Stereocontrolled synthesis of 2-aryl tetralones. Application in the synthesis of B/C hexahydrobenzo[c]phenanthridine alkaloids

Article abstract of DOI:10.1016/S0957-4166(00)00042-2

Hexahydrobenzo[c]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereoselective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of (+)-(S,S)-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-iodoethane electrophiles. Subsequent transformations (intramolecular Friedel-Crafts acylation, stereocontrolled reductive amination and Pictet-Spengler cyclization) yielded the target heterocycles in good overall yields and in excellent stereoselectivities. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00042-2

Tetrahedron: Asymmetry 11 (2000) 1227±1237
Stereocontrolled synthesis of 2-aryl tetralones.
Application in the synthesis of B/C
hexahydrobenzo[c]phenanthridine alkaloids1
Jose L. Vicario, Dolores Badõa,* Esther Domõnguez and Luisa Carrillo
Â
Departamento de Quõmica Organica, Facultad de Ciencias, Universidad del Pais Vasco, PO Box 644, 48080 Bilbao, Spain
Â
Received 4 January 2000; accepted 25 January 2000
Abstract
Hexahydrobenzo[c]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereo-
selective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of
(+)-(S,S)-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-
iodoethane electrophiles. Subsequent transformations (intramolecular Friedel±Crafts acylation, stereo-
controlled reductive amination and Pictet±Spengler cyclization) yielded the target heterocycles in good
overall yields and in excellent stereoselectivities. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The hexahydrobenzo[c]phenanthridine alkaloids are a small class of isoquinoline alkaloids that
are characterized by the basic skeleton shown in Fig. 1 and they are structurally divided into two
classes,2 one is the chelidonine group of alkaloids and the other is the corynoline group with an
additional 10b-methyl group at the ring junction. Most of the synthetic studies on benzo[c]-
phenanthridines have been focused on fully aromatized derivatives because most of them have
shown interesting antitumor3 and antileukemic4 properties as well as inhibiting HIV 1 and 2 reverse
transcriptases5 and DNA topoisomerases I and II.6 However, only limited e€orts towards the
synthesis of B/C hexahydrobenzo[c]phenanthridines have been reported4a,7 and are mainly focused
towards basic studies with only a few being directed towards stereocontrolled procedures.8 As a
result of the interesting potential biological activities shown by this group of alkaloids there is a
growing interest in determining structure±activity relationships and in developing new structural
analogues of these compounds with improved pharmacological properties. Additionally, in the case
of the hexahydro-derivatives, where several stereogenic centers are present, the design of prep-
arative procedures for stereocontrolled synthesis becomes a ®eld of interest for organic chemists.
* Corresponding author. E-mail: qopbaurm@lg.ehu.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00042-2

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J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
Figure 1.
On the other hand, 2-aryl tetralones have been reported to be extremely versatile synthons for
the preparation of benzophenanthridine alkaloids9 although the latter are always in fully
aromatized form. In relation it should be pointed out that if the 2-aryl tetralone moiety is prepared in
an enantioselective fashion it should o€er access to chiral non-racemic hexahydrobenzo[c]phenan-
thridines by careful control of the stereochemical course of the reactions along the synthetic pathway.
Recently we have reported a general and ecient method for the stereocontrolled synthesis of
2-alkyl-substituted aryl benzyl ketones starting from chiral non-racemic a-substituted arylacetic
acids obtained by diastereoselective alkylation of (+)-(S,S)-pseudoephedrine based arylacet-
amides.10 In this context and in connection with our research e€orts in the ®eld of the asymmetric
synthesis of isoquinoline alkaloids8c,10,11 we decided to survey the possibilities of conveniently
functionalized 2-substituted arylacetic acids as valuable precursors for the synthesis of enantiopure
2-aryl tetralones and thus develop synthetic methodology for access to chiral hexahydrobenzo-
[c]phenanthridines (Fig. 2).
Figure 2.
2. Results and discussion
The synthesis starts with the alkylation of several arylacetic based (+)-(S,S)-pseudoephedrine
amides with 2-aryl-1-iodoethane derivatives yielding products in good yields and excellent
1
stereoselectivities, as H NMR analysis of the crude products indicated. The amides 2 were
hydrolyzed and subjected to intramolecular Friedel±Crafts acylation reaction yielding the desired
2-aryl tetralones in more than 99% enantiomeric excess by chiral HPLC analysis under conditions
optimized for racemic standards (Scheme 1 and Table 1).12 The selected Lewis acid employed to
activate the acyl chloride in the acylation reaction was critical such that use of the standard
AlCl3, when methylenedioxy bridges were present in the starting acid, led to complex mixtures
being obtained from which products arising from the breaking of the methylenedioxy could be
detected. This diculty could be circumvented with the use of the milder SnCl4 Lewis acid.
The stereochemistry of the newly created stereogenic center was assigned as (S) according to a
previously reported mechanism10 in which the adduct of the pseudoephedrine amide alkylation
should arise from the attack to the preformed Z enolate from the less hindered Si face of an
intermediate in an opened staggered conformation, which remains rigid by the help of bridging
solvent or iPrNH (from LDA) molecules.

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
1229
Scheme 1. Reagents and conditions: (i) (1) LDA, LiCl, THF, 78ꢀC; (2) ArCH2CH2I, THF, 0ꢀC. (ii) 4 M H2SO4,
dioxane, re¯ux. (iii) (1) SOCl2, toluene, re¯ux; (2) Lewis acid, CH2Cl2, 20ꢀC
Table 1
Yields and enantioselectivities in the synthesis of the ketones 4
Proceeding with the synthesis, the tetralones 4a±d were subjected to a stereocontrolled reduc-
tive amination procedure by forming a non-isolated imine intermediate with benzylamine in the
presence of Et3N and TiCl4 as the carbonyl activator and water scavenger, followed by NaBH4
reduction of the CˆN double bond (Scheme 2). In this way the required amines 5 were obtained
as only the syn diastereoisomers. Careful temperature control was necessary during this proced-
ure since on reaching temperatures over 20ꢀC the amines 5 were obtained with a signi®cant loss
of enantiomeric purity (e.e. 70% at 0ꢀC), although always as only the syn isomers. This indi-
cates that the stereogenic center at C2 is able to exert a very e€ective 1,2 asymmetric induction on
the new stereogenic center created during the reduction of the CˆN bond and that at tempera-
tures higher than 20ꢀC epimerization takes place at this original stereogenic center, therefore
leading to a loss of the enantiomeric purity in the ®nal products. This racemization process is
Scheme 2. Reagents and conditions: (i) (1) TiCl4, BnNH2, Et3N, THF, 78ꢀC; (2) NaBH4, MeOH, 20ꢀC. (ii) HCHO,
1 M HCl, 60ꢀC

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J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
most probably due to a fast imine±enamine tautomerism process in the non-isolated intermediate
imine. The thus obtained 2-aryl-1,2,3,4-tetrahydro-1-naphthylamines were subjected to a stan-
dard Pictet±Spengler cyclization procedure yielding the target heterocycles in high yields.
The relative stereochemistry of the newly created stereogenic center during the reductive
amination step was determined as cis by NOE di€erence spectroscopic experiments which also
established the stereochemistry of the B/C ring junction in the ®nal benzo[c]phenanthridines to be
cis and therefore the absolute stereochemistry of the stereogenic centers in the ®nal heterocycles
6a±d could be assigned as (4bR,10bS) (Table 2). The observed stereochemistry of the naphthyl-
amines 5a±d arising from the hydride reduction of the CˆN bond of the imine derived from the
tetralones 4a±d is consistent with a transition state in which the hydride reagent attacks from the
less hindered face of the CˆN plane, which is opposite to the 2-aryl substituent and therefore
a€ording the products with a relative cis stereochemistry as the only detectable isomer. The
determination of enantiomeric purities by chiral HPLC analysis under conditions optimized for a
racemic standard13 showed that all the products 5a±d and 6a±d were >99% which also indicates
that all the synthetic steps proceeded without any isomerization, especially concerning the very
sensitive benzylic position in the tetralones 4a±d.
Table 2
Yields and enantioselectivities in the synthesis of the benzo[c]phenanthridines 6a±d
In conclusion, a high yield synthetic procedure has been established for the asymmetric synth-
esis of hexahydrobenzo[c]phenanthridines with a cis B/C ring junction. This method also allows
the introduction of di€erent substitution patterns on the A and D aromatic rings by careful
selection of the starting arylacetic acid and 2-aryl-1-iodoethane electrophiles, opening a general
way for the preparation of a wide range of these types of alkaloids.
3. Experimental
3.1. General procedures
Melting points were determined in unsealed capillary tubes and are uncorrected. IR spectra
were obtained on KBr pellets (solids) or CHCl3 solution (oils). NMR spectra were recorded at
ꢀ
1
20±25 C, running at 250 MHz for H and 62.8 MHz for 13C in CDCl3 solution, and resonances
are reported in ppm relative to tetramethylsilane unless otherwise stated. Assignment of indivi-
dual 13C resonances are supported by DEPT experiments. 1H±{1H} NOE experiments were carried

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
1231
out in the di€erence mode by irradiation of all the lines of a multiplet.14 Mass spectra were
recorded under electron impact at 70 eV. TLC was carried out with 0.2 mm thick silica gel plates
(Merck Kiesegel GF254). Visualization was accomplished by UV light or by spraying with
Dragendor€'s reagent.15 Flash chromatography16 on silica gel was performed with Merck
Kiesegel 60 (230±400 mesh). Determination of enantiomeric excesses was performed by chiral
HPLC analysis of non-crystallized samples using a Chiracel OD column with a UV detector
with the eluents and ¯ow rates as indicated in each case. All solvents used in reactions were dried
and puri®ed according to standard procedures.17 n-BuLi was titrated with diphenylacetic acid
periodically prior to use. All air- or moisture-sensitive reactions were performed under argon. The
glassware was oven dried (140ꢀC) overnight and purged with argon. Amides 1a±c are known
compounds8c and the 2-aryl-1-iodoethanes employed for their alkylation were prepared by iod-
ination of the corresponding 2-arylethanols by standard procedure.18
3.2. General procedure for the asymmetric alkylation of the pseudoephedrine amides 1
3.2.1. Synthesis of (+)-[2S,10S,20S]-N-(20-hydroxy-10-methyl-20-phenylethyl)-N-methyl-2,4-bis(3,4-
dimethoxyphenyl)butanamide 2a
Over a cooled ( 78ꢀC) suspension of LiCl (738 mg, 17.42 mmol) and LDA (5.90 mmol) in dry
THF (20 mL) was slowly added a cooled solution (0ꢀC) of the amide 1a (1.00 g. 2.90 mmol) in
dry THF (10 mL). The mixture was stirred for 1 h at 78ꢀC and 15 min at 0ꢀC after which a
solution of the 2-(3,4-dimethoxyphenyl)-1-iodoethane (3.39 g, 11.61 mmol) in dry THF (5 mL)
was added at once. The reaction was stirred for 2±3 h at 0ꢀC and quenched with saturated
Na2CO3 (20 mL). The mixture was extracted with CH2Cl2 (3Â30 mL) and the combined organic
fractions were collected, dried over Na2SO4, ®ltered and the solvent was removed in vacuo
a€ording crude 2a which was puri®ed by ¯ash column chromatography (hexanes:ethyl acetate
20
1
2:8). Yield: 85%. ‰ꢀŠD +89.4 (c=0.3, CH2Cl2). H NMR (CDCl3) (2:1 rotamer ratio; only
resonances from the major rotamer are reported): 1.11 (d, 3H, J=6.6 Hz); 2.48 (m, 4H); 2.67 (s, 3H);
3.51 (t, 1H, J=6.9 Hz); 3.86 (s, 12H); 3.92 (m, 1H); 4.13 (bs, 1H); 4.56 (d, 1H, J=6.7 Hz); 6.62±
6.82 (m, 6H); 7.26±7.37 (m, 5H). 13C NMR (CDCl3) (2:1 rotamer ratio; only resonances from the
major rotamer are reported): 13.5; 27.0; 32.9; 36.4; 47.8; 55.4; 55.5; 57.4; 75.6; 110.0; 110.7; 111.4;
119.9; 125.9; 126.3; 127.6; 128.1; 129.1; 131.6; 133.9; 141.9; 146.7; 147.5; 148.2; 148.7; 174.5. IR
(CHCl3): 3389; 1625. MS (EI) m/z (rel. int): 507 (M+,1), 489 (2), 342 (9), 325 (18), 178 (57), 164
(7), 151 (100), 147 (26), 107 (8), 105 (3), 91 (11), 79 (3), 77 (6), 56 (16). Anal. calcd for
C30H37NO6: C, 70.98; H, 7.35; N, 2.76. Found: C, 74.06; H, 7.39; N, 2.70.
3.2.2. (+)-[2S,10S,20S]-N-(20-Hydroxy-10-methyl-20-phenylethyl)-N-methyl-2-(3,4,5-trimethoxy-
phenyl)-4-(3,4-dimethoxyphenyl)butanamide 2b
20
1
Yield: 83%. ‰ꢀŠD =+58.2 (c=0.2, CH2Cl2). H NMR (CDCl3) (2:1 rotamer ratio; only
resonances from the major rotamer are reported): 1.08 (d, 3H, J=6.7 Hz); 2.45 (m, 4H); 2.66 (s, 3H);
3.45 (t, 1H, J=7.2 Hz); 3.76 (s, 6H); 3.78 (s, 3H); 3.80 (s, 3H); 3.84 (s, 3H); 4.11 (m, 1H); 4.51 (m,
2H); 6.42 (s, 2H); 6.60±6.77 (m, 3H); 7.24±7.32 (m, 5H). 13C NMR (CDCl3) (2:1 rotamer ratio;
only resonances from the major rotamer are reported): 13.8; 27.0; 33.1; 36.5; 48.7; 55.2; 55.8;
57.6; 60.5; 76.3; 104.2; 110.7; 111.2; 120.0; 126.0; 127.3; 127.5, 128.0; 133.9; 134.9; 136.3; 142.3;
146.8; 148.4; 153.1; 174.5. IR (CHCl3): 3405; 1640. MS (EI) m/z (rel. int): 537 (M+,1), 355 (3),
266 (4), 212 (100), 208 (5), 151 (13), 134 (9), 129 (7), 91 (12), 79 (2), 77 (7), 56 (4). Anal. calcd for
C31H39NO7: C, 69.25; H, 7.31; N, 2.61. Found: C, 69.21; H, 7.36; N, 2.58.

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J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
3.2.3. (+)-[2S,10S,20S]-N-(20-Hydroxy-10-methyl-20-phenylethyl)-N-methyl-4-(3,4-dimethoxy-
phenyl)-2-(3,4-methylenedioxyphenyl)butanamide 2c
20
1
Yield: 81%. ‰ꢀŠD =+74.3 (c=0.2, CH2Cl2). H NMR (CDCl3) (2:1 rotamer ratio; only reso-
nances from the major rotamer are reported): 1.01 (d, 3H, J=6.4 Hz); 2.32 (m, 4H); 2.55 (s, 3H);
3.37 (t, 1H, J=7.0 Hz); 3.73 (s, 6H); 3.97 (m, 1H); 4.35 (d, 1H, J=7.9 Hz); 4.47 (bs, 1H); 5.79 (s,
2H); 6.50±6.69 (m, 6H); 7.15±7.26 (m, 5H). 13C NMR (CDCl3) (2:1 rotamer ratio; only reso-
nances from the major rotamer are reported): 13.6; 27.2; 32.8; 36.5; 47.7; 55.4; 55.5; 57.5, 75.6;
100.7; 107.8; 110.8; 111.3; 120.0; 120.8; 126.0; 127.1; 127.9; 128.3; 132.9; 133.9; 141.9; 146.1;
146.8; 147.7; 148.4; 174.3. IR (CHCl3): 3420; 1636. MS (EI) m/z (rel. int.): 491 (M+,1), 473 (2),
309 (25), 207 (4), 162 (46), 151 (100), 147 (37), 135 (8), 107 (11), 105 (6), 91 (20), 79 (6), 77 (11), 56
(34). Anal. calcd for C29H33NO6: C, 70.86; H, 6.77; N, 2.85. Found: C, 70.89; H, 6.82; N, 2.79.
3.2.4. (+)-[2S,10S,20S]-N-(20-Hydroxy-10-methyl-20-phenylethyl)-N-methyl-2-(3,4-dimethoxy-
phenyl)-4-(3,4-methylenedioxyphenyl)butanamide 2d
20
1
Yield: 78%. ‰ꢀŠD =+65.9 (c=0.2, CH2Cl2). H NMR (CDCl3) (3:1 rotamer ratio; only reso-
nances from the major rotamer are reported): 1.04 (d, 3H, J=6.6 Hz); 2.34 (m, 4H); 2.58 (s, 3H);
3.39 (t, 1H, J=7.1 Hz); 3.76 (s, 3H); 3.78 (s, 3H); 4.06 (m, 1H); 4.36 (bs, 1H); 4.49 (d, 1H, J=7.7
Hz); 5.83 (s, 2H); 6.48±6.73 (m, 6H); 7.19±7.30 (m, 5H). 13C NMR (CDCl3) (3:1 rotamer ratio;
only resonances from the major rotamer are reported): 13.7; 27.0; 33.0; 36.6; 47.8; 55.5; 55.6;
57.4; 75.9; 100.4; 107.8; 108.5; 109.9; 111.0; 119.9; 121.0; 125.9; 127.2; 128.0; 132.5; 133.7; 139.0;
143.3; 145.2; 147.6; 148.9; 174.7. IR (CHCl3): 3396; 1629. MS (EI) m/z (rel. int.): 491 (M+,1), 325
(13), 187 (5), 178 (41), 163 (9), 151 (6), 147 (24), 135 (100), 105 (7), 91 (10), 79 (9), 77 (21), 56 (21).
Anal. calcd for C29H33NO6: C, 70.86; H, 6.77; N, 2.85. Found: C, 70.90; H, 6.74; N, 2.81.
3.3. General procedure for the hydrolysis of the pseudoephedrine amides 3
3.3.1. Synthesis of (+)-(S)-2,4-bis(3,4-dimethoxyphenyl)butanoic acid 3a
A solution of the amide 2a (775 mg, 2.15 mmol) in dioxane (17 mL) was slowly added to a
cooled (0ꢀC) 4 M H2SO4 solution (17 mL). When the addition was complete the mixture was
re¯uxed for 2 h. The reaction was quenched with water, carefully basi®ed to pH=12 and washed
with EtOAc (3Â20 mL). The aqueous layer was carefully driven to pH=3 and extracted with
CH2Cl2 (3Â20 mL). After drying (Na2SO4), ®ltering and removing the solvent from the basic
organic extracts it was possible to recover, after crystallization (hexanes/EtOAc), pure (+)-(S,S)-
pseudoephedrine in 83% yield. The collected organic acidic fractions were dried over Na2SO4,
®ltered and the solvent was removed in vacuo yielding the acid 3a as a yellowish oil. Yield: 93%.
20
1
‰ꢀŠD =+52.5 (c=0.2, CH2Cl2). H NMR (CDCl3): 1.96 (m, 1H); 2.29 (m, 1H); 2.46 (t, 2H,
J=7.4 Hz); 3.42 (t, 1H, J=7.3 Hz); 3.74 (s, 6H); 3.76 (s, 6H); 6.58±6.80 (m, 6H); 7.5±8.1 (bs, 1H).
13C NMR (CDCl3): 32.6; 34.3; 49.7; 55.3; 55.4; 110.6; 110.8; 111.3; 119.9 130.5; 133.3; 146.7;
147.8; 148.2; 148.5; 177.9. IR (CHCl3): 3318; 1731. MS (EI) m/z (rel. int.): 361 (M++1, 11), 360
(M+, 33), 207 (17), 196 (61), 178 (21), 165 (37), 164 (26), 163 (22), 152 (58), 151 (100), 137 (17), 121
(20), 107 (19), 91 (22), 77 (19). Anal. calcd for C20H24O6: C, 66.65; H, 6.71. Found: C, 66.72; H, 6.59.
3.3.2. (+)-(S)-2-(3,4,5-Trimethoxyphenyl)-4-(3,4-dimethoxyphenyl)butanoic acid 3b
20
1
Yield: 95%. ‰ꢀŠD =+29.8 (c=0.2, CH2Cl2). H NMR (CDCl3): 2.02 (m, 1H); 2.34 (m, 1H);
2.51 (t, 2H, J=7.5 Hz); 3.43 (t, 1H, J=7.6 Hz); 3.77 (s, 3H); 3.79 (s, 3H); 3.80 (s, 6H); 3.83 (s,
3H); 6.47 (s, 2H); 6.62±6.74 (m, 3H); 9.4±9.8 (bs, 1H). 13C NMR (CDCl3): 32.8; 34.4; 50.6; 55.5;

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
1233
55.6; 55.8; 60.5; 104.7; 110.8; 111.4; 120.0; 133.2; 136.9; 147.0; 148.4; 148.5; 152.9; 178.9. IR
(CHCl3): 3405; 1718. MS (EI) m/z (rel. int.): 390 (M+, 21), 181 (100), 148 (9), 136 (5), 91 (4), 77
(4), 65 (3). Anal. calcd for C21H26O7: C, 64.60; H, 6.71. Found: C, 64.69; H, 6.66.
3.3.3. (+)-(S)-4-(3,4-Dimethoxyphenyl)-2-(3,4-methylenedioxyphenyl)butanoic acid 3c
20
1
Yield: 94%. ‰ꢀŠD =+32.5 (c=0.5, CH2Cl2). H NMR (CDCl3): 2.04 (m, 1H); 2.30 (m, 1H);
2.49 (t, 2H, J=7.3 Hz); 3.43 (t, 1H, J=7.5 Hz); 3.81 (s, 6H); 5.89 (s, 2H); 6.52±6.80 (m, 6H); 7.4±
7.9 (bs, 1H). 13C NMR (CDCl3): 32.6; 34.3; 49.9; 55.5; 55.6; 100.8; 108.0; 109.5; 110.8; 111.3;
120.0; 121.4; 131.4; 133.3; 146.7; 146.9; 147.6; 148.4; 179.7. IR (CHCl3): 3461; 1720. MS (EI) m/z
(rel. int.): 344 (M+, 10), 300 (23), 298 (69), 283 (26), 267 (42), 164 (26), 163 (22), 152 (100), 151
(67), 136 (80), 121 (48), 107 (28), 91 (56), 79 (30), 77 (87), 65 (48), 51 (53). Anal. calcd for
C19H20O6: C, 66.27; H, 5.85. Found: C, 66.32; H, 5.78.
3.3.4. (+)-(S)-2-(3,4-Dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)butanoic acid 3d
20
1
Yield: 90%. ‰ꢀŠD =+31.0 (c=0.1, CH2Cl2). H NMR (CDCl3): 1.99 (m, 1H); 2.31 (m, 1H);
2.45 (t, 2H, J=7.3 Hz); 3.43 (t, 1H, J=7.7 Hz); 3.80 (s, 6H); 5.85 (s, 2H); 6.51±6.88 (m, 6H); 9.5±
10.0 (bs, 1H). 13C NMR (CDCl3): 32.8; 34.4; 49.8; 55.5; 100.5; 107.8; 108.6; 110.7; 110.8; 120.0;
120.9; 130.2; 134.6; 145.4; 147.3; 148.0; 148.5; 179.4. IR (CHCl3): 3450; 1711. MS (EI) m/z (rel.
int.): 344 (M+, 10), 298 (100), 267 (60), 237 (24), 209 (16), 165 (20), 159 (21), 152 (13), 145 (28),
135 (13), 121 (48), 91 (10), 77 (25). Anal. calcd for C19H20O6: C, 66.27; H, 5.85. Found: C, 66.35;
H, 5.89.
3.4. General procedure for the intramolecular Friedel±Crafts acylation of the acids 3
3.4.1. Synthesis of (+)-(2S)-6,7-dimethoxy-2-(3,4-dimethoxyphenyl)-3,4-dihydronaphthalen-1(2H)-
one 4a
To a cooled (0ꢀC) solution of the starting acid 3a (380 mg, 1.11 mmol) in dry toluene (15 mL)
was slowly added SOCl2 (0.17 mL, 2.53 mmol). The mixture was stirred for 15 min at 0ꢀC and
re¯uxed for 4 h. The volatiles were removed in vacuo and the resulting red oil was dissolved in
dry CH2Cl2 (10 mL) and was added dropwise within 40 min to a stirred suspension of AlCl3
(358 mg, 2.46 mmol) in dry CH2Cl2 (20 mL) at 20ꢀC. The reaction was stirred at this tempera-
ture for 2 h and quenched with 4 M HCl (10 mL). The mixture was extracted with CH2Cl2 (3Â20
mL) and the combined organic fractions were collected, dried over Na2SO4, ®ltered and the sol-
vent was removed in vacuo yielding the pure ketone 4a after ¯ash column chromatography pur-
i®cation (hexanes:ethyl acetate 1:1). An analytically pure sample was obtained by crystallization
20
1
in EtOH. Yield: 78%, mp 144±146 (EtOH). ‰ꢀŠD =+55.3 (c=0.2, CH2Cl2). H NMR (CDCl3):
2.35 (m, 2H); 2.95 (m, 2H); 3.67 (t, 1H, J=9.1 Hz); 3.82 (s, 3H); 3.83 (s, 3H); 3.89 (s, 3H); 3.92 (s,
3H); 6.67±6.82 (m, 4H); 7.55 (s, 1H). 13C NMR (CDCl3): 28.0; 31.4; 52.8; 55.4; 55.5; 55.7; 108.4;
109.8; 110.7; 111.4; 119.9; 125.5; 132.3; 138.6; 147.4; 147.5; 148.4; 153.1; 196.9. IR (KBr): 1666.
MS (EI) m/z (rel. int.): 342 (M+, 62), 204 (27), 191 (86), 178 (67), 152 (18), 151 (61), 150 (100),
135 (11), 107 (12), 91 (14), 79 (10), 77 (20), 51 (7). Anal. calcd for C20H22O5: C, 70.16; H, 6.48.
Found: C, 70.22; H, 6.41.
3.4.2. (+)-(2S)-6,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydronaphthalen-1(2H)one 4b
1
20
Yield: 71%, mp 164±167 (EtOH). ‰ꢀŠD =+23.9 (c=0.1, CH2Cl2). H NMR (CDCl3): 2.25 (m,
2H); 2.86 (m, 2H); 3.54 (t, 1H, J=8.9 Hz); 3.68 (s, 6H); 3.71 (s, 3H); 3.78 (s, 3H); 3.81 (s, 3H);

1234
J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
6.28 (s, 2H); 6.57 (s, 1H); 7.43 (s, 1H). 13C NMR (CDCl3): 28.4; 31.7; 54.0; 55.8; 55.9; 60.5; 105.3;
108.6; 110.0; 125.6; 135.8; 138.4; 147.8; 152.9; 153.4; 154.2; 196.8. IR (KBr): 1668. MS (EI) m/z (rel.
int.): 372 (M+, 100), 357 (11), 204 (39), 191 (58), 181 (39), 178 (39), 150 (61), 135 (9), 107 (9), 91 (9),
79 (8), 77 (14), 63 (4), 51 (4). Anal. calcd for C21H24O6: C, 67.73; H, 6.50. Found: C, 67.80; H, 6.46.
3.4.3. (+)-(2S)-6,7-Dimethoxy-2-(3,4-methylenedioxyphenyl)-3,4-dihydronaphthalen-1(2H)one 4c
The same procedure as indicated above was employed but SnCl4 was employed as Lewis acid
and the acylation step was performed for 6 h. Yield: 74%, mp 120±123 (EtOH). ‰ꢀŠ2D0=+28.6
1
(c=0.2, CH2Cl2). H NMR (CDCl3): 2.34 (m, 2H); 2.93 (m, 2H); 3.66 (dd, 1H, J=5.9, 9.4 Hz);
3.91 (s, 3H); 3.94 (s, 3H); 5.92 (s, 2H); 6.60±6.89 (m, 4H); 7.55 (s, 1H). 13C NMR (CDCl3): 28.0;
31.5; 53.0; 55.7; 55.8; 100.6; 108.0; 108.5; 108.6; 109.8; 121.2; 125.6; 133.5; 138.6; 146.1; 147.4;
147.7; 153.2; 196.8. IR (KBr): 1654. MS (EI) m/z (rel. int.): 326 (M+, 69), 204 (13), 191 (90), 178
(62), 150 (100), 135 (28), 107 (12), 91 (10), 89 (12), 79 (9), 77 (22), 63 (10), 51 (8). Anal. calcd for
C19H18O5: C, 69.93; H, 5.56. Found: C, 70.01; H, 5.62.
3.4.4. (+)-(2S)-6,7-Methylenedioxy-2-(3,4-dimethoxyphenyl)-3,4-dihydronaphthalen-1(2H)one 4d
The same procedure as indicated above was employed but SnCl4 was employed as Lewis acid
and the acylation step was performed for 6 h. Yield: 76%, mp 136±139 (EtOH). ‰ꢀŠ2D0=+20.6
(c=0.3, CH2Cl2). 1H NMR (CDCl3): 2.33 (m, 2H); 2.93 (m, 2H); 3.63 (t, 1H, J=8.6 Hz); 3.81 (s,
3H); 3.82 (s, 3H); 5.97 (s, 2H); 6.63±6.80 (m, 4H); 7.47 (s, 1H). 13C NMR (CDCl3): 28.7; 31.2;
53.1; 55.5; 101.4; 106.3; 107.7; 110.8; 111.4; 120.0; 127.2; 132.1; 140.7; 146.7; 147.6; 148.5; 151.8;
196.4. IR (KBr): 1670. MS (EI) m/z (rel. int.): 326 (M+, 100), 188 (22), 175 (46), 165 (10), 163
(55), 151 (49), 134 (69), 104 (14), 76 (21), 63 (4), 53 (3), 51 (6). Anal. calcd for C19H18O5: C, 69.93;
H, 5.56. Found: C, 69.88; H, 5.59.
3.5. General procedure for the reductive amination of the ketones 4
3.5.1. Synthesis of (+)-(1R,2S)-N-benzyl-6,7-dimethoxy-2-(3,4-dimethoxyphenyl)-1,2,3,4-tetra-
hydro-1-naphthylamine 5a
To a stirred solution of the ketone 4a (2.17 g, 5.00 mmol), Et3N (2.08 mL, 15.00 mmol) and
benzylamine (0.60 mL, 5.50 mmol) in THF (30 mL) at 78ꢀC was slowly added a 1 M CH2Cl2
solution of TiCl4 (5.00 mL, 5.00 mmol). The mixture was stirred for 5 min at 78ꢀC and for 1 h
at 20ꢀC after which a MeOH (20 mL) solution of NaBH4 (851 mg, 22.5 mmol) was added
dropwise within 30 min. The reaction was stirred for 2 h at 20ꢀC and quenched with saturated
Na2CO3 (20 mL). The mixture was extracted with CH2Cl2 (3Â15 mL) and the combined organic
fractions were collected, dried over Na2SO4, ®ltered and the solvent was removed in vacuo
yielding the separated pure amine 5a after ¯ash column chromatography puri®cation (hexanes:ethyl
20
1
acetate 1:1). Yield: 80%. ‰ꢀŠD =+53.5 (c=0.2, CH2Cl2). H NMR (CDCl3): 1.64 (bs, 1H); 1.96
(m, 1H); 2.48 (m, 1H); 2.73 (m, 1H); 2.81 (m, 1H); 3.11 (dt, J=2.9, 14.1 Hz); 3.38 (d, 1H, J=13.8
Hz); 3.47 (d, 1H, J=13.7 Hz); 3.77 (s, 3H); 3.81 (d, 1H, J=2.9 Hz); 3.85 (s, 6H); 3.90 (s, 3H);
6.51 (s, 1H); 6.62 (s, 1H); 6.82 (d, 1H, J=5.6 Hz); 6.88 (s, 1H); 7.05 (dd, 1H, J=1.6, 5.6 Hz);
7.21±7.27 (m, 5H). 13C NMR (CDCl3): 22.9; 28.7; 44.1; 52.1; 55.7; 55.8; 58.2; 110.8; 111.3; 111.4;
119.8; 126.6; 128.0; 128.1; 128.5; 131.2; 136.1; 140.7; 140.9; 146.7; 147.4; 147.8; 148.7. IR
(CHCl3): 3330. MS (EI) m/z (rel. int.): 433 (M+, 1), 326 (100), 311 (40), 163 (14), 151 (24), 145
(15), 107 (8), 91 (2), 76 (3), 63 (2). Anal. calcd for C27H31NO4: C, 74.80; H, 7.21; N, 3.23. Found:
C, 78.89; H, 7.15; N, 3.19.

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
1235
3.5.2. (+)-(1R,2S)-N-Benzyl-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-1-
naphthylamine 5b
20
1
Yield: 70%. ‰ꢀŠD =+60.5 (c=0.1, CH2Cl2). H NMR (CDCl3): 1.51 (bs, 1H); 1.97 (m, 1H);
2.49 (m, 1H); 2.69 (m, 1H); 2.78 (m, 1H); 3.01 (dt, J=2.6, 14.1 Hz); 3.40 (d, 1H, J=13.7 Hz); 3.47
(d, 1H, J=13.7 Hz); 3.76 (s, 3H); 3.81 (s, 6H); 3.83 (s, 3H); 3.85 (s, 3H); 3.95 (d, 1H, J=2.6 Hz);
6.49 (s, 1H); 6.53 (s, 2H); 6.53 (s, 1H); 7.19±7.31 (m, 5H). 13C NMR (CDCl3): 22.4; 28.4; 44.5;
51.9; 55.3; 55.4; 55.6; 58.0; 60.5; 104.7; 110.9; 111.5; 126.3; 127.6; 127.8; 130.9; 136.0; 139.2; 140.4;
146.4; 147.6; 152.6; 152.8. IR (CHCl3): 3340. MS (EI) m/z (rel. int.): 463 (M+, 1), 356 (100), 341 (64),
252 (4), 237 (3), 225 (4), 207 (2), 189 (3), 178 (9), 165 (6), 145 (7), 135 (3), 127 (3), 115 (3), 89 (2),
76 (4). Anal. calcd for C28H33NO5: C, 72.55; H, 7.18; N, 3.02. Found: C, 72.50; H, 7.21; N, 3.06.
3.5.3. (+)-(1R,2S)-N-Benzyl-6,7-dimethoxy-2-(3,4-methylenedioxyphenyl)-1,2,3,4-tetrahydro-1-
naphthylamine 5c
20
1
Yield: 72%. ‰ꢀŠD =+59.3 (c=0.3, CH2Cl2). H NMR (CDCl3): 1.51 (bs, 1H); 1.87 (m, 1H);
2.38 (m, 1H); 2.76 (m, 1H); 2.85 (m, 1H); 3.02 (dt, J=2.7, 14.3 Hz); 3.31 (d, 1H, J=13.7 Hz); 3.47
(d, 1H, J=13.7 Hz); 3.73 (s, 3H); 3.82 (s, 3H); 3.93 (d, 1H, J=2.7 Hz); 5.92 (s, 2H); 6.45 (s, 1H);
6.57 (s, 1H); 6.76 (s, 1H); 6.83 (d, 1H, J=5.6 Hz); 7.06 (dd, 1H, J=1.6, 5.6 Hz); 7.12±7.27 (m,
5H). 13C NMR (CDCl3): 22.9; 28.5; 44.1; 52.2; 55.5; 55.6; 58.2; 100.5; 107.8; 108.6; 111.0; 111.6;
120.8; 126.5; 128.0; 128.2; 131.0; 137.3; 140.5; 140.7; 145.7; 146.6; 147.4; 147.7. IR (CHCl3): 3321.
MS (EI) m/z (rel. int.): 417 (M+, 1), 310 (100), 295 (33), 267 (3), 252 (2), 249 (3), 237 (4), 209 (5),
207 (3), 189 (3), 165 (14), 151 (2), 145 (14), 135 (37), 126 (6), 105 (4), 89 (5), 76 (4), 63 (4). Anal.
calcd for C26H27NO4: C, 74.80; H, 6.52; N, 3.35. Found: C, 78.70; H, 6.58; N, 3.29.
3.5.4. (+)-(1R,2S)-N-Benzyl-6,7-methylenedioxy-2-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-1-
naphthylamine 5d
20
1
Yield: 82%. ‰ꢀŠD =+44.3 (c=0.3, CH2Cl2). H NMR (CDCl3): 1.48 (bs, 1H); 1.92 (m, 1H);
2.42 (m, 1H, H4ax); 2.77 (m, 1H); 2.83 (m, 1H); 3.15 (dt, J=2.6, 14.1 Hz); 3.39 (d, 1H, J=13.7
Hz); 3.48 (d, 1H, J=13.7 Hz); 3.75 (d, 1H, J=2.6 Hz); 3.88 (s, 3H); 3.90 (s, 3H); 5.90 (s, 2H);
6.43 (s, 1H); 6.55 (s, 1H); 6.78 (s, 1H); 6.83 (d, 1H, J=5.6 Hz); 7.10 (dd, 1H, J=1.6, 5.6 Hz);
7.29±7.29 (m, 5H). 13C NMR (CDCl3): 22.8; 28.9; 43.8; 51.8; 55.6; 55.7; 58.9; 100.6; 107.8; 108.6;
111.8; 111.0; 121.1; 126.4; 128.2; 128.4; 131.3; 137.1; 140.5; 140.6; 145.7; 146.2; 147.1; 147.7. IR
(CHCl3): 3320. MS (EI) m/z (rel. int.): 417 (M+, 1), 310 (100), 308 (4), 295 (24), 165 (12), 151
(18), 135 (9), 126 (4), 107 (15), 89 (7), 76 (6), 63 (4). Anal. calcd for C26H27NO4: C, 74.80; H, 6.52;
N, 3.35. Found: C, 78.73; H, 6.61; N, 3.40.
3.6. General procedure for the Pictet±Spengler cyclization of the amines 5
3.6.1. Synthesis of ( )-(4bR,10bS)-N-benzyl-4b,5,6,10b,11,12-hexahydro-2,3,8,9-tetramethoxy-
benzo[c]phenanthridine 6a
A solution of the amine 5a (107 mg, 0.24 mmol) and formaldehyde (0.12 mL, 1.42 mmol) in 1 M
HCl (10 mL) was stirred for 16 h at 60ꢀC. Saturated Na2CO3 (10 mL) was added and the mixture
was extracted with CH2Cl2 (3Â15 mL). The combined organic fractions were collected, dried over
Na2SO4, ®ltered and the solvent was removed in vacuo yielding the pure heterocycle after ¯ash
column chromatography puri®cation (hexanes:ethyl acetate 1:1). Yield: 93%. ‰ꢀŠ2D0= 88.3
(c=0.1, CH2Cl2). 1H NMR (CDCl3): 2.05 (m, 1H); 2.45 (m, 1H); 2.66 (m, 2H); 3.19 (m, 1H); 3.51
(d, 1H, J=16.2 Hz); 3.65 (d, 1H, J=16.2 Hz); 3.74 (d, 1H, J=15.1 Hz); 3.79 (s, 3H); 3.83 (s, 3H);

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J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
3.88 (d, 1H, J=15.1 Hz); 3.91 (s, 3H); 3.94 (s, 3H); 4.05 (d, 1H, J=5.1 Hz); 6.41 (s, 1H); 6.53 (s, 1H);
6.86 (s, 1H); 7.24±7.40 (m, 6H). 13C NMR (CDCl3): 26.7; 27.3; 32.5; 50.2; 52.8; 55.6; 55.9; 59.0;
109.3; 110.0; 110.7; 112.3; 126.5; 126.7; 126.8; 128.1; 128.3; 128.4; 129.0; 130.2; 140.4; 147.2; 147.5;
147.8. MS (EI) m/z (rel. int.): 445 (M+, 1), 281 (31), 207 (100), 191 (14), 177 (7), 167 (19), 151
(10), 146 (59), 147 (21), 133 (19), 128 (11), 117 (23), 105 (26), 96 (25), 91 (39), 79 (19), 77 (25), 65 (10),
57 (64). Anal. calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14. Found: C, 75.54; H, 7.06; N, 3.18.
3.6.2. ( )-(4bR,10bS)-N-Benzyl-4b,5,6,10b,11,12-hexahydro-2,3,7,8,9-pentamethoxy-benzo[c]-
phenanthridine 6b
20
1
Yield: 94%. ‰ꢀŠD = 67.6 (c=0.2, CH2Cl2). H NMR (CDCl3): 2.02 (m, 1H); 2.42 (m, 1H);
2.66 (m, 2H); 3.15 (m, 1H); 3.53 (d, 1H, J=16.2 Hz); 3.62 (d, 1H, J=16.2 Hz); 3.71 (s, 3H); 3.76
(d, 1H, J=15.3 Hz); 3.86 (s, 6H); 3.83 (d, 1H, J=15.3 Hz); 3.89 (s, 3H); 3.94 (s, 3H); 4.06 (d, 1H,
J=5.3 Hz); 6.52 (s, 1H); 6.68 (s, 1H); 7.19±7.71 (m, 6H). 13C NMR (CDCl3): 26.0; 29.0; 30.1;
43.9; 55.0; 55.5; 55.7; 56.0; 60.0; 106.3; 110.6; 111.9; 126.2; 126.7; 127.1; 128.8; 128.9; 129.2; 129.5;
130.6; 141.3; 145.6; 147.4; 148.0; 150.3. MS (EI) m/z (rel. int.): 475 (M+, 1), 385 (3), 325 (4), 223
(6), 205 (3), 167 (4), 149 (100), 132 (2), 104 (11), 76 (11), 65 (7), 57 (55), 51 (7). Anal. calcd for
C29H33NO5: C, 73.24; H, 6.99; N, 2.95. Found: C, 73.31; H, 7.06; N, 2.83.
3.6.3. ( )-(4bR,10bS)-N-Benzyl-4b,5,6,10b,11,12-hexahydro-2,3-dimethoxy-8,9-methylenedioxy-
benzo[c]phenanthridine 6c
20
1
Yield: 88%. ‰ꢀŠD = 97.1 (c=0.6, CH2Cl2). H NMR (CDCl3): 1.96 (m, 1H); 2.37 (m, 1H);
2.59 (m, 2H); 3.15 (m, 1H); 3.57 (d, 1H, J=16.2 Hz); 3.66 (d, 1H, J=16.2 Hz); 3.73 (d, 1H,
J=15.1 Hz); 3.78 (s, 3H); 3.82 (d, 1H, J=15.1 Hz); 3.91 (s, 3H); 3.99 (d, 1H, J=4.9 Hz); 5.85 (s,
2H); 6.33 (s, 1H); 6.47 (s, 1H); 6.82 (s, 1H); 7.21±7.32 (m, 6H). 13C NMR (CDCl3): 26.1; 27.0;
32.2; 50.0; 52.6; 55.4; 55.7; 58.6; 100.2; 106.4; 106.8; 110.5; 111.8; 126.6; 126.7; 127.9; 128.2; 129.4;
129.9; 131.2; 138.9; 140.8; 145.4; 147.0; 147.5. MS (EI) m/z (rel. int.): 429 (M+, 1), 355 (100), 320
(26), 292 (40), 277 (11), 248 (16), 190 (9), 167 (11), 131 (9), 95 (16). Anal. calcd for C27H27NO4: C,
75.50; H, 6.34; N, 3.26. Found: C, 75.56; H, 6.28; N, 3.31.
3.6.4. ( )-(4bR,10bS)-N-Benzyl-4b,5,6,10b,11,12-hexahydro-2,3-methylenedioxy-8,9-dimethoxy-
benzo[c]phenanthridine 6d
20
1
Yield: 86%. ‰ꢀŠD = 91.6 (c=0.1, CH2Cl2). H NMR (CDCl3): 1.93 (m, 1H); 2.31 (m, 1H);
2.63 (m, 2H); 3.11 (m, 1H); 3.56 (d, 1H, J=16.2 Hz); 3.61 (d, 1H, J=16.2 Hz); 3.70 (d, 1H,
J=15.1 Hz); 3.77 (s, 3H); 3.82 (d, 1H, J=15.1 Hz); 3.94 (s, 3H); 4.03 (d, 1H, J=5.1 Hz); 5.87 (s,
2H); 6.31 (s, 1H); 6.47 (s, 1H); 6.80 (s, 1H); 7.20±7.36 (m, 6H). 13C NMR (CDCl3): 26.0; 27.2;
32.5; 50.4; 53.1; 55.5; 55.7; 58.9; 100.0; 106.3; 106.8; 110.4; 111.8; 126.5; 126.7; 127.8; 128.1; 129.5;
130.1; 131.2; 138.5; 140.9; 145.3; 147.0; 147.4. MS (EI) m/z (rel. int.): 429 (M+, 1), 367 (10), 355
(100), 320 (11), 292 (32), 277 (25), 190 (19), 167 (4), 131 (6), 95 (11), 91 (7), 77 (26), 56 (22). Anal.
calcd for C27H27NO4: C, 75.50; H, 6.34; N, 3.26. Found: C, 75.51; H, 6.41; N, 3.20.
Acknowledgements
Financial support from the Basque Government (a fellowship to J.L.V.) from the University of
the Basque Country (project UPV 37/98) and from the Spanish DGES (Project PB98-0600) is
gratefully acknowledged.

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 1227±1237
1237
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