One-pot enzymatic desymmetrization and Ugi MCR

Article abstract of DOI:10.1016/j.tet.2005.04.032

A new approach to the synthesis of chiral peptidomimetics is reported. It combines an enzymatic desymmetrization of 3-phenylglutaric anhydrides with a subsequent Ugi multi-component reaction in a one-pot, two-step procedure. NMR and CD spectroscopy was used to assign the configurations of obtained products. Our synthetic method is very efficient and it can easily be extended to other types of multi-component reactions and can be used for the preparation of chiral peptidomimetic libraries.

Full text of DOI:10.1016/j.tet.2005.04.032

Tetrahedron 61 (2005) 6064–6072
One-pot enzymatic desymmetrization and Ugi MCR
Anna Fryszkowska,a Jadwiga Frelekb and Ryszard Ostaszewskia,b,
*
aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
bInstitute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 24 November 2004; revised 29 March 2005; accepted 15 April 2005
Available online 13 May 2005
Abstract—A new approach to the synthesis of chiral peptidomimetics is reported. It combines an enzymatic desymmetrization of
3-phenylglutaric anhydrides with a subsequent Ugi multi-component reaction in a one-pot, two-step procedure. NMR and CD spectroscopy
was used to assign the configurations of obtained products. Our synthetic method is very efficient and it can easily be extended to other types
of multi-component reactions and can be used for the preparation of chiral peptidomimetic libraries.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The generation of chiral combinatorial libraries by one-pot
methodologies is much more challenging.20 To gain access
to the optically active reactants for MCRs at least one
additional step is required. Routinely chiral compounds are
obtained via stereoselective synthesis paths (including
enzymatic resolution) or by chiral HPLC resolution of
enantiomers. Unfortunately, constructing a combinatorial
library for pharmaceutical purposes or asymmetric synthesis
means that additional step(s) is/are involved.21 In most cases,
different types of chiral auxiliaries are used in these syntheses.
This leads to substantial complication of the overall processes,
since not all auxiliaries are cheap and readily available in both
enantiomeric forms. Moreover, two additional steps are
required for introduction and efficient removal of these
groups. Recently, we announced a novel approach towards
the synthesis of chiral combinatorial libraries.22
Multi-component reactions (MCRs) are of great interest for
medicinal chemistry.1 MCRs can be efficiently used in the
synthesis of chiral compounds.2 They are also useful in
peptidomimetic synthesis due to their ability to generate a
large number of compounds efficiently in one or two
synthetic steps.3,4 Commonly used MCRs include the Ugi
reaction.5,6 These reactions are especially attractive as a
one-pot tandem processes with other reactions.
Only a few examples can be found in the literature, in which
one-pot, two-step and one-pot, three-step methodologies
involving Ugi condensation were applied.7–19 In the
significant majority of these processes, the Ugi MCR is
followed by a subsequent modification of the Ugi product,
as acidic hydrolysis or hydroxyaminolysis7 or post-
condensation modifications leading to cyclic products.8,9
In this paper we present the results of our studies on the
Scheme 1. Combination of enzymatic desymmetrization with Ugi condensation.
Keywords: Enzyme; Desymmetrization; Peptidomimetic.
*
Corresponding author. Tel.: C48 22 632 32 21; fax: C48 22 632 66 81; e-mail: rysza@icho.edu.pl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.032

A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
6065
Scheme 2. The synthesis of monoesters 4.
combination of multi-component reactions with enzymatic
procedures (Scheme 1).
provided access to different enantiomers (Table 1). The
reactions reached full conversion within a few days and
gave monoacids (4) in over 95% yields, while the same
racemic esters were obtained in 91, 89, 63% for 4a, 4b and
4c, respectively, according to the literature procedures.23,24
Our idea is based on the combination of enzymatic
procedures with multi-component condensations as a one-
pot, two-step reaction. We propose to use a meso reagent
(3) as a substrate, which can be enzymatically desym-
metrized into the desired optically active product (4). In this
way, two steps: enzymatic reaction and subsequent reaction
can be combined in one step. This two-step, one-pot
approach is much simpler then the ones currently used,
and application of chiral auxiliaries is omitted. We are
unaware of precedent methodology combining an enzy-
matic procedure with an MCC.
Absolute configurations of monoacids 4a and 4b were
established by comparison to literature data (vide infra). We
observed that while Novozym 435 and Chirazyme catalysed
formation of (S)-4a monoacid (78 and 80% ee, respect-
ively), the immobilized Amano PS lipase showed an
opposite selectivity ((R)-enantiomer formed with 66% ee).
Desymmetrization of anhydrides 3b and 3c led to the
formation of respective monoacids with lower enantiomeric
excess. According to our expectation, the enzyme changes
the stereoselectivity and the kinetics of the desymmetriza-
tion reaction. An influence of substituent on phenyl ring is
also observed. The presence of these substituents (4-Cl, for
4b and 4-OMe, for 4c) led to longer reaction time and
lowered the optical purity.
2. Results
The 3-phenylglutaric anhydrides (3), required for the
synthesis, were obtained according to the procedures
described previously23,24 from appropriate benzaldehydes
(1) and ethyl acetylacetate (2) in yields of 41% for 3a, 80%
for 3b, and 19% for 3c (Scheme 2).
Our initial idea of combination of Ugi four-component
condensations with enzymatic desymmetrization was based
on the assumption that both experimental procedures can be
performed simultaneously, in the same solvent. Initially, we
tried to perform the Ugi reaction in ethereal solvents, using
racemic monoester 4a, butylamine, 2-naphthaldehyde and
ethyl isocyanoacetate as reagents (entry 1 in Table 2). The
reaction did not occur. Addition of alcohol was necessary to
complete the reaction. In the mixture of isopropyl ether
and methanol (2:1, v/v) the reaction proceeded in 24 h and
the desired product was obtained in 6% yield (entry 2 in
Table 2). It is already known that aromatic aldehydes are
not good substrates for Ugi reaction. For isovaleraldehyde,
n-butylamine and benzyl isocyanate, the yield increased to
82% (entry 6 in Table 2). Interestingly, upon dilution of this
Since the carboxylic acid is one of the reactants in Ugi
MCR, we decided to generate these chiral reagents from
respective cyclic anhydrides 3. Enzymatic desymmetriza-
tion of meso-anhydrides with alcohols is known in
literature,25–30 but it has been never applied for 3-phenyl-
glutaric anhydrides.
For the preparation of chiral monoesters 4, the following
immobilized enzymes were used: Novozym 435 (CAL-B),
Chirazyme L-2, c-f, c-3 lyso (CAL-B) and immobilized
Amano PS lipase. Enzymes not only carried out the
desymmetrization efficiently but the change of the enzyme
Table 1. Enzymatic desymmetrization of anhydrides 1
Entry
Lipase
4a
4b
4c
Time
(days)
Time
(h)
Yield
(%)
ee20a
(%)
Conf.
Time
(days)
Yield
(%)
ee20b
(%)
Conf.
Yield
(%)
ee20b
(%)
Conf.
1
2
3
Novozym 435
Chirazyme L-2
Amano PS
48
48
48
99
99
95
78
80
66
(S)
(S)
(R)
5
4
4
99
99
99
54
60
14
(S)
(S)
(R)
13
7
7
99
99
99
68
73
52
(S)
(S)
(S)
immob.
Reagents and conditions: To the solution of anhydride 3 (0.05 mmol) in iso-propyl ether (1 mL) ethanol (0.075 mmol) was added, followed by respective
lipase: Novozym 435–7.6 mg; Chirazyme L-2, c.-f., c-3, Amano PS—6.2 mg. The reaction was conducted until it reached full conversion and ee was
determined by HPLC on Chiracel OD-H column.

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A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
Table 2. The synthesis of products 5a–i
Entry
5
Acid 4
R2
R3
R4
Solventa
Ugi MCR
Enzymatic and Ugi reaction
Time
(days)
Yield
Time
(days)
Yield
[a]D (benzene)
1
2
3
4
5
6
7
8
5a
5a
5a
5b
5c
5d
5d
5e
5f
4a
4a
(S)-4a
(S)-4a
(S)-4a
4a
(S)-4a
(S)-4b
(S)-4c
(S)-4a
(S)-4a
(S)-4a
2-Naph
2-Naph
2-Naph
p-Br-Ph
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
CH2COOEt
CH2COOEt
CH2COOEt
Bn
CH2COOEt
Bn
Bn
Bn
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Bn
A
B
B
B
B
B
B
B
B
B
B
B
4
1
1
17
9
4
5
7
7
4
0
6
6
—
—
6
2
15
9
32
49
82
81
70
72
80
23
33
31
49
—
65
61
78
67
25
—
K4.0 (c 1.29)
K0.9 (c 1.30)
2
2
2
2
15
K0.4 (c 1.31)
K4.9 (c 1.27)
K3.0 (c 1.28)
C9.0 (c 1.50)
K13.8 (c 1.43)
9
Bn
Bn
10
11
12
5g
5h
5i
i-Bu
p-Br-Ph
2-Naph
Bn
CH2COOEt
Bn
Bn
17
2
a Solvents: A—i-Pr2O, rt; B—i-Pr2O/MeoH, 2:1, v/v, rt.
reaction mixture the yield of reaction decreased to 65%
(concentrations of substrates are 0.042 and 0.170 M).
Further, dilution decreased the yield to 44% and the reaction
became poorly reproducible. In order to preserve repro-
ducibility, all experiments were performed at concentration
of substrates 0.1 M.
yield similar to that for Ugi reaction of racemic acid (entry 7
versus entry 6 in Table 3). Desymmetrization of 3-(4-
chlorophenyl)-anhydride (3b) combined with Ugi conden-
sation is also straightforward. The corresponding product
5e, obtained in one-pot, two-step methodology, was formed
in slightly lower yield (entry 8 in Table 3) in respect of the
two-pot process.
In the next experiments, we applied our two-step, one-pot
approach based on combination of enzymatic desymme-
trization of anhydrides 3 with subsequent Ugi MCR for the
synthesis of compounds 5. The same compounds were
obtained in Ugi MCR with chiral or racemic acids 4. The
results are presented in Table 2.
It is evident from the data presented in Table 3, that the
combination of enzymatic desymmetrization with Ugi MCR
proceeds efficiently. In most cases, the yields of the one-pot,
two-step procedure are similar to the yields of Ugi reaction
performed on pure monoacid 4.
In Ugi reaction with racemic acid 4a, product 5a was
obtained in 6% yield (entry 3 in Table 2). The same yield
was obtained when the reaction was repeated with chiral
acid (S)-4a or when enzymatic desymmetrization was
combined with Ugi MCR (entry 3 in Table 2). Better yields
were obtained for p-bromobenzaldehyde as a substrate
(entry 4 in Table 2) and our approach led to formation of the
desired product in almost the same yield as for the two
separate reactions. Optical rotation of compound 5b proved
that a chiral, nonracemic product 5c was obtained. For
isovaleraldehyde, the two-step approach leads to formation
of a 1:1 diastereoisomeric mixture of products 5c in 49%
yield (entry 5 in Table 3). Our two-step but one-pot
approach did not change the yield of reaction, and optical
rotation of products proved that racemisation did not occur.
It is interesting to note that Ugi reaction of racemic acid 4a
proceeds in 82% yield (entry 6 in Table 2). The same, but
chiral product was obtained in lower, 67% yield, in two-step
process. Our one-pot two-step process proceeds in 81%
We observed that all the products 5 consisted of a syn/anti
diastereoisomeric mixture, in approximately 1:1 ratio on
newly formed C-7 chiral centres, what was evident from
NMR and HPLC data.
In the case of products 5c–f, the diastereoisomers were
separated by preparative TLC. Relative configurations at
C-3 and C-7 carbons were assigned by 1H NMR
spectroscopy. The most distinctive 1H NMR data of
separated diastereoisomers of compounds 5c–f are shown
in Table 3.
The analysis of proton spectra led us to a conclusion that all
less polar diastereoisomers of compounds 5c–f-possess the
same anti configuration, at C-3 and C-7 carbon atoms.
Analogously, the more polar diastereoisomers possess
relative syn configuration.
The most significant difference is observed for NH protons,
Table 3. The most distinctive 1H NMR data for peptidomimetic 5c–f diastereoisomers
Entry
Comp.
Chemical shifts d (ppm) and coupling constant Jgem (Hz)
a
NH
NHCH2R
CH2CHPh
CH3
1
2
3
4
5
6
7
8
5c anti
5c syn
5d anti
5d syn
5e anti
5e syn
5f anti
5f syn
6.55
7.00
6.66
6.95
6.67
6.91
6.68
6.96
3.76; 3.85 JgemZ18.0
3.85; 3.98
4.17; 4.33 JgemZ14.9
4.35
4.18; 4.34 JgemZ14.8
4.35
4.17; 4.34 JgemZ14.9
4.35
2.66; 2.80 JgemZ15.4
2.60–2.80
2.63; 2.75 JgemZ15.5
2.64; 2.69
2.63; 2.73 JgemZ16.6
2.55–2.71
2.59; 2.73 JgemZ15.4
2.55–2.71
0.84–0.96 (m)
0.79 (d, JZ6.5)
0.83–0.92 (m)
0.79 (d, JZ6.5)
0.84–0.92
0.77 (d, JZ6.5)
0.82–0.92 (m)
0.79 (d, JZ6.5)
a For one of the CH3 groups from i-Bu chain.

A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
6067
which are shifted downfield for all syn compounds (Dd
0.28–0.45 ppm, Table 3). We postulate that intramolecular
hydrogen bond formation can be responsible for this
phenomenon. In case of opposite diastereoisomers such a
bond is weakened due to steric repulsion. Spectral data
suggest that the syn diastereoisomers can be folded
analogously, as it is observed in b-turn mimetics,31 while
the anti diastereoisomers possess an open chain
conformation.
2.1. Attempt to assign the absolute configurations by CD
spectroscopy
Figure 1. CD spectra of compounds (3S,7S)-5d (......), (3S,7S)-5c
(———), (3S,7R)-5d ( – – – –), and (3S,7R)-5c (_ _ _ _ _ _) recorded in
acetonitrile.
An effort was also made to assign unambiguously the
absolute configuration to compounds syn-5d, anti-5d and
syn-5c, anti-5c. For this purpose, circular dichroism
spectroscopy was chosen. UV and CD data of compounds
5c and 5d are presented in Table 4. As can be seen from the
table, the less polar components of both reaction mixtures,
namely compounds syn-5c and syn-5d, displayed the same
shape of their CD curves in the 250–185 nm spectral range
(Fig. 1).
$ $ $
the most pronounced CE at ca. 230 nm poses a sum of
contributions stemming from the amide, ester and phenyl
groups. It has to be added that, due to the conformational
mobility, different rotamers also contribute to the overall
spectrum with their own CD. Therefore, the absolute
configuration assignment to the second stereogenic centre
(C-7) is impossible only on the basis of CD spectroscopy.
Additional data is required to correlate the absolute
configuration and the sign of the specific CD band.
Nevertheless, on the basis of the same signs of the CE
around 230 nm, we are able to state that the less and the
more polar products have the same absolute configuration at
the carbon atom directly attached to the tertiary amide
nitrogen. Further study allowing the determination of the
absolute configuration at this stereogenic centre is in
progress in our laboratory.
Analogously, in the same spectral region (Table 4), CD
curves of more polar components anti-5d and anti-5c are
similar to each other, that is, the signs of particular Cotton
effects (CEs) are the same with very similar amplitudes.
In addition, their CD curves are in a mirror–image
relationship to those of the less polar compounds. The
only exception to this regularity presents the long-
wavelength CE occurring at 268 nm being negative for all
compounds investigated. This CE, associated with an
electronic absorption observed at 257 nm, can be attributed
1
to the Lb benzene transition. According to the benzene
sector rule, the negative sign of this CE points unam-
biguously to the (S) absolute configuration at the stereogenic
centre contiguous to the benzene ring.32 Thus, (3S,7S)
configuration can be assumed for the syn diastereoisomer
and (3S,7R) for the anti diastereoisomers. The presence of
an additional phenyl substituent in compounds (3S,7S)-5d
and (3S,7R)-5d (entries 1 and 2 in Table 4) does not affect
3. Conclusions
We developed a general, simple and efficient method for
chiral peptidomimetic preparation. Combination of the
enzymatic and Ugi reactions gave us access to the optically
active compounds 5. Both reactions can be performed
separately or successively, without isolation of the inter-
mediates. The latter approach evidently simplifies the
overall process. In our opinion, the one-pot enzymatic
desymmetrization followed by Ugi reaction can be readily
extended to prepare chiral, Ugi-type combinatorial libraries
starting from achiral substrates. This efficient process opens
new options in organic chemistry. It can be easily extended
to other types of reactions and used to generate chiral
peptidomimetic libraries as well. According to our knowl-
edge, this is the first example of combination of enzymatic
procedures with multi-component conden-sations.
1
this assignment because the sign of the Lb CE depends
exclusively upon the chirality of the chiral centre directly
linked to the benzene ring. Thus, the configuration assign-
ment made on the basis of the benzene sector rule
corroborates nicely with the assignment previously done
on the basis of NMR spectroscopy.
Independent determination of the absolute configuration at
the second stereogenic centre, however, remains a much
more difficult task. Different functional groups, present in
the molecules, have their own contributions to the overall
CD spectrum approximately at the same energy range. Thus,
In enzymatic reactions, one can control the stereochemistry
Table 4. UV and CD data of compounds 5c and 5d—peptidomimetics obtained by Ugi reaction and diastereoisomers separations recorded in acetonitrile
Entry
Comp.
UV
CD
3 (l)
D3 (l)
1
2
3
4
(3S,7S)-5c (syn)
(3S,7R)-5c (anti)
(3S,7S)-5d (syn)
(3S,7R)-5d (anti)
280 (257)
260 (257)
450 (257)
480 (257)
15 900 (205sh)
14 700 (205sh)
24 500 (207sh)
24 300 (207sh)
C3.10 (193.0)
K0.69 (197.0)
C12.1 (191.5)
K1.68 (197.5)
K0.46 (210.5)
K4.56 (228.5)
C6.92 (229.5)
K9.23 (229.5)
C6.96 (230.5)
K0.05 (268.0)
K0.03 (268.0)
K0.03 (268.0)
K0.02 (268.0)
C1.17 (207.0sh)
K2.40 (210.5sh)
C1.16 (209.5)
UV and CD values are given as 3 (nm) and D3 (nm), respectively.

6068
A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
of C-3 carbon atom. Unfortunately, the C-7 center formed
in the Ugi reaction cannot be controlled. The resulting
mixtures of diastereoisomers can be readily separated using
column chromatography.
procedures23,24 in 40% yield as white crystals (EtOAc/
1
hexane): mp 104–105 8C (lit. 104–10533); H NMR d 2.86
(dd, JZ11.3, 17.2 Hz, 2H), 3.08 (dd, JZ4.5, 17.2 Hz, 2H),
3.30–3.50 (m, 1H), 6.90–7.40 (m, 5H); 13C NMR d 34.7,
37.7, 126.8, 128.7, 129.9, 139.7, 166.6.
An attempt was made to assign relative configuration in
obtained products using NMR and CD spectroscopy. By
proton NMR, the relative configurations of less polar
diastereoisomers were assigned to be anti. Spectral data
suggest that all more polar, syn diastereoisomers are folded,
as it is analogously observed in b-turn mimetics. Currently,
the absolute configurations of chiral products cannot be
assigned using CD spectroscopy. Further studies into
unambiguous configuration assignment by CD spectroscopy
are in progress in our laboratory.
4.2.2. 3-(4-Chlorophenyl)glutaric acid anhydride 2b. The
anhydride 3b was prepared in 80% overall yield as white
crystals (EtOAc/hexane): mp 126 8C (lit. 131–13334); RfZ
0.36 (CHCl3/MeOH/HCOOH, 100:2:0.05); 1H NMR d 2.82
(dd, JZ11.4, 17.2 Hz, 2H), 3.08 (dd, JZ4.5, 17.2 Hz, 2H),
3.34–3.50 (m, 1H), 6.91 (d, JZ8.4 Hz, 2H), 7.12 (d, JZ
8.8 Hz, 2H); 13C NMR d 34.2, 37.6, 37.8, 128.1, 128.2,
130.1, 134.6, 138.0, 166.0; Anal. Calcd for C11H9ClO3: C,
58.81; H, 4.04. Found: C, 58.19; H, 4.05.
4.2.3. 3-(4-Methoxyphenyl)glutaric acid anhydride 3c.
The anhydride 3c was prepared in 19% overall yield as
white crystals (EtOAc/hexane): 155–156 8C (lit. 155–
15735); RfZ0.60 (hexane/EtOAc, 6:4); 1H NMR d 2.82
(dd, JZ11.2, 17.0 Hz, 2H), 3.08 (dd, JZ4.5, 17.0 Hz, 2H),
3.31–3.44 (m, 1H), 3.81 (s, 1H), 6.91 (d, JZ8.4 Hz, 2H),
7.12 (d, JZ8.8 Hz, 2H); 13C NMR d 13C NMR d 33.3, 37.3,
55.3, 114.7, 127.3, 131.0, 159.1, 166.0; Anal. Calcd for
C12H12O4: C, 65.45; H, 5.49. Found: C, 65.90; H, 5.44.
4. Experimental
4.1. General
NMR spectra were recorded in CDCl3 with TMS as an
internal standard using a 200 MHz Varian Gemini 200 or a
500 MHz Bruker DRX 500 Avance spectrometers. Chemi-
cal shifts are reported in ppm and coupling constants (J) are
given in Hertz (Hz). MS spectra were recorded on an API-
365 (SCIEX) apparatus. IR spectra in CHCl3 were recorded
with a Perkin Elmer FT-IR Spectrum 2000 apparatus.
Optical rotations were measured in 1 dm cell of 1 mL
capacity using a Jasco DIP-360 polarimeter operating at
589 nm. HPLC analyses were performed on a LC-6A
Shimadzu apparatus with an UV SPD-6A detector and a
Chromatopac C-R6A analyser.
4.3. General procedure for chemical synthesis of 3-aryl-
glutaric acid monoethyl esters (4)
Model racemic monoethyl esters 4 were obtained by the
procedure described before24 in 91% yield for 4a yield 89%
for 4b, 63% for 4c, respectively. Spectral and physical data
are in accordance with data obtained for chiral monoesters 4
obtained in enzymatic reaction.
The determination of enantiomeric excess of monoesters 4
was performed on a Chiracel OD-H column 4.6 mm!
250 mm (from Diacel Chemical Ind., Ltd) equipped with
a pre-column (4 mm!10 mm, 5 m). The determination of
diastereoisomeric ratio of the Ugi products 5 was performed
4.4. General procedure of synthesis of chiral monoesters
of 3-arylglutaric acids (4) with Novozym 435 in iso-
propyl ether
˚
on a Kromasil SI 60 A column (4.6 mm!250 mm) from
Eka Chemicals.
To the solution of anhydride (3, 0.5 mmol) dissolved in iso-
propyl ether (10 mL), lipase (75.0 mg) and absolute ethanol
(0.80 mmol) were added. The reaction was carried out at
room temperature and its progress was monitored by TLC
(CHCl3/MeOH/HCOOH, 100:2:0.05). The enzyme was
filtered off and residue was concentrated to give a monoester
4 as colourless oil. The product was recrystallized from
Et2O/hexane (or EtOAc/hexane).
CD spectra were measured using a JASCO J-715 spectro-
polarimeter in 1 cm and 1 mm cells in acetonitrile at
concentrations approximately of 2!10K4 M. The elemen-
tal analyses were performed on a CHN Perkin–Elmer 240
apparatus. Melting points are uncorrected. All reactions
were monitored by TLC on Merck silica gel plates 60 F254
.
Preparative TLC was performed on 0.5 mm Kieselgel 60
F254 preparative plates. Column chromatography was
performed on Merck silica gel 60/230–400 mesh.
4.4.1. (S)-3-Phenylglutaric acid monoethyl ester, (S)-4a.
The reaction reached full conversion after 43 h to give
(S)-4a in 99% yield as a colourless oil. After crystallisation
(Et2O/hexane), the ester was obtained as white crystals in
66% yield. Mp 58–59 8C (lit. 59–6024); [a]D20 K9.5 (c 1.10,
benzene) (lit. [a]2D5 9.47 (c 1.1, benzene) for (R)-enantio-
mer)36; HPLC analysis [hexane/i-PrOH/CH3COOH,
185:14:1; lZ226 nm; 1.0 ml/min; tR(S)Z8.26 min,
tR(R)Z8.95 min)] 78% ee; RfZ0.24 (CHCl3/MeOH/
HCOOH, 100:2:0.05); 1H NMR (200 MHz, CDCl3): d
1.15 (t, JZ7.1 Hz, 3H), 2.68–2.81 (m, 4H), 3.10–3.25
(m, 1H), 4.08 (q, JZ7.1 Hz, 2H), 7.28 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 14.7, 38.6, 41.3, 61.1, 113.4, 127.8,
129.1, 142.8, 156.9, 172.1, 178.1; IR (CHCl3) nmax: 3513
(OH), 1727 (C]O) cmK1; LSIMS (C), NBA, (m/z), 259
Immobilized lipase Amano PS-C was purchased from
Amano. Chirazyme L-2, c.-f., c-3, lyo. (C. antarctica lipase
type B) was purchased from Roche. Novozym 435 was
purchased from Novo Nordisk. All the chemicals were
obtained from common chemical suppliers. The solvents
were of analytical grade.
4.2. Chemistry
4.2.1. 3-Phenylglutaric acid anhydride (3a). The anhy-
dride 3a was obtained according to the literature

A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
6069
([MCNa]C, 56%), 237 ([MCH]C, 100%); LSIMS (C),
NBACNaOAc, (m/z), 281 ([MC2Na]C, 100%), 259 ([MC
Na]C, 41%).
Subsequently, the aldehyde (1.1 mmol), the amine
(1.1 mmol) and the isonitrile (1.0 mmol) were added to
the resulting solution cooled to 0 8C. The reaction was
allowed to warm up to room temperature and its progress
was monitored by TLC. When the reaction was completed,
the solvent was removed in vacuo and the residue was
poured into 10 mL of EtOAc. The organic solution was
washed consecutively with hydrochloric acid (1 M, 10 mL),
sodium hydroxide (1 M, 10 mL), saturated sodium sulphite
solution (10 mL) and brine (10 mL), and dried (MgSO4).
The solvent was evaporated and the product was isolated by
flash chromatography.
4.4.2. (S)-3-(4-Chlorophenyl)glutaric acid monoethyl
ester, (S)-4b. The reaction reached full conversion after
4 days to give (S)-4b as an oil in 99% yield. After
crystallisation, the ester was obtained as white crystals in
61% yield. Mp 56 8C (Et2O/hexane); [a]2D0 K3.8 (c 0.90,
CHCl3); HPLC analysis [hexane/i-PrOH/CH3COOH,
185:14:1; lZ226 nm; 1.0 ml/min; tR(S)Z9.0 min, tR(R)Z
9.8 min]; RfZ0.27 (CHCl3/MeOH/HCOOH, 100:2:0.05);
1H NMR (200 MHz, CDCl3): d 1.15 (t, JZ7.1 Hz, 3H), 2.69
(m, 4H), 3.60 (m, 1H), 4.03 (q, JZ7.1 Hz, 2H), 7.15 (d, JZ
8.6 Hz, 2H), 7.34 (d, JZ8.6 Hz, 2H), 10.7 (s, 1H); 13C NMR
(50 MHz, CDCl3) d 14.7, 38.0, 40.7, 41.1, 61.2, 115.1,
129.2, 129.3, 129.4, 133.3, 141.2, 171.8, 177.8; Anal. Calcd
for C13H15ClO4: C, 57.68; H, 5.59. Found: C, 57.59; H,
5.74.
4.6.1. Compound 5a (syn/anti mixture). Yellow oil, RfZ
0.24 (hexane/EtOAc/CH3COOH, 7:3:0.17); 1H NMR
(200 MHz, CDCl3) d: 0.80–1.50 (m, 13H), 2.40–2.90 (m,
4H), 3.15–3.30 (m, 2H), 3.47 (q, JZ7.0 Hz, 2H), 3.70–3.90
(m, 1H), 4.00–4.10 (m, 2H), 4.47 (m, 2H), 5.83 (s, 1H,
rotamers), 6.07 (s, 1H, rotamers), 6.23 (m, 1H, NHanti), 6.46
(m, 1H, NHsyn), 6.8–7.8 (m, 12H). MS (ESI): m/zZ583
([MCNa]C, 100%); (ESI-MS HR: m/z Calcd for
C33H40N2O6Na: 583.2779. Found: 583.2783.
4.4.3. (S)-3-(4-Methoxyphenyl)glutaric acid monoethyl
ester, (S)-4c. The reaction reached full conversion after 19
days to give (S)-4c as an oil in 93% yield. After crystal-
lisation (Et2O/hexane), the ester was obtained as white
crystals in 71% yield. Mp 75–77 8C (lit. 7837); [a]D20 C8.3 (c
0.95, EtOH); HPLC analysis [hexane/i-PrOH/CH3COOH
193:6:1; lZ226 nm; 0.7 ml/min; tR(S)Z26.5 min, tR(R)Z
29.1 min] 69% ee; RfZ0.28 (CHCl3/MeOH/HCOOH,
4.6.2. Compound 5b (syn/anti mixture). Yellow oil; RfZ
0.32 (hexane/EtOAc, 7:3); [a]3D2 K4.0 (c 1.29, benzene); 1H
NMR (200 MHz, CDCl3) d 0.71–0.81 (m, 3H), 1.12 (t, JZ
7.1 Hz, 3H), 1.00–1.50 (m, 4H), 2.68–2.90 (m, 4H), 3.10–
3.30 (m, 2H), 3.68–3.90 (m, 1H), 3.93–4.15 (m, 2H), 4.44
(dd, JZ5.9, 10.5 Hz, 2H), 5.62 (s, 1H, rotamers), 5.87 (s,
1H, rotamers), 6.45–6.60 (m, 1H, NHanti), 6.83–6.90 (m,
1H, NHsyn), 7.04 (dd, JZ8.6, 16.4 Hz, 2H), 7.15–7.30 (m,
10H), 7.37 (d, JZ8.6 Hz, 2H); 13C NMR (50 MHz, CDCl3)
d:13.5, 14.0, 19.9, 31.6, 38.6, 38.8, 39.3, 39.4, 40.4, 43.6,
46.5, 60.3, 61.2, 62.7, 122.0, 126.7, 126.8, 127.0, 127.3,
127.5, 127.6, 128.5, 130.5, 130.6, 131.5, 134.2, 137.9,
142.8, 169.2, 171.7, 172.1; MS (ESI): m/zZ617 ([MC
Na]C, 100%), 615 ([MCNa]C; 76%); ESI-MS HR: m/z
Calcd for C32H37N2O4NaBr: 617.1829. Found: m/z:
617.1796.
1
100:2:0.05); H NMR (200 MHz, CDCl3): d 1.20 (t, JZ
7.2 Hz, 3H), 2.74 (m, 4H), 3.63 (m, 1H), 3.83 (s, 3H), 4.09
(q, JZ7.2 Hz, 2H), 6.9 (d, JZ7.0 Hz, 2H), 7.19 (d, JZ
7.2 Hz, 2H); 13C NMR (50 MHz, CDCl3) d 14.6, 41.1, 41.1,
55.9, 60.9, 114.8, 129.4, 136.0, 159.4, 172.9, 174.8; Anal.
Calcd for C14H18O5: C, 63.15; H, 6.81. Found: C, 63.12; H,
6.81.
4.5. General procedure for synthesis of compounds 5
To a solution of monoester 4 (1.0 mmol) in iso-propyl ether/
methanol mixture (2:1, v/v, 5 mL), aldehyde (1.1 mmol),
amine (1.1 mmol) and isonitrile (1.0 mmol) were added
subsequently at 0 8C. The reaction was allowed to warm up
to room temperature and its progress was monitored by
TLC. After the reaction was completed, the solvent was
removed in vacuo and the residue was poured into 10 mL of
EtOAc. The organic solution was washed consecutively
with hydrochloric acid (1 M, 10 mL), sodium hydroxide
(1 M, 10 mL), saturated sodium sulphite solution (10 mL)
and brine (10 mL), and dried (MgSO4). The solvent was
evaporated and the product 5 was isolated by flash
chromatography.
4.6.3. Compound 5c (syn/anti mixture). Reaction time:
9 days. The product was purified by flash chromatography
to give two fractions Rf1Z0.26—anti-diastereoisomer
and Rf2Z0.15—syn-diastereoisomer (hexane/EtOAc, 7:3) in
34
Dsyn/anti
49% total yield as viscous transparent oil. [a]
(c 1.30, benzene).
K0.9
4.6.4. Compound (3S,7R)-5c (anti-diastereoisomer).
1
Transparent oil; RfZ0.26 (hexane/EtOAc, 7:3); H NMR
(500 MHz, CDCl3) d 0.84–0.096 (m, 9H) 1.15 (t, JZ7.1 Hz,
3H), 1.26 (t, JZ7.1 Hz, 3H), 1.25–1.32 (m, 2H), 1.35–1.45
(m, 2H), 1.48–1.56 (m, 2H), 1.75–1.81 (m, 1H), 2.66 (dd,
JZ7.7, 15.4 Hz, 1H), 2.71–2.77 (m, 2H), 2.80 (dd, JZ7.1,
15.4 Hz, 1H), 3.05–3.20 (m, 2H), 3.76 (dd, JZ5.7, 18.0 Hz,
1H), 3.85 (dd, JZ6.0, 18.0 Hz, 1H), 3.77–3.82 (m, 1H),
4.04 (dq, JZ2.6, 7.1 Hz, 2H), 4.17 (q, JZ7.1 Hz, 2H), 4.96
(t, JZ7.0 Hz, 1H), 6.55 (br s, 1H), 7.17–7–21 (m, 1H),
7.22–7.30 (m, 4H); 13C NMR (125 MHz, CDCl3) 13.6, 14.0,
14.1, 20.2, 22.2, 22.5, 22.8, 24.7, 32.2, 36.7, 38.9, 39.7,
40.5, 41.1, 45.5, 60.4, 61.1, 126.8, 127.4, 128.5, 143.1,
169.4, 171.8, 172.7; MS (ESI): m/zZ513 ([MCNa]C,
64%), 491 ([MCH]C, 100%), ESI-MS HR: m/z Calcd for
C27H43N2O6: 491.3121. Found: m/z: 491.3134.
4.6. General experimental procedure for tandem
enzymatic-Ugi reaction
To a solution of glutaric anhydride 3 (1.0 mmol) in 10 mL
of iso-propyl ether, lipase (150 mg) and ethanol
(1.50 mmol, 90 mL, 99.8% pure) were added. The reaction
was carried out at room temperature and its progress was
monitored by TLC. After all the substrate reacted, the
enzyme was filtered off and washed with iso-propyl ether
and concentrated to 1% of volume, then iso-propyl ether/
methanol mixture (2:1, v/v, 5 mL) was added.

6070
A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
4.6.5. Compound (3S,7S)-5c (syn diastereoisomer).
Transparent oil; RfZ0.15 (hexane/EtOAc, 7:3); H NMR
two separated diastereoisomers. ESI-MS: m/zZ552 ([MC
Na]C, 5%), 551 ([MCNa]C, 100%); ESI-MS HR: m/z
1
(500 MHz, CDCl3) d 0.79 (d, JZ6.5 Hz, 3H), 0.85 (d, JZ
6.6 Hz, 3H), 0.88–0.97 (m, 3H), 1.15 (t, JZ7.1 Hz, 3H),
1.26 (t, JZ7.1 Hz, 3H), 1.24–1.32 (m, 2H), 1.35–1.55 (m,
4H), 1.68–1.75 (m, 1H), 2.60–2.80 (m, 4H), 3.05–3.20 (m,
2H), 3.73–3.84 (m, 1H), 3.85 (d, JZ5.3 Hz, 1H), 3.98 (d,
JZ6.3 Hz, 1H), 4.00–4.08 (m, 2H), 4.17 (q, JZ7.1 Hz, 2H),
4.97 (t, JZ7.4 Hz, 1H), 7.00 (t, JZ5.3 Hz, 1H), 7.17–7.30
(m, 5H); 13C NMR (125 MHz, CDCl3) d 13.6, 14.0, 14.1,
20.3, 22.1, 22.8, 24.5, 31.9, 36.5, 38.8, 39.6, 40.7, 41.1,
60.4, 61.1, 126.8, 127.2, 127.4, 128.5, 143.1, 169.5, 172.0,
172.1, 172.8; MS (ESI): m/zZ513 ([MCNa]C, 50%), 491
([MCH]C, 100%), ESI-MS HR: m/z Calcd for
C27H43N2O6: 491.3121. Found: m/z: 491.3105.
Calcd for [MCNa]C, C30H41M2O4NaCl: 551.2647. Found:
26
Dsyn/anti
551.2650; [a]
K4.9 (c 1.27, benzene). The dia-
stereoisomers (in 1.1:1 ratio) were separated by PTLC (RfZ
0.15 and 0.14, respectively, hexane/i-PrOH, 95:5; 8 times
reversed).
4.6.10. Compound (3S,7R)-5e (anti-diastereoisomer).
Colourless oil; RfZ0.41 (hexane/EtOAc, 7:3); 1H NMR
(500 MHz, CDCl3) d 0.84–0.92 (m, 9H), 1.15 (t, 3H, JZ
7.1 Hz), 1.18–1.33 (m, 4H), 1.35–1.48 (m, 1H), 1.50–1.59
(m, 1H), 1.73–1.85 (m, 1H), 2.63 (dd, JZ7.8, 15.6 Hz, 1H),
2.67–2.73 (m, 2H), 2.73 (dd, JZ7.0, 15.6 Hz, 1H), 3.05–
3.20 (m, 2H), 3.73 (quintet, JZ7.3 Hz, 1H), 4.01 (dq, JZ
3.5, 7.1 Hz, 2H), 4.18 (dd, JZ5.6, 14.8 Hz, 1H), 4.34 (dd,
JZ6.4, 14.8 Hz, 1H), 4.91 (t, JZ6.0 Hz, 1H), 6.67 (br s,
1H), 7.13–7.19 (m, 4H), 7.20–7.30 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 13.6, 14.1, 20.2, 22.2, 22.8, 24.7, 32.0,
36.7, 38.1, 39.4, 40.4, 43.2, 45.2, 60.5, 127.2, 127.6, 128.5,
128.6, 128.7, 132.6, 138.3, 141.6, 171.3, 171.5, 172.2;
ESI-MS: m/zZ552 ([MCNa]C, 6%), 551 ([MCNa]C,
100%); ESI-MS HR: m/z Calcd for [MCNa]C,
C30H41N2O4NaCl: 551.2647. Found: 551.2661.
4.6.6. Compound (3S,7RS)-5d. Reaction time: 2 days. The
product was purified by flash chromatography (RfZ0.23,
hexane/EtOAc, 8:2) and obtained as a colourless oil in
1
65% yield. The H NMR spectrum was a superposition
of 2 separate diastereoisomers. ESI-MS: m/zZ517
([MCNa]C, 100%); ESI-MS HR: m/z Calcd for
[MCNa]C, C30H42N2O4Na: 517.3037. Found: 517.3028;
26
[a]
Dsyn/anti
K0.4 (c 1.31, benzene). The diastereoisomers
(in 1.1:1 ratio) were separated by preparative TLC (RfZ
0.16 and 0.15, hexane/i-PrOH, 95:5; 6 times reversed).
4.6.11. Compound (3S,7S)-5e (syn-diastereoisomer).
Colourless oil, RfZ0.41 (hexane/EtOAc, 7:3).1H NMR
(500 MHz, CDCl3) d 0.77 (d, JZ6.5 Hz, 3H), 0.84–0.90 (m,
6H), 1.14 (t, JZ7.1 Hz, 3H), 1.17–1.34 (m, 4H), 1.35–1.44
(m, 1H), 1.49–1.57 (m, 1H), 1.67–1.74 (m, 1H), 2.55–2.71
(m, 4H), 3.08–3.15 (m, 2H), 3.74 (quintet, JZ7.3 Hz, 1H),
3.99 (dq, JZ7.1, 4.5 Hz, 2H), 4.35 (d, JZ5.9 Hz, 2H), 4.92
(t, JZ7.3 Hz, 1H), 6.91 (br s, 1H), 7.13 (dd, JZ1.8, 6.6 Hz,
2H), 7.19–7.27 (m, 5H), 7.28–7.32 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 13.5, 13.9, 20.1, 22.0, 22.7,, 24.4, 31.8,
36.4, 38.0, 39.1, 40.5, 43.2, 44.7, 60.4, 127.1, 127.6, 128.3,
128.4, 128.5, 132.4, 138.2, 141.3, 171.2, 171.5, 172.1; ESI-
MS: m/zZ552 ([MCNa]C, 6%), 551 ([MCNa]C, 100%);
ESI-MS HR: m/z Calcd for [MCNa]C, C30H41N2O4NaCl:
