Synthesis and antitrypanosomal activity of 2-aminomethyl-1-(2-oxyphenyl) naphthalenes

Article abstract of DOI:10.1016/j.tet.2004.05.076

A broad variety of enantiopure axially chiral 2-aminomethyl-1-(2-oxyphenyl) naphthalenes were prepared via short and efficient synthetic pathways by using the 'lactone method' for the regio- and stereoselective construction of the biaryl axis. Their in vi

Full text of DOI:10.1016/j.tet.2004.05.076

Tetrahedron 60 (2004) 6335–6344
Synthesis and antitrypanosomal activity
of 2-aminomethyl-1-(2-oxyphenyl)naphthalenesq
a
a
a
Gerhard Bringmann,a Robert-Michael Pfeifer, Petra Schreiber, Kristina Hartner,
,
*
Nikolaus Kocher,b Reto Brun,c Karl Peters,d Eva-Maria Petersd and Matthias Breuninga
a
¨
¨
¨
¨
Institute of Organic Chemistry, University of Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
b
Institute of Inorganic Chemistry, University of Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
cSwiss Tropical Institute, Socinstr. 57, CH-4002 Basel, Switzerland
dMax Planck Institute for Solid State Research, Heisenbergstraße 1, D-70506 Stuttgart, Germany
Received 26 December 2003; revised 21 May 2004; accepted 21 May 2004
Dedicated to Professor Dr. Helmut Quast on the occasion of his 70th birthday
Abstract—A broad variety of enantiopure axially chiral 2-aminomethyl-1-(2-oxyphenyl)naphthalenes were prepared via short and efficient
synthetic pathways by using the ‘lactone method’ for the regio- and stereoselective construction of the biaryl axis. Their in vitro activity
against Trypanosoma cruzi, the causative agent of Chagas’ disease, was evaluated. In particular, the M-configured atropisomers, with the
2-oxy function equipped with an O-triflate group, were found to exhibit good antitrypanosomal activities (down to IC50¼1.6 mg/mL),
combined with low levels of cytotoxicity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Chagas’ disease (American trypanosomiasis), caused by the
parasitic protozoa Trypanosoma cruzi, is a serious threat to
people living in Central and South America, where it is
endemic in 21 countries.1 According to the World Health
Organization (WHO), a total of 16–18 million people are
infected, causing ca. 50.000 casualties a year, and 100
million, that is, one fourth of the population of these
countries, are at risk.1 Current treatments of Chagas’ disease
are based on nifurtimox (1)2,3 or benznidazol (2)4–6 (Fig. 1).
These two compounds show poor clinical efficiency and
cause numerous unfavorable side effects, like nausea, skin
rashes, peripheral neuritis, bone-marrow depression,
weight loss, and sleeping disorders.7 All this emphasizes
the necessity to develop new drugs for the treatment of
Chagas’ disease.
We have recently discovered a new class of natural
products with, in part, high antitrypanosomal activities,
the naphthylisoquinoline alkaloids like, for example,
q Part 109 in the series ‘Novel Concepts in Directed Biaryl Synthesis’, for
part 108, see Ref. 20.
Keywords: Axially chiral biaryls; Atropisomerism; Asymmetric synthesis;
Antitrypanosomal activity; Chagas’ disease.
Figure 1. Nifurtimox (1) and benznidazol (2), drugs currently used for the
treatment of Chagas’ disease, the likewise antitrypanosomal naphthyliso-
quinoline alkaloids dioncophylline A (3) and ancistrotanzanine B (4), and
general structure of the simplified target structures 5.
*
Corresponding author. Tel.: þ49-931-8885323; fax: þ49-931-8884755;
e-mail address: bringman@chemie.uni-wuerzburg.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.076

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G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
dioncophylline A (3) and ancistrotanzanine B (4), which
show low IC50 values against T. cruzi of 0.70 and 1.5 mg/
mL, respectively. Although total synthetic pathways have
been developed, thus making these and other naphthyliso-
quinolines accessible,8 there is urgent demand for the search
of even more active analogs with simpler and thus easier-to-
access structures. This prompted us to synthesize a variety
of closely related biaryls in order to establish structure–
activity relationships. In this paper, we report on a group of
related, still axially chiral, but simplified 2-aminomethyl-1-
(2-oxyphenyl)naphthalenes of type 5, some of which exhibit
excellent antitrypanosomal activities, in particular their
O-triflate derivatives.
2. Results and discussion
2.1. Chemistry
All biaryls were synthesized in a stereochemically homo-
geneous form, by using the ‘lactone method’.8 The
stereochemical key step of this procedure is the atropo-
enantioselective ring cleavage of configurationally unstable
biaryl lactones like 6 (Scheme 1), here with the sodium salt
of (1R)-phenylethylamine [(R)-7], yielding the dia- and
enantiomerically pure biaryl amide (M,R)-8 in 84% yield.9
O-Isopropylation of the phenolic hydroxy function of
(M,R)-8 delivered the protected amide (M,R)-9; its antici-
pated structure and absolute configuration were confirmed
by X-ray diffraction analysis. N-Methylation of (M,R)-9,
reduction of the amide function, and deprotection of the
phenolic OH group delivered the biaryl amide (M,R)-12.
Scheme 1. Synthesis of the enantiopure biaryl aminophenol (M,R)-12 and
molecular structure of (M,R)-9·EtOH (hydrogen atoms omitted for reasons
of clarity).
The secondary biaryl amines (M,R)-16 and (M,S)-16 were
prepared by amination of the enantiopure O-benzylated
bromide (M)-1410 with (R)- or (S)-phenylethylamine
[(R)-7 or (S)-7] and subsequent deprotection of the
phenolic oxygen function with BCl3 (Scheme 2). The
derivative (M)-13, with the biaryl axis as the only element of
chirality, was synthesized by treatment of (M)-14 with
benzylamine.
Table 1. Antitrypanosomal activities and cytotoxicities
Compound IC50 [mg/mL] T. cruzi IC50/MIC [mg/mL] cytotoxicity (L6)
Standard
(M,R)-9
(M)-13
0.4a
5.8
0.005b
92
7.2
Starting from (M,R)-12 and (M,R)-16, a series of differently
O-functionalized biaryl amines were synthesized, using
established standard procedures (Scheme 3). O-Sulfonyl-
ation of the tertiary biaryl amine (M,R)-12 provided (M,R)-
17, (M,R)-18, and (M,R)-19 (for its molecular structure, see
Fig. 2), and acylation with Mosher acid gave (M,R)-20. The
MOM ether (M,R)-21 and the acetate (M,R)-22 were
prepared from the secondary amine (M,R)-16.
5.6
(M,R)-15
(M,S)-15
(M,S)-16
(M,R)-17
(M,R)-18
(M,R)-19
(M,S)-19
(P,R)-19
(P,S)-19
(M,R)-20
(M,R)-21
(M,R)-22
(M,R)-24
(M,S)-24
(P,R)-24
(P,S)-24
(M)-25
42.9
4.6
1.8
.90
.90
10
14.5
37.8
2.5
)1.6
11.3
49.5
10.9
2.1
1.4
2.4
5.3
1.4
.90
n.e.c
.90
).90
.90
n.e.c
.90
11.7
2.8
Since the initial screening against T. cruzi had provided the
aminotriflate (M,R)-19 as the most active compound (see
Table 1, Section 2.2), we synthesized several structurally
related biarylic triflates. For an investigation of the influence
of the two elements of chirality, the biaryl axis and the
benzylic stereocenter, we prepared, exemplarily for 19, all
of its four stereoisomers, (M,R)-19 (also accessible from
(M,R)-12, see Scheme 3), (M,S)-19, (P,S)-19, and (P,R)-19,
from the O-methylated bromides (M)-23 and (P)-2311 by
amination and subsequent O-deprotection and O-triflation
(Scheme 4). In order to investigate whether the stereocenter
in the N-containing side chain is necessary, we analogously
14.1
n.e.c
5.5
3.4
8.5
2.9
4.6
n.e.c
n.e.c
n.e.c
67
(P)-25
(M)-26
(P)-26
9.0
.90
a
Benznidazole (2).
Podophyllotoxin.
N.e.¼not evaluated.
b
c

G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
6337
Scheme 2. Synthesis of the secondary biaryl amines (M)-13, (M,R)-16, and (M,S)-16.
Scheme 3. Synthesis of (M,R)-17–22. (a) p-Toluenesulfonic acid, NEt3; (b) p-bromophenylsulfonic acid, NEt3; (c) Tf2O, DABCO; (d) (R)-Mosher acid, DCC,
DMAP; (e) MOMCl, NaH; (f) AcCl, pyridine.
synthesized the exclusively axially chiral amines (M)-26
and (P)-26.
2.2. Antitrypanosomal activity
The 2-aminomethyl-1(2-oxyphenyl)naphthalene derivatives
thus synthetically available were evaluated against T. cruzi
using rat skeletal myoblasts (L-6 cells) in vitro. The results
are summarized in Table 1. Good antitrypanosomal
activities with IC50 values ,3 mg/mL were found for the
biaryls (M,S)-16, (M,R)-19, (M,S)-19, (M,R)-21, (M,R)-22,
(M,R)-24, (P,R)-24, and (P)-25. Since these compounds
possess different substituents on the phenolic oxygen (Me,
MOM, Ac, Tf), the substitution pattern at this site does not
Figure 2. Molecular structure of (M,R)-19 in the crystal (hydrogen atoms
omitted for reasons of clarity).

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G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
Scheme 4. Synthesis of the enantio- and diastereomerically pure triflates 19 and 26. (a) N-methylbenzylamine; (b) (S)-N-methyl-1-phenylethylamine;
(c) (R)-N-methyl-1-phenylethylamine; (d) 1. HBr; 2. Tf2O, DABCO.
seem to be essential for attaining high antitrypanosomal
activities. The levels of cytotoxicity of these biaryls, by
contrast, are significantly influenced by the nature of this
substituent: Only the O-triflate derivatives (M,R)-19 and
(M,S)-19 were virtually non-toxic (IC50/MIC.90 mg/mL)
and exhibited quite promising activity-to-cytotoxicity ratios
of more than 35 and 55, respectively. The stereochemical
orientation at the biaryl axis plays an important role, too:
In the case of the O-triflate derivatives 19 and 26, the
M-configured biaryls were always more active than their
P-atropisomers, for example, (M,S)-19: IC50¼1.6 mg/mL
vs. (P,S)-19: IC50¼49.5 mg/mL, while for the O-alkyl
substituted compounds 24 and 25, the opposite behavior
was observed. No such trend is obvious for the stereogenic
center in the N-alkyl side chain. Nevertheless, the increased
steric demand of the N-1-phenylethyl group compared to
that of the N-benzyl moiety seems to be advantageous, as
deduced from their higher activities, for example, (M,S)-19
(IC50¼1.6 mg/mL) and (M,R)-19 (IC50¼2.5 mg/mL) vs.
(M)-26 (IC50¼4.6 mg/mL). Thus, the most promising
derivative found within these investigations is the very
active and virtually nontoxic, axially chiral and, simul-
taneously, centrochiral biaryl (M,S)-19 (IC50¼1.6 mg/mL)
possessing an O-triflate substituent and the N21-phenyl-
ethyl side chain.
3. Conclusion
Axially chiral 2-aminomethyl-1-(2-oxyphenyl)naphthalene

G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
6339
derivatives have proven to be easily prepared in short,
directed synthetic sequences, leading to enantio- and
diastereomerically pure material. Several representatives
of this class of compounds possess significant activities
against the protozoan parasite T. cruzi, without any notable
cytotoxicities. The as yet most promising compound is the
O-triflated aminophenol (M,S)-19, which provides a good
antitrypanosomal activity of IC50¼1.6 mg/mL combined
with a low level of cytotoxicity (IC50/MIC.90 mg/mL),
now making in vivo experiments a rewarding goal. This
work is under investigation.
methyl-N-(1-phenylethyl)naphthalene-2-carboxamide
[(M,R)-10]. A suspension of the amide (M,R)-9 (1.32 g,
2.94 mmol), MeI (19.8 mL, 835 mg, 5.88 mmol), NaOH
(2.41 g, 60.3 mmol), NBu4I (109 mg, 294 mmol), and
K2CO3 (4.90 g, 1.23 mmol) in benzene (80 mL) was
refluxed for 3 d. Aqueous NH3 (2 N, 30 mL) was added at
room temperature. After 30 min of stirring, the solvent was
removed in vacuo, the residue was taken up in diethyl ether
(30 mL) and filtered through a plug of celite. The crude
product was purified by column chromatography (petroleum
ether/diethyl ether¼5:1) yielding (M,R)-10 as white crys-
1
tals; mp 156–158 8C. [a]2D0¼þ237.2 (c 1.0, CHCl3). H
NMR (CDCl3, 250 MHz): 5:1-mixture of interconverting
rotational isomers with respect to the N–CvO–bond;
major isomer: d 7.91–7.86 (m, 2H), 7.51–7.29 (m, 4H),
7.19–7.16 (m, 3H), 6.83 (br., 3H), 6.62 (s, 1H), 6.02 (q,
J¼7.0 Hz, 1H), 4.25 (sept., J¼6.1 Hz, 1H), 2.49 (s, 6H),
2.05 (s, 3H), 1.55 (d, J¼7.0 Hz, 3H), 0.77 (d, J¼6.1 Hz,
3H), 0.71 (d, J¼6.1 Hz, 3H); minor isomer: d 7.81–7.74 (m,
2H), 6.67 (s, 1H), 5.16 (q, J¼7.0 Hz, 1H), 4.40 (sept., J¼
6.1 Hz, 1H), 2.41 (s, 6H), 2.07 (s, 3H), 0.98 (d, J¼6.1 Hz,
3H), 0.86 (d, J¼6.1 Hz, 3H). 13C NMR (CDCl3, 63 MHz):
major isomer: d 171.2, 155.6, 141.6, 140.3, 138.4, 138.2,
133.1, 132.9, 132.4, 128.5, 127.8, 127.4, 127.0, 126.4,
126.2, 126.0, 125.9, 124.3, 123.5, 123.0, 110.6, 69.3, 49.4,
30.9, 21.9, 21.7, 21.5, 20.4, 15.4; minor isomer: d 171.9,
140.6, 140.2, 134.5, 133.1, 132.6, 127.9, 127.1, 126.7,
126.6, 124.0, 123.5, 111.3, 69.9, 55.6, 27.8, 22.8, 22.0, 21.5,
19.3. IR (KBr): n 3025, 2973, 2922, 1635, 1618, 1449, 1312,
1117, 1083, 817, 758, 703, 597 cm21. MS: m/z 451 (Mþ,
73), 408 (8), 392 (4), 274 (100). Anal. calcd for C31H33NO2:
C, 82.45; H, 7.36; N, 3.10; found C, 81.69; H, 7.06; N, 2.99.
4. Experimental
4.1. General
Melting points were determined with a Kofler melting point
apparatus and are uncorrected. Optical rotations were
measured with a Perkin–Elmer polarimeter. IR spectra
were scanned from KBr pellets or neat using a Perkin–
Elmer spectrophotometer model 1420. H and 13C NMR
1
spectra were recorded with a Bruker AC 250 (250 MHz) or a
Bruker Avance 400 (400 MHz) instrument using the
deuterated solvent as an internal reference; J values are
given in Hertz. Elemental analyses were performed in the
Institute of Inorganic Chemistry of the University of
Wu¨rzburg. Mass spectra were measured on a Finnigan
MAT 2000 mass spectrometer at 70 eV. All reactions with
moisture and/or air sensitive materials were carried out with
flame-dried glassware using the Schlenk tube technique
under inert argon atmosphere. The enantiopure biaryls
(M,R)-89 and (M)-1410 were synthesized according to
literature procedures. The melting points and elemental
analyses of some of the amines were measured using their
hydrochlorides or hydrobromides, which were prepared by
treatment of an ethereal solution of the free amine with
gaseous HCl or aqueous HBr.
4.1.3. (M,R)-1-(2-Isopropoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,R)-11]. To a solution of (M,R)-10 (1.36 g, 2.94 mmol)
in THF (80 mL), LAH (1.12 g, 29.4 mmol) was added and
the reaction was stirred for 3 h. After hydrolysis with 0.1 N
HCl (20 mL), the aqueous phase was extracted with diethyl
ether (100 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. Purification of the
residue by chromatography on silica gel (petroleum ether/
diethyl ether¼3:1!diethyl ether) afforded (M,R)-11
(1.23 g, 2.65 mmol, 90%) as a colorless oil; [a]2D0¼þ23.8
(c 1.25, CHCl3). 1H NMR (250 MHz, CDCl3): d 7.86–7.80
(m, 3H), 7.40–7.10 (m, 8H), 6.76 (s, 1H), 6.64 (s, 1H), 4.21
(sept., J¼6.1 Hz, 1H), 3.49 (q, J¼6.7 Hz, 3H, NCHCH3),
3.38 (d, J¼14 Hz, 1H), 3.31 (d, J¼14 Hz, 1H), 2.42 (s, 3H),
2.02 (s, 3H), 1.77 (s, 3H), 1.24 (d, J¼6.7 Hz, 3H), 0.85 (d,
J¼6.1 Hz, 3H), 0.76 (d, J¼6.1 Hz, 3H). 13C NMR (63 MHz,
CDCl3): d 155.7, 145.4, 138.6, 137.7, 136.2, 134.3, 132.6,
128.0, 127.7, 127.5, 126.9, 126.7, 126.5, 125.9, 125.3,
125.1, 124.7, 122.7, 111.8, 69.5, 63.2, 56.3, 38.8, 30.9, 21.8,
21.7, 20.0, 18.1. IR (neat): n 3050, 2970, 1605, 1450, 1308,
1114, 1069, 817, 760, 698 cm21. MS: m/z 437 (70, Mþ),
422 (73), 332 (34), 303 (95), 259 (100), 43 (3). MS (EI)
exact mass calcd for: C31H35NO: 437.2719; found
437.2711.
4.1.1. (M,R)-1-(2-Isopropoxy-4,6-dimethylphenyl)-N-(1-
phenylethyl)naphthalene-2-carboxamide [(M,R)-9]. A
suspension of (M,R)-8 (1.16 g, 2.94 mmol), isopropyl iodide
(1.18 mL, 11.8 mmol), and Cs2CO3 (1.92 g, 5.88 mmol) in
acetone (120 mL) was stirred for 2 d at room temperature.
The inorganic salts were removed by filtration and the
residue was chromatographed on silica gel (petroleum
ether/diethyl ether¼10:1!1:1) yielding (M,R)-9 (1.22 g,
2.79 mmol, 95%) as colorless crystals; mp 143 8C. [a]2D0¼
216.4 (c 1.3, CHCl3). 1H NMR (CDCl3, 250 MHz): d
7.92–7.85 (m, 3H), 7.60–7.21 (m, 6H), 6.91–6.84 (m, 4H),
6.60 (d, J¼6.0 Hz, 1H), 5.12 (sept., J¼6.1 Hz, 1H), 4.37
(qui., J¼6.1 Hz, 1H), 2.49 (s, 3H), 1.76 (s, 3H), 1.45 (d,
J¼6.9 Hz, 3H), 1.10 (d, J¼6.1 Hz, 3H), 0.92 (d, J¼6.1 Hz,
3H). 13C NMR (CDCl3, 63 MHz): d 168.6, 155.0, 143.1,
139.2, 138.8, 134.1, 134.0, 132.9, 132.1, 128.1, 127.9,
127.6, 126.7, 126.5, 126.3, 126.2, 126.0, 125.6, 124.8,
123.9, 112.1, 70.3, 49.1, 22.4, 21.7, 21.7, 21.5, 19.7. IR
(KBr): n 3447, 2928, 1649, 1519, 1102, 805 cm21. MS: m/z
437 (Mþ, 26), 274 (100), 259 (9), 120 (22). Anal. calcd for
C30H31NO2: C, 82.34; H, 7.14; N, 3.20; found C, 81.82; H,
7.24; N, 2.94.
4.1.4. (M,R)-1-(2-Hydroxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,R)-12]. (M,R)-11 (524 mg, 1.20 mmol) was dissolved
in HBr (20 mL, 48% in HOAc) and heated to reflux
4.1.2. (M,R)-1-(2-Isopropoxy-4,6-dimethylphenyl)-N-

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G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
overnight. The solvent was removed under reduced
pressure, and the residue was dissolved in MeOH (20 mL)
and filtered through a plug of basic alumina (activity 3).
Purification by column chromatography (silica gel, petro-
leum ether/ethyl acetate¼1:1) gave (M,R)-12 (430 mg,
1.09 mmol, 91%) as a yellow oil; [a]2D0¼225.8 (c 1.2,
127.0, 126.7, 126.1, 125.5, 125.2, 120.7, 63.5, 56.7, 38.4,
21.3, 20.0, 18.2. IR (neat): n 3060, 2970, 2925, 2846, 2782,
1641, 1620, 1576, 1453, 1374, 1281, 1190, 1092, 1068,
1027, 947, 788 cm21. MS: m/z: 615/613 (9/9, Mþ), 600/598
(25/23), 510/508 (7/7), 260 (100), 105 (39). MS (EI) exact
mass calcd for C34H32BrNO3S: 613.12862; found
613.12755.
1
CHCl3). H NMR (400 MHz, acetone-d6): d 8.12 (s, br.,
1H), 7.91–7.88 (m, 2H), 7.78 (d, J¼12.8 Hz, 1H), 7.44–
7.19 (m, 8H), 6.61 (s, 2H), 3.59 (q., J¼6.8 Hz, 1H), 3.56 (d,
J¼12.1 Hz, 1H), 3.35 (d, J¼12.1 Hz, 1H), 2.36 (s, 3H), 2.07
(s, 3H), 1.71 (s, 3H), 1.26 (d, J¼6.8 Hz, 3H). 13C NMR
(100 MHz, acetone-d6): d 156.0, 144.5, 139.0, 138.7, 136.9,
135.3, 134.1, 133.9, 128.9, 128.8, 128.7, 128.0, 127.7,
126.7, 126.4, 126.1, 123.9, 123.2, 116.0, 64.2, 57.4, 38.8,
21.4, 20.2, 18.3. IR (neat): n 3057, 2971, 2913, 2846, 1614,
4.2.3. (M,R)-1-[2-(3,3,3-Trifluoro-2-methoxy-2-phenyl-
propanoyloxy)-4,6-dimethylphenyl]-2-[N-methyl-N-(1-
phenylethyl)aminomethyl]naphthalene [(M,R)-20].
A
solution of (M,R)-12 (50.0 mg, 126 mmol), (R)-Mosher
acid (32.1 mg, 138 mmol), 29.0 mg DCC (138 mmol), and a
catalytic amount of DMAP in dry dichloromethane (2 mL)
was stirred for 12 h. The precipitate was filtered off, the
mixture concentrated in vacuo and the crude product
purified by column chromatography (silica gel, diethyl
ether) to give (M,R)-20 (65.1 mg, 106 mmol, 84%) as a
yellow oil; [a]2D0¼þ4.0 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.79–7.85 (m, 3H), 7.18–7.43 (m, 9H), 7.12 (s,
1H), 7.03 (t, J¼7.8 Hz), 6.87 (s, 1H), 6.81 (d, J¼7.8 Hz),
3.40 (q, J¼6.6 Hz, 1H), 3.29 (d, J¼13.9 Hz, 1H), 3.24 (d,
J¼13.9 Hz, 1H), 2.77 (s, 3H), 2.46 (s, 3H), 1.91 (s, 3H),
1.86 (s, 3H), 1.11 (d, J¼6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 190.7, 165.0, 148.4, 144.7, 139.5, 138.6, 136.7,
132.7, 132.3, 131.8, 131.5, 129.7, 129.2, 129.0, 128.7,
128.1, 128.0, 127.8, 127.7, 127.5, 127.2, 126.9, 126.6,
126.2, 125.7, 125.4, 124.3, 119.7, 63.4, 56.4, 54.6, 38.6,
29.7, 29.0, 21.3, 19.8, 17.8. IR (neat): n 3060, 2930, 2854,
1763, 1741, 1712, 1652, 1620, 1508, 1495, 1451, 1360,
1346, 1267, 1228, 1185, 1120, 1080, 1032, 1002, 891, 864,
817, 764, 746, 727, 700 cm21. MS: m/z 611 (1, Mþ), 189
(17), 83 (100). MS (EI) exact mass calcd for C38H36F3NO3:
611.2647; found 611.2647.
1565, 1494, 1312, 1154, 1048, 838, 809, 762, 702 cm21
.
MS: m/z 395 (Mþ, 11), 380 (10), 291 (34), 303 (95), 259
(100). MS (EI) exact mass calcd for: C28H29NO 395.2256;
found 395.2257.
4.2. General procedure for the preparation of the
arylsulfonic esters (M,R)-17 and (M,R)-18
The aminoalcohol (M,R)-12 (1.0 equiv.) was treated at 0 8C
in dry dichloromethane [5 mL/mmol (M,R)-12] with
triethylamine (1.5 equiv.) and p-toluenesulfonic acid or
p-bromophenylsulfonic acid (1.1 equiv.). The reaction
mixture was stirred overnight and the solvent was removed
in vacuo. The crude product was chromatographed on silica
gel (petroleum ether/diethyl ether¼5:1) to give (M,R)-17 or
(M,R)-18.
4.2.1. (M,R)-2-[N-Methyl-N-(1-phenylethyl)aminomethyl]-
1-(2-(4-methylbenzenesulfonyloxy)-4,6-dimethyl-
phenyl)]naphthalene [(M,R)-17]. Yield: 53%. [a]2D0¼
1
þ17.1 (c 1.0, CHCl3). H NMR (400 MHz, acetone-d6): d
4.2.4. (M)-2-Bromomethyl-1-(2-methoxy-4,6-dimethyl-
phenyl)naphthalene [(M)-23]. A suspension of (M)-2-
hydroxymethyl-1-(2-hydroxy-4,6-dimethylphenyl)naphtha-
lene12 (320 mg, 1.15 mmol), methyl iodide (220 mL,
490 mg, 3.45 mmol), and Cs2CO3 (318 mg, 2.30 mmol)
in acetone (20 mL) was stirred for 12 h at room
temperature. The solvent was removed in vacuo and
the residue purified by column chromatography (silica
gel, petroleum ether/ ethyl ether¼10:1!1:1) to give a
colorless oil, which was dissolved in dichloromethane
(10 mL). PPh3 (520 mg, 1.98 mmol) and (CBrCl2)2
(646 mg, 1.98 mmol) were added. After 1 h of stirring,
the solvent was removed in vacuo and the resulting oil
was filtered through a plug of silica gel. Crystallization
from dichloromethane/petroleum ether delivered (M)-23
(350 mg, 986 mmol, 99%) as pale yellow needles; mp
148–149 8C. [a]D20¼þ35.1 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.87–7.84 (m, 2H), 7.64 (d,
J¼8.4 Hz, 1H), 7.47–7.43 (m, 1H), 7.34–7.30 (m, 2H),
6.82 (s, 1H), 6.71 (s, 1H), 4.41 (d, J¼9.8 Hz, 1H), 4.37
(d, J¼9.8 Hz, 1H), 3.60 (s, 3H), 1.83 (s, 3H), 1.49 (s,
3H). 13C NMR (100 MHz, CDCl3): d 157.2, 138.9,
138.6, 135.2, 133.3, 133.1, 132.5, 128.1, 127.5, 126.4,
126.2, 126.1, 123.4, 122.5, 109.3, 55.6, 33.1, 21.8, 19.9.
IR (KBr): n 3050, 3025, 2912, 1610, 1575, 1460, 1313,
1238, 830, 761 cm21. MS: m/z 356/354 (22/23, Mþ),
275 (100), 260 (47), 245 (26), 229 (21). Anal. calcd for
C20H19BrO: C, 67.61; H, 5.39; found C, 68.05; H, 5.67.
7.89 (s, 1H), 7.87 (s, 1H), 7.78 (d, J¼8.2 Hz, 1H), 7.44 (t,
J¼7.1 Hz, 1H), 7.31–7.23 (m, 8H), 7.01 (d, J¼8.4 Hz, 1H),
6.88–6.83 (m, 4H), 1.19 (d, J¼6.1 Hz, 3H), 3.41 (q, J¼
6.1 Hz, 1H), 3.35 (s, 2H), 2.49 (s, 3H), 2.27 (s, 3H), 1.94 (s,
3H), 1.81 (s, 3H). 13C NMR (400 MHz, acetone-d6): d
148.8, 145.6, 145.4, 140.5, 139.7, 137.4, 134.1, 133.6,
133.0, 132.5, 130.7, 130.1, 129.9, 128.9, 128.7, 128.5,
128.2, 127.8, 127.7, 127.5, 126.8, 126.3, 125.9, 120.7, 64.4,
57.5, 38.9, 21.5, 21.2, 20.2, 18.8. IR (neat): n 3058, 3029,
2973, 2924, 2844, 2782, 1618, 1598, 1493, 1451, 1370,
1284, 1191, 1178, 1155, 1093, 1027, 946, 855, 815, 777,
701, 669 cm21. MS: m/z 549 (Mþ, 19), 534 (41), 272 (7),
260 (100). MS (EI) exact mass calcd for C35H35NO3S:
549.2338; found 549.2338.
4.2.2. (M,R)-1-(2-(4-Bromobenzene sulfonyloxy-4,6-
dimethylphenyl)-2-[N-methyl-N-(1-phenylethyl)amino-
methyl]naphthalene [(M,R)-18]. Yield: 40%. [a]2D0¼
þ29.6 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
7.78–7.68 (m, 3H), 7.40 (t, J¼7.08 Hz, 1H), 7.32–7.26 (m,
5H), 7.24–7.19 (m, 2H), 7.12 (s, 1H), 6.98 (d, J¼8.5 Hz,
1H), 6.90 (d, J¼8.7 Hz, 2H), 6.65 (d, J¼8.6 Hz, 2H), 3.41
(q, J¼6.7 Hz, 1H), 3.33 (d, J¼13.9 Hz, 1H), 3.24 (d, J¼
13.9 Hz, 1H), 2.48 (s, 3H), 1.91 (s, 3H), 1.78 (s, 3H), 1.20
(d, J¼6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 147.7,
144.7, 139.7, 138.9, 136.7, 134.8, 132.4, 132.1, 131.3,
131.2, 129.4, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5,

G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
6341
4.2.5. (P)-2-Bromomethyl-1-(2-methoxy-4,6-dimethyl-
phenyl)naphthalene [(P)-23]. In an analogous way, (P)-
23 was prepared from (P)-2-hydroxymethyl-1-(2-hydroxy-
4,6-dimethylphenyl)naphthalene12 according to procedure
4.9. [a]2D0¼235.4 (c 1.0, CHCl3). All other spectroscopic
and physical data were identical to those of (M)-23.
acetone-d6): d 7.92–7.88 (m, 2H), 7.70 (d, J¼8.3 Hz, 1H),
7.45–7.41 (mc, 1H), 7.36–7.08 (m, 10H), 6.91–6.86 (m,
4H), 4.87 (s, 2H), 3.65 (q, J¼6.5 Hz, 1H), 3.49 (d, J¼
12.4 Hz, 1H), 3.42 (d, J¼12.4 Hz, 1H), 2.41 (s, 3H), 1.78 (s,
3H), 1.16 (d, J¼6.5 Hz, 3H). 13C NMR (100 MHz, acetone-
d6): d¼157.2, 147.0, 139.1, 138.5, 137.7, 133.9, 133.5,
129.0, 128.9, 128.5, 128.1, 127.9, 127.4, 127.33, 127.28,
126.6, 126.3, 126.0, 125.4, 124.4, 111.2, 70.4, 59.0, 51.0,
25.2, 21.7, 20.0. IR (neat): n 3400, 3012, 2999, 2915, 2895,
4.3. General procedure for the preparation of different
amines from the bromides (M)-14, (M)-23, and (P)-23
1592, 1577, 1478, 1300, 1258, 1082, 1019, 811, 692 cm21
.
To a solution of (M)-14, (M)-23, or (P)-23 in dichloro-
methane (2–4 mL/mmol bromide) the respective amine
(2.0 equiv.) was added. The reaction mixture was stirred
until complete conversion was detected by TLC (deacti-
vated silica gel, petroleum ether/diethyl ether¼5:1). The
solution was made alkaline with 2 N NaOH and was
exhaustively extracted with diethyl ether. The combined
organic layers were dried over MgSO4 and the solvent was
removed in vacuo. Purification of the crude product by
column chromatography (petroleum ether/diethyl
ether¼10:1) gave the desired amine.
MS: m/z 471 (Mþ, 43), 456 (23), 380 (29), 350 (43), 259
(100), 91 (84). Anal. calcd for C34H33NO·HBr: C, 73.91; H,
6.20; N, 2.53; found C, 73.96; H, 6.48; N, 2.69.
4.3.4. (M,R)-1-(2-Methoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,R)-24]. Yield: 84%. Characterized as the hydrochloride
(M,R)-24·HCl. Mp 141 8C (dichloromethane/petroleum
ether). [a]2D0¼221.7 (c 0.95, CHCl3). H NMR (400 MHz,
1
acetone-d6): d 7.89–7.87 (m, 3H), 7.43–7.39 (mc, 1H),
7.35–7.23 (m, 5H), 7.20–7.17 (m, 2H), 6.84 (s, 1H), 6.81
(s, 1H), 3.48 (s, 3H), 3.37 (d, J¼13.6 Hz, 1H), 3.31 (d,
J¼13.6 Hz, 1H), 2.42 (s, 3H), 2.02 (s, 3H), 1.75 (s, 3H),
1.21 (d, J¼6.6 Hz, 3H). 13C NMR (100 MHz, acetone-d6): d
158.2, 146.0, 139.1, 138.8, 137.0, 135.0, 133.8, 133.5,
128.9, 128.2, 127.9, 127.7, 127.4, 126.5, 126.2, 125.8,
124.6, 123.8, 110.0, 64.0, 57.1, 55.5, 39.1, 21.7, 20.0, 18.4.
IR (neat): n 2929, 2853, 1612, 1573, 1451, 1314, 1239,
1165, 1097, 1028, 941, 830, 814, 763, 701 cm21. MS: m/z
409 (Mþ, 40), 394 (45), 332 (7), 304 (19), 290 (17), 275
(100), 260 (38), 245 (18), 105 (25). Anal. calcd for
C29H31NO·HCl: C, 78.09; H, 7.23; N, 3.14; found C,
78.64; H, 7.32; N, 3.18.
4.3.1. (M)-1-(2-Benzyloxy-4,6-dimethylphenyl)-2-(N-
benzylaminomethyl)naphthalene [(M)-13]. Yield: 53%.
Characterized as the hydrobromide (M)-13·HBr. Mp 174 8C
(dichloromethane/petroleum ether). [a]2D0¼þ39.4 (c 0.9,
1
CHCl3). H NMR (400 MHz, actone-d6): d 7.92–7.90 (m,
2H), 7.81 (d, J¼8.6 Hz, 1H), 7.45–7.41 (mc, 1H), 7.36–
7.29 (m, 2H), 7.24–7.16 (m, 5H), 7.11–7.05 (m, 3H), 6.91–
6.86 (m, 4H), 4.93 (d, J¼12.4 Hz, 1H), 4.88 (d, J¼12.4 Hz,
1H), 3.66–3.64 (m, 4H), 2.40 (s, 3H), 1.80 (s, 3H). 13C
NMR (63 MHz, CDCl3): d 156.2, 139.6, 138.4, 137.1,
135.2, 134.3, 133.0, 132.7, 128.2, 128.1, 128.0, 127.4,
127.3, 126.8, 126.4, 125.9, 125.7, 125.3, 124.6, 124.0,
111.7, 70.1, 53.2, 51.6, 21.7, 19.7. IR (neat): n 3057, 3031,
2920, 2852, 1607, 1569, 1449, 1313, 1163, 1091, 817,
694 cm21. MS: m/z 457 (Mþ, 15), 366 (54), 350 (26), 246
(7), 91 (100). Anal. calcd for C33H31NO·HBr: C, 73.60; H,
5.99; N, 2.60; found C, 74.31; H, 6.04; N, 2.80.
4.3.5. (P,S)-1-(2-Methoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(P,S)-24]. Characterized as the hydrochloride (P,S)-24·HCl.
[a]2D0¼þ18.9 (c 0.5, CHCl3). All other spectroscopic and
physical data were identical to those of (M,R)-24·HCl.
4.3.2. (M,R)-1-(2-Benzyloxy-4,6-dimethylphenyl)-2-[N-
(1-phenylethyl)amino-methyl]naphthalene [(M,R)-15].
Yield: 82%. [a]D20¼þ59.3 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.88–7.83 (m, 2H), 7.57 (d, J¼
8.3 Hz, 1H), 7.44–7.41 (mc, 1H), 7.39–7.32 (m, 1H), 7.29–
7.04 (m, 7H), 6.81–6.72 (m, 4H), 4.78 (s, 2H), 3.60 (q, J¼
6.5 Hz, 1H), 3.51 (d, J¼12.6 Hz, 1H), 3.47 (d, J¼12.6 Hz,
1H), 2.43 (s, 3H), 1.79 (s, 3H), 1.13 (d, J¼6.5 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 156.4, 145.8, 138.32, 138.26,
137.2, 136.3, 134.2, 132.9, 132.8, 128.2, 128.1, 127.9,
127.18, 127.16, 126.6, 126.3, 125.7, 125.1, 124.7, 123.8,
111.4, 69.8, 57.5, 50.4, 24.3, 21.7, 19.7. IR (neat): n 3057,
2960, 2920, 1610, 1573, 1493, 1452, 1375, 1315, 1165,
1095, 820, 736 cm21. MS: m/z: 471 (Mþ, 31) [M þ], 456
(13), 380 (27), 350 (35), 259 (88), 91 (100). Anal. calcd for
C34H33NO: C, 86.59; H, 7.05; N, 2.97; found C, 87.40; H,
7.15; N, 2.85.
4.3.6. (M,S)-1-(2-Methoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,S)-24]. Yield: 75%. Characterized as the hydrochloride
(M,S)-24·HCl. Mp 129 8C (dichloromethane/petroleum
1
ether). [a]2D0¼2103.8 (c 1.1, CHCl3). H NMR (400 MHz,
CDCl3): d 7.87 (d, J¼8.1 Hz, 1H), 7.82 (d, J¼8.6 Hz, 1H),
7.81 (d, J¼8.1 Hz, 1H), 7.38–7.33 (m, 3H), 7.28–7.25 (m,
4H), 7.20–7.15 (m, 1H), 6.77 (s, 1H), 6.66 (s, 1H), 3.52 (s,
3H), 3.44 (q, J¼6.7 Hz, 1H), 3.39 (d, J¼13.6 Hz, 1H), 3.20
(d, J¼13.6 Hz, 1H), 2.43 (s, 3H), 2.04 (s, 3H), 1.60 (s, 3H),
1.26 (d, J¼6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
157.2, 145.2, 138.5, 138.0, 136.2, 133.9, 132.7, 132.5,
128.1, 127.9, 127.5, 127.0, 126.5, 125.6, 125.5, 124.9,
123.9, 123.0, 109.0, 63.7, 56.4, 55.2, 38.5, 21.7, 19.7, 18.6.
IR (KBr): n 3056, 3027, 2970, 2932, 1610, 1575, 1452,
1315, 1097, 909, 702 cm21. MS: m/z 409 (Mþ, 41) [M þ],
394 (41), 275 (100). Anal. calcd for C29H31NO·HCl: C,
78.09; H, 7.23; N, 3.14; found C, 77.92; H, 7.33; N, 3.23.
4.3.3. (M,S)-1-(2-Benzyloxy-4,6-dimethylphenyl)-2-[N-
(1-phenylethyl)aminomethyl]naphthalene
Yield: 71%. Characterized as the hydrobromide (M,S)-
15·HBr. Mp 156 8C (dichloromethane/petroleum ether).
[a]2D0¼þ31.4 (c 1.0, CHCl3). 1H NMR (400 MHz,
[(M,S)-15].
4.3.7. (M,S)-1-(2-Methoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,S)-24]. Characterized as the hydrochloride (M,S)-
24·HCl. [a]2D0¼þ99.2 (c 1.0 in CHCl3). All other

6342
G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
spectroscopic and physical data were identical to those of
(P,R)-24·HCl.
4.4.3. (M,R)-1-(2-Methoxymethoxy-4,6-dimethylphenyl)-
2-[N-(1-phenylethyl)aminomethyl]naphthalene [(M,R)-
21]. NaH (9.11 mg, 368 mmol) was added to a solution of
(M,R)-16 (70.4 mg, 184 mmol) in diethyl ether (10 mL).
MOMCl (32 mL, 368 mmol) was added after 30 min and
stirring was continued for 16 h. The solvent was removed in
vacuo and the residue purified by column chromatography
(petroleum ether/diethyl ether¼2:1) to give (M,R)-21
(62 mg, 146 mmol, 79%) as a yellowish oil; [a]2D0¼þ79.5
4.3.8. (M)-2-(N-Benzyl-N-methylaminomethyl)-1-
(2-methoxy-4,6-dimethylphenyl)naphthalene [(M)-25].
Yield: 94%. Characterized as the hydrochloride (M)-
25·HCl. Mp 126 8C (dichloromethane/petroleum ether).
[a]2D0¼229.1 (c 0.7, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.94 (d, J¼8.2 Hz, 1H), 7.87–7.83 (m, 2H),
7.42–7.37 (mc, 1H), 7.33–7.27 (m, 6H), 7.22 (d, J¼6.7 Hz,
1H), 6.81 (s, 1H), 6.69 (s, 1H), 3.55 (s, 3H), 3.49–3.30 (m,
4H), 2.46 (s, 3H), 2.08 (s, 3H), 1.76 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 157.2, 139.9, 138.4, 138.1, 135.6,
134.0, 132.7, 132.5, 128.8, 128.1, 127.9, 127.2, 126.8,
126.7, 125.0, 123.9, 123.0, 109.1, 62.2, 59.3, 55.3, 42.4,
21.8, 19.7. IR (KBr): n 3056, 3020, 2945, 2919, 1619, 1575,
1494, 1461, 1097, 789, 735 cm21. MS: m/z 395 (Mþ, 68),
364 (8), 304 (40), 275 (37), 274 (100), 91 (51). Anal. calcd
for C28H29NO·HCl: C, 77.85; H, 7.00; N, 3.24; found: C,
77.84; H, 7.21; N, 3.18.
1
(c 0.8, CHCl3). H NMR (400 MHz, acetone-d6): d 7.91–
7.88 (m, 2H), 7.74 (d, J¼8.6 Hz, 1H), 7.44–7.40 (mc, 1H),
7.34–7.14 (m, 7H), 6.96 (s, 1H), 6.85 (s, 1H), 4.87 (d, J¼
6.7 Hz, 1H), 4.80 (d, J¼6.7 Hz, 1H), 3.68 (q, J¼6.5 Hz,
1H), 3.45 (s, 2H), 2.93 (s, 3H), 2.41 (s, 3H), 1.72 (s, 3H),
1.22 (d, J¼6.5 Hz, 3H). 13C NMR (100 MHz, acetone-d6): d
156.0, 147.1, 139.1, 138.7, 137.7, 134.7, 133.8, 133.5,
129.1, 128.8, 128.3, 127.9, 127.3, 126.6, 126.2, 126.0,
125.7, 125.0, 113.9, 94.9, 58.8, 55.8, 50.6, 25.0, 21.7, 19.9.
IR (neat): n 3054, 2958, 2922, 2855, 1613, 1574, 1491,
1450, 1310, 1209, 1150, 1100, 1049, 991, 820, 757 cm21
.
MS: m/z 425 (Mþ, 48), 410 (26), 380 (49), 320 (42), 259
(100), 105 (70). Anal. calcd for C29H31NO2·HCl: C, 75.39;
H, 6.98; N, 3.03; found C, 75.17; H, 6.65; N, 2.87.
4.3.9. (P)-2-(N-Benzyl-N-methylaminomethyl)-1-(2-
methoxy-4,6-dimethylphenyl)naphthalene
[(P)-25].
[a]2D0¼þ27.6 (c 1.0, CHCl3). All other spectroscopic and
physical data were identical to those of (M)-25.
4.4.4. (M,R)-1-(2-Acetoxy-4,6-dimethylphenyl)-2-[N-
methyl-N-(1-phenylethyl)aminomethyl]naphthalene
[(M,R)-22]. A solution of (M,R)-16 (90.1 mg, 236 mmol),
pyridine (38 mL, 472 mmol), and acetyl chloride (34 mL,
472 mmol) in dichloromethane (5 mL) was stirred at room
temperature for 16 h, followed by hydrolysis with water
(5 mL). After extraction with diethyl ether (20 mL), the
combined organic layers were dried over MgSO4, filtered,
and evaporated in vacuo. The crude product was purified by
column chromatography, affording (M,R)-22 (41.3 mg,
97.6 mmol, 41%) as a colorless oil; [a]2D0¼þ47.0 (c 0.9,
CHCl3). 1H NMR (400 MHz, acetone-d6): d 7.92–7.88 (m,
2H), 7.76 (d, J¼8.6 Hz, 1H), 7.45–7.41 (mc, 1H), 7.33–
7.16 (m, 7H), 7.07 (s, 1H), 6.94 (s, 1H), 3.71 (q, J¼6.6 Hz,
1H), 3.47 (d, J¼12.9 Hz, 1H), 3.42 (d, J¼12.9 Hz, 1H), 2.42
(s, 3H), 1.79 (s, 3H), 1.51 (s, 3H), 1.24 (d, J¼6.6 Hz, 3H).
13C NMR (100 MHz, acetone-d6): d 169.0, 150.1, 147.0,
139.3, 139.1, 137.9, 133.5, 133.0, 132.8, 129.6, 129.0,
128.9, 128.7, 128.4, 128.1, 127.3, 126.6, 126.5, 126.1,
121.8, 58.7, 50.0, 21.1, 20.2, 19.9. IR (neat): n 3330, 3057,
2964, 2922, 2857, 1703, 1620. 1453, 1368, 1620, 1453,
1368, 1317, 1246, 1205, 1151, 1107, 1045, 871, 820, 758,
702 cm21. MS: m/z 423 (Mþ, 20), 408 (30), 318 (100), 259
(37), 105 (37). MS (EI) exact mass calcd for C29H29NO2:
423.2198; found 423.2194.
4.4. General procedure for the debenzylation of the
amines (M)-15
To a solution of the amine (M)-15 in dichloromethane
[10 mL/mmol (M)-15], a 1.0 M solution of BCl3 in
n-hexane (2.0 equiv.) was added at 0 8C. After 40 min of
stirring, the reaction mixture was cautiously hydrolyzed
with water [15 mL/mmol (M)-15], made alkaline with
K2CO3, and exhaustively extracted with dichloromethane.
The combined organic layers were dried over MgSO4 and
the solvent was removed in vacuo. The resulting oily
product (M)-16 was purified by chromatography (petroleum
ether/diethyl ether¼1:1).
4.4.1. (M,R)-1-(2-Hydroxy-4,6-dimethylphenyl)-2-[N-(1-
phenylethyl)amino-methyl]naphthalene
[(M,R)-16].
Yield: 95%. Mp 132 8C (dichloromethane/petroleum
ether). [a]2D0¼þ13.2 (c 1.2, CHCl3). All other spectro-
scopic and physical data were identical to those
reported in ref.10
4.4.2. (M,S)-1-(2-Hydroxy-4,6-dimethylphenyl)-2-[N-(1-
phenylethyl)amino-methyl]naphthalene [(M,S)-16].
Yield: 69%. Mp 127 8C (dichloromethane/petroleum
1
ether). [a]2D0¼þ35.0 (c 1.0, CHCl3). H NMR (400 MHz,
4.5. General procedure for the preparation of the
aminotriflates 19 and 26
CDCl3): d 7.84 (d, J¼7.9 Hz, 1H), 7.82 (d, J¼8.2 Hz, 1H),
7.48–7.39 (mc, 1H), 7.38–7.23 (mc, 8H), 6.90 (s, 1H), 6.79
(s, 1H), 3.74 (q, J¼6.7 Hz, 1H), 3.58 (s, 2H), 2.42 (s, 3H),
1.71 (s, 3H), 1.35 (d, J¼6.7 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 155.4, 144.2, 138.6, 138.0, 135.0, 133.4, 133.1,
128.8, 128.3, 127.9, 127.4, 126.8, 126.5, 126.3, 126.2,
125.8, 124.7, 123.3, 118.1, 58.7, 51.4, 22.5, 21.3, 20.1. IR
(KBr): n 3500–2200, 3230, 3030, 2930, 2890, 2830, 1595,
1435, 1295, 1085, 1035, 805, 695. MS: m/z: 381 (Mþ, 54)
[Mþ], 366 (40), 276 (39), 261 (100), 260 (75), 259 (69), 120
(22), 105 (32). Anal. calcd for C27H27NO: C, 85.00; H, 7.13;
N, 3.67; found C, 85.39; H, 7.37; N, 3.65.
A solution of 24 or 25 in 48% aqueous HBr (5 mL/mmol
amine) was refluxed for 6 h. The solvent was removed in
vacuo, the residue dissolved in MeOH (5 mL/mmol amine)
and passed through a plug of celite. The solvent was
evaporated under reduced pressure and the residue was
dissolved in dry dichloromethane (5 mL/mmol amine)
under nitrogen at room temperature. DABCO (2.0 equiv.)
and triflic anhydride (2.0 equiv.) were added. The reaction
mixture was stirred at room temperature for 16 h, the
solvent was removed in vacuo and the product was purified

G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
6343
by column chromatography (petroleum ether/diethyl
ether¼5:1).
141.0, 140.3, 137.1, 133.9, 133.0, 131.7, 131.2, 129.6,
129.5, 129.2, 129.0, 127.7, 127.2, 126.5, 126.0, 120.5,
119.9, 119.3 (q, JC–F¼319 Hz), 63.2, 60.3, 42.5, 21.2, 20.0.
IR (neat): n 3058, 3033, 2924, 2839, 1621, 1556, 1511,
1496, 1225, 945, 822 cm21. MS: m/z 513 (Mþ, 29), 422
(24), 259 (100), 91 (49). Anal. calcd for C28H26F3NO3S: C,
65.48; H, 5.10; N, 2.73; S, 6.24; found C, 65.73; H, 5.40; N,
2.59; S, 5.91.
4.5.1. (M,R)-1-(2-Trifluoromethanesulfonyloxy-4,6-
dimethylphenyl)-2-[N-methyl-N-(1-phenylethyl)amino-
methyl]naphthalene [(M,R)-19]. Yield: 71%. Mp 37 8C
(diethyl ether/petroleum ether). [a]2D0¼214.7 (c 1.0,
CHCl3). 1H NMR (400 MHz, acetone-d6): d 8.00–7.93
(m, 2H), 7.85 (d, J¼8.6 Hz, 1H), 7.45 (mc, 1H), 7.41–7.36
(m, 2H), 7.29–7.28 (m, 4H), 7.26–7.18 (m, 3H), 3.46 (q,
J¼6.8 Hz, 1H), 3.39 (d, J¼11.8 Hz, 1H), 3.35 (d, J¼
11.8 Hz, 1H), 2.52, (s, 3H), 2.01 (s, 3H), 1.90 (s, 3H), 1.21
(d, J¼6.8 Hz, 3H). 13C NMR (100 MHz, acetone-d6): d
148.7, 145.2, 141.7, 140.9, 137.5, 133.8, 133.0, 131.6,
131.2, 129.4, 129.3, 129.2 (q, JC–F¼324 Hz), 128.9, 128.3,
128.1, 127.6, 127.1, 126.4, 125.9, 119.7, 64.9, 57.6, 39.1,
21.1, 20.1, 19.1. IR (neat): n 3005, 2912, 1592, 1395, 1202,
1120, 805 cm21. MS: m/z 527 (Mþ, 16), 512 (38), 422 (7),
259 (100). Anal. calcd for C29H28F3NO3S: C, 66.02; H, 5.35;
N, 2.65; S, 6.08; found C, 65.87; H, 5.48; N, 2.60; S, 5.94.
4.5.6. (P)-1-(2-Trifluoromethanesulfonyloxy-4,6-di-
methylphenyl)-2-(N-benzyl-N-methylaminomethyl)-
naphthalene [(P)-26]. [a]2D0¼þ48.5 (c 0.8, CHCl3). All
other spectroscopic and physical data were identical to those
of (M)-26.
4.6. Biological testing
4.6.1. Trypanosoma cruzi. Rat skeletal myoblasts (L-6
cells) were seeded in 96-well microtiter plates at 2000
cells/well/100 mL in RPMI 1640 medium with 10% FBS
and 2mM L-glutamine. After 24 h of incubation at 37 8C
in 5% CO2 in air, 50 mL of a trypanosome suspension
containing 5000 trypomastigote T. cruzi [Tulahuen C2C4
strain, containing the b-galactosidase (Lac Z) gene] from
culture were added to the wells. 48 h later the medium was
removed from the wells and replaced by 100 mL fresh
medium with or without a serial drug dilution. Seven 3-fold
dilutions were used covering a range from 90 mg/mL to
0.123 mg/mL. Each drug was tested in duplicate. Active
compounds were tested twice for confirmation. After 96 h of
incubation the plates were inspected under an inverted
microscope to assure growth of the controls and sterility.
Then the substrate CPRG/Nonidet (50 mL) was added to all
wells. The color reaction that developed during the
following 2–4 h was read photometrically at 540 nm.
Data were transferred into a graphic program (e.g.,
EXCEL), sigmoidal inhibition curves determined and IC50
values calculated.13
O-Triflation of the phenol (M,R)-12 according to the general
procedure 4.15 delivered (M,R)-19 in 89% yield.
4.5.2. (P,S)-1-(2-Trifluoromethanesulfonyloxy-4,6-
dimethylphenyl)-2-[N-methyl-N-(1-phenylethyl)amino-
methyl]naphthalene [(P,S)-19]. [a]2D0¼þ15.2 (c 1.0,
CHCl3). All other spectroscopic and physical data were
identical to those of (M,R)-19.
4.5.3. (M,S)-1-(2-Trifluoromethanesulfonyloxy-4,6-
dimethylphenyl)-2-[N-methyl-N-(1-phenylethyl)amino-
methyl]naphthalene [(M,S)-19]. Yield: 76%. [a]2D0¼þ22.6
1
(c 0.8, CHCl3). H NMR (400 MHz, CDCl3): d 7.90–7.82
(m, 3H), 7.41 (mc, 1H), 7.33–7.27 (m, 4H), 7.25–7.24 (m,
1H), 7.20–7.16 (m, 3H), 7.10 (s, 1H), 3.45 (q, J¼6.5 Hz,
3H), 3.35 (d, J¼13.9 Hz, 1H), 3.28 (d, J¼13.9 Hz, 1H), 2.46
(s, 3H), 2.01 (s, 3H), 1.80 (s, 3H), 1.22 (t, J¼6.5 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 147.7, 144.6, 140.6, 139.4,
136.6, 132.8, 132.7, 132.1, 130.4, 130.1, 128.7, 128.6,
128.5, 128.0, 127.6, 127.5, 127.2, 127.0, 126.7, 126.4,
126.3, 126.1, 125.4, 125.3, 125.1, 119.0, 118.0, 63.6, 56.5,
38.5, 21.2, 19.8, 18.0. IR (neat): n 3061, 3029, 2967, 2017,
1631, 1451, 1213, 938, 822 cm21. MS: m/z 527 (Mþ, 41),
512 (100), 422 (17), 259 (74), 244 (65). Anal. calcd for
C29H28F3NO3S: C, 66.02; H, 5.35; N, 2.65; S, 6.08; found
C, 65.95; H, 5.49; N, 2.60; S, 5.94.
4.6.2. Cytotoxicity. Cytotoxicity was assessed in the same
assay using noninfected L-6 cells and the same serial
drug dilution. The MIC was determined microscopically
after 4 d.
4.7. Crystallographic part
4.7.1. Crystal structure of (M,R)-9·EtOH. Crystals of
(M,R)-9·EtOH suited for an X-ray structure analysis were
obtained from EtOH. The data were collected on a Bruker
AXS P4-diffractometer using a graphite monochromated
4.5.4. (P,R)-1-(2-Trifluoromethanesulfonyloxy-4,6-di-
methylphenyl)-2-[N-methyl-N-(1-phenylethyl)amino-
methyl]naphthalene [(P,R)-19]. [a]2D0¼223.5 (c 0.9,
CHCl3). All other spectroscopic and physical data were
identical to those of (M,S)-19.
˚
Mo Ka radiation (l¼0.71073 A) at room temperature. The
structure was solved by direct methods and refined by full-
matrix anisotropic least square calculations with the aid of
the programs SHELXS14 and SHELXL,14 respectively.
4.5.5. (M)-1-(2-Trifluoromethanesulfonyloxy-4,6-di-
methylphenyl)-2-(N-benzyl-N-methylaminomethyl)-
naphthalene [(M)-26]. Yield: 82%. Mp 52 8C (diethyl
4.7.2. Crystal structure of (M,R)-19. Crystal data for
compound (M,R)-19 were collected from a shock cooled
crystal on a BRUKER SMART-APEX diffractometer with a
1
ether/petroleum ether). [a]2D0¼253.8 (c 1.0, CHCl3). H
˚
NMR (400 MHz, CDCl3): d 8.01 (d, J¼8.6 Hz, 1H), 7.98 (s,
1H), 7.95 (d, J¼7.4 Hz, 1H), 7.48 (dt, J¼7.0, 1.3 Hz, 1H),
7.39 (dt, J¼7.0, 1.4 Hz, 2H), 7.32–7.30 (m, 7H), 3.46–3.39
(m, 3H), 3.36 (d, J¼13.7 Hz, 1H), 2.53 (s, 3H), 2.07 (s, 3H),
1.90 (s, 3H). 13C NMR (100 MHz, CDCl3): d 148.6, 141.4,
D8-goniometer (graphite Mo Ka radiation, l¼0.71073 A)
equipped with a low temperature device15 in v-scan mode at
100(2) K. The data were integrated with SAINT16 and an
empirical adsorption correction was applied (SADABS).17
The structure was solved by direct methods (SHELXS97)18

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G. Bringmann et al. / Tetrahedron 60 (2004) 6335–6344
6. Bestetti, R. B. Lancet 1996, 347, 913–914.
and refined by full matrix least square calculations against
F 2 (SHELXL97).19 All non-hydrogen atoms were refined
with anisotropic displacement parameters. All hydrogen
atoms were assigned ideal positions using a riding model
with Uiso constrained to 1.2 (and 1.5) times Ueq value of the
parent atom.
7. (a) Boainain, E. Rev. Goiana di Medicina 1979, 25, 1–60.
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1607–1612. (f) Nagel, R.; Nepomnaschy, I. Mutat. Res. 1983,
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Crystallographic data (excluding structure factors) reported
in this publication have been deposited with Cambridge
Crystallographic Data Center as supplementary publication
no. CCDC-226172. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: (internat.) þ44-1223-336-
033; e-mail: deposit@ccdc.cam.ac.uk].
`
Cordoba, J. C.; Maior, I. S.; Solorzano, E. Am. J. Trop. Med.
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Acknowledgements
8. (a) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999,
525–558. (b) Bringmann, G.; Breuning, M.; Pfeifer, R.-M.;
Schenk, W.; Kamikawa, K.; Uemura, M. J. Organomet. Chem.
2002, 661, 31–47. (c) Bringmann, G.; Tasler, S.; Pfeifer,
R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49–65.
(d) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34,
615–624.
This work was supported by the Deutsche Forschungsge-
meinschaft (SFB 630 ‘Recognition, Preparation, and Func-
tional Analysis of Agents against Infectious Diseases’, by
the Ministry of Research (Center of Excellence BIOTEC-
marin, by the Fonds der Chemischen Industrie, by the
Freistaat Bayern (research fellowship for R.-M.P.), and
by the UNDP/World Bank/WHO Special Programme
for Research and Training in Tropical Diseases (TDR).
The technical assistance of Elke Gobright is highly
acknowledged.
9. Bringmann, G.; Breuning, M.; Tasler, S.; Endress, H.; Ewers,
¨
C. L. J.; Gobel, L.; Peters, K.; Peters, E.-M. Chem. Eur. J.
1999, 5, 3029–3038.
10. Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1998,
9, 667–679.
11. Peters, K.; Peters, E. M.; von Schnering, H. G.; Bringmann,
G.; Schupp, O. Z. Krist. 1994, 209, 801–802.
12. Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Org.
Synth. 2001, 79, 72–83.
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¨
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14. Sheldrick, G.M. SHELXTL Program Package, Bruker AXS
Inc., Madison, WI, 2001.
¨
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¨
¨
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