A Unified Strategy for the Syntheses of the Isoquinolinium Alkaloids Berberine, Coptisine, and Jatrorrhizine

Article abstract of DOI:10.1021/acs.orglett.8b01702

Total syntheses of the antibacterial alkaloids berberine, coptisine, and jatrorrhizine have been achieved in four steps through a unified route. The key step of this strategy is an efficient intramolecular Friedel-Crafts alkoxyalkylation which, following oxidation, establishes the isoquinolinium core of these natural products. Herein, the design and development of this synthetic strategy, which has enabled the shortest and most efficient syntheses of these alkaloids reported to date, is described.

Full text of DOI:10.1021/acs.orglett.8b01702

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Unified Strategy for the Syntheses of the Isoquinolinium Alkaloids
Berberine, Coptisine, and Jatrorrhizine
Luis M. Mori-Quiroz, Sidnee L. Hedrick, Andrew R. De Los Santos, and Michael D. Clift*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
S
* Supporting Information
ABSTRACT: Total syntheses of the antibacterial alkaloids berberine, coptisine, and jatrorrhizine have been achieved in four
steps through a unified route. The key step of this strategy is an efficient intramolecular Friedel−Crafts alkoxyalkylation which,
following oxidation, establishes the isoquinolinium core of these natural products. Herein, the design and development of this
synthetic strategy, which has enabled the shortest and most efficient syntheses of these alkaloids reported to date, is described.
ntibacterial resistance constitutes an ever-increasing
public health threat around the world.1 Contrary to the
fully synthetic berberine analogues for biological testing.
Additionally, we have demonstrated that this synthetic strategy
enables the preparation of the structurally related congeners
coptisine and jatrorrhizine, both of which have antibacterial
activity of unknown origin.13
Pictet and Gams published the first purported synthesis of
berberine in 1911;14 however, Buck and Davis later contested
this report by demonstrating that the key annulation utilized in
Pictet’s synthesis delivered an isomeric alkaloid as opposed to
berberine.15 Successful total syntheses of berberine have been
reported by Kametani,16 Donohoe,17 Anand,18 and Tong19
(Scheme 1). Kametani completed the first total synthesis of
berberine in 1969, which required more than six steps and
proceeded with low overall efficiency.16 In 2014, Donohoe
A
global need to access new treatment options, very few
antibiotics have been developed over the past couple of
decades2 and the current development pipeline is very limited.3
Therefore, there is a growing urgency4 for the development of
new treatment regimes. This has spurred efforts to discover
and identify new antibiotic classes that operate through novel
modes of action.
Filamenting temperature-sensitive mutant Z (FtsZ) is a
prokaryotic tubulin homologue that is necessary for bacterial
cell division and is conserved among all bacteria,5 making it a
potential antibacterial target.6 Berberine (1a, Figure 1),7 an
Scheme 1. Previous Total Syntheses of Berberine
Figure 1. Antibacterial isoquinolinium alkaloids of interest.
alkaloid isolated from plant tissues with a long history of use in
Chinese folk medicine and a wide range of interesting
biological activities (e.g., antifungal, antimalarial, antidiabetic,
and anticancer activities),8 has been shown to exhibit moderate
antibacterial activity by inhibiting FtsZ assembly.9 Semi-
synthetic berberine analogues that show improved binding
affinity for FtsZ display a corresponding increase in
antibacterial potency.10 However, structure−activity relation-
ship (SAR) studies have thus far been limited to derivatives
accessible by modification of natural berberine.11,12 To
facilitate the study of as-of-yet unknown SAR studies, our
laboratory has devised a short and efficient total synthesis of
berberine that will enable the preparation of a wide range of
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
developed a more efficient synthetic route to berberine that
featured a carefully designed, palladium-catalyzed enolate
arylation.17 This route required seven total steps (five steps
longest linear sequence) and provided berberine in an
impressive 50% overall yield. Anand and Tong also devised
synthetic routes to berberine; however, these strategies
proceeded with modest overall efficiency (24% and 19%
yield, respectively).18,19 Common to these previous approaches
has been the need to access prefunctionalized precursors (e.g.,
aryl bromides and aryl acetylenes) in order to execute the key
step of the synthesis.
employed as a method to enable the synthesis of novel natural
product analogs for biological testing.
Our total synthesis of berberine began with the preparation
of tetrahydroisoquinoline 5ab (Scheme 3). A Pictet−Spengler
Scheme 3. Synthesis of Tetrahydroisoquinoline 5ab and
Unsuccessful Pomeranz−Fritsch Annulation
As part of our efforts to develop new antibacterials that
target FtsZ, herein we report a new synthetic route to
berberine, coptisine, and jatrorrhizine that features classical
synthetic transformations that proceed without the use of
transition-metal catalysts or prefunctionalized synthetic inter-
mediates. This approach provides berberine in only four steps
with a 53% overall yield and, therefore, constitutes the most
concise and efficient total synthesis of berberine to date. Our
synthetic approach has also been applied to the preparation of
coptisine (four steps, 39% yield) and jatrorrhizine (four steps,
20% yield), highlighting the versatility and efficiency of our
strategy. It is worth noting that Song reported a related
strategy that facilitated the construction of several berberine
analogues;20 this strategy enabled the construction of the
isoquinolinium core of the natural product in five steps with
overall yields ranging from 12% to 34%, depending on the
substitution pattern of the analogue in question. Unfortunately,
this route was never used to construct berberine itself and
therefore cannot be directly compared to the work reported in
this manuscript. We anticipate that this route will be useful for
the future preparation of fully synthetic analogues of these
alkaloids, which could be used for SAR studies directed toward
identifying new inhibitors of FtsZ assembly as potential
antibacterials.
reaction between commercially available 3,4-
(methylenedioxy)phenethylamine (2ab) and 2,2-dimethoxya-
cetaldehyde (3) in the presence of trifluoroacetic acid afforded
tetrahydroisoquinoline 5ab in 69% yield. Unfortunately, efforts
to convert 5ab directly into berberine by way of Pomeranz−
Fritsch reaction with 2,3-dimethoxybenzaldehyde (4ac) failed.
This result is consistent with the absence of literature reports
that utilize the Pomeranz−Fritsch protocol to access
isoquinoliniums from acetals bearing secondary amines; to
the best of our knowledge, all reports detailing the application
of this annulation involve the conversion of primary amine
derivatives into neutral isoquinolines.
To solve this issue, an alternative annulation tactic was
pursued (Scheme 4). Toward this end, a reductive amination
Scheme 4. Completion of the Total Synthesis of Berberine
Our retrosynthetic analysis involved disconnection of the
isoquinolinium core of these natural products, which revealed
three simple building blocks, phenethylamine 2, acetal 3, and
benzaldehyde derivative 4, as potential precursors (Scheme 2).
Scheme 2. A Unified Synthetic Approach to the Berberine
Family of Alkaloids
was carried out using tetrahydroisoquinoline 5ab and 2,3-
dimethoxybenzaldehyde (4ac), which provided tertiary amine
6 in 79% yield. This intermediate was then treated with triflic
acid to promote a Friedel−Crafts alkoxyalkylation that
presumably delivers intermediate 7, which undergoes sub-
sequent E1 elimination of methanol to afford lambertine (8).22
This intermediate was characterized by NMR analysis of the
crude reaction mixture and subsequently isolated as the
corresponding iminium triflate (55%, not shown). Oxidation of
lambertine using iodine in the presence of potassium acetate
produced berberine (1a) in almost quantitative yield. This
concise and highly efficient synthesis of berberine proceeded in
54% overall yield and required only four synthetic operations.
We planned to construct tetrahydroisoquinoline 5, using a
Pictet−Spengler reaction. We recognized that there were
several possible annulation strategies that would likely enable
the assembly of tetrahydroisoquinoline 5 and aldehyde 4,
including direct union via the Pomeranz−Fritsch reaction.21
More importantly, this strategy would divide the target into
two fragments of roughly equal complexity (e.g., 2 and 4) that
could then be united using 2,2-dimethoxyacetaldehyde (3) as a
linchpin. Such a strategy would likely be valuable when
B
DOI: 10.1021/acs.orglett.8b01702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To demonstrate the versatility of our synthetic strategy, we
applied it in the syntheses of two berberine congeners:
coptisine (1b, Scheme 5) and jatrorrhizine (1c, Scheme 6).
features an initial Pictet−Spengler reaction, followed by a two-
step annulation protocol involving reductive amination and
subsequent Friedel−Crafts alkoxyalkylation, which ultimately
forges the key isoquinolinium ring of each natural product.
Subsequent oxidation delivers the targeted natural products.
We are currently utilizing this synthetic strategy to target fully
synthetic analogues of berberine, coptisine, and jatrorrhizine
for biological study as potential antibacterial agents that
operate by inhibition of FtsZ assembly.
Scheme 5. Total Synthesis of Coptisine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01702.
1
Experimental procedures and H, 13C, and 19F NMR
spectra (PDF)
AUTHOR INFORMATION
■
Scheme 6. Total Synthesis of Jatrorrhizine
Corresponding Author
*E-mail: mclift@ku.edu.
ORCID
Luis M. Mori-Quiroz: 0000-0001-8546-7264
Michael D. Clift: 0000-0001-6441-9802
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from The
University of Kansas, the NIH Chemical Biology of Infectious
Disease CoBRE Grant (P20 GM113117), the NIH Dynamic
Aspects of Chemical Biology Training Grant
(T32GM008545), and the NIH PREP Program at The
University of Kansas (5R25GM078441). Support for the
NMR instrumentation used in this study was provided by NIH
Shared Instrumentation Grants (S10RR024664 and
S10OD16360) and NSF Major Instrumentation Grants
(9977422 and 1625923).
Coptisine was prepared via reductive amination of 5ab using
2,3-(methylenedioxy)benzaldehyde (4b) to deliver tertiary
amine 9 in 57% yield. Triflic acid promoted Friedel−Crafts
cyclization followed by oxidation with iodine afforded
coptisine (1b) in quantitative yield, thereby completing a
four step total synthesis that proceeded in 39% overall yield.
Our synthesis compares favorably with the most efficient total
synthesis of coptisine previously reported (four steps, 43%
overall yield).23
To access jatrorrhizine, phenethylamine 2c and 2,2-
dimethoxyacetaldehyde (3) were engaged in a Pictet−Spengler
reaction to provide tetrahydroisoquinoline 5c in 82% yield as a
mixture of regioisomeric products (rr = 1.0:6.7). This
inseparable mixture of regioisomers was utilized in a reductive
amination with 2,3-dimethoxybenzaldehyde (4ac) to afford
tertiary amine 10 in 60% yield (also as a mixture of isomers,
3.3:1.0 ratio in favor of the isomer shown). Friedel−Crafts
cyclization and subsequent oxidation delivered isomerically
pure jatrorrhizine (1c) in 41% yield. This rapid synthesis of
jatrorrhizine required just four steps and proceeded in 20%
overall yield. To the best of our knowledge, this is first total
synthesis of this alkaloid.
REFERENCES
■
(1) (a) Levy, S. B.; Marshall, B. Antibacterial resistance worldwide:
causes, challenges and responses. Nat. Med. 2004, 10, S122−129.
(b) Davies, J.; Davies, D. Microbiol. Mol. Biol. Rev. 2010, 74, 417−433.
(2) Brown, E. D.; Wright, G. D. Nature 2016, 529, 336−343.
(3) Antibacterial Agents in Clinical Development: An Analysis of the
Antibacterial Clinical Development Pipeline, Including Tuberculosis;
World Health Organization, Geneva, 2017; No. WHO/EMP/IAU/
2017.12.
(4) Bush, K.; Courvalin, P.; Dantas, G.; Davies, J.; Eisenstein, B.;
Huovinen, P.; Jacoby, G. A.; Kishony, R.; Kreiswirth, B. N.; Kutter, E.;
Lerner, S. A.; Levy, S.; Lewis, K.; Lomovskaya, O.; Miller, J. H.;
Mobashery, S.; Piddock, L. J. V.; Projan, S.; Thomas, C. M.; Tomasz,
A.; Tulkens, P. M.; Walsh, T. R.; Watson, J. D.; Witkowski, J.; Witte,
W.; Wright, G.; Yeh, P.; Zgurskaya, H. I. Nat. Rev. Microbiol. 2011, 9,
894−896.
̈
(5) (a) Bi, E.; Lutkenhaus, J. Nature 1991, 354, 161−164. (b) Lowe,
J.; Amos, L. A. Nature 1998, 391, 203−206. (c) Romberg, L.; Levin,
P. A. Annu. Rev. Microbiol. 2003, 57, 125−154.
́
(6) (a) Schaffner-Barbero, C.; Martín-Fontecha, M.; Chacon, P.;
In conclusion, we have developed a unified synthetic route
that provides rapid and efficient access to the isoquinolinium
alkaloids berberine, coptisine, and jatrorrhizine. Our strategy
Andreu, J. M. ACS Chem. Biol. 2012, 7, 269−277. (b) Li, X.; Ma, S.
Eur. J. Med. Chem. 2015, 95, 1−15. (c) Haranahalli, K.; Tong, S.;
Ojima, I. Bioorg. Med. Chem. 2016, 24, 6354−6369. (d) Hurley, K. A.;
C
DOI: 10.1021/acs.orglett.8b01702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Santos, T. M. A.; Nepomuceno, G. M.; Huynh, V.; Shaw, J. T.;
Weibel, D. B. J. Med. Chem. 2016, 59, 6975−6998.
(7) Perkin, W. H. J. Chem. Soc., Trans. 1889, 55, 63−90.
(8) (a) Iwasa, K.; Kim, H.-S.; Wataya, Y.; Lee, D.-U. Eur. J. Med.
Chem. 1998, 33, 65−69. (b) Bian, X.; He, L.; Yang, G. Bioorg. Med.
Chem. Lett. 2006, 16, 1380−1383. (c) Sun, Y. Y.; Xun, K. L.; Wang, Y.
T.; Chen, X. P. Anti-Cancer Drugs 2009, 20, 757−769.
(9) Domadia, P. N.; Bhunia, A.; Sivaraman, J.; Swarup, S.; Dasgupta,
D. Biochemistry 2008, 47, 3225−3234.
(10) Sun, N.; Chan, F.-Y.; Lu, Y.-J.; Neves, M. A. C.; Lui, H.-K.;
Wang, Y.; Chow, K.-Y.; Chan, K.-F.; Yan, S.-C.; Leung, Y.-C.;
Abagyan, R.; Chan, T.-H.; Wong, K.-Y. PLoS One 2014, 9,
No. e97514.
(11) (a) Iwasa, K.; Lee, D.-U.; Kang, S.-I.; Wiegrebe, W. J. Nat. Prod.
1998, 61, 1150−1153. (b) Ball, A. R.; Casadei, G.; Samosorn, S.;
Bremner, J. B.; Ausubel, F. M.; Moy, T. I.; Lewis, K. ACS Chem. Biol.
2006, 1, 594−600. (c) Zhang, L.; Chang, J.-J.; Zhang, S.-L.; Damu, G.
L. V.; Geng, R.-X.; Zhou, C.-H. Bioorg. Med. Chem. 2013, 21, 4158−
4169. (d) Jeyakkumar, P.; Zhang, L.; Avula, S. R.; Zhou, C.-H. Eur. J.
Med. Chem. 2016, 122, 205−215. (e) Wang, J.; Yang, T.; Chen, H.;
Xu, Y.-N.; Yu, L.-F.; Liu, T.; Tang, J.; Yi, Z.; Yang, C.-C.; Xue, W.;
Yang, F. Eur. J. Med. Chem. 2017, 127, 424−433.
(12) Synthetic berberine analogues have been studied: Parhi, A.; Lu,
S.; Kelley, C.; Kaul, M.; Pilch, D. S.; LaVoie, E. Bioorg. Med. Chem.
Lett. 2012, 22, 6962−6966.
(13) (a) Wang, L. J.; Ye, X.-L.; Li, X.-G.; Sun, Q.-L.; Yu, G.; Cao, X.-
G.; Liang, Y.-T.; Zhang, H.-S.; Zhou, J.-Z. Planta Med. 2008, 74, 290−
292. (b) Jiang, X.-F.; Ye, X.-L.; Zhang, B.; Li, X.-G.; Liu, X. Asian J.
Chem. 2011, 23, 3849−3852.
(14) Pictet, A.; Gams, A. Ber. Dtsch. Chem. Ges. 1911, 44, 2480−
2485.
(15) Buck, J. S.; Davis, R. M. J. Am. Chem. Soc. 1930, 52, 660−664.
(16) Kametani, T.; Noguchi, I. J. Chem. Soc. C 1969, 2036−2038.
(17) (a) Gatland, A. E.; Pilgrim, B. S.; Procopiou, P. A.; Donohoe,
T. J. Angew. Chem., Int. Ed. 2014, 53, 14555−14558. (b) Pilgrim, B.
S.; Gatland, A. E.; McTernan, C. T.; Procopiou, P. A.; Donohoe, T. J.
Org. Lett. 2013, 15, 6190−6193. (c) Donohoe, T. J.; Pilgrim, B. S.;
Jones, G. R.; Bassuto, J. A. Proc. Natl. Acad. Sci. U. S. A. 2012, 109,
11605−11608.
(18) (a) Reddy, V.; Jadhav, A. S.; Anand, R. V. Org. Biomol. Chem.
2015, 13, 3732−3741. (b) Asao, N.; Yudha, S. S.; Nogami, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526−5528.
(c) Zheng, D.; Chen, Z.; Liu, J.; Wu, J. Org. Biomol. Chem. 2011, 9,
4763−4765. (d) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959−4962.
(19) (a) Zhou, S.; Tong, R. Chem. - Eur. J. 2016, 22, 7084−7089.
(b) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.;
Yang, Z. Org. Lett. 2004, 6, 3155−3158.
(20) (a) Yang, P.; Song, D.-Q.; Li, Y.-H.; Kong, W.-J.; Wang, Y.-X.;
Gao, L.-M.; Liu, S.-Y.; Cao, J.-D.; Jiang, J.-D. Bioorg. Med. Chem. Lett.
2008, 18, 4675−4677. (b) Wang, Y.-X.; Kong, W.-J.; Li, Y.-H.; Tang,
S.; Li, Z.; Li, Y.-B.; Shan, Y.-Q.; Bi, C.-W.; Jiang, J.-D.; Song, D.-Q.
Bioorg. Med. Chem. 2012, 20, 6552−6558.
(21) Wang, Z. Comprehensive Organic Name Reactions and Reagents;
John Wiley & Sons: 2010; Chapter 509, pp 2256−2259.
(22) Chatterjee, R.; Maiti, P. C. J. Indian Chem. Soc. 1955, 32, 609−
610.
̈
(23) (a) Spath, E.; Posega, R. Eur. J. Inorg. Chem. 1929, 4, 1029−
1033. (b) Hu, Y.-R.; Zou, Z.-Y.; Wang, Y.-S.; Li, X.-G. Chin. J. Med.
Chem. 2014, 6, 455−458.
D
DOI: 10.1021/acs.orglett.8b01702
Org. Lett. XXXX, XXX, XXX−XXX