Synthesis of the Tricyclic Picrotoxane Motif by an Oxidative Cascade Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b01806

An oxidative cascade cyclization of β-keto esters has been developed for the construction of the tricyclic picrotoxane motif in a single step, and DFT calculations suggested a possible cationic cyclization mechanism. This cascade cyclization can be operat

Full text of DOI:10.1021/acs.orglett.9b01806

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of the Tricyclic Picrotoxane Motif by an Oxidative Cascade
Cyclization
Jingming Cao,† Waygen Thor,‡ Shenkun Yang,† Mengxun Zhang,† Wenli Bao,† Lizhi Zhu,†,§
Wei Yang,*,† Yuen-Kit Cheng,*,‡ and Chi-Sing Lee*,†,‡,∥
†State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen University Town, Xili,
Shenzhen 518055, China
‡Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
§Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University,
Health Science Centre, Shenzhen 518035, China
∥Institute for Research and Continuing Edition (Shenzhen), Hong Kong Baptist University, Industrialization Complex Building,
Shenzhen Virtual University Park, Shenzhen 518000, China
S
* Supporting Information
ABSTRACT: An oxidative cascade cyclization of β-keto esters has been
developed for the construction of the tricyclic picrotoxane motif in a single
step, and DFT calculations suggested a possible cationic cyclization mechanism.
This cascade cyclization can be operated on a 20 g scale to obtain a 77% total
yield of the tricyclic products, which in turn can be converted to versatile
intermediates for further elaboration to picrotoxanes and their structurally related
compounds.
toxic to humans and mammals. Picrotoxane poisoning can lead
to central nervous system and respiratory irritation, vomiting,
convulsions, and fatality. Particularly, picrotoxinin (the first
picrotoxane isolated from Menispermun cocculus)2a was found
to be one of the most potent plant toxins; its lethality is
comparable to that of strychnine.3 This neurotoxin also
exhibits potent antagonistic activities against γ-aminobutyric
acid (GABA) and has been developed into a useful tool for
neuropharmacological studies.4 Because of their structural
complexity and interesting biological activities, a large number
of synthetic efforts for the picrotoxanes have been reported.5−7
Recently, Shenvi8 proposed that (−)-jiadifenolide (another
type of neurotropic sesquiterpenoid also bearing a similar cis-
hydrindane core with fused γ-lactones9) and picrotoxinin may
have overlap in their biological mechanisms due to their
structural similarity. To study the structure−activity relation-
ship (SAR) of picrotoxanes and other structurally or
functionally related natural products, we decided to develop
a general synthetic entry to picrotoxanes and their structurally
related compounds. In our previous biomimetic synthetic
study of yezo’otogirin C,10 β-keto ester ( )-1 underwent
Mn(III)-prompted 5-exo radical cyclization11 according to
Beckwith’s transition-state model (Figure 2a).12 The resulting
tertiary radical intermediate I can either react with a molecular
he picrotoxane natural product family is a large collection
Tof sesquiterpenes and sesquiterpene alkaloids that share a
highly functionalized cis-hydrindane core (Figure 1).1,2 Some
of the picrotoxanes contain a γ-lactone, γ-lactol, pyrrolidine, or
tetrahydrofuran ring that is fused into C2 and C11 of the cis-
hydrindane core, constituting a highly congested tricyclic
skeleton (Figure 1).2a−f Most picrotoxanes are reported to be
Received: May 24, 2019
Figure 1. Examples of picrotoxane natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the use of a stronger oxidant. According to the DFT
calculations of the cation intermediates, cyclization of cation
V to give VI and then VII is energetically favorable (the ΔG
values for V → VI and VI → VII are −31.4 and −9.9 kcal/mol,
respectively). These results suggest that cyclization of the β-
keto ester substrate to give the expected tricyclic product is
more favorable through the cationic pathway.
On the basis of these calculations, β-keto esters 4a and 4b
were prepared via a domino Michael/carboxylation reaction
according to the literature procedure14 in order to study the
conditions of the cascade cyclization reaction in both the
radical and cationic pathways. The oxidative cascade
cyclization of 4a was first examined using a variety of single-
electron oxidants. As shown in Table 1, oxidative cascade
a
Table 1. Oxidative Cascade Cyclization of β-Keto Esters
Figure 2. (a) Our previous work. (b) The aim of this work: a general
synthetic approach toward the tricyclic picrotoxane core.
oxygen under aerobic conditions, giving the peroxy-bridged
compound ( )-2 in good yield, or cyclize and dehydrate
anaerobically into picrotoxane-like compound ( )-3 in modest
yields. Inspired by this biomimetic strategy, we decided to
develop an oxidative cascade cyclization of 4a, which was
anticipated to provide the tricyclic ring system of ( )-5 in a
single operation. Without the geminal dimethyl group, the five-
membered acetal moiety of ( )-5 could be further elaborated
to either a γ-lactone, γ-lactol, pyrrolidine, or tetrahydrofuran,
leading to the tricyclic core structures of a variety of the
picrotoxanes (Figure 2b). However, the critical issue in this
strategy is the stability of the primary radical III generated in
situ after the initial 5-exo radical cyclization of 4a. This primary
radical could be highly unstable and thus could equilibrate
back to the open form, leading to a variety of side products.
To investigate the feasibility of our proposed strategy, DFT
calculations on radicals II, III, and IV were carried out using
the B3LYP-D3 functional.13 As shown in Figure 3, radical II is
more exergonic than III by 0.7 kcal/mol, and radical III is
more exergonic than radical IV by 5.4 kcal/mol. These results
suggested that cyclization of the β-keto ester substrate to give
the expected tricyclic product through the radical pathway is
unfavorable. One of the possible solutions to this problem is to
further oxidize radical II to the corresponding cation (V) by
products (yield,
b
entry
1
R
conditions
%)
c
H
Mn(OAc)2·4H2O (2 equiv), Mn(OAc)3·
2H2O (0.2 equiv), O2
Mn(OAc)3·2H2O (2 equiv), O2
−
2
H
( )-5 (12),
8 (8)
( )-7 (47)
( )-5 (28),
8 (6)
( )-5 (27),
( )-6 (36)
c
3
4
Me Mn(OAc)3·2H2O (2 equiv), O2
H
Mn(OAc)3·2H2O (2 equiv), Ar
5
H
Mn(OAc)3·2H2O (2 equiv), Cu(OAc)2·
H2O (1 equiv), Ar
a
b
The general procedures were followed. Isolated yields. 70%
recovered starting material.
cyclization of β-keto ester 4a using the optimal conditions in
our previous study (Mn(OAc)2·4H2O with a catalytic amount
of Mn(OAc)3·2H2O under aerobic conditions)15 did not
provide any expected product, with recovery of about 70% of
the starting material (entry 1). Interestingly, switching to 2
equiv of Mn(OAc)3·2H2O under aerobic conditions led to
tricyclic product ( )-5, but in only 12% yield along with an 8%
yield of side product 8 (entry 2). Side product 8 could result
from side reactions of radical II, which is more stable than
radical III according to the DFT calculations. On the other
hand, oxidative cyclization of β-keto ester 4b under aerobic
conditions led to peroxy-bridged compound ( )-7 in 47%
yield (entry 3). These results indicated that molecular oxygen
can be trapped by the tertiary radical generated in situ from β-
keto ester 4b but not the primary radical III generated in situ
from β-keto ester 4a. Because of this, the oxidative cascade
cyclization of β-keto ester 4a with 2 equiv of Mn(OAc)3·2H2O
was carried out under argon, which improved the yield of
( )-5 to 28% with a similar yield of side product 8 (entry 4).
The efficiency of the oxidative cascade cyclization was slightly
improved by using the anaerobic conditions, but the formation
of the side product was not suppressed. Since Cu(II) salts are
known to be much more efficient than Mn(III) salts for
oxidation of radicals to cations,16 a variety of Cu(II) salts were
used as co-oxidants. After a brief survey of the conditions, the
oxidative cascade cyclization of ( )-4a was optimized by using
2 equiv of Mn(OAc)3·2H2O with 1 equiv of Cu(OAc)2·H2O,
Figure 3. DFT calculations on key intermediates in both the radical
and cationic pathways using the B3LYP-D3 functional. The
calculations shown are based on the conformers of II and V
preoriented for cyclization (see the Supporting Information for
details).
B
DOI: 10.1021/acs.orglett.9b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of the Tricyclic Picrotoxane Motif and Highly Functionalized Intermediates
which gave two separable tricyclic products, ( )-5 and ( )-6,
in a 3:4 ratio in 63% overall isolated yield (entry 5).
functionalized tricyclic intermediates that could be versatile
precursors for the synthesis of picrotoxanes and their
structurally related compounds for SAR studies.
With the oxidative cascade cyclization developed, this
reaction was employed for the synthesis of the tricyclic core
of picrotoxanes. As shown in Scheme 1, Diels−Alder reaction
of Danishefsky’s diene17 with methyl acrylate gave silyl enol
ether 9 (not isolated). Lithium aluminum hydride reduction of
9 followed by acid hydrolysis with aqueous HF afforded
( )-10 in 62% yield over the two steps.18 After protection of
the resulting primary alcohol as the TBS ether, domino
Michael/carboxylation of enone ( )-11 provided β-keto ester
( )-12 in one pot in 92% yield with excellent diastereose-
lectivity.14 Oxidative cascade cyclization of ( )-12 using our
optimized conditions could be carried out on a 20 g scale and
resulted in tricyclic products ( )-13 and ( )-14 in 55% and
22% yield, respectively. Compound ( )-14 was converted to
( )-13 in 74% yield using triethyl orthoformate with a
catalytic amount of p-toluenesulfonic acid.19 With ( )-13 in
hand, TBS deprotection followed by sequential oxidation
afforded carboxylic acid ( )-15, which was characterized
unambiguously by X-ray crystallography. Esterification and
selenoxide fragmentation afforded ester ( )-17. This advanced
intermediate contains the tricyclic picrotoxane skeleton and
the functionalities required for further elaboration, such as
installation of the isopropyl or other alkyl group at C4.
Moreover, the ethyl acetal can be readily hydrolyzed under
acidic conditions and then eliminated using oxalyl chloride/
DMSO and triethylamine to afford compound ( )-19. The
alkene moiety of intermediate ( )-19 could undergo either
epoxidation or dihydroxylation and then cyclization to give the
γ-lactone at C3 and C5.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01806.
■
S
Experimental procedures, characterization details, and
1H and 13C NMR spectra of all new compounds (PDF)
Accession Codes
CCDC 1868618 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: weiyangscu@gmail.com.
*E-mail: ykcheng@hkbu.edu.hk.
*E-mail: cslee-chem@hkbu.edu.hk.
ORCID
Chi-Sing Lee: 0000-0002-3564-8224
Notes
The authors declare no competing financial interest.
In summary, an oxidative cascade cyclization of β-keto esters
for the construction of the tricyclic picrotoxane motif has been
developed under the inspiration of our previously reported
biomimetic synthetic strategy toward yezo’otogirin C. Hinted
by the possible cationic pathway based on the DFT
calculations, the cyclization conditions were optimized using
2 equiv of Mn(OAc)3·2H2O with 1 equiv of Cu(OAc)2·H2O,
which gave good yields of the tricyclic products in a single
operation. This reaction can be operated on a 20 g scale, and
the cyclized products can be converted to several highly
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Grants 21502002, 21572006, and
21871017), the Natural Science Foundation of Guangdong
Province, China (Grant 2017A030313042), the Shenzhen
Science and Technology Innovation Committee (Grants
JCYJ20160428153421635 and JCYJ20160330095659560),
and Peking University Shenzhen Graduate School and Hong
Kong Baptist University (RC-SGT2/18-19/SCI/005) for
C
DOI: 10.1021/acs.orglett.9b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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