, HÀC(1')); 2.82 (br. s,
2 OH); 2.54 ( s, CH3); 2.57 2.20 (m, HaÀC(1'')); 2.38 (dd, 3J(3',4'b) ˆ 4.7, HbÀC(4')); 2.23 2.15
(m, HbÀC(1'')); 1.32 (t, 3J(H,H) ˆ 7.1, MeCH2); 1.42 1.30 (m, 2 HÀC(2'')); 1.26 1.18 (m, 2 HÀC(3'')); 0.83
(t, 3J(H,H) ˆ 7.2, 3 HÀC(4'')). 13C-NMR (75.4MHz, CDCl 3): 164.0 (COOEt); 159.2, 150.9 (C(2), C(5)); 113.9
(C(3)); 109.6 (C(4)); 74.7 (C(2')); 68.7 (C(3')); 67.2 (C(1')); 60.0 (MeCH2); 59.0 (C(4')); 53.6 (C(1'')); 29.5
‡
(C(2'')); 20.3 (C(3'')); 14.2 (MeCH2); 13.8, 13.7 (2 C, C(4''), Me). FAB-MS: 334(100, [ M ‡ Na] ). EI-MS: 311
.
‡
‡
(100, M ). HR-EI-MS: 311.1731 (C16H25NO5 ; calc. 311.1732).
Data of 10: 141 mg (44% overall from 6). Syrup. [a]2D5 ˆ ‡8(c ˆ 0.5, CH2Cl2). 1H-NMR (300 MHz, CDCl3):
7.33 7.21 ( m, Ph); 6.61 (s, HÀC(4)); 4.28 (q, 3J(H,H) ˆ 7.1, MeCH2); 4.30 4.25 (m, HÀC(3')); 4.21
(t, 3J(1',2') ˆ 3J(2',3') ˆ 6.3, HÀC(2')); 3.85 (d, 2J(H,H) ˆ 13.0, PhCH); 3.54( d, HÀC(1')); 3.38
(dd, 3J(3',4'a) ˆ 6.0, 3J(4'a,4'b) ˆ 10.5, HaÀC(4')); 3.34( d, PhCH), 2.58 (s, Me); 2.4 1 (dd, 3J(3',4'b) ˆ 4.7,
HbÀC(4')); 1.34( t, MeCH2). 13C-NMR (75.4MHz, CDCl 3): 163.9 (COOEt); 159.1, 150.8 (C(2), C(5)); 137.6
(C(1) of Ph); 128.7 127.0 (5 C, Ph); 114.0 (C(3)); 109.6 (C(4)); 75.0 (C(2')); 68.6 (C(3')); 66.6 (C(1')); 60.0
‡
(MeCH2); 58.6 (C(4')); 57.4(Ph CH2); 14.2 (MeCH2); 13.7 (Me). FAB-MS: 368 (100, [M ‡ Na] ). EI-MS: 345
.
‡
‡
(100, M ). HR-EI-MS: 345.1578 (C19H23NO5 ; calc. 345.1576).
Ethyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (3c). Procedure A. A
soln. of 10 (41 mg, 0.12 mmol) in MeOH (3 ml) was hydrogenated over 10% Pd/C (15 mg) at 1 atm for 1.5 h.
Filtration of the catalyst and evaporation gave 3c (30 mg, 98%). White solid.
Procedure B. To a soln. of 14 (92 mg, 0.19 mmol) in MeOH (5 ml), 1m MeONa/MeOH (3 drops) was
‡
added. The mixture was stirred at r.t. for 20 min, made neutral with Amberlyst IR-120 (H ), and filtered, and the
resin washed with MeOH. The filtrate was hydrogenated over 10% Pd/C (20 mg) at 1 atm for 2 h. Filtration of
the catalyst and evaporation gave 3c (49 mg, 100%). White solid. [a]2D5 ˆ À44 (c ˆ 1.5, MeOH). 1H-NMR
(300 MHz, CD3OD): 6.55 (s, HÀC(4)); 4.25 (q, 3J(H,H) ˆ 7.1, MeCH2); 4.17 4.08 (m, HÀC(2'), HÀC(3'));
3.99 (d, 3J(1',2') ˆ 7.5, HÀC(1')); 3.27 (dd, 3J(3',4'a) ˆ 5.1, 3J(4'a,4'b) ˆ 12.0, HaÀC(4')); 2.87 (dd, 3J(3',4'b) ˆ 3.0,
HbÀC(4')); 2.54( s, Me); 1.34( t, MeCH2). 13C-NMR (75.4MHz): 165.5 ( COOEt); 160.2, 153.7 (C(2), C(5));
115.2 (C(3)); 108.8 (C(4)); 77.3 (C(2')); 72.3 (C(3')); 61.3 (MeCH2); 60.3 (C(1')); 52.5 (C(4')); 14.6 (MeCH2);
.
‡
‡
13.8 (Me). EI-MS: 255 (100, M ). HR-EI-MS: 255.1105 (C12H17NO5 ; calc. 255.1107). Anal. calc. for
C12H17NO5: C 56.49, H 6.72, N 5.49; found: C 56.45, H 6.61, N 5.81.
Ethyl 5-{(1R,2S,3R)- and (1S,2S,3R)-1-Azido-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl}-2-
methylfuran-3-carboxylate (12 and 13, resp.). Chlorination of 6 (1.17 mmol) with NCS (207.9 mg, 1.56 mmol)
and Me2S (120.7 ml, 1.17 mmol) as described above gave 7/8, which were dissolved in dry DMF (2 ml), and NaN3
(0.15 g, 2.3 mmol) was added. The mixture was stirred for 15 min at r.t., diluted with CH2Cl2 (60 ml), and
washed with H2O (40 ml) and brine. The org. layer was dried (Na2SO4) and evaporated, and the residue purified
by CC (SiO2, ether/petroleum ether 1:3 ! 1:1): 2 :1 mixture of epimers 12 and 13 (0.34g, 64% overall from 6).
Syrup. IR (12/13): 3491 (OH), 2984, 2926, 2111 (N3), 1705 (CO), 1358, 1175. 1H-NMR (500 MHz, CDCl3; 12):
7.78 (d, 3J(2'',3'') ˆ 3J(5'',6'') ˆ 8.3, HÀC(2') and HÀC(6'') of Ph); 7.35 (d, HÀC(3'') and HÀC(5'') of Ph); 6.73
(s, HÀC(4)); 4.74 (d, 3J(1',2') ˆ 4.7, HÀC(1')); 4.30 4.19 (m, MeCH2, CH2(4')); 3.95 (dd, 3J(2',3') ˆ 7.7,
HÀC(2')); 3.74 3.72 ( m, HÀC(3')); 2.56 (s, Me of Ts); 2.4 4 s, M( e); 1.34( t, 3J(H,H) ˆ 7.1, MeCH2).
1H-NMR (500 MHz, CDCl3; 13): 7.78 (d, 3J(2'',3'') ˆ 3J(5'',6'') ˆ 8.3, HÀC(2'') and HÀC(6'') of Ph); 7.35
(d, HÀC(3') and HÀC(5'') of Ph); 6.71 (s, HÀC(4)); 4.82 (d, 3J(1',2') ˆ 1.1, HÀC(1')); 4.30 4.19 (m, MeCH2,
CH2(4')); 3.91 (m, HÀC(2'), HÀC(3')); 2.56 (s, Me of Ts); 2.44 (s, Me); 1.32 (t, 3J(H,H) ˆ 7.1, MeCH2).
13C-NMR (125.7 MHz, CDCl3; 12): 163.5 (COOEt); 159.9, 146.2 (C(2), C(5)); 145.2 (C(1'') of Ph); 132.2 (C(4'')
of Ph); 129.9 (2 C, C(3'') and C(5'') of Ph); 127.9 (2 C, C(2'') and C(6'') of Ph); 114.4 (C(3)); 111.4 (C(4)); 72.1
(C(2')); 71.0 (C(4')); 69.9 (C(3')); 60.3 (MeCH2); 59.5 (C(1')); 21.5 (Me of Ts); 14.2 (MeCH2); 13.8 (Me).
