Total synthesis of Akuammiline alkaloid (-)-vincorine via intramolecular oxidative coupling

Article abstract of DOI:10.1021/ja303602f

An asymmetric total synthesis of the Akuammiline alkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key steps include Pd-catalyzed direct C-H functionalization of indole derivatives, organocatalyzed asymmetric M

Full text of DOI:10.1021/ja303602f

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Communication
Total synthesis of Akuammiline alkaloid (-)-
vincorine via intramolecular oxidative coupling
Weiwei Zi, Weiqing Xie, and Dawei Ma
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja303602f • Publication Date (Web): 22 May 2012
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Total Synthesis of Akuammiline Alkaloid (-)-Vincorine via
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Intramolecular Oxidative Coupling
Weiwei Zi, Weiqing Xie and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
Supporting Information Placeholder
In our previous work, we achieved the first asymmetric total
synthesis of (ꢀ)ꢀcommunesin F via formation of the spiroꢀ
ABSTRACT: An asymmetric total synthesis of Akuammiline
alkaloid (ꢀ)ꢀvincorine (18 steps from 5ꢀmethoxytryptamine,
5% overall yield) is described. The key steps include Pdꢀ
catalyzed direct CꢀH functionalization of indole derivatives,
organocatalyzed asymmetric Michael addition of aldehydes to
alkylidene malonates, as well as intramolecular oxidative couꢀ
pling between indole and malonate moieties.
indoline intermediate 8 through an intramolecular oxidative
coupling of 3ꢀsubstituted indole 7 (Figure 2).10 As an extenꢀ
sion of this work, we designed another type of intramolecular
oxidative coupling11 by using compounds 9 as the substrates,
in which the coupling might occur between indole and maloꢀ
nate moieties. If this reaction worked, we would be able to obꢀ
tain tricyclic intermediates 10, which could be used for synꢀ
thesizing vincorine and related alkaloids.
3,4aꢀDisubstitutedꢀ2,3,4,4aꢀtetrahydroꢀ1Hꢀcarbazoleꢀ4ꢀ
carboxylic acid methyl ester (1) and its heteroatom captured
form (2) are highly congested polycyclic ring systems,1 which
are common skeletons for Akuammilineꢀtype alkaloids, such as
strictamine (3),2 scholarisine A (4),3 vincorine (5)4 and aspidoꢀ
phylline A (6).5 Because of their interesting biological activity
and inspiring architecture, these alkaloids have garnered conꢀ
siderable interest in the synthetic community.6ꢀ9 In 2009, Qin
group completed the first total synthesis of (±)ꢀvincorine,7 in
which their intramolecular cyclopropanation and subsequent
ringꢀopening strategy was employed for elaborating a key triꢀ
cyclic intermediate. Quite recently, Garg and coworkers reꢀ
ported the total synthesis of (±)ꢀaspidophylline A by utilizing
the interrupted Fischer indolization reaction as a key step,8 and
Smith group disclosed an elegant synthesis of (+)ꢀscholarisine
A that is featured with a reductive cyclization cascade to form
the cageꢀshaped tricyclic intermediate.9
Figure 2. Two types of intramolecular oxidative coupling pathꢀ
ways
TBSO
BocN
HN
TBSO
BocHN
21
4N
Me
Me
Me
Me
N
N
2
H
15
H
H
15
7
7
16
CO2Me
16
CO2Me
CO2Me
H
H
CO2Me
OMe
(-)-Vincorine ( )
OMe
OMe
12
11
5
MeO2C
Boc
CO2Me
CHO
MeO2C
CO2Me
OTBS
16
H
N
N
15
+
MeO
7
MeO
SeAr
NHBoc
NHBoc
13
Figure 1. