trans-3,4-Disubstituted pyrrolidines by 1,3-dipolar cycloaddition: Enantioselective approaches and their limitations

Article abstract of DOI:10.1016/S0957-4166(99)00244-X

In the presence of a chiral Lewis acid as co-catalyst, the acid- catalysed 1,3-dipolar cycloaddition reaction yielding trans-3,4-disubstituted pyrrolidines from an azomethine ylide and achiral α,β-unsaturated dipolarophiles proceeded with low enantioselectivity. Therefore a number of α,β-unsaturated dipolarophiles linked to chiral auxiliaries were examined as substrates. Camphorsultam was the best auxiliary and gave good diastereoselectivity (dr=74:26). When combining chiral Lewis acids with a dipolarophile linked to a chiral auxiliary, the enantio-selectivity could be slightly increased. As judged by ¹³C NMR, the small effect of the chiral Lewis acids on selectivity was probably due to breakdown of the initially formed complex with the dipolarophile caused by the dipole precursor.

Full text of DOI:10.1016/S0957-4166(99)00244-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2605–2616
trans-3,4-Disubstituted pyrrolidines by 1,3-dipolar cycloaddition:
enantioselective approaches and their limitations
Staffan Karlsson,a,b Fusen Han,c Hans-Erik Högberg b and Patrizia Caldirola a,∗
aMedicinal Chemistry Department, Pharmacia & Upjohn AB, Rapsgatan 7, SE-751 82 Uppsala, Sweden
bDepartment of Chemistry and Process Technology, Mid Sweden University, SE-851 70 Sundsvall, Sweden
cStructure, Analytical & Medicinal Chemistry, Pharmacia & Upjohn Inc., 301 Henrietta Street, Kalamazoo, MI 49007, USA
Received 26 May 1999; accepted 15 June 1999
Abstract
In the presence of a chiral Lewis acid as co-catalyst, the acid-catalysed 1,3-dipolar cycloaddition reaction
yielding trans-3,4-disubstituted pyrrolidines from an azomethine ylide and achiral α,β-unsaturated dipolarophiles
proceeded with low enantioselectivity. Therefore a number of α,β-unsaturated dipolarophiles linked to chiral
auxiliaries were examined as substrates. Camphorsultam was the best auxiliary and gave good diastereoselectivity
(dr=74:26). When combining chiral Lewis acids with a dipolarophile linked to a chiral auxiliary, the enantio-
selectivity could be slightly increased. As judged by 13C NMR, the small effect of the chiral Lewis acids on
selectivity was probably due to breakdown of the initially formed complex with the dipolarophile caused by the
dipole precursor. © 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Substituted, stereoisomerically pure pyrrolidines are important building blocks for the synthesis of
many natural products and pharmaceuticals.1–3 Compounds containing a pyrrolidine ring can be prepared
in a simple manner using a one-step 1,3-dipolar cycloaddition reaction between a dipolarophile and
nitrogen-containing 1,3-dipoles.4,5
Chiral copper(II)-containing Lewis acids have been successfully used in some enantioselective elec-
trocyclic reactions e.g. of the Diels–Alder type, in which the catalyst forms a complex with the
dienophile.6–8
The use of chiral auxiliaries attached to a dipolarophile in 1,3-dipolar cycloaddition reactions with
azomethine ylides has been briefly described previously.9,10 The present study describes our efforts to
develop enantio- and diastereoselective methods for the preparation of trans-3,4-disubstituted pyrroli-
∗
Corresponding author. E-mail: patrizia.caldirola@eu.pnu.com
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00244-X

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dines in 1,3-dipolar cycloadditions using either enantiopure Lewis acid catalysts or chiral auxiliaries or
a combination of both.
2. Results and discussion
It is known that acid-catalysed transformation of N-benzyl-N-methoxymethyl-N-trimethylsilylmethyl-
amine 2 (Scheme 1) generates a 1,3-dipole, the azomethine ylide 3, which reacts in situ with a number
of substituted alkenes.4,5,11–14
Scheme 1. 1,3-Dipolar cycloadditions between dipole 3 and chiral/achiral dipolarophiles 1a–g in the presence or absence of
chiral Lewis acid 6 or 7
The cycloaddition reaction of prochiral dipolarophile trans-1a with 2 in the presence of Cu(II)-
(S,S)-bis(isopropyloxazolin-20 -yl)pyridine [(S,S)-ip-pybox]15 7 furnished (3S,4R)-4a with 8% ee and in
quantitative yield (entry 10, Table 1). Reaction with the oxazolidinone-derived prochiral dipolarophile
trans-1b in the presence of Cu(II)-(S)-isopropylidenebis(4-phenyloxazoline) 6A gave (3S,4R)-4b in 2%
ee (entry 12). This established that when using only a chiral Lewis acid catalyst in this type of reaction,
it was possible to obtain a certain but low enantioselectivity. Therefore, this approach did not encourage
further investigation.
Instead we turned our attention to the use of chiral auxiliaries attached to the dipolarophile. Thus, we
prepared the trans-cinnamoyl esters or amides 1c–g from the reaction of cinnamoyl chloride with either
the conjugate bases of the oxazolidines c–e or the sultam f or with the sugar-derived alcohol g (Scheme 1).
When a cinnamoyl derivative 1c–g and compound 2 were treated with trifluoracetic acid the ylide 3 was

S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
2607
Table 1
Diastereomeric ratio in 1,3-dipolar cycloaddition reaction in CH2Cl2 between 1a, 1b or 1c and 2 in
the presence of a chiral Lewis acida
produced in situ and reacted with the cinnamoyl derivative furnishing a mixture of trans-3,4-disubstituted
pyrrolidines 4 and 5 in good yields and with low to good diastereoselectivities (see Table 2).
Since the dipole precursor 2 showed a tendency to dimerise under certain reaction conditions, a large
excess of this was sometimes required. The diastereomeric mixtures of (3S,4R)-4c–f and (3R,4S)-5c–f
were easily separated by column chromatography, whereas that of the diastereomeric esters 4g and 5g
was not. In some cases low temperatures gave low conversions (entries 3 and 5, Table 2). For some
substrates a slight improvement in the diastereomeric ratio (dr), was observed going from lower to higher
temperatures (entries 4–7). The camphorsultam auxiliary f gave the best diastereoselectivity (entries 6
and 7).
Table 2
Diastereomeric ratio in 1,3-dipolar cycloaddition reaction between 1c–g and 2a,b

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An X-ray crystallographic structure determination performed on the major diastereomer obtained from
dipolarophile 1d established that this diastereomer was 4d having the absolute configuration (3S,4R)
16,17
in the pyrrolidine ring (see Fig. 1). Ethanolysis of 4d with Ti(OiPr)4
in the presence of a large
excess of ethanol gave a (−)-ester which was (3S,4R)-4a. The products 4b,c,e–g or 5b,c,e–g gave the
enantiomerically pure ester 4a or 5a or alternatively a mixture of enantiomers in the case of ethanolysis
of 4b and 5b. The specific rotations of the esters obtained were used for the assignments of the
configurations of the major product in each reaction. Surprisingly the (R)-oxazolidinone auxiliaries c and
e both gave the same chiral induction as the (S)-oxazolidinone auxiliary d [(3S,4R)-configuration in the
pyrrolidine ring as the major diastereomer]. The reason for this reversal of diastereoselectivity is unclear.
A possible explanation might be that the cycloaddition reaction can take place via two conformers of
the dipolarophile, either the U- or the Z-conformer (see Fig. 2). The U-conformer of 1c would lead to
(3S,4R)-4c as would the Z-conformer of 1d. Molecular modelling (CS Chem3D Pro™ 4.0) indicated that
the energy differences between the high energy U- and the low energy Z-conformer of dipolarophiles 1c
and 1d were 3.5 and 5.5 kcal/mol, respectively. Therefore it is possible that the dipolarophile 1c reacts
mainly via U-1c, whereas the higher energy difference for 1d forces it to react directly from the low
energy conformation Z-1d (see Fig. 2).
Figure 1. Structure and solid state conformation of (−)-(3S,4R)-1-benzyl-4-phenyl-3-[(40-(S)-tert-butyl-20-oxazolidinone-30-yl)-
carbonyl]-pyrrolidine (4d)
In an effort to influence the diastereoselectivity in the 1,3-dipolar cycloaddition between dipole
3 and dipolarophile 1c, the chiral enantiopure Cu(II)-containing Lewis acids (6A and 6B)6,8 were
tried as catalysts. In these cases one enantiomer of the dipolarophile would be expected to enhance
enantioselectivity (matched case), whereas the other would have the opposite effect (mismatched case).
When combining 6A and the enantiomer of 1c we observed a decrease in diastereomeric ratio. Therefore,

S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
2609
Figure 2. Proposed reaction path via two low energy conformers of 1c and 1d. It is assumed that ∆G*U and ∆G*Z are
approximately equal for both reactions of dipole 3 with 1c and 1d and that ∆G*U<∆G*Z for the individual reactions
the combination of 6A with 1c represented the matched case. It was found that reactions performed
in the presence of either the chiral Lewis acids 6A or 6B generally gave a slight improvement in
−
diastereoselectivity (see Table 1). Substituting the counterion TfO− with the less nucleophilic SbF6
did not lead to any improvement in the dr.8
The formation of a complex between the dipolarophile 1a and the chiral Lewis acid 7 was established
by 13C NMR. Thus, different chemical shifts of the carbonyl carbon of the dipolarophile 1a were observed
in the absence (167 ppm) and in the presence (171 ppm) of the Lewis acid. However, the chemical shift
of the uncomplexed starting material (167 ppm) was restored upon addition of the dipole precursor 2
and this clearly indicated a competition between the dipolarophile and 2 for the chiral Lewis acid. In an
effort to minimise such a competition, compound 2 and CF3COOH were slowly added to a mixture of
the dipolarophile 1c and an excess of the chiral Lewis acid 6B, resulting in a 16% improvement of the dr
at the expense of yield (entry 6, Table 1).
The results obtained in the reactions performed in the presence of the chiral catalysts 6A, 6B or 7
indicated that the diastereoselectivity in this cycloaddition was mainly controlled by the substrate rather
than by the chiral Lewis acid.
We also examined the effects of the solvent. Thus reactions performed with oxazolidinones 1c and 1e
in toluene both led to an improvement of the dr compared with that obtained with dichloromethane.
In contrast, when using the camphorsultam 1f, dichloromethane seemed to be the solvent of choice
(Table 3).
3. Conclusion
In conclusion some trans-3,4-disubstituted pyrrolidines have been prepared in relatively high dia-
stereomeric ratios using an approach where a chiral substrate is reacted with the dipole 3. The cam-
phorsultam auxiliary f was found to be the most effective. In general, the diastereoselectivities increased
slightly with increasing temperature. By changing the solvent, a relatively large effect on the dr was
observed. The use of chiral Lewis acids as catalysts in these reactions did not significantly improve

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Table 3
Diastereomeric ratio in 1,3-dipolar cycloaddition reaction between 1c, 1e, or 1f and 2 either in the
absence or the presence of chiral Lewis acid 6B (Y=TfO−) in different solvents at room temperaturea,b
the diastereomeric ratios. This was probably due to the ability of the dipole precursor 2 to displace the
dipolarophile initially complexed with the Lewis acid.
4. Experimental
All chemicals were used as received unless otherwise stated. THF was distilled from Na/benzophenone
1
and freshly used. The other solvents were dried and stored over molecular sieves (4 Å). H NMR and
13C NMR spectra were recorded with a Jeol EX 270 or a Bruker DRX 500 spectrometer operating at
270/67.5 or 500/125 MHz using Me4Si as internal standard. TLC was performed on silica gel plates
(60 F254, Merck) and flash column chromatography on silica gel 60 (230–400 mesh). GC analyses were
carried out using a capillary column cross-linked 5% phenylmethylsilicone, 10 m, 0.53 mm i.d., df=0.26
µm, carrier gas N2 (6 psi). The elemental analyses (C, H and N) were performed by Mikro Kemi AB,
SE-752 28 Uppsala, Sweden. Melting points are uncorrected and determined in open glass capillaries
on an electrothermal melting point apparatus. Optical rotations were measured with a Perkin–Elmer 241
MC polarimeter in a 1 dm cell. The reaction yields were estimated by either quantitative GC analysis or
by 1H NMR. The determination of yield percentages of 4 and 5 by GC analysis were based on peak-area
measurements corrected with response factors calculated from a standard solution of each component to
1
be examined using (ꢀ)-4b as internal standard. The H NMR determination of yield percentages were
based on peak-area measurements of products 4, 5 and unreacted 1.
4.1. General method for amidation18
A solution of CH3MgCl in THF (2.2 M, 2.4 mL, 5.3 mmol) was added dropwise to a stirred solution
of the chiral or achiral auxiliaries b–f (5.2 mmol), respectively, in THF (40 mL) at 0°C. The mixture
was stirred at 0°C for 10 min followed by slow addition of cinnamoyl chloride (6 mmol) in THF (10
mL). The mixture was stirred at 0°C for 10 min and for an additional hour at room temperature. The
reaction was quenched with NH4Cl (10 ml, saturated aqueous solution). The volatiles were evaporated
and the residue was treated with CH2Cl2 (100 mL). The organic phase was washed with NaHCO3 (40 ml,
saturated aqueous solution) and with NH4Cl (40 ml, saturated aqueous solution). The organic layer was

S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
2611
separated, dried (MgSO4) and concentrated to give 1b–f in purity >95% (GC). No further purification
was performed unless otherwise stated.
4.2. 3-[(E)-3-Phenyl-2-propenoyl]-2-oxazolidinone 1b
Compound 1b (1.2 g, 96%) was obtained as a colourless solid from cinnamoyl chloride (0.5 g, 3
mmol) and 2-oxazolidinone (0.34 g, 2.6 mmol) according to the general method for amidation. Purity
>99% (GC), m.p. 148–150°C (lit.19 151.0–152.5°C). Anal. calcd for C12H11NO3: C, 66.4; H, 5.1; N, 6.4.
Found: C, 66.0; H, 5.0; N, 6.4.
4.3. 3-[(E)-3-Phenylpropenoyl]-4-(R)-phenyl-2-oxazolidinone 1c
Compound 1c (1.5 g, 98%) was obtained as a colourless solid from cinnamoyl chloride (1.0 g, 6 mmol)
and (R)-4-phenyl-2-oxazolidinone (0.85 g, 5.2 mmol) according to the general method for amidation.
Purity 98% (GC), m.p. 158–160°C. [α]D25=−10.8 (c=1.0, CH2Cl2). 1H NMR (270 MHz, CDCl3) δ 4.32
(dd, 1H, J=4.0, 8.9 Hz); 4.74 (t, 1H, J=8.9 Hz); 5.56 (dd, 1H, J=4.0, 8.9 Hz); 7.3–7.6 (m, 10H, arom);
7.78 (d, 1H, J=15.8 Hz); 7.94 (d, 1H, J=15.8 Hz). 13C NMR (67.5 MHz, CDCl3) δ 57.8, 70.0, 116.8,
126.0, 128.6 (2Cs), 128.7 (2Cs), 128.8 (2Cs), 129.2 (2Cs), 130.7, 134.4, 139.0, 146.7, 153.8, 164.7. Anal.
calcd for C18H15NO3: C, 73.7; H, 5.2; N, 4.8. Found: C, 73.8; H, 5.2; N, 4.7.
4.4. 3-[(E)-3-Phenylpropenoyl]-4-(S)-tert-butyl-2-oxazolidinone 1d
Compound 1d (0.56 g, 86%) was obtained as a colourless solid from cinnamoyl chloride (0.47 g,
2.8 mmol) and (S)-4-tert-butyl-2-oxazolidinone (0.35 g, 2.4 mmol) according to the general method
for amidation. The crude product was further recrystallized from c-hexane. Purity ≥99% (GC), m.p.
99–100°C, [α]D25=+115.4 (c=0.5, CH2Cl2); 1H NMR (270 MHz, CDCl3) δ 0.98 (s, 9H); 4.29 (dd, 1H,
J=7.5, 9.2 Hz); 4.33 (dd, 1H, J=1.8, 9.2 Hz); 4.60 (dd, 1H, J=1.8, 7.5 Hz); 7.37–7.41 (m, 3H); 7.60–7.63
(m, 2H); 7.85 (d, 1H, J=15.7 Hz); 7.95 (d, 1H, J=15.7 Hz). 13C NMR (67.5 MHz, CDCl3) δ 25.7 (3Cs),
36.0, 61.0, 65.3, 117.2, 128.6 (2Cs), 128.9 (2Cs), 130.6, 134.6, 146.4, 154.8, 165.6. Anal. calcd for
C16H19NO3: C, 70.3; H, 7.0; N, 5.1. Found: C, 70.3; H, 7.0; N, 4.9.
4.5. 3-[(E)-3-Phenylpropenoyl]-3a-(R)-cis-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-2-oxazolidinone 1e
Compound 1e (0.99 g, 95%) was obtained as a colourless solid from cinnamoyl chloride (0.67 g, 4.0
mmol) and 3a-(R)-cis-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (0.60 g, 3.4 mmol) according
to the general method for amidation. Purity >99% (GC), m.p. 185–188°C. [α]D25=−280 (c=1.0, CH2Cl2).
1H NMR (270 MHz, CDCl3) δ 3.41–3.42 (m, 2H); 5.33–5.35 (m, 1H); 6.07 (d, 1H, J=6.9 Hz); 7.28–7.41
(m, 6H); 7.60–7.63 (m, 2H); 7.73 (d, 1H, J=7.6 Hz); 7.92 (d, 1H, J=15.7 Hz); 7.95 (d, 1H, J=15.8 Hz).
13C NMR (67.5 MHz, CDCl3) δ 38.0, 63.3, 78.1, 117.0, 125.2, 127.5, 128.2, 128.6 (2Cs), 128.9 (2Cs),
129.9, 130.7, 134.6, 139.2, 139.5, 146.5, 153.1, 165.6. Anal. calcd for C19H15NO3·0.1H2O: C, 74.3; H,
5.0; N, 4.6. Found: C, 74.1; H, 5.0; N, 4.5.
4.6. 3-[(E)-3-Phenylpropenoyl]-1(S),5(R)-camphorsultam 1f
Compound 1f (1.25 g, 97%) was obtained as a colourless solid from cinnamoyl chloride (1.1 g, 6.4
mmol) and (−)-(1S)-2,10-camphorsultam according to the general method for amidation. Purity 97%

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S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
1
(GC), m.p. 183–186°C. [α]D25=−94.0 (c=1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ 1.00 (s, 3H);
1.21 (s, 3H); 1.35–1.50 (m, 2H); 1.88–1.98 (m, 3H); 2.12–2.23 (m, 2H); 3.48 (d, 1H, J=13.7 Hz);
3.55 (d, 1H, J=13.7 Hz); 4.00 (dd, 1H, J=5.3, 7.3 Hz); 7.17 (d, 1H, J=15.5 Hz); 7.37–7.39 (m, 3H);
7.57–7.61 (m, 2H); 7.79 (d, 1H, J=15.5 Hz). 13C NMR (125 MHz, CDCl3) δ 19.9, 20.9, 26.6, 32.9, 38.6,
44.8, 47.9, 48.6, 53.2, 65.3, 117.5, 128.6 (2Cs), 128.8 (2Cs), 130.6, 134.4, 145.6, 164.3. Anal. calcd for
C19H23NO3S: C, 66.1; H, 6.7; N, 4.0. Found: C, 65.8; H, 6.7; N, 4.1.
4.7. 3-[(E)-3-Phenylpropenoyl]-1,2,5,6-di-O-isopropylidene-D-glycofuranosyl-ester 1g
A solution of cinnamoyl chloride (430 mg, 2.6 mmol) in CH2Cl2 (5 mL) was added dropwise to a
solution of 1,2,5,6-di-O-isopropylidene-D-glycofuranose (473 mg, 1.8 mmol) in CH2Cl2 (30 mL) and
pyridine (8 mL) at room temperature under an N2 atmosphere. The mixture was refluxed overnight, the
volatiles evaporated and the residue was purified by column chromatography [SiO2, ethyl acetate (20%)
in n-hexane as eluent] to give 1g (0.7 g, 100%) as an oil with purity >99% (GC). [α]D25=−39.7 (c=1.0,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 3H); 1.32 (s, 3H); 1.42 (s, 3H); 1.54 (s, 3H); 4.11–4.14
(m, 2H); 4.27–4.33 (m, 2H); 4.58 (d, 1H, J=3.7 Hz); 5.40 (d, 1H, J=2.5 Hz); 5.93 (d, 1H, J=3.7 Hz);
6.43 (d, 1H, J=16.0 Hz); 7.37–7.41 (m, 3H); 7.51–7.55 (m, 2H); 7.72 (d, 1H, J=16.0 Hz). 13C NMR
(125 MHz, CDCl3) δ 25.3, 26.2, 26.7, 26.8; 67.1, 72.5, 76.2, 79.9, 83.4, 105.1, 109.3, 112.3, 117.1,
128.2 (2Cs), 129.0 (2Cs), 130.6, 134.1, 146.0, 165.5. Anal. calcd for C21H26O7: C, 64.6; H, 6.7. Found:
C, 65.0; H, 6.6.
4.8. N-Benzyl-N-(methoxymethyl)-trimethylsilylmethylamine 2
Compound 2 was prepared following the same procedure as reported by Hosomi et al.4 1H NMR (270
MHz, CDCl3) δ 0.04 (s, 9H); 2.22 (s, 2H); 3.27 (s, 3H); 3.79 (s, 2H); 4.03 (s, 2H); 7.28–7.35 (m, 5H).
13C NMR (67.5 MHz, CDCl3) δ −1.5 (3Cs), 42.8, 55.3, 59.5, 88.4, 126.8, 128.1 (2Cs), 128.7 (2Cs),
139.7.
4.9. General method for the 1,3-dipolar cycloaddition5
4.9.1. Method A
TFA (0.2 mL, 1 M solution in CH2Cl2) was added dropwise at 0°C to a solution of N-benzyl-N-
(methoxymethyl)-trimethylsilylmethylamine 2 (332 mg, 1.4 mmol) and chiral or achiral dipolarophiles
1b–g (0.7 mmol) in dry CH2Cl2 (3 mL). The reaction was stirred at 0°C for 3 h, then quenched
with NaHCO3 (5 mL, saturated aqueous solution) followed by the addition of CH2Cl2 (20 mL). The
organic phase was separated and washed with NH4Cl (saturated aqueous solution). The organic layer
was collected, dried (Na2SO4) and concentrated to give a residue consisting of two diastereoisomers or
racemates in quantitative yield. The residue was further purified by flash column chromatography (SiO2)
to give the two diastereoisomers 4c–g and 5c–g separated from each other, or (ꢀ)-4b which was obtained
as a racemate and used as internal standard.
