A convenient formation of aporphine core via benzyne chemistry: Conformational analysis and synthesis of (R)-aporphine

Article abstract of DOI:10.1016/j.tetlet.2015.10.083

Total synthesis of (R)-aporphine has been accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2] cycloaddition reaction followed by a hydrogen migration, leading to aporphine core in good yield, which was subjected to a 1D gradient NOE experiment, conformational analysis, and simple transformations, including a small scale resolution process, to afford enantiomerically enriched aporphine alkaloid.

Full text of DOI:10.1016/j.tetlet.2015.10.083

Accepted Manuscript
A convenient formation of aporphine core via benzyne chemistry: conforma-
tional analysis and synthesis of (R)-aporphine
Givago P. Perecim, Alessandro Rodrigues, Cristiano Raminelli
PII:
S0040-4039(15)30280-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.083
TETL 46912
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 September 2015
21 October 2015
26 October 2015
Please cite this article as: Perecim, G.P., Rodrigues, A., Raminelli, C., A convenient formation of aporphine core
via benzyne chemistry: conformational analysis and synthesis of (R)-aporphine, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.10.083
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A convenient formation of aporphine core
via benzyne chemistry: conformational
analysis and synthesis of (R)-aporphine
Leave this area blank for abstract info.
Givago P. Perecim, Alessandro Rodrigues, Cristiano Raminelli*
———
 Corresponding author. Tel.: +55 11 3385 4137; fax: +55 11 4043 6428; e-mail: raminelli@unifesp.br

1
Tetrahedron Letters
A convenient formation of aporphine core via benzyne chemistry: conformational
analysis and synthesis of (R)-aporphine
Givago P. Perecim, Alessandro Rodrigues, Cristiano Raminelli
Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua Prof. Artur Riedel, 275, Diadema 09972-270, SP, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Total synthesis of (R)-aporphine has been accomplished by an approach that employs in the key
step a sequence of transformations involving a [4+2] cycloaddition reaction followed by a
hydrogen migration, leading to aporphine core in good yield, which was subjected to a 1D
gradient NOE experiment, conformational analysis, and simple transformations, including a
small scale resolution process, to afford enantiomerically enriched aporphine alkaloid.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
(R)-aporphine
Aporphine core
Benzyne chemistry
Conformational analysis
1D gradient NOE experiment
———
 Corresponding author. Tel.: +55 11 3385 4137; fax: +55 11 4043 6428; e-mail: raminelli@unifesp.br

2
Tetrahedron
Aporphine alkaloids compose a class of isoquinoline
alkaloids which can be found in several families of plants.1
Considering structural features, aporphine skeletons are
constituted by four rings (A-D), with a nitrogen atom present in
the B ring. Besides, aporphine alkaloids can be classified into at
least five groups, namely, aporphines, oxoaporphines,
aristolactams, azafluoranthenes and proaporphines.2
From the pharmacological perspective, aporphinoids present
important biological properties, involving, for example, anti-HIV
activity,3 anticancer activity,4 and dopaminergic activities.5 In
this sense, (R)-(-)-apomorphine hydrochloride, an example of an
aporphine prototype, has currently been employed in erectile
dysfunction treatment6 and Parkinson's disease therapy.7
Scheme 1. Retrosynthetic analysis for (R)-aporphine (1).
(R)-Aporphine (1) was planned by small scale resolution
process from (±)-aporphine (2) obtained by transformations
employing aporphine core 3 achieved by [4+2] cycloaddition
reaction followed by hydrogen migration between 1-
methyleneisoquinoline 4 and benzyne 6 formed under mild
reaction conditions (Scheme 1).
Taking into account the pharmacological properties exhibited
by aporphinoids, several synthetic approaches have been reported
allowing access to aporphine cores.8-11 The most widespread
approaches are those based on biosynthetic routes, having in
common the formation of the
C
ring, employing 1-
benzyltetrahydroisoquinoline intermediates,8-10 which are well
exemplified by the Pschorr reaction.8 In addition, over the last
decades, approaches based on benzyne chemistry, involving
Intermediate 4 was obtained by minor modifications of well-
established transformations.13-14 Commercially available amine 5
was allowed to react with acetic anhydride in pyridine, leading to
the formation of the corresponding amide 8 in quantitative
yield.13 Amide 8 was converted by Bischler-Napieralski reaction
reactions
arenediazonium-2-carboxylates,
between
1-methyleneisoquinolines
which
and
provide
dehydroaporphines in moderate yields, have experienced a
remarkable development.11 However, the formation of
dehydroaporphines can be pointed as a negative aspect related
with the use of arynes to synthesize aporphinoids, once the
reduction of dehydroaporphines to aporphines is not a well-
documented transformation and the procedures reported in the
literature involve expensive metal9d or harsh conditions.9e
Moreover, some researchers have discouraged the use of
arenediazonium-2-carboxylates for safety reasons.11a In this
context, our research group has explored an approach that
employs reactions between isoquinoline derivatives and silylaryl
triflates in the presence of CsF, providing aporphine cores instead
of dehydroaporphines, under mild reaction conditions, through
[4+2] cycloaddition reactions followed by hydrogen migrations,12
in total syntheses of aporphine alkaloids (Figure 1).
to heterocyclic intermediate
9 in a
quantitative yield.13
Compound 9 was treated with acetic anhydride in pyridine to
produce intermediate 5 in an isolated yield of 74%14 (Scheme 2).
Scheme 2. Synthesis of intermediate 5.
Allowing the reaction between isoquinoline derivative 4 and
1.5 equiv of benzyne precursor 7 in the presence of 3 equiv of
CsF at room temperature for 24 h, intermediate 3 was obtained in
an isolated yield of 77%. In this transformation, compounds 4
and
7 were partially recovered and the corresponding
dehydroaporphine was not observed (Scheme 3).
Figure 1. Approaches to produce aporphine compounds.
Accordingly, herein we wish to report the total synthesis of
(R)-aporphine (1), employing as key step the reaction between 1-
methyleneisoquinoline (4), which can be considered a relatively
nonpolar diene, and 2-(trimethysilyl)phenyl triflate (7) in the
presence of CsF, to produce aporphine core 3, under mild
reaction conditions. Then, compound 3 was subjected to a 1D
gradient NOE experiment, conformational analysis, and simple
transformations, including a small scale resolution process, to
afford enantiomerically enriched aporphine alkaloid 1, according
to the retrosynthetic analysis outlined in Scheme 1.
Scheme 3. Preparation and proposed mechanisms for the
aporphine core 3.
Reaction involving relatively nonpolar diene 4 and benzyne 6
resulted in compound
transformations involving
3
presumably by a sequence of
[4+2] cycloaddition reaction
a
followed by a hydrogen migration (Scheme 3).
1
By performing H and 13C NMR spectra for intermediate 3,
we observed a mixture of rotamers or diastereomers in CDCl3

3
solution at room temperature (please, see Supplementary
Material). To distinguish between the existence of rotamers or
diastereomers, we carried out a 1D gradient NOE experiment for
compound 3, in CDCl3 solution at room temperature, irradiating
one of two signals corresponding to hydrogens attached to the 6a
position and observed two negative peaks at 5.31 ppm (A) and
4.78 ppm (B), confirming the existence of equilibrating
rotamers, instead of a mixture of diastereomers, in a ratio of 2:1
(Figure 2).15
respectively, can give some support to the absence of solvent
effect observed.
A gradual increase in energy was observed when the dihedral
angle (C1–C16–C15–C14) of biphenyl system present in the rotamer
3a was varied from -23o to +6o (Figure 4a). Structure
optimizations for the boat conformer 3e showed relatively high
energies in gas phase and chloroform (Figure 4b).
Figure 4. (a) Variation of axial dihedral angle for the rotamer 3a.
(b) Energies for the boat conformer 3e in the gas phase and
chloroform.
Total synthesis of (R)-(-)-aporphine (1) was archived from
aporphine core 3 by modifications of published procedures.18-20
(±)-Noraporphine (11) was obtained by hydrolysis of
intermediate 3 employing lithium hydroxide in a mixture of
ethanol/water (2:1) under microwave heating in a moderate yield
of 55%.18 Compound 11 was N-alkylated by reaction with a 37%
aqueous solution of formaldehyde followed by reduction with
sodium borohydride, to afford (±)-aporphine (2) in 83% yield.19
Alkaloid 2 was subjected to a small scale resolution process
employing (+)-DBTA,20 which provided (R)-(-)-aporphine (1) in
an isolated yield of 41% and with 81% ee (Scheme 4).
Figure 2. 1D gradient NOE experiment for the compound 3 in
CDCl3 solution at room temperature in a NMR spectrometer
operating at 600 MHz.
In an attempt to understand the fluxional behavior of 3 in
solution, we carried out a computational analysis to identify
energetically viable conformers for 3.16 Conformational analysis
was performed by DFT calculations at M062X/6-311+G(d,p)
theory level employing SCIPCM method to evaluate the solvent
effect.17 Taking into consideration the conformational
equilibrium, rotamer 3a appeared as the global energy minimum
with populations of 65.7 and 68.2% in the gas phase and
chloroform, respectively (Figure 3). Conversion of rotamer 3a to
rotamer 3d, the second most stable conformer, presenting
populations of 34.2% and 31.8% in the gas phase and
chloroform, respectively, takes place through rotamers 3b and 3c,
i.e., two other less stable local minima (Figure 3). In addition, B
ring flipping (3a to 3b and 3c to 3d) and the rotation around the
N–CO bond (3a to 3d and 3b to 3c) are presented in Figure 3.
Scheme 4. Synthesis of (R)-(-)-aporphine (1).
The structures of compounds 1, 2, 4, 8, 9, and 11 were
assigned according to their GC/MS, IR, 1H and 13C NMR spectra.
The structure of compound 3 was assigned according to its
1
GC/MS, IR, H, 13C, DEPT, COSY, and HSQC NMR spectra.
All substances produced (1-4, 8, 9, and 11) are known and their
spectral data are in accordance with those already published.
In summary, we have employed a concise route toward the
synthesis of (R)-(-)-aporphine (1). Our approach involves the
formation of aporphine core (3) by reaction between relatively
nonpolar isoquinoline derivative (4) and 2-(trimethysilyl)phenyl
triflate (7) promoted by CsF. The formation of aporphine core (3)
proceeded under mild reaction conditions and in good yield
presumably through [4+2] cycloaddition reaction followed by
hydrogen migration. 1D gradient NOE experiment and
conformational analysis provided significant details about
structural features for compound 3. The chemistry disclosed
Figure 3. Conformational analysis for the aporphine core 3.
Boltzmann distribution calculations provided a ratio of 2:1 for
rotamers 3a and 3d, respectively, both in the gas phase and
chloroform, which is according to the ratio obtained by 1H NMR
experiment performed in CDCl3. Similar dipole moment values,
namely, 3.7 and 3.5 D, calculated for structures 3a and 3d,

4
Tetrahedron
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emerging as a trustworthy alternative to produce aporphinoids.
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Acknowledgments
We are grateful to FAPESP (Brazil) (Fundação de Amparo à
Pesquisa do Estado de São Paulo - Brazil) for financial support.
G.P.P.
Aperfeiçoamento de Pessoal de Nível Superior - Brazil) for
fellowship.
thanks
CAPES
(Brazil)
(Coordenação
de
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Supplementary data (experimental procedures, computational
details, characterization data and RMN spectra) associated with
this article can be found, in the online version, at
http://dx.doi.org/XXX.