Synthesis of N-substituted (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diols: Search for new glycosidase inhibitors

Article abstract of DOI:10.1002/hlca.200490282

N-Substituted (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diols 9 and 10, respectively, were derived from (+)-L-and (-)-D-tartaric acid, respectively. Compounds 9k, 91, and 9m with the N-substituents, BnNH(CH₂) ₂, 4-PhC₆H₄

Full text of DOI:10.1002/hlca.200490282

Helvetica Chimica Acta ± Vol. 87 (2004)
3167
Synthesis of N-Substituted (3S,4S)- and (3R,4R)-Pyrrolidine-3,4-diols:
Search for New Glycosidase Inhibitors
by Robert èysek and Pierre Vogel*
Á
Â
 Â
Laboratoire de glycochimie et de synthese asymetrique, Ecole Polytechnique Federale de Lausanne, BCH,
CH-1015Lausanne-Dorigny
N-Substituted (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diols 9 and 10, respectively, were derived from (‡)-l-
and (À)-d-tartaric acid, respectively. Compounds 9k, 9l, and 9m with the N-substituents, BnNH(CH2)2, 4-
PhC6H4CH2NH(CH2)2 and 4-ClC6H4CH2NH(CH2)2, respectively, showed modest inhibitory activities toward a-
d-amyloglucosidases from Aspergillus niger and from Rhizopus mold (Table 1). Unexpectedly, several (3R,4R)-
pyrrolidine-3,4-diols 10 showed inhibitory activities toward a-d-mannosidases from almonds and from jack bean
(Table 3). N-Substitution by the NH2(CH2)2 group, i.e., 10g, led to the highest potency.
Introduction. ± Inhibitors of a-d-glucosidases [1][2] have manifested in vitro anti-
HIV activities [3]. Among them, 1-deoxynojirimycin (1) [4][5] and N-butyl-1-
deoxynojirimycin (2) [6] (Fig. 1) have shown promising results as they exhibit little
toxicity.
Fig. 1. Inhibitors of a-d-glucosidases
The polyhydroxyalkaloid 1 and derivatives have been isolated from mulberry trees
(Morus alba L.) [7] and silkworms (Bombyx mori L.) [8] together with (2R,3R,4R)-2-
ꢀ 2004 Verlag Helvetica Chimica Acta AG, Zürich

3168
Helvetica Chimica Acta ± Vol. 87 (2004)
(hydroxymethyl)pyrrolidine-3,4-diol (3) and derivatives such as 4. The latter alkaloids
are also a-d-glucosidase inhibitors [8][9]. The crude drug ꢁSohaku-hiꢂ, the root bark of
mulberry trees, is used in some formulas of Japanese-Oriental (Kampo) medicine. Silk
powder, silkworm powder, and mulberry leaves and fruits have been developed as
natural functional food in Korea and Japan (antihyperglycemic effect) [8][10]. The
(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol (5) has been extracted
from Derris elliptica (Wa l l ) Benth (leguminosal), and found to inhibit a-d-
glucosidases, b-d-glucosidases, b-d-galactosidases, invertase (yeast), b-d-xylosidases,
and trehalases [9][11]. Conjugation of 5 as arenesulfonamides 6 or carboxamides 7
constitute b-d-glucosidase inhibitors in the nanomolar range [12]. Fewer pyrrolidine-
2,3-diols with the (3S,4S) configuration are known [1][9][13]. Among them (2S,3S,4S)-
2-(hydroxymethyl)pyrrolidine-3,4-diol and lentiginosine (8) [14] are good inhibitors of
a-d-glucosidases. Lentiginosine can be seen as an N-alkylated pyrrolidinediol
derivative. There is an urgent need for new anti-HIV therapies. Orally active and
inexpensive compounds should be found, and HIV-entry inhibition is one possible
target for the discovery of new drugs (see, e.g., [15]). As it is known that N-substitution
of pyrrolidine derivatives can improve their glycosidase inhibitory activity, we
envisioned that readily available (3R,4R)- and (3S,4S)-pyrrolidine-3,4-diol could
generate useful compounds by N-substitution. Because they bear only two OH groups
and a lipophilic moiety, they are expected to be compatible with the requirement of
orally active drugs. Furthermore, we have demonstrated for (2R,3R,4S)- [16] and
(2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol [17] that N-substitution of their pri-
mary amine moiety leads to more-potent and more-selective a-d-mannosidase
inhibitors. We report here the synthesis of (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diol
derivatives 9 and 10 and present preliminary results on their inhibitory activities toward
several glycosidases.
Fig. 2. Pyrrolidine-3,4-diol derivatives 9 and 10
The best a-d-glucosidase (amyloglucosidase from Aspergillus niger and from
Rhizopus mold) inhibitors happen to be compounds 9l (R ˆ 4-PhC6H4CH2NH(CH2)2
and 9m (R ˆ 4-ClC6H4CH2NH(CH2)2). Unfortunately these compounds are less potent
a-d-glucosidase inhibitors than lentiginosine (8) or the more-polar polyhydroxypyrro-
lidine derivatives 3 ± 7.
Results and Discussion. ± Synthesis ofNew Pyrrolidine-3,4-diol Derivatives . Our
initial studies used (‡)-l-tartaric acid ((R,R)-11) as starting material for the synthesis
of (3S,4S)-pyrrolidine-3,4-diols. The known N-benzyl [18] and nonsubstituted [19][20]
systems 9a and 9b were obtained readily applying published procedures (Scheme 1).
The O-silylated derivatives 12a and 12b were also obtained under standard conditions

Helvetica Chimica Acta ± Vol. 87 (2004)
3169
[18]. Direct N-methylation (NaH, THF, MeI) of 12b produced derivative 13 in 50%
yield. After desilylation with Bu4NF in aqueous THF, impure 9c (contaminated with
Bu4NF and Bu3N) was obtained. The crude reaction mixture was then treated with
Ac2O/pyridine at 208. This generated diacetate 14 (82%) that could be purified by flash
chromatography (silica gel). Subsequent methanolysis under Zemplenꢂs conditions
afforded pure 9c (95%).
Scheme 1. Synthesis ofDerivative 9c from (‡)-l-Tartaric Acid
The N-ethyl [13], N-propyl, and N-butyl derivatives 9d ± f were obtained on heating
9a under reflux with EtBr, PrBr, and BuBr, respectively, without solvent (formation of
the corresponding quaternary ammonium bromides 15). Subsequent hydrogenolysis
(20% Pd(OH)2/C in MeOH, 208, 5days) produced 9d (36%), 9e (37%), and 9f
(37%)1), respectively, in moderate yields (Scheme 2). An alternative route was to heat
Scheme 2. Synthesis of N-Alkylated Derivatives 9d ± f
1
)
Compound 9f was also obtained from (‡)-l-tartaric acid and butanamine via (3R,4R)-1-butyl-3,4-
dihydroxypyrrolidine-2,5-dione (see Exper. Part) and LiAlH4 reduction of the latter (yield 28% over two
steps; not shown).

3170
Helvetica Chimica Acta ± Vol. 87 (2004)
the dihydroxy bis-tosylate 18 (obtained from (R,R)-11 via 16 and 17 [21][22]) with the
corresponding primary amines (Scheme 3). Unfortunately, yields were even poorer
than those observed with reactions of Scheme 2.
Scheme 3. Synthesis ofDerivatives 9e ± j
The known dibenzyloxy bis-ditosylate 19 [23] reacted with propanamine and
butanamine giving pyrrolidine-3,4-diols 20e (92%) and 20f (92%), respectively.
Subsequent hydrogenolysis (H2, Pd(OH)2/C, MeOH, AcOEt) afforded 9e (82%) and
9f (82%), respectively (Scheme 3). With diamines H2N(CH2)2NH2, H2N(CH2)2NHEt,
H2N(CH2)2NMe2, and H2N(CH2)3NH2, bis-tosylate 19 yielded the corresponding
pyrrolidine-3,4-diols 20g ± j that were debenzylated to the corresponding N-substituted
(3S,4S)-pyrrolidine-3,4-diols 9g ± j in good yields. (Aminoethyl)pyrrolidinediol 9g was
also obtained by amidification of (2R,3R)-2,3-di-O-benzyltartaric acid [24] with
H2N(CH2)2NH2 [25]. Amide reduction with LiAlH4 (26%) and subsequent debenzyl-
ation (89%) under standard conditions produced 9g.
Reductive amination of benzaldehyde (21), [1,1'-biphenyl]-4-carboxaldehyde (22),
and 4-chlorobenzaldehyde (23) with (aminoethyl)pyrrolidinediol 9g (MeOH, 208; then
NaBH(OAc)3) [16] provided pyrrolidine-3,4-diols 9k (73%), 9l (73%), and 9m (77%),
respectively. Similarly, reductive amination of benzaldehyde (21) with (aminopropyl)-
pyrrolidinediol 9j gave pyrrolidine-3,4-diol 9n (42%) (Scheme 4).

Helvetica Chimica Acta ± Vol. 87 (2004)
Scheme 4. Synthesis ofDerivatives 9k ± n
3171
All enantiomers of 9, i.e., pyrrolidine-3,4-diols 10, were prepared in the same way
starting from (À)-d-tartaric acid. The structures of all the new compounds were
confirmed by their elemental analyses or high-resolution mass spectrometry and by
their spectral data (see Exper. Part).
Glycosidase Inhibition Assays. Pyrrolidine-3,4-diols 9 and 10 were evaluated for
their inhibitory activities toward 25commercially available glycosidases at 1 m m
concentration and under optimum pH conditions [13]. The following enzymes were
not inhibited by any of the derivatives 9 and 10: a-d-galactosidases from coffee beans,
from Aspergillus niger, and from Escherichia coli; b-d-galactosidases from E. coli, from
A. niger, from A. orizae, and jack beans; a-d-glucosidases from rice and from bakers
yeast (isomaltase); b-d-mannosidase from Helix pomatia; b-d-xylosidase from A.
niger; a-d-N-acetylgalactosaminidase from chicken liver; b-d-N-acetylglucosaminidase
from jack bean and from bovine epididymis A and B.
None of compounds 9 and 10 inhibited a-d-glucosidase from yeast, except (3R,4R)-
1-(3-aminopropyl)pyrrolidine-3,4-diol (10j). The latter enzyme was inhibited by 95%
at 1 mm of 10j. A Ki ˆ 2.8 mm (noncompetitive) was evaluated (Fig. 3).
As shown in Table 1, a-d-amyloglucosidases from A. niger and from Rhizopus mold
were inhibited weakly by the derivatives 9. At first glance, the inhibitory activities of
the corresponding enantiomers 10 were, in some cases, weaker (see 10b,c,h,l,m,j) and in
others stronger (see 10g,n). These results are quite deceiving in comparison with the
good inhibitory activities and selectivities toward a-d-mannosidases that were found by
ꢁdressing upꢂ the primary amino group of (2R,3R,4S)- and (2S,3R,4S)-2-(amino-
methyl)pyrrolidine-3,4-diol by benzylic groups. From the comparison of the inhibitory
activities of pyrrolidinediols 9b,c with those of aminopyrrolidinediols 9g ± n, it can be
stated that the introduction of a second amino function does not significantly improve
the activity of (3S,4S)-pyrrolidine-3,4-diols. Improvement is the highest with the ([1,1'-
biphenyl]-4-ylmethyl)amino and (4-chlorobenzyl)amino derivatives 9l and 9m, re-
spectively (see Table 1).
A few derivatives 9 and 10 showed inhibitory activities toward b-d-glucosidases
(Table 2). A priori, there is no structural element (a- or b-substituent at C(2)) that
should make these compounds to be recognized better by a-d-glucosidases then by b-d-
glucosidases. We observed that fewer derivatives of 9 and 10 inhibited b-d-glucosidases
than a-d-glucosidases. The most-potent compound, (3R,4R)-1-(2-aminoethyl)pyrroli-
dine-3,4-diol (10g), inhibited b-d-glucosidase from Caldocellum saccharolyticum by
81% at 1 mm concentration.

3172
Helvetica Chimica Acta ± Vol. 87 (2004)
Fig. 3. Lineweaver-Burk plots for the inhibition of a-d-glucosidase from jack bean (pH 5.258) by (3R,4R)-1-(3-
~
&
aminopropyl)pyrrolidine-3,4-diol (10j). ˆ 0 mm (control), . ˆ 16 mm, ˆ 32 mm.
Unexpectedly, several pyrrolidine-3,4-diols 10 inhibited a-d-mannosidases (Ta-
ble 3). This was not the case with enantiomers 9. The origin of this selectivity is not
obvious at this moment. (2R,3R,4S)- and (2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-
diols are better a-d-mannosidase inhibitors than cis-pyrrolidine-3,4-diols [16].
Benzylation of the primary amino groups of the former compounds enhanced their
inhibitory activities and selectivities toward these enzymes. It is thus not a surprise to
find that 10k ± n are better a-d-mannosidase inhibitors than 10a ± f.
Compounds 9 and 10 were also tested for their inhibitory activities toward a-l-
fucosidase from bovine epididymis. Only aminopyrrolidinediol 10g was recognized by
this enzyme. The inhibitory activity remained modest as at 1 mm concentration, 53% of
inhibition was observed (IC50 ca. 400 mm).
Conclusions. ± The (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diol derivatives 9 and 10
were readily obtained from l- and d-tartaric acid, respectively. Contrary to the natural
lentiginosine (8; Fig. 1), a potent inhibitor of a-d-amyloglucosidases with a (3S,4S)-1-
alkylpyrrolidine-3,4-diol moiety, the monocyclic analogues 9a,c,f are weak inhibitors of
these enzymes. N-Substitution by a 2-aminoethyl (see 9g) or 3-aminopropyl (see 9j)
group does not improve the inhibitory activities. Slight enhancements of the inhibitory
activities toward a-d-amyloglucosidases are observed, however, when the primary
amino group of 9g is benzylated or alkylated by a [1,1'-biphenyl]-4-ylmethyl or a 4-
chlorobenzyl group (9l and 9m). This contrasts with the significant inhibitory and
selectivity enhancements toward a-d-mannosidases observed with (2R,3R,4S)- and

Helvetica Chimica Acta ± Vol. 87 (2004)
3173
Table 1. Inhibitory Activity (% of inhibition) ofPyrrolidine-3,4-diols 9 and 10 toward a-d-Amyloglucosidases at
1 mm Concentration ofthe Inhibitor and Optimal pH a). n.m. ˆ not measured.
R
9a ± e, g ± n
10a ± e, g ± n
a-d-Aminoglucosidase
a-d-Aminoglucosidase
Aspergillus niger Rhizopus mold Aspergillus niger Rhizopus mold
9a
b
c
d
e
Bn
H
Me
Et
0
30% [13]
0
72%
53% [13]
0
0 [13]
55% [13]
0
38%
0
72%
78%
69%
45%
0
20%
0
31%
0
53%
45%
36%
23%
44%
0
48%
n.m.
n.m.
0
36%
0
47%
38%
33%
38%
n.m.
n.m.
48%
40%
0
0
46%
0
20%
51%
Pr
HO(CH2)2
HO(CH2)3
H2N(CH2)2
EtNH(CH2)2
Me2N(CH2)2
BnNH(CH2)2
g
h
i
k
l
m
j
n
33%
32%
0
32%
56%
23%
23%
47%
4-PhÀC6H4CH2NH(CH2)2 58%
4-ClÀC6H4CH2NH(CH2)2
H2N(CH2)3
45%
39%
0
BnNH(CH2)3
a
)
Table 2. Inhibitory Activity (% of inhibition) ofSome Pyrrolidine-3,4-diols 9 and 10 toward b-d-Glucosidases
from Almonds and from Caldocellum saccharolyticum at 1 mm Concentration and optimal pHa)
Almonds
C. saccharol.
Almonds
C. saccharol.
R
9a
c
e
f
g
i
j
k
l
30
36
0
36
0
0
0
0
0
0
27
0
0
0
24
22
0
10a
0
0
23
72
0
0
0
0
0
0
0
0
0
81
0
0
0
0
Bn
Me
Pr
Bu
c
e
f
g
i
j
k
l
H2N(CH2)2
Me2N(CH2)2
H2N(CH2)3
BnNH(CH2)2
4-PhÀC6H4CH2NH(CH2)2
48
a) All other derivatives 9 and 10 did not inhibit these enzymes.
(2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol upon N-benzylation of their primary
amino group [16][17]. (3R,4R)-Pyrrolidine-3,4-diol and its N-alkyl and N-benzyl
derivatives 10 are poorer inhibitors of a-d-amyloglucosidases than corresponding
enantiomers 9. Compound 10j, (3R,4R)-1-(3-aminopropyl)pyrrolidine-3,4-diol, is

3174
Helvetica Chimica Acta ± Vol. 87 (2004)
Table 3. Inhibitory Activity (% of inhibition) ofSome Pyrrolidine-3,4-diols 9 and 10 toward a-d Mannosidases
from Almonds and from Jack Beans at 1 mm Concentration and Optimal pHa)
Almonds
Jack beans
Almonds
Jack beans
R
9c
d
e
32
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10c
d
e
g
h
k
l
m
n
46
31
27
32
28
53
54
54
47
36
0
0
81
23
65
65
70
51
Me
Et
Pr
g
NH2(CH2)2
h
k
l
m
n
EtNH(CH2)2
BnNH(CH2)2
4-PhÀC6H4CH2NH(CH2)2
4-ClÀC6H4CH2NH(CH2)2
BnNH(CH2)3
a) All other derivatives 9 and 10 did not inhibit these enzymes.
exceptional as it is the unique derivative recognized by a-d-glucosidase from yeast as it
inhibits this enzyme with Ki ˆ 2.8 mm (mixed type). Unexpectedly, (3R,4R)-1-(2-
aminoethyl)pyrrolidine-3,4-diol (10g) and its derivatives N-benzylated at the primary
amino group inhibit a-d-mannosidases from almonds and jack beans.
Â
Â
We are grateful to the Office Federal de la Recherche et de la Science (OFES, European FP6 project,
TRIoH) for financial support. We thank also Miss Catherine Schütz for the enzymatic measurements and Mr. F.
Â
Sepulveda and S. Reddy Dubbaka for their technical help.
Experimental Part
General. All commercially available reagents (Fluka, Aldrich, Acros Organics) were used without further
purification. Solvents were dried by standard methods. Light petroleum ether used refers to the fraction boiling
between 40 ± 608. Solvents after reactions and extractions were evaporated in a rotatory evaporator. Liquid/solid
flash chromatography (FC): silica gel 60 (Merck No. 9385, 240 ± 400 mesh) or neutral alumina. TLC (reaction
monitoring): Merck silica gel 60F254 plates; detection by UV light, Pancaldi reagent ((NH4)6MoO4, Ce(SO4)2,
H2SO4, H2O), KMnO4, or 1% ninhydrin in MeOH. Melting points: Büchi SMP-20 apparatus; uncorrected.
Optical rotations: at 258; Jasco DIP-370 polarimeter or Jasco P-1020 polarimeter; [a]D in 10À1 deg cm2 gÀ1. IR
Spectra: Perkin-Elmer 1420 spectrometer; in cmÀ1 1H-NMR Spectra: Bruker ARX-400 spectrometer
.
(400 MHz); d(H) in ppm rel. to the solventꢂs residual 1H signal (CDCl3, d(H) 7.27; CD3OD, d(H) 3.31) as
internal reference, J in Hz; all assignments were confirmed by 2D-COSY-45and 2D-NOESY experiments.
13C-NMR Spectra: same instrument as for 1H (100.6 MHz); d(C) in ppm rel. to the solventꢂs C-signal (CDCl3,
d(C) 77.0; CD3OD, d(C) 49.0) as internal reference, J in Hz; all assignments were confirmed by 2D-HMQC. MS:
Nermag R-10-10c spectrometer, chemical-ionization (NH3) mode; m/z (% rel. to the base peak (ˆ100%)).
Elemental analyses: Ilse Beetz, D-96301 Kronach, Germany.
(3S,4S)-1-Benzylpyrrolidine-3,4-diol (9a). According to [18] from commercially available (‡)-l-tartaric
25
25
25
25
25
acid ((R,R)-11; Fluka): 9a (31% in 2 steps). [a] ˆ ‡7, [a] ˆ ‡8, [a] ˆ ‡10, [a] ˆ ‡15, [a] ˆ ‡17
589
577
546
535
405
(c ˆ 1.1, CHCl3 ([18a]: [a]2D5 ˆ ‡8.3 (c ˆ 1.1, CHCl3)).
25
25
(3S,4S)-Pyrrolidine-3,4-diol (9b). According to [19][20], from 9a: (97%). [a] ˆ ‡13, [a] ˆ ‡14,
589
577
[a] ˆ ‡15, [a] ˆ ‡23, [a] ˆ ‡27 (c ˆ 1.4, MeOH) ([19]: [a]2D5 ˆ ‡12.4 (c ˆ 2.4, MeOH)).
25
25
25
546
535
405
(3S,4S)-1-Benzyl-3,4-bis{[(tert-butyl)dimethylsilyl]oxy}pyrrolidine (12a). According to [18a], from 9a: 12a
(95%). [a] ˆ ‡57, [ a] ˆ ‡60, [a] ˆ ‡68, [a] ˆ ‡116, [a] ˆ ‡139 (c ˆ 1.0, CHCl3) ([18a]: [a]D25
ˆ
25
25
25
25
25
589
577
546
535
405
‡58.3 (c ˆ 1.0, CHCl3)).
(3S,4S)-3,4-Bis{[(tert-butyl)dimethylsilyl]oxy}pyrrolidine (12b). According to [18a], from 9a: 12b (85%).
[a] ˆ ‡33, [a] ˆ ‡34, [a] ˆ ‡40, [a] ˆ ‡64, [a] ˆ ‡75( c ˆ 1.0, CHCl3) ([18a]: [a]2D5 ˆ ‡35.9 (c ˆ
25
25
25
25
25
589
577
546
535
405
0.88, CHCl3)).
(2S,3S)-Butane-1,4-diol Bis[4-methylbenzenesulfonate] (18). According to [21][22], from diethyl (‡)-l-
25
tartrate (Fluka): 18 (36% in 4 steps). [a] ˆ À4.9 (c ˆ 2.1, acetone) ([22]: [a]2D5 ˆ À4.6 (c ˆ 2.1, acetone)).
589

Helvetica Chimica Acta ± Vol. 87 (2004)
3175
(2S,3S)-2,3-Bis(benzyloxy)butane-1,4-diol bis[4-Methylbenzenesulfonate] (19). According to [23] from
25
25
25
25
diethyl (‡)-l-tartrate (Fluka): 19 (54% in 3 steps). [a] ˆ ‡13, [a] ˆ ‡12, [a] ˆ ‡16, [a] ˆ ‡28,
589
577
546
535
[a] ˆ ‡35( c ˆ 1.0, CHCl3) ([23b]: [a]2D5 ˆ ‡14.58 (c ˆ 4.8, CHCl3)).
25
405
(3S,4S)-3,4-Bis{[(tert-butyl)dimethylsilyl]oxy}-1-methylpyrrolidine (13). To
a
soln. of 12b (1.0 g,
3.01 mmol) in dry THF (10 ml) cooled to 08, 60% NaH dispersion in mineral oil (0.14 g, 3.62 mmol) was
added. The suspension was stirred at 08 for 25min prior to addition of MeI (0.16 ml, 2.56mmol). The mixture
was stirred at 08 for another 15min and then at 20 8 for 45min (TLC monitoring). Excess of NaH was destroyed
by addition of MeOH. The mixture was evaporated and the residue submitted to FC (20 ± 40% AcOEt/hexane):
25
25
25
25
25
0.52 g (50%) of 13. Yellowish oil. [a] ˆ ‡44, [a] ˆ ‡47, [a] ˆ ‡51, [a] ˆ ‡85, [a] ˆ ‡100 (c ˆ 1.2,
589
577
546
535
405
CHCl3). IR (film) 2955, 2929, 2857, 1472, 1256, 1104, 1069, 835, 776. 1H-NMR (400 MHz, CDCl3): 4.10
(t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.6, HÀC(3), HÀC(4)); 2.82 (dd, 2J ˆ 9.8, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.8, HbÀC(2),
HbÀC(5); 2.39 (dd, 2J ˆ 9.8, 3J(2a,3) ˆ 3J(5a,4) ˆ 4.4, HaÀC(2), HaÀC(5); 2.31 (s, MeÀC(1)); 0.88 (s, 2 Bu);
t
0.07, 0.05(2 s, 4 MeSi). 13C-NMR (100.6 MHz, CDCl3): 80.6 (d, 1J(C,H) ˆ 147, C(3), C(4)); 63.3 (t, 1J(C,H) ˆ
137, C(2), C(5)); 42.9 (q, 1J(C,H) ˆ 133, MeÀC(1)); 25.8 (3q, 1J(C,H) ˆ 125, 2 Me3C); 18.0 (s, Me3C); À4.6
(q, 1J(C,H) ˆ 119, 2 MeSi); À4.8 (q, 1J(C,H) ˆ 119, 2 MeSi). CI-MS (NH3): 346 (100, [M ‡ H] ), 345(20), 344
‡
‡
‡
(3), 288 (9), 280 (2), 141 (2), 82 (1), 73 (1). HR-MALDI-TOF-MS: 346.2534 (C17H40NO2Si2 , [M ‡ H] ; calc.
346.2589). Anal. calc. for C17H39NO2Si2 (345.252): C 59.07, H 11.37; found: C 58.99, H 11.20.
(3S,4S)-1-Methylpyrrolidine-3,4-diol Diacetate (14). A soln. of 9c (0.048 g, 0.41 mmol) and N,N-
dimethylpyridin-4-amine (DMAP, 0.01 g) in Ac2O/pyridine 1:2 (2 ml) was stirred at 208 (TLC monitoring).
After 1 h, the mixture was poured into H2O, extracted with CH2Cl2 (3Â), dried (Na2SO4), and evaporated. The
25
residue was purified by FC (2 ± 6% MeOH/CH2Cl2): 0.068 g (82%) of 14. Light yellowish oil. [a] ˆ ‡51,
589
25
25
25
[a] ˆ ‡56, [a] ˆ ‡102, [a] ˆ ‡119 (c ˆ 0.215, CHCl3). UV (CHCl3): 241 (290), 226 (105), 207 (106). IR
577
535
405
(film): 2967, 2942, 2785, 1737, 1454, 1372, 1232, 1158, 1048, 1021, 850. 1H-NMR (400 MHz, CDCl3): 5.10
(t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.6, HÀC(3), HÀC(4)); 3.06 (dd, 2J ˆ 10.5, 3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2),
HbÀC(5)); 2.51 (dd, 2J ˆ 10.5, 3J(2a,3) ˆ 3J(5a,4) ˆ 3.5, HaÀC(2), HaÀC(5)); 2.36 (s, MeÀC(1)); 2.07 (s, 2 Me-
CO). 13C-NMR (100.6 MHz, CDCl3): 170.3 (s, 2 MeCO); 78.3 (d, 1J(C,H) ˆ 156, C(3), C(4)); 60.6 (t, 1J(C,H) ˆ
139, C(2), C(5)); 41.9 (q, 1J(C,H) ˆ 134, MeÀC(1)); 20.9 (q, 1J(C,H) ˆ 130, 2 MeCO). CI-MS (NH3): 202 (10,
‡
‡
[M ‡ H] ), 201 (3, M ), 182 (12), 152 (11), 141 (87), 127 (14), 115 (52), 100 (9), 98 (100), 96 (5). HR-MALDI-
‡
‡
TOF-MS: 224.0890 (C9H15NO4Na , [M ‡ Na] ; calc. 224.0899).
(3S,4S)-1-Methylpyrrolidine-3,4-diol (9c). To a soln. of 13 (0.28 g, 0.81 mmol) in THF (5ml), Bu 4NF ´ H2O
(0.25g, 0.81 mmol) was added. The mixture was stirred at 20 8 for 3 h (TLC control), the solvent evaporated,
and the crude product separated by FC (CH2Cl2/MeOH/30% aq. NH3 soln. 30 :19 :1): 0.086 g (ca. 90%) of 9c.
Acetylation of crude 9c (Ac2O/pyridine 2 :1, 208, 1 h; 82% yield) and deacetylation (Na/MeOH, 08, 15min;
25
25
25
25
yield 95%) gave pure 9c. White solid. M.p. 55 ± 578. [a] ˆ ‡22, [a] ˆ ‡25, [a] ˆ ‡46, [a] ˆ ‡5 4 (c ˆ
589
577
535
405
1
0.28, MeOH). IR (KBr): 3367, 2940, 1595, 1471, 1340, 1280, 1079, 998, 851, 674. H-NMR (400 MHz, CDCl3):
4.14 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.2, HÀC(3), HÀC(4)); 3.00 (dd, 2J ˆ 10.4, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.9,
HbÀC(2), HbÀC(5)); 2.53 (dd, 2J ˆ 10.4, 3J(2a,3) ˆ 3J(5a,4) ˆ 3.6, HaÀC(2), HaÀC(5); 2.36 (s, MeÀC(1)).
13C-NMR (100.6 MHz, CDCl3): 78.9 (d, 1J(C,H) ˆ 148, C(3), C(4)); 62.5( t, 1J(C,H) ˆ 138, C(2), C(5)); 42.4
(q, 1J(C,H) ˆ 134, MeÀC(1)). CI-MS (NH3): 118 (91, [M ‡ H] ), 117 (100, M ), 116 (11), 100 (10), 97 (8), 85
‡
‡
‡
‡
(24), 83 (37), 73 (7), 70 (6). HR-MALDI-TOF-MS: 118.5853 (C5H12NO2 , [M ‡ H] ; calc. 118.0868).
(3S,4S)-N-Alkylpyrrolidine-3,4-diols 9d ± f by Method A: General Procedure. A soln. of 9a (0.43 g,
2.22 mmol) in bromoethane (6 ml) (or PrBr, BuBr) was heated under reflux for 6 h. After evaporation, the
residue was dissolved in MeOH (10 ml) and stirred under H2 for 5days in the presence of 20% Pd(OH) 2/C
(0.27 g). The mixture was then filtered through Celite, the filtrate evaporated, and the residue purified by FC
(CH2Cl2/MeOH/30% NH3 aq. soln. 38 :11:1).
25
(3S,4S)-1-Ethylpyrrolidine-3,4-diol (9d). By Method A: 0.104 g (36%) of 9d. White solid. [a] ˆ ‡23,
589
25
25
25
[a] ˆ ‡23, [a] ˆ ‡43, [a] ˆ ‡5 1 c(ˆ 0.52, MeOH). ([13]: [a]2D6 ˆ ‡36.5( c ˆ 0.43, MeOH). HR-
577
535
405
‡
‡
MALDI-TOF-MS: 132.1034 (C6H14NO2 , [M ‡ H] ; calc. 132.1025).
(3S,4S)-N-Alkylpyrrolidine-3,4-diols 9e and 9f by Method B: General Procedure. Propanamine (0.38 ml,
4.58 mmol) and 1,4-di-O-tosyl-l-treitol 19 (0.7 g, 1.15mmol) were reacted in 1,4-dioxane (4 ml) under reflux
and stirring for ca. 14 h, under Ar (TLC control). The mixture was evaporated. The crude product was washed
with H2O and extracted with CHCl3 (3Â). The residue was purified by FC (25± 40% AcOEt/hexane): 0.34 g
(92%) of 20e as pale yellow oil. The oil 20e (0.275g, 0.84 mmol) was dissolved in MeOH/AcOEt 1:1 (15ml)
and stirred under H2 for ca. 2 days (TLC control) in the presence of 20% Pd(OH)2/C (0.1 g). The soln. was
filtered through a pad of Celite, the filtrate evaporated, and the residue purified by FC (CH2Cl2/MeOH/30% aq.
NH3 soln.): 38 :11:1): 0.1 g (82%) of 9e. White solid.

3176
Helvetica Chimica Acta ± Vol. 87 (2004)
25
25
25
25
(3S,4S)-3,4-Bis(benzyloxy)-1-propylpyrrolidine (20e). [a] ˆ ‡24, [a] ˆ ‡27, [a] ˆ ‡28, [a]
ˆ
589
577
546
535
25
‡47, [a] ˆ ‡5 2 (c ˆ 0.41, CHCl3). IR (film) 3030, 2958, 2931, 2874, 2791, 1497, 1454, 1334, 1111, 1028, 735,
405
697. UV (MeCN): 217 (5382), 206 (4733), 189 (833). 1H-NMR (400 MHz, CDCl3): 7.38 ± 7.26 (m, 10 arom. H);
4.55 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.51 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.07 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.7,
HÀC(3), HÀC(4)); 2.91 (dd, 2J ˆ 10.0, 3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5)); 2.61 (dd, 2J ˆ 10.0,
3J(2a,3) ˆ 3J(5a,4) ˆ 4.0, HaÀC(2), HaÀC(5)); 2.47 ± 2.32 (m, 2 HÀC(1')); 1.53 (sext., 3J(2',1') ˆ 3J(2',3') ˆ 7.4,
2 HÀC(2')); 0.92 (t, 3J(3',2') ˆ 7.3, Me(3')). 13C-NMR (100.6 MHz, CDCl3): 138.2 (s, 2 arom. C); 128.4
(d, 1J(C,H) ˆ 160, 4 arom. C); 127.8 (d, 1J(C,H) ˆ 159, 4 arom. C); 127.7 (d, 1J(C,H) ˆ 159, 2 arom. C); 83.5
(d, 1J(C,H) ˆ 146, C(3), C(4)); 71.4 (t, 1J(C,H) ˆ 141, 2 PhCH2O); 58.7 (t, 1J(C,H) ˆ 141, C(2), C(5)); 58.5
(t, 1J(C,H) ˆ 130, C(1')); 21.5( t, 1J(C,H) ˆ 130, C(2')); 12.00 (q, 1J(C,H) ˆ 125, C(3')). CI-MS (NH3): 326 (100,
‡
[M ‡ H] ), 296 (11), 219 (6), 112 (10), 108 (5), 91 (38), 84 (7), 72 (13). HR-MALDI-TOF-MS: 326.0772
‡
‡
(C21H28NO2 , [M ‡ H] ; calc. 326.2120).
(3S,4S)-1-Propylpyrrolidine-3,4-diol (9e). By Method A 37% and by Method B 82% of 9e. White solid.
25
25
25
25
25
M.p. 72 ± 758. [a] ˆ ‡5 , a[ ] ˆ ‡7, [a] ˆ ‡6, [a] ˆ ‡6, [a] ˆ ‡8 (c ˆ 0.32, CHCl3). IR (KBr) 3308,
589
577
546
535
405
2972, 2720, 1635, 1437, 1337, 1227, 1085, 1019, 975, 752. 1H-NMR (400 MHz, CDCl3): 4.15( t, 3J(2,3) ˆ 3J(3,4) ˆ
3J(4,5) ˆ 4.4, HÀC(3), HÀC(4)); 3.00 (dd, 2J ˆ 10.3, 3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5)); 2.55
(dd, 2J ˆ 10.3, J(2a,3) ˆ 3J(5a,4) ˆ 3.8, HaÀC(2), HaÀC(5)); 2.50 ± 2.35 ( m, 2 HÀC(1')); 1.52 (sext., J(2',1') ˆ
3J(2',3') ˆ 7.4, 2 HÀC(2')); 0.90 (t, 3J(3',2') ˆ 7.3, Me(3')). 13C-NMR (100.6 MHz, CDCl3): 78.2 (d, 1J(C,H) ˆ 148,
C(3), C(4)); 60.5( t, 1J(C,H) ˆ 138, C(2), C(5)); 58.7 (t, 1J(C,H) ˆ 130, C(1')); 21.0 (t, 1J(C,H) ˆ 126, C(2')); 11.9
3
3
(q, 1J(C,H) ˆ 125, C(3')). CI-MS (NH3): 146 (100, [M ‡ H] ), 145(4, M ), 116 (35), 84 (3), 72 (3). HR-
‡
‡
‡
‡
MALDI-TOF-MS: 146.1167 (C7H16NO2 , [M ‡ H] ; calc. 146.1181). Anal. calc. for C7H15NO2 (145.110):
C 57.90, H 10.41, N 9.65; found: C 58.17, H 10.26, N 9.64.
(3S,4S)-3,4-Bis(benzyloxy)-1-butylpyrrolidine (20f). By Method B, after FC (AcOEt/hexane 1:4): 20f
25
25
25
25
25
(92%). Pale yellow oil. [a] ˆ ‡23, [a] ˆ ‡24, [a] ˆ ‡29, [a] ˆ ‡48, [a] ˆ ‡5 8 (c ˆ 0.32, CHCl3). IR
589
577
546
535
405
(film) 3031, 2955, 2928, 2861, 2791, 1497, 1455, 1334, 1111, 1028, 735, 697. UV (MeCN): 215 (5218), 200 (3762),
189 (639). 1H-NMR (400 MHz, CDCl3): 7.37 ± 7.27 (m, 10 arom. H); 4.55 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.51
(br. d, 3J ˆ 11.9, 1 PhCH2O); 4.06 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.6, HÀC(3), HÀC(4)); 2.91 (dd, 2J ˆ 10.0,
3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5); 2.62 (dd, 2J ˆ 10.0, 3J(2a,3) ˆ 3J(5a,4) ˆ 4.0, HaÀC(2), HaÀC(5));
2.51 ± 2.35 (m, 2 HÀC(1')); 1.54 ± 1.44 (m, 2 HÀC(2')); 1.34 (sext., 3J(3',2') ˆ 3J(3',4') ˆ 7.4, 2 HÀC(3')); 0.92
(t, 3J(4',3') ˆ 7.3, Me(4')). 13C-NMR (100.6 MHz, CDCl3): 138.1 (s, 2 arom. C); 128.4 (d, 1J(C,H) ˆ 160,
4 arom. C); 127.8 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.7 (d, 1J(C,H) ˆ 160, 2 arom. C); 83.4 (d, 1J(C,H) ˆ 147,
C(3), C(4)); 71.4 (t, 1J(C,H) ˆ 141, 2 PhCH2O); 58.7 (t, 1J(C,H) ˆ 137, C(2), C(5)); 56.4 (t, 1J(C,H) ˆ 131,
C(1')); 30.4 (t, 1J(C,H) ˆ 121, C(2')); 20.7 (t, 1J(C,H) ˆ 121, C(3')); 14.0 (q, 1J(C,H) ˆ 125, C(4')). CI-MS (NH3):
‡
340 (100, [M ‡ H] ), 296 (13), 248 (3), 233 (5), 126 (12), 108 (6), 91 (37), 98 (4), 86 (13), 82 (2). HR-MALDI-
‡
‡
TOF-MS: 340.2256 (C22H30NO2 , [M ‡ H] ; calc. 340.2277).
(3R,4R)-1-Butyl-3,4-dihydroxypyrrolidine-2,5-dione. (‡)-(2R,3R)-Tartaric acid (20 g, 133.2 mmol) was
added to xylene (mixture of isomers, Fluka; 120 ml) in a flask fitted with a water separator and condensor. To
the vigorously stirred and refluxing xylene soln. was added butanamine (13.4 ml, 133.25mmol) within 20 min.
Heating under reflux was continued for ca. 4 h. The soln. was cooled in an ice bath, and the crystalline product
was filtered off and washed with cold hexane (3Â). Recrystallization from AcOEt gave 14.9 g (60%) of the
25
25
25
pyrrolidinedione. Pale yellow powder. M.p. 118 ± 1208 (from AcOEt). [a] ˆ ‡111, [a] ˆ ‡118, [a]
ˆ
589
577
546
25
25
‡135, [a] ˆ ‡226, [a] ˆ ‡236 (c ˆ 1.25, MeOH). UV (MeOH): 216 (1739). IR (film): 3412, 2957, 2874,
535
405
1786, 1680, 1450, 1403, 1340, 1194, 1091, 995, 819, 650. 1H-NMR (400 MHz, CDCl3): 4.41 (br. s, HÀC(3),
HÀC(4)); 3.58 ± 3.45 (m, 2 HÀC(1')); 1.58 (quint., 3J(2',1') ˆ 3J(2',3') ˆ 7.3, 2 HÀC(2')); 1.34 (sext., 3J(3',2') ˆ
3J(3',4') ˆ 7.4, 2 HÀC(3')); 0.96 (t, 3J(4',3') ˆ 7.3, Me(4')). 13C-NMR (100.6 MHz, CDCl3): 176.1 (s, C(3), C(4));
76.1 (t, 1J(C,H) ˆ 145, C(2), C(5)); 39.2 (t, 1J(C,H) ˆ 141, C(1')); 30.7 (t, 1J(C,H) ˆ 127, C(2')); 20.9 (t, 1J(C,H) ˆ
121, C(3')); 13.9 (q, 1J(C,H) ˆ 125, C(4')). CI-MS (NH3): 187 (100, [M ‡ H] ), 176 (2), 164 (4), 146 (2), 108 (4),
‡
‡
‡
105(2), 91 (27), 71 (2). HR-MALDI-TOF-MS: 226.0485(C 8H13KNO4 , [M ‡ K] ; calc. 226.0482).
(3S,4S)-1-Butylpyrrolidine-3,4-diol (9f). By Method A, after FC (CH2Cl2/MeOH/30% aq. NH3 soln.
25
25
30 :19 :1): 9f (37%). White solid. Method B, from 20f: 9f (82%). White solid. M.p. 35± 37 8. [a] ˆ ‡5 , [a]
ˆ
589
577
25
25
25
‡5 , [a] ˆ ‡8, [a] ˆ ‡10, [a] ˆ ‡10 (c ˆ 0.5, CHCl3). IR (film) 3358, 3125, 2957, 2810, 1474, 1391, 1335,
546
535
405
1278, 1150, 1094, 1031, 848. 1H-NMR (400 MHz, CDCl3): 4.14 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.4, HÀC(3),
HÀC(4)); 2.99 (dd, 2J ˆ 10.2, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.9, HbÀC(2), HbÀC(5)); 2.51 (dd, 2J ˆ 10.2, 3J(2a,3) ˆ
3J(5a,4) ˆ 3.6, HaÀC(2), HaÀC(5)); 2.51 ± 2.39 (m, 2 HÀC(1')); 1.52 ± 1.44 (m, 2 HÀC(2')); 1.33
(sext., 3J(3',2') ˆ 3J(3',4') ˆ 7.3, 2 HÀC(3')); 0.93 (t, 3J(4',3') ˆ 7.3, Me(4')). 13C-NMR (100.6 MHz, CDCl3): 77.7
(d, 1J(C,H) ˆ 150, C(3), C(4)); 60.4 (t, 1J(C,H) ˆ 138, C(2), C(5)); 56.5 (t, 1J(C,H) ˆ 132, C(1')); 29.8

Helvetica Chimica Acta ± Vol. 87 (2004)
3177
(t, 1J(C,H) ˆ 124, C(2')); 20.6 (t, 1J(C,H) ˆ 124, C(3')); 13.9 (q, 1J(C,H) ˆ 125, C(4')). CI-MS (NH3): 160 (100,
‡
‡
‡
[M ‡ H] ), 159 (5, M ), 117 (5), 116 (57), 98 (3), 86 (4). HR-MALDI-TOF-MS: 160.1339 (C8H18NO2 , [M ‡
‡
H] ; calc. 160.1338). Anal. calc. for C8H17NO2 (159.126): C 60.35, H 10.76, N 8.80; found: C 60.76, H 10.68,
N 8.60.
(3S,4S)-3,4-Bis(benzyloxy)pyrrolidine-1-ethanamine (20g). By Method B, after FC (MeOH/CHCl3/30%
25
25
25
25
aq. NH3 soln. 95:5:2): 20g (85%). Pale yellow oil. [a] ˆ ‡25, [a] ˆ ‡26, [a] ˆ ‡28, [a] ˆ ‡46,
589
577
546
535
25
[a] ˆ ‡5 4 (c ˆ 0.78, CHCl3). UV (MeCN): 260 (522), 215 (6308), 190 (1110). IR (film): 3366, 3030, 2928,
405
2797, 1586, 1496, 1454, 1334, 1206, 1104, 1028, 737, 698. 1H-NMR (400 MHz, CDCl3): 7.14 ± 7.04 (m, 10 arom. H);
4.31 (br. d, 3J ˆ 12.6, 1 PhCH2O); 4.27 (br. d, 3J ˆ 11.9, 1 PhCH2O); 3.83 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.7,
HÀC(3), HÀC(4)); 2.68 (dd, 2J ˆ 9.9, 3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5)); 2.55 (t, 3J(a,b) ˆ 6.2,
2 HÀC(a)); 2.38 (dd, 2J ˆ 9.9, 3J(2a,3) ˆ 3J(5a,4) ˆ 4.0, HaÀC(2), HaÀC(5)); 2.35± 2.21 (m, 2 HÀC(b)); 1.49
(br. s, NH2). 13C-NMR (100.6 MHz, CDCl3): 138.0 (s, 2 arom. C); 128.4 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.8
(d, 1J(C,H) ˆ 160, 4 arom. C); 127.7 (d, 1J(C,H) ˆ 159, 2 arom. C); 83.5 (d, 1J(C,H) ˆ 146, C(3), C(4)); 71.5
(t, 1J(C,H) ˆ 141, 2 PhCH2O); 59.2 (t, 1J(C,H) ˆ 131, C(b)); 58.7 (t, 1J(C,H) ˆ 137, C(2), C(5)); 40.3
‡
(t, 1J(C,H) ˆ 134, C(a)). CI-MS (NH3): 327 (100, [M ‡ H] ), 297 (8), 296 (29), 237 (2), 112 (2), 108 (6), 91
‡
‡
(27), 82 (3). HR-MALDI-TOF-MS: 327.2079 (C20H27N2O2 , [M ‡ H] ; calc. 327.2073).
(3S,4S)-3,4-Bis(benzyloxy)-N-ethylpyrrolidine-1-ethanamine (20h). FC (MeOH/CH2Cl2/30% aq. NH3 soln.
25
25
25
25
25
30 :19 :1) gave 20h (45%). Pale yellow oil. [a] ˆ ‡27, [a] ˆ ‡27, [a] ˆ ‡29, [a] ˆ ‡48, [a] ˆ ‡57
589
577
546
535
405
(c ˆ 0.48, CHCl3). UV (MeCN): 217 (5100), 201 (3829), 187 (504). IR (film): 3312, 3030, 2928, 2890, 2805, 1496,
1454, 1334, 1205, 1114, 1028, 737, 698. 1H-NMR (400 MHz, CDCl3): 7.37 ± 7.27 (m, 10 arom. H); 4.54 (br. d, 3J ˆ
12.1, 1 PhCH2O); 4.50 (br. d, 3J ˆ 12.1, 1 PhCH2O); 4.06 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.7, HÀC(3), HÀC(4));
2.92(dd, 2J ˆ 9.7,3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5));2.73 ± 2.52(m, HaÀC(2),HaÀC(5), 2 HÀC(a)),
2 HÀC(b), MeCH2); 2.00 (br. s, NH); 1.12 (t, 3J ˆ 7.2, MeCH2). 13C-NMR (100.6 MHz, CDCl3): 138.0
(s, 2 arom. C); 128.4 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.8 (d, 1J(C,H) ˆ 160, arom. C); 127.7 (d, 1J(C,H) ˆ 158,
arom. C); 83.5( d, 1J(C,H) ˆ 147, C(3), C(4)); 71.5( t, 1J(C,H) ˆ 141, 2 PhCH2O); 58.7 (t, 1J(C,H) ˆ 137, C(2),
C(5)); 55.9 (t, 1J(C,H) ˆ 131, C(b)); 47.7 (t, 1J(C,H) ˆ 132, C(a)); 44.2 (t, 1J(C,H) ˆ 133, MeCH2); 15.2
‡
(q, 1J(C,H) ˆ 126, MeCH2). CI-MS (NH3): 355 (3, [M ‡ H] ), 298 (2), 297 (17), 296 (68), 160 (3), 138 (3), 105
‡
‡
(2), 91 (100), 84 (6), 82 (5), 72 (3). HR-MALDI-TOF-MS: 355.2381 (C22H31N2O2 , [M ‡ H] ; calc. 355.2386).
Anal. calc. for C22H30N2O2 (354.231): C 74.54, H 8.53, N 7.90; found: C 74.55, H 8.60, N 7.80.
(3S,4S)-3,4-Bis(benzyloxy)-N,N-dimethylpyrrolidine-1-ethanamine (20i). FC (CH2Cl2/MeOH/30% aq.
25
25
25
25
NH3 soln. 90 :9 :1) gave 20i (87%). Pale yellow oil. [a] ˆ ‡19, [a] ˆ ‡20, [a] ˆ ‡22, [a] ˆ ‡36,
589
577
546
535
25
[a] ˆ ‡44 (c ˆ 56, CHCl3). UV (MeCN): 260 (470), 217 (5470), 203 (4385), 187 (612). IR (film): 2942, 2814,
405
2769, 1496, 1455, 1336, 1264, 1205, 1153, 1099, 736, 698. 1H-NMR (400 MHz, CDCl3): 7.37 ± 7.27 (m, 10 arom. H);
4.53 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.50 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.05( t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.4,
HÀC(3), HÀC(4)); 2.94 (dd, 2J ˆ 9.8, 3J(2a,3) ˆ 3J(5a,4) ˆ 6.0, HbÀC(2), HbÀC(5); 2.69 ± 2.45 (m, 2 HÀC(a),
2 HÀC(b)); 2.63 (dd, 2J ˆ 9.8, 3J(2b,3) ˆ 3J(5b,4)ˆ 4.1, HaÀC(2), HaÀC(5)); 2.29 (br. s, 2 MeN). 13C-NMR
(100.6 MHz, CDCl3): 138.0 (s, 2 arom. C), 128.4 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.8 (d, 1J(C,H) ˆ 160,
4 arom. C); 127.7 (d, 1J(C,H) ˆ 159, 2 arom. C); 83.3 (d, 1J(C,H) ˆ 146, C(3), C(4)); 71.5( t, 1J(C,H) ˆ 141,
2 PhCH2O); 59.00 (t, 1J(C,H) ˆ 137, C(2), C(5)); 57.7, 54.1 (2t, 1J(C,H) ꢀ 134, C(a), C(b)); 45.7 (q, 1J(C,H) ˆ
‡
133, 2 MeN). CI-MS (NH3): 355 (100, [M ‡ H] ), 297 (4), 296 (15), 244 (2), 243 (11), 108 (3), 91 (12), 72 (2).
‡
‡
HR-MALDI-TOF-MS: 355.2336 (C22H31N2O2 , [M ‡ H] ; calc. 355.2386). Anal. calc. for C22H30N2O2 (354.231):
C 74.54, H 8.53, N 7.90; found: 74.48, H 8.51, N 7.88.
(3S,4S)-3,4-Bis(benzyloxy)pyrrolidine-1-propanamine (20j). By Method B, after FC (MeOH/CHCl3/30%
25
25
25
25
aq. NH3 soln. 95:5:2): 20j (81%). Pale yellow oil. [a] ˆ ‡23, [a] ˆ ‡27, [a] ˆ ‡26, [a] ˆ ‡42,
589
577
546
535
25
[a] ˆ ‡5 2 (c ˆ 0.52, CHCl3). UV (MeCN): 260 (448), 216 (4589), 199 (3207), 188 (521). IR (film): 3362,
405
3030, 2931, 2796, 1586, 1496, 1454, 1391, 1335, 1309, 1205, 1103, 1028, 847, 737, 698. 1H-NMR (400 MHz, CDCl3):
7.38 ± 7.27 (m, 10 arom. H); 4.54 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.50 (br. d, 3J ˆ 11.9, 1 PhCH2O); 4.05( t, 3J(2,3) ˆ
3J(3,4) ˆ 3J(4,5) ˆ 4.6, HÀC(3), HÀC(4)); 2.90 (dd, 2J ˆ 9.9, 3J(2b,3) ˆ 3J(5b,4)ˆ 6.0, HbÀC(2), HbÀC(5));
2.75( t, 3J(a,b) ˆ 6.7, 2 HÀC(a)); 2.60 (dd, 2J ˆ 9.9, 3J(2a,3) ˆ 3J(5a,4) ˆ 4.1, HaÀC(2), HaÀC(5)); 2.54 ± 2.41
(m, 2 HÀC(g)); 1.65( quint., 3J(b,g) ˆ 3J(b,a) ˆ 7.1, 2 H ÀC(b)); 1.51 (br. s, NH2). 13C-NMR (100.6 MHz,
CDCl3): 138.1 (s, 2 arom. C); 128.4 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.8 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.7
(d, 1J(C,H) ˆ 159, 2 arom. C); 83.5 (d, 1J(C,H) ˆ 147, C(3), C(4)); 71.4 (t, 1J(C,H) ˆ 141, 2 PhCH2O); 58.8
(t, 1J(C,H) ˆ 137, C(2), C(5)); 54.2 (t, 1J(C,H) ˆ 130, C(g)); 40.7 (t, 1J(C,H) ˆ 136, C(a)); 32.0 (t, 1J(C,H) ˆ 125,
‡
‡
C(b)). CI-MS (NH3): 341 (100, [M ‡ H] ), 340 (2, M ), 296 (2), 284 (3), 125(4), 124 (7), 108 (5), 91 (19), 82
‡
‡
(3), 81 (11). HR-MALDI-TOF-MS: 341.2226 (C21H29N2O2 , [M ‡ H] ; calc. 341.2229). Anal. calc. for
C21H28N2O2 (340.459): C 74.08, H 8.29; found: C 73.88, H 8.01.