4.9.2. Method B8
Dipolarophile 1 (a,b or c) (0.068 mmol) was added to a stirred solution of chiral Lewis acid prepared
from Cu(OTf)2 (0.068 mmol) and 6A or 6B or 7 (0.068 mmol) in different solvents (0.5 mL) at room
temperature. The mixture was stirred overnight followed by addition of trifluoroacetic acid (0.2 mL,

S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
2613
0.5 M) and 2 (0.34 mmol). The reaction was stirred for 3 h followed by the work-up procedure used in
method A for isolation or directly analysed after extraction with NaHCO3 (aq. sat.) and drying (Na2SO4).
4.9.3. Method C8
Dipolarophile (1a or 1c, 0.068 mmol) was added to a stirred solution of chiral Lewis acid prepared
from AgSbF6 (0.136 mmol), CuCl2 (0.068 mmol) and 6A or 6B or 7 (0.068 mmol) in CH2Cl2 (0.5 mL).
The mixture was stirred overnight followed by addition of trifluoroacetic acid (0.2 mL, 0.5 M) and 2
(0.34 mmol). The reaction was stirred for 3 h followed by the work-up procedure used in method A or B.
4.10. (−)-(3S,4R)- and (+)-(3R,4S)-Ethyl-1-benzyl-4-phenylpyrrolidine-3-carboxylate (−)-4a and (+)-
5a20
Ti(OiPr)4 (10 equiv.) was added to a solution of one of the compounds 4c–g or 5c–g (1 equiv.) in
EtOH. The reaction was heated at reflux temperature overnight. The volatiles were evaporated and the
residue was purified by column chromatography [SiO2, ethyl acetate (30%) in n-hexane as eluent] to give
(−)-4a or (+)-5a (80%).
1
(−)-(3S,4R)-4a and (+)-(3R,4S)-5a: H NMR (270 MHz, CDCl3) δ 1.20 (t, 3H, J=7.1 Hz); 2.74–3.09
(m, 5H); 3.67–3.74 (m, 3H); 4.12 (dq, 2H, J=7.1 Hz); 7.20–7.38 (m, 10H). 13C NMR (67.5 MHz, CDCl3)
δ 14.2, 46.9, 51.8, 57.4, 59.9, 60.7, 61.8, 126.5, 127.0, 127.4 (2Cs), 128.3 (2Cs), 128.5 (2Cs), 128.6
(2Cs), 138.8, 144.2, 174.2.
(−)-(3S,4R)-4a: [α]D25=−43.5 (c=1.0, CH2Cl2); (−)-4a·HCl. Anal. calcd for C20H23NO2·HCl·0.5H2O:
C, 67.7; H, 7.1; N, 4.0. Found: C, 68.1; H, 7.3; N, 4.0.
(+)-(3R,4S)-5a: [α]D25=+39.5 (c=1.0, CH2Cl2); (+)-5a·HCl. Anal. calcd for C20H23NO2·HCl·0.5H2O:
C, 67.7; H, 7.1; N, 4.0. Found: C, 67.7; H, 7.0; N, 4.0.
4.11. (ꢀ)-trans-1-Benzyl-4-phenyl-3-(20 -oxazolidinone-30 -yl)-carbonyl-pyrrolidine (ꢀ)-4b
Compound (ꢀ)-4b was prepared and isolated, according to the general method for 1,3-dipolar
cycloaddition (method A), from 1b (0.54 g, 2.5 mmol) and 2 (1.2 g, 5.0 mmol). The crude mixture was
purified by column chromatography [SiO2, ethyl acetate (30%) in n-hexane as eluent] to give (ꢀ)-4b (0.7
g, 2 mmol) as an oil in >99% purity (GC). The free base was transformed into the hydrochloride salt (ꢀ)-
4b·HCl. 1H NMR (500 MHz, CDCl3) δ 2.68 (t, 1H, J=8.6 Hz); 2.81 (dd, 1H, J=5.6, 9.6 Hz); 3.17 (t, 1H,
J=7.6 Hz); 3.23 (t, 1H, J=9.4 Hz); 3.61 (d, 1H, J=12.9 Hz); 3.73 (d, 1H, J=12.9 Hz); 3.93 (t, 2H, J=7.9
Hz); 4.05 (q, 1H, J=7.4 Hz); 4.12–4.25 (m, 1H); 4.28–4.32 (m, 2H); 7.16–7.36 (m, 10H). 13C NMR (125
MHz, CDCl3) δ 42.8, 45.5, 50.8, 58.2, 59.9, 61.9, 62.0, 126.6, 127.0, 127.8 (2Cs), 128.2 (2Cs), 128.5
(2Cs), 128.7 (2Cs), 138.8, 143.0, 153.1, 173.6. HCl-salt: Anal. calcd for C21H22N2O3·HCl·0.5H2O: C,
63.7; H, 6.1; N, 7.1. Found: C, 64.0; H, 6.2; N, 7.1.
4.12. (−)-(3S,4R)- and (−)-(3R,4S)-1-Benzyl-4-phenyl-3-[(40 -(R)-phenyl-20-oxazolidinon-30 -yl)-
carbonyl]-pyrrolidine 4c and 5c
Compounds 4c and 5c were prepared and isolated, according to the general method for the 1,3-dipolar
cycloaddition (method A) from 1c (0.2 g, 0.68 mmol) and 2 (0.3 g, 1.36 mmol). The mixture of 4c and 5c
was separated by column chromatography [SiO2, ethyl acetate (gradient 20–40%) in n-hexane as eluent]
to give 4c (143 mg, 0.34 mmol) and 5c (112 mg, 0.26 mmol) as colourless solids in purity >99% (GC).

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S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
(3S,4R)-4c: [α]D25=−147.0 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 2.66 (t, 1H, J=8.6 Hz);
2.74 (dd, 1H, J=5.6, 9.6 Hz); 3.09 (t, 1H, J=8.4 Hz); 3.28 (t, 1H, J=9.6 Hz); 3.54 (d, 1H, J=12.9 Hz);
3.72 (d, 1H, J=13.2 Hz); 4.00 (q, 1H, J=7.8 Hz); 4.13–4.22 (m, 2H); 4.60 (t, 1H, J=8.9 Hz); 5.37 (dd,
1H, J=4.1, 8.8 Hz); 7.20–7.40 (m, 15H). 13C NMR (125 MHz, CDCl3) δ 44.9, 51.6, 57.8, 58.0, 59.7,
61.9, 70.0, 125.7 (2Cs), 126.6, 126.9, 127.8 (2Cs), 128.2 (2Cs), 128.5 (4Cs), 128.6, 129.3 (2Cs), 138.9,
139.0, 143.2, 153.3, 172.8. M.p. for C27H26N2O3·HCl·0.25H2O: 130–134°C. HCl-salt: Anal. calcd for
C27H26N2O3·HCl·0.25H2O: C, 69.4; H, 5.9; N, 6.0. Found: C, 69.2; H, 5.9; N, 6.0.
1
(3R,4S)-5c: [α]D25=−10.0 (c=0.5, CH2Cl2); H NMR (500 MHz, CDCl3) δ 2.69 (t, 1H, J=8.4 Hz);
2.85 (dd, 1H, J=5.9, 9.6 Hz); 3.09 (t, 1H, J=8.4 Hz); 3.22 (t, 1H, J=9.4 Hz); 3.63 (d, 1H, J=13.2 Hz);
3.73 (d, 1H, J=13.2 Hz); 3.79 (q, 1H, J=7.6 Hz); 4.15 (dd, 1H, J=4.3, 8.9 Hz); 4.30–4.38 (m, 1H); 4.61 (t,
1H, J=8.9 Hz); 5.40 (dd, 1H, J=4.3, 8.8 Hz); 7.10–7.36 (m, 15H). 13C NMR (125 MHz, CDCl3) δ 46.9,
50.7, 57.9, 58.0, 59.9, 61.5, 69.7, 125.8 (2Cs), 126.5, 126.9, 127.5 (2Cs), 128.2 (2Cs), 128.4 (2Cs), 128.6
(3Cs), 129.1 (2Cs), 138.7, 138.9, 142.7, 153.3, 173.8. M.p. for C27H26N2O3·HCl·0.5H2O: 188–190°C.
Anal. calcd for C27H26N2O3·HCl·0.5H2O: C, 68.7; H, 6.0; N, 5.9. Found: C, 69.0; H, 6.2; N, 5.8.
4.13. (−)-(3S,4R)- and (+)-(3R,4S)-1-Benzyl-4-phenyl-3-[(40 -(S)-tert-butyl-20-oxazolidinone-30 -
yl)-carbonyl]-pyrrolidine 4d and 5d
Compounds 4d and 5d were prepared and isolated, according to the general method for the 1,3-dipolar
cycloaddition (method A), from 1d (0.42 g, 1.5 mmol) and 2 (0.71 g, 3.0 mmol). The mixture of 4d and
5d was separated by column chromatography [SiO2, ethyl acetate (gradient 10% and 20%) in n-hexane
as eluent] and further purified from by-products by recrystallisation from n-hexane to give 4d (0.28 g,
0.7 mmol) and 5d (0.12 g, 0.3 mmol) as colourless solids in >99% purity (GC).
(3S,4R)-4d: [α]D25=−20.8 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 0.72 (s, 9H); 2.68 (t, 1H,
J=8.6 Hz); 2.75 (dd, 1H, J=6.3, 9.4 Hz); 3.09–3.12 (m, 2H); 3.60 (d, 1H, J=13.1 Hz); 3.69 (d, 1H, J=13.1
Hz); 3.88 (q, 1H, J=7.8 Hz); 4.08 (dd, 1H, J=7.7, 9.2 Hz); 4.13 (dd, 1H, J=1.6, 9.2 Hz); 4.36–4.41 (m,
2H); 7.11–7.30 (m, 10H). 13C NMR (125 MHz, CDCl3) δ 25.4 (3Cs), 35.6, 47.9, 50.2, 57.8, 59.9, 61.0,
61.7, 64.9, 126.6, 126.9, 127.6 (2Cs), 128.2 (2Cs), 128.4 (2Cs), 128.6 (2Cs), 138.9, 142.4, 154.1, 174.3.
M.p. 97–99°C. Anal. calcd for C25H30N2O3: C, 73.9; H, 7.4; N, 6.9. Found: C, 73.8; H, 7.6; N, 7.0.
(3R,4S)-5d: [α]D25=+81.8 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 0.82 (s, 9H); 2.57 (t, 1H,
J=8.7 Hz); 2.88 (dd, 1H, J=4.8, 9.7 Hz); 3.15–3.22 (m, 2H); 3.50 (d, 1H, J=13 Hz); 3.74 (d, 1H, J=13
Hz); 4.00–4.10 (m, 3H); 4.15 (dd, 1H, J=1.5, 7.7 Hz); 4.35 (dd, 1H, J=1.5, 7.6 Hz); 7.11–7.29 (m, 10H).
