Silver acetate-catalysed asymmetric 1,3-dipolar cycloadditions of imines and chiral acrylamides

Article abstract of DOI:10.1016/j.tet.2005.02.009

N-Metallated azomethine ylides were generated by the reaction of arylidene glycine imines with AgOAc and triethylamine. These azomethine ylides undergo cycloaddition to chiral acrylamides with excellent diastereoselectivity. The configuration of two of the cycloadducts was confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.tet.2005.02.009

Tetrahedron 61 (2005) 3745–3753
Silver acetate-catalysed asymmetric 1,3-dipolar cycloadditions
of imines and chiral acrylamides
a,
b
b
c
d
*
´
Miklos Nyerges, David Bendell, Andrea Arany, David E. Hibbs, Simon J. Coles,
Michael B. Hursthouse,d Paul W. Groundwaterb and Otto Meth-Cohnb
aResearch Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology,
Technical University of Budapest, PO Box 91, H-1521 Budapest, Hungary
bSunderland Pharmacy School—Drug Design and Molecular Modelling, University of Sunderland, Sunderland SR1 3SD, UK
cDepartment of Chemistry, Cardiff University, PO Box 912, Cardiff CF1 3TB, UK
dDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 2 November 2004; revised 21 January 2005; accepted 3 February 2005
Abstract—N-Metallated azomethine ylides were generated by the reaction of arylidene glycine imines with AgOAc and triethylamine.
These azomethine ylides undergo cycloaddition to chiral acrylamides with excellent diastereoselectivity. The configuration of two of the
cycloadducts was confirmed by X-ray crystallography.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the use of chiral esters (mainly menthyl-esters,5 or
those with a chiral controller at the b-position6), chiral
a,b-unsaturated ketones,7 and bicyclic lactams,8 with use of
N-acryloyl-(S)-proline esters as the only chiral alkenes.9
Thus, the wide range of easily available and cheap chiral
amines10 and amino acids still remained unexplored as
chiral auxiliaries in cycloadditions reactions. In this paper11
we demonstrate the utilization of these chiral elements in
the 1,3-dipolar cycloadditions of azomethine ylides to
acrylamides.
1,3-Dipolar cycloadditions are very important tools for the
construction of five membered heterocycles.1 The ease of
generation of 1,3-dipoles, coupled with the highly regio-,
and stereoselective nature of their cycloaddition reactions,
has resulted in a number of syntheses which utilize such a
reaction as a key step.2 One of the major challenges now for
1,3-dipolar cycloadditions is the preparation of optically
active compounds.3
The proline structure is present in many compounds with
interesting biological features. The most direct strategy for
the synthesis of functionalized proline derivatives is the
1,3-dipolar cycloaddition reaction of in situ generated
carboxy-stabilized azomethine ylide and a dipolarophile.
The asymmetric version of this reaction allows the synthesis
of enantiomerically enriched prolines with the simultaneous
creation of up to four stereochemically defined centers.
Chiral acrylate esters and amides, have been widely
evaluated as chirality sources in asymmetric Diels–Alder
reactions.4 In contrast fewer examples of chiral inductions
in the 1,3-dipolar cycloadditions of azomethine ylides have
been reported. To date, most attention has been devoted to
2. Results and discussion
Starting from the corresponding amines,12 acrylamides
2a,13 2b,14 2c,15 2d,12b were prepared by simple acylation
with acryloyl chloride in dichloromethane in the presence of
triethylamine. The acrylamide 2e was prepared by the
modification of a literature procedure16 since, in this case,
the simple acylation of ephedrine (1) with acryloyl chloride,
led to a mixture of the N-acylated 2e and N,O-diacylated
product (2f). When acrylic acid was activated by ethyl
chloroformate, however, the secondary nitrogen of the
intermediate was acylated selectively, to give 2e as a single
product (Scheme 1).
Keywords: Amines; Asymmetric; Azomethine ylide; Cycloaddition;
Pyrrolidine.
These alkenes were then reacted with azomethine ylides,
derived from arylidene glycine imines 3 in the presence of
AgOAc and triethylamine at room temperature, employing
*
Corresponding author. Tel.: C36 1 462213; fax: C36 1 4633648;
e-mail: mnyerges@mail.bme.hu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.009

3746
M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
Scheme 1.
Scheme 2.
dry toluene as the solvent (Scheme 2). In accordance with
previous results,5a this metallo-azomethine ylide cyclo-
addition exhibited regio- and stereospecific formation of
the expected syn-endo cycloadducts, but the diastereo-
selectivities and yields varied depending upon the nature of
the chiral auxillary and the substituents on the aryl group
(Table 1).
The most promising results were achieved using (1R,2S)-
(K)-ephedrine as the chiral element: the corresponding
alkene 2e gave, in most of the cycloadditions studied, a
single diastereoisomer in good yield.
In the case of imine 3c in all cases, depending on the
reaction time a small amount of didehydroaminoacid 6 was
always isolated from the reaction mixture. The formation of
this compound has been observed and explained in our
earlier papers (Scheme 3).17
The acrylamides 2a and 2b, derived from the corresponding
a-phenylethylamine reacted only with moderate diastereo-
selectivity (entry 1–4), but in most cases both pyrrolidine
isomers were readily obtained, in pure form, from these
cycloadduct mixtures after repeated recrystallisations. The
chiral dipolarophile 2c based on (R,R)-bis-a-phenylethyl-
amine as the chiral auxillary also resulted in the formation
of diastereoisomeric mixtures. In contrast, the cyclic
C2-symmetric pyrrolidine derivative 2d (RZH) showed
complete diastereoselectivity in all cases.
The relative configuration of the cycloadducts of series 4
and 5 were determined by NOE studies of representative
examples. The all-cis configuration of these pyrrolidines in
all cases has been confirmed by the observed NOE effects
between H-2 and H-5 (2–4%) and H-5 and H-4 (3–6%). The
absolute configuration of two cycloadducts (4a1 and 4c1)
has been established by X-ray crystallography. To compare

M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
Table 1. Synthesis of pyrrolidines 3 and 4 from acrylamides 2 and glycine imines 1
3747
Entry
Acrylamide
Imine
R1
R2
R3
Products
Reaction
time
Yield (%)
Ratio (4:5)
1
2
3
4
5
6
7
8
2a
2b
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2e
3a
3a
3b
3c
3d
3a
3b
3c
3a
3b
3c
3a
3b
3e
3d
H
H
Cl
H
H
H
Cl
H
H
Cl
H
H
Cl
H
H
H
H
H
H
MeO
H
H
H
H
H
H
H
H
H
MeO
H
H
Cl
NO2
MeO
H
Cl
NO2
H
Cl
NO2
H
4a1, 5a1
4b1, 5b1
4b2, 5b2
4b3, 5b3
4b4, 5b4
4c1, 5c1
4c2, 5c2
4c3, 5c3
4d1, 5d1
4d2, 5d2
4d3, 5d3
4e1, 5e1
4e2, 5e2
4e3, 5e3
4e4, 5e4
48 h
48 h
36 h
24 h
24 h
36 h
80 h
24 h
24 h
48 h
24 h
24 h
48 h
24 h
24 h
77a
74a
70a
82a
71a
65a
51a
67a
78b
66a
85b
76b
57b
75b
81b
1.8:1
1:1.8
1:1.5
1:1
1:1.2
1:1
1:2
1:1.7
1:0
1:0
1:0
1:0
9
10
11
12
13
14
15
Cl
MeO
MeO
10:1
1:0
1:0
a Isolated yield after flash chromatography.
b Isolated yield after recrystallisation.
Scheme 3.
the configurations of the other products to those of these
configurations, the cycloadducts were hydrolysed to the
diacids 6 by ethanolic hydrochloric acid and re-esterified
by the means of thionyl chloride in dry EtOH. The diesters
7 were then purified by chromatography and the optical
rotations were compared (Scheme 4).
Scheme 5.
In an earlier attempt for the comparison of the absolute
stereochemistry of the resulted cycloadducts, the reaction of
4a1 and 4e1 with PhLi and PhMgBr was attempted. To our
surprise in spite of the large excess of organometallic
reagents (PhMgCl or PhLi) the amide functions remained
intact and in both cases, only transformation of the
carbethoxy functionality was observed (Scheme 5).
In summary, N-metallated azomethine ylides were gener-
ated by the reaction of arylidene glycine imines 3 with
AgOAc and triethylamine. These azomethine ylides
undergo cycloaddition to chiral acrylamides 2 to give
chiral pyrrolidines, 4 and 5, with excellent diastereo-
selectivity. Single diastereoisomers were obtained from
the reaction of the ylides with the dipolarophiles 2d and
2e (Figs. 1 and 2).
Figure 1. Crystal structure of 4a1.
Scheme 4.

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M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
3.1.2. (R,R)-2,5-Diphenyl-1-acroyl-pyrrolidine (2d, RZ
H). (R,R)-2,5-Diphenyl-pyrrolidine (0.30 g, 1.35 mmol) has
been dissolved in dry CH2Cl2 (10 mL) and at 0 8C
triethylamine (0.28 mL, 2 mmol) was added. After 5 min
acroyl chloride (0.24 g, 0.22 mL, 2.7 mM) was added
dropwise. After 12 h stirring at room temperature the
mixture was washed with saturated sodium hydrocarbonate
solution (2!5 mL), water (5 mL), brine (5 mL) and dried
over magnesium sulfate. The evaporation of the solvent
followed by flash chromatography has yielded the product
as a white solid (0.35 g, 93%). Mp 111–2 8C; [a]2D3ZC106
1
(c 0.83, CHCl3); H NMR (270 MHz, CDCl3): 7.20–6.85
(m, 10H, Ph), 6.00 (m, 2H, CH]), 5.35 (d, 1H, JZ7.9 Hz,
CH]), 5.17 (t, 2H, JZ9.9 Hz, CH-Ph), 2.34 (m, 1H, CH2),
2.13 (m, 1H, CH2), 1.56 (m, 2H, CH2); 13C NMR: 165.0,
143.7, 142.8, 128.8 (3!C), 128.4 (2!C), 128.0, 127.4,
126.7, 125.4 (2!CH), 125.3 (2!CH), 62.2, 62.1, 33.1,
30.3; IR (KBr, cmK1): 3061, 2986, 2929, 1651, 1609, 1391,
1306, 1074; CIMS (m/z, rel intensity %): 278 (MC1, 100),
146 (10), 73 (10); HRMS: Calcd: 277.1467 for C19H19NO;
Found: 277.1470.
Figure 2. Crystal structure of 4c1.
3. Experimental
3.1. General
3.1.3. (1R,2S)-N-(2-Hydroxy-1-methyl-2-phenyl-ethyl)-
N-methyl-acrylamide (2e) and (1R,2S)-N-(2-acroyloxy-
1-methyl-2-phenyl-ethyl)-N-methyl-acrylamide (2f).
Method A. (K)-Ephedrine hydrochloride (4.0 g, 20 mmol)
was suspended in dry dichlormethane (50 mL) and triethyl-
amine (4.22 g, 5.8 mL) was added in one portion. After
10 min stirring the mixture was cooled down to 0 8C and
acryloyl chloride (2.64 g, 2.81 mL, 21 mM) was added
dropwise. The reaction mixture was allowed to warm up to
room temperature and it was stirred for 5 h. Then it was
washed with water (25 mL), saturated NaHCO3 solution
(25 mL), brine (25 mL), dried over magnesium sulfate and
evaporated to yield an oil which is a mixture of 2e and 2f.
These products were separated by column chromatography
(eluent: petrolether–ethyl acetate 1:1) to yield 2e (1.38 g,
31.5%), and 2f (2.18 g, 40%).
Melting points were determined on a Gallenkamp apparatus
and are uncorrected. Elemental analyses were performed on
a Perkin–Elmer 240 8C or Carlo Erba 1106 Elemental
Analyser. IR spectra were recorded on a Perkin–Elmer 1600
series FTIR or Unicam research series FTIR spectro-
1
photometer using sodium chloride plates. H NMR spectra
were acquired on a Jeol GSX 270 FT NMR at 270 MHz.
Coupling constants are given in Hz and all chemical shifts
are relative to an internal standard of tetramethylsilane.
13C NMR spectra were obtained on a Jeol GFX 270 FT
NMR (68 MHz) spectrometer. Low resolution electron
impact mass spectra were obtained on a Trio 2000 VG.
High resolution spectra were obtained on a VG ZAB-E
spectrometer (E.P.S.R.C. Mass Spectrometry Service
Centre, Swansea). Thin layer chromatography was per-
formed on Merck silica gel 60F254. All solvents were
purified according to standard procedures.
Method B. Acrylic acid (6.30 g, 6.0 mL, 87.5 mM) was
dissolved in dry CH2Cl2 (30 mL) and triethylamine (8.8 g,
12.5 mL) was added. The mixture was cooled down to 0 8C
and methyl chlorofomate (9.5 g, 8.4 mL) was added
dropwise. After an hour stirring at 0 8C this mixture was
slowly transferred to a flask containing (K)-ephedrine
hydrochloride (8.0 g, 39.8 mM) and triethylamine (5.7 mL)
in dry CH2Cl2 (50 mL). The reaction mixture was stirred at
room temperature overnight and then washed with 2%
aqueous NaOH (40 mL), water (30 mL) and brine (30 mL).
The organic phase was dried over magnesium sulfate,
evaporated to yield a yellow oil which was purified by flash
chromatography to yield the product (2e only) as a
colourless oil (7.67 g, 88%).
3.1.1. S-(R*,R*)]-(K)-N,N-Bis-(1-phenyl-ethyl)-acryl-
amide (2c). [S-(R*,R*)]-(K)-bis-(a-Phenyl-ethyl)-amine
(0.50 g, 1.90 mM) has been dissolved in dry CH2Cl2
(10 mL) and at 0 8C triethylamine (0.70 mL, 5 mmol) was
added. After 5 min acroyl chloride (0.25 g, 0.23 mL,
2.8 mM) was added dropwise. After 12 h stirring at room
temperature the mixture was washed with saturated sodium
hydrocarbonate solution (2!5 mL), water (5 mL), brine
(5 mL) and dried over magnesium sulfate. The evaporation
yielded a colourless oil (0.49 g, 92%); [a]2D3ZC213 (c 1,
1
CHCl3); H NMR (270 MHz, CDCl3): 7.2 (m, 10H, Ph),
6.28 (dd, 1H, JZ2.6, 16.5 Hz, CH2]), 6.11 (dd, 1H, JZ
9.9, 16.5 Hz, CH2]), 5.97 (br s, 1H, CH), 5.40 (dd, 1H, JZ
2.6, 9.9 Hz, CH]), 4.98 (br s, 1H, CH), 1.74 (br d, 6H, JZ
6.6 Hz, 2!CH3), 13C NMR: 166.7 (C]O), 141.1 (CH),
130.6 (2!q), 128.3 (overlapping CHs), 127.6 (overlapping
CHs), 126.7 (overlapping CHs), 55.2 (CH), 20 (broad,
CH3); IR (film, cmK1): 3058, 3037, 2976, 2936, 1642, 1601,
1428, 1303, 1246, 1204, 1163, 1086, 1059; CIMS (m/z, rel
intensity %): 280 (MC1, 3), 174 (83), 120 (51), 105 (100),
55 (49); HRMS: Calcd: 279.1623 for C19H21NO; Found:
279.1628.
