Derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

Article abstract of DOI:10.3987/COM-05-10571

-The following derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid have been prepared in their (S)-form and as racemates: hydrochloride of methyl ester, N-carboxy anhydride, and N-acetyl derivative. All the substances were fully characterised

Full text of DOI:10.3987/COM-05-10571

HETEROCYCLES, Vol. 68, No. 1, 2006
59
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 59 – 69. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd September, 2005, Accepted, 11th November, 2005, Published online, 15th November, 2005. COM-05-10571
DERIVATIVES OF 1,2,3,4-TETRAHYDROISOQUINOLINE-
3-CARBOXYLIC ACID
1
1
2
Petr Jansa, Vladimír Macháček,* and Valerio Bertolasi
1
Department of Organic Chemistry, Faculty of Chemical Technology, University
of Pardubice, 53210 Pardubice, Czech Republic
E-mail: vladimir.machacek@upce.cz
2
Università di Ferrara, Dipartimento di Chimica and Centro di Strutturistica
Diffrattometrica, Via L.Borsari 46, I-441 00 Ferrara, Italy
Abstract – The following derivatives of 1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid have been prepared in their (S)-form and as racemates:
hydrochloride of methyl ester, N-carboxy anhydride, and N-acetyl derivative. All
1
13
the substances were fully characterised by elemental analyses, H and C NMR
spectra, and optical rotation, as the case may be; the N-carboxy anhydride was
also characterised by means of X-Ray diffraction. Also identified was the
intermediate of the reaction of the title acid with phosgene, the N-chlorocarbonyl
derivative, and the respective methyl ester was prepared. The dioxopiperazine of
the title acid was prepared and characterised both in pure (S,S)-form and in the
form of a mixture of two racemates. The optically pure dioxopiperazine was
prepared by a reaction of the N-carboxy anhydride in solid phase.
INTRODUCTION
,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic acid) is a chiral α-amino acid, not occurring in
1
nature, and easily accessible even in optically pure form. The interest in the derivatives of this acid is
motivated by their very varied biological activities. Tic acid derivatives act as inhibitors in a number of
1
-8
enzymatic processes (for a survey, see Refs ); some of them (such as e.g. the HIV protease inhibitor
®
9-11
Saquinavir ) have already been introduced into clinical practice. The bridge formation of amino group
with benzene ring restricts the conformational freedom of Tic acid, which allows preparations of peptides
2
,12-15
with defined tertiary structure.
Selected macrocyclic peptides containing Tic acid can even block the
From the standpoint of biological activity also interesting are small
1
6,17
biosynthesis of peptides.

60
HETEROCYCLES, Vol. 68, No. 1, 2006
3
,4,6,7,18-21
molecules containing the structural motif of Tic acid.
The present paper describes synthesis and
identification of selected Tic acid derivatives, both in optically pure and in racemic forms.
RESULTS AND DISCUSSION
O
9
6
10
0a∗
1
8
7
1
O 2
1
CO R
N
∗
2
3
4
5
O
N
5. (S)
6. (R,S)
R2
O
1
2
1
2
3
4
7
8
9
1
. (S), R =H, R =H
1
2
1
16
15
13
12
. (R,S), R =H, R =H
1
N
4
∗15a
11
10
1
2
2
3
. (S), R =CH , R =H + HCl
3
1
2
. (R,S), R =CH , R =H + HCl
a,b. (S), R =H, R =COCl
a,b. (S), R =CH , R =COCl
a,b. (S), R =CH , R =COCH
3
∗
7a
1
2
N
6
7
1
2
4
5
8
9
3
1
2
3
3
O
1
2
0a,b. (R,S), R =CH , R =COCH
3
3
11. (7aS; 15aS)
1
1
2. (7aR,S; 15aR,S)
3. (7aR,S; 15aS,R)
The racemic Tic acid (2) was prepared by the Pictet–Spengler reaction from racemic phenylalanine and
2
2
formaldehyde. The esterification of Tic acid (2) with methanol proceeds almost quantitatively to give
the ester (4). N-Carboxy anhydrides are usual intermediates in peptide syntheses. As a rule, they are
prepared by reactions of α-amino acids with phosgene. This preparation procedure was also adopted for
23,24
the pre- paration of N-carboxy anhydride (5) in several patents;
however, the prepared substance (5)
was used further in situ without being identified and its physical constants determined. According to
1
Ref., N-carboxy anhydride (5) was for the first time isolated in the yield of 66% after the reaction of Tic
acid (1) with di(tert-butyl) dicarbonate and PCl
3
. The procedure adopted by us for the preparation of
Cl
compound (5) by the reaction of Tic acid (1) with a solution of phosgene in a mixture of THF and CH
2
2
gives a 95% yield of N-carboxy anhydride (5) with higher mp and somewhat higher optical purity. The
same procedure as that for the (S)-enantiomer was also adopted for the racemic N-carboxy anhydride (6),
the yield being similar.
