Total syntheses of (+)-bernumidine and its unnatural enantiomer

Article abstract of DOI:10.1016/j.tetlet.2018.08.046

Total syntheses of (+)-bernumidine and its unnatural enantiomer were accomplished through chemoenzymatic dynamic kinetic resolution and ruthenium(II)-catalyzed enantioselective hydrogenation, which provided (R)-salsolidine propyl carbamate and N-acetyl (S

Full text of DOI:10.1016/j.tetlet.2018.08.046

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Total syntheses of (+)-bernumidine and its unnatural enantiomer
Bianca K. Corrêa, Tamiris R.C. Silva, Cristiano Raminelli
PII:
S0040-4039(18)31047-5
https://doi.org/10.1016/j.tetlet.2018.08.046
TETL 50221
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Reference:
Tetrahedron Letters
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12 July 2018
14 August 2018
22 August 2018
Please cite this article as: Corrêa, B.K., Silva, T.R.C., Raminelli, C., Total syntheses of (+)-bernumidine and its
unnatural enantiomer, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.046
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Total syntheses of (+)-bernumidine and its
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Bianca K. Corrêa, Tamiris R. C. Silva, Cristiano Raminelli

1
Tetrahedron Letters
Total syntheses of (+)-bernumidine and its unnatural enantiomer
Bianca K. Corrêa, Tamiris R. C. Silva, 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 syntheses of (+)-bernumidine and its unnatural enantiomer were accomplished through
chemoenzymatic dynamic kinetic resolution and ruthenium(II)-catalyzed enantioselective hydrogenation,
which provided (R)-salsolidine propyl carbamate and N-acetyl (S)-salsolidine in high yields and enantiomeric
excesses, respectively. Both enantiomers of salsolidine were accessed and converted into (+)- and (-)-
bernumidine via simple and efficient transformations.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
(+)-Bernumidine
Bernumidine enantiomer
MOR ligands
Chemoenzymatic DKR
Enantioselective hydrogenation
(+)-Bernumidine (1a) is an benzylisoquinoline alkaloid
isolated for the first time from leaves of Berberis nummularia1
and (-)-bernumidine (1b) is its unnatural enantiomer.2 Although
plants of the genus Berberis have been employed for centuries
throughout the world because of tonic, antimicrobial, and
sedative properties,2,3 to the best of our knowledge, no research
concerning biological activities for (+)-bernumidine (1a) or even
for (-)-bernumidine (1b) has been published until the present
moment. Nevertheless, a recent study has disclosed that a
racemic bernumidine derivative, i.e., where the piperonyl moiety
was changed by 4-hydroxy-3,5-dimethylbenzyl group, was
identified as a novel chemical scaffold with binding affinity to
the µ opioid receptor (MOR) in vitro, combined with MOR
antagonist properties. Moreover, in vivo, the same substance has
been highly effective in antagonizing morphine-induced
antinociception in mice.4 Despite the important discoveries
involving a bernumidine derivative in medicinal chemistry,4 in
preparative organic chemistry we realized a lack of synthetic
routes to produce both enantiomers of bernumidine (1a and 1b).
In 2001, the synthesis of racemic bernumidine was reported by
Vallée and coworkers through the alkylation of racemic
salsolidine.2 In that article, authors also resolved racemic
salsolidine by precipitating one of the enantiomers with D-(-)-
tartaric acid, further performing the alkylation of the entantiomer
isolated to provide (+)-bernumidine (1a). However, there is no
synthesis of (-)-bernumidine (1b) reported so far. Accordingly,
enantioselective approaches for the syntheses of (+)-bernumidine
(1a) and (-)-bernumidine (1b), which could be employed in the
preparation of both enantiomers of a variety of bernumidine
derivatives, would be of considerable importance. Thus, we
examined the literature and found a practical, scalable, and
efficient chemoenzymatic dynamic kinetic resolution (DKR) of
secondary amines using an iridium-based amine racemization
catalyst under significantly mild conditions, which was employed
to the formation of (R)-salsolidine propyl carbamate in high yield
and enantiomeric excess.5 In addition, the operationally refined
enantioselective hydrogenation of enamides catalyzed by
BINAP-ruthenium(II) complexes was the method of choice to
obtain N-acetyl (S)-salsolidine also in high yield and
enantiomeric excess.6
In our retrosynthetic analysis (+)-bernumidine (1a) and its
unnatural enantiomer (1b) are obtained from (R)-salsolidine (2a)
and (S)-salsolidine (2b), which are produced from valuable
approaches employing isoquinoline intermediates 5 and 6,
respectively, both obtained from 3,4-dimethoxyphenethylamine
(7) (Scheme 1).
———
 Corresponding author. Tel.: +55-11-4044-0500 (extension line: 3473); fax: +55-11-4043-6428; e-mail: raminelli@unifesp.br

2
Tetrahedron
Scheme 1. Retrosynthetic analysis for (+)-bernumidine (1a) and its unnatural enantiomer (1b).
Intermediates 5 and 6 were prepared by minor modifications
of well-established reactions.7-10 Commercially available 3,4-
dimethoxyphenethylamine (7) was treated with acetic anhydride
Chemoenzymatic DKR of intermediate 5 was performed
through an experimentally simple protocol on a 0.2 g scale.
According to the literature,5 when the same transformation was
carried out on a 3 g scale, compound 11 was obtained in 82%
yield and with 96% ee. Afterwards, (R)-salsolidine propyl
carbamate (11) was subjected to a base hydrolysis using
LiOH·H2O in a mixture of ethanol/water (2:1) under microwave
heating (90 W) at 180 oC for 1 h,11 leading to (R)-salsolidine (2a)
in quantitative yield (Scheme 3).
in
pyridine
to
produce
corresponding
N-(3,4-
dimethoxyphenethyl)acetamide (8) in 97% yield.7 Acetamide 8
was converted by Bischler-Napieralski reaction to heterocyclic
compound 9 in 94% yield.8 Intermediate 9 was reduced in the
presence of NaBH4 leading to 6,7-dimethoxy-1-methyl-1,2,3,4-
tetrahydroisoquinoline (5) in 74% isolated yield.9 Afterwards,
intermediate 9 was also allowed to react with acetic anhydride in
pyridine leading to the formation of 1-(6,7-dimethoxy-1-
methylene-3,4-dihydroisoquinolin-2(1H)-yl)ethenone (6) in 88%
isolated yield10 (Scheme 2).
Intermediate
6 was asymmetrically reduced employing
hydrogen (20 atm) and (S)-Ru(AcO)2(BINAP) (2.7 mol%) as
catalyst in ethanol/dichloromethane (5:1) at room temperature for
72 h to produce (S)-salsolidine acetate (12) in 94% isolated yield
and with 90% ee6 (Scheme 4).
Scheme 4. Enantioselective hydrogenation and base hydrolysis
providing (S)-salsolidine (2b).
Scheme 2. Syntheses of intermediates 5 and 6.
Asymmetric reduction of intermediate 6 provided (S)-
salsolidine acetate (12) employing 20 atm pressure of hydrogen
for 72 h under strictly inert atmosphere and anhydrous
conditions. According to previous report,6 the reduction of
intermediate 6 gave (S)-salsolidine acetate (12) in 100%
conversion and with 96% ee employing 4 atm pressure of
hydrogen for 48 h also under strictly inert atmosphere and
anhydrous conditions. Subsequently, (S)-salsolidine acetate (12)
was hydrolyzed using LiOH·H2O in a mixture of ethanol/water
(2:1) under microwave heating (90 W) at 180 oC for 1 h,11
affording (S)-salsolidine (2b) in 85% (Scheme 4).
Intermediate 5 was treated with 3-methoxyphenylpropyl
5b,c
carbonate (10)5b employing [IrCp*I2]2
(0.2 mol%) and
Candida rugosa lipase (1117 U/mg) as catalysts in toluene
o
saturated with water at 40 C for 48 h to produce (R)-salsolidine
propyl carbamate (11) in 68% isolated yield and with 99% ee5
(Scheme 3).
Although chemoenzymatic DKR represents
a practical,
scalable, and efficient transformation to produce (R)-salsolidine
propyl carbamate (11) only this enantiomer can be accessed
through this approach.5 In spite of the ruthenium(II)-catalyzed
enantioselective hydrogenation may be considered operationally
laborious, this method can be used to produce (S)-salsolidine
acetate (12) and also its enantiomer just by changing the chiral
BINAP ligand employed.6
Scheme 3. Chemoenzymatic DKR and base hydrolysis providing
(R)-salsolidine (2a).

3
Piperonyl alcohol (4) was converted to piperonyl bromide (3)
using PBr3 in 86% yield.12 Then, (R)-salsolidine (2a) and (S)-
salsolidine (2b) were allowed to react with piperonyl bromide (3)
in the presence of K2CO3, under extensively optimized
conditions, which were achieved performing the transformation
in different temperatures and times, using conventional and
microwave heating, leading to (+)-bernumidine (1a) and (-)-
bernumidine (1b), respectively, both in an isolated yield of 85%
(Scheme 5).
Acknowledgments
We are grateful to São Paulo Research Foundation (FAPESP)
(Grant Number: 2017/21990-0) and to National Council for
Scientific and Technological Development (CNPq) for financial
support. B.K.C. and T.R.C.S. thank Coordination of
Improvement of Higher Level Personnel (CAPES) for the
fellowships.
References and notes
1. Karimov, A.; Shakirov, R. Chem. Nat. Compd. 1993, 29, 335.
2. Pinet, S.; Chavant, P. Y.; Averbuch-Pouchot, M.-T.; Vallée, Y. J.
Chem. Research (S) 2001, 65.
3. Mokhber-Dezfuli, N.; Saeidnia, S.; Gohari, A. R.; Kurepaz-
Mahmoodabadi, M. Pharmacogn. Rev. 2014, 8, 8.
4. Kaserer, T.; Lantero, A.; Schmidhammer, H.; Spetea, M.;
Schuster, D. Sci. Rep. 2016, 6, 21548.
5. (a) Verho, O.; Bäckvall, J.-E. J. Am. Chem. Soc. 2015, 137, 3996.
(b) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Process Res.
Dev. 2007, 11, 642. (c) Stirling, M.; Blacker, J.; Page, M. I.
Tetrahedron Lett. 2007, 48, 1247.
6. (a) Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.;
Kobs, U.; Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124,
6649. (b) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.;
Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297. (c)
Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M. J. Am. Chem. Soc.
1986, 108, 7117.
7. (a) Moreno, L.; Cabedo, N.; Boulangꢀ, A.; Pꢁrraga, J.; Galꢁn, A.;
Leleu, S.; Sanz, M.-J.; Cortes, D.; Franck, X. Eur. J. Med. Chem.
2013, 69, 69. (b) Liu, D.; Venhuis, B. J.; Wikstrꢂm, H. V.;
Dijkstra, D. Tetrahedron 2007, 63, 7264.
8. (a) Brossi, A.; Dolan, L. A.; Teitel, S. Org. Synth. 1988, 6, 1. (b)
Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74. (c)
Kꢃrti, L.; Czakꢄ, B. Strategic Applications of Named Reactions in
Organic Synthesis; Elsevier Academic Press: San Diego, 2005; pp
62.
9. (a) Lee, K. M.; Kim, J. C.; Kang, P.; Lee, W. K.; Eum, H.; Ha, H.-
J. Tetrahedron 2012, 68, 883. (b) Cho, B. T.; Kang, S. K.
Tetrahedron 2005, 61, 5725.
10. (a) Leroy, C.; Dupas, G.; Bourguignon, J.; Quꢀguiner, G.
Tetrahedron 1994, 50, 13135. (b) Atanes, N.; Castelo, L.; Guitiꢁn,
E.; Saꢁ, C.; Saꢁ, J. M.; Suau, R. J. Org. Chem. 1991, 56, 2984. (c)
Gꢄmez, B.; Martín, G.; Guitiꢁn, E.; Castedo, L.; Saꢁ, J. M.
Tetrahedron 1993, 49, 1251.
Scheme 5. Transformations to achieve (+)-bernumidine (1a) and
(-)-bernumidine (1b).
(+)-Bernumidine (1a) and (-)-bernumidine (1b) were obtained
after 6 steps with overall yields of 39% and 54%, respectively.
Furthermore, both enantiomers of bernumidine (1a and 1b) were
achieved through short and efficient routes with enantiomeric
excesses ≥ 90%.
The structures of compounds 2a,b and 3-12 were assigned
1
according to their LRMS, IR, H, and 13C NMR spectra. DEPT
135, COSY, and HSQC NMR spectra were obtained to confirm
11. (a) Muraca, A. C. A.; Perecim, G. P.; Rodrigues, A.; Raminelli, C.
Synthesis 2017, 49, 3546. (b) Perecim, G. P.; Rodrigues, A.;
Raminelli, C. Tetrahedron Lett. 2015, 56, 6848.
the structure of compound 11. The structures of compounds 1a,b
1
were assigned according to their LRMS, IR, H, 13C, DEPT 135,
12. Angle, S. R.; Choi, I.; Tham, F. S. J. Org. Chem. 2008, 73, 6268.
COSY, and HSQC NMR spectra. Compound 1b provided HRMS
that is in agreement with the proposed structure. The optical
rotation of compound 1a matched the one reported for the natural
bernumidine1 (Supporting Information).
Supplementary Material
Supplementary
data
(experimental
procedures,
In summary, total syntheses of (+)-bernumidine and its
characterization data, and RMN spectra) associated with this
article can be found, in the online version, at
http://dx.doi.org/XXX.
unnatural
chemoenzymatic dynamic kinetic resolution and ruthenium(II)-
catalyzed enantioselective hydrogenation, respectively.
enantiomer
were
accomplished
through
Chemoenzymatic DKR represents a practical, scalable, and
efficient transformation to produce (R)-salsolidine propyl
carbamate, however, only this enantiomer can be accessed
through this method. Although ruthenium(II)-catalyzed
enantioselective hydrogenation may be considered operationally
laborious, this approach can be used to produce (S)-salsolidine
acetate (12) and also its enantiomer. Short and efficient routes
were developed for both enantiomers of bernumidine (1a and 1b)
and we expect that these routes may be employed for the
preparation of bernumidine derivatives with application in
medicinal chemistry.

4
Tetrahedron
Highlights
 Synthetic routes were developed for (+)-
bernumidine and its unnatural enantiomer.
 Total synthesis of (+)-bernumidine was
accomplished through chemoenzymatic
DKR.
 Bernumidine unnatural enantiomer was
achieved
via
enantioselective
hydrogenation.