Asymmetric total synthesis of Apocynaceae hydrocarbazole alkaloids (+)-deethylibophyllidine and (+)-limaspermidine

Article abstract of DOI:10.1021/jacs.5b01926

An unprecedented asymmetric catalytic tandem aminolysis/aza-Michael addition reaction of spirocyclic para-dienoneimides has been designed and developed through organocatalytic enantioselective desymmetrization. A unified strategy based on this key tandem

Full text of DOI:10.1021/jacs.5b01926

Article
pubs.acs.org/JACS
Asymmetric Total Synthesis of Apocynaceae Hydrocarbazole
Alkaloids (+)-Deethylibophyllidine and (+)-Limaspermidine
Ji-Yuan Du,† Chao Zeng,† Xiao-Jie Han,† Hu Qu,† Xian-He Zhao,† Xian-Tao An,† and Chun-An Fan*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222
Tianshui Nanlu, Lanzhou 730000, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An unprecedented asymmetric catalytic tandem
aminolysis/aza-Michael addition reaction of spirocyclic para-
dienoneimides has been designed and developed through organo-
catalytic enantioselective desymmetrization. A unified strategy based
on this key tandem methodology has been divergently explored for
the asymmetric total synthesis of two natural Apocynaceae alkaloids,
(+)-deethylibophyllidine and (+)-limaspermidine. The present
studies not only enrich the tandem reaction design concerning the
asymmetric catalytic assembly of a chiral all-carbon quaternary
stereocenter contained in the densely functionalized hydrocarbazole
synthons but also manifest the potential for the application of the
asymmetric catalysis based on the para-dienone chemistry in
asymmetric synthesis of natural products.
be one of the key issues in the asymmetric synthesis of
structurally related hydrocarbazole alkaloids.
INTRODUCTION
The alkaloids with a densely functionalized hydrocarbazole
scaffold (Figure 1), which are widely present in many natural
■
Importantly, the catalytic asymmetric construction of a chiral
all-carbon quaternary stereocenter, especially embedded in the
synthetically interesting, multifunctionalized building blocks, is
one of the most challenging and dynamic research areas in
modern organic synthesis.4 Recently, by focusing on the
enantioselective assembly of the hydrocarbazole-containing
subunits I (Scheme 1), several asymmetric catalytic methods
have been elegantly developed on the basis of Heck
cyclization,5a−d [4 + 2] cycloaddition,5e−g formal [4 + 2]
cycloaddition,5j,k formal [3 + 3] cycloaddition,5h,i and Fischer
indolization,5l tactically showing the direct approach for the
simultaneous formation of a C−C bond centered on the chiral
quaternary carbon atom. To our knowledge, however, the
strategy of enantioselective desymmetrization6 has still not
been explored in the installation of functionalized hydro-
carbazoles I, wherein the indirect approach for accessing such a
stereogenic center from the prochiral quaternary carbon atom
would be involved. To address this point, particularly associated
with potential for use in the synthesis of hydrocarbazole
alkaloids (Figure 1), a highly functionalized new hydro-
carbazole synthon A (Scheme 1) is conceived in terms of the
general model I. Stimulated by accessing such an intriguing
tricyclic building block A as well as recent progress in para-
dienone chemistry,7−10 an unprecedented asymmetric catalytic
tandem aminolysis/aza-Michael addition11 (Scheme 1) could
Figure 1. Selected members of hydrocarbazole alkaloids.
sources, constitute one structurally unique class of plant-derived
nitrogen containing natural products.1 Because of their high
structural diversity and various biological properties,2 some of
these alkaloids have become attractive targets for synthetic
chemists to develop the methodologies and strategies in
synthesis design over the past half century.3 Chemically, from a
synthetic point of view, how to expeditiously establish such a
privileged functionalized hydrocarbazole nucleus I with the
crucial C4a all-carbon quaternary stereocenter (Figure 1) would
Received: February 24, 2015
© XXXX American Chemical Society
A
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Scheme 1. Design for the Asymmetric Synthesis of
Functionalized Hydrocarbazole Units with All-Carbon
Quaternary Stereocenter
Scheme 2. Retrosynthetic Analysis
According to these retrosynthetic considerations (Scheme 2),
the target-oriented model using spirocyclic para-dienoneimide
1a as substrate and benzylamine 2a as nucleophilic initiator was
then set up for our synthetic studies (Scheme 3). On the basis
of the bifunctional catalysis mode involving Brønsted acid and
base,14 a series of amine thiourea catalysts (4a−4d, 4f−4h, and
4j−4k) as well as its analogues (4e and 4i) were evaluated for
be designed in connection with our previous exploration of
tandem alcoholysis/oxa-Michael addition in the formal syn-
thesis of morphine.9f Strategically, this methodology design
could provide a new synthetic consideration for the multi-
functionalized hydrocarbazole synthon A with the crucial C4a
all-carbon quaternary stereocenter.
Scheme 3. Model of the Key Asymmetric Tandem Reaction
RESULTS AND DISCUSSION
■
To explore such topics driven by natural product synthesis, two
representative Apocynaceae hydrocarbazole alkaloids, (+)-dee-
thylibophyllidine1c,12 (also known as desethylibophyllidine)
and (+)-limaspermidine,1c,13 are selected as targets in this case.
Considering the occurrence of the common hydrocarbazole
core, a unified retrosynthetic analysis could be evolved to show
the divergent strategy (Scheme 2). For (+)-deethylibophylli-
dine, the unsaturated ester moiety in its ring C could be
stepwise introduced by chemoselective imine-forming oxidation
of arylamine unit and subsequent carboalkoxylation from the
synthon C-1, which could be accessed by the reduction of
synthon D-1. For (+)-limaspermidine, the 2-hydroxyethyl
group in its fused ring C/D system could arise from the
reduction of synthon C-2, which could be installed by a
deconjugative alkylation of enone moiety of synthon D-2.
Retrosynthetically, the structurally unified synthons D-1 and D-
2 could be generally elaborated from the common tricyclic
hydrocarbazole synthon A″ by using stereoselective intra-
molecular aza-Michael addition for the formation of ring E and
regioselective olefin oxidation/intramolecular aldol condensa-
tion for the forging of ring D. Followed by this methodology
design (Scheme 1), a key asymmetric catalytic tandem
aminolysis/aza-Michael addition of spirocyclic para-dienone
synthon B″ could be strategically envisioned for the
enantioselective construction of crucial functionalized hydro-
carbazole building block A″.
B
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this asymmetric tandem reaction at 25 °C in the optimized
solvent of PhCl.15 In terms of the enantioselectivity and
reactivity of the current model, the chiral tertiary amine
thiourea 4a,16 which was derived from the structural
combination of a rigid chiral cyclohexanediamine framework
bearing a pyrrolidine moiety with an achiral N-thiourea
substituent, gave the optimum results for the formation of
the desired hydrocarbazole 3aa17−19 with 94% ee in 51% yield.
Encouraged by the positive result obtained, we then focused
our preliminary efforts on the exploration of the generality of
substrate scope in this key tandem aminolysis/aza-Michael
addition (Table 1). First, to probe the structure influences of
ycarbonyl and phenylsulfonyl) were also investigated. Analo-
gously, the tandem reaction of 1i (R1 = H, R2 = 1-
adamantoxycarbonyl) with benzylamine 2a (R3 = PhCH2)
under the standard conditions could deliver the product 3ia in
48% yield with 93% ee. Interestingly, while employing 1j (R1 =
H, R2 = phenylsulfonyl) as substrate in the presence of
benzylamine 2a (R3 = PhCH2) under the optimized conditions,
an enhanced reactivity for the formation of hydrocarbazole
product 3ja in 60% yield was observed with a significantly
shortened reaction time of 2 h. To our surprise, however, no
enantiodiscrimination in this case was achieved,20 clearly
indicating the fact that the increased chemical stability of
achiral N-aryl sulfonamide anion, generated in situ from the
initial aminolysis of tandem reaction, resulted in an
unexpectedly negative impact to the enantiocontrol in the
subsequent intramolecular aza-Michael addition.
Table 1. Generality of Enantioselective Tandem Aminolysis/
a,b
Aza-Michael Addition
In addition to the evaluation of para-dienoneimides as
substrates, various nucleophilic amines were also investigated.
Compared with benzylamine 2a (R3 = PhCH2), it was found
that a series of benzylamine analogues 2b−2g (R3 = allyl,
propargyl, 4-methoxybenzyl, 4-bromobenzyl, 1-naphthalenyl-
methyl, and 2-furanylmethyl) also could be effective in the
current enantioselective tandem aminolysis/aza-Michael addi-
tion, affording the expected products 3ab−3ag in reasonable
yields with high enantioselectivities of up to 96% ee.19 Notably,
while using homobenzylamine 2h (R3 = PhCH2CH2) as a one-
carbon homologue of 2a (R3 = benzyl) in this reaction, a
decreased enantioselectivity was observed in the formation of
product 3ah (82% ee). When the aliphatic amine 2i (R3 =
cyclohexylmethyl) as a fully hydrogenated analogue of 2a (R3 =
benzyl) was subjected to the present tandem reaction, a lower
level of enantiocontrol for 3ai (56% ee) was detected
analogously.
Having primarily developed this unprecedented key tandem
methodology proposed in the retrosynthetic analysis (Scheme
2), we then focused our attention to probe such target-oriented
synthesis, which could be strategically based on the unique
multifunctionalized hydrocarbazole 3ab19 (Table 1) that
resulted from our asymmetric organocatalytic tandem ami-
nolysis/aza-Michael addition reaction. To access the structur-
ally unified synthons D-1 and D-2 (Scheme 2), as shown in
Scheme 4, a divergent approach to the pentacyclic building
blocks 7a and 7b was therefore developed. Commenced with
the tricyclic carbazole 3ab (90% ee), the base-promoted
intramolecular aza-Michael addition could smoothly deliver the
versatile tetracyclic precursor 5 in 85% yield in a diastereomeri-
cally defined manner. Divergently, the aldehydes 6a and 6b
could be selectively obtained from 5 by ozonolysis and
palladium-catalyzed anti-Markovnikov oxidation,21 respectively.
Particularly, it should be noted that the transformation of 5 to
6b under the hydroboration/oxidation conditions (BH3·THF/
H2O2) only gave a complicated reaction mixture. Subsequently,
the assembly of enone moiety by intramolecular aldol
condensation of 6a and 6b afforded the pentacyclic
intermediates 7a and 7b, respectively, which could be further
elaborated for the asymmetric synthesis of (+)-deethylibophyl-
lidine and (+)-limaspermidine.
a
Performed with 1a−1j (0.05 mmol) and 2a−2i (0.25 mmol) in the
presence of catalyst 4a (0.005 mmol) in PhCl (1.0 mL) at 25 °C. The
yields refer to the isolated products, and the ee’s were determined by
chiral high-performance liquid chromatography (HPLC) analysis.
b
The absolute configuration of 3ab was established by X-ray
crystallographic analysis of a later-stage pentacyclic intermediate 9
(Scheme 5), and accordingly the reaction enantioselectivity in other
cases was assigned by analogy. PMB = 4-methoxybenzyl, PBB = 4-
bromobenzyl.
para-dienoneimides, a variety of N-Boc-protected substrates
1a−1h having different substituents (R2 = Boc, R1 = H, OMe,
Me, Cl, Br, and 1,3-butadiene-1,4-diyl) on the phenyl ring were
examined by using benzylamine 2a (R3 = PhCH2) as
nucleophile under the optimized conditions, leading to the
desired hydrocarbazole products 3aa−3ha in moderate to good
yields with good to high enantioselectivities of up to 95% ee.
Compared with these N-Boc-protected cases (R2 = Boc) in
para-dienoneimides, two additional examples 1i−1j having
different N-substituted groups (R1 = H, R2 = 1-adamantox-
As a member of the Apocynaceae alkaloids, (+)-deethylibo-
phyllidine was originally isolated from the bark of Taber-
naemontana albiflora and Anacampta disticha in 1980,12 and its
biogenetic pathway has been illuminated from tryptamine and
secologanin.22 Over the past three decades, since the
pioneering synthetic study by Kuehne in 1981, the chemical
C
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9, followed by LiAlH4-mediated amide reduction, furnished the
reductive product 10 in 75% yield over two steps. The
chemoselective Swern oxidation of secondary arylamine motif
in 10 resulted in the formation of imine intermediate 11, which
sequentially underwent the further methoxycarbonylation/
enamine tautomerization in the presence of lithium diisopropyl
amide (LDA) and Mander’s reagent, giving the final desired
(+)-deethylibophyllidine in 34% yield over two steps. The
NMR spectroscopic data are identical to those from previous
racemic syntheses,12,23e and the specific rotation of our
synthetic (+)-deethylibophyllidine ([α]2D0 = +413 (c = 1.0,
MeOH)) was consistent with the reported value.12 Importantly,
the absolute configuration of (+)-deethylibophyllidine was
unambiguously confirmed by our first enantioselective total
synthesis.
Scheme 4. Divergent Synthesis of Pentacyclic Building
Blocks 7a and 7b
a
To further explore the synthetic diversity of tandem
methodology, we then pursued our current studies in an effort
toward the asymmetric synthesis of another member of the
Apocynaceae alkaloids, (+)-limaspermidine, which was initially
isolated from the trunk bark of a small Venezuelan tree A.
rhombeosignatum MARKGRAF in 1979.13 Biologically, its
synthetic pathway is also associated with tryptamine and
secologanin.22 Regarding its chemical synthesis in racemic
form, efforts have been devoted to the strategies featured by
Ban’s N-acyliminium cyclization/aldol condensation,25a−c
Overman’s aza-Cope rearrangement/Mannich cyclization,25d
Banwell’s Raney-cobalt-mediated tandem reductive cycliza-
tion,25f and Qiu’s Diels−Alder cycloaddition.25g Recently, the
chiral synthesis of its non-natural enantiomer was revealed by
Shao on the basis of asymmetric palladium-catalyzed
decarboxylative allylation.26 Our enantioselective synthesis of
(+)-limaspermidine, as outlined in Scheme 6, commenced with
a
Conditions: (a) NaOH (aq.), THF; (b) O3, CH2Cl2, then Me2S; (c)
p-TsOH, PhH; (d) Pd(MeCN)2Cl2, CuCl, O2, HMPA, (CH2Cl)2.
routes for the racemic synthesis of deethylibophyllidine have
been mainly developed on the basis of [4 + 2] cyclo-
addition,23a,b,g [3 + 2] cycloaddition,23h crisscross annula-
tion,23d,f and Fischer indolization/Pummerer rearrange-
ment.23c,e However, it should be noted that there is still no
report on its asymmetric synthesis. Our chiral synthesis of
(+)-deethylibophyllidine, as shown in Scheme 5, began with a
Scheme 5. Asymmetric Synthesis of
(+)-Deethylibophyllidine
Scheme 6. Asymmetric Synthesis of (+)-Limaspermidine
the acidic removal of the N-Boc group of the structurally
unified synthon 7b, readily producing arylamine 12 (90% ee) in
96% yield. To further enhance its optical purity, amine 12 (90%
ee) was readily recrystallized to yield an enantiomerically
enriched amine 12 (99% ee, 79% yield). After the N-
benzylation of 12 with BnBr/K2CO3 in 99% yield, amide 13
was subjected to a three-step protocol involving sequential
enone/amide reduction and Swern oxidation, giving the tertiary
amine 14 in 66% yield over three steps. Unfortunately, the
attempts for direct chemoselective reduction of the amide
highly stereoselective hydrogenation of pentacyclic building
block 7a, giving the functionalized ketone 8 in almost
quantitative yield. The subsequent acidic deprotection of the
N-Boc group afforded the amine 9 (90% ee) in 85% yield, and
pleasingly its enantiopurity could be further enhanced through
a homochiral crystallization to provide an optically pure amine
9 (99% ee, 75% yield), thereby leading to a definite assignment
of absolute stereochemistry of its hydrocarbazole skeleton by X-
ray crystallography.24 The Wolff−Kishner ketone reduction of
D
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group in the presence of the enone moiety failed.27 With the
enone intermediate 14 in hand, a deconjugative C-alkylation
with methyl bromoacetate in the presence of t-BuOK/t-BuOH
straightforwardly released the advanced precursor 16 in 45%
yield, in which an additional all-carbon quaternary stereocenter
was stereospecifically assembled on the rigid pentacyclic
framework. Then, the smooth transformation of ketone 15 to
olefin 16 was implemented in 73% yield by Bamford−Stevens
reaction. Notably, the resulting alkene units in 16 allow for the
possibility of future application in the synthesis of some other
structurally related Aspidosperma and Strychnos alkaloids and
analogues. Following a three-step sequence involving olefin
hydrogenation, ester reduction, and reductive debenzylation,
the asymmetric synthesis of (+)-limaspermidine could be
accomplished in 93% yield from intermediate 16. The absolute
configuration of our synthetic (+)-limaspermidine ([α]2D0 = +32
(c = 0.5, CHCl3)) was also confirmed by single-crystal X-ray
crystallography,24 and the NMR spectroscopic characteristics
were in accord with those reported in the literature.25d,f,g,26
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CONCLUSION
■
In conclusion, driven by the asymmetric synthesis of hydro-
carbazole alkaloids, an unprecedented enantioselective catalytic
tandem aminolysis/aza-Michael addition of spirocyclic para-
dienoneimides has been designed and developed under
bifunctional catalysis on the basis of enantioselective
desymmetrization, providing a new method for the expeditious
assembly of multifunctionalized hydrocarbazole building blocks
bearing the crucial all-carbon quaternary stereocenter. On the
basis of this key asymmetric tandem methodology, the chiral
total synthesis of two Apocynaceae alkaloids, (+)-deethylibo-
phyllidine and (+)-limaspermidine, has been preliminarily
explored, manifesting the potential in the first enantioselective
synthesis of such natural products. The present studies not only
chemically enrich the tandem reaction design concerning the
asymmetric catalytic construction of a chiral all-carbon
quaternary stereocenter embedded in the synthetically useful
functionalized hydrocarbazole building blocks but also
strategically illustrate a potential of asymmetric catalysis based
on para-dienone chemistry in the asymmetric synthesis of
architecturally related hydrocarbazole alkaloids.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. X-ray data for
compound 9 and the synthetic (+)-limaspermidine (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*fanchunan@lzu.edu.cn
Notes
The authors declare no competing financial interest.
Fischer indolization, see: (l) Martínez, A.; Webber, M. J.; Muller, S.;
̈
List, B. Angew. Chem., Int. Ed. 2013, 52, 9486.
ACKNOWLEDGMENTS
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We are grateful for financial support from NSFC (21322201,
21290180), PCSIRT (IRT1138), FRFCU (lzujbky-2013-ct02),
and the 111 Project of MOE (111-2-17).
E
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