Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids

Article abstract of DOI:10.1002/anie.202102416

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, N_a-methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.

Full text of DOI:10.1002/anie.202102416

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Total Synthesis
Hot Paper
Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids
Zhao Yang+, Qiuyuan Tan+, Yan Jiang, Jiaojiao Yang, Xiaojiao Su, Zhen Qiao, Wenqiang Zhou,
Ling He, Hanyue Qiu, and Min Zhang*
Abstract: We report here a concise, collective, and asymmetric
total synthesis of sarpagine alkaloids and biogenetically related
koumine alkaloids, which structurally feature a rigid cage
scaffold, with l-tryptophan as the starting material. Two key
bridged skeleton-forming reactions, namely tandem sequential
oxidative cyclopropanol ring-opening cyclization and ketone
a-allenylation, ensure concurrent assembly of the caged
sarpagine scaffold and installation of requisite derivative
handles. With a common caged intermediate as the branch
point, by taking advantage of ketone and allene groups therein,
total synthesis of five sarpagine alkaloids (affinisine, norma-
cusine B, trinervine, Na-methyl-16-epipericyclivine, and vello-
simine) with various substituents and three koumine alkaloids
(koumine, koumimine, and N-demethylkoumine) with more
complex cage scaffolds has been accomplished.
widely or thoroughly evaluated, probably because of their
natural paucity.[1]
The intriguingly diverse, structurally complex architec-
tures and the biological profiles of above-mentioned alkaloids
inspired our interest. With the objective of developing a new
and efficient strategy that enable collective total synthesis of
both sarpagine[5,6] and koumine[6h,7] alkaloids, ideally from
a common late-stage intermediate, we embarked on a syn-
thetic program toward these two natural product families.
Our synthetic strategy (Scheme 1) involved the synthesis of
sarpagine alkaloids with various substituents, for example,
ester, aldehyde, or alcohol, on C16 together with vinyllidene
or oxygenated ethyl substituents on C20. This could be
achieved using an advanced cage intermediate 1 with versatile
ketone and allene groups at the corresponding positions.
Meanwhile, with intermediate 1 as the branchpoint, the
scaffold of koumine alkaloids could be built by a p-Lewis
Introduction
acid-catalyzed biomimetic indolyl addition to the allene unit
[8]
À
Sarpagine alkaloids belong to the monoterpene indole
alkaloid family, and more than 100 members have been
isolated, mainly from the Apocynaceae (e.g. Alstonia and
Rauvolfia genera) and Gelsemiaceae (e.g. Gelsemium genus)
plant families (some representative members are shown in
Figure 1A).[1] Structurally, sarpagine alkaloids feature a di-
versely substituted, cage-shaped scaffold, which can be
disassembled into two bridged substructures, namely indole-
fused azabicyclo[3.3.1]nonane and azabicyclo[2.2.2]octane
(Figure 1B). Ajmaline (trade name Gilurytmal), which is
a prominent congener of sarpagine alkaloids, has been used as
a diagnostic drug to induce arrhythmic contractions in
patients suspected of having Brugada syndrome (Fig-
ure 1C).[2] Koumine alkaloids, which are biogenetically de-
rived from sarpagine alkaloids,[3] have more complex cage
scaffolds and show a broad spectrum of biological properties,
such as antitumor, antiinflammatory, analgesic, and immuno-
modulatory effects (Figure 1C).[4] However, the potential
biological activities of sarpagine alkaloids have not been
after a C3 N bond breakage. We envisioned that the cage
scaffold of 1 could be assembled by two critical bridged
skeleton-forming steps: 1) ketone a-allenylation to form the
bicyclo[2.2.2]octane moiety, and 2) intramolecular oxidative
cyclopropanol cyclization to form the bicyclo[3.3.1]nonane
moiety. The bicyclo[2.2.2]octane moiety is most commonly
constructed by a-vinylation of a ketone via a palladium-
catalyzed coupling process.[5,6] Instead of a vinyl group
introduction at C20 via this known method, our proposed
strategy installs a more versatile allene group. This would
increase the potential for late-stage structural diversifica-
tions.[9] To access the azabicyclo[3.3.1]nonane motif, seminal
and effective methods such as Dieckmann cyclization,[5] olefin
metathesis,[6a,b] indolyl Friedel–Crafts reaction,[6c,d] and [5+2]-
cycloaddition/ring enlargement,[6e,f] have been developed. We
envisioned that a tandem amine oxidation and cyclopropanol
ring-opening cyclization of substrate 5a would allow rapid
assemble of the azabicyclo[3.3.1]nonane skeleton and intro-
duction of a versatile ketone group.[10] Enantiopure 5a with
a dictating chiral carbon center can be directly synthesized via
Kulinkovich cyclopropanation of a carboxyl ester,[11] which
can be easily derived from the cheap chiral starting material
l-tryptophan.[12]
[*] Z. Yang,[+] Q. Tan,[+] Y. Jiang, J. Yang, X. Su, Z. Qiao, W. Zhou, L. He,
H. Qiu, Prof. Dr. M. Zhang
Chongqing Key Laboratory of Natural Product Synthesis and Drug
Research, Innovative Drug Research Centre, School of Pharmaceut-
ical Sciences, Chongqing University
Results and Discussion
55 Daxuecheng South Road, Shapingba, Chongqing 401331 (China)
E-mail: minzhang@cqu.edu.cn
Bicyclo[3.3.1]nonane Skeleton Construction
[+] These authors contributed equally to this work.
First, We explored the feasibility of constructing the
bicyclo[3.3.1]nonane motif via the proposed tandem amine
oxidation and cyclopropanol ring-opening cyclization (Ta-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102416.
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Figure 1. A) Selected sarpagine alkaloids with ester, aldehyde, or alcohol substituents at C16 and vinyllidene or oxygenated ethyl substituents at
C20. B) Caged core framework of sarpagine alkaloids. C) Selected ajmaline and koumine alkaloids.
Scheme 1. Retrosynthetic analysis of sarpagine and koumine alkaloids.
ble 1). We recently developed an oxidative cyclopropanol
ring-opening cyclization cascade of tetrahydroisoquinoline-
type substrates for generation of bridged bicyclo-
[3.3.1]nonanes.[13] Although similar in principle, methods that
involve tetrahydroisoquinolines are not usually applicable to
the homologous tetrahydro-b-carbolines, particularly if that
selective oxidation of C3-H is involved (see 5a in Scheme 1
for carbon numbering).[14] Inherent issues arising from the
electron-rich indole motif, such as selectivity for C3-H over
C6-H and proneness to aromatization by over-oxidation, need
to be addressed.[15] Additionally, ring-opening addition of
cyclopropanol to iminium ions or imines is underexplored,
although cyclopropanol is widely used as a nucleophilic C3
synthon.[11] Appropriate oxidants and catalysts are key to the
success for the tetrahydro-b-carbolines. Chiral cyclopropanol
5a was prepared in three steps from l-tryptophan (Sche-
me 2A) and then evaluated under the original conditions for
the tetrahydroisoquinolines (CuCl2/air).[13] Although the
desired bridged product 6a was indeed observed in the messy
reaction mixture, however, the isolated yield was low
(< 20%) and inconsistent.[16] After extensive screening of
oxidants and other reaction parameters,[16] a one-pot tandem
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Table 1: Applicable substrate scope for the tandem sequential amine oxidation and cyclopropanol ring-opening cyclization.
Reaction conditions: 5 (0.1 mmol), DEAD (0.11 mmol), CHCl3 (2 mL), rt, 3 h, followed by addition of CuCl2 (0.02 mmol), 3–8 h.
sequential process[17] with diethyl azodicarboxylate
(DEAD)[18] as the oxidant and CuCl2 as the catalyst was
identified as the best choice; 6a was obtained in 60% yield.[19]
Because sarpagine alkaloids have alkoxyl groups at various
indole-ring positions, and to obtain bridged products with
more handles for analogue synthesis, cyclopropanols 5 with
various substituents on the indole ring were prepared in 10–
78% yields over 2–5 steps and tested in this tandem
sequential process. Table 1 shows that substrates with elec-
tronically different substituents at the 5-position of the indole
ring, for example, F, Cl, Br, Me, and MeO, readily participated
in this tandem sequential oxidative cyclization (6d–6h).
Notably, cyclopropanols with a bromine atom or methoxy
group at the problematic 4-position of the indole ring were
viable substrates (6i and 6j). Bromine atoms and methoxy
groups at the 6- and 7-positions of the indole ring were well
tolerated (6k–6n). A substrate with a methylenedioxy sub-
stituent on the indole ring gave 6o in a comparable yield.
[2.2.2]octane skeleton via ketone a-allenylation. Generally,
allenes have more versatile reactivities than alkenes, there-
fore installation of an allene unit on the core framework
enables synthesis of more diverse natural products and their
analogues.[9] Although great progress has been made in a-
functionalization of ketones, methods for a-allenylation of
ketones via a SN2’ propargyl substitution are less known.[21]
Our initial efforts to achieve this reaction through a direct
SN2’ reaction under basic conditions (e.g. LDA, tBuOK) were
fruitless. We then turned our attention from a single-activa-
tion model to a multiple-activation one.[22–24] In Magnusꢀ
work, a secondary amine-catalyzed Michael addition of
a ketone to an activated alkyne was used to build the
bicyclo[2.2.2]octane skeleton.[7a,b] We envisioned that an
appropriate amine could activate the ketone via formation
of an enamine similarly, and a p-acidic metal could simulta-
neously activate the alkyne group via complexation with the
triple bond, thus facilitating this bridged-skeleton forming
reaction. Although gold has been used to promote the
cyclization of preformed enol silyl ethers to alkynes, an
À
Bicyclo[2.2.2]octane Skeleton Construction
alkene group, which was formed after protonation of the C
Au bond, was generated rather than an allene group.[9] We
envisioned that with a suitable leaving group at the propargyl
position and use of an appropriate metal, a formal SN2’
substitution would take place to afford an allene. Extensive
screening of various leaving groups, metals, and amines,
showed that treatment of 3 with pyrrolidine and AgNTf2 was
the best choice, and provided caged intermediate 1 in 75%
yield along with the 7-endo-dig cyclization byproduct 24 in
11% yield (Schemes 2A and 3A).[16] To test the application
scope of this method, four representative substrates were
prepared and subjected to the typical reaction conditions
Another critical step in the assembly of the sarpagine cage
scaffold is construction of the bicyclo[2.2.2]octane motif. As
shown in Scheme 2A, gram quantities of 6a were obtained by
a sequence of reactions, namely Pictet-Spengler reaction of
l)-tryptophan,[20] N-arylation and carboxylic acid esterifica-
tion, Kulinkovich cyclopropanation of the carboxyl ester, and
our one-pot tandem sequential amine oxidation/cyclopropa-
nol ring-opening cyclization. Dearylation of 6a and alkylation
of the free amine with 9 afforded 3 in good yield. With 3 in
hand, we explored the feasibility of constructing the bicyclo-
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Scheme 2. Collective asymmetric total synthesis of sarpagine and koumine alkaloids. Reactions and conditions: a) CuI, PMPI, K2CO3, DMSO,
1008C, 5 h, then MeI, 08C to rt, 20 min, 52%; b) Ti(OiPr)4, EtMgBr, THF, 8 h, 82%; c) DEAD, CHCl3, 3 h, then CuCl2, 6 h, 55%; d) BBr3, CH2Cl2,
À788C to 08C, 24 h, then PIFA, CH3CN/H2O, 08C, 1 min; e) 9, K2CO3, CH3CN, reflux, 60% (two steps); f) AgNTf2, pyrrolidine, toluene, 908C,
30 min, 75%; g) Me3SOI, NaH, DMSO, rt, 6 h, 90%; h) Me3SI, NaH, DMSO/THF, 658C to 08C, then rt, 6 h, 92%; i) MABR, CH2Cl2, À788C, 1 h,
75% for 12, 78% for 15; j) DIBAL-H, THF, À308C, 2 h, 88% for 13, 86% for 17; k) Pd/C, H2, MeOH, À408C, 3 h, E/Z>20:1, 82% for
vellosimine, 78% for normacusine B, 65% for affinisine, 76% for Na-methyl-16-epipericyclivine; l) TIPSOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h, then
t
BH3·THF, THF, À788C, 20 min, 81%; m) CuCl, dppf, BuONa, B2pin2, MeOH, THF, rt, 30 min; NaBO3·4H2O; HCl (2 M), THF, 808C, 2 h, 40%;
n) NIS, K2CO3, MeOH, 4 h, 70%; o) TrocCl, Na2CO3, TBAI, H2O/CHCl3, 8 h, 62%; p) JohnPhosAuCl, AgBF4, CH2Cl2, rt, 1 h, then DBU, rt, 3 h,
64%; q) TFA, Et3SiH, CH2Cl2, rt, 8 h, 91%; r) Zn, AcOH, THF/H2O, 658C, 40 min; s) PhIO, CH2Cl2, rt, 40 min, 84% for 23, 73% for koumimine;
t) Zn, AcOH, THF/H2O, 658C, 40 min, 92%; u) HCHO, NaBH3CN, MeOH/CH2Cl2, rt, 40 min, 77%.
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of epoxide 14 was ascertained by X-ray crystallographic
analysis, and the same configuration was analogously assigned
to 11.[19] Treatment of 14 with MABR and DIBAL-H
provided 15 and 17, respectively. Treatment of aldehyde 15
with NIS and K2CO3 in MeOH gave 16. Partial hydrogenation
of the allene unit of 16 and 17 enabled total synthesis of Na-
methyl-16-epipericyclivine[19] and affinisine as well. Unlike
other sarpagine alkaloids, trinervine has a characteristic
oxygenated ethyl group at C20, which can be readily installed
by hydroboration/oxidation of the allene unit. After protec-
tion of the free hydroxyl group and bridge-head nitrogen
atom of 13 as a borane-complexed silyl ether, hydroboration/
oxidation of the allene group via Maꢀs protocol[25] and then
deprotection of the silyl group and decomplexation of borane
with HCl in one step furnished trinervine with good efficiency.
In short, the concise total synthesis of five sarpagine alkaloids
with different substituents at C16 and C20 was accomplished
by simple manipulations of ketone and allene groups from
intermediate 1.
Total Synthesis of Koumine Alkaloids
The reduction and oxidation of the allene unit, as
described above, enabled diversified synthesis of five sarpa-
À
gine alkaloids. Formation of a C20 C7 bond via a biomimetic
Scheme 3. Results of a-allenylation of various ketones. Typical condi-
tions: AgNTf2, pyrrolidine, toluene, 908C.
À
indolyl addition to the allene unit after breakage of the C3 N
bond would allow facile access to koumine alkaloids (Sche-
me 2C). Inspired by Sakaiꢀs work,[26] rupture of the C3 N
À
(Scheme 3).[16] Reaction of 25 or 27 only resulted in complex
reaction mixtures without generation of azabicyclo-
[3.2.1]octane 26 or azabicyclo[2.2.2]octane 28 (Scheme 3B).
To our delight, 29 produced the expected allene 30 in 53%
yield and 6-endo-dig cyclization product 31 in 41% yield
(Scheme 3C). Reaction of 32 provided only the 5-endo-dig
cyclization product 33 in 90% yield (Scheme 3D). A possible
rationale for the successful preparation of 1 via ketone a-
allenylation under the typical conditions is the specific and
rigid architecture of precursor 3.
bond was achieved by treating aldehyde 12 with TrocCl to
provide 2 as a single diastereomer, presumably via a SN2
reaction of water. Although there are a few precedents for
dearomative addition of indole to an allene unit, to the best of
our knowledge, use of this type of reaction in the synthesis of
complex natural products is unknown.[9,27] Upon exposure of 2
to a cationic gold salt formed in situ, indolyl addition to the
À
allene unit occurred and the C20 C7 bond was forged.
