β-Lactam derivatives as enzyme inhibitors: Peptidic derivatives of (RS)-2-oxo-4-phenylazetidine-1-alkanoic acids

Article abstract of DOI:10.1007/s00706-007-0639-9

4-Phenylazetidine-2-one was transformed into 4-phenylazetidine-1-alkanoic acids, which were reacted in the presence of diphenylphosphoroazidate with amino acid esters and dipeptide esters yielding β-lactam peptides with different spacers between the lacta

Full text of DOI:10.1007/s00706-007-0639-9

Monatshefte fu¨r Chemie 138, 627–634 (2007)
DOI 10.1007/s00706-007-0639-9
Printed in The Netherlands
b-Lactam Derivatives as Enzyme Inhibitors: Peptidic Derivatives of
(RS)-2-Oxo-4-phenylazetidine-1-alkanoic Acids
ꢀ
Ali Elriati1, Karin Achilles, Jutta Loose, and Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
Received November 21, 2006; accepted (revised) December 2, 2006; published online April 23, 2007
# Springer-Verlag 2007
Summary. 4-Phenylazetidine-2-one was transformed into
[5]. A number of natural inhibitors of elastase is
4-phenylazetidine-1-alkanoic acids, which were reacted in the
presence of diphenylphosphoroazidate with amino acid esters
and dipeptide esters yielding ꢀ-lactam peptides with different
spacers between the lactam ring and the peptide moiety. All
structures were established by elementary analyses, HPLC,
optical rotation, and spectroscopic data and all new com-
pounds were tested as inhibitors of PPE using standard pro-
cedures. Four compounds exhibited a weak activity compared
with the standard inhibitor trifluoroacetyl-L-val-L-tyr-L-val.
known, some inhibitors are (or were) used in the
therapy of emphysema, and great effort was done
to find effective and orally applicable compounds,
but until today the great success was not reported
[6]. The active center of elastase seems to be similar
to the active center of transpeptidases. Therefore,
experiments are reported to use ꢀ-lactam structures
as elastase inhibitors, and indeed, some of these
experiments were successful [7]. We have reported
about the synthesis of elastase inhibitors based on
the saccharin nucleus [8], and the ꢀ-lactam structure
[9]. In continuation of these results we report here
about the synthesis and properties of peptidic deri-
vatives of (RS)-2-oxo-4-phenylazetidine-1-alkanoic
acids. These compounds we hoped should be able
to attack the active center of the enzyme by the
ꢀ-lactam moiety, whereas the peptidic side chain
should be able to improve the selectivity. We selected
as building blocks for the side chain the amino acids
L-alanine, L-phenylalanine, L-valine, and L-leucine,
as these amino acids could fit into the pockets around
the active center of elastase. Furthermore, we intro-
duced spacers between the ꢀ-lactam ring and the pep-
tidic side chain.
Keywords. ꢀ-Lactam peptides; Elastase inhibitors; ꢀ-Lactam
1-alkanoic acids.
Introduction
Elastase is a human serine protease from which at
least two forms are known. The human pancreatic
elastase (HPE, EC 3.4.21.36) produced in the pan-
creas is liberated into the intestine, whereas the hu-
man neutrophil or leukocyte elastase (HNE, HLE,
EC 3.4.21.37) produced in the medulla ossium and
stored in the granula of polymorphous leucocytes
plays an important role in the metabolism of human
peptides as fibrin, hemoglobin, albumins, caseins,
and elastin [1]. Elastin is responsible for the elasti-
city of the lung tissue, and excessive activity of elas-
tase might cause a number of diseases like ARDS
[2], cystic fibrosis [3], arthritis [4], and emphysema
Results and Discussion
ꢀ
greifswald.de
Corresponding author. E-mail: ottohh@pharmazie.uni-
As the ꢀ-lactam moiety we used 4-phenylazetidin-
2-one (1) prepared according to literature [10]. The
1
From the Ph.D. Thesis A.E., University of Greifswald, 2003

628
A. Elriati et al.
alkylation with !-bromoalkanoic esters was suc-
cessful when we used the solid–liquid-phase transfer
method with Bu4NBr and KOH in THF [11]. We
obtained the ꢀ-lactam-N-alkanoyl esters 2a–2d after
purification by CC as colorless liquids with yields of
20–70% [12]. Compound 3 was isolated from the
reaction between 1 and ethyl 2-bromopropionate.
The hydrolysis of the ester groups using enzymat-
ic methods [13] was not successful, but by hydro-
lysis with NaOH in H2O at maximum 60ꢁC we
obtained the ꢀ-lactam-N-alkanoic acids 4a–4d as
colorless viscous liquids with yields up to 87%.
Esters and acids were characterized mainly by their
spectroscopic data. The IR spectra showed intensive
carbonyl bands. These were found in the spectra of
the acetates 2a and 3 around 1770 cmꢂ1, whereas in
the spectra of the other esters and of all acids these
1
bands were registered around 1730 cmꢂ1. All H
NMR (200 MHz) spectra were characterized by an
AMX system of the ꢀ-lactam protons at ca. 2.8–2.9
Scheme 1

ꢀ-Lactam Derivatives as Enzyme Inhibitors
629
chased from Serva, Suc-(Ala)3-pNA from Fluka. THF was
stored with CaCl2, refluxed with Na and benzophenone, and
distilled prior to use. Other solvents were dried=purified accord-
ing to literature procedures. (RS)-4-Phenylazetidin-2-one (1)
see Ref. [10].
and 3.3–3.5 (3-H), and 4.6–4.9 ppm (4-H) and
coupling constants of 2.1–2.4, 5.0–5.3, and 14.6–
15.9 Hz establishing the intact ꢀ-lactam ring.
The salts of amino acid esters and of dipeptide
esters were synthesized using standard procedures
described in Ref. [14]. The reactions of these build-
ing blocks with the acids 4a–4d were performed
under an N2 atmosphere in dry DMF with diphenyl-
phosphoroazidate (DPPA) and Et3N at 0ꢁC. The
compounds were purified by CC (AcOEt), and all
compounds were isolated as viscous liquids. We ob-
tained by this way the amino acid ester derivatives
6a–6f and the dipeptide derivatives 5a–5v.
Synthesis of 2a–2d and 3. General Procedure
Compound 1 (1.61 g, 11mmol), 10 mmol !-bromoalkanoic
ester, and 0.36g Bu4NBr were dissolved in 50 cm3 THF,
0.67g pulv. KOH (11 mmol) was added, and the mixture
was stirred for 6–12h. Then, the mixture was filtrated, con-
centrated in vacuo, and the residue was crystallized or purified
by CC.
Ethyl (RS)-2-(2-oxo-4-phenylazetidin-1-yl)acetate
(2a, C13H15NO3)
As expected, the HPLC analyses (RP-18 column)
of 6a–6f showed for these compounds two peaks
with a ratio of 1:1 (or 3:2) indicating that these com-
pounds were isolated as mixtures of diastereoiso-
From ethyl bromoacetate (1.67g, 10mmol), CC (AcOEt).
Yield 1.65 g (71%); colorless liquid; Rf ¼ 0.57; IR: ꢃꢀ¼
1
3030, 2983 (CH), 1769 (CO) cmꢂ1; H NMR: ꢁ ¼ 1.71 (t,
J ¼ 7.15 Hz, Me), 2.82 (dd, JAX ¼ 2.4 Hz, JAM ¼ 14.8Hz,
3-H), 3.31 (d, J ¼ 17.8Hz, 1H, CH2), 3.40 (dd, JMX ¼ 5.2 Hz,
JAM ¼ 14.8Hz, 30-H), 4.16 (m, CH2), 4.35 (d, J ¼ 17.8Hz, 1H,
CH2), 4.78 (dd, JAX ¼ 2.4 Hz, JMX ¼ 5.2 Hz, 4-H), 7.26 (m, 5
ar H) ppm.
1
mers. This was established by the H NMR spectra
(see Experimental). Furthermore, the structures were
in agreement with the IR data showing the NH-bands
around 3300cmꢂ1 and 3 carbonyl bands, ca. 1730–
1750 (ꢀ-lactam CO), 1650–1670 (ester CO), and
1540 cmꢂ1 (amide CO). Similar results were obtained
from analyzing 5a–5v. In some cases, the separation
of the signals of the diastereoisomers in the HPLC
spectra was possible only when we used a chiral
column with chiral adsorbent. All dipeptide deriva-
tives were formed as 1:1 mixtures of diastereoiso-
mers, which were not separated.
Testing the biological activity of these compounds
was done as described earlier [9]. Compounds 5g, 5i,
5l, and 6a showed a weak activity against PPE com-
pared to that of the standard inhibitor trifluoroacetyl-
L-val-L-tyr-L-val.
