Unified enantioselective total syntheses of (?)-scholarisine G, (+)-melodinine E, (?)-leuconoxine and (?)-mersicarpine

Article abstract of DOI:10.1039/c8cc09949a

A unified strategy enabled the enantioselective syntheses of (?)-scholarisine G, (+)-melodinine E, (?)-leuconoxine and (?)-mersicarpine from a common 2-alkylated indole intermediate bearing an all-carbon quaternary stereogenic center. The Smith-modified Madelung indole synthesis was used to couple simple o-toluidine with chiral lactone (+)-8, incorporating the key elements for further cyclizations. Lactone (+)-8 was prepared via a palladium-catalyzed intermolecular asymmetric allylic alkylation. The unified and protecting-group-free reaction sequences allowed the synthesis of these alkaloids in a maximum of 10 steps and with high efficiency.

Full text of DOI:10.1039/c8cc09949a

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DOI: 10.1039/C8CC09949A
Journal Name
COMMUNICATION
Unified Enantioselective Total Syntheses of ()-Scholarisine G, (+)-
Melodinine E, ()-Leuconoxine and ()-Mersicarpine
Yao Liu and Honggen Wang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
ABSTRACT:
syntheses of ()-scholarisine G, (+)-melodinine E, ()-leuconoxine have a fused tetracyclic 6/5/6/7 ring system characterized by an
and ()-mersicarpine from common 2-alkylated indole unusual tetrahydro-2H-azepine ring and a hemiaminal motif. The
A
unified strategy enabled the enantioselective quaternary stereogenic centers. ()-Mersicarpine (4),3f however,
a
intermediate bearing an all-carbon quaternary stereogenic center. structural complexity, along with the intriguing bioactivities have
The Smith-modified Madelung indole synthesis was used to couple rendered these alkaloids popular targets in total synthesis.5-8
simple o-toluidine with a chiral lactone (+)-8, incorporating the key Specifically, the biosynthetic interrelationship of these compounds
elements for further cyclizations. The lactone (+)-8 was prepared has inspired several unified synthetic strategies towards their
via
a
palladium-catalyzed intermolecular asymmetric allylic synthesis.6i,7f,8 Nevertheless, only a handful of enantioselective total
alkylation. The unified and protecting-group-free reaction synthesis has been reported.7,8
sequences allowed the synthesis of these alkaloids in a maximum
of 10 steps and high efficiency.
The intrinsic challenge to fulfil an enantioselective total
synthesis lies on the construction of the all-carbon quaternary
stereogenic carbon center.6,9 In 2010, Fukuyama and co-
workers reported the first total synthesis of ()-mersicarpine
(4).7a The key chiral intermediate ketoester (B) was prepared via
an asymmetric Michael addition. Upon 7-step synthetic
O
O
O
H
HO
N
N
N
N
O
N
N
O
O
1
2
3
(-)-leuconoxine
manipulations
including
the
Eschenmoser-Tanabe
(-)-scholarisine G
(+)-melodinine E
fragmentation, Sonogashira cross-coupling reaction and gold-
catalyzed cyclization, a 2-substituted indole (C) with a chiral
quaternary carbon center was assembled, which was further
elaborated to the final product. Intriguingly, in an effort to
synthesize ()-rhazinal, Luo observed an unexpected
N
OH
OH
N
N
N
O
N
N
O
O
H
H
O
5
(-)-leuconolam
4
6
(-)-rhazinilam
(-)-mersicarpine
aziridination/rearrangement/oxidation
tandem
reaction
leading to the total synthesis of ()-mersicarpine (4) based on a
similar alkenylated indole intermediate (D).7d Starting from the
same chiral intermediate (B), Tokuyama and co-workers
accomplished a concise total synthesis of ()-mersicarpine via
the key Fischer indole synthesis and DIBAL-H-mediated
reductive ring-expansion reaction.7b,7c In 2013, Zhu and co-
workers disclosed an enantioselective total synthesis of
leuconolam-leuconoxine-mersicarpine group monoterpene
indole alkaloids8 based on an elegantly integrated
Fig. 1 The leuconolam-leuconoxine-mersicarpine group of alkaloids
The leuconolam-leuconoxine-mersicarpine triads are structurally
complex and biologically interesting Aspido-sperma-derived
monoterpene indole alkaloids (Fig 1).1 Biosynthetically, these natural
products share the same biogenetic origin from vincadifformine,2 but
feature intriguingly different ring connectivities. ()-Scholarisine G
(1),3a,e (+)-melodinine
E
(2)3b and ()-leuconoxine (3)3c-e are
pentacyclic alkaloids
comprising
an
interesting
[5.5.6.6]diazafenestrane core4 with two or three contiguous
oxidation/reduction/cyclization
(iORC)
process.10
The
palladium-catalyzed enantioselective decarboxylative allylation
was utilized to construct the chiral center. The same strategy
was utilized by Liang and Stoltz by employing an optically active
allylated lactone (8),7f prepared from an intramolecular
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China. E-mail: wanghg3@mail.sysu.edu.cn
†
Electronic
supplementary
information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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palladium-catalyzed asymmetric decarboxylative allylic
View Article Online
DOI: 10.1039/C8CC09949A
alkylation of N-benzyloxy cyclic imide (K),11 as key intermediate.
In 2010, Fukuyama et al.7a and in 2017, Luo et al.7d
In 2015, Kawasaki & Higuchi et al.7g
O
OH
MeO2
C
MeO2
C
N
desymmetric
lactamization
OH
R
12 steps
N
asymmetric
Michael addition
O
O
O
O
O
7 steps
3 steps
N
N
N
H
OMe
N
N
Et
2 steps
H
MeO2
C
O
O
B
O
N
O
4
(-)-mersicarpine
CO2Me
A
2 (+)-melodinine E
C
D
: R = H
: R = CH=CHCO2Me
In 2015, Gaich et al.6g,6h,7e
O
O
O
In 2012, Tokuyama et al.7b,7c
HON
Cl
NH
H
N
HO
N
O
O
S
O
O
2 steps
10 steps
CbzN
NH
HO
OH
OEt
reductive ring-
expansion reaction
N
O
OEt
N
3 steps
3 steps
B
N
N
H
H
O
Q
R
1
(-)-scholarisine G
3
(-)-leuconoxine
CO2Me
E
P
F
HO
HO
In 2015, Liang et al.7f
O
In 2013, Zhu et al.8
N3
H2N
N3
enantioselective
O
O
O
O
decarboxylative allylation
6 steps
7 steps
3 steps
O
O
O
BnO
N
O
O
Et
O
O
O
NH2
O
G
H
NO2
CO2Me
CO2Me
NHBoc
CO2Me
8
K
I
J
M
Scheme 1. Reported Enantioselective Total Syntheses of the Leuconolam-leuconoxine-mersicarpine Group Alkaloids
In another vein from Kawasakivia and Higuchi, the phosphoric acid-
catalyzed desymmetric lactamization of prochiral indole-
prepared via a palladium-catalyzed intermolecular asymmetric
allylation developed by Hou.13 The Smith-modified Madelung
indole synthesis would provide a pivotal indole derivative with
the chiral center being installed. The hydroxyl and vinyl
functionality in 10 serve as valuable handles for further
transformation. Therefore, upon proper functional group
manipulation, lactam (13) is expected to be obtained. This
species could be further elaborated to Zhu8 and Dai’s6i
intermediates via oxidation of the indole motif,6a,14 paving the
way for ()-scholarisine G (1) and ()-mersicarpine (4) synthesis,
respectively.
a
substituted diester (O) provided the key enantio-merically enriched
Kerr’s intermediate with moderate ee 74%.7g In 2015, Gaich realized
an enantioselective total synthesis of ()-leuconoxine (3) by
employing a photoinduced domino macrocyclization/transannular
cyclization involving the Witkop cyclization.6g,6h,7e The optically active
precursor (P) was obtained via the diastereoselective alkylation of
ethyl 2-ethylacetoacetate (R) using chiral 1,2-diol (S) as an acetal
chiral auxiliary.
N3
N
O
Our synthesis commenced with the preparation of the allylated
lactone (+)-8 starting from 3-ethyltetrahydro-2H-pyran-2-one
and allyl methyl carbonate (7). In the presence of palladium
catalyst and (R)-DM-BINAP ligand as developed by Hou,13 (+)-(8)
was obtained in 72% yield and 89% ee (Equation 1).
OH
OH
N
N
O
O
(-)-Mersicarpine (4)
Dai's intermediate (13a)
oxidation
OH
N3
O
Smith-modified
Madelung synthesis
(R)-DM-BINAP (5 mol%)
Me
FGI
O
O
+
O
[Pd(C3H5)2]2 (2.5 mol%)
Et
NH2
(1)
cyclization
OCO2Me
+
N
H
N
O
O
9
8
Et
(+)-8
LDA (1.1 equiv), LiCl (2.0 equiv)
THF, -78 oC, 72 %, 89% ee
13
10
O
7
FGI/oxidation
O
O
The key Smith-modified Madelung indole synthesis was started
with the preparation of N-silylated o-toluidine (9a) by reacting
o-toluidine (9) with stoichiometric amount of n-butyllithium
and followed by quenching with chlorotrimethylsilane (Scheme
3). Without isolation, this intermediate was exposed to 2.2
equivalents of sec-butyllithium solution at low temperature to
form a reactive lithium dianion (9b). Upon slow addition of
O
HO
N
N
aldol condensation
2, 3
N
N
O
O
Zhu's intermediate (15)
(-)-Scholarisine G (1)
Scheme 2. Proposed Synthetic Strategy
lactone (+)-8,
a cascade acylation/heteroatom Peterson
The notable feature of Smith-modified Madelung indole
synthesis12 in the construction of 2-quantenary carbon sub-
stituted indole inspired us to explore a novel enantioselective
synthesis of leuconolam-leuconoxine-mersicarpine alkaloids
starting from simple o-toluidine (9) and chiral lactone (8)
(Scheme 2). The latter is commercially available and could be
olefination/isomerization proceeded smoothly to produce the
2-quantenary carbon substituted indole ()-10 in an overall 85%
yield.
2 | J. Name., 2012, 00, 1-3
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O
some other synthetic samples.6i,e,7f We assumed the differences can
View Article Online
O
Me
Et
nBuLi(1.01 equiv)
sBuLi(2.2 equiv)
Li
Li
(+)-8
Me
DOI: 10.1039/C8CC09949A
be a result of different quality, therefore different acidity of CDCl3
N
NH
used for NMR studies.16
then TMSCl(1.01 equiv)
NH2
TMS
TMS
9
9a
9b
OH
N3
DPPA (1.02 equiv)
DIAD (1.2 equiv)
OLi
OLi
OH
BH3SMe2 (1.1 equiv), THF, 0 o
C
heteroatom - Peterson
olefination
isomerization
protonation
then NaOH, H2O2, 0 oC, 71%
PPh3 (1.2 equiv)
THF, 0 oC, 98 %
N
H
N
H
- Me3SiO
N
N
H
NLi O
TMS
(-)-10
(+)-11
N3
oxone (2.4 equiv)
EDTA (0.1 equiv)
TBAS (0.1 equiv)
9c
9d
(-)-10
N3
NMO (3.0 equiv)
TPAP (5 mol%)
Scheme 3. Smith-modified Madelung Synthesis
N
H
4 Å, MeCN, rt, 68%
NaHCO3 (17.0 equiv)
N
MeCN/ H2O/ acetone, 0 o
C
(-)-12
O
HO
(+)-13
The hydroxyl group in indole ()-10 was then replaced by azido
in good yield via a Mitsunobu reaction in the presence of
N3
N
O
OH
PPh3 (2.0 equiv)
diisopropyl azodiformate (DIAD), triphenylphosphine
and
OH
N
O
THF, H2O, rt
64%
N
diphenylphosphonic azide (DPPA) (Scheme 4). The maintaining
o
O
of low temperature (0 C) is crucial for this step as a higher
4
)
(-)-Mersicarpine (
13a
temperature (room temperature) led to significant amount of
intramolecular nitrogen alkylation product. Following
Scheme 4. Syntheses of (-)-Mersicarpine
a
hydroboration/oxidation of the C=C bond, the azidoindole (+)-
11 was converted to ()-12 in good efficiency (71% yield).
Exposure of ()-12 to Ley oxidation15 (TPAP and NMO, at rt)
resulted in an intramolecular N-acylation reaction to afford N-
acyl indole (+)-13 in 68% yield. With (+)-13 in hand, we next
explored the synthesis of ()-mersicarpine (4). Previous studies
indicated that 2-substituted indole could be easily oxidized with
various oxidants to form a keto hemiaminal structure.14 Indeed,
subjection of (+)-13 to Kerr’s conditions6a (oxone, acetone)
afforded the desired keto hemiaminal (13a). Upon the in-situ
treatment with PPh3, 13a underwent Staudinger-aza-Wittig
cyclization to give (-)-Mersicarpine (4) in 64% yield over two
steps. It should be noted the same intermediate 13a has been
obtained in Dai’s (±)-mersicarpine synthesis via a Witkop-
Winterfeldt oxidative cleavage of an advanced indole structure.
O
oxone (2.4 equiv)
EDTA (0.1 equiv)
TBAS (0.1 equiv)
N3
THF+H2O, rt
NH
PPh3 (1.2 equiv)
then Ac2O (1.5 equiv)
NaHCO3 (17.0 equiv)
N
N
MeCN/ H2O/ acetone, 0 o
C
DIPEA, DCM, rt, 88%
O
(+)-13
O
(+)-14
O
O
O
NH
O
HO
N
N
TFA/DCM 1:1
O
LDA (3.0 equiv)
OH
THF, -78 o
77%
C
rt
N
N
N
65%
O
O
O
1
)
(+)-15
(-)-Scholarisine G (
14a
O
O
H
N
N
Burgess Reagent (2.5 equiv)
Pd/C, H2, MeOH, rt
94%
CH3CN, 70 o
99%
C
N
N
O
O
3
(-)-leuconoxine (
)
2
(+)-Melodinine E (
)
Scheme 5. Synthesis of ()-Scholarisine G, (+)-Melodinine E and ()-Leuconoxine
The azide intermediate (+)-13 could also be converted to leuconoxine
family alkaloids (Scheme 5). Thus, (+)-13 was first reduced with
triphenylphosphine and then acetylated by a follow-up treatment
with acetic anhydride to give acetamide (+)-14. Under similar indole
oxidation conditions with oxone as described above, the keto
hemiaminal 14a was produced. Without isolation, 14a was converted
under acidic conditions to Zhu’s intermediate (+)-15 for their
leuconolam-leuconoxine indole alkaloid syntheses in 65% yield over
two steps. An LDA-promoted intramolecular aldol cyclization
provided leuconoxine in a good yield of 77%. Previously, mesylation
In
conclusion,
we
have
accomplished
divergent
enantioselective syntheses of four monoterpene indole
alkaloids: ()-scholarisine G (1), (+)-melodinine E (2), ()-
leuconoxine (3) and ()-mersicarpine (4). The syntheses feature
a palladium-catalyzed intermolecular asymmetric allylation to
construct a optically active lactone, a Smith-modified Madelung
indole synthesis to quickly forge
a quaternary carbon-
substituted indole, and an oxone-mediated indole oxidation to
form Dai’ and Zhu’s intermediates, respectively. Efforts were
also attempted to improve the synthetic efficiency of
transforming Zhu’s intermediates (15) to the leuconoxine group
alkaloid. No protecting group is needed for the whole processes,
al-lowing concise syntheses of the title natural products in a
maximum of 10 steps with high efficiency.
of the tertiary hydroxyl group in ()-scholarisine G (1) followed by
base-promoted elimination was used to prepare (+)-melodinine E (2).
We found that higher efficiency could be obtained when treating ()-
scholarisine G (1) with Burgess reagent (2.5 equiv) in acetonitrile at
70 oC. Finally, hydrogenation of (+)-melodinine E (2) delivered
another member ()-leuconoxine (3) in 94% yield. The spectroscopic
data of (+)-melodinine E (2) and ()-leuconoxine (3) (1H and 13C NMR)
matched well those reported in the literature. Interestingly, the NMR
Acknowledgement
Generous financial support from the Key Project of Chinese
National Programs for Fundamental Research and Develop-
spectra of our synthetic ()-scholarisine G (1) matches with that of
Zhu,8a but shows discrepancies with the isolated samples3a,e and ment (2016YFA0602900), the National Natural Science Foun-
This journal is © The Royal Society of Chemistry 20xx
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Wang, J. Zhu, J. Am. Chem. Soc., 2014, 136, 15102; (c) C.
dation of China (21472250), and the "1000-Youth Talents Plan"
are gratefully acknowledged.
Piemontesi, Q.Wang, J. Zhu, Angew. Chem. Int.VEiedw.A2rt0ic1le6O,n5lin5e,
DOI: 10.1039/C8CC09949A
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Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CC09949A
O
HO
N
N
O
O
1
(-)-scholarisine G
N
OH
N
O
Smith-modified
Madelung synthesis
Me
O
2
(+)-melodinine E
O
+
Et
(+)-8
NH2
N
H
O
9
H
N
(-)-10
N
O
N
OH
3
(-)-leuconoxine
N
O
4
(-)-mersicarpine
A unified strategy enabled the enantioselective syntheses of ()-scholarisine G, (+)-melodinine E, ()-
leuconoxine and ()-mersicarpine from a common 2-alkylated indole bearing an all-carbon quaternary
stereogenic center.