Divergent total syntheses of pseudoberberine and nitidine through C[sbnd]H vinylation and switchable 6π electrocyclizations

Article abstract of DOI:10.1016/j.tetlet.2021.152839

Quaternary protoberberine alkaloids and quaternary benzophenanthridine alkaloids are two biosynthetically related natural product families of biological importance. Although significant advances have been achieved in the synthetic chemistry of these alkal

Full text of DOI:10.1016/j.tetlet.2021.152839

Tetrahedron Letters 66 (2021) 152839
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent total syntheses of pseudoberberine and nitidine through CAH
vinylation and switchable 6p electrocyclizations
Xunjin Jiang a,1, Zhixiong Zeng a,1, Dong Shi a, Chenguang Liu a, Yandong Zhang a,b,
⇑
a Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, China
b Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Quaternary protoberberine alkaloids and quaternary benzophenanthridine alkaloids are two biosynthet-
ically related natural product families of biological importance. Although significant advances have been
achieved in the synthetic chemistry of these alkaloids, a unified approach to these tetracyclic pyridinium-
contained alkaloids remains elusive until our recent report. Herein, we report a concise, modular, diver-
gent approach to two of them, pseudoberberine and nitidine, based on our newly developed strategy in
five and seven steps. The key transformations include an Ag-promoted annulation, an isoquinoline-direc-
Revised 19 November 2020
Accepted 4 January 2021
Available online 1 February 2021
Keywords:
Alkaloids
CAH activation
6p-electrocyclization
ted CAH vinylation, and switchable aza-6
p
- or all-carbon-6
p
-electrocyclization.
Ó 2021 Elsevier Ltd. All rights reserved.
Pseudoberberine
Nitidine
Introduction
derived from a common intermediate (S)-reticuline (III), through
different annulation modes (Scheme 1a) [6]. This conclusion indi-
cates that the C5-C6 carbons in QPAs and the C5-C6 carbons in
QBAs share a common biological origin (Scheme S1 gives a detailed
biosynthetic proposal). Although the intriguing therapeutic values
of these alkaloids have spurred intense synthetic efforts [7], includ-
ing some success in transforming QPAs to QBAs
(in eight steps) [8], a unified solution for the synthesis of these
tetracyclic pyridinium-contained alkaloids remains elusive.
Our interest in the quaternary pyridinium-containing alkaloids
was sparked during the development of anticancer agents based on
a quaternary protoberberine scaffold as the privileged core struc-
ture [9]. Recently, we developed a unified two-step strategy by
the combination of Rh-catalyzed C–H vinylation and two
switchable electrocyclizations for the concise and divergent
synthesis of two distinct azatricycles, including dihydropyridoiso-
quinoliniums and dihydrobenzoquinolines, which was successfully
applied for the synthesis of berberine and chelerythrine [10].
Herein, we report our late-stage divergent syntheses [11] of the
other two bioactive members of QPA and QBA family, pseudober-
berine and nitidine, through our newly developed synthetic
technology.
Quaternary pyridinium-containing alkaloids are a large group of
secondary metabolites, which exhibit diverse biological activities,
such as antibacterial, anticancer, antimalarial, and hypolipidemic
effects [1]. Among them, quaternary protoberberine alkaloids
(QPAs) [2] and quaternary benzophenanthridine alkaloids (QBAs)
[3] (Fig. 1) are two biosynthetically related family natural products
and have received the most attention from either synthetic che-
mists or medicinal chemists. QPAs are widely found in such plant
family as berberidaceae, fumariaceae, and papaveraceae, and repre-
sent an important family of natural products with a broad spec-
trum of biological activities. Owing to the presence of the highly
polarized iminium bond, positive charge, and relatively planar
skeleton, these molecules interact with their biological targets
[4]. Often as natural congeners from those herbs, QBAs also consti-
tute a large group of bioactive molecules.
Interestingly, many natural products bearing the same sub-
stituents on aromatic rings in QPA and QBA families occur in pairs
[5], such as berberine with chelerythrine, pseudoberberine with
nitidine, and coptisine with sanguinarine (Fig. 1). Despite their sig-
nificant structural differences, the biosynthetic studies demon-
strated that those two natural product families were both
Results and discussion
⇑
Corresponding author.
E-mail address: ydzhang@xmu.edu.cn (Y. Zhang).
These authors contributed equally to this work.
As outlined in Scheme 1b, we envisioned that pseudoberberine
(1) and nitidine (2) could both arise from the common
1
https://doi.org/10.1016/j.tetlet.2021.152839
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

X. Jiang, Z. Zeng, D. Shi et al.
Tetrahedron Letters 66 (2021) 152839
be introduced via C–H vinylation [14] directed by the intrinsic iso-
quinoline group. We expected the regioselectivity of vinylation
could be controlled by the steric effect. The isoquinoline interme-
diate 4 could be assembled from bromobenzaldehde 5 and phenyl
alkyne 6 through Sonogashira coupling [15] and subsequent
annulation.
As depicted in Scheme 2, our synthesis commenced with the
commercially available materials 5 and 6. Sonogashira coupling
of 5 and 6 in the presence of Pd(PPh3)2Cl2 and CuI afforded alde-
hyde 7 in 97% yield. Then the pyridine B ring was formed through
an Ag-promoted annulation [16] in the presence of NH4OAc to
deliver isoquinoline 4 in 87% yield. When 4 was treated with
[Cp*RhCl2]2 (5 mmol%) and pinacol vinylborate (1.4 equiv) with
Cu(OAc)2 (1.0 equiv) and BQ (1.0 equiv) as oxidants at 70 °C,
unfortunately, the C–H vinylation exclusively occurred at C1 posi-
tion instead of the desired less hindered C4a position. We attribu-
ted this unexpected regioselectivity to the stabilizing effect of the
methylenedioxy group [17] on the rhodacycle intermediate. As
shown in Scheme 2, 4 reacted with Rh-catalyst via a directed C–
H bond activation to afford a relatively stable rhodium complex
A, which further underwent Suzuki coupling to generate the unde-
sired vinylation product 8. The replacement of the methylene-
dioxy group with a bulky group was expected to solve this
problem (see below). With the undesired vinylation product 8 in
Fig. 1. Selected QPAs and QBAs.
hand, we were curious about its fate towards the 6
clizations. After a brief screening of reaction conditions, we found
that 8 could be converted to the corresponding aza-6 -electrocy-
clization product 9, a constitutional isomer of pseudoberberine, in
33% yield upon treatment with NH4Cl in a mixed solvent of H2O
and toluene (1:1 v/v) at 150 °C. The structure of 9 was unambigu-
ously confirmed by X-ray crystallography (see inset image,
Scheme 2) in conjunction with spectroscopic data. Scheme 3.
p-electrocy-
isoquinoline-substituted styrene intermediate 3 through either
aza-6 - [12] or all-carbon-6 -electrocyclization [13]. Specifically,
the dihydropyridnium C ring of pseudoberberine (1) could be con-
structed from 3 through aza-6 -electrocyclization followed by the
addition of a molecule of HCl, while the phenyl C ring of nitidine
(2) could be formed via all-carbon-6 -electrocyclization and sub-
sequent oxidative aromatization. The vinyl group at C4a of 3 could
p
p
p
p
p
Scheme 1. Biosynthetic proposal and our synthetic strategy for pseudoberberine and nitidine.
2

X. Jiang, Z. Zeng, D. Shi et al.
Tetrahedron Letters 66 (2021) 152839
10 [18] through a similar synthetic sequence. We anticipated that
bis-silyl group could not only increase the steric hindrance around
the C1–H but also exclude the possible coordination of rhodacycle
intermediate with the C2 oxygen atom. To our great delight, by
exposure of 12 to the C–H vinylation conditions, the regioselectiv-
ity was reversed to exclusively deliver the desired vinylation pro-
duct 13 in 76% yield.
A one-pot deprotection-reprotection
manipulation converted the bis-silyl group to the methylene
group, furnishing the common precursor
electrocyclizations.
3 for the 6p-
With styrene compound 3 in hand, our synthesis entered into
the final stage. Heating 3 and NH4Cl in a mixed solvent of H2O
and toluene (3:1 v/v) delivered pseudoberberine (1) with a high-
atom economy, albeit in modest yield (28%). Further screening of
solvents and temperatures did not lead to significant improvement
in the yield of 1. When 3 was irradiated with UV light (254 nm) in
the presence of benzophenone under O2 atmosphere, [19] norni-
tidine [20] (14) was obtained in 37% yield. We found that the
absence of benzophenone led to the formation of 14 in a much
lower yield. Based on Zhang’s methylation method, [21], the formal
synthesis of nitidine (2) was achieved.
Conclusions
Scheme 2. Unexpected regioselectivity of CAH vinylation.
In summary, we have developed a concise, modular, divergent
approach to QPA and QBA alkaloids pseudoberberine and nitidine
in five steps and seven steps, featuring an Ag-promoted annulation,
an isoquinoline-directed C–H vinylation, and switchable aza-6
all-carbon-6 -electrocyclization. Furthermore, constitutional
isomer of pseudoberberine (9) was also prepared through an unex-
pected C–H vinylation followed by an aza-6 -electrocyclization.
p- or
p
a
p
Our approach is more superior to the early-stage divergent bio-
genetic or chemical syntheses. The current modular strategy would
also allow for the synthesis of diverse analogs, which would further
facilitate our ongoing anticancer research based on these QPAs and
QBAs.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
Scheme 3. Regioselective CAH vinylation.
Financial support from the National Natural Science Foundation
of China (21772164 and 21572187), NCETFJ, and PCSIRT. We are
also grateful for the financial support from the Guangdong Provin-
cial Key Laboratory of Chemical Genomics, Peking University Shen-
zhen Graduate School.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152839.
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