Ethyl (RS)-3-(2-oxo-4-phenylazetidin-1-yl)propionate
(2b, C14H17NO3)
From ethyl 3-bromopropionate (1.81 g, 11mmol), at 0ꢁC, 1–
2 h, CC (Cyclohexane=AcOEt 1=1). Yield 1.75g (71%); color-
less liquid; Rf ¼ 0.55; IR: ꢃꢀ¼ 3031 (CH), 2981, 2930 (CH),
1731 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 1.24 (t, J ¼ 7.2 Hz, Me), 2.48
(dt, J ¼ 6.8 Hz, J ¼ 14.0Hz, CH2), 2.76 (dd, JAX ¼ 2.2 Hz,
JAM ¼ 14.6Hz, 3-H), 3.17 (dt, J ¼ 6.8 Hz, J ¼ 14.0 Hz, 1H,
CH2), 3.32 (dd, JMX ¼ 5.2 Hz, JAM ¼ 14.6Hz, 30-H), 3.63 (dt,
J ¼ 6.8 Hz, J ¼ 14.0Hz, 1H, CH2), 4.01 (m, CH2), 4.60 (dd,
JAX ¼ 2.3 Hz, JMX ¼ 5.2Hz, 4-H), 7.34 (m, 10 ar H) ppm.
Ethyl (RS)-4-(2-oxo-4-phenylazetidin-1-yl)butyrate
(2c, C15H19NO3)
From ethyl 4-bromobutyrate (1.95 g, 10mmol), CC (Cyclo-
hexane=AcOEt 1=1). Yield 0.55 g (21%); colorless liquid;
Rf ¼ 0.4; IR: ꢃꢀ¼ 2956 (CH), 1731 (CO) cmꢂ1
;
1H NMR:
Experimental
ꢁ ¼ 1.23 (t, J ¼ 7.2 Hz, Me), 1.79 (m, CH2), 2.3 (m, CH2),
2.81 (dd, JAX ¼ 2.1 Hz, JAM ¼ 14.6 Hz, 3-H), 2.89 (dt, J ¼ 6.5,
14.6Hz, 1H, CH2), 3.36 (dd, JMX ¼ 5.0 Hz, JAM ¼ 14.6 Hz,
30-H), 4.09 (q, J ¼ 7.2 Hz, CH2), 4.65 (dd, JAX ¼ 2.1 Hz,
JMX ¼ 5.0 Hz, 4-H), 7.31 (m, 5 ar H) ppm.
General: Mp: PHMX 80=2778 (Ku¨stner, Dresden) appara-
tus. IR Spectra: Perkin-Elmer FTIR 1600; in KBr or as film
(cmꢂ1), if not noted otherwise. NMR Spectra: Bruker DPX
1
200 (200 MHz), ARX 300 (300 MHz) for H; ꢁ (ppm) rel.
to TMS as internal standard, J in Hz; H-values from DPX
1
Ethyl (RS)-5-(2-oxo-4-phenylazetidin-1-yl)valerianate
(2d, C16H21NO3)
200 spectra in CDCl3, if not noted otherwise. Mass Spec-
tra: Intectra AMD 402=3. Optical rotation: Polatronic D.
Elementary analyses: Perkin-Elmer Analyzer 2400 CHN,
From ethyl 5-bromovalerianate (2.05g, 10mmol), CC (Cyclo-
hexane=AcOEt 1=1). Yield 1.45 g (51%); colorless liquid; Rf ¼
¨
Pharmazeutisches Institut der Universitat Greifswald. All
compounds gave satisfactory elemental analyses or were
proven by high resolution MS. Column chromatography (CC)
with Silica Gel 60 Merck Nr. 7734 or 9385. HPLC with
LaChrom apparatus series 7000 Merck Hitachi, LiChrospher
250-4, RP-18, 5 ꢂm, and LiChroCART 250-4, (S,S)-Whelk-O1,
5 ꢂm. PPE (Porcine pancreatic elastase, ꢃ200 U=mg) was pur-
0.4; IR: ꢃꢀ¼ 3030, 2951 (CH), 1734 (CO), 1397, 701 cmꢂ1
;
1H NMR: ꢁ ¼ 1.25 (t, J ¼ 7.1 Hz, Me), 1.57 (m, 2CH2), 2.27
(m, CH2), 2.77 (dd, JAX ¼ 1.7 Hz, JAM ¼ 14.6 Hz, 3-H), 2.85
(m, 1H, CH2), 3.34 (dd, JMX ¼ 5.1 Hz, JAM ¼ 14.75 Hz, 30-H),
3.43 (m, 1H, CH2), 4.08 (q, J ¼ 7.1 Hz, CH2), 4.55 (dd,
JAX ¼ 2.24Hz, JMX ¼ 5.1 Hz, 4-H), 7.34 (m, 5 ar H) ppm.

630
A. Elriati et al.
Ethyl (RS)-2-methyl-2-(2-oxo-4-phenylazetidin-1-yl)acetate
(3, C14H17NO3)
Synthesis of Dipeptide Ester Salts
The following dipeptide ester salts were prepared in anal-
ogy to the method reported in Ref. [9], Venz C.: L-Ala-
L-Val-OMe-HCl, yield 0.29 g (84%), C9H19N2O3Cl;
L-Phe-L-Leu-OMe-HCl, yield 0.81g (98%), C16H24N2O3Cl; L-
Phe-L-Phe-OMe-HCl, yield 0.6g (100%), C19H23N2O3Cl;
L-Phe-L-Val-OMe-HCl, yield 1.57g (95%), C15H23N2O3Cl;
L-Val-L-Leu-OMe-HCl, yield 2.12 g (87%), C12H25N2O3Cl; L-
Val-L-Phe-OMe-HCl, yield 1.57 g (95%), C15H23N2O3Cl;
L-Val-L-Val-OMe-HCl, yield 1.44g (90%), C11H23N2O3Cl.
From ethyl 2-bromopropionate (1.81 g, 11 mmol), CC
(AcOEt). Yield 0.91g (33%); colorless liquid; Rf ¼ 0.75; IR:
1
ꢃꢀ¼ 3031, 2984 (CH), 1767 (CO) cmꢂ1; H NMR: ꢁ ¼ 1.25
(t, J ¼ 7.0 Hz, Me), 1.48 (d, J ¼ 7.4 Hz, Me), 2.82 (dd, JAX
¼
2.5 Hz, JAM ¼ 14.8Hz, 3-H), 3.40 (dd, JMX ¼ 5.3 Hz,
JAM ¼ 14.8Hz, 30-H), 4.01 (q, J ¼ 7.4 Hz, CH), 4.67 (dd,
JAX ¼ 2.5 Hz, JMX ¼ 5.3 Hz, 4-H), 7.31 (m, 5 ar H) ppm.
Synthesis of 4a–4d. General Procedure
Ester 2 (8.6mmol) and 20cm3 1 N NaOH were warmed to
60ꢁC for 20 min. The mixture was cooled to room temper-
ature, twice extracted with 50 cm3 AcOEt, the aqueous layer
was acidified with dil. HCl to pH ꢄ 2, and extracted with
3ꢅ50 cm3 AcOEt. The combined extracts were dried
(Na2SO4), and the solvent was removed in vacuo.
Synthesis of the ꢀ-Lactam Peptides 5 and 6. General
Procedure
Under N2, the ꢀ-lactam alkanoic acid and the amino acid ester
salt or the dipeptide ester salt were dissolved in 20 cm3 DMF,
and 1.1 eq. of diphenylphosphoroazidate, and 2.1 eq. of Et3N
were added. The mixture was stirred for 10h at 0ꢁC. Then,
100 cm3 AcOEt were added, and the mixture was washed with
3ꢅ50cm3 H2O, once with a satd. solution of NaHCO3, and
twice with a satd. solution of NaCl. The organic layer was
separated, dried (Na2SO4), and the solvent was evaporated
in vacuo. The residue was purified by CC with AcOEt. All pro-
ducts were obtained as colorless viscous liquids, if not other-
wise noted.
(RS)-2-(2-oxo-4-phenylazetidin-1-yl)acetic acid
(4a, C11H11NO3)
From 2a. Yield 1.5 g (87%); colorless liquid; IR: ꢃꢀ¼ 3432
(OH), 2988 (CH), 1735 (CO), 758, 700 cmꢂ1 1H NMR:
;
ꢁ ¼ 2.9 (dd, JAX ¼ 2.2 Hz, JAM ¼ 14.95 Hz, 3-H), 3.45 (d,
J ¼ 18.2Hz, 1H, CH2), 3.49 (dd, JMX ¼ 5.1 Hz, JAM
¼
14.95 Hz, 30-H), 4.38 (d, J ¼ 18.2Hz, 1H, CH2), 4.89 (dd,
JAX ¼ 2.3 Hz, JMX ¼ 5.1 Hz, 4-H), 7.36 (m, 5 ar H), 8.41 (s,
br, COOH) ppm.
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-valyl-L-
valine methyl ester (5a, C22H31N3O5)
From 4a (0.3g, 1.53mmol) and L-Val-L-Val-OMe-HCl
20
(0.43 g, 1.61mmol). Yield 0.31 g (49%); Rf ¼ 0.60; ½ꢄꢆD
¼
(RS)-3-(2-oxo-4-phenylazetidin-1-yl)propionic acid
(4b, C12H13NO3)
ꢂ43.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3380, 3317 (NH),
1
2977 (CH), 1731, 1702, 1651, 1543 (CO) cmꢂ1; H NMR:
From 2b. Yield 0.6 g (62%); colorless liquid; IR: ꢃꢀ¼ 3484
ꢁ ¼ 0.88, 0.91 (2d, J ¼ 7.1 Hz, MeVal), 0.94, 0.97 (2d, J ¼
6.9 Hz, MeVal), 1.28 (m, ꢀ-HVal), 2.11 (m, ꢀ-HVal), 2.92 (dd,
JAM ¼ 2.4 Hz, JAX ¼ 14.9 Hz, H-3), 3.47 (dd, JMX ¼ 5.2 Hz,
JAM ¼ 14.9Hz, 30-H), 3.52 (d, J ¼ 14.1Hz, 1H, CH2), 3.74
(s, OMe), 4.22 (d, J ¼ 14.0 Hz, 1H, CH2), 4.28 (m, ꢄ-HVal),
4.50 (m, ꢄ-HVal), 4.79 (dd, JAX ¼ 2.4 Hz, JMX ¼ 5.2 Hz, 4-H),
6.28 (m, N–HVal), 6.87 (d, J ¼ 8.4 Hz, N–HVal), 7.24 (m, 5
ar H) ppm; HPLC: k10 ¼ 1.57, k20 ¼ 2.26, t0 ¼ 2.13 (RP-18,
MeCN=H2O 1=1), ratio of diastereoisomers 49:51.
(OH), 3031, 2981 (CH), 1731 (CO) 701 cmꢂ1 1H NMR:
;
ꢁ ¼ 2.52 (dt, J ¼ 6.7 Hz, J ¼ 16.8Hz, CH2), 2.80 (dd, JAX
¼
2.2 Hz, JAM ¼ 14.75 Hz, 3-H), 3.16 (dt, J ¼ 6.8, 14.15 Hz, 1H,
CH2), 3.36 (dd, JMX ¼ 5.1 Hz, JAM ¼ 14.75 Hz, 30-H), 3.64 (dt,
J ¼ 6.6, 14.5 Hz, 1H, CH2), 4.61 (dd, JAX ¼ 2.3 Hz, JMX
5.1 Hz, 4-H), 7.31 (m, 5 ar H), 10.31 (s, br, COOH) ppm.
¼
(RS)-4-(2-oxo-4-phenylazetidin-1-yl)butyric acid
(4c, C13H15NO3)
From 2c. Yield 0.95g (53%); colorless liquid; 1H NMR:
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-valyl-L-
ꢁ ¼ 1.72–1.93 (m, CH2), 2.33–2.40 (m, CH2), 2.81(dd, JAX
¼
leucine methyl ester (5b, C23H33N3O5)
From 4a (0.2 g, 0.99 mmol) and L-Val-L-Leu-OMe-HCl
2.2 Hz, JAM ¼ 14.8Hz, 3-H), 2.92 (dt, J ¼ 7.5 Hz, 14.5Hz, 1H,
CH2), 3.33 (dd, JMX ¼ 5.1 Hz, JAM ¼ 14.8 Hz, 30-H), 3.43 (dt,
20
(0.3g, 1.02mmol). Yield 0.22 g (51%); Rf ¼ 0.77; ½ꢄꢆD
¼
J ¼ 7.5, 14.5 Hz, 1H, CH2), 4.58 (dd, JAX ¼ 2.2 Hz, JMX
¼
ꢂ46.25ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3265 (NH), 3068,
5.1 Hz, 4-H), 7.30–7.45 (m, 5 ar H), 10.55 (s, br, COOH)
ppm.
2959 (CH), 1762, 1650, 1548 (CO) cmꢂ1 1H NMR:
;
ꢁ ¼ 0.89, 0.91 (2d, J ¼ 7.0 Hz, MeVal), 0.93, 0.94 (2d, J ¼
6.4 Hz, MeLeu), 1.48–1.62 (m, 2 ꢀ-H, ꢅ-HLeu), 2.08–2.14
(m, ꢀ-HVal), 2.96 (dd, JAX ¼ 2.5 Hz, JAM ¼ 14.9 Hz, 3-H),
3.41 (d, J ¼ 16.9 Hz, 1H, CH2), 3.51 (dd, JMX ¼ 5.4 Hz,
JAM ¼ 14.9 Hz, 30-H), 3.72 (s, OMe), 4.27 (d, J ¼ 16.9 Hz,
1H, CH2), 4.29 (m, ꢄ-HVal), 4.56 (m, ꢄ-HLeu), 4.82 (dd,
JAX ¼ 2.5 Hz, JMX ¼ 5.4 Hz, 4-H), 6.53, 6.65 (d, J ¼ 7.9 Hz,
N–HVal), 6.88, 6.92 (d, J ¼ 8.5 Hz, N–HLeu), 7.35 (m, 5 ar
H) ppm; HPLC: k0 ¼ 2.60, t0 ¼ 1.89 (RP-18, MeCN=H2O
1=1), k10 ¼ 11.79, k20 ¼ 12.09, t0 ¼ 2.23 (RP-18, MeCN=H2O
3=7), ratio of diastereoisomers 46:54.
(RS)-5-(2-oxo-4-phenylazetidin-1-yl)valerianic acid
(4d, C14H17NO3) [12]
From 2d. Yield 1.37g (76%); colorless liquid; IR: ꢃꢀ¼ 3434
(OH), 2951 (CH), 1732 (CO), 759, 701 cmꢂ1 1H NMR:
;
ꢁ ¼ 1.58 (m, 2CH2), 2.3 (m, CH2), 2.83 (dd, JAX ¼ 2.8 Hz,
JAM ¼ 14.7Hz, 3-H), 2.87 (m, 1H, CH2), 3.36 (dd, JMX
¼
4.95Hz, JAM ¼ 14.7Hz, 30-H), 3.47 (m, 1H, CH2), 4.57 (dd,
JAX ¼ 2.8 Hz, JMX ¼ 5.8 Hz, 4-H), 7.24 (m, 5 ar H), 10.86 (s,
br, COOH) ppm.

ꢀ-Lactam Derivatives as Enzyme Inhibitors
631
J ¼ 16.8Hz, 1H, CH2), 4.41–4.57 (m, ꢄ-HAla, ꢄ-HVal), 4.82–
4.84 (dd, JAX ¼ 2.0 Hz, JMX ¼ 5.2 Hz, 4-H), 6.90 (d, J ¼ 8.7 Hz,
N–HVal), 7.16 (d, J ¼ 7.3 Hz, N–HAla), 7.29–7.34 (m, 5 ar H)
ppm; HPLC: k0 ¼ 4.74, t0 ¼ 2.39 (RP-18, MeCN=H2O 3=7).
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-phenylala-
nyl-L-phenylalanine methyl ester (5c, C30H31N3O5)
From 4a (0.21 g, 1.04 mmol) and L-Phe-L-Phe-OMe-HCl
(0.35 g, 1.08 mmol). Yield 0.1 g (19%); Rf ¼ 0.40; IR: ꢃꢀ¼
3286 (NH), 3060, 2926 (CH), 1774, 1753, 1731, 1692,
1655, 1546 (CO) cmꢂ1
;
1H NMR: ꢁ ¼ 2.84–2.94 (dd,
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-valyl-L-
JAX ¼ 2.3 Hz, JAM ¼ 14.8 Hz, 3-H), 2.98–3.14 (m, 2 ꢀ-HPhe),
3.23–3.45 (dd, JMX ¼ 5.2 Hz, JAM ¼ 14.8Hz, 30-H; 2d, J ¼
16.8Hz, 1H, CH2), 3.70 (s, OMe), 3.98–4.13 (2d, J ¼ 16.8 Hz,
Hz, 1H, CH2), 4.37–4.41 (dd, JAX ¼ 2.3 Hz, JMX ¼ 5.2 Hz,
4-H), 4.52–4.66 (m, ꢄ-HPhe), 4.70–4.79 (m, ꢄ-HPhe), 6.20,
6.27 (2d, J ¼ 7.0Hz, N–H), 6.57, 6.74 (2d, J ¼ 7.3 Hz, N–
H), 6.95–7.38 (m, 15 ar H) ppm; HPLC: k0 ¼ 1.36, t0 ¼ 2.13
(RP-18, MeCN=H2O 4=6).
phenylalanine methyl ester (5g, C26H31N3O5)
From 4a (0.3g, 1.46mmol) and L-Val-L-Phe-OMe-HCl
20
(0.59 g, 1.51 mmol). Yield 212 mg (31%); Rf ¼ 0.70; ½ꢄꢆD
¼
ꢂ31.75ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3290 (NH), 2965
1
(CH), 1731, 1681, 1537 (CO) cmꢂ1; H NMR: ꢁ ¼ 0.79 (d,
J ¼ 6.8 Hz, MeVal), 0.85 (d, J ¼ 6.7 Hz, MeVal), 1.98–2.20 (m,
ꢀ-HVal), 2.89–2.97 (d, JAM ¼ 14.6Hz, 3-H), 3.01–3.19 (m, 2
ꢀ-HPhe), 3.37–3.52 (dd, JMX ¼ 5.2 Hz, JAM ¼ 13.8Hz, 30-H),
3.46 (d, J ¼ 16.5Hz, 1H, CH2), 3.70, 3.71 (2s, OMe), 4.15 (d,
J ¼ 16.5 Hz, 1H, CH2), 4.25 (m, ꢄ-HVal), 4.76–4.79 (dd,
JAX ¼ 2.5 Hz, JMX ¼ 5.2 Hz, 4-H), 4.83 (m, ꢄ-HPhe), 6.40,
6.54 (2d, J ¼ 7.8 Hz, N–HVal), 6.74, 6.79 (2d, J ¼ 8.6 Hz, N-
HPhe), 7.06–7.39 (m, 10 ar H) ppm; HPLC: k10 ¼ 2.89,
k20 ¼ 3.22, t0 ¼ 2.01 (RP-18, MeCN=H2O 4=6); ratio of dia-
stereoisomers 45:55.
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-phenylala-
nyl-L-valine methyl ester (5d, C26H31N3O5)
From 4a (0.41 g, 1.98 mmol) and L-Phe-L-Val-OMe-HCl
20
(0.57 g, 2.06mmol). Yield 0.11 g (12%); Rf ¼ 0.70; ½ꢄꢆD
¼
ꢂ28.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3287 (NH), 3064,
1
2964 (CH), 1734, 1660, 1643, 1536 (CO) cmꢂ1; H NMR:
ꢁ ¼ 0.83 (d, J ¼ 6.8 Hz, MeVal), 0.88 (d, J ¼ 6.95 Hz, MeVal),
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]propionyl}-L-valyl-
2.03–2.13 (m, ꢀ-HVal), 2.83–2.92 (dd, JAX ¼ 2.3 Hz, JAM
¼
14.8Hz, 3-H), 2.95–3.09 (m, CH2Phe), 3.26–3.49 (m, 1H,
L-Leucine methyl ester (5h, C24H35N3O5)
From 4b (0.14 g, 657 ꢂmol) and L-Val-L-Leu-OMe-HCl
CH2; dd, JMX ¼ 5.2 Hz, JAM ¼ 14.8Hz, 30-H), 3.68 (s, OMe),
20
4.05–4.26 (m, 1H, CH2), 4.38–4.51 (m, ꢄ-HVal; dd, JAX
¼
(200mg, 686 ꢂmol). Yield 89 mg (30%); Rf ¼ 0.57; ½ꢄꢆD
¼
ꢂ47.2ꢁ cm2 gꢂ1 (c ¼ 0.65, MeOH); IR: ꢃꢀ¼ 3473 (NH), 2993
2.3 Hz, JMX ¼ 5.2 Hz, 4-H), 4.72–4.79 (m, ꢄ-HPhe), 6.93 (d,
J ¼ 8.2 Hz, N–HVal), 6.97 (d, J ¼ 6.8 Hz, N–HPhe), 7.16–7.42
(m, 15 ar H) ppm; HPLC: k0 ¼ 15.78, t0 ¼ 2.23 (RP-18,
MeCN=H2O 3=7).
1
(CH), 1757, 1643, 1540 (CO) cmꢂ1; H NMR: ꢁ ¼ 0.93 (d,
J ¼ 6.6 Hz, 2 MeLeu), 0.95 (d, J ¼ 6.7 Hz, 2 MeVal), 1.60 (m, 2
ꢀ-HLeu, ꢅ-HLeu), 2.0–2.11 (m, ꢀ-HVal), 2.48–2.59 (m, CH2),
2.75–2.82 (d, JAM ¼ 14.6Hz, 3-H), 3.21–3.33 (m, 1H, CH2,
30-H), 3.36 (m, 1H, CH2), 3.70, 3.71 (2s, OMe), 4.36 (m,
ꢄ-HLeu), 4.56–4.59 (m, ꢄ-HVal, 4-H), 6.84 (d, J ¼ 8.8 Hz,
N–HLeu), 6.96 (d, J ¼ 7.8 Hz, N–HVal), 7.31–7.34 (m, 5
ar H) ppm; HPLC: k10 ¼ 6.97, k20 ¼ 7.33, t0 ¼ 2.01 (RP-18,
MeCN=H2O 4=6); ratio of diastereoisomers 49:51.
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-phenylala-
nyl-L-leucine methyl ester (5e, C27H33N3O5)
From 4a (0.25 g, 1.2 mmol) and L-Phe-L-Leu-OMe-TFA (0.5g,
1.26mmol). Yield 0.24 g (42%); colorless solid; Rf ¼ 0.4; IR:
ꢃꢀ¼ 3290 (NH), 3064, 2955 (CH), 1746, 1651, 1543 (CO)
1
cmꢂ1; H NMR: ꢁ ¼ 0.9 (d, 2 MeLeu), 1.45–1.58 (m, 2 ꢀ-H,
N-{-3-(RS)-2-oxo-4-phenylazetidin-1-yl]propionyl}-L-phenyl-
alanyl-L-phenylalanine methyl ester (5i, C31H33N3O5)
From 4b (0.34 g, 1.53mmol) and L-Phe-L-Phe-OMe-HCl
(0.7g, 1.58mmol). Yield 0.35 g (43%); Rf ¼ 0.64 (AcOEt=
ꢅ-HLeu), 2.85–2.94 (dd, JAX ¼ 2.4 Hz, JAM ¼ 14.9Hz, 3-H),
3.0–3.12 (m, CH2Phe), 3.32–3.40 (2d, J ¼ 16.8Hz, 1H,
CH2), 3.43 (dd, JBX ¼ 5.0 Hz, JAM ¼ 14.9Hz, 30-H), 3.71 (s,
OMe), 4.08 (2d, J ¼ 16.9Hz, 1H, CH2), 4.45 (m, ꢄ-HLeu),
4.60 (dd, JAX ¼ 2.5 Hz, JMX ¼ 5.0 Hz, 4-H), 4.7 (m, ꢄ-HPhe),
6.09 (2d, J ¼ 7.8 Hz, N–HLeu), 6.54, 6.69 (2d, J ¼ 7.4 Hz,
N–HPhe), 7.23 (m, 10 ar H) ppm; HPLC: k0 ¼ 4.39, t0 ¼
2.20 (RP-18, MeCN=H2O 1=1), k10 ¼ 1.08, k20 ¼ 1.22, t0 ¼
2.41 ((S,S)-Whelk 01, n-hexane=2-propanol 1=1); ratio of
diastereoisomers 46:54.
20
cyclohexane 1=1); ½ꢄꢆD ¼ ꢂ17.0ꢁ cm2 gꢂ1 (c ¼ 1.0, MeOH);
IR: ꢃꢀ¼ 3289 (NH), 3061, 2950 (CH), 1745, 1645, 1543 (CO)
cmꢂ1
;
1H NMR (300 MHz): ꢁ ¼ 2.37–2.44 (m, CH2), 2.77
(dd, JAX ¼ 2.3 Hz, JAM ¼ 14.7Hz, 3-H), 2.97–3.07 (m, 4 ꢀ-
HPhe), 3.09–3.16 (m, 1H, CH2), 3.21–3.3 (dd, JMX ¼ 5.25Hz,
JAM ¼ 14.7Hz, 30-H), 3.50 (m, 1H, CH2), 3.67, 3.68 (2s,
OMe), 4.39–4.52 (dd, JAX ¼ 2.3 Hz, JMX ¼ 5.2 Hz, 4-H),
4.56–4.64 (m, ꢄ-HPhe), 4.70–4.79 (m, ꢄ-HPhe), 6.00, 6.19
(2d, J ¼ 7.6 Hz, N–HPhe), 6.27, 6.35 (2d, J ¼ 7.7 Hz, N–HPhe),
7.00–7.36 (m, 15 ar H) ppm; HPLC: k0 ¼ 3.36, t0 ¼ 1.89
(RP-18, MeCN=H2O 1=1), k0 ¼ 7.80, t0 ¼ 1.89 (Chiralcel
OJ-R, MeCN=H2O 3=7).
