Synthesis and α-mannosidase inhibitory evaluation of (2R,3R,4S)- and (2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol derivatives

Article abstract of DOI:10.1002/hlca.200390153

The synthesis of 46 derivatives of (2R,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward α-mannosidases from jack bean (B) and almonds (A) are evaluated (Table). The most-potent inhibitors

Full text of DOI:10.1002/hlca.200390153

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis and a-Mannosidase Inhibitory Evaluation of (2R,3R,4S)- and
(2S,3R,4S)-2-(Aminomethyl)pyrrolidine-3,4-diol Derivatives
by Florence Popowycz, Sandrine Gerber-Lemaire, Eliazar Rodriguez-GarcÌa, Catherine Sch¸tz,
and Pierre Vogel*
¬
¬ ¬
Institut de chimie moleculaire et biologique, Ecole Polytechnique Federale de Lausanne, BCH,
CH-1015Lausanne
The synthesis of 46 derivatives of (2R,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol is reported (Scheme 1
and Fig. 3), and their inhibitory activities toward a-mannosidases from jack bean (B) and almonds (A) are
evaluated (Table). The most-potent inhibitors are (2R,3R,4S)-2-{[([1,1'-biphenyl]-4-ylmethyl)amino]methyl}-
pyrrolidine-3,4-diol (3fs; IC50(B) ˆ 5 mm, Ki ˆ 2.5 mm) and (2R,3R,4S)-2-{[(1R)-2,3-dihydro-1H-inden-1-ylami-
no]methyl}pyrrolidine-3,4-diol (3fu; IC50(B) ˆ 17 mm, Ki ˆ 2.3 mm). (2S,3R,4S)-2-(Aminomethyl)pyrrolidine-
3,4-diol (6, RˆH) and the three 2-(N-alkylamino)methyl derivatives 6fh, 6fs, and 6f are prepared (Scheme 2)
and found to inhibit also a-mannosidases from jack bean and almonds (Table). The best inhibitor of these series
is (2S,3R,4S)-2-{[(2-thienylmethyl)amino]methyl}pyrrolidine-3,4-diol (6o; IC50(B) ˆ 105 mm, Ki ˆ 40 mm). As
expected (see Fig. 4), diamines 3 with the configuration of a-d-mannosides are better inhibitors of a-
mannosidases than their stereoisomers 6 with the configuration of b-d-mannosides. The results show that an
aromatic ring (benzyl, [1,1'-biphenyl]-4-yl, 2-thienyl) is essential for good inhibitory activity. If the C-chain that
separates the aromatic system from the 2-(aminomethyl) substituent is longer than a methano group, the
inhibitory activity decreases significantly (see Fig. 7). This study shows also that a-mannosidases from jack bean
and from almonds do not recognize substrate mimics that are bulky around the O-glycosidic bond of the
corresponding a-d-mannopyranosides. These observations should be very useful in the design of better a-
mannosidase inhibitors.
Introduction.
The specific inhibition of N-linked glycoprotein-processing a-
mannosidases may provide a useful anticancer strategy [1]. Clinical trials have shown
that swainsonine (1), a natural a-mannosidase inhibitor that contains a 4-amino-4-
deoxy-mannofuranoyl moiety [2][3], reduces solid tumors and hematological malig-
nancies [4]. Analogues 2 have also shown interesting properties (Fig. 1) [5 ].
H
N
H
N
H
N
N
R
HO
NHR
NHR
HO
NHR
H
HO
OH
HO
HO
OH
HO
OH
OH
3 R = ArCH2
4 R = H
5 R = ArCH2
6
1 R = H
2 R = ArCH2CH2
Fig. 1. Swainsonine and synthetic analogues
Mannosidase inhibitors mediate increased secretion of mutant a1-antitrypsin Z.
They are, thus, leads in the development of drugs for the chemoprophylaxis of liver
injury and emphysema in patients with a1-antitrypsin Z deficiency [6]. Simpler

Helvetica Chimica Acta Vol. 86 (2003)
1915
synthetic analogues of swainsonine are also potent a-mannosidase inhibitors [3][7].
Mannostatin A and B isolated from the soil microorganism Streptoverticillum verticillus
[8] and a synthetic analogue [9] are probably the most-potent inhibitors of a-
mannosidases reported so far [7][10]. Often, a-mannosidase inhibitors that are
monosaccharide mimics [11][12] inhibit also other types of glycosidases [13], in
particular a-l-fucosidases [11][14]. To become a drug, a good inhibitor must satisfy a
number of conditions [15], apart from its low toxicity and enzyme specificity. One of
these is membrane permeability, which often requires the presence of lyophilic groups.
In a preliminary note, we have demonstrated that (2R,3R,4S)-3,4-dihydroxypyrrolidin-
2-yl derivatives such as 3 are selective a-mannosidase inhibitors. In the case of 3f (R ˆ
PhCH2), derived from the weak and nonselective inhibitor 4 and benzaldehyde,
competitive inhibition (Ki ˆ 7.4 mm) of a-mannosidase from jack bean has been found
[16]. This enzyme was chosen because it is a useful model for mammalian a-
mannosidases such as Golgi a-mannosidase II [17]. Similar results have been reported
by Saotome and co-workers [18] with derivative 5. In the meantime, we have shown that
imines resulting from the reaction of vicinal diamino compounds 4 with aromatic
aldehydes can model the inhibitory activities of the corresponding products of
reduction, the diamino derivatives 3. This constitutes an efficient tool for the fast
discovery of glycosidase inhibitors (and possibly inhibitors of other enzymes) that has
led us to prepare further analogues of diamino compounds 3 [19]. We report here their
synthesis and their inhibitory activities toward a-mannosidase from jack bean (B) and
a-mannosidase from almonds (A). The study allows us to approach a structure-activity
relationship that should be useful in the design of better a-mannosidase inhibitors, and
hopefully of potent anticancer drugs. The most-potent a-mannosidase inhibitors
reported in this paper are shown in Fig. 2. They are all competitive inhibitors that
inhibit a-mannosidase from jack bean better than a-mannosidase from almonds.
H
N
H
N
H
N
S
Me
NHCH2
NHCH2
Ph
N
H
H
HO
OH
HO
OH
HO
OH
3oa
3fu
3fs
IC50(B) = 5 µM
Ki = 2.3 µM
IC50(B) = 17 µM
Ki = 2.3 µM
IC50(B) = 10 µM
Ki = 3.5 µM
Fig. 2. The most-potent new competitive a-mannosidase inhibitors. B ˆ jack bean.
We have also prepared a few 2-epimers 6 of the diamino compounds 3 (see
Fig. 3). As expected from our working hypothesis (see model of Fig. 4) for the
inhibition of a-mannosidases, diamino derivatives 6 are less active, in general, than
their 2-epimers 3.
Results and Discussion. Synthesis. Following Fleet×s method [20], we converted d-
gulonolactone to 7 that was then transformed into aldehyde 8 (33% overall yield based

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Helvetica Chimica Acta Vol. 86 (2003)
HN
HN
HN
HN
NH(CH2)5OH
N
O
a
b
c
d
ea
HN
OPh
NHCH2Ph
eb
ec
f
Cl
X
HN
HN
HN
HN
X
F
X
fa X = Me
fb X = Me
fd X = OH
fg X = MeO
fj X = F
fc X = Me
fe X = OH
fh X = MeO
fk X = F
fr
ff X = MeO
fi X = F
fl X = Cl
fo X = Br
fm X = Cl
fp X = Br
fn X = Cl
fq X = Br
Ph
HN
HN
HN
HN
fs
fu
ft
fv
NH(CH2)2Ph
NH(CH2)3Ph
NH(CH2)4Ph
HN
N
HN
Ph
Ph
g
h
i
j
k
HN
HN
HN
HN
HN
N
N
N
NO2
l
la
m
n
HN
HN
HN
S
S
S
S
o
oa
ob
oc
HN
Ar
CO2Me
HN
Ar
CO2H
HN
S
p
q
r
Ar = 4–OH–C6H4
Ar = 4–OH–C6H4
Fig. 3. NR Groups in 3, 6, 9, and 18 with corresponding key letters. Compounds 3fa fe, 3fs, 3k, and 3oa oc
were prepared by Method B; 3p was prepared by Method C; 6 (R ˆ H), 6f, 6fh, 6fs, 6fu, and 6o were derived
from d-ribose; all other compounds were obtained according to Method A (see Scheme 1, below).

Helvetica Chimica Acta Vol. 86 (2003)
1917
O
O
O
O
O
HO
HO
H
H
^
N
=
HO
HO
HO
HO
Ar
H
N
sugar
O
H
O
H
O
O
O
Fig. 4. Dicationic mimics of a transition or intermediate structure of an a-mannosidase-catalyzed hydrolysis of an
a-d-mannopyranoside
on d-gulonolactone, seven steps) [21] (Scheme 1, Method A). Aldehyde 8 reacted with
1 equiv. of primary amine RNH2, in anhydrous 1,2-dichloroethane at 208, giving the
corresponding imines that were reduced in situ with NaBH(OAc)3 into the corre-
sponding amines 9 (65 90% yield). Deprotection in acidic medium (CF 3COOH/H2O
4 :1 or 4n HCl) provided the corresponding diamines 3 in quantitative yields1).
Hydrogenolysis (H2, Pd(OH)2/charcoal, MeOH) of the benzylamino derivative 3f,
followed by acid-mediated deprotection afforded diamino derivative 4 (for an
alternative synthesis of 4, see [22]). Primary-amino compound 10 [16] was used to
generate a number of derivatives 3 by reductive amination with aldehydes in 1,2-
dichloroethane (Scheme 1, Method B). Acetamido derivatives 12f [16], 12i, and 13
were prepared by acetylation of 9 under classical conditions (Ac2O, pyridine, N,N-
dimethylpyridin-4-amine (DMAP)) followed by hydrolysis of the resulting crude
acetamides 11 (see [16]). The synthesis of the 2-(2-thienyl)ethyl derivative 3p could not
be carried out via reductive amination of 2-(2-thienyl)ethanal with 10 as we could not
find a suitable method for the oxidation of 2-(2-thienyl)ethanol (14). We, thus,
transformed 14 to the corresponding mesylate 15 by esterification with methanesul-
fonyl chloride and Et3N. Coupling of 15 with 10 (NaHCO3, NaI, THF/DMSO, 208)
afforded diamino compound 9p in a mediocre yield (25%), which was hydrolyzed in
acidic medium to provide derivative 3p (100%) (Scheme 1, Method C).
Diamino compound 6 (R ˆ H) was derived from d-ribose following the method
described by Kim and co-workers (Scheme 2) [23]. The intermediate primary alcohol
derivative 16 was oxidized under Swern conditions (88% yield) and reductive
amination with benzylamine, 4-methoxybenzylamine, (1R)-2,3-dihydro-1H-inden-1-
amine and 2-thiophene-2-methanamine afforded the corresponding protected diamino
compounds 18, which were hydrolyzed under acidic conditions (CF3COOH/H2O 4 :1)
1
)
For the key letters a d, ea ec, f, fa fv, g l, la, m o, oa oc, and p r, see Fig. 3.

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 1. Synthesis of Derivatives 3 and N-Acetamido Derivatives 12 and 131)
Method A:
Boc
N
Boc
N
O
O
OHC
RNH2
[20]
[21]
D-gulonolactone
NaBH(OAc)3
O
O
O
O
8
7
Boc
N
CF3COOH
H2O
3a–d, 3ea–ec, 3f, 3ff–fr, 3ft–3fv, 3g–i, 3l, 3la, 3m–o, 3q, 3r
RHN
O
O
9
Method B:
Boc
N
Boc
N
H2, Pd(OH)2C
MeOH
4N HCl
or
CF3COOH/H2O
R'CHO
3fa–fe, 3fs, 3k, 3oa–oc
9f
H2N
RHN
NaBH(OAc)3
O
O
O
O
9
10
R = R'CH2
Method C:
Boc
CF3COOH
S
N
10, NaI, NaHCO3
X
3o
H2O
S
N
DMSO / THF
H
14 X = OH
15 X = MeSO3
O
O
9p
H
Boc
N
N
CF3COOH
H2O
R
R
Ac2O, DMAP
pyridine
N
N
9
Ac
Ac
HO
OH
O
O
12f R = PhCH2
i R = Ph(CH2)4
13 R = AcO(CH2)4
11
to give derivatives 6f [24], 6fh, 6fu [24], and 6o, respectively. Derivative 6fs was
obtained by debenzylation of 18f and subsequent reductive amination with [1,1'-
biphenyl]-4-carboxaldehyde in the presence of NaBH(OAc)3 to produce 18fs in 58%
yield. Quantitative acidic treatment gave the desired diamine 6fs.
To complete our study, we also prepared hydrazone 19 and N-hydroxy derivative 20
as outlined in Scheme 3.
Inhibitory Activities.
The 4-nitrophenyl a-d-mannopyranoside was used as
substrate, and the commercially available a-mannosidase (EC 3.2.1.24) from jack bean
and from almonds were used as catalysts of buffered (pH 5.0) hydrolysis [25]. Our
results are summarized in the Table.

Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2. Synthesis of Derivatives 61)
1919
Boc
N
Boc
N
OHC
Swern
[23]
RNH2
D-ribose
HO
96%
NaBH(OAc)3
O
O
O
O
17
16
Boc
N
CF3COOH / H2O
or 4N HCl
6(R=H), 6f, 6fh, 6fu, 6o
RHN
O
O
18
Boc
Ph
CHO
N
OF3COOH / H2O
H2 / Pd(OH)2C
18fs
H2N
6fs
18f
NaBH(OAc)3
77%
MeOH
78%
O
O
18 (R=H)
Scheme 3
H
N
1. PhNHNH2, NaBH(OAc)3
PhHNN
2. 1M HCl
75%
HO
OH
19
8
H
N
Ph
1. PhCH2NHOH, NaBH(OAc)3
N
2. CF3COOH / H2O
62%
OH
HO
OH
20
As expected, diamino compounds 3 that have the configuration of a-d-mannosides
for centers C(1), C(2), and C(3) (carbohydrate numbering) are better inhibitors than
their stereoisomers 6, the configuration of which corresponds to b-d-mannosides.
Surprisingly, the unsubstituted primary-amino derivative 6 (R ˆ H) is more active than
its isomer 4 toward the two enzymes used in this study (6 (R ˆ H): IC50(B) ˆ 30 mm,
IC50(A) ˆ 165 mm; 4: IC50(B) ˆ 150 mm, IC50(A) ˆ 1000 mm). The largest selectivity
between diamino derivatives 3 and 6 is observed with the most-potent derivatives such
as 3fs (IC50(B) ˆ 5 mm) vs. 6fs (IC50(B) ˆ 800 mm) and 3fu (IC50(B) ˆ 17 mm) vs. 6fu

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Helvetica Chimica Acta Vol. 86 (2003)
Table. Inhibitory Activities toward a-Mannosidase from Jack Bean (B) and from Almonds (A) of (2R,3R,4S)-3,4-
Dihydroxypyrrolidin-2-yl Derivatives 3 and of (2S,3R,4S)-3,4-dihydroxypyrrolidin-2-yl Derivatives 6. Percentage of
inhibition at 1mm concentration, IC50 and Ki values in mm, when measured at optimal pH and 258. All inhibitors are
competitive (Lineweaver-Burk plots), except when indicated; m.t. ˆ mixed type of inhibition. n.i. ˆ no inhibition at
1mm concentration.
4
3a
3b
3c
3d
3ea
3eb
3ec
3f
3fa
3fb
B
IC50
Ki
A
IC50
Ki
81%
150
53
51%
1000
58%
650
60%
560
44%
n.i.
62%
560
190
n.i.
83%
250
56
87%
130
66
92%
60
7.4
69%
230
95%
45
11
78%
170
71
95%
60
10 (m.t.)
79%
200
46%
53%
1000
21%
n.i.
31%
45%
52
3fc
3fd
3fe
3ff
3fg
3fh
3fi
3fj
3fk
3fl
3fm
B
IC50
Ki
A
IC50
Ki
98%
20
3.0 (m.t.)
85%
62
97%
34
8.4
82%
140
60
97%
23
5.0
86%
80
20
86%
96%
71540
9.2
83%
87
98%
91%
29
20
69%
450
88%
95%
93%
94%
1051305
20 (m.t.)
74%
36
38
7.0
80%
70
36
58%
9.5
78%
270
13
12
73%
280
74%
170
53
300
35
47
54
3fn
3fo
3fp
3fq
3fr
3fs
3ft
3fu
3fv
3g
3h
B
95%
94%
95%
96%
78%
99%
85%
98%
80%
68%
87%
IC50
Ki
A
IC50
Ki
3536
10
73%
270
13075355 5 220 25
300
200
11
10
82..532.5
78%
140
77%
220
80%
140
39
53%
1000
82%
75
20
74%
350
89%
105
21
47%
45%
67%
520
47
3i
3j
3k
3l
3la
3m
3n [16]
3o
3oa
3ob
3oc
B
IC50
Ki
A
IC50
Ki
68%
380
120
n.i.
97%
16
9.5170
78%
150
5
66%
440
90%
70
88%
174
n.i.
89%
8510
3.5 18
68%
350
98%
92%
26
6.4
75%
130
96%
44
19
26
34
26
47%
n.i.
48%
77%
110
53%
n.i.
86%
100
98
81%
135
61 33
3
31
3p
3q
3r
6 (R ˆ H)
6f [24]
6fh
6fs
6o
6fu [24]
B
IC50
Ki
A
IC50
Ki
72%
260
n.i.
n.i.
92%
30
92
67%
165n.i.
97
72%
361
6 1055
44%
2952030
n.i.
88%
110
57%
800
84%
105397
73%
40
12
50%
n.i.
n.i.
60%
85%
83
58%
38%
15
13595
(IC50(B) ˆ 397 mm). In all cases, a-mannosidase from jack bean (B) responds better
than a-mannosidase from almonds (A) toward our diamino compounds. The selectivity
factor (IC50(B)/IC50(A)) never surpass 8, except for the most-potent inhibitors such as
3fs, for which it reaches a value of 15.
It has been found, from a statistical analysis with eleven proteins, that molecular
motifs containing a 1,1'-biphenyl moiety are high-affinity ligands for proteins [26]. It is,
thus, not surprising that the ([1,1'-biphenyl]-4-ylmethyl)amino derivative 3fs shows the
lowest IC50 value of all our diamino compounds. Considering inhibition constants, the

Helvetica Chimica Acta Vol. 86 (2003)
1921
(dihydroindenyl)amino derivative 3fu is also a good inhibitor of a-mannosidase from
jack bean, as well as the [(5-methyl-2-thienyl)methyl]amino derivative 3oa (IC50(B) ˆ
17 and 10 mm, Ki ˆ 2.3 and 3.5 mm, resp.). In agreement with our working hypothesis
(see model of Fig. 4), all our inhibitors are competitive (Fig. 5). Exceptions are 3fb, 3ff,
and 3fc with a-mannosidase from jack bean, as well as 6f [24] for the inhibition of a-
mannosidase from almonds that all showed mixed-type inhibition (Fig. 6).
Fig. 5. LineweaverÀBurk plots for the inhibition of a-mannosidase from jack bean (pH 5, 258) by (2R,3R,4S)-2-
{[([1,1'-biphenyl]-4-ylmethyl)amino]methyl}pyrrolidine-3,4-diol (3fs)
Fig. 6. LineweaverÀBurk plots for the inhibition of a-mannosidase from jack bean (pH 5, 258) by (2R,3R,4S)-2-
{[(3-methylbenzyl)amino]methyl}pyrrolidine-3,4-diol (3fb)
The 3,5-dimethylphenylamino derivative 3ea is a weak inhibitor, whereas the
benzylamino derivative 3f and its substituted analogues are potent inhibitors. The

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Helvetica Chimica Acta Vol. 86 (2003)
inhibitory activity decreases significantly on increasing the length of the alkane chain
separating the phenyl group from the aminomethyl moiety, as summarized in Fig. 7.
Interestingly, rigidification of the C3-alkane chain of 3h by a (E)-double bound
improves the inhibitory activity (see 3k: IC50(B) ˆ 16 mm, Ki ˆ 9.5 mm). Exchange of the
phenyl group of 3f by a pyridin-2-yl group (see 3m: IC50(B) ˆ 174 mm) results in a
decrease in activity. With the imidazol-1-yl derivative 3n [16], no inhibition was
detected at 1 mm concentration. In contrast, the (2-(thienyl)methyl)amino analogues
3o, and especially 3oa, are as potent a-mannosidase inhibitors as 3f and 3fc,
respectively. The results obtained with 3a d demonstrate that the presence of an
aromatic ring is essential for good inhibitory activity. The poor inhibition observed with
3ea, 3eb, 3ec, 3fr, 3ft, 3fv, 3j, 3q, and 3r suggest that the a-mannosidases (A, B) assayed
in this work cannot accommodate voluminous groups in the vicinity of the amino-
methyl moiety of the inhibitor. It appears, therefore, that the active sites of these
enzymes are like a mouth that closes onto the −glycosidic× bond of the substrates once
they have penetrated them. This hypothesis is consistent with the observation of better
inhibitory activities for the para-substituted benzylamino derivatives (see 3fc, 3fe, 3fh,
3fk, 3fn, and 3fq) than for the corresponding meta-substituted (see 3fb, 3fd, 3fg, 3fj,
3fm, and 3fp) and ortho-substituted analogues (see 3fa, 3ff, 3fi, 3fl, and 3fo). The
nature of the para-substituent does not significantly affect the inhibitory activity
(Fig. 7).
H
3f (n = 1) 3g (n = 2) 3h (n = 3) 3i (n = 4)
N
(CH2)nPh
N
IC50(B) [µM]
60
300
200
380
H
OH
HO
H
N
3fh
MeO Me OH Br Cl
10 20 23 30 35 36 60
3fc 3fe 3fq 3fn 3fk 3f
N
H
X
F
H
IC50(B) [µM]
X
OH
HO
Fig. 7. Selected inhibitory data
In the case of the (2-thienylmethyl)amino derivatives 3o, 5-methyl (see 3oa:
IC50(B) ˆ 10 mm) and 5-ethyl (see 3oc: IC50(B) ˆ 26 mm), substitutions of the thiophene
ring lead to improved activities in comparison with the 3-methyl substitution (see 3ob:
IC50(B) ˆ 44 mm), a trend that parallels that found for the corresponding benzylamines
3f.
In agreement with our model (see Fig. 4), the 2-(acetamidomethyl)pyrrolidine-3,4-
diols 12f, 12i, and 13 do not inhibit a-mannosidases A and B. Probably, the same steric
factor invoked above can be retained in these cases, together with the fact that the
acetamido groups, being less basic than the corresponding amino moieties, cannot
make a strong electrostatic interaction with the carboxylic acid of the active site. This
hypothesis is consistent with the observation that the N-hydroxy derivatives, e.g. 20, do
not inhibit a-mannosidases. Phenylhydrazone 19 was prepared to imitate benzylamine
3f. Perhaps the rigidity of the imino double bond and the weaker basicity of the

Helvetica Chimica Acta Vol. 86 (2003)
1923
hydrazone function compared with that of a secondary amine are the cause of its lack of
inhibitory activity toward a-mannosidase from jack bean and from almonds.
Conclusions.
(2R,3R,4S)-2-[(Benzylamino)methyl]pyrrolidine-3,4-diols substi-
tuted at the para-position of the benzyl group are active a-mannosidase inhibitors with
Ki values in the low mm range. They are more active than their (2S,3R,4S)-epimers.
Substitution at the benzylic CH2 group or at the ortho- and meta-position of the
aromatic ring decreases the inhibitory activity. N-Acetylation and N-hydroxylation of
the benzylamino group result in a complete loss of the inhibitory activity. (2R,3R,4S)-2-
{[(5-alkyl-2-thienyl)-
amino]methyl}pyrrolidine-3,4-diols are also potent inhibitors of a-mannosidase from
jack bean.
This work was supported by the Swiss National Science Foundation (Grant No 2100-063567.00/1) and the
¬
¬
Office Federal de l×Enseignementetde la Recherche (COST D13/0001/99). We are grateful to the Serono
Pharmaceutical Research Institute (Plan-les-Ouates, Switzerland) for the generous gift of primary amines and to
¬
Mr. Martial Rey and Mr. Francisco Sepulveda for their technical assistance.
Experimental Part
General. All commercially available reagents (Fluka, Aldrich) were used without further purification.
Solvents were dried by standard methods. The light petroleum ether used refers to the fraction boiling at 40 608.
Solns. after reactions and extractions were evaporated in a rotatory evaporator under reduced pressure. Liquid/
solid flash chromatography (FC): silica gel 60 (Merck No. 9385, 240-400 mesh). TLC (reaction monitoring):
Merck silica gel 60F254 plates; detection by UV light, Pancaldi reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, H2O)
or KMnO4. IR Spectra: Perkin-Elmer 1420 spectrometer; in cmÀ1. Optical rotations: at r.t.; Jasco DIP-370
polarimeter; [a]d in 10À1 deg cm2 gÀ1 1H-NMR Spectra: Bruker ARX-400 spectrometer (400 MHz); d(H) in
.
ppm rel. to the solvent×s residual 1H signal (CHCl3, d(H) 7.27; CH3OD, d(H) 3.31) as internal reference; all 1H
assignments were confirmed by 2D-COSY-45and 2D-NOESYexperiments. 13C-NMR Spectra: same instrument
as for 1H (100.6 MHz); d(C) in ppm rel. to the solvent×s C-signal (CDCl3, d(C) 77.0; CD3OD, d(C) 49.8) as
internal reference; all 13C assigments were confirmed by 2D-HMQC; coupling constants J in Hz. MS: Nermag R
10-10C, chemical-ionization (NH3) mode; m/z (% rel. to the base peak (ˆ100%)). Elemental analyses: Ilse
Beetz, D-96301 Kronach, Germany.
Diamino Compounds 3 by Method A: Reductive Amination of N-[(tert-Butoxy)carbonyl]-2,5-imino-2,5-
dideoxy-l-ribose (8). NaBH(OAc)3 (1.4 equiv.) was added portionwise to stirred 0.5m aldehyde 8 and 0.5m
primary amine RNH2 in abs. ClCH2CH2Cl at 208. After complete disappearance of 8 (TLC control), the soln.
was poured into sat. NaHCO3 soln. (5ml per mmol of 8). The aq. phase was extracted with AcOEt (10 ml per
mmol of 8, 3 times), the combined org. extract dried (MgSO4) and evaporated, and the residue submitted to FC
(silica gel, Merck 7734 or 9385) [27]: pure 9.
Diamino Compounds 9 by Method B: Reductive Amination of tert-Butyl (3aR,4R,6aS)-4-(Amino-
methyl)tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (10). NaBH(OAc)3 (1.4 equiv.)
was added portionwise to stirred 0.5m amino derivative 10 and 0.5m aldehyde RCHO in abs. ClCH2CH2Cl at
208. After complete disappearance of 10 (TLC control), the soln. was poured into sat. aq. NaHCO3 soln. (5ml
per mmol of 10). The aq. phase was extracted with AcOEt (10 ml per mmol of 10, 3 times), the combined org.
extract dried (MgSO4) and evaporated and the residue submitted to FC (silica gel, Merck 7734 or 9385) [27]:
pure 9.
Deprotection of 9 to 3. Method Aa: A 5 10% soln. of 9 in CF3COOH/H2O 4 :1 was stirred at 208 for 1 h.
After evaporation, the residue was purified by FC (silica gel).
Method Ab: A 5 10% soln. of 9 in 4m aq. HCl was stirred at 208 for 1 h. After evaporation, the residue was
purified by FC (silica gel or alumina).
tert-Butyl (3aR,4R,6aS)-4-[(Cyclopropylamino)methyl]tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]-
pyrrole-5-carboxylate (9a). By Method A, with 8 (108 mg, 0.40 mmol), cyclopropylamine (23 mg, 0.40 mmol),
NaBH(OAc)3 (118 mg, 0.56 mmol), and ClCH2CH2Cl (3 ml). FC (CH2Cl2/MeOH 97:3) gave 54 mg (43%) of

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9a, 1.3 :1 mixture of rotamers a and b. [a] ˆ À37, [a] ˆ À39, [a] ˆ À42, [a] ˆ À72, [a] ˆ À87 (c ˆ
0.78, CH2Cl2). UV (MeCN): 274 (1155), 200 (4520). IR (film): 2980, 2935, 1690, 1475, 1410, 1210, 1175, 1125,
1055, 980, 860, 830, 770. 1H-NMR (400 MHz, MeOD): 4.73 (m, HÀC(6a)); 4.57 (m, HÀC(3a)); 4.12
(m, HÀC(4)); 3.76 (d, 2J ˆ 12.8, 1 HÀC(6)); 3.37 (m, 1 HÀC(6)); 2.72 (m, 2 HÀC(1')); 2.20 (m, HÀC(1''));
1.47 (s, (t-Bu)a); 1.46 (s, (t-Bu)b); 1.39 (s, 1 Me); 1.28 (s, 1 Me); 0.46 (m, 2 HÀC(2'')); 0.34 (m, 2 HÀC(3'')).
13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.3 (s, NCOOa); 113.4 (s); 85.3 (d, 1J(C,H) ˆ 157, C(3a)a);
84.8 (d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 151, C(6a)b); 80.9
(d, 1J(C,H) ˆ 158, C(6a)a); 65.5 (d, 1J(C,H) ˆ 147, C(4)a); 65.2 (d, 1J(C,H) ˆ 146, C(4)b); 53.7 (t, 1J(C,H) ˆ 147,
C(6)a); 53.1 (t, 1J(C,H) ˆ 144, C(6)a); 50.9 (t, 1J(C,H) ˆ 146, C(1')a); 50.7 (t, 1J(C,H) ˆ 145, C(1')b); 32.0
(d, 1J(C,H) ˆ 172, C(1'')a); 31.9 (d, 1J(C,H) ˆ 171, C(1'')a); 29.6 (q, 1J(C,H) ˆ 128, Me3C); 28.1 (q, 1J(C,H) ˆ
129, Me); 25.8 (q, 1J(C,H) ˆ 126, Me); 7.8 (t, 1J(C,H) ˆ 162, C(2'')a); 7.5( t, 1J(C,H) ˆ 161, C(2'')b); 7.2
‡
(t, 1J(C,H) ˆ 161, C(3'')b); 7.0 (t, 1J(C,H) ˆ 162, C(3'')a). CI-MS (NH3): 313 (67, [M ‡ H] ), 297 (1), 257 (92),
239 (7), 182 (11), 142 (9), 112 (17), 84 (10). Anal. calc. for C16H28N2O4 (312.43): C 61.51, H 9.03; found: C 61.49,
H 9.03.
(2R,3R,4S)-2-[(Cyclopropylamino)methyl]pyrrolidine-3,4-diol (3a). By Method Aa, with 9a (30 mg). FC
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(MeCN/NH4OH 4 :1) gave 23 mg (100% of 3a). [a] ˆ ‡79, [a] ˆ ‡82, [a] ˆ ‡92, [a] ˆ ‡139 (c ˆ
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0.10, MeOH). UV (MeCN): 204 (785). IR (KBr): 3420, 3110, 2950, 1680, 1445, 1370, 1205, 1135, 1055, 1020, 840,
800, 725. 1H-NMR (400 MHz, D2O): 4.30 (m, HÀC(4)); 3.99 (dd, 3J(3,4) ˆ 4.6, 3J(3,2) ˆ 8.0, HÀC(3)); 3.47
(ddd, 3J(2,1') ˆ 4.2, 3J(2,3) ˆ 8.0, 3J(2,1') ˆ 8.0, HÀC(2)); 3.37 (dd, 3J(5,4) ˆ 4.9, 2J ˆ 12.6, 1 HÀC(5)); 3.17
(m, 1 HÀC(5), 1 HÀC(1')); 2.99 (dd, 3J(1',2) ˆ 8.0, 2J ˆ 13.6, 1 HÀC(1')); 2.36 (m, HÀC(1'')); 0.65
(m, 2 HÀC(2''); 0.51 (m, 2 HÀC(3'')). 13C-NMR (100.6 MHz, D2O): 76.9 (d, 1J(C,H) ˆ 145, C(3)); 72.6
(d, 1J(C,H) ˆ 148, C(4)); 61.8 (d, 1J(C,H) ˆ 143, C(2)); 52.3 (t, 1J(C,H) ˆ 144, C(5), C(1')); 32.2 (d, 1J(C,H) ˆ
176, C(1'')); 7.0 (t, 1J(C,H) ˆ 162, C(2'')); 6.8 (t, 1J(C,H) ˆ 164, C(3'')). CI-MS (NH3): 173 (40, [M ‡ H] ), 155
‡
(3), 143 (22), 133 (6), 112 (31), 102 (51), 85 (35).
tert-Butyl (3aR,4R,6aS)-4[(Cyclopentylamino)methyl]tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]pyr-
role-5-carboxylate (9b). By Method A, with 8 (141 mg, 0.52 mmol), cyclopentylamine (44 mg, 0.52 mmol),
NaBH(OAc)3 (154 mg, 0.73 mmol), and ClCH2CH2Cl (3 ml). FC (CH2Cl2/MeOH 95:5) gave 80 mg (47% of
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9b), 1.1:1 mixture of rotamers a and b. [a] ˆ À49, [a] ˆ À48, [a] ˆ À47, [a] ˆ À78, [a] ˆ À98 (c ˆ
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0.63, CH2Cl2). UV (MeCN): 273 (1905), 199 (3000). IR (film): 2955, 2870, 1695, 1455, 1405, 1210, 1170, 1125,
1055, 975, 860, 770. 1H-NMR (400 MHz, MeOD): 4.76 (m, HÀC(6a)); 4.62 (m, HÀC(3a)); 4.13 (m, HÀC(4));
3.79 (m, 1 HÀC(6)); 3.42 (m, 1 HÀC(6)); 3.12 (m, HÀC(1'')); 2.64 (d, 3J(1',4) ˆ 7.0, 2 H ÀC(1')); 1.90
(m, 2 HÀC(2'')); 1.73 (m, 2 HÀC(5'')); 1.58 (m, 2 HÀC(4'')); 1.51 (s, (t-Bu)b); 1.50 (s, (t-Bu)a); 1.42 (s, 1 Me);
1.36 (m, 2 HÀC(3'')); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.6 (s, NCOOb); 157.3 (s, NCOOa);
113.4 (s); 85.4 (d, 1J(C,H) ˆ 156, C(3aa)); 84.9 (d, 1J(C,H) ˆ 156, C(3ab)); 82.4 (s, Me3CO2); 82.1 (s, Me3COb);
81.6 (d, 1J(C,H) ˆ 158, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.8 (d, 1J(C,H) ˆ 147, C(4)a); 65.4
(d, 1J(C,H) ˆ 147, C(4)b); 61.6 (d, 1J(C,H) ˆ 139, C(1'')b); 61.3 (d, 1J(C,H) ˆ 132, C(1'')a); 53.7 (t, 1J(C,H) ˆ
144, C(6)b); 53.1 (t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1')); 34.5( t, 1J(C,H) ˆ 127, C(2''), C(3'')); 29.6
(q, 1J(C,H) ˆ 128, Me3Ca); 29.5( q, 1J(C,H) ˆ 126, Me3Cb); 28.1 (q, 1J(C,H) ˆ 126, Me); 25.8 (C(4''), C(5''),
‡
‡
Me). CI-MS (NH3): 341 (87, [M ‡ H] ), 340 (8, M ), 325(7), 285(32), 243 (8), 187 (12), 142 (9), 98 (100), 84
(24). Anal. calc. for C18H32N2O4 (340.49): C 63.50, H 9.47; found: C 63.52, H 9.54.
(2R,3R,4S)-2-[(Cyclopentylamino)methyl]pyrrolidine-3,4-diol (3b). By Method Aa, with 9b (44 mg). FC
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(MeCN/NH4OH 4 :1) gave 25mg (100% of 3b). [a] ˆ ‡74, [a] ˆ ‡74, [a] ˆ ‡96, [a] ˆ ‡147 (c ˆ
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0.21, MeOH). IR (KBr): 3420, 2955, 1560, 1420, 1110, 810. 1H-NMR (400 MHz, D2O): 4.21 (m, HÀC(4)); 3.87
(dd, 3J(3,4) ˆ 5.1, 3J(3,2) ˆ 7.8, HÀC(3)); 3.48 (q, 3J ˆ 7.1, H ÀC(1'')); 3.25( m, HÀC(2), 1 HÀC(5)); 3.17
(dd, 3J(1',2) ˆ 4.2, 2J ˆ 11.7, 1 HÀC(1')); 2.92 (m, 1 HÀC(5), 1 HÀC(1')); 2.07 (m, 2 HÀC(5'')); 1.75
(m, 2 HÀC(4'')); 1.62 (m, 2 HÀC(3'')); 1.57 (m, 2 HÀC(2'')). 13C-NMR (100.6 MHz, D2O): 77.8 (d, C(3));
73.4 (d, C(4)); 62.1 (d, C(1'')); 60.9 (d, C(2)); 52.7, 52.2 (2t, C(5), C(1')); 32.6 (t, C(2''), C(5'')); 26.1 (t, C(3''),
‡
C(4'')). CI-MS (NH3): 201 (100, [M ‡ H] ), 116 (2), 98 (40), 85(21).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-4-{[(5-hydroxypentyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9c). By Method A, with 8 (153 mg, 0.56 mmol), 5-aminopentan-1-ol (58 mg,
0.56 mmol), NaBH(OAc)3 (166 mg, 0.78 mmol), and ClCH2CH2Cl (4 ml). FC (CH2Cl2/MeOH 4 :1) gave 80 mg
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(40% of 9c), 1.2 :1 mixture of rotamers a and b. [a] ˆ À30, [a] ˆ À35, [a] ˆ À37, [a] ˆ À62, [a
ˆ
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À74 (c ˆ 0.49, CH2Cl2). UV (MeCN): 201 (4530). IR (film): 3420, 2980, 2935, 2865, 1680, 1480, 1455, 1410, 1370,
1210, 1160, 1130, 1055, 975, 855, 770. 1H-NMR (400 MHz, MeOD): 4.77 (m, HÀC(6a)); 4.63 (d, 3J(3a,6a) ˆ 6.0,
HÀC(3a)b);4.60(d, 3J(3a,6a) ˆ 5.7,HÀC(3a)a);4.19(t, 3J(4,1') ˆ 7.1, H ÀC(4)b);4.13(t, 3J(4,1') ˆ 7.0,HÀC(4)a);
3.86 (d, 3J(6,6a) ˆ 5.3, 1 HÀC(6)b); 3.83 (d, 3J(6,6a) ˆ 5.2, 1 HÀC(6)a); 3.59 (t, 3J(5'',4'') ˆ 6.5, 2 HÀC(5'')); 3.42

Helvetica Chimica Acta Vol. 86 (2003)
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(d, 3J(6,6a) ˆ 4.6, 1 HÀC(6)a); 3.39 (d, 3J(6,6a) ˆ 4.3, 1 HÀC(6)b); 2.68 (m, 2 HÀC(1'), 2 HÀC(1'')); 1.57
(m, 2 HÀC(2''), 2 HÀC(4'')); 1.51 (s, (t-Bu)b); 1.50 (s, (t-Bu)a); 1.41 (m, 2 HÀC(3''), 1 Me); 1.33 (s, 1 Me).
13C-NMR (100.6 MHz, MeOD): 163.2 (s, NCOOb); 163.0 (s, NCOOa); 113.5( s); 85.4 (d, 1J(C,H) ˆ 157, C(3a)b);
84.8 (d, 1J(C,H) ˆ 158, C(3a)a); 82.5( s, Me3COb); 82.4 (s, Me3COa); 81.6 (d, 1J(C,H) ˆ 161, C(6a)a); 80.9
(d, 1J(C,H) ˆ 157, C(6a)b); 65.5 (d, 1J(C,H) ˆ 145, C(4)a)); 64.9 (d, 1J(C,H) ˆ 149, C(4)b); 63.6 (t, 1J(C,H) ˆ 141,
C(5'')); 53.6 (t, 1J(C,H) ˆ 131, C(6)a); 53.0 (t, 1J(C,H) ˆ 133, C(6)b); 51.3 (t, 1J(C,H) ˆ 132, C(1')); 50.9
(t, 1J(C,H) ˆ 130, C(1'')); 34.3 (t, 1J(C,H) ˆ 125, C(2'')); 31.1 (t, 1J(C,H) ˆ 126, C(4'')); 30.7 (t, 1J(C,H) ˆ 126,
C(3'')); 29.5( q, 1J(C,H) ˆ 126, Me3C); 28.0 (q, 1J(C,H) ˆ 126, Me); 25.8 (q, 1J(C,H) ˆ 125, Me). CI-MS (NH3):
‡
‡
359 (100, [M ‡ H] ), 358 (71, M ), 303 (11), 285(3), 243 (3), 143 (3), 116 (68), 85(5). Anal. calc. for
C18H34N2O5 (358.47): C 60.31, H 9.56, N 7.81, O 22.32; found: C 60.16, H 9.60, N 7.73, O 22.51.
(2R,3R,4S)-2-{[(5-Hydroxypentyl)amino]methyl}pyrrolidine-3,4-diol (3c). By Method Aa, with 9c
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(15mg). FC (MeCN/NH 4OH 4 :1) gave 11 mg (100% of 3c). [a] ˆ ‡8, [a] ˆ ‡13, [a] ˆ ‡22, [a]
ˆ
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‡28 (c ˆ 0.2, MeOH). IR (film): 3415, 2985, 1620, 1400, 1265, 1115, 800, 670, 605, 470. 1H-NMR (400 MHz,
D2O): 4.45( m, HÀC(4)); 4.28 (m, HÀC(3)); 3.87 (m, HÀC(2)); 3.66 (m, 1 HÀC(5), 2 HÀC(1'), 2 HÀC(5''));
3.49 (m, 1 HÀC(5)); 3.24 (m, 2 HÀC(1'')); 1.82 (m, 2 HÀC(2'')); 1.65( m, 2 HÀC(4'')); 1.51 (m, 2 HÀC(3'')).
13C-NMR (100.6 MHz, D2O): 76.4 (C(3)); 71.2 (C(4)); 63.7 (C(5'')); 58.7 (C(2)); 53.1 (C(5)); 51.0 (C(1'')); 49.4
(C(1')); 33.1 (C(4'')); 27.7 (C(2'')); 24.6 (C(3'')).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-(morpholin-4-ylmethyl)-5H-[1,3]dioxolo[4,5-c]pyr-
role-5-carboxylate (9d). By Method A, with 8 (125mg, 0.46 mmol), morpholine (40 ml, 0.46 mmol), NaB-
H(OAc)3 (137 mg, 0.64 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt/light petroleum ether 4 :1) gave 116 mg
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(73% of 9d), 1.5:1 mixture of rotamers a and b. [a] ˆ À10, [a] ˆ À9, [a] ˆ À13, [a] ˆ À17, [a]
ˆ
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À20 (c ˆ 0.30, CH2Cl2). UV (MeCN): 203 (1740). IR (film): 2980, 2935, 2855, 2810, 1695, 1480, 1455, 1410, 1370,
1270, 1210, 1170, 1120, 1055, 1010, 865, 770, 735, 665, 635. 1H-NMR (400 MHz, CDCl3): 4.76 4.72
(m, HÀC(6a)); 4.70 (d, 3J(3a,6a) ˆ 6.8, HÀC(3a)a); 4.68 (d, 3J(3a,6a) ˆ 6.8, HÀC(3a)b); 4.23 4.20
(m, HÀC(4)b); 4.06 4.03 (m, HÀC(4)a); 3.87 (d, 2J ˆ 12.8, 1 HÀC(6)a)); 3.80 (d, 2J ˆ 13.1, 1 HÀC(6)b));
3.70 (m, 2 HÀC(2''), 2 HÀC(6'')); 3.35 3.31 ( m, 2 HÀC(6)); 2.58 2.42 (2m, 2 HÀC(3''), 2 HÀC(5'')); 2.34
(dd, 3J(1',4) ˆ 4.7, ˆ 12.8, 1 HÀC(1')); 2.25( dd, 3J(1',4) ˆ 9.5, 2J ˆ 12.8, 1 HÀC(1')); 1.47 (s, t-Bu); 1.33
2
(2s, 2 Me). 13C-NMR (100.6 MHz, CDCl3): 154.3 (NCOO); 111.6 (Me2C); 83.7 (C(3a)a); 82.8 (C(3a)b); 79.8
(Me3CO); 79.5(C(6a) b); 78.6 (C(6a)a); 67.0 (C(2''), C(6'')); 61.4 (C(4)a); 61.0 (C(4)b); 58.6 (C(6)a); 57.7
(C(6)b); 54.2 (C(3''), C(5'')); 51.9 (C(1')b); 51.4 (C(1')a); 28.4 (Me3C); 26.9 (Me); 25.1 (Me). CI-MS (NH3): 343
‡
(110, [M ‡ H] ), 287 (7), 100 (51). Anal. calc. for C17H30N2O5 (342.43): C 59.58, H 8.83, N 8.18; found: C 59.50,
H 8.81, N 8.13.
(2R,3R,4S)-2-(Morpholin-4-ylmethyl)pyrrolidine-3,4-diol (3d). By Method Aa, with 9d (40 mg). FC
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(MeCN/NH4OH 4 :1) gave 25mg (100% of 3d). [a] ˆ ‡23 (c ˆ 0.2, MeOH). UV (MeCN): 199 (2100).
577
IR (film): 3400 3000, 1430, 1200, 1135, 910, 805, 775. 1H-NMR (400 MHz, D2O): 4.08 4.05( m, HÀC(4)); 3.66
(t, 3J(2'',3'') ˆ 3J(6'',5'') ˆ 4.4, 2 HÀC(2''), 2 HÀC(6'')); 3.65( m, HÀC(3)); 3.15 3.11 ( m, HÀC(2), 1 HÀC(5));
2.76 (dd, 3J(4,5) ˆ 2.8, 2J ˆ 12.5, 1 HÀC(5)); 2.62 (dd, 3J(1',2) ˆ 3.2, 2J ˆ 13.3, 1 HÀC(1')); 2.55 2.39
(m, 2 HÀC(3''), 2 HÀC(5''), 1 HÀC(1')). 13C-NMR (100.6 MHz, D2O): 77.8 (C(3)); 72.8 (C(4)); 68.6 (C(2''),
‡
C(6'')); 63.5 (C(2)); 60.1 (C(5)); 55.3 (C(3''), C(5'')); 52.5 (C(1')). CI-MS (NH3): 203 (40, [M ‡ H] ), 100 (100).
tert-Butyl (3aR,4R,6aS)-4-{[3,5-Dimethylphenyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9ea). By Method A, with 8 (136 mg, 0.50 mmol), 3,5-dimethylaniline (61 mg,
0.50 mmol), NaBH(OAc)3 (148 mg, 0.70 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt/light petroleum ether
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1:9) gave 90 mg (48% of 9ea), 1.7:1 mixture of rotamers a and b. [a] ˆ À21, [a] ˆ À21, [a] ˆ À23,
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[a] ˆ À38, [a] ˆ À45( c ˆ 0.49, CH2Cl2). UV (MeCN): 251 (8830), 215 (14205). IR (film): 3390, 2980, 1695,
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1680, 1605, 1520, 1470, 1455, 1415, 1340, 1160, 1125, 1055, 860, 820, 770, 695, 665. 1H-NMR (400 MHz, MeOD):
6.30 (m, 3 arom. H); 4.76 (m, HÀC(6a)); 4.68 (m, HÀC(3a)); 4.22 (m, HÀC(4)); 3.78 (d, 2J ˆ 12.9, 1 HÀC(6)a);
3.69 (d, 2J ˆ 12.9, 1 HÀC(6)b); 3.39 (dd, 3J(6,6a) ˆ 5.0, J ˆ 12.9, 1 HÀC(6)b); 3.33 (dd, 3J(6,6a) ˆ 5.0, J ˆ 12.9,
1 HÀC(6)a); 3.17 (m, 2 HÀC(1')); 2.21 (s, arom. Me); 1.50 (s, (t-Bu)b); 1.46 (s, (t-Bu)a); 1.41 (s, 1 Me); 1.32
(s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.4 (s, NCOOa); 157.3 (s, NCOOb); 150.5 (s, arom. C); 140.6
(s, 2 arom. C); 120.9 (d, 1J(C,H) ˆ 155, arom. C); 113.4 (s); 112.3 (d, 1J(C,H) ˆ 154, 2 arom. C); 85.1
(d, 1J(C,H) ˆ 157, C(3a)a); 84.8 (d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.7
(d, 1J(C,H) ˆ 158, C(6a)b); 81.0 (d, 1J(C,H) ˆ 149, C(6a)a); 65.5 (d, 1J(C,H) ˆ 146, C(4)b); 65.3 (d, 1J(C,H) ˆ
149, C(4)a); 54.2 (t, 1J(C,H) ˆ 143, C(6)b); 53.2 (t, 1J(C,H) ˆ 144, C(6)a); 45.6 (t, 1J(C,H) ˆ 136, C(1')b); 45.1
(t, 1J(C,H) ˆ 136, C(1')a); 29.6 (q, 1J(C,H) ˆ 123, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.9 (q, 1J(C,H) ˆ 128,
2
2
‡
‡
Me); 22.6 (q, 1J(C,H) ˆ 126, arom. Me). CI-MS (NH3): 377 (100, [M ‡ H] ), 376 (46, M ), 321 (20), 303 (3),
176 (1), 134 (50), 85 (4).

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Helvetica Chimica Acta Vol. 86 (2003)
(2R,3R,4S)-2-{[(3,5-Dimethylphenyl)amino]methyl}pyrrolidine-3,4-diol (3ea). By Method Aa, with 9ea
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(22 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3ea). [a] ˆ ‡24, [a] ˆ ‡26, [a] ˆ ‡25, [a]
ˆ
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‡35( c ˆ 0.25, MeOH). IR (film): 3405, 3235, 3065, 1670, 1605, 1435, 1430, 1205, 1185, 1135, 845, 800, 725, 665.
1H-NMR (400 MHz, D2O): 6.62 (s, 1 arom. H); 6.55 (s, 2 arom. H); 4.46 (m, HÀC(4)); 4.25( dd, 3J(3,4) ˆ 4.1,
3J(3,2) ˆ 8.5, HÀC(3)); 3.83 (ddd, 3J(2,1') ˆ 4.2, 3J(2,3) ˆ 8.5, 3J(2,1') ˆ 8.5, HÀC(2)); 3.61 (m, 1 HÀC(5),
2 HÀC(1')); 3.42 (d, 2J ˆ 13.0, 1 HÀC(5)); 2.29 (s, 2 arom. Me). 13C-NMR (100.6 MHz, D2O): 150.0 (s, arom.
C); 142.7 (s, 2 arom. C); 122.9 (d, 1J(C,H) ˆ 158, arom. C); 114.0 (d, 1J(C,H) ˆ 151, 2 arom. C); 75.5
(d, 1J(C,H) ˆ 146, C(3)); 71.8 (d, 1J(C,H) ˆ 155, C(4)); 62.2 (d, 1J(C,H) ˆ 146, C(2)); 51.9 (t, 1J(C,H) ˆ 148,
C(5)); 45.3 (t, 1J(C,H) ˆ 136, C(1')); 22.9 (q, 1J(C,H) ˆ 127, arom. Me). CI-MS (NH3): 237 (100, [M ‡ H] ), 219
‡
(1), 146 (1), 135(85), 121 (14), 102 (39), 85(21).
(2R,3R,4S)-2-[([1,1'-Biphenyl]-4-ylamino)methyl]pyrrolidine-3,4-diol (3eb). By Method A, with 8 (72 mg,
0.27 mmol), [1,1'-biphenyl]-4-amine (45mg, 0.27 mmol), NaBH(OAc) 3 (79 mg, 0.38 mmol), and ClCH2CH2Cl
(2.5ml). Then, by Method Aa, with crude 9eb (27 mg). FC (MeCN/NH4OH 2 :1) gave 18 mg (100% of 3eb).
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[a] ˆ ‡160, [a] ˆ ‡346 (c ˆ 0.70, MeOH). UV (MeCN): 292 (7300), 213 (6200). 1H-NMR (400 MHz,
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MeOD): 7.57 (d, 3J ˆ 7.5, 2 arom. H); 7.49 (d, 3J ˆ 7.5, 2 arom. H); 7.40 (dd, 3J ˆ 7.5, 3J ˆ 7.6, 2 arom. H); 7.26
(t, 3J ˆ 7.6, 1 arom. H); 6.85( d, 3J ˆ 7.5, 2 arom. H); 4.32 (ddd, 3J(4,5) ˆ 4.2, 3J(4,3) ˆ 4.2, 3J(4,5) ˆ 1.7, HÀC(4));
4.12 (dd, 3J(3,4) ˆ 4.2, 3J(3,2) ˆ 8.6, HÀC(3)); 3.82 (ddd, 3J(2,1') ˆ 1.8, 3J(2,3) ˆ 9.2, 3J(2,1') ˆ 8.6, HÀC(2));
3.69 (dd, 3J(5,4) ˆ 4.2, J ˆ 14.5, 1 HÀC(5)); 3.52 (m, 1 HÀC(5), 1 HÀC(1')); 3.31 (dd, 3J(1',2) ˆ 1.8, 2J ˆ 12.5,
2
HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 151.2, 144.9, 134.7 (arom. C); 117.1, 129.6, 129.7, 131.3, 132.2 (arom.
‡
C); 77.4 (C(3)); 73.5(C(4)); 64.1 (C(2)); 53.4 (C(5)); 46.9 (C(1 ')). CI-MS (NH3): 285(100, [ M ‡ H] ), 170 (7),
116 (11).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(4-phenoxyphenyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9ec). By Method A, with 8 (121 mg, 0.45mmol), 4-phenoxybenzenamine
(83 mg, 0.45mmol), NaBH(OAc) 3 (134 mg, 0.63 mmol), and ClCH2CH2Cl (4 ml). FC (Et2O/light petroleum
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ether 2 :3) gave 141 mg (72% of 9ec), 1.6 :1 mixture of rotamers a and b. [a] ˆ À8, [a] ˆ À9, [a] ˆ À12,
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[a] ˆ À20, [a] ˆ À26 (c ˆ 0.46, CH2Cl2). UV (MeCN): 254 (18900), 212 (15485). IR (film): 3020, 2980,
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2935, 1685, 1590, 1510, 1490, 1410, 1370, 1215, 1160, 1130, 1055, 870, 760, 670. 1H-NMR (400 MHz, MeOD): 7.26
(m, 2 arom. H); 6.98 (t, 3J ˆ 7.3, 1 arom. H); 6.87 (m, 4 arom. H); 6.71 (m, 2 arom. H); 4.77 (t, 3J(6a,3a) ˆ 5.3,
3J(6a,6) ˆ 5.3, HÀC(6a)); 4.68 (m, HÀC(3a)); 4.23 (m, HÀC(4)); 3.82 (d, 2J ˆ 12.9, 1 HÀC(6)a); 3.71 (d, 2J ˆ
12.8, 1 HÀC(6)b); 3.38 (m, 2 HÀC(6)); 3.16 (m, 2 HÀC(1')); 1.49 (s, (t-Bu)b); 1.47 (s, (t-Bu)a); 1.41 (s, 1 Me);
1.31 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 161.4 (s, arom. C); 157.3 (s, NCOOb); 157.1 (s, NCOOa); 149.4
(s, arom. C); 147.1 (s, arom. C); 131.4 (d, 1J(C,H) ˆ 159, 2 arom. C); 123.7 (d, 1J(C,H) ˆ 161, arom. C); 123.0
(d, 1J(C,H) ˆ 165, 2 arom. C); 118.8 (d, 1J(C,H) ˆ 154, 2 arom. C); 115.3 (d, 1J(C,H) ˆ 159, arom. C); 115.2
(d, 1J(C,H) ˆ 158, arom. C); 113.4 (s); 85.2 (d, 1J(C,H) ˆ 157, C(3a)a); 84.8 (d, 1J(C,H) ˆ 157, C(3a)b); 82.4
(s, Me3COa); 82.1 (s, Me3COb); 81.5( d, 1J(C,H) ˆ 159, C(6a)b); 80.8 (d, 1J(C,H) ˆ 158, C(6a)a); 65.3
(d, 1J(C,H) ˆ 146, C(4)b); 64.9 (d, 1J(C,H) ˆ 148, C(4)a); 54.1 (t, 1J(C,H) ˆ 143, C(6)b); 53.1 (t, 1J(C,H) ˆ 144,
C(6)a); 45.8 (t, 1J(C,H) ˆ 136, C(1')b); 45.5 (t, 1J(C,H) ˆ 136, C(1')a); 29.6 (q, 1J(C,H) ˆ 127, Me3C); 28.0
(q, 1J(C,H) ˆ 126, Me); 25.9 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3): 441 (100, [M ‡ H] ), 440 (33, M ), 385(30),
334 (4), 242 (4), 198 (19), 142 (3), 85(8). Anal. calc. for C 25H32N2O5 (440.56): C 68.16, H 7.32; found: C 68.18, H
7.41.
‡
‡
(2R,3R,4S)-2-{[(4-Phenoxyphenyl)amino]methyl}pyrrolidine-3,4-diol (3ec). By Method Aa, with 9ec
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(40 mg). FC (MeCN/NH4OH 4 :1) gave 40 mg (100% of 3ec). [a] ˆ ‡30, [a] ˆ ‡30, [a] ˆ ‡40,
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[a] ˆ ‡52, [a] ˆ ‡55 (c ˆ 0.19, MeOH). UV (MeCN): 306 (2850), 250 (17225), 208 (20385). IR (film):
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3060, 2990, 1665, 1510, 1440, 1180, 1140, 890, 840, 800, 745, 725, 690, 665. 1H-NMR (400 MHz, MeOD): 7.30
(m, 2 arom. H); 7.02 (t, 3J ˆ 7.4, 1 arom. H); 6.89 (m, 4 arom. H); 6.77 (m, 2 arom. H); 4.32 (m, HÀC(4)); 4.11
(dd, 3J(3,2) ˆ 8.8, 3J(3,4) ˆ 4.1, HÀC(3)); 3.77 (ddd, 3J(2,1') ˆ 3.7, 3J(2,3) ˆ 8.8, 3J(2,1') ˆ 8.8, HÀC(2)); 3.62
(dd, 3J(1',2) ˆ 3.7, 2J ˆ 14.3, 1 HÀC(1')); 3.52 (m, 1 HÀC(1'), 1 HÀC(5)); 3.30 (dd, 3J(5,4) ˆ 1.9, 2J ˆ 12.6,
1 HÀC(5)). 13C-NMR (100.6 MHz, MeOD): 161.3 (s, arom. C); 150.5 (s, arom. C); 146.6 (s, arom. C); 131.4
(d, 1J(C,H) ˆ 159, 2 arom. C); 124.0 (d, 1J(C,H) ˆ 168, arom. C); 122.9 (d, 1J(C,H) ˆ 161, 2 arom. C); 118.9
(d, 1J(C,H) ˆ 161, 2 arom. C); 116.2 (d, 1J(C,H) ˆ 159, 2 arom. C); 75.7 (d, 1J(C,H) ˆ 145, C(3)); 71.9
(d, 1J(C,H) ˆ 152, C(4)); 62.3 (d, 1J(C,H) ˆ 146, C(2)); 51.7 (t, 1J(C,H) ˆ 149, C(5)); 45.7 (t, 1J(C,H) ˆ 138,
‡
C(1')). CI-MS (NH3): 301 (100, [M ‡ H] ), 283 (3), 263 (8), 237 (2), 209 (85), 186 (62), 163 (2), 129 (6), 102
(52).
tert-Butyl (3aR,4R,6aS)-4-[(Benzylamino)methyl]tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]pyrrole-
5-carboxylate (9f). By Method A, with 8 (3.05g, 11.3 mmol), benzylamine (1.2 ml, 11.3 mmol), NaBH(OAc) 3
(3.34 g, 15.8 mmol), and ClCH2CH2Cl (100 ml). FC (AcOEt/light petroleum ether 8 :2) gave 3.0 g (74% of 9f),