13C NMR (125 MHz, CDCl3) δ 25.6 (3Cs), 35.8, 44.5, 51.9, 59.0, 59.7, 60.9, 62.1, 65.3, 126.5, 126.9,
127.8 (2Cs), 128.2 (2Cs), 128.5 (2Cs), 128.6 (2Cs), 138.8, 143.3, 154.1, 173.4. M.p. 119–121°C. Anal.
calcd for C25H30N2O3: C, 73.9; H, 7.4; N, 6.9. Found: C, 74.0; H, 7.4; N, 7.0.
4.14. (−)-(3S,4R)- and (−)-(3R,4S)-1-Benzyl-4-phenyl-3-[(30 a-(R)-cis-30,30a,80,80a-tetrahydro-2H-
indeno-(1,2-d)-oxazol-20 -one-30-yl)-carbonyl]-pyrrolidine 4e and 5e
Compounds 4e and 5e were prepared and isolated, according to the general method for the 1,3-dipolar
cycloaddition (method A), from 1e (0.50 g, 1.6 mmol) and 2 (0.76 g, 3.2 mmol). The mixture of 4e and
5e was separated by column chromatography [SiO2, ethyl acetate (gradient 15 and 30%) in n-hexane as
eluent] to give 4e (0.31 g, 0.72 mmol) and 5e (0.26 g, 0.58 mmol) as colourless solids in purity >99%
(GC).
1
(3S,4R)-4e: [α]D25=−185 (c=1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ 2.68–2.74 (m, 2H);
3.17–3.24 (m, 2H); 3.29–3.37 (m, 2H); 3.59 (d, 1H, J=13.2 Hz); 3.73 (d, 1H, J=13.2 Hz); 4.13–4.21

S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
2615
(m, 2H); 5.16–5.19 (m, 1H); 5.89 (d, 1H, J=6.9 Hz); 7.17–7.62 (m, 13H); 7.61 (d, 1H, J=7.6 Hz). 13
C
NMR (125 MHz, CDCl3) δ 37.9, 45.3, 51.1, 58.3, 59.7, 62.1, 63.2, 78.2, 125.2, 126.6, 126.8, 126.9, 127.8
(2Cs), 128.2 (2Cs), 128.3, 128.5 (4Cs), 129.8, 138.8, 139.2, 139.4, 143.1, 152.6, 173.9. M.p. 63–66°C.
Anal. calcd for C28H26N2O3·0.1H2O: C, 76.4; H, 6.0; N, 6.4. Found: C, 76.2; H, 6.0; N, 6.4.
(3R,4S)-5e: [α]D25=−67.0 (c=1.0, CH2Cl2). H NMR (500 MHz, CDCl3) δ 2.71 (t, 1H, J=8.5 Hz);
1
2.87 (dd, 1H, J=5.7, 9.6 Hz); 3.19–3.23 (m, 2H); 3.28–3.38 (m, 2H); 3.66 (d, 1H, J=13.0 Hz); 3.75 (d,
1H, J=13.0 Hz); 4.09 (q, 1H, J=7.6 Hz); 4.21–4.25 (m, 1H); 5.21–5.24 (m, 1H); 5.93 (d, 1H, J=7.0 Hz);
7.12–7.38 (m, 13H); 7.56 (d, 1H, J=7.7 Hz). 13C NMR (125 MHz, CDCl3) δ 38.0, 45.8, 50.7, 58.0, 59.9,
61.5, 63.4, 77.8, 125.1, 126.5, 127.0, 127.2, 127.6 (2Cs), 128.1, 128.3 (2Cs), 128.4 (2Cs), 128.7 (2Cs),
129.8, 138.8, 139.0, 139.4, 142.8, 152.5, 174.2. M.p. 114–116°C. Anal. calcd for C28H26N2O3·0.1H2O:
C, 76.4; H, 6.0; N, 6.4. Found: C, 76.2; H, 6.0; N, 6.4.
4.15. (−)-(3S,4R)- and (−)-(3R,4S)-1-Benzyl-4-phenyl-3-[(10 S,50R)-camphorsultam-30-yl)-carbonyl]-
pyrrolidine 4f and 5f
Compounds 4f and 5f were prepared and isolated, according to the general method for the 1,3-dipolar
cycloaddition (method A), from 1f (278 mg, 0.8 mmol) and 2 (0.38 g, 1.6 mmol). The mixture of 4f and
5f was separated by column chromatography [SiO2, ethyl acetate (15%) in n-hexane as eluent] to give 4f
(230 mg, 0.49 mmol) and 5f (78 mg, 0.16 mmol) as colourless solids in >99% purity (GC).
(3S,4R)-4f: [α]D25=−119.8 (c=0.5, CH2Cl2); H NMR (500 MHz, CDCl3) δ 0.94 (s, 3H); 1.04 (s,
1
3H); 1.26–1.38 (m, 2H); 1.85–1.89 (m, 3H); 2.06–2.07 (m, 2H); 2.67 (t, 1H, J=8.4 Hz); 2.82 (dd,
1H, J=5.9, 9.6 Hz); 3.14 (t, 1H, J=8.4 Hz); 3.23 (t, 1H, J=9.5 Hz); 3.36 (d, 1H, J=13.7 Hz); 3.42 (d,
1H, J=13.7 Hz); 3.61 (d, 1H, J=13.1 Hz); 3.73–3.77 (m, 2H); 3.86 (t, 1H, J=6.3 Hz); 4.04 (q, 1H,
J=7.3 Hz); 7.15–7.34 (m, 10H). 13C NMR (125 MHz, CDCl3) δ 19.8, 20.8, 26.4, 32.8, 38.4, 44.6, 45.1,
47.7, 48.3, 51.9, 53.0, 59.2, 59.7, 61.5, 65.3, 126.4, 126.9, 127.6 (2Cs), 128.2 (2Cs), 128.4 (2Cs), 128.6
(2Cs), 138.9, 142.8, 172.7. M.p. for C28H34N2O3S·HCl·0.5H2O: 123–129°C. HCl-salt: Anal. calcd for
C28H34N2O3S·HCl·0.5H2O: C, 64.2; H, 6.9; N, 5.3. Found: C, 64.6; H, 6.8; N, 5.4.
(3R,4S)-5f: [α]D25=−2.0 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H); 0.88 (s, 3H);
1.26–1.33 (m, 2H); 1.77–1.92 (m, 4H); 2.02 (dd, 1H, J=7.8, 13.8 Hz); 2.81 (dd, 1H, J=7.8, 9.2 Hz);
2.97 (dd, 1H, J=7.3, 9.5 Hz); 3.12 (dd, 1H, J=7.8, 9.2 Hz); 3.18 (t, 1H, J=8.9 Hz); 3.33 (d, 1H, J=13.8
Hz); 3.38 (d, 1H, J=13.8 Hz); 3.67 (d, 1H, J=13.1 Hz); 3.74 (q, 1H, J=7.8 Hz); 3.78–3.82 (m, 3H);
7.15–7.37 (m, 10H). 13C NMR (125 MHz, CDCl3) δ 19.8, 20.5, 26.4); 32.8, 38.5, 44.7, 47.6, 48.1,
50.3, 51.5, 53.1, 57.8, 60.1, 61.2, 65.2, 126.7, 126.9, 127.5 (2Cs), 128.2 (2Cs), 128.4 (2Cs), 128.6
(2Cs), 139.1, 141.6, 173.8. M.p. for C28H34N2O3S·HCl·1.5H2O: 124–127°C. HCl-salt: Anal. calcd for
C28H34N2O3S·HCl·1.5H2O: C, 62.0; H, 7.1; N, 5.2. Found: C, 62.4; H, 6.9; N, 5.4.
4.16. (−)-(3S,4R)- and (+)-(3R,4S)-1-Benzyl-4-phenyl-3-[(10 ,20,50,60-di-O-isopropyliden-D-
glycofuranosyl)-carbonyl]-pyrrolidine 4g and 5g
Compounds 4g and 5g were prepared and isolated, according to the general method for the 1,3-dipolar
cycloaddition (method A), from 1g (300 mg, 0.77 mmol) and 2 (365 mg, 1.54 mmol) with the exception
for the work-up procedure where the organic phase was washed only with NaHCO3. The mixture of 4g
and 5g was separated by several flash column chromatographies [SiO2, diethylether (10%) in CH2Cl2 as
eluent]. Pure fractions were collected to give 4g and 5g as colourless oils in a total yield of 95%.
(3S,4R)-4g: [α]D25=−32.8 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.25 (s, 3H); 1.29 (s, 3H);
1.38 (s, 3H); 1.50 (s, 3H); 2.72 (dd, 1H, J=6.5, 9.3 Hz); 2.93 (dd, 1H, J=6.5, 9.4 Hz); 2.99 (t, 1H, J=8.8

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S. Karlsson et al. / Tetrahedron: Asymmetry 10 (1999) 2605–2616
Hz); 3.06 (t, 1H, J=8.7 Hz); 3.11 (q, 1H, J=7.1 Hz); 3.63 (d, 1H, J=12.9 Hz); 3.66–3.69 (m, 1H); 3.73
(d, 1H, J=13.3 Hz); 3.92–3.94 (m, 2H); 3.98–4.02 (m, 1H); 4.15 (dd, 1H, J=3.0, 8.2 Hz); 4.40 (d, 1H,
J=3.6 Hz); 5.25 (d, 1H, J=3.1 Hz); 5.76 (d, 1H, J=3.7 Hz); 7.19–7.37 (m, 10H). 13C NMR (125 MHz,
CDCl3) δ 25.2, 26.2, 26.7, 26.9, 47.2, 51.5, 57.1, 59.8, 62.0, 67.5, 72.4, 76.3, 79.8, 83.4, 105.0, 109.3,
112.3, 126.7, 127.1, 127.4 (2Cs), 128.3 (2Cs), 128.5 (2Cs), 128.6 (2Cs), 138.8, 143.8, 172.9. Anal. calcd
for C30H37NO7: C, 68.8; H, 7.1; N, 2.7. Found: C, 68.4; H, 7.0; N, 2.6.
(3R,4S)-5g: [α]D25=+2.0 (c=0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.20 (s, 3H); 1.28 (s, 3H);
1.36 (s, 3H); 1.49 (s, 3H); 2.77 (dd, 1H, J=6.7, 9.3 Hz); 2.92 (dd, 1H, J=7.1, 9.1 Hz); 2.99–3.07 (m, 2H);
3.10–3.15 (m, 1H); 3.64–3.71 (m, 3H); 3.88 (dd, 1H, J=4.0, 7.3 Hz); 3.96–4.01 (m, 2H); 4.13 (dd, 1H,
J=3.0, 8.0 Hz); 4.38 (d, 1H, J=3.6 Hz); 5.24 (d, 1H, J=3.1 Hz); 5.72 (d, 1H, J=3.7 Hz); 7.16–7.35 (m,
10H). 13C NMR (125 MHz, CDCl3) δ 25.1, 26.2, 26.7 (2Cs), 47.2, 51.8, 57.0, 59.9, 61.8, 67.5, 72.3,
76.3, 80.1, 83.4, 105.1, 109.3, 112.3, 126.7, 127.1, 127.5 (2Cs), 128.2 (2Cs), 128.6 (4Cs), 138.7, 143.6,
172.6. Anal. calcd for C30H37NO7: C, 68.8; H, 7.1; N, 2.7. Found: C, 69.2; H, 7.4; N, 2.6.
Acknowledgements
We would like to thank Dr. Carmen Medina for the structural information and Dr. Martin Haraldsson
for valuable suggestions.
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