Rapid access to reverse-turn peptidomimetics by a three-component Ugi reaction of 3,4-dihydroisoquinoline

Article abstract of DOI:10.1007/s10593-018-2202-5

[Figure not available: see fulltext.] Peptidomimetics have raised a considerable attention in the last decades due to their potential application as therapeutic agents. In this perspective, multicomponent reactions are an excellent tool to rapidly afford a large number of drug candidates having a great structural diversity. We report here on the use of the three-component Ugi reaction for the synthesis of a library of potential reverse-turn mimetics, based on the constrained tetrahydroisoquinoline heterocyclic scaffold. The ability of the target compounds to mimic secondary structure of peptides was evaluated by means of computational tools and NMR studies. We were able to demonstrate that by using the appropriate starting materials, a β-turn or a β-sheet mimetic is obtained.

Full text of DOI:10.1007/s10593-018-2202-5

DOI 10.1007/s10593-018-2202-5
Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
Rapid access to reverse-turn peptidomimetics
by a three-component Ugi reaction of 3,4-dihydroisoquinoline
Arianna Rossetti1, Alessandro Sacchetti1,2*, Marta Gatti1,
Andrea Pugliese1, Gabriella Roda3
1
Dipartimento di Chimica, Materiali e Ingegneria Chimica ''G. Natta'', Politecnico di Milano,
32 Piazza Leonardo da Vinci, 20133 Milano, Italy; e-mail alessandro.sacchetti@polimi.it
2
INSTM, National Consortium of Materials Science and Technology, Local Unit Politecnico di Milano,
32 Piazza Leonardo da Vinci, I-20133 Milano, Italy; e-mail alessandro.sacchetti@polimi.it
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano,
25 Via Mangiagalli, 20133 Milano, Italy; e-mail gabriella.roda@unimi.it
3
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(11), 1214–1219
Submitted July 7, 2017
Accepted after revision October 27, 2017
Peptidomimetics have raised a considerable attention in the last decades due to their potential application as therapeutic agents. In this
perspective, multicomponent reactions are an excellent tool to rapidly afford a large number of drug candidates having a great structural
diversity. We report here on the use of the three-component Ugi reaction for the synthesis of a library of potential reverse-turn mimetics,
based on the constrained tetrahydroisoquinoline heterocyclic scaffold. The ability of the target compounds to mimic secondary structure
of peptides was evaluated by means of computational tools and NMR studies. We were able to demonstrate that by using the appropriate
starting materials, a β-turn or a β-sheet mimetic is obtained.
Keywords: peptidomimetics, tetrahydroisoquinoline, multicomponent reaction, Ugi reaction.
In the last decades, the field of peptidomimetics has
been thoroughly investigated as a promising access to
novel and efficient therapeutic agents.1–6 Many strategies
toward the reproduction of the most relevant secondary
structures have been proposed. Reverse turns have been
identified as a main target in the relevant PPI (protein-
protein interactions) process.2,4,7–11 In particular, γ-turns
and β-turns have been studied both as a recognition motif
and a β-sheet inducer toward more complex structures. A
common way to obtain the desired geometry of a secondary
structure mimetics is to design rigid scaffolds able to
correctly arrange the residues in the space, this way
promoting the binding to the desired target. Heterocyclic
scaffolds have been extensively used to this goal.12,13
and inefficient synthetic sequences are often required. With
this regards, multicomponent reactions14–18 can be very
effective in the synthesis of complex and highly functio-
nalized scaffolds in few steps and often in high yields.
Recently some examples of multicomponent approaches to
the synthesis of potential peptidomimetics have been
reported,19–21 mainly based on the Ugi reaction. The Ugi
reaction is a well-known and much exploited four-
component reaction involving the use of an amine, an
aldehyde, a carboxylic acid, and an isocyanide to produce
an amino acid derivative.22,23
Following the above considerations and based on our
experience in the preparation of peptidomimetics,24–32 we
have designed the synthesis of a reverse-turn mimetics,
easily achievable applying this strategy, starting from
tetrahydroisoquinoline scaffolds. Tetrahydroisoquinoline
The exploitation of constrained peptidomimetics in
medicinal chemistry is often limited by the fact that long
0009-3122/17/53(11)-1214©2017 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
moiety is present in a large number of natural compounds
(58 and 54%), whereas with toluene and THF only a 23–
34% yield could be observed. The best results were
achieved when using methanol at room temperature (84%).
Increasing the temperature did not provide any
improvement.
and pharmacologically active molecules.33 The great
structural diversity of this class of molecules is often due to
the presence of many different substituents and functional
groups on the piperidine ring. These heterocyclic scaffolds
are most often prepared by cyclization procedures (e.g.,
Pictet–Spengler and Bischler–Napieralski reactions)
allowing the formation of the piperidine ring with the
concomitant introduction of substituent in the key C-1
position. Further elaborations of these structures lead to a
variety of derivatives. Beside the interest for their
biological activities that spread from antimalarials to opioid
mimetics, tetrahydroisoquinolines have been proposed, due
to their rigid polycyclic structures, as efficient peptide
secondary structure inducers in the field of peptido-
mimetics.28
By using these reaction conditions, we prepared a small
combinatorial library of compounds 1a–l with different
side chains attached to the tetrahydroisoquinoline ring
system. Three alkyl isocyanides were used, viz. benzyl
isocyanide, cyclohexyl isocyanide, and tert-butyl iso-
cyanide. In order to better test the reverse-turn capability of
the final products, ethyl isocyanoacetate was also used as a
mimetic of a glycine residue. For the acidic component,
two N-protected amino acids were employed, N-acetyl-
glycine and N-Cbz-L-alanine. Moreover, 1-pentenoic acid
was selected because of its expectedly easy removal from
the final product, thus allowing the possibility of further
decoration on the tetrahydroisoquinoline nitrogen. In
addition, chloroacetic acid was also employed in order to
explore the possibility to obtain a fused diketopiperazine
ring by a post-Ugi cyclization (Scheme 2). The isolated
final products are listed in Figure 1.
Following these observations we became interested in
the design of a new library of peptidomimetics 1a–l based
on the 1-carboxytetrahydroisoquinoline scaffold by means
of a three-component Ugi reaction34–36 (Scheme 1) using
the preformed imine 2. The starting material 2 could be
easily obtained by a Bischler–Napieralski cyclization of the
related formamide precursor.
In order to set up the reaction conditions, we first tested
compound 2 with acetic acid and benzyl isocyanide in
different solvents and temperature, stirring the mixture for
24 h to afford compound 1a (Table 1). The use of
dichloromethane and acetonitrile produced moderate yields
Scheme 2
Scheme 1
In most of the cases, the reactions proceeded smoothly,
and after 24–48 h the solvent was evaporated and the crude
product purified by column chromatography. In a few
cases, a solid precipitated out or could be easily recovered
after treatment of the crude product with a methanol–
hexane mixture. All products could be isolated in moderate
to good yields. When N-Cbz-L-alanine was used, a 1:1
diastereoisomeric mixture was obtained (products 1e,f).
The two diastereoisomers could be efficiently separated by
column chromatography.
Table 1. Optimization of the reaction conditions
for the preparation of compound 1a
Solvent T, °C Conversion*, % Solvent T, °C Conversion*, %
CH2Cl2
CH2Cl2
THF
25
60
25
60
25
44
58
31
34
84
MeOH
MeCN
MeCN
PhMe
PhMe
60
25
60
25
60
79
51
54
23
27
To explore the possibility to obtain a diketopiperazine
derivative as a useful modification toward more complex
scaffolds, compound 1j was reacted with a base to promote
the intramolecular cyclization (Scheme 2). The use of
strong bases (NaH or t-BuOK) yielded a mixture of
inseparable products. Methanolic NaOH afforded the
product in a 12% conversion yield (measured from GC/MS
THF
MeOH
* Conversion was measured by GC/MS analysis or by 1H NMR of the
crude product.
1
and H NMR of the crude product), whereas with cesium
Me
N
O
Me
N
O
Ac
N
O
Cbz
N
O
N
O
N
H
N
H
Cl
CH2
O
O
O
O
O
HN
R
HN
R
HN
R
HN
R
HN
R
1a R = Bn (84%)
1b
1c R = Cy (72%)
1d
1e R = Bn (55%)
1f
1g R = Bn (81%)
1j R = Bn (79%)
1h
1k
1l
R = CH2COOEt (68%)
R = t-Bu (66%)
R = CH2COOEt (48%)
R = Cy (74%)
R = Cy (81%)
1i
R = CH2COOEt (64%)
R = t-Bu (68%)
Figure 1. Structures and isolated yields of compounds 1a–l prepared according to Scheme 1.
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
Table 2. Conformational analysis of amino acis derivatives 1c–f.
Me
Results are reported as percentage of conformers containing the
indicated bond or distance
O
N
N
N2H
N
O
O
OBn
Com-
Total
H
O
a
O
a
O
a bond, % b bond, % c bond, % d < 7 Å, %
Me
NH
N1H
pound conformers*
b
d
58
39
69
21
33
25
16
31
23
76
45
88
40
36
1
n.a.**
n.a.
n.a.
n.a.
33
81
54
1c
R
1d
1c,d
1e
(S,S)-1e
(R,S)-1e
(S,S)-1f
(R,S)-1f
n.a.
n.a.
n.a.
n.a.
Me
0
O
N
9
N2
O
0
16
OBn
H
O
N1H
a
c
* Number of conformers within 6 kcal/mol from the global minimum.
** Not applicable to the given structure.
O
OEt
1f
the two diastereoisomers are observed: for the (S,S)-isomer
there is a prevalence for type a bond, while in the (R,S)-
isomer some tendency toward the β-turn conformation is
also revealed. Notably, the presence of the N-Cbz-alanine
in compound 1f promoted the formation of the H-bond c.
In order to confirm the presence of the computationally
predicted H-bonds, variable temperature NMR experiments
were performed on compound 1c and on one of the two
diastereoisomers of compound 1f. For compound 1c,
values of Δδ/ΔT corresponding to –7.7 ppb/K for N1H and
–6.3 ppb/K for N2H were measured. Similarly, for
compound 1f the detected values of Δδ/ΔT were –6.1 ppb/K
for N1H and –5.4 ppb/K for N2H. According to literature,40–43
these values are in agreement with the presence of
intramolecular hydrogen bonds, thus supporting the presence
of stabilized secondary structures. Figure 3 shows the
structures of compounds 1c, (S,S)-1f, and (R,S)-1f as
obtained from the calculations.
In this work, we reported the use of a three-component
Ugi reaction as an effective tool for the rapid creation of
new peptidomimetic scaffolds based on the tetrahydro-
isoquinoline moiety. By this approach, we could prepare a
combinatorial library of derivatives with different
components. For some of them, a computer-aided investi-
gation of the conformational properties was performed,
thus predicting their ability to mimic some classical reverse-
turn peptide structures. Variable-temperature NMR studies
finally supported the presence of intramolecular hydrogen
Figure 2. Definition of the geometrical parameters for the reverse-
turn evaluation of compounds 1c–f.
carbonate in acetonitrile the conversion was 16%. In the
1H NMR spectrum, we could observe the disappearance of
the CH2Cl signal at 4.15 ppm and the presence of a new
AB system of the diketopiperazine ring CH2 group in the
form of two doublets (J = 14.3 Hz) at 4.22 and 4.35 ppm.
Also the chemical shifts of other signals in the aliphatic
region of the spectrum were altered. In the GC/MS
chromatogram, a peak having the m/z value of the
molecular ion of compound 3 (306) was also detected.
However, due to the presence of a great number of by-
products we could not isolate the pure product.
We then investigated the ability to adopt a reverse turn-
like conformation for compounds 1c–f by means of compu-
tational tools. A conformational analysis was performed
with the use of a Monte Carlo search and a molecular
mechanics energy minimization with the MMFF94 force
field (as implemented in the Spartan'08 software suite).37
Reverse turns of the γ (seven-membered H-bond ring) and
β (ten-membered H-bond ring) type are stabilized by
intramolecular hydrogen bonds and defined according to
the H-bonds pattern. In addition, for the β-turn, a favorable
condition is d < 7 Å (the distance between α-carbon atoms
separated by three amino acid residues, see Fig. 2). We
could identify three most common hydrogen bonds in our
models: the a and b hydrogen bond patterns, related to the γ-
and β-turn, respectively, and the H-bond c. Interestingly
this latter pattern is found in antiparallel β-sheet motifs.38
Attention has been turned to these structures in recent years
because of their possible implication in protein aggregation
diseases.39
Detailed analysis of the results is presented in Table 2.
Only conformers within 6 kcal/mol from the global
minimum were considered. All the scaffolds are able to
adopt a classic γ-turn-like conformation through the pre-
sence of the a H-bond. The presence of a N-acetylglycine
residue (compounds 1c,d) promoted the formation of a
β-turn, in particular for compound 1c (81% of conformers
with d < 7 Å); in all cases, the analysis of the dihedral
angles established the presence of a type II β-turn. As
expected, for compounds 1e,f some differences between
Figure 3. Compound 1c (I) and its superimposition with a type II
β-turn model (II). Structures of (S,S)-1f (III) and (R,S)-1f (IV).
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
bond patterns. According to the different residues present
methanol (10 ml). The reaction mixture was stirred at room
temperature for 2 days and concentrated in vacuo. A crude
oil was obtained. After purification by silica gel column
chromatography (eluent varied from n-hexane–EtOAc, 7:3,
to pure EtOAc), the desired product was obtained as oil or
foamy solid.
on the tetrahydroisoquinoline scaffold, a γ-turn, β-turn, or
an antiparallel β-sheet could be recognized.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance 400 spectrometer (400 and 100 MHz, respecti-
vely). Chemical shifts are expressed in ppm relative to
TMS for 1H NMR spectra and relative to CDCl3
(77.16 ppm) or DMSO-d6 (39.51 ppm) signal for 13C NMR
spectra. Some 13C NMR spectra have been recorded using
the APT pulse sequence; the signals of CH and CH3 are
positive while those of CH2 and quaternary carbons are
negative. GC/MS analyses were performed on an Agilent
instrument equipped with an EI source by using an HP-5
MS column (30 m × 0.25 mm × 0.25 μm, Agilent). The
following temperature program was employed: 60°C
(1 min)/6°Cꢀmin−1/150°C (1 min)/12°Cꢀmin−1/280°C (5 min).
Elemental analyses were carried out on a PerkinElmer
Series II analyzer. All reactions were monitored by TLC on
precoated silica gel 60 F254; spots were visualized with
UV light (254 nm) or by treatment with 1% aqueous
KMnO4 solution. Products were purified by flash
chromatography on silica gel 60 (230–400 mesh). The
enantiomeric excess was determined by HPLC on a
Chiralpak AD column (eluent 9:1, hexane–2-PrOH, 9:1,
flow rate 0.75 ml/min). All solvents were distilled and
dried over sodium or calcium chloride, when necessary,
prior to use. All chemicals were purchased from com-
mercial sources and used directly, unless indicated
otherwise. Calculations were performed with the suite
Spartan'08.37
2-Acetyl-N-benzyl-1,2,3,4-tetrahydroisoquinoline-
1-carboxamide (1a).45 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.36–7.10 (9H, m, H Ar); 6.84 (1H, br. s, NH);
5.94 (1H, s, CH); 4.48–4.32 (2H, m, CH2Ph); 3.81 (1H,
ddd, J = 12.8, J = 8.2, J = 4.7) and 3.74–3.64 (1H, m,
CH2); 3.06 (1H, dt, J = 15.8, J = 4.7) and 2.95–2.85 (1H,
m, CH2); 2.18 (3H, s, CH3). 13C NMR spectrum (CDCl3),
δ, ppm: 170.7; 170.6; 138.4; 134.9; 132.2; 128.5; 128.2
(2C); 127.9; 127.6 (2C); 127.4; 127.1; 126.7; 57.4; 43.5;
43.1; 28.8; 21.7. Found, %: C 74.11; H 6.61; N 9.11.
C19H20N2O2. Calculated, %: C 74.00; H 6.54; N 9.08.
Ethyl
(2-acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl-
carbonyl)glycinate (1b). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.43 (1H, br. s, NH); 7.39–7.32 (1H, m,
H Ar); 7.25–7.14 (3H, m, H Ar); 6.05 (1H, s, CH); 4.17
(2H, q, J = 7.2, CH2CH3); 4.00–3.96 (2H, m, CH2); 3.90
(1H, ddd, J = 12.7, J = 8.2, J = 4.9) and 3.74 (1H, ddd,
J = 12.2, J = 6.5, J = 5.1, CH2); 3.14–3.02 (1H, m) and
2.97–2.90 (1H, m, CH2); 2.23 (3H, s, CH3); 1.25 (3H, t,
J = 7.2, CH2CH3). 13C NMR spectrum (CDCl3), δ, ppm:
170.7; 170.5; 169.4; 134.6; 131.6; 128.0; 127.9; 127.5;
126.5; 61.1; 56.7; 42.9; 41.3; 28.6; 21.5; 13.9. Found, %:
C 63.11; H 6.64; N 9.21. C16H20N2O4. Calculated, %:
C 63.14; H 6.62; N 9.20.
2-(Acetylglycyl)-N-cyclohexyl-1,2,3,4-tetrahydroiso-
quinoline-1-carboxamide (1c). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 8.09 (1H, d, J = 7.9, NH); 8.00
(1H, t, J = 5.6, NH); 7.35–7.12 (4H, m, H Ar); 5.62 (1H, s,
CH); 4.05 (2H, d, J = 5.6, CH2); 4.02–3.91 (1H, m) and
3.61 (1H, ddd, J = 12.1, J = 7.3, J = 4.8, CH2); 3.02 (1H,
ddd, J = 15.5, J = 7.3, J = 4.9) and 2.87–2.78 (1H, m,
CH2); 1.87 (3H, s); 1.72–1.67 (1H, m), 1.65–1.60 (2H, d,
J = 10.9), 1.56–1.51 (2H, m), and 1.28–1.06 (6H, m,
CH(CH2)5). 13C NMR spectrum (DMSO-d6), δ, ppm:
169.9; 169.8; 168.8; 135.6; 133.2; 128.5; 127.7; 127.5;
126.6; 57.6; 48.2; 41.4; 32.8; 32.6; 28.6; 25.7; 25.0; 24.9;
24.7; 22.9. Found, %: C 67.22; H 7.59; N 11.77.
C20H27N3O3. Calculated, %: C 67.20; H 7.61; N 11.76.
2-(Acetylglycyl)-N-(tert-butyl)-1,2,3,4-tetrahydroiso-
3,4-Dihydroisoquinoline (2).44 2-Phenylethylamine
(30.0 g, 0.248 mol) and ethyl formate were heated at reflux
for 2 days. Removal of excess ethyl formate under vacuum
gave the N-phenethylformamide in quantitative yield (37.0 g)
1
as a colorless oil. H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 8.10 (1H, s, CHO); 7.29 (2H, t, J = 7.2, H Ar);
7.24–7.13 (3H, m, H Ar); 6.7–6.2 (1H, br. s, NH); 3.50
(2H, t, J = 7.0, CH2); 2.81 (2H, t, J =7.0, CH2). 13C NMR
spectrum (CDCl3), δ, ppm: 161.4; 138.6; 128.8; 128.7;
126.6; 39.2; 35.5. Crude 2-phenylethylamine (7.0 g,
0.47 mol) and polyphosphoric acid (20 ml) were heated at
160°C overnight. The reaction mixture was cooled to room
temperature and made basic with 5 M NaOH; a white
precipitate formed. The precipitate was filtered off, and the
filtrate was extracted three times with ethyl acetate. The
combined organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo to yield compound 2
1
quinoline-1-carboxamide (1d). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.43–7.08 (4H, m, H Ar); 6.66 (1H, br. s,
NH); 6.08 (1H, br. s); 5.75 (1H, s, CH); 4.25–4.18 (1H, m)
and 4.13 (1H, dd, J = 17.5, J = 4.5, CH2); 3.85 (1H, dd, J = 7.1,
J = 5.1) and 3.61 (1H, ddd, J = 12.3, J = 7.1, J = 5.1, CH2);
3.06 (1H, ddd, J = 15.9, J = 7.2, J = 5.3) and 2.94–2.80
(1H, m, CH2); 2.06 (3H, s, CH3); 1.30 (9H, s, t-Bu).
13C NMR spectrum (CDCl3), δ, ppm: 170.3; 168.8; 168.3;
134.6; 131.8; 128.5; 128.0; 127.4; 126.9; 60.2; 58.6; 41.8;
41.3; 28.6 (3C); 28.4; 23.0. Found, %: C 65.20; H 7.61;
N 12.71. C18H25N3O3. Calculated, %: C 65.23; H 7.60;
N 12.68.
1
(5.0 g, 81%) as a pale-yellow oil. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 8.31 (1H, t, J = 2.3, H Ar); 7.36–
7.20 (3H, m, H Ar); 7.19–7.05 (1H, m, H Ar); 3.83–3.70
(2H, m, CH2); 2.81–2.69 (2H, m, CH2). 13C NMR spectrum
(CDCl3), δ, ppm: 160.7; 136.7; 131.7; 128.9; 127.8; 127.6;
127.5; 47.8; 25.4
Synthesis of peptidomimetics 1a–l by three-compo-
nent Ugi reaction (General method). The carboxylic acid
(4.27 mmol) and the isocyanide (4.27 mmol) were added to
a stirred solution of compound 2 (0.560 g, 4.27 mmol) in
Benzyl {(2S)-1-[1-(benzylcarbamoyl)-3,4-dihydroiso-
quinolin-2(1H)-yl]-1-oxopropan-2-yl}carbamate
(1e).
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
1
Diastereoisomer A. H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.38–7.13 (14H, m, H Ar); 6.99 (1H, br. s, NH);
5.92 (1H, s, CH); 5.56 (1H, d, J = 7.1, NH); 5.10 (1H, d,
J = 12.1) and 4.88 (1H, d, J = 12.1, CH2); 4.73 (1H, quin,
J = 6.9, CH); 4.58–4.32 (2H, m, CH2); 4.12–3.88 (1H, m)
and 3.84–3.72 (1H, m, CH2); 3.05 (1H, dt, J = 15.9,
J = 5.8) and 2.92 (1H, ddd, J = 15.2, J = 9.0, J = 6.3, CH2);
1.33 (3H, d, J = 6.9, CH3). 13C NMR spectrum (CDCl3), δ,
ppm: 173.0; 169.6; 138.4; 136.3; 134.3; 131.9; 128.6;
128.5; 128.4; 128.2 (3C); 128.1 (3C); 127.8 (3C); 127.4;
127.2; 126.8; 66.9; 60.3; 58.0; 47.2; 43.6; 28.8; 14.2.
Found, %: C 71.33; H 6.20; N 8.90. C28H29N3O4.
Calculated, %: C 71.32; H 6.20; N 8.91.
137.1; 134.8; 132.0; 128.5; 128.2 (2C); 127.9 (2C); 127.6;
127.4; 127.2; 126.6; 115.3; 57.4; 43.6; 42.2; 32.9; 28.9;
28.8. Found, %: C 75.80; H 6.93; N 8.06. C22H24N2O2.
Calculated, %: C 75.83; H 6.94; N 8.04.
N-Cyclohexyl-2-(pent-4-enoyl)-1,2,3,4-tetrahydroiso-
1
quinoline-1-carboxamide (1h). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.25–7.13 (4H, m, H Ar); 6.47 (1H, d, J = 8.3,
NH); 5.92–5.80 (2H, m, CH and CH=CH2); 5.12–4.94 (2H,
m, CH=CH2); 3.84–3.64 (3H, m, CH2, CH(CH2)5); 3.03
(1H, dt, J = 15.7, J = 5.2) and 2.89 (1H, ddd, J = 15.7, J = 8.5,
J = 5.3, CH2); 2.64–2.39 (4H, m, CH2CH2CH=CH2); 1.86–
1.79 (1H, m), 1.70–1.52 (2H, m), 1.35–1.10 (3H, m), and
1.40–1.10 (4H, m, CH(CH2)5). 13C NMR spectrum
(CDCl3), δ, ppm: 172.3; 169.4; 137.1; 134.7; 132.1; 128.3;
127.8; 127.6; 126.6; 115.5; 57.4; 48.3; 42.2; 32.9; 32.8
(2C); 29.1; 28.9; 25.5; 24.6 (2C). Found, %: C 74.07;
H 8.32; N 8.25. C21H28N2O2. Calculated, %: C 74.08;
H 8.29; N 8.23.
Diastereoisomer B. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.37–7.13 (14H, m, H Ar); 6.67 (1H, br. s, NH);
5.92 (1H, s, CH); 5.68–5.51 (1H, m, NH); 5.21–4.90 (2H,
m, CH2); 4.78–4.67 (1H, m, CH); 4.51–4.29 (2H, m, CH2);
3.86–3.72 (2H, m, CH2); 3.10–2.85 (2H, m, CH2); 1.32
(3H, d, J = 6.9, CH3). 13C NMR spectrum (CDCl3), δ, ppm:
172.5; 170.1; 155.6; 138.4; 136.4; 134.6; 131.5; 128.6
(2C); 128.5; 128.3 (2C); 128.1 (2C); 128.0; 127.7 (2C);
127.5; 127.3; 127.1; 126.7; 66.8; 57.5; 47.2; 43.6; 41.9;
28.8; 18.6. Found, %: C 71.31; H 6.23; N 8.94.
C28H29N3O4. Calculated, %: C 71.32; H 6.20; N 8.91.
Ethyl 2-{[(benzyloxycarbonyl)-L-alanyl]-1,2,3,4-tetra-
hydroisoquinolin-1-ylcarbonyl}glycinate (1f). Diastereo-
Ethyl [2-(pent-4-enoyl)-1,2,3,4-tetrahydroisoquinolin-
1
1-ylcarbonyl]glycinate (1i). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.32–7.15 (4H, m, H Ar); 7.12 (1H, br. s,
NH); 6.02 (1H, s, CH); 5.86 (1H, dtt, J = 16.6, J = 10.0,
J = 6.1, CH=CH2); 5.11–4.96 (2H, m, CH=CH2); 4.16 (2H,
q, J = 7.1, CH2CH3); 3.97 (2H, AB system, J = 18.1,
J = 5.5, CH2); 3.83 (1H, ddd, J = 12.8, J = 8.1, J = 4.8) and
3.75 (1H, dt, J = 12.3, J = 5.7, CH2); 3.04 (1H, dt, J = 15.7,
J = 5.6) and 2.89 (1H, ddd, J = 15.6, J = 8.2, J = 5.1, CH2);
2.65–2.36 (4H, m, CH2CH2CH=CH2); 1.24 (3H, t, J = 7.2,
CH2CH3). 13C NMR spectrum (CDCl3), δ, ppm: 172.6;
170.7; 169.4; 137.1; 134.7; 131.7; 128.1; 128.0; 127.7;
126.6; 115.3; 61.2; 57.0; 42.2; 41.4; 32.9; 28.9; 28.8; 14.0.
Found, %: C 66.24; H 7.04; N 8.10. C19H24N2O4.
Calculated, %: C 66.26; H 7.02; N 8.13.
1
isomer A. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
7.45–7.19 (8H, m, H Ar); 7.19–7.12 (1H, m, NH); 6.03
(1H, d, J = 7.5, NH); 5.99 (1H, s, CH); 5.09 (2H, s, CH2);
4.78 (1H, t, J = 7.0, CH); 4.20–4.12 (1H, m, CH2); 4.12
(2H, q, J = 7.1, CH2CH3); 4.07–3.93 (2H, m, CH2); 3.88–
3.75 (2H, m, CH2); 3.10 (1H, dd, J = 13.9, J = 7.8) and
2.95–2.82 (1H, m, CH2); 1.34 (3H, d, J = 6.8, CH3); 1.19
(3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (CDCl3),
δ, ppm: 172.8; 170.0; 169.5; 156.0; 136.4; 134.4; 131.5;
128.4; 128.0 (2C); 127.9; 127.8 (2C); 126.7 (2C); 61.1;
57.6; 47.3; 42.2; 41.4; 28.6; 20.8; 18.2; 14.1; 14.0. Found, %:
C 64.25; H 6.23; N 9.01. C25H29N3O6. Calculated, %:
C 64.23; H 6.25; N 8.99.
N-Benzyl-2-(2-chloroacetyl)-1,2,3,4-tetrahydroiso-
1
quinoline-1-carboxamide (1j). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.31–7.16 (9H, m, H Ar); 6.90 (1H, br. s,
NH); 5.88 (1H, s, CH); 4.40 (2H, d, J = 5.8, CH2); 4.20–
4.09 (2H, m, CH2); 3.91 (1H, ddd, J = 12.9, J = 8.4,
J = 4.7) and 3.76 (1H, dt, J = 12.5, J = 5.6, CH2); 3.09 (1H,
dt, J = 15.8, J = 5.3) and 2.97 (1H, ddd, J = 16.0, J = 8.4,
J = 5.1, CH2). 13C NMR spectrum (CDCl3), δ, ppm: 169.7;
166.7; 138.0; 134.4; 131.2; 128.6 (2C); 128.4; 127.9;
127.7; 127.5 (2C); 127.4; 126.9; 58.0; 43.7; 42.8; 41.3;
28.7. Found, %: C 66.55; H 5.56; N 8.14. C19H19ClN2O2.
Calculated, %: C 66.57; H 5.59; N 8.17.
Diastereoisomer B. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.39–7.16 (9H, m, H Ar); 6.79 (1H, br. s, NH);
6.00 (1H, s, CH); 5.71 (1H, br. s, NH); 5.12–5.02 (2H, m,
CH2); 4.77 (1H, br. s, CH); 4.17 (2H, q, J = 7.0, CH2CH3);
4.04 (1H, dd, J = 18.2, J = 5.2) and 3.92 (1H, dd, J = 18.2,
J = 5.2, CH2); 3.86–3.71 (2H, m, CH2); 3.01–2.91 (2H, m,
CH2); 1.45 (3H, d, J = 6.8, CH3); 1.29 (3H, t, J = 7.1,
CH2CH3). 13C NMR spectrum (CDCl3), δ, ppm: 172.7; 170.0;
169.4; 156.6; 134.5; 131.0; 128.5; 128.4 (2C); 128.0; 127.9
(2C); 127.8; 126.8; 66.8; 61.6; 61.4; 57.0; 47.3; 41.9; 41.5;
40.0; 28.7; 18.8; 14.1. Found, %: C 64.24; H 6.26; N 9.02.
C25H29N3O6. Calculated, %: C 64.23; H 6.25; N 8.99.
N-Benzyl-2-(pent-4-enoyl)-1,2,3,4-tetrahydroisoquinoline-
2-(2-Chloroacetyl)-N-cyclohexyl-1,2,3,4-tetrahydroiso-
1
quinoline-1-carboxamide (1k). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.28–7.15 (4H, m, H Ar); 6.27 (1H, d,
J = 8.1, NH); 5.79 (1H, s, CH); 4.24–4.11 (2H, m, CH2);
3.95–3.77 (2H, m, CH(CH2)5 and CH2); 3.76–3.68 (1H, m,
CH2); 3.10–2.88 (2H, m, CH2); 1.93–1.80 (2H, m), 1.67–
1.50 (2H, m), 1.40–1.27 (2H, m), and 1.25–1.10 (4H, m,
CH(CH2)5). 13C NMR spectrum (CDCl3), δ, ppm: 168.7;
166.8; 134.3; 133.6; 128.5; 127.8; 127.7; 126.8; 57.9; 48.5;
42.7; 41.2; 32.8 (2C); 28.8; 25.5; 24.6 (2C). Found, %:
C 64.59; H 6.88; N 8.35. C18H23ClN2O2. Calculated, %:
C 64.57; H 6.92; N 8.37.
1
1-carboxamide (1g). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.33–7.14 (9H, m, H Ar); 6.89 (1H, br. s, NH);
5.96 (1H, s, CH); 5.92–5.77 (1H, m, CH=CH2); 5.12–4.94
(2H, m, CH=CH2); 4.42 (2H, d, J = 5.9, CH2); 3.81–3.68
(2H, m, CH2); 3.06 (1H, dt, J = 15.7, J = 5.5) and 2.95–
2.85 (1H, m, CH2); 2.60–2.36 (4H, m, CH2CH2CH=CH2).
13C NMR spectrum (CDCl3), δ, ppm: 172.5; 170.4; 138.3;
N-(tert-Butyl)-2-(2-chloroacetyl)-1,2,3,4-tetrahydroiso-
1
quinoline-1-carboxamide (1l). H NMR spectrum (CDCl3),
1218

Chemistry of Heterocyclic Compounds 2017, 53(11), 1214–1219
21. Scheffelaar, R.; Nijenhuis, R. A. K.; Paravidino, M.; Lutz, M.;
δ, ppm (J, Hz): 7.35–7.10 (4H, m, H Ar); 6.24 (1H, br. s,
NH); 5.75 (1H, s, CH); 4.27–4.10 (2H, m, CH2); 3.93–3.77
(2H, m, CH2); 3.09–2.93 (2H, m, CH2); 1.32 (9H, s, t-Bu).
13C NMR spectrum (CDCl3), δ, ppm: 167.1; 161.4; 134.2;
131.4; 128.7; 128.5; 127.8; 126.8; 58.3; 51.6; 42.7; 41.1;
28.8; 28.7 (3C). Found, %: C 62.25; H 6.82; N 9.10.
C16H21ClN2O2. Calculated, %: C 62.23; H 6.85; N 9.07.
Spek, A. L.; Ehlers, A. W.; de Kanter, F. J. J.; Groen, M. B.;
Orru, R. V. A.; Ruijter, E. J. Org. Chem. 2009, 74, 660.
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2012, 10(45), 9004.
25. Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A.
Tetrahedron 2010, 66, 4474.
1
The Supplementary information file containing the H
and 13C NMR spectra of compounds 1a–l is available at the
26. Airaghi, F.; Fiorati, A.; Lesma, G.; Musolino, M.; Sacchetti, A.;
Silvani, A. Beilstein J. Org. Chem. 2013, 9, 147.
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