Helvetica Chimica Acta Vol. 86 (2003)
1927
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1.2 :1 mixture of rotamers a and b. [a] ˆ À36, [a] ˆ À37, [a] ˆ À40, [a] ˆ À68, [a] ˆ À82 (c ˆ 0.57,
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CH2Cl2). UV (MeCN): 211 (8065). IR (film): 3340, 2980, 2935, 1695, 1455, 1405, 1210, 1160, 1125, 1055, 980,
860, 740, 700. H-NMR (400 MHz, MeOD): 7.35( m, 5arom. H); 4.76 ( m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.9,
1
HÀC(3a)a);4.58(d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b);4.15(t, 3J(4,1') ˆ 6.5,HÀC(4)b);4.08(t, 3J(4,1') ˆ 6.5,HÀC(4)a);
3.85 3.75( m, 1 HÀC(6), 2 HÀC(1'')); 3.36 (m, 1 HÀC(6)); 2.64 (m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.42 (s, t-Bu);
1.32 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 141.8 (s, arom. C); 130.3
(d, 1J(C,H) ˆ 159, 3 arom. C); 129.0 (d, 1J(C,H) ˆ 157, 2 arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 156, C(3a)a);
84.9 (d, 1J(C,H) ˆ 157, C(3a)b); 82.2 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 152, C(6a)b); 80.9
(d, 1J(C,H) ˆ 158, C(6a)a); 65.9 (d, 1J(C,H) ˆ 146, C(4)a); 65.2 (d, 1J(C,H) ˆ 143, C(4)b); 55.1 (t, 1J(C,H) ˆ 135,
C(1'')); 53.8 (t, 1J(C,H) ˆ 145, C(6)b); 53.3 (t, 1J(C,H) ˆ 143, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127,
Me3C); 28.1 (q, 1J(C,H) ˆ 122, Me); 25.8 (q, 1J(C,H) ˆ 129, Me). CI-MS (NH3): 363 (100, [M ‡ H] ), 336 (13),
‡
307 (37), 247 (9), 178 (11), 153 (19), 120 (50). Anal. calc. for C20H30N2O4 (362.49): C 66.27, H 8.34; found: C
66.35, H 8.26.
(2R,3R,4S)-2-[(Benzylamino)methyl]pyrrolidine-3,4-diol (3f). By Method Aa, with 9f (23 mg). FC
(MeCN/NH4OH 4 :1) gave 25mg (100% of 3f). IR(film): 3450, 1675, 1435, 1205, 1130, 845, 800, 760, 725,
700. 1H-NMR (400 MHz, D2O): 7.54 (m, 5arom. H); 4.37 ( ddd, 3J(4,5) ˆ 1.6, 3J(4,5) ˆ 4.2, 3J(4,3) ˆ 4.2,
HÀC(4)); 4.29 (m, HÀC(1'')); 4.16 (dd, 3J(3,4) ˆ 4.2, 3J(3,2) ˆ 8.6, HÀC(3)); 3.73 (ddd, 3J(2,1') ˆ 4.2, 3J(2,3) ˆ
8.6, 3J(2,1') ˆ 8.6, HÀC(2)); 3.52 (dd, 3J(5,4) ˆ 4.2, 2J ˆ 13.1, 1 HÀC(5)); 3.46 (m, 2 HÀC(1')); 3.37
(dd, 3J(5,4) ˆ 1.6, 2J ˆ 13.1, 1 HÀC(5)). 13C-NMR (100.6 MHz, D2O): 134.2 (s, arom. C); 132.2 (d, 1J(C,H) ˆ
157, 2 arom. C); 131.9 (d, 1J(C,H) ˆ 159, arom. C); 131.7 (d, 1J(C,H) ˆ 162, 2 arom. C); 76.6 (d, 1J(C,H) ˆ 146,
C(3)); 71.7 (d, 1J(C,H) ˆ 156, C(4)); 59.6 (d, 1J(C,H) ˆ 145, C(2)); 54.4 (t, 1J(C,H) ˆ 145, C(1'')); 52.8
‡
‡
(t, 1J(C,H) ˆ 146, C(5)); 49.6 (t, 1J(C,H) ˆ 144, C(1')). CI-MS (NH3): 223 (100, [M ‡ H] ), 222 (43, M ), 211
(4), 120 (22), 91 (25), 77 (29).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(2-methylbenzyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fa). By Method B, with 10 (148 mg, 0.54 mmol), o-tolualdehyde (65mg,
0.54 mmol), NaBH(OAc)3 (161 mg, 0.76 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 139 mg (68% of
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9fa), 1.15:1 mixture of rotamers a and b. [a] ˆ À51, [a] ˆ À56, [a] ˆ À64, [a] ˆ À115, [a] ˆ À141
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(c ˆ 0.40, CH2Cl2). UV (MeCN): 250 (3400), 211 (15000). IR (film): 3335, 2980, 2935, 1700, 1455, 1405, 1210,
1170, 1125, 1055, 975, 860, 745. 1H-NMR (400 MHz, MeOD): 7.30 (m, 1 arom. H); 7.17 (m, 3 arom. H); 4.74
(m, HÀC(6a)); 4.65( d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.61 (d, 3J(3a,6a) ˆ 5.7, HÀC(3a)b); 4.20 4.15
(m, HÀC(4)); 3.81 (m, 1 HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.72 (m, 2 HÀC(1')); 2.37 (s, arom.
Me); 1.50 (s, 1 Me); 1.44 (s, (t-Bu)b); 1.43 (s, (t-Bu)a); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5
(NCOOb); 157.1 (NCOOa); 139.7 (arom. C); 138.3 (arom. C); 132.1 (arom. C); 130.3 (arom. C); 129.0 (arom.
C); 127.7 (arom. C); 113.3 (Me2C); 85.6 (C(3a)a); 85.0 (C(3a)b); 82.2 (Me3COa); 82.1 (Me3COb); 81.6 (C(6a)b);
80.8 (C(6a)a); 65.9 (C(4)a); 65.3 (C(4)b); 53.9 (C(6)b); 53.3 (C(6a)); 52.8 (C(1'')); 50 49 (C(1')); 29.6 (Me3C);
‡
‡
27.9 (Me); 25.6 (Me); 20.0 (arom. Me). CI-MS (NH3): 378 (98, [M ‡ H] ), 377 (100, M ), 321 (47), 277 (8), 238
(9), 187 (6), 134 (27), 105(54), 85(5). Anal. calc. for C 21H32N2O4 (376.51): C 66.99, H 8.57; found: C 66.86, H
8.50.
(2R,3R,4S)-2-{[(2-Methylbenzyl)amino]methyl}pyrrolidine-3,4-diol (3fa). By Method Aa, with 9fa
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(30 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3fa). [a] ˆ ‡12, [a] ˆ ‡16, [a] ˆ ‡16,
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[a] ˆ ‡31, [a] ˆ ‡33 (c ˆ 0.39, MeOH). UV (MeCN): 265 (350), 210 (3250). IR (film): 3060, 1660, 1420,
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1200, 1135, 840, 800, 750, 720. H-NMR (400 MHz, MeOD): 7.43 (d, 3J ˆ 6.7, 1 arom. H); 7.27 (m, 3 arom. H);
4.27 (ddd, 3J(4,5) ˆ 1.5, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.12 (AB, 2 HÀC(1'')); 4.06 (dd, 3J(3,4) ˆ 4.0,
3J(3,2) ˆ 8.6, HÀC(3)); 3.72 (ddd, 3J(2,1') ˆ 4.1, 3J(2,3) ˆ 8.6, 3J(2,1') ˆ 8.6, HÀC(2)); 3.49 (dd, 3J(5,4) ˆ 4.0,
2J ˆ 12.6, 1 HÀC(5)); 3.40 3.29 (m, 1 HÀC(5), 2 HÀC(1')); 2.42 (s, arom. Me). 13C-NMR (100.6 MHz,
MeOD): 139.1 (s, arom. C); 135.5 (s, arom. C); 132.6 (d, 1J(C,H) ˆ 158, arom. C); 131.4 (d, 1J(C,H) ˆ 159, arom.
C); 130.5( d, 1J(C,H) ˆ 161, arom. C); 128.2 (d, 1J(C,H) ˆ 161, arom. C); 76.3 (d, 1J(C,H) ˆ 145, C(3)); 71.7
(d, 1J(C,H) ˆ 149, C(4)); 61.0 (d, 1J(C,H) ˆ 148, C(2)); 52.2, 52.0 (2t, 1J(C,H) ˆ 149, 1J(C,H) ˆ 145, C(5),
1
C(1'')); 50 49 (C(1')); 22.2 (q, 1J(C,H) ˆ 127, arom. Me). CI-MS (NH3): 237 (100, [M ‡ H] ), 134 (9), 122 (2),
‡
105(24), 85(12).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(3-methylbenzyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fb). By Method B, with 10 (100 mg, 0.37 mmol), m-tolualdehyde (44 mg,
0.37 mmol), NaBH(OAc)3 (109 mg, 0.51 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 40 mg (30% of
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9fb), 1.2 :1 mixture of rotamers. [a] ˆ À30, [a] ˆ À30, [a] ˆ À40, [a] ˆ À76, [a] ˆ À96 (c ˆ 0.43,
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CH2Cl2). UV (MeCN): 213 (11770). IR (film): 3335, 2980, 2935, 1695, 1610, 1455, 1405, 1370, 1210, 1170, 1125,
1055, 975, 860, 770, 700. 1H-NMR (400 MHz, MeOD): 7.24 7.08 (m, 4 arom. H); 4.76 (m, HÀC(6a)); 4.63

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Helvetica Chimica Acta Vol. 86 (2003)
(d, 3J(3a,6a) ˆ 5.7, HÀC(3a)a); 4.57 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b); 4.20 (m, HÀC(4)b); 4.09 (m, HÀC(4)a);
3.83 3.71 (m, 1 HÀC(6), 2 HÀC(1'')); 3.37 (m, 1 HÀC(6)); 2.65( m, 2 HÀC(1')); 2.35( s, arom. Me); 1.49
(s, 1Me); 1.42 (s, t-Bu); 1.31 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.6 (s, NCOOb); 157.3 (s, NCOOa);
141.6 (s, arom. C); 140.0 (s, arom. C); 131.0 (d, 1J(C,H) ˆ 155, arom. C); 130.3 (d, 1J(C,H) ˆ 159, arom. C); 129.8
(d, 1J(C,H) ˆ 157, arom. C); 127.3 (d, 1J(C,H) ˆ 156, arom. C); 113.5 (s); 85.5 (d, 1J(C,H) ˆ 156, C(3a)a); 84.9
(d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.2 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 151, C(6a)b); 80.9
(d, 1J(C,H) ˆ 157, C(6a)a); 65.8 (d, 1J(C,H) ˆ 149, C(4)a); 65.1 (d, 1J(C,H) ˆ 142, C(4)b); 55.0 (t, 1J(C,H) ˆ
134, C(1'')); 53.7 (t, 1J(C,H) ˆ 143, C(6)b); 53.2 (t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ
127, Me3C); 28.0 (q, 1J(C,H) ˆ 129, Me); 25.8 (q, 1J(C,H) ˆ 126, Me); 22.3 (q, 1J(C,H) ˆ 126, arom. Me). CI-MS
‡
(NH3): 377 (100, [M ‡ H] ), 321 (46), 277 (3), 243 (4), 187 (9), 134 (37), 105(67), 77 (11). Anal. calc. for
C21H32N2O4 (376.51): C 66.99, H 8.57; found: C 67.01, H 8.60.
(2R,3R,4S)-2-{[(3-Methylbenzyl)amino]methyl}pyrrolidine-3,4-diol (3fb). By Method Aa, with 9fb
25
25
25
(40 mg). FC (MeCN/NH4OH 4 :1) gave 25mg (100% of 3fb). [a] ˆ ‡12, [a] ˆ ‡14, [a] ˆ ‡15,
589
577
546
25
25
[a] ˆ ‡20, [a] ˆ ‡21 (c ˆ 0.34, MeOH). UV (MeCN): 262 (920), 217 (3000), 205(860). IR (film): 3070,
435
405
1650, 1470, 1440, 1175, 840, 800, 725, 700. 1H-NMR (400 MHz, MeOD): 7.35 7.22 ( m, 4 arom. H); 4.27
(ddd, 3J(4,5) ˆ 1.4, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.16 (s, 2 HÀC(1'')); 4.08 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ
8.9, HÀC(3)); 3.77 (ddd, 3J(2,1') ˆ 5.0, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9, HÀC(2)); 3.52 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6,
1 HÀC(5)); 3.43 3.31 (m, 1 HÀC(5), 2 HÀC(1')); 2.39 (s, arom. Me). 13C-NMR (100.6 MHz, MeOD): 140.8
(s, arom. C); 135.2 (s, arom. C); 132.2 (d, 1J(C,H) ˆ 157, arom. C); 131.6 (d, 1J(C,H) ˆ 159, arom. C); 130.8
(d, 1J(C,H) ˆ 161, arom. C); 128.6 (d, 1J(C,H) ˆ 160, arom. C); 76.4 (d, 1J(C,H) ˆ 144, C(3)); 71.4 (d, 1J(C,H) ˆ
155, C(4)); 59.9 (d, 1J(C,H) ˆ 147, C(2)); 54.1 (t, 1J(C,H) ˆ 142, C(1'')); 52.4 (t, 1J(C,H) ˆ 149, C(5)); 50 49
(C(1')); 22.2 (q, 1J(C,H) ˆ 127, arom. Me). CI-MS (NH3): 237 (100, [M ‡ H] ), 205(1), 154 (2), 134 (19), 120
‡
(4), 105(31), 85(14).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(4-methylbenzyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fc). By Method B, with 10 (105mg, 0.39 mmol), p-tolualdehyde (46 mg,
0.39 mmol), NaBH(OAc)3 (114 mg, 0.54 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 42 mg (29% of
25
25
25
25
25
9fc), 1.3 :1 mixture of rotamers a and b. [a] ˆ À41, [a] ˆ À44, [a] ˆ À47, [a] ˆ À81, [a] ˆ À95( c ˆ
589
577
546
435
405
0.42, CH2Cl2). UV (MeCN): 273 (1300), 265 (1475), 212 (13870). IR (film): 2980, 2935, 1695, 1690, 1515, 1480,
1455, 1405, 1380, 1365, 1210, 1170, 1125, 1055, 975, 860, 805, 770. 1H-NMR (400 MHz, MeOD): 7.22 (m, 4 arom.
H); 4.74 (m, HÀC(6a)); 4.63 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.57 (d, 3J(3a,6a) ˆ 5.7, HÀC(3a)b); 4.18
(t, 3J(4,1') ˆ 6.6, HÀC(4)b); 4.07 (t, 3J(4,1') ˆ 6.4, HÀC(4)a); 3.77 (m, 1 HÀC(6), 2 HÀC(1'')); 3.37
(m, 1 HÀC(6)); 2.62 (m, HÀC(1')); 2.34 (s, arom. Me); 1.50 (s, 1 Me); 1.42 (s, t-Bu); 1.31 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 157.6 (s, NCOOb); 157.3 (s, NCOOa); 138.7 (s, 2 arom. C); 130.9 (d, 1J(C,H) ˆ 158,
2 arom. C); 130.2 (d, 1J(C,H) ˆ 157, 2 arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157,
C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 154, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a);
65.9 (d, 1J(C,H) ˆ 147, C(4)a); 65.3 (d, 1J(C,H) ˆ 145, C(4)b); 54.8 (t, 1J(C,H) ˆ 134, C(1'')); 53.8 (t, 1J(C,H) ˆ
144, C(6)b); 53.3 (t, 1J(C,H) ˆ 143, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 128,
‡
Me); 25.8 (q, 1J(C,H) ˆ 127, Me); 22.0 (q, 1J(C,H) ˆ 126, arom. Me). CI-MS (NH3): 377 (100, [M ‡ H] ), 343
(2), 321 (28), 275(3), 187 (4), 105(65), 77 (6). Anal. calc. for C 21H32N2O4 (376.52): C 66.99, H 8.57; found: C
67.17, H 8.55.
(2R,3R,4S)-2-{[(4-Methylbenzyl)amino]methyl}pyrrolidine-3,4-diol (3fc). By Method Aa, with 9fc
25
25
25
(42 mg). FC (MeCN/NH4OH 4 :1) gave 26 mg (100% of 3fc). [a] ˆ ‡6, [a] ˆ ‡10, [a] ˆ ‡13 (c ˆ
589
577
546
0.43, MeOH). UV (MeCN): 260 (870), 219 (4300), 204 (750). IR (film): 3415, 3060, 2905, 1675, 1470, 1435,
1180, 1135, 840, 800, 725. 1H-NMR (400 MHz, MeOD): 7.39 (d, 3J ˆ 8.0, 2 arom. H); 7.27 (d, 3J ˆ 8.0, 2 arom. H);
4.26 (ddd, 3J(4,5) ˆ 1.5, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.15( s, 2 HÀC(1'')); 4.06 (dd, 3J(3,4) ˆ 4.0,
3J(3,2) ˆ 8.9, HÀC(3)); 3.73 (ddd, 3J(2,1') ˆ 4.8, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9, HÀC(2)); 3.50 (dd, 3J(5,4) ˆ 4.0,
2J ˆ 12.6, 1 HÀC(5)); 3.45 3.34 (m, 1 HÀC(5), 2 HÀC(1')); 2.39 (s, arom. Me). 13C-NMR (100.6 MHz,
MeOD): 141.1 (s, arom. C); 132.2 (s, arom. C); 131.5( d, 1J(C,H) ˆ 159, 4 arom. C); 76.4 (d, 1J(C,H) ˆ 144,
C(3)); 71.5( d, 1J(C,H) ˆ 151, C(4)); 60.1 (d, 1J(C,H) ˆ 146, C(2)); 53.9 (t, 1J(C,H) ˆ 147, C(1'')); 52.4
(t, 1J(C,H) ˆ 145, C(5)); 50 49 (C(1')); 22.1 (q, 1J(C,H) ˆ 135, arom. Me). CI-MS (NH3): 237 (100, [M ‡
‡
H] ), 211 (2), 134 (19), 122 (8), 105(28), 85(10).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-{[(3-hydroxybenzyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fd). By Method B, with 10 (94 mg, 0.35mmol), 3-hydroxybenzaldehyde
(42 mg, 0.35mmol), NaBH(OAc) 3 (102 mg, 0.48 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 76 mg
25
25
25
25
25
(58% of 9fd), 1.3 :1 mixture of rotamers a and b. [a] ˆ À27, [a] ˆ À29, [a] ˆ À37, [a] ˆ À67, [a]
ˆ
589
577
546
435
405
À79 (c ˆ 0.44, CH2Cl2). UV (MeCN): 281 (2310), 274 (2510), 206 (9360). IR (film): 3335, 2980, 2935, 1690,

Helvetica Chimica Acta Vol. 86 (2003)
1929
1590, 1455, 1415, 1370, 1275, 1245, 1210, 1160, 1130, 1055, 860, 785, 740, 700. 1H-NMR (400 MHz, MeOD): 7.17
(m, 1 arom. H); 6.81 (m, 2 arom. H); 6.71 (d, 3J ˆ 7.3, 1 arom. H); 4.77 (m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.8,
HÀC(3a)a); 4.59 (d, 3J(3a,6a) ˆ 5.6, HÀC(3a)b); 4.18 (dd, 3J(4,1') ˆ 6.5, 3J(4,1') ˆ 6.6, HÀC(4)b); 4.08
(dd, 3J(4,1') ˆ 6.6, 3J(4,1') ˆ 6.7, HÀC(4)a); 3.75( m, 1 HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.65
(m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.44 (s, (t-Bu)a); 1.43 (s, (t-Bu)b); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz,
MeOD): 159.5 (s, arom. C); 157.6 (s, NCOOb); 157.3 (s, NCOOa); 143.3 (s, arom. C); 131.3 (d, 1J(C,H) ˆ 158,
arom. C); 121.3 (d, 1J(C,H) ˆ 159, arom. C); 117.0 (d, 1J(C,H) ˆ 158, arom. C); 116.0 (d, 1J(C,H) ˆ 159, arom.
C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157, C(3a)b); 82.4 (s, Me3COa); 82.2
(s, Me3COb); 81.6 (d, 1J(C,H) ˆ 157, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.9 (d, 1J(C,H) ˆ 146, C(4)a);
65.3 (d, 1J(C,H) ˆ 146, C(4)b); 55.0 (t, 1J(C,H) ˆ 135, C(1'')); 53.8 (t, 1J(C,H) ˆ 143, C(6)b); 53.3 (t, 1J(C,H) ˆ
144, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 127,
‡
Me). CI-MS (NH3): 379 (100, [M ‡ H] ), 343 (6), 323 (22), 273 (5), 217 (3), 153 (47 ), 136 (79), 84 (9).
(2R,3R,4S)-2-{[(3-Hydroxybenzyl)amino]methyl}pyrrolidine-3,4-diol (3fd). By Method Aa, with 9fd
25
(40 mg). FC (MeCN/NH4OH 4 :1) gave 25mg (100% of 3fd). [a] ˆ ‡16 (c ˆ 0.22, CH2Cl2). UV (MeCN):
589
222 (4995). IR (KBr): 3420, 2930, 1675, 1590, 1460, 1280, 1200, 1135, 790, 695. 1H-NMR (400 MHz, MeOD): 7.17
3
3
(t, 3J ˆ 7.8, arom. H); 6.86 6.71 (m, 3 arom. H); 4.16 (ddd, 3J(4,5) ˆ 2.5, J(4,5) ˆ 4.5, J(4,3) ˆ 4.5, HÀC(4));
3
3.85( dd, 3J(3,4) ˆ 4.5, J(3,2) ˆ 7.9, HÀC(3)); 3.81 (s, 2 HÀC(1'')); 3.38 (m, HÀC(2)); 3.30 (dd, 3J(5,4) ˆ 4.5,
2J ˆ 12.4, 1 HÀC(5)); 3.08 (dd, 3J(5,4) ˆ 2.5, 2J ˆ 12.4, 1 HÀC(5)); 2.98 (dd, 3J(1',2) ˆ 4.4, 2J ˆ 12.8, 1 HÀC(1'));
2.80 (dd, 3J(1',2) ˆ 8.6, 2J ˆ 12.8, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 159.6 (s, arom. C); 142.0 (s, arom.
C); 131.9 (d, 1J(C,H) ˆ 160, arom. C); 121.5( d, 1J(C,H) ˆ 160, arom. C); 117.2 (d, 1J(C,H) ˆ 157, arom. C); 116.2
(d, 1J(C,H) ˆ 159, arom. C); 76.8 (d, 1J(C,H) ˆ 146, C(3)); 72.7 (d, 1J(C,H) ˆ 152, C(4)); 62.6 (d, 1J(C,H) ˆ 143,
C(2)); 55.0 (t, 1J(C,H) ˆ 136, C(1'')); 52.3 (t, 1J(C,H) ˆ 142, C(5)); 51.2 (t, 1J(C,H) ˆ 136, C(1')). CI-MS (NH3):
‡
239 (100, [M ‡ H] ), 229 (2), 124 (17), 107 (33), 85(21).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-4-{[(4-hydroxybenzyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fe). By Method B, with 10 (98 mg, 0.36 mmol), 4-hydroxybenzaldehyde
(44 mg, 0.36 mmol), NaBH(OAc)3 (107 mg, 0.50 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 57 mg
25
25
25
25
25
(42% of 9fe), 1.3 :1 mixture of rotamers a and b. [a] ˆ À30, [a] ˆ À33, [a] ˆ À40, [a] ˆ À72, [a]
ˆ
589
577
546
435
405
À96 (c ˆ 0.37, CH2Cl2). UV (MeCN): 277 (3320), 224 (11945), 204 (12075). IR (film): 3340, 2980, 2935, 1675,
1610, 1515, 1455, 1415, 1370, 1260, 1215, 1165, 1125, 1055, 975, 855, 830, 760. 1H-NMR (400 MHz, MeOD): 7.16
(d, 3J ˆ 8.5, 2 arom. H); 6.77 (m, 2 arom. H); 4.75( m, HÀC(6a)); 4.61 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.56
(d, 3J(3a,6a) ˆ 5.7, HÀC(3a)b); 4.18 (t, 3J(4,1') ˆ 6.7, HÀC(4)b); 4.06 (t, 3J(4,1') ˆ 6.6, HÀC(4)a); 3.79 3.64
(m, 1 HÀC(6), 2 HÀC(1'')); 3.36 (m, 1 HÀC(6)); 2.62 (m, 2 HÀC(1')); 1.49 (s, 1 Me); 1.42 (s, (t-Bu)a); 1.41
(s, (t-Bu)b); 1.31 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 158.6 (s, arom. C); 157.6 (s, NCOOb); 157.3
(s, NCOOa); 132.4 (s, arom. C); 131.6 (d, 1J(C,H) ˆ 157, 2 arom. C); 117.0 (d, 1J(C,H) ˆ 158, 2 arom. C); 113.4
(s); 85.5 (d, 1J(C,H) ˆ 157, C(3a)a); 84.9 (d, 1J(C,H) ˆ 156, C(3a)b); 82.4 (s, Me3COa); 82.2 (s, Me3COb); 81.6
(d, 1J(C,H) ˆ 155, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.8 (d, 1J(C,H) ˆ 148, C(4)a); 65.1 (d, 1J(C,H) ˆ
146, C(4)b); 54.5 (t, 1J(C,H) ˆ 136, C(1'')); 53.7 (t, 1J(C,H) ˆ 145, C(6)b); 53.2 (t, 1J(C,H) ˆ 144, C(6)a); 50 49
(C(1')); 29.5( q, 1J(C,H) ˆ 129, Me3C); 28.0 (q, 1J(C,H) ˆ 125, Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3):
‡
‡
380 (75, [M ‡ H] ), 379 (100, M ), 323 (17), 273 (27), 217 (21), 171 (1), 136 (14), 107 (7), 71 (9). Anal. calc. for
C20H30N2O5 (378.50): C 63.47, H 7.99; found: C 63.28, H 7.95.
(2R,3R,4S)-2-{[(4-Hydroxybenzyl)amino]methyl}pyrrolidine-3,4-diol (3fe). By Method Aa, with 9fe
25
25
25
(37 mg). FC (MeCN/NH4OH 4 :1) gave 23 mg (100% of 3fe). [a] ˆ ‡35, [a] ˆ ‡39, [a] ˆ ‡40 (c ˆ
589
577
546
0.37, MeOH). UV (MeCN): 276 (1250), 224 (4895), 207 (790). IR (KBr): 3400, 2940, 1735, 1705, 1605, 1515,
1455, 1255, 1170, 1105, 1030, 835, 770. H-NMR (400 MHz, MeOD): 7.21 (d, 3J ˆ 8.6, 2 arom. H); 6.79 (d, 3J ˆ
1
8.6, 2 arom. H); 4.09 (m, HÀC(4)); 3.77 (s, 2 HÀC(1'')); 3.74 (dd, 3J(3,4) ˆ 4.9, 3J(3,2) ˆ 7.6, HÀC(3)); 3.23
(ddd, 3J(2,1') ˆ 4.8, 3J(2,3) ˆ 7.6, 3J(2,1') ˆ 8.1, HÀC(2)); 3.20 (dd, 3J(5,4) ˆ 4.8, 2J ˆ 12.2, 1 HÀC(5)); 2.94
(dd, 3J(5,4) ˆ 3.0, 2J ˆ 12.2, 1 HÀC(5)); 2.90 (dd, 3J(1',2) ˆ 4.8, 2J ˆ 12.3, 1 HÀC(1')); 2.72 (dd, 3J(1',2) ˆ 8.1,
2J ˆ 12.3, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 158.9 (s, arom. C); 131.8 (d, 1J(C,H) ˆ 156, 2 arom. C);
131.3 (s, arom. C); 117.1 (d, 1J(C,H) ˆ 158, 2 arom. C); 77.7 (d, 1J(C,H) ˆ 144, C(3)); 73.2 (d, 1J(C,H) ˆ 151,
C(4)); 62.7 (d, 1J(C,H) ˆ 143, C(2)); 54.7 (t, 1J(C,H) ˆ 136, C(1'')); 52.9 (t, 1J(C,H) ˆ 141, C(5)); 52.6
(t, 1J(C,H) ˆ 135, C(1')). CI-MS (NH3): 239 (61, [M ‡ H] ), 229 (2), 208 (12), 159 (5), 133 (100), 102 (80),
‡
85(26).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-4-{[(2-methoxybenzyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9ff). By Method A, with 8 (94 mg, 0.35mmol), 2-methoxybenzylamine
(47 mg, 0.35mmol), NaBH(OAc) 3 (104 mg, 0.49 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 78 mg
25
25
25
25
25
(58% of 9ff), 1.3 :1 mixture of rotamers a and b. [a] ˆ À24, [a] ˆ À27, [a] ˆ À32, [a] ˆ À56, [a]
ˆ
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1930
Helvetica Chimica Acta Vol. 86 (2003)
À70 (c ˆ 0.53, CH2Cl2). UV (MeCN): 272 (2730), 218 (9720), 206 (9500). IR (film): 2980, 2935, 2840, 1690,
1
1600, 1590, 1495, 1465, 1405, 1370, 1240, 1215, 1175, 1125, 1055, 1030, 975, 860, 755, 665. H-NMR (400 MHz,
MeOD): 7.28 (m, 2 arom. H); 6.96 (m, 2 arom. H); 4.73 (m, HÀC(6a)); 4.56 (m, HÀC(3a)); 4.15( dd, 3J(4,1') ˆ
6.8, 3J(4,1') ˆ 6.2, HÀC(4)b); 4.09 (dd, 3J(4,1') ˆ 6.8, 3J(4,1') ˆ 6.2, HÀC(4)a); 3.87 (s, MeO); 3.80
2
(m, 1 HÀC(6), 1 HÀC(6)b, 2 HÀC(1'')); 3.34 (m, 1 HÀC(6)b); 3.23 (dd, 3J(6,6a) ˆ 4.8, J ˆ 12.9, 1 HÀC(6)a);
2.63 (m, 2 HÀC(1')); 1.50 (s, Me); 1.43 (s, (t-Bu)b); 1.41 (s, (t-Bu)a); 1.31 (s, Me). 13C-NMR (100.6 MHz,
MeOD): 160.1 (arom. C); 157.6 (NCOOb); 157.3 (NCOOa); 132.0 (arom. C); 130.7 (arom. C); 130.3 (arom. C);
122.3 (arom. C); 113.5(Me 2C); 112.4 (arom. C); 85.6 (C(3a)a); 85.0 (C(3a)b); 82.4 (Me3COa); 82.2 (Me3COb);
81.6 (C(6a)b); 80.9 (C(6a)a); 65.8 (C(4)a); 65.3 (C(4)b); 56.5 (MeO); 53.7 (C(6)b); 53.0 (C(6)a); 50 49 (C(1'),
‡
C(1'')); 29.5( Me3C); 28.0 (Me); 25.8 (Me). CI-MS (NH3): (100, [M ‡ H] ), 392 (61), 337 (27), 273 (9), 217 (6),
171 (2), 150 (22), 121 (27), 91 (15). Anal. calc. for C21H32N2O5 (392.53): C 64.26, H 8.22, N 7.14; found: C 63.88,
H 8.06, N 7.19.
(2R,3R,4S)-2-{[(2-Methoxybenzyl)amino]methyl}pyrrolidine-3,4-diol (3ff). By Method Aa, with 9ff
25
25
25
(30 mg). FC (MeCN/NH4OH 4 :1) gave 32 mg (100% of 3ff). [a] ˆ ‡14, [a] ˆ ‡15, [a] ˆ ‡16,
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577
546
25
25
[a] ˆ ‡29, [a] ˆ ‡36 (c ˆ 0.31, MeOH). UV (MeCN): 274 (1540), 220 (4065), 202 (4725). IR (film): 3040,
435
405
1670, 1500, 1440, 1325, 1290, 1255, 1200, 1135, 1025, 840, 800, 760, 725. 1H-NMR (400 MHz, MeOD): 7.41
(m, 2 arom. H); 7.08 (d, 3J ˆ 8.2, 1 arom. H); 7.01 (ddd, 3J ˆ 7.5, J ˆ 8.2, 4J ˆ 0.6, 1 arom. H); 4.23 (ddd, 3J(4,5) ˆ
3
1.8, 3J(4,5) ˆ 4.1, 3J(4,3) ˆ 4.2, HÀC(4)); 4.14 (s, 2 HÀC(1'')); 3.98 (dd, 3J(3,4) ˆ 4.2, 3J(3,2) ˆ 8.5, HÀC(3));
3.94 (s, MeO); 3.62 (ddd, 3J(2,1') ˆ 4.6, 3J(2,3) ˆ 8.5, 3J(2,1') ˆ 8.5, HÀC(2)); 3.40 (dd, 3J(5,4) ˆ 4.1, 2J ˆ 12.5,
1 HÀC(5)); 3.22 (m, 1 HÀC(1'), 1 HÀC(5)); 3.13 (dd, 3J(1',2) ˆ 4.6, 2J ˆ 13.3, 1 HÀC(1')). 13C-NMR
(100.6 MHz, MeOD): 158.4 (s, arom. C); 132.9 (d, 1J(C,H) ˆ 157, arom. C); 132.5 (d, 1J(C,H) ˆ 160, arom.
C); 124.7 (s, arom. C); 122.7 (d, 1J(C,H) ˆ 162, arom. C); 112.7 (d, 1J(C,H) ˆ 160, arom. C); 76.7 (d, 1J(C,H) ˆ
144, C(3)); 72.1 (d, 1J(C,H) ˆ 149, C(4)); 60.6 (d, 1J(C,H) ˆ 145, C(2)); 56.9 (q, 1J(C,H) ˆ 145, MeO); 52.4
(t, 1J(C,H) ˆ 144, C(1'')); 50 49 (C(5), C(1')). CI-MS (NH3): 253 (81, [M ‡ H] ), 235(6), 192 (5), 163 (3), 150
‡
(53), 136 (33), 121 (100), 108 (52), 91 (35).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-4-{[(3-methoxybenzyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fg). By Method A, with 8 (97 mg, 0.36 mmol), 3-methoxybenzylamine
(49 mg, 0.36 mmol), NaBH(OAc)3 (106 mg, 0.50 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 77 mg
25
25
25
25
25
(55% of 9fg), 1.2 :1 mixture of rotamers a and b. [a] ˆ À20, [a] ˆ À22, [a] ˆ À29, [a] ˆ À51, [a]
ˆ
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577
546
435
405
À64 (c ˆ 0.49, CH2Cl2). UV (MeCN): 273 (2435), 203 (15120). IR (film): 2980, 2940, 1695, 1600, 1585, 1490,
1455, 1405, 1370, 1265, 1210, 1160, 1125, 1055, 860, 780, 740, 695. 1H-NMR (400 MHz, MeOD): 7.26 (m, 1 arom.
H); 6.96 (s, 1 arom. H); 6.93 (d, 3J ˆ 7.5, 1 arom. H); 6.84 (d, 3J ˆ 7.5, 1 arom. H); 4.76 (m, HÀC(6a)); 4.65
(d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.59 (d, 3J(3a,6a) ˆ 5.6, HÀC(3a)b); 4.19 (m, HÀC(4)b); 4.08 (m, HÀC(4)a);
3.82 (s, MeO); 3.79 (m, 2 HÀC(1''), 1 HÀC(6)); 3.38 (m, 1 HÀC(6)); 2.65( m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.43
(s, t-Bu); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 162.2 (s, arom. C); 15 7.5 s(, NCOOb); 157.2
(s, NCOOa); 143.4 (s, arom. C); 131.3 (d, 1J(C,H) ˆ 159, arom. C); 122.4 (d, 1J(C,H) ˆ 158, arom. C); 115.7
(d, 1J(C,H) ˆ 158, arom. C); 114.7 (d, 1J(C,H) ˆ 161, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 156, C(3a)a); 85.0
(d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 143, C(6a)b); 80.9
(d, 1J(C,H) ˆ 158, C(6a)a); 65.9 (d, 1J(C,H) ˆ 148, C(4)a); 65.3 (d, 1J(C,H) ˆ 145, C(4)b); 56.5 (q, 1J(C,H) ˆ
144, MeO); 55.1 (t, 1J(C,H) ˆ 135, C(1'')); 53.8 (t, 1J(C,H) ˆ 143, C(6)b); 53.3 (t, 1J(C,H) ˆ 144, C(6)a); 50 49
(C(1')); 29.5( q, 1J(C,H) ˆ 126, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3):
‡
393 (94, [M ‡ H] ), 363 (8), 337 (24), 287 (5), 258 (100), 231 (9), 166 (70), 121 (42), 91 (12). Anal. calc. for
C21H32N2O5 (392.53): C 64.26, H 8.22; found: C 64.36, H 8.29.
(2R,3R,4S)-2-{[(3-Methoxybenzyl)amino]methyl}pyrrolidine-3,4-diol (3fg). By Method Aa, 9fg (33 mg).
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25
25
25
FC (MeCN/NH4OH 4 :1) gave 21 mg (100% of 3fg). [a] ˆ ‡16, [a] ˆ ‡26, [a] ˆ ‡26, [a] ˆ ‡37,
589
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546
435
25
[a] ˆ ‡42 (c ˆ 0.12, MeOH). UV (MeCN): 275 (1625), 220 (4555), 204 (6325). IR (film): 3055, 1670, 1435,
405
1265, 1205, 1140, 1040, 895, 840, 800, 725, 700. 1H-NMR (400 MHz, MeOD): 7.32 (m, 1 arom. H); 7.05
(m, 2 arom. H); 6.93 (m, 2 arom. H); 4.25( m, HÀC(4)); 4.05( s, 2 HÀC(1'')); 4.02 (dd, 3J(3,2) ˆ 8.8, J(3,4) ˆ
3
4.1, HÀC(3)); 3.84 (s, MeO); 3.65( ddd, 3J(2,1') ˆ 4.6, J(2,3) ˆ 8.8, J(2,1') ˆ 8.8, HÀC(2)); 3.46 (dd, 3J(5,4) ˆ
4.1, 2J ˆ 12.6, 1 HÀC(5)); 3.27 (m, 1 HÀC(5), 1 HÀC(1')); 3.15( dd, 3J(1',2) ˆ 8.8, 2J ˆ 13.4, 1 HÀC(1')).
13C-NMR (100.6 MHz, MeOD): 164.2 (s, arom. C); 139.2 (s, arom. C); 131.8 (d, 1J(C,H) ˆ 160, arom. C); 123.1
(d, 1J(C,H) ˆ 160, arom. C); 116.3 (d, 1J(C,H) ˆ 158, arom. C); 115.9 (d, 1J(C,H) ˆ 166, arom. C); 76.2
(d, 1J(C,H) ˆ 145, C(3)); 71.8 (d, 1J(C,H) ˆ 154, C(4)); 61.1 (d, 1J(C,H) ˆ 147, C(2)); 56.6 (t, 1J(C,H) ˆ 144,
MeO); 54.4 (t, 1J(C,H) ˆ 144, C(1'')); 52.1 (t, 1J(C,H) ˆ 148, C(5)); 50 49 (C(1')). CI-MS (NH3): 253 (100,
3
3
‡
[M ‡ H] ), 240 (28), 222 (18), 197 (2), 184 (10), 150 (9), 121 (12), 102 (6).

Helvetica Chimica Acta Vol. 86 (2003)
1931
tert-Butyl (3aR,4R,6aS)-Tetrahydro-4-{[(4-methoxybenzyl)amino]methyl}-2,2-dimethyl-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9fh). By Method A, with 8 (134 mg, 0.49 mmol), 4-methoxybenzylamine
(65 ml, 0.49 mmol), NaBH(OAc)3 (145mg, 0.69 mmol), and ClCH 2CH2Cl (3 ml). FC (AcOEt) gave 157 mg
25
25
25
25
25
(81% of 9fh), 1.2 :1 mixture of rotamers a and b. [a] ˆ À32, [a] ˆ À36, [a] ˆ À39, [a] ˆ À68, [a]
ˆ
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546
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À83 (c ˆ 0.58, CH2Cl2). UV (MeCN): 276 (2905), 225 (11910), 203 (11315). IR (film): 2980, 2935, 2835, 1695,
1
1690, 1610, 1515, 1455, 1405, 1245, 1175, 1125, 1055, 1040. H-NMR (400 MHz, MeOD): 7.26 (m, 2 arom. H);
6.89 (m, 2 arom. H); 4.73 (m, HÀC(6a)); 4.62 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.56 (d, 3J(3a,6a) ˆ 5.8,
HÀC(3a)b); 4.18 (dd, 3J(4,1') ˆ 6.5, 3J(4,1') ˆ 6.8, HÀC(4)b); 4.06 (dd, 3J(4,1') ˆ 6.7, 3J(4,1') ˆ 6.6, HÀC(4)a);
3.79 (s, MeO); 3.73 (m, 1HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.62 (m, 2 HÀC(1')); 1.49 (s, Me); 1.42
(s, (t-Bu)a); 1.41 (s, (t-Bu)b); 1.31 (s, 2 Me). 13C-NMR (100.6 MHz, MeOD): 161.2 (s, arom. C); 157.5
(s, NCOOb); 157.2 (s, NCOOa); 133.7 (s, arom. C); 131.5( d, 1J(C,H) ˆ 158, 2 arom. C); 115.7 (d, 1J(C,H) ˆ
159, 2 arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa);
82.2 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 148, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.9 (d, 1J(C,H) ˆ 145,
C(4)a); 65.2 (d, 1J(C,H) ˆ 144, C(4)b); 56.5 (q, 1J(C,H) ˆ 144, MeO); 54.5 (t, 1J(C,H) ˆ 135, C(1'')); 53.8
(t, 1J(C,H) ˆ 143, C(6)b); 53.3 (t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1
‡
(q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 393 (100, [M ‡ H] ), 337 (15), 273 (13), 187
(1), 150 (5), 121 (24), 84 (33). Anal. calc. for C21H32N2O5 (392.53): C 64.26, H 8.22; found: C 64.31, H 8.09.
(2R,3R,4S)-2-{[(4-Methoxybenzyl)amino]methyl}pyrrolidine-3,4-diol (3fh). By Method Aa, with 9fh
25
25
25
(33 mg). FC (MeCN/NH4OH 4 :1) gave 30 mg (100% of 3fh). [a] ˆ ‡9, [a] ˆ ‡12, [a] ˆ ‡13,
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577
546
25
25
[a] ˆ ‡25, [a] ˆ ‡29 (c ˆ 0.30, MeOH). UV (MeCN): 274 (1785), 228 (10225), 202 (9235). IR (film):
435
405
3055, 1660, 1515, 1470, 1445, 1345, 1305, 1255, 1180, 1130, 1030, 840, 815, 800, 740, 725, 705. 1H-NMR (400 MHz,
MeOD): 7.39 (d, 3J ˆ 8.7, 2 arom. H); 6.96 (d, 3J ˆ 8.7, 2 arom. H); 4.23 (m, HÀC(4)); 4.05( s, 2 HÀC(1'')); 4.01
(dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.6, HÀC(3)); 3.82 (s, MeO); 3.64 (ddd, 3J(2,1') ˆ 4.3, 3J(2,3) ˆ 8.6, 3J(2,1') ˆ 8.6,
HÀC(2)); 3.43 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.26 (m, 1 HÀC(5), 1 HÀC(1')); 3.17 (dd, 3J(1',2) ˆ 8.6,
2J ˆ 13.4, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 162.3 (s, arom. C); 132.7 (d, 1J(C,H) ˆ 163, 2 arom. C);
128.4 (s, arom. C); 116.1 (d, 1J(C,H) ˆ 164, 2 arom. C); 76.4 (d, 1J(C,H) ˆ 145, C(3)); 71.8 (d, 1J(C,H) ˆ 154,
C(4)); 60.7 (d, 1J(C,H) ˆ 146, C(2)); 56.6 (t, 1J(C,H) ˆ 144, MeO); 53.8 (t, 1J(C,H) ˆ 141, C(1'')); 52.3
(t, 1J(C,H) ˆ 147, C(5)); 50 49 (C(1')). CI-MS (NH3): 253 (100, [M ‡ H] ), 215(3), 180 (2), 150 (7), 121
‡
(84), 102 (16), 77 (26).
tert-Butyl (3aR,4R,6aS)-4-{[(2-Fluorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fi). By Method A, with 8 (67 mg, 0.25mmol), 2-fluorobenzylamine (31 mg,
0.25mmol), NaBH(OAc) 3 (73 mg, 0.35mmol), and ClCH 2CH2Cl (3 ml). FC (AcOEt/light petroleum ether
25
25
25
8 :2) gave 52 mg (55% of 9fi), 1.3 :1 mixture of rotamers a and b. [a] ˆ À26, [a] ˆ À27, [a] ˆ À33,
589
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546
25
25
[a] ˆ À61, [a] ˆ À73 (c ˆ 0.36, CH2Cl2). UV (MeCN): 268 (1800), 262 (1910), 206 (11900). IR (film): 3340,
435
405
2980, 2935, 1695, 1585, 1490, 1455, 1405, 1160, 1125, 1055, 975, 860, 760. 1H-NMR (400 MHz, MeOD): 7.44
(m, 3J ˆ 7.5, 1 arom. H); 7.32 (m, 1 arom. H); 7.19 (m, 1 arom. H); 7.10 (m, 1 arom. H); 4.77 (m, HÀC(6a)); 4.65
(d, 3J(3a,6a) ˆ 5.7, HÀC(3a)a); 4.61 (d, 3J(3a,6a) ˆ 5.6, HÀC(3a)b); 4.18 (t, 3J(4,1') ˆ 6.4, HÀC(4)b); 4.09
(t, 3J(4,1') ˆ 6.3, HÀC(4)a); 3.87 (m, 1 HÀC(6), 2 HÀC(1'')); 3.39 (m, 1 HÀC(6)); 2.67 (m, 2 HÀC(1')); 1.50
(s, 1 Me); 1.44 (s, (t-Bu)b); 1.43 (s, (t-Bu)a); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 165.4 (d, 2J(C,F) ˆ
245, arom. C); 157.6 (s, NCOOb); 157.3 (s, NCOOa); 132.5( s, arom. C); 131.0 (d, 1J(C,H) ˆ 161, arom. C); 126.2
(d, 1J(C,H) ˆ 161, arom. C); 117.1 (d, 1J(C,H) ˆ 160, 2J(C,C,F) ˆ 22, arom. C); 116.9 (d, 1J(C,H) ˆ 160, arom.
C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 154, C(3a)a); 85.0 (d, 1J(C,H) ˆ 155, C(3a)b); 82.4 (s, Me3COa); 82.2
(s, Me3COa); 81.6 (d, 1J(C,H) ˆ 156, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.9 (d, 1J(C,H) ˆ 144, C(4)a);
65.3 (d, 1J(C,H) ˆ 145, C(4)b); 53.8 (t, 1J(C,H) ˆ 142, C(6)b); 53.2 (t, 1J(C,H) ˆ 143, C(6)a); 50 49 (C(1')); 48.3
(t, 1J(C,H) ˆ 136, C(1'')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 126, Me); 25.8 (q, 1J(C,H) ˆ 125,
‡
Me). CI-MS (NH3): 381 (100, [M ‡ H] ), 325(53), 272 (6), 232 (31), 186 (15), 142 (21), 109 (41), 84 (7). Anal.
calc. for C20H29FN2O4 (380.48): C 63.14, H 7.68; found: C 63.07, H 7.64.
(2R,3R,4S)-2-{[(2-Fluorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fi). By Method Aa, with 9fi
25
25
25
(31 mg). FC (MeCN/NH4OH 4 :1) gave 19 mg (100% of 3fi). [a] ˆ ‡17, [a] ˆ ‡19, [a] ˆ ‡22,
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546
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25
[a] ˆ ‡38, [a] ˆ ‡45( c ˆ 0.26, MeOH). UV (MeCN): 273 (6705), 260 (5500), 213 (1775). IR (film): 3385,
435
405
1675, 1440, 1200, 1140, 840, 800, 760, 720. 1H-NMR (400 MHz, MeOD): 7.55 (t, 3J ˆ 7.6, 1 arom. H); 7.48
(m, 1 arom. H); 7.26 (m, 2 arom. H); 4.27 (m, HÀC(4), 2 HÀC(1'')); 4.07 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 9.0,
HÀC(3)); 3.75( m, HÀC(2)); 3.51 (dd, 3J(5,4)ˆ 3.9, 2J ˆ 12.6, 1 HÀC(5)); 3.45 3.32 (m, 2 HÀC(1'),
1 HÀC(5)). 13C-NMR (100.6 MHz, MeOD): 165.0 (d, 1J(C,F) ˆ 245, arom. C); 133.7 (2d, 1J(C,H) ˆ 167,
2 arom. C); 133.3 (s, arom. C); 127.1 (d, 1J(C,H) ˆ 160, arom. C); 117.6 (dd, 1J(C,H) ˆ 161, 2J(C,F) ˆ 22, arom.
C); 76.4 (d,1J(C,H) ˆ 144, C(3)); 71.4 (d, 1J(C,H) ˆ 154, C(4)); 60.0 (d, 1J(C,H) ˆ 143, C(2)); 52.4 (t, 1J(C,H) ˆ

1932
Helvetica Chimica Acta Vol. 86 (2003)
‡
148, C(5)); 50 49 (C(1')); 47.4 (t, 1J(C,H) ˆ 145, C(1'')). CI-MS (NH3): 241 (15, [M ‡ H] ), 209 (1), 138 (54),
124 (16), 109 (100), 102 (41), 85(47).
tert-Butyl (3aR,4R,6aS)-4-{[(3-Fluorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fj). By Method A, with 8 (111 mg, 0.41 mmol), 3-fluorobenzylamine (51 mg,
0.41 mmol), NaBH(OAc)3 (122 mg, 0.57 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 104 mg (67%
25
25
25
25
25
of 9fj), 1.1:1 mixture of rotamers a and b. [a] ˆ À24, [a] ˆ À25, [a] ˆ À31, [a] ˆ À59, [a] ˆ À73
589
577
546
435
405
(c ˆ 0.43, CH2Cl2). UV (MeCN): 269 (3440), 262 (3580), 205 (18190). IR (film): 3335, 2980, 2935, 1695, 1590,
1490, 1455, 1405, 1250, 1210, 1170, 1125, 1055, 975, 865, 785, 685. 1H-NMR (400 MHz, MeOD): 7.36 (m, 1 arom.
H); 7.17 (m, 2 arom. H); 7.00 (m, 1 arom. H); 4.77 (m, HÀC(6a)); 4.67 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.61
(d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.18 (dd, 3J(4,1') ˆ 6.4, 3J(4,1') ˆ 6.8, HÀC(4)b); 4.08 (dd, 3J(4,1') ˆ 6.4,
3J(4,1') ˆ 6.5, HÀC(4)a); 3.80 (m, 1 HÀC(6), 2 HÀC(1'')); 3.39 (m, 1 HÀC(6)); 2.65( m, 2 HÀC(1')); 1.50
(s, 1 Me); 1.44 (s, (t-Bu)a); 1.43 (s, (t-Bu)b); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 165.3 (d, 1J(C,F) ˆ
246, arom. C); 157.5 (s, NCOOb); 157.2 (s, NCOOa); 145.0 (s, arom. C); 132.0 (d, 1J(C,H) ˆ 163, arom. C); 125.9
(d, 1J(C,H) ˆ 161, arom. C); 116.6 (dd, 1J(C,H) ˆ 160, 2J(C,F) ˆ 22, arom. C); 115.5 (dd, 1J(C,H) ˆ 163,
2J(C,F) ˆ 21, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 157, C(3a)a); 84.9 (d, 1J(C,H) ˆ 159, C(3a)b); 82.2 (s,
Me3COa); 82.1 (s, Me3COa); 81.6 (d, 1J(C,H) ˆ 155, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.9 (d, 1J(C,H) ˆ
146, C(4)a); 65.2 (d, 1J(C,H) ˆ 146, C(4)b); 54.5 (t, 1J(C,H) ˆ 135, C(1'')); 53.9 (t, 1J(C,H) ˆ 143, C(6)b); 53.4
(t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1')); 29.6 (q, 1J(C,H) ˆ 128, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8
‡
(q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 381 (100, [M ‡ H] ), 325(51), 281 (14), 243 (4), 187 (8), 138 (26), 109
(41), 85(8). Anal. calc. for C 20H29FN2O4 (380.48): C 63.14, H 7.68; found: C 63.09, H 7.64.
(2R,3R,4S)-2-{[(3-Fluorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fj). By Method Aa, with 9fj
25
25
25
25
(40 mg). FC (MeCN/NH4OH 4 :1) gave 25mg (100% of 3fj). [a] ˆ ‡3, [a] ˆ ‡5 , a[ ] ˆ ‡7, [a]
ˆ
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546
435
25
‡25, [a] ˆ ‡36 (c ˆ 0.15, MeOH). UV (MeCN): 268 (1330), 216 (3500). IR (film): 3410, 1675, 1445, 1200,
405
1140, 840, 800, 725. H-NMR (400 MHz, MeOD): 7.42 (m, 1 arom. H); 7.25( m, 2 arom. H); 7.11 (dt, 3J ˆ 8.1,
1
4J ˆ 1.8, 1 arom. H); 4.26 (ddd, 3J(4,5) ˆ 1.6, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.09 (AB, HÀC(1'')); 4.06
(dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.8, HÀC(3)); 3.71 (ddd, 3J(2,3) ˆ 8.8, 3J(2,1') ˆ 8.8, 3J(H(2,1') ˆ 4.2, HÀC(2)); 3.49
(dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.33 (m, 1 HÀC(1')); 3.28 (m, 1 HÀC(5)); 3.22 (dd, 3J(1',2) ˆ 8.8, J ˆ
2
13.4, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 166.5( d, 1J(C,F) ˆ 249, arom. C); 140.2 (s, arom. C); 132.5
(d, 1J(C,H) ˆ 163, arom. C); 126.9 (d, 1J(C,H) ˆ 163, arom. C); 117.6 (dd, 1J(C,H) ˆ 148, 2J(C,F) ˆ 22, arom. C);
117.3 (dd, 1J(C,H) ˆ 150, 2J(C,F) ˆ 22, arom. C); 76.1 (d, 1J(C,H) ˆ 144, C(3)); 71.6 (d, 1J(C,H) ˆ 150, C(4));
60.9 (d, 1J(C,H) ˆ 146, C(2)); 53.9 (t, 1J(C,H) ˆ 141, C(1'')); 52.1 (t, 1J(C,H) ˆ 149, C(5)); 50 49 (C(1')). CI-MS
‡
(NH3): 241 (100, [M ‡ H] ), 223 (1), 138 (11), 126 (6), 102 (26), 85(32).
tert-Butyl (3aR,4R,6aS)-4-{[(4-Fluorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo-
[4,5-c]pyrrole-5-carboxylate (9fk). By Method A, with 8 (91 mg, 0.34 mmol), 4-fluorobenzylamine (42 mg,
0.34 mmol), NaBH(OAc)3 (100 mg, 0.47 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 102 mg (80% of
25
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25
25
25
9fk), 1.1:1 mixture of rotamers a and b. [a] ˆ À39, [a] ˆ À40, [a] ˆ À47, [a] ˆ À80, [a] ˆ À97 (c ˆ
589
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0.51, CH2Cl2). UV (MeCN): 272 (1845), 265 (2070), 207 (12370). IR (film): 3335, 2980, 2935, 1700, 1685, 1680,
1600, 1510, 1480, 1455, 1400, 1370, 1225, 1180, 1165, 1125, 1055, 980, 855, 825, 770. 1H-NMR (400 MHz, MeOD):
7.38 (d, 3J ˆ 8.2, 2 arom. H); 7.07 (m, 2 arom. H); 4.76 (m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.59
(d, 3J(3a,6a) ˆ 5.6, HÀC(3a)b); 4.18 (dd, 3J(4,1') ˆ 6.5, 3J(4,1') ˆ 6.7, HÀC(4)b); 4.07 (dd, 3J(4,1') ˆ 6.5,
3J(4,1') ˆ 6.4, HÀC(4)a); 3.76 (m, 1 HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.64 (m, 2 HÀC(1')); 1.49
(s, 1 Me); 1.42 (s, (t-Bu)a); 1.41 (s, (t-Bu)b); 1.31 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 164.3 (d, 2J(C,F) ˆ
245, arom. C); 157.5 (s, NCOOb); 157.2 (s, NCOOa); 137.9 (s, arom. C); 132.1 (d, 1J(C,H) ˆ 160, 2 arom. C);
117.0 (dd, 1J(C,H) ˆ 163, 2J(C,F) ˆ 22, arom. C); 116.8 (dd, 1J(C,H) ˆ 163, 2J(C,F) ˆ 22, arom. C); 113.4 (s); 85.5
(d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ 158, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6
(d, 1J(C,H) ˆ 155, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.9 (d, 1J(C,H) ˆ 146, C(4)a); 65.2 (d, 1J(C,H) ˆ
145, C(4)b); 55.0 (t, 1J(C,H) ˆ 135, C(1'')); 54.3 (t, 1J(C,H) ˆ 145, C(6)b); 53.8 (t, 1J(C,H) ˆ 144, C(6)a); 50 49
(C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 124, Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3):
‡
‡
382 (100, [M ‡ H] ), 381 (75, M ), 325(29), 279 (1), 217 (6), 138 (11), 109 (27), 85(4). Anal. calc. for
C20H29FN2O4 (380.48): C 63.14, H 7.68, N 7.36; found: C 63.11, H 7.72, N 7.27.
(2R,3R,4S)-2-{[(4-Fluorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fk). By Method Aa, with 9fk
25
25
25
(30 mg). FC (MeCN/NH4OH 4 :1) gave 19 mg (100% of 3fk). [a] ˆ ‡9, [a] ˆ ‡15, [a] ˆ ‡19 (c ˆ
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0.21, MeOH). UV (MeCN): 271 (3060), 214 (2615). IR (film): 3200, 3050, 2890, 1660, 1440, 1265, 1195, 1135,
840, 800, 735. 1H-NMR (400 MHz, MeOD): 7.60 (m, 2 arom. H); 7.22 (dd, 3J ˆ 8.8, 2 arom. H); 4.29
(m, HÀC(4), 2 HÀC(1'')); 4.12 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 9.2, HÀC(3)); 3.85( m, HÀC(2)); 3.57
(dd, 3J(5,4) ˆ 3.9, 2J ˆ 12.7, 1 HÀC(5)); 3.52 (m, 2 H, HÀC(1')); 3.39 (m, 1 HÀC(5)). 13C-NMR (100.6 MHz,

Helvetica Chimica Acta Vol. 86 (2003)
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MeOD): 165.6 (d, 1J(C,F) ˆ 247, arom. C); 134.2 (d, 1J(C,H) ˆ 161, 2 arom. C); 130.1 (s, arom. C); 117.8
(dd, 1J(C,H) ˆ 167, 2J(C,F) ˆ 27, 2 arom. C); 76.5( d, 1J(C,H) ˆ 145, C(3)); 71.2 (d, 1J(C,H) ˆ 150, C(4)); 59.3
(d, 1J(C,H) ˆ 140, C(2)); 53.2 (t, 1J(C,H) ˆ 144, C(1'')); 52.6 (t, 1J(C,H) ˆ 146, C(5)); 50 49 (C(1')). CI-MS
‡
(NH3): 241 (11, [M ‡ H] ), 215 (3), 200 (19), 171 (25), 153 (6), 142 (43), 124 (41), 109 (100), 95 (25), 85 (33).
tert-Butyl (3aR,4R,6aS)-4-{[(2-Chlorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fl). By Method A, with 8 (90 mg, 0.33 mmol), 2-chlorobenzylamine (47 mg,
0.33 mmol), NaBH(OAc)3 (99 mg, 0.46 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt/light petroleum ether
25
25
25
1:1) gave 95mg (72% of 9fl), 1.4 :1 mixture of rotamers a and b. [a] ˆ À23, [a] ˆ À25, [a] ˆ À29,
589
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546
25
25
[a] ˆ À55, [a] ˆ À70 (c ˆ 0.52, CH2Cl2). UV (MeCN): 210 (14140). IR (film): 3335, 2980, 1680, 1595, 1575,
435
405
1415, 1160, 1055, 975, 860, 755, 675. 1H-NMR (400 MHz, MeOD): 7.49 (m, 1 arom. H); 7.41 (m, 1 arom. H); 7.33
(m, 2 arom. H); 4.78 (m, HÀC(6a)); 4.67 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)a); 4.64 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b);
4.18 (t, 3J(4,1') ˆ 6.2, HÀC(4)a); 4.09 (t, 3J(4,1') ˆ 6.4, HÀC(4)b); 3.92 (m, 2 HÀC(1'')); 3.80 (d, 2J ˆ 12.8,
1 HÀC(6)); 3.39 (m, 1 HÀC(6)); 2.68 (m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.44 (s, (t-Bu)a); 1.43 (s, (t-Bu)b); 1.33
(s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 139.2 (s, arom. C); 135.6
(s, arom. C); 132.2 (d, 1J(C,H) ˆ 159, arom. C); 131.4 (d, 1J(C,H) ˆ 166, arom. C); 130.6 (d, 1J(C,H) ˆ 156, arom.
C); 129.0 (d, 1J(C,H) ˆ 162, arom. C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 158, C(3a)b);
82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 156, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.9
(d, 1J(C,H) ˆ 146, C(4)a); 65.4 (d, 1J(C,H) ˆ 143, C(4)b); 53.9 (t, 1J(C,H) ˆ 143, C(6)b); 53.3 (t, 1J(C,H) ˆ 144,
C(6)a); 52.5 (t, 1J(C,H) ˆ 138, C(1'')); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 128, Me3C); 28.1 (q, 1J(C,H) ˆ 127,
Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 397 (100, M ), 341 (39), 295(3), 264 (14), 242 (8), 217 (21),
‡
154 (19), 125 (24), 89 (6). Anal. calc. For C20H29ClN2O4 (396.53): C 60.52, H 7.36; found: C 60.42, H 7.22.
(2R,3R,4S)-2-{[(2-Chlorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fl). By Method Aa, with 9fl
25
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25
(28 mg). FC (MeCN/NH4OH 4 :1) gave 18 mg (100% of 3fl). [a] ˆ ‡7, [a] ˆ ‡10, [a] ˆ ‡12 (c ˆ
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0.60, MeOH). UV (MeCN): 261 (590), 217 (2985). IR (film): 3200, 3065, 2900, 1665, 1470, 1445, 1185, 840, 800,
760, 725, 680. 1H-NMR (400 MHz, MeOD): 7.59 (m, 1 arom. H); 7.49 (m, 1 arom. H); 7.38 (m, 2 arom. H); 4.26
(m, HÀC(4), 2 HÀC(1'')); 4.07 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 8.7, HÀC(3)); 3.73 (ddd, 3J(2,3) ˆ 8.7, 3J(2,1') ˆ 8.7,
3J(2,1') ˆ 4.2, HÀC(2)); 3.50 (dd, 3J(5,4) ˆ 3.9, 2J ˆ 12.6, 1 HÀC(5)); 3.34 3.15 (m, 2 HÀC(1'), 1 HÀC(5)).
13C-NMR (100.6 MHz, MeOD): 136.2 (s, arom. C); 135.0 (s, arom. C); 133.1 (d, 1J(C,H) ˆ 161, arom. C); 132.0
(d, 1J(C,H) ˆ 165, arom. C); 131.7 (d, 1J(C,H) ˆ 165, arom. C); 129.4 (d, 1J(C,H) ˆ 163, arom. C); 76.1
(d, 1J(C,H) ˆ 144, C(3)); 71.6 (d, 1J(C,H) ˆ 150, C(4)); 61.0 (d, 1J(C,H) ˆ 146, C(2)); 52.1 (t, 1J(C,H) ˆ 149,
‡
C(5)); 51.7 (t, 1J(C,H) ˆ 144, C(1'')); 50 49 (C(1')). CI-MS (NH3): 257 (100, M ), 241 (3), 154 (15), 142 (4),
125(19), 102 (18), 85(26).
tert-Butyl (3aR,4R,6aS)-4-{[(3-Chlorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fm). By Method A, with 8 (109 mg, 0.40 mmol), 3-chlorobenzylamine (57 mg,
0.40 mmol), NaBH(OAc)3 (119 mg, 0.56 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 86 mg (54% of
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9fm), 1.1:1 mixture of rotamers a and b. [a] ˆ À27, [a] ˆ À31, [a] ˆ À32, [a] ˆ À53, [a] ˆ À65
589
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546
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(c ˆ 0.44, CH2Cl2). UV (MeCN): 211 (11315). IR (film): 3340, 2980, 2935, 1705, 1685, 1600, 1575, 1475, 1460,
1400, 1370, 1210, 1160, 1125, 1055, 975, 860, 780, 685. 1H-NMR (400 MHz, MeOD): 7.42 (s, 1 arom. H); 7.31
(m, 3 arom. H); 4.77 (m, HÀC(6a)); 4.67 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)a); 4.61 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b);
4.18 (dd, 3J(4,1') ˆ 6.5, 3J(4,1') ˆ 6.9, HÀC(4)b); 4.07 (dd, 3J(4,1') ˆ 6.6, 3J(4,1') ˆ 6.3, HÀC(4)a); 3.79
(m, 1 HÀC(6), 2 HÀC(1'')); 3.40 (m, 1 HÀC(6)); 2.66 (m, 2 HÀC(1')); 1.47 (s, 1 Me); 1.44 (s, (t-Bu)a); 1.43
(s, (t-Bu)b); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 144.5( s, arom.
C); 136.2 (s, arom. C); 131.8 (d, 1J(C,H) ˆ 163, arom. C); 130.2 (d, 1J(C,H) ˆ 160, arom. C); 129.0 (d, 1J(C,H) ˆ
166, arom. C); 128.6 (d, 1J(C,H) ˆ 162, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 159, C(3a)a); 84.9 (d, 1J(C,H) ˆ
162, C(3a)b); 82.3 (s, Me3COb); 82.2 (s, Me3COa); 81.6 (d, 1J(C,H) ˆ 154, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159,
C(6a)a); 65.9 (d, 1J(C,H) ˆ 147, C(4)a); 65.2 (d, 1J(C,H) ˆ 147, C(4)b); 54.5 (t, 1J(C,H) ˆ 134, C(1'')); 53.9
(t, 1J(C,H) ˆ 143, C(6)b); 53.4 (t, 1J(C,H) ˆ 141, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1
‡
(q, 1J(C,H) ˆ 125, Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 397 (100, [M ‡ H] ), 363 (3), 341 (56), 297
(5), 261 (14), 216 (6), 142 (8), 125 (16), 85 (5). Anal. calc. for C 20H29ClN2O4 (396.53): C 60.52, H 7.36, N 7.06;
found: C 60.56, H 7.29, N 6.95.
(2R,3R,4S)-2-{[(3-Chlorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fm). By Method Aa, with 9fm
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25
(32 mg). FC (MeCN/NH4OH 4 :1) gave 21 mg (100% of 3fm). [a] ˆ ‡16, [a] ˆ ‡16, [a] ˆ ‡21 (c ˆ
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0.56, MeOH). UV (MeCN): 217 (3545). IR (film): 3075, 1670, 1650, 1470, 1440, 1200, 1130, 840, 800, 725.
1H-NMR (400 MHz, MeOD): 7.56 (s, 1 arom. H); 7.42 (m, 3 arom. H); 4.26 (m, HÀC(4)); 4.15( AB, 2J ˆ 16.1,
2 HÀC(1'')); 4.07 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 8.9, HÀC(3)); 3.74 (ddd, 3J(2,1') ˆ 4.4, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9,
HÀC(2)); 3.51 (dd, 3J(5,4) ˆ 3.9, 2J ˆ 12.6, 1 HÀC(5)); 3.38 3.32 (m, 1 HÀC(5), 2 HÀC(1')). 13C-NMR

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Helvetica Chimica Acta Vol. 86 (2003)
(100.6 MHz, MeOD): 138.9 (s, arom. C); 136.6 (s, arom. C); 132.4 (d, 1J(C,H) ˆ 164, arom. C); 131.4
(d, 1J(C,H) ˆ 166, arom. C); 130.8 (d, 1J(C,H) ˆ 163, arom. C); 129.7 (d, 1J(C,H) ˆ 165, arom. C); 76.2
(d, 1J(C,H) ˆ 144, C(3)); 71.4 (d, 1J(C,H) ˆ 155, C(4)); 60.4 (d, 1J(C,H) ˆ 146, C(2)); 53.6 (t, 1J(C,H) ˆ 141,
‡
C(1'')); 52.3 (t, 1J(C,H) ˆ 144, C(5)); 50 49 (C(1')). CI-MS (NH3): 257 (62, M ), 243 (19), 223 (9), 203 (3), 173
(7), 159 (41), 133 (100), 116 (87), 98 (16).
tert-Butyl (3aR,4R,6aS)-4-{[(4-Chlorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fn). By Method A, with 8 (94 mg, 0.35mmol), 4-Chlorobenzylamine (49 mg,
0.35mmol), NaBH(OAc) 3 (103 mg, 0.49 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 99 mg (72% of
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9fn), 1.1:1 mixture of rotamers a and b. [a] ˆ À37, [a] ˆ À39, [a] ˆ À42, [a] ˆ À71, [a] ˆ À84 (c ˆ
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0.45, CH2Cl2). UV (MeCN): 219 (12370). IR (film): 3335, 2980, 2935, 1705, 1680, 1600, 1490, 1455, 1400, 1365,
1210, 1170, 1125, 1090, 1055, 1015, 975, 860, 805, 770. H-NMR (400 MHz, MeOD): 7.35( m, 4 arom. H); 4.77
1
(m, HÀC(6a)); 4.66 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.60 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.18 (dd, 3J(4,1') ˆ 6.6,
3J(4,1') ˆ 6.1, HÀC(4)b); 4.07 (dd, 3J(4,1') ˆ 6.4, 3J(4,1') ˆ 6.3, HÀC(4)a); 3.77 (m, 1 HÀC(6), 2 HÀC(1'')); 3.38
(m, 1 HÀC(6)); 2.65( m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.43 (s, t-Bu); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz,
MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 140.8 (s, arom. C); 134.6 (s, arom. C); 131.9 (d, 1J(C,H) ˆ 163,
2 arom. C); 129.5( d, 1J(C,H) ˆ 165, 2 arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ
158, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 155, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158,
C(6a)a); 65.9 (d, 1J(C,H) ˆ 147, C(4)a); 65.2 (d, 1J(C,H) ˆ 146, C(4)b); 54.3 (t, 1J(C,H) ˆ 134, C(1'')); 53.9
(t, 1J(C,H) ˆ 144, C(6)b); 53.4 (t, 1J(C,H) ˆ 143, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1
‡
‡
(q, 1J(C,H) ˆ 124, Me) ; 25.8 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3): 398 (100, [M ‡ H] ), 397 (82, M ), 363 (1),
341 (44), 297 (4), 266 (21), 243 (4), 187 (5), 142 (15), 125 (27), 89 (6). Anal. calc. for C20H29ClN2O4 (396.53): C
60.52, H 7.36, N 7.06; found: C 60.42, H 7.22, N 6.96.
(2R,3R,4S)-2-{[(4-chlorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fn). By Method Aa, with 9fn
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(42 mg). FC (MeCN/NH4OH 4 :1) gave 27 mg (100% of 3fn). [a] ˆ ‡13, [a] ˆ ‡15, [a] ˆ ‡18,
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[a] ˆ ‡31, [a] ˆ ‡36 (c ˆ 0.78, MeOH). UV (MeCN): 221 (4720). IR (film): 3070, 1670, 1495, 1435, 1200,
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1135, 1015, 840, 800, 725, 600. 1H-NMR (400 MHz, MeOD): 7.49 (d, 3J ˆ 8.5, 2 arom. H); 7.42 (d, 3J ˆ 8.5,
2 arom. H); 4.26 (m, HÀC(4)); 4.13 (AB, 2J ˆ 16.5, 2 HÀC(1'')); 4.07 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 8.9, HÀC(3));
3.73 (ddd, 3J(2,1') ˆ 4.4, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9, HÀC(2)); 3.51 (dd, 3J(5,4) ˆ 3.9, 2J ˆ 12.6, 1 HÀC(5));
3.38 3.27 (m, 1 HÀC(5), 2 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 136.6 (s, arom. C); 135.1 (s, arom. C);
133.0 (d, 1J(C,H) ˆ 162, 2 arom. C); 130.9 (d, 1J(C,H) ˆ 167, 2 arom. C); 76.2 (d, 1J(C,H) ˆ 143, C(3)); 71.4
(d, 1J(C,H) ˆ 151, C(4)); 60.4 (d, 1J(C,H) ˆ 146, C(2)); 53.5 (t, 1J(C,H) ˆ 141, C(1'')); 52.3 (t, 1J(C,H) ˆ 141,
‡
C(5)); 50 49 (C(1')). CI-MS (NH3): 257 (100, M ), 211 (6), 180 (17), 154 (20), 142 (33), 133 (24), 116 (14), 102
(30), 85(22).
tert-Butyl (3aR,4R,6aS)-4-{[(2-Bromobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fo). By Method A, with 8 (94 mg, 0.35mmol), 2-bromobenzylamine (77 mg,
0.35mmol), NaBH(OAc) 3 (103 mg, 0.49 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 92 mg (60% of
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9fo), 1.1:1 mixture of rotamers a and b. [a] ˆ À32, [a] ˆ À33, [a] ˆ À37, [a] ˆ À55, [a] ˆ À76 (c ˆ
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0.43, CH2Cl2) UV (MeCN): 218 (8385), 201 (1440), 196 (1490). IR (film): 3335, 2980, 2935, 1690, 1455, 1405,
1370, 1210, 1160, 1125, 1055, 975, 860, 755, 660. 1H-NMR (400 MHz, MeOD): 7.61 (d, 3J ˆ 8.1, 1 arom. H); 7.47
(d, 3J ˆ 7.5, 1 arom. H); 7.39 (m, 1 arom. H); 7.22 (t,3J ˆ 7.5, 1 arom. H); 4.77 (m, HÀC(6a)); 4.67 (d, 3J(3a,6a) ˆ
6.0, HÀC(3a)a); 4.63 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.18 (t, 3J(4,1') ˆ 6.2, HÀC(4)b); 4.09 (t, 3J(4,1') ˆ 6.3,
HÀC(4)a); 3.91 (s, 2 HÀC(1'')); 3.79 (d, 2J ˆ 12.9, 1 HÀC(6), 1 HÀC(6)b); 3.41 (d, 3J(6,6a) ˆ 5.0, 1 HÀC(6)b);
3.38 (d, 3J(6,6a) ˆ 5.1, 1 HÀC(6)a); 2.67 (m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.44 (s, (t-Bu)b); 1.43 (s, (t-Bu)a); 1.33
(s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 140.7 (s, arom. C); 134.8
(d, 1J(C,H) ˆ 159, arom. C); 132.4 (d, 1J(C,H) ˆ 151, arom. C); 131.0 (d, 1J(C,H) ˆ 163, arom. C); 129.6
(d, 1J(C,H) ˆ 170, arom. C); 125.8 (s, arom. C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157,
C(3a)b); 82.3 (s, Me3COa); 82.2 (s, Me3COa); 81.6 (d, 1J(C,H) ˆ 155, C(6a)b); 80.6 (d, 1J(C,H) ˆ 158, C(6a)a);
65.9 (d, 1J(C,H) ˆ 146, C(4)a); 65.4 (d, 1J(C,H) ˆ 144, C(4)b); 55.0 (t, 1J(C,H) ˆ 134, C(1'')); 53.9 (t, 1J(C,H) ˆ
144, C(6)b); 53.3 (t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1')); 29.6 (q, 1J(C,H) ˆ 128, Me3C); 28.1 (q, 1J(C,H) ˆ 128,
1 Me); 25.8 (q, 1J(C,H) ˆ 126, 1 Me). CI-MS (NH3): 444 (67), 443 (100), 442 (78), 441 (71), 387 (19), 385(22),
354 (10), 352 (7), 243 (8), 200 (22), 198 (23), 142 (13), 118 (5), 85 (7). Anal. calc. for C20H29BrN2O4 (441.39): C
54.43, H 6.62, N 6.35; found: C 54.61, H 65.61, N 6.40.
(2R,3R,4S)-2-{[(2-Bromobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fo). By Method Aa, with 9fo
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(79 mg). FC (MeCN/NH4OH 4 :1) gave 54 mg (100% of 3fo). [a] ˆ ‡3, [a] ˆ ‡7, [a] ˆ ‡9 (c ˆ 0.43,
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MeOH). UV (MeCN): 279 (10480), 259 (8630), 217 (2810). IR (film): 3200, 3065, 1670, 1440, 1200, 1135, 1030,
840, 800, 755, 720. 1H-NMR (400 MHz, MeOD): 7.55 (dd, 3J ˆ 8.0, 4J ˆ 1.0, 1 arom. H); 7.55 (dd, 3J ˆ 7.6, 4J ˆ 1.5,

Helvetica Chimica Acta Vol. 86 (2003)
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1 arom. H); 7.40 (td, 3J ˆ 7.6, 4J ˆ 1.0, 1 arom. H); 7.26 (td, 3J ˆ 8.0, 4J ˆ 1.5, 1 arom. H); 4.27 (m, HÀC(4)); 4.10
3
3
3
(s, 2 HÀC(1'')); 4.03 (dd, 3J(3,4) ˆ 4.0, J(3,2) ˆ 8.4, HÀC(3)); 3.66 (ddd, 3J(2,1') ˆ 3.9, J(2,3) ˆ 8.4, J(2,1') ˆ
8.4, HÀC(2)); 3.45( dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.39 3.00 (m, 1 HÀC(5), 2 HÀC(1')). 13C-NMR
(100.6 MHz, MeOD): 134.9 (d, 1J(C,H) ˆ 167, arom. C); 132.7 (d, 1J(C,H) ˆ 161, arom. C); 132.4 (s, arom. C);
131.6 (d, 1J(C,H) ˆ 165, arom. C); 129.9 (d, 1J(C,H) ˆ 164, arom. C); 126.0 (s, arom. C); 75.9 (d, 1J(C,H) ˆ 145,
C(3)); 71.8 (d, 1J(C,H) ˆ 149, C(4)); 61.9 (d, 1J(C,H) ˆ 144, C(2)); 54.5 (t, 1J(C,H) ˆ 141, C(1'')); 51.8
(t, 1J(C,H) ˆ 143, C(5)); 50 49 (C(1')). CI-MS (NH3): 303 (37), 301 (38), 229 (15), 202 (34), 200 (51), 188
(82), 186 (100), 171 (31), 169 (30), 158 (25), 156 (28), 106 (74), 84 (55).
tert-Butyl (3aR,4R,6aS)-4-{[(3-Bromobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fp). By Method A, with 8 (153 mg, 0.56 mmol), 3-bromobenzylamine (126 mg,
0.56 mmol), NaBH(OAc)3 (168 mg, 0.79 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 129 mg (52% of
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9fp), 1.2 :1 mixture of rotamers a and b. [a] ˆ À29, [a] ˆ À33, [a] ˆ À34, [a] ˆ À53, [a] ˆ À67 (c ˆ
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0.78, CH2Cl2). UV (MeCN): 260 (1280), 219 (7725). IR (film): 3340, 2980, 2935, 1680, 1570, 1475, 1455, 1405,
1365, 1210, 1170, 1125, 1055, 860, 775, 685, 670. 1H-NMR (400 MHz, MeOD): 7.57 (s, 1 arom. H); 7.42
(m, 1 arom. H); 7.31 (m, 1 arom. H); 7.25( m, 1 arom. H); 4.75( m, HÀC(6a)); 4.65( d, 3J(3a,6a) ˆ 5.8,
HÀC(3a)a);4.59(d, 3J(3a,6a) ˆ 5.7,HÀC(3a)b);4.17(t, 3J(4,1') ˆ 6.5,HÀC(4)b);4.05(t, 3J(4,1') ˆ 6.3,HÀC(4)a);
3.84 3.73 (m, 1 HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.62 (m, 2 HÀC(1')); 1.49 (s, 1 Me); 1.43 (s, (t-
Bu)a); 1.42 (s, (t-Bu)b); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa);
144.8 (s, arom. C); 133.2 (d, 1J(C,H) ˆ 165, arom. C); 132.0 (d, 1J(C,H) ˆ 168, 2 arom. C); 129.0 (d, 1J(C,H) ˆ
164, arom. C); 124.3 (s, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ 158, C(3a)b); 82.3
(s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 152, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.9
(d, 1J(C,H) ˆ 147, C(4)a); 65.2 (d, 1J(C,H) ˆ 147, C(4)b); 54.4 (t, 1J(C,H) ˆ 136, C(1'')); 53.9 (t, 1J(C,H) ˆ 144,
C(6)b); 53.4 (t, 1J(C,H) ˆ 145, C(6)a); 50 49 (C(1')); 29.6 (q, 1J(C,H) ˆ 126, Me3C); 28.1 (q, 1J(C,H) ˆ 127,
Me); 25.8 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3): 444 (83), 443 (100), 442 (62), 441 (74), 387 (28), 385(32), 343
(19), 341 (20), 243 (7), 200 (18), 198 (19), 142 (16), 119 (3), 85(9). Anal. calc. for C 20H29BrN2O4 (441.39): C
54.43, H 6.62, N 6.35; found: C 54.52, H 6.71, N 6.32.
(2R,3R,4S)-2-{[(3-Bromobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fp). By Method Aa, with 9fp
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(100 mg). FC (MeCN/NH4OH 4 :1) gave 68 mg (100% of 3fp). [a] ˆ ‡18, [a] ˆ ‡19, [a] ˆ ‡23,
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[a] ˆ ‡38, [a] ˆ ‡43 (c ˆ 0.43, MeOH). UV (MeCN): 275(13430), 259 (10790), 216 (3330). IR (film):
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3065, 1670, 1435, 1265, 1200, 1140, 840, 800, 735. 1H-NMR (400 MHz, MeOD): 7.69 (d, 4J ˆ 1.4, 1 arom. H); 7.53
(dd, 3J ˆ 7.9, 4J ˆ 1.0, 1 arom. H); 7.45( dd, 3J ˆ 7.7, 4J ˆ 1.0, 1 arom. H); 7.34 (dd, 3J ˆ 7.7, 3J ˆ 7.9, 1 arom. H); 4.28
(m, HÀC(4)); 4.06 (m, HÀC(3), 2 HÀC(1'')); 3.72 (ddd, 3J(2,1') ˆ 4.0, 3J(2,3) ˆ 8.8, 3J(2,1') ˆ 8.8, HÀC(2));
3.51 (dd, 3J(5,4)ˆ 4.1, 2J ˆ 12.6, 1 HÀC(5)); 3.35 (m, 1 HÀC(5)); 3.30 3.20 (m, 2 HÀC(1')). 13C-NMR
(100.6 MHz, MeOD): 140.6 (arom. C); 134.0 (arom. C); 133.2 (arom. C); 132.4 (arom. C); 129.8 (arom. C);
124.5(arom. C); 76.0 (C(3)); 71.6 (C(4)); 61.2 (C(2)); 53.9 (C(1 '')); 52.1 (C(5)); 50 49 (C(1')). CI-MS (NH3):
303 (97), 301 (100), 279 (1), 223 (11), 171 (4), 133 (9), 102 (18).
tert-Butyl (3aR,4R,6aS)-4-{[(4-Bromobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9fq). By Method A, with 8 (102 mg, 0.37 mmol), 4-bromobenzylamine (83 mg,
0.37 mmol), NaBH(OAc)3 (112 mg, 0.53 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 47 mg (28% of
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9fq), 1.1:1 mixture of rotamers a and b. [a] ˆ À35, [a] ˆ À41, [a] ˆ À45, [a] ˆ À55, [a] ˆ À73 (c ˆ
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0.31, CH2Cl2). UV (MeCN): 222 (16595). IR (film): 2980, 1685, 1460, 1405, 1160, 1055, 1010. 1H-NMR
(400 MHz, MeOD): 7.50 (m, 2 arom. H); 7.30 (d, 3J ˆ 8.5, 2 arom. H); 4.77 (m, HÀC(6a)); 4.66 (d, 3J(3a,6a) ˆ
6.1, HÀC(3a)a); 4.61 (d, 3J(3a,6a) ˆ 5.5, HÀC(3a)b); 4.15( t, 3J(4,1') ˆ 7.1, H ÀC(4)b); 4.08 (t, 3J(4,1') ˆ 6.5,
HÀC(4)a); 3.80 3.73 (m, 1 HÀC(6), 2 HÀC(1'')); 3.39 (m, 1 HÀC(6)); 2.65( m, 2 HÀC(1')); 1.50 (s, 1 Me);
1.44 (s, (t-Bu)a); 1.43 (s, (t-Bu)b); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2
(s, NCOOa); 141.3 (s, arom. C); 133.4 (d, 1J(C,H) ˆ 168, 2 arom. C); 132.2 (d, 1J(C,H) ˆ 158, 2 arom. C); 122.6
(s, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 152, C(3a)a); 84.9 (d, 1J(C,H) ˆ 160, C(3a)b); 82.3 (s, Me3COa); 82.1
(s, Me3COb); 81.6 (d, 1J(C,H) ˆ 153, C(6a)b); 80.9 (d, 1J(C,H) ˆ 160, C(6a)a); 65.9 (d, 1J(C,H) ˆ 146, C(4)a);
65.3 (d, 1J(C,H) ˆ 148, C(4)b); 54.4 (t, 1J(C,H) ˆ 137, C(1'')); 53.9 (t, 1J(C,H) ˆ 144, C(6)b); 53.4 (t, 1J(C,H) ˆ
142, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 126, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 126,
Me). CI-MS (NH3): 443 (100), 441 (83), 415(3), 413 (3), 387 (19), 385(23), 363 (6), 274 (16), 243 (4), 218 (19),
142 (10), 85(5). Anal. calc. for C 20H29BrN2O4 (441.39): C 54.43, H 6.62, N 6.35; found: C 54.70, H 6.61, N 6.43.
(2R,3R,4S)-2-{[(4-Bromobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fq). By Method Aa, with 9fq
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(30 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3fq). [a] ˆ ‡9, [a] ˆ ‡13, [a] ˆ ‡22 (c ˆ
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0.26, MeOH). UV (MeCN): 275(6000), 222 (6900). 1H-NMR (400 MHz, MeOD): 7.60 (d, 3J ˆ 8.6, 2 arom. H);
7.43 (d, 3J ˆ 8.6, 2 arom. H); 4.28 (ddd, 3J(4,5) ˆ 1.4, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.12 (AB, 2J ˆ 11.2,

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Helvetica Chimica Acta Vol. 86 (2003)
2 HÀC(1'')); 4.08 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.9, HÀC(3)); 3.74 (ddd, 3J(2,1') ˆ 4.4, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9,
HÀC(2)); 3.52 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.39 3.29 (m, 1 HÀC(5), 2 HÀC(1')). 13C-NMR
(100.6 MHz, MeOD): 135.9 (s, arom. C); 133.9 (d, 1J(C,H) ˆ 168, 2 arom. C); 133.3 (d, 1J(C,H) ˆ 163, 2 arom.
C); 124.6 (s, arom. C); 76.3 (d, 1J(C,H) ˆ 143, C(3)); 71.5( d, 1J(C,H) ˆ 151, C(4)); 60.5 (d, 1J(C,H) ˆ 148, C(2));
53.6 (t, 1J(C,H) ˆ 141, C(1'')); 52.2 (t, 1J(C,H) ˆ 136, C(5)); 50 49 (C(1')). CI-MS (NH3): 303 (96), 301 (100),
279 (3), 223 (14), 188 (10), 186 (11), 133 (23), 102 (20).
tert-Butyl (3aR,4S,6aS)-4-{[(2-Chloro-6-fluorobenzyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]di-
oxolo[4,5-c]pyrrole-5-carboxylate (9fr). By Method A, with 8 (82 mg, 0.30 mmol), 2-chloro-6-fluorobenzyl-
amine (48 mg, 0.30 mmol), NaBH(OAc)3 (89 mg, 0.42 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt/light
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petroleum ether 8 :2) gave 87 mg (69% of 9fr), 1.2 :1 mixture of rotamers a and b. [a] ˆ À41, [a] ˆ À42,
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[a] ˆ À48, [a] ˆ À73, [a] ˆ À92 (c ˆ 0.46, CH2Cl2). UV (MeCN): 273 (1745), 266 (1935), 220 (9940). IR
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(film): 3340, 3085, 2980, 2935, 1700, 1605, 1580, 1455, 1405, 1245, 1210, 1170, 1125, 1055, 860, 780, 725. 1H-NMR
(400 MHz, MeOD): 7.32 (m, 2 arom. H); 7.13 (m, arom. H); 4.73 (m, HÀC(6a)); 4.61 (d, 3J(3a,6a) ˆ 5.7,
HÀC(3a)a);4.58(d, 3J(3a,6a) ˆ 5.6,HÀC(3a)b);4.13(t, 3J(4,1') ˆ 6.0,HÀC(4)b);4.05(t, 3J(4,1') ˆ 6.1,HÀC(4)a);
4.00 (br. s, 2 HÀC(1'')); 3.76 (d, 2J ˆ 12.9, 1 HÀC(6)); 3.36 (m, 1 HÀC(6)); 2.64 (m, 2 HÀC(1')); 1.47 (s, 1 Me);
1.43 (s, (t-Bu)a); 1.41 (s, (t-Bu)b); 1.30 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 163.9 (d, 1J(C,F) ˆ 242, arom.
C); 157.5 (s, NCOOb); 157.2 (s, NCOOa); 137.4 (s, arom. C); 131.7 (d, 1J(C,H) ˆ 166, arom. C); 127.5
(d, 1J(C,H) ˆ 170, arom. C); 127.2 (d, 2J(C,F) ˆ 29, arom. C); 116.1 (dd, 1J(C,H) ˆ 161, 2J(C,F) ˆ 20, arom.
C); 113.4 (s); 85.7 (d, 1J(C,H) ˆ 158, C(3a)a); 85.0 (d, 1J(C,H) ˆ 158, C(3a)b); 82.3 (s, Me3COa); 82.1
(s, Me3COb); 81.6 (d, 1J(C,H) ˆ 155, C(6a)b); 80.8 (d, 1J(C,H) ˆ 159, C(6a)a); 66.0 (d, 1J(C,H) ˆ 147, C(4)a);
65.5 (d, 1J(C,H) ˆ 147, C(4)b); 53.9 (t, 1J(C,H) ˆ 145, C(6)b); 53.3 (t, 1J(C,H) ˆ 144, C(6)a); 50 49 (C(1')); 45.5
(t, 1J(C,H) ˆ 139, C(1'')); 29.5( q, 1J(C,H) ˆ 128, Me3C); 28.1 (q, 1J(C,H) ˆ 128, Me); 25.8 (q, 1J(C,H) ˆ 126,
‡
‡
Me). CI-MS (NH3): 416 (100, [M ‡ H] ), 415(80, M ), 383 (5), 359 (37), 313 (4), 271 (3), 243 (13), 215 (6),
172 (35), 143 (25), 107 (3), 85 (12). Anal. calc. for C 20H28ClFN2O4 (414.92): C 57.90, H 6.80, N 6.75; found: C
57.99, H 6.72, N 6.61.
(2R,3R,4S)-2-{[(2-Chloro-6-fluorobenzyl)amino]methyl}pyrrolidine-3,4-diol (3fr). By Method Aa, with
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9fr (30 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3fr). [a] ˆ ‡10, [a] ˆ ‡13, [a] ˆ ‡17 (c ˆ
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0.59, MeOH). UV (MeCN): 273 (14075), 216 (4460). IR (film): 3065, 1670, 1650, 1470, 1205, 1145, 840, 800, 725.
1H-NMR (400 MHz, MeOD): 7.44 7.34 (m, 2 arom. H); 7.18 (t, 3J ˆ 8.4, 2 arom. H); 4.26 (m, HÀC(4)); 4.21
(s, 2 HÀC(1'')); 4.03 (dd, 3J((3,4) ˆ 3.9, 3J(3,2) ˆ 8.6, HÀC(3)); 3.66 (ddd, 3J(2,1') ˆ 3.9, 3J(2,3) ˆ 8.6, 3J(2,1') ˆ
8.6, HÀC(2)); 3.46 (dd, 3J(5,4) ˆ 3.9, 2J ˆ 12.5, HÀC(5)); 3.29 (dd, 3J(5,4) ˆ 1.6, 2J ˆ 12.5, HÀC(5)); 3.21
(dd, 3J(1',2) ˆ 3.9, 2J ˆ 13.3, 1 HÀC(1')); 3.12 (m, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 164.1
(d, 1J(C,F) ˆ 248, arom. C); 137.7 (s, arom. C); 132.7 (d, 1J(C,H) ˆ 165, arom. C); 127.7 (d, 1J(C,H) ˆ 169,
arom. C); 120.4 (s, arom. C); 116.4 (dd, 1J(C,H) ˆ 165, 2J(C,F) ˆ 23, arom. C); 76.0 (d, 1J(C,H) ˆ 144, C(3));
71.7 (d, 1J(C,H) ˆ 153, C(4)); 61.7 (d, 1J(C,H) ˆ 146, C(2)); 51.9 (t, 1J(C,H) ˆ 145, C(5)); 50 49 (C(1')); 45.1
‡
‡
(t, 1J(C,H) ˆ 144, C(1'')). CI-MS (NH3): 275(100, M ), 257 (12, [M À H2O] ), 239 (6), 205(5), 177 (25), 160
(42), 143 (27), 126 (35), 102 (17).
tert-Butyl (3aR,4R,6aS)-4-{[([1,1'-Biphenyl]-4-ylmethyl)amino]methyl}tetrahydro-2,2-dimethyl-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (9fs). By Method B, with 10 (104 mg, 0.38 mmol), [1,1'-biphenyl]-4-
carboxaldehyde (70 mg, 0.38 mmol), NaBH(OAc)3 (113 mg, 0.53 mmol), and ClCH2CH2Cl (3 ml). FC
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(AcOEt) gave 124 mg (74%of 9fs), 1.3 :1 mixture of rotamers a and b. [a] ˆ À30, [a] ˆ À32, [a]
ˆ
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À36, [a] ˆ À67, [a] ˆ À84 (c ˆ 0.45, CH2Cl2). UV (MeCN): 251 (22873), 215 (17570). IR (film): 3020,
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2935, 1690, 1455, 1410, 1370, 1215, 1160, 1130, 1055, 775, 755, 670. 1H-NMR (400 MHz, MeOD): 7.61 (m, 4 arom.
H); 7.42 (m, 4 arom. H); 7.34 (m, 1 arom. H); 4.74 (m, HÀC(6a)); 4.65( d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.59
(d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.20 (t, 3J(4,1') ˆ 6.7, HÀC(4)b); 4.09 (t, 3J(4,1') ˆ 6.3, HÀC(4)a); 3.80
(m, 1 HÀC(6), 2 HÀC(1'')); 3.38 (m, 1 HÀC(6)); 2.66 (m, 2 HÀC(1')); 1.49 (s, 1 Me); 1.42 (s, (t-Bu)a); 1.41
(s, (t-Bu)b); 1.26 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.3 (s, NCOOb); 157.2 (s, NCOOa); 143.1 (s, arom.
C); 142.6 (s, arom. C); 141.0 (s, arom. C); 130.8 (d, 1J(C,H) ˆ 162, arom. C); 129.2 (d, 1J(C,H) ˆ 160, arom. C);
128.7 (d, 1J(C,H) ˆ 159, arom. C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 155, C(3a)b);
82.0 (s, Me3COb); 81.9 (s, Me3COa); 81.7 (d, (C,H) ˆ 50, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 66.0
(d, 1J(C,H) ˆ 146, C(4)a); 65.3 (d, 1J(C,H) ˆ 149, C(4)b); 54.8 (t, 1J(C,H) ˆ 131, C(1'')); 53.9 (d, J(C,H) ˆ 143,
1
C(6)b); 53.4 (d, 1J(C,H) ˆ 144, C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 126,
Me); 25.8 (q, 1J(C,H) ˆ 125, Me). CI-MS (NH3): 439 (100, [M ‡ H] ), 383 (6), 339 (2), 273 (10), 215(13), 196
‡
(31), 167 (93), 142 (36), 85(14). Anal. calc. for C 26H34N2O4 (438.60): C 71.21, H 7.81; found: C 71.19, H 7.73.
(2R,3R,4S)-2-{[([1,1'-Biphenyl]-4-ylmethyl)amino]methyl}pyrrolidine-3,4-diol (3fs). By Method Aa, from
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9fs (44 mg). FC (MeCN/NH4OH 4 :1) gave 30 mg (100% of 3fs). [a] ˆ ‡21, [a] ˆ ‡23, [a] ˆ ‡24,
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[a] ˆ ‡38, [a] ˆ ‡40 (c ˆ 0.37, MeOH). UV (MeCN): 260 (9050), 253 (9660), 211 (10000). IR (film): 3420,
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1685, 1410, 1205, 1140, 840, 800, 765, 725, 700. 1H-NMR (400 MHz, MeOD): 7.67 (m, 4 arom. H); 7.54
(m, 2 arom. H); 7.46 (m, 2 arom. H); 7.36 (m, arom. H); 4.25( ddd, 3J(4,5) ˆ 1.7, 3J(4,3) ˆ 4.0, 3J(4,5) ˆ 4.0,
HÀC(4)); 4.09 (AB, 2 HÀC(1'')); 4.03 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.5, HÀC(3)); 3.67 (ddd, 3J(2,1') ˆ 4.1,
3J(2,3) ˆ 8.7, 3J(2,1') ˆ 8.7, HÀC(2)); 3.46 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.29 3.25 (m, 1 HÀC(1'),
1 HÀC(5)); 3.15 (dd, 3J(1',2) ˆ 8.9, 2J ˆ 13.3, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 143.3 (arom. C);
142.7 (arom. C); 137.0 (arom. C); 131.5, 130.8, 129.4, 129.2, 128.8 (9 arom. C); 76.2 (C(3)); 71.8 (C(4)); 61.3
‡
(C(2)); 54.2 (C(1'')); 52.1 (C(5)); 50 49 (C(1')). CI-MS (NH3): 299 (100, M ), 280 (8), 265(3), 229 (3), 211
(21), 184 (9), 167 (67), 152 (6), 115 (4), 85 (17).
tert-Butyl (3aR,4R,6aS)-4-[(Benzhydrylamino)methyl]tetrahydro-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]-
pyrrole-5-carboxylate (9ft). By Method A, with 8 (138 mg, 0.51 mmol), a-phenylbenzenemethanamine
(93 mg, 0.51 mmol), NaBH(OAc)3 (151 mg, 0.71 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt/light petroleum
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ether 2 :8) gave 174 mg (78% of 9ft), 1.5:1 mixture of rotamers a and b. [a] ˆ À21, [a] ˆ À26, [a]
ˆ
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À27, [a] ˆ À49, [a] ˆ À5 9 (c ˆ 0.54, CH2Cl2). UV (MeCN): 208 (16775). IR (film): 3060, 2980, 2935, 1690,
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1490, 1455, 1410, 1265, 1210, 1170, 1125, 1055, 870, 740, 705. 1H-NMR (400 MHz, MeOD): 7.41 (m, 4 arom. H);
7.32 (m, 4 arom. H); 7.21 (m, 2 arom. H); 4.86 (m, HÀC(1'')); 4.72 (m, HÀC(6a)); 4.65( d, 3J(3a,6a) ˆ 5.9,
HÀC(3a)a); 4.57 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.19 (t, 3J(4,1') ˆ 6.4, HÀC(4)b); 4.13 (t, 3J(4,1') ˆ
6.5, HÀC(4)a); 3.78 (m, 1 HÀC(6)); 3.41 (d, 3J(6,6a) ˆ 4.9, HÀC(6)b); 3.38 (d, 3J(6,6a) ˆ 5.0, HÀC(6)a); 2.65
(m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.43 (s, (t-Bu)b); 1.38 (s, (t-Bu)a); 1.32 (s, 1 Me). 13C-NMR (100.6 MHz,
MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 146.1 (s, 2 arom. C); 130.3 (d, 1J(C,H) ˆ 154, 4 arom. C); 129.3,
129.1 (d, 1J(C,H) ˆ 158, 4 arom. C); 128.9 (d, 1J(C,H) ˆ 145, 2 arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 156,
C(3a)a); 85.0 (d, 1J(C,H) ˆ 158, C(3a)b); 82.2 (s, Me3COb); 82.1 (s, Me3COa); 81.6 (d, 1J(C,H) ˆ 155, C(6a)b);
80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 69.2 (d, 1J(C,H) ˆ 136, C(1'')a); 69.0 (d, 1J(C,H) ˆ 136, C(1'')b); 66.2
(d, 1J(C,H) ˆ 147, C(4)a); 65.5 (d, 1J(C,H) ˆ 146, C(4)b); 54.1 (t, 1J(C,H) ˆ 144, C(6)b); 53.5 (t, 1J(C,H) ˆ 143,
C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.9 (q, 1J(C,H) ˆ 129, Me).
‡
‡
CI-MS (NH3): 440 (100, [M ‡ H] ), 439 (76, M ), 383 (24), 337 (2), 271 (1), 215(13), 167 (53), 142 (7), 91 (5).
Anal. calc. for C26H34N2O4 (438.59): C 71.21, H 7.81; found: C 71.27, H 7.73.
(2R,3R,4S)-2-[(Benzhydrylamino)methyl]pyrrolidine-3,4-diol (3ft). By Method Aa, with 9ft (32 mg). FC
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(MeCN/NH4OH 4 :1) gave 21 mg (100% of 3ft). [a] ˆ ‡30, [a] ˆ ‡32, [a] ˆ ‡35, [a] ˆ ‡42 (c ˆ
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0.35, MeOH). UV (MeCN): 223 (88300), 203 (1385). IR (film): 3305, 3030, 1675, 1455, 1205, 1135, 840, 800, 720,
705. 1H-NMR (400 MHz, MeOD): 7.44 (m, 4 arom. H); 7.34 (m, 4 arom. H); 7.24 (m, 2 arom. H); 4.91
(s, HÀC(1'')); 4.20 (ddd, 3J(4,5) ˆ 2.4, 3J(4,5) ˆ 4.4, 3J(4,3) ˆ 4.4, HÀC(4)); 3.92 (dd, 3J(3,4) ˆ 4.4, 3J(3,2) ˆ 8.5,
HÀC(3)); 3.50 (ddd, 3J(2,1') ˆ 4.3, 3J(2,3) ˆ 8.5, 3J(2,1') ˆ 8.5, HÀC(2)); 3.38 (dd, 3J(5,4) ˆ 4.4, 2J ˆ 12.4,
1 HÀC(5)); 3.17 (dd, 3J(5,4) ˆ 2.4, 2J ˆ 12.4, 1 HÀC(5)); 2.95 (dd, 3J(1',2) ˆ 4.3, 2J ˆ 13.0, 1 HÀC(1')); 2.77
(dd, 3J(1',2) ˆ 8.5, 2J ˆ 13.0, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 145.8 (s, arom. C); 145.7 (s, arom. C);
130.4 (d, 1J(C,H) ˆ 149, 4 arom. C); 129.3 (d, 1J(C,H) ˆ 156, 4 arom. C); 129.0 (d, 1J(C,H) ˆ 164, 2 arom. C);
76.1 (d, 1J(C,H) ˆ 145, C(3)); 72.2 (d, 1J(C,H) ˆ 153, C(4)); 69.1 (d, 1J(C,H) ˆ 136, C(1'')); 63.3 (d, 1J(C,H) ˆ
‡
145, C(2)); 52.0 (t, 1J(C,H) ˆ 147, C(5)); 50 49 (C(1')). CI-MS (NH3): 299 (100, [M ‡ H] ), 226 (2), 196 (15),
182 (24), 167 (51), 133 (3), 120 (8), 102 (15), 85 (8).
tert-Butyl (3aR,4R,6aS)-4-[(1R)2,3-Dihydro-1H-inden-1-ylamino]methyl}tetrahydro-2,2-dimethyl-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (9fu). By Method A, with 8 (179 mg, 0.66 mmol), (1R)-2,3-dihydro-
1H-inden-1-amine (88 mg, 0.66 mmol), NaBH(OAc)3 (196 mg, 0.92 mmol), and ClCH2CH2Cl (4 ml). FC
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(AcOEt) gave 179 mg (70% of 9fu), 1.1 :1 mixture of rotamers a and b. [a] ˆ À63, [a] ˆ À66, [a] ˆ À67,
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[a] ˆ À104, [a] ˆ À180 (c ˆ 0.53, CH2Cl2). UV (MeCN): 272 (3015), 266 (3110), 217 (10235), 203 (1695).
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IR (film): 3330, 2980, 2935, 1695, 1475, 1455, 1405, 1365, 1210, 1160, 1125, 1055, 975, 860, 750. 1H-NMR
(400 MHz, MeOD): 7.38 (m, 1 arom. H); 7.25( m, 3 arom. H); 4.77 (m, HÀC(6a)); 4.71 (d, 3J(3a,6a) ˆ 5.8,
HÀC(3a)a); 4.67 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.31 (t, 3J(1'',2'')) ˆ 6.6, HÀC(1'')); 4.18 (t, 3J(4,1') ˆ 6.6,
HÀC(4)b); 4.11 (t, 3J(4,1') ˆ 6.5, HÀC(4)a); 3.82 (d, 3J(6,6a) ˆ 6.7, 1 HÀC(6)b); 3.78 (d, 3J(6,6a) ˆ 6.9,
1 HÀC(6)a); 3.44 (m, 1 HÀC(6)a , 1 HÀC(6)b); 3.06 (m, 1 HÀC(3'')); 2.87 2.75( m, 1 HÀC(3''),
2 HÀC(1')); 2.39 (m, 1 HÀC(2'')); 1.90 (m, 1 HÀC(2'')); 1.51 (s, 1 Me); 1.48 (s, (t-Bu)b); 1.44 (s, (t-Bu)a); 1.34
(s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOa); 157.2 (s, NCOOb); 146.3 (s, arom. C); 145.8
(s, arom. C); 129.5( d, 1J(C,H) ˆ 159, arom. C); 128.2 (d, 1J(C,H) ˆ 154, arom. C); 126.6 (d, 1J(C,H) ˆ 157, arom.
C); 126.0 (d, 1J(C,H) ˆ 152, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ 157, C(3a)b);
82.3 (s, Me3COa); 82.2 (s, Me3COa); 81.5( d, 1J(C,H) ˆ 157, C(6a)b); 80.8 (d, 1J(C,H) ˆ 158, C(6a)a); 66.1
(d, 1J(C,H) ˆ 144, C(4)a); 65.6 (d, 1J(C,H) ˆ 144, C(4b)); 65.0 (d, 1J(C,H) ˆ 139, C(1'')a); 64.8 (d, 1J(C,H) ˆ 142,
C(1'')b); 53.9 (t, 1J(C,H) ˆ 144, C(6)b); 53.4 (t, 1J(C,H) ˆ 144, C(6)a); 48.5( t, 1J(C,H) ˆ 136, C(1')b); 48.2

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Helvetica Chimica Acta Vol. 86 (2003)
(t, 1J(C,H) ˆ 134, C(1')a); 34.5( t, 1J(C,H) ˆ 130, C(2'')a); 34.4 (t, 1J(C,H) ˆ 129, C(2'')b); 32.0 (t, 1J(C,H) ˆ 131,
C(3'')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3):
‡
‡
390 (100, [M ‡ H] ), 389 (81, M ), 363 (3), 333 (28), 289 (15), 242 (4), 215 (10), 179 (6), 117 (33), 91 (6). Anal.
calc. for C22H32N2O4 (388.53): C 68.01, H 8.30, N 7.21; found: C 67.93, H 8.25.
(2R,3R,4S)-2-{[(1R)-2,3-Dihydro-1H-inden-1-ylamino]methyl}pyrrolidine-3,4-diol (3fu). By Method Aa,
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with 9fu (40 mg). FC (MeCN/NH4OH 4 :1) gave 25mg (100% of 3fu). [a] ˆ ‡10, [a] ˆ ‡16, [a] ˆ ‡18,
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[a] ˆ ‡23 (c ˆ 0.36, MeOH). UV (MeCN): 272 (1010), 218 (3590), 204 (670). IR (film): 3090, 2860, 1695,
435
1670, 1650, 1435, 1190, 1150, 1025, 975, 840, 800, 760, 725. 1H-NMR (400 MHz, MeOD): 7.55 (d, 3J ˆ 7.3, arom.
H); 7.30 (m, 3 arom. H); 4.66 (dd, 3J(1'',2'') ˆ 5.0, 3J(1'',2'') ˆ 7.3, HÀC(1'')); 4.26 (ddd, 3J(4,5) ˆ 1.3, 3J(4,5) ˆ
4.0, 3J(4,3) ˆ 4.0, HÀC(4)); 4.07 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.7, HÀC(3)); 3.70 (ddd, 3J(2,1') ˆ 4.1, 3J(2,3) ˆ 8.7,
3J(2,1') ˆ 8.7, HÀC(2)); 3.48 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.37 (m, 1 HÀC(5), 2 HÀC(1')); 3.18
(m, 1 HÀC(3'')); 2.95( m, 1 HÀC(3'')); 2.52 (m, 1 HÀC(2'')); 2.14 (m, 1 HÀC(2'')). 13C-NMR (100.6 MHz,
MeOD): 146.6 (s, arom. C); 141.9 (s, arom. C); 131.0 (d, 1J(C,H) ˆ 160, arom. C); 128.7 (d, 1J(C,H) ˆ 166, arom.
C); 127.1 (d, 1J(C,H) ˆ 161, 2 arom. C); 76.3 (d, 1J(C,H) ˆ 144, C(3)); 71.6 (d, 1J(C,H) ˆ 155, C(4)); 65.6
(d, 1J(C,H) ˆ 146, C(1'')); 61.1 (d, 1J(C,H) ˆ 146, C(2)); 52.2 (t, 1J(C,H) ˆ 146, C(5)); 47.3 (t, 1J(C,H) ˆ 141,
C(1')); 32.5( t, 1J(C,H) ˆ 132, C(2'')); 31.9 (t, 1J(C,H) ˆ 132, C(3'')). CI-MS (NH3): 249 (100, [M ‡ H] ), 229
‡
(20), 211 (26), 195(2), 146 (14), 133 (38), 117 (51), 102 (28), 85(20).
(2R,3R,4S)-2-{[(9-Anthrylmethyl)amino]methyl}pyrrolidine-3,4-diol (3fv). By Method B, with 10 (113 mg,
0.41 mmol), anthracene-9-carboxaldehyde (86 mg, 0.41 mmol), NaBH(OAc)3 (123 mg, 0.58 mmol), and
ClCH2CH2Cl (4 ml). Then by Method Aa, with crude 9fv (45mg). FC (MeCN/NH 4OH 4 :1) gave 30 mg
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(100% of 3fv). [a] ˆ ‡5 , [a] ˆ ‡8, [a] ˆ ‡12 (c ˆ 0.10, CH2Cl2). UV (MeCN): 272 (10130), 255 (9015),
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215(3140). 1H-NMR (400 MHz, MeOD): 8.62 (s, 1 arom. H); 8.49 (d, 3J ˆ 8.9, 2 arom. H); 8.13 (d, 3J ˆ 8.5,
2 arom. H); 7.65( m, 2 arom. H); 7.57 (m, 2 arom. H); 5.10 (AB, HÀC(1'')); 4.26 (ddd, 3J(4,5) ˆ 1.8, 3J(4,5) ˆ 4.0,
3J(4,3) ˆ 4.0, HÀC(4)); 4.07 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.4, HÀC(3)); 3.73 (ddd, 3J(2,1') ˆ 4.3, 3J(2,3) ˆ 8.4,
3J(2,1') ˆ 8.4, HÀC(2)); 3.48 (m, 1 HÀC(5), 2 HÀC(1')); 3.29 (dd, 3J(5,4)ˆ 1.8, 2J ˆ 12.5, 1 HÀC(5)).
13C-NMR (100.6 MHz, MeOD): 136.3 (arom. C); 133.9 (arom. C); 132.9 (arom. C); 131.3 (2 arom. C); 130.8
(arom. C); 128.8 (2 arom. C); 127.2 (2 arom. C); 127.0 (arom. C); 125.7 (2 arom. C); 76.3 (C(3)); 71.7 (C(4));
‡
61.4 (C(2)); 52.1 (C(1')); 50 49 (C(5)); 46.5 (C(1'')). CI-MS (NH3): 322 (11, M ), 251 (4), 208 (100), 192 (50),
180 (42), 152 (45), 115 (46), 102 (70), 91 (44).
tert-Butyl(3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4{[(2-phenylethyl)amino]methyl}-5H-[1,3]dioxolo[4,5-c]-
pyrrole-5-carboxylate (9g). By Method A, with 8 (85mg, 0.31 mmol), 2-phenylethylamine (38 mg, 0.31 mmol),
NaBH(OAc)3 (93 mg, 0.44 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 80 mg (68% of 9g), 1.05:1
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mixture of rotamers a and b. [a] ˆ À32, [a] ˆ À35, [a] ˆ À43, [a] ˆ À75, [a] ˆ À93 (c ˆ 0.40,
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CH2Cl2). UV (MeCN): 210 (9065). IR (film): 3585, 2980, 2935, 1690, 1455, 1410, 1370, 1215, 1170, 1125, 1055,
860, 755, 700, 665. 1H-NMR (400 MHz, MeOD): 7.25( m, 5arom. H); 4.71 ( m, HÀC(6a)); 4.57 (m, HÀC(3a));
4.13 (dd, 3J(4,1') ˆ 6.6, 3J(4,1') ˆ 6.4, HÀC(4)b); 4.08 (dd, 3J(4,1') ˆ 6.6, 3J(4,1') ˆ 6.5, HÀC(4)a); 3.80 (d, 2J ˆ
12.9, 1 HÀC(6)a); 3.76 (d, 2J ˆ 13.1, 1 HÀC(6)b); 3.28 (m, 1 HÀC(6), 1 HÀC(6)b); 2.88 2.80 (m, 2 HÀC(1''),
2 HÀC(2'')); 2.67 (m, 2 HÀC(1')); 1.47 (s, (t-Bu)b); 1.45( s, (t-Bu)a); 1.41 (s, 1 Me); 1.30 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 157.4 (s, NCOOb); 157.3 (s, NCOOa); 141.9 (s, arom. C); 130.6 (d, 1J(C,H) ˆ 157, arom.
C); 130.5( d, 1J(C,H) ˆ 160, arom. C); 130.4 (d, 1J(C,H) ˆ 160, arom. C); 128.2 (d, 1J(C,H) ˆ 161, arom. C);
128.1 (d, 1J(C,H) ˆ 161, arom. C); 113.4 (s); 85.5 (d, 1J(C,H) ˆ 158, C(3a)a); 84.9 (d, 1J(C,H) ˆ 157, C(3a)b);
82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 153, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.8
(d, 1J(C,H) ˆ 146, C(4)a); 65.3 (d, 1J(C,H) ˆ 146, C(4)b); 53.8 (t, 1J(C,H) ˆ 143, C(6)b); 53.1 (t, 1J(C,H) ˆ 142,
C(6)a); 52.9, 52.8 (2t, 1J(C,H) ˆ 126, 1J(C,H) ˆ 127, C(1'), C(1'')); 37.7 (t, 1J(C,H) ˆ 129, C(2'')); 29.6
(q, 1J(C,H) ˆ 127, Me3C); 28.0 (q, 1J(C,H) ˆ 126, Me); 25.8 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3): 377 (100,
‡
[M ‡ H] ), 321 (41), 303 (5), 285(16), 229 (22), 211 (1), 185(23), 134 (32), 105(30), 91 (14). Anal. calc. for
C21H32N2O4 (376.53): C 66.99, H 8.57; found: C 67.01, H 8.46.
(2R,3R,4S)-2-{[(2-Phenylethyl)amino]methyl}pyrrolidine-3,4-diol (3g). By Method Aa, with 9g (25mg).
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FC (MeCN/NH4OH 4 :1) gave 16 mg (100% of 3g). [a] ˆ ‡12, [a] ˆ ‡13, [a] ˆ ‡13, [a] ˆ ‡30,
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[a] ˆ ‡35( c ˆ 0.32, MeOH). UV (MeCN): 260 (475), 208 (4140). IR (film): 3030, 1675, 1435, 1205, 1135, 840,
405
800, 750, 725, 700. 1H-NMR (400 MHz, MeOD): 7.38 7.27 (m, 5arom. H); 4.25 ( m, HÀC(4)); 4.03
(dd, 3J(3,4) ˆ 4.1, 3J(3,2) ˆ 8.7, HÀC(3)); 3.68 (ddd, 3J(2,1') ˆ 4.3, 3J(2,3) ˆ 8.7, 3J(2,1') ˆ 8.7, HÀC(2)); 3.46
(dd, 3J(5,4) ˆ 3.8, 2J ˆ 12.6, 1 HÀC(5)); 3.40 3.20 (m, 2 HÀC(1'), 2 HÀC(1''), HÀC(5)); 3.00 (t, 3J(2'',1'') ˆ
7.9, 2 HÀC(2'')). 13C-NMR (100.6 MHz, MeOD): 139.6 (s, arom. C); 130.6 (d, 1J(C,H) ˆ 161, 3 arom. C); 128.8
(d, 1J(C,H) ˆ 161, 2 arom. C); 76.4 (d, 1J(C,H) ˆ 145, C(3)); 71.7 (d, 1J(C,H) ˆ 154, C(4)); 60.2 (d, 1J(C,H) ˆ

Helvetica Chimica Acta Vol. 86 (2003)
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148, C(2)); 52.0 (t, 1J(C,H) ˆ 148, C(1'')); 50 49 (C(1'), C(5)); 35.3 (t, 1J(C,H) ˆ 129, C(2'')). CI-MS (NH3): 237
‡
(100, [M ‡ H] ), 145(5), 134 (20), 116 (3), 102 (21), 85(18).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4{[(3-phenylpropyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9h). By Method A, with 8 (89 mg, 0.33 mmol), 3-phenylpropylamine (44 mg,
0.33 mmol), NaBH(OAc)3 (97 mg, 0.46 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 53 mg (40% of
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9h), 1.1:1 mixture of rotamers a and b. [a] ˆ À25, [a] ˆ À26, [a] ˆ À33, [a] ˆ À163, [a] ˆ À204
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(c ˆ 0.46, CH2Cl2). UV (MeCN): 261 (1985), 210 (17890). IR (film): 3335, 2980, 2935, 1695, 1495, 1480, 1455,
1
1405, 1365, 1210, 1170, 1125, 1055, 975, 860, 745, 700. H-NMR (400 MHz, MeOD): 7.28 (m, 5arom. H); 4.76
(m, HÀC(6a)); 4.60 (m, HÀC(3a)); 4.17 (t, 3J(4,1') ˆ 6.4, HÀC(4)b); 4.11 (t, 3J(4,1') ˆ 6.9, HÀC(4)a); 3.82
(m, 1 HÀC(6)); 3.40 (m, 1 HÀC(6)); 2.66 (m, 2 HÀC(1'), 2 HÀC(1''), 2 HÀC(2'')); 1.85( m, 2 HÀC(3'')); 1.50
(s, t-Bu); 1.43 (s, 1 Me); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.6 (s, NCOOb); 157.3 (s, NCOOa);
144.1 (s, arom. C); 130.2 (d, 1J(C,H) ˆ 160, 4 arom. C); 127.7 (d, 1J(C,H) ˆ 161, arom. C); 113.5( s); 85.4
(d, 1J(C,H) ˆ 156, C(3a)a); 84.8 (d, 1J(C,H) ˆ 156, C(3a)b); 82.4 (s, Me3COa); 82.2 (s, Me3COb); 81.6
(d, 1J(C,H) ˆ 156, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.6 (d, 1J(C,H) ˆ 147, C(4)a); 65.2 (d, 1J(C,H) ˆ
145, C(4)b); 53.7 (t, 1J(C,H) ˆ 144, C(6)b); 53.1 (t, 1J(C,H) ˆ 145, C(6)a); 50 49 (C(1'), C(1'')); 35.4
(t, 1J(C,H) ˆ 127, C(2'')); 33.2 (t, 1J(C,H) ˆ 126, C(3'')); 29.6 (q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 125,
Me); 25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 392 (100, [M ‡ H] ), 391 (89, M ), 335(27), 285(2), 243 (5),
178 (13), 148 (35), 117 (4), 91 (25). Anal. calc. for C22H34N2O4 (390.55): C 67.70, H 8.78; found: C 67.66, H 8.66.
(2R,3R,4S)-2-{[(3-Phenylpropyl)amino]methyl}pyrrolidine-3,4-diol (3h). By Method Aa, with 9h (20 mg).
‡
‡
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FC (MeCN/NH4OH 4 :1) gave 13 mg (100% of 3h). [a] ˆ ‡1, [a] ˆ ‡2, [a] ˆ ‡5 (c ˆ 0.32, MeOH).
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UV (MeCN): 322 (755), 216 (2490), 203 (640). IR (film): 3055, 1670, 1440, 1265, 1205, 1145, 1040, 845, 800, 740,
705. 1H-NMR (400 MHz, MeOD): 7.35 7.20 ( m, 5arom. H); 4.24 ( ddd, 3J(4,5) ˆ 1.5, 3J(4,5) ˆ 4.0, 3J(4,3) ˆ 4.0,
HÀC(4)); 4.04 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.8, HÀC(3)); 3.68 (ddd, 3J(2,1') ˆ 5.1, 3J(2,3) ˆ 8.8, 3J(2,1') ˆ 8.8,
HÀC(2)); 3.48 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.38 (m, 2 HÀC(1')); 3.29 (dd, 3J(5,4) ˆ 1.5, 2J ˆ 12.6,
1 HÀC(5)); 3.08 (m, 2 HÀC(1'')); 2.75( t, 3J(3'', 2'') ˆ 7.5, 2 H ÀC(3'')); 2.07 (m, 2 HÀC(2'')). 13C-NMR
(100.6 MHz, MeOD): 142.6 (s, arom. C); 130.5( d, 1J(C,H) ˆ 160, 2 arom. C); 130.2 (d, 1J(C,H) ˆ 160, 2 arom.
C); 128.2 (d, 1J(C,H) ˆ 161, arom. C); 76.7 (d, 1J(C,H) ˆ 144, C(3)); 71.6 (d, 1J(C,H) ˆ 152, C(4)); 59.6
(d, 1J(C,H) ˆ 146, C(2)); 52.6 (t, 1J(C,H) ˆ 144, C(5)); 50 49 (C(1'), C(1'')); 34.5( t, 1J(C,H) ˆ 129, C(3'')); 30.3
‡
(t, 1J(C,H) ˆ 130, C(2'')). CI-MS (NH3): 251 (100, [M ‡ H] ), 148 (9), 136 (2), 115(2), 102 (18), 85(21).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(4-phenylbutyl)amino]methyl}-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate (9i). By Method A, with 8 (130 mg, 0.48 mmol), 4-phenylbutylamine (76 ml, 0.48 mmol),
NaBH(OAc)3 (142 mg, 0.67 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt) gave 100 mg (52% of 9i), 1.2 :1
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mixture of rotamers a and b. [a] ˆ À39, [a] ˆ À42, [a] ˆ À47, [a] ˆ À79, [a ˆ À94 (c ˆ 0.35,
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CH2Cl2). IR (film): 3325, 3000, 2980, 2935, 2860, 1695, 1605, 1495, 1455, 1405, 1365, 1210, 1170, 1125, 1055, 975,
860, 750, 700, 665. 1H-NMR (400 MHz, MeOD): 7.30 7.16 (m, 5arom. H); 4.71 ( m, HÀC(6a)); 4.58
(m, HÀC(3a)); 4.14 (m, HÀC(4)b); 4.04 (m, HÀC(4)a); 3.89 (d, 2J ˆ 12.9, 1 HÀC(6)a); 3.78 (d, 2J ˆ 12.9,
1 HÀC(6)b); 3.35( dd, 3J(6,6a) ˆ 5.1, 2J ˆ 12.9, 1 HÀC(6)); 2.68 2.60 (m, 2 HÀC(1'), 2 HÀC(1''), 2 HÀC(4''));
1.68 1.61 (m, 2 HÀC(2'')); 1.56 1.49 (m, 2 HÀC(3'')); 1.46 (s, t-Bu); 1.45( s, 1 Me); 1.31 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 154.6 (NCOO); 125.7 (arom. C); 111.5 (Me2C); 83.9 (C(3a)a); 83.2 (C(3a)b); 79.8
(Me3CO); 79.5(C(6a) b); 78.8 (C(6a)a); 63.7 (C(4)a); 63.4 (C(4)b); 52.4 (C(6)b); 51.9 (C(6)a); 50.2 (C(1')a); 49.8
(C(1')b); 49.8 (C(1'')); 35.8 (C(4'')); 29.8 (C(2'')); 29.1 (C(3'')); 28.4 (Me3C); 27.0 (Me); 25.0 (Me). CI-MS
‡
(NH3): 405(100, [ M ‡ H] ), 349 (21), 162 (71), 91 (67). Anal. calc. for C23H36N2O4 (404.55): C 68.29, H 8.97, N
6.92; found: C 68.16, H 8.95, N 6.92.
(2R,3R,4S)-2-{[(4-Phenylbutyl)amino]methyl}pyrrolidine-3,4-diol (3i). By Method Aa, with 9i (20 mg).
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FC (MeCN/NH4OH 4 :1) gave 13 mg (100% of 3i). [a] ˆ ‡10, [a] ˆ ‡10, [a] ˆ ‡20, [a] ˆ ‡60,
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[a] ˆ ‡68 (c ˆ 0.50, H2O). UV (MeCN): 209 (6100). IR (film): 3500 2800, 1670, 1440, 1205, 1135, 840, 800,
405
725, 700. 1H-NMR (400 MHz, MeOD): 7.28 7.14 (m, 5arom. H); 4.20 ( ddd, 3J(4,5) ˆ 1.3, 3J(4,5) ˆ 4.1, 3J(4,3) ˆ
4.1, HÀC(4)); 3.99 (dd, 3J(3,4) ˆ 4.1, 3J(3,2) ˆ 9.1, HÀC(3)); 3.54 (ddd, 3J(2,1') ˆ 5.0, 3J(2,3) ˆ 9.1, 3J(2,1') ˆ 9.1,
HÀC(2)); 3.38 3.25( m, 1 HÀC(5), 2 HÀC(1')); 3.17 (dd, 3J(5,4) ˆ 1.3, 2J ˆ 13.2, 1 HÀC(5)); 3.04 2.97
(m, 2 HÀC(1'')); 2.57 (m, 2 HÀC(4'')); 1.60 (m, 2 HÀC(2''), 2 HÀC(3'')). 13C-NMR (100.6 MHz, MeOD):
144.7, 131.2, 131.1, 128.6 (arom. C); 76.8 (C(3)); 71.7 (C(4)); 59.0 (C(2)); 53.1 (C(5)); 50.9 (C(1'')); 50.1 (C(1'));
‡
36.8 (C(4'')); 27.5, 30.0 (C(2''), C(3'')). CI-MS (NH3): 265(100, [ M ‡ H] ), 162 (78), 91 (99).
tert-Butyl (3aR,4R,6aS)-4-{[(1-Benzylpiperidin-4-yl)amino]methyl}tetrahydro-2,2-dimethyl-5H-[1,3]di-
oxolo[4,5-c]pyrrole-5-carboxylate (9j). By Method A, with 8 (100 mg, 0.37 mmol), 1-benzylpiperidin-4-amine
(76 ml, 0.37 mmol), NaBH(OAc)3 (110 mg, 0.52 mmol), and ClCH2CH2Cl (2.5ml). FC (CH 2Cl2/MeOH 4 :1):

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Helvetica Chimica Acta Vol. 86 (2003)
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125mg (76% of 9j), 1:1 mixture of rotamers a and b. [a] ˆ À26, [a] ˆ À32, [a] ˆ À35, [a] ˆ À59,
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[a] ˆ À69 (c ˆ 0.29, CH2Cl2). UV (MeCN): 217 (26400), 190 (2520). IR (film): 2980, 2935, 2800, 1695, 1455,
405
1
1405, 1215, 1200, 1120, 1055, 980, 860, 740, 700. H-NMR (400 MHz, MeOD): 7.36 7.27 (m, 5arom. H); 4.74
(m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b); 4.61 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)a); 4.12 (m, HÀC(4)b);
4.07 (m, HÀC(4)a); 3.82 (d, 2J ˆ 12.6, 1 HÀC(6)b); 3.79 (d, 2J ˆ 12.7, 1 HÀC(6)a); 3.57 (s, ArCH2); 3.41
(dd, 3J(6,6a) ˆ 4.7, 2J ˆ 12.7, 1 HÀC(6)b); 3.35( dd, 3J(6,6a) ˆ 4.8, 2J ˆ 12.6, 1 HÀC(6)a); 2.92 (m, HaxÀC(2''),
HaxÀC(6'')); 2.70 (m, 2 HÀC(1')); 2.56 (m, HÀC(4'')); 2.13 (m, HeqÀC(2''), HeqÀC(6'')); 1.92 (m, HaxÀC(3''),
HaxÀC(5'')); 1.49 (s, t-Bu); 1.46 (m, HeqÀC(3''), HeqÀC(5'')); 1.42 (s, 1 Me); 1.32 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 157.6, 157.3 (NCOO); 139.1, 139.0 (arom. C); 131.7, 130.2, 129.4 (5 arom. C); 113.4
(Me2C); 85.4, 84.8 (C(3a)); 82.4. 82.2 (Me3CO); 81.6, 80.9 (C(6a)); 65.9, 65.4 (C(4)); 64.7 (C(6)); 56.4, 56.2
(C(4'')); 54.0 (C(1')); 53.8, 53.2 (C(2''), C(6'')); 47.8 (ArCH2); 33.5, 33.4, 33.3, 33.2 (C(3''), C(5'')); 29.6 (Me3C);
‡
28.1 (Me); 25.8 (Me). CI-MS (NH3): 446 (29, [M ‡ H] ), 372 (5), 273 (6), 203 (100), 91 (87). Anal. calc. for
C25H39N3O4 (445.60): C 67.39, H 8.82, N 9.43; found: C 67.37, H 8.83, N 9.51.
(2R,3R,4S)-2-{[(1-Benzylpiperidin-4-yl)amino]methyl}pyrrolidine-3,4-diol (3j). By Method Aa, with 9j
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(40 mg). FC (MeCN/NH4OH 5:1) gave 30 mg (100% of 3j). [a] ˆ ‡307, [a] ˆ ‡374, [a] ˆ ‡477,
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[a] ˆ ‡609 (c ˆ 1.0, MeOH). UV (MeCN): 213 (1800). IR (film): 3500 2900, 1675, 1635, 1575, 1435, 1370,
435
1205, 840, 800, 725, 705. 1H-NMR (400 MHz, D2O/MeOD 75 :25): 7.57 7.51 (m, 5arom. H); 4.38 ( m, HÀC(4));
4.36 (s, ArCH2); 4.23 (dd, 3J(3,4) ˆ 3.8, 3J(3,2) ˆ 9.5, HÀC(3)); 3.85( m, HÀC(2)); 3.69 3.62 (m, HÀC(4''),
1 HÀC(1'), 1 HÀC(5)); 3.56 (dd, 3J(5,4) ˆ 2.5, J ˆ 12.3, 1 HÀC(5)); 3.46 (d, 2J ˆ 13.1, 1 HÀC(1')); 3.15, 2.47,
2
1.99, 1.47 (4m, 2 HÀC(2''), 2 HÀC(3''), 2 HÀC(5''), 2 HÀC(6'')). 13C-NMR (100.6 MHz, D2O/MeOD 75:25):
138.7 (arom. C); 133.0, 132.2, 131.2 (5 arom. C); 75.7 (C(3)); 70.3 (C(4)); 62.4 (C(2)); 58.1 (C(5)); 55.0 (C(4''));
‡
52.5 (C(1')); 52.0 (C(2''), C(6'')); 46.0 (ArCH2); 27.1 (C(3''), C(5'')). CI-MS (NH3): 306 (56, [M ‡ H] ), 279 (4),
203 (17), 172 (17), 91 (100).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{{[(2E)-3-phenylprop-2-enyl]amino}methyl}-5H-
[1,3]dioxolo [4,5-c]pyrrole-5-carboxylate (9k). By Method B, with 10 (105mg, 0.39 mmol), cinnamaldehyde
(51 mg, 0.39 mmol), NaBH(OAc)3 (114 mg, 0.54 mmol), and ClCH2CH2Cl (4 ml). FC (AcOEt) gave 35mg
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(24% of 9k), 1.15:1 mixture of rotamers a and b. [a] ˆ À26, [a] ˆ À28, [a] ˆ À33, [a] ˆ À60, [a]
ˆ
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À75( c ˆ 0.36, CH2Cl2). UV (MeCN): 250 (22560), 210 (24845). IR (film): 3340, 2980, 2935, 1695, 1600, 1455,
1415, 1170, 1055, 970, 860, 745, 695. 1H-NMR (400 MHz, MeOD): 7.43 (m, 2 arom. H); 7.33 (m, 2 arom. H); 7.25
(m, 1 arom. H); 6.60 (d, 3J(3'',2'') ˆ 15.9, HÀC(3'')); 6.33 (m, HÀC(2'')); 4.77 (m, HÀC(6a)); 4.67
(d, 3J(3a,6a) ˆ 5.7, HÀC(3a)a); 4.64 (d, 3J(3a,6a) ˆ 5.7, HÀC(3a)b); 4.20 (t, 3J(4,1') ˆ 6.7, HÀC(4)b); 4.15
(t, 3J(4,1') ˆ 6.7, HÀC(4)a); 3.84 (d, 3J(6,6a) ˆ 5.2, 1 HÀC(6)b); 3.81 (d, 3J(6,6a) ˆ 5.5, 1 HÀC(6)a); 3.41
(m, 1 HÀC(6)a), 1 HÀ(6)b, 2 HÀC(1'')); 2.75( m, 2 HÀC(1')); 1.50 (s, (t-Bu)b); 1.48 (s, (t-Bu)a); 1.43
(s, 1 Me); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.6 (s, NCOOb); 157.3 (s, NCOOa); 139.3 (s, arom.
C); 134.2 (d, 1J(C,H) ˆ 151, C(3'')); 130.4 (d, 1J(C,H) ˆ 159, 2 arom. C); 129.4 (d, 1J(C,H) ˆ 155, arom. C); 129.2
(d, 1J(C,H) ˆ 152, C(2'')); 128.2 (d, 1J(C,H) ˆ 158, 2 arom. C); 113.5 (s); 85.4 (d, 1J(C,H) ˆ 156, C(3a)a); 84.9
(d, 1J(C,H) ˆ 156, C(3a)b); 82.4 (s, Me3COa); 82.2 (s, Me3COb); 81.7 (d, 1J(C,H) ˆ 155, C(6a)b); 80.9
(d, 1J(C,H) ˆ 158, C(6a)a); 65.8 (d, 1J(C,H) ˆ 148, C(4)a); 65.2 (d, 1J(C,H) ˆ 144, C(4)b); 53.7 (t, 1J(C,H) ˆ
141, C(6)b); 53.1 (C(6)a), C(1'')); 50 49 (C(1')); 29.6 (q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 126, Me);
25.8 (q, 1J(C,H) ˆ 126, Me). CI-MS (NH3): 390 (67, [M ‡ H] ), 389 (100, M ), 333 (60), 287 (5), 243 (2), 187
(5), 117 (84), 91 (14). Anal. calc. for C22H32N2O4 (388.53): C 68.01, H 8.30; found: C 67.95, H 8.15.
(2R,3R,4S)-2-{{[(2E)-3-Phenylprop-2-enyl]amino}methyl}pyrrolidine-3,4-diol (3k). By Method Aa, with
‡
‡
25
25
25
9k (35mg). FC (MeCN/NH 4OH 4 :1) gave 23 mg (100% of 3k). [a] ˆ ‡11, [a] ˆ ‡11, [a] ˆ ‡15( c ˆ
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0.33, MeOH). UV (MeCN): 272 (20100), 259 (19000), 217 (6870). IR (film): 3205, 3060, 1670, 1445, 1200, 1135,
970, 840, 800, 725, 695. 1H-NMR (400 MHz, MeOD): 7.49 (m, 2 arom. H); 7.36 7.28 (m, 3 arom. H); 6.86
(d, 3J(3'',2'') ˆ 15.9, HÀC(3'')); 6.33 (dt, 3J(2'',1'') ˆ 7.1, 3J(2'',3'') ˆ 15.9, HÀC(2'')); 4.25( ddd, 3J(4,5) ˆ 1.3,
3J(4,5) ˆ 3.9, 3J(4,3) ˆ 3.9, HÀC(4)); 4.08 (dd, 3J(3,4) ˆ 3.9, 3J(3,2) ˆ 9.0, HÀC(3)); 3.85( m, 2 HÀC(1'')); 3.75
(m, HÀC(2)); 3.51 (dd, 3J(5,4)ˆ 3.9, 2J ˆ 12.6, 1 HÀC(5)); 3.45 (m, 2 HÀC(1')); 3.31 (m, 1 HÀC(5)).
13C-NMR (100.6 MHz, MeOD): 140.0 (C(3'')); 130.0 (arom. C); 130.6, 130.5, 128.7 (5 arom. C); 121.5
(C(2'')); 76.5 (C(3)); 71.4 (C(4)); 59.7 (C(2)); 52.6, 52.2 (C(1''), C(5)); 48.6 (C(1')). CI-MS (NH3): 249 (4, [M ‡
‡
H] ), 169 (3), 146 (11), 132 (30), 117 (100), 102 (38), 91 (31), 85(25), 77 (23).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{{[(1R)-1-phenylethyl]amino}methy}-5H-[1,3]dioxo-
lo[4,5-c] pyrrole-5-carboxylate (9l). By Method A, with 8 (100 mg, 0.37 mmol), (aR)-a-methylbenzenemethan-
amine (47 ml, 0.37 mmol), NaBH(OAc)3 (110 mg, 0.52 mmol), and ClCH2CH2Cl (2.5ml). FC (AcOEt/light
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petroleum ether 4 :1) gave 96 mg (69% of 9l), 1.3 :1 mixture of rotamers a and b. [a] ˆ À23, [a] ˆ À32,
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[a] ˆ À40, [a] ˆ À68, [a] ˆ À83 (c ˆ 0.30, CH2Cl2). IR (film): 3330, 3060, 2980, 2935, 1695, 1680, 1480,
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Helvetica Chimica Acta Vol. 86 (2003)
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1455, 1405, 1370, 1210, 1170, 1125, 1055, 970, 865, 765, 700, 665. 1H-NMR (400 MHz, MeOD): 7.36 7.27
3
3
(m, 5arom. H); 4.75( dd, 3J(HÀC(6a,6) ˆ 5.8, J(6a,3a) ˆ 5.8, HÀC(6a)a); 4.71 (dd, 3J(6a,6) ˆ 5.9, J(6a,3a) ˆ
5.9, HÀC(6a)b); 4.59 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)a); 4.49 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.14 (t, 3J(4,1') ˆ 5.7,
HÀC(4)b); 4.02 (t, 3J(4,1') ˆ 7.0, HÀC(4)a); 3.89 (q, 3J ˆ 6.5, HÀC(1'')); 3.77 (d, 2J ˆ 13.1, 1 HÀC(6)); 3.29
(dd, 3J(6,6a) ˆ 5.8, 2J ˆ 13.1, 1 HÀC(6)); 2.60 (dd, 3J(1',4) ˆ 5.7, 2J ˆ 12.2, 1 HÀC(1')b); 2.53 (dd, 3J(1',4) ˆ 7.0,
2J ˆ 12.4, 1 HÀC(1')a); 2.44(d, 2J ˆ 12.2, 1 HÀC(1')b); 2.42 (d, 2J ˆ 12.4, 1 HÀC(1')a); 1.52 (s, (t-Bu)b); 1.43
(s, (t-Bu)a); 1.38 (d, 3J ˆ 6.5, 1 Mea); 1.37 (d, 3J ˆ 6.5, 1 Meb); 1.30 (s, 1 Me); 1.32 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 146.4, 129.6, 128.2, 127.8 (arom. C); 112.5(Me 2C); 84.6 (C(3a)a); 84.2 (C(3a)b); 81.5
(Me3CO); 80.8 (C(6a)b); 80.1 (C(6a)a); 65.2 (C(4)a); 64.6 (C(4)b); 59.4 (C(6)a); 59.1 (C(6)b); 53.0 (C(1')b); 52.3
(C(1')a); 50 49 (C(1'')); 28.7 (Me3C); 27.2 (Me); 24.9 (Me); 24.3 (MeÀC(1'')a); 24.2 (MeÀC(1'')b). CI-MS
‡
(NH3): 377 (100, [M ‡ H] ), 321 (7), 215(4), 105(9). Anal. calc. for C 21H32N2O4 (376.49): C 66.99, H 8.57, N
7.44; found: C 70.01, H 8.54, N 7.41.
(2R,3R,4S)-2-{{[(1R)-1-Phenylethyl]amino}methyl}pyrrolidine-3,4-diol (3l). By Method Aa, with 9l
25
(30 mg). FC (MeCN/NH4OH 4 :1) gave 21 mg (100% of 3l). [a] ˆ ‡8 (c ˆ 0.80, MeCN). UV (MeCN):
589
196 (6000). IR (film): 3500 3000, 1675, 1430, 1200, 1135, 835, 800, 720, 700. 1H-NMR (400 MHz, MeOD): 7.43
3
3
7.36 (m, 5arom. H); 4.21 ( q, 3J ˆ 6.8, HÀC(1'')); 4.16 (ddd, 3J(4,5) ˆ 4.1, J(4,3) ˆ 4.3, J(4,5) ˆ 1.4, HÀC(4));
3.87 (dd, 3J(3,4) ˆ 4.3, 3J(3,2) ˆ 8.7, HÀC(3)); 3.48 (ddd, 3J(2,3) ˆ 8.7, 3J(2,1') ˆ 8.9, 3J(2,1') ˆ 4.2, HÀC(2));
3.26 (dd, 3J(5,4) ˆ 4.2, 2J ˆ 13.0, 1 HÀC(5)); 3.23 (m, 1 HÀC(1'), 2 HÀC(5)); 2.87 (dd, 3J(1',2) ˆ 8.9, 2J ˆ 13.4,
1 HÀC(1')); 1.52 (d, 2J ˆ 6.8, MeÀC(1'')). 13C-NMR (100.6 MHz, MeOD): 140.5, 131.8, 131.7, 130.0 (arom. C);
76.6 (C(3)); 72.0 (C(4)); 61.1 (C(1'')); 60.3 (C(2)); 52.6 (C(5)); 48.7 (C(1')); 21.9 (MeÀC(1')). CI-MS (NH3):
‡
237 (100, [M ‡ H] ), 134 (42), 120 (30), 105(73), 85(20).
(2R,3R,4S)-2-{{[(1S)-1-(4-Nitrophenyl)ethyl]amino}methyl}pyrrolidine-3,4-diol (3la). By Method A, with
8 (100 mg, 0.37 mmol), (aS)-a-methyl-4-nitrobenzenemethanamine (75mg, 0.37 mmol), NaBH(OAc) 3
(110 mg, 0.52 mmol), and ClCH2CH2Cl (3 ml). Then by Method Aa, with crude 9la (100 mg). FC (MeCN/
25
NH4OH 4 :1) gave 66 mg (100% of 3la). [a] ˆ ‡6 (c ˆ 0.38, MeOH). UV (MeCN): 272 (3100), 216 (2550).
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1H-NMR (400 MHz, MeOD): 8.30 (d, 3J ˆ 8.7, 2 arom. H); 7.76 (d, 3J ˆ 8.7, 2 arom. H); 4.32 (q, 3J ˆ 6.7,
HÀC(1'')); 4.27 (m, HÀC(4)); 4.04 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.8, HÀC(3)); 3.67 (ddd, 3J(2,3) ˆ 8.8, 3J(2,1') ˆ
9.1, 3J(2,1') ˆ 3.8, HÀC(2)); 3.54 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.33 (dd, 3J(5,4) ˆ 1.5, 2J ˆ 12.6,
1 HÀC(5)); 3.20 (dd, 3J(1',2) ˆ 9.1, 2J ˆ 13.5, 1 HÀC(1')); 3.07 (dd, 3J(1',2) ˆ 3.8, 2J ˆ 13.5, 1 HÀC(1')); 1.60
(d, 3J ˆ 6.7, MeÀC(1'')). 13C-NMR (100.6 MHz, MeOD): 151.7 (arom. C); 132.1 (2 arom. C); 127.6 (2 arom. C);
122.2 (arom. C); 77.5(C(3)); 73.1 (C(4)); 63.1 (C(2)); 62.2 (C(1 '')); 53.7 (C(5)); 49.6 (C(1')); 24.2 (MeÀC(1')).
‡
CI-MS (NH3): 282 (100, [M ‡ H] ), 180 (2), 151 (3), 102 (16), 85 (7). Anal. calc. for C13H19N3O4 (281.31): C
55.51, H 6.81, N 14.94; found: C 55.48, H 6.79, N 14.90.
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(pyridin-2-ylmethyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c] pyrrole-5-carboxylate (9m). By Method A, with 8 (96 mg, 0.35mmol), pyridine-2-methanamine
(38 mg, 0.35mmol), NaBH(OAc) 3 (105mg, 0.50 mmol), and ClCH 2CH2Cl (3 ml). FC (AcOEt) gave 82 mg
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25
25
25
25
(64% of 9m), 1.4 :1 mixture of rotamers a and b. [a] ˆ À34, [a] ˆ À35, [a] ˆ À38, [a] ˆ À68, [a]
ˆ
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À83 (c ˆ 0.37, CH2Cl2). UV (MeCN): 261 (4560), 205 (8220). IR (film): 3330, 2980, 2935, 1690, 1590, 1570, 1475,
1460, 1405, 1370, 1210, 1175, 1125, 1055, 995, 975, 860, 760. 1H-NMR (400 MHz, MeOD): 8.53 (m, 1 arom. H);
7.85( t, 3J ˆ 7.7, 1 arom. H); 7.51 (d, 3J ˆ 7.7, 1 arom. H); 7.34 (m, 1 arom. H); 4.79 (m, HÀC(6a)); 4.69
(d, 3J(3a,6a) ˆ 6.0, HÀC(3a)a); 4.66 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b); 4.17 (dd, 3J(4,1') ˆ 6.0, 3J(4,1') ˆ 6.3,
HÀC(4)b); 4.11 (dd, 3J(4,1') ˆ 6.1, 3J(4,1') ˆ 6.4, HÀC(4)a); 3.94 (m, 2 HÀC(1'')); 3.80 (m, 1 HÀC(6)); 3.41
(m, 1 HÀC(6)); 2.71 (m, 2 HÀC(1')); 1.50 (s, 1 Me); 1.45( s, (t-Bu)a); 1.44 (s, (t-Bu)b); 1.34 (s, 1 Me). 13C-NMR
(100.6 MHz, MeOD): 161.5( s, arom. C); 157.4 (s, NCOOb); 157.2 (s, NCOOa); 150.7 (d, 1J(C,H) ˆ 180, arom.
C); 139.5( d, 1J(C,H) ˆ 164, arom. C); 124.8 (d, 1J(C,H) ˆ 164, arom. C); 124.5( d, 1J(C,H) ˆ 166, arom. C);
113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 84.9 (d, 1J(C,H) ˆ 156, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb);
81.6 (d, 1J(C,H) ˆ 150, C(6a)b); 80.9 (d, 1J(C,H) ˆ 159, C(6a)a); 65.9 (d, 1J(C,H) ˆ 148, C(4)a); 65.5
(d, 1J(C,H) ˆ 145, C(4)b); 56.1 (t, 1J(C,H) ˆ 136, C(1'')); 54.0 (t, 1J(C,H) ˆ 142, C(6)b); 53.3 (t, 1J(C,H) ˆ 143,
C(6)a); 50 49 (C(1')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 129, Me); 25.8 (q, 1J(C,H) ˆ 128, Me).
‡
CI-MS (NH3): 364 (100, [M ‡ H] ), 348 (3), 308 (10), 264 (28), 215(16), 171 (3), 121 (99), 93 (43). Anal. calc.
for C19H29N3O4 (363.48): C 62.79, H 8.04, N 11.56; found: C 62.83, H 7.97, N 11.37.
(2R,3R,4S)-2-{[(Pyridin-2-ylmethyl)amino]methyl}pyrrolidine-3,4-diol (3m). By Method Aa, with 9m
25
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25
(20 mg). FC (MeCN/NH4OH 4 :1) gave 12 mg (100% of 3m). [a] ˆ ‡9, [a] ˆ ‡9, [a] ˆ ‡18 (c ˆ 0.22,
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MeOH). UV (MeCN): 256 (4460), 211 (5895). IR (film): 3300, 2930, 1675, 1595, 1435, 1200, 1130, 835, 800, 760,
720. H-NMR (400 MHz, MeOD): 8.54 (m, 1 arom. H); 7.84 (m, 1 arom. H); 7.47 (d, 3J ˆ 7.8, 1 arom. H); 7.34
1
(m, 1 arom. H); 4.20 (m, HÀC(4)); 3.99 (m, 2 HÀC(1'')); 3.92 (dd, 3J(3,4) ˆ 4.3, 3J(3,2) ˆ 7.7, H ÀC(3)); 3.42

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Helvetica Chimica Acta Vol. 86 (2003)
(m, HÀC(2)); 3.38 (m, 1 HÀC(5)); 3.16 (dd, 3J(5,4) ˆ 2.5, 2J ˆ 12.3, 1 HÀC(5)); 3.00 (dd, 3J(1',2)) ˆ 4.3, 2J ˆ
13.0, 1 HÀC(1')); 2.87 (dd, 3J(1',2) ˆ 7.9, 2J ˆ 13.0, 1 HÀC(1')). 13C-NMR (100.6 MHz, MeOD): 161.2 (s, arom.
C); 150.6 (d, 1J(C,H) ˆ 179, arom. C); 139.7 (d, 1J(C,H) ˆ 164, arom. C); 125.0 (d, 1J(C,H) ˆ 161, arom. C);
124.7 (d, 1J(C,H) ˆ 166, arom. C); 76.2 (d, 1J(C,H) ˆ 143, C(3)); 72.7 (d, 1J(C,H) ˆ 152, C(4)); 63.4
(d, 1J(C,H) ˆ 145, C(2)); 55.6 (t, 1J(C,H) ˆ 136, C(1'')); 52.1 (t, 1J(C,H) ˆ 145, C(5)); 50 49 (C(1')). CI-MS
‡
(NH3): 224 (7, [M ‡ H] ), 220 (8), 191 (3), 163 (2), 143 (8), 121 (54), 109 (19), 93 (100), 79 (20).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{[(2-thienylmethyl)amino]methyl}-5H-[1,3]dioxo-
lo[4,5-c]pyrrole-5-carboxylate (9o). By Method A, with 8 (103 mg, 0.38 mmol), thiophene-2-methanamine
(43 mg, 0.38 mmol), NaBH(OAc)3 (113 mg, 0.53 mmol), and ClCH2CH2Cl (3 ml). FC (AcOEt/light petroleum
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25
25
ether 2 :1) gave 109 mg (78% of 9o), 1.4 :1 mixture of rotamers a and b. [a] ˆ À41, [a] ˆ À44, [a]
ˆ
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À49, [a] ˆ À86, [a] ˆ À104 (c ˆ 0.57, CH2Cl2). UV (MeCN): 238 (8655), 205 (7090). IR (film): 2980, 1695,
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1605, 1515, 1455, 1410, 1370, 1260, 1170, 1125, 1055, 850, 735, 700. 1H-NMR (400 MHz, MeOD): 8.00
(m, HÀC(5''')); 7.30 (m, HÀC(3''')); 7.01 (m, HÀC(4''')); 4.76 (m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.9,
HÀC(3a)a); 4.60 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b); 4.14 (dd, 3J(4,1') ˆ 6.2, 3J(4,1') ˆ 6.4, HÀC(4)b); 4.06
(dd, 3J(4,1') ˆ 6.2, 3J(4,1') ˆ 6.3, HÀC(4)a); 3.99 (m, 2 HÀC(1'')); 3.78 (d, 3J(6,6a) ˆ 4.7, 2 HÀC(6)b); 3.75
(d, 3J(6,6a) ˆ 4.7, 2 HÀC(6)a); 2.68 (m, 2 HÀC(1')); 1.49 (s, (t-Bu)b); 1.44 (s, (t-Bu)a); 1.42 (s, 1 Me); 1.31
(s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.4 (s, NCOOb); 157.2 (s, NCOOa); 133.4 (d, 1J(C,H) ˆ 167,
C(5''')); 128.5( d, 1J(C,H) ˆ 167, C(4''')); 126.4 (d, 1J(C,H) ˆ 166, C(3''')); 113.3 (s); 85.6 (d, 1J(C,H) ˆ 157,
C(3a)a); 85.0 (d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.6 (d, 1J(C,H) ˆ 151, C(6a)b);
80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 65.9 (d, 1J(C,H) ˆ 147, C(4)a); 65.3 (d, 1J(C,H) ˆ 146, C(4)b); 54.1 (t, 1J(C,H) ˆ
144, C(6)b); 53.5 (t, 1J(C,H) ˆ 143, C(6)a); 50 49 (C(1'), C(1'')); 29.6 (q, 1J(C,H) ˆ 127, Me3C); 28.1
(q, 1J(C,H) ˆ 129, Me); 25.9 (q, 1J(C,H) ˆ 127, Me). CI-MS (NH3): 369 (6, [M ‡ H] ), 368 (4, M ), 313 (12),
267 (4), 187 (5), 142 (19), 97 (100). Anal. calc. for C18H28N2O4S (368.51): C 58.67, H 7.66; found: C 58.77, H 7.68.
(2R,3R,4S)-2-{[(2-Thienylmethyl)amino]methyl}pyrrolidine-3,4-diol (3o). By Method Aa, with 9o
(48 mg). FC (MeCN/NH4OH 4 :1) gave 29 mg (100% of 3o). IR (film): 3100, 1680, 1435, 1200, 1140, 840,
800, 725. 1H-NMR (400 MHz, D2O): 7.56 (d, 3J ˆ 5.1, HÀC(5''')); 7.26 (d, 3J ˆ 3.4, HÀC(3''')); 7.17
(m, HÀC(4''')); 4.40 (m, HÀC(4)); 4.39 (s, 2 HÀC(1'')); 4.15( dd, 3J(3,4) ˆ 4.2, 3J(3,2) ˆ 8.6, HÀC(3)); 3.70
(ddd, 3J(2,1') ˆ 4.6, 3J(2,3) ˆ 8.6, 3J(2,1') ˆ 8.6, HÀC(2)); 3.55 (dd, 3J(5,4) ˆ 4.2, 2J ˆ 13.0, 1 HÀC(5)); 3.36
‡
‡
(m, 1 HÀC(5), 1 HÀC(1')); 3.24 (dd, 3J(1',2) ˆ 8.6, J ˆ 13.5, 1 HÀC(1')). 13C-NMR (100.6 MHz, D2O): 131.5
2
(d, 1J(C,H) ˆ 170, C(3''')); 130.0 (d, 1J(C,H) ˆ 169, C(5''')); 129.8 (d, 1J(C,H) ˆ 170, C(4''')); 76.3 (d, 1J(C,H) ˆ
145, C(3)); 71.8 (d, 1J(C,H) ˆ 154, C(4)); 60.6 (d, 1J(C,H) ˆ 145, C(2)); 52.4 (t, 1J(C,H) ˆ 145, C(5)); 49.3
(t, 1J(C,H) ˆ 140, C(1')); 48.5( t, 1J(C,H) ˆ 143, C(1'')). CI-MS (NH3): 229 (100, [M ‡ H] ), 211 (42, [M ‡ H À
‡
‡
H2O] ), 191 (3), 158 (6), 114 (10), 97 (37), 85 (9).
tert-Butyl (3aR,4S,6aS)-Tetrahydro-2,2-dimethyl-4-{{[(5-methyl-2-thienyl)methyl]amino}methyl}-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (9oa). By Method B, with 10 (130 mg, 0.48 mmol), 5-methylthio-
phene-2-carboxaldehyde (60 mg, 0.48 mmol), NaBH(OAc)3 (142 mg, 0.67 mmol), and ClCH2CH2Cl (4 ml). FC
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(AcOEt/light petroleum ether 2 :1) gave 115mg (63% of 9oa), 1.3 :1 mixture of rotamers a and b. [a] ˆ À51,
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[a] ˆ À52, [a] ˆ À55, [a] ˆ À88, [a] ˆ À123 (c ˆ 0.27, CH2Cl2). UV (MeCN): 291 (1065), 239 (8425).
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IR (film): 3330, 2980, 2935, 1695, 1455, 1405, 1370, 1210, 1165, 1125, 1055, 855, 800. 1H-NMR (400 MHz,
MeOD): 6.75( d, 3J ˆ 3.3, 1 arom. H); 6.62 (br. s, 1 arom. H); 4.76 (m, HÀC(6a)); 4.65( d, 3J(3a,6a) ˆ 5.8,
HÀC(3a)a); 4.61 (d, 3J(3a,6a) ˆ 5.9, HÀC(3a)b); 4.15( t, 3J(4,1') ˆ 6.1, HÀC(4)b); 4.06 (t, 3J(4,1') ˆ
6.1, HÀC(4)a); 3.90 (m, 2 HÀC(1'')); 3.78 (d, 2J ˆ 12.9, 1 HÀC(6)); 3.42 (m, 1 HÀC(6)); 2.67 (AB, 2 HÀC(1'));
2.46 (s, arom. Me); 1.50 (s, 1 Me); 1.46 (s, (t-Bu)a); 1.43 (s, (t-Bu)b); 1.33 (s, 1 Me). 13C-NMR (100.6 MHz,
MeOD): 157.5 (s, NCOOa); 157.2 (s, NCOOb); 143.0 (s, arom. C); 141.0 (s, arom. C); 127.4 (d, 1J(C,H) ˆ 164,
arom. C); 126.6 (d, 1J(C,H) ˆ 164, arom. C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157,
C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.7 (d, 1J(C,H) ˆ 157, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a);
66.0 (d, 1J(C,H) ˆ 146, C(4)a); 65.4 (d, 1J(C,H) ˆ 144, C(4)b); 54.1 (t, 1J(C,H) ˆ 145, C(6)b); 53.5 (t, 1J(C,H) ˆ
144, C(6)a); 50 49 (C(1'), C(1'')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 126, Me); 25.8
(q, 1J(C,H) ˆ 127, Me); 16.1 (q, 1J(C,H) ˆ 128, arom. Me). CI-MS (NH3): 384 (100, [M ‡ H] ), 383 (80, M ),
327 (39), 281 (7), 243 (2), 215(10), 187 (2), 111 (56), 85(7). Anal. calc. for C 19H30N2O4S (382.54): C 59.66, H
7.91, N 7.32; found: C 59.61, H 7.94, N 7.22.
‡
‡
(2R,3R,4S)-2-{{[(5-Methyl-2-thienyl)methyl]amino}methyl}pyrrolidine-3,4-diol (3oa). By Method Aa,
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with 9oa (31 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3oa). [a] ˆ ‡6, [a] ˆ ‡14, [a]
ˆ
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‡17, [a] ˆ ‡31 (c ˆ 0.14, MeOH). UV (MeCN): 238 (3255). IR (film): 3200, 3065, 1670, 1445, 1200, 1140,
435
840, 800, 725. 1H-NMR (400 MHz, MeOD): 7.00 (d, 3J ˆ 3.3, 1 arom. H); 6.74 (d, 3J ˆ 3.3, 1 arom. H); 4.28
(m, HÀC(4), 2 HÀC(1'')); 4.07 (dd, 3J(3,4) ˆ 4.0, 3J(3,2) ˆ 8.8, HÀC(3)); 3.71 (ddd, 3J(2,1') ˆ 4.5, 3J(2,3) ˆ 8.8,

Helvetica Chimica Acta Vol. 86 (2003)
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3J(2,1') ˆ 8.8, HÀC(2)); 3.52 (dd, 3J(5,4) ˆ 4.0, 2J ˆ 12.6, 1 HÀC(5)); 3.34 3.26 (m, 1 HÀC(5), 2 HÀC(1'));
2.50 (s, arom. Me). 13C-NMR (100.6 MHz, MeOD): 143.9 (s, arom. C); 135.7 (s, arom. C); 131.0 (d, 1J(C,H) ˆ
165, arom. C); 127.4 (d, 1J(C,H) ˆ 166, arom. C); 76.2 (d, 1J(C,H) ˆ 144, C(3)); 71.5( d, 1J(C,H) ˆ 152, C(4));
60.4 (d, 1J(C,H) ˆ 147, C(2)); 52.2 (t, 1J(C,H) ˆ 149, C(5)); 48.6, 48.4 (2t, 1J(C,H) ˆ 141, C(1'), C(1'')); 16.1
‡
‡
(q, 1J(C,H) ˆ 129, arom. Me). CI-MS (NH3): 243 (96, [M ‡ H] ), 242 (12, M ), 229 (61), 211 (67), 195(19), 179
(49), 161 (16), 145(37), 133 (88), 111 (100), 86 (18).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{{[(3-methyl-2-thienyl)methyl]amino}methyl}-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (9ob). By Method B, with 10 (139 mg, 0.51 mmol), 3-methylthio-
phene-2-carboxaldehyde (64 mg, 0.51 mmol), NaBH(OAc)3 (151 mg, 0.71 mmol), and ClCH2CH2Cl (4 ml). FC
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(AcOEt/light petroleum ether 1:1) gave 84 mg (43% of 9ob), 1.4 :1 mixture of rotamers a and b. [a] ˆ À41,
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[a] ˆ À48, [a] ˆ À57, [ a] ˆ À111, [a] ˆ À146 (c ˆ 0.37, CH2Cl2). UV (MeCN): 238 (7250). IR (film):
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3330, 2980, 2930, 1690, 1455, 1405, 1210, 1170, 1125, 1055, 765, 770, 710. 1H-NMR (400 MHz, MeOD): 7.18
(m, 1 arom. H); 6.80 (m, 1 arom. H); 4.75( m, HÀC(6a)); 4.64 (m, HÀC(3a)); 4.06 (m, HÀC(4)); 3.91
(s, 2 HÀC(1'')); 3.76 (d, 2J ˆ 12.8, 1 HÀC(6)); 3.40 (m, 1 HÀC(6)); 2.68 (m, 2 HÀC(1')); 2.22 (s, arom. Me);
1.49 (s, 1 Me); 1.45( s, (t-Bu)a); 1.42 (s, (t-Bu)b); 1.31 (s, 1 Me). 13C-NMR (100.6 MHz, MeOD): 157.5
(s, NCOOb); 157.2 (s, NCOOa); 138.3 (s, arom. C); 136.1 (s, arom. C); 131.8 (d, 1J(C,H) ˆ 162, arom. C);
124.7 (d, 1J(C,H) ˆ 186, arom. C); 113.4 (s); 85.6 (d, 1J(C,H) ˆ 157, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157, C(3a)b);
82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.7 (d, 1J(C,H) ˆ 157, C(6a)b); 80.9 (d, 1J(C,H) ˆ 158, C(6a)a); 66.0
(d, 1J(C,H) ˆ 146, C(4)a); 65.4 (d, 1J(C,H) ˆ 146, C(4)b); 54.1 (t, 1J(C,H) ˆ 142, C(6)b); 53.5 (t, 1J(C,H) ˆ 144,
C(6)a); 50 49 (C(1')); 47.4 (t, 1J(C,H) ˆ 136, C(1'')); 29.5( q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me);
25.8 (q, 1J(C,H) ˆ 127, Me); 14.6 (q, 1J(C,H) ˆ 127, arom. Me). CI-MS (NH3): 384 (100, [M ‡ H] ), 383 (93,
‡
‡
M ), 327 (28), 281 (4), 215(8), 171 (2), 111 (54), 85(8). Anal. calc. for C 19H30N2O4S (382.54): C 59.66, H 7.91, N
7.32; found: C 59.75, H 7.98, N 7.31.
(2R,3R,4S)-2-{{[(3-Methyl-2-thienyl)methyl]amino}methyl}pyrrolidine-3,4-diol (3ob). By Method Aa,
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with 9ob (30 mg). FC (MeCN/NH4OH 4 :1) gave 20 mg (100% of 3ob). [a] ˆ ‡18, [a] ˆ ‡19, [a]
ˆ
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‡21, [a] ˆ ‡31 (c ˆ 0.37, MeOH). UV (MeCN): 274 (2245), 237 (5135), 198 (845). IR (film): 3055, 1670,
435
1440, 1310, 1200, 1025, 840, 800, 725. 1H-NMR (400 MHz, MeOD): 7.38 (d, 3J ˆ 5.1, 1 arom. H); 6.92 (d, 3J ˆ 5.1,
1 arom. H); 4.32 (s, HÀC(1'')); 4.26 (ddd, 3J(4,5) ˆ 1.4, 3J(4,5) ˆ 3.9, 3J(4,3) ˆ 3.9, HÀC(4)); 4.08 (dd, 3J(3,4) ˆ
3.9, 3J(3,2) ˆ 8.9, HÀC(3)); 3.74 (ddd, 3J(2,1') ˆ 4.7, 3J(2,3) ˆ 8.9, 3J(2,1') ˆ 8.9, HÀC(2)); 3.52 (dd, 3J(5,4) ˆ 3.9,
2J ˆ 12.6, 1 HÀC(5)); 3.39 3.32 (m, 1 HÀC(5), 2 HÀC(1')); 2.31 (s, arom. Me). 13C-NMR (100.6 MHz,
MeOD): 140.1 (s, arom. C); 132.2 (d, 1J(C,H) ˆ 166, arom. C); 131.1 (s, arom. C); 127.4 (d, 1J(C,H) ˆ 179, arom.
C); 76.3 (d, 1J(C,H) ˆ 144, C(3)); 71.4 (d, 1J(C,H) ˆ 154, C(4)); 60.3 (d, 1J(C,H) ˆ 147, C(2)); 52.3 (t, 1J(C,H) ˆ
145, C(5)); 48.4 (t, 1J(C,H) ˆ 141, C(1')); 46.4 (t, 1J(C,H) ˆ 142, C(1'')); 14.7 (q, 1J(C,H) ˆ 128, arom. Me). CI-
‡
MS (NH3): 243 (33, [M ‡ H] ), 144 (3), 134 (17), 116 (32), 93 (69), 76 (100).
tert-Butyl (3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-4-{{[(5-ethyl-2-thienyl)methyl]amino}methyl}-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (9oc). By Method B, with 10 (106 mg, 0.39 mmol), 5-ethylthiophene-
2-carboxaldehyde (55 mg, 0.39 mmol), NaBH(OAc)3 (115mg, 0.54 mmol), and ClCH 2CH2Cl (4 ml). FC
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(AcOEt/light petroleum ether 1:1) gave 111 mg (72% of 9oc), 1.3 :1 mixture of rotamers a and b. [a] ˆ À49,
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[a] ˆ À58, [a] ˆ À67, [a] ˆ À131, [a] ˆ À174 (c ˆ 0.37, CH2Cl2). UV (MeCN): 290 (1705), 240
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(11745), 210 (2765). IR (film): 3360, 3045, 2850, 1675, 1435, 1340, 1200, 1135, 840, 800, 720. 1H-NMR (400 MHz,
MeOD): 6.76 (d, 3J ˆ 3.3, 1 arom. H); 6.65(br. s, 1 arom. H); 4.76 (m, HÀC(6a)); 4.64 (d, 3J(3a,6a) ˆ 5.5,
HÀC(3a)a); 4.59 (d, 3J(3a,6a) ˆ 5.8, HÀC(3a)b); 4.14 (t, 3J(4,1') ˆ 6.3, HÀC(4)b); 4.05( dd, 3J(4,1') ˆ 6.1,
3J(4,1') ˆ 6.5, HÀC(4)a); 3.90 (AB, 2 HÀC(1'')); 3.77 (d, 2J ˆ 12.8, 1 HÀC(6)); 3.39 (m, 1 HÀC(6)); 2.82
(q, 3J ˆ 7.5, MeCH2); 2.68 (AB, 2 HÀC(1')); 1.49 (s, 1 Me); 1.45( s, (t-Bu)a); 1.42 (s, (t-Bu)b); 1.32 (s, 1 Me); 1.30
(t, 3J ˆ 7.5, MeCH2). 13C-NMR (100.6 MHz, MeOD): 157.5 (s, NCOOb); 157.2 (s, NCOOa); 148.8 (s, arom. C);
142.6 (s, arom. C); 127.3 (d, 1J(C,H) ˆ 166, arom. C); 124.8 (d, 1J(C,H) ˆ 165, arom. C); 113.4 (s); 85.6
(d, 1J(C,H) ˆ 158, C(3a)a); 85.0 (d, 1J(C,H) ˆ 157, C(3a)b); 82.3 (s, Me3COa); 82.1 (s, Me3COb); 81.7
(d, 1J(C,H) ˆ 157, C(6a)b); 80.9 (d, 1J(C,H) ˆ 157, C(6a)a); 66.0 (d, 1J(C,H) ˆ 147, C(4)a); 65.3 (d, 1J(C,H) ˆ
147, C(4)b); 54.0 (t, 1J(C,H) ˆ 146, C(6)b); 53.5 (t, 1J(C,H) ˆ 142, C(6)a); 50 49 (C(1'), C(1'')); 29.5
(q, 1J(C,H) ˆ 127, Me3C); 28.1 (q, 1J(C,H) ˆ 127, Me); 25.8 (q, 1J(C,H) ˆ 127, Me); 25.3 (t, 1J(C,H) ˆ 125,
MeCH2); 14.6 (q, 1J(C,H) ˆ 123, MeCH2). CI-MS (NH3): 397 (100, [M ‡ H] ), 341 (16), 295(2), 215(2), 125
‡
(25), 84 (6). Anal. calc. for C20H32N2O4S (396.57): C 60.58, H 8.13, N 6.75; found: C 60.64, H 8.10, N 6.61.
(2R,3R,4S)-2-{{[(3-Ethyl-2-thienyl)methyl]amino}methyl}pyrrolidine-3,4-diol (3oc). By Method Aa, with
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9oc (30 mg). FC (MeCN/NH4OH 4 :1) gave 19 mg (100% of 3oc). [a] ˆ ‡11, [a] ˆ ‡12, [a] ˆ ‡15( c ˆ
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0.50, MeOH). UV (MeCN): 239 (1790), 204 (270). IR (film): 3080, 1670, 1435, 1200, 840, 800, 725. H-NMR
(400 MHz, MeOD): 7.02 (d, 3J ˆ 3.4, 1 arom. H); 6.77 (d, 3J ˆ 3.4, 1 arom. H); 4.30 (s, 2 HÀC(1'')); 4.26