3178
Helvetica Chimica Acta ± Vol. 87 (2004)
(3S,4S)-1-(2-Aminoethyl)pyrrolidine-3,4-diol (9g). By Method B, after FC (MeOH/CHCl3/30% aq. NH3
25
25
25
25
25
soln. 20 :3 :2): 9g (85%). Colorless oil. [a] ˆ ‡30, [a] ˆ ‡32, [a] ˆ ‡37, [a] ˆ ‡59, [a] ˆ ‡67 (c ˆ
589
577
546
535
405
0.52, MeOH). IR (film): 3343, 2938, 1578, 1474, 1333, 1237, 1150, 1093, 1043, 874. 1H-NMR (400 MHz, CD3OD):
4.05( t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.8, HÀC(3), HÀC(4)); 2.97 (dd, 2J ˆ 10.1, 3J(2b,3) ˆ 3J(5b,4) ˆ 5.5,
HbÀC(2), HbÀC(5)); 2.77 (t, 3J(2',1') ˆ 6.3, 2 HÀC(2')); 2.67 ± 2.53 (m, 2 HÀC(1')); 2.51 (dd, 2J ˆ 10.1,
3J(2a,3) ˆ 3J(5a,4) ˆ 3.1, HaÀC(2), HaÀC(5)). 13C-NMR (100.6 MHz, CD3OD): 79.0 (d, 1J(C,H) ˆ 148, C(3),
C(4)); 61.6 (t, 1J(C,H) ˆ 137, C(2), C(5)); 59.0 (t, 1J(C,H) ˆ 131, C(1')); 40.5( t, 1J(C,H) ˆ 136, C(2')). CI-MS
‡
‡
(NH3): 147 (100, [M ‡ H] ), 146 (3, M ), 145(17), 127 (2), 121 (2), 116 (20), 104 (20), 85(2), 75(4). HR-
‡
‡
MALDI-TOF-MS: 147.1934 (C6H15N2O2 , [M ‡ H] ; calc. 147.1134). Anal. calc. for C6H14N2O2 (146.188):
C 49.30, H 9.65; found: C 49.43, H 9.26.
(3S,4S)-1-[(2-Ethylamino)ethyl]pyrrolidine-3,4-diol (9h). By Method B, after FC (MeOH/CH2Cl2/30% aq.
25
25
25
25
25
NH3 soln. 30 :19 :1): 9h (88%). Pale yellow oil. [a] ˆ ‡15, [a] ˆ ‡18, [a] ˆ ‡23, [a] ˆ ‡31, [a]
ˆ
589
577
546
535
405
‡48 (c ˆ 0.38, MeOH). IR (film): 3283, 2930, 2815, 1668, 1471, 1454, 1332, 1119, 1093, 1041, 844. 1H-NMR
(400 MHz, CD3OD): 4.05( t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.9, HÀC(3), HÀC(4)); 2.98 (dd, 2J ˆ 10.1, J(2b,3) ˆ
3
3J(5b,4)ˆ 5.4, HbÀC(2), HbÀC(5)); 2.80 ± 2.61 (m, 2 HÀC(1'), 2 HÀC(2'), 2 HÀC(1'')); 2.52 (dd, 2J ˆ 10.1,
3J(2a,3) ˆ 3J(5a,4) ˆ 3.2, HaÀC(2), HaÀC(5)); 1.19 (t, 3J(2'',1'') ˆ 7.2, Me(2'')). 13C-NMR (100.6 MHz, CD3OD):
79.0 (d, 1J(C,H) ˆ 149, C(3), C(4)); 61.5( t, 1J(C,H) ˆ 137, C(2), C(5)); 55.5 (t, 1J(C,H) ˆ 133, C(1')); 47.9
(t, 1J(C,H) ˆ 137, C(2')); 44.5( t, 1J(C,H) ˆ 136, C(1'')); 14.0 (q, 1J(C,H) ˆ 126, C(2'')). CI-MS (NH3): 175(2,
‡
[M ‡ H] ), 130 (6), 117 (13), 116 (100), 99 (6), 98 (3), 82 (2), 72 (7). HR-MALDI-TOF-MS: 175.1417
‡
‡
(C8H19N2O2 , [M ‡ H] ; calc. 175.1447).
(3S,4S)-1-[2-(Dimethylamino)ethyl]pyrrolidine-3,4-diol (9i). By Method B (89%), after FC (CH2Cl2/
25
25
MeOH/30% aq. NH3 soln. 30 :9 :1): 9i (87%). White crystals. M.p. 63 ± 658 (from THF): [a] ˆ ‡4, [a]
ˆ
589
577
25
25
25
‡6, [a] ˆ ‡5 , [a] ˆ ‡7, [a] ˆ ‡13 (c ˆ 0.9, CHCl3) ([24]: [a]D ˆ ‡2.9 (c ˆ 0.90, CHCl3). IR (KBr): 3332,
546
535
405
2953, 2815, 1466, 1313, 1039, 850, 686. 1H-NMR (400 MHz, CDCl3): 4.03 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.7,
HÀC(3), HÀC(4)); 2.99 (dd, 2J ˆ 10.0, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.5, HbÀC(2), HbÀC(5); 2.77 ± 2.49 (m, HaÀC(2),
HaÀC(5), 2 HÀC(1'), 2 HÀC(2')); 2.21 (br. s, 2 MeN). 13C-NMR (100.6 MHz, CDCl3): 79.0 (d, 1J(C,H) ˆ 148,
C(3), C(4)); 61.7 (t, 1J(C,H) ˆ 137, C(2), C(5)); 58.4, 54.9 (2t, 1J(C,H) ꢀ 133, C(1'), C(2')); 45.7 (q, 1J(C,H) ˆ
‡
134, 2 MeN). CI-MS (NH3): 175(2, [ M ‡ H] ), 130 (3), 117 (12), 116 (100), 98 (2), 72 (9), 70 (3). HR-MALDI-
‡
‡
TOF-MS. 175.2410 (C8H19O2O2 , [M ‡ H] ; calc. 175.1447).
(3S,4S)-1-(3-Aminopropyl)pyrrolidine-3,4-diol (9j). By Method B, after FC (MeOH/CHCl3/30% aq. NH3
25
25
25
25
25
soln. 20 :3 :2): 9j (84%). Pale yellow oil. [a] ˆ ‡27, [a] ˆ ‡22, [a] ˆ ‡28, [a] ˆ ‡48, [a] ˆ ‡55 (c ˆ
589
577
546
535
405
0.52, MeOH). IR (film): 3346, 3288, 2933, 2807, 1599, 1470, 1453, 1392, 1334, 1149, 1093, 1044. 1H-NMR
(400 MHz, CD3OD): 4.05( t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 4.0, HÀC(3), HÀC(4)); 2.95( dd, 2J ˆ 10.0, J(2b,3) ˆ
3
3J(5b,4)ˆ 5.6, HbÀC(2), HbÀC(5)); 2.70 (t, 3J(3',2') ˆ 7.0, 2 HÀC(3')); 2.56 ± 2.45 (m, HaÀC(2), HaÀC(5),
2 HÀC(1')); 1.68 (sext., 3J(2',1') ˆ 3J(2',3') ˆ 7.2, 2 H ÀC(2')). 13C-NMR (100.6 MHz, CD3OD): 78.9
(d, 1J(C,H) ˆ 148, C(3), C(4)); 61.7 (t, 1J(C,H) ˆ 137, C(2), C(5)); 55.7 (t, 1J(C,H) ˆ 132, C(1')); 41.0
(t, 1J(C,H) ˆ 134, C(3')); 32.2 (t, 1J(C,H) ˆ 126, C(2')). CI-MS (NH3): 161 (6, [M ‡ H] ), 144 (4), 117 (13),
‡
116 (100), 104 (9), 99 (5), 98 (7), 94 (4), 87 (4), 82 (10), 81 (72), 80 (4),70 (8). HR-MALDI-TOF-MS: 161.1204
‡
‡
(C7H17N2O2 , [M ‡ H] ; calc. 161.1212). Anal. calc. for C7H16N2O2 (160.121): C 52.48, H 10.07, N 17.49; found:
52.98, H 10.16, N 17.67.
Reductive Aminations with 9g and 9j: General Procedure. NaBH(OAc)3 (1.4 equiv.) was added portionwise
to a stirred soln. of 9g or 9j (0.4 mmol) and an appropriate aldehyde (0.4 mmol; PhCHO (21), 4-PhC6H4CHO
(22), 4-ClC6H4CHO (23)) in abs. MeOH (2 ml) at 208. After complete disappearance of 9g or 9j (TLC control),
the solvent was evaporated and the residue subjected to FC (hexane/AcOEt 3 :7, then pure AcOEt, then
MeOH/CH2Cl2/30% aq. NH3 soln. 30 :19 :1).
25
25
25
(3S,4S)-1-[2-(Benzylamino)ethyl]pyrrolidine-3,4-diol (9k). Oil (73%). [a] ˆ ‡15, [a] ˆ ‡15, [a]
ˆ
589
577
535
25
‡29, [a] ˆ ‡34 (c ˆ 0.27, MeOH). IR (KBr): 3328, 2929, 2826, 1566, 1470, 1453, 1407, 1334, 1150, 1098, 749.
405
UV (MeOH): 260 (282), 216 (3008), 212 (2657). 1H-NMR (400 MHz, CD3OD): 7.39 ± 7.27 (m, 5arom. H); 4.02
(t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.7, HÀC(3), HÀC(4)); 3.83 (br. s, PhCH2N); 2.94 (dd, 2J ˆ 10.1, 3J(2b,3) ˆ
3J(5b,4)ˆ 5.4, HbÀC(2), HbÀC(5)); 2.77 ± 2.53 ( m, 2 HÀC(2'), 2 HÀC(1')); 2.94 (dd, 2J ˆ 10.1, 3J(2a,3) ˆ
3J(5a,4) ˆ 3.3, HaÀC(2), HaÀC(5)). 13C-NMR (100.6 MHz, CD3OD): 139.6 (s, 1 arom. C); 129.7
(d, 1J(C,H) ˆ 158, 1 arom. C; 129.6 (d, 1J(C,H) ˆ 160, 2 arom. C); 128.5( d, 1J(C,H) ˆ 160, 2 arom. C); 78.8
(d, 1J(C,H) ˆ 149, C(3), C(4)); 61.4 (t, 1J(C,H) ˆ 137, C(2), C(5 )); 5 5 t.8, 1J((C,H) ˆ 134, C(1')); 54.0
(t, 1J(C,H) ˆ 135, PhCH2N); 47.4 (t, 1J(C,H) ˆ 136, C(2')). CI-MS (NH3): 219 (1), 133 (2), 120 (26), 117 (99),
116 (100), 106 (9), 99 (20), 91 (82), 89 (6), 83 (9), 79 (4), 70 (4). HR-MALDI-TOF-MS: 259.1428
‡
‡
(C13H20N2NaO2 , [M ‡ Na] ; calc. 259.1422).

Helvetica Chimica Acta ± Vol. 87 (2004)
3179
25
(3S,4S)-1-{2-[([1,1'-Biphenyl-4-yl]methyl)amino]ethyl}pyrrolidine-3,4-diol (9l). Oil (73%). [a] ˆ ‡7,
589
25
25
25
[a] ˆ ‡8, [a] ˆ ‡12, [a] ˆ ‡12 (c ˆ 0.27, MeOH). IR (KBr): 3355, 2934, 2818, 1570, 1487, 1411, 1338,
577
535
405
1
1154, 1093, 763. UV (MeOH): 272 (5682), 218 (4704), 214 (4358), 199 (943). H-NMR (400 MHz, CD3OD):
7.71 ± 7.63 (m, 4 arom. H); 7.56 (m, 2 arom. H); 7.49 ± 7.45( m, 2 arom. H); 7.39 ± 7.35( m, 1 arom. H); 4.13 (br. s,
ArCH2N); 4.05( m, HÀC(3), HÀC(4)); 3.07 (dd, 2J ˆ 10.3, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.0, HbÀC(2), HbÀC(5)); 3.03
(t, 3J(2',1') ˆ 6.1, 2 HÀC(2')); 2.92 ± 2.81 (m, 2 HÀC(1')); 2.61 (dd, 2J ˆ 10.3, 3J(2a,3) ˆ 3J(5a,4) ˆ 2.7, HaÀC(2),
HaÀC(5)). 13C-NMR (100.6 MHz, CD3OD): 142.8 (s, 1 arom. C); 141.6 (s, 1 arom. C); 134.7 (s, 1 arom. C);
131.0 (d, 1J(C,H) ˆ 159, 2 arom. C); 129.9 (d, 1J(C,H) ˆ 161, 2 arom. C); 128.7 (d, 1J(C,H) ˆ 161, 1 arom. C);
128.5( d, 1J(C,H) ˆ 160, 2 arom. C); 128.0 (d, 1J(C,H) ˆ 159, 2 arom. C); 78.8 (d, 1J(C,H) ˆ 151, C(3), C(4));
61.4 (t, 1J(C,H) ˆ 139, C(2), C(5)); 55.8 (t, 1J(C,H) ˆ 135, C(1')); 54.0 (t, 1J(C,H) ˆ 140, ArCH2N); 47.4
(t, 1J(C,H) ˆ 140, C(2')). CI-MS (NH3): 250 (1), 197 (7), 182 (16), 167 (88), 164 (8), 153 (23), 141 (2), 139 (5),
129 (7), 117 (90), 116 (100), 107 (12), 99 (20), 91 (12), 83 (15), 80 (10), 70 (9). HR-MALDI-TOF-MS: 335.1709
‡
‡
(C19H24N2NaO2 , [M ‡ Na] ; calc. 335.1735).
25
25
(3S,4S)-1-{2-[(4-Chlorobenzyl)amino]ethyl}pyrrolidine-3,4-diol (9m). Oil (77%). [a] ˆ ‡11, [a]
ˆ
589
577
25
25
‡10, [a] ˆ ‡20, [a] ˆ ‡23 (c ˆ 0.35, MeOH). IR (KBr): 3381, 2929, 2817, 1560, 1491, 1472, 1407, 1334,
535
405
1151, 1090, 1015, 805. UV (MeOH): 267 (391), 225 (3499), 212 (2560). 1H-NMR (400 MHz, CD3OD): 7.39 ± 7.34
(m, 4 arom. H); 4.03 (t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.9, HÀC(3), HÀC(4)); 3.80 (br. s, ArCH2N); 2.95
(dd, 2J ˆ 10.1, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.5, HbÀC(2), HbÀC(5)); 2.73 ± 2.63 (m, 2 HÀC(2'), 2 HÀC(1')); 2.50
(dd, 2J ˆ 10.1, 3J(2a,3) ˆ 3J(5a,4) ˆ 3.5, HaÀC(2), HaÀC(5)). 13C-NMR (100.6 MHz, CD3OD): 138.9 (s, 1 ar-
om. C); 134.1 (s, 1 arom. C); 131.3 (d, 1J(C,H) ˆ 160, 2 arom. C); 129.5( d, 1J(C,H) ˆ 166, 2 arom. C); 78.8
(d, 1J(C,H) ˆ 148, C(3), C(4)); 61.4 (t, 1J(C,H) ˆ 138, C(2), C(5)); 56.0 (t, 1J(C,H) ˆ 135, C(1')); 53.4
(t, 1J(C,H) ˆ 135, ArCH2N); 47.4 (t, 1J(C,H) ˆ 135, C(2')). CI-MS (NH3): 155 (3), 140 (2), 127 (8), 125 (24),
‡
116 (100), 106 (2), 99 (8), 89 (8), 84 (3), 81 (4), 75(5), 70 (3). HR-MALDI-TOF-MS: 270.1109 (C 13H19ClN2O2 ,
M ; calc. 270.1135).
‡
25
25
(3S,4S)-1-[3-(Benzylamino)propyl]pyrrolidine-3,4-diol (9n). Oil (42%). [a] ˆ ‡13, [a] ˆ ‡15,
589
577
25
25
[a] ˆ ‡27, [a] ˆ ‡31 (c ˆ 0.27, MeOH). IR (KBr): 3387, 2925, 2826, 1560, 1452, 1409, 1336, 1148, 1096,
535
405
1
746, 702. UV (MeOH): 216 (2965), 206 (1626). H-NMR (400 MHz, CD3OD): 7.41 ± 7.31 (m, 5arom. H); 4.06
(t, 3J(2,3) ˆ 3J(3,4) ˆ 3J(4,5) ˆ 3.2, HÀC(3), HÀC(4)); 3.92 (br. d, 3J ˆ 13.3, 1 H, PhCH2N); 3.87 (br. d, 3J ˆ
13.3, 1 H, PhCH2N); 3.00 (dd, 2J ˆ 10.3, 3J(2b,3) ˆ 3J(5b,4)ˆ 5.3, HbÀC(2), HbÀC(5)); 2.82 (t, 3J(3',2') ˆ 6.8,
2 HÀC(3')); 2.71 ± 2.59 (m, 2 HÀC(1')); 2.60 (dd, 2J ˆ 10.3, 3J(2a,3) ˆ 3J(5a,4) ˆ 2.7, HaÀC(2), HaÀC(5)); 1.79
(quint., 3J(2',1') ˆ 3J(2',3') ˆ 6.9, 2 HÀC(2')). 13C-NMR (100.6 MHz, CD3OD): 138.0 (s, 1 arom. C); 130.0
(d, 1J(C,H) ˆ 158, 2 arom. C); 129.7 (d, 1J(C,H) ˆ 160, 2 arom. C); 129.0 (d, 1J(C,H) ˆ 161, 1 arom. C); 78.5
(d, 1J(C,H) ˆ 149, C(3), C(4)); 61.4 (t, 1J(C,H) ˆ 138, C(2), C(5)); 56.3 (t, 1J(C,H) ˆ 129, C(1')); 53.6
(t, 1J(C,H) ˆ 137, PhCH2N); 49.6 (t, 1J(C,H) ˆ 134, C(3')); 27.1 (t, 1J(C,H) ˆ 135, C(2')). CI-MS (NH3): 151 (1,
‡
[M ‡ H] ), 215(2), 147 (5), 132 (8), 126 (8), 117 (61), 107 (33), 106 (40), 95(7), 91 (100), 81 (39), 77 (5), 72
‡
‡
(8), 70 (25). HR-MALDI-TOF-MS: 250.1609 (C14H22N2O2 ; M ; calc. 250.1681).
(3R,4R)-1-Benzylpyrrolidine-3,4-diol (10a). According to [18][26], from commercially available (À)-d-
25
25
25
25
tartaric acid (S,S)-11; Fluka): 10a (35% in 2 steps). [a] ˆ À7, [a] ˆ À10, [a] ˆ À10, [a] ˆ À15,
589
577
546
535
25
25
25
25
25
25
[a] ˆ À17 (c ˆ 1.0, CHCl3): [a] ˆ À34, [a] ˆ À36, [a] ˆ À39, [a] ˆ À66, [a] ˆ À80 (c ˆ 1.0,
405
589
577
546
535
405
MeOH) ([26]: [a]2D5 ˆ À32.5( c ˆ 1.0, MeOH)).
25
25
(3R,4R)-Pyrrolidine-3,4-diol (10b). According to [19][20], from 10a: 10b (87%). [a] ˆ À13, [a]
ˆ
589
577
25
25
25
‡
À14, [a] ˆ À14, [a] ˆ À22, [a] ˆ À25( cˆ 2.0, MeOH). CI-MS (NH3): 104 (100, [M‡ H] ), 103 (5), 85 (3).
546
535
405
(3R,4R)-1-Benzyl-3,4-bis{[(tert-butyl)dimethylsilyl]oxy}pyrrolidine (ent-12a). According to [18a], from
25
25
25
25
25
10a: ent-12a (91%). [a] ˆ À57, [ a] ˆ À58, [a] ˆ À67, [a] ˆ À114, [a] ˆ À132 (c ˆ 1.0, CHCl3).
589
577
546
535
405
(3R,4R)-3,4-Bis{[(tert-butyl)dimethylsilyl]oxy}pyrrolidine (ent-12b). According to [18a], from ent-12a:
25
25
25
25
25
ent-12b (82%). [a] ˆ À33, [a] ˆ À36, [a] ˆ À40, [a] ˆ À63, [a] ˆ À74 (c ˆ 1.0, CHCl3). HR-
589
577
546
535
405
‡
‡
MALDI-TOF-MS: 331.2369 (C17H40NO2Si2 , M ; calc. 331.2363).
(3R,4R)-Bis(benzyloxy)butane-1,4-diol Bis[4-methylbenzenesulfonate] (ent-19). According to [23], from
25
25
25
25
diethyl (À)-d-tartrate (Fluka): ent-19 (54% in 3 steps). [a] ˆ À14, [a] ˆ À11, [a] ˆ À18, [a] ˆ À28,
589
577
546
535
[a] ˆ À34 (c ˆ 1.0, CHCl3) ([23b]: [a]2D5 ˆ ‡14.74 (c ˆ 4.8, CHCl3)).
25
405
(3R,4R)-3,4-Bis{[(tert-butyl)dimethylsilyl]oxy}-1-methylpyrrolidine (ent-13). As described for 13: ent-13
25
25
25
25
25
(79%). Yellowish oil. [a] ˆ À45, [a] ˆ À47, [a] ˆ À54, [a] ˆ À92, [a] ˆ À124 (c ˆ 1.2, CHCl3). HR-
589
577
546
535
405
‡
‡
MALDI-TOF-MS: 345.2516 (C17H39NO2Si2 , [M ‡ H] ; calc. 345.2519).
(3R,4R)-1-Methylpyrrolidine-3,4-diol Diacetate (ent-14). As described for 14: ent-14: (75%). Light
25
25
25
25
yellowish oil. [a] ˆ À50, [a] ˆ À53, [a] ˆ À99, [a] ˆ À120 (c ˆ 0.22, CHCl3). HR-MALDI-TOF-MS:
589
577
535
405
‡
‡
224.0827 (C9H15NaO4 , [M ‡ Na] ; calc. 224.0899).

3180
Helvetica Chimica Acta ± Vol. 87 (2004)
(3R,4R)-1-Methylpyrrolidine-3,4-diol (10c). FC (CH2Cl2/MeOH/30% aq. NH3 soln. 30 :19 :1) gave a white
25
25
25
25
solid. M.p. 55 ± 578. [a] ˆ À22, [a] ˆ À25, [a] ˆ À47, [a] ˆ À5 4 (c ˆ 0.28, MeOH). HR-MALDI-TOF-
589
‡
577
535
405
‡
MS: 117.0790 (C5H12NO2 , M ‡ H] ; calc. 117.0790).
(3R,4R)-1-Ethylpyrrolidine-3,4-diol (10d). By Method A, after FC (CH2Cl2/MeOH/30% aq. NH3 soln.
25
25
25
25
38 :11:1): 10d (36%). White solid. [a] ˆ À23, [a] ˆ À23, [a] ˆ À43, [a] ˆ À5 1 c( ˆ 0.51, MeOH).
589
577
535
405
‡
‡
HR-MALDI-TOF-MS: 132.1098 (C6H14NO2 , [M ‡ H] ; calc. 132.1025).
(3R,4R)-1-Propylpyrrolidine-3,4-diol (10e). By Method A, after FC (CH2Cl2/MeOH/30% aq. NH3 soln.
25
25
25
25
25
30 :19 :1): 10e (37%). White solid. [a] ˆ À5 , a[ ] ˆ À6, [a] ˆ À7, [a] ˆ À9, [a] ˆ À10 (c ˆ 0.35,
589
577
546
535
405
‡
‡
MeOH). HR-MALDI-TOF-MS: 146.1183 (C7H16NO2 , [M ‡ H] ; calc. 146.1181).
(3R,4R)-1-Butylpyrrolidine-3,4-diol (10f). By Method A, after FC (CH2Cl2/MeOH/30% aq. NH3 soln.
25
25
25
25
25
30 :19 :1): 10f (37%). White solid. M.p. 35± 37 8. [a] ˆ À5 , [a] ˆ À4, [a] ˆ À6, [a] ˆ À10, [a] ˆ À11
589
577
546
535
405
‡
‡
(c ˆ 0.42, MeOH). HR-MALDI-TOF-MS: 182.1187 (C8H17NNaO2 , [M ‡ H] ; calc. 182.1157).
(3R,4R)-3,4-Bis(benzyloxy)pyrrolidine-1-ethanamine (ent-20g). By Method B, after FC (MeOH/CHCl3/
25
25
25
25
30% aq. NH3 soln. 95:5:2): ent-20g (86%). Pale yellow oil. [a] ˆ À23, [a] ˆ À26, [a] ˆ À28, [a]
ˆ
589
577
546
535
25
‡
‡
À46, [a] ˆ À5 3 (c ˆ 0.73, CHCl3). HR-MALDI-TOF-MS: 327.2012 (C20H27N2O2 , [M ‡ H] ; calc. 327.2073).
405
(3R,4R)-3,4-Bis(benzyloxy)-N-ethylpyrrolidine-1-ethanamine (ent-20h). By Method B, after FC (MeOH/
25
25
25
CH2Cl2/30% aq. NH3 soln. 30 :19 :1): ent-20h (83%). Pale yellow oil. [a] ˆ À25, [a] ˆ À23, [a] ˆ À28,
589
577
546
25
25
‡
‡
[a] ˆ À48, [a] ˆ À55 (c ˆ 0.67, CHCl3). HR-MALDI-TOF-MS: 355.2712 (C22H31N2O2 , [M ‡ H] ; calc.
535
405
355.2386).
(3R,4R)-3,4-Bis(benzyloxy)-N,N-dimethylpyrrolidine-1-ethanamine (ent-20i). By Method B, after FC
25
25
(CH2Cl2/MeOH/30% aq. NH3 soln. 90 :9 :1): ent-20i (74%). Pale yellow oil. [a] ˆ À18, [a] ˆ À22,
589
577
25
25
25
‡
[a] ˆ À23, [a] ˆ À39, [a] ˆ À48 (c ˆ 0.54, CHCl3). HR-MALDI-TOF-MS: 355.4912 (C22H31N2O2 ,
546
535
405
‡
[M ‡ H] ; calc. 355.2386).
(3R,4R)-3,4-Bis(benzyloxy)pyrrolidine-1-propanamine (ent-20j). By Method B, after FC (MeOH/CHCl3/
25
25
25
25
30% aq. NH3 soln. 95:5:2): ent-20j (81%). Pale yellow oil. [a] ˆ À23, [a] ˆ À25, [a] ˆ À29, [a]
ˆ
589
577
546
535
25
‡
‡
À47, [a] ˆ À5 2 (c ˆ 0.61, CHCl3). HR-MALDI-TOF-MS: 363.2047 (C21H29N2O2 , [M ‡ Na] ; calc. 363.2048).
405
(3R,4R)-1-(2-Aminoethyl)pyrrolidine-3,4-diol (10g). By Method B, after FC (MeOH/CHCl3/30% aq. NH3
25
25
25
25
25
soln. 20 :3 :2): 10g (88%). Colorless oil. [a] ˆ À30, [a] ˆ À33, [a] ˆ À38, [a] ˆ À54, [a] ˆ À82 (c ˆ
589
577
546
535
405
‡
‡
0.52, MeOH). HR-MALDI-TOF-MS: 147.1138 (C6H15N2O2 , [M ‡ H] ; calc. 147.1134).
(3R,4R)-1-[(2-Ethylamino)ethyl]pyrrolidine-3,4-diol (10h). By Method B, after FC (MeOH/CH2Cl2/30%
25
25
25
25
25
aq. NH3 soln. 90 :9 :1): 10h (97%). Colorless oil. [a] ˆ À16, [a] ˆ À24, [a] ˆ À23, [a] ˆ À39, [a]
ˆ
589
577
546
535
405
‡
‡
À5 3 (c ˆ 0.47, MeOH). HR-MALDI-TOF-MS: 175.1449 (C8H19N2 O2 , [M ‡ H] ; calc. 175.1447).
(3R,4R)-1-[2(Dimethylamino)ethyl]pyrrolidine-3,4-diol (10i). By Method B, after FC (CH2Cl2/MeOH/
25
25
25
30% aq. NH3 soln. 30 :9 :1): 10i (77%). White crystals. M.p. 63 ± 658. [a] ˆ À4, [a] ˆ À6, [a] ˆ À5,
589
577
546
25
25
‡
‡
[a] ˆ À8, [a] ˆ À15( c ˆ 0.91, CHCl3). HR-MALDI-TOF-MS: 175.1441 (C8H19N2O2 , [M ‡ H] ; calc.
535
405
175.1447).
(3R,4R)-1-(3-Aminopropyl)pyrrolidine-3,4-diol (10j). FC (MeOH/CHCl3/30% aq. NH3 soln. 20 :3 :2): 10j
25
25
25
25
25
(92%). Colorless oil. [a] ˆ À25, [a] ˆ À26, [a] ˆ À28, [a] ˆ À46, [a] ˆ À55 (c ˆ 0.52, MeOH).
589
577
546
‡
535
405
‡
HR-MALDI-TOF-MS: 161.1203 (C7H17N2O2 , [M ‡ H] ; calc. 161.1290).
(3R,4R)-1-[2-(Benzylamino)ethyl]pyrrolidine-3,4-diol (10k). As described for 9k ± n, after FC (MeOH/
25
25
25
25
CHCl3/30% aq. NH3 soln. 20 :3 :2): 10k (55%). Colorless oil. [a] ˆ À15, [a] ˆ À14, [a] ˆ À26, [a]
ˆ
589
577
535
405
‡
‡
À27 (c ˆ 0.27, MeOH). HR-MALDI-TOF-MS: 237.1607 (C13H21N2O2 , [M ‡ H] ; calc. 237.1603).
(3R,4R)-1-{2-[([1,1'-Biphenyl]-4-ylmethyl)amino]ethyl}pyrrolidine-3,4-diol (10l). FC (MeOH/CH2Cl2/
25
25
25
25
30% aq. NH3 soln. 30 :19 :1) gave 10l (68%). Colorless oil. [a] ˆ À8, [a] ˆ À6, [a] ˆ À11, [a]
ˆ
589
577
535
405
‡
‡
À11 (c ˆ 0.265, MeOH). HR-MALDI-TOF-MS: 313.0366 (C19H25N2O2 , [M ‡ H] ; calc. 313.1916).
(3R,4R)-1-{2-[(4-Chlorobenzyl)amino]ethyl}pyrrolidine-3,4-diol (10m). FC (MeOH/CH2Cl2/30% aq. NH3
25
25
25
25
soln. 30 :19 :1) gave 10m (62%). Colorless oil. [a] ˆ À9, [a] ˆ À8, [a] ˆ À14, [a] ˆ À14 (c ˆ 0.25,
589
577
535
405
‡
‡
MeOH). HR-MALDI-TOF-MS: 271.2422 (C13H20ClN2O2 , [M ‡ H] ; calc. 271.1213).
(3R,4R)-1-[3(Benzylamino)propyl]pyrrolidine-3,4-diol (10n). FC (MeOH/CH2Cl2/30% aq. NH3 soln.
25
25
25
25
30 :19 :1) gave 10n (38%). Colorless oil. [a] ˆ À15, [a] ˆ À15, [a] ˆ À26, [a] ˆ À27 (c ˆ 0.27,
589
577
535
405
‡
‡
MeOH). HR-MALDI-TOF-MS: 251.1336 (C14H23N2O2 , [M ‡ H] ; calc. 251.1336).

Helvetica Chimica Acta ± Vol. 87 (2004)
3181
REFERENCES
[1] I. Robina, A. J. Moreno-Vargas, A. T. Carmona, P. Vogel, Curr. Drug Metab. 2004, 5, 329.
[2] R. A. Gruters, J. J. Neefjes, M. Tersmette, R. E. de Goede, A. Tulp, H. G. Huisman, F. Miedema, H. L.
Ploegh, Nature (London) 1987, 330, 74; D. C. Montefiori, W. E. Robinson Jr., W. M. Mitchell, Proc. Natl.
Acad. Sci. U.S.A. 1988, 85, 9248; A. Karpas, G. W. Fleet, R. A. Dwek, S. Petursson, S. K. Namgoong, N. G.
Ramsden, G. S. Jacob, T. W. Rademacher, Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229; P. S. Sunkara, D. L.
Taylor, M. S. Kang, T. L. Bowlin, P. S. Liu, A. S. Tyms, A. Sjoerdsma, Lancet 1989, 1, 1206; R. M. Ruprecht,
L. D. Bernard, R. Bronson, M. A. Gama Sosa, S. Mullaney, J. Acquired Immune Defic. Syndr. 1991, 4, 48.
[3] P. Greimel, J. Spreitz, A. E. Stütz, T. W. Wrodnigg, Curr. Top. Med. Chem. 2003, 3, 513; L. A. G. M. van der
Broek, in ꢁCarbohydrates in Drug Designꢂ, Eds. Z. J. Witczak and K. A. Nieforth, Marcel Dekker, New
York, 1997, p. 472.
[4] E. Fenouillet, J. C. Gluckman, J. Gen. Virol. 1991, 72, 1919.
[5] M.-J. Papandreou, R. Barbouche, R. Guieu, M. P. Kieny, E. Fenouillet, Mol. Pharmacol. 2002, 61, 186.
[6] A. Varki, Glycobiology 1993, 3, 97.
[7] N. Asano, K. Oseki, E. Tomioka, H. Kizo, K. Matsui, Carbohydr. Res. 1994, 259, 243; N. Asano, K. Oseki, H.
Kizu, K. Matsui, J. Med. Chem. 1994, 37, 3701; N. Asano, H. Kizu, K. Oseki, E. Tomioka, K. Matsui, M.
Okamoto, M. Baba, J. Med. Chem. 1995, 38, 2349; see also: A. Kato, I. Adachi, M. Miyauchi, K. Ikeda, T.
Komae, H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash, M. R. Wormald, G. W. J. Fleet, N. Asano,
Carbohydr. Res. 1999, 316, 95 .
[8] N. Asano, T. Yamashita, K. Yasuda, K. Ikeda, H. Kizu, Y. Kameda, A. Kato, R. J. Nash, H. S. Lee, K. S.
Ryu, J. Agric. Food Chem. 2001, 49, 4208.
[9] C. Ekhart, M. H. Fechter, P. Hadwiger, E. Mlaker, A. E. Stütz, A. Tauss, T. M. Wrodnigg, in ꢁIminosugars as
Glycosidase Inhibitors: Nojirimycin and Beyondꢂ, Ed. A. E. Stütz, Wiley-VCH, Weinheim, 1999, p. 253.
[10] K. S. Ryu, H. S. Lee, S. H. Chung, P. D. Kang, Korean J. Seric Sci. 1997, 39, 79; S. H. Chung, M. S. Kim, K. S.
Ryu, Korean J. Seric Sci. 1997, 39, 86; W. B. Kim, W. Y. Choung, K. S. Ryu, Korean J. Seric Sci. 1999, 41, 129.
[11] S. V. Evans, L. E. Fellows, T. K. M. Shing, G. W. J. Fleet, Phytochemistry 1985, 24, 1953; A. A. Watson, R. J.
Nash, M. R. Wormald, D. J. Harvey, S. Dealler, E. Lees, N. Asano, H. Kizu, A. Kato, R. C. Griffiths, A. J.
Cairns, G. W. J. Fleet, Phytochemistry 1997, 46, 255.
[12] T. M. Wrodnigg, S. G. Withers, A. E. Stütz, Bioorg. Med. Chem. Lett. 2001, 11, 1063.
[13] F. Cardona, A. Goti, S. Picasso, P. Vogel, A. Brandi, J. Carbohydr. Chem. 2000, 19, 585.
[14] I. Pastuszak, R. J. Molyneux, L. F. James, A. D. Elbein, Biochemistry 1990, 29, 1886; A. Brandi, S. Cicchi,
F. M. Cordero, R. Frignoli, A. Goti, S. Picasso, P. Vogel, J. Org. Chem. 1995, 60, 6806.
Â
[15] L. A. Colley, S. R. Lewin, J. Clin. Virology 2003, 26, 121; J. A. Este, Curr. Med. Chem. 2003, 10, 1617; B. M.
Oꢂ Hara, W. C. Olson, Pharmacology 2002, 2, 523; W. S. Blair, P.-F. Lin, N. A. Meanwell, O. B. Wallace,
Drug Discov. Today 2000, 5, 183.
[16] F. Popowycz, S. Gerber-Lemaire, R. Demange, E. Rodriguez-García, A. T. Carmona Asenjo, I. Robina, P.
Vogel, Bioorg. Med. Chem. Lett. 2001, 11, 2489; S. Gerber-Lemaire, F. Popowycz, E. Rodriguez-García,
A. T. Carmona Asenjo, I. Robina, P. Vogel, ChemBioChem 2002, 3, 466; F. Popowycz, S. Gerber-Lemaire,
C. Schütz, P. Vogel, Helv. Chim. Acta 2004, 87, 800.
[17] F. Popowycz, S. Gerber-Lemaire, E. Rodriguez-García, C. Schütz, P. Vogel, Helv. Chim. Acta 2003, 86,
1914; A. T. Carmona Asenjo, F. Popowycz, S. Gerber-Lemaire, E. Rodriguez-García, C. Schütz, P. Vogel, I.
Robina, Bioorg. Med. Chem. 2003, 11, 4897; A. J. Moreno-Vargas, C. Schütz, R. Scopelliti, P. Vogel, J. Org.
Chem. 2003, 68, 5632.
[18] a) Y. Arakawa, S. Yoshifuji, Chem. Pharm. Bull. 1991, 39, 2219; b) C. M. Wong, J. Buccini, J. Te Raa, Can. J.
Chem. 1968, 46, 3091.
[19] M. T. H. Axamawaty, G. W. J. Fleet, K. A. Hannah, S. K. Namgoong, M. L. Sinnott, Biochem. J. 1990, 266, 245.
[20] U. Nagel, Angew. Chem., Int. Ed. 1984, 23, 435.
Ê
[21] A. Dahlgren, J. Branalt, I. Kvarnströem, I. Nilsson, D. Musil, B. Samuelsson, Bioorg. Med. Chem. 2002, 10,
1567; P. W. Feit, J. Med. Chem. 1964, 7, 14.
[22] V. Schurig, B. Koppenhoefer, W. Buerkle, J. Org. Chem. 1980, 45, 538.
[23] a) H. Nemoto, S. Takamatsu, Y. Yamamoto, J. Org. Chem. 1991, 56, 1321; b) A. F. Cunningham Jr., E. P.
Kündig, J. Org. Chem. 1988, 53, 1823.
[24] J. Ohwada, Y. Inouye, M. Kimura, H. Kakisawa, Bull. Chem. Soc. Jpn. 1990, 63, 287.
[25] M. Yatagai, M. Zama, T. Yamagishi, M. Hida, Bull. Chem. Soc. Jpn. 1984, 57, 739.
[26] J. Skarzewski, A. Gupta, Tetrahedron: Asymmetry 1997, 8, 1861.
Received September 20, 2004