The structure of N-carboxy anhydride (5) was determined by means of X-Ray diffraction. An ORTEP
2
5
view is shown in Figure 1. The six-membered ring C3-C4-C5-C10-C11-N1 exhibits an envelope
1
26
T 2 2
conformation E with puckering parameters of: Q = 0.418(2) Å, φ = –10.9(5)°, θ = 49.5(3)°. The
other rings are essentially planar. The molecules, in the crystal, are linked in chains by means of short
…
carbonyl-carbonyl dipolar interactions, C=O C=O, of carboxy anhydride moieties as shown in Figure 2
…
having the O1 C2 distance of 2.954(3) Å much shorter than the sum of van der Waals radii of 3.22 Å.

HETEROCYCLES, Vol. 68, No. 1, 2006
61
…
Figure 1. ORTEP view of (5) displaying
Figure 2. Dipole-dipole C1=O1 C2=O3 interactions
thermal ellipsoids at 30% probability.
in the crystal packing between carbonyl groups.
These attractive interactions, which can be competitive with hydrogen bonds, assume an important role in
2
7-31
organic and biological systems for their molecular recognition properties.
form a layered structure (Figure 3).
In the crystal, the molecules
Figure 3. The crystal packing of 5 viewed down the crystallographic a axis.
The molecular structure determined by X-Ray is in accordance with the optimum conformation calculated
3
2,33
34
at the level of B3LYP /TZVP.
We found out that the pure N-carboxy anhydride (5) is not obtained if, in the preparation of compound (5)
and processing of the reaction mixture, the heating above rt is omitted. Besides the N-carboxy anhydride,

62
HETEROCYCLES, Vol. 68, No. 1, 2006
the reaction mixture contains further two structurally similar substances with a skeleton close to that of
1
13
the starting Tic acid (according to H and C NMR spectra) but containing one additional carbonyl group
35
(
δ 150.26 and 149.09) of the carbamoyl chloride type (for N,N-dimethylcarbamoyl chloride
3
6
3
δ 148.2, for N,N-diethylcarbamoyl chloride δ 148.5 in CDCl ). The amount of these substances
decreases with time, their ratio being maintained (7a/7b = 10/12); their transformation only produces
N-carboxy anhydride (5). At enhanced temperature, the decrease in the amount of substances (7a,b) is
fast, or, as the case may be, their formation cannot be observed at all. These substances (7a,b) were
ascribed the structure of (3S)-N-chlorocarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. They
are conformational iso- mers differing in the conformation of the –NCOCl group as the consequence of
partial double bond character of NC bond. Carbonyl chloride (7) is an intermediate in the formation of
N-carboxy anhydride, and it cannot be separated from the N-carboxy anhydride. Its structure was
suggested by means of the NMR spectra.
In order to further confirm the structure of carbamoyl chloride, we also carried out the reaction of phosgene
with the hydrochloride of ester (3). Also in this case, we observed formation of analogous isomeric
1
13
carbamoyl chlorides (8a,b). These substances could be isolated and identified by their H and C NMR
spectra and elemental analyses.
The hindered rotation causing formation of conformational isomers can also be observed in the spectra of
methyl (3S)-N-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9) and racemic methyl ester (10) too.
Symmetrical dioxopiperazines can be prepared under mild conditions by a reaction of hydrochloride of
ester of α-amino acid with N-carboxy anhydride in the presence of a base. Using this method, we
prepared (7aS,15aS)-5,8,13,16-tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (11) in a yield of
5
2 % from compounds (3, 5) and triethylamine. From the NMR spectra it is obvious that there takes place
partial inversion of configuration as the consequence of the presence of acidic hydrogen atom next to the
carbonyl group, diastereoisomer (13) being formed. The optical purity of compound (11) is 90 %.
Dioxopiperazine (11) is also formed by 15 h boiling of N-carboxy anhydride (5) in toluene. However, the
yield is only 56 %, the rest being formed by peptides. The optical purity of the dioxopiperazine (11) thus
1
prepared is, according to the H NMR spectra, better than in the previous case, namely 97 %. Surprisingly,
the highest yield of dioxopiperazine (11) was obtained by 10 h heating of N-carboxy anhydride (5) at
1
00 °C in inert atmosphere without solvent. The crude product contains 98 % (7aS,15aS)-5,8,13,16-
tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (11) with the diastereoisomeric purity of 100 %.
The easy formation of dioxopiperazine (11) by heating N-carboxy anhydride (5) to temperatures below its
mp without solvent can probably be explained by the character of the crystal lattice of N-carboxy
anhydride, in which pairs of molecules are placed in layers with their anhydride groups oriented against
each other (Figure 2).

HETEROCYCLES, Vol. 68, No. 1, 2006
63
The reaction of racemic N-carboxy anhydride (6) with racemic ester (4) produces two racemates of
dioxopiperazine: (7aS,15aS) + (7aR,15aR) (12) and (7aS,15aR) + (7aR,15aS) (13). Using the method of
addition of compound (11), we found out that the stereoisomers are present in this mixture at a ratio of
1
2/13 = 17/3.
ACKNOWLEDGEMENTS
The authors (V.M. and P.J.) acknowledge the financial support by the Ministry of Youth, Sports and
Education of the Czech Republic (project No. MSM 002 162 7501).
EXPERIMENTAL
The NMR spectra were measured at 298 K with Bruker AVANCE 500 spectrometer equipped with 5 mm
1
13
broadband probe at the frequencies of 500.13 MHz ( H) and 125.77 MHz ( C) and with a Bruker AMX
1
13
3
60 spectrometer at the frequencies 360.14 MHz ( H) and 90.57 MHz ( C) in DMSO-d
6
, CDCl
3
, and
on
O (δ 0.02). The C NMR spectra
were calibrated on the central signal of the solvent multiplet (δ 39.6 for DMSO-d , δ 77.0 for CDCl ), and
1
D
2
O. The H NMR spectra were calibrated in CDCl
3
on hexamethyldisiloxane (δ 0.05), in DMSO-d
6
1
3
the central signal of the solvent multiplet (δ 2.55), and on DSS in D
2
6
3
2
on DSS (δ 1.6) for D O. The carbon NMR spectra were measured in standard way and by means of the
APT pulse sequence.
Melting points were determined with a Kofler hot stage microscope and were not corrected. The
elemental analyses were carried out with a FISONS EA 1108 automatic analyser. Optical rotations were
measured on PERKIN ELMER 341 Polarimeter at λ 589.3 nm and 298 K.
The crystal data for the compound (5) were collected at the room temperature using a Nonius Kappa CCD
α
diffractometer with graphite monochromated Mo K radiation and corrected for Lorentz and polarization
3
7
effects. The structures were solved by direct methods SIR97 and refined using full-matrix least-squares
with anisotropic non-hydrogen atoms and isotropic hydrogens. All the calculations were performed using
3
8
39
40
SHELXL-97 and PARST inplemented in WINGX.
Crystal data: (5), C11
H
9
NO
3
; monoclinic, space group P2
1
, a = 6.8994(3), b = 7.1160(4), c = 10.0425(5)
3
-3
Å, β = 107.646(1)°, V = 469.85(4) Å , Z = 2, Dc = 1.436 g cm . Intensity data collected with θ ≤ 30°;
2
421 independent reflections measured; 1500 observed [I >2σ(I)]. Final R index = 0.0445 (observed
reflections), Rw = 0.1110 (all reflections), S = 0.971.
Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 283185. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or on application to CCDC, Union
Road, Cambridge CB2 1EZ, UK [fax: (+44)1223-336033, e-mail: deposit@ccdc.cam.ac.uk

64
HETEROCYCLES, Vol. 68, No. 1, 2006
The starting (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1) (CMS Chemicals LTD), mp
2
D
0
3
31 °C (decomp), the content of 99.1% according to titration with HClO
4
, and
[
α
]
= –175.8° (c = 1.1N
2
2
20
aq NaOH), Ref. gives
[
α
]D = –177.4° (c = 1.1N aq NaOH).
1
H NMR (D O) (as the tert-butylammonium salt prepared in situ) δ 7.23-7.09 (4H, m, arom.), 4.80 (bs,
2
+
2
2
N H
3
+NH+HDO), 3.98 (1H, d, H(1a), J=16.3 Hz), 3.92 (1H, d, H(1b), J=16.3 Hz), 3.40 (1H, dd, H(3),
3
3
2
3
2
J=4.5 Hz, J=10.8 Hz), 3.02 (1H, dd, H(4a), J=16.5 Hz, J=4.5 Hz,), 2.81 (1H, dd, H(4b), J=16.5 Hz,
3
13
J=10.8 Hz,), 1.13 (9H, s, (C(CH
32.19, 131.94 (arom, 2xC
NC(CH ), 44.02 (ArCH N), 29.30 (ArCH
3
)
3
). C NMR (D
2
O) (as the tert-butylammonium salt) δ 177.37 (COO),
1
q
), 126.73, 123.74, 123.66, 123.40 (arom, 4xCH), 55.19 (CHCO), 44.89
(
3
)
3
2
2
C), 27.90 (NC(CH ).
3 3
)
22
(
±)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (2) was prepared according to Ref., yield 91%.
1
13
H and C NMR spectra (tert-butylammonium salt) in D
2
O were identical with the tert-butylammonium
salt of compound (1).
Hydrochloride of methyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3) was prepared from
(
S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1) and SOCl
2
in dry methanol by a known
2
2,41
22
procedure
with practically quantitative yield. mp 248-250°C (decomp), (methanol-ether). Ref. gives
mp 250-255 °C, (decomp), (methanol-ether). The product recrystallised from a mixture of chloroform-ether
2
D
0
20
22
melts at 261-263°C (decomp),
[
α
]
= –155.1° (c = 1, CHCl
3
),
[
α
]D = –128.2° (c = 1, CH
3
OH). Ref.
20
gives
[
α
]
D
3
= –104.1° (c = 1, CH OH). For the NMR spectral analysis, the product was washed with
saturated solution of HCl in ether.
1
+
2
H NMR (DMSO-d
6
2
) δ 10.03 (2H, br s, NH ), 7.32-7.30 (4H, m, arom.), 4.41 (1H, d, H(1a), J=16.2 Hz),
2
3
3
2
4
.36 (1H, d, H(1b), J=16.2 Hz), 4.61 (1H, dd, H(3), J=5.2 Hz, J=11.2 Hz), 3.35 (1H, dd, H(4a), J=16.9
3
2
3
13
Hz, J=5.2 Hz), 3.20 (1H, dd, H(4b), J=16.9 Hz, J=11.2 Hz), 3.86 (3H, s, OCH ). C NMR (DMSO-d )
3
6
δ 169.08 (COO), 131.05, 130.70 (arom, 2xC
OCH ), 53.41 (CHCO), 44.09 (ArCH N), 28.27 (ArCH
Hydrochloride of methyl (±)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (4) was prepared from
±)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2) in the same way and in practically quantitative
q
), 129.12, 128.47, 127.98, 126.92 (arom, 4xCH), 53.53
(
3
2
2
C).
(
4
1
yield. Its mp is 250-252 °C (decomp), (methanol-ether), Ref. gives mp 302-303 °C (decomp),
4
2
(
methanol- ether), and Ref. gives mp 278 °C (chloroform-ether). For the NMR analysis, the product was
1
13
6
washed with saturated solution of HCl in ether. H and C NMR spectra in DMSO-D were identical with
those of compound (3).
(
10aS)-10,10a-Dihydro[1,3]oxazolo[3,4-b]isoquinoline-1,3(5H)-dione (5): A suspension of 7.1 g (40
mmol) (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1) in 100 mL of dry THF was treated with a
solution of 8 g (80 mmol) of COCl in 50 mL of CH Cl added at –30 °C with vigorous stirring. The
2
2
2

HETEROCYCLES, Vol. 68, No. 1, 2006
65
reaction mixture was kept at the temperature of –30 °C for another 1 h and then stirred with spontaneous
increase in temperature up to rt, and further stirred at rt overnight. The resulting clear solution was rid of
all the solvents and rest of phosgene by means of vacuum distillation, keeping the temperature below
40 °C. The yield was 7.8 g (95 %) of yellowish crystals, mp 183-185 °C (cyclohexane), mp 152-153 °C
2
D
0
1
20
(
ether),
[
α
]
= –188.2° (c = 2.1, CHCl
3
), Ref. gives mp 150°C (ether) and
[
α
]D = –187° (c = 2.1,
1
2
CHCl
3
). H NMR (CDCl
3
) δ 7.28-7.16 (4H, m, arom.), 4.93 (1H, d, H(1a), J=16.6 Hz), 4.48 (1H, d,
2
3
3
2
3
H(1b), J=16.6 Hz), 4.36 (1H, dd, H(3), J=4.7 Hz, J=11.4 Hz), 3.31 (1H, dd, H(4a), J=15.3 Hz, J=4.7
2
3
13
Hz ), 3.05 (1H, dd, H(4b), J=15.3 Hz, J=11.4 Hz). C NMR (CDCl
NCOO), 129.76, 129.74 (arom, 2xC ), 129.57, 127.80, 127.62, 126.62 (arom, 4xCH), 54.54 (CHCO),
2.36 (ArCH N), 30.45 (ArCH C).
10a±)-10,10a-Dihydro[1,3]oxazolo[3,4-b]isoquinoline-1,3(5H)-dione (6): Compound (6) was prepared
3
) δ 168.33 (CCOO), 150.73
(
q
4
2
2
(
1
13
in the same way as compound (5) with a yield of 90 %, mp 180-183°C (cyclohexane). H and C NMR
spectra in CDCl were identical with those of compound (5).
Methyl (3S)-N-chlorocarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8): A suspension of
.17 g (0.75 mmol) of hydrochloride of methyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3) in 20
mL of dry THF was treated with a solution of 0.15 g (1.5 mmol) COCl in 10 mL of CH Cl added at the
3
0
2
2
2
temperature of –30 °C with vigorous stirring. The reaction mixture was kept at the temperature of –30 °C
for another 1 h and then stirred with spontaneous increase in temperature up to rt, and further stirred at rt
overnight. The resulting clear solution was rid of all the solvents and rest of phosgene by means of
vacuum distillation, keeping the temperature below rt. The yield was 0.19 g yellowish oily product
(
practically quantitative yield). The NMR spectral analysis showed that the product is a mixture of two
isomers (the integral intensities are in the ratio 8a/8b = 11/10). The unambiguous assignment of signals to
the individual isomers was carried out by means of NOE. Anal. Calcd for C12 Cl: C, 56.82; H,
H12NO
3
4
.77; N 5.52; Cl, 13.98. Found: C, 57.05; H, 4.95; N, 5.66; Cl, 13.69.
1
2
Isomer (8a): H NMR (CDCl
3
) δ 7.36-7.16 (4H, m, arom.), 4.96 (1H, d, H(1a), J)=16.0 Hz), 4.80 (1H, d,
2
3
3
2
3
H(1b), J=16.0 Hz), 5.24 (1H, dd, H(3), J=3.4 Hz, J=5.6 Hz ), 3.31 (1H, dd, H(4a), J=15.5 Hz, J=3.4
2
3
13
Hz), 3.21 (1H, dd, H(4b), J=15.5 Hz, J=5.6 Hz), 3.64 (3H, s, OCH
COO), 150.26 (NCOCl), 131.36, 131.03 (arom, 2xC ), 128.26, 127.43, 127.29, 126.16 (arom, 4xCH),
N), 31.07 (ArCH C).
3 3
). C NMR (CDCl ) δ 169.74
(
q
5
5.50 (OCH
3
), 52.71 (CHCO), 48.42 (ArCH
2
2
1
2
Isomer (8b): H NMR (CDCl
3
) δ 7.36-7.16 (4H, m, arom.), 4.86 (1H, d, H(1a), J=16.4 Hz), 4.70 (1H, d,
2
3
3
2
3
H(1b), J=16.4 Hz), 5.21 (1H, dd, H(3), J=3.6 Hz, J=5.7 Hz), 3.33 (1H, dd, H(4a), J=15.8 Hz, J=3.6
2
3
13
Hz), 3.26 (1H, dd, H(4b), J=15.8 Hz, J=5.7 Hz), 3.65 (3H, s, OCH
3 3
). C NMR (CDCl ) δ 170.06
(
COO), 149.09 (NCOCl), 131.12, 130.91 (arom, 2xC ), 128.06, 127.41, 127.26, 126.16 (arom, 4xCH),
q
3 2 2
57.68 (OCH ), 52.84 (CHCO), 47.23 (ArCH N), 31.52 (ArCH C).

66
HETEROCYCLES, Vol. 68, No. 1, 2006
Methyl (3S)-N-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9): The synthesis was performed
4
3
in analogy with Ref. The reaction flask was charged with 5 g (22.0 mmol) of hydrochloride of methyl
S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3), 1.25 g (15.3 mmol) of anhydrous sodium acetate
and 11.35 mL (120.4 mmol) of acetic anhydride. The suspension formed was stirred at a temperature of
0-60 °C for 1 h, whereupon the reaction mixture was poured in 50 mL of H O and immediately
extracted with 3 × 25 mL of CHCl . The chloroform extract was partially concentrated and extracted once
more with 50 mL H O. The organic phase was dried with anhydrous Na SO and all the solvents were
evaporated to leave an oily product. The product was further purified by flash chromatography (mobile
phase: CH OH, stationary phase: silica gel 60 μm). After recrystallisation from cyclohexane with
charcoal, the yield was 4.6 g (90%) white crystals, mp 93-96 °C,
NMR spectral analysis shows that the product is a mixture of two isomers (the integral intensities are in
(
5
2
3
2
2
4
3
2
0
[
α
]
D
3
= +35.6° (c = 1, CHCl ). The
the ratio 9a/9b = 5/2). Anal. Calcd for C13
.93.
H15NO
3
: C, 66.94; H, 6.48; N, 6.00. Found: C 66.68; H, 6.61; N,
5
1
2
Isomer (9a): H NMR (CDCl
3
) δ 7.22-7.11 (4H, m, arom.), 4.72 (1H, d, H(1a), J=15.8 Hz), 4.66 (1H, d,
2
3
3
2
3
H(1b), J=15.8 Hz), 5.49 (1H, dd, H(3), J=3.5 Hz, J=6.3 Hz ), 3.25 (1H, dd, H(4a), J=15.9 Hz, J=3.5
2
3
13
Hz), 3.11 (1H, dd, H(4b), J=15.9 Hz, J=6.3 Hz), 3.61 (3H, s, OCH
CDCl ) δ 171.39, 170.61 (2xCO), 132.10, 131.97 (arom, 2xC ), 128.47, 127.15, 126.88, 126.00 (arom,
xCH), 52.26 (CHCO), 51.06 (OCH ), 46.31 (ArCH N), 30.80 (ArCH
3 3
), 2.25 (3H, s, CH ). C NMR
(
3
q
4
3
2
2
3
C), 21.91 (CH ).
1
2
Isomer (9b): H NMR (CDCl
3
) δ 7.22-7.11 (4H, m, arom.), 4.93 (1H, d, H(1a), J=17.3 Hz ), 4.49 (1H, d,
2
3
3
2
3
H(1b), J=17.3 Hz), 4.78 (1H, dd, H(3), J=2.8 Hz, J=6.0 Hz), 3.34 (1H, dd, H(4a), J=15.6 Hz, J=2.8
2
3
13
Hz), 3.19 (1H, dd, H(4b), J=15.6 Hz, J=6.0 Hz), 3.60 (3H, s, OCH
CDCl ) δ 170.94, 170.54 (2xCO), 132.59, 131.00 (arom, 2xC ), 128.00, 127.06, 126.74, 126.58 (arom,
xCH), 55.67 (OCH ), 52.61 (CHCO), 43.34 (ArCH N), 31.82 (ArCH C), 21.80 (CH ).
3 3
), 2.16 (3H, s, CH ). C NMR
(
3
q
4
3
2
2
3
Methyl (±)-N-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (10): Compound (10) was prepared
in the same way as methyl (3S)-N-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9) in the yield of
9
2 %. After flash chromatography, the product was isolated as an oily substance. The NMR spectral
analysis shows that also in this case the product is a mixture of two isomers (the integral intensities are in
the ratio of 5/2). The NMR spectra are identical with those of methyl (3S)-N-acetyl-1,2,3,4-tetra-
hydroisoquinoline-3-carboxylate (9).
(
7aS,15aS)-5,8,13,16-Tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (11)
Procedure A: The synthesis was performed in analogy with the procedures described in Refs. : 0.16 g
0.78 mmol) of (10aS)-10,10a-dihydro[1,3]oxazolo[3,4-b]isoquinoline-1,3(5H)-dione (5) was added into
a solution prepared by addition of 0.24 mL (1.74 mmol) dry NEt to a solution of 0.20 g (0.89 mmol) of
hydrochloride of methyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3) in 10 mL dry CH Cl at
1
,44
(
3
2
2

HETEROCYCLES, Vol. 68, No. 1, 2006
67
–
75 °C. The solution was stirred at –75 °C for another 2 h, whereupon the reaction mixture was stirred
overnight with spontaneous increase in the temperature to rt. The obtained solution was concentrated, and
the evaporation residue was dissolved in 50 mL of toluene. The toluene solution was extracted with 20
2 2 4
mL H O and then with 20 mL 3% hydrochloric acid. Then it was dried with anhydrous Na SO and rid of
all the solvent. After recrystallisation from methanol, the yield was 0.13 g (52 %) of yellowish crystals.
The NMR spectra indicate that the product has been isolated in 90% diastereoisomeric purity.
Procedure B: 0.16 g (0.78 mmol) of (10aS)-10,10a-dihydro[1,3]oxazolo[3,4-b]isoquinoline-1,3(5H)-
dione (5) was dissolved in toluene and boiled 12 h. After evaporation of all the solvent, the yield was
0
.15 g of brownish product. The NMR spectra indicate that the product is present in the isolated mixture
in an amount of 56% (The rest are peptides.). The diastereoisomeric purity of product is 97 %.
Procedure C: 0.16 g (0.78 mmol) of (10aS)-10,10a-dihydro[1,3]oxazolo[3,4-b]isoquinoline-1,3(5H)-
dione (5) was heated without solvent under argon at 100 °C for a period of 10 h. The product was then
analysed by NMR spectrum without purification. It was found out that the isolated mixture contains 98 %
of the product with diastereoisomeric purity of 100 %. By dissolving in CHCl
3
and removal of insoluble
portions by filtration, and after evaporation of all the CHCl , the yield was 0.15 g (95 %) pure
3
2
D
0
diastereoisomer of product, mp 198-200°C,
[
α
]
= –378.1° (c = 1, CHCl
3
18 2 2
). Anal. Calcd for C20H N O :
C, 75.45; H, 5.70; N 8.80. Found: C, 75.49; H, 5.91; N, 8.58.
1
2
H NMR (CDCl
3
) δ 7.29-7.17 (8H, m, arom.), 5.41 (2H, d, H(5a), H(13a), J=17.1 Hz), 4.36 (2H, d,
2
3
3
H(5b), H(13b), J=17.1 Hz), 4.31 (2H, dd, H(7a), H(15a), J=3.6 Hz, J=12.2 Hz), 3.47 (2H, dd, H(8a),
2
3
2
3
13
H(16a), J=16.2 Hz, J=3.6 Hz), 3.03 (2H, dd, H(8b), H(16b), J=16.2 Hz, J=12.2 Hz). C NMR
CDCl ) δ 164.11 (2xCCON), 132.31, 131.38 (arom, 2x2xC ), 128.80, 127.13, 127.10, 126.35 (arom,
x4xCH), 55.75 (2xCHCO), 44.05 (2xArCH N), 34.23 (2xArCH C).
,8,13,16-Tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (a mixture of diastereoisomeric
(
3
q
2
2
2
5
racemates (12) and (13)): A mixture of isomers of 5,7,12,14-tetrahydro-6aH,13aH-5a,12a-
diazapentacene- 6,13-dione was prepared by Procedure A from compounds (4) and (6) as the
(
7aS,15aS)-5,8,13,16- tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (11) in the yield of 63 %,
with mp 183-191 °C. The NMR spectral analysis shoved that the product is a mixture of two
diastereoisomers (in the isolated mixture, the integral intensities of the diastereoisomers are in the ratio of
1
2/13 = 17/3). The structure of major isomer was confirmed by addition of (7aS,15aS)-5,8,13,16-
tetrahydro-7aH,15aH-6,14-diazapentacene-7,15-dione (11) directly into the mixture of the
diastereoisomers. Anal. Calcd for C H N O : C, 75.45; H, 5.70; N, 8.80. Found: C, 75.72; H, 5.66; N,
2
0
18
2
2
8
.67.
1
2
Diastereoisomer (13): H NMR (CDCl ) δ 7.30-7.15 (8H, m, arom.), 5.43 (2H, d, H(5a), H(13a), J=17.3
3
2
3
3
Hz), 4.38 (2H, d, H(5b), H(13b), J=17.3 Hz), 4.31 (2H, dd, H(7a), H(15a), J=3.2 Hz, J=12.2 Hz ), 3.54

68
HETEROCYCLES, Vol. 68, No. 1, 2006
2
3
2
3
(
2H, dd, H(8a), H(16a), J=16.2 Hz, J=3.2 Hz), 3.06 (2H, dd, H(8b), H(16b), J=16.2 Hz, J=12.2 Hz).
1
3
C NMR (CDCl
3
) δ 164.11 (2xCCON), 132.31, 131.38 (arom, 2x2xC
q
), 128.84, 127.13, 127.03, 126.30
C).
(
arom, 2x4xCH), 55.41 (2xCHCO), 44.41 (2xArCH
2
N), 34.22 (2xArCH
2
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