Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry

Article abstract of DOI:10.1016/j.tet.2020.131461

Total syntheses of (S)- and (R)-nuciferine were accomplished through approach involving diastereoselective reaction between a chiral dihydroisoquinoline enamide and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate promoted by CsF, affording a separable mixture of diastereoisomers, which provided (S)- and (R)-nuciferine via simple and efficient transformations.

Full text of DOI:10.1016/j.tet.2020.131461

Journal Pre-proof
Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry
Givago P. Perecim, Victor M. Deflon, Gabriel R. Martins, Leandro M.C. Pinto, Gleison
A. Casagrande, Diogo Oliveira-Silva, Cristiano Raminelli
PII:
S0040-4020(20)30633-5
https://doi.org/10.1016/j.tet.2020.131461
TET 131461
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 March 2020
Revised Date: 22 July 2020
Accepted Date: 29 July 2020
Please cite this article as: Perecim GP, Deflon VM, Martins GR, Pinto LMC, Casagrande GA, Oliveira-
Silva D, Raminelli C, Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry,
Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131461.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract

Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry
Givago P. Perecima, Victor M. Deflonb, Gabriel R. Martinsc, Leandro M. C. Pintoc,
Gleison A. Casagrandec, Diogo Oliveira-Silvaa, Cristiano Raminellia,*
a
Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua
Prof. Artur Riedel, 275, Diadema 09972-270, SP, Brazil
b Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador São Carlense, 400, São
Carlos 13566-590, SP, Brazil
c
Instituto de Química, Universidade Federal de Mato Grosso do Sul, Av. Senador Filinto Muller, 1555,
Campo Grande 79074-460, MS, Brazil
*
Corresponding author. Tel.: +55-11-4044-0500 (3473); fax: +55-11-4043-6428; e-mail:
raminelli@unifesp.br
Abstract
Total syntheses of (S)- and (R)-nuciferine were accomplished through approach
involving diastereoselective reaction between a chiral dihydroisoquinoline enamide and
2-(trimethylsilyl)phenyl trifluoromethanesulfonate promoted by CsF, affording a
separable mixture of diastereoisomers, which provided (S)- and (R)-nuciferine via
simple and efficient transformations.
Keywords: Stereoselective synthesis; Chiral auxiliary; Benzyne chemistry; DFT
calculations; Aporphine alkaloids.
1. Introduction
Aporphine alkaloids are structurally characterized by a tetracyclic core containing a
nitrogen atom and represent an important family of biosynthetic derivatives of
isoquinoline alkaloids.1 Aporphine compounds have important biological properties, for
example, anticancer,2 antiviral,3 anti-inflammatory,4 anti-HIV,5 and leishmanicidal
activities.6 Among the aporphines, (±)-nuciferine may be featured due to its high
affinity for the serotonin 5-HT2A receptor, which in therapeutic terms is related to
several disorders, including schizophrenia, insomnia, and ischaemic heart disease.7
1

Because of the significant biological properties presented by aporphinoids, some
synthetic approaches to produce aporphine cores have been developed.8-15 The most
widespread approach is based on biosynthetic routes and employs
benzyltetrahydroisoquinoline intermediates for the C ring formation8-14 through various
transformations: 1) Pschorr reaction,9 2) phenolic couplings,8,10 3) nonphenolic
couplings,8,11 4) photochemical reactions,12 5) acid-catalyzed reactions,13 and 6)
palladium-catalyzed reactions.14 Complementarily, the approach that employs benzyne
chemistry in the construction of the aporphine core has been extensively explored.15-17
In this context, one can mention the reaction between 1-methyleneisoquinolines and
arenodiazonium-2-carboxylates carried out under acidic conditions, which affords
dehydroaporphines in moderate yields,16 as well as the reaction between 1-
methyleneisoquinolines and silylaryl triflates promoted by a source of fluoride ions,
which allows the formation of aporphines in relatively high yields17 (Scheme 1).
Scheme 1. Approaches to produce aporphine compounds.
In general, the reactions involving benzyltetrahydroisoquinoline intermediates8-14
lead to aporphinoids in relatively low yields, employ transition metals, require high
temperatures and strongly acidic conditions. Alternatively, the reaction between 1-
methyleneisoquinolines
and
arenediazonium-2-carboxylates
produces
dehydroaporphines in moderate yields.16 However, the use of anthranilic acid-derived
aryne precursors has been discouraged for safety reasons.15 Furthermore, a limited
number of procedures is available for the reduction of dehydroaporphines to
aporphines,12d,12e which is not a general transformation. Considering the reaction
between 1-methyleneisoquinolines and silylaryl triflates, which has been explored in
2

our research group,17 the introduction of chirality in the aporphine core may be
considered a great challenge. Accordingly, in the present work we describe the total
syntheses of (S)- and (R)-nuciferine through unprecedented approach involving
diastereoselective reaction between chiral auxiliary-based isoquinoline compound and
2-(trimethylsilyl)phenyl trifluoromethanesulfonate promoted by CsF, affording a
separable mixture of diastereoisomers, which provided (S)- and (R)-nuciferine by
simple and efficient transformations.
2. Results and Discussion
Our retrosynthetic analysis for (S)-nuciferine (1a) and (R)-nuciferine (1b) is outlined
in Scheme 2. Aporphine compounds 1a and 1b were prepared through the formation of
a separable mixture of diastereoisomers 2a,b, which was obtained by [4 + 2]
cycloaddition reaction followed by hydrogen migration between chiral intermediate 3
and benzyne precursor 7.17 Chiral auxiliary-based intermediate 3 was produced from
3,4-dimethoxyphenethylamine (4) and L-proline (5).17-20 Benzyne precursor 7 was
obtained from a commercial source.
Scheme 2. Retrosynthetic analysis for (S)-nuciferine (1a) and (R)-nuciferine (1b).
Total syntheses of (S)-nuciferine (1a) and (R)-nuciferine (1b) were initiated through
the production of chiral intermediate 3.17-20 Thus, 3,4-dimethoxyphenethylamine (4)
was treated with acetic anhydride and pyridine leading to N-(3,4-
dimethoxyphenethyl)acetamide (8) in 97% yield.17,18 Amide 8 was converted by
Bischler-Napieralski reaction to 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (9) in
90% yield.17,18 Concurrently, L-proline (5) was protected with p-toluenesulfonyl
chloride in the presence of sodium hydroxide affording (S)-1-tosylpyrrolidine-2-
carboxylic acid (10) in 98% yield.19 Protected amino acid 10 was allowed to react with
3

