Stereoselective reduction of chiral trans-3-acetyl 4-alkylpyrrolidin-2- ones

Article abstract of DOI:10.1016/S0957-4166(99)00031-2

A number of trans-3-acetyl-4-alkylpyrrolidin-2-ones 8a-d and 11a,b were prepared and reduction of the keto group, carried out with KBH₄ in CH₃OH, led mainly to 3-hydroxyethylpyrrolidin-2-ones 13a-d and 19a,b with high stereoselection. Configuration of the newly formed stereogenic centre on the hydroxyethyl chain was assigned by ¹H NMR data supported by molecular mechanic calculations and eventually confirmed by X-ray diffraction analysis of p-iodobenzoate derivative 15.

Full text of DOI:10.1016/S0957-4166(99)00031-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 587–605
Stereoselective reduction of chiral trans-3-acetyl-
4-alkylpyrrolidin-2-ones
Roberta Galeazzi,a Silvano Geremia,b,† Giovanna Mobbilia and Mario Orena a,∗
aDipartimento di Scienze dei Materiali e della Terra, Università di Ancona, Via Brecce Bianche, I-60131 Ancona, Italy
bDipartimento di Scienze Chimiche, Università di Trieste, Via Giorgieri 1, I-34127 Trieste, Italy
Received 31 December 1998; accepted 21 January 1999
Abstract
A number of trans-3-acetyl-4-alkylpyrrolidin-2-ones 8a–d and 11a,b were prepared and reduction of the keto
group, carried out with KBH4 in CH3OH, led mainly to 3-hydroxyethylpyrrolidin-2-ones 13a–d and 19a,b with
high stereoselection. Configuration of the newly formed stereogenic centre on the hydroxyethylchain was assigned
1
by H NMR data supported by molecular mechanic calculations and eventually confirmed by X-ray diffraction
analysis of p-iodobenzoate derivative 15. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The continued interest for stereoselective synthesis of the β-lactam ring stems from a variety of
antibiotics featuring a β-lactam moiety, in particular carbapenems1 such as epi-thienamycin 1,2 (+)-PS-5,
2,3 thienamycin 3a4 and its 1β-methyl derivative 3b (Scheme 1).5
Scheme 1.
∗
†
Corresponding author. E-mail: orena@popcsi.unian.it
Author to whom inquiries concerning the X-ray structure analysis should be addressed.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00031-2

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In the past few years we have investigated new procedures aimed at synthesising trans-3,4-
disubstituted pyrrolidin-2-ones6–8 and we report herein the stereoselective preparation of pyrrolidin-
2-ones 6 bearing three contiguous stereogenic centres by reducing the carbonyl group at the 3-acetyl
chain, leading to trans-3-hydroxyethyl-4-alkylpyrrolidin-2-ones,9 and the structural assignment of the
reduction products. These compounds could be precursors of substituted azetidinones 4,10 intermediates
to carbapenems, through ring contraction of derivative 5, which is currently being studied in our
laboratory (Scheme 2).
Scheme 2.
2. Results and discussion
We recently discovered a stereoselective approach to trans-3,4-disubstituted pyrrolidin-2-ones by
conjugate addition and this process was expected to be a highly attractive method for preparation of
substrates having the same configuration as 4 at both C-3 and C-4.8 Thus, amides 7a,b were treated with
NaH in THF at −78°C to give pyrrolidin-2-ones 8a,b and 9a,b in high yield and good diastereoselection
but the major component of the reaction mixtures was product 9, having opposite configurations at both
C-3 and C-4 with respect to 4 (Scheme 3).11 Moreover, both 8b and 9b resulted in 70:30 unseparability
(RS) mixture at C-2 of the propanoate chain.12 In addition, cyclisation of 10a, carried out under the
same conditions, led to a diastereomeric mixture of 11a and 12a in 70:30 d.r. and 11a having the
same configuration as 4 at both C-3 and C-4 (Scheme 3). trans-3,4-Disubstituted pyrrolidin-2-ones 8a,b,
9a,b, 11a and 12a were easily separated by silica gel chromatography and the absolute configuration of
stereocentres on the heterocyclic ring was determined by 1H NMR data supported by molecular mechanic
calculations.6–8
Scheme 3.

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589
On the contrary, higher diastereoselection was observed when amides 7a,b underwent cyclisation on
treatment with sodium ethoxide in ethanol at −78°C, to give 8a,b and 9a,b, and the major component of
the diastereomeric mixtures was product 8, having the required configuration at both C-3 and C-4. This
result was ascribed to a thermodynamic vs. kinetic control occurring at the cyclisation stage, and studies
are currently underway in order to obtain a deeper insight about this stereodivergent cyclisation.
With pyrrolidin-2-ones 8a,b in hand, we prepared 3-acetyl pyrrolidin-2-ones 8c,d and 11b by cyclisa-
tion of chiral acyclic amides induced by Mn(III) as previously reported,7a,b in order to check generality
of the reduction outcome on a range of substrates.
Compounds 8a–d were then treated with KBH4 in CH3OH at −15°C (Scheme 4), and 3-hydroxyethyl
derivatives 13a–d were obtained in good yield, together with minor amounts of their diastereomers
14a–d, which were separated easily by silica gel chromatography. On the contrary, when the reaction
was performed under the same conditions by using NaBH4, mixtures of 13 and 14 were recovered in
good yield but with 60:40 d.r.13,14
Scheme 4.
Configuration of the newly formed stereogenic centre of both diastereomers 13a–d and 14a–d was
1
assigned by means of H NMR data supported by molecular mechanic calculations. In fact, in the
minimum energy conformers of compounds 13a and 14a (A and B, respectively), a hydrogen bond links
the hydroxy and the amidic carbonyl groups (Fig. 1).15,16
Figure 1. Minimum energy conformations of compounds 13a (A) and 14a (B)
Thus, in conformer A, H-3 and H-100 are antiperiplanar, in agreement with the large coupling constant
observed in the 1H NMR spectrum of 13a (J=7.9 Hz). On the contrary, in conformer B they lie gauche,
and accordingly the coupling constant observed for 14a has a low value (3.5 Hz). In addition, the observed
deshielding effect of the CHOH proton in 14a with respect to 13a can be ascribed to the presence of a
minor conformer of 14a, in which H-100 lies in the carbonyl plane.17 The same trend was observed even
for coupling constants and chemical shift values of compounds 13b–d and 14b–d, respectively (Table 1).
Thus, on the basis of 1H NMR data, the configuration of the newly introduced stereogenic centre at C-100
for the major diastereomers 13a–d was assigned as S.18,19
Eventually, in order to obtain crystalline compounds suitable for X-ray diffraction analysis, the p-
iodobenzoates 15 and 16 were prepared, and configuration of the stereogenic centre C-100 in 13a was
confirmed as S by X-ray diffraction analysis of 15 (Scheme 5; Fig. 2).20,21

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Table 1
Selected coupling constants (J) and chemical shifts (δ) for the CHOH proton
Scheme 5.
Figure 2. The ORTEP drawing of compound 15

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591
The vicinal coupling constants were not diagnostic for structural assignment of compounds 15 and 16,
their value being 2.8 and 3.5 Hz, respectively. This is in agreement with molecular mechanic calculations
since, in the lowest energy conformation of both diastereomers, H-3 and H-100 lie gauche (Fig. 3). On
the other hand, the chemical shifts showed the same trend observed for compounds 13a and 14a. In
fact, by inspection of the most stable rotamers A0 and B0 of 15 and 16, respectively, only in B0 is H-100
deshielded by the amidic carbonyl group (Fig. 4).15,16,22 Thus, for both 15 and 16 configuration at C-100
can be assigned by inspection of the H-100 chemical shift value.
Figure 3. Minimum energy conformations of compounds 15 (A0) and 16 (B0) (R=p-I-C6H4CO)
Figure 4. re- and si-Attack of the incoming hydride ion to 8a
In order to extend the reliability of this assignment to other derivatives, TBDMS ethers 17 and 18 were
prepared starting from 13d and 14d, respectively, and the same trend as for 15 and 16 was observed for
both coupling constants and chemical shifts (Scheme 6).
Scheme 6.
We then carried out the reduction reaction starting from pyrrolidin-2-ones 11a,b, which only differs
from 8a and 8d, respectively, by the configuration of the stereogenic centre at the phenethyl group. The
reaction proceeded with high diastereoselection, leading mainly to 19a,b, together with minor amounts
of 20a,b (Scheme 7).
Minimum energy conformations for 19a and 20a confirmed the presence of an intramolecular hydro-
gen bond, as for both 13a and 14a.15,16 Moreover, the vicinal coupling constants and chemical shifts of
H-100 of compounds 19a,b and 20a,b showed the same trend observed for 13a,d and 14a,d, respectively
(Table 1). The corresponding derivatives 21a,b and 22a,b were prepared, but crystals suitable for X-
ray diffraction were not obtained, which could usefully result in unambiguous establishment of the
configuration at 100. On the other hand, the values of both coupling constants and chemical shifts for
21a,b and 22a,b were in agreement with those observed for compounds 15, 17 and 16, 18, respectively,

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Scheme 7.
and it seemed reasonable to assume that the configuration at C-100 is S in the major products 19a,b,
the stereoselection of the reduction not being affected by configuration at C-100 of the phenethyl group
(Scheme 8).
Scheme 8.
The stereoselection of the reduction process could eventually be understood by conformational
analysis, since the carbonyl groups of compound 8a lie anti to each other, the anti conformer result
favoured by 2.89 kcal/mol over the syn conformer.15,16 Thus, hydride ion approaches the keto group
from the less hindered re-face, to preferentially give 13a, where the new stereogenic centre has the S
configuration at the hydroxyethyl chain (Fig. 4). On the contrary, when hydride ion approaches from the
si-face of the keto group, leading to 14a, a severe steric interaction occurs, where the attack proceeds
from the concave site of a concave:convex shaped molecule.23
Since in carbapenem (+)-PS-5, 2, an ethyl chain is present, we first studied removal of the hydroxy
group starting from 13a. The corresponding methanesulphonyl derivative 23 was prepared and then
treated with LAH in THF to give 3-ethylpyrrolidin-2-one 24, suitable for conversion into 2 after cleavage
of the phenethyl group and ring contraction (Scheme 9).24
Scheme 9.
Although in pyrrolidin-2-one 13a both the hydroxyethyl chain and the ring centres have the same
configuration as in 1,25 the final task of this work was to invert the configuration at C-100 in order to obtain
products having the same configuration at the hydroxyethyl chain as carbapenem 3a. Thus, starting from
13a, we first carried out an inversion reaction with DEAD–triphenylphosphine to give in good yield 16,26
in which the stereogenic centre at the hydroxyethyl chain has the required R configuration. Otherwise, the

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593
inversion of the stereogenic centre in 13a was performed by treating 21b with the p-iodobenzoate anion
on a polymeric support level.27 In this case, however, 16 was obtained in a lower yield, owing to the
formation of a minor amount of the side product 25, derived from 16 by an anti-elimination process. The
geometry of the double bond of 16, established as Z by 1H NMR data, further confirmed the structural
assignment of 13a (Scheme 10).
Scheme 10.
3. Conclusion
With the method in hand for construction of pyrrolidin-2-ones having three stereogenic centres with
definite configuration, we are currently studying in our laboratory the contraction of the γ-lactam to the β-
lactam ring proceeding via the functionalisation at C-5,28 with the aim of obtaining intermediates suitable
for conversion into both carbapenems 3a and 3b. In addition, further studies are currently underway in
order to modify the stereochemical outcome of the reduction reaction25 and to directly obtain compounds
in which the stereogenic centre at the hydroxyethyl chain has R configuration.
4. Experimental
4.1. General
Melting points were measured on an Electrothermal IA 9000 apparatus and are uncorrected. IR
spectra were recorded in CHCl3 on a Nicolet Fourier Transform Infrared 20-SX spectrophotometer.
Diastereomeric ratios were determined by GC analysis using a Chrompack 9001 instrument equipped
1
with a Chrompack 7720 capillary column (50 m×0.25 mm i.d.; stationary phase CP-Sil-5 CB). H
and 13C NMR spectra were recorded at 200 MHz and 50 MHz, respectively, on a Varian Gemini
200 spectrometer, using CDCl3 as a solvent. Chemical shifts (δ) are reported in ppm relative to TMS
and coupling constants (J) in hertz. Assignments were aided by decoupling and homonuclear two-
dimensional experiments. Optical rotations were measured at 20°C on a Perkin–Elmer 241 polarimeter.
Mass spectra (GC–MS) were obtained by electron impact at 70 eV on a Hewlett–Packard spectrometer
5890, series II, using an HP-5 capillary column (30 m×0.25 mm i.d.; stationary phase 5% phenyl methyl
silicone). Flash chromatography was performed with silica gel 60 (230–400 mesh).

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4.2. Materials
Compounds 8c, 8d and 11b were prepared following the reported procedure.7b
4.3. (3S,4S,10R)-3-Acetyl-1-(10-phenylethyl)-4-(propen-2-yl)pyrrolidin-2-one 8c
[α]D 145.1 (c 1, CHCl3). GC–MS: m/z 271 (M+), 256, 228, 187, 172, 160, 124, 105, 91, 77. Anal.
calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.20; H, 7.81; N, 5.12.
4.4. (3S,4R,10R)-3-Acetyl-4-ethenyl-1-(10 -phenylethyl)pyrrolidin-2-one 8d
[α]D 163.3 (c 1, CHCl3). GC–MS: m/z 257 (M+), 242, 214, 200, 186, 173, 160, 132, 120, 105, 91, 77.
Anal. calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.73; H, 7.4 1; N, 5.48.
4.5. Preparation of 3-oxobutanamides 7a,b and 10
A solution containing the appropriate amine (20 mmol) and N,N-dimethylaminopyridine (0.3 g) in dry
THF (70 ml) at −15°C was slowly added to a solution containing diketene (1.8 g; 22 mmol) in dry THF
(20 ml). After 1 h the solvent was removed under reduced pressure at 20°C and the residue purified by
silica gel chromatography (cyclohexane:ethyl acetate, 7:3) to give amides 7a,b or 10 (rotameric mixtures)
as colourless oils.
4.6. (E,R)-N-(3-Ethoxycarbonyl-2-propenyl)-N-(1-phenylethyl)-3-oxobutanamide 7a
The title compound was obtained in 77% yield as a colourless oil starting from (E,R)-N-(3-
ethoxycarbonyl-2-propenyl)-N-(1-phenylethyl)amine.8 IR: 1725, 1665 cm−1. 1H NMR: 1.24 (t, 3H, 40%,
J=7.1), 1.27 (t, 3H, 60%, J=7.1), 1.50 (d, 3H, 60%, J=6.9), 1.60 (d, 3H, 40%, J=6.9), 2.28 (s, 3H, 60%),
2.31 (s, 3H, 40%), 3.48–3.94 (m, 2H), 3.50 (s, 2H, 60%), 3.71 (s, 2H, 40%), 4.14 (q, 2H, 40%, J=7.1),
4.16 (q, 2H, 60%, J=7.1), 5.05 (q, 1H, 40%, J=6.9), 5.77 (ddd, 1H, J=15.8, J=1.7, J=1.6), 6.08 (q, 1H,
60%, J=6.9), 6.65 (dt, 1H, 60%, J=15.8, J=4.8), 6.73 (dt, 1H, 40%, J=15.8, J=4.8), 7.18–7.42 (m, 5 ArH).
13C NMR: 14.7, 16.7 (40%), 17.1 (60%) 30.3 (40%), 30.9 (60%), 44.1 (40%), 45.2 (60%), 50.7 (60%),
51.9 (40%), 56.8 (60%), 60.8 (40%), 61.2 (60%), 61.9 (40%), 122.7 (40%), 123.1 (60%), 127.1 (60%),
127.3 (40%), 128.0 (60%), 128.3 (40%), 128.5 (40%), 129.2 (60%), 140.0 (40%), 140.3 (60%), 144.2
(40%), 144.6 (60%), 166.1 (60%), 166.5 (40%), 167.1 (40%), 167.8 (60%), 172.1 (40%), 172.7 (60%).
[α]D 112.3 (c 1, CHCl3). GC–MS: m/z 317 (M+), 302, 274, 260, 246, 230, 188, 166, 155, 132, 105, 91,
77. Anal. calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.06; H, 7.22; N, 4.37.
4.7. (E,R)-N-[3-Ethoxycarbonyl-2-butenyl]-N-(1-phenylethyl)-3-oxobutanamide 7b
Starting from (E,R)-N-[3-ethoxycarbonyl-2-buten-1-yl]-N-(1-phenylethyl)amine,8 the title compound
was obtained in 77% yield. IR: 1715, 1701, 1663, 1630 cm−1. 1H NMR: 1.22 (t, 3H, J=7.2, 30%), 1.23
(t, 3H, J=7.2, 70%), 1.49 (d, 3H, J=7.0, 70%), 1.57 (d, 3H, J=7.0, 30%), 1.66 (s, 3H, 70%), 1.92 (s, 3H,
30%), 2.25 (s, 3H, 70%), 2.28 (s, 3H, 30%), 3.46 (s, 2H, 70%), 3.55–3.84 (m, 2H), 3.68 (s, 2H, 30%),
4.10 (q, 2H, J=7.2, 30%), 4.12 (q, 2H, J=7.2, 70%), 5.05 (q, 1H, J=7.2, 30%), 6.05 (q, 1H, J=7.2, 70%),
6.29 (t, 1H, J=6.0, 70%), 6.43 (t, 1H, J=6.0, 30%), 7.15–7.41 (m, 5 ArH). 13C NMR: 12.8 (30%), 12.9
(70%), 14.7 (70%), 16.8 (30%), 18.8 (30%), 22.6 (70%), 30.9, 41.6 (30%), 42.7 (70%), 50.7 (70%), 51.7

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595
(30%), 56.6 (70%), 61.0 (30%), 61.2 (70%), 61.3 (30%), 127.2, 127.3, 127.5, 127.8, 128.0, 128.2, 128.4,
128.7, 129.0, 129.1, 129.3 (70%), 129.8 (30%), 138.6 (70%), 139.0 (30%), 140.0 (30%), 140.3 (70%),
167.1 (30%), 167.4 (70%), 176.3. [α]D 93.6 (c 1, CHCl3). GC–MS: m/z 331 (M+), 316, 288, 230, 202,
180, 152, 126, 105, 77. Anal. calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.81; H, 7.55;
N, 4.18. Anal. calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.83; H, 7.56; N, 4.33.
4.8. (E,S)-N-(3-Ethoxycarbonyl-2-propenyl)-N-(1-phenylethyl)-3-oxobutanamide 10
The title compound was obtained in 77% yield starting from (E,S)-N-(3-ethoxycarbonyl-2-propenyl)-
N-(1-phenylethyl)amine.8 [α]D −111.9 (c 1, CHCl3). Anal. calcd for C18H23NO4: C, 68.12; H, 7.30; N,
4.41. Found: C, 68.08; H, 7.18; N, 4.38.
4.9. Cyclisation of the 3-oxobutanamides 7a,b and 10 with NaH in THF (Method A)8
4.9.1. General procedure
A solution containing amides 7a,b, or 10 (10 mmol) in dry THF (30 ml) was slowly added at −78°C
to a suspension of NaH (0.48 g; 10 mmol; 50% dispersion in mineral oil) in dry THF (20 ml). After
1 h solid NH4Cl (5 g) was added and the temperature raised to 20°C. The mixture was poured into
water (50 ml) and after extraction with ethyl acetate (2×100 ml) and drying (Na2SO4), the organic layer
was evaporated under reduced pressure. The residue was chromatographed by silica gel chromatography
(cyclohexane:ethyl acetate, 7:3) to give 8a, 8b, 9a, 9b, 11a and 12a as colourless oils.
4.10. Ethyl (3S,4R,10R)-[3-acetyl-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]acetate 8a and its isomer
(3R,4S,10R) 9a
Following cyclisation Method A, and starting from 7a, compounds 8a and 9a were obtained in 77%
overall yield as colourless oils. D.r. (3S,4R,10R)-8a:(3R,4S,10R)-9a, 30:70. Isomer (3S,4R,10R)-8a: IR:
1735, 1668 cm−1. 1H NMR: 1.19 (t, 3H, J=6.5), 1.52 (d, 3H, J=7.1), 2.23 (dd, 1H, J=16.2, J=8.4), 2.35
(dd, 1H, J=16.2, J=7.2), 2.44 (s, 3H), 2.58 (dd, 1H, HA, JAB=9.7, JAX=6.1), 3.14 (m, 1H, HX), 3.39 (d,
1H, HY, J=7.2), 3.58 (dd, 1H, HB, JAB=9.7, JBX=8.1), 4.06 (q, 2H, J=6.5), 5.45 (q, 1H, J=7.1), 7.21–7.42
(m, 5 ArH). 13C NMR: 14.6, 16.6, 30.2, 30.8, 38.0, 46.5, 50.1, 61.2, 62.1, 127.6, 128.2, 129.1, 140.0,
168.9, 171.7. [α]D 107.2 (c 1, CHCl3). GC–MS: m/z 317 (M+), 302, 274, 272, 230, 214, 188, 166, 132,
105, 91, 77. Anal. calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.07; H, 7.27; N, 4.37.
Isomer (3R,4S,10R)-9a: IR: 1735, 1670 cm−1. 1NMR: 1.23 (t, 3H, J=6.5), 1.54 (d, 3H, J=7.2), 2.38 (dd,
1H, J=8.5, J=2.8), 2.45 (s, 3H), 2.47 (dd, 1H, J=8.5, J=2.2), 2.95 (dd, 1H, HA, JAB=8.8, JAX=6.3), 3.07
(m, 1H, HX), 3.25 (dd, 1H, HB, JAB=8.8, JBX=7.5), 3.46 (d, 1H, HY, JXY=7.4), 5.42 (q, 1H, J=7.2),
7.22–7.41 (m, 5 ArH). 13C NMR: 14.6, 16.7, 30.3, 30.8, 38.1, 46.5, 50.0, 61.2, 61.9, 127.3, 128.1, 129.1,
139.9, 169.0, 171.7. [α]D 130.6 (c 1, CHCl3). GC–MS: m/z 317 (M+), 302, 274, 272, 230, 214, 188, 166,
132, 105, 91, 77. Anal. calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.16; H, 7.27; N,
4.45.
4.11. Ethyl (2RS,30S,40R,100R)-2-[30-acetyl-20-oxo-10-(100-phenylethyl)pyrrolidin-40 -yl]propanoate 8b
and its isomer (2RS,30R,40S,100R) 9b
Following cyclisation Method A, and starting from 7b, diastereomers 8b and 9b were obtained in
76% overall yield as colourless oils. D.r. (2RS,30S,40R,100R)-8b:(2RS,30S,40R,100S)-9b, 30:70. (2RS) ratio

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(unassigned): 70:30. IR: 1725, 1710, 1668 cm−1. Isomer (2RS,30S,40R,100R)-8b: 1H NMR: 1.09 (d, 3H,
70%, J=7.1), 1.10 (d, 3H, 30%, J=7.0), 1.22 (t, 3H, 70%, J=7.1), 1.23 (t, 3H, 30%, J=7.1), 1.51 (d,
3H, 70%, J=7.1), 1.52 (d, 3H, 30%, J=7.1), 2.38–2.52 (m, 1H), 2.42 (s, 3H, 30%), 2.44 (s, 3H; 70%),
2.90–3.19 (m, 3H, HA+HB+HX), 3.56 (d, 1H, HY, 30%, J=7.2), 3.61 (d, 1H, HY, 70%, J=7.2), 4.06 (q,
2H, 30%, J=7.1), 4.07 (q, 2H, 70%, J=7.2), 5.40 (q, 1H, 30%, J=7.1), 5.41 (q, 1H, 70%, J=7.1), 7.15–7.38
(m, 5 ArH). 13C NMR: 14.6 (70%), 14.7 (30%), 14.9 (70%), 15.2 (30%), 16.6, 30.9 (30%), 31.0 (70%),
35.6 (30%), 36.1 (70%), 42.4 (30%), 43.0 (70%), 44.5 (30%), 44.8 (70%), 49.9 (70%), 50.0 (30%),
60.2 (30%), 60.5 (70%), 61.2 (30%), 61.3 (70%), 127.3, 128.1, 129.1, 139.9, 169.2 (30%), 169.3 (70%),
174.7, 203.7 (30%), 203.8 (70%). Anal. calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C,
68.81; H, 7.57; N, 4.20. Isomer (2RS,30R,40S,100R)-9b: 1H NMR: 0.97 (d, 3H, J=7.0), 1.13 (t, 3H, 70%,
J=7.1), 1.15 (t, 3H, 30%, J=7.1), 1.48 (d, 3H, 70%, J=7.2), 1.49 (d, 3H, 30%, J=7.2), 2.34 (dq, 1H, J=7.1,
J=7.5), 2.42 (s, 3H, 30%), 2.45 (s, 3H, 70%), 2.63 (dd, 1H, HA, 70%, JAX=6.3, JAB=9.9), 2.64 (dd, 1H,
HA, 30%, JAX=6.8, JAB=9.8), 2.87–3.20 (m, 1H, HX), 3.43 (dd, 1H, HB, 30%, J=8.6, J=9.8), 4.34 (dd,
1H, HB, 30%, JBX=8.6, JAB=9.7), 3.47 (dd, 1H, HB, 70%, JBX=8.8, JAB=9.8), 3.51 (d, 1H, HY, 70%,
J=7.2), 3.55 (d, 1H, HY, 30%, J=7.2), 3.98 (q, 2H, 30%, J=7.1), 4.00 (q, 2H, 70%, J=7.1), 5.41 (q, 1H,
70%, J=7.2), 5.42 (q, 1H, J=7.2), 7.19–7.38 (m, 5 ArH). 13C NMR: 14.6, 14.8 (30%), 14.9 (70%), 16.6,
31.0, 35.4 (70%), 36.0 (30%), 42.5 (70%), 42.8 (30%), 44.5 (30%), 44.9 (70%), 50.1 (30%), 50.2 (70%),
60.0 (70%), 60.7 (30%), 61.1 (30%), 61.2 (70%), 127.6, 128.2, 129.1, 139.9, 168.9 (70%), 169.2 (30%),
174.7, 203.7. GC–MS: m/z 331 (M+), 318, 302, 274, 230, 202, 133, 126, 120, 105, 91, 77. Anal. calcd
for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.79; H, 7.55; N, 4.19.
4.12. Ethyl (3S,4R,10S)-[3-acetyl-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]acetate 11a and its isomer
(3R,4S,10S) 12a
Following cyclisation Method A, and starting from 10, compounds 11a and 12a were obtained as
colourless oils, in 77% overall yield. D.r. (3S,4R,10S)-10a:(3R,4S,10S)-11a, 72:28. Isomer (3S,4R,10S)-
11a: [α]D −129.2 (c 1, CHCl3). Isomer (3R,4S,10S)-12a: [α]D −106.5 (c 1, CHCl3). GC–MS: m/z 317
(M+), 302, 274, 272, 230, 214, 188, 166, 132, 105, 91, 77. Anal. calcd for C18H23NO4: C, 68.12; H, 7.30;
N, 4.41. Found: C, 68.06; H, 7.26; N, 4.37.
4.13. Cyclisation of amides 7a,b with sodium ethoxide in ethanol (Method B)
4.13.1. General procedure
To a solution containing amides 7a,b (20 mmol) in dry ethanol (30 ml) was slowly added at −78° a
solution containing sodium ethoxide [20 mmol; prepared by dissolving Na (480 mg; 20 mmol) in dry
ethanol (20 ml)]. After 1 h, solid NH4Cl (5.0 g) was added and the temperature raised to 20°C. After
addition of water (50 ml), the mixture was extracted with ethyl acetate (3×100 ml) and dried (Na2SO4).
The solvent was evaporated under reduced pressure and the residue purified by silica gel chromatography,
to give pyrrolidin-2-ones 8a,b and 9a,b as colourless oils.
4.14. Ethyl (3S,4R,10R)-[3-acetyl-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]acetate 8a and its isomer
(3R,4S,10R) 9a
Following cyclisation Method B, and starting from 7a, compounds 8a and 9a were obtained in 80%
overall yield as colourless oils. D.r. (3S,4R,10R)-8a:(3R,4S,10R)-9a, 85:15. Isomer (3S,4R,10R)-8a: [α]D
107.2 (c 1, CHCl3). GC–MS: m/z 317 (M+), 302, 274, 272, 230, 214, 188, 166, 132, 105, 91, 77. Anal.

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597
calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.12; H, 7.30; N, 4.39. Isomer (3R,4S,10R)-
9a: [α]D 130.6 (c 1, CHCl3). GC–MS: m/z 317 (M+), 302, 274, 272, 230, 214, 188, 166, 132, 105, 91,
77. Anal. calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.15; H, 7.25; N, 4.38.
4.15. Ethyl (2RS,30S,40R,100R)-2-[30-acetyl-20-oxo-10-(100-phenylethyl)pyrrolidin-40 -yl]propanoate 8b
and its isomer (2RS,30R,40S,100R) 9b
Following cyclisation Method B, and starting from 7b, diastereomers 8b and 9b were obtained in
84% overall yield as colourless oils. D.r. (2RS,30S,40R,100R)-8b:(2RS,30S,40R,100S)-9b, 80:20. (2RS) ratio
(unassigned): 70:30. Isomer (2RS,30S,40R,100R)-8b: GC–MS: m/z 331 (M+), 318, 302, 274, 230, 202, 133,
126, 120, 105, 91, 77. Anal. calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.80; H, 7.58;
N, 4.24. Isomer (2RS,30S,40R,100S)-9b: GC–MS: m/z 331 (M+), 318, 302, 274, 230, 202, 133, 126, 120,
105, 91, 77. Anal. calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.82; H, 7.56; N, 4.20.
4.16. Reduction of pyrrolidin-2-ones 8a–d and 14a,b
4.16.1. General procedure
To a solution containing pyrrolidin-2-ones 4a–d or 11a,b (10 mmol) in dry methanol (50 ml) at −15°C,
KBH4 (0.7 g; 10 mmol) was added and the mixture stirred for 1 h. Then solid NH4Cl (2.0 g) and H2O
(40 ml) were added and the mixture extracted with ethyl acetate (3×100 ml). After drying (Na2SO4)
and removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (ethyl
acetate) to give diastereomeric alcohols 13 and 14 or 19 and 20 as colourless oils.
4.17. Ethyl (3S,4R,10R,100S)-[3-(100-hydroxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]acetate 13a
and its (3S,4R,100R,100R) isomer 14a
By reduction of 8a, a 95:5 diastereomeric mixture of 13a and 14a was obtained in 90% overall yield.
GC–MS: m/z 319 (M+), 304, 274, 260, 188, 132, 105, 91, 77. Isomer (3S,4R,10R,100S)-13a: IR: 3415,
1725, 1673 cm−1. 1H NMR: 1.20 (d, 3H, J=6.2), 1.21 (t, 3H, J=7.0), 1.50 (d, 3H, J=7.0), 2.08–2.22 (m,
1H), 2.25–2.45 (m, 2H), 2.55–2.73 (m, 1H), 2.97 (dd, 1H, HA, JAX=6.2, JAB=10.0), 3.24 (dd, 1H, HB,
JBX=7.9, JAB=10.0), 3.89 (dq, 1H, J=6.2, J=7.9), 4.70 (br s, 1H, OH), 5.45 (q,1H, J=7.0), 7.15–7.39 (m,
5 ArH). 13C NMR: 14.6, 16.7, 21.2, 31.0, 39.3, 47.4, 49.5, 53.6, 61.3, 69.6, 127.4, 128.1, 129.1, 129.2,
140.1, 172.1, 175.4. [α]D 108.8 (c 1, CHCl3). Isomer (3S,4R,10R,100R)-14a: IR: 3425, 1735, 1670 cm−1.
1H NMR: 1.23 (t, 3H, J=7.2), 1.24 (d, 3H, J=6.4), 1.51 (d, 3H, J=7.0), 2.25–2.66 (m, 3H), 2.98 (dd, 1H,
HA, JAX=5.8, JAB=10.3), 3.26 (dd, 1H, HB, JBX=7.5, JAB=10.3), 3.75 (br s, 1H, OH), 4.11 (q, 2H, J=7.2),
4.17 (dq, 1H, J=6.4, J=3.5), 5.49 (q, 1H, J=7.0), 7.19–7.41 (m, 5 ArH). 13C NMR: 14.8, 16.5, 20.8, 31.2,
39.6, 47.5, 50.0, 53.4, 61.2, 69.5, 127.4, 128.3, 129.1, 129.4, 140.2, 172.0, 175.6. [α]D 98.6 (c 1, CHCl3).
Anal. calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.66; H, 7.83, N, 4.41.
4.18. Ethyl (2RS,30S,40S,100R,1000S)-2-[30-(1000-hydroxyethyl)-10 -(100-phenylethyl)-20-oxopyrrolidin-
40-yl]propanoate 13b and its (2RS,30S,40S,100R,1000R) isomer 14b
By reduction of 8b, compounds 13b and 14b were obtained in 82% overall yield and d.r. 95:5. The
stereocentre at C-2 was present as unassigned configurational mixture RS 70:30. GC–MS: m/z 333 (M+),
318, 288, 274, 214, 188, 172, 132, 120, 110, 105, 91. Isomer (2RS,30S,40S,100R,1000S)-13b: IR: 3418,
1
1722, 1670 cm−1. H NMR: 1.14 (d, 3H, 70%, J=7.1), 1.15 (d, 3H, 30%, J=7.1), 1.21 (d, 3H, J=6.3),

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1.25 (t, 3H, J=7.1), 1.51 (d, 3H, 70%, J=7.1), 1.52 (d, 3H, 30%, J=7.1), 2.15–2.45 (m, 2H, H+HY),
2.51–2.73 (m, 1H, HX), 2.98 (dd, 1H, 70%, HB, JBX=8.9, JAB=10.1), 2.99 (dd, 1H, 70%, HB, JBX=8.9,
JAB=10.2), 3.11 (dd, 1H, 30%, HA, JAX=5.5, JAB=10.2), 3.18 (dd, 1H, 70%, HA, JAX=5.5, JAB=10.2),
3.87 (dq, 1H, J=6.3, J=7.0), 4.09 (q, 2H, 30%, J=7.1), 4.13 (q, 2H, 70%, J=7.1), 4.27 (br s, 1H, OH), 5.48
(q, 1H, J=7.1), 7.21–7.41 (m, 5 ArH). 13C NMR: 12.7 (30%), 14.6 (30%), 14.7 (70%), 15.4 (70%), 16.3,
16.4, 21.1, 35.5 (30%), 36.7 (70%), 42.2 (70%), 42.5 (70%), 43.3 (30%), 44.3 (70%), 49.4, 52.2, 61.2,
69.4, 127.4, 128.1, 129.1, 140.0, 174.8, 175.1 (70%), 175.2 (30%). Isomer (2RS,30S,40S,100R,1000R)-14b:
1
IR: 3418, 1722, 1670 cm−1. H NMR: 0.91 (d, 3H, 30%, J=7.0), 1.02 (d, 3H, 70%, J=7.0), 1.09 (t,
3H, 70%, J=7.1), 1.18 (t, 3H, 30%, J=7.1), 1.25 (d, 3H, J=6.3), 1.49 (d, 3H, 70%, J=7.2), 1.50 (d, 3H,
30%, J=7.2), 2.21–2.54 (m, 3H, H+HX+HY), 2.71 (dd, 1H, HA, JAX=4.7, JAB=10.1), 3.39 (dd, 1H, HB,
J
BX=8.6, JAB=10.1), 3.87–4.06 (m, 3H), 4.10 (br s, 1H, OH), 5.44 (q, 1H, J=7.2), 7.18–7.39 (m, 5 ArH).
13C NMR: 13.1 (30%), 14.5, 14.8 (70%), 16.4, 21.0, 35.4 (30%), 36.5 (70%), 42.2 (30%), 42.7 (70%),
42.9 (30%), 45.1 (70%), 49.7, 52.2 (70%), 52.4 (30%), 61.0, 69.2, 127.5, 128.1, 129.0, 139.9, 174.9,
175.0. Anal. calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.39; H, 8.14; N, 4.16.
4.19. (3S,4S,10R,100S)-3-(100-Hydroxyethyl)-1-(10 -phenylethyl)-4-(propen-2-yl)pyrrolidin-2-one 13c
and its (3S,4S,10R,100R) isomer 14c
By reduction of 8c, diastereomers 13c and 14c were obtained in 85% overall yield and d.r. 96:4.
GC–MS: m/z 273 (M+), 258, 240, 189, 174, 162, 124, 105, 91, 77. Isomer (3S,4S,10R,100S)-13c: IR:
1
3425, 1670, 900 cm−1. H NMR: 1.17 (d, 3H, J=6.2), 1.52 (d, 3H, J=7.2), 1.72 (s, 3H), 2.40–2.65 (m,
2H, HX+HY), 2.95–3.11 (m, 2H, HA+HB), 3.83 (dq, 1H, J=6.2, J=7.1), 4.84 (m, 2H), 5.16 (br s, 1H,
OH), 5.48 (q, 1H, J=7.2), 7.21–7.41 (m, 5 ArH). 13C NMR: 16.6, 19.7, 21.0, 43.6, 46.2, 49.4, 51.0, 70.3,
114.3, 127.3, 128.1, 129.1, 140.2, 143.7, 176.0. [α]D 89.7 (c 0.5, CHCl3). Anal. calcd for C17H22NO2: C,
74.97; H, 8.14; N, 5.14. Found: C, 74.93; H, 8.11; N, 5.10. Isomer (3S,4S,10R,100R)-14c: IR: 3425, 1670,
915 cm-1. 1H NMR: 1.15 (d, 3H, J=6.2), 1.50 (d, 3H, J=7.2), 1.72 (s, 3H), 2.40–2.65 (m, 2H, HX+HY),
2.95–3.11 (m, 2H, HA+HB), 4,21 (dq, 1H, J=6.2, J=3.6), 4.84 (m, 2H), 5.20 (br s, 1H, OH), 5.48 (q,
1H, J=7.2), 7.21–7.41 (m, 5 ArH). 13C NMR: 16.7, 19.7, 21.2, 43.6, 46.4, 49.6, 51.2, 70.3, 114.5, 127.4,
128.3, 129.2, 140.4, 143.3, 176.7. [α]D 92.1 (c 0.5, CHCl3). Anal. calcd for C17H22NO2: C, 74.97; H,
8.14; N, 5.14. Found: C, 74.91; H, 8.09; N, 5.08.
4.20. (3S,4R,10R,100S)-4-Ethenyl-3-(100-hydroxyethyl)-1-(10 -phenylethyl)pyrrolidin-2-one 13d and its
(3S,4R,10R,100R) isomer 14d
By reduction of 8d, diastereomers 13d and 14d were obtained in 86% overall yield and d.r. 93:7.
GC–MS: m/z 259 (M+), 244, 226, 214, 200, 172, 132, 105, 91, 77. Isomer (3S,4R,10R,100S)-13d: IR:
1
3352, 1665, 905 cm−1. H NMR: 1.20 (d, 3H, J=6.2), 1.53 (d, 3H, J=7.1), 2.28 (dd, 1H, J=8.8, J=8.7),
2.44–2.64 (m, 1H), 3.03 (dd, 1H, HA, JAX=9.9, JAB=12.3), 3.07 (dd, 1H. HB, JBX=9.7, JAB=12.3), 3.87
(dq, 1H, J=6.2, J=8.7), 4.55 (br s, 1H, OH), 5.04–5.16 (m, 2H), 5.46 (q, 1H, J=7.1), 5.75 (ddd, 1H, J=8.3,
J=9.9, J=17.3), 7.22–7.43 (m, 5 ArH). 13C NMR: 16.6, 21.7, 40.9, 46.9, 49.5, 53.6, 70.2, 118.0, 127.4,
128.2, 129.2, 138.8, 140.2, 176.1. [α]D 153.1 (c 1, CHCl3). Anal. calcd for C16H21NO2: C, 74.10; H,
8.16; N, 5.40. Found: C, 74.04, H, 8.12; N, 5.34. Isomer (3S,4R,10R,100R)-14d: IR: 3350, 1668, 901
1
cm−1. H NMR: 1.24 (d, 3H, J=6.7), 1.53 (d, 3H, J=7.1), 2.59 (dd, 1H, J=3.5, J=9.5), 2.71–2.94 (m,
1H), 2.97–3.06 (m, 2H, HA+HB), 3.10 (br s, 1H, OH), 4.25 (dq, 1H, J=6.7, J=3.5), 5.15–5.03 (m, 2H),
5.49 (q, 1H, J=7.1), 5.77 (ddd, 1H, J=8.0, J=10.0, J=17.1), 7.21–7.42 (m, 5 ArH). 13C NMR: 16.7, 20.1,

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599
38.6, 46.8, 49.4, 54.0, 66.8,117.4, 127.3, 127.4, 127.6, 128.0, 129.1,138.9, 140.4, 174.7. [α]D 130.3 (c
1, CHCl3). Anal. calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.06; H, 8.20; N, 5.36.
4.21. Ethyl (3S,4S,10S,100S)-[3-(100-hydroxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]acetate 19a
and its (3S,4S,10S,100R) isomer 20a
By reduction of 11a, diastereomers 19a and 20a were obtained in 90% overall yield and d.r. 95:5.
GC–MS: m/z 319 (M+), 304, 286, 274, 260, 188, 170,132, 105, 91, 77. Isomer (3S,4S,10S,100S)-19a: IR:
3425, 1728, 1668 cm−1. 1H NMR: 1.20 (t, 3H, J=7.1), 1.25 (d, 3H, J=6.3), 1.53 (d, 3H, J=7.1), 2.01–2.31
(m, 2H), 2.34–2.48 (m, 1H, HX), 2.51–2.68 (m, 2H, HA+HY), 3.59 (dd, 1H, HB, JBX=8.0, JAB=9.9), 3.94
(dq, 1H, J=6.3, J=8.1), 4.07 (q, 2H, J=7.1), 4.71 (br s, 1H, OH), 5.47 (q, 1H, J=7.1), 7.19–7.38 (m, 5
ArH). 13C NMR: 14.6, 16.7, 21.2, 31.1, 39.2, 47.4, 49.7, 53.7, 61.2, 69.5, 127.6, 128.2, 129.1, 139.9,
1
172.1, 175.3. [α]D −137.6 (c 1, CHCl3). Isomer (3S,4S,10S,100R)-20a: IR: 3433, 1725, 1665 cm−1. H
NMR: 1.20 (t, 3H, J=7.1), 1.27 (d, 3H, J=6.5), 1.53 (d, 3H, J=7.1), 2.06 (br s, 1 H, OH), 2.25 (dd, 1H,
J=8.8, J=16.3), 2.35–2.71 (m, 4H, H+HA+HX+HY), 3.57 (m, 1H, HB), 4.07 (q, 2H, J=7.1), 4.19 (dq, 1H,
J=4.0, J=6.5), 5.49 (q, 1H, J=7.1), 7.20–7.41 (m, 5 ArH). 13C NMR: 14.6, 16.6, 20.4, 30.0, 39.3, 47.5,
49.7, 54.5, 61.2, 67.4, 127.6, 128.1, 128.8, 129.1, 140.0, 172.1, 174.6. [α]D −148.3 (c 1, CHCl3). Anal.
calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.64; H, 7.81; N, 4.44.
4.22. (3S,4R,10S,100S)-4-Ethenyl-3-(100-hydroxyethyl)-1-(10 -phenylethyl)pyrrolidin-2-one 19b and its
(3S,4R,10S,100R) isomer 20b
By reduction of 11b, diastereomers 19b and 20b were obtained in 90% overall yield and d.r. 95:5.
GC–MS: m/z 259 (M+), 244, 226, 214, 200, 172, 132, 105, 91, 77. Isomer (3S,4R,10S,100S)-19b: IR:
3435, 1670, 903 cm−1. 1H NMR: 1.21 (d, 3H, J=6.5), 1.42 (br s, 1H, OH), 1.55 (d, 3H, J=7.0), 2.20 (dd,
1H, HY, J=8.1 J=9.2), 2.56–2.75 (m, 2H, HX+HA), 3.28–3.44 (m, 1H, HB), 3.90 (dq, 1H, J=6.5, J=8.0),
5.02–5.18 (m, 2H), 5.48 (q, 1H, J=7.0), 5.66 (ddd, 1H, J=17.1, J=10.1, J=8.0), 7.21–7.42 (m, 5 ArH).
13C NMR: 16.8. 21.6, 40.7, 46.8, 49.7, 53.7, 69.9, 117.7, 127.6, 128.2, 129.1, 138.8, 139.8, 175.9. [α]D
−103.6 (c 1, CHCl3). Anal. calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.03; H. 8.11;
1
N, 5.35. Isomer (3S,4R,10S,100R)-20b: IR: 3430, 1675, 905 cm−1. H NMR: 1. 25 (d, 3H, J=6.5), 1.54
(d, 3H, J=7.0), 2.48 (dd, 1H, HY, J=9.1, J=3.4), 2.64 (dd, 1H, HA, JAX=8.0, JAB=9.5), 2.81–3.01 (m, 1H,
HX), 3.14 (br s, 1H, OH), 3.37 (dd, 1H, HB, JBX=8.4, JAB=9.5), 4.28 (dq, 1H, J=6.5, J=9.1), 4.98–5.16
(m, 2H), 5.50 (q, 1H, J=7.0), 5.67 (ddd, 1H, J=17.1, J=10.1, J=8.2), 7.21–7.42 (m, 5 ArH). 13C NMR:
16.8, 20.6, 37.8, 46.9, 49.7, 54.7, 66.6, 116.8, 127.6, 128.1, 129.1, 139.5, 140.1, 174.7. [α]D −114.3 (c
0.3, CHCl3). Anal. calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.05; H. 8.13; N, 5.33.
4.23. Synthesis of p-iodobenzoates 15, 16, 21a and 22a
4.23.1. General procedure
To a solution containing compounds 13a, 14a, 19a or 20a (5 mmol), triethylamine (0.7 ml) and DMAP
(100 mg) in ethyl acetate (50 ml) at rt, was added a solution di p-iodobenzoyl chloride (1.4 g; 5 mmol)
in ethyl acetate (20 ml). After 12 h the mixture was poured into H2O (50 ml) and extracted with ethyl
acetate (3×100 ml). After drying (Na2SO4) and removal of the solvent at reduced pressure, the residue
was purified by silica gel chromatography (cyclohexane:ethyl acetate, 50:50) to give esters 15, 16, 21a
or 22a as white solids.

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4.24. Ethyl (3S,4R,10R,100S)-[3-(100-p-iodobenzoyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]-
acetate 15
The title compound was obtained in 78% yield starting from 13a. M.p. 78–80°C. IR: 1718, 1663, 1654
1
cm−1. H NMR: 1.24 (t, 3H, J=7.2), 1.50 (d, 3H, J=6.5), 1.52 (d, 3H, J=7.2), 2.36–2.68 (m, 4H), 2.99
(dd, 1H, HB, JBX=5.4, JAB=9.9), 3.24 (dd, 1H, HA, JAX=7.6, JAB=9.9), 4.00 (q, 2H, J=7.2), 5.52 (dq, 1H,
J=2.8, J=6.5), 5.54 (q, 1H, J=7.2), 7.32 (m, 5 ArH), 7.57 (d, 2ArH, J=8.5), 7.73 (d, 2 ArH, J=8.5). 13C
NMR: 14.6, 16.6, 17.4, 31.1, 39.0, 46.8, 49.4, 52.1, 61.3, 71.9, 101.3, 127.5, 128.1, 129.1, 130.1, 131.5,
138.2, 140.4, 165.8, 171.7, 171.9. [α]D 126.3 (c 1, CHCl3). GC–MS: m/z 549 (M+), 504, 318, 286, 274,
231, 132, 105, 77. Anal. calcd for C25H28NO5I: C, 54.65; H, 5.14; N, 2.55. Found: C, 54.61; H, 5.12; N,
2.53.
4.25. X-Ray crystal structure analysis for 15
Crystal data: C25H28INO5, MW=549.91. Monoclinic. Space group P212121(#19), a=7.973(1) Å,
b=13.504(2) Å, c=23.192(2) Å, β=98.53(1)°, V=744.5(3) Å3, Z=4, D(calc)=1.46 g/cm3. Reflections
(3439) were collected on a CAD4 Enraf–Nonius single crystal diffractometer at room temperature by
ω scan technique using graphite-monochromated MoKα radiation (λ=0.71073 Å). The structure was
solved using direct methods and refined through a full-matrix least-squares method with unit weights
for 2382 observed reflections with I≥3σ(I). Non-hydrogen atoms were treated anisotropically.20 The
hydrogen atoms were calculated from the carbon positions and added as fixed contributions with isotropic
thermal parameters of 1.3 times the value of Beq of the atoms to which they are attached. R=0.047 and
Rw=0.040.21 The ORTEP drawing is shown in Fig. 2 together with the atom numbering system.29
4.26. Ethyl (3S,4R,10R,100R)-[3-(100-p-iodobenzoyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]-
acetate 16
The title compound was obtained in 69% yield starting from 14a. M.p. 88–90°C. IR: 1718, 1661, 1657
1
cm−1. H NMR: 1.24 (t, 3H, J=7.2), 1.45 (d, 3H, J=6.5), 1.48 (d, 3H, J=7.2), 2.46 (dd, 1H, HY, J=3.5,
J=5.6), 2.47 (dd, 1H, J=8.3, J=16.1), 2.71–2.88 (m, 1H, HX), 3.02 (dd, 1H, HA, JAX=4.6, JAB=10.1),
3.30 (dd, 1H, HB, JBX=8.2, JAB=10.1), 5.46 (q, 1H, J=7.2), 5.61 (dq, 1H, J=6.5, J=3.5), 6.98–7.24 (m, 5
ArH), 7.49 (d, 2H, J=8.5), 7.68 (d, 2H, J=8.5). 13C NMR: 14.7, 16.4, 18.6, 29.5, 40.4, 47.4, 49.4, 53.5,
61.3, 71.5, 101.1, 127.4, 128.0, 128.9, 130.1, 131.4, 138.2, 139.9, 165.3, 172.0, 172.1. [α]D 133.2 (c 1,
CHCl3). GC–MS: m/z 549 (M+), 504, 318, 286, 274, 231, 132, 105, 77. Anal. calcd for C25H28NO5I: C,
54.65; H, 5.14; N, 2.55. Found: C, 54.59; H, 5.10; N, 2.56.
4.27. Ethyl (3S,4R,10S,100S)-[3-(100-p-iodobenzoyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]-
acetate 21a
The title compound was obtained in 66% yield starting from 19a. M.p. 78–80°C. IR: 1715, 1660, 1655
cm−1. 1H NMR: 1.18 (t, 3H, J=7.1), 1.53 (d, 3H, J=6.6), 1.54 (d, 3H, J=7.1), 2.28 (dd, 1H, J=8.5, J=16.1),
2.44–2.73 (m, 4H, H+HA+HX+HY), 3.52 (dd, 1H, HB, J=7.2, J=9.3), 4.06 (q, 2H, J=6.6), 5.53 (dq, 1H,
J=6.6, J=2.8), 5.55 (q, 1H, J=7.1), 7.22–7.41 (m, 5 ArH), 7.71 (d, 2H, J=8.5), 7.80 (d, 2H, J=8.5). 13C
NMR: 14.6, 16.7, 17.4, 31.2, 39.0, 46.9, 52.4, 61.2, 72.0, 101.4, 127.6, 128.2, 129.1, 131.5, 138.2, 140.5,
165.7, 171.6, 171.8. [α]D −32.6 (c 1, CHCl3). GC–MS: m/z 549 (M+), 504, 318, 286, 274, 231, 132, 105,
77. Anal. calcd for C25H28NO5I: C, 61.86; H, 5.81; N, 2.89. Found: C, 61.81; H, 5.77; N, 2.85.

R. Galeazzi et al. / Tetrahedron: Asymmetry 10 (1999) 587–605
601
4.28. Ethyl (3S,4R,10S,100R)-[3-(100-p-iodobenzoyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]-
acetate 22a
The title compound was obtained in 64% yield starting from 20a. M.p. 87–89°C. IR: 1712, 1664, 1658
cm−1. 1H NMR: 1.18 (t, 3H, J=7.1), 1.48 (d, 3H, J=6.5), 1.51 (d, 3H, J=7.1), 2.24 (dd, 1H, J=8.5, J=16.3),
2.42–2.71 (m, 4H, H+HA+HX+HY), 3.57 (dd, 1H, HB, J=7.2, J=9.2), 4.06 (q, 2H, J=6.6), 5.24 (q, 1H,
J=7.1), 5.63 (dq, 1H, J=6.5, J=3.3), 7.21–7.42 (m, 5 ArH), 7.73 (d, 2H, J=8.6), 7.81 (d, 2H, J=8.6). 13
C
NMR: 14.6, 16.5, 17.6, 30.5, 40.2, 47.3, 52.6, 62.3, 72.4, 101.6, 128.2, 128.4, 129.4, 130.9, 138.4, 141.2,
166.3, 171.4, 172.1. [α]D −117.8 (c 1, CHCl3). GC–MS: m/z 549 (M+), 504, 318, 286, 274, 231, 132,
105, 77. Anal. calcd for C25H28NO5I: C, 61.86; H, 5.81; N, 2.89. Found: C, 61.90; H, 5.75; N, 2.93.
4.29. Preparation of t-butyldimethylsilyl ethers 17 and 18
4.29.1. General procedure
To a solution containing either compound 13a or 14a (1.3 g; 5 mmol), triethylamine (0.5 g; 5
mmol) and imidazole (0.35 g; 5 mmol) in dichloromethane (20 ml) at 0°C, was added a solution of
t-butyldimethylsilyl chloride (0.75 g; 5 mmol) in dichloromethane (10 ml). After 12 h the mixture was
poured into H2O (20 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was dried
(Na2SO4) and after removal of the solvent under reduced pressure, the residue was purified by silica gel
chromatography (cyclohexane:ethyl acetate, 70:30) to give ethers 17 and 18, respectively, as colourless
oils.
4.30. (3S,4R,10R,100S)-3-(100-t-Butyldimethylsilyloxyethyl)-4-ethenyl-1-(10 -phenylethyl)pyrrolidin-
2-one 17
1
The title compound was obtained in 78% yield starting from 13a. IR (CHCl3): 1668, 904 cm−1. H
NMR: 0.04 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.22 (d, 3H, J=6.4), 1.51 (d, 3H, J=7.0), 2.47 (dd, 1H, J=3.5,
J=7.4), 2.81–3.01 (m, 1H), 3.02–3.06 (m, 2H), 4.27 (dq, 1H, J=3.5, J=6.4), 4.95–5.10 (m, 2H), 5.49 (q,
1H, J=7.0), 5.81 (ddd, 1H, J=6.7, J=9.5, J=17.1), 7.22–7.37 (m, 5 ArH). 13C NMR: 16.4, 18.5, 20.5,
26.3, 37.7, 46.4, 49.1, 55.6, 68.2, 115.7, 127.5, 127.7, 127.9, 128.9, 140.1, 140.6, 173.3. [α]D 88.4 (c 1,
CHCl3). GC–MS: m/z 374 (MH+). 358, 316, 259, 212, 168, 105, 91,77. Anal. calcd for C22H35NO2Si:
C, 70.73; H, 9.44; N, 3.75. Found: C, 70.68; H, 9.41; N, 3.80.
4.31. (3R,4S,10S,100S)-3-(100-t-Butyldimethylsilyloxyethyl)-4-ethenyl-1-(10 -phenylethyl)pyrrolidin-
2-one 13
The title compound was obtained in 79% yield starting from 14a. IR: 1668, 904 cm−1. 1H NMR: 0.00
(s, 3H), 0.06 (s, 3H), 0.82 (s, 3H), 1.17 (d, 3H, J=6.6), 1.50 (d, 3H, J=7.1), 2.27 (dd, 1H, J=1.8, J=8.3),
2.97 (dd, 1H, J=8.8, J=8.7), 3.07 (dd, 1H, J=9,3, J=8.7), 3.09–3.28 (m, 1H), 4.54 (dq, 1H, J=1.8, J=6.6),
4.99–5.15 (m, 2H), 5.44 (q, 1H, J=7.1), 5.82 (ddd, 1H, J=8.1, J=10.1, J=17.2), 7.22–7.38 (m, 5 ArH).
13C NMR: −4.3, −4.0, 16.8, 23.1, 26.3, 35.9, 47.0, 49.8, 55.8, 67.0, 116.3, 127.7, 127.8, 128.9, 140.5,
141.0, 173.9. [α]D 58.6 (c 1, CHCl3). GC–MS: m/z 374 (MH+), 358, 316, 259, 212, 168, 105, 91,77.
Anal. calcd for C22H35NO2Si: C, 70.73; H, 9.44; N, 3.75. Found: C, 70.76; H, 9.39; N, 3.71.

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R. Galeazzi et al. / Tetrahedron: Asymmetry 10 (1999) 587–605
4.32. Preparation of p-toluenesulphonates 21b and 22b
4.32.1. General procedure
To a solution containing either compound 19a or 20a (1.6 g; 5 mmol) in pyridine (10 ml) at 0°C,
was added a solution of p-toluenesulphonyl chloride (0.96 g; 5 mmol) in pyridine (5 ml). After 12 h the
mixture was poured into H2O (10 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was
subsequently washed with 2 M HCl and then dried (Na2SO4). After removal of the solvent under reduced
pressure, the residue was purified by silica gel chromatography (cyclohexane:ethyl acetate, 50:50) to give
p-toluenesulphonates 21b and 22b, respectively, as colourless oils.
4.33. Ethyl (3S,4R,10S,100S)-[2-oxo-1-(10 -phenylethyl)-3-(100 -p-toluenesulphonyloxyethyl)pyrrolidin-4-
yl]acetate 21b
Starting from 19a, the title product was obtained in 81% yield. IR: 1725, 1671 cm−1. 1H NMR: 1.21 (t,
3H, J=7.2), 1.26 (d, 3H, J=6.5), 1.47 (d, 3H, J=7.1), 2.22 (dd, 1H, J=8.7, J=16.5), 2.44 (s, 3H), 2.46–2.81
(m, 4H, H+HA+HX+HY), 3.55 (dd, 1H, HB, JBX=7.9, JAB=9.8), 4.08 (q, 2H, J=7.2), 5.05 (dq, 1H, J=3.5,
J=6.5), 5.44 (q, 1H, J=7.1), 7.18–7.38 (m, 5 ArH), 7.31 (d, 2H, J=8.5), 7.81 (d, 2H, J=8.5). 13C NMR:
14.6, 16.6, 17.1, 22.2, 38.9, 46.9, 49.6, 52.8, 61.2, 79.8, 96.6, 127.6, 128.1, 128.3, 129.1, 130.4, 134.2,
139.9, 145.3, 171.1,172.0. [α]D −62.3 (c 1, CHCl3). GC–MS: m/z 302 (M+–TsO−), 234, 226, 198, 170,
133, 105, 91. Anal. calcd for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96. Found: C, 63.34; H, 6.55; N, 2.92.
4.34. Ethyl (3S,4R,10S,100R)-[2-oxo-1-(10-phenylethyl)-3-(100 -p-toluenesulphonyloxyethyl)pyrrolidin-
4-yl]acetate 22b
Starting from 20a, the title product was obtained in 80% yield. IR: 1728, 1670 cm−1. 1H NMR: 1.18 (t,
3H, J=7.1), 1.24 (d, 3H, J=6.4), 1.42 (d, 3H, J=7.0), 2.18–2.33 (m, 2H), 2.40–2.65 (m, 2H), 2.45 (s, 3H),
2.75 (m, 1H), 3.54 (dd, 1H, HB, JBX=7.9, JAB=10.0), 4.05 (q, 2H, J=7.1), 5.08 (dq, 1H, J=4.3, J=6.4),
5.36 (q, 1H, J=7.0), 7.21–7.43 (m, 7 ArH), 7.83 (d, 2H, J=8.3). 13C NMR: 14.6, 16.6, 17.1, 22.2, 38.9,
46.9, 49.6, 52.8, 61.2, 79.8, 96.6, 127.6, 128.1, 128.3, 129.1, 130.4, 134.2, 139.9, 145.3, 171.1, 172.0.
]α]D −69.2 (c 1, CHCl3). GC–MS: m/z 302 (M+–TsO−), 234, 226, 198, 170, 133, 105, 91. Anal. calcd
for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96. Found: C, 63.33; H, 6.54; N, 2.91.
4.35. Ethyl (3S,4R,10R,100S)-[3-(100-methanesulphonyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-
yl] acetate 23
To a solution containing pyrrolidin-2-one 13a (1.6 g; 5 mmol), triethylamine (1 ml) and DMAP (100
mg) dry ethyl acetate (30 ml) at 0°C, was added a solution of methanesulphonyl chloride (0.6 g; 5
mmol) in ethyl acetate (5 ml). After 3 h the mixture was poured into H2O (30 ml) and extracted with
ethyl acetate (3×100 ml). After drying (Na2SO4) and removal of the solvent in vacuo, the residue was
chromatographed on silica gel (cyclohexane:ethyl acetate, 50:50) to give 23 in 85% yield, as a colourless
oil. IR: 1722, 1667 cm−1. 1H NMR: 1.99 (t, 3H, J=7.1), 1.39 (d, 3H, J=6.5), 1.47 (d, 3H, J=7.2), 2.25–2.51
(m, H), 2.54–2.75 (m, 2H), 2.91 (s, 3H), 2.89–3.04 (dd, 1H), 3.21 (dd, 1H, HB, JBX=7.3, JAB=10.3), 4.08
(q, 2H, J=7.1), 5.19 (dq, 1H, J=6.5, J=3.0), 5.43 (q, 1H, J=7.2), 7.18–7.38 (m, 5 ArH). 13C NMR: 14.6,
16.5, 17.9, 20.4, 30.3, 39.3, 46.8, 49.4, 52.8, 61.3, 79.3, 127.3, 127.5, 128.0, 129.1, 140.1, 171.0, 171.9.
[α]D 76.5 (c 1, CHCl3). GC–MS: m/z 302 (M+–MsO−), 234, 226, 198, 170, 133, 105, 91. Anal. calcd for
C19H27NO6S: C, 57.41; H, 6.85; N, 3.53. Found: C, 57.35; H, 6.81; N, 3.50.

R. Galeazzi et al. / Tetrahedron: Asymmetry 10 (1999) 587–605
603
4.36. (3R,4R,10R)-3-Ethyl-4-(200-hydroxyethyl)-1-(10 -phenylethyl)pyrrolidin-2-one 24
To a solution of compound 23 (1.3 g; 3.0 mmol) in dry THF (30 ml) under argon, LiAlH4 (0.2 g; 5
mmol) was added and the reaction stirred for 1 h at rt. Then methanol (1 ml) and H2O (30 ml) were
added and the mixture extracted with ethyl acetate (2×100 ml). After drying (Na2SO4) and removal
of the solvent under reduced pressure, the residue was purified by silica gel chromatography (ethyl
1
acetate:cyclohexane, 80:20) to give 24 in 79% yield as colourless oil. IR: 3350, 1675 cm−1. H NMR:
0.94 (t, 3H, J=7.4), 1.48 (d, 3H, J=7.2), 1.58–1.84 (m, 3H), 1.95–2.17 (m, 1H, HX), 2.23 (br s, 1H,
OH), 2.90 (dd, 1H, HA, JAX=6.9, JAB=9.8), 3.07 (dd, 1H, HB, JBX=7.9, JAB=9.8), 5.46 (q, 1H, J=7.2),
7.18–7.38 (m, 5 ArH). 13C NMR: 11.4, 16.5, 23.2, 34.0, 37.6, 47.1, 49.2, 50.0, 61.1, 127.4, 127.8, 129.0,
140.8, 176.2. [α]D 126.3 (c 1, CHCl3). GC–MS: m/z 261 (M+), 246, 188, 170, 105, 91, 77. Anal. calcd
for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.49: H, 8.84; N, 5.33.
4.37. Ethyl (3S,4R,10R,100R)-[3-(100-p-iodobenzoyloxyethyl)-2-oxo-1-(10 -phenylethyl)pyrrolidin-4-yl]-
acetate 16
4.37.1. Method A
To a solution containing 13a (1.3 g; 5 mmol), triphenylphosphine (2.6 g; 10 mmol), and 4-iodobenzoic
acid (2.5 g; 10 mmol) in dry THF (50 ml), diethyl azodicarboxylate (0.17 g; 10 mmol) dissolved in dry
THF (15 ml) was added at 20°C. After 1 h the solvent was removed under reduced pressure, the residue
dissolved in ethyl acetate (100 ml) and the organic layer washed first with a saturated NaHCO3 solution
(100 ml), then with water (100 ml) and eventually dried (Na2SO4). The solvent was then evaporated
and the residue purified by silica gel chromatography (cyclohexane:ethyl acetate, 70:30) to give p-
iodobenzoate 16 in 71% yield as a white solid.
4.37.2. Method B
To a solution containing 23 (1.3 g; 3.0 mmol) in benzene (40 ml) ion exchange resin Amberlyst
A 26 in the p-iodobenzoate form (5 g) was added and the mixture refluxed for 5 h. After filtra-
tion and removal of the solvent under reduced pressure, the residue was chromatographed on si-
lica gel (cyclohexane:ethyl acetate, 70:30) to give at first ethyl (Z,4R,10R)-[3-ethyliden-2-oxo-1-(10 -
phenylethyl)pyrrolidin-4-yl]acetate 25 in 21% yield as a colourless oil: IR: 1724, 1664 cm−1. 1H NMR:
1.21 (t, 3H, J=7.2), 1.53 (d, 3H, J=7.2), 2.18 (dd, 3H, J=7.3, J=1.8), 2.34 (dd, 1H, J=8.9, J=16.2), 2.53
(dd, 1H, J=4.8, J=16.2), 2.95 (dd, 1H, HA, JAX=3.9, JAB=8.7), 2.90–3.15 (m, 1H, HX), 3.17 (dd, 1H, HB,
J
BX=7.5, JAB=8.7), 4.08 (q, 2H, J=7.2), 5.53 (q, 1H, J=7.2), 5.89 (dq, 1H, J=7.3, J=1.9), 7.17–7.35 (m, 5
ArH). 13C NMR: 13.7, 14.7, 16.5, 33.8, 40.2, 46.0, 49.1, 61.1, 127.7, 127.9, 129.0, 132.7, 134.1, 140.5,
168.0, 172.1. [α]D 113.6 (c 1, CHCl3). GC–MS: m/z 301 (M+), 286, 258, 214, 197, 152, 110, 105, 91,
77. Anal. calcd for C18H23NO3: C, 71.73; H, 7.69; N, 4.65. Found: C, 71.68; H, 7.71; N, 4.61. By further
elution, p-iodobenzoate 16 was obtained in 65% yield as a white solid.
Acknowledgements
This research was supported by M.U.R.S.T. (Rome) within the project ‘Chimica dei Composti Organici
di Interesse Biologico’.

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Washington, DC, 1982; (c) Lii, J.; Gallion, S.; Bender, C.; Wikstrom, H.; Allinger, N. L., Flurchick, K. M.; Teeter, M. M.
J. Comput. Chem. 1989, 10, 503–511; (d) Lipkowitz, K. B., QCPE Bulletin, Indiana University 12, 1 (Feb. 1982). The
program is enclosed in Hyperchem package, release 5.01, available from Hypercube, Gainesville, Florida, USA.
16. The search for low energy conformations was run using a BATCHMIN program included in MacroModel, Version 5.5.
All calculations were carried out on a Silicon Graphics Indigo 2 R10000 workstation. For a reference, see: Mohamadi,
F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Canfield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J.
Comput. Chem. 1990, 11, 440–448.
17. Whereas conformer I of 13a is practically missing (∆E=2.44 kcal/mol with respect to A), conformer II of 14a is
significantly present (∆E=0.64 kcal/mol with respect to B).

R. Galeazzi et al. / Tetrahedron: Asymmetry 10 (1999) 587–605
605
18. A number of stereoselective reductions of 3-acetyl azetidinones are reported in the literature. For examples see: (a)
Bouffard, F. A.; Christensen, B. G. J. Org. Chem. 1981, 46, 2208–2212; (b) Reider, P. J.; Grabowski, E. J. J. Tetrahedron
Lett. 1982, 23, 2293–2296; (c) Chiba, T.; Nakai, T. Chemistry Lett. 1985, 651–654; (d) Chiba, T.; Nagatsuma, M.; Nakai, T.
Chemistry Lett. 1985, 1343–1346; (e) Chiba, T.; Nakai, T. Tetrahedron Lett. 1985, 26, 4647–4648; (f) Ito, Y.; Kobayashi,
Y.; Kawabata, T.; Takase, M.; Terashima, S. Tetrahedron 1989, 45, 5767–5790; (g) Kawabata, T.; Kimura, Y.; Ito, Y.;
Terashima, S.; Sasaki, A.; Sunagawa, M. Tetrahedron Lett. 1986, 27, 6241–6244; (h) Kawabata, T.; Kimura, Y.; Ito, Y.;
Terashima, S.; Sasaki, A.; Sunagawa, M. Tetrahedron 1988, 44, 2149–2165.
19. It is worth mentioning that for 3-hydroxyethyl azetidinones neither coupling constants or chemical shifts are useful tools
for determining the configuration of the stereogenic centre in every case at the hydroxyethyl chain. See Ref. 18a.
20. All calculations were carried out on a VAX 2000 by using the program package Molen, An Interactive Structure Solution
Procedure, Enraf-Nonius, Delft, The Netherlands, 1990.
21. Atom coordinates, anisotropic thermal parameters and tables of bond lengths and angles are deposited at the Cambridge
Crystallographic Data Centre, University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK.
22. Only in conformer III of compound 15 does H-100 lie on the plane of the carbonyl group, but this conformer is not
significantly present (∆E=6.23 kcal/mol with respect to A0).
23. The low chelating effect of the potassium ion, further diminished by the high cation solvating ability of methanol, could
explain the absence of the chelation effect.
24. Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett. 1993, 3, 2415–2418.
25. Schmitt, S. M.; Johnston, D. B. R.; Christensen, B. G. J. Org. Chem. 1980, 45, 1142–1148.
26. Grynkiewicz, G.; Burzynska, H. Tetrahedron 1976, 32, 2109–2111.
27. Cardillo, G.; Orena, M.; Sandri, S.; Tomasini C. J. Org. Chem. 1984, 49, 3951–3954.
28. The functionalisation at the C-5 of the pyrrolidin-2-one ring is currently studied according reported methods: (a)
Murahashi, S. I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112,
7820–7822; (b) Cainelli, G.; Da Col, M.; Galletti, P.; Giacomini, D. Synlett. 1997, 923–924.
29. Johnson, C. K. ORTEP Report ORNL-3794 Oak Ridge National Laboratory, Tennessee, USA, 1965.