13C-NMR (125.7 MHz, CDCl3; 13): 163.5 (COOEt); 159.6, 147.7 (C(2), C(5)); 145.2 (C1'') of Ph); 132.2 (C(4'')
of Ph); 129.9 (2 C, C(3'') and C(5'') of Ph); 127.9 (2 C, C(2'') and C(6'') of Ph); 114.4 (C(3)); 110.2 (C(4)); 72.0
(C(2')); 71.1 (C(4')); 69.5 (C(3')); 60.3 (MeCH2); 58.5 (C(1')); 21.5 (Me of Ts); 14.2 (MeCH2); 13.7 (Me). FAB-
‡
‡
MS (12/13): 476 (100, [M ‡ Na] ). HR-FAB-MS: 476.1099 ([C19H23N3O8S ‡ Na] ); calc. 476.1103).
Ethyl 5-{(2R,3S,4R)-3,4-Bis(acetyloxy)-1-[(phenylmethoxy)carbonyl]pyrrolidin-2-yl}-2-methylfuran-3-car-
boxylate (14) and Ethyl 5-{(2S,3S,4R)-3,4-Bis(acetyloxy)-1-[(phenylmethoxy)carbonyl]pyrrolidin-2-yl}-2-meth-
ylfuran-3-carboxylate (15). The mixture 12/13 2 :1 (277 mg, 0.61 mmol) in abs. EtOH (7 ml) was hydrogenated
over 10% Pd/C (30 mg) at 1 atm for 1 h. The catalyst was then removed by filtration and the solvent evaporated.
The crude product was dissolved in EtOH/H2O 1 :1 (5 ml) and cooled to 08. NaHCO3 (168 mg, 2 mmol) and
benzyl carbonochloridate (193 ml, 1.5 mmol) were added, and mixture was stirred at r.t. for 1.5 h. Then sat. aq.

Helvetica Chimica Acta Vol. 86 (2003)
1907
NaHCO3 soln. (1.5 ml) was added at 08 and the mixture stirred for 10 min. The solvent was evaporated and the
residue conventionally acetylated with Ac2O/pyridine for 6 h. The resulting residue was purified by CC (SiO2,
Et2O/petroleum ether 1 :2 ! 2.1): 14 (115 mg, 40% overall) followed by 15 (56 mg, 20% overall). Colorless oils.
1
Data of 14: [a]2D5 ˆ À1 (c ˆ 1, CH2Cl2). H-NMR (300 MHz, (D6)DMSO, 908): 7.42 7.21 (m, arom. H of
Cbz), 6.50 (s, HÀC(4)); 5.42 5.37 (m, HÀC(2'), HÀC(3')); 5.12, 5.01 (d, 2J(H,H) ˆ 12.7, CH2 of Cbz); 4.84
(d, 3J(1',2') ˆ 3.3, HÀC(1')); 4.23 (q, 3J(H,H) ˆ 7.1, MeCH2); 3.94( dd, 3J(3',4'a) ˆ 5.6, 3J(4'a,4'b) ˆ 11.6,
HaÀC(4')); 3.56 (dd, 3J(3',4'b) ˆ 5.1, HbÀC(4')); 2.47 (s, Me); 2.03, 2.02 (s, 2 MeCO); 1.23 (t, MeCH2).
13C-NMR (75.4MHz, (D 6)DMSO, 908): 168.9, 168.7 (2 MeCO); 162.3 (COOEt); 157.6 (CO of Cbz); 153.4,
148.9 (C(2), C(5)); 136.0 (C(1) of Ph); 127.7 126.7 (5 C, arom. C of Cbz); 113.6 (C(3)); 107.8 (C(4)); 73.9, 69.0
(C(2'), C(3')); 66.0 (CH2 of Cbz); 59.3 (MeCH2); 57.4(C(1 ')); 47.8 (C(4')); 19.7 (2 MeCO); 13.6 (MeCH2); 12.8
(Me).
Data for 15: [a]2D5 ˆ ‡4 0 (c ˆ 0.6, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO, 908): 7.32 7.16 (m, arom. H
of Cbz); 6.30 (s, HÀC(4)); 5.44 (dd, 3J(1',2') ˆ 7.2, 3J(2',3') ˆ 4.8, HÀC(2')); 5.39 5.34( m, HÀC(3')); 5.14
(d, HÀC(1')); 5.07, 4.96 (d, 2J(H,H) ˆ 12.7,CH2 of Cbz); 4.20 (q, 3J(H,H) ˆ 7.1, MeCH2); 3.88 (dd, 3J(3',4'a) ˆ
5.8, 3J(4'a,4'b) ˆ 11.8, HaÀC(4')); 3.54( dd, 3J(3',4'b) ˆ 3.8, HbÀC(4')); 2.43 (s, Me); 1.93, 1.84( s, 2 MeCO), 1.25
(t, MeCH2). 13C-NMR (75.4MHz, (D 6)DMSO, 908): 169.3, 168.9 (2 MeCO); 163.1 (COOEt); 157.3 (CO of
Cbz); 153.9, 149.3 (C(2), C(5)); 136.8 (C(1) of Ph); 128.2 127.3 (5 C, arom. C of Cbz); 113.9 (C(3)); 108.6
(C(4)); 71.4 (C(2')); 69.9 (C(3')); 66.4(CH of Cbz); 59.7 (MeCH2); 55.3 (C(1')); 49.2 (C(4')); 20.2, 20.0
2
‡
(2 MeCO); 14.1 (MeCH2); 13.2 (Me). CI-MS: 474 (15, [M ‡ H] ). Anal. calc. for C24H27NO9: C 60.88, H 5.75,
N 2.96; found: C 60.71, H 5.99, N 2.58.
Ethyl 5-[(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (4c). To a soln. of 15
(95 mg, 0.20 mmol) in MeOH (5 ml), 1m NaMeO/MeOH (3 drops) was added. The mixture was stirred at r.t. for
‡
20 min, made neutral with Amberlyst IR-120 (H ), and filtered, and the resin washed with MeOH. The filtrate
was hydrogenated over 10% Pd/C (20 mg) at 1 atm for 2 h. The catalyst was removed by filtration and the
solvent evaporated: 4c (47 mg, 92%). Colorless oil. [a]2D5 ˆ À33 (c ˆ 1, MeOH). IR: 3300 2780 (OH, NH);
1707 (CO), 1541, 1398, 1227, 1101. 1H-NMR (300 MHz, CD3OD): 6.62 (s, HÀC(4)); 4.33 4.24 (m, HÀC(3'));
4.26 (q, 3J(H,H) ˆ 7.1, MeCH2); 4.12 (t, 3J(1',2') ˆ 3J(2',3') ˆ 4.3, HÀC(2')); 4.07 (d, HÀC(1')); 3.07
(dd, 3J(3',4'a) ˆ 7.3, 2J(4'a,4'b) ˆ 11.5, HaÀC(4')); 2.92 (dd, 3J(3',4'b) ˆ 6.1, HbÀC(4')); 2.53 (s, Me); 1.32
(t, MeCH2). 13C-NMR (75.4MHz, CD 3OD): 165.7 (COOEt); 159.7, 152.1 (C(2), C(5)); 115.2 (C(3)); 109.3
(C(4)); 74.0, 73.9 (C(2'), C(3')); 61.2 (MeCH2); 60.5 (C(1')); 51.9 (C(4')); 14.6 (MeCH2); 13.7 (Me). CI-MS: 256
‡
‡
(10, [M ‡ H] ). HR-CI-MS: 256.1183 ([C12H17NO5 ‡ H] ; calc. 256.1185). Anal. calc. for C12H17NO5: C 56.49,
H 6.72, N 5.49; found: C 56.59; H 6.53, N 5.78.
(2R,3S,4R)-2-[4-(Hydroxymethyl)-5-methylfuran-2-yl]pyrrolidine-3,4-diol (16). To a suspension of LiAlH4
(15 mg, 0.4mmol) in dry THF (0.5 ml), a soln. of 3c (51 mg, 0.2 mmol) in dry THF (2 ml) was added under N2.
The mixture was stirred for 15 min at r.t. The soln. was diluted with Et2O (10 ml), and sat. aq. Na2SO4 soln. was
added. The solid was filtered and washed with EtOH and the filtered soln. evaporated: 16 (38 mg, 90%).
Colorless oil. [a]2D5 ˆ À27 (c ˆ 0.3, MeOH). 1H-NMR (300 MHz, CD3OD)1): 6.58 (s, HÀC(4)); 4.48 4.33
(m, HÀC(2'), HÀC(3')); 4.39 (s, CH2OH); 4.44 (d, 3J(1',2') ˆ 8.8, HÀC(1')); 3.51 (dd, 3J(3',4'a) ˆ 3.5,
2J(4'a,4'b) ˆ 12.5, HaÀC(4')); 3.21 (dd, 3J(3',4'b) ˆ 1.8, HbÀC(4')); 2.30 (s, Me). 13C-NMR (75.4MHz,
CD3OD)1): 152.3, 146.0 (C(2), C(5)); 121.9 (C(3)); 114.1 (C(4)); 75.5 (C(2')); 71.1 (C(3')); 58.6 (C(1')); 56.1
‡
‡
(CH2OH); 50.9 (C(4')); 11.6 (Me). CI-MS: 214(70, [ M ‡ H] ), 196 (100, [M À H2O ‡ H] ). HR-CI-MS:
‡
214.1068 ([C10H15NO4 ‡ H] ; calc. 214.1079).
5-{(2R,3S,4R)-3,4-Dihydroxy-1-[(phenylmethoxy)carbonyl]pyrrolidin-2-yl}-2-methylfuran-3-carboxylic
Acid (17). A soln. of 14 (100 mg, 0.21 mmol) in EtOH/1n NaOH 2 :1 (6 ml) was heated at 608 for 6 h. Then
Amberlyst IR-120 (H ) was added until pH was reached. The mixture was filtered, the resin washed with EtOH,
‡
the filtrate evaporated, and the residue purified by CC (SiO2, CH2Cl2/MeOH 40 :1 ! 15 :1): 17 (53 mg, 72%).
Colorless oil. [a]2D5 ˆ ‡17 (c ˆ 2, MeOH). IR: 3579 2054(OH, CO OH), 1688 (CO), 1425, 1356, 1227, 1101.
1H-NMR (300 MHz, (D6)DMSO, 908): 7.34 7.18 ( m, Ph); 6.35 (s, HÀC(4)); 5.07, 4.98 (d, 2J(H,H) ˆ 12.8, CH2
of Cbz); 4.56 (d, 3J(1',2') ˆ 4.1, HÀC(1')); 4.18 (m, HÀC(3')); 4.04 (t, 3J(2',3') ˆ 4.1, HÀC(2')); 3.60
2
(dd, 3J(3',4'a) ˆ 5.7, J(4'a,4'b) ˆ 10.8, HaÀC(4')); 3.40 (dd, 3J(3',4'b) ˆ 5.3, HbÀC(4')); 2.45 (s, Me). 13C-NMR
(75.4MHz, (D 6)DMSO, 908): 163.9 (COOH); 156.5 (CO of Cbz); 153.9, 150.9 (C(2), C(5)); 136.4(C(1) of Ph);
127.7 126.7 (5 C, Ph); 114.2 (C(3)); 107.1 (C(4)); 75.2 (C(2')); 68.7 (C(3')); 65.5 (CH2 of Cbz); 59.9 (C(1')); 50.4
‡
‡
(C(4')); 12.7 (Me). CI-MS: 362 (65, [M ‡ H] ). HR-CI-MS: 362.1222 ([C18H19NO7 ‡ H] ; calc. 362.1239).
5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylic Acid (3d). A soln. of 17 (53 mg,
0.15 mmol) in MeOH/THF 3 :1 (4ml) was hydrogenated over 10% Pd/C (15 mg) as described above for 3c/3d
(34mg, 94%). White solid. [ a]2D5 ˆ À77 (c ˆ 2.7, MeOH). IR: 3615 2117 (OH, NH, COOOH), 1615 (CO),

1908
Helvetica Chimica Acta Vol. 86 (2003)
1582, 1443, 1103. 1H-NMR (500 MHz, CD3OD): 6.69 (s, HÀC(4)); 4.44 (dd, 3J(1',2') ˆ 8.6, 3J(2',3') ˆ 3.8,
HÀC(2')); 4.41 (d, HÀC(1')); 4.33 4.30 (m, HÀC(3')); 3.51 (dd, 3J(3',4'a) ˆ 4.4, 2J(4'a,4'b) ˆ 12.5, HaÀC(4'));
3.21 (dd, 3J(3',4'b) ˆ 1.9, HbÀC(4')); 2.51 (s, Me). 13C-NMR (75.4MHz, CD 3OD): 171.2 (COOH); 159.1, 145.9
(C(2), C(5)); 120.9 (C(3)); 113.8 (C(4)); 75.5 (C(2')); 71.2 (C(3')); 58.4(C(1 ')); 50.9 (C(4')); 13.7 (Me). CI-MS:
‡
‡
228 (100, [M ‡ H] ). HR-CI-MS: 228.0869 ([C10H13NO5 ‡ H] ; calc. 228.0872).
5-{(2S,3S,4R)-3,4-Dihydroxy-1-[(phenylmethoxy)carbonyl]pyrrolidin-2-yl}-2-methylfuran-3-carboxylic
Acid (18). A soln. of 15 (90 mg, 0.19 mmol) in EtOH/1m NaOH 2 :1 (6 ml) was treated as described for 17.
Purification by CC (SiO2, CH2Cl2/MeOH 40 :1 ! 15 :1) gave 18 (46 mg, 69%). Colorless oil. [a]2D5 ˆ À26 (c ˆ
1.8, CH3OH). IR: 3580 2190 (OH, COOH), 1686 (CO), 1422, 1356, 1227, 1101. 1H-NMR (300 MHz,
(D6)DMSO, 908): 7.32 7.19 (m, Ph); 6.37 (s, HÀC(4)); 5.07, 4.95 (d, 2J(H,H) ˆ 12.8, CH2 of Cbz); 4.83
(d, 3J(1',2') ˆ 6.7,HÀC(1')); 4.22 (dd, 3J(2',3') ˆ 4.6,HÀC(2')); 4.14 (m, HÀC(3')); 3.65 (dd, 3J(3',4'a) ˆ 5.9,
2J(4'a,4'b) ˆ 11.1, HaÀC(4')); 3.38 (dd, 3J(3',4'b) ˆ 4.6, HbÀC(4')); 2.42 (s, Me). 13C-NMR (75.4MHz,
(D6)DMSO, 908): 164.2 (COOH); 155.8 (CO of Cbz); 153.8, 150.3 (C(2), C(5)); 136.4 (C(1) of Ph); 127.6
126.5 (5 C, Ph); 114.1 (C(3)); 107.9 (C(4)); 71.6 (C(2')); 69.2 (C(3')); 65.5 (CH2 of Cbz); 57.2 (C(1')); 51.0
‡
‡
(C(4')); 12.7 (Me). CI-MS: 362 (4, [M ‡ H] ). HR-CI-MS: 362.1222 ([C18H19NO7 ‡ H] ; calc. 362.1239).
5-[(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylic Acid (4d). A soln. of 18 (46 mg,
0.13 mmol) in MeOH/THF 3 :1 (4ml) was hydrogenated as described for 3d/4d (28 mg, 92%). Colorless oil.
[a]2D5 ˆ À10 (c ˆ 1, MeOH). IR: 3643 2141 (OH, NH, COOH), 1692 (CO), 1580, 1425, 1227, 1103. H-NMR
1
(300 MHz, CD3OD): 6.83 (s, HÀC(4)); 4.56 (d, 3J(1',2') ˆ 3.0, HÀC(1')); 4.48 (m, HÀC(3')); 4.26 (t, 3J(2',3') ˆ
3.5, HÀC(2')); 3.48 (dd, 3J(3',4'a) ˆ 8.0, 2J(4'a,4'b) ˆ 11.4, HaÀC(4')); 3.14( dd, 3J(3',4'b) ˆ 7.4, H bÀC(4')); 2.50
(s, Me). 13C-NMR (75.4MHz, CD 3OD): 171.3 (COOH); 158.2, 144.6 (C(2), C(5)); 120.9 (C(3)); 114.1 (C(4));
‡
72.7 (C(2')); 72.2 (C(3')); 59.7 (C(1')); 49.0 (C(4')); 13.6 (Me). FAB-MS: 228 (100, [M ‡ H] ). HR-CI-MS:
‡
228.0872 ([C10H13NO5 ‡ H] ; calc. 228.0872).
Esters 3e g. General Procedure. To a soln. of ROH (x mmol) and 2,6-dichlorobenzoyl chloride (y mmol) in
dry pyridine (z ml), a soln. of 17 (50 mg, 0.139 mmol) in dry DMF (0.9 ml) was added. The mixture was stirred
for 5 h. Then the soln. was diluted with CH2Cl2 (50 ml) and washed with 1m HCl, sat. aq. NaHCO3 soln., and
brine. The org. layer wasdried (Na2SO4) and evaporated and the residue purified by CC (SiO2, CH2Cl2/MeOH
80 :1 ! 60 :1). The obtained protected alkyl ester was dissolved in MeOH or THF (4ml) (see below) and
hydrogenated over 10% Pd/C (20 mg) at 1 atm for 1 h. The catalyst was removed by filtration and the solvent
evaporated. The following esters were prepared in this manner.
Methyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (3e): ROH ˆ MeOH;
x ˆ 0.556 mmol; y ˆ 0.60; z ˆ 2 ml. Purification of the protected methyl ester by CC (SiO2, CH2Cl2/MeOH
20 :1 ! 10 :1) followed by hydrogenolysis (MeOH) gave 3e (5.7 mg, 37% overall). White solid. [a]2D5 ˆ À45
(c ˆ 0.3, MeOH). IR: 3412 (OH, NH); 2920, 1717 (CO), 1588, 1443, 1236, 1101. 1H-NMR (400 MHz, CD3OD):
6.61 (s, HÀC(4)); 4.21 (m, HÀC(3')); 4.15 (dd, 3J(1',2') ˆ 7.6, 3J(2',3') ˆ 5.0, HÀC(2')); 4.04 (d, HÀC(1')); 3.84
(s, COOMe); 3.33 (dd, 3J(3',4'a) ˆ 5.2, 2J(4'a,4'b) ˆ 12.1, HaÀC(4')); 2.93 (dd, 3J(3',4'b) ˆ 3.1); 2.59 (s, Me).
13C-NMR (100.5 MHz, CD3OD): 165.9 (COOMe); 160.4, 153.8 (C(2), C(5)); 114.7 (C(3)); 108.8 (C(4)); 77.3
.
‡
‡
(C(2')); 72.3 (C(3')); 60.2 (C(1')); 52.5 (C(4')); 13.7 (Me). CI-MS: 242 (8, [M ‡ H] ). EI-MS: 241 (7, M ). HR-
‡
EI-MS: 241.0955 (C11H15NO5 ; calc. 241.0950).
i-
1-Methylethyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (3f). ROH ˆ
PrOH; x ˆ 12.7 mmol; y ˆ 0.38 mmol; z ˆ 0.8 ml. Purification of the protected 1-methylethyl ester by CC
(SiO2, CH2Cl2/MeOH 80 :1 ! 60 :1) followed by hydrogenolysis in THF gave 3f (6.3 mg, 19% overall). White
solid. [a]2D5 ˆ À32 (c ˆ 0.2, MeOH). IR: 3396 (OH, NH); 2922, 1731 (CO), 1588, 1406, 1105. 1H-NMR
(400 MHz, CD3OD): 6.59 (s, HÀC(4)); 5.16 (sept., 2J(H,H) ˆ 6.2, Me2CH), 4.20 (td, 3J(3',4'b) ˆ 3.1, 3J(3',4'a) ˆ
3J(3',2') ˆ 5.1, HÀC(3')); 4.14 (dd, 3J(1',2') ˆ 7.7, H ÀC(2')); 4.03 (d, HÀC(1')); 3.31 (dd, 2J(4'a,4'b) ˆ 12.1,
HaÀC(4')); 2.92 (dd, HbÀC(4')); 2.58 (s, Me); 1.36 (d, Me2CH). 13C-NMR (100.5 MHz, CD3OD): 165.1
(COOiPr); 160.1, 153.6 (C(2), C(5)); 115.5 (C(3)); 108.8 (C(4)); 77.3 (C(2')); 72.3 (C(3')); 68.9 (Me2CH), 60.3
.
‡
‡
(C(1')); 52.5 (C(4')); 22.2 (Me2CH); 13.8 (Me). EI-MS: 269 (14, M ). HR-EI-MS: 269.1260 (C13H19NO5 ; calc.
269.1263).
Butyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (3g): ROH ˆ BuOH; x ˆ
0.27 mmol; y ˆ 0.27 mmol; z ˆ 1.2 ml. Purification of the protected butyl ester by CC (SiO2, CH2Cl2/MeOH
80 :1 ! 60 :1) followed by hydrogenolysis in THF gave 3g (14.2 mg, 37% overall). Colorless oil. [a]2D5 ˆ À30
(c ˆ 0.4, MeOH). IR: 3420 (OH, NH), 2926, 1719 (CO), 1588, 1406, 1103. 1H-NMR (400 MHz, CD3OD): 6.60
(s, HÀC(4)); 4.27 (t, 2J(H,H) ˆ 7.4, CH 2 of Bu); 4.19 (m, HÀC(3')); 4.14 (dd, 3J(1',2') ˆ 7.6, 3J(2',3') ˆ 5.0,
HÀC(2')); 4.03 (d, HÀC(1')); 3.31 (dd, 3J(3',4'a) ˆ 5.2, 2J(4'a,4'b) ˆ 12.1, HaÀC(4')); 2.91 (dd, 3J(3',4'b) ˆ 3.1,
HbÀC(4')); 2.57 (s, Me), 1.74( m, CH2 of Bu), 1.51 (m, CH2 of Bu), 1.02 (t, CH2 of Bu). 13C-NMR (100.5 MHz,

Helvetica Chimica Acta Vol. 86 (2003)
1909
CD3OD): 165.3 (COOBu); 160.2, 153.9 (C(2), C(5)); 115.2 (C(3)); 108.7 (C(4)); 77.3 (C(2')); 72.3 (C(3')); 65.1
(CH2 of Bu); 60.3 (C(1')); 52.5 (C(4')); 31.9 (CH2 of Bu); 20.3 (CH2 of Bu); 14.0 (Me of Bu); 13.8 (Me). CI-MS:
.
.
‡
‡
‡
284(17, [ M ‡ H] ). EI-MS: 283 (12, M ). HR-EI-MS: 283.1422 (C14H21NO5 ; calc. 283.1420).
Amides 3h,i: General Procedure. To a soln. of 17 (20 mg, 0.055 mmol) in dry DMF (0.75 ml), PyBOP (1H-
benzotriazol-1-yloxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate; 34mg, 0.06 mmol), iPr2Etn (24 ml,
0.14mmol), and RNH 2 (0.06 mmol) were added. The mixture was stirred 30 min at r.t. and then evaporated.