oxalyl chloride using N,N-dimethylformamide in catalytic amount to give (S)-1-
tosylpyrrolidine-2-carbonyl chloride (11) in 87% yield.20 Subsequently, we carried out
the reaction between dihydroisoquinoline 9 and chiral acid chloride 11 in the presence
of triethylamine and obtained chiral isoquinoline compound 3 in 88% isolated yield17
(Scheme 3). The conditions for the preparation of compound 3 were optimized after an
extensive series of experiments.
Scheme 3. Synthesis of intermediate 3.
Afterwards, allowing the key reaction between chiral isoquinoline compound 3 and
benzyne precursor 7 in the presence of CsF using acetonitrile as solvent,17 we observed
the formation of a mixture containing diastereoisomers 2a and 2b in the proportion of
2.3:1, respectively, according to liquid chromatography-high resolution mass
spectrometry (LC-HRMS) analysis (Scheme 4). Derivatives of diastereoisomers 2a and
2b containing pyrrolidine rings protected with Boc or Cbz groups could not be obtained
by transformations outlined in Schemes 3 and 4.
Scheme 4. Preparation of diastereoisomers 2a and 2b.
4

Compounds 2a and 2b formed a mixture inseparable by column chromatography or
preparative thin-layer chromatography. Thus, the mixture containing compounds 2a and
2b was isolated by column chromatography to remove the remaining starting materials
and unidentified by-products. Then, diastereoisomers 2a and 2b were separated by
preparative high-performance liquid chromatography (HPLC) in yields of 22% and
10%, respectively (Scheme 4).
The structure of the major diastereoisomer 2a was unequivocally confirmed by X-ray
analysis (Figure 1) (see Supporting Information).
Figure 1. ORTEP representation of compound 2a.
DFT calculations were carried out to evaluate the stereochemical pathway that led to
the formation of diastereoisomers 2a and 2b in the proportion of 2.3:1, respectively
(Scheme 4). According to the calculations in acetonitrile, the reaction between
compound 3 and benzyne (6), presumably generated in the reaction medium, provided
intermediates A and A’ through a concerted [4 + 2] cycloaddition reaction, involving
transition states with a considerable difference in energy, namely, TS (A) with 7.91 kcal
mol-1 and TS (A’) with 12.37 kcal mol-1. Then, intermediates A and A’ were converted
to diastereoisomers 2a and 2b by a hydrogen migration via TS (2a) and TS (2b)
transition states with energies of 10.42 kcal mol-1 and 11.48 kcal mol-1, respectively.
The total process is spontaneous by -38.41 kcal mol-1 considering compound 2a and by
-21.48 kcal mol-1 taking into account compound 2b. Optimized geometries in Cartesian
coordinates for all species can be found in the Supporting Information. The obtained
results have illustrated that the concerted [4 + 2] cycloaddition reaction may be
considered the determining step for the diastereoselectivity of the transformation
(Figure 2).
5

minor diastereoisomer
[4 + 2] cycloaddition reaction
MeO
MeO
MeO
MeO
MeO
N
N
N
N
H
H
O
O
N
CH2
S
S
O
O
O
O
N
MeO
O
hydrogen
migration
S
O
A'
2b
O
3
Me
O
Me
O
MeO
MeO
MeO
MeO
6
)
benzyne (
Me
N
N
H
N
N
H
S
S
O
O
O
O
A
2a
Me
Me
major diastereoisomer
Figure 2. Proposed stereochemical pathway evaluated by DFT calculations for
diastereoisomers 2a and 2b.
Afterwards, diastereoisomers 2a and 2b were subjected to basic hydrolysis reaction
with lithium hydroxide in a mixture of ethanol/water (2:1) under microwave heating,17a,c
affording (S)-nornuciferine (12a) and (R)-nornuciferine (12b) in yields of 87% and
68%, respectively. No attempt was made to recover the chiral auxiliary. Then, we
submitted (S)-nornuciferine (12a) and (R)-nornuciferine (12b) to N-methylation reaction
with formaldehyde followed by sodium borohydride reduction17 leading to (S)-
6

nuciferine (1a) and (R)-nuciferine (1b) in yields of 91% and 84%, respectively (Scheme
5). The total syntheses of (S)-nuciferine (1a) and (R)-nuciferine (1b) were accomplished
through 6 reaction steps with overall yields of 13% and 4%, respectively.
Scheme 5. Transformations to achieve (S)-nuciferine (1a) and (R)-nuciferine (1b).
The structures of compounds 8, 9, 10, and 11 were assigned according to their
LRMS, IR, 1H, and 13C NMR spectra. HRMS, IR, 1H, and 13C spectra were obtained to
confirm the structure of compound 3. The structures of compounds 2a and 2b were
1
13
assigned according to their HRMS, IR, H, C, and HSQC NMR spectra. Compounds
1
12a and 1a had their structures assigned by LRMS, IR, H, and 13C NMR spectra.
1
Compound 12b and 1b had their structures confirmed by LRMS and H NMR spectra.
Solid substances (8, 9, 11, 3, 2a, 2b, 1a and 1b) had their melting point values
determined and chiral compounds (10, 11, 3, 2a, 2b, 12a, 12b, 1a, and 1b) had their
optical rotation measured. The optical rotations of compounds 1a and 1b matched those
reported for the corresponding natural products (S)-nuciferine21 and (R)-nuciferine.14c
Chiral HPLC analyses were performed to confirm the high enantiomeric purity of
compound 1a.
3. Conclusions
In summary, the total syntheses of (S)-nuciferine (1a) and (R)-nuciferine (1b) were
accomplished through unprecedented approach involving diastereoselective reaction
between chiral auxiliary-based isoquinoline compound 3 and benzyne precursor 7
promoted by CsF, affording a separable mixture of diastereoisomers 2a and 2b, which
provided (S)-nuciferine (1a) and (R)-nuciferine (1b), respectively, via simple and
efficient transformations. The stereochemical pathway for the reaction between
compound 3 and benzyne (6) was outlined by DFT calculations in acetonitrile. The
7

chemistry disclosed in this work represents an advance for the stereoselective synthesis
of aporphine alkaloids involving benzyne chemistry.
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded on a spectrometer operating at 300 MHz and
1
75 MHz, respectively. H NMR spectra were taken in deuterated solvents and the
chemical shifts are given in ppm with respect to TMS used as internal standard, except
when indicated in the spectrum. 13C NMR spectra were taken in deuterated solvents and
the chemical shifts are given in ppm with respect to the deuterated solvent used as
reference. HSQC spectra were registered on a 300 MHz NMR spectrometer. IR spectra
were obtained using attenuated total reflectance (ATR) or KBr pellets in the 4000-400
cm-1 region. Mass spectra were carried out employing a gas chromatograph coupled to a
quadrupole mass spectrometer using electron ionization at 70 eV. High-resolution mass
spectra were obtained using a hybrid quadrupole/time-of-flight (Q-Tof) mass
spectrometer. Melting point values are uncorrected. Specific optical rotation analyses
were obtained with a digital polarimeter using a short cuvette (0.5 dm) and the D-line of
o
the sodium lamp (589 nm) at 21-25 C. Diastereoisomers 2a and 2b were quantified in
mixture via LC-PDA-HRMS analysis (mobile phases: (A) MeOH and (B) 10 mM
aqueous solution of ammonium formate (70:30); column: Restek Ultra PFPP 100 x 2.1
mm, 3 µm; flow: 0.1 mL/min; column temperature: r.t.). Diastereoisomers 2a and 2b
were separated via preparative HPLC (mobile phase: (A) H2O + 20 mM ammonium
formate and (B) MeOH/ACN 85:15 (33:67); column: Phenomenex Luna Phenyl-Hexyl
150 x 21.20 mm, 5 µm; flow: 15 mL/min; column temperature: r.t.). Chiral HPLC
analyses for (±)-nuciferine and (S)-nuciferine (1a) are shown in Figures 2S, 3S, and 4S
available in the Supporting Information. (±)-Nuciferine was obtained according to the
literature.17b Column chromatography separations were carried out using 70-230 mesh
silica gel. Preparative TLC separations were carried out using silica gel matrix with
inorganic binder and fluorescent indicator. Commercially obtained reagents were
employed without further purification. High purity CsF (99.99%) was used in the
experiments. Solvents were treated when necessary according to the literature.22 MeCN
was distilled from CaH2 under anhydrous conditions prior to use.22 n-BuLi was titrated
against s-BuOH using 1,10-phenanthroline as indicator under N2 atmosphere.23 LDA
was generated following the typical procedure before use.24 Suitable single crystals for
8

X-ray diffraction were grown by slow evaporation of a solution 1:1 (v/v)
methanol/dichloromethane containing 2a. The data were collected on a BRUKER
KAPPA APEX II Duo diffractometer using graphite-monochromated CuKa radiation (λ
= 1.54178 Å) at 296 K. Standard procedures were used for data reduction and multi-
scan absorption correction was applied. The structure was solved using direct methods
with SHELXS-9725 and refined with anisotropic displacement factors for all non-
hydrogen atoms and with the hydrogen atoms being positioned using the riding model
of SHELXL-2014.26 Additional crystal data and refinement details for 2a are presented
in Table 1S and bond lengths [Å] and angles [°] are shown in Table 2S that are
available in the Supporting Information. Crystallographic information on the structure
determination has been deposited at Cambridge Crystallographic Data Center. CCDCD
1993331
data
can
be
obtained
free
or
of
from
charge
via
http://www.ccdc.cam.ac.uk/conts/retrieving.html,
the
Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)
1223 336 033; or e-mail: de-posit@ccdc.cam.ac.uk. All quantum mechanical
calculations were carried out using Gaussian 16 (Revision B.01)27 employing the
Becke's three-parameter hybrid exchange functional combined with Lee-Yang-Parr
correlation functional (B3LYP)28,29 at the 6-31+G(d,p) level. The geometry optimization
was computed using Berny's optimization algorithm and the calculations of harmonic
vibrational frequencies were also performed for all the stationary points. For each
optimized ground state, the frequency analysis showed the absence of imaginary
frequencies, whereas each transition state showed a single imaginary frequency. The
energies reported in this work include the zero-point vibrational energy corrections
(ZPVE) and are not scaled. All transition structures (TSs) were obtained using the
QST2/QST3 as implemented in Gaussian. Visual inspection of the corresponding
normal mode was used to confirm that the correct transition state had been found. The
Self-Consistent Isodensity Polarizable Continuum Model (SCIPCM)30 model approach
was used for the single point calculations in acetonitrile. The 3D structural
representations were generated using CYLview software.31
4.2. General procedures
N-(3,4-dimethoxyphenethyl)acetamide (8)17,18
To a round-bottomed flask equipped with a reflux condenser were added 3,4-
dimethoxyphenethylamine (4) (1.81 g, 10 mmol, 1.70 mL), acetic anhydride (1.17 g,
9

11.5 mmol, 1.10 mL), and dry pyridine (870 mg, 11 mmol, 0.90 mL). The mixture was
o
maintained under stirring and anhydrous conditions at 90 C for 2 hours. Afterwards,
the reaction mixture was poured into a beaker containing crushed ice (40 g), and the
resulting mixture was stirred with a glass rod for 5 min. Then, the mixture was extracted
with ethyl acetate (3 x 50 mL). The organic phase was washed with 10% (w/v) aqueous
solution of NaHCO3 (100 mL), saturated aqueous solution of CuSO4 (100 mL), and
dried over MgSO4. After filtration, the solvent was evaporated under reduced pressure,
affording desired product 8. Yield: 2.17 g (97%); off-white solid; m.p. 99-100 °C (m.p.
1
lit.32 100-102 °C); Rf = 0.81 (eluent: methanol); H NMR (300 MHz, CDCl3, ppm): δ
6.82-6.79 (m, 1H), 6.74-6.72 (m, 2H), 5.96 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.48 (q, J
= 6.7 Hz, 2H), 2.76 (t, J = 7.1 Hz, 2H), 1.94 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm):
δ 170.0, 148.8, 147.4, 131.2, 120.4, 111.7, 111.2, 55.7, 55.6, 40.6, 35.0, 23.0; IR (KBr,
cm-1) 3251.9, 3080.3, 2972.3, 2927.9, 1663.7, 1608.6, 1566.2, 1516.0, 1417.6, 1377.1,
1261, 4, 1035.7; GC/MS (m/z, %): 223 (7.3), 180 (0.3), 164 (100.0), 151 (41.6), 121
(4.1), 108 (3.4), 107 (7.9). Characterization data are in accordance with the
literature.17b,32
6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (9)17,18
To a round-bottomed flask equipped with a reflux condenser were added N-(3,4-
dimethoxyphenethyl) acetamide (8) (0.89 g, 4 mmol) and toluene (4.50 mL). The
mixture was heated to 40 °C under stirring and N2 atmosphere. Then, POCl3 (1.47 g, 9.6
mmol, 0.90 mL) was added dropwise using syringe and needle. The reaction was
maintained under reflux for 2 hours and cooled using an ice bath for 4 h. The solvent
was evaporated under reduced pressure, affording an intermediate salt (m.p. 146-149 ºC
(m.p. lit.18b 148-152 ºC)). After that, the intermediate salt was dissolved in water (10
mL) and a 40% (w/v) aqueous solution of NaOH (10 mL) was added to the mixture,
which was maintained under stirring for 10 minutes. The reaction was extracted with
CHCl3 (3 x 20 mL). The organic phase was washed with distilled water (10 mL) and
dried over MgSO4. After filtration, the solvent was evaporated under reduced pressure,
affording desired product 9. Yield: 0.74 g (90%); brownish solid; m.p. 102-103 °C (m.p.
1
lit.18b 105-107 °C); Rf = 0.38 (eluent: methanol); H NMR (300 MHz, CDCl3, ppm): δ
6.99 (s, 1H), 6.69 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3,63 (tq, J = 7.6 Hz, 1.4 Hz, 2H),
13
2.64 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 1.4 Hz, 3H); C NMR (75 MHz, CDCl3, ppm): δ
163.6, 150.8, 147.4, 131.0, 122.4, 110.1, 108.9, 56.1, 55.9, 46.9, 25.7, 23.3; IR (KBr,
10

cm-1) 2993.5, 2962.6, 2922.1, 1602.8, 1514.1, 1408.4, 1350.1, 1213.2, 1060.8; GC/MS
(m/z, %): 205 (100.0), 190 (57.9), 174 (21.5), 160 (21.4), 147 (12.8), 132 (4.3).
Characterization data are in accordance with the literature.17b,32
(S)-1-tosylpyrrolidine-2-carboxylic acid (10)19
To a round-bottomed flask containing L-proline (9) (5.76 g, 50 mmol) was added a 2 M
aqueous solution of NaOH (50 mL, 100 mmol) under stirring at 0 oC. The mixture was
warmed to room temperature and a solution of p-toluenesulfonyl chloride (9.53 g, 50
mmol) in diethyl ether (10 mL) was added dropwise using syringe and needle. The
reaction was maintained under stirring at 0 °C for 4 hours. Afterwards, at room
temperature, the aqueous solution was separated from the organic phase and acidified to
pH 2 with concentrated HCl. The mixture was extracted with ethyl acetate (3 x 15 mL).
The organic phase was washed with 10% aqueous solution of NaCl (20 mL) and dried
over MgSO4. After filtration, the solvent was evaporated under reduced pressure,
affording desired product 10. Yield: 13.18 g (98%); yellowish oil; Rf = 0.56 (eluent:
1
EtOAc); [ꢀ]ꢂꢁꢃ = -89.8° (c = 3.05 MeOH) ([ꢀ]ꢂꢁꢄ lit.19 = -83.9° (c = 3.05 MeOH)); H
NMR (300 MHz, CDCl3, ppm): δ 9.32 (s, 1H), 7.76-7.73 (m, 2H), 7.33-7.31 (m, 2H),
4.26 (dd, J = 7.9 Hz, 3.8 Hz, 1H), 3.53-3.46 (m, 1H), 3.29-3.21 (m, 1H), 2.42 (s, 3H),
2.12-1.90 (m, 3H), 1.78-1.69 (m, 1H); 13C NMR (75 MHz, CDCl3, ppm): δ 176.7,
144.0, 134.3, 129.8, 127.5, 60.3, 48.7, 30.6, 24.6, 21.5; IR (KBr, cm-1) 3570.2, 3485.3,
3089.9, 2978.0, 2552.8, 1764.8, 1494.8, 1344.3, 1093.6; GC/MS (m/z, %): 224 (82.3),
155 (63.6), 91 (100.0), 70 (35.5). Characterization data are in accordance with the
literature.19
(S)-1-tosylpyrrolidine-2-carbonyl chloride (11)20
To a round-bottomed flask containing (S)-1-tosylpyrrolidine-2-carboxylic acid (10)
(1.21 g, 4.5 mmol) and toluene (35 mL) were added oxalyl chloride (1.07 mL 12.3
mmol) dropwise using syringe and needle and dimethylformamide (DMF) (5 µL). The
mixture was maintained under stirring at room temperature for 6 hours. Afterwards, the
reaction was evaporated under reduced pressure. To the round-bottomed flask
containing the material obtained was added hot hexane (100 mL) and the mixture was
capped and maintained in the refrigerator for 12 hours. After vacuum filtration, desired
product 11 was obtained. The crystallization process was performed 6 times. Yield: 1.12
g (87%); off-white solid; m.p. 57-58 °C (m.p. lit.20 = 57-59 °C); Rf = 0.72 (eluent:
11

1
EtOAc); [ꢀ]ꢂꢁꢃ = -69.1° (c = 2.1 MeOH) ([ꢀ]ꢂꢁꢅ lit.20 = -64.1° (c = 2.1 benzene); H
NMR (300 MHz, CDCl3, ppm): δ 7.76-7.74 (m, 2H), 7.35-7.32 (m, 2H), 4.62 (t, J = 6.8
Hz, 1H), 3.53-3.46 (m, 1H), 3.40-3.34 (m, 1H), 2.44 (s, 3H), 2.23-2.16 (m, 2H), 2.02-
13
1.93 (m, 1H), 1.87-1.81 (m, 1H); C NMR (75 MHz, CDCl 3, ppm): δ 174.0, 144.2,
134.9, 129.9, 127.5, 68.7, 48.6, 30.6, 24.3, 21.6; IR (KBr, cm-1) 2951.0, 2891.3, 1811.1,
1597.0, 1344.3, 1155.3, 1010.7, 943.1, 663.5; GC/MS (m/z, %): 224 (100.0), 155 (56.9),
91 (65.0). Characterization data are in accordance with the literature.20
(S)-(6,7-dimethoxy-1-methylene-3,4-dihydroisoquinoline-2(1H)-yl)(1-
tosylpyrrolidin-2-yl)methanone (3)17
To
a
round-bottomed flask were added 6,7-dimethoxy-1-methyl-3,4-
dihydroisoquinoline (9) (205 mg, 1 mmol), (S)-1-tosylpyrrolidine-2-carbonyl chloride
(11) (350 mg, 1.2 mmol), dichloromethane (10 mL), and dry triethylamine (0.21 mL,
1.5 mmol). The round-bottomed flask was capped with a rubber septum. Then, the
reaction was cooled to 0 °C and maintained under stirring for 1 hour. Afterwards, the
mixture was evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel using a mixture of ethyl acetate/hexane (1.25:0.75) as
eluent, affording desired product 3. Yield: 0.40 g (88%); yellowish solid; m.p. 146-148
°C; Rf = 0.52 (eluent: ethyl acetate/hexane (1.25:0.75); [ꢀ]ꢂꢁꢆ = -148.5° (c = 0.1 MeOH);
1H NMR (300 MHz, CDCl3, ppm): δ 7.47-7.44 (m, 2H), 7.11-7.08 (m, 2H), 7.01 (s, 1H)
6.53 (s, 1H), 5.50 (s, 1H), 4.93 (s, 1H), 4.89 (t, J = 7.8 Hz, 1H), 4.19-4.12 (m, 1H), 3.86
(s, 3H), 3.80 (s, 3H), 3.36-3.58 (m, 1H), 3.51-3.44 (m, 1H), 3.35-3.27 (m, 1H), 2.92-
2.82 (m, 1H), 2.68-2.60 (m, 1H), 2.30 (s, 3H), 2.02-1.80 (m, 3H), 1.67-1.61 (m, 1H);
13C NMR (75 MHz, CDCl3, ppm): δ 200.2, 171.2, 150.0, 147.7, 143.1, 143.0, 135.6,
129.4, 127.5, 123.3, 111.4, 106.6, 104.4, 62.6, 57.4, 56.1, 55.9, 49.0, 31.9, 28.4, 24.9,
21.5; IR (KBr, cm-1) 3431.4, 3132.4, 2968.4, 2939.5, 2883.6, 1668.4, 1606.7, 1512.1,
1408.4, 1338.6, 1271.0, 1157.2, 1074.3; HRMS calculated for [C24H29N2O5S]+
457.1792, found [C24H29N2O5S]+ 457.1799.
(S)-1,2-Dimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl)((S)-1-
tosylpyrrolidin-2-yl)methanone
(2a)
and
(R)-1,2-dimethoxy-6a,7-dihydro-4H-
dibenzo[de,g] quinolin-6(5H)-yl)((S)-1-tosylpyrrolidin-2-yl) methanone (2b)17
To a vial (20 mL) were added chiral intermediate 3 (228 mg, 0.5 mmol), silylphenyl
triflate 6 (223 mg, 0.75 mmol), acetonitrile (5 mL), and CsF (228 mg, 1.5 mmol). The
12

vial was sealed using a cap, and and the mixture was maintained under stirring at room
temperature for 24 hours. Afterwards, brine (20 mL) was added to the mixture, which
was extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over MgSO4.
After filtration, the solvent was evaporated under reduced pressure. The residue was
pre-purified by column chromatography on silica gel using a mixture of ethyl
acetate/hexane (1.25:0.75) as eluent, affording a mixture containing desired
diastereoisomers 2a and 2b (Rf = 0.62) in the ratio of 2.3:1, respectively, according to
LC-HRMS analysis. Diastereoisomers 2a and 2b were separated via preparative HPLC.
Diastereoisomer 2a. Yield: 59.6 mg (22%); off-white solid; m.p. 99-101 °C; Rf = 0.63
1
(eluent: ethyl acetate); [ꢀ]ꢂꢁꢃ = +60.8º (c = 0.07 MeOH); H NMR (300 MHz, CDCl3,
ppm) (for a mixture of rotamers in a ratio of 2:1): δ 8.49 (d, J = 7.4 Hz, 1H), 8.40 (d, J =
7.5 Hz, 2H), 7.83 (d, J = 7.8 Hz, 4H), 7.48 (d, J = 7.0 Hz, 2H), 7.41-7.24 (m, 13H), 7,
08 (d, J = 7.0 Hz, 2H), 6.70 (s, 1H), 6.66 (s, 2H), 4.97-4.46 (m, 6H), 4.54 (s, 1H), 4.21
(d, J = 12.6 Hz, 2H), 3.89 (s, 9H), 3.66 (s, 9H), 3.50-3.47 (m, 6H), 3.34 (t, J = 12.1 Hz,
2H), 3.16 (t, J = 14.2 Hz, 1H), 2.93-2.82 (m, 4H), 2.76-2.59 (m, 7H), 2.45 (s, 6H), 2.34
13
(s, 3H), 2.11-2.03 (m, 7H), 1.99-1.93 (m, 3H), 1.82-1.74 (m, 3H); C NMR (75 MHz,
CDCl3, ppm) (for a mixture of rotamers): δ 171.8, 169.7, 152.2, 152.0, 145.8, 145.6,
143.3, 136.6, 136.1, 135.6, 135.5, 135.1, 135.0, 131.7, 131.6, 131.4, 131.3, 130.1,
129.5, 128.9, 128.8, 128.4, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4,
127.4, 127.2, 126.8, 126.1, 125.3, 125.2, 111.6, 111.1, 59.9, 58.7, 57.1, 57.0, 55.9, 52.9,
52.9, 51.2, 48.9, 48.9, 48.3, 41.0, 37.9, 37.3, 33.7, 32.0, 30.6, 29.6, 25.1, 24.6, 21.5,
21.4; IR (KBr, cm-1) 2916.4, 2835.4, 1639.4, 1597.6, 1492.9, 1421.5, 1334.7, 1109.1,
1159.2, 1039.6, 937.4, 663.5; HRMS calculated for [C30H33N2O5S]+ 533.2105, found
[C30H33N2O5S]+ 533.2107. Diastereoisomer 2b. Yield: 26.1 mg (10%); off-white solid;
m.p. 121-123 °C; Rf = 0.65 (eluent: ethyl acetate); [ꢀ]ꢂꢁꢇ = -231.3º (c = 0.07 MeOH); 1H
NMR (300 MHz, CDCl 3, ppm) (for a mixture of rotamers in a ratio of 1:1): δ 8.49 (d, J
= 7.0 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.2 Hz,
2H), 7.47-7.29 (m, 6H), 7.24-7.19 (m, 4H), 6.70 (s, 1H), 6.69 (s, 1H), 5.03-4.87 (m,
2H), 4.74 (dd, J = 8.5 Hz, 3.3 Hz, 1H), 4.48 (dd, J = 13.8 Hz, 3.1 Hz, 1H), 4.29-4.17
(m, 2H), 3.90 (s, 6H), 3.67 (s, 6H), 3.54-3.47 (m, 2H), 3.41-3.06 (m, 7H), 2.95 (dd, J =
13.5 Hz, 3.9 Hz, 1H), 2.81-2.70 (m, 4H), 2.41 (s, 3H), 2.33 (s, 3H), 2.13-2.10 (m, 2H),
13
2.06-1.99 (m, 3H), 1.94-1.87 (m, 2H), 1.72-1.68 (m, 1H); C NMR (75 MHz, CDCl3,
ppm) (for a mixture of rotamers): δ 171.0, 169.8, 152.4, 152.0, 145.7, 143.4, 143.3,
136.5, 136.4, 136.1, 136.0, 131.6, 131.5, 126.9, 126.9, 126.1, 126.0, 125.1, 129.9,
13

129.9, 129.5, 129.4, 129.2, 129.1, 128.6, 128.5, 128.4, 128.3, 128.0, 127.7, 127.6,
127.5, 127.5, 127.4, 127.4, 111.5, 111.2, 60.0, 58.7, 58.6, 55.9, 52.8, 50.9, 48.5, 48.0,
41.0, 36.8, 36.4, 33.7, 31.9, 31.3, 30.6, 29.9, 29.6, 29.3, 24.8, 24.7, 21.5, 21.4; IR (KBr,
cm-1) 2924.1, 1728.2, 1649.4, 1595.1, 1448.5, 1443.5, 1338.2, 1155.3, 1107.1, 1031.9,
663.5, 590.2; HRMS calculated for [C30H33N2O5S]+ 533.2105, found [C30H33N2O5S]+
533.2114.
(S)-nornuciferine (12a)17
To a microwave tube (10 mL) were added diastereoisomer 2a (41.3 mg, 0.078
mmol), ethanol/water (2:1) (6 mL), and lithium hydroxide (32.8 mg, 0.78 mmol). The
tube was sealed using a cap and the mixture was stirred under microwave heating at 180
°C (50 W) for 60 minutes. Then, the reaction was cooled to room temperature and
distilled water (10 mL) was added. The mixture was extracted with dichloromethane (3
× 15 mL). The organic phase was dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by preparative thin layer
chromatography on silica gel using methanol as eluent, affording (S)-nornuciferine
(12a). Yield: 19.0 mg (87%); yellowish oil; Rf = 0.26 (eluent: methanol); [ꢀ]ꢁꢂꢇ
=
1
+131.9º (c = 0.19 EtOH) ([ꢀ]ꢂꢁꢂ lit33 = +140º (c = 0.18 EtOH)); H NMR (300 MHz,
CDCl3, ppm): δ 8.30 (d, J = 7.8 Hz, 1H), 7.19-7.11 (m, 3H), 6.54 (s, 1H), 3.77 (s, 3H),
3.70 (dd, J = 13.4 Hz, 4.5 Hz, 1H), 3.57 (s, 3H), 3.26-3.23 (m, 1H) 2.95-2.83 (m, 2H),
2.76-2.56 (m, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 152.0, 145.1, 136.1, 132.1,
128.8, 128.7, 128.3, 127.7, 127.3, 126.9, 126.4, 111.7, 60.1, 55.8, 53.5, 43.0, 37.4, 29.1;
IR (KBr, cm-1) 3324.5, 2928.1, 2835.5, 2316.6, 1593.3, 1451.5, 1423.5, 1251.9, 1248.0,
1034.8, 754.2; GC/MS (m/z, %): 281 (49.3), 280 (100.0), 264 (17.7), 250 (22.2), 236
(18.0), 221 (16.2), 165 (16.0). Characterization data are in accordance with the
literature.17b
(R)-Nornuciferine (12b)17
To a microwave tube (10 mL) were added diastereoisomer 2b (12.8 mg, 0.024
mmol), ethanol/water (2:1) (6 mL), and lithium hydroxide (10.1 mg, 0.24 mmol). The
tube was sealed using a cap and the mixture was stirred under microwave heating at 180
°C (50 W) for 60 minutes. Then, the reaction was cooled to room temperature and
distilled water (10 mL) was added. The mixture was extracted with dichloromethane (3
× 15 mL). The organic phase was dried over MgSO4. After filtration, the solvent was
14

evaporated under reduced pressure. The residue was purified by preparative thin layer
chromatography on silica gel using methanol as eluent, affording (R)-nornuciferine
(12b). Yield: 4.6 mg (68%); yellowish oil; Rf = 0.26 (eluent: methanol); [ꢀ]ꢂꢁꢇ = -131.4º
1
(c = 0.19 EtOH) (([ꢀ]ꢂꢁꢂ lit14c = -105.2º (c = 1 EtOH)). H NMR and LRMS data
obtained for compound 12b were similar to those obtained for (S)-nornuciferine (12a).
(S)-nuciferine (1a)17
To a round-bottomed flask were added (S)-nornuciferine (12a) (19.0 mg, 0.068
mmol), methanol (11 mL), and a 37% (w/v) aqueous solution of formaldehyde (0.2 mL,
6.8 mmol). The mixture was maintained under magnetic stirring at room temperature
for 30 minutes. Then, NaBH4 (77 mg, 2.04 mmol) was added and the reaction was
maintained under magnetic stirring at room temperature for 1 hour. Afterwards, brine
(30 mL) was added to the mixture, which was extracted with ethyl acetate (3 x 35 mL).
The organic phase was dried over MgSO4. After filtration, the solvent was evaporated
under reduced pressure. The residue was purified by preparative thin layer
chromatography on silica gel using methanol as eluent, affording (S)-nuciferine (1a).
Yield: 18.2 mg (91%); yellowish solid; m.p. 163-165 °C (m.p. lit.34 163-165 °C); Rf =
0.5 (eluent: methanol); [ꢀ]ꢂꢁꢂ = +125.4º (c = 1 EtOH), [ꢀ]ꢁꢂꢂ = +87.9º (c = 0.1 EtOH)
([ꢀ]ꢁꢂꢆ lit21 = +165º (c = 0.26 EtOH), [ꢀ]ꢂꢁꢂ lit14c for (R)-nuciferine = -125.4º (c = 1
1
EtOH)); H NMR (300 MHz, CDCl3, ppm): δ 8.30 (d, J = 7.8 Hz, 1H), 7.25-7.16 (m,
3H), 6.56 (s, 1H), 3.81 (s, 3H), 3.57 (s, 3H), 3.18-3.08 (m, 1H), 3.06-2.98 (m, 3H),
2.65-2.42 (m, 3H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 151.9, 144.9,
136.1, 131.9, 128.4, 128.2, 127.8, 127.3, 127.2, 127.0, 126.7, 110.9, 62.1, 60.2, 55.7,
53.1, 43.7, 34.7, 28.8; IR (KBr, cm-1) 2950.1, 2930.8, 2834.4, 1594.2, 1451.4, 1321.2,
1301.0, 1249.9, 1035.8; GC/MS (m/z, %): 295 (32.0), 293 (100.0), 278 (45.6), 264
(16.9), 250 (18.3), 235 (34.9). Characterization data are in accordance with the
literature.17b
(R)-nuciferine (1b)17
To a round-bottomed flask were added (R)-nornuciferine (12b) (4.5 mg, 0.016
mmol), methanol (6 mL), and a 37% (w/v) aqueous solution of formaldehyde (0.05 mL,
1.6 mmol). The mixture was maintained under magnetic stirring at room temperature
for 30 minutes. Then, NaBH4 (18 mg, 0.48 mmol) was added and the reaction was
maintained under magnetic stirring at room temperature for 1 hour. Afterwards, brine
15

(10 mL) was added to the mixture, which was extracted with ethyl acetate (3 x 15 mL).
The organic phase was dried over MgSO4. After filtration, the solvent was evaporated
under reduced pressure. The residue was purified by preparative thin layer
chromatography on silica gel using methanol as eluent, affording (R)-nuciferine (1b).
Yield: 3.9 mg (84%); yellowish solid; m.p. 168-169 °C (m.p. lit.35 168 °C); Rf = 0.5
(eluent: metanol); [ꢈ]ꢊꢉꢊ = -87.9º (c = 0.1 EtOH) ([ꢈ]ꢉꢊꢊ lit14c = -125.4º (c = 1 EtOH));
1H NMR and LRMS data obtained for compound 1b were similar to those obtained for
(S)-nuciferine (1a).
5. Acknowledgments
We are grateful to São Paulo Research Foundation (FAPESP) (Grant Numbers:
2009/54011-8 and 2017/21990-0) and to National Council for Scientific and
Technological Development (CNPq) for financial support. G.P.P. thanks the
Coordination for the Improvement of Higher Education Personnel (CAPES) for the
fellowship.
6. Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/.
7. References
1. (a) Shakirov, R.; Vinogradova, V. I.; Aripova, S. F.; Sultankhodzhaev, M. N.;
Bessonova, I. A.; Akhmedzhanova, V. I.; Tulyaganov, T. S.; Salimov, B. T. In
Natural Compounds (Alkaloids): Plant Sources, Structure and Properties; Azimova,
S. S.; Yunusov, M. S., Eds.; Springer: New York, 2013, p 336. (b) Osorio, E. J.;
Robledo, S. M.; Bastida, J. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
San Diego, 2008, Vol. 66, p 126.
2. (a) Wiart, C. Lead Compounds from Medicinal Plants for the Treatment of Cancer;
Academic Press: Waltham, 2013, p 35. (b) Qing, Z.-X.; Huang, J.-L.; Yang, X.-Y.;
Liu, J.-H.; Cao, H.-L.; Xiang, F.; Cheng, P.; Zeng, J.-G. Curr. Med. Chem. 2018, 25,
5088. (c) Liu, C.-M.; Kao, C.-L.; Wu, H.-M.; Li, W.-J.; Huang, C.-T.; Li, H.-T.;
Chen, C.-Y. Molecules 2014, 19, 17829. (d) Suresh, H. M.; Shivakumar, B.;
Shivakumar, S. I. Int. J. Plant Res. 2012, 2, 57.
3. (a) Qing, Z.-X.; Yang, P.; Tang, Q.; Cheng, P.; Liu, X.-B.; Zheng Y.-J.; Liu, Y.-S.;
Zeng, J.-G. Curr. Org. Chem. 2017, 21, 1920. (b) Mohamed, S. M.; Hassan, E. M.;
Ibrahin, N. A. Nat.l Prod. Res. 2010, 24, 1395.
16

4. Guo, Y.-G.; Ding, Y.-H.; Wu, G.-J.; Zhu, S.-L.; Sun, Y.-F.; Yan S.-K.; Qian, F.; Jin,
H.-Z.; Zhang, W.-D. Fitoterapia 2018, 127, 96.
5. (a) Singh, I. P.; Bodiwala, H. S. Nat. Prod. Rep. 2010, 27, 1781. (b) Kashiwada, Y.;
Aoshima, A.; Ikeshiro, Y.; Chen, Y.-P.; Furukawa, H.; Itoigawa, M.; Fujioka, T.;
Mihashi, K.; Cosentino, L. M.; Morris-Natschke, S. L.; Lee, K.-H. Bioorg. Med.
Chem. 2005, 13, 443.
6. (a) Hung, J.; Castillo, J.; Jiménez, G.; Hasegawa, M.; Rodriguez, M. Spectrochim.
Acta A Mol. Biomol. Spectrosc. 2003, 59, 3177. (b) Lorenzo, V. P.; Lúcio, A. S. S.
C.; Scotti, L.; Tavares, J. F.; Filho, J. M. B.; Lima, T. K. S.; Rocha, J. C.; Scotti, M.
T. Curr. Pharm. Des. 2016, 22, 5196.
7. Munusamy, V.; Yap, B. K.; Buckle, M. J. C.; Doughty, S. W.; Chung, L. Y. Chem.
Biol. Drug. Des. 2013, 81, 250.
8. Hoshino, O. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1995, Vol. 16, p 503.
9. (a) Li, J. J. Name Reactions: A Collection of Detailed Mechanisms and Synthetic
Applications, 4th ed.; Springer-Verlag: Berlin, 2009, p 450. (b) Smith, M. B.; March,
J. March’s Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 6th
ed.; John Wiley & Sons: Hoboken, 2007, p 925. (c) Laali, K. K.; Shokouhimehr, M.
Curr. Org. Synth. 2009, 6, 193. (d) Leake, P. H. Chem. Rev. 1956, 56, 27.
10.
(a) Schwartz, M. A.; Pham, P. T. K. J. Org. Chem., 1988, 53, 2318. (b) Shamma,
M.; Slusarchyk, W. A. Chem. Rev. 1964, 64, 59. (c) Franck, B.; Blaschke, G.;
Schlingloff, G. Tetrahedron Lett. 1962, 10, 439.
11.
(a) Landais, Y.; Rambault, D.; Robin J. P. Tetrahedron Lett. 1987, 28, 543. (b)
Dickman, D. A.; Meyers, A. I. Tetrahedron Lett. 1986, 27, 1465. (c) Adesomoju, A.
A.; Davis, W. A.; Rajaraman, R.; Pelletier J. C.; Cava, M. P. J. Org. Chem., 1984,
49, 3220. (d) Ammar, H. A.; Sciff, J. P. L.; Slatkin, D. J. Heterocycles 1983, 20, 451.
12.
(a) Chuang, T.-H.; Li, C.-F.; Lee, H.-Z.; Wen, Y.-C. J. Org. Chem. 2013, 78,
4974. (b) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000. (c) Barolo, S.
M.; Teng, X.; Cuny, G. D.; Rossi, R. A. J. Org. Chem. 2006, 71, 8493. (d) Lenz, G.
R. J. Org. Chem. 1988, 53, 4447. (e) Cava, M. P.; Stern, P.; Wakisaka, K.
Tetrahedron 1973, 29, 2245. (f) Kupchan, S. M.; Moniot, J. L.; Kanojia, R. M.;
O’Brien, J. J. Org. Chem. 1971, 36, 2413.
13.
(a) Hoshino, O.; Umezawa, B. The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1989, Vol. 36, Chapter 2. (b) Hoshino, O.; Ogasawara, H.; Arasawa, M.;
17

Suzuki, M.; Lizima, A. Heterocycles 1993, 35, 1005. (c) Abramovitch, R. A.;
Chinnasamy, P.; Evertz, K.; Huttner, G. J. Chem. Soc, Chem. Commun. 1989, 3. (d)
Hoshino, O.; Ohtani, M.; Umezawa, B.; Litaka, Y. Heterocycles 1982, 17, 283.
14.
(a) Hellal, M.; Singh, S.; Cuny, G. D. Tetrahedron 2012, 68, 1674. (b) Lee, K.
M.; Kim, J. C.; Kang, P.; Lee, W. K.; Eum, H.; Ha, H.-J. Tetrahedron 2012, 68, 883.
(c) Lafrance, M.; Blaquière, N.; Fagnou, K. Eur. J. Org. Chem. 2007, 811. (d)
Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (e) Lafrance, M.;
Blaquière, N.; Fagnou, K. Chem. Commun. 2004, 2874.
15.
(a) Takikawa, H.; Nishii, A.; Sakai, T.; Suzuki, K. Chem. Soc. Rev. 2018, 47,
8030. (b) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
16.
(a) Atanes, N.; Castelo, L.; Guitián, E.; Saá, C.; Saá, J. M.; Suau, R. J. Org.
Chem. 1991, 56, 2984. (b) Gómez, B.; Martín, G.; Guitián, E.; Castedo, L.; Saá, J.
M. Tetrahedron 1993, 49, 1251. (c) Atanes, N.; Castedo, L.; Cobas, A.; Guitián, E.;
Saá, C.; Saá, J. M. Tetrahedron 1989, 45, 7947.
17.
(a) Muraca, A. C. A.; Perecim, G. P.; Rodrigues, A.; Raminelli, C. Synthesis,
2017, 49, 1. (b) Rossini, A. F. C.; Muraca, A. C. A.; Casagrande, G. A.; Raminelli,
C. J. Org. Chem. 2015, 80, 10033. (c) Perecim, G. P.; Rodrigues, A.; Raminelli, C.
Tetrahedron Lett. 2015, 56, 6848.
18.
(a) Moreno, L.; Cabedo, N.; Boulangé, A.; Párraga, J.; Galán, A.; Leleu, S.;
Sanz, M.-J.; Cortes, D.; Franck, X. Eur. J. Med. Chem. 2013, 69, 69. (b) Brossi, A.;
Dolan, L. A.; Teitel, S. Org. Synth. 1988, Coll. Vol. 6, 1.
19.
20.
Han, Z.; Wang, R.; Zhou, Y.; Liu, L. Eur. J. Org. Chem. 2005, 934.
Gruzdev, D. A.; Vakarov, S. A.; Levit, G. L.; Krasnov, V. P. Chem. Heterocycl.
Comp. 2014, 49, 1795.
21.
(a) Heng, H. L.; Chee, C. F.; Chin, S. P.; Ouyang, Y.; Wang, H.; Buckle, M. J.
C.; Herr, D. R.; Paterson, I. C.; Doughty S. W.; Rahman, N. A.; Chung, L. Y. Med.
Chem. Commun. 2018, 9, 576. (b) Pfeifer, S.; Kuehn, L. Pharmazie 1967, 22, 221.
22.
Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th ed.;
Butterworth-Heinemann: Oxford, 1996.
23.
24.
Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
Leonard, J.; Lygo, B.; Procter, G. Advanced Practical Organic Chemistry, 2nd
ed.; CRC Press: Boca Raton, 1998, 102.
25.
26.
Sheldrick, G. M. Acta Cryst. 2008, A64, 112.
Sheldrick, G. M. Acta Cryst. 2015, C71, 3.
18

27.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.;
Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci,
B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-
Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.;
Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.;
Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.;
Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi,
J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16
(B.01); Gaussian, Inc.: Wallingford, CT, 2016.
28.
Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
29.
30.
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch, M. J. J. Phys.
Chem. 1996, 100, 16098.
31.
Legault, C. Y. CYLview version 1.0 BETA; Université de Sherbrooke, 2009,
http://www.cylview.org.
32.
Soni, R.; Cheung, F. K.; Clarkson, G. C.; Martins, J. E. D.; Graham, M. A.;
Wills, M. Org. Biomol. Chem. 2011, 9, 3290.
33.
119.
34.
35.
Ziyaev, R.; Abdusamatov, A.; Yunusov, S. Y. Chem. Nat. Compd. 1974, 10,
Pfeifer, S.; Kuehn, L. Pharmazie 1968, 23, 199.
Preininger, V.; Santavy, F. Acta Universitatis Palackianae Olomucensis,
Facultatis Medicae 1966, 5.
19

Highlights
•
Total syntheses of (S)- and (R)-nuciferine were accomplished through
unprecedented approach involving benzyne chemistry.
•
Reaction between chiral dihydroisoquinoline enamide and benzyne precursor
afforded a separable mixture of diastereoisomers.
The stereochemical pathway for the key transformation was evaluated by DFT
calculations.
•
•
The structure of the major diastereoisomer was unequivocally confirmed by X-
ray analysis.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: