Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification

Article abstract of DOI:10.1021/acs.orglett.0c01472

We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff-Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (-)-aspidospermidine, (-)-limaspermidine, and (+)-17-demethoxy-N-acetylcylindrocarine and the formal total synthesis of (-)-1-acetylaspidoalbidine.

Full text of DOI:10.1021/acs.orglett.0c01472

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Letter
Total Syntheses of Dihydroindole Aspidosperma Alkaloids:
Reductive Interrupted Fischer Indolization Followed by Redox
Diversification
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́
́
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Gabor Martin, Peter Angyal, Orsolya Egyed, Szilard Varga,* and Tibor Soos*
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ABSTRACT: We report a novel reductive interrupted Fischer
indolization process for the concise assembly of the 20-oxoaspido-
spermidine framework. This rapid complexity generating route paves
the way toward various dihydroindole Aspidosperma alkaloids with
different C-5 side chain redox patterns. The end-game redox
modulations were accomplished by modified Wolff−Kishner reaction
and photo-Wolff rearrangement, enabling the total synthesis of
(−)-aspidospermidine, (−)-limaspermidine, and (+)-17-demethoxy-N-
acetylcylindrocarine and the formal total synthesis of (−)-1-
acetylaspidoalbidine.
ithout rival in the field of total synthesis has been the
positions not only broadens the list of natural products (e.g.,
(−)-minovincine (2) and (−)-limaspermidine (4)) but also
serves as a biogenetic link toward structurally more complex,
even cage-like derivatives of Aspidofractinine and Aspidoalbine
alkaloids (e.g., 3 and 6 in Figure 1). Despite their
(bio)synthetic and biological potential, this subset of natural
products has received relatively less attention in stereoselective
synthetic programs.6
W
sustained interest to devise synthetic routes to
Aspidosperma alkaloids (e.g., the archetypal 1 in Figure 1).1
Recently, our laboratory developed a short and scalable
(60g) synthetic route for the stereoselective synthesis of
Aspidosperma tricyclic ketone core 7 with C-5 methoxycar-
bonyl group and employed this advanced intermediate for the
concise syntheses of (−)-minovincine (2) and (−)-aspido-
fractinine (3) (Scheme 1).7 A key element of these syntheses
was the rapid buildup of much of the complexities of the
targets through the sequence of organocascade and anionic
cascade reactions. These routes are strategically aligned with
the Stork−Dolfini synthesis3a of aspidospermidine but
delivering C-20 oxidized intermediates and natural products.
As an outgrowth of our synthetic studies, we sought the
development of the syntheses of C-21 oxygenated and C-20
reduced subclasses of Aspidosperma alkaloids. We surmised
Figure 1. Structure of (−)-aspidospermidine (1) and its related C-20
and C-21 oxidized alkaloids 2−6.
Their important biological activities and stereochemically rich
pentacyclic scaffolds have rendered these compounds attractive
targets for synthetic programs.2 Over the last few decades,
various elegant and innovative synthetic approaches have been
reported and many of these strategies have made profound
contributions to modern organic synthesis.3 Recently, trends
such as divergent syntheses4 and “ideal synthesis”5 have come
to the front, forcing practitioners to advance methodologies
and strategies in an integrative manner.
Received: April 28, 2020
A subset of the Aspidosperma alkaloids is featuring an
oxidized side chain at the C-5 position (Figure 1, alkaloids 2−
6). This subtle but momentous modification in C-20 or C-21
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© XXXX American Chemical Society
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A

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natural products 4−6. Accordingly, the heart of our plan was
the rapid construction of dihydroindole 814 from diketone 14.
We envisioned that the Fisher indolization of 14 can be halted
at the stage 9; thus, the previously reported Mannich
cyclization to cage-like 15 can be avoided. Thus, imino 9
will be accessible which can be selectively reduced into 8.
We have recently disclosed the concise asymmetric synthesis
of tricyclic diketone 14 via organocatalytic and anionic cascade
reactions (Scheme 1) followed by chemo- and regioselective
acetyl group formation at C-5.7b Thus, using easily available
compounds 10 and 11, the stereochemically complex
intermediate 14 can be assembled in only four steps. In
order to access the dihydroindole intermediate 8 for the
planned diversification, we required optimal conditions to
secure the pentacyclic indolenine 9 formation (Scheme 2).
First, various reaction temperatures were employed in attempts
to divert the course of the original Mannich−Fisher
indolization of 14 to 15. However, we could not reverse or
halt the cascade reaction to afford indolenine 9.15 Neither
higher nor lower reaction temperature gave a synthetically
relevant yield of 9, indicating that the final Mannich reaction
step of the interrupted Fisher indolization16 to oxoaspido-
fractinine 15 is both kinetically and thermodynamically
preferred. Nevertheless, a fortunate observation guided our
further development. After carefully analyzing the products of
the Mannich−Fischer indolization process at 80 °C, we found
that besides the three major components (oxoaspidofractinine
15, indolenine 9, and 3H-indole 16) the selectively reduced
dihydroindole 8 could be detected. Importantly, prolonged
reaction times resulted in an increased yield of this product,
which suggested the reversibility of the Mannich step.
Additionally, we probed this reductive retro-Mannich step by
heating oxoaspidofractinine 15 at 100 °C with BF3·OEt2 in
ethanol for 2 days. Delightfully, we isolated indolenine 9 and
dihydroindole 8 along with unreacted starting material 15,
which unambiguously proved the existence of the reductive
retro-Mannich step (Scheme 2).
Scheme 1. Previous Work and Retrosynthetic Plan toward
Various Subclasses of Aspidosperma Alkaloids
We rationalized that this chemoselective reduction of the
imine moiety is analogous with a Meerwein−Ponndorf−Verley
Scheme 2. Study of the Retro-Mannich Step and Lewis Acid
Mediated Solvent Assisted Reduction
that advanced intermediate 14 might be used for a unified
approach that has a late stage redox diversification. Herein, we
describe our successful forays that led to total syntheses of
(−)-limaspermidine (4)8,9 and (+)-17-demethoxy-N-acetylcy-
lindrocarine (5)10,11 and the formal total synthesis of (−)-1-
acetylaspidoalbidine (6)12 and the parent member of
Aspidosperma alkaloids, the (−)-aspidospermidine (1).13
Our retrosynthetic analysis of the targeted indole alkaloids is
illustrated in Scheme 1. The pentacycle 8 was expected to
serve as a common intermediate for redox diversification. We
envisaged to employ Wolff−Kishner reduction to afford
(−)-aspidospermidine (1) and Wolff rearrangement to
accomplish a C-20 to C-21 redox swap for C-21 oxidized
a
Reaction conditions: (a) EtOH, 85 °C; (b) EtOH, 100 °C, 2 days.
B
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type reduction,17 in which the hydride source was the sacrifical
alcohol solvent. In light of this, we employed isopropanol as a
solvent to amplify the effectiveness of the reductive trans-
formation and raised the reaction temperature from 85 to 115
°C. Gratifyingly, these modifications gave the desired
compound 8 as the major product (63% yield) besides the
16 3H-indole (32% yield), the byproduct of Fischer
indolization (Scheme 3).
With the key intermediate 20-oxoaspidospermidine (8) in
our hand, we proceeded to perform the requisite redox
modifications (Schemes 3 and 4). First, the (−)-aspidospermi-
dine (1) was synthesized using a modified Wolff−Kishner
reduction process (Scheme 3).18 Presumably owing to the
steric hindrance of the carbonyl group, optimization of
reaction conditions was required. Finally, we found that the
telescopic application of Huang−Minlon and Cram modifica-
tion resulted in the highest yield. The spectroscopic data and
optical rotation of 1 were fully consistent with reported values.
To sum up, using our tactical modification of the original
Stork−Dolfini synthesis,3a (−)-aspidospermidine (1) could be
accessed in a stereoselective manner in eight steps and 14%
overall yield.
Finally, (+)-17-demethoxy-N-acetylcylindrocarine (9) was
then achieved through a two-step deprotection/acylation
sequence to finish our synthetic endeavor. All spectroscopic
data as well as the optical rotation data for our synthetic
(−)-limaspermidine (4) and (+)-17-demethoxy-N-acetylcylin-
drocarine (5) were consistent with the previously reported
values.
In summary, we expanded our previous cascade-sequence-
based methodology toward the syntheses of dihydroindole
Aspidosperma alkaloids with different C-5 side chain redox
patterns. Most importantly, a highly efficient reductive
interrupted Fisher indole synthesis was developed that delivers
an advanced pentacyclic intermediate 8 in a simple, one-pot
manner with excellent regio- and chemoselectivity. This key
intermediate 8 was then transformed into (−)-aspidospermi-
dine (1) in a straightforward manner. Furthermore, using
pentacyclic 8, we completed the total synthesis of two C-21
oxygenated alkaloids (−)-limaspermidine (4) and (+)-17-
demethoxy-N-acetylcylindrocarine (5) via an oxidation state
swap approach using photo-Wolff rearrangement. These
concise total syntheses provide further demonstration of the
power of the sequential organo- and anionic cascade reactions
for rapid assembling of stereochemically complex indole
alkaloid skeleta, while also directly providing the desired
oxidation state at the challenging C-20 or C-21 positions.
Scheme 3. Reductive Interrupted Fisher Indolization and
Completion of the Total Synthesis of (−)-Aspidospermidine
a
(1)
Scheme 4. Completion of the Total Synthesis of
(−)-Limaspermidine (4) and (+)-17-Demethoxy-N-
acetylcylindrocarine (5) via a Wolff Rearrangement
a
a
i
Reagents and conditions: (a) PhNHNH2, PrOH, 85 °C, then BF3·
OEt2, 115 °C; (b) DEG, 130−210 °C; (c) DMSO, 130 °C; DEG =
diethylene glycol, DMSO = dimethyl sulfoxide.
Next, the formation of the C-21 oxidized side chain was
probed via a formal “redox swap”, the Wolff rearrangement
(Scheme 4).19 Our preliminary studies indicated that the
protection of the dihydroindole NH moiety was essential to
avoid undesired alkylation or polymerization reactions during
the photo, thermal, or metal salt (e.g., Ag, Rh) activated Wolff
rearrangement. Thus, the desired diazo compound 17 was
generated by protection of 8 with Boc2O followed by diazo
transfer utilizing Danheiser’s method.20 To our delight, the
subsequent redox swap proceeded smoothly through photo-
chemical Wolff rearrangement that afforded ester 18. This
ester was then reduced with DIBAL, followed by the removal
of the Boc group to afford (−)-limaspermidine (4). This route
also constitutes a formal asymmetric total synthesis of the
Aspidoalbine alkaloid (−)-1-acetylaspidoalbidine (6), as this
target can be accessed in two steps from limaspermidine.12
a
Reaction conditions: (a) THF, 50 °C; (b) THF, −78 °C then
MeCN,rt; (c) UV irradiation (312 nm), MeOH, THF, rt; (d) THF,
−78 to 0 °C; (e) CH2Cl2, 0 °C; (f) CH2Cl2, 0 °C; (g) CH2Cl2, rt;
TFA = trifluoroacetic acid, THF = tetrahydrofuran, LiHMDS =
lithium bis(trimethylsilyl)amide, DIBAL = diisobutylaluminum
hydride.
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01472.
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Experimental procedures, characterization data, and
NMR spectral data of new compounds (PDF)
FAIR data file, including the primary NMR FID files, for
compounds 1, 4, 5, 8, 8′, 9, 14, 15, 16, 17, and 18 (ZIP)
AUTHOR INFORMATION
Corresponding Authors
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̀
2013, 135, 13334−13337. (m) Wagnieres, O.; Xu, Z.; Wang, Q.; Zhu,
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Chem., Int. Ed. 2019, 58, 12595−12598.
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E. E.; Zografos, A. L. Chem. Soc. Rev. 2012, 41, 5613−5625. (b) Li, L.;
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Chem. Sci. 2016, 7, 866−880.
́
Szilard Varga − Institute of Organic Chemistry, Research Centre
for Natural Sciences, Budapest H-1117, Hungary;
orcid.org/0000-0001-9611-5168; Email: varga.szilard@
ttk.hu
́
Tibor Soos − Institute of Organic Chemistry, Research Centre for
Natural Sciences, Budapest H-1117, Hungary; orcid.org/
0000-0002-2872-4313; Email: soos.tibor@ttk.hu
Authors
́
Gabor Martin − Institute of Organic Chemistry, Research Centre
for Natural Sciences, Budapest H-1117, Hungary
́
Peter Angyal − Institute of Organic Chemistry, Research Centre
for Natural Sciences, Budapest H-1117, Hungary;
orcid.org/0000-0003-4514-2187
Orsolya Egyed − Instrumentation Center, Research Centre for
Natural Sciences, Budapest H-1117, Hungary
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01472
(6) Selected paper about the total synthesis from C-20 and C-21
oxidized alkaloids: (a) Langlois, N.; Andriamialisoa, R. Z. J. Org.
Chem. 1979, 44, 2468−2471. (b) Kuehne, M. E.; Li, Y.-L. Org. Lett.
1999, 1, 1749−1750. Selected asymmetric syntheses for C-20 or C-
21 oxidized Aspidosperma alkaloids: (c) Gagnon, D.; Spino, C. J. Org.
Chem. 2009, 74, 6035−6041. (d) Laforteza, B. N.; Pickworth, M.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2013, 52, 11269−11272.
(e) Kang, T.; White, K. L.; Mann, T. J.; Hoveyda, A. H.; Movassaghi,
M. Angew. Chem., Int. Ed. 2017, 56, 13857−13860.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is dedicated to the memory of Prof. Dr. Gyorgy
■
̈
́
Hajos. We are grateful for financial support provided by the
National Research, Development and Innovation Office (FK
́
124863, K 125385). We also thank Dr. Daniel Fegyverneki
(Institute of Organic Chemistry, Research Centre for Natural
Sciences) for helpful discussions.
́
́
́
(7) (a) Berkes, B.; Ozsvath, K.; Molnar, L.; Gati, T.; Holczbauer, T.;
́
Kardos, Gy.; Soos, T. Chem. - Eur. J. 2016, 22, 18101−18106.
(b) Varga, Sz.; Angyal, P.; Martin, G.; Egyed, O.; Holczbauer, T.;
́
Soos, T. Angew. Chem. Int. Ed. 2020, DOI: 10.1002/anie.202004769.
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Med. 1979, 37, 165−167.
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