Compound 2e. Colourless oil; [a]2D3ZK162 (c 2.4, CHCl3);
1H NMR (270 MHz, CDCl3): 7.37–7.21 (m, 5H, Ph), 6.48
(dd, 1H, JZ10.5, 16.5 Hz,]CH2-trans), 6.29 (dd, 1H, JZ
2.6, 16.5 Hz, CH]), 5.88 (dd, 1H, JZ2.6, 10.5 Hz,]CH2-
cis), 4.88 (d, 1H, JZ3.3 Hz, H-2), 4.50 (dq, 1H, JZ3.3,
7.3 Hz, H-1), 2.79 (s, 3H, NMe), 1.20 (d, 1H, JZ7.3 Hz,
13
CH3); C NMR: 168.0 (C]O), 141.8 (Ph-10C), 128.2 and
128.1 (overlapping, 4!CH), 127.4 (CH), 126.2 (2!CH),
76.5 (C-2), 58.1 (NMe), 33.1 (C-1), 11.7 (CH3); IR (film,

M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
3749
cmK1): 3386 (br, OH), 3035, 2982, 2942, 1639, 1588, 1480,
1450, 1412, 1334, 1275, 1250, 1125, 1042; CIMS (m/z, rel
intensity %): 220 (MC1, 38), 202 (base peak), 148 (17), 112
(12); HRMS: Calcd: 219.1259 for C13H17NO2; Found:
219.1257.
JZ7.3 Hz, 2H, OCH2), 3.99 (dd, 1H, JZ6.6, 9.9 Hz, H-2),
3.10 (ddd, 1H, JZ3.3, 5.9, 6.6 Hz, H-4), 2.76 (broad s, 1H,
NH), 2.61 (ddd, 1H, JZ6.6, 9.9, 13.9 Hz, H2K3), 2.29
(ddd, 1H, JZ3.3, 6.6, 13.9 Hz, H2-3), 1.32 (t, 3H, JZ
7.3 Hz, Me), 1.11 (d, 1H, JZ7.3 Hz, Me); 13C NMR: 173.4
(C]O), 171.9 (C]O), 143.5 (Ph-10C), 138.3 (Ph-10C),
127.4 (4!CH), 126.8 (CH), 126.4 (CH), 126.2 (2!CH),
126.1 (2!CH), 64.7, 61.1, 58.0, 49.9, 48.1, 33.5, 21.5, 14.1;
CIMS (m/z, rel intensity %): 367 (MC, base peak), 293 (19),
105 (20); IR (nujol, cmK1): 3332, 1738, 1648, 1527, 1214,
1059, 1011; HRMS: Calcd: 366.1943 for C22H26N2O3;
Found: 366.2015.
Compound 2f. Colourless oil; [a]2D3ZK198 (c 2.0, CHCl3);
1H NMR (270 MHz, CDCl3): 7.40–7.26 (m, 5H, Ph), 6.51–
5.70 (m, 7H), 5.60 (dd, 1H, JZ2, 10 Hz), 5.12 (m, 1H, CH),
2.90 (s, 3H, NMe), 1.25 (d, 3H, JZ7 Hz, CH3); 13C NMR:
166.7, 165.0, 137.7, 131.7, 131.3, 128.6, 128.3, 128.1,
127.8, 126.7, 56.5, 52.5, 30.8, 12.8; IR (film, cmK1): 3480,
3034, 2904, 2910, 1726, 1646, 1611, 1478, 1437, 1412,
1266, 1187, 1046, 979; CIMS (m/z, rel intensity %): 274
(MC1,18), 230 (10), 202 (base peak), 148 (10), 112 (22);
HRMS: Calcd: 273.1365 for C16H19NO3; Found: 273.1360.
3.2.3. (S,S,S,R)-Ethyl,5-(2,4-dichlorophenyl)-4-[(10-phe-
nylethyl)carbamoyl]-pyrrolidine-2-carboxylate (5b2).
White powder; mp 171–2 8C; [a]2D3ZC116 (c 1.2,
1
CHCl3); H NMR (270 MHz, CDCl3): 7.51 (d, 1H, JZ
3.2. AgOAc catalysed cycloaddition reactions—general
procedure
7.9 Hz, Ar), 7.33–7.12 (m, 5H, Ar), 6.93 (dd, 1H, JZ1.8,
7.9 Hz, Ar), 6.42 (d, 1H, JZ7.9 Hz, Ar), 4.73 (m, 1H,
CHCH3), 4.57 (d, 1H, JZ6.0 Hz, H-5), 4.29 (q, 2H, JZ
7.3 Hz, OCH2), 3.96 (dd, 1H, JZ6.1, 9.5 Hz, H-2), 3.35
(ddd, 1H, JZ3.2, 6.0, 6.7 Hz, H-4), 2.70 (br s, 1H, NH),
2.53 (ddd, 1H, JZ6.7, 9.5, 13.8 Hz, H2K3), 2.35 (ddd, 1H,
JZ3.2, 6.1, 13.8 Hz, H2-3), 1.29 (t, 3H, JZ7.3 Hz, Me),
1.08 (d, 3H, JZ8.6 Hz, Me); 13C NMR: 173.4 (C]O),
170.9 (C]O), 143.0 (q), 134.5 (q), 133.8 (q), 133.3 (q),
129.1 (2!CH), 128.6 (2!CH), 127.6 (CH), 127.6 (CH),
126.4 (CH), 125.9 (CH), 62.6, 61.2, 58.1, 47.3, 33.6, 21.0,
14.2; IR (nujol, cmK1): 3306, 1734, 1644, 1527, 1213, 1123,
1090, 1050, 1019; CIMS (m/z, rel intensity %): 477 (MC,
4), 463 (12), 435 (base peak), 401 (15), 361 (14), 262 (17),
140 (20), 105 (34); HRMS: Calcd: 434.1164 for
C22H24Cl2N2O3; Found: 434.1152.
A mixture of imine (1.2 equiv) AgOAc (1.5 equiv),
appropriate dipolarophile (1 equiv) and Et3N (1.1 equiv)
in dry toluene (5 mL for 1 mmol of imine) protected from
the light with aluminium was stirred at room temperature for
12–48 h. The reaction was then quenched by addition of
saturated aqueous ammonium chloride solution and ether.
The mixture was filtered through a pad of Celite. The
organic layer was separated, washed with water, brine and
dried over magnesium sulfate, filtered and the solvent
evaporated. The residue was purified by flash chromato-
graphy and/or recrystallisation to afford the cycloadducts.
3.2.1. Ethyl,5-phenyl-4-[(10-phenylethyl)carbamoyl]-
pyrrolidine-2-carboxylate (4a1 and 5b1). Colourless
1
crystals; H NMR (270 MHz, CDCl3): 7.27–7.15 (m, 8H,
3.2.4. (R,R,R,R)-Ethyl,5-(2,4-dichlorophenyl)-4-[(10-phe-
nylethyl)carbamoyl]-pyrrolidine-2-carboxylate (4b2).
White powder; mp 162–3 8C; [a]2D3ZC78 (c 0.8, CHCl3);
1H NMR (270 MHz, CDCl3): 7.52 (d, 1H, JZ7.9 Hz, Ar),
7.37–7.10 (m, 5H, Ar), 6.94 (dd, 1H, JZ1.9, 7.9 Hz, Ar),
6.27 (d, 1H, JZ7.9 Hz, Ar), 4.73 (quintet, 1H, CHCH3),
4.52 (d, 1H, JZ6.0 Hz, H-5), 4.31 (q, 2H, JZ7.3 Hz,
OCH2), 3.98 (dd, 1H, JZ6.5, 9.8 Hz, H-2), 3.31 (ddd, 1H,
JZ3.2, 6.0, 6.7 Hz, H-4), 2.70 (br s, 1H, NH), 2.55 (ddd,
1H, JZ6.7, 9.8, 13.9 Hz, H2K3), 2.39 (ddd, 1H, JZ3.2,
6.5, 13.9 Hz, H2-3), 1.34 (t, 3H, JZ7.3 Hz, Me), 1.30 (d,
3H, JZ8.6 Hz, Me); 13C NMR: 173.3 (C]O), 171.1
(C]O), 143.0 (q), 134.5 (q), 133.6 (q), 133.3 (q), 128.9
(2!CH), 128.4 (2!CH), 127.7 (CH), 127.5 (CH), 126.4
(CH), 125.9 (CH), 62.4, 61.2, 58.4, 47.4, 33.8, 21.8, 14.2;
CIMS (m/z, rel intensity %): 477 (MC, 14), 435 (base peak),
401 (5), 361 (24), 262 (37); HRMS: Calcd: 434.1164 for
C22H24Cl2N2O3; Found: 434.1174.
Ph), 6.95—6.92 (m, 2H, Ph), 6.58 (broad d, 1H, JZ7.3 Hz,
NHCO), 4.71 (m, 1H, CH3CH), 4.41 (d, 1H, JZ5.9 Hz,
H-5), 4.27 (dq, 2H, OCH2), 3.98 (dd, 1H, JZ6.0, 9.9 Hz,
H-2), 3.06 (ddd, 1H, JZ2.6, 5.9, 6.6 Hz, H-4), 2.76 (broad s,
1H, NH), 2.60 (ddd, 1H, JZ6.6, 9.9, 13.9 Hz, H2K3), 2.38
(ddd, 1H, JZ2.6, 6.0, 13.9 Hz, H2-3), 1.32 (t, 3H, JZ
7.3 Hz, Me), 1.11 (d, 1H, JZ7.3 Hz, Me); 13C NMR: 173.5
(C]O), 171.7 (C]O), 143.2 (Ph-10C), 138.2 (Ph-10C),
128.4 (4!CH), 127.3 (CH), 128.8 (CH), 126.4 (2!CH),
126.2 (2!CH), 65.1, 61.1, 58.1, 50.0, 48.3, 33.8, 21.3, 14.2;
CIMS (m/z, rel intensity %): 367 (MC, base peak), 293 (12),
246 (8), 105 (10); IR (nujol, cmK1): 3322, 1737, 1648,
1526, 1214, 1059, 1009.
(R,R,R,S)-4a1. Mp 145–6 8C; [a]2D3ZK100 (c 1.0, CHCl3)
HRMS: Calcd: 366.1943 for C22H26N2O3; Found:
366.1933.
(S,S,S,R)-5b1: Mp 143–4 8C; [a]2D3ZC100 (c 1.0, CHCl3);
HRMS: Calcd: 366.1943 for C22H26N2O3; Found:
366.2074.
3.2.5. (S,S,S,R)-Ethyl,5-(4-nitrophenyl)-4-[(10-phenyl-
ethyl)carbamoyl]-pyrrolidine-2-carboxylate
(5b3).
White needles; mp 189–90 8C; [a]2D3ZC148 (c 1.5,
1
CHCl3); H NMR (270 MHz, CDCl3): 7.87 (d, 1H, JZ
3.2.2. (R,R,R,R)-Ethyl,5-phenyl-4-[(10-phenylethyl)car-
bamoyl]-pyrrolidine-2-carboxylate (4b1). White powder;
mp 151–2 8C; [a]D23ZC130 (c 1.7, CHCl3); 1H NMR
(270 MHz, CDCl3): 7.39—7.17 (m, 8H, Ph), 7.04 (dd, 2H,
JZ1.4, 7.5 Hz, Ph), 6.81 (broad d, 1H, JZ7.9 Hz, NHCO),
4.71 (m, 1H, CH3CH), 4.45 (d, 1H, JZ6.6 Hz, H-5), 4.15 (q,
8.6 Hz, Ar-30H and 50H), 7.31 (d, 1H, JZ8.6 Hz, Ar-20H
and 60H), 7.21 (m, 3H, Ph), 7.03 (m, 2H, Ph), 4.78 (sextett,
1H, PhCH), 4.51 (d, 1H, JZ6.6 Hz, H-5), 4.29 (dq, 2H,
OCH2), 4.05 (dd, 1H, JZ5.9, 10.6 Hz, H-2), 3.17 (ddd, 1H,
JZ2.5, 6.6, 8.6 Hz, H-4), 2.71 (ddd, 1H, JZ5.9, 8.6, 14 Hz,
H2K3), 2.35 (ddd, 1H, JZ2.5, 5.9, 14 Hz, H2-3), 1.35 (t,

3750
M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
3H, JZ6.6 Hz, CH3), 1.26 (d, 3H, JZ6.6 Hz, CH3); 13C
NMR: 173.8 (C]O), 170.7 (C]O), 145.7 (Ar-10H), 132.0
(Ph-10C), 128.4 (2!CH), 127.3 (3!CH), 126.4 (2!CH),
123.3 (2!CH), 64.2, 61.5, 57.6, 50.1, 48.2, 33.5, 21.1 (Me),
14.2 (Me); IR (nujol, cmK1): 3290, 1726, 1642, 1548, 1521,
1343, 1262, 1203, 1106, 1021; CIMS (m/z, rel intensity %):
412 (MC, base peak), 382 (29), 338 (7), 289 (10), 167 (10),
105 (13); HRMS: Calcd: 411.1794 for C22H25N3O5; Found:
411.1808.
1445, 1378, 1279, 1201, 1178, 1102; HRMS: Calcd
538.1790 for C30H32Cl2N2O3; Found: 538.1791.
3.2.9.
(S,S,S,R,R)-Ethyl,5-(2,4-dichlorophenyl)-4-
[[bis(10-phenylethyl)]carbamoyl]-pyrrolidine-2-carboxyl-
ate (4c2). White powder; mp 170 8C; [a]2D3ZK95 (c 0.25,
CHCl3); H NMR (270 MHz, CDCl3): 7.56 (d, 1H, JZ
1
8.5 Hz, Ar), 7.33–7.01 (m, 8H, Ar), 6.75–6.71 (m, 4H, Ar),
4.99 (br s, 1H, PhCH), 4.65 (q, 1H, JZ6.6 Hz, PhCH), 4.48
(d, 1H, JZ6.0 Hz, H-5), 4.23 (dq, 2H, OCH2), 3.89 (dd, 1H,
JZ7.3, 9.3 Hz, H-2), 3.10 (br s, 1H, H-4), 2.51 (ddd, 1H,
JZ7.9, 9.3, 13.2 Hz, H2K3), 2.27 (ddd, 1H, JZ4.0, 7.3,
13.2 Hz, H2-3), 1.38 (d, 3H, JZ6.6 Hz, Me), 1.34 (t, 3H,
JZ7.3 Hz, Me), 1.25 (d, 3H, JZ6.6 Hz, Me); 13C NMR:
173.5 (C]O), 172.5 (C]O), 141.4 (q), 141.1 (q), 134.7 (q),
133.9, 133.4, 129.0, 128.7, 128.0, 127.7, 127.5, 127.1,
126.8, 126.6 (15!C, overlapping), 66.7, 61.3, 51.9, 47.7,
36.6, 31.2, 20.5, 17.9, 14.1; CIMS (m/z, rel intensity %): 539
(MC, base peak), 105 (80); IR (film, cmK1): 2979, 2938,
1737, 1626, 1452, 1377, 1211, 1109; HRMS: Calcd
538.1790 for C30H32Cl2N2O3; Found: 538.1786.
3.2.6. (R,R,R,R,R)-Ethyl,5-phenyl-4-[[bis(10-phenyl-
ethyl)]carbamoyl]-pyrrolidine-2-carboxylate (4c1).
Colourless needles; mp 172–3 8C; [a]2D3ZK158 (c 0.96,
1
CHCl3); H NMR (270 MHz, CDCl3): 7.31–7.02 (m, 11H,
Ph), 6.77–6.71 (m, 4H, Ph), 5.31 (broad d, 1H, JZ6.6 Hz,
PhCH), 4.70 (q, 1H, JZ7.3 Hz, PhCH), 4.23 (dq, 2H,
OCH2), 3.95 (d, 1H, JZ7.3 Hz, H-5), 3.87 (t, 1H, JZ
8.6 Hz, H-2), 3.43 (dd, 1H, JZ5.3, 7.3 Hz, H-4), 2.53–2.02
(m, 2H, H2K3), 1.46 (d, 3H, JZ7.3 Hz, CH3), 1.42 (d, 3H,
JZ7.3 Hz, CH3), 1.29 (t, 3H, JZ7.3 Hz, CH3); 13C NMR:
173.90 (C]O), 173.1 (C]O), 141.1 (2!Ph-10C), 138.7
(Ph-1 C), 128.4, 128.3, 128.0, 127.8, 127.2, 126.9 (15!CH,
overlapping), 67.4, 61.0, 52.4, 52.1, 47.2, 36.9, 30.0, 19.5,
16.9, 14.3; IR (nujol, cmK1): 1737, 1627, 1604, 1453, 1293,
1262, 1195, 1177, 1102, 1025, 949; CIMS (m/z, rel intensity
%): 471 (MC, base peak), 397 (10), 367 (15), 280 (12), 246
(9), 105 (22); HRMS: Calcd: 470.2569 for C30H34N2O3;
Found: 470.2573.
3.2.10. (S,S,S,R,R)-Ethyl,5-(4-nitrophenyl)-4-[[bis(10-
phenylethyl)]carbamoyl]-pyrrolidine-2-carboxylate
(5c3). White powder; mp 212–3 8C; [a]2D3ZK179 (c 1.2,
1
CHCl3); H NMR (270 MHz, CDCl3): 8.03 (d, 2H, JZ
8.6 Hz, Ar), 7.25–7.04 (m, 10H, Ph), 6.49 (d, 2H, JZ
8.6 Hz, Ar), 5.82 (broad q, 1H, JZ6.6 Hz, CHPh), 4.65 (q,
1H, JZ7.2 Hz, CHPh), 4.25 (dq, 2H, OCH2), 3.90 (t, 1H,
JZ8.6 Hz, H-2), 3.79 (d, 1H, JZ7.9 Hz, H-5), 3.42 (ddd,
1H, JZ1.4, 5.3, 7.9 Hz, H-4), 2.57 (ddd, 1H, JZ5.3, 8.6,
13.5 Hz, H2K3), 2.32 (ddd, 1H, JZ1.4, 8.6, 13.5 Hz, H2-3),
1.68 (d, 3H, JZ6.5 Hz, Me), 1.47 (d, 3H, JZ6.5 Hz, Me),
1.31 (t, 3H, JZ7.3 Hz, Me); 13C NMR: 173.8 (C]O),
172.7 (C]O), 146.8 (q), 141.0 (q), 140.7 (q), 128.7, 128.6,
128.5, 128.3, 128.2, 127.8, 127.6 (overlapping CHs), 127.2
(CH), 122.8 (CH), 66.1, 61.1, 51.6, 51.0, 48.6, 37.0, 29.6,
20.1, 16.4, 14.2; IR (KBr, cmK1): 2977, 2933, 1734, 1626,
1517, 1494, 1442, 1345, 1240, 1201, 1105, 1035, 841;
CIMS (m/z, rel intensity %): 516 (MC1, 100), 486 (10), 412
(9), 280 (10), 105 (30); HRMS: Calcd 515.2402 for
C30H33N3O5; Found: 515.2407.
3.2.7. (S,S,S,R,R)-Ethyl,5-phenyl-4-[[bis(10-phenyl-
ethyl)]carbamoyl]-pyrrolidine-2-carboxylate (5c1).
White powder; mp 156–8 8C; [a]2D3ZK121 (c 0.42,
1
CHCl3); H NMR (270 MHz, CDCl3): 7.35–7.12 (m, 11H,
Ph), 6.78–6.73 (m, 4H, Ph), 5.38 (broad d, 1H, JZ6.9 Hz,
PhCH), 4.66 (q, 1H, JZ6.8 Hz, PhCH), 4.27 (dq, 2H,
OCH2), 3.98 (d, 1H, JZ7.6 Hz, H-5), 3.91 (t, 1H, JZ
8.6 Hz, H-2), 3.48 (dd, 1H, JZ5.1, 7.6 Hz, H-4), 2.35–2.22
(m, 2H, H2-3), 1.47 (d, 3H, JZ6.8 Hz, CH3), 1.41 (d, 3H,
JZ6.8 Hz, CH3), 1.31 (t, 3H, JZ7.5 Hz, CH3); 13C NMR:
174.8, 172.9, 141.8, 140.9, 138.1, 129.1, 128.1, 127.9,
127.6, 127.4, 127.1, 126.8, 126.3, 125.9, 68.0, 51.7, 50.7,
48.6, 35.8, 30.1, 21.0, 17.4, 14.2; IR (nujol, cmK1): 1739,
1625, 1604, 1452, 1296, 1197, 1109, 1027, 949; CIMS (m/z,
rel intensity %): 471 (MC, base peak), 397 (15), 367 (25),
105 (36); HRMS: Calcd: 470.2569 for C30H34N2O3; Found:
470.2573.
3.2.11. (R,R,R,R,R)-Ethyl,5-(4-nitrophenyl)-4-[[bis(10-
phenylethyl)]carbamoyl]-pyrrolidine-2-carboxylate
(4c3). White powder; mp 201–3 8C; [a]2D3ZK142 (c 0.34,
1
CHCl3); H NMR (270 MHz, CDCl3): 8.14 (d, 2H, JZ
8.6 Hz, Ar), 7.29–7.02 (m, 10H, Ph), 6.73 (d, 2H, JZ
8.6 Hz, Ar), 5.70 (broad s, 1H, CHPh), 4.65 (q, 1H, JZ
7.2 Hz, CHPh), 4.27 (dq, 2H, OCH2), 3.70 (t, 1H, JZ
8.6 Hz, H-2), 3.76 (d, 1H, JZ7.0 Hz, H-5), 3.05 (broad q,
1H, H-4), 1.97 (broad m, 1H, H2K3), 1.72 (broad m, 1H,
H2-3), 1.59 (d, 3H, Me), 1.32 (d, 3H, Me), 1.29 (t, 3H, JZ
6.9 Hz, Me); 13C NMR: 173.8 (C]O), 172.6 (C]O), 146.8
(q), 141.1 (q), 140.6 (q), 128.7, 128.6, 128.4, 128.3, 128.2,
127.9 (overlapping CHs), 126.1 (CH), 123.0 (CH), 66.8,
61.2, 51.6, 51.3, 47.4, 35.6, 29.9, 21.2, 17.7, 14.2; CIMS (m/z,
rel intensity %): 516 (MC1, 100), 412 (13), 105 (30); HRMS:
Calcd 515.24022 for C30H33N3O5; Found: 515.240545.
3.2.8.
(S,S,S,R,R)-Ethyl,5-(2,4-dichlorophenyl)-4-
[[bis(10-phenylethyl)]carbamoyl]-pyrrolidine-2-carboxyl-
ate (5c2). White powder; mp 184–6 8C; [a]2D3ZK102
(c 0.88, CHCl3); H NMR (270 MHz, CDCl3): 7.61 (d,
1
1H, JZ8.6 Hz, Ar), 7.39—7.03 (m, 8H, Ar), 6.78–6.77 (m,
4H, Ar), 5.64 (br s, 1H, PhCH), 4.90 (q, 1H, JZ6.6 Hz,
PhCH), 4.48 (d, 1H, JZ6.0 Hz, H-5), 4.25 (dq, 2H, OCH2),
3.70 (br dd, 1H, H-2), 3.42 (br s, 1H, H-4), 1.90 (broad ddd,
1H, H2K3), 1.75 (broad ddd, 1H, H2-3), 1.54 (d, 3H, JZ
6.6 Hz, Me), 1.30 (t, 3H, JZ7.2 Hz, Me), 1.22 (d, 3H, JZ
6.6 Hz, Me); 13C NMR: 173.6 (C]O), 172.7 (C]O), 141.3
(q), 141.1 (q), 134.8 (q), 133.5, 133.1, 128.9, 128.4, 128.0,
127.7, 127.3, 126.8, 126.7 (15!C, overlapping), 66.9, 61.1,
51.9, 47.6, 36.3, 29.6, 20.5, 17.8, 14.3; CIMS (m/z, rel
intensity %): 539 (MC, base peak), 505 (10), 435 (12), 280
(30), 105 (70); IR (film, cmK1): 2976, 2931, 1738, 1629,
3.2.12. (R,R,R,R,R)-Ethyl,4-[(20,50-trans-diphenylpyrro-
lidinyl)-1-carbonyl]-5-phenyl-pyrrolidine-2-carboxylate
(4d1). White powder; mp 203 8C; [a]2D3ZC262 (c 2.2,

M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
3751
1
CHCl3); H NMR (270 MHz, CDCl3): 7.39 (m, 10H, Ph),
pyrrolidine-2-carboxylate (4e1). White powder; mp 182–
3 8C; [a]2D3ZK101 (c 1.0, CHCl3); H NMR (270 MHz,
1
7.20 (d, 1H, JZ7.2 Hz, Ph), 7.02 (m, 2H, Ph), 6.28 (d, 2H,
JZ7.8 Hz, Ph), 5.26 (d, 1H, JZ7.9 Hz) and 5.17 (d, 1H, JZ
7.9 Hz, H-20 and H-50), 4.20 (q, 2H, JZ6.6 Hz, OCH2), 4.19
(d, 1H, JZ7.3 Hz, H-5), 3.70 (t, 1H, JZ8.6 Hz, H-2), 3.20
(dt, 1H, JZ4.5, 7.9 Hz, H-4), 2.24 (m, 2H, CH2), 2.11 (m,
1H, CH2), 1.90 (m, 1H, CH2), 1.67 (d, 1H, JZ6.6 Hz, CH2),
1.50 (d, 1H, JZ6.6 Hz, CH2), 1.25 (t, 3H, JZ6.6 Hz, CH3);
13C NMR: 173.4 (C]O), 172.5 (C]O), 143.6 (Ph-10C),
142.6 (Ph-10C), 138.5 (Ph-10C), 128.9 (2!CH), 128.7 (2!
CH), 128.5 (2!CH), 127.4 (CH), 127.3 (CH), 126.9 (2!
CH), 125.9 (CH), 125.4 (2!CH), 124.8 (2!CH), 66.5,
62.9, 62.0, 60.9, 60.1, 47.8, 36.5, 32.7, 30.4, 14.1 (CH3); IR
(nujol, cmK1): 1737, 1622, 1424, 1318, 1260, 1169, 1090,
1031; CIMS (m/z, rel intensity %): 469 (MC1, base peak),
395 (10), 278 (12), 192 (10); HRMS: Calcd: 468.2413 for
C30H32N2O3; Found: 468.2400.
CDCl3): 7.40–7.15 (m, 8H, Ar), 4.61 (d, 1H, JZ6.6 Hz,
CHOH), 4.40 (d, 1H, JZ4.0 Hz, H-5), 4.27 (dq, 2H, OCH2),
4.10 (broad m, 2H, OH C CH-CH3), 3.84 (t, 1H, JZ7.9 Hz,
H-2), 3.57 (ddd, 1H, JZ4.0, 7.3, 10.7 Hz, H-4), 2.80 (m,
1H, H2-3), 2.47 (s, 3H, NMe), 2.35 (m, 1H, H2K3), 1.33 (t,
3H, JZ7.1 Hz, CH3), 0.72 (d, 3H, JZ7.3 Hz, CH3); 13C
NMR: 173.6 (C]O), 172.8 (C]O), 141.7, 134.7, 133.7,
133.2, 129.2, 128.5, 127.9 (2!CH), 127.3, 127.1, 126.1
(2!CH), 76.5, 62.3, 59.8, 56.8, 43.5, 34.8, 32.5, 14.2, 11.4;
IR (KBr, cmK1): 3377, 2987, 1736, 1621, 1476, 1449, 1413,
1374, 1206, 1104, 1048; CIMS (m/z, rel intensity %): 479
(MC, base peak), 463 (20), 314 (31), 280 (15), 176 (10), 148
(52), 135 (22), 107 (25); HRMS: Calcd: 478.1426 for
C24H28Cl2N2O4; Found: 478.1409.
3.2.16. (R,R,R,R,S)-Ethyl,4-[(20-hydroxy-10-methyl-20-
phenyl-ethyl)carbamoyl]-5-(2,4-dichlorophenyl)-pyrro-
lidine-2-carboxylate (4e2). White powder; mp 182–3 8C;
[a]2D3ZK101 (c 1.0, CHCl3); 1H NMR (270 MHz, CDCl3):
7.40–7.15 (m, 8H, Ar), 4.61 (d, 1H, JZ6.6 Hz, CHOH),
4.40 (d, 1H, JZ4.0 Hz, H-5), 4.27 (dq, 2H, OCH2), 4.10
(broad m, 2H, OHCCH–CH3), 3.84 (t, 1H, JZ7.9 Hz,
H-2), 3.57 (ddd, 1H, JZ4.0, 7.3, 10.7 Hz, H-4), 2.80 (m,
1H, H2-3), 2.47 (s, 3H, NMe), 2.35 (m, 1H, H2K3), 1.33 (t,
3H, JZ7.1 Hz, CH3), 0.72 (d, 3H, JZ7.3 Hz, CH3); 13C
NMR: 173.6 (C]O), 172.8 (C]O), 141.7, 134.7, 133.7,
133.2, 129.2, 128.5, 127.9 (2!CH), 127.3, 127.1, 126.1
(2!CH), 76.5, 62.3, 59.8, 56.8, 43.5, 34.8, 32.5, 14.2, 11.4;
IR (film, cmK1): 3377, 2987, 1736, 1621, 1476, 1449, 1413,
1374, 1206, 1104, 1048; CIMS (m/z, rel intensity %): 479
(MC, base peak), 463 (20), 314 (31), 280 (15), 176 (10), 148
(52), 135 (22), 107 (25); HRMS: Calcd: 478.1426 for
C24H28Cl2N2O4; Found: 478.1419.
3.2.13. (R,R,R,R,R)-Ethyl,5-(2,4-dichlorophenyl)-4-
[(20,50-trans-diphenylpyrrolidinyl)-1-carbonyl]-pyrro-
lidine-2-carboxylate (4d2). White powder; mp 211 8C;
[a]2D3ZC47 (c 0.2, CHCl3); H NMR (270 MHz, CDCl3):
1
7.52 (d, 1H, JZ2.6 Hz, Ar), 7.51–7.01 (m, 10H, Ar), 6.42
(dd, 2H, JZ2.0, 8.2 Hz, Ar), 5.31 (d, 1H, JZ7.2 Hz,
NCHPh), 5.27 (d, 1H, JZ7.2 Hz, NCHPh), 4.20 (d, 1H, JZ
7.2 Hz, H-5), 4.19 (q, 2H, JZ7.0 Hz, OCH2), 3.65 (t, 1H,
JZ8.6 Hz, H-2), 3.47 (ddd, 1H, JZ1.9, 3.7, 7.2 Hz, H-4),
2.33 (m, 2H, CH2), 1.93 (m, 1H, CH2), 1.81 (m, 1H, CH2),
1.70 (m, 1H, CH2), 1.55 (m, 1H, CH2), 1.26 (t, 3H, JZ
7.0 Hz, CH3); 13C NMR: 173.2 (C]O), 172.7 (C]O),
143.5 (q), 142.8 (q), 133.3, 132.9, 129.2, 128.8, 128.7,
128.6, 127.5, 127.4, 127.0, 125.8, 124.9 (16!C, overlap-
ping), 66.3, 63.0, 62.1, 61.0, 60.1, 47.9, 36.4, 32.8, 30.2,
14.1; IR (nujol, cmK1): 1735, 1624, 1427, 1269, 1204, 1178,
1095, 1031; CIMS (m/z, rel intensity %): 537 (MC, 100),
503/501 (14), 278 (38), 205 (17), 149 (60), 85 (99); HRMS:
Calcd: 536.1633 for C30H30Cl2N2O3; Found: 536.1636.
3.2.17. (R,R,R,R,S)-Ethyl,5-(4-methoxyphenyl)-4-[(20-
hydroxy-10-methyl-20-phenyl-ethyl)carbamoyl]-pyrro-
lidine-2-carboxylate (4e3). White needles, mp. 134–5 8C;
[a]2D3ZK59 (c, 1.3, CHCl3); 1H NMR (270 MHz, CDCl3):
7.28–7.14 (m, 7H, Ar), 6.80 (d, 2H, JZ7.5 Hz, Ar), 4.55 (br
s, 1H, OH), 4.41 (d, 1H, JZ4 Hz, H-5), 4.28 (m, 3H, CHOH
and, CH2CH3), 4.11 (m, 1H, CHCH3), 3.81 (t, 1H, JZ
8.0 Hz, H-2), 3.73 (s, 3H, OMe), 3.33 (dd, 1H, JZ7, 13 Hz,
H-4), 2.75 (br s, 1H, NH), 2.45 (m, 1H, H2-3), 2.35 (s, 3H,
NCH3), 2.27 (m, 1H, H2K3), 1.33 (t, 3H, JZ8.7 Hz, CH3),
0.72 (d, 3H, JZHz, CH3); 13C NMR: 173.4 (q), 173.3 (q),
159.1 (q), 141.9 (q), 130.6 (q), 128.2 (2!CH), 127.9 (2!
CH), 127.1 (CH), 126.1 (2!CH), 113.5 (2!CH), 76.5,
65.6, 60.9, 59.9, 57.0, 55.2, 46.6, 34.6, 32.4, 14.1, 11.0; IR
(nujol, cmK1): 3184, 1739, 1609, 1521, 1402, 1259, 1231,
1104, 1027; EIMS (m/z, rel intensity %): 441 (MC1, 6), 367
(10), 333 (10), 307 (19), 276 (base peak), 174 (34), 147 (49),
105 (38); HRMS: Calcd: 442.2467 for C25H34N2O5; Found:
442.2463.
3.2.14. (R,R,R,R,R)-Ethyl,5-(4-nitrophenyl)-4-[(20,50-
trans-diphenylpyrrolidinyl)-1-carbonyl]-pyrrolidine-2-
carboxylate (4d3). White powder; mp 222–3 8C; [a]2D3ZC
1
34 (c 0.17, CHCl3); H NMR (270 MHz, CDCl3): 8.09 (d,
2H, JZ8.6 Hz, Ar), 7.44–7.31 (m, 5H, Ar), 7.18 (d, 2H, JZ
6.6 Hz, Ar), 7.07 (t, 1H, JZ7.3 Hz, Ar), 6.95 (t, 2H, JZ
7.3 Hz, Ar), 6.52 (d, 2H, JZ7.3 Hz, Ar), 5.25 (d, 1H, JZ
7.3 Hz, CHPh), 5.16 (d, 1H, JZ7.3 Hz, CHPh), 4.24 (d, 1H,
JZ7.3 Hz, H-5), 4.20 (q, 2H, JZ7.3 Hz, OCH2), 3.69
(t, 1H, JZ8.6 Hz, H-2), 3.25 (ddd, 1H, JZ3.3, 4.6, 7.9 Hz,
H-4), 2.51–2.19 (m, 2H, CH2), 2.01 (ddd, 1H, JZ4.6, 7.3,
13.2 Hz, H2K3), 1.88–1.72 (m, 2H, CH2), 1.58 (dd, 1H, JZ
5.3, 11.9 Hz, CH2), 1.27 (t, 3H, JZ7.3 Hz, CH3); 13C
NMR:172.9 (C]O), 172.2 (C]O), 147.1 (q), 146.2 (q),
143.6 (q), 142.6 (q), 129.0 (2!CH), 127.9 (2!CH), 127.8
(2!CH), 127.7 (2!CH), 126.6 (CH), 125.4 (2!CH),
125.1 (2!CH), 123.6 (2!CH), 66.1, 63.2, 62.0, 61.1, 60.2,
47.8, 36.3, 33.4, 30.0, 14.2; IR (nujol, cmK1): 1736, 1611,
1511, 1416, 1353, 1309, 1272, 1187, 1171, 1063, 1028;
CIMS (m/z, rel intensity %): 514 (MC1, base peak), 484
(12), 440 (8), 278 (10), 237 (12); HRMS: Calcd: 513.2264
for C30H31N3O5; Found: 513.2259.
3.2.18. (R,R,R,R,S)-Ethyl,5-(3,4-dimethoxyphenyl)-4-
[(20-hydroxy-10-methyl-20-phenyl-ethyl)carbamoyl]-pyr-
rolidine-2-carboxylate (4e4). White needles, mp. 155 8C;
[a]2D3ZK46 (c, 1.5, CHCl3); 1H NMR (270 MHz, CDCl3):
7.29–7.18 (m, 5H, Ph), 6.87 (d, 1H, JZ2.0 Hz, Ar-20H),
6.82 (dd, 1H, JZ2.0, 8.0 Hz, Ar-60H), 6.76 (d, 1H, JZ
8.0 Hz, Ar-50H), 4.47 (d, 1H, JZ3.3 Hz, CHOH), 4.37–4.22
3.2.15. (R,R,R,R,S)-Ethyl,4-[(20-hydroxy-10-methyl-
20-phenyl-ethyl)carbamoyl]-5-(2,4-dichlorophenyl)-

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M. Nyerges et al. / Tetrahedron 61 (2005) 3745–3753
1
(m, 4H, OCH2, H-2 and H-4), 4.11 (dq, 1H, JZ3.3, 7.3 Hz,
CH–CH3), 3.85 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.38 (ddd,
1H, JZ2.0, 5.3, 7.9 Hz, H-4), 2.39 (ddd, 1H, JZ2.0, 7.9,
13.2 Hz, H2-3), 2.34 (s, 3H, NMe), 2.32 (ddd, 1H, JZ5.3,
8.6, 13.2 Hz, H2K3), 1.34 (t, 3H, JZ7.3 Hz, CH3), 0.78 (d,
3H, JZ7.3 Hz, CH3); 13C NMR: 173.9 (C]O), 173.4
(C]O), 148.8 (2!q), 141.8 (q), 131.6 (q), 128.0 (2!CH),
127.4 (CH), 126.2 (2!CH), 119.5 (CH), 110.8 (CH), 110.5
(CH), 76.9 (CHOH), 66.1, 61.0, 60.1, 57.9, 55.9 (2!MeO),
46.8, 34.8, 32.9, 14.2, 11.4; IR (nujol, cmK1): 3181, 1737,
1608, 1519, 1402, 1305, 1256, 1238, 1195, 1141, 1104,
1023; CIMS (m/z, rel intensity %): 471 (MC1, base peak),
453 (18), 397 (8), 337 (10), 306 (28), 252 (12), 202 (18), 166
(20), 148 (42), 107 (13);HRMS: Calcd: 470.2417 for
C26H34N2O6; Found: 470.2415.
CHCl3); H NMR (270 MHz, CDCl3): 7.67 (d, 2H, JZ
7.3 Hz, Ph), 7.61 (d, 2H, JZ7.3 Hz, Ph), 7.35–7.12 (m,
14H, Ph), 7.03 (d, 2H, JZ7.9 Hz, Ph), 5.78 (s, 1H, NHCO),
5.21 (d, 1H, JZ7.9 Hz, H-5), 4.68 (quintet, 1H, CH3CH),
4.49 (t, 1H, JZ7.0 Hz, H-2), 2.84 (ddd, 1H, JZ2.6, 7.9,
9.2 Hz, H-4), 2.27 (ddd, 1H, JZ2.6, 7.0, 14.5, H2K3), 2.00
(ddd, 1H, JZ7.0, 9.2, 14.5 Hz, H2-3), 0.82 (d, 1H, JZ
13
6.6 Hz, Me), C NMR: 172.3 (C]O), 147.5 (Ph-10C),
146.4 (Ph-10C), 142.9 (Ph-10C), 139.2 (Ph-10C), 128.4,
128.2, 127.7, 127.2, 126.9, 126.4, 126.1, 126.0, 125.8,
(overlapping CHs), 112.1, 76.2, 65.8, 63.6, 50.4, 48.4, 37.3,
29.7, 20.6; IR (nujol, cmK1): 3152, 1591, 1301, 1259, 1203,
1128, 1035; CIMS (m/z, rel intensity %): 477 (MC1,3), 459
(6), 293 (10), 257 (18), 229 (18), 183 (90), 159 (50), 85 (87),
57 (100); HRMS: Calcd: 476.2464 for C32H32N2O2; Found:
476.2467.
3.2.19. (R,R,R)- or (S,S,S)-Diethyl, 5-phenyl-pyrrolidine-
2,4-dicarboxylate (8). Preparation from homochiral
cycloadducts—General procedure. The corresponding
cycloadduct (3 or 4, 1.0 mM) was dissolved in ethanol
(20 mL) and concentrated hydrochloric acid (3 mL) was
added. The reaction mixture was refluxed overnight, then all
the solvents were removed, and the residue was dried in
vacuo. The obtained white powder was suspended in dry
ethanol (10 mL) and thionyl chloride was added (0.2 mL).
After 1 h reflux, when all the solids dissolved again the
solvents were removed in vacuo and the residue was
redissolved in ether–triethylamine mixture (25 mL/1 mL).
This solution was washed with water and brine, dried over
magnesium sulfate and evaporated in vacuo. The remaining
oil was purified by column chromatography to yield the
corresponding enantiomer of the title diester as a colurless
oil; [a]2D3ZG88 (c 1.0, CHCl3); 1H NMR (270 MHz,
CDCl3): 7.30 (m, 5H, Ph), 4.54 (d, 1H, JZ7.9 Hz, H-5),
4.29 (q, 2H, JZ6.6 Hz, OCH2), 3.96 (t, 1H, JZ7.9 Hz,
H-2), 3.70 (dq, 2H, OCH2), 3.31 (dd, 1H, JZ7.3, 13.8 Hz,
H-4), 2.78 (br s, 1H, NH), 2.41 (m, 2H, H2-3), 1.33 (t, 3H,
CH3), 0.82 (t, 3H, JZ6.6 Hz, CH3); 13C NMR: 173.3
(C]O), 1702.6 (C]O), 139.2 (Ph-10C), 128.1 (2!CH),
127.5 (Ph-4 C), 126.9 (2!CH), 65.9, 61.2, 60.2, 60.1, 49.7,
33.6, 14.2, 13.6; IR (film, cmK1): 3351, 2980, 2905, 1732,
1451, 1378, 1198, 1166, 1111, 1037; CIMS (m/z, rel
intensity %): 292 (MC1, 100), 246 (22), 218 (55), 191 (13),
144 (10), 117 (9), 29 (41); HRMS: Calcd: 291.1470 for
C16H21NO4; Found: 291.1463.
3.3.2. 2-(Diphenyl-hydroxy-methyl)-4-[(20-hydroxy-10-
methyl-20-phenyl-ethyl)carbamoyl]-5-phenyl-pyrro-
lidine (10). Yield: 0.92 g (91%); white powder; mp 232 8C;
[a]2D3ZK15 (c 0.26, CHCl3); 1H NMR (270 MHz, CDCl3):
7.65 (d, 2H, JZ6.6 Hz, Ph), 7.63 (d, 2H, JZ7.3 Hz, Ph),
7.37–7.10 (m, 16H, Ph), 6.14 (br s, 1H, OH), 4.49–4.43 (m,
3H, H-2, H-5 and CHOH), 4.05 (br m, 1H, CH3CH), 3.40
(dt, 1H, JZ4.0, 7.9 Hz, H-4), 2.35 (ddd, 1H, JZ4.0, 7.3,
13.9 Hz, H2K3), 2.21 (s, 3H, NMe), 1.91 (ddd, 1H, JZ7.3,
8.0, 13.9, H2-3), 0.63 (d, 2H, JZ6.8 Hz, CH3); 13C NMR:
175.3 (C]O), 147.5 (q), 146.7 (q), 141.7 (q), 139.1 (q),
128.1, 127.5, 127.0, 126.4, 126.1, (overlapping CHs), 77.7,
65.9, 63.9, 58.2, 45.6, 33.0, 30.6, 11.0; IR (nujol, cmK1):
3164, 1594, 1309, 1253, 1203, 1128, 1024; CIMS (m/z, rel
intensity %): 521 (MC,2), 337 (4), 319 (5), 211 (7), 183
(base peak), 148 (32), 105 (27); HRMS: Calcd MHC:
521.2804 for C34H37N2O3; Found: MHC 521.2805.
Acknowledgements
N.M. thanks the National Foundation for Science and
Research, Hungary (OTKA Project No. T 032221) and
NATO/Royal Society for grants. We sincerely thank the
EPSRC for grant in support of A.A.
References and notes
3.3. Grignard reaction
A Grignard reagent, freshly prepared from the addition of
Mg (0.52 g, 21.6 mmol) to benzyl bromide (2.6 mL,
21.6 mmol) in anhyd Et2O (50 mL) at room temperature
for 1 h, was transferred to a solution of 4a1 (0.73 g, 2 mmol)
or 4e1 (0.79 g, 2 mmol) in anhyd Et2O (25 mL) at 0 8C via a
cannula. The reaction mixture was refluxed under N2 for
2 h, quenched by H2O (15 mL). The organic layer was
washed with H2O (50 mL) brine (50 mL), dried (MgSO4)
and rotary evaporated to give a crude product which was
purified by column chromatography (30% EtOAc/petro-
leum ether).
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11. Part of this work has been published in preliminary form: