Biomimetic Total Synthesis of Dysoxylum Alkaloids

Article abstract of DOI:10.1021/acs.joc.9b02093

A five-step total synthesis of Dysoxylum alkaloids has been achieved using a biomimetic approach from zanthoxylamide protoalkaloids. The synthesis featured a direct amidation and a Bischler-Napieralski reaction to form the dihydroisoquinoline ring, which

Full text of DOI:10.1021/acs.joc.9b02093

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Article
Biomimetic Total Synthesis of Dysoxylum Alkaloids
Carlos E. Puerto Galvis, and Vladimir V. Kouznetsov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02093 • Publication Date (Web): 05 Nov 2019
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Biomimetic Total Synthesis of Dysoxylum Alkaloids
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Carlos E. Puerto Galvis and Vladimir V. Kouznetsov*
a
Laboratorio de Química Orgánica y Biomolecular, CMN, Universidad Industrial de Santander. Parque
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Tecnológico Guatiguará, Km 2 Vía Refugio, Piedecuesta 681011, Colombia. Tel: +57 7 634 4000 Ext.
3593.
MeO
MeO
MeO
MeO
HN
O
N
Five steps
Amidation
Hydrogenation
Bischler-Napieralski
AHT reaction
H
O
Reductive amination
O
O
O
Zanthosine
(S)-Dysoxyline
Isolated from
Isolated from
Zanthoxylum rubescens
Dysoxylum lenticellare
Abstract: A five-step total synthesis of Dysoxylum alkaloids has been achieved using a biomimetic
approach from zanthoxylamide protoalkaloids. The synthesis featured a direct amidation and a
Bischler-Napieralski reaction to form the dihydroisoquinoline ring, which was then subjected to a
Noyori asymmetric transfer hydrogenation to establishing the stereogenic center at C-1. Our synthetic
sequence provides an important perspective on the biosynthetic origin of Dysoxylum alkaloids, since
six natural alkaloids and twelve synthetic analogues were obtained with high enantioselectivity and
in overall yields up to 68 %. In addition, we describe the acute toxicity toward zebrafish embryos of
Dysoxylum alkaloids, comparing their toxicity with their corresponding zanthoxylamide
protoalkaloids and establishing an enantioselectivity-toxicity relationship.
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Introduction
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Dysoxylum alkaloids are a family of 1-phenethyl-tetrahydroisoquinolines with seven
members having identified to date: (S)-dysoxyline,1 (S)-autumnaline,2 (S)-homolaudanosine,1
(+)-colchiethanamine,3 (+)-colchiethine,3 (-)-isoautumnaline4 and (S)-(+)-O,O-dimethyl-
autumnaline (Figure 1).5
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MeO
MeO
MeO
HO
MeO
MeO
HO
N
N
N
N
MeO
H
H
H
H
MeO
OH
MeO
O
O
OMe
OMe
OH
(S)-Dysoxyline
(S)-Autumnaline
(S)-Homolaudanosine (+)-Colchiethanamine
HO
HO
MeO
N
N
N
MeO
H
MeO
MeO
H
H
MeO
OH
MeO
OMe
OMe
OMe
OMe
(+)-Colchiethine
(-)-Isoautumnaline (S)-(+)-O,O-Dimethylautumnaline
Figure 1. Representative Dysoxylum alkaloids.
These alkaloids are known since Leary isolated (S)-dysoxyline (0.01 %) and (S)-
homolaudanosine (0.03 %) from the leaves of Dysoxylum lenticellare in 1983,1 and their
medical interest started when Ilesanmi reported their cardiac activity in 1986.6 However, the
very low content of these compounds in natural sources has been the major drawback during
the exploration of their pharmacological profile. Thus, the responsibility of preparing these
alkaloids at multi-gram scale in a laboratory lays on the organic chemistry. (S)-
Homolaudanosine was the first synthetized derivative of this family (1987),7 and although
several elegant works have been reported during the last nine years for the total synthesis of
Dysoxylum alkaloids,8 none of them were attempted to mimic their biosynthesis, so these
approaches involved many synthetic steps, were directed to obtain one or a few compounds
and resulted in poor overall yields (Table 1).9-15
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Table 1. Strategies developed for the total synthesis of Dysoxylum alkaloids.
Overall
Year
Alkaloid(s)
Strategy
Steps
yield [%]
7
8
9
Asymmetric
Allylation9
2011
(S)-Homolaudanosine
8
30
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(S)-Dysoxyline
(+)-Colchiethanamine
(+)-Colchiethine
18
17
17
17
12
14
Julia-Kocienski
reaction10
2012
A3 coupling
alkynylation11
2014
2014
(S)-Dysoxyline
5
7
39
24
41
Pictet-Spengler
Reaction12
(R)-(+)-Colchiethine
Mukaiyama-
Mannich13
2015
2016
(±)-Homolaudanosine
(±)-Dysoxyline
6
3
Lithiation14
42
49
33
(±)-Homolaudanosine
(±)-Dysoxyline
Double
alkylation15
2019
5
To the best of our knowledge, the biosynthetic pathway for (S)-dysoxyline and their
related Dysoxylum alkaloids has not been reported so far, but they stand as one of the key
intermediates in the biosynthesis of complex alkaloids like homoaporphines,16 colchicine17
and (−)-melanthioidine.18 Thereby, and based on the biosynthetic pathway of reticuline and
coclaurine,19
simple
tetrahydroisoquinoline
alkaloids,
where
N-phenethyl-2-
phenylacetamides are the pivotal intermediates of their biogenesis. We suspected that a
specific family of amides could be involved in the biosynthetic origins of Dysoxylum
alkaloids, and during the course of our synthetic study of zanthoxylamide protoalkaloids,20
the structural relationship of these natural compounds with the Dysoxylum alkaloids were
clearly determined.
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Keeping the above considerations in mind, our biogenetic hypothesis was focused in the
chemical transformation of zanthoxylamide protoalkaloids, into the more complex
Dysoxylum alkaloids, supporting our proposal in some recognized facts that could established
the biosynthetic pathway for (S)-dysoxyline and their related alkaloids. First, tyrosine and
phenylalanine are the natural building blocks during the biosynthesis of N-phenylethyl
cinnamamides,21 the isoquinoline scaffold is prepared in nature by several enzymes
(strictosidine synthase or “Pictet-Spenglerase”) and this process resembles the Bischler-
Napieralski reaction (BNR),22 and finally, acyclic and cyclic imines are reduced by
NAD(P)H-dependent enzymes found in several plant alkaloid biosynthetic pathways, which
is moreover similar to the Asymmetric Transfer Hydrogenation (ATH) reaction or Noyori
reduction.23,24
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Herein, we report the total synthesis of the representative members of the Dysoxylum
alkaloid family, including six natural alkaloids and twelve synthetic analogues, with (S)- and
(R)-configuration. Furthermore, we describe the in vivo toxicological profile of these
compounds and its relationship with the stereogenic center at C-1 of the
tetrahydroisoquinoline scaffold.
Results and discussion
Biomimetic Total Synthesis of Dysoxylum Alkaloids
To test our biogenetic hypothesis, we selected a library of nine zanthoxylamide
protoalkaloids 3a-i, easily prepared from commercially available phenylethylamines 1 and
cinnamic acids 2a-i under the catalysis of tris-(2,2,2-trifluoroethyl) borate (B(OCH2CF3)3)
based on our previous report (Table 2).20 This series of compounds 3a-i were obtained in
good to excellent yields and under mild reaction conditions. Despite that our main goal is to
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report the synthesis of Dysoxylum alkaloids from zanthoxylamides, we also focused our
efforts in offers a possible scale-up synthesis of 1-phenethyl-tetrahydroisoquinolines for
further pharmaceutical purposes in four steps by starting from the propanamide 3b. This
compound was easily obtained from the respective 3-(4-methoxyphenyl) propionic acid 2b
(93 %), demonstrating that our amidation process is suitable for the synthesis of amides from
more commercially available, structural diversity, and in some cases, cheaper propionic acid
derivatives (Table 2).
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Table 2. Synthesis of zanthoxylamide protoalkaloids 3a-i mediated by B(OCH2CF3)3.a
MeO
MeO
R1
R2
R3
HN
O
MeO
MeO
NH2
B(OCH2CF3)3
HO
+
MeCN, 100 °C
24 h
3a-3i
81-93 %
O
b
1
2a-i
R1
R3
R2
MeO
MeO
MeO
MeO
MeO
HN
O
HN
O
HN
O
MeO
3cc
81 %
OMe
O
3ac
86 %
3bc
OMe
OMe
93 %
MeO
MeO
MeO
MeO
MeO
MeO
HN
HN
O
HN
O
3dc MeO
3ec
OMe
O
O
3f
88 %
OAc
O
OMe
81 %
86 %
MeO
MeO
MeO
MeO
MeO
MeO
HN
O
HN
O
HN
MeO
OMe
OMe
R1
OAc
3i
92 %
3g
88 %
3h
90 %
OAc
OAc
OMe
a
Reaction conditions: phenylethylamine 1 (2 mmol), cinnamic acid 3a-i (2 mmol), B(OCH2CF3)3
b
c
(0.5 equiv), CH3CN (0.5 M), 100 °C, 24 h. Isolated yield after column chromatography (SiO2).
Compounds previously reported under this approach.20
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The relevance of the last statement is that in principle, compounds 3a-i could be used as
precursors of the BNR to furnished the desired 3,4-dihydroisoquinoline core. However, in a
previous study,25 our group found that the α,β-unsaturation present in the N-phenylethyl
cinnamamides 3a-i unfavored the cyclization reaction under the common reaction conditions
of the BNR, forcing the use of the ionic liquid [bmim]PF6 as a solvent which lead the
formation of the desired 3,4-dihydroisoquinolines as PF6-salts, derivatives that resulted to be
unreactive toward the ATH reaction conditions.
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Thus, our strategy demanded the reduction of the C=C bond of α,β-cinnamamides 3a-i
prior to the cyclization process. Fortunately, this step was performed in almost quantitative
yields through the Pd/C-catalyzed hydrogenation reaction under atmospheric H2, furnishing
the corresponding N-phenethyl-3-phenylpropanamides 4a-h which were used in the next step
without further purification (Scheme 1).
Scheme 1. Synthesis of N-phenethyl-3-phenylpropanamides 4a-h
MeO
MeO
HN
O
HN
O
MeO
MeO
H2
10 % Pd/C,
EtOH, 12 h
3a 3c-i
4a-h
>99 %
,
R1
R3
R1
R3
R2
R2
Thereby, the amides 3b and 4a-h were used as starting materials of the BNR, where the
optimal reaction conditions were found to be POCl3 (1.5 equiv) at 50 °C in acetonitrile as a
solvent to furnish the respective 1-phenethyl-3,4-dihydroisoquinolines 5a-i in excellent
yields (94-99 %) and as free-bases (Table 3).
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Table 3. Biomimetic strategy for the construction of isoquinoline scaffold 5a-i.a
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6
7
8
MeO
MeO
MeO
MeO
HN
O
N
POCl3
CH3CN, 50 °C
24 h
9
3b
4a-i
and
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5a-i
R1
R3
b R1
R3
94-99 %
R2
R2
MeO
MeO
MeO
MeO
MeO
N
N
N
MeO
OMe
5cc
98 %
5ac
94 %
5bc
OMe
N
OMe
N
97 %
MeO
MeO
MeO
MeO
MeO
MeO
N
OMe
5dc MeO
99 %
5e
O
5f
98 %
OAc
N
O
N
OMe
N
99 %
MeO
MeO
MeO
MeO
MeO
MeO
MeO
OMe
OMe
R1
OAc
5i
99 %
5g
95 %
5h
99 %
OAc
OAc
OMe
a
Reaction conditions: propanamides 4a-i (1.5 mmol), POCl3 (2.25 mmol, 1.5 equiv), and CH3CN
(0.3 M), 50 °C, 24. Isolated yield after column chromatography (SiO2). c Known compounds (see
b
Experimental Section for details).
With 1-phenethyl-3,4-dihydroisoquinolines 5a-i in hand, we then focused our efforts in
check our biogenetic hypothesis by studying the transfer hydrogenation of 3,4-
dihydroisoquinolines 5a-i into the desired chiral tetrahydroisoquinolines. Transfer
hydrogenation is one of the most effective reactions for obtaining chiral secondary amines,26
and as far as we know, this powerful tool has not been used for the synthesis Dysoxylum
alkaloids.
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In order to study the Ru-catalyzed ATH reaction, we employed the dihydroisoquinoline
5a as a model substrate, however this reaction will lead to the corresponding
tetrahydroisoquinoline 6a, which we found early that could be an unstable intermediate.25
Thereby, guided by the work of Ma and co-workers,11 who studied the racemization in the
N-methylation step during the total synthesis of (S)-dysoxyline, and demonstrated that the
enantiopurity of intermediate 6a will be retained if the N-methylation was performed a 0°C,
we decided to perform an ATH reaction/reductive amination sequence to obtain the desired
alkaloid 7a, without the isolation of 6a due to its poor stability and the fact that the obtained
enantioselectivity of the ATH reaction will be the same of the global process (Table 4).
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Table 4. Screening of the reaction conditions for the Ru-catalyzed ATH reaction/reductive
amination sequence to obtain 7a.a
Ts
Ph
N
Ru
MeO
MeO
MeO
MeO
MeO
MeO
N
Cl
Ph
H2
N
NH
N
Ru
(S, S)- TsDPEN
CH3
C
(
H2O)n
H Source
Solvent, T
NaBH3CN, ZnCl2
MeOH, 0 °C, 6 h
5a
(R)-6a
(R)-7a
Entry H Source (ratio/equiv) Solvent (M/ratio)
T (°C)
Yield
ee %c
(%)b
N.R.d
78
1
2
3
4
5
6
H2(g) (1 atm)
HCO2H/Et3N (1.1/1)
HCO2H/Et3N (2.5/1)
HCOONa (5)
MeOH
MeOH
MeOH
25
60
60
60
60
40
-
62
91
87
88
93
81
80
86
89
H2O/MeOH (1/3)
H2O/DMF (1/3)
H2O/DMF (1/3)
HCOONa (5)
HCOONa (5)
7
8
HCOONa (5)
HCOONa (5)
H2O/DMF (1/1)
H2O/DMF (1/1)
40
25
92
64
95
89
a ATH reaction: 5a (0.5 mmol), (S,S)-RuTsDPEN (2 mol %), H source, solvent (3 mL), temperature.
Reductive amination: (R)-6a (0.5 mmol), (CH2O)n (1.5 mmol), NaBH3CN (0.55 mmol), ZnCl2 (0.25
mmol), MeOH (10 mL). b Isolated yield after two steps and after column chromatography. c The ee%
d
value of 7a was determined by HPLC equipped with a column with chiral stationary phase. N.R.
No Reaction.
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Our first attempt was based on the report that molecular hydrogen could be used as a
hydrogen source in ATH reactions,27 however, under atmospheric pressure and at room
temperature, the reaction did not proceed (Table 4, entry 1). Therefore, we screened for better
hydrogen sources that could also provide the desired product and mediate the asymmetric
proton transfer. Among these, the formic acid (HCO2H) and triethylamine Et3N) azeotropic
system,28 in different ratios, furnished the desired tetrahydroisoquinoline 7a, after the high-
yield methylation step, in moderate yield and good ee% (Table 4, entries 2 and 3). Next, we
turned to sodium formate (HCOONa) as an alternative hydrogen source,29 allowing to
perform the reaction under aqueous media with an organic co-solvent. After screening
between methanol (MeOH) and dimethylformamide (DMF) as organic solvents, we noted
that at 60 °C compound 7a was obtained with better yield and ee% when H2O/DMF mixture
was used as a solvent system in a 1/3 ratio (Table 4, entries 4 and 5).30 However, when the
reaction temperature was lowered to 40 °C to control the energy of the transition state,31 a
considerable increase in the enantioselectivity of 7a resulted, and in order to favored the
dissolution of HCOONa,32 the solvent system H2O/DMF was then established in a 1/1 ratio,
furnishing to our delight, the 1-phenethyl-tetrahydroisoquinoline 7a after to steps in 92 %
yield and 95 ee% (Table 4, entry 7). Finally, carrying out the reaction at room temperature
gave 7a with lower yield and ee% (Table 4, entry 8). It is worth to noted that these results
can be compared with the first approach developed by Noyori and coworkers, in which the
corresponding 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6c could be isolated using the
same catalyst but with different hydrogen sources with 72 % yield and 77 ee%.26c
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To date, the synthetic and biological studies regarding Dysoxylum alkaloids have been
focused exclusively on the (S)-enantiomers, nevertheless, one member of this family, the (-
)-isoautumnaline, exhibits a R-configuration at C-1, but its biological properties, as well as
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for the other members with this configuration (e.g. (R)-dysoxyline), are completely unknown.
Fortunately, one of the main features of our biomimetic strategy is the possibility to obtain
both (R)- and (S)-enantiomers of Dysoxylum alkaloids from the same precursor. Thus, using
the chiral catalyst (S,S)-RuTsDPEN under the established optimized reaction conditions
(Table 4, entry 7), a library of nine alkaloids with (R)-configuration (R)-7a-i were obtained
in excellent yields (90-97 %) and enantioselectivities (87-95 ee%), including the alkaloid
(−)-isomethylautumnaline (R)-7i with 81 % overall yield (Table 5).
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Table 5. Biomimetic total synthesis of (R)-Dysoxylum alkaloids (R)-7a-i.a
Ts
Ph
N
MeO
MeO
MeO
MeO
Ru
N
Cl
Ph
H2
N
N
CH3
Ru
1. (S,S)- TsDPEN
HCOONa
H2O/DMF (1/1), 40 °C
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2.
C
(
H2O)n
NaBH3CN, ZnCl2
MeOH, 0 °C, 6 h
R3
R5
R3
R5
R4
R4
b,c
5a-i
(R)-7a-i
90-97 %
87-95 ee %
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
CH3
CH3
CH3
OMe
(R)-7a
(R)-7b
93 %, 91 ee%
(R)-7c
92 %, 92 ee%
OMe
OMe
92 %, 95 ee%
MeO
MeO
MeO
CH3 MeO
MeO
N
N
N
CH
3 MeO
CH3
MeO
(R)-7d
OMe
O
(R)-7e
O
OMe
OH
90 %, 90 ee%
(R)-7f
97 %, 88 ee%
MeO
MeO
94 %, 87 ee%
MeO
MeO
MeO
N
N
N
CH3
CH3
MeO
CH3
OH
OMe
MeO
OMe
OMe
92 %, 89 ee%
OH
91 %, 89 ee%
OH
(R)-7g
(R)-7h
(R)-7i
90 %, 94 ee%
a ATH reaction: 5a-i (0.5 mmol), (S,S)-RuTsDPEN (2 mol %), HCOONa (2.5 mmol), (H2O/DMF)
(3 mL, 1/1), 40 °C, 12 h. Reductive amination: (R)-6a-i (0.5 mmol), (CH2O)n (1.5 mmol), NaBH3CN
(0.55 mmol), ZnCl2 (0.25 mmol), MeOH (10 mL), 6 h. b Isolated yield after two steps and after column
c
chromatography. The ee% value of (R)-7a-i was determined by HPLC equipped with a chiral
column.
These results allow to establish that either the electronic or steric effects of the substituents
in both aromatic rings, affected the course of the reaction or the asymmetric hydrogen transfer
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to the C=N bond, whereas the sequence of the last synthetic step, without the isolation of
(R)-6a-i, did not induce the racemization of these intermediates (Table 5).
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Finally, the total synthesis of the main members of the Dysoxylum alkaloid family, along
with other synthetic alkaloids, (S)-7a-i was achieved using the chiral catalyst (R,R)-
RuTsDPEN in good to excellent yields (86-95 %) and enantioselectivities (86-97 ee%)
(Table 6). Remarkably, the enantiomerically enriched (S)-homolaudanosine (S)-7c, (S)-(+)-
O,O-dimethyl-autumnaline (S)-7d and (S)-dysoxyline (S)-7e were obtained in five steps with
73 %, 68 % and 79 % overall yield, respectively. Whereas the wide structural diversity of
cinnamic acids 2a-l, enable the synthesis of (S)-O-methylcolchiethine (S)-7c and (+)-
methylcolchiethanamine (S)-7f with 82 and 68 % overall yield, respectively, from the
respective zanthoxylamide protoalkaloids (Table 6).
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Table 6. Biomimetic total synthesis of (S)-Dysoxylum alkaloids (S)-7a-i.a
5
6
7
8
Ts
Ph
N
MeO
MeO
MeO
MeO
Ru
N
Cl
Ph
H2
N
N
CH3
9
Ru
1. (R,R)- TsDPEN
HCOONa
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H2O/DMF (1/1), 40 °C
2.
C
(
H2O)n
NaBH3CN, ZnCl2
MeOH, 0 °C, 6 h
R3
R5
R3
R5
R4
R4
b,c
5a-i
(S)-7a-i
86-95 %
89-97 ee %
MeO
MeO
MeO
MeO
N
N
N
MeO
CH3
CH3
CH3 MeO
OMe
OMe
94 %, 91 ee%
MeO
(S)-7a
95 %, 93 ee%
OMe
(S)-7b
(S)-7c
91 %, 92 ee%
MeO
MeO
N
N
N
MeO
CH3
CH3
MeO
CH3 MeO
MeO
OMe
O
OH
O
OMe
(S)-7d
86 %, 94 ee%
(S)-7e
(S)-7f
90 %, 93 ee%
94 %, 93 ee%
MeO
MeO
MeO
MeO
MeO
N
N
N
MeO
CH3
CH3
CH3
OH
OMe
MeO
OMe
OMe
92 %, 89 ee%
OH
95 %, 97 ee%
OH
90 %, 95 ee%
(S)-7g
(S)-7h
(S)-7i
a ATH reaction: 5a-i (0.5 mmol), (R,R)-RuTsDPEN (2 mol %), HCOONa (2.5 mmol), (H2O/DMF)
(3 mL, 1/1), 40 °C, 12 h. Reductive amination: (S)-6a-i (0.5 mmol), (CH2O)n (1.5 mmol), NaBH3CN
(0.55 mmol), ZnCl2 (0.25 mmol), MeOH (10 mL), 6 h. b Isolated yield after two steps and after column
chromatography. c The ee% value of (S)-7a-i was determined by HPLC equipped with a chiral
column.
The mechanism of the ATH reaction of cyclic imines has been extensively investigated,
and taken these works under consideration, a mechanistic proposal for the generation of the
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chiral centre in both (R)- and (S)-enantiomers of Dysoxylum alkaloids is proposed (Scheme
2). Firstly, one of the main role of HCOONa, besides activate the pre-catalyst RuTsDPEN
into the real catalyst, the hydride complex H-RuTsDPEN,33 is to form formic acid under the
aqueos medium to protonate the dihydroisoquinoline 5 since this substrate enters into the
catalytic cycle as an iminium species 8 (Scheme 2). Then, 8 approaches to the ruthenium
central atom through the N+-H⋯O=S hydrogen bond with the sulfonyl group of the tosyl
moiety present in the TsDPEN ligand, which is also guided by the CH-π interaction between
the η6-arene ligand (p-cymene) and the aromatic ring of the dihydroisoquinoline ion 8, the
synergy of these both processes are the responsible for the origin of the enantioselectivity
throughout the ATH reaction, by generating the respective transition states TS1 and TS2
accordingly to the configuration of the catalyst RuTsDPEN (Scheme 2).34 Finally, the
hydrogen atom is asymmetrically transferred from the ruthenium complex to the electron-
withdrawing carbon C-1 of the dihydroisoquinoline ion 8, through the respective transition
states TS1* and TS2*, to furnishing the corresponding (R)-7 and (S)-7 enantiomers (Scheme
2).
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Scheme 2. Proposed reaction mechanism for the ATH reaction during the biomimetic
synthesis of Dysoxylum alkaloids.
Interaccion 6
N+–H----O=S
CH-
Approach
N
N
H
H
MeO
MeO
H
H
H
Asymetric
transfer
NH
O
N
O
N
Ru
(S, S)- TsDPEN
Ph
H
O
Ph
O
S
S
Ru
Ru
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H
N
N
H
Ph
Ph
H
Ph
Ph
TS1*
TS1
(R)-7
MeO
MeO
MeO
MeO
N
N
H
COOH
H2O
H
O
N
O
N
O
O
-
S
-CO2
S
H
COO
Ru
H
Ru
OOC
8
5
H2O
H
H
N
H
N
H
Ph
Ph
Ph
Ph
Interaccion 6
CH-
N+–H----O=S
Approach
MeO
MeO
Ru
(R, R)- TsDPEN
H
Asymetric
transfer
N
N
O
O
O
N
H
H
O
NH
S
N
S
Ru
Ru
H
H
Ph
Ph
H
H
N
H
N
H
Ph
Ph
Ph
Ph
TS2
TS2*
(S)-7
In vivo toxicity assessment in zebrafish embryos
The zebrafish embryo model is one of the well-established protocols in modern in vivo
studies for rapidly assessing the toxicity of diverse natural and synthetic molecules of
interest.35-39 Moreover, this biological tool has been successfully used to identify and study
the different biological and toxicological activities of chiral compounds, referred as
enantioselective toxicity.40 Thereby, this approach was adapted in our laboratory, with some
modifications, for the toxicological assessment of both (R)- and (S)-enantiomers of
Dysoxylum alkaloids, comparing their toxicity with the previous LC50 values reported for
their corresponding zanthoxylamide protoalkaloids (Table 7).20
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Table 7. Zebrafish embryo LC50 values determined for both (R)- and (S)-enantiomers of
Dysoxylum alkaloids and their corresponding zanthoxylamide protoalkaloids.a
MeO
MeO
MeO
MeO
MeO
MeO
N
N
HN
O
N
HN
O
N
MeO
CH3
MeO
CH3
MeO
MeO
CH3
MeO
MeO
CH3
7
8
9
OMe
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OMe
OMe
OMe
LC50 = 203.4  8.1
MeO
3a
LC50 = 263.6  5.8
(S)-7a
LC50 = 35.4 ± 3.1
3b
(R)-7a
LC50 = 23.7 ± 1.3
(S)-7b
LC50 = 24.6 ± 2.1
MeO
(R)-7b
LC50 = 15.2 ± 1.7
MeO
MeO
MeO
MeO
N
N
HN
O
N
HN
O
N
MeO
CH3
MeO
CH3
MeO
MeO
CH3
MeO
MeO
CH3
OMe
MeO
OMe
OMe
MeO
OMe
OMe
MeO
OMe
OMe
(S)-7c
LC50 = 45.7 ± 2.5
OMe
OMe
(R)-7c
LC50 = 32.8 ± 1.4
OMe
OMe
LC50 = 157.2  5.9
MeO
OMe
3c
3d
(S)-7d
(R)-7d
LC50 = 272.5  5.0
LC50 = 48.9 ± 1.4
LC50 = 36.8 ± 1.7
MeO
MeO
MeO
MeO
MeO
N
N
HN
O
O
N
HN
O
N
MeO
CH3
MeO
CH3
MeO
MeO
CH3
MeO
MeO
CH3
O
O
O
OH
O
OH
O
OAc
LC50 = 192.5  5.6
MeO
3e
LC50 = 276.9  0.5
(S)-7e
LC50 = 19.0 ± 2.6
3f
(R)-7e
LC50 = 14.9 ± 0.9
(S)-7f
(R)-7f
LC50 = 18.1 ± 1.1
LC50 = 12.1 ± 1.1
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
HN
O
N
HN
O
N
MeO
CH3
CH3
MeO
MeO
CH3
MeO
CH3
OMe
OH
OMe
OH
OMe
OAc
OH
OMe
OH
OMe
OAc
LC50 = 177.4  1.3
OMe
3g
(S)-7g
LC50 = 22.6 ± 1.0
3h
(R)-7g
(S)-7h
(R)-7h
LC50 = 211.0  7.5
LC50 = 14.5 ± 0.8
LC50 = 27.8 ± 1.4
LC50 = 22.2 ± 0.5
MeO
MeO
MeO
N
HN
O
N
MeO
CH3
MeO
MeO
CH3
MeO
OMe
MeO
OMe
MeO
OMe
OH
OH
OAc
3i
(S)-7i
LC50 = 30.0 ± 1.1
(R)-7i
LC50 = 162.0  7.1
LC50 = 24.1 ± 1.5
a LC50 values are the mean ± SEM of three different experiments in triplicate.
From the results depicted in Table 7, it is important to mention in first place that
zanthoxylamide protoalkaloids 3a-i (avg. LC50 = 217 μM) resulted to be 20-fold less toxic to
zebrafish embryos than Dysoxylum alkaloids 7a-i (avg. LC50 = 25 μM); and within this series
of tetrahydroisoquinolines, the (R)-enantiomers (avg. LC50 = 21 μM) resulted to be slightly
toxic in comparison with the (S)-enantiomers (avg. LC50 = 30 μM).
It was found that independent of the configuration of the stereogenic centre at C-1, the
inclusion of hydroxyl groups at the aromatic ring of the phenyl ethyl motif, enhance the
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toxicity of both (R)- and (S)-enantiomers, (R)-7f (LC50 = 12.1 μM) and (S)-7f (LC50 = 18.1
μM) (Table 7). However, the inclusion of one, two, or three, methoxy groups at this ring
reduces the toxicity as was observed for derivatives (R)-7d (LC50 = 36.8 μM) and (S)-7d
(LC50 = 48.9 μM), the less toxic compounds among the series of Dysoxylum alkaloids (Table
7).
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Finally, the most representative member of the Dysoxylum family, the (S)-dysoxyline (S)-
7e, which previously exhibited a significant in vivo cardioactivity,6 showed a moderate
toxicity (LC50 = 19.0 µM), contributing to reveal its pharmacological profile.
Conclusions
In conclusion, we have accomplished the total synthesis of Dysoxylum alkaloids by
developing a biomimetic approach for the first time from zanthoxylamide protoalkaloids.
Our strategy involved five synthetic and efficient steps, where the sequence: amidation,
hydrogenation and Bischler-Napierlaski reaction allowed the construction of the isoquinoline
core, that enable the later study the ATH reaction/reductive amination sequence. For the
purposes of our study, these key steps were readily extended to the asymmetric synthesis of
both (R)- and (S)-enantiomers of Dysoxylum alkaloids, furnishing the synthetic (R)-7a-i and
natural (S)-7a-i derivatives that will lead further biological studies in order to explore their
cardiac activity and the effect of the stereochemistry of C-1 carbon, since these alkaloids are
low-abundance natural products and most of them possess the (S)-configuration at C-1.
Nevertheless, the access to cyclic amines (R)-6a-i and (S)-6a-i could be of great interest in
the synthesis of more complex compounds and deserves a deep study. Finally, the brevity,
high efficiency and high stereoselectivity of our biomimetic hypothesis afford a potentially
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evidence of the biosynthesis of Dysoxylum alkaloids and revealed for the first time their
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toxicological profile for further pharmacological studies.
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Experimental section
General information. Unless otherwise noted, all reactions have been carried out with distilled
and dried solvents and under atmosphere pressure. All work-up and purification procedures were
carried out with reagent grade solvents (purchased from Aldrich and Merck) in air. Thin-layer
chromatography (TLC) was performed using Merck silica gel 60 F254 precoated plates (0.25 mm).
Column chromatography was performed using spherical silica gel 70Å, 40-75 µm or on a Biotage®
Automated Liquid Chromatography System Isolera One® using Biotage® SNAP Ultra 25 μm HP-
Sphere 10 g silica gel cartridges.
Infrared (FT-IR) spectra were recorded on a Lumex Infralum FT-02 spectrometer, and the wave
numbers of the absorption peaks are listed in cm-1. Peaks/Bands are characterized according to the
functional group. 1H NMR spectra were recorded on a Bruker Avance-400 (400 MHz) spectrometer.
Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl3: δ
7.26 ppm; DMSO-d6: δ 2.50 ppm). Data were reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, dd = doublet of doublets, br = broad, m = multiplet), coupling constants
(Hz) and integration. 13C NMR spectra were recorded on a Bruker Avance-400 (400 MHz)
spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from solvent
resonance as the internal standard (CDCl3: δ 77.00 ppm; DMSO-d6: δ 40.45 ppm). On DEPT-135
spectra, the signals of CH3 and CH carbons are shown with positive phase (+), while CH2 carbons are
shown with negative phase (-). Quaternary carbons are not shown. HPLC analyses were performed
on a Hitachi L-2000 pump and Hitachi L-2420 UV/Vis detector. The enantiomeric excesses (ee) were
determined using a Kromasil® 5-Amycoat™ (250 × 4.6 mm) column. Optical rotations were
measured with an Optical ActivityTD Series 19-79-38/A digital polarimeter with 1-dm-long cell.
High resolution mass spectra (HRMS) were measured on a Thermo Scientific LTQ Orbitrap XL
apparatus. Melting points were measured on a Fisher Johns melting point apparatus and are
uncorrected.
General procedure and characterization data of zanthoxylamide protoalkaloids 3a-i. In a 50
mL vial equipped with a magnetic stir bar was added the respective cinnamic acid 2a-i (2 mmol), the
vial was sealed and the air was evacuated establishing an Argon atmosphere and anhydrous MeCN
(8 mL, 0.5 M) was added. Then, B(OCH2CF3)3 (1 mmol, 0.5 equiv.) was added dropwise into the
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stirred solution at room temperature. After 10 minutes, the corresponding 3,4-
dimethoxyphenylethylamine 1 was added in one portion and the reaction mixture was stirred at 100
°C in an oil bath for 24 hours. After cooling to room temperature, the mixture was extracted with
AcOEt (3 x 20 mL). The organic layers were combined, dried over with Na2SO4, filtered and
concentrated under reduced pressure. The crude material was purified by silica gel column
chromatography (20-30% AcOEt in petroleum ether) to furnished the desired zanthoxylamide
protoalkaloids 3a-i.
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N-(3,4-Dimethoxyphenylethyl) cinnamamide (3a). Following general procedure, compound 3a
was obtained as a white solid 0.53 g (1.72 mmol, 86 %); Rf [hexane-EtOAc, 1:1] = 0.64; m.p. = 122-
124 ºC (lit. 119-120 °C41); IR (KBr Disk): 3317 (NH), 3070 (CH2-Ar), 2962 (OCH3), 1651(C=O), 1619

(C=C), 1542 (NH), 1326 (CH2-Ar), 1234 (C-N) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.61 (1H, d, J
= 15.6 Hz, =CHPh), 7.47-7.44 (2H, m, 6 and 7-HAr), 7.34-7.31 (3H, m, 6’, 7’ and 8’-HAr), 6.80 (1H,
d, J = 7.9 Hz, 10-HAr), 6.74 (2H, d, J = 8.8 Hz, 5’ and 9’-HAr), 6.36 (1H, d, J = 15.6 Hz, =CHCO),
5.94 (1H, t, J = 6.7 Hz, NH), 3.84 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.62 (2H, q, J = 6.7 Hz, -
CH2NH), 2.83 (2H, t, J = 6.9 Hz, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 166.0, 149.0,
147.7, 141.0 (+), 134.8, 131.4, 129.7 (+), 128.8 (+, 2C), 127.8 (+, 3C), 120.7 (+), 111.9 (+), 111.4
(+), 55.9 (+), 55.9 (+), 41.0 (-), 35.2 (-). HRMS (ESI): calcd. for C19H22NO3 [M+H]+: 312.1594,
found: 312.1589.
N-(3,4-Dimethoxyphenethyl)-3-(4-methoxyphenyl)propanamide (3b). Following general
procedure, compound 3b was obtained as a white solid 0.64 g (1.86 mmol, 93 %) from 3-(4-
methoxyphenyl)propanoic acid and 3,4-dimethoxyphenylethylamine 1; Rf [hexane-EtOAc, 1:1] =
0.66; m.p. = 118-120 ºC; IR (KBr Disk): 3301 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1635 (C=O), 1542

(NH), 1511 (C-N), 1234 (C-N) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.08 (2H, d, J = 8.5 Hz, 6’ and
8’-HAr), 6.80 (2H, d, J = 8.6 Hz, 5’ and 9’-HAr), 6.76 (1H, d, J = 8.1 Hz, 9-HAr), 6.66-6.59 (2H, m 6
and 10-HAr), 5.46 (1H, t, J = 6.8 Hz, NH), 3.85 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.77 (3H, s,
OCH3), 3.44 (2H, q, J = 6.8 Hz, -CH2NH), 2.87 (2H, t, J = 7.6 Hz, -CH2CO), 2.68 (2H, t, J = 7.0 Hz,
-CH2Ph), 2.87 (2H, t, J = 7.6 Hz, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.2, 158.0,
149.0, 147.6, 132.9, 131.3, 129.3 (2C, +), 120.6 (+), 113.9 (2C, +), 111.8 (+), 111.2 (+), 55.9 (+),
55.9 (+), 55.3 (+), 40.7 (-), 38.8 (-), 35.3 (-), 30.9 (-). HRMS (ESI): calcd. for C20H26NO4 [M+H]+:
344.1856, found: 344.1853. Spectral data were in accordance with those reported in the literature.42
N-(3,4-Dimethoxyphenylethyl)-3,4-dimethoxycinnamamide (3c). Following general procedure,
compound 3c was obtained as a white solid 0.60 g (1.62 mmol, 81 %); Rf [hexane-EtOAc, 1:1] =
0.44; m.p. = 123-125 ºC; IR (KBr Disk): 3301 (NH), 2931 (OCH3), 1650 (C=O), 1619 (C=C), 1511 (C-
N), 1265 (C-N), 1141 (C-O) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.52 (1H, d, J = 15.5 Hz, =CHPh),
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7.00 (1H, dd J = 8.3, 1.8 Hz, 9-HAr), 6.95 (1H, d, J = 1.9 Hz, 6-HAr), 6.76 (2H, dd, J = 8.5, 4.3 Hz, 8’
and 9’-HAr), 6.72-6.69 (2H, m, 10 and 5’-HAr), 6.24 (1H, d, J = 15.5 Hz, =CHCO), 6.02 (1H, t, J =
6.9 Hz, NH), 3.84 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.80 (6H, s, 2xOCH3), 3.59 (2H, q J = 6.9 Hz,
-CH2NH), 2.80 (2H, t, J = 7.0 Hz, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 166.2, 150.5,
149.0, 149.0, 147.6, 140.7 (+), 131.4, 127.7, 121.9 (+), 120.6 (+), 118.6 (+), 112.0 (+), 111.4 (+),
111.0 (+), 109.6 (+), 55.9 (2C, +), 55.8 (+), 55.8 (+), 40.9 (-), 35.2 (-). HRMS (ESI): calcd. for
C21H26NO5 [M+H]+: 372.1805, found: 372.1800. Spectroscopy data agree with those reported in the
literature.43
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N-(3,4-Dimethoxyphenylethyl)-3,4,5-trimethoxycinnamamide (3d). Following general procedure,
compound 3d was obtained as a white solid 0.65 g (1.62 mmol, 81 %); Rf [hexane-EtOAc, 1:1] =
0.36; m.p. = 128-130 ºC (lit. 127-128 °C44); IR (KBr Disk): 3286 (NH), 2931 (OCH3), 1650 (C=O)
,
1619 (C=C), 1511 (C-N), 1265 (C-N), 1141 (C-O) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.52 (1H,
d, J = 15.5 Hz, =CHPh), 6.82 (1H, d J = 8.0 Hz, 9-HAr), 6.77-6.73 (2H, m, 6 and 10-HAr), 6.70 (2H,
s, 5’ and 9’-HAr), 6.23 (1H, d, J = 15.5 Hz, =CHCO), 5.68 (1H, t, J = 6.8 Hz, NH), 3.86 (12H, s,
4xOCH3), 3.85 (3H, s, OCH3), 3.64 (2H, q, J = 6.8 Hz, -CH2NH), 2.83 (2H, t, J = 6.8 Hz, -CH2Ph).
13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 165.9, 153.5 (3C), 149.2, 147.8, 141.1 (+), 131.4, 130.4,
120.8 (+), 120.0 (+), 112.1 (+), 111.5 (+), 105.0 (2C, +), 61.0 (+), 56.2 (2C, +), 56.0 (+), 56.0 (+),
40.9 (-), 35.2 (-). HRMS (ESI): calcd. for C22H28NO6 [M+H]+: 402.1911, found: 402.1915.
N-(3,4-Dimethoxyphenylethyl)-3,4-methylenedioxycinnamamide (3e). Following general
procedure, compound 3e was obtained as a white solid 0.61 g (1.72 mmol, 86 %); Rf [hexane-EtOAc,
1:1] = 0.39; m.p. = 165-167 ºC (lit. 159-161 °C44); IR (KBr Disk): 3301 (NH), 3070 (CH2-Ar), 2977

(OCH3), 2900 (-OCH2O-), 1650 (C=O), 1619 (C=N), 1542 (NH), 1326 (CH2-Ar), 1249 (C-N) cm-1; 1H NMR
(400 MHz, CDCl3): δ(ppm): 7.51 (1H, d, J = 15.3 Hz, =CHPh), 6.94 (2H, d, J = 7.8 Hz, 7 and 10-HAr),
6.81-6.76 (2H, m, 8’ and 9’-HAr), 6.74 (2H, d, J = 9.7 Hz, 5’ and 6-HAr), 6.16 (1H, d, J = 15.4 Hz,
=CHCO), 5.96 (2H, s, -OCH2O-), 5.84 (1H, t, J = 6.3 Hz, NH), 3.84 (6H, s, 2xOCH3), 3.60 (2H, q, J
= 6.3 Hz, -CH2NH), 2.81 (2H, t, J = 6.7 Hz, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 166.1,
149.1, 149.0, 148.2, 147.7, 140.8 (+), 131.4, 129.2, 123.9 (+), 120.7 (+), 118.7 (+), 111.9 (+), 111.4
(+), 108.5 (+), 106.3 (+), 101.5 (-), 55.9 (+), 55.9 (+), 41.0 (-), 35.3 (-). HRMS (ESI): calcd. for
C20H22NO5 [M+H]+: 356.1492, found: 356.1488.
N-(3,4-Dimethoxyphenylethyl)-4-acetoxycinnamamide (3f). Following general procedure,
compound 3f was obtained as a white solid 0.65 g (1.76 mmol, 88 %); Rf [hexane-EtOAc, 1:1] = 0.31;
m.p. = 143-145 ºC; IR (KBr Disk): 3301 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1758 (C=O), 1650 (C=O)
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1619 (C=C), 1542 (NH), 1203 (C-N) cm-1; H NMR (400 MHz, CDCl3): δ(ppm): 7.55 (1H, d, J = 15.6
Hz, =CHPh), 7.44 (2H, d, J = 8.6 Hz, 6’ and 8’-HAr), 7.05 (2H, d, J = 8.6 Hz, 5’ and 9’-HAr), 6.79
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(1H, d, J = 8.7 Hz, 10-HAr), 6.74-6.72 (2H, m, 6 and 9-HAr), 6.28 (1H, d, J = 15.6 Hz, =CHCO), 5.98
(1H, t, J = 6.9 Hz, NH), 3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.60 (2H, q, J = 6.9 Hz, -CH2NH),
2.81 (2H, t, J = 7.0 Hz, -CH2Ph), 2.28 (3H, s, CH3). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 169.3,
166.1, 151.7, 149.1, 147.8, 140.1 (+), 132.5, 131.3, 128.9 (2C, +), 122.1 (2C, +), 120.7 (+), 120.7 (+),
112.0 (+), 111.5 (+), 56.0 (+), 55.9 (+), 41.1 (-), 35.2 (-), 21.2 (-). HRMS (ESI): calcd. for C21H24NO5
[M+H]+: 370.1649, found: 370.1653.
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N-(3,4-Dimethoxyphenylethyl)-4-acetoxy-3-methoxycinnamamide (3g). Following general
procedure, compound 3g was obtained as a white solid 0.70 g (1.76 mmol, 88 %); Rf [hexane-EtOAc,
1:1] = 0.22; m.p. = 78-80 ºC; IR (KBr Disk): 3440 (NH), 3008 (CH2-Ar), 2900 (OCH3), 1697 (C=O), 1666
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(C=O), 1619 (C=C), 1511 (NH), 1419 (CH2-Ar), 1280 (C-N) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
7.54 (1H, d, J = 15.6 Hz, =CHPh), 7.06-7.01 (2H, m, J = 8.6 Hz, 5’ and 9’-HAr), 6.99 (1H, d, J = 8.1
Hz, 8’-HAr), 6.80 (1H, d, J = 8.3 Hz, 10-HAr), 6.75-6.72 (2H, m, 6 and 9-HAr), 6.26 (1H, d, J = 15.6
Hz, =CHCO), 5.85 (1H, t, J = 6.8 Hz, NH), 3.84 (6H, s, OCH3), 3.81 (3H, s, OCH3), 3.61 (2H, q, J =
13
6.8 Hz, -CH2NH), 2.81 (2H, t, J = 7.0 Hz, -CH2Ph), 2.30 (3H, s, CH3). C{1H} NMR (101 MHz,
CDCl3): δ(ppm): 169.0, 165.8, 151.3, 149.1, 147.8, 140.9, 140.4 (+), 133.9, 131.4, 123.2 (+), 121.0 (+),
120.7 (+), 120.6 (+), 112.0 (+), 111.5 (+), 111.4 (+), 56.0 (+), 55.9 (+), 55.9 (+), 41.0 (-), 35.2 (-),
20.7 (+). HRMS (ESI): calcd. for C22H26NO6 [M+H]+: 400.1755, found: 400.1751.
N-(3,4-Dimethoxyphenylethyl)-3-acetoxy-4-methoxycinnamamide (3h). Following general
procedure, compound 3h was obtained as a white solid 0.71 g (1.80 mmol, 90 %); Rf [hexane-EtOAc,
1:1] = 0.25; m.p. = 126-128 ºC; IR (KBr Disk): 3317 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1758 (C=O)
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1650 (C=O), 1604 (C=C), 1265 (C-N) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.49 (1H, d, J = 15.5
Hz, =CHPh), 7.29-7.26 (1H, m, J = 8.6 Hz, 8’-HAr), 7.16 (1H, d, J = 2.1 Hz, 5’-HAr), 6.90 (1H, d, J =
8.6 Hz, 9’-HAr), 6.79 (1H, d, J = 8.7 Hz, 10-HAr), 6.74-6.71 (2H, m, 6 and 9-HAr), 6.18 (1H, d, J =
15.5 Hz, =CHCO), 5.95 (1H, t, J = 6.8 Hz, NH), 3.83 (6H, s, OCH3), 3.81 (3H, s, OCH3), 3.58 (2H,
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q, J = 6.8 Hz, -CH2NH), 2.81-2.76 (2H, m, -CH2Ph), 2.28 (3H, s, CH3). C{1H} NMR (101 MHz,
CDCl3): δ(ppm): 166.1, 162.6, 152.3, 149.1, 147.7, 139.9, 139.7 (+), 131.5, 128.0, 127.4 (+), 121.5 (+),
120.7 (+), 119.4 (+), 112.3 (+), 112.0 (+), 111.4 (+), 56.0 (+), 55.9 (+), 55.9 (+), 41.0 (-), 35.2 (-),
20.6 (+). HRMS (ESI): calcd. for C22H26NO6 [M+H]+: 400.1755, found: 400.1750.
N-(3,4-Dimethoxyphenylethyl)-4-acetoxy-3,5-dimethoxycinnamamide (3i). Following general
procedure, compound 3i was obtained as a white solid 0.79 g (1.84 mmol, 92 %); Rf [hexane-EtOAc,
1:1] = 0.17; m.p. = 133-135 ºC; IR (KBr Disk): 3363 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1758 (C=O)
,
1666 (C=O), 1604 (C=C), 1511 (NH), 1203 (C-N) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.51 (1H,
d, J = 15.5 Hz, =CHPh), 6.80 (1H, d, J = 8.1 Hz, 10-HAr), 6.75-6.73 (2H, m, 6 and 9-HAr), 6.69 (2H,
s, 5’ and 9’-HAr), 6.26 (1H, d, J = 15.5 Hz, =CHCO), 5.82 (1H, t, J = 6.8 Hz, NH), 3.85 (6H, s, OCH3),
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OAc). C{1H} NMR (101 MHz, CDCl3): δ(ppm): 168.7, 165.7, 152.4 (2C), 149.1, 147.8, 140.7 (+),
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133.2, 131.4, 129.9, 121.0 (+), 120.7 (+), 112.0 (+), 111.5 (+), 104.4 (2C, +), 56.2 (2C, +), 56.0 (+),
55.9 (+), 40.9 (-), 35.2 (-), 20.5 (+). HRMS (ESI): calcd. for C23H28NO7 [M+H]+: 430.1860, found:
430.1864.
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General procedure and characterization data of N-phenethyl-3-phenylpropanamides 4a-h.
In a 25 mL vial equipped with a magnetic stir bar was added the respective zanthoxylamide
protoalkaloids 3a-i (1.5 mmol), Pd/C (10 wt-%, 50 mg, 5 mg Pd, 0.05 mmol) the vial was sealed and
the air was evacuated establishing a hydrogen atmosphere for 10 min. Then, EtOH (10 mL) was added
in one portion and the reaction mixture was stirred at room temperature for 12 hours. The mixture
was passed through a pad of celite, washed with EtOH (2 x 10 mL) and the combined filtrate was
concentrated in a rotary evaporator to yield the pure N-phenethyl-3-phenylpropanamides 4a-i in
quantitative yield.
N-(3,4-Dimethoxyphenethyl)-3-phenylpropanamide (4a). Following general procedure,
compound 4a was obtained as a white solid 0.47 g (1.5 mmol, >99 %); Rf [hexane-EtOAc, 2:1] =
0.65; m.p. = 120-122 ºC; IR (KBr Disk): 3301 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1635 (C=O), 1542

(C-N), 1326 (CH2-Ar), 1234 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.20 (2H, t, J = 7.3 Hz, 5’
and 9’-HAr), 7.11 (3H, dd, J = 12.0, 7.1 Hz, 6’, 7’ and 8’-HAr), 6.69 (1H, d, J = 8.1 Hz, 10-HAr), 6.58
(1H, s, 6-HAr), 6.54 (1H, d, J = 8.1 Hz, 9-HAr), 5.41 (1H, br. s, NH), 3.78 (3H, s, OCH3), 3.76 (3H, s,
OCH3), 3.38 (2H, q, J = 6.6 Hz, -CH2NH), 2.86 (2H, t, J = 7.6 Hz, 2’-CH2), 2.61 (2H, t, J = 7.0 Hz, -
CH2Ph), 2.35 (2H, t, J = 7.7 Hz, 3’-CH2). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.1, 149.0,
147.6, 140.9, 131.3, 128.5 (2C, +), 128.4 (2C, +), 126.3 (+), 120.6 (+), 111.7 (+), 111.2 (+), 55.9 (+),
55.9 (+), 40.7 (-), 38.5 (-), 35.2 (-), 31.7 (-). HRMS (ESI): calcd. for C19H24NO3 [M+H]+: 314.1751,
found: 314.1755. Spectral data were in accordance with those reported in the literature.42
N-(3,4-Dimethoxyphenethyl)-3-(3,4-dimethoxyphenyl)propanamide (4b). Following general
procedure, compound 4b was obtained as a white solid 0.56 g (1.5 mmol, >99 %); Rf [hexane-EtOAc,
2:1] = 0.43; m.p. = 84-86 ºC (lit. 95-96 °C45); IR (KBr Disk): 3332 (NH), 3054 (CH2-Ar), 2931 (OCH3)
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1635 (C=O), 1589 (C-N), 1465 (CH2-Ar), 1234 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.76 (2H,
d, J = 8.1 Hz, 9 and 8’-HAr), 6.71-6.68 (2H, m, 5’ and 9’-HAr), 6.66 (1H, d, J = 1.9 Hz, 6-HAr), 6.60
(1H, dd, J = 8.1, 1.9 Hz, 10-HAr), 5.44 (1H, t, J = 6.8 Hz, NH), 3.84 (3H, s, OCH3), 3.83 (9H, s,
OCH3), 3.45 (2H, q, J = 6.8 Hz, -CH2NH), 2.88 (2H, t, J = 7.6 Hz, 2’-CH2), 2.68 (2H, t, J = 6.9 Hz, -
CH2Ph), 2.40 (2H, t, J = 7.6 Hz, 3’-CH2). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.2, 149.0,
148.9, 147.7, 147.4, 133.5, 131.3, 120.6 (+), 120.2 (+), 111.7 (+), 111.6 (+), 111.2 (+), 111.2 (+),
55.9 (+), 55.9 (2C, +), 55.8 (+), 40.7 (-), 38.9 (-), 35.3 (-), 31.4 (-). HRMS (ESI): calcd. for C21H28NO5
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N-(3,4-Dimethoxyphenethyl)-3-(3,4,5-trimethoxyphenyl)propanamide (4c). Following general
procedure, compound 4c was obtained as a white solid 0.61 g (1.5 mmol, >99 %); Rf [hexane-EtOAc,
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2:1] = 0.35; m.p. = 111-113 ºC; IR (KBr Disk): 3301 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1650 (C=O)
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1589 (C-N), 1542 (NH), 1342 (CH2-Ar), 1249 (C-N) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.76 (1H,
d, J = 8.1 Hz, 9-HAr), 6.66 (1H, d, J = 1.9 Hz, 6-HAr), 6.60 (1H, dd, J = 8.1, 1.9 Hz, 10-HAr), 6.39
(2H, s, 5’ and 9’-HAr), 5.46 (1H, t, J = 6.9 Hz, NH), 3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.81
(6H, s, 2xOCH3), 3.79 (3H, s, OCH3), 3.45 (2H, q, J = 6.9 Hz, -CH2NH), 2.87 (2H, t, J = 7.6 Hz, 2’-
CH2), 2.69 (2H, t, J = 7.0 Hz, -CH2Ph), 2.40 (2H, t, J = 7.6 Hz, 3’-CH2). 13C{1H} NMR (101 MHz,
CDCl3): δ(ppm): 172.0, 153.2 (2C), 149.0, 147.7, 136.8, 136.3, 131.27, 120.6 (+), 111.8 (+), 111.3 (+),
105.2 (2C, +), 60.9 (+), 56.1 (2C, +), 55.9 (+), 55.9 (+), 40.7 (-), 38.8 (-), 35.3 (-), 32.2 (-). HRMS
(ESI): calcd. for C22H30NO6 [M+H]+: 404.2068, found: 404.2065.
N-(3,4-Dimethoxyphenethyl)-3-(3,4-methylendioxyphenyl)propanamide (4d). Following general
procedure, compound 4d was obtained as a white solid 0.53 g (1.5 mmol, >99 %); Rf [hexane-EtOAc,
2:1] = 0.38; m.p. = 151-153 ºC; IR (KBr Disk): 3270 (NH), 3085 (CH2-Ar), 2931 (OCH3), 2894 (-OCH2O-)
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1635 (C=O), 1558 (C-N), 1425 (CH2-Ar), 1234 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.78 (1H,
d, J = 8.1 Hz, 9-HAr), 6.70 (1H, d, J = 7.9 Hz, 8’-HAr), 6.67-6.65 (2H, m, 10 and 5’-HAr), 6.64-6.60
(2H, m, 6 and 9’-HAr), 5.90 (2H, s, -OCH2O-), 5.42 (1H, br. s., NH), 3.85 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 3.45 (2H, q, J = 6.9 Hz, -CH2NH), 2.85 (2H, t, J = 7.6 Hz, 2’-CH2), 2.69 (2H, t, J = 7.0 Hz, -
CH2Ph), 2.37 (2H, t, J = 7.6 Hz, 3’-CH2). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.1, 149.1,
147.7 (2C), 146.0, 134.7, 131.3, 121.2 (+), 120.6 (+), 111.8 (+), 111.3 (+), 108.9 (+), 108.1 (+), 100.9
(-), 56.0 (+), 55.9 (+), 40.7 (-), 38.8 (-), 35.3 (-), 31.5 (-). HRMS (ESI): calcd. for C20H24NO5 [M+H]+:
358.1649, found: 358.1653.
N-(3,4-Dimethoxyphenethyl)-3-(4-acetoxyphenyl)propanamide
procedure, compound 4e was obtained as a white solid 0.55 g (1.5 mmol, >99 %); Rf [hexane-EtOAc,
2:1] = 0.30; m.p. = 125-127 ºC; IR (KBr Disk): 3317 (NH), 3054 (CH2-Ar), 2931 (OCH3), 1758 (C=O)
(4e).
Following
general
,
1650 (C=O), 1542 (C-N), 1465 (CH2-Ar), 1265 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.15 (2H,
d, J = 8.6 Hz, 6’ and 8’-HAr), 6.96 (2H, d, J = 8.6 Hz, 5’ and 9’-HAr), 6.77 (1H, d, J = 8.1 Hz, 9-HAr),
6.67 (1H, d, J = 1.9 Hz, 6-HAr), 6.63 (1H, dd, J = 8.1, 2.0 Hz, 10-HAr), 5.42 (1H, t, J = 7.0 Hz, NH),
3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.43 (2H, q, J = 7.0 Hz, -CH2NH), 2.91 (2H, t, J = 7.6 Hz,
2’-CH2), 2.68 (2H, t, J = 7.1 Hz, -CH2Ph), 2.39 (2H, t, J = 7.6 Hz, 3’-CH2), 2.26 (3H, s, CH3). 13C{1H}
NMR (101 MHz, CDCl3): δ(ppm): 172.0, 169.7, 149.1 (2C), 147.7, 138.5, 131.4, 129.4 (2C, +), 121.6
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(2C, +), 120.7 (+), 111.9 (+), 111.4 (+), 56.0 (+), 55.9 (+), 40.7 (-), 38.4 (-), 35.2 (-), 31.1 (-), 21.1
(+). HRMS (ESI): calcd. for C21H26NO5 [M+H]+: 372.1805, found: 372.1808.
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N-(3,4-Dimethoxyphenethyl)-3-(4-acetoxy-3-methoxyphenyl)propanamide
(4f).
Following
general procedure, compound 4f was obtained as a white solid 0.59 g (1.5 mmol, >99 %); Rf [hexane-
9
EtOAc, 2:1] = 0.21; m.p. = 108-110 ºC; IR (KBr Disk): 3317 (NH), 3070 (CH2-Ar), 2931 (OCH3), 1758
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
(C=O), 1635 (C=O), 1542 (C-N), 1425 (CH2-Ar), 1234 (C-C) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
6.91 (1H, d, J = 8.0 Hz, 9-HAr), 6.79-6.76 (2H, m, 5’ and 8’-HAr), 6.72 (1H, dd, J = 8.0, 1.9 Hz, 9’-
HAr), 6.67 (1H, d, J = 1.9 Hz, 6-HAr), 6.64 (1H, dd, J = 8.1, 2.0 Hz, 10-HAr), 5.46 (1H, t, J = 7.0 Hz,
NH), 3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.45 (2H, q, J = 7.0 Hz, -CH2NH),
2.91 (2H, t, J = 7.6 Hz, 2’-CH2), 2.69 (2H, t, J = 7.0 Hz, -CH2Ph), 2.40 (2H, t, J = 7.6 Hz, 3’-CH2),
2.28 (3H, s, CH3). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 171.9, 169.3, 151.0, 149.1, 147.7, 140.0,
138.1, 131.3, 122.7 (+), 120.7 (+), 120.4 (+), 112.7 (+), 111.9 (+), 111.4 (+), 56.0 (+), 55.8 (+), 55.9
(+), 40.7 (-), 38.5 (-), 35.3 (-), 31.7 (-), 20.7 (+). HRMS (ESI): calcd. for C22H28NO6 [M+H]+:
402.1911, found: 402.1915.
N-(3,4-Dimethoxyphenethyl)-3-(3-acetoxy-4-methoxyphenyl)propanamide
(4g).
Following
general procedure, compound 4g was obtained as a white solid 0.60 g (1.5 mmol, >99 %); Rf [hexane-
EtOAc, 2:1] = 0.24; m.p. = 89-91 ºC; IR (KBr Disk): 3332 (NH), 3008 (CH2-Ar), 2931 (OCH3), 1758
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
(C=O), 1650 (C=O), 1511 (C-N), 1450 (CH2-Ar), 1265 (C-C) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
6.98 (1H, dd, J = 8.4, 1.8 Hz, 9’-HAr), 6.85-6.83 (2H, m, 5’ and 8’-HAr), 6.77 (1H, d, J = 8.1 Hz, 9-
HAr), 6.67 (1H, d, J = 8.1 Hz, 6-HAr), 6.63 (1H, dd, J = 8.0, 1.6 Hz, 10-HAr), 5.53 (1H, t, J = 6.8 Hz,
NH), 3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.42 (2H, q, J = 6.8 Hz, -CH2NH),
2.86 (2H, t, J = 7.5 Hz, 2’-CH2), 2.67 (2H, t, J = 7.0 Hz, -CH2Ph), 2.36 (2H, t, J = 7.5 Hz, 3’-CH2),
2.28 (3H, s, CH3). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.0, 169.2, 149.5, 149.1, 147.7, 139.6,
133.5, 131.4, 126.6 (+), 122.8 (+), 120.7 (+), 112.5 (+), 111.9 (+), 111.4 (+), 56.0 (+), 55.9 (+), 55.9
(+), 40.7 (-), 38.5 (-), 35.2 (-), 30.7 (-), 20.7 (+). HRMS (ESI): calcd. for C22H28NO6 [M+H]+:
402.1911, found: 402.1909.
N-(3,4-Dimethoxyphenethyl)-3-(4-acetoxy-3,5-dimethoxyphenyl)propanamide (4h). Following
general procedure, compound 4h was obtained as a white solid 0.64 g (1.5 mmol, >99 %); Rf [hexane-
EtOAc, 2:1] = 0.16; m.p. = 96-98 ºC; IR (KBr Disk): 3363 (NH), 3008 (CH2-Ar), 2931 (OCH3), 1758
1

(C=O), 1666 (C=O), 1511 (C-N), 1465 (CH2-Ar), 1265 (C-C) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
6.77 (1H, d, J = 8.1 Hz, 9-HAr), 6.67 (1H, d, J = 1.9 Hz, 6-HAr), 6.63 (1H, dd, J = 8.1, 1.8 Hz, 10-
HAr), 6.42 (2H, s, 5’ and 9’-HAr), 5.52 (1H, br. s., NH), 3.84 (6H, s, OCH3), 3.76 (6H, s, OCH3), 3.44
(2H, q, J = 6.9 Hz, -CH2NH), 2.89 (2H, t, J = 7.6 Hz, 2’-CH2), 2.69 (2H, t, J = 7.0 Hz, -CH2Ph), 2.39
(2H, t, J = 7.6 Hz, 3’-CH2), 2.30 (3H, s, OAc). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 172.0, 169.0,
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152.0 (2C), 149.1, 147.7, 139.6, 131.3, 127.0, 120.7 (+), 111.9 (+), 111.4 (+), 105.0 (2C, +), 56.1
(2C, +), 55.9 (+), 55.9 (+), 40.8 (-), 38.6 (-), 35.2 (-), 32.3 (-), 20.5 (+). HRMS (ESI): calcd. for
C23H30NO7 [M+H]+: 432.2017, found: 432.2013.
7
General procedure and characterization data of 1-phenethyl-3,4-dihydroisoquinolines 5a-i.
A 10 mL reactor vial equipped with a magnetic stir bar was charged with the corresponding N-
phenethyl-3-phenylpropanamides 3b and 4a-h (1.5 mmol) and anhydrous acetonitrile (CH3CN) (5
mL). The resulting solution was stirred at room temperature until complete dissolution of the amide
and phosphoryl chloride (POCl3) (2.25 mmol, 1.5 equiv) was added in one portion. Then, the system
was heated at 50°C in an oil bath for 24 hours. After cooling to room temperature, the solvent was
evaporated under reduced pressure and the crude reaction mixture was suspended in crushed ice,
treated with aqueous NaHCO3 (1 M) to pH = 8, and then extracted with CH2Cl2 (3 x 10 mL). Finally,
the combined organic extracts were dried over Na2SO4, concentrated, and purified by flash column
chromatography on silica gel (10% MeOH in CH2Cl2) to afford the desired 1-phenethyl-3,4-
dihydroisoquinolines 5a-i.
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6,7-Dimethoxy-1-phenethyl-3,4-dihydroisoquinoline (5a). Following general procedure,
compound 5a was obtained as a yellow solid 0.42 g (1.41 mmol, 94 %); Rf [CH2Cl2/MeOH 8:1] =
0.52; m.p. = 81-83 ºC; IR (KBr Disk): 2993 (CH2-Ar), 2838 (OCH3), 1604 (C=N), 1511 (C-N), 1465 (CH2-
Ar), 1265 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.33-7.28 (2H, m, 5’ and 9’-HAr), 7.27-7.18
(3H, m, 6’, 7’ and 8’-HAr), 6.96 (1H, s, 8-HAr), 6.71 (1H, s, 5-HAr), 3.92 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 3.70-3.64 (2H, m, -CH2N), 3.03-2.97 (4H, m, 2’ and 3’-CH2), 2.65-2.59 (2H, m, -CH2Ph).
13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 165.9, 150.7, 147.5, 142.1, 131.5, 128.5 (4C, +), 126.0 (+),
122.0, 110.3 (+), 108.4 (+), 56.2 (+), 56.0 (+), 47.0 (-), 37.9 (-), 33.2 (-), 25.9 (-). HRMS (ESI): calcd.
for C19H22NO2 [M+H]+: 296.1645, found: 296.1649. Spectral data were in accordance with those
reported in the literature.43
6,7-Dimethoxy-1-(4-methoxyphenethyl)-3,4-dihydroisoquinoline (5b). Following general
procedure, compound 5b was obtained as a yellow solid 0.47 g (1.45 mmol, 97 %); Rf [CH2Cl2/MeOH
8:1] = 0.51; m.p. = 143-145 ºC; IR (KBr Disk): 2915 (CH2-Ar), 2854 (OCH3), 1650 (C=N), 1511 (C-N)
,
1465 (CH2-Ar), 1280 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.15 (2H, d, J = 8.6 Hz, 6’ and
8’-HAr), 6.95 (1H, s, 8-HAr), 6.84 (2H, d, J = 8.7 Hz, 5’ and 9’-HAr), 6.70 (1H, s, 5-HAr), 3.91 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.67-3.61 (2H, m, -CH2N), 2.97-2.92 (4H, m, 2’ and
3’-CH2), 2.66-2.57 (2H, m, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 166.0, 157.9, 150.7,
147.5, 134.1, 131.5, 129.4 (2C, +), 122.0, 113.9 (2C, +), 110.3 (+), 108.5 (+), 56.2 (+), 56.0 (+), 55.3
(+), 47.0 (-), 38.2 (-), 32.4 (-), 25.9 (-). HRMS (ESI): calcd. for C20H24NO3 [M+H]+: 326.1751, found:
326.1747. Spectral data were in accordance with those reported in the literature.43
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6,7-Dimethoxy-1-(3,4-dimethoxyphenethyl)-3,4-dihydroisoquinoline (5c). Following general
procedure, compound 5c was obtained as a yellow solid 0.52 g (1.47 mmol, 98 %); Rf [CH2Cl2/MeOH
6
7
8:1] = 0.48; m.p. = 95-97 ºC (lit. 89-91 °C46); IR (KBr Disk): 2931 (CH2-Ar), 2838 (OCH3), 1604 (C=N)
,
1511 (C-N), 1465 (CH2-Ar), 1265 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.96 (1H, s, 8-HAr),
6.80 (1H, d, J = 8.6 Hz, 8’-HAr), 6.77-6.74 (2H, m, 5’ and 9’-HAr), 6.70 (1H, s, 5-HAr), 3.91 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.68-3.62 (2H, m, -CH2N), 2.98-
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2.91 (4H, m, 2’ and 3’-CH2), 2.64-2.59 (2H, m, -CH2Ph). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm)
:
166.3, 151.0, 149.0, 147.6, 147.4, 134.6, 131.7, 122.0, 120.3 (+), 112.0 (+), 111.4 (+), 110.5 (+),
108.8 (+), 56.3 (+), 56.1 (+), 56.0 (+), 55.9 (+), 46.8 (-), 38.0 (-), 33.0 (-), 26.0 (-). HRMS (ESI):
calcd. for C21H26NO4 [M+H]+: 356.1856, found: 356.1860.
6,7-Dimethoxy-1-(3,4,5-trimethoxyphenethyl)-3,4-dihydroisoquinoline (5d). Following general
procedure, compound 5d was obtained as a yellow solid 0.52 g (1.48 mmol, 99 %); Rf [CH2Cl2/MeOH
8:1] = 0.42; m.p. = 104-106 ºC; IR (KBr Disk): 2993 (CH2-Ar), 2838 (OCH3), 1604 (C=N), 1511 (C-N)
,
1465 (CH2-Ar), 1265 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.03 (1H, s, 8-HAr), 6.77 (1H, s,
5-HAr), 6.41 (2H, s, 5’ and 9’-HAr), 3.96 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.81 (6H, s, 2xOCH3),
3.80 (3H, s, OCH3), 3.74-3.69 (2H, m, -CH2N), 3.17-3.11 (2H, m, 2’-CH2), 2.96 (2H, dd, J = 8.7, 6.7
Hz, 3’-CH2), 2.81-2.75 (2H, m, -CH2Ph).13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 183.2, 153.4 (3C),
148.2, 136.4, 132.9, 123.5 (+), 122.0, 110.7 (+), 110.05 (s), 105.4 (+, 2C), 60.9 (+), 56.4 (+, 2C), 56.1
(+, 2C), 50.0 (-), 37.0 (-), 33.9 (-), 25.7 (-). HRMS (ESI): calcd. for C22H28NO5 [M+H]+: 386.1962,
found: 386.1966. Spectral data were in accordance with those reported in the literature.47
6,7-Dimethoxy-1-(3,4-methylendioxyphenethyl)-3,4-dihydroisoquinoline (5e). Following general
procedure, compound 5e was obtained as a yellow solid 0.50 g (1.48 mmol, 99 %); Rf [CH2Cl2/MeOH
8:1] = 0.50; m.p. = 125-127 ºC; IR (KBr Disk): 2915 (CH2-Ar), 2777 (-OCH2O-), 1604 (C=N), 1496 (C-
N), 1465 (CH2-Ar), 1295 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.98 (1H, s, 8-HAr), 6.79 (1H,
s, 5-HAr), 6.70 (1H, d, J = 1.3 Hz, 5’-HAr), 6.65 (1H, d, J = 7.8 Hz, 8’-HAr), 6.61 (1H, dd, J = 7.9, 1.4
Hz, 9’-HAr), 5.87 (2H, s, -OCH2O-), 3.98 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.84-3.79 (2H, m, -
CH2N), 3.47 (2H, t, J = 7.6 Hz, 2’-CH2), 3.06 (2H, t, J = 7.5 Hz, -CH2Ph), 2.93 (2H, t, J = 7.6 Hz, 3’-
CH2).13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 176.2, 156.2, 148.7, 147.9, 146.5, 133.6, 132.3, 121.6
(+), 117.6 (-), 111.3 (+), 111.0 (+), 109.0 (+), 108.5 (+), 101.0 (-), 56.6 (+), 56.4 (+), 40.7 (-), 34.8
(-), 34.5 (-), 25.5 (-). HRMS (ESI): calcd. for C20H22NO4 [M+H]+: 340.1543, found: 340.1539.
6,7-Dimethoxy-1-(4-acetoxyphenethyl)-3,4-dihydroisoquinoline
procedure, compound 5f was obtained as a yellow solid 0.51 g (1.47 mmol, 98 %); Rf [CH2Cl2/MeOH
8:1] = 0.45; m.p. = 132-134 ºC; IR (KBr Disk): 2931 (CH2-Ar), 2854 (OCH3), 1758 (C=O), 1604 (C=N)
(5f).
Following
general
,
1511 (C-N), 1465 (CH2-Ar), 1280 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.23 (2H, d, J = 8.5
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Hz, 6’ and 8’-HA), 6.99 (2H, d, J = 8.5 Hz, 5’ and 9’-HA), 6.95 (1H, s, 8-HAr), 6.70 (1H, s, 5-HAr),
3.91 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.68-3.61 (2H, m, -CH2N), 3.00-2.97 (4H, m, 2’ and 3’-
CH2), 2.64-2.58 (2H, m, -CH2Ph), 2.28 (3H, s, OAc).13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 169.8,
157.1, 151.1, 149.0, 147.7, 139.6, 131.6, 129.5 (2C, +), 121.8, 121.6 (2C, +), 110.5 (+), 108.6 (+),
56.3 (+), 56.1 (+), 46.8 (-), 37.6 (-), 32.5 (-), 25.9 (-), 21.2 (+). HRMS (ESI): calcd. for C21H24NO4
[M+H]+: 354.1700, found: 354.1704.
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6,7-Dimethoxy-1-(4-acetoxy-3-methoxyphenethyl)-3,4-dihydroisoquinoline (5g). Following
general procedure, compound 5g was obtained as a yellow solid 0.54 g (1.42 mmol, 95 %); Rf
[CH2Cl2/MeOH 8:1] = 0.42; m.p. = 119-121 ºC; IR (KBr Disk): 2931 (CH2-Ar), 2838 (OCH3), 1758
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
(C=O), 1604 (C=N), 1511 (C-N), 1465 (CH2-Ar), 1280 (C-C) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
6.96 (1H, s, 8-HAr), 6.93 (1H, d, J = 8.0 Hz, 8’-HAr), 6.84 (1H, d, J = 1.8 Hz, 5’-HAr), 6.79 (1H, dd, J
= 8.0, 1.8 Hz, 9’-HAr), 6.70 (1H, s, 5-HAr), 3.91 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.79 (3H, s,
OCH3), 3.68-3.62 (2H, m, -CH2N), 2.98-2.95 (4H, m, 2’ and 3’-CH2), 2.64-2.59 (2H, m, -CH2Ph),
2.30 (3H, s, CH3). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 169.4, 165.9, 151.0, 150.9, 147.7, 141.1,
138.0, 131.6, 122.6 (+), 122.0, 120.6 (+), 112.9 (+), 110.5 (+), 108.6 (+), 56.4 (+), 56.1 (+), 55.9 (+),
46.9 (-), 37.8 (-), 33.1 (-), 25.9 (-), 20.8 (+). HRMS (ESI): calcd. for C22H26NO5 [M+H]+: 384.1805,
found: 384.1808.
6,7-Dimethoxy-1-(3-acetoxy-4-methoxyphenethyl)-3,4-dihydroisoquinoline (5h). Following
general procedure, compound 5h was obtained as a yellow solid 0.56 g (1.48 mmol, 99 %); Rf
[CH2Cl2/MeOH 8:1] = 0.43; m.p. = 82-84 ºC; IR (KBr Disk): 2931 (CH2-Ar), 2838 (OCH3), 1758 (C=O)
,
1604 (C=N), 1511 (C-N), 1465 (CH2-Ar), 1280 (C-C) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.05 (1H,
dd, J = 8.3, 2.1 Hz, 9’-HAr), 6.95 (1H, s, 8-HAr), 6.90-6.86 (2H, m, 5’ and 8’-HAr), 6.69 (1H, s, 5-HAr),
3.90 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.64 (2H, t, J = 7.5 Hz, -CH2N), 2.97-
2.89 (4H, m, 2’ and 3’-CH2), 2.63-2.57 (2H, m, -CH2Ph), 2.29 (3H, s, CH3). 13C{1H} NMR (101
MHz, CDCl3): δ(ppm): 169.2, 166.0, 150.9, 149.3, 147.6, 139.6, 134.6, 131.6, 126.7 (+), 122.8 (+),
121.9, 112.5 (+), 110.4 (+), 108.6 (+), 56.3 (+), 56.0 (+), 46.8 (-), 37.6 (-), 32.1 (-), 25.9 (-), 20.7 (+).
HRMS (ESI): calcd. for C22H26NO5 [M+H]+: 384.1805, found: 384.1809.
6,7-Dimethoxy-1-(4-acetoxy-3,5-dimethoxyphenethyl)-3,4-dihydroisoquinoline (5i). Following
general procedure, compound 5i was obtained as a yellow solid 0.61 g (1.48 mmol, 99 %); Rf
[CH2Cl2/MeOH 8:1] = 0.39; m.p. = 104-105 ºC; IR (KBr Disk): 2931 (CH2-Ar), 2838 (OCH3), 1758
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
(C=O), 1635 (C=N), 1511 (C-N), 1465 (CH2-Ar), 1280 (C-C) cm-1; H NMR (400 MHz, CDCl3): δ(ppm)
:
7.01 (1H, s, 8-HAr), 6.72 (1H, s, 5-HAr), 6.47 (2H, s, 5’ and 9’-HAr), 3.93 (3H, s, OCH3), 3.89 (3H, s,
OCH3), 3.77 (6H, s, OCH3), 3.71-3.66 (2H, m, -CH2N), 3.21-3.15 (2H, m, 2’-CH2), 3.00 (2H, dd, J =
13
9.3, 6.7 Hz, -CH2Ph), 2.71-2.64 (2H, m, 3’-CH2), 2.31 (3H, s, CH3). C{1H} NMR (101 MHz,
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CDCl3): δ(ppm): 169.1, 169.0, 152.7, 152.1 (2C), 148.1, 139.4, 132.3, 127.1, 120.6, 110.6 (+), 109.5
(+), 105.3 (2C, +), 56.4 (+), 56.2 (+), 44.9 (-), 36.4 (-), 34.1 (-), 25.8 (-), 20.5 (+). HRMS (ESI): calcd.
for C23H28NO6 [M+H]+: 414.1911, found: 414.1907.
7
General procedure and characterization data of (R)-7a-i and (S)-7a-i Dysoxylum alkaloids.
In a 10 mL vial equipped with a magnetic stir bar was added the respective 1-phenethyl-3,4-
dihydroisoquinoline 5a-i (0.5 mmol), (S,S)- or (R,R)-RuTsDPEN (10 µmol, 2 mol %) and HCOONa
(2.5 mmol, 5 equiv). The vial was sealed and the air was evacuated establishing an Argon atmosphere.
Then, 3 mL of H2O/DMF (1/1) was added in one portion and the reaction mixture was stirred at 40
°C in an oil bath for 12 hours. After completion of the reaction (TLC), the reaction mixture was
cooled, quenched with distilled water and extracted with CH2Cl2 (3 x 20 mL). The organic layers
were combined, dried over with Na2SO4, filtered and concentrated under reduced pressure to afford
the crude product in quantitative yield. The desired 1-phenethyl-1,2,3,4-tetrahydroisoquinoline 6a-i
was obtained sufficiently pure to be used in the next step without any further purification. A solution
of the respective 1,2,3,4-tetrahydroisoquinoline 6a-i (0.5 mmol), paraformaldehyde ((CH2O)n) (1.5
mmol) and methanol (4 mL), in a 25 ml round-bottom flask, was added dropwise into a stirred
solution of sodium cyanoborohydride (NaBH3CN) (0.55 mmol, 1.1 equiv.), zinc chloride (ZnCl2)
(0.25 mmol, 0.5 equiv.) and methanol (4 mL). Then, the mixture was stirred for 6 hours at 0 °C and
the reaction was quenched with NaHCO3 (1 M) and extracted with CH2Cl2 (3 x 20 mL). The organic
layers were combined, dried over with Na2SO4, filtered and concentrated under reduced pressure. The
crude material was purified by silica gel column chromatography (10% MeOH in CH2Cl2) to
furnished the desired (R)-7a-i and (S)-7a-i Dysoxylum alkaloids
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(R)-6,7-Dimethoxy-N-methyl-1-phenethyl-1,2,3,4-tetrahydroisoquinoline ((R)-7a). Following
general procedure, compound (R)-7a was obtained as a yellow oil 0.13 g (0.44 mmol, 89 %); Rf
[CH2Cl2/MeOH 10:1] = 0.65; IR (liquid film): 2931 (CH2-Ar), 2838 (OCH3), 2792 (N-C), 1604 (C-C)
,
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1511 (C-N), 1218 (CH3), 1110 (C-O) cm-1; H NMR (400 MHz, CDCl3): δ(ppm): 7.29-7.24 (2H, m, 5’
and 9’-HAr), 7.19-7.14 (3H, m, 6’, 7’ and 8’-HAr), 6.57 (1H, s, 8-HAr), 6.54 (1H, s, 5-HAr), 3.85 (3H,
s, OCH3), 3.82 (3H, s, OCH3), 3.42 (1H, t, J = 5.3 Hz, CHa-N), 3.18-3.10 (1H, m, CHb-N), 2.80-2.67
(4H, m, -CH2Ph and 3’-CH2), 2.61-2.52 (1H, m, 1-CH), 2.48 (3H, s, NCH3), 2.09-2.03 (2H, m, 2’-
CH2). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 147.4, 147.3, 143.1, 129.9, 128.5 (2C, +), 128.4 (2C,
+), 126.9, 125.7 (+), 111.4 (+), 110.1 (+), 62.9 (+), 56.1 (+), 55.9 (+), 48.9 (-), 42.8 (+), 36.9 (-), 31.7
(-), 25.7 (-). ee value: 95 % (HPLC conditions: KROMASIL® 5-CelluCoat 4.6 x 250 mm, elute:
hexane/i-PrOH = 90/10, 0.1 % DEA, λ = 254 nm, flow rate: 1.0 mL/min, 25 °C); tR1 = 6.06 min
[훼]25
(minor, 2.5 %), tR2 = 8.36 min (major, 97.4 %),
for C20H26NO2 [M+H]+: 312.1958, found: 312.1962.
= -11.4 (c = 0.025, EtOH). HRMS (ESI): calcd.
퐷
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(R)-6,7-Dimethoxy-1-(4-methoxyphenethyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline ((R)-7b).
Following general procedure, compound (R)-7b was obtained as a yellow oil 0.15 g (0.46 mmol, 93
%); Rf [CH2Cl2/MeOH 10:1] = 0.61; IR (liquid film): 2931 (CH2-Ar), 2838 (OCH3), 2792 (N-C), 1604

(C-C), 1511 (C-N), 1249 (CH3), 1033 (C-O) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 7.12 (2H, d, J =
8.7 Hz, 6’ and 8’-HAr), 6.84 (2H, d, J = 8.7 Hz, 5’ and 9’-HAr), 6.59 (1H, s, 8-HAr), 6.56 (1H, s, 5-
HAr), 3.88 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.44 (1H, t, J = 5.4 Hz, CHa-N),
3.22-3.13 (1H, m, CHb-N), 2.81-2.66 (4H, m, -CH2Ph and 3’-CH2), 2.55 (1H, dd, J = 15.1, 7.8 Hz, 1-
CH), 2.49 (3H, s, NCH3), 2.09-2.00 (2H, m, 2’-CH2). 13C{1H} NMR (101 MHz, CDCl3): δ(ppm): 157.6,
147.2, 147.2, 134.9, 129.9, 129.3 (2C, +), 126.7, 113.7 (2C, +), 111.3 (+), 110.0 (+), 62.7 (+), 56.0
(+), 55.8 (+), 55.2 (+), 48.1 (-), 42.6 (+), 37.1 (-), 30.7 (-), 25.4 (-). ee value: 91 % (HPLC conditions:
KROMASIL® 5-CelluCoat 4.6 x 250 mm, elute: hexane/i-PrOH = 90/10, 0.1 % DEA, λ = 254 nm,
[훼]25
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flow rate: 1.0 mL/min, 25 °C); tR1 = 6.88 min (minor, 4.7 %), tR2 = 11.07 min (major, 95.3 %),
퐷
= -5.9 (c = 0.025, EtOH). HRMS (ESI): calcd. for C21H28NO3 [M+H]+: 342.2064, found: 342.2068.
(R)-6,7-Dimethoxy-1-(3,4-dimethoxyphenethyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline ((R)-
7c). Following general procedure, compound (R)-7c was obtained as a yellow oil 0.17 g (0.46 mmol,
92 %); Rf [CH2Cl2/MeOH 10:1] = 0.59; IR (liquid film): 2931 (CH2-Ar), 2838 (OCH3), 2792 (N-C), 1604

(C-C), 1511 (C-N), 1265 (CH3), 1041 (C-O) cm-1; 1H NMR (400 MHz, CDCl3): δ(ppm): 6.81 (1H, d, J =
7.9 Hz, 8’-HAr), 6.76-6.72 (2H, m, 5’ and 9’-HAr), 6.60 (1H, s, 8-HAr), 6.56 (1H, s, 5-HAr), 3.88 (3H,
s, OCH3), 3.87 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.45 (1H, t, J = 5.4 Hz, CHa-
N), 3.21-3.14 (1H, m, CHb-N), 2.83-2.66 (4H, m, -CH2Ph and 3’-CH2), 2.55 (1H, dd, J = 14.7, 8.3
Hz, 1-CH), 2.50 (3H, s, NCH3), 2.05 (2H, ddd, J = 7.9, 7.0, 3.6 Hz, 2’-CH2). 13C{1H} NMR (101
MHz, CDCl3): δ(ppm): 148.8, 147.3, 147.3, 147.1, 135.6, 129.9, 126.8, 120.2 (+), 112.0 (+), 111.4 (+),
111.3 (+), 110.2 (+), 62.7 (+), 56.1 (+), 56.0 (+), 55.9 (2C, +), 48.1 (-), 42.8 (+), 37.1 (-), 31.3 (-),
25.4 (-). ee value: 91 % (HPLC conditions: KROMASIL® 5-CelluCoat 4.6 x 250 mm, elute: hexane/i-
PrOH = 90/10, 0.1 % DEA, λ = 254 nm, flow rate: 1.0 mL/min, 25 °C); tR1 = 13.35 min (minor, 4.4
[훼]2퐷5
%), tR2 = 21.84 min (major, 95.6 %),
= -3.9 (c = 0.025, EtOH). HRMS (ESI): calcd. for
C22H30NO4 [M+H]+: 372.2169, found: 372.2165.
(R)-6,7-Dimethoxy-1-(3,4,5-trimethoxyphenethyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline ((R)-
7d). Following general procedure, compound (R)-7d was obtained as a yellow oil 0.19 g (0.48 mmol,
97 %); Rf [CH2Cl2/MeOH 10:1] = 0.52; IR (liquid film): 2931 (CH2-Ar), 2838 (OCH3), 2792 (N-C), 1589
1

(C-C), 1511 (C-N), 1249 (CH3), 1026 (C-O) cm-1; H NMR (400 MHz, CDCl3): δ(ppm): 6.58 (1H, s, 8-
HAr), 6.54 (1H, s, 5-HAr), 6.39 (2H, s, 5’ y 9’-HAr) 3.85 (3H, s, OCH3), 3.83 (6H, s, OCH3), 3.83 (3H,
s, OCH3), 3.81 (3H, s, OCH3), 3.43 (1H, t, J = 5.5 Hz, CHa-N), 3.19-3.11 (1H, m, CHb-N), 2.81-2.64
(4H, m, -CH2Ph and 3’-CH2), 2.52 (1H, dd, J = 14.5, 7.1 Hz, 1-CH), 2.48 (3H, s, NCH3), 2.05 (2H,
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