Diastereoselective synthesis of 1-benzyltetrahydroisoquinoline derivatives from amino acids by 1,4 chirality transfer

Article abstract of DOI:10.1002/ejoc.200200705

L-Amino acids (L-Ala, L-Phe, L-Val, L-Pro) were used as a source of chirality in the diastereoselective synthesis of tetrahydroisoquinoline derivatives. The key step was the Pictet-Spengler condensation of ketoamides 4 and 10, which proceeded under very m

Full text of DOI:10.1002/ejoc.200200705

FULL PAPER
Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives from
Amino Acids by 1,4 Chirality Transfer[‡]
Anna Zawadzka,[a] Andrzej Leniewski,[a] Jan K. Maurin,[b,c] Krystyna Wojtasiewicz,[a]
Aleksandra Siwicka,[a] Dariusz Blachut,[a] and Zbigniew Czarnocki*[a]
Keywords: Alkaloids / Amino acids / Asymmetric synthesis
L-Amino acids (
L-Ala,
L-Phe,
L-Val,
L-Pro) were used as a
reogenic center. Surprisingly, L-Pro gave the opposite result.
source of chirality in the diastereoselective synthesis of tetra-
hydroisoquinoline derivatives. The key step was the
Pictet−Spengler condensation of ketoamides 4 and 10, which
The stereochemistry of 6d and 12a were established on the
basis of X-ray crystallographic data.
proceeded under very mild conditions.
L
-Ala,
L
-Phe and
L
-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Val gave rise the R-configuration at the newly formed ste-
Germany, 2003)
Recently, the main interest has been focused on the use
of naturally occurring compounds in the stereoselective
syntheses. Amino acids and their derivatives have been
found to be efficient chiral inductors and therefore are used
often in the synthesis of chiral, enantiomerically enriched
heterocycles.[20Ϫ24]
Interesting applications of amino acids and their deriva-
tives in the synthesis of tetrahydroisoquinoline and β-carbo-
line alkaloids and related systems have recently appeared in
the literature.
Itoh et al. used -alanine derivatives as chiral auxiliaries
in the asymmetric addition of nucleophiles to the C-1 posi-
tion of isoquinolines.[25] They also reported the use of a
chiral auxiliary derived from -proline for the preparation
of both enantiomers of 1-allyl-1,2,3,4-tetrahydro-β-carbo-
line.[26]
Waldmann et al.[27] showed that readily available amino
acid esters could be applied as efficient chiral auxiliary
groups in the asymmetric PictetϪSpengler reactions that
gave tetrahydro-β-carbolines with high diastereoselectivity.
The chiral induction derived from several N-alkylated am-
ino acid esters (-alanine, -valine, -leucine and -iso-
leucine) was elaborated under the conditions of
PictetϪSpengler condensation. It was found that increasing
the size of the amino acid side chain had a positive effect
on the diastereoselectivity of the process.[27]
Introduction
Notable developments in the stereocontrolled synthesis
of tetrahydroisoquinolines and related systems have been
observed within the last two decades. Because of their wide
distribution and significant biological activities, tetrahydro-
isoquinolines have received considerable attention.[1Ϫ3]
Because of appreciable stereodiscrimination of organic
compounds in living systems, the physiological activity of
tetrahydroisoquinolines depends on their stereochemistry,
especially at the C-1 carbon atom. Tetrahydroisoquinolines
that have a reactive substituent at this position are valuable
substrates for the synthesis of many isoquinoline alka-
loids.[4,5] The need for asymmetric induction at the C-1
carbon atom in the isoquinoline system was inspired,
at least partially, by requirements of the pharmaceutical in-
dustry together with the parallel development of modern
methodologies.
Several methods of stereoselective synthesis of these com-
pounds, using chiral building blocks, auxiliaries or reagents,
have been reported, mainly in the asymmetric
PictetϪSpengler cyclization,[6Ϫ10] BischlerϪNapieralski
reactions,[11Ϫ13] as well as other[14Ϫ19] methods.
[‡]
Part II. Part I: Ref.[29]
[a]
In our laboratory we have already used some amino acids
as chiral inductors in the diastereoselective synthesis of 1-
substituted tetrahydroisoquinoline derivatives.[28,29] Here we
report our detailed results obtained when selected -amino
acids were applied as starting materials in the stereocon-
trolled synthesis of benzyltetrahydroisoquinoline deriva-
tives.
Faculty of Chemistry, Warsaw University,
Pasteur St. 1, 02-093, Warsaw, Poland
E-mail: czarnoz@chem.uw.edu.pl
[b]
National Institute of Public Health,
Chelmska 30/34, 00-750, Warsaw, Poland
[c]
Institute of Atomic Energy,
05-400, Otwock-Swierk, Poland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2003, 2443Ϫ2453
DOI: 10.1002/ejoc.200200705
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2443

Z. Czarnocki et al.
Table 1. Chemical yields of all products obtained
FULL PAPER
Results and Discussion
The work presented here was influenced by Lawton’s
concept[30] of the role of the peptide chain in the biosynthe-
sis of isoquinoline alkaloids. Although the full details of
this communication have never been published, the idea still
seems to be a very attractive one since the role of the chiral-
ity induction by amino acids (peptides) is obvious and
many modern synthetic approaches try to mimic biological
conditions. Probably the most fruitful and effective methods
are based on the chemistry of N-acyliminium ions, which
were introduced by Speckamp[31] and have been widely ap-
plied in different areas of synthetic organic chemistry,[32]
including stereocontolled transformations towards chiral,
non-racemic tetrahydroisoquinolines and related sys-
tems.[33,34]
2
3
4
5
6
8
9
10
11
12
a
b
c
d
e
f
g
h
i
50% 100%
Ϫ
70% 100% 93% 78% 68% 6.2% 60%
95% 76% 54% Ϫ
100% 69% 51% 11% 77% Ϫ
48% Ϫ 51% Ϫ
100% 69% 65% Ϫ
97% 85% 51% Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
65% Ϫ
51%
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
89% Ϫ
57% Ϫ
Ϫ
Ϫ
48% Ϫ
75% 97% 55% Ϫ
95% 83.6% 55% Ϫ
Ϫ
Ϫ
92% Ϫ
These preliminary results prompted us to investigate the
During the reinvestigation of this ‘‘achiral’’ approach,[30]
we found that amide 3a (Scheme 1) could be prepared ef-
ficiently from 2-(3,4-dimethoxyphenyl)ethylamine when
blocked sarcosine 1a was used as a starting compound in a
BOP-mediated coupling.[35]
stereocontrolled PictetϪSpengler-type condensation and
the chiral induction at the C-11b[36] carbon atoms in the
formation of compounds 6c, 6d, 6f, 6g and 6i.
Thus, the analogous reaction sequences were carried out
using protected -alanine 1b, N-methyl--alanine 1c, -val-
ine 1e, N-methyl--valine 1f, -phenylalanine 1h and N-
methyl--phenylalanine 1i. Condensation with 2-(3,4-di-
methoxyphenyl)ethylamine and subsequent deblocking of
the nitrogen atom under hydrogenolytic conditions (H2, Pd/
C), afforded amides 3bϪi in good chemical yields.
Treatment of the amides 3bϪi with arylpyruvic acids in
the presence of BOP reagent[35] gave isolable ketoamides
4bϪi, which is in contrast to the earlier findings when
sarcosine was employed.
The PictetϪSpengler condensation on amides 4bϪi gave
interesting results. When -Ala 1b, -Val 1e and -Phe 1h
were used as chiral inductors, no cyclization products of the
appropriate ketoamides 4b, 4e and 4h were formed, prob-
ably because the cyclization step is disfavored by a partial
or complete enolization that precludes cyclization for either
geometric or deactivation reasons.[37]
In the contrary, good results were obtained when N-
methyl--alanine was used as a chiral inductor. Amide 3c,
coupled with phenylpyruvic acid, gave diketoamide 4c in
good yield. Subsequent treatment of 4c with hydrogen chlo-
ride in dry methanol at 0 °C promoted the PictetϪSpengler
cyclization and afforded 6c as the mixture of diastereoiso-
mers in an 87:13 ratio, which was indicated by the 1H NMR
spectroscopic analysis of the crude reaction mixture. Al-
Scheme 1
Treatment of 3a with 1 equiv. of 2-oxo-3-phenylpropa- though both diastereoisomers of 6c could be separated
noic acid, again in the presence of BOP reagent, gave di- chromatographically, we were unable to obtain a single
rectly the hydroxylactam derivative 5a in 70% yield (yields crystal suitable for an X-ray crystallography study. To estab-
for all products are given in Table 1). Despite prolonged lish the stereochemistry of the newly formed chiral center
efforts, we were unable to isolate ketoamide 4a in this reac- at C-11b, amide 3c was reacted with m-chlorophenylpyruvic
tion sequence. Compound 5a underwent
a
facile acid to form a product that might have better crystallization
PictetϪSpengler-type condensation with methanolic hydro- properties. The analogous reaction sequence yielded dia-
gen chloride at 0 °C, affording a diketopiperazine derivative stereoisomers (3S,11bR)-6d and (3S,11bS)-6d with surpris-
6a almost quantitatively. In the chemistry of isoquinolines, ingly high selectivity (99.7:0.3, based on 1H NMR spec-
such an easy cyclization of non-phenolic derivatives is quite troscopy). A single crystal of the dominant component was
rare and, thus, this reaction provides further evidence for subjected to an X-ray crystallographic analysis, which indi-
the significant influence of the peptide-like moiety in this cated the R configuration at the C-11b carbon atom (Fig-
process.
ure 1).
2444
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Eur. J. Org. Chem. 2003, 2443Ϫ2453

Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives
FULL PAPER
Scheme 2
Figure 1. The structure and ORTEP diagram of compound
(3S,11bR)-6d
Similar results were obtained when N-methyl--valine
was used as a chiral inductor. Amide 3f was isolated in 85%
yield with no observable racemization.[38] Subsequent coup-
ling with arylpyruvic acids and the PictetϪSpengler cycliza-
tion at 0 °C afforded the final derivatives 6f (89%) and 6g
(57%) as single diastereoisomers.
Finally, compound 4i underwent efficient stereocon-
trolled PictetϪSpengler-type condensation with methanolic
hydrogen chloride, giving two diastereoisomers of 6i in a
ratio of 89:11 in 92% chemical yield.
All the predominant diastereoisomers 6c, 6d, 6f, 6g and
6i seem to bear the same sense of chirality as was proved
to exist for 6d. This conclusion can be drawn from the com-
1
parison of H NMR spectra for each diastereoisomer. In
Figure 2. The structure and ORTEP diagram of compound
(8aS,13aS)-12a.
the (3S,11bR) series, 6c, 6d, 6f, 6g and 6i display more pro-
found deshielding effects for H-11 than in the respective
(3S,11bS) series.
Also, the sign of the optical rotation seems to follow the
The unexpected results for the condensation step (iv), in
above suggestions for the same sense of chirality in all the which the -proline-derived sequence led to the prevalence
major diastereoisomers, but obviously this feature is only of the S diastereoisomer whereas an opposite tendency was
indicative. Completely unexpected results were obtained observed for all other products derived from -amino acids,
when -proline was used as a chiral synthon. In the anal- asked for some rationale. We thought that quantum mech-
ogous reaction sequence, amide 9a was formed in 78% anical methods might give us some useful hints in this re-
yield (Scheme 2).
gard. It appears reasonable to assume that the
Further coupling with phenylpyruvic acid and m-chloro- PictetϪSpengler cyclization occurs via N-acyliminium ions
phenylpyruvic acid gave 10a and 10b, respectively, as rela- derived from structures 5 or 11 and is kinetically controlled
tively unstable compounds. Their instability appeared to be by the energy differences of the appropriate transition states
due partially to facile condensation to the intermediate or intermediates.[40] Since their exact configuration and
hydroxy compounds 11a and 11b, respectively, which, in conformation could not be designated easily, we decided,
turn underwent acid-catalyzed PictetϪSpengler conden- with some discomfort, to concentrate first on the thermo-
sation to yield the final diketopiperazines 12a and 12b, both dynamic properties of the products. Thus, model com-
as mixtures of diastereoisomers (ca. 95:5). The single-crys- pounds were studied using molecular mechanical, semi-em-
tal X-ray crystallographic analysis of the major component pirical and finally ab initio methods. Sets of compounds
of 12a revealed, surprisingly, the S configuration at the (Figure 3) were built on the basis of the molecular struc-
newly formed chiral center at C-13a[39] (Figure 2).
tures of (3S,11bR)-6d and (8aS,13aS)-12a obtained from
Eur. J. Org. Chem. 2003, 2443Ϫ2453
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2445

Z. Czarnocki et al.
FULL PAPER
the X-ray crystallography studies, but by replacing meth- (8aS,13aS)-12aЈ and (8aS,13aR)-12aЈ (µ ϭ 1.4767 and
oxyl groups and chlorine atom with hydrogen atoms to save 1.4532 D, respectively).
on computation time.
All the results shown above, including the unambiguous
assignments of the stereochemistries of compounds 6d and
12a, clearly indicate that our first hypothesis[30] were incor-
rect with regard to the configuration at the C-11b carbon
atoms in diketopiperazines derived from acyclic amino ac-
ids (Val, Phe). Therefore, direct extension of the stereoch-
emical outcome of the process that utilizes substrates that
may appear similar (e.g., a series of -amino acids) can lead
to a severe error in judgment. Nevertheless, we stress that
the different chirality induction in the PictetϪSpengler re-
action from acyclic -amino acids and -proline makes our
approach ‘‘enantiodivergent-like’’ and, therefore, more at-
tractive from the point of view of stereocontrolled synthesis.
Figure 3. Model compounds (3S,11bR)-6dЈ and (8aS,13aS)-12aЈ
Experimental Section
NMR spectra were recorded on a Varian Unity Plus spectrometer
operating at 500 MHz for H NMR and 125 MHz for 13C NMR
1
Figure 4. Model compounds (3S,11bS)-6dЈ and (8aS,13aR)-12aЈ
spectroscopy. Tetramethylsilane (TMS) or solvents were used as in-
ternal standards. Chemical shifts are reported in ppm. Coupling
constants (J) are reported in hertz and multiplicities are represented
as s ϭ singlet, d ϭ doublet, t ϭ triplet and q ϭ quadruplet. Mass
spectra were collected on an AMD 604 apparatus; high-resolution
mass spectra were acquired using LSIMS (positive-ion mode). Op-
tical rotations were measured on a PerkinϪElmer 247 MC polar-
imeter. TLC analyses were performed on Merck 60 silica gel glass
plates and visualized using a UV hand lamp and iodine vapor.
Column chromatography was carried out at atmospheric pressure
using silica gel (230Ϫ400 or under 400 mesh, Merck). X-ray crys-
tallographic intensity data for (3S,11bR)-6d and (8aS,13aS)-12a
The conformational analysis using molecular mechanics
was performed for two pairs of compounds, (3S,11bR)-6dЈ/
(3S,11bS)-6dЈ and (8aS,13aS)-12aЈ/(8aS,13aR)-12aЈ (Fig-
ure 3 and 4), after initial semi-empirical optimization.
Then, the final optimization of the structure of the lowest-
energy conformer for either compound was performed
using ab initio quantum chemical methods. The
HartreeϪFock method was applied with the standard
6Ϫ31G** basis set.
were measured at T ϭ 293 K on a Kuma KM4 diffractometer with
˚
For the model compounds (3S,11bR)-6dЈ and (3S,11bS)- Mo-Kα radiation (λ ϭ 0.71073 A). The structures were solved by
direct methods from SHELXS-97[42]and refined by using the
6dЈ, the calculated total energies (Ϫ1066.73981696 and
SHELXL-97 software.[43]
Ϫ1066.73245403 e.u.,[41] respectively) differed by only
Ϫ4.62 kcal/mol, showing that compound (3S,11bR)-6dЈ is
energetically more stable than its diastereoisomer
Benzyl 2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}-2-oxoethyl(meth-
yl)carbamate (2a): 2-(3,4-Dimethoxyphenyl)ethylamine (2.76 g,
(3S,11bS)-6dЈ. Contradictory results were obtained for the 15.2 mmol) and triethylamine (3.38 mL, 30.45 mmol) were added
to a solution of Cbz-sarcosine 1a (3.4 g, 15.2 mmol) in dry THF
(100 mL). BOP (7.42 g, 16.75 mmol) was introduced to the result-
ant mixture, stirring was continued for 2 h and then the mixture
was left at room temperature overnight. After evaporation of the
THF, the residue was dissolved in chloroform (100 mL), washed
with saturated sodium chloride solution (2 ϫ 20 mL) and water
(20 mL). The organic phase was then dried (MgSO4) and the sol-
vent was evaporated to give a white crystalline product, which was
then purified, by chromatography on silica gel. Elution with 2% (v/
v) methanol in chloroform gave compound 2a (2.85 g 50%): m.p.
second model (proline-derived molecules), which now fav-
ored the compound (8aS,13aS)-12aЈ having the opposite
configuration at the respective carbon atom. The difference
in total energies for the diastereoisomers (8aS,13aS)-12aЈ
and
(8aS,13aR)-12aЈ
(Ϫ1104.61822265
and
Ϫ1104.61393160 e.u., respectively) is Ϫ2.69 kcal/mol. These
variations in the stability of diastereoisomers were magni-
fied by soluteϪsolvent interactions. Under the influence of
methanol, these preferences became of Ϫ5.80 and Ϫ5.62
kcal/mol for diastereoisomers 6dЈ(3S,11bS) and 12aЈ(8a- 108 °C. IR (KBr): ν˜ ϭ 3330, 2825Ϫ3075, 1690, 1675, 1520, 1260,
1240, 1160 cmϪ1 1H NMR (500 MHz, CDCl3); two stable rota-
.
S,13aR), respectively, which is in accordance with the exper-
imental observations and might suggest possible thermo-
dynamic control at the level of the transition state, which is
apparently ‘‘product-like’’.
Atomic charge distributions and resultant dipole mo-
ments for all model molecules were also derived from the
mers are visible: δ ϭ 7.39Ϫ7.28 (m, 5 H, Harom), 6.79Ϫ6.62 (m, 3
H, Harom), 6.20 and 5.97 (two br. s, 1 H, NH), 5.12 (br. s, 2 H,
PhCH2), 3.86 and 3.88 (two s, 3 H each, 2 ϫ OCH3), 3.82 (s, 2 H,
CH2CO), 3.48 (br. s, 2 H, NHCH2CH2), 2.92 (br. s, 3 H, NCH3),
2.74 and 2.68 (two br. s, 1 H each, NHCH2CH2) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 168.8, 156.9, 149.0, 147.7, 136.2, 131.1,
128.2, 128.5, 127.9, 120.6, 111.8, 111.3, 67.6, 55.9, 55.8, 53.4, 40.6,
35.5, 35.1 ppm. LSIMS (ϩ) (M ϭ 386.44 for C21H26N2O5): m/z
(%) ϭ 773 [2M ϩ H]ϩ (4), 409 [M ϩ Na]ϩ (23), 387 [M ϩ H]ϩ
above
calculations.
Interestingly,
diastereoisomers
(3S,11bR)-6dЈ and (3S,11bS)-6dЈ differ significantly in their
dipole moments (µ ϭ 0.7637 and 2.0569 D, respectively),
whereas there is virtually no difference for molecules (70), 343 (33), 279 (6), 255 (6), 225 (9), 164 (97), 97 (31).
2446  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2443Ϫ2453

Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives
FULL PAPER
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(methylamino)acetamide (3a):
Concd. HCl (3 mL) was added to a solution of compound 2a
(2.0 g, 5.18 mmol) in ethanol (200 mL). The resulting solution was
then hydrogenated over palladium-on-charcoal catalyst (0.2 g) at
50 °C for 2 h with vigorous stirring. After completion of the reac-
tion, the catalyst was removed by filtration through Celite. The
solvent was evaporated and the residue was taken up into saturated
sodium bicarbonate solution and extracted with chloroform. Dry-
ing (MgSO4) and evaporation afforded compound 3a as a yellow-
orange oil in quantitative yield (1.3 g). 1H NMR (500 MHz,
13C NMR (125 MHz, CDCl3): δ ϭ 166.9, 163.0, 148.8, 147.1,
134.9, 130.4, 128.4, 127.9, 127.6, 127.3, 112.9, 110.9, 66.6, 56.1,
55.8, 50.8, 47.7, 36.6, 34.0, 29.2 ppm. LSIMS (ϩ) (M ϭ 380.44 for
C22H24N2O4): m/z (%) ϭ 403 [M ϩ Na]ϩ (37), 381 [M ϩ H]ϩ (19),
199 (12), 120 (7), 105 (22), 91 (21), 81 (12).
Benzyl (1S)-2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}-1-methyl-2-
oxoethylcarbamate (2b): compound 1b (3 g, 13.45 mmol) was con-
verted into carbamate 2b, following the procedure described for the
synthesis of 2a, as a white crystalline product (4.93 g, 95%): m.p.
143Ϫ145 °C. [α]2D3 ϭ Ϫ13.9 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3300,
CDCl3):
δ ϭ 7.27 (br. s, 1 H, exchangeable with D2O,
3100Ϫ2830, 1690, 1650, 1550, 1530, 1520, 1260 cmϪ1 1H NMR
.
NHCH2CH2), 6.84Ϫ6.72 (m, 3 H, Harom), 3.88 and 3.87 (two s, 3
H each, 2 ϫ OCH3), 3.53 (app q, 2 H, J ϭ 6.4 Hz, NHCH2CH2),
3.21 (s, 2 H, CH2CO), 2.79 (t, J ϭ 7.0 Hz, 2 H, NHCH2CH2), 2.35
(s, 3 H, NCH3), 1.69 (s, 1 H, exchangeable with D2O, NHCH3)
ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 171.3, 148.9, 147.6, 131.5,
120.6, 111.9, 111.3, 55.9, 55.8, 54.6, 40.2, 36.7, 35.4 ppm. M ϭ
252.31 for C13H20N2O3.
(500 MHz, CDCl3): δ ϭ 7.38Ϫ7.30 (m, 5 H, Harom), 6.78 (m, 1 H,
Harom), 6.70 (br. s, 2 H, Harom), 6.10 (br. s, 1 H, NHCH2CH2), 5.30
(br. s, 1 H, NHCHCH3), 5.08 (qAB, 2 H, J ϭ 12.0 Hz, PhCH2),
4.16 (m, 1 H, H-1), 3.86 and 3.84 (two s, 3 H each, 2 ϫ OCH3),
3.48 (m, 2 H, NHCH2CH2), 2.74 (app t, 2 H, NHCH2CH2), 1.34
(d, J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 172.1, 155.9, 149.0, 147.7, 136.1, 131.1, 128.6, 128.3, 128.1,
120.6, 111.8, 111.3, 67.0, 55.9, 55.8, 50.6, 40.8, 35.2, 18.6 ppm.
LSIMS (ϩ) (M ϭ 386.44 for C21H26N2O5): m/z (%) ϭ 409 [M ϩ
Na]ϩ (100), 387 [M ϩ H]ϩ (3), 223 (7).
3-Benzyl-4-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-1-methyl-
piperazine-2,5-dione (5a): Despite prolonged efforts, we were unable
to isolate the ketoamide 4a. Compound 3a was directly converted
into 5a. Thus, compound 3a (0.85 g, 3.38 mmol) was introduced to
a stirred solution of phenylpyruvic acid (0.55 g, 3.38 mmol) in dry
THF (20 mL) and then Et3N (0.75 mL, 6.76 mmol) and BOP
(1.65 g, 3.72 mmol) were added at room temperature. After 2 h of
stirring, the mixture was left overnight. The solvent was evaporated
in vacuo and the residue was dissolved in dichloromethane (10 mL)
and washed with a solution of saturated sodium chloride and water.
The organic phase was dried (MgSO4) and the solvent was evapo-
rated giving a yellow oil, which was purified by chromatography
on silica gel using 2% (v/v) methanol in chloroform to give white
crystals of 5a (942 mg, 70%): m.p. 86Ϫ88 °C. IR (KBr): ν˜ ϭ 3200,
2830Ϫ3100, 1650, 1520, 1460 cmϪ1. 1H NMR (200 MHz, CDCl3):
δ ϭ 7.29 (m, 3 H, Harom), 7.02 (m, 2 H, Harom), 6.85 (m, 3 H,
(2S)-2-Amino-N-[2-(3,4-dimethoxyphenyl)ethyl]propanamide (3b):
The procedure described for the synthesis of 3a was applied to 2b
(4 g, 10.4 mmol) and gave 3b (2.0 g, 76%) as a yellow crystalline
product: m.p. 48Ϫ50 °C. [α]2D3 ϭ ϩ7.6 (c ϭ 1.0, CHCl3). IR (KBr):
ν˜ ϭ 3360, 3320, 3090Ϫ2840, 1650, 1630, 1520, 1260, 1220, 1140
cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ 7.32 (br. s, 1 H, NH,
.
exchangeable with D2O), 6.75 (m, 1 H, Harom), 6.69 (m, 2 H,
Harom), 3.82 and 3.80 (two s, 3 H each, 2 ϫ OCH3), 3.42 (m, 2 H,
NHCH2CH2), 2.71 (app t, 2 H, NHCH2CH2), 2.59 (d, J ϭ 9.5 Hz,
1 H, H-2), 1.92 (br. s, 2 H, exchangeable with D2O, NH2), 1.25 (d,
J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ
175.7, 148.9, 147.6, 131.6, 120.7, 111.9, 111.3, 55.9, 55.8, 50.7, 40.3,
35.3, 21.8 ppm. LSIMS (ϩ) (M ϭ 252.31 for C13H20N2O3): m/z
(%) ϭ 275 [M ϩ Na]ϩ (10), 253 [M ϩ H]ϩ (100), 180 (13).
Harom), 4.06 (m, 1 H, NCH2CH2), 3.91 and 3.88 (two s, 3 H each,
2 ϫ OCH3), 3.47 (m, 1 H, NCH2CH2), 3.38 (dAB, 1 H, J ϭ 17.6 Hz,
N(CH3)CH2), 3.18 (dAB, 1 H, J ϭ 13.7 Hz, PhCH2), 3.14 (dAB, 1
H, J ϭ 13.7 Hz, PhCH2), 2.95 (m, 2 H, NCH2CH2), 2.80 (s, 3 H,
NCH3), 2.18 (dAB, 1 H, J ϭ 17.6 Hz, N(CH3)CH2), 1.9 (br. s, 1 H,
OH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 167.0, 162.7, 148.9,
147.6, 133.4, 131.8, 130.1, 128.6, 128.0, 120.9, 112.2, 111.3, 85.8,
55.9, 51.1, 46.2, 44.4, 35.4, 33.3 ppm. EI-MS (M ϭ 398.45 for
C22H26N2O5): m/z ϭ (%) 398 [M]ϩ (10), 307 (25), 289 (28), 261 (2),
164 (100).
N-((1S)-2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}-1-methyl-2-oxo-
ethyl)-2-oxo-3-phenylpropanamide (4b): The procedure described for
the synthesis of 5a was applied to 3b (0.5 g, 1.98 mmol) and pro-
vided 4b (427 mg, 54%) as a white crystalline product: m.p.
146Ϫ150 °C. [α]2D3 ϭ Ϫ19.7 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3310,
1
3100Ϫ2850, 1650, 1520 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ
7.45 (m, 1 H, Harom), 7.34Ϫ7.20 (m, 4 H, Harom), 6.82Ϫ6.66 (m, 3
H, Harom), 6.08 (br. s, 1 H, NHCH2CH2), 4.33 (m, 1 H, H-1), 4.16
(qAB, 2 H, J ϭ 16.0 Hz, PhCH2), 3.86 and 3.83 (two s, 3 H each,
11b-Benzyl-9,10-dimethoxy-2-methyl-7,11b-dihydro-2H-pyrazino-
[2,1-a]isoquinoline-1,4(3H,6H)-dione (6a): Acetyl chloride (1 mL)
was added to ice-cooled dry methanol (30 mL) and after 15 min
compound 5a (200 mg, 0.5 mmol) was added in one portion and
the mixture was left for two weeks in a refrigerator at 0 °C. The
solvent was evaporated in vacuo and the residue was dissolved in
chloroform (50 mL). The organic phase was washed with sodium
bicarbonate solution (20 mL), water (20 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was subjected to
column chromatography on silica gel. Elution with 1% (v/v) meth-
anol in chloroform gave a white crystalline compound 6a in quanti-
2
ϫ
OCH3), 3.48 (m,
2
H, NHCH2CH2), 2.74 (m,
2 H,
NHCH2CH2), 1.96 (br. s,
1
H, exchangeable with D2O,
NHCHCH3), 1.37 (d, J ϭ 6.5 Hz, 3 H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 195.0, 170.9, 159.6, 149.0, 147.7, 132.4,
130.9, 129.8, 128.7, 127.3, 120.6, 111.9, 111.3, 55.9, 55.8, 49.0, 43.1,
40.8, 35.0, 18.0 ppm. LSIMS (ϩ) (M ϭ 398.45 for C22H26N2O5):
m/z (%) ϭ 421 [M ϩ Na]ϩ (61), 399 [M ϩ H]ϩ (20), 301 (12).
Benzyl (1S)-2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}-1-methyl-2-
oxoethyl(methyl)carbamate (2c): Following the procedure described
for the synthesis of 2a, compound 1c (2 g, 8.44 mmol) was con-
tative yield (190 mg): m.p. 187Ϫ192 °C. IR (KBr): ν˜ ϭ 3320, verted into 2c (3.38 g, 100%), which was obtained as a white crys-
1
2850Ϫ3100, 1670, 1650, 1525 cmϪ1. H NMR (500 MHz, CDCl3):
δ ϭ 8.11 (s, 1 H, Harom-11), 7.32Ϫ7.11 (m, 5 H, Harom), 6.58 (s, 1 IR (KBr): ν˜ ϭ 3350, 3090Ϫ2825, 1675, 1520, 1330, 1260, 1230,
H, Harom-8), 5.07 (app dt, NCH2CH2), 4.01 and 3.88 (two s, 3 H
1170 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.33 (m, 5 H, Harom),
each, 2 ϫ OCH3), 3.45 and 2.35 (dAB, 2 H, J ϭ 17.3 Hz, H-3), 3.60 6.79Ϫ6.64 (m, 3 H, Harom), 5.17 (q, J ϭ 4.5 Hz, 1 H, H-1), 5.12
and 3.30 (dAB, 2 H, J ϭ 13.7 Hz, PhCH2), 3.06 (m, 2 H, (qAB, 2 H, J ϭ 12.0 Hz, PhCH2), 4.74 (br. s, 1 H, NH), 3.86 and
NCH2CH2), 2.68 (m, 1 H, NCH2CH2), 2.70 (s, 3 H, NCH3) ppm. 3.82 (two s, 3 H each, 2 ϫ OCH3), 3.46 (m, 2 H, NHCH2CH2),
talline product: m.p. 85Ϫ87 °C. [α]2D3 ϭ Ϫ51.3 (c ϭ 1.0, CHCl3).
Eur. J. Org. Chem. 2003, 2443Ϫ2453
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2447

Z. Czarnocki et al.
FULL PAPER
2.77 (s, 3 H, NCH3), 2.71 (m, 2 H, NHCH2CH2), 1.33 (d, J ϭ 7.0
2830Ϫ3100, 1650, 1520, 1260 cmϪ1. 1H NMR (500 MHz, CDCl3):
δ ϭ 8.22 (s, 1 H, Harom-11), 7.34Ϫ7.12 (m, 5 H, Harom), 6.58 (s, 1
Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 171.1,
157.4, 149.0, 147.7, 136.3, 131.2, 128.8, 128.6, 128.5, 120.6, 111.7, H, Harom-8), 4.98 (ddd, 1 H, J1 ϭ 12.5, J2 ϭ 5.5, J3 ϭ 1.5 Hz,
111.3, 67.7, 55.9, 55.8, 55.8, 40.7, 35.2, 27.4, 19.0 ppm. M ϭ 400.47
for C22H28N2O5.
NCH2CH2), 3.98 and 3.87 (two s, 3 H each, 2 ϫ OCH3), 3.73 (q,
J ϭ 7.0 Hz, 1 H, H-3), 3.74 and 3.32 (qAB, 2 H, J ϭ 14 Hz,
PhCH2), 3.26 (td, 1 H, J1 ϭ 12.5, J2 ϭ 3.5 Hz, NCH2CH2), 3.08
(m, 1 H, NCH2CH2), 2.75 (s, 3 H, NCH3), 2.67 (m, 1 H,
NCH2CH2), 0.44 (d, J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 166.2, 165.9, 148.4, 147.2, 135.6, 130.6,
128.6, 128.5, 127.5, 127.2, 111.7, 111.2, 67.3, 57.3, 56.1, 55.8, 47.1,
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(methylamino)-
propanamide (3c): The procedure described for the synthesis of 3a
was applied to 2c (3.38 g, 8.44 mmol) to give 3c (1.54 g, 69%) as a
white crystalline product: m.p. 77Ϫ80 °C. [α]2D3 ϭ Ϫ6.0 (c ϭ 1.0,
CHCl3). IR (KBr): ν˜ ϭ 3300, 3100, 2980Ϫ2770, 1640, 1520, 1230,
37.2, 32.7, 28.7, 18.0 ppm. LSIMS (ϩ) (M
ϭ 394.46 for
1130 cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ 7.22 (br. t, 1 H,
.
C23H26N2O4): m/z (%) ϭ 395 (28) [M ϩ H]ϩ, 303 (42), 95 (40), 81
(41). HR LSIMS: C23H27N2O4 (calcd.: 395.19708, found
395.20085).
NH), 6.82Ϫ6.72 (m, 3 H, Harom), 3.87 and 3.86 (two s, 3 H each,
2 ϫ OCH3), 3.51 (m, 2 H, NHCH2CH2), 3.08 (q, J ϭ 7.0 Hz, 1 H,
H-2), 2.78 (app t, 2 H, NHCH2CH2), 2.30 (s, 3 H, NCH3), 1.25 (d,
J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ Minor Diastereoisomer (3S,11bS)-6c (selected data): 1H NMR
174.8, 148.9, 147.6, 131.5, 120.7, 111.9, 111.3, 60.4, 55.9, 55.8, 40.1,
(500 MHz, CDCl3): δ ϭ 8.11 (s, 1 H, Harom-11), 6.59 (s, 1 H, Harom-
35.4, 35.2, 19.7 ppm. M ϭ 266.34 for C14H22N2O3.
8), 2.74 (s, 3 H, NCH3) ppm.
N-[(1S)-2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}-1-methyl-2-oxo-
ethyl]-N-methyl-2-oxo-3-phenylpropanamide (4c): The procedure de-
scribed for the synthesis of 5a was applied to 3c (0.86 g, 3.2 mmol)
to give 4c (675 mg, 51%) as an oil: [α]2D3 ϭ Ϫ96.4 (c ϭ 1.0, CHCl3).
3-(3-Chlorophenyl)-N-[(1S)-2-{[2-(3,4-dimethoxyphenyl)ethyl]-
amino}-1-methyl-2-oxoethyl]-N-methyl-2-oxopropanamide (4d):
Compound 3c (566 mg, 2.13 mmol) was introduced at room tem-
perature to a stirred solution of m-chlorophenylpyruvic acid
IR (film): ν˜ ϭ 3350, 3100Ϫ2850, 1650, 1520, 1450, 1270, 1230, (465 mg, 2.34 mmol) in dry THF (20 mL), followed by the addition
1050 cmϪ1 1H NMR (500 MHz, CDCl3), two stable conformers of Et3N (0.47 mL, 4.26 mmol) and BOP reagent (1.035 g,
present (I:II, 4:3): δ ϭ 7.20Ϫ7.40 (m, 10 H, Harom), 6.80 (m, 2 H, 23.4 mmol). After 2 h of stirring, the mixture was left overnight.
arom), 6.70 (m, 4 H, Harom), 6.37 (br. t, 1 H, NH) (I), 5.85 (br.t, The solvent was then evaporated in vacuo and the residue was dis-
.
H
1 H, NH) (II), 4.27 and 4.04 (qAB, 2 H, J ϭ 14.5 Hz, PhCH2) (I),
solved in dichloromethane (10 mL) and washed with saturated so-
4.02 and 3.92 (qAB, 2 H, J ϭ 14.5 Hz, PhCH2) (II), 3.82 (q, J ϭ dium chloride solution. The organic phase was dried (MgSO4) and
6.5 Hz, 1 H, H-1) (I), 4.93 (q, J ϭ 6.5 Hz, 1 H, H-1) (II), 3.86 and the solvent was evaporated giving a yellow oil that was purified by
3.85, 3.88 and 3.84 (four s, 3 H each, 4 ϫ OCH3), 3.30Ϫ3.56 (m, chromatography on silica gel using 2% (v/v) methanol in chloro-
4 H, NHCH2CH2), 2.71 (m, 4 H, NHCH2CH2), 2.63 (s, 3 H, form to give compound 4d (501 mg, 48%) as an oil: [α]2D3 ϭ Ϫ82.7
NCH3) (I), 2.51 (s, 3 H, NCH3) (II), 0.83 (d, J ϭ 7.0 Hz, 3 H,
(c ϭ 1.0, CHCl3). 1H NMR (500 MHz, CDCl3), two stable con-
formers present (I:II, 10:9): δ ϭ 7.29 (m, 4 H, Harom), 7.24 (m, 2
CH3) (I), 1.22 (d, J ϭ 7.0 Hz, 3 H, CH3) (II) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 198.6, 196.7, 169.4, 168.7, 167.2, 166.7, H, Harom), 7.11 (m, 2 H, Harom), 6.79 (m, 2 H, Harom), 6.70 (m, 4
149.0, 149.0, 147.7, 147.7, 131.1, 131.1, 131.0, 130.5, 130.0, 130.0, H, Harom), 6.42 (br. t, J ϭ 4.9 Hz, 1 H, NH) (I), 5.90 (br. t, J ϭ
129.9, 129.9, 129.4, 129.4, 129.0, 129.0, 128.0, 127.8, 120.7, 120.6,
111.8, 111.7, 111.4, 111.3, 55.9, 55.9, 55.9, 55.8, 47.2, 47.0, 41.0, PhCH2) (I), 4.00 (m, 2 H, PhCH2) (II), 4.93 (d, J ϭ 6.8 Hz, 1 H,
40.9, 35.2, 35.2, 30.2, 27.4, 13.6, 12.8 ppm. LSIMS (ϩ) (M ϭ H-1) (II), 3.45 (d, J ϭ 6.8 Hz, 1 H, H-1) (I), 3.86 and 3.84, 3.88
4.9 Hz, 1 H, NH) (II), 4.22 and 3.97 (qAB, 2 H, J ϭ 14.6 Hz,
412.48 for C23H28N2O5): m/z (%) ϭ 435 [M ϩ Na]ϩ (100), 413 [M and 3.86 (four s, 3 H each, 4 ϫ OCH3), 3.53 (m, 2 H, NHCH2CH2)
ϩ H]ϩ (2).
(I), 3.39 (m, 2 H, NHCH2CH2) (II), 2.73 (m, 4 H, NHCH2CH2),
2.68 (s, 3 H, NCH3) (I), 2.63 (s, 3 H, NCH3) (II), 1.27 (d, J ϭ 6.8
Hz, 3 H, CH3) (II), 0.99 (d, J ϭ 6.8 Hz, 3 H, CH3) (I) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 198.0, 196.0, 169.4, 168.6, 166.7,
166.3, 149.0, 149.0, 147.7, 147.7, 135.0, 134.8, 133.4, 132.9, 131.0,
130.9, 130.5, 130.2, 129.9, 129.9, 128.2, 128.1, 128.1, 128.0, 120.6,
120.6, 111.8, 111.7, 111.3, 111.3, 55.9, 55.9, 55.8, 55.4, 51.9, 51.9,
46.4, 46.4, 35.2, 35.2, 30.4, 27.7, 13.9, 12.9 ppm. LSIMS (ϩ) (M ϭ
446.92 for C23H27ClN2O5): m/z (%) ϭ 469 [M ϩ Na]ϩ (26), 447 [M
ϩ H]ϩ (41), 395 (20), 266 (30), 95 (35), 81 (37).
(6S)-3-Benzyl-4-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-1,6-
dimethylpiperazine-2,5-dione (5c): The procedure described for the
synthesis of 5a was applied to 3c (0.86 g, 3.2 mmol) to give 5c
(146 mg, 11%) as an unstable oil: 1H NMR (500 MHz, CDCl3):
δ ϭ 7.23 (m, 3 H, Harom), 6.95 (m, 2 H, Harom), 6.83 (m, 3 H,
Harom), 4.10 (m, 1 H, NCH2CH2), 3.91 and 3.87 (two s, 3 H each,
2 ϫ OCH3), 3.48 (m, 1 H, NCH2CH2), 3.17 (qAB, 2 H, J ϭ 13.5 Hz,
PhCH2), 2.85 (m, 2 H, NCH2CH2), 2.77 (s, 3 H, NCH3), 2.30 (q,
J ϭ 6.5 Hz, 1 H, N(CH3)CHCH3), 1.71 (s, 1 H, OH), 1.34 (d, J ϭ
6.5 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 167.1, (3S,11bRS)-11b-(3-Chlorobenzyl)-9,10-dimethoxy-2,3-dimethyl-
165.7, 148.9, 147.6, 133.6, 131.9, 130.1, 128.5, 127.9, 121.0, 112.2, 7,11b-dihydro-2H-pyrazino[2,1-a]isoquinoline-1,4(3H,6H)-dione
111.3, 86.0, 55.9, 55.9, 55.7, 46.4, 44.5, 35.3, 31.5, 18.2 ppm. M ϭ (6d): Following the procedure described for the synthesis of 6a,
412.48 for C23H28N2O5.
compound 4d (670 mg, 1.5 mmol) was converted into a mixture of
diastereoisomers 6d (324 mg, 51%; 99.7:0.3 ratio based on 1H
NMR spectroscopy) in the form of a white crystalline product.
(3S,11bRS)-11b-Benzyl-9,10-dimethoxy-2,3-dimethyl-7,11b-dihydro-
2H-pyrazino[2,1-a]isoquinoline-1,4(3H,6H)-dione (6c): Following
the procedure described for the synthesis of 6a, compound 4c
(970 mg, 2.3 mmol) was converted into a mixture of diastereoiso-
Major Diastereoisomer (3S,11bR)-6d: M.p. 186Ϫ190 °C. [α]2D3
ϭ
1
Ϫ120.6 (c ϭ 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 8.18
mers 6c (699 mg, 77%) as an oil with 87:13 diastereoisomeric ratio (s, 1 H, Harom-11), 7.23 (m, 3 H, Harom), 7.02 (m, 1 H, Harom), 6.58
1
(based on the H NMR spectrum of the crude reaction mixture).
Column chromatography on Al2O3 using cyclohexane/ethyl acetate
(s, 1 H, Harom-8), 4.96 (ddd, 1 H, J1 ϭ 12.5, J2 ϭ 5.0, J3 ϭ 1.5 Hz,
NCH2CH2), 3.97 and 3.86 (two s, 3 H each, 2 ϫ OCH3), 3.77 (q,
(7:3, v/v) allowed the isolation of (3S,11bR)-6c. Data for J ϭ 7.0 Hz, 1 H, H-3), 3.73 and 3.28 (two dAB, 1 H each, J ϭ
(3S,11bR)-6c: [α]2D3 ϭ Ϫ135.1 (c ϭ 1.0, CHCl3). IR (KBr):
13.5 Hz, PhCH2), 3.23 (td, 1 H, J1 ϭ 15.0, J2 ϭ 3.5 Hz,
2448
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2443Ϫ2453

Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives
NCH2CH2), 3.09 (m, 1 H, NCH2CH2), 2.79 (s, 3 H, NCH3), 2.67
ν˜ ϭ 3360, 3050Ϫ2825, 1680, 1670, 1520, 1260, 1160 cmϪ1
FULL PAPER
.
1H
(dd, 1 H, J1 ϭ 16.0, J2 ϭ 2.0 Hz, NCH2CH2), 0.57 (d, J ϭ 7.0 Hz, NMR (500 MHz, CDCl3): δ ϭ 7.35 (m, H Harom), 6.14 (br. t, 1 H,
3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 165.9, 165.9, NH), 5.13 (s, 2 H, PhCH2), 3.86 and 3.82 (two s, 3 H each, 2 ϫ
148.5, 147.2, 137.6, 134.5, 130.6, 129.8, 128.7, 128.2, 127.6, 127.2,
111.4, 111.2, 67.2, 57.2, 56.0, 55.9, 46.6, 37.3, 32.7, 28.5, 18.3 ppm.
OCH3), 3.98 (d, J ϭ 10.5 Hz, 1 H, H-1), 3.47 (m, 2 H,
NHCH2CH2), 2.87 (s, 3 H, NCH3), 2.71 (t, J ϭ 7.5 Hz, 2 H,
LSIMS (ϩ) (M ϭ 428.90 for C23H25ClN2O4): m/z (%) ϭ 429 [M NHCH2CH2), 2.27 [m, 1 H, CH(CH3)2], 0.91 and 0.85 (two d, 3 H
ϩ H]ϩ(34), 303 (100), 273 (8), 190 (6), 107 (10), 91 (10), 81 (10).
each, J ϭ 6.5 Hz, 2ϫCH3) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 170.1, 157.4, 149.0, 147.6, 136.5, 131.2, 128.5, 128.1, 127.5,
120.6, 111.8, 111.3, 67.4, 65.4, 55.9, 55.8, 40.4, 35.4, 29.8, 26.0,
19.6, 18.6 ppm. LSIMS (ϩ) (M ϭ 428.52 for C24H32N2O5): m/z
(%) ϭ 467 [M ϩ K]ϩ (1), 451 [M ϩ Na]ϩ (100), 429 [M ϩ H]ϩ (4),
301 (5).
Minor Diastereoisomer (3S,11bS)-6d (selected data): 8.03 (s, 1 H,
H
arom-11), (5.86 (dd, 1 H, J1 ϭ 16, J2 ϭ 2 Hz, NCH2CH2) ppm.
Benzyl (1S)-1-({[2-(3,4-Dimethoxyphenyl)ethyl]amino}carbonyl)-2-
methylpropylcarbamate (2e): Following the procedure described for
the synthesis of 2a, compound 1e (2 g, 8 mmol) was converted into
2e (3.3 g, 100%), which was obtained as a white crystalline product:
m.p. 142Ϫ144 °C with decomposition. [α]2D3 ϭ Ϫ8.4 (c ϭ 1.0,
CHCl3). IR (KBr): ν˜ ϭ3300, 2950, 1700, 1650, 1500Ϫ1550, 1300
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-methyl-2-(methylamino)-
butanamide (3f): The procedure described for the synthesis of 3a
was applied to 2f (3.5 g, 8.19 mmol). Compound 3f (2.04 g, 85%)
was obtained as a white crystalline product: m.p. 52Ϫ54 °C. [α]2D3
ϭ
cmϪ1
.
1H NMR (500 MHz, CDCl3): δ ϭ 7.37Ϫ7.29 (m, 5 H,
Ϫ20.4 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3340, 3320, 3100Ϫ2810,
1620, 1520, 1270, 1050 cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ
7.23 (br. t, 1 H, NHCH2CH2), 6.80 (dAB, 1 H, J ϭ 8.5 Hz, Harom
5), 6.75 (dAB, 1 H, J ϭ 8.5 Hz, Harom-6), 6.74 (dAB, 1 H, J ϭ 2.0 Hz,
arom-2), 3.87 and 3.86 (two s, 3 H each, 2 ϫ OCH3), 3.54 (m, 2
Harom), 6.78 (m, 1 H, Harom), 6.70 (br. s, 2 H, Harom), 6.09 (br. s, 1
.
H, NHCH2CH2), 5.40 [d, J ϭ 9.0 Hz, 1 H, NHCHCH(CH3)2],
5.07 (qAB, 2 H, J ϭ 11.5 Hz, PhCH2), 3.85 and 3.84 (two s, 3 H
each, 2 ϫ OCH3), 3.90 (q, J ϭ 6.5 Hz, 1 H, H-1), 3.55 (m, 1
H, NHCH2CH2), 3.45 (m, 1 H, NHCH2CH2), 2.24 (app t, 2 H,
NHCH2CH2), 2.07 [m, 1 H, CH(CH3)2], 0.92 and 0.88 (two d, 3 H
each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 171.1, 156.4, 149.0, 147.7, 136.2, 131.1, 128.5, 128.2, 128.0,
120.6, 111.8, 111.3, 67.0, 60.6, 55.9, 55.8, 40.7, 35.3, 31.0, 19.2, 17.8
ppm. LSIMS (ϩ) (M ϭ 414.49 for C23H30N2O5): m/z (%) ϭ 437
[M ϩ Na]ϩ (27), 415 [M ϩ Na]ϩ (16), 371 (14), 164 (57), 91 (100).
-
H
H, NHCH2CH2), 2.78 (m, 2 H, NHCH2CH2), 2.73 (d, J ϭ 4.5 Hz,
1 H, H-2), 2.29 (s, 3 H, NCH3), 2.06 [m, 1 H, CH(CH3)2], 0.96 and
0.84 (two d, 3 H each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 173.4, 148.9, 147.6, 131.6, 120.6, 111.9,
111.3, 70.8, 55.9, 55.8, 40.0, 36.2, 35.6, 31.3, 19.6, 17.7 ppm.
LSIMS (ϩ) (M ϭ 294.39 for C16H26N2O3): m/z (%) ϭ 295 [M ϩ
H]ϩ (100).
(2S)-2-Amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-3-methylbutan-
amide (3e): The procedure described for the synthesis of 3a was
applied to 2e (7 g, 16.91 mmol) to give 3e (3.25 g, 69%) as a white
crystalline product: m.p. 51Ϫ55 °C. [α]2D3 ϭ Ϫ22.4 (c ϭ 1.0,
CHCl3). IR (KBr): ν˜ ϭ 3300Ϫ3400, 2900Ϫ3000, 1700, 1500, 1200,
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-methyl-2-[methyl(2-oxo-3-
phenylpropanoyl)amino]butanamide (4f): The procedure described
for the synthesis of 5a was applied to 3f (1.67 g, 5.68 mmol) and
provided 4f (1.27 g, 51%) as an oil. Data for 4f: [α]2D3 ϭ Ϫ30.6 (c ϭ
1
1.0, CHCl3). H NMR (500 MHz, CDCl3); two stable conformers
1
1250, 1050 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.34 (br. s, 1
present (I:II, 11:10): δ ϭ 7.37Ϫ7.14 (m, 10 H, Harom), 6.82Ϫ6.65
(m, 6 H, Harom), 6.70 (m, 1 H, NH) (I), 5.94 (br. t, J ϭ 5.5 Hz, 1
H, NH) (II), 4.25 and 4.06 (qAB, 2 H, J ϭ 15.0 Hz, PhCH2) (I),
4.04 and 3.97 (qAB, 2 H, J ϭ 15.0 Hz, PhCH2) (II), 4.22 (d, J ϭ
10.5 Hz, 1 H, H-2) (II), 3.31 (d, J ϭ 10.5 Hz, 1 H, H-2) (I), 3.88
(s, 3 H, OCH3), 3.85 (s, 9 H, 3 ϫ OCH3), 3.52 (m, 2 H,
NHCH2CH2) (I), 3.38 (m, 2 H, NHCH2CH2) (II), 2.79 (s, 3 H,
NCH3) (I), 2.72 (m, 4H NHCH2CH2), 2.65 (s, 3 H, NCH3) (II),
2.22 [m, 2 H, CH(CH3)2], 0.88 and 0.61 (two d, 3 H each, J ϭ
6.5 Hz, 2 ϫ CH3) (I), 0.71 and 0.27 (two d, 3 H each, J ϭ 6.8 Hz,
2 ϫ CH3) (II) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 198.9,
196.7, 168.4, 167.9, 167.4, 166.2, 149.0, 148.9, 147.7, 147.6, 131.0,
131.0, 131.0, 131.0, 130.1, 129.9, 129.1, 129.0, 128.0, 127.8, 120.7,
120.7, 111.8, 111.7, 111.4, 111.3, 66.2, 62.7, 55.9, 55.9, 55.8, 55.8,
47.1, 46.8, 40.7, 40.6, 35.3, 35.3, 30.6, 28.2, 25.4, 25.3, 19.5, 19.5,
18.1, 17.6 ppm. LSIMS (ϩ) (M ϭ 440.53 for C25H32N2O5): m/z
(%) ϭ 441 [M ϩ H]ϩ (30), 260 (47), 164 (68), 91 (41), 86 (56).
H, NH, exchangeable with D2O), 6.81 (m, 1 H, Harom), 6.74 (m, 2
H, Harom), 3.87 and 3.86 (two s, 3 H each, 2 ϫ OCH3), 3.55 (m, 1
H, NHCH2CH2), 3.48 (m, 1 H, NHCH2CH2), 3.20 (d, J ϭ 3.5 Hz,
1 H, H-2), 2.77 (m, 2 H, NHCH2CH2), 2.29 [m, 1 H, CH(CH3)2],
1.36 (br. s, 2 H, exchangeable with D2O, NH2), 0.97 and 0.78 (two
d, 3 H each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 174.3, 148.9, 147.6, 131.6, 120.6, 111.9, 111.3, 60.2,
55.9, 55.8, 40.3, 35.5, 30.7, 19.7, 15.9 ppm. LSIMS (ϩ) (M ϭ
280.36 for C15H24N2O3): m/z (%) ϭ 303 [M ϩ Na]ϩ (49), 281 [M]ϩ
(39), 176 (84), 97 (95).
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-methyl-2-[(2-oxo-3-phen-
ylpropanoyl)amino]butanamide (4e): The procedure described for
the synthesis of 5a was applied to 3e (1 g, 3.57 mmol) to give 4e
(988 mg, 65%) as an oil: [α]2D3 ϭ Ϫ13.5 (c ϭ 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ ϭ 7.33Ϫ7.20 (m, 5 H, Harom), 6.77 (m, 1 H,
Harom), 6.69 (m, 1 H, Harom), 6.19 (app. t, 1 H, NHCH2CH2), 4.16
and 3.60 (qAB, 2 H, J ϭ 16.0 Hz, PhCH2), 4.09 (m, 1 H, H-2), 3.84
and 3.83 (two s, 3 H each, 2 ϫ OCH3), 3.53 (m, 1 H, NHCH2CH2),
3.44 (m, 1 H, NHCH2CH2), 2.76 (br. s, 1 H, NHCHCH(CH3)2],
2.74 (m, 2 H, NHCH2CH2), 2.11 [m, 1 H, CH(CH3)2], 0.89 and
0.86 (two d, 3 H each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 195.1, 169.9, 159.9, 149.0, 147.7, 132.5,
131.0, 129.8, 128.7, 127.2, 120.6, 111.8, 111.3, 56.0, 55.9, 55.8, 43.2,
40.8, 35.2, 31.0, 19.2, 18.0 ppm. M ϭ 426.50 for C24H30N2O5.
(3S,11bR)-11b-Benzyl-3-isopropyl-9,10-dimethoxy-2-methyl-7,11b-
dihydro-2H-pyrazino[2,1-a]isoquinoline-1,4(3H,6H)-dione 6f: Fol-
lowing the procedure described for the synthesis of 6a, compound
4f (256 mg, 0.58 mmol) was converted into (3S,11bR)-6f (196 mg,
89%), which was obtained as an oil. Data for (3S,11bR)-6f: [α]2D3
ϭ
Ϫ48.4 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3100Ϫ2820, 1670, 1650,
1
1510, 1250, 1220 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.95 (s,
1 H, Harom-11), 7.2 (m, 5 H, Harom), 6.56 (s, 1 H, Harom-8), 4.78
(ddd, 1 H, J1 ϭ 12.5, J2 ϭ 5.5, J3 ϭ 1.0 Hz, NCH2CH2), 3.94 and
3.86 (two s, 3 H each, 2 ϫ OCH3), 3.61 (d, J ϭ 4.0 Hz, 1 H, H-3),
3.85 and 3.37 (qAB, 2 H, J ϭ 14 Hz, PhCH2), 3.30 (m, 1 H,
NCH2CH2), 3.17 (m, 1 H, NCH2CH2), 2.86 (s, 3 H, NCH3), 2.60
Benzyl (1S)-1-({[2-(3,4-Dimethoxyphenyl)ethyl]amino}carbonyl)-2-
methylpropyl(methyl)carbamate (2f): The procedure described for
the synthesis of 2a was applied to 1f (2.24 g, 8.45 mmol) to give 2f
(3.5 g, 97%) as an oil: [α]2D3 ϭ Ϫ61.6 (c ϭ 1.0, CHCl3). IR (film):
Eur. J. Org. Chem. 2003, 2443Ϫ2453
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2449

Z. Czarnocki et al.
(m, 1 H, NCH2CH2), 1.67 [m, 1 H, CH(CH3)2], 0.83 and 0.21 (two NHCH2CH2), 5.42 (d, J ϭ 7.5 Hz, 1 H, NHCHCH2Ph), 5.05 (qAB
FULL PAPER
,
d, 3 H each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 166.3, 165.5, 148.5, 147.1, 135.9, 130.7, 129.4, 128.5,
127.3, 126.7, 111.4, 110.6, 68.0, 67.1, 56.0, 55.8, 46.3, 38.1, 31.7,
27.4, 20.0, 16.4 ppm. EI-MS (M ϭ 422.52 for C25H30N2O4): m/z
2 H, J ϭ 12.5 Hz, PhCH2), 4.32 (q, J ϭ 7.0 Hz, 1 H, H-1), 3.82 (s,
6 H, 2 ϫ OCH3), 3.37 (m, 2 H, NHCH2CH2), 3.04 (m, 2 H,
CHCH2Ph), 2.66Ϫ2.52 (m, 2 H, NHCH2CH2) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 170.6, 155.8, 149.0, 147.7, 136.4, 136.1,
(%) ϭ 422 [Mϩ](3), 331 (100), 303 (17), 260 (24), 245 (14). HR EI: 131.0, 129.3, 128.7, 128.5, 128.2, 128.0, 127.0, 120.5, 111.7, 111.2,
calcd. for C25H30N2O4 422.220; found 422.221.
67.0, 56.5, 55.9, 55.8, 40.7, 38.8, 35.0 ppm. EI-MS (M ϭ 462.54
for C27H30N2O5): m/z (%) ϭ 462 [M]ϩ (33), 354 (49), 220 (3), 210
(1), 164 (100), 151 (10), 91 (20).
(2S)-2-{[3-(3-Chlorophenyl)-2-oxopropanoyl](methyl)amino}-N-[2-
(3,4-dimethoxyphenyl)ethyl]-3-methylbutanamide 4g: The procedure
described for the synthesis of 4d was applied to 3f (0.75 g,
2.5 mmol) to give 4g (486 mg, 48%) as an oil: [α]2D3 ϭ Ϫ75.2 (c ϭ
(2S)-2-Amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenylpro-
panamide (3h): The procedure described for the synthesis of 3a was
applied to 2h (2 g, 4.3 mmol) to give 3h (1.37 g, 97%) as a white
1
1.0, CHCl3). H NMR (500 MHz, CDCl3); two stable conformers
present (I:II, 15:16): δ ϭ 7.20Ϫ7.30 (m, 8 H, Harom), 7.07Ϫ7.16 (m, crystalline product: m.p. 100Ϫ104 °C. [α]2D3 ϭ Ϫ31.4 (c ϭ 1.0,
2 H, Harom), 6.65Ϫ6.82 (m, 6 H, Harom), 6.70 (m, 1 H, NH) (I), CHCl3). IR (film): ν˜ ϭ 3350, 3285, 3080Ϫ2840, 1640, 1520, 1470,
5.96 (br. t, J ϭ 5.9 Hz, 1 H, NH) (II), 4.19 and 4.07 (qAB, 2 H,
J ϭ 15.6 Hz, PhCH2) (II), 4.05 and 3.92 (qAB, 2 H, J ϭ 14.6 Hz,
PhCH2) (I), 4.23 (d, J ϭ 10.7 Hz, 1 H, H-2) (II), 3.35 (d, J ϭ 10.7
Hz, 1 H, H-2) (I), 3.87 (s, 3 H, OCH3), 3.85 (s, 9 H, 3 ϫ OCH3),
1270, 1230, 1140, 1025 cmϪ1
7.34Ϫ7.20 (m, 6 H, Harom and NH), 6.80 (d, J ϭ 7.8 Hz, 1 H,
arom-5), 6.71 (s, 1 H, Harom-2), 6.69 (s, 1 H, Harom-6), 3.86 (s, 6
H, 2 ϫ OCH3), 3.58 (dd, 1 H, J1 ϭ 13.7, J2 ϭ 4.1 Hz, CHCH2Ph),
.
1H NMR (500 MHz, CDCl3): δ ϭ
H
3.54 (m, 2 H, NHCH2CH2) (II), 3.42 (m, 2 H, NHCH2CH2) (I), 3.51 (m, 2 H, NHCH2CH2), 3.25 (dd, 1 H, J1 ϭ 9.3, J2 ϭ 4.1 Hz,
2.74 (s, 3 H, NCH3) (II), 2.81 (s, 3 H, NCH3) (I), 2.73 (m, 2 H, CHCH2Ph), 2.74 (app t, 2 H, NHCH2CH2), 2.69 (dd, 2 H, J1
ϭ
NHCH2CH2) (II), 2.73 (m, 2 H, NHCH2CH2) (I), 2.25 [m, 1 H, 13.7, J2 ϭ 9.3 Hz, H-2), 1.38 (br. s, 2 H, exchangeable with D2O,
CH(CH3)2] (II), 2.25 [m, 1 H, CH(CH3)2] (I), 0.89 and 0.75 (two
d, 3 H each, J ϭ 6.9 Hz, 2 ϫ CH3) (II), 0.66 and 0.38 (two d, 3 H
NH2) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 174.1, 148.9, 147.6,
137.9, 131.5, 129.3, 128.7, 126.8, 120.6, 111.8, 111.2, 55.9, 55.8,
each, J ϭ 6.8 Hz, 2 ϫ CH3) (I) ppm. 13C NMR (125 MHz, CDCl3): 56.4, 41.0, 40.4, 35.4 ppm. EI-MS (M ϭ 328.41 for C19H24N2O3):
δ ϭ 198.2, 195.9, 168.4, 167.8, 167.0, 165.8, 149.1, 149.0, 147.8,
m/z (%) ϭ 328 [M]ϩ (9), 237 (15), 220 (2), 209 (15), 192 (4), 180
147.7, 134.9, 134.8, 133.3, 133.2, 131.0, 131.0, 130.3, 130.2, 130.0, (9), 164 (100), 151 (11), 126 (5), 120 (85), 103 (7), 91 (8), 77 (4).
130.0, 128.3, 128.1, 128.0, 128.0, 120.7, 120.7, 111.9, 111.7, 111.4,
N-[(1S)-1-Benzyl-2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-oxo-
ethyl]-2-oxo-3-phenylpropanamide (4h): The procedure described for
111.4, 66.3, 62.9, 55.9, 55.9, 55.8, 55.7, 46.5, 46.3, 40.7, 40.6, 35.6,
35.3, 30.7, 28.3, 25.5, 25.4, 19.5, 19.4, 18.1, 17.9 ppm. LSIMS (ϩ)
the synthesis of 5a was applied to 3h (1.5 g, 4.6 mmol) and provided
(M ϭ 474.98 for C25H31ClN2O5): m/z (%) ϭ 497 [M ϩ Na]ϩ (22),
4h (1.2 g, 55%) as white crystals: m.p. 123Ϫ128 °C. [α]2D3 ϭ Ϫ6.8
475 [M ϩ H]ϩ (39), 266 (14), 164 (39), 120 (18), 107 (27), 86 (33),
(c ϭ 0.88, CHCl3). IR (KBr): ν˜ ϭ 3320, 3300, 3090Ϫ2825, 1675,
83 (29).
1520, 1250, 1225 cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ
.
(3S,11bR)-11b-(3-Chlorobenzyl)-3-isopropyl-9,10-dimethoxy-2- 7.60Ϫ7.00 (m, 10 H, Harom), 6.65 (d, J ϭ 7.9 Hz, 1 H, Harom-5),
methyl-7,11b-dihydro-2H-pyrazino[2,1-a]isoquinoline-1,4(3H,6H)-
dione (6g): Following the procedure described for the synthesis of
6a, compound 4g (76 mg, 0.16 mmol) was converted into
6.52 (d, J ϭ 1.8 Hz, 1 H, Harom-2), 6.45 (dd, 1 H, J1 ϭ 8.2, J2 ϭ
1.8 Hz, Harom-6), 5.57 (t, J ϭ 5.3 Hz, 1 H, NHCH2CH2), 4.39 (m,
1 H, H-1), 4.07 (s, 2 H, PhCH2), 3.77 (s, 6 H, 2 ϫ OCH3), 3.31 (m,
2 H, NHCH2CH2), 2.98 (m, 2 H, CHCH2Ph), 2.62 (d, J ϭ 10.1
(3S,11bR)-6g (42 mg, 57%), which was obtained as an oil.: [α]2D3
ϭ
Ϫ71.0 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3300Ϫ3500, 1650, 1500, Hz, 1 H, NHCHCH2Ph), 2.51 (m, 2 H, NHCH2CH2) ppm. 13C
1
1200 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.91 (s, 1 H, Harom
-
NMR (125 MHz, CDCl3): δ ϭ 194.6, 169.0, 159.4, 149.0, 147.7,
136.1, 132.4, 130.7, 130.0, 129.2, 129.2, 128.7, 127.3, 127.2, 120.5,
111.6, 111.2, 55.7, 55.7, 54.8, 43.1, 40.6, 38.3, 34.9 ppm. EI-MS
11), 7.19 (m, 3 H, Harom), 7.09 (m, 1 H, Harom), 6.57 (s, 1 H, Harom
-
8), 4.80 (dd, 1 H, J1 ϭ 12.5, J2 ϭ 5.5 Hz, NCH2CH2), 3.93 and
3.87 (two s, 3 H each, 2 ϫ OCH3), 3.64 (d, J ϭ 3.5 Hz, 1 H, H-3), (M ϭ 474.55 for C28H30N2O5): m/z (%) ϭ 474 [M]ϩ (39), 355 (4),
3.85 and 3.31 (two dAB, 1 H each, J ϭ 14.0 Hz, PhCH2), 3.33 (m,
1 H, NCH2CH2), 3.20 (td, 1 H, J1 ϭ 16.0, J2 ϭ 5.0 Hz,
NCH2CH2), 2.87 (s, 3 H, NCH3), 2.62 (dd, 1 H, J1 ϭ 16.0, J2 ϭ
3.0 Hz, NCH2CH2), 1.73 [m, 1 H, CH(CH3)2], 0.87 and 0.21 (two
d, 3 H each, J ϭ 7.0 Hz, 2 ϫ CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 165.9, 165.5, 148.6, 147.2, 137.9, 134.3, 130.8, 129.7,
129.2, 129.0, 127.4, 126.5, 111.5, 110.2, 67.8, 67.0, 56.0, 55.8, 45.6,
38.1, 34.8, 31.6, 27.2, 19.8, 16.1 ppm. LSIMS (ϩ) (M ϭ 456.96 for
C25H29ClN2O4): m/z (%) ϭ 479 [M ϩ Na]ϩ (2), 457 [M ϩ H]ϩ
(33), 331 (98), 120 (8), 107 (14), 89 (13). HR LSIMS: calcd. for
C25H29CLN2O4 457.189; found 457.191.
266 (2), 208 (2), 164 (100), 151 (6), 120 (8), 91 (10).
Benzyl (1S)-1-Benzyl-2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-
oxoethyl(methyl)carbamate (2i): Following the procedure described
for the synthesis of 2a, compound 1i (2 g, 6.39 mmol) was con-
verted into 2i (2.89 g, 95%), which was obtained as an oil: [α]2D3
ϭ
Ϫ39.3 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 3350, 2830Ϫ3100, 1690,
1675, 1520, 1450 cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ
.
7.40Ϫ7.10 (m, 10 H, Harom), 6.73 (dAB, 1 H, J ϭ 8.0 Hz, Harom-5),
6.66 (s, 1 H, Harom-2), 6.61 (dAB, 1 H, J ϭ 8.0 Hz, Harom-6), 6.08
(br. s, 1 H, NH), 5.06 (qAB, 1 H, J ϭ 12.4 Hz, PhCH2), 4.92 (qAB
,
1 H, J ϭ 11.6 Hz, PhCH2), 4.86 (app t, 1 H, J ϭ 7.8 Hz, H-1),
3.85 and 3.81 (two s, 3 H each, 2 ϫ OCH3), 3.44 (m, 2 H,
NHCH2CH2), 3.33 (dd, 1 H, J1 ϭ 14.6, J2 ϭ 7.1 Hz, CHCH2Ph),
2.95 (dd, 1 H, J1 ϭ 14.1, J2 ϭ 8.8 Hz, CHCH2Ph), 2.76 (s, 3 H,
NCH3), 2.66 (m, 2 H, NHCH2CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 170.0, 157.0, 149.1, 147.6, 137.3, 136.4, 131.2, 129.0,
1H 129.0, 128.5, 128.0, 127.6, 126.6, 120.6, 111.8, 111.3, 67.4, 60.3,
55.9, 55.8, 40.7, 35.2, 34.1, 30.4 ppm. LSIMS (ϩ) (M ϭ 476.56 for
Benzyl
(1S)-1-Benzyl-2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-
oxoethylcarbamate (2h): Following the procedure described for the
synthesis of 2a, compound 1h (7 g, 23.4 mmol) was converted into
2h (8 g, 75%), which was obtained as a white crystalline product:
m.p. 145Ϫ146 °C. [α]2D3 ϭ ϩ4.9 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ
3320, 3110Ϫ2830, 1680, 1650, 1525, 1275, 1230, 1170 cmϪ1
.
NMR (500 MHz, CDCl3): δ ϭ 7.36Ϫ7.13 (m, 10 H, Harom), 6.73
(d, J ϭ 8.0 Hz, 1 H, Harom-5), 6.61 (d, J ϭ 2.0 Hz, 1 H, Harom-2), C28H32N2O5): m/z (%) ϭ 499 [M ϩ Na]ϩ (6), 477 [M ϩ H]ϩ (56),
6.54 (dd, 1 H, J ϭ 8.0 Hz, Harom-6), 5.81 (t, J ϭ 5.5 Hz, 1 H, 433 (16), 369 (6), 296 (10), 224 (24), 164 (100), 134 (36).
2450
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2443Ϫ2453

Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives
FULL PAPER
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(methylamino)-3-phen-
ylpropanamide (3i): The procedure described for the synthesis of 3a
was applied to 2i (2 g, 4.2 mmol) to give 3i (1.2 g, 83.6%) as a white
crystalline product: m.p. 75Ϫ82 °C. [α]2D3 ϭ Ϫ36.7 (c ϭ 0.76,
Minor Diastereoisomer (3S,11bS)-6i: [α]2D3 ϭ Ϫ47.1 (c ϭ 1.28,
CHCl3). IR (film): ν˜ ϭ 3025, 3000, 2930, 2870, 1660, 1520, 1450,
1
1270 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.88 (s, 1 H, Harom
-
11), 7.28Ϫ6.74 (m, 10 H, Harom), 6.30 (s, 1 H, Harom-8), 4.83 (ddd,
1 H, J1 ϭ 12.6, J2 ϭ 5.0, J3 ϭ 1.5 Hz, NCH2CH2), 3.94 and 3.86
CHCl3). IR (KBr): ν˜ ϭ 3350, 3320, 2800Ϫ3050, 1650, 1520 cmϪ1
.
1H NMR (500 MHz, CDCl3): δ ϭ 7.33Ϫ7.18 (m, 6 H, Harom and (two s, 3 H each, 2 ϫ OCH3), 3.88 (m, 1 H, H-3), 3.52 and 3.22
NHCH2CH2), 6.82Ϫ6.69 (m, 3 H, Harom), 3.86 and 3.85 (two s, 3
(dAB, 2 H, J ϭ 14 Hz, PhCH2), 3.12 (m, 1 H, NCH2CH2), 3.09 (m,
H each, 2 ϫ OCH3), 3.51 (m, 2 H, NHCH2CH2), 3.17 (m, 2 H, 1 H, NCH2CH2), 2.90 (m, 1 H, NCH2CH2), 2.84 (s, 3 H, NCH3),
CHCH2Ph), 2.75 (t, J ϭ 6.5 Hz, 2 H, NHCH2CH2), 2.64 (m, 1 H,
2.45 (m, 1 H, CHCH2Ph), 1.92 (m, 1 H, CHCH2Ph) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 166.3, 164.3, 148.9, 147.1, 135.3,
H-2), 2.18 (s, 3 H, NCH3), 1.47 (br. s, 1 H, exchangeable with D2O,
NHCH3) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 173.3, 149.0, 133.7, 129.8, 129.4, 128.1, 128.1, 127.9, 127.3, 126.9, 125.9, 111.2,
147.7, 137.6, 131.5, 129.1, 128.7, 126.9, 120.7, 111.9, 111.4, 66.1, 110.0, 66.2, 61.5, 56.0, 55.9, 48.1, 36.9, 36.5, 33.4, 28.1 ppm.
55.9, 55.9, 40.2, 39.3, 35.4, 35.4 ppm. LSIMS (ϩ) (M ϭ 342.43 for
LSIMS (ϩ) (M ϭ 470.56 for C29H30N2O4): m/z (%) ϭ 471 [M ϩ
C20H26N2O3): m/z (%) ϭ 685 [2M ϩ H]ϩ (8), 343 [M ϩ H]ϩ (66), H]ϩ(24), 413 (3), 391 (6), 379 (21).
251 (18), 134 (100), 107 (8), 91 (14).
Benzyl
(2S)-2-({[2-(3,4-Dimethoxyphenyl)ethyl]amino}carbonyl)-
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[methyl(2-oxo-3-phen-
ylpropanoyl)amino]-3-phenylpropanamide (4i): The procedure de-
scribed for the synthesis of 5a was applied to 3i (1 g, 2.92 mmol)
providing 4i (788 mg, 55%) as an oil: [α]2D3 ϭ Ϫ69.2 (c ϭ 1.0,
pyrrolidine-1-carboxylate (8a): Following the procedure described
for the synthesis of 2a, compound 7a (6 g, 24.1 mmol) was con-
verted into 8a (9.22 g, 93%), which was obtained as a white solid:
m.p. 103Ϫ105 °C. [α]2D3 ϭ Ϫ54.7 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ
CHCl3). IR (film): ν˜ ϭ 3100Ϫ2850, 1675, 1520 cmϪ1 1H NMR
.
1
3300, 1650, 1500, 1450, 1250 cmϪ1. H NMR (500 MHz, CDCl3):
(500 MHz, CDCl3); two stable conformers present (I:II, 2:1): δ ϭ
7.38Ϫ6.98 (m, 20 H, Harom), 6.85Ϫ6.58 (m, 6 H, Harom), 6.41 (br.
t, 1 H, NH) (I), 5.83 (br. t, 1 H, NH) (II), 5.10 (t, J ϭ 7.8 Hz, 1
H, H-2) (II), 4.19 (dd, 1 H, J1 ϭ 9.6, J2 ϭ 5.1 Hz, H-2) (I), 4.05
δ ϭ 7.33 (m, 5 H, Harom), 6.77 (dAB, 1 H, J ϭ 8.0 Hz, Harom),
6.62Ϫ6.75 (m, 2 H, Harom), 5.95 (br. s, 1 H, NH), 5.12 (br. qAB, 2
H, J ϭ 12.0 Hz, PhCH2), 4.30 (br. s, 1 H, H-2), 3.86 and 3.83 (two
s, 3 H each, 2 ϫ OCH3), 3.44 (m, 2 H, NHCH2CH2), 3.43 (m, 2
H, NCHCH2CH2CH2), 2.52Ϫ2.28 (br. m, 2 H, NHCH2CH2), 2.32
and 2.88 (qAB, 2 H, J ϭ 18.3 Hz, PhCH2) (I), 3.92 and 3.81 (qAB
,
2 H, J ϭ 14.4 Hz, PhCH2) (II), 3.86 and 3.84 (two s, 3 H each, 2
ϫ OCH3), 3.80 (s, 6 H, 2 ϫ OCH3), 3.54 (m, 1 H, NHCH2CH2)
(I), 3.39 (m, 1 H, NHCH2CH2) (I), 3.31 (m, 2 H, NHCH2CH2)
(II), 3.14 (dd, 2 H, J1 ϭ 14.7, J2 ϭ 4.9 Hz, CHCH2Ph) (I), 2.84
(m, 2 H, CHCH2Ph) (II), 2.83 (s, 3 H, NCH3) (I), 2.69 (m, 4 H,
NHCH2CH2), 2.59 (s, 3 H, NCH3) (II) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 199.5, 196.6, 168.3, 167.9, 167.4, 166.9, 149.0, 149.0,
147.7, 147.6, 137.4, 136.5, 131.6, 131.2, 130.9, 130.9, 129.8, 129.7,
129.1, 129.1, 128.9, 128.9, 128.7, 128.6, 127.7, 127.5, 127.2, 126.9,
120.7, 120.6, 111.7, 111.6, 111.3, 111.3, 55.9, 62.6, 57.3, 55.8, 55.8,
55.7, 46.8, 45.5, 41.0, 40.9, 35.2, 35.2, 33.7, 33.4, 30.9, 28.3 ppm.
LSIMS (ϩ) (M ϭ 488.57 for C29H32N2O5): m/z (%) ϭ 511[M ϩ
Na]ϩ (36), 489 [M ϩ H]ϩ (10), 107 (14), 81 (22).
(br. s,
1
H, NCHCH2CH2CH2), 2.10 (br. s,
1
H,
NCHCH2CH2CH2), 1.88 (br. m, 2 H, NCHCH2CH2CH2) ppm.
13C NMR (125 MHz, CDCl3): δ ϭ 171.5, 156.1, 149.1, 147.7,
136.4, 131.5, 128.6, 128.2, 127.9, 120.6, 112.0, 111.3, 67.3, 60.7,
55.9, 55.9, 47.4, 47.0, 35.2, 28.3, 24.5 ppm. EI-MS (M ϭ 412.48
for C23H28N2O5): m/z (%) ϭ 412 [M]ϩ (2), 164 (100), 91 (64), 70 (6).
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]pyrrolidine-2-carboxamide
(9a): The procedure described for the synthesis of 3a was applied to
8a (9.22 g, 22.3 mmol) to give 9a (5.2 g, 78%) as a white crystalline
product: m.p. 65Ϫ66.5 °C. [α]2D3 ϭ Ϫ24.4 (c ϭ 1.0, CHCl3). IR
(KBr): ν˜ ϭ 3300, 1650, 1500, 1200 cmϪ1 1H NMR (500 MHz,
.
CDCl3): δ ϭ 7.69 (br. s, 1 H, NHCH2CH2), 6.80 (d, J ϭ 8.5 Hz, 1
H, Harom), 6.73 (m, 2 H, Harom), 3.87 and 3.86 (two s, 3 H each, 2
ϫ OCH3), 3.71 (m, 1 H, H-2), 3.51 (m, 1 H, NHCH2CH2), 3.44
(m, 1 H, NHCH2CH2), 2.96 (m, 1 H, NHCHCH2CH2CH2), 2.80
(m, 1 H, NHCHCH2CH2CH2), 2.76 (t, J ϭ 7.0 Hz, 2 H,
NHCH2CH2), 2.15 (br. s, 1 H, NHCHCH2CH2CH2), 2.11 (m, 1
H, NHCHCH2CH2CH2), 1.87 (m, 1 H, NHCHCH2CH2CH2), 1.65
(3S,11bRS)-3,11b-Dibenzyl-9,10-dimethoxy-2-methyl-7,11b-di-
hydro-2H-pyrazino[2,1-a]isoquinoline-1,4(3H,6H)-dione (6i): Fol-
lowing the procedure described for the synthesis of 6a, compound
4i (530 mg, 1.09 mmol) was converted into a mixture of dia-
stereoisomers 6i in 92% yield (471 mg), which was obtained as an
oil. Column chromatography on Al2O3 using cyclohexane/ethyl
acetate (20:3, v/v) and careful re-chromatography allowed the sep-
aration of 6i into (3S,11bR)-6i and (3S,11bS)-6i (in an 89:11 ratio
based on the 1H NMR spectrum of the crude reaction mixture).
(m,
2
H, NHCHCH2CH2CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 175.1, 148.9, 147.6, 131.6, 120.7, 111.9, 111.3, 60.6,
55.9, 55.8, 47.2, 40.2, 35.4, 30.7, 26.1 ppm. EI-MS (M ϭ 278.35 for
C15H22N2O3): m/z (%) ϭ 278 [Mϩ](2), 209 (15), 164 (13), 70 (100).
Data for the predominant diastereoisomer (3S,11bR)-6i: [α]2D3
Ϫ110.1 (c ϭ 1.05, CHCl3). IR (film): ν˜ ϭ 3020, 2930, 2850, 1650,
1610, 1510, 1425, 1400, 1340, 1330 cmϪ1
ϭ
(2S)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(2-oxo-3-phenylpro-
.
1H NMR (500 MHz, panoyl)pyrrolidine-2-carboxamide (10a): The procedure described
CDCl3): δ ϭ 8.15 (s, 1 H, Harom-11), 7.41Ϫ6.98 (m, 10 H, Harom), for the synthesis of 5a was applied to 9a (1.2 g, 4.32 mmol) and
6.56 (s, 1 H, Harom-8), 4.95 (ddd, 1 H, J1 ϭ 12.6, J2 ϭ 5.0, J3 ϭ
provided 10a (1.39 g, 68%) as an oil: [α]2D3 ϭ Ϫ55.4 (c ϭ 1.0,
1.5 Hz, NCH2CH2), 3.96 and 3.86 (two s, 3 H each, 2 ϫ OCH3), CHCl3). IR (KBr): ν˜ ϭ 3300Ϫ3500, 1050Ϫ1200, 500 cmϪ1 1H
3.96 (m, 1 H, H-3), 3.63 and 3.33 (dAB, 2 H, J ϭ 14 Hz, PhCH2), NMR (500 MHz, CDCl3); two stable conformers present and com-
3.18 (m, 1 H, J1 ϭ 12.5, J2 ϭ 3.5 Hz, NCH2CH2), 3.07 (m, 1 H, pound 11a formed during measurement of the NMR spectrum:
.
NCH2CH2), 2.64 (m, 1 H, J1 ϭ 15.0, J2 ϭ 1.5 Hz, NCH2CH2), δ ϭ 7.36Ϫ7.19 (m, Harom), 7.08 (m, Harom), 6.84Ϫ6.82 (m, Harom),
2.50 (s, 3 H, NCH3), 2.40 (m, 1 H, J1 ϭ 14.5, J2 ϭ 4.0 Hz, 6.54 (m), 5.67 (m), 4.66 (m), 4.44 (m), 4.41 (m), 4.33 (m), 4.08 (m),
CHCH2Ph), 1.90 (m, 1 H, CHCH2Ph) ppm. 13C NMR (125 MHz, 3.95 (m), 3.89, 3.88, 3.86, 3.85, 3.84 and 3.81 (six s, 3 H each, 6 ϫ
CDCl3): δ ϭ 166.7, 165.2, 148.4, 147.1, 138.5, 135.9, 130.9, 128.9, OCH3), 3.84 (m), 3.64 (m), 3.60 (m), 3.45 (m), 3.36 (m), 3.12 (m),
128.8, 128.6, 128.3, 127.7, 127.4, 126.7, 111.9, 111.1, 67.5, 64.3,
2.90 (m), 2.80 (m), 2.73 (m), 2.63 (m), 2.56 (m), 2.25 (m), 2.15 (m),
56.1, 55.8, 47.1, 41.1, 37.6, 34.9, 28.6 ppm. LSIMS (ϩ, 8 kV): 2.01 (m), 1.89 (m), 1.77 (m), 1.74 (m), 1.63 (m), 1.55 (m), 1.27 (m),
m/z (%) ϭ 471 [M ϩ H]ϩ (29), 379 (40), 365 (2), 329 (3), 279 (4),
1.16 (m) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 197.5, 196.4,
176 (11).
171.2, 170.0, 166.3, 165.2, 164.1, 164.0, 149.1, 149.0, 148.9, 147.7,
Eur. J. Org. Chem. 2003, 2443Ϫ2453
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2451

Z. Czarnocki et al.
FULL PAPER
147.7, 147.6, 133.6, 132.9, 132.0, 131.9, 131.3, 131.1, 130.4, 130.1,
34.5, 29.6, 28.6, 21.0 ppm. EI-MS (5 kHz, M ϭ 407.20 for
129.8, 128.9, 128.6, 128.5, 127.8, 127.6, 127.2, 120.9, 120.7, 120.6, C24H26N2O4): m/z (%) ϭ 315 [M Ϫ C7H7]ϩ (100), 287 (33), 190
112.3, 112.1, 112.0, 111.4, 111.4, 111.3, 86.6, 70.3, 61.2, 60.5, 59.1,
56.0, 55.9, 55.9, 55.9, 55.9, 55.9, 47.9, 47.2, 46.2, 45.6, 45.5, 45.4,
44.2, 43.5, 41.0, 40.9, 35.7, 35.6, 35.2, 35.1, 32.0, 30.2, 29.5, 27.2,
26.9, 25.5, 25.0, 24.1, 22.2, 22.0 ppm. EI-MS (M ϭ 424.49 for
C24H28N2O5): m/z (%) ϭ 424 [M]ϩ (6), 164 (100), 151 (9), 91 (20),
70 (23).
(20), 175 (7), 91 (3).
(2S)-1-[3-(3-Chlorophenyl)-2-oxopropanoyl]-N-[2-(3,4-dimethoxy-
phenyl)ethyl]pyrrolidine-2-carboxamide (10b): The procedure de-
scribed for the synthesis of 4d was applied to 9a (254 mg,
0.92 mmol) and provided 10b (274 mg, 65%) as an oil: [α]2D3
ϭ
1
Ϫ37.5 (c ϭ 1.0, CHCl3). H NMR (500 MHz, CDCl3); two stable
conformers present and a compound without a carbonyl group:
δ ϭ 8.07 (br. t, 1 H, NH), 7.30Ϫ7.19 (m, Harom), 7.17Ϫ7.12 (m,
Harom), 6.90 (m, Harom), 6.84Ϫ6.64 (m, Harom), 6.56 (br. t, 1 H,
NH), 5.62 (br. t, 1 H, NH), 4.52 (m), 4.48 (m), 4.30 (m), 4.05 (m),
3.89, 3.88, 3.87, 3.86, 3.84, and 3.83 (six s, 3 H each, 6 ϫ OCH3),
3.70Ϫ3.59 (m), 3.58Ϫ3.53 (m), 3.52Ϫ3.45 (m), 3.40Ϫ3.30 (m), 3.08
(m), 3.00Ϫ2.96 (m), 2.91Ϫ2.84 (m), 2.82Ϫ2.65 (m), 2.62Ϫ2.52 (m),
2.29 (m), 2.15 (m), 2.00 (m), 1.84 (m) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 196.9, 195.7, 171.3, 171.2, 166.1, 165.6, 163.7, 163.1,
149.0, 149.0, 148.8, 147.7, 147.6, 147.6, 135.5, 135.3, 134.6, 134.3,
134.2, 133.4, 131.0, 130.4, 130.2, 129.9, 129.7, 129.6, 128.5, 128.4,
128.0, 127.9, 120.9, 120.7, 120.6, 112.2, 112.0, 112.0, 111.3, 111.3,
111.2, 61.1, 60.8, 60.4, 56.0, 55.9, 55.9, 55.9, 55.8, 55.7, 48.2, 47.5,
45.7, 45.4, 44.9, 44.7, 44.1, 40.9, 40.9, 35.6, 35.1, 35.0, 32.3, 29.6,
(8aS)-3-Benzyl-2-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxyhexa-
hydropyrrolo[1,2-a]pyrazine-1,4-dione (11a): The procedure de-
scribed for the synthesis of 5a was applied to 9a (1.2 g, 4.32 mmol)
providing 11a (127 mg, 6.2%) as an oil: 1H NMR (500 MHz,
CDCl3): δ ϭ 8.13 (m, 2 H, Harom), 7.59 (m, 1 H, Harom), 7.45 (m,
2 H, Harom), 6.80Ϫ6.70 (m, 3 H, Harom), 5.39 (br. s, 1 H, OH), 4.18
(m, 1 H, H-8a), 3.88 (m, 2 H, PhCH2), 3.85 and 3.84 (two s, 3 H
each, 2 ϫ OCH3), 3.71 (m, 1 H, NCHCH2CH2CH2), 3.52 (m, 1 H,
NCH2CH2), 3.43 (m, 1 H, NCH2CH2), 2.74 (m, 2 H, NCH2CH2),
2.48 (m,
1
H, NCHCH2CH2CH2), 2.12 (m,
1
H,
NCHCH2CH2CH2), 2.02 (m, 1 H, NCHCH2CH2CH2), 1.88 (m, 2
H, NCHCH2CH2CH2) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ
168.4, 163.1, 148.8, 147.5, 134.0, 133.4, 131.7, 130.2, 128.5, 120.8,
112.1, 111.2, 89.6, 60.8, 55.9, 55.8, 47.1, 44.3, 35.5, 35.0, 29.4, 22.8
ppm. M ϭ 424.49 for C24H28N2O5.
27.3, 22.4, 22.1, 21.1 ppm. LSIMS (ϩ) (M
ϭ 458.93 for
C24H27ClN2O5): m/z (%) ϭ 459 [M ϩ H]ϩ(15), 441 (14), 333 (11),
(8aS,13aRS)-13a-Benzyl-2,3-dimethoxy-5,8a,9,10,11,13a-hexa-
hydro-8H-pyrrolo[1Ј,2Ј:4,5]pyrazino[2,1-a]isoquinoline-8,13(6H)-
dione (12a): Following the procedure described for the synthesis of
6a, compound 10a (530 mg, 1.25 mmol) was converted into a mix-
ture of diastereoisomers 12a (320 mg, 60%; 92:8 ratio based on GC-
MS analysis of the crude reaction mixture). Preparative chromatog-
raphy on Al2O3 by using ethyl acetate/methanol (20:3) allowed the
separation of 12a into (8aS,13aS)-12a and (8aS,13aR)-12a.
316 (14), 277 (12), 164 (90), 81 (32).
(8aS,13aRS)-13a-(3-Chlorobenzyl)-2,3-dimethoxy-5,8a,9,10,11,13a-
hexahydro-8H-pyrrolo[1Ј,2Ј:4,5]pyrazino[2,1-a]isoquinoline-8,13-
(6H)dione (12b): Following the procedure described for the syn-
thesis of 6a, compound 10b (159 mg, 0.35 mmol) was converted
into a mixture of diastereoisomers 12b (80 mg, 51%; 93:7 ratio
based on GC-MS analysis of the crude reaction mixture): [α]2D3
ϩ96.5 (c ϭ 1.0, CHCl3).
ϭ
Major Diastereoisomer (8aS,13aS)-12a: M.p. 117Ϫ120 °C. [α]2D3
ϭ
Major Diastereoisomer (8aS,13aS)-12b: 1H NMR (500 MHz,
CDCl3): δ ϭ 7.87 (s, 1 H, Harom-1), 7.18Ϫ7.32 (m, 3 H, Harom),
7.00 (m, 1 H, Harom), 6.56 (s, 1 H, Harom-4), 4.99 (m, 1 H,
NCH2CH2), 4.00 and 3.87 (two s, 3 H each, 2 ϫ OCH3), 3.94 and
3.54 (qAB, 2 H, J ϭ 14.5 Hz, PhCH2), 3.57 (m, 1 H, NCH2CH2),
3.39 (m, 1 H, NCH2CH2), 2.86 (m, 2 H, NCHCH2CH2CH2), 2.62
(m, 1 H, NCH2CH2), 2.50 (dd, 1 H, J1 ϭ 11.0, J2 ϭ 6.0 Hz, H-
ϩ215.6 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3400Ϫ3550, 1650, 1550,
1
1450, 1350 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.89 (s, 1 H,
Harom-1), 7.28 (m, 3 H, Harom), 7.14 (m, 2 H, Harom), 6.56 (s, 1 H,
Harom-4), 4.99 (m, 1 H, NCH2CH2), 4.01 and 3.87 (two s, 3 H each,
2 ϫ OCH3), 3.56 and 3.36 (qAB, 2 H, J ϭ 13.5 Hz, PhCH2), 3.55
(m, 1 H, NCH2CH2), 3.32 (m, 1 H, NCH2CH2), 2.86 (m, 2 H,
NCHCH2CH2CH2), 2.62 (m, 1 H, NCH2CH2), 2.34 (dd, 1 H, J1 ϭ
10.7, J2 ϭ 5.7 Hz, H-8a), 2.12 (m, 1 H, NCHCH2CH2CH2), 1.83
(m, 1 H, NCHCH2CH2CH2), 1.64 (m, 1 H, NCHCH2CH2CH2),
1.57 (m, 1 H, NCHCH2CH2CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 166.7, 165.3, 148.4, 146.8, 135.0, 130.5, 130.5, 128.4,
128.4, 128.1, 127.9, 126.8, 114.0, 110.8, 68.2, 57.7, 56.2, 55.9, 46.9,
45.4, 36.9, 29.7, 29.3, 21.1 ppm. EI-MS (M ϭ 407.20 for
C24H26N2O4): m/z (%) ϭ 315 [M Ϫ C7H7]ϩ (100), 287 (33), 190
(20), 175 (7), 91 (3). HR EI: calcd. for C24H27N2O4 407.19708,
found 407.19651.
8a), 2.18 (m,
1 H, NCHCH2CH2CH2), 1.88 (m, 1 H,
NCHCH2CH2CH2), 1.67 (m, 2 H, NCHCH2CH2CH2) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 166.4, 165.0, 148.4, 146.8, 137.0,
134.4, 130.4, 129.7, 128.8, 128.1, 128.0, 126.3, 113.7, 110.7, 67.9,
57.8, 56.2, 55.8, 45.5, 46.4, 37.0, 29.8, 29.2, 21.1 ppm. EI-MS (M ϭ
440.92 for C24H25ClN2O4): m/z (%) ϭ 440 [M Ϫ H]ϩ (0.002), 315
(100), 287 (38), 190 (19), 175 (7), 91 (3).
Minor Diastereoisomer (8aS,13aR)-12b (selected data): 1H NMR
(500 MHz, CDCl3): δ ϭ 8.10 (s, 1 H, Harom-1), 7.18Ϫ7.32 (m, 3 H,
Harom), 6.87 (m, 1 H, Harom), 6.60 (s, 1 H, Harom-4), 5.02 (m, 1 H,
NCH2CH2), 3.89 and 3.88 (two s, 3 H each, 2 ϫ OCH3), 3.89 and
3.77 (qAB, 2 H, J ϭ 14.0 Hz, PhCH2), 2.72 (m, 1 H, H-8a), 0.57
(app. q, 1 H, NHCHCH2CH2CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 167.4, 165.0, 148.5, 147.4, 137.5, 134.2, 130.1, 129.6,
128.5, 128.4, 128.1, 126.3, 111.4, 109.9, 68.2, 58.1, 56.0, 55.9, 47.0,
45.3, 36.6, 29.9, 28.4, 21.0 ppm. EI-MS: m/z (%) ϭ 440 [M Ϫ H]ϩ
(0.6), 315 (20), 287 (9), 164 (100), 151 (12), 91 (3).
Minor Diastereoisomer (8aS,13aR)-12a: 1H NMR (500 MHz,
CDCl3): δ ϭ 8.16 (s, 1 H, Harom-1), 7.28 (m, 3 H, Harom), 7.14 (m,
2 H, Harom), 6.61 (s, 1 H, Harom-4), 5.07 (ddd, 1 H, J1 ϭ 12.8, J2 ϭ
5.7, J3 ϭ 0.7 Hz, NCH2CH2), 3.97 and 3.88 (two s, 3 H each, 2 ϫ
OCH3), 3.74 and 3.34 (qAB, 2 H, J ϭ 13.8 Hz, PhCH2), 3.77 (m, 1
H, NCHCH2CH2CH2), 3.72 (m, 1 H, NCH2CH2), 3.57 (m, 1 H,
NCH2CH2), 3.08 (m, 1 H, NCHCH2CH2CH2), 2.73 (dd, 1 H, J1 ϭ
15.7, J2 ϭ 2.8 Hz, NCH2CH2), 2.12 (dd, 1 H, J1 ϭ 12.0, J2
ϭ
6.5 Hz, H-8a), 2.01 (m, 1 H, NCHCH2CH2CH2), 1.86 (m, 1 H, X-ray Data for (3S,11bR)-6d: C23H25ClN2O4, Mr ϭ 428.90, ortho-
˚
NCHCH2CH2CH2), 1.57 (m, 1 H, NCHCH2CH2CH2), 0.39 (app
rhombic P212121, a ϭ 7.2867(15), b ϭ 10.430(2), c ϭ 27.795(6) A,
q, 1 H, NCHCH2CH2CH2) ppm. 13C NMR (125 MHz, CDCl3): α ϭ β ϭ γ ϭ 90°, V ϭ 2112.5(7) A , Z ϭ 4, ρx ϭ 1.349 g·cmϪ3
,
3
˚
δ ϭ 165.0, 164.7, 148.4, 147.4, 135.5, 130.3, 130.3, 128.3, 128.3,
127.9, 127.4, 126.4, 111.4, 110.3, 68.4, 58.7, 56.0, 55.1, 47.6, 45.2, tion: Kuma KM4 κ-axis diffractometer, λ(Mo-Kα) ϭ 0.71073 A,
F(000) ϭ 904, µ(Mo-Kα) ϭ 0.213 mmϪ1, T ϭ 293 K. Data collec-
˚
2452
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2443Ϫ2453

Diastereoselective Synthesis of 1-Benzyltetrahydroisoquinoline Derivatives
FULL PAPER
[21]
E. N. Jacobsen, Synthesis 1996, 792Ϫ815 and references ther-
ein.
S. Laabs, W. Münch, J. W. Bats, V. Nubbemeyer, Tetrahedron
2002, 58, 1317Ϫ1334.
V. A. Soloshonok, X. Tang, V. J. Hruby, Tetrahedron 2001,
57, 6375Ϫ6382.
G. M. Coppola, H. F. Schuster, Asymmetric Synthesis: Con-
struction of Chiral Molecules Using Amino Acids, John Wiley &
Sons, New York, 1987.
T. Itoh, K. Nagata, M. Miyazaki, K. Kameoka, A. Ohsawa,
Tetrahedron 2001, 57, 8827Ϫ8839.
T. Itoh, Y. Matsuya, Y. Enomoto, A. Ohsawa, Tetrahedron
2001, 57, 7277Ϫ7289.
H. Waldmann, G. Szmidt, Tetrahedron 1994, 50, 11865Ϫ11884.
Z. Czarnocki, J. B. Mieczkowski, Pol. J. Chem. 1995, 69,
1447Ϫ1450.
A preliminary account of this work has been published. See:
A. Zawadzka, A. Leniewski, J. K. Maurin, K. Wojtasiewicz, Z.
Czarnocki, Org. Lett. 2001, 3, 997Ϫ999.
colorless crystals 0.2ϫ0.25ϫ0.45 mm, unit cell parameters by least-
squares for 25 reflections with 15.6 Ͻ 2θ Ͻ 18.2°, 2978 data col-
[22]
lected, 1335 with I Ն 2σ(I). Structure solution and refinement: di-
rect methods (SHELXS-97[42]), least-squares on F2 (SHELXL-
[23]
97[43]), final R ϭ 0.0501 and wR ϭ 0.1562 (observed reflections).
Several weak CHϪO hydrogen bonds were detected involving mol-
ecules related by translation along the a direction. Benzyl rings of
the neighbouring molecules are in a stacking arrangement.
[24]
[25]
CCDC-166095 (12a) and -207277 (6d) contain the supplementary
crystallographic data. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
[26]
[27]
[28]
[29]
[1]
J. Lundstorom, The Alkaloids, Vol. 21 (Ed.: A. Brossi), Aca-
[30]
[31]
G. E. Krejcarek, B. W. Dominy, R. G. Lawton, J. Chem. Soc.,
Chem. Commun. 1968, 1450Ϫ1452.
H. Hiemstra, W. N. Speckamp, in The Alkaloids (Ed.: A.
Brossi), Academic Press, New York, 1988, Vol. 32, pp.
271Ϫ339.
B. E. Maryanoff, D. F. McComsey, B. A. Duhl-Emswiler, J.
Org. Chem. 1983, 48, 5062Ϫ5074.
demic Press, New York, 1983, pp. 255Ϫ327.
M. A. Collins, The Alkaloids, Vol. 21 (Ed.: A. Brossi), Aca-
[2]
demic Press, New York, 1983, pp. 329Ϫ358.
A. Brossi, The Alkaloids, Vol. 43 (Ed.: G. A. Cordell), Aca-
[3]
demic Press, San Diego, 1993, pp. 119Ϫ183.
Z. Czarnocki, D. B. MacLean, W. A. Szarek, Can. J. Chem.
[32]
[33]
[34]
[35]
[4]
1986, 64, 2205Ϫ2210.
Z. Czarnocki, D. B. MacLean, W. A. Szarek, Bull. Soc. Chim.
[5]
D. L. Comins, M. M. Badwi, Tetrahedron Lett. 1991, 32,
2995Ϫ2996.
Belg. 1986, 95, 749Ϫ770.
[6]
K. T. Wanner, H. Beer, G. Hofner, M. Ludwig, Eur. J. Org.
Chem. 1998, 2019Ϫ2029 and references therein.
Castro’s reagent is benzotriazol-1-yl-oxy-tris(dimethylamino)-
phosphoniumhexafluorophosphate. See: B. Castro, G. Evin, C.
Selve, R. Seyer, Tetrahedron Lett. 1975, 1219.
The numbering mode for compounds 6 in Scheme 1 is shown
in Figure 1 and is based on IUPAC rules.
We thank the referee of this paper for this suggestion.
The ratio of S:R Ն 99.5:0.5 was determined on a ChiraDex
column (Merck).
E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797Ϫ1842 and
references therein.
[7]
X. Liu, J. M. Cook, Tetrahedron Lett. 2000, 41, 6299Ϫ6303.
[8]
S. Yu, O. M. Berner, J. M. Cook, J. Am. Chem. Soc. 2000,
122, 7827Ϫ7828.
[36]
[9]
T. Wang, J. M. Cook, Org. Lett. 2000, 2, 2057Ϫ2059.
[10]
P. Yu, T. Wang, J. Li, J. M. Cook, J. Org. Chem. 2000, 65,
[37]
[38]
3173Ϫ3191.
[11]
Z. Arazny, Z. Czarnocki, Tetrahedron: Asymmetry 2000, 11,
2793Ϫ2800.
[39]
[40]
[12]
The numbering scheme of 12a and 12b is shown in Figure 2
and is based on IUPAC rules.
T. Wirth, G. Fragale, Synthesis 1998, 162.
[13]
B. Wunsch, S. Nerdinger, Tetrahedron Lett. 1995, 36, 8003.
[14]
The PictetϪSpengler cyclization appears to be non-reversible
which, in turn, causes relative configurational stability of 1-
substituted tetrahydroisoquinolines [M. Shamma, The Isoquin-
oline Alkaloids. Chemistry and Pharmacology, Academic Press,
1972, chapter 2]. We believe that this non-reversibility is also
valid in our case. Pure diastereoisomers of the final diketopip-
erazines were subjected to multi-hour heating under reflux with
HCl/H2O (1:1) after which time we were not able to detect any
epimerization or hydrolysis products (unpublished results).
L. F. Tietze, Y. Zhou, E. Töpken, Eur. J. Org. Chem. 2000,
2247Ϫ2252.
[15]
G. J. Meuzelaar, R. A. Sheldon, Eur. J. Org. Chem. 1999,
2315Ϫ2321.
D. Taniyama, M. Hasegawa, K. Tomioka, Tetrahedron: Asym-
[16]
metry 1999, 10, 221Ϫ223.
T. Morimoto, N. Suzuki, K. Achiwa, Tetrahedron: Asymmetry
[17]
1998, 9, 183Ϫ187.
J. Kang, J. B. Kim, K. H. Cho, B. T. Cho, Tetrahedron: Asym-
[18]
[41]
[42]
[43]
The value of 1 e.u. is 627.51 kcal molϪ1
.
metry 1997, 8, 657Ϫ660.
Y. Ukaji, Y. Kenmoku, K. Inomata, Tetrahedron: Asymmetry
[19]
G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467Ϫ473.
G. M. Sheldrick, SHELXL-97 Program for X-ray Structure Re-
finement, University of Göttingen, Germany, 1997.
Received December 17, 2002
1996, 7, 53Ϫ56.
[20]
F. J. Sardina, H. Rapoport, Chem. Rev. 1996, 96, 1825Ϫ1872
and references therein.
Eur. J. Org. Chem. 2003, 2443Ϫ2453
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2453