Synthesis of the Proposed Structures of Parvistemoamide and Their Transformations to Stemoamide Derivatives

Article abstract of DOI:10.1021/acs.orglett.1c01045

The proposed structures of parvistemoamide have been achieved by macrolactamization, but none of the characterization data of synthetic samples matched with those of the natural sample. The transformation of the highly strained 10-membered lactam ring in parvistemoamide into the pyrrolo[1,2-a]-azepine nucleus in stemoamide is accomplished for the first time by either transannular cyclization or Pilli's transformation. This research may promote the total synthesis of other more complex stemoamide-type or medium-sized-ring-containing Stemona alkaloids.

Full text of DOI:10.1021/acs.orglett.1c01045

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Letter
Synthesis of the Proposed Structures of Parvistemoamide and Their
Transformations to Stemoamide Derivatives
Fei Cao,∇ Weiwei Gao,∇ Xiaodong Wang, Zhihan Zhang, Gaofeng Yin, Yuqing Wang, Zhao Li,
Tao Shi,* Yongsheng Hou, Jinhong Chen, and Zhen Wang*
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ABSTRACT: The proposed structures of parvistemoamide have been
achieved by macrolactamization, but none of the characterization data
of synthetic samples matched with those of the natural sample. The
transformation of the highly strained 10-membered lactam ring in
parvistemoamide into the pyrrolo[1,2-a]-azepine nucleus in stemoa-
mide is accomplished for the first time by either transannular cyclization
or Pilli’s transformation. This research may promote the total synthesis
of other more complex stemoamide-type or medium-sized-ring-
containing Stemona alkaloids.
edium-sized rings (8−11 atoms) play an important role
Min biologically active natural products, medicines, and
cyclic peptides,1 but the syntheses of medium-sized rings still
remain a challenge because of their unfavorable transannular
interactions and entropic factors.2 Stemona is a traditional
herbal medicine in China and Japan that, besides containing a
large number of bioactive seven-membered azepine skeletons,
possesses medium-sized alkaloids as some of its main
components.3 Although medium-sized alkaloids are most likely
some of the indispensable active components of Stemona,4 they
have never been investigated in pharmacology, which is mainly
due to limitations such as the low yields in the plant, the low
isolation efficiency, and the high difficulty of the synthesis.
Therefore, accomplishing the total syntheses of medium-sized-
ring-containing Stemona alkaloids may promote research on
the substance basis of the activities of Stemonaceae plants.
Parvistemoamide (3), which was isolated from Stemona
parviflora by Xu and co-workers, was the first identified and
one of the most representative medium-sized Stemona
alkaloids.4e It belongs to the miscellaneous group in Pilli’s
classification4d and is characterized by a highly strained 10-
membered lactam and four continuous stereocenters. How-
ever, the stereochemistry at the C9a and C10 positions
remains ambiguous; Xu and co-workers proposed two kinds of
stereochemistry, one is C9a−α-OH and C10−α-Me4e,5b and
the other one is C9a−β-OH and C10−β-Me.5c After Xu’s
seminal research, the topic of Stemona alkaloids has been
reviewed by several groups, and the two structures proposed by
Xu and co-workers appeared in some of these publications.4d,5a
In 2006, Greger and co-workers showcased the structure of
parvistemoamide as C9a−α-OH and C10−α-Me,4c whereas
the stereochemistry at C9a was reversed in their latest review
(Figure 1).4a The above confusing stereochemistry at the C9a
Figure 1. (A) Stemoamide-type and medium-sized Stemona alkaloids
and the reported transformation between parvistemoamide and
stemoamide. (B) Reported structures of parvistemoamide at present.
Received: June 8, 2021
Published: August 9, 2021
https://doi.org/10.1021/acs.orglett.1c01045
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6222−6226
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and C10 positions of parvistemoamide largely hinders the
synthetic and pharmacological studies on parvistemoamide and
medium-sized-ring-containing Stemona alkaloids.
successfully achieved, parvistemoamide (3) could be synthe-
sized and, more importantly, the stereochemistry of
parvistemoamide and its transformation relationship with
stemoamide (4) would be clearly revealed, which may further
promote the total syntheses of other more complex
stemoamide-type alkaloids.
At same time as reporting the isolation of parvistemoamide,
Xu simultaneously reported that the 10-membered lactam in
parvistemoamide (3) may come from the pyrrolo[1,2-a]-
azepine nucleus in stemoamide (4) by C9a−N oxidative
cleavage.4e Afterward, Pilli and co-workers revealed their
synthetic study on parvistemoamide in 2005 and proposed a
possible biomimetic conversion of parvistemoamide to
stemoamide via oxidation at C9a, a nucleophilic attack by an
activated form of the amide nitrogen, and the following
dehydration and reduction of the intermediate N-acyliminium
ion,5a which is different from Xu’s proposal4e (Figure 1).
However, in Pilli’s work only a 5:1 mixture of two lactams with
C9a−α-OH and C10−α-Me and C9a−β-OH, C10−β-Me was
achieved, and no any NMR data were provided.5a More
importantly, neither Xu’s nor Pilli’s viewpoint on the
transformation relationship between parvistemoamide and
stemoamide has been studied by experiments until now,
although many elegant formal or total synthesis studies toward
stemoamide have been revealed.6 Therefore, the relative
configuration of parvistemoamide and its transformation
relationship with stemoamide are still unsolved mysteries.
In this regard, accomplishing the total syntheses of the
possible structures of parvistemoamide may help to confirm its
stereochemistry and, more importantly, promote the study of
the transformation relationship of Stemona alkaloids. In the
continuation of our research interest in Stemona alkaloids,7 we
herein (A) report the total syntheses of four stereoisomers of
parvistemoamide (3) via macrolactamization and (B) reveal
the transformations of the possible structures of parvistemoa-
mide (3) to stemoamide (4) and 9a-epi-stemoamide by
transannular cyclization or Pilli’s transformation, although the
unambiguous structural determination for parvistemoamide
was not accomplished in this work.
With the above retrosynthetic analysis in mind, we
commenced the synthesis of stereoisomers 3a−3d, which
encompass the two structures proposed for parvistemoamide
(3) by Xu and co-workers4e,5c (Scheme 2). Starting from
ketone 6,8 the protection of the ketone carbonyl group with
1,3-dimercaptopropane and the hydrolysis of the methyl ester
with LiOH generated carboxylic acid 7. Under the promotion
of TMSI, the carboxybenzyl group (Cbz) in 7 was deprotected
to render the unprotected amine, which was then subjected to
the Corey−Nicolaou macrolactamization reaction to construct
the 10-membered lactam 8 in a 50% yield in a rather high-
dilution solvent (c = 1.0 × 10−3 M). Then, the above-generated
unprotected amide was protected by Boc to deliver 9 in a 71%
yield, which was identified by X-ray analysis. Sequentially, 9
underwent the oxidative deprotection of the 1,3-dithiane
protecting group by PIFA, affording ketone 10 in a 72% yield.
We subsequently studied the stereoselective reduction of
ketone 10. When subjecting ketone 10 to reducing reagents
such as sterically hindered LiAl(tBuO)3H, the Boc-protected
10-membered lactam in the desired product was susceptible to
nucleophilic ring opening, and an unexpected lactam−lactone
exchange product formed via the ring opening of lactam and
the lactonization of the amide carbonyl group with the newly
formed hydroxyl group (see the Supporting Information (SI)).
This is mainly due to the existence of Boc weakening the p−π
conjugation effect between the amide nitrogen atom and the
amide carbonyl group, thus weakening the C−N bond and
increasing the electrophilicity of amide carbonyl group.9
Pleasingly, when the reaction mixture was flash-quenched
with 3 M HCl, only a single diastereoisomer with C9a−α-OH
was afforded in a 73% yield. The subsequent sequential
C9a−α-OH protection by TES and the stereospecific
methylation at C10 rendered 11a smoothly. When 11a was
treated with BF3·OEt2, TES was removed prior Boc, the
lactam−lactone exchange byproduct was formed (see the SI).
After exhaustive attempts, Mg(ClO4)2, which was compatible
with the sensitive TES, was considered as the most appropriate
reagent to remove Boc.
Based on the structural characters of parvistemoamide, we
propose the following retro-synthetic strategy (Scheme 1). The
Scheme 1. Retro-Synthetic Analysis of Stemoamide and
Parvistemoamide
Then, TES was deprotected by CAN, accomplishing the
synthesis of 3a. After the attempted introduction of a double
bond in C10 failed (see the SI), the most commonly employed
chiral adjustment method in the synthetic studies on Stemona
alkaloids was used. As a result, 3a (β-Me) and 3b (α-Me) were
obtained in a 39% total yield in a diastereoselective ratio of 1:1
when 3a was subjected to K2CO3/MeOH. The structures of 3a
(CCDC 2068248) and 3b (CCDC 2068262) were confirmed
by X-ray crystallographic analysis, and 3b was found to be
identical to the structure proposed by Xu.4e,5b However, the
1H and 13C NMR data of neither 3a nor 3b are the same as
those of the natural sample. One of the most significant
differences in the1H NMR data is that there is an additional set
10-membered lactam ring in parvistemoamide is proposed to
be constructed via the macrolactamization of the amphoteric
compound 5, which can be further traced back to ketone 6 via
the protection of the keto-carbonyl group and the deprotection
of the ester and amine. Ketone 6 is a known compound and
could be easily obtained.8 On the other hand, parvistemoamide
may be derived from stemoamide via the C9a−N oxidative
cleavage proposed by Xu,4e or stemoamide could come from
parvistemoamide via the C−N bond formation proposed by
Pilli5a or transannular cyclization. If the above proposal is
of peaks at 2.80−3.0 ppm in our reported data. As for the 13
C
NMR data, it is obvious that both 3a and 3b are not the
naturally occurring parvistemoamide.
Thus, we have to resort to the epimers at the C9a position.
After several trials, NaBH4 gave a 3.8:1 ratio of two
diastereoisomers in favor of β-OH (see the SI). Following a
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a
Scheme 2. Total Syntheses of Parvistemoamide (3) and Three of Its Epimers
a
Non-hydrogen atoms are shown as 30% ellipsoids.
similar reaction sequence, including TES protection, methyl-
ation, and the removal of Boc and TES, the newly formed
alcohol was further transformed into another epimer of
parvistemoamide 3c (CCDC 2068263) with C9a−β-OH and
unexpected C10−β-Me, which was proposed by Xu.5c Then,
Greger’s structure 3d was synthesized through the epimeriza-
tion of 3c under the promotion of K2CO3 or the Mitsunobu
Scheme 3. Transformation Studies from the 5/10 Skeleton
of Parvistemoamide to the 5/7/5 Skeleton of Stemoamide
1
reaction and ester hydrolysis of 3b. Nevertheless, the H and
13C NMR data of 3c and 3d were still not in accordance with
those of the reported compound, which is analogous to the
cases of 3a and 3b. At this point, stereoisomers 3a−3d
proposed for parvistemoamide have been synthesized, but
none of the characterization data of the synthetic compounds
were in accordance with those originally reported, indicating
that in the original paper the proposed structure of
parvistemoamide may be incorrect. We hypothesize that the
following transformation relationship studies may help to
confirm the real stereochemistry of parvistemoamide. Among
the four synthesized epimers of parvistemoamide, we chose 3a
to study Pilli’s transformation relationship between parviste-
moamide and stemoamide (Scheme 3). Under the conditions
of DMP oxidation and NaCNBH3 reduction, 3a was proven to
convert to stemoamide through the ketone intermediate 13. In
order to find more direct evidence to reveal the transformation
relationship between parvistemoamide and stemoamide, we
investigated the conditions of the direct conversion of
parvistemoamide into stemoamide. When subjecting 3a to 6
M HCl, TsOH, or CSA, the desired carbocation intermediate
15 was not formed, which further blocked the C−N bond
formation in stemoamide (4) through the nucleophilic attack
of a nitrogen atom to the carbocation 15. Pleasingly, treating
3a with MsCl could render the methanesulfonylated
intermediate 14. OMs as a good leaving group in 14 was
easily substituted by a nitrogen atom in the presence of either
K2CO3 or NaH, thus providing the thermodynamically more
stable stemoamide (4) in a 53% or 47% yield, respectively. In
addition, isomers 3b−3d were respectively subjected to the
same nucleophilic transannular cyclization. As a result, 3b with
C9−α-OH was transformed into stemoamide (4), while 3c
and 3d bearing C9−β-OH were transformed into 9a-epi-
stemoamide, indicating that the C10−Me could epimerize in
this reaction process (see the SI). We hypothesized that the
feasibility of the above transformations may be supported by
releasing the high ring tension of the 10-membered lactam.10
Noteably, this transannular cyclization from the 5/10 bicyclic
skeleton of parvistemoamide to the 5/7/5 tricyclic skeleton of
stemoamide (4) was first proposed and identified by
experiments.
Since the transformation of parvistemoamide to stemoamide
via C−N bond formation in our transannular cyclization or
Pilli’s proposal has been identified by experiments, we
wondered if Xu’s transformation relationship scheme is feasible
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in chemical transformations (Scheme 4). After obtaining a
large amount of stemoamide, which was synthesized by
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Verification of Xu’s Transformation
a
Relationship
AUTHOR INFORMATION
■
Corresponding Authors
Zhen Wang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Ministry of Education of China,
Lanzhou 730000 Gansu, China; School of Pharmacy,
Lanzhou University, Ministry of Education of China,
Lanzhou 730000 Gansu, China; orcid.org/0000-0003-
4134-1779; Email: zhenw@lzu.edu.cn
Tao Shi − School of Pharmacy, Lanzhou University, Ministry
of Education of China, Lanzhou 730000 Gansu, China;
Email: shit18@lzu.edu.cn
Authors
Fei Cao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Ministry of Education of China,
Lanzhou 730000 Gansu, China
Weiwei Gao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Ministry of Education of China,
Lanzhou 730000 Gansu, China
Xiaodong Wang − School of Pharmacy, Lanzhou University,
Ministry of Education of China, Lanzhou 730000 Gansu,
China
Zhihan Zhang − Department of Chemistry, Southern
University of Science and Technology, Shenzhen 518055
Guangdong, China; orcid.org/0000-0002-1758-3914
Gaofeng Yin − School of Pharmacy, Lanzhou University,
Ministry of Education of China, Lanzhou 730000 Gansu,
China
Yuqing Wang − School of Pharmacy, Lanzhou University,
Ministry of Education of China, Lanzhou 730000 Gansu,
China
Zhao Li − School of Pharmacy, Lanzhou University, Ministry
of Education of China, Lanzhou 730000 Gansu, China
Yongsheng Hou − School of Pharmacy, Lanzhou University,
Ministry of Education of China, Lanzhou 730000 Gansu,
China
a
Non-hydrogen atoms are shown as 30% ellipsoids.
employing Chida and Sato’s concise synthetic strategy,11
stemoamide (4) underwent an oxidation at the position
adjacent to the amide nitrogen atom by RuCl3·3H2O/NaIO4.12
However, the desired 5/10 skeleton was not observed, and
only compound 16 was obtained in a 85% yield. Unfortunately,
subsequent extensive attempts at C−N cleavage to accomplish
the direct or indirect conversion of the 5/7/5 skeleton into the
5/10 skeleton proved to be in vain, and only the corresponding
dehydration products 19a−19c or the methylated product 19d
were generated (see the SI). From the failure of the above
attempts, we realize that although a strong resonance effect
between the nitrogen lone pair and the antibonding orbital
(π*) of the carbonyl group exists,13 which may further weaken
the adjacent C9a−N bonds, cleaving the adjacent C9a−N
bonds seems to still be difficult due to the high C−N bond
dissociation energy (BDE).14 Meanwhile, it would be tough for
a thermodynamically more stable 5/7/5 tricyclic skeleton to
overcome a high strain energy to form a highly strained ten-
membered lactam in classic transformations (see the SI).
In conclusion, we accomplished the total syntheses of the
possible structures of parvistemoamide. More importantly, we
verified the transformations of the possible structures of
parvistemoamide to stemoamide and 9a-epi-stemoamide via
either the transannular cyclization or Pilli’s transformation
proposal. This transformation may promote the collective total
syntheses of other parvistemoamide- or stemoamide-related
Stemona alkaloids. Synthetic and biological studies on other
Stemona alkaloids are underway in our laboratory.
Jinhong Chen − School of Pharmacy, Lanzhou University,
Ministry of Education of China, Lanzhou 730000 Gansu,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01045
Author Contributions
∇F.C. and W.G. contributed equally.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01045.
■
sı
Notes
The authors declare no competing financial interest.
Experimental procedures, spectroscopic data, and
checkcif reports for crystallographic data (PDF)
ACKNOWLEDGMENTS
■
This study was financially supported by the Gansu Province
Science Foundation for Distinguished Young Scholars
(20JR5RA304) and the Recruitment Program of Global
Experts. This work was technically supported by Lanzhou
University.
Accession Codes
CCDC 2068213, 2068248, 2068262−2068263, 2068265−
2068266, and 2068268 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Letter
(8) Brito, G. A.; Sarotti, A. M.; Wipf, P.; Pilli, R. A. Cascade
cyclization triggered by imine formation. Formal synthesis of the
alkaloid ( )-stemoamide and its 9a-epimer. Tetrahedron Lett. 2015,
56, 6664−6668.
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