551.2647. Found: 551.2630.
4.6.7. Compound (3S,7R)-5d (anti-diastereoisomer).
Transparent oil; H NMR (500 MHz, CDCl3) d 0.83–0.92
1
(m, 9H), 1.14 (t, 3H, JZ7.1 Hz), 1.17–1.33 (m, 4H) 1.36–
1.48 (m, 1H), 1.49–1.61 (m, 1H), 1.69–1.84 (m, 1H), 2.63
(dd, JZ7.5, 15.5 Hz, 1H), 2.66–2.72 (m, 2H), 2.75 (dd, JZ
7.3, 15.5 Hz, 1H), 3.05–3.15 (m, 2H), 3.73 (quintet, 1H, JZ
7.3 Hz), 4.01 (dq, JZ3.6, 7.1 Hz, 2H), 4.17 (dd, JZ5.6,
14.9 Hz, 1H), 4.33 (dd, JZ6.4, 14.9 Hz, 1H), 4.94 (br s,
1H), 6.66 (br s, 1H), 7.13–7.31 (m, 10H); 13C NMR
(125 MHz, CDCl3) d 13.6, 14.0, 20.2, 22.2, 22.9, 24.7, 32.0,
36.7, 38.8, 39.7, 40.5, 43.2, 45.2, 60.4, 126.8, 126.9, 127.1,
127.2, 127.3, 127.5, 127.7, 128.4, 128.5, 128.6, 138.4,
143.0, 171.4, 171.8, 172.5; ESI-MS: m/zZ517 ([MCNa]C,
100%); ESI-MS HR: m/z Calcd for [MCNa]C,
C30H42N2O4Na: 517.3037. Found: 517.3062.
4.6.12. Compound (3S,7RS)-5f. Reaction time: 2 days.
The product was purified by flash chromatography
(RfZ0.36, hexane/EtOAc, 7:3) and obtained as colour-
less oil in 78% yield. 1H NMR spectrum was superposition
of two separated diastereoisomers. ESI-MS: m/zZ547
([MCNa]C, 100%); ESI-MS HR: m/z Calcd for
4.6.8. Compound (3S,7S)-5d (syn-diastereoisomer).
1
Transparent oil; RfZ0.23 (hexane/EtOAc, 8:2); H NMR
(500 MHz, CDCl3) d 0.79 (d, JZ6.5 Hz, 3H), 0.82–0.97 (m,
6H), 1.12 (t, JZ7.1 Hz, 3H), 1.18–1.33 (m, 4H), 1.35–1.45
(m, 1H), 1.47–1.57 (m, 1H), 1.70–1.77 (m, 1H), 2.64 (dd,
JZ5.4, 7.3 Hz, 2H)), 2.69 (dd, JZ7.3, 8.5 Hz, 2H), 3.05–
3.15 (m, 2H), 3.75 (quintet, JZ7.3 Hz, 1H), 3.98 (dq, JZ
4.3, 7.1 Hz, 2H), 4.35 (d, JZ6.0 Hz, 2H), 4.94 (t, 1H, JZ
7.4 Hz), 6.95 (br s, 1H), 7.14–7.31 (m, 10H); 13C NMR
(125 MHz, CDCl3) d 13.6, 14.0, 20.2, 22.1, 22.2, 22.9, 24.6,
31.9, 36.6, 38.8, 39.5, 40.8, 43.3, 45.0, 60.4, 126.8, 127.1,
127.2, 127.7, 128.5, 128.6, 138.4, 140.1, 171.5, 172.0,
172.6; ESI-MS: m/zZ518 517 ([MCNa]C, 100%); ESI-MS
HR: m/z Calcd for [MCNa]C, C30H42N2O4Na: 517.3037.
Found: 517.3020.
[MCNa]C, C31H44N2NaO4: 547.3137. Found: 547.3139;
26
Dsyn/anti
[a]
K3.0 (c 1.28, benzene). The diastereoisomers
(in 2.4:1 ratio) were separated by PTLC (RfZ0.15 and
0.14, hexane/i-PrOH, 95:5; 11 times reversed).
4.6.13. Compound (3S,7R)-5f (anti-diastereoisomer).
Colourless oil; RfZ0.36 (hexane/EtOAc, 7:3); 1H NMR
(500 MHz, CDCl3) d 0.82–0.92 (m, 9H), 1.14 (t, JZ7.1 Hz,
3H), 1.18–1.35 (m, 4H) 1.36–1.47 (m, 1H), 1.50–1.59 (m,
1H), 1.75–1.83 (m, 1H), 2.59 (dd, JZ7.7, 15.4 Hz, 1H),
2.62–2.69 (m, 2H), 2.73 (dd, JZ7.2, 15.4 Hz, 1H), 3.10 (t,
JZ8.1 Hz, 2H), 3.73 (s, 3H), 3.68–3.80 (m, 1H), 4.01 (dq,
JZ7.3, 4.0 Hz, 2H), 4.17 (dd, JZ5.7, 14.9 Hz, 1H), 4.34
(dd, JZ5.9, 14.8 Hz, 1H), 4.94 (t, JZ7.0 Hz, 1H), 6.68
(br s, 1H), 6.77–6.82 (m, 2H), 7.09–7.19 (m, 2H), 7.20–7.32
(m, 5H); 13C NMR (125 MHz, CDCl3) d 13.6, 14.1, 20.2,
4.6.9. Compound (3S,7RS)-5e. Reaction time: 2 days. The
product was purified by flash chromatography (RfZ0.41,
hexane/EtOAc, 7:3) and obtained in 61% yield as colourless
1
oil that solidified. H NMR spectrum was superposition of

A. Fryszkowska et al. / Tetrahedron 61 (2005) 6064–6072
6071
22.2, 22.9, 24.7, 32.1, 36.7, 38.1, 39.9, 41.0, 43.2,
Acknowledgements
45.3, 55.2, 60.4, 113.9, 127.1, 127.2, 127.5, 127.7, 128.2,
128.3, 128.4, 128.5, 135.0, 138.4, 158.4, 171.5, 171.9,
172.7.
This work was supported by Polish State Committee for
Scientific Research, grant no. PBZ-MIN-007/P04/2003.
4.6.14. Compound (3S,7S)-5f (syn-diastereoisomer).
Colourless oil; RfZ0.36 (hexane/EtOAc, 7:3); [a]2D6 K0.4
(c 1.31, benzene); H NMR (500 MHz, CDCl3) d 0.79 (d,
1
References and notes
3H, JZ6.5 Hz), 0.83–0.90 (m, 6H), 1.14 (t, 3H, JZ7.1 Hz),
1.17–1.34 (m, 4H), 1.35–1.45 (m, 1H), 1.49–1.57 (m, 1H),
1.68–1.76 (m, 1H), 2.55–2.71 (m, 4H), 3.07–3.15 (m, 2H),
3.76 (s, 3H), 3.74–3.67 (m, 1H), 3.94–4.05 (m), 4.35 (d, JZ
6.0 Hz, 2H), 4.93 (t, JZ7.3 Hz, 1H), 6.80 (d, JZ8.7 Hz,
2H), 6.96 (br s, 1H), 7.11 (d, JZ8.7 Hz, 2H), 7.20–7.32 (m,
5H); 13C NMR (125 MHz, CDCl3) d 13.6, 14.1, 20.3, 22.2,
22.9, 24.6, 32.0, 36.6, 38.1, 39.7, 41.0, 43.3, 45.0, 55.2,
60.4, 113.9, 127.2, 127.7, 128.2, 128.4, 128.5, 135.0, 138.4,
158.4, 171.5, 172.1, 172.8.
1. Ripka, A. S. D.; Rich, H. Curr. Opin. Chem. Biol. 1998, 2, 441.
2. Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
3. Domling, A. Curr. Opin. Chem. Biol. 2000, 4, 318.
4. Bienayme, H.; Hulme, C.; Oddon, G.; Schmidt, P. Chem. Eur.
J. 2000, 6, 3321.
5. Obrecht, D.; Villalgordo, J. M. Solid-supported combinatorial
and parallel synthesis of small-molecular-weight compound
libraries.; Tetrahedron organic chemistry series; Pergamon:
New York, 1998; Vol. 17; Chapters 1 and 4.
6. Ugi, I.; Karl, R.; Lohberg, S. The Passerini and Ugi reaction. In
Comprehensive organic chemistry; Trost, B. M., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; pp 1083–1109.
7. Floyd, C. D.; Harnett, L. A.; Patel, S.; Sarglou, L.; Whittaker,
M. Synlett 1998, 637.
4.6.15. Compound (3S,7RS)-5g. Colourless oil; RfZ0.41
26
(hexane/EtOAc, 7:3); [a]
C9.0 (c 1.50, benzene);
Dsyn/anti
1H NMR (200 MHz, CDCl3) ( 0.60–0.88 (m, 6H), 1.14 (dt,
JZ1.0, 7.1 Hz, 3H), 1.20–1.50 (m, 2H), 1.61–1.78 (m, 1H),
2.48–2.78 (m, 4H), 3.68–3.84 (m, 1H), 4.01 (dq, JZ3.1,
7.1 Hz, 2H), 4.30–4.41 (m, 2H), 4.41–4.53 (m, 2H),
5.06 (dt, JZ3.2, 7.0 Hz, 1H), 6.57 (t, JZ5.7 Hz, 1Hanti),
6.95 (t, JZ5.7 Hz, 1Hsyn), 7.02–7.40 (m, 15H); 13C NMR
(50 MHz, CDCl3) ( 14.1, 22.4, 22.6, 22.7, 25.0, 25.1, 36.9,
37.0, 38.6, 40.0, 40.1, 40.4, 40.7, 43.3, 48.3, 48.4, 56.0,
56.1, 60.3, 125.9, 126.7, 127.1, 127.2, 127.5,
127.9.128.3, 128.4, 128.6, 127.1, 137.2, 138.1, 142.7,
142.8, 170.3, 170.4, 171.5, 171.6, 173.7; MS (ESI): m/zZ
551 ([MCNa]C, 100%), 529 ([MCH]C, 18%), ESI-MS
HR m/z Calcd for C33H40N2O4Na: 551.2880. Found: m/z:
551.2877.
8. Bossio, R.; Marcos, C. F.; MarcaFini, S.; Pepino, R. Synthesis
1997, 1389.
9. Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998, 39, 2735.
10. Hulme, C.; Ma, L.; Morrisette, M.; Burns, C. J. Tetrahedron
Lett. 1998, 39, 1113.
11. Hulme, C.; Peng, J.; Lourdias, B.; Menard, P.; Krolikowski, P.;
Kumar, V. Tetrahedron Lett. 1998, 39, 8047.
12. Hulme, C.; Peng, J.; Tang, S. Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. J. Org. Chem. 1998, 63, 8021.
13. Hulme, C.; Ma, L.; Romano, J.; Morrisette, M. Tetrahedron
Lett. 1999, 40, 7925.
14. Hulme, C.; Ma, L.; Romano, J.; Morton, G.; Tang, S. Y.;
Cherrier, M. P.; Choi, S.; Salvino, J.; Labaudiniere, R.
Tetrahedron Lett. 2000, 41, 1889.
4.6.16. Compound (3S,7RS)-5h (syn/anti mixture). Yel-
low oil; RfZ0.20 (hexane/EtOAc, 7:3); [a]
26
Dsyn/anti
15. Tempest, P.; Ma, V.; Thomas, S.; Kelly, M. G.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4959.
C13.8
1
(c 1.43, benzene); H NMR (200 MHz, CDCl3) d 1.09 (t,
JZ7.0 Hz, 3H), 2.48–2.85 (m, 4H), 3.68–3.90 (m, 1H), 4.01
(q, JZ7.0 Hz, 2H), 4.30–4.70 (m, 4H), 5.63 (s, 1H,
rotamers), 5.90 (s, 1H, rotamers), 6.23–6.38 (m, 1Hanti),
6.48–6.58 (m, 1Hsyn), 6.80–7.50 (m, 19H); 13C NMR
(50 MHz, CDCl3) d 14.0, 32.0, 38.5, 39.4 39.9, 40.5, 43.6,
49.8, 50.5, 60.3, 60.4, 61.7, 63.0, 122.3, 122.4, 125.9, 126.6,
126.9, 127.1, 127.2, 127.4, 127.5, 128.3, 128.4, 128.7,
131.0, 131.4, 131.6, 136.4, 137.6, 142.6, 142.7, 171.6,
172.5, 172.8; MS (ESI): m/zZ651 ([MCNa]C, 100%),
649 ([MCNa]C, 58%); ESI-MS HR m/z Calcd for
C35H35N2O4NaBr: 651.1649. Found: 651.1651.
16. Nixej, T.; Kelly, M.; Semin, D.; Hulme, C. Tetrahedron Lett.
2002, 43, 3681.
17. Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851.
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11657.
19. Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L.
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1999; Chapters 1 and 4.
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4.6.17. Compound (3S,7RS)-5i (syn/anti mixture). Yellow
oil; RfZ0.33 (hexane/EtOAc/CH3COOH, 7:3:0.17); 1H
NMR (200 MHz, CDCl3) d 1.03 (dt, JZ2.0, 7.1 Hz, 3H),
1.17 (dt, JZ2.1, 7.1 Hz, 3H), 2.4–2.8 (m, 4H), 3.7 (m, 1H),
3.92 (m, 2H), 4.1 (m, 4H), 4.47 (m, 2H), 5.83 (s, 1H,
rotamers), 6.07 (s, 1H, rotamers), 6.23 (m, 1Hsyn, 6.46 (m,
1H, 1Hanti, 6.8–7.8 (m, 17H); MS (ESI): m/zZ617 ([MC
Na]C, 100%), ESI-MS HR m/z Calcd for C36H38N2O6Na:
617.2627. Found: (m/z): 617.2643.
22. Ostaszewski, R.; Portlock, D. E.; Fryszkowska, A.; Jeziorska,
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