The residue was diluted with CH2Cl2 and washed with 1m HCl and brine. The org. layer was dried (Na2SO4) and
evaporated. Purification of the residue by CC (SiO2, CH2Cl2/MeOH 60 :1 ! 30 :1) gave the protected amide
derivative that was dissolved in MeOH (2 ml) and hydrogenated over 10% Pd/C (15 mg) at 1 atm for 1 h. The
catalyst was removed by filtration, and the solvent was evaporated. The following amides were obtained in this
manner.
N-{{5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-yl}carbonyl}glycine Ethyl Ester (3h):
With RNH2 ˆ glycine ethyl ester hydrochloride, 3h (15 mg, 84% overall) was obtained. Colorless oil. [a]D25
ˆ
À44 (c ˆ 0.7, MeOH). IR: 3422 (OH, NH), 1732, 1651 (CO), 1539, 1404, 1223, 1103. 1H-NMR (300 MHz,
CD3OD)1): 6.62 (s, HÀC(4)); 4.22 4.12 (m, HÀC(2'), HÀC(3'), MeCH2); 4.03 (d, 3J(1',2') ˆ 7.3, HÀC(1'));
4.01 (s, NHCH2); 3.31 (dd (overlapped by MeOH), 3J(3',4'a) ˆ 5.4, HaÀC(4')); 2.91 (dd, 3J(3',4'b) ˆ 2.8,
2J(4'a,4'b) ˆ 12.0, HbÀC(4')); 2.52 (s, Me); 1.26 (t, 3J(H,H) ˆ 7.1, MeCH2). 13C-NMR (75.4MHz, CD 3OD):
171.6 (COOEt); 166.7 (CONH); 158.2, 153.0 (C(2), C(5)); 117.1 (C(3)); 107.6 (C(4)); 77.2 (C(2')); 72.3 (C(3'));
.
‡
62.3 (MeCH2); 60.4(C(1 ')); 52.4(C(4 ')); 42.0 (CH2NH); 14.5 (MeCH2). EI-MS: 312 (23, M ). HR-EI-MS:
‡
312.1318 (C14H20N2O6 ; calc. 312.1321).
5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methyl-N-phenylfuran-3-carboxamide (3i): With RNH2 ˆ
Ph,NH2 3i (2.8 mg, 17% overall) was obtained. Colorless oil. [a]2D2 ˆ À4 6 (c ˆ 0.7, MeOH). 1H-NMR (300 MHz,
CD3OD): 7.60 (d, 3J(H,H) ˆ 7.5, HÀC(2) and HÀC(6) of Ph); 7.32 (t, HÀC(3) and HÀC(5) of Ph); 7.11
(t, HÀC(4) of Ph); 6.80 (s, HÀC(4)); 4.22 4.15 (m, HÀC(2'), HÀC(3')); 4.06 (d, 3J(1',2') ˆ 7.0, HÀC(1')); 3.35
(m, HaÀC(4')); 2.93 (dd, 3J(3',4'b) ˆ 2.8, 2J(4'a,4'b) ˆ 13.4, HbÀC(4')); 2.57 (s, Me). 13C-NMR (75.4MHz,
CD3OD): 164.7 (CONH); 158.7, 153.5 (C(2), C(5)); 139.7 (C(1) of Ph); 129.9 (C2) and C(6) of Ph); 125.5 (C(4)
of Ph); 122.4(C(3) and C(5) of Ph); 118.1 (C(3)); 107.7 (C(4)); 77.3 (C(2 ')); 72.3 (C(3')); 60.6 (C(1')); 52.5
‡
‡
(C(4')); 13.7 (Me). CI-MS: 303 (100, [M ‡ H] ). HR-CI-MS: 303.1329 ([C16H18N2O4 ‡ H] ; calc. 303.1345).
Amides 19 21: General Procedure. To a soln. of 17 (0.1 mmol) in dry DMF (1 ml), PyBOP (1.2 equiv.),
iPr2EtN (1.2 equiv.), and R1R2NH (1.2 equiv.) were added. The mixture was stirred for 30 min and then
evaporated. The residue was diluted with CH2Cl2 and washed with 1m HCl and brine. The org. layer was dried
(Na2SO4) and evaporated. Purification of the resulting residue by CC (SiO2, CH2Cl2/MeOH 80 :1 ! 40 :1) gave
the protected amide derivative, which was dissolved in dry THF (4ml) and hydrogenated over 10% Pd/C at
1 atm for 1 h. The catalyst was removed by filtration, the solvent evaporated, and the corresponding residue
purified by CC (SiO2, CH2Cl2/MeOH 25 :1 ! 6 :1). The following compounds were prepared in this manner.
5-[(2R,3S,4R)-3,4-Dihydroxy-1-(4-hydroxybutyl)pyrrolidin-2-yl]-2-methyl-N-(1-methylethyl)furan-3-car-
boxamide (19): With R1R2NH ˆ iPrNH2, 19 (15 mg, 46% overall) was obtained. Colorless oil. [a]D25 ˆ ‡10 (c ˆ
0.7, MeOH). IR: 3324(OH, NH), 2936, 1634(CO), 1588, 1530, 1406, 1101. 1H-NMR (400 MHz, CD3OD): 6.67
(s, HÀC(4)); 4.22 (m, HÀC(3)); 4.20 (m, Me2CH); 4.13 (dd, 3J(2',3') ˆ 5.9, 3J(1',2') ˆ 7.1, H ÀC(2')); 3.56 3.50
(m, HaÀC(4'), CH2(4'')); 3.48 (d, HÀC(1')); 2.70 (m, HaÀC(1')); 2.56 (s, Me); 2.44 (dd, 3J(4'b,3') ˆ 4.9,
2J(4'a,4'b) ˆ 10.4, HbÀC(4')); 2.36 (m, HbÀC(1'')); 1.55 1.50 (m, CH2(2''), CH2(3'')); 1.25 (d, 3J(H,H) ˆ 6.6,
Me2CH). 13C-NMR (100.5 MHz, CD3OD): 165.6 (CONHiPr); 157.6, 152.6 (C(2), C(5)); 117.7 (C(3)); 108.9
(C(4)); 76.1 (C(2')); 70.1 (C(3')); 68.5 (C(1')); 62.7 (C(4'')); 59.8 (C(4')); 55.9 (C(1'')); 42.4 (Me2CH); 31.6, 25.4
.
‡
‡
(C(2''), C(3'')); 22.6 (Me2CH); 13.7 (Me). EI-MS: 340 (22, M ). HR-EI-MS: 340.2003 (C17H28N2O5 ; calc.
340.1998).
5-[(2R,3S,4R)-3,4-Dihydroxy-1-(4-hydroxybutyl)pyrrolidin-2-yl]-N,N-diethyl-2-methylfuran-3-carboxa-
mide (20). With R1R2NH ˆ Et2NH, 20 (18 mg, 22% overall) was obtained. Colorless oil. [a]2D5 ˆ ‡11 (c ˆ 0.7,
MeOH). IR: 3391 (OH), 2934, 1666 1603 (CO), 1443, 1221, 1101. 1H-NMR (400 MHz, CD3OD): 6.40
(s, HÀC(4)); 4.23 (m, HÀC(3')); 4.13 (dd, 3J(2',3') ˆ 5.9, 3J(1',2') ˆ 7.0, HÀC(2')); 3.55 3.50 (m, HÀC(1'),
HaÀC(4'), CH2(4''), 2 MeCH2); 2.70 (m, HaÀC(1'')); 2.44 (dd, 3J(4'b,3') ˆ 4.9, 2J(4'a,4'b) ˆ 10.4, HbÀC(4'));
2.40 (m, HbÀC(1'')); 2.36 (s, Me); 1.58 1.4 9 (m, CH2(''), CH2(3'')); 1.23 (br. s, 2 MeCH2). 13C-NMR
(100.5 MHz, CD3OD): 168.1 (CONHEt2); 153.6, 153.2 (C(2), C(5)); 118.1 (C(3)); 109.5 (C(4)); 76.3 (C(2'));
70.1 (C(3')); 68.4(C(1 ')); 62.8 (C(4'')); 59.9 (C(4')); 55.9 (C(1'')); 44.6, 40.9 (2 MeCH2); 31.6, 25.4(C(2 ''),
.
‡
‡
C(3'')); 14.6, 13.2 (2 MeCH2); 12.8 (Me). EI-MS: 354(22,
M ). HR-EI-MS: 354.2157 (C18H30N2O5 ; calc.
354.2155).

1910
Helvetica Chimica Acta Vol. 86 (2003)
N-{{5-[(2R,3S,4R)-3,4-Dihydroxy-1-(4-hydroxybutyl)pyrrolidin-2-yl]-2-methylfuran-3-yl}carbonyl}-l-phe-
nylalanine Methyl Ester (21). With R1R2NH ˆ H2NÀPheÀOMe 21 (18 mg, 39% overall) was obtained.
Colorless oil. [a]2D5 ˆ À21 (c ˆ 0.8, MeOH). IR: 3367 (OH, NH); 2934, 2857, 1736 (CO), 1642 (CO), 1528, 1443,
1227, 1101, 849, 700. 1H-NMR (400 MHz, CD3OD)1): 7.31 7.24( m, Ph); 6.64( s, HÀC(4')); 4.82 (dd, 3J(H,Ha of
Bn) ˆ 5.4, 3J(H,Hb of Bn) ˆ 9.4, HNCHCOOMe), 4.22 (m, HÀC(3')); 4.12 (dd, 3J(2',3') ˆ 5.9, 3J(1',2') ˆ 7.0,
HÀC(2')); 3.76 (s, COOMe); 3.57 3.51 (m, HaÀC(4'), CH2(4'')); 3.49 (d, HÀC(1')); 3.29 (dd, 2J(H,H) ˆ 13.8,
PhCH); 3.11 (dd, PhCH); 2.70 (m, HaÀC(1'')); 2.47 (s, Me); 2.45 (dd, 3J(4'b,3') ˆ 4.9, 2J(4'a,4'b) ˆ 10.4,
HbÀC(4')); 2.37 (m, HbÀC(1'')); 1.59 1.48 (m, CH2(2''), CH2(3'')). 13C-NMR (100.5 MHz, CD3OD)1): 173.8
(COOMe); 166.2 (CONH); 158.1, 152.8 (C(2), C(5')); 138.5 (C(1) of Ph); 130.2, 129.5, 127.8 (Ph); 117.0 (C(3));
108.9 (C(4)); 76.1 (C(2')); 70.1 (C(3')); 68.5 (C(1')); 62.8 (C(4'')); 59.8 (C(4')); 55.9 (C(1'')); 55.3 (PhCH2); 52.8
.
‡
(COOMe); 38.1 (CH of HNÀPheÀOMe); 31.6, 25.4(C(2 ''), C(3'')); 13.6 (Me). EI-MS: (30, M ). HR-EI-MS:
‡
460.2208 (C24H32N2O5 ; calc. 460.2209).
5-{(2R,3S,4R)- and (2S,3S,4R)-1-[(9H-Fluoren-9-ylmethoxy)carbonyl]-3,4-dihydroxypyrrolidin-2-yl}-2-
methylfuran-3-carboxylic Acid (22 and 23, resp.). The mixture 3c/4c 2 :1 (0.77 g, 3.01 mmol) was dissolved in
EtOH/1m NaOH (80 ml) and heated for 6 h at 608. The mixture was then neutralized with Amberlyst IR-120
‡
(H ), filtered, and evaporated. The residue was dissolved in dry pyridine (2 ml) and cooled to 08.
Chlorotrimethylsilane (2.3 ml, 18.24mmol) was added dropwise. The mixture was allowed to warm to r.t.
and stirred for 45 min. The soln. was then cooled to 08 and 9H-fluoren-9-ylmethyl carbonochloridate (1.19 g,
4.46 mmol) was added. The mixture was warmed to r.t. and stirred for 1.5 h. Then, the soln. was cooled again to
08, H2O (6 ml) was added, and the soln. stirred for 1 h at r.t. Finally, the solvent was evaporated and the residue
purified by CC (SiO2, CH2Cl2/MeOH 15 :1 ! 8 :1): 22/23 2 :1 (1.11 g, 82% overall). White solid. IR: 3600 2350
(OH, COOH)), 1690 (CO), 1418, 1223, 1103, 1024, 743. 1H-NMR (300 MHz, CD3OD; mixture of conformers of
22/23): 7.75 7.23 (m, arom. H of Fmoc); 6.37, 6.28 (br. s, each, HÀC(4)); 4.40 4.08 (m, CH and CH2 of Fmoc,
HÀC(1'), HÀC(2'), HÀC(3'), HÀC(4')); 3.75 3.40 (m, HÀC(4')); 2.49, 2.47 (s, each, Me). 13C-NMR
(75.4MHz, CD 3OD; mixture of conformers of 22/23): 167.3 (COOH); 159.8, 159.7, 152.2 (C(2), C(5)); 145.2,
142.6, 128.7, 128.1, 125.9, 120.9 (arom. C of Fmoc); 116.1 (C(3)); 110.0, 109.0 (C(4)); 77.6, 70.6, 62.2, 59.1, 51.7
(C(1'), C(2'), C(3'), C(4')); 68.5 (CH2 of Fmoc); 49.9 48.2 (CH of Fmoc); 13.7 (Me). FAB-MS: 472 (33, [M ‡
.
‡
‡
‡
Na] ), 494 (15, [M À 1 ‡ 2Na] ). HR-FAB-MS: 472.1377 ([C25H23NO7 ‡ Na] ; calc. 472.1372).
Amides (3b,j,k and 4b,j,k): General Procedure. To a soln. of 22/23 2 :1 (0.1 mmol) in dry DMF (1 ml),
PyBOP (1.2 equiv.), Pr2EtN (1.2 equiv.), and R1R2NH (1.2 equiv.) was added. The mixture was stirred for
i
30 min and then evaporated. The residue was diluted with CH2Cl2 and washed with 1m HCl and brine. The org.
layer was dried (Na2SO4) and evaporated and the residue acylated conventionally with Ac2O/pyridine. The
resulting residue was purified by CC (SiO2, Et2O/petroleum ether 1:2 ! 5 :1) to give, separately, the two O-
acetylated 1'-epimeric1) amides that were, independently, dissolved in MeOH (2 ml). Then 1m NaOMe/MeOH
(4drops) was added and the mixture stirred at r.t. for 20 min. The solvent was evaporated and the residue
dissolved in DMF (2 ml) and treated with Et2NH (30 equiv.). The mixture was stirred for 15 min and then
evaporated, and the resulting residue purified by CC (SiO2, CH2Cl2/MeOH 20 :1 ! 6 :1). The following
compounds were prepared in this manner.
5-[(2R,3S,4R)- and (2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methyl-N-(phenylmethyl)furan-3-carbox-
amide (3b and 4b): With R1R2NH ˆ PhCH2NH2, 3b (9.8 mg, 46% overall) and 4b (3.8 mg, 36% overall) were
obtained. Colorless oils.
Data of 3b: [a]2D5 ˆ À55 (c ˆ 0.8, MeOH). IR: 3388 (NH, OH), 2917, 2830, 1640 (CO), 1404, 1221, 1103,
739. 1H-NMR (400 MHz, CD3OD): 7.36 7.23 (m, Ph); 6.73 (s, HÀC(4)); 4.53 (s, CH2 of Bn); 4.26 4.22
(m, HÀC(2'), HÀC(3')); 4.15 (d, 3J(1',2') ˆ 7.3, HÀC(1')); 3.38 (dd (overlapped by MeOH), HaÀC(4')); 3.01
(dd, 3J(3',4'b) ˆ 2.3, 2J(4'a,4'b) ˆ 12.0, HbÀC(4')); 2.58 (s, Me). 13C-NMR (100.5 MHz, CD3OD): 166.1
(CONHBn); 158.3, 151.9 (C(2), C(5)); 140.3, 129.5, 128.5, 128.1 (6 C, Ph); 117.6 (C(3)); 108.3 (C(4)); 76.9
.
‡
(C(2')); 72.1 (C(3')); 60.0 (C(1')); 52.2 (C(4')); 43.9 (PhCH2); 13.7 (Me). EI-MS: 316 (13, M ). HR-EI-MS:
‡
316.1415 (C17H20N2O4 ; calc. 316.1423).
Data of 4b: [a]2D5 ˆ À22 (c ˆ 0.6, MeOH). IR: 3388 (NH, OH), 2917, 2830, 1640 (CO), 1404, 1103, 1028,
739. 1H-NMR (400 MHz, CD3OD): 7.34 7.25 ( m, Ph); 6.73 (s, HÀC(4')); 4.52 (s, PhCH2); 4.37 (m, HÀC(3'));
4.23 (d, 3J(1',2') ˆ 3.9, HÀC(1')); 4.19 (t, 3J(2',3') ˆ 4.1, HÀC(2')); 3.20 (dd, 3J(3',4'a) ˆ 7.5, 2J(4'a,4'b) ˆ 11.5,
HaÀC(4')); 2.99 (dd, 3J(3',4'b) ˆ 6.3, HbÀC(4')); 2.55 (s, Me). 13C-NMR (100.5 MHz, CD3OD): 166.3
(CONHBn); 157.5, 150.6 (C(2), C(5)); 140.4, 129.5, 128.4, 128.1 (6 C, Ph); 117.6 (C(3)); 108.5 (C(4)); 73.7,
.
‡
73.5 (C(2'), C(3')); 60.3 (C(1')); 51.3 (C(4')); 43.8 (PhCH2); 13.6 (Me). EI-MS: 316 (4, M ). HR-EI-MS:
‡
316.1435 (C17H20N2O4 ; calc. 316.1423).

Helvetica Chimica Acta Vol. 86 (2003)
1911
5-[(2R,3S,4R)- and (2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methyl-N-(1-methylethyl)furan-3-carboxa-
mide (3j and 4j, resp.): With R1R2NH ˆ iPrNH2, 3j (7.5 mg, 41% overall) and 4j (2.9 mg, 35% overall) were
obtained. Colorless oils.
Data of 3j: [a]2D5 ˆ À70 (c ˆ 0.6, MeOH). IR: 3356 (NH, OH), 1634 (CO), 1534, 1400, 1103. 1H-NMR
(400 MHz, CD3OD): 6.67 (s, HÀC(4)); 4.24 4.12 (m, HÀC(2'), HÀC(3'), Me2CH); 4.06 (d, 3J(1',2') ˆ 7.5,
HÀC(1')); 3.33 (dd, HaÀC(4')); 2.95 (dd, 3J(3',4'b) ˆ 3.0, 2J(4'a,4'b) ˆ 12.1, HbÀC(4')); 2.56 (s, Me); 1.25
(d, 3J(H,H) ˆ 6.6, Me2CH). 13C-NMR (100.5 MHz, CD3OD): 165.5 (CONHiPr); 157.6, 152.7 (C(2), C(5)); 117.8
(C(3)); 107.7 (C(4)); 77.2 (C(2')); 72.3 (C(3')); 60.4(C(1 ')); 52.4(C(4 ')); 42.4 (Me2CH); 22.6 (Me2CH); 13.6
.
‡
‡
(Me). EI-MS: 268 (18, M ). HR-EI-MS: 268.1425 (C13H20N2O4 ; calc. 268.1423).
Data of 4j: [a]2D5 ˆ À10 (c ˆ 0.3, MeOH). IR: 3325 (NH, OH), 2930, 1634(CO), 1588, 1402, 1101. 1H-NMR
(400 MHz, CD3OD): 6.88 (s, HÀC(4)); 4.50 4.45 (m, HÀC(1'), HÀC(3')); 4.29 (t, 3J(1',2') ˆ 3J(2',3') ˆ 3.9,
HÀC(2')); 4.18 (sept., 3J(H,H) ˆ 6.6, Me2CH); 3.38 (dd (overlapped by MeOH), HaÀC(4')); 3.15
(dd, 3J(3',4'b) ˆ 6.8, 2J(4'a,4'b) ˆ 11.6, HbÀC(4')); 2.55 (s, Me); 1.25 (d, 3J(H,H) ˆ 6.6, Me2CH). 13C-NMR
(100.5 MHz, CD3OD): 165.3 (CONHiPr); 157.7, 147.9 (C(2), C(5)); 118.2 (C(3)); 110.1 (C(4)); 73.2, 72.8 (C(2'),
‡
C(3')); 59.9 (C(1')); 50.2 (C(4')); 42.5 (Me2CH), 22.6 (Me2CH); 13.5 (Me). CI-MS: 269 (8, [M ‡ H] ). EI-MS:
.
‡
‡
(8, M ). HR-EI-MS: 268.1429 (C13H20N2O4 ; calc. 268.1423).
5-[(2R,3S,4R)- and (2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-N,N-diethyl-2-methylfuran-3-carboxamide
(3k and 4k): With R1R2NH ˆ Et2NH, 3k (7.3 mg, 39% overall) and 4k (3.1 mg, 36% overall) were obtained.
Colorless oils.
Data of 3k: [a]2D5 ˆ À50 (c ˆ 0.3, MeOH). IR: 3412 (NH, OH), 2922, 1595 1700 (CO), 1443, 1101.
1H-NMR (400 MHz, CD3OD): 6.42 (s, HÀC(4)); 4.24 4.18 (m, HÀC(2'), HÀC(3')); 4.10 (d, 3J(1',2') ˆ 7.5,
HÀC(1')); 3.52 (br. s, 2 MeCH2); 3.38 (dd (overlapped by MeOH), HaÀC(4')); 2.97 (dd, 3J(3',4'b) ˆ 2.5,
2J(4'a,4'b) ˆ 12.0, HbÀC(4')); 2.36 (s, Me); 1.22 (br. s, 2 MeCH2).13C-NMR (100.5 MHz, CD3OD): 168.0
(CONEt2); 153.7, 152.9 (C(2), C(5)); 118.2 (C(3)); 108.5 (C(4)); 77.2 (C(2')); 72.2 (C(3')); 60.2 (C(1')); 52.3
.
‡
(C(4')); 44.6, 40.9 (MeCH2); 14.6, 13.1 (MeCH2); 12.8 (Me). EI-MS: 282 (14, M ). HR-EI-MS: 282.1577
‡
(C14H22N2O4 ; calc. 282.1579).
Data of 4k: [a]2D5 ˆ À13 (c ˆ 0.3, MeOH). IR: 3404 (NH, OH), 2974, 2932, 1661 1542 (CO), 1443, 1383,
1101. 1H-NMR (400 MHz, CD3OD): 6.55 (s, HÀC(4)); 4.44 4.39 (m, HÀC(3')); 4.31 (d, 3J(1',2') ˆ 3.9,
HÀC(1')); 4.23 (t, 3J(2',3') ˆ 3.9, HÀC(2')); 3.52 (br. s, 2 MeCH2); 3.26 (dd, 3J(3',4'a) ˆ 7.5, 2J(4'a,4'b) ˆ
11.5,HaÀC(4')); 3.04( dd, 3J(3',4'b) ˆ 6.4, HbÀC(4')); 2.36 (s, Me); 1.23 (d, 2 MeCH2). 13C-NMR (100.5 MHz,
CD3OD): 168.1 (CONEt2); 153.5, 150.2 (C(2), C(5)); 118.3 (C(3)); 109.6 (C(4)); 73.5, 73.3 (C(2'), C(3')); 60.2
.
‡
(C(1')); 51.0 (C(4')); 44.6, 40.9 (MeCH2); 14.6, 13.2, (MeCH2); 12.8 (Me). EI-MS: 282 (15, M ). HR-EI-MS:
‡
282.1584(C 14H22N2O4 ; calc. 282.1579).
5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-N-ethyl-2-methylfuran-3-carboxamide (3l). As described for
3b,j,k, with 22 (46 mg, 0.1 mmol) and EtNH2 but omitting acetylation and deacetylation with 1m NaOMe/
MeOH. Fmoc Deprotection gave 3l (14.2 mg, 56% overall). Colorless oil. [a]2D5 ˆ À51 (c ˆ 0.5, MeOH). IR:
3347 (NH, OH), 2928, 1634 (CO), 1588, 1445, 1101, 856, 748. 1H-NMR (400 MHz, CD3OD): 6.67 (s, HÀC(4));
4.25 4.21 (m, HÀC(2'), HÀC(3')); 4.13 (d, J(1',2') ˆ 7.1, H ÀC(1')); 3.39 3.34( m (overlapped by MeOH),
HaÀC(4'), MeCH2); 3.00 (dd, 3J(3',4'b) ˆ 2.5, 2J(4'a,4'b) ˆ 12.1, HbÀC(4')); 2.57 (s, Me); 1.23 (t, 3J(H,H) ˆ 7.3,
MeCH2). 13C-NMR (100.5 MHz, CD3OD): 166.1 (CONHEt); 157.9, 151.9 (C(2), C(5)); 117.7 (C(3)); 108.2
(C(4)); 76.9 (C(2')); 72.1 (C(3')); 60.1 (C(1')); 52.2 (C(4')); 35.2 (MeCH2); 15.0 (MeCH2); 13.6 (Me). CI-MS:
.
‡
‡
‡
255 (23, [M ‡ H] ). EI-MS: 254(12, M ). HR-EI-MS: 254.1262 (C12H18N2O4 ; calc. 254.1267).
S-Phenyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carbothioate (3a) and Methyl 5-
[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (3e). To a soln. of 22/23 (104mg,
0.23 mmol) in dry THF (1.3 ml), thiophenol (30 ml, 0.3 mmol), DCC (63 mg, 0.3 mmol), and DMAP (3 mg)
were added. The mixture was stirred for 2 h and evaporated and the residue acetylated conventionally with
Ac2O/pyridine. Purification of the residue by CC (SiO2, Et2O/petroleum ether 1 :2 ! 2 :1) gave 24 (69 mg, 48%)
and 25 (26 mg, 18%).
Diasteroisomer 24 was dissolved in MeOH (2 ml), and 1m NaMeO/MeOH was added until a basic pH was
‡
reached. The mixture was left to stand at r.t. for 20 min, then made neutral with Amberlyst IR-120 (H ), filtered,
and evaporated. The residue was dissolved in DMF (2 ml), Et2NH (30 equiv.) was added, the mixture stirred for
15 min at r.t. and then evaporated, and the residue purified by CC (SiO2, CH2Cl2/MeOH 20 :1 ! 6 :1): 3a (8 mg,
23%) as colorless oil followed by 3e (7 mg, 28%; see above). 3a: [a]2D5 ˆ À34( c ˆ 0.3; MeOH). IR: 3375 (NH,
OH), 2922, 1721 (CO), 1665, 1589, 1406, 1105. 1H-NMR (400 MHz, CD3OD); 7.54 7.48 ( m, Ph); 6.81
(s, HÀC(4)); 4.24 4.17 (m, HÀC(2'), HÀC(3')); 4.10 (d, 3J(1',2') ˆ 7.5, HÀC(1')); 3.35 (dd (overlapped by
MeOH), HaÀC(4')); 2.96 (dd, 3J(3',4'b) ˆ 2.8, 2J(4'a,4'b) ˆ 12.0, HbÀC(4')); 2.59 (s, Me). 13C-NMR

1912
Helvetica Chimica Acta Vol. 86 (2003)
(100.5 MHz, CD3OD): 185.6 (COSEt); 158.5, 154.5 (C(2), C(5)); 136.2, 130.6, 130.3 (5 C, Ph); 128.5 (C(1) of
Ph); 121.7 (C(3)); 107.6 (C(4)); 77.4 (C(2')); 72.3 (C(3')); 60.2 (C(1')); 52.5 (C(4')); 14.2 (Me). CI-MS: 320 (83,
.
‡
‡
‡
[M ‡ H] ). EI-MS: 319 (5, M ). HR-EI-MS: 319.0884(C 16H17NO4S ; calc. 319.0878).
Methyl 5-[(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carboxylate (4e). As described for
3a/3e, with diastereoisomer 25 (see above; 26 mg, 0.041 mmol) in MeOH (3 ml), 1m NaOMe/MeOH, and
Et2NH/DMF: 4e (5.5 mg, 56%) (the (1'S)-epimer1) 4a of 3a was not observed). Colorless oil. [a]D25 ˆ À27 (c ˆ
0.3, MeOH). IR: 3375 (NH, OH), 1719 (CO), 1589, 1406, 1101. 1H-NMR (400 MHz, CD3OD): 6.70
(s, HÀC(4)); 4.36 (m, HÀC(3')); 4.20 4.48 (m, HÀC(2'), HÀC(1')); 3.84( s, COOMe); 3.18 (dd, 3J(3',4'a) ˆ
7.4, 2J(4'a,4'b) ˆ 11.5, HaÀC(4')); 3.00 (dd, 3J(3',4'b) ˆ 6.2, HbÀC(4')); 2.58 (s, Me). 13C-NMR (100.5 MHz,
CD3OD): 170.4( COOMe); 159.9, 151.6 (C(2), C(5)); 114.7 (C(3)); 109.7 (C(4)); 73.8, 73.7 (C(2'), C(3')); 60.3
.
.
‡
‡
(C(1')); 51.8 (COOMe); 51.6 (C(4')); 13.7 (Me). CI-MS: 242 (14, [M ‡ H] ). EI-MS: 241 (8, M ). HR-EI-MS:
‡
241.0945 (C11H15NO5 ; calc. 241.0950).
S-Ethyl 5-[(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-2-methylfuran-3-carbothioate (3m). To a soln. of 22
(40 mg, 0.09 mmol) in dry THF (1.5 ml), ethanethiol (14 ml, 0.18 mmol), DCC (38 mg, 0.18 mmol), and DMAP
(3 mg) were added. The mixture was stirred for 2 h at r.t. and then evaporated. Purification of the residue by CC
(SiO2, CH2Cl2/MeOH 80 :1 ! 65 :1) gave the protected thioester 26 (13 mg, 0.026 mmol), which was dissolved
in DMF (1.5 ml). Et2NH (30 equiv.) was added and the soln. stirred for 15 min at r.t. The solvent was evaporated
and the resulting residue purified by CC (SiO2, CH2Cl2/MeOH 20.1 ! 6 :1): 3m (5.3 mg, 27% overall).
Colorless oil. [a]2D5 ˆ À70 (c ˆ 0.4, MeOH). IR: 3359 (NH, OH), 2928, 1651 (CO), 1570, 1406, 1103, 878.
1H-NMR (400 MHz, CD3OD): 6.71 (s, HÀC(4)); 4.24 4.18 (m, HÀC(2'), HÀC(3')); 4.10 (d, 3J(1',2') ˆ 7.4,
HÀC(1')); 3.36 (dd (overlapped by MeOH), HaÀC(4')); 3.04( q, 3J(H,H) ˆ 7.4, MeCH2); 2.97 (dd, 3J(3',4'b) ˆ
2.6, 2J(4'a,4'b) ˆ 12.0, HbÀC(4')); 2.60 (s, Me); 1.33 (t, MeCH2). 13C-NMR (100.5 MHz, CD3OD): 187.5
(COSEt); 157.7, 153.4(C(2 '), C(5)); 122.6 (C(3)); 108.1 (C(4)); 77.2 (C(2')); 72.2 (C(3')); 60.0 (C(1')); 52.3
.
‡
‡
(C(4')); 23.7 (MeCH2); 15.4( MeCH2); 14.2 (Me). EI-MS: 271 (13, M ). HR-EI-MS: 271.0875 (C12H17NO4S ;
calc. 271.0878).
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Received September 25, 2002