Subsequent treatment of 19 with DBU enabled isomerization
of the aldehyde group, and subsequent trapping by the newly
generated hydroxyl group provided hemiacetal 20 as a single
diastereomer. This completed assembly of the core frame-
work of koumine alkaloids. Reaction of 20 with TFA/Et3SiH
reduced the hemiacetal and imine units. Removal of the Troc
group of 21 and then oxidation of 22 installed two imine units
and provided koumimine. Oxidation of 21 and subsequent
removal of the Troc group of 23 generated N-demethylkou-
mine. Finally, reductive methylation of N-demethylkoumine
with HCHO/NaBH3CN delivered koumine in good yield.
Total Synthesis of Sarpagine Alkaloids
Having accessed the key intermediate 1 with ketone and
allene groups on the cage skeleton, the stage was set for the
diversified total synthesis of sarpagine alkaloids (Sche-
me 2B). Corey–Chaykovsky reaction of 1 with Me3SOI as
the ylide precursor afforded epoxide 11 as a single diastereo-
mer in 90% yield. Treatment of 11 with methylaluminum
bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) generated
an epoxide-rearranged product, namely aldehyde 12, whereas Conclusion
treatment with DIBAL-H led to the reductive epoxide-
opening product, that is, alcohol 13. Both 12 and 13 under-
went partial allene hydrogenation to give the natural products
vellosimine and normacusine B in good yields with > 20:1 E/
Z selectivities. Corey–Chaykovsky reaction of 1 with Me3SI as
the ylide precursor generated an epoxide unit with simulta-
neous introduction of a methyl group on the indole nitrogen
atom, to furnish 14 with high efficiency. The stereochemistry
In conclusion, we have developed a tandem sequential
oxidative cyclopropanol ring-opening cyclization and a coop-
erative organo/metal-assisted ketone a-allenylation for build-
ing the bicyclo[3.3.1]nonane and bicyclo[2.2.2]octane skele-
tons, respectively. These two methods enabled assembly of
the caged core framework of sarpagine alkaloids and
installation of two critical functional groups, that is, ketone
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branch point, and by diverse derivatization of the ketone and
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thesis of five sarpagine alkaloids (affinisine, normacusine B,
trinervine, Na-methyl-16-epipericyclivine, and vellosimine)
with various decorating groups was achieved from l-trypto-
phan. As a further extension of the synthetic value of the
allene group, a biomimetic indolyl addition to allene unit after
a skeleton rupture enabled rapid assembly of the koumine
cage scaffold and thus a straightforward synthesis of three
koumine alkaloids (koumine, koumimine, and N-demethyl-
koumine).
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À
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Manuscript received: February 17, 2021
Revised manuscript received: March 24, 2021
Accepted manuscript online: March 29, 2021
Version of record online: && &&
,
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&&&&
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Research Articles
Total Synthesis
Z. Yang, Q. Tan, Y. Jiang, J. Yang, X. Su,
Z. Qiao, W. Zhou, L. He, H. Qiu,
M. Zhang*
&&&& — &&&&
Asymmetric Total Synthesis of Sarpagine
and Koumine Alkaloids
Two key bridged skeleton-forming reac-
tions, namely tandem sequential oxida-
tive cyclopropanol ring-opening cycliza-
tion and ketone a-allenylation, assembled
the cage-shaped sarpagine scaffold. By
late-stage diversifications of the ketone
and allene groups, a concise, collective,
and asymmetric total synthesis of two
classes of indole alkaloids including five
sarpagine alkaloids and three koumine
alkaloids has been accomplished.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!