N-{-2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-alanyl-L-
valine methyl ester (5f, C20H27N3O5)
From 4a (0.3g, 1.46mmol) and L-Ala-L-Val-OMe-HCl (0.48 g,
1.51 mmol). Yield 0.26 g (46%); Rf ¼ 0.53; IR: ꢃꢀ¼ 3307
1
(NH), 3065, 2965 (CH), 1746, 1653, 1540 (CO) cmꢂ1; H
NMR: ꢁ ¼ 0.87 (d, J ¼ 6.8 Hz, MeVal), 0.90 (d, J ¼ 6.7 Hz,
MeVal), 1.31–1.35 (d, J ¼ 7.0 Hz, MeAla), 2.06–2.22 (m,
ꢀ-HVal), 2.86–2.95 (dd, JAX ¼ 2.0 Hz, JAM ¼ 14.8 Hz, 3-H),
5.2 Hz, JAM ¼ 14.8Hz, 30-H), 3.72 (s, OMe), 4.18–4.26 (d,
N-{-3-[(RS)-2-oxo-4-phenylazetidin-1-yl]propionyl}-L-phenyl-
alanyl-L-valine methyl ester (5j, C27H33N3O5)
From 4b (0.15 g, 700 ꢂmol) and L-Phe-L-Val-OMe-HCl
3.38–3.46 (d, J ¼ 16.7 Hz, 1H, CH2), 3.42–3.52 (dd, JMX
¼
20
(0.2 g, 500 ꢂmol). Yield 0.11 g (33%); Rf ¼ 0.72; ½ꢄꢆD
¼

632
A. Elriati et al.
ꢂ10.0ꢁ cm2 gꢂ1 (c ¼ 1.1, AcOEt); IR: ꢃꢀ¼ 3284 (NH), 3064,
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-valyl-L-
leucine methyl ester (5n, C25H37N3O5)
2967(CH), 1741, 1645, 1548 (CO) cmꢂ1
;
1H NMR: ꢁ ¼
0.81–0.84 (d, J ¼ 7.0 Hz, MeVal), 0.84–0.88 (d, J ¼ 7.2 Hz,
MeVal), 2.05 (m, ꢀ-HVal), 2.42 (m, CH2), 2.73–2.81 (d,
3-H), 3.05–3.08 (m, CH2Phe), 3.19–3.39 (m, 1H, CH2,
30-H), 3.49 (m, 1H, CH2), 3.69 (s, OMe), 4.39–4.45 (m,
ꢄ-HPhe), 4.47–4.54 (m, 4-H), 4.65–4.72 (m, ꢄ-HVal), 6.25,
6.39 (2d, J ¼ 8.0 Hz, N–HPhe), 6.60 (d, N–HVal), 7.23–7.38
(m, 10 ar H) ppm; HPLC: k0 ¼ 0.69, t0 ¼ 1.89 (RP-18,
MeCN=H2O 7=3).
From 4c (0.4g, 1.71 mmol) and L-Val-L-Leu-OMe-HCl
(0.44 g, 1.78 mmol). Yield 0.26 g (33%); Rf ¼ 0.55 (AcOEt=
20
cyclohexane 1=1); ½ꢄꢆD ¼ ꢂ52.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH);
IR: ꢃꢀ¼ 3294 (NH), 3060 (CH), 2959, 2872 (CH), 1750,
1
1642, 1543 (CO) cmꢂ1; H NMR: ꢁ ¼ 0.93 (d, J ¼ 6.9 Hz, 2
MeVal), 0.96 (d, J ¼ 6.4 Hz, 2 MeLeu), 1.69 (m, ꢅ-HLeu), 1.73
(m, ꢀ-HLeu), 176 (m, CH2), 2.13 (m, ꢀ-HVal), 2.16 (m, CH2),
2.88 (dd, JAX ¼ 2.2 Hz, JAM ¼ 14.6 Hz, 3-H), 3.05 (d, 1H,
CH2), 3.31 (dd, JMX ¼ 5.1 Hz, JAM ¼ 14.6Hz, 30-H), 3.52–
3.59 (m, 1H, CH2), 3.70 (s, OMe), 4.34 (m, ꢄ-HVal), 4.44
(m, ꢄ-HLeu), 4.60 (dd, JAX ¼ 2.2 Hz, JMX ¼ 5.1 Hz, 4-H),
7.11 (d, J ¼ 8.8 Hz, N–H), 7.18 (d, J ¼ 8.9 Hz, N–H), 7.34
(m, 5 ar H) ppm; HPLC: k10 ¼ 14.15, k20 ¼ 14.99, t0 ¼ 2.23
(RP-18, MeCN=H2O 3=7); ratio of diastereoisomers 57:43.
N-{-3-[(RS)-2-oxo-4-phenylazetidin-1-yl]propionyl}-L-phenyl-
alanyl-L-leucine methyl ester (5k, C28H35N3O5)
From 4b (0.15 g, 700 ꢂmol) and L-Phe-L-Leu-OMe-HCl
20
(0.31 g, 730 ꢂmol). Yield 0.22 g (63%); Rf ¼ 0.93; ½ꢄꢆD
2956 (CH), 1747, 1645, 1550 (CO) cmꢂ1
¼
ꢂ19.0ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3284 (NH), 3064,
;
1H NMR:
ꢁ ¼ 0.87 (d, J ¼ 5.4 Hz, 2 MeLeu), 1.42–1.55 (m, ꢅ-H, 2 ꢀ-
HLeu), 2.34–2.58 (m, CH2), 2.73–2.79 (dd, JAX ¼ 2.4 Hz,
JAM ¼ 14.6Hz, 3-H), 3.04–3.09 (m, CH2Phe), 3.31 (m, 1H,
CH2), 3.38 (dd, JMX ¼ 5.1 Hz, JMB ¼ 14.6 Hz, 30-H), 3.5 (m,
1H, CH2), 3.69, 3.70 (2s, OMe), 4.38–4.42 (dd, JAX ¼ 2.4 Hz,
JMX ¼ 5.2 Hz, 4-H), 4.52–4.55 (m, ꢄ-HLeu), 4.66–4.77 (m, ꢄ-
HPhe), 6.32–6.43 (2d, J ¼ 8.0, 8.0 Hz, N–HLeu), 6.45–6.52 (2d,
J ¼ 6.0, 8.0 Hz, N–HPhe), 7.23–7.38 (m, 10 ar H) ppm; HPLC:
k0 ¼ 3.51, t0 ¼ 2.01 (RP-18, MeCN=H2O 4=6).
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-phenyl-
alanyl-L-leucine methyl ester (5o, C29H37N3O5)
From 4c (0.41 g, 1.73mmol) and L-Phe-L-Leu-OMe-HCl
20
(0.53 g, 1.80mmol). Yield 0.24 g (27%); Rf ¼ 0.67; ½ꢄꢆD
¼
ꢂ27.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3287 (NH), 3063,
1
2955, 2869 (CH), 1751, 1643, 1547 (CO) cmꢂ1; H NMR:
ꢁ ¼ 0.89 (d, 2 Me), 1.56 (m, ꢅ-H, 2 ꢀ-HLeu), 1.71 (m, CH2),
2.18–2.21 (m, CH2), 2.77–2.87 [(m, 1H, CH2), (dd, JAX
¼
2.9 Hz, JAM ¼ 14.6Hz, 3-H), 3.04–3.22 (m, 2 ꢀ-HPhe), 3.30–
3.40 (m, 1H, CH2; dd, JMX ¼ 5.0 Hz, JAM ¼ 14.6Hz, 30-H),
3.69 (s, OMe), 4.53–4.55 {(m, 4-H, ꢄ-HLeu), 4.71–4.78 (m,
ꢄ-HPhe), 6.43 (2d, N-HLeu), 6.81–6.99 (m, N–HPhe), 7.35 (m,
10 ar H) ppm; HPLC: k10 ¼ 10.39, k20 ¼ 10.69, t0 ¼ 1.83
(RP-18, MeCN=H2O 4=6); ratio of diastereoisomers 48:52.
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-alanyl-L-
valine methyl ester (5l, C22H31N3O5)
From 4c (0.33 g, 1.6 mmol) and L-Ala-L-Val-OMe-HCl (0.3g,
1.74mmol). Yield 0.1 g (15%); Rf ¼ 0.66; IR: ꢃꢀ¼ 3302 (NH),
1
3067, 2964, 2934 (CH), 1744, 1649, 1545 (CO) cmꢂ1; H
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-phenyl-
NMR: ꢁ ¼ 0.88 (d, J ¼ 6.9 Hz, MeVal), 0.89 (d, J ¼ 6.6 Hz,
MeVal), 0.92 (d, J ¼ 6.0 Hz, MeAla), 1.22–1.32 (m, CH2),
2.03 (m, CH2), 2.13 (m, ꢀ-HVal), 2.95 (dd, JAX ¼ 2.2 Hz,
JAM ¼ 14.9Hz, 3-H), 3.43 (m, 1H, CH2), 3.55 (dd,
JMX ¼ 5.3 Hz, JAM ¼ 14.9Hz, 30-H), 3.73, 3.74 (2s, OMe),
4.00–4.35 (2m, 1H, CH2, ꢄ-HAla), 4.47–4.55 (m, ꢄ-HVal),
4.79–4.83 (dd, JAX ¼ 2.3 Hz, JMX ¼ 5.1Hz, 4-H), 6.44–6.55
(m, N–H), 6.86 (d, J ¼ 7.8 Hz, N–H), 7.34 (m, 5 ar H) ppm.
alanyl-L-valine methyl ester (5p, C28H35N3O5)
From 4c (0.3g, 1.28 mmol) and L-Phe-L-Val-OMe-HCl
20
(0.52 g, 1.33mmol). Yield 0.38 g (60%); Rf ¼ 0.58; ½ꢄꢆD
¼
ꢂ11.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3290 (NH), 3064,
2962 (CH), 1749, 1645,1541 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.81–
0.89 (d, J ¼ 7.0 Hz, 2 MeVal), 1.56–173 (m, CH2), 2.04–2.26
(m, ꢀ-HVal, CH2), 2.70–2.91 (dd, JAX ¼ 2.2 Hz, JAM ¼ 14.6Hz,
3-H, m, 1H, CH2), 2.97–3.22 (m, 2 ꢀ-HPhe), 3.31–3.45 (dd,
JMX ¼ 5.0 Hz, JAM ¼ 14.8Hz, 30-H, m, 1H, CH2), 3.69 (s,
OMe), 4.38–4.47 (m, ꢄ-HVal), 4.50–4.55 (dd, JAX ¼ 2.1 Hz,
JMX ¼ 4.95Hz, 4-H), 4.66–4.80 (m, ꢄ-HPhe), 6.36, 6.50 (2d,
J ¼ 7.2 Hz, N–HVal), 6.75, 6.81 (2d, J ¼ 8.6 Hz, N–HPhe),
7.11–7.40 (m, 10 ar H) ppm; HPLC: k0 ¼ 5.51, t0 ¼ 1.89
(RP-18, MeCN=H2O 1=1).
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-valyl-L-
valine methyl ester (5m, C24H35N3O5)
From 4c (0.4g, 1.71 mmol) and L-Val-L-Val-OMe-HCl
20
(0.41 g, 1.78 mmol). Yield 0.1 g (12%); Rf ¼ 0.59; ½ꢄꢆD
¼
ꢂ35.25ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3300 (NH), 3067,
1
2964, 2934 (CH), 1732, 1644, 1548 (CO) cmꢂ1; H NMR:
ꢁ ¼ 0.90, 0.92 (d, J ¼ 6.9 Hz, MeVal), 0.95, 0.98 (d, J ¼
7.0 Hz, MeVal), 1.67–1.86 (m, CH2), 2.07–2.22 (m, 2
ꢀ-HVal), 2.29–2.42 (m, CH2), 2.81–2.91 (dd, JAX ¼ 2.15 Hz,
JAM ¼ 14.8 Hz, 3-H), 3.00–3.13 (m, 1H, CH2), 3.33–3.41
(dd, JMX ¼ 5.2 Hz, JAM ¼ 14.8 Hz, 30-H), 3.44–3.62 (m, 1H,
CH2), 3.70 (s, OMe), 4.36–4.47 (m, ꢄ-HVal), 4.50–4.57 (m,
ꢄ-HVal), 4.60–4.64 (dd, JAX ¼ 2.15 Hz, JMX ¼ 5.2 Hz, 4-H),
7.03–7.19 (m, 2 N–H), 7.31–7.44 (m, 5 ar H) ppm; HPLC:
k0 ¼ 1.67, t0 ¼ 2.13 (RP-18, MeCN=H2O 1=1), k10 ¼ 8.40,
k20 ¼ 8.72, t0 ¼ 2.23 (RP-18, MeCN=H2O 3=7); ratio of dia-
stereoisomers 42:58.
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-valyl-L-
phenylalanine methyl ester (5q, C28H35N3O5)
From 4c (0.3 g, 1.28 mmol) and L-Val-L-Phe-OMe-HCl
20
(0.52 g, 1.33 mmol). Yield 169 mg (27%); Rf ¼ 0.41; ½ꢄꢆD
¼
2
ꢂ31.25ꢁ cm gꢂ1 (c ¼ 2, MeOH); IR:
ꢃꢀ¼ 3291 (NH), 3063,
2960 (CH), 1748, 1641, 1540 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.84
(d, J ¼ 7.1 Hz, MeVal), 0.92 (d, J ¼ 8.0 Hz, MeVal), 1.57–1.87
(m, CH2), 2.00–2.22 (m, ꢀ-HVal), 2.22–2.37 (m, CH2), 2.76–
2.90 (dd, JAX ¼ 2.1 Hz, JAM ¼ 14.6Hz, 3-H), 3.00–3.26 (m,
1H, CH2, CH2Phe), 3.32–3.57 (m, 1H, CH2), 3.34–3.44 (dd,

ꢀ-Lactam Derivatives as Enzyme Inhibitors
633
JMX ¼ 5.1 Hz, JAM ¼ 14.6Hz, 30-H), 3.69 (s, OMe), 4.25–4.32
(m, ꢄ-HVal), 4.55–4.60 (dd, JAX ¼ 2.1 Hz, JMX ¼ 5.1 Hz, 4-H),
4.82–4.94 (m, ꢄ-HPhe), 6.71–6.78 (2d, J ¼ 8.2, 7.3Hz, N–
HVal), 6.91–6.94 (2d, J ¼ 8.8, 8.0 Hz, N–HPhe), 7.13–7.37
(m, 10 ar H) ppm; HPLC: k0 ¼ 5.76, k0 ¼ 6.01, t0 ¼ 1.89
(RP-18, MeCN=H2O 1=1), k101¼ 8.18, k202¼ 8.65, t0 ¼ 2.01
(RP-18, MeCN=H2O 4=6); ratio of diastereoisomers 54:46.
ꢂ24.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3292 (NH), 3063,
2956 (CH), 1746, 1643, 1540 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.84
(d, J ¼ 6.15Hz, MeVal), 0.92 (d, J ¼ 6.6 Hz, MeVal),1.48–1.78
(m, 2CH2), 2.04–2.11 (m, ꢀ-HVal), 2.16–2.33 (m, CH2), 2.77–
2.91 (dd, JAX ¼ 2.7 Hz, JAM ¼ 14.3Hz, 3-H, m, 1H, CH2), 3.08
(dd, J ¼ 6.2, 14.5 Hz, 2 ꢀ-HPhe), 3.29–3.48 (dd, JMX ¼ 5.4 Hz,
JAM ¼ 14.9Hz, 30-H, m, 1H, CH2), 3.69, 3.71 (2s, OMe),
4.20–4.34 (m, ꢄ-HVal), 4.53–4.60 (dd, JAX ¼ 2.6 Hz, JMX
¼
5.2 Hz, 4-H), 4.81–4.94 (dd, J ¼ 6.1, 7.8Hz, ꢄ-HPhe), 6.19
(d, J ¼ 8.3 Hz, N–HVal), 6.39 (d, J ¼ 7.9 Hz, N–HPhe), 7.08–
7.36 (m, 10 ar H) ppm; HPLC: k0 ¼ 5.61, t0 ¼ 1.89 (RP-18,
MeCN=H2O 1=1), k10 ¼ 32.99, k20 ¼ 35.57, t0 ¼ 2.39 (RP-18,
MeCN=H2O 3=7); ratio of diastereoisomers 21:79.
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-phenyl-
alanyl-L-phenylalanine methyl ester (5r, C32H35N3O5)
From 4c (0.3g, 1.28mmol) and L-Phe-L-Phe-OMe-HCl
20
(0.58 g, 1.61mmol). Yield 0.28 g (41%); Rf ¼ 0.61; ½ꢄꢆD
¼
ꢂ13.75ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3278 (NH), 3061,
2949 (CH), 1732, 1651, 1538 (CO) cmꢂ1
;
1H NMR: ꢁ ¼
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-phe-
nylalanyl-L-phenylalanine methyl ester (5v, C33H37N3O5)
From 4d (0.3g, 1.21mmol) and L-Phe-L-Phe-OMe-HCl
(0.55 g, 1.25mmol). Yield 0.14g (10%); Rf ¼ 0.55; IR: ꢃꢀ¼
1.57–1.78 (m, CH2), 2.04–2.20 (m, CH2), 2.66–3.14 (dd,
JAX ¼ 2.2 Hz, JAM ¼ 14.6Hz, 3-H), 2.66–2.76 (m, 1H, CH2),
2.89–3.14 (m, 4 ꢀ-HPhe), 3.25–3.40 (m, 1H, CH2), 3.30–3.40
(dd, JMX ¼ 5.0 Hz, JAM ¼ 14.6 Hz, 30-H), 3.67 (s, OMe), 4.50–
4.54 (dd, JAX ¼ 2.2 Hz, JMX ¼ 5.0 Hz, 4-H), 4.59–4.70 (m,
ꢄ-HPhe), 4.78 (m, ꢄ-HPhe), 6.70 (d, J ¼ 7.8 Hz, N–HPhe),
6.79 (d, J ¼ 7.4 Hz, N–HPhe), 7.06–7.39 (m, 15 ar H) ppm;
HPLC: k0 ¼ 11.12, t0 ¼ 2.12 (RP-18, MeCN=H2O 3=7),
k10 ¼ 7.30, k20 ¼ 7.97, t0 ¼ 2.73 ((S,S)-Whelk 01, n-hexane=2-
propanol 1=1); ratio of diastereoisomers 54:46.
3281 (NH), 3061, 2949 (CH), 1747, 1642, 1543 (CO) cmꢂ1
;
1H NMR: ꢁ ¼ 1.39–1.66 (m, 2 CH2), 2.04–2.12 (m, CH2),
2.76–2.83 (dd, JAX ¼ 2.2 Hz, JAM ¼ 14.4Hz, 3-H), 2.92–3.15
(m, 1H, CH2, 4 ꢀ-HPhe), 3.27–3.37 (dd, JMX ¼ 5.2 Hz, JAM
¼
14.4Hz, 30-H), 3.33–3.43 (m, 1H, CH2), 3.67, 3.68 (2s, OMe),
4.51–4.55 (dd, JAX ¼ 2.2 Hz, JMX ¼ 5.2 Hz, 4-H), 4.55–4.66
(dd, J ¼ 7.2, 7.4 Hz, ꢄ-HPhe), 4.7–4.8 (dd, J ¼ 6.2, 7.2 Hz,
ꢄ-HPhe), 6.12 (d, J ¼ 7.4 Hz, N–HPhe), 6.24 (d, J ¼ 7.5 Hz,
N–HPhe), 6.98–7.39 (m, 15 ar H) ppm; HPLC: k0 ¼ 5.85,
t0 ¼ 1.89 (RP-18, MeCN=H2O 1=1), k0 ¼ 9.65, t0 ¼ 1.89
(Chiralcel OJ-R, MeCN=H2O 3=7).
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-valyl-
L-leucine methyl ester (5s, C26H39N3O5)
From 4d (0.32 g, 1.21mmol) and L-Val-L-Leu-OMe-HCl
(0.45 g, 1.26mmol). Yield 0.39 g (67%); Rf ¼ 0.54; IR: ꢃꢀ¼
3290 (NH), 3066, 2958 (CH), 1750, 1645,1540 (CO) cmꢂ1
;
1H NMR: ꢁ ¼ 0.92 (d, J ¼ 6.0 Hz, 2 MeLeu), 0.95 (d, J ¼
7.0 Hz, 2 MeVal), 1.49–1.62 (m, 2CH2, 2 ꢀ-H, ꢅ-HLeu),
2.02–2.20 (m, CH2, ꢀ-HVal), 2.72–2.86 (m, 3-H, 1H, CH2),
3.31–3.43 (m, 30-H, 1H, CH2), 3.72 (s, OMe), 4.25–4.33 (m,
ꢄ-HVal), 4.55–4.58 (m, ꢄ-HLeu, 4-H), 6.31 (d, J ¼ 8.6 Hz,
N-HLeu), 6.51 (d, J ¼ 7.8 Hz, N–HVal), 7.33 (m, ar H) ppm;
HPLC: k0 ¼ 2.46, t0 ¼ 2.13 (RP-18, MeCN=H2O 1=1).
N-{2-[(RS)-2-oxo-4-phenylazetidin-1-yl]acetyl}-L-valine
methyl ester (6a, C17H22N2O4)
From 4a (0.3 g, 1.46 mmol) and L-Val-OMe-HCl (0.26 g,
20
1.52 mmol). Yield 0.46 g (99%); Rf ¼ 0.66; ½ꢄꢆD
¼
ꢂ18.00ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3291 (NH), 3061,
2959 (CH), 1754, 1649, 1540 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.92,
0.93 (2d, each J ¼ 6.8 Hz, 2 MeVal), 2.15 (m, ꢀ-HVal), 2.91–
2.98 (dd, JAX ¼ 2.4 Hz, JAM ¼ 14.9Hz, 3-H), 3.41–3.56 (m,
1H, CH2), 3.47 (dd, JMX ¼ 5.2 Hz, JAM ¼ 14.9Hz, 30-H),
3.74 (s, OMe), 4.14 (m, 1H, CH2), 4.47 (dd, J ¼ 4.9, 8.5 Hz,
ꢄ-HVal), 4.82 (dd, JAX ¼ 2.4 Hz, JMX ¼ 5.2 Hz, 4-H), 6.74 (d,
J ¼ 8.2 Hz, N–HVal), 7.26 (m, 5 ar H) ppm; HPLC: k10 ¼ 6.74,
k20 ¼ 7.27, t0 ¼ 1.81 (RP-18, MeCN=H2O 4=6), ratio of diaster-
eoisomers 54:46.
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-phe-
nylalanyl-L-valine methyl ester (5t, C29H37N3O5)
From 4d (0.3g, 1.21mmol) and L-Phe-L-Val-OMe-HCl
20
493 mg (1.26 mmol). Yield 0.2 g (32%); Rf ¼ 0.54; ½ꢄꢆD
¼
ꢂ10.80ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3287 (NH), 3064,
2962 (CH), 1748, 1640, 1542 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.81
(d, J ¼ 7.1 Hz, MeVal), 0.84 (d, J ¼ 6.9 Hz, MeVal), 1.41–1.59
(m, 2CH2), 2.04–2.15 (m, ꢀ-HVal, CH2), 2.79–2.85 (m, 3-H,
1H, CH2), 3.04 (d, J ¼ 7.1 Hz, 2 ꢀ-HPhe), 3.28–3.41 (dd,
JMX ¼ 5.1 Hz, JAM ¼ 14.5Hz, 30-H, m, 1H, CH2), 3.69 (s,
OMe), 4.39–4.46 (dd, J ¼ 5.0, 8.4 Hz, ꢄ-HVal), 4.53 (dd,
JAX ¼ 2.4 Hz, JMX ¼ 5.0 Hz, 4-H), 4.62–4.73 (dd, J ¼ 7.4,
14.7Hz, ꢄ-HPhe), 6.29 (d, J ¼ 4.2 Hz, N–HVal), 6.38 (d,
J ¼ 6.8 Hz, N–HPhe), 7.23–7.39 (m, 10 ar H) ppm; HPLC:
k0 ¼ 5.10, t0 ¼ 1.89 (RP-18, MeCN=H2O 1=1).
N-{-3-[(RS)-2-oxo-4-phenylazetidin-1-yl]propionyl}-L-
alanine benzyl ester (6b, C22H24N2O4)
From 4b (0.5 g, 2.28 mmol) and L-Ala-OBn-tosylate
20
(0.83 g, 2.37 mmol). Yield 0.43 g (50%); Rf ¼ 0.45; ½ꢄꢆD
¼
ꢂ29.0ꢁ cm2 gꢂ1 (c ¼ 1.0, MeOH); IR: ꢃꢀ¼ 3323 (NH), 3065,
2924 (CH), 1733, 1669, 1540 (CO) cmꢂ1 1H NMR:
;
ꢁ ¼ 1.37, 1.42 (2d, each J ¼ 7.2 Hz, MeAla), 2.44–2.57 (m,
CH2), 2.77 (dd, JAX ¼ 3.6 Hz, JAM ¼ 14.7 Hz, 3-H), 3.20 (m,
1H, CH2), 3.28 (dd, JMX ¼ 4.2 Hz, JAM ¼ 14.7 Hz, 30-H), 3.54
(m, 1H, CH2), 4.52 (m, ꢄ-HAla), 4.57 (dd, JAX ¼ 3.6 Hz,
JMX ¼ 4.2 Hz, 4-H), 5.17 (d, J ¼ 2.2 Hz, CH2benzyl), 6.40 (s,
br, N–H), 7.30–7.35 (m, 10 ar H) ppm; HPLC: k0 ¼ 0.74,
t0 ¼ 1.78 (RP-18, MeCN=H2O 3=7), k10 ¼ 1.13, k20 ¼ 2.02,
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-valyl-
L-phenylalanine methyl ester (5u, C29H37N3O5)
From 4d (0.3g, 1.21mmol) and L-Val-L-Phe-OMe-HCl
20
(0.5g, 1.25mmol). Yield 0.14 g (23%); Rf ¼ 0.39; ½ꢄꢆD
¼

634
A. Elriati et al.: ꢀ-Lactam Derivatives as Enzyme Inhibitors
t0 ¼ 1.80 (Chiralcel OJ-R, MeCN=H2O 4=6); ratio of
Acknowledgements
diastereoisomers 52:48.
We wish to thank Degussa AG, Frankfurt, for the generous
support with amino acids, E. Merck KGaA, Darmstadt, for the
support with chromatography materials, and the ,,Fonds der
Chemischen Industrie‘‘ for financial support.
N-{-4-[(RS)-2-oxo-4-phenylazetidin-1-yl]butyryl}-L-valine
methyl ester (6c, C19H26N2O4)
From 4c (0.3 g, 1.28 mmol) and L-Val-OMe-HCl (0.22 g,
20
1.34 mmol). Yield 0.25 g (57%); Rf ¼ 0.69; ½ꢄꢆD
¼
ꢂ15.25ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3299 (NH), 3033,
2963 (CH), 1740, 1654, 1540 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.95,
0.97 (2d, each J ¼ 6.8 Hz, 2 MeVal), 1.76 (m, CH2), 2.19 (m,
ꢀ-HVal), 2.33 (m, CH2), 2.85 (dd, JAX ¼ 2.0 Hz, JAM ¼ 14.7 Hz,
References
[1] Crystal RG (1992) Drugs of the Future 17: 387
[2] Merritt TA, Cochrane CG, Holcomb K, Bohl B, Hallman
M, Strayer D, Edwards D, Gluck L (1983) J Clin Invest
72: 656; Petty TL (1991) Ann NY Acad Sci 624: 267
[3] Jackson AH, Hill SL, Afford SC, Stockley RA (1984) J
Respir Dis 65: 114; Nadel JA (1991) Ann NY Acad Sci
624: 286
[4] Ekerot L, Ohlsson K (1984) Adv Exp Med Biol 167: 335
[5] Eriksson S (1991) Eur Respir J 4: 1041; Snider GL,
Ciccolella DE, Morris SM, Stone PJ, Lucey EC
(1991) Ann NY Acad Sci 624: 45
3-H), 3.31 (dt, J ¼ 8.5, 14.5 Hz, 1H, CH2), 3.35 (dd, JMX
¼
5.2 Hz, JAM ¼ 14.7Hz, 30-H), 3.62 (dt, J ¼ 8.3, 14.5Hz, 1H,
CH2), 3.72 (s, OMe), 4.48 (dd, J ¼ 4.5, 8.7Hz, ꢄ-HVal), 4.59
(dd, JAX ¼ 2.2 Hz, JMX ¼ 5.2 Hz, 4-H), 7.06 (d, J ¼ 8.25Hz,
N–HVal), 7.31 (m, 5 ar H) ppm; HPLC: k0 ¼ 9.27, t0 ¼ 2.12
(RP-18, MeCN=H2O 3=7).
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-valine
methyl ester (6d, C20H28N2O4)
From 4d (0.3g, 1.21 mmol) and L-Val-OMe-HCl (0.21 g,
[6] For a review see: Elriati A (2003) Thesis University of
Greifswald
20
1.26 mmol). Yield 0.26 g (57%); Rf ¼ 0.52; ½ꢄꢆD
¼
ꢂ18.50ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3330 (NH), 2963
(CH), 1742, 1650, 1537 (CO) cmꢂ1; 1H NMR: ꢁ ¼ 0.91, 0.93
(2d, each J ¼ 6.7 Hz, 2 MeVal), 1.51 (m, CH2), 1,67 (m, CH2),
[7] Doherty JB, Shah SK, Finke PE, Dorn CP, Hagmann WK,
Hale JJ, Kissinger AL, Thompson KR, Brause K,
Chandler GO, Knight WB, Maycock AL, Ashe BM
(1993) Prod Natl Acad Sci USA 90: 8727; Chabin R,
Green BG, Gale P, Maycock AL, Weston H, Dorn CP,
Finke PE, Hagmann WK, Hale JJ, MacCoss M, Shah SK,
Underwood D, Knight JB (1993) Biochem 32: 8970;
Green BG, Chabin R, Mills S, Underwood DJ, Shah
SK, Kuo D, Gale P, Maycock AL, Liesch J, Burgey CS,
Dohrety JP, Dorn CP, Finke PE, Hagmann WK, Hale JJ,
MacCossM,WstlerWM,KnightWB(1995)Biochem34:
14331; Underwood DJ, Green BG, Chabin R, Mills S,
Doherty LB, Fine PE, MacCoss M, Shah SK, Burgey CS,
Dickinson TA, Griffin PR, Lee TE, Swiderek KM, Covery
T, Westler WM, Knight WB (1995) Biochem 34: 14344;
Cvetovich RJ, Chartrain M, Hartner F, Jun W, Roberge C,
Amato JS, Grabowski EJ (1996) J Org Chem 61: 6575;
Wilmouth RC, Westwood NJ, Anderson K, Brownlee W,
Claridge TDW, Clifton IJ, Pritchard GJ, Aplin RT,
Schofield CJ (1998) Biochem 37: 17506
[8] Rode H, Koerbe S, Besch A, Methling K, Loose J, Otto
H-H (2006) Bioorg Med Chem 14: 2789; Rode H, Sprang
T, Besch A, Loose J, Otto H-H (2005) Pharmazie 60: 723
[9] Schneider M, Otto H-H (2001) Arch Pharm Pharm Med
Chem 334: 167; Venz C, Otto H-H (2001) Pharmazie
56: 686; Achilles K, Schirmeister T, Otto H-H (2000)
Arch Pharm Pharm Med Chem 333: 243; Achilles K,
Schneider M, Schirmeister T, Otto H-H (2000) Pharma-
zie 55: 798
2.07 (m, ꢀ-HVal), 2.26 (m, CH2), 2.82 (dd, JAX¼ 2.0 Hz, JAM
¼
14.4Hz, 3-H), 2.86 (m, 1H, CH2), 3.35 (dd, JMX ¼ 4.6 Hz,
JAM ¼ 14.5Hz, 30-H), 3.43 (m, 1H, CH2), 3.73 (s, OMe), 4.50
(dd, J ¼ 5.1, 8.8 Hz, ꢄ-HVal), 4.57 (dd, JAX ¼ 2.8 Hz, JMX
¼
4.6 Hz, 4-H), 6.21 (d, J ¼ 5.6, N–HVal), 7.42 (m, 5 ar H)
ppm; HPLC: k0 ¼ 2.82, t0 ¼ 1.89 (RP-18, MeCN=H2O 1=1).
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-
aspartic acid dibenzyl ester (6e, C32H34N2O6)
From 4d (0.5 g, 1.02 mmol) and L-Asp(OBn)2-HCl
20
(1.0 g, 2.1 mmol). Yield 0.31 g (55%); Rf ¼ 0.64; ½ꢄꢆD
¼
ꢂ11.9ꢁ cm2 gꢂ1 (c ¼ 2, MeOH); IR: ꢃꢀ¼ 3305 (NH), 3062,
2949 (CH), 1737, 1672, 1537 (CO) cmꢂ1 1H NMR:
;
ꢁ ¼ 1.44 (m, 2CH2), 2.15 (m, CH2), 2.79 (m, CH2Asp), 3.02
(dd, J ¼ 2.9, 14.4Hz, 3-H), 3.29 (dd, J ¼ 5.2, 14.4 Hz, 30-H),
3.37 (m, 1H, CH2), 3.84 (m, 1H, CH2), 4.53 (dd, J ¼ 2.9,
5.2 Hz, 4-H), 4.87 (m, ꢄ-HAsp), 5.05, 5.13 (2d, 2CH2benzyl),
6.48 (d, J ¼ 7.8, N–H), 7.33 (m, 15 ar H) ppm; HPLC:
k0 ¼ 9.81, t0 ¼ 1.89 (RP-18, MeCN=H2O 1=1), k10 ¼ 21.68,
k20 ¼ 22.94, t0 ¼ 1.89 (Chiralcel OJ-R, MeCN=H2O 3=7), ratio
of diastereoisomers 60:40.
N-{-5-[(RS)-2-oxo-4-phenylazetidin-1-yl]valerianyl}-L-
alanine benzyl ester (6f, C24H28N2O4)
From 4d (0.5g, 2.02 mmol) and L-Ala-OBn-tosylate (0.74 g,
20
2.10mmol). Yield 0.2g (24%); Rf ¼ 0.50; ½ꢄꢆD
¼
[10] Graf R (1963) Liebigs Ann Chem 661: 111
[11] Reuschling D, Pietsch H, Linkies A (1978) Tetrahedron
Lett 7: 615
[12] Achilles K (1997) Thesis University of Freiburg, and [9]
[13] Drauz K, Waldmann H (ed) (1995) Hydrolysis and
Formation of C–O– Bonds, VCH Weinheim
[14] DeimerKH, Thamm PT, StelzelP (1974) inHouben-Weyl
Methoden der organischen Chemie, Thieme Stuttgart
vol XV=1, 315; Wendleberger (1974) in vol XV=2, 111
ꢂ31.83ꢁ cm2 gꢂ1 (c ¼ 1.0, MeOH); IR: ꢃꢀ¼ 3452 (NH), 2929
1
(CH), 1735, 1652, 1540 (CO) cmꢂ1; H NMR: ꢁ ¼ 1.35 (d,
J ¼ 7.1 Hz, MeAla), 1.59 (m, 2CH2), 2.20 (m, CH2), 2.71–2.78
(m, 3-H, 1H, CH2), 3.26–3.42 (m, 30-H, 1H, CH2), 4.54–4.61
(m, 4-H, ꢄ-HAla), 5.12 (dd, CH2benzyl), 7.01 (d, J ¼ 7.3 Hz, N–
H), 7.30 (m, 10 ar H) ppm; HPLC: k0 ¼ 0.86, t0 ¼ 1.78 (RP-
18, MeCN=H2O 7=3), k10 ¼ 1.28, k20 ¼ 1.46, t0 ¼ 1.89 (Chiral-
cel OJ-R, MeCN=H2O 4=6), ratio of diastereoisomers 52:48.

¨
Verleger: Springer-Verlag GmbH, Sachsenplatz 4–6, 1201 Wien, Austria. – Herausgeber: Osterreichische Akademie der Wissenschaften, Dr.-Ignaz-Seipel-Platz 2,
¨
1010 Wien, und Gesellschaft Osterreichischer Chemiker, Eschenbachgasse 9, 1010 Wien, Austria. – Redaktion: Getreidemarkt 9=163-OC, 1060 Wien, Austria. –
Satz und Umbruch: Thomson Press Ltd., Chennai, India. – Offsetdruck: Krips bv, Kaapweg 6, 7944 HV Meppel, The Netherlands. – Verlagsort: Wien. –
Herstellungsort: Meppel. – Printed in The Netherlands.