Total Synthesis of (-)-Picrinine, (-)-Scholarisine C, and (+)-5-β-Methoxyaspidophylline

Article abstract of DOI:10.1021/acs.orglett.1c02393

The first asymmetric total synthesis of three picrinine-type akuammiline alkaloids, (-)-picrinine, (-)-scholarisine C, and (+)-5-β-methoxyaspidophylline, has been accomplished. The synthesis features an efficient acid-promoted oxo-bridge ring-opening and further carbonyl O-cyclization to assemble the furoindoline scaffold, an unusual Dauben-Michno oxidation to construct the requisite α,β-unsaturated aldehyde functionality, and a nickel-mediated reductive Heck reaction to forge the [3.3.1]-azabicyclic core.

Full text of DOI:10.1021/acs.orglett.1c02393

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Letter
Total Synthesis of (−)-Picrinine, (−)-Scholarisine C, and (+)-5-β-
Methoxyaspidophylline
Peng Zou, Hongjian Yang, Jian Wei, Taimin Wang,* and Hongbin Zhai*
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ABSTRACT: The first asymmetric total synthesis of three picrinine-type akuammiline alkaloids, (−)-picrinine, (−)-scholarisine C,
and (+)-5-β-methoxyaspidophylline, has been accomplished. The synthesis features an efficient acid-promoted oxo-bridge ring-
opening and further carbonyl O-cyclization to assemble the furoindoline scaffold, an unusual Dauben−Michno oxidation to
construct the requisite α,β-unsaturated aldehyde functionality, and a nickel-mediated reductive Heck reaction to forge the [3.3.1]-
azabicyclic core.
s a family of complex indole monoterpenoids, the
akuammiline alkaloids have been mainly isolated from
picrinine (4),6 scholarisine K (8),7 scholarisine A (9),8 and a
few other akuammiline alkaloids have been achieved over the
past years.9 Several significant methods have been developed to
construct the core of akuammiline alkaloids and the related
natural products. For example, a copper-catalyzed intra-
molecular cyclopropanation/ring-opening/ring closure cascade
was applied to install the indoline scaffold by the Qin group.4a
Garg and co-workers accomplished the total synthesis of
several akuammiline alkaloids via an interrupted Fischer
indolization.3a,j,5a,6 The MacMillan group introduced an
asymmetric Diels−Alder and iminium cyclization cascade to
assemble the tetracyclic core.4c The Ma group developed an
intramolecular oxidative coupling reaction to forge the
tetracyclic indoline motif.4b,5b
A
the Apocynaceae class.1 Several representative members of
akuammiline alkaloids are depicted in Figure 1. This family of
Picrinine (4), scholarisine C (5), and 5-β-methoxyaspido-
phylline (6) belong to the picrinine-type akuammiline alkaloids
that share the same C5 aldehyde oxidation state. Picrinine (4)
is a structurally complex alkaloid first isolated from Alstonia
scholaris in 1965.10 It features a fused furoindoline core, a
[3.3.1]-azabicycle, and a highly functionalized cyclohexyl ring
bearing five contiguous stereocenters. Its unique connectivity
at C5 results in an intriguing bis(N,O-acetal) moiety. It was
reported that picrinine (4) showed anti-inflammatory activity
Figure 1. Representative akuammiline alkaloids.
Received: July 17, 2021
alkaloids possesses a wide range of bioactivities, such as
anticancer, antimalarial, and anti-inflammatory activities.2 Due
to the challenging cagelike structures together with the diverse
bioactivities, akuammiline alkaloids have held the attention of
synthetic chemists for decades. The total syntheses of
strictamine (1),3 vincorine (2),4 aspidophylline A (3),5
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in vitro by inhibition of the 5-lipoxygenase enzyme.11
Scholarisine C (5) and 5-β-methoxyaspidophylline (6) were
isolated from Alstonia scholaris by the Luo group in 2009 and
2008, respectively.12 Compared with picrinine (4), the linkage
of N4 to the furoindoline core is replaced by an acetal moiety
in both scholarisine C (5) and 5-β-methoxyaspidophylline (6).
The distinctive C5 aldehyde oxidation state of picrinine-type
akuammiline alkaloids rendered the synthesis even more
challenging. The first total synthesis of ( )-picrinine (4) was
achieved by Garg and co-workers featuring a Pd-catalyzed
enolate cyclization to assemble the [3.3.1]-azabicyclic core and
a key Fischer indolization reaction to forge the carbon
scaffold.6 However, the total synthesis of scholarisine C (5)
and 5-β-methoxyaspidophylline (6) has not been reported to
date.
mediated intramolecular reductive Heck reaction. Unsaturated
aldehyde 16 might be obtained from aldehyde 12 through an
acid-promoted oxo-bridge ring opening and aminal/acetal
formation followed by a Dauben−Michno oxidation of
secondary allylic alcohol. Aldehyde 12 would be accessible
from (−)-10.
Our synthesis commenced with construction of the
furoindoline scaffold and establishment of the C5 aldehyde
oxidation state. Known intermediate (−)-10 could be rapidly
obtained through a previously reported eight-step protocol
featuring an asymmetric hydrogenation of the α,β-acetylenic
ketone moiety, a gold(I)-catalyzed cascade cyclization, and a
stereoselective azidoalkoxylation.5e,13,14 Desilylation of tetra-
cycle 10 provided the corresponding alcohol, which was
directly subjected to Dess−Martin periodinane (DMP)
oxidation to generate aldehyde 12. We then focused on the
assembly of the furoindoline core in the natural products 4−6
(Scheme 2). Exposure of 12 to PTSA in methanol produced
Recently, our group developed an efficient strategy for the
asymmetric assembly of tricycle (−)-10 (Scheme 1a), which
Scheme 1. Our Synthetic Plan for Akuammiline Alkaloids
and Retrosynthetic Analysis of Alkaloids 4−6
Scheme 2. Synthesis of Unsaturated Ester 19
the desired tetracycle 13 as an inseparable mixture of
diastereoisomers at C5 in good yield (d.r. = 2:1). The reaction
presumably proceeded through acid-promoted oxo-bridge ring
opening of 12 to give intermediate 17, the iminium ion moiety
of which was attacked by the pendant aldehyde oxygen atom
followed by solvolysis to produce 13 (Scheme 2).15
Next, we turned our attention to assembling the α,β-
unsaturated ester moiety. The presence of a secondary allylic
alcohol moiety in compound 13 promoted us to explore an
unusual PCC-mediated oxidative rearrangement to construct
the α,β-unsaturated aldehyde, which had proved to be a
powerful method for the synthesis of α,β-unsaturated ketones
starting usually from tertiary allylic alcohols.16 Upon
completion of the ring-opening reaction/recyclization of 12,
the solvent was removed and the resulting residue was treated
with PCC and PTSA in dichloromethane. Indeed, α,β-
unsaturated aldehyde 16 was obtained as an inseparable
mixture of two diastereomers in 63% combined yield (d.r. =
2:1). Pinnick oxidation of compound 16 followed by
esterification with TMSCHN2 produced unsaturated ester 19
in 69% yield over the two steps (Scheme 2).
was further employed to complete the asymmetric total
synthesis of (−)-aspidophylline A (3).5e By modifying the
oxidation state and connectivity at C5, intermediate (−)-10
could theoretically be used to access another subset of the
akuammiline alkaloids. Herein, we wish to report our
asymmetric total synthesis of picrinine-type akuammiline
alkaloids (−)-picrinine (4), (−)-scholarisine C (5), and
(+)-5-β-methoxyaspidophylline (6). The retrosynthetic anal-
ysis for the natural products 4−6 is delineated in Scheme 1b.
The target alkaloids 4−6 could be derived from pentacycle 14,
and the second N,O-acetal linkage in picrinine (4) might be
assembled via a late-stage N,O-acetalization. The [3.3.1]-
azabicycle in 14 could be constructed by a [Ni(cod)2]-
With ester 19 in hand, efforts were devoted to construction
of the [3.3.1]-azabicycle. Reduction of the azide moiety in 19
B
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under the Staudinger conditions17 gave the corresponding
primary amine, and the subsequent N-allylation with (Z)-1-
bromo-2-iodo-2-butene (20) afforded 21a and 21b (Scheme
3). Note that the configuration of 21a would lead to that of
optical rotation data of our synthetic sample of 4−6 are
essentially consistent with those recorded in the litera-
ture.6,10,12
In summary, we have accomplished the first asymmetric
total synthesis of three complex picrinine-type akuammiline
alkaloids, picrinine (4), scholarisine C (5), and 5-β-
methoxyaspidophylline (6). The current synthetic work
features an efficient acid-promoted oxo-bridge ring-opening
and further carbonyl O-cyclization to assemble the furoindo-
line core, an unusual Dauben−Michno oxidation of a
secondary allylic alcohol to construct the requisite α,β-
unsaturated aldehyde moiety, and a nickel-mediated intra-
molecular reductive Heck reaction to install the [3.3.1]-
azabicyclic core. By modifying the oxidation state at C5,
intermediate 10 may serve as a common precursor for the total
synthesis of additional akummiline alkaloids.
Scheme 3. Synthesis of Pentacycles 14a and 14b
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02393.
14a.18 N-Formylation of 21a was achieved under the standard
conditions to provide vinyl iodides 15a in 88% yield. A nickel-
mediated cyclization was applied to the closure of the final ring
of the target alkaloids, furnishing the desired pentacycle 14a in
60% yield.19 The structure of 14a was confirmed by an X-ray
crystallographic analysis of ( )-14a.18 Similarly, 21b could be
transformed to 14b in two steps. Both 14a and 14b would be
useful for the further reactions.
Experimental details, NMR data, and characterization
data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 4−6, 10, 12, 14−16, 19, and 21 (ZIP)
Accession Codes
CCDC 2096665 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 emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Having constructed the pentacyclic framework, we pro-
ceeded to the final stage of the total synthesis of alkaloids 4−6
(Scheme 4). We expected that N1 deprotection of 14a would
Scheme 4. Completion of the Total Synthesis of
Akuammiline Alkaloids 4−6
AUTHOR INFORMATION
Corresponding Authors
■
Hongbin Zhai − The State Key Laboratory of Chemical
Oncogenomics, Guangdong Provincial Key Laboratory of
Nano-Micro Materials Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China; Institute of Marine
Biomedicine, Shenzhen Polytechnic, Shenzhen 518055,
China; Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin), Tianjin 300071, China;
orcid.org/0000-0003-2198-1357; Email: zhaihb@
pkusz.edu.cn
Taimin Wang − The State Key Laboratory of Chemical
Oncogenomics, Guangdong Provincial Key Laboratory of
Nano-Micro Materials Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China; Institute of Marine
Biomedicine, Shenzhen Polytechnic, Shenzhen 518055,
China; Email: wangtm@szpt.edu.cn
afford 5-β-methoxyaspidophylline (6). However, it was quite
challenging to selectively deprotect the Boc group in 14a. We
finally found that selective removal of Boc group20,4b could be
achieved by treatment of 14a with silica gel under reduced
pressure, providing 5β-methoxyaspidophylline (6) in 47% yield
(63% brsm). By contrast, deprotection of both N1 and N4 in
14b was effected by gaseous HCl (produced in situ from
AcCl/MeOH) to afford scholarisine C (5, 41%) and picrinine
(4, 24%), the latter of which was presumably generated from 5
via N,O-acetalization. Furthermore, scholarisine C (5) could
be transformed into picrinine (4) in 76% yield in the presence
Authors
Peng Zou − The State Key Laboratory of Chemical
Oncogenomics, Guangdong Provincial Key Laboratory of
Nano-Micro Materials Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
Hongjian Yang − The State Key Laboratory of Chemical
Oncogenomics, Guangdong Provincial Key Laboratory of
1
of PTSA. The H and 13C NMR spectroscopic data and the
C
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Nano-Micro Materials Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
Jian Wei − The State Key Laboratory of Chemical
Oncogenomics, Guangdong Provincial Key Laboratory of
Nano-Micro Materials Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02393
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the State Key Basic Research Program of the PRC
(Grant 2018YFC0310900), National Natural Science Founda-
tion of China (Grants 21871018, 21732001, 21672017, and
21901014), Guangdong Science and Technology Program
(Grant 2017B030314002), Shenzhen Science and Technology
Program (Grant No. KQTD20190929174023858), Shenzhen
Science and Technology Innovation Committee (Grants
GXWD20201231165807007-20200812100115001 and
JCYJ20180504165454447), Industry and Information Tech-
nology Bureau of Shenzhen Municipality (Grant
201806151622209330), Shenzhen-Hong Kong Institute of
Brain Science-Shenzhen Fundamental Research Institutions
(Grant 2019SHIBS0004), the third foster plan in 2019
“Molecular Imaging Probe Preparation and Characterization
of Key Technologies and Equipment” for the development of
key technologies and equipment in major science and
technology infrastructure in Shenzhen, and the National Ten
Thousand Talent Program (the Leading Talent Tier) for the
financial support. We are grateful to Prof. Zhiqiang Ma of
South China University of Technology for the enlightening
discussion.
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Huang, X.; Shen, L.; Qin, Y. Total synthesis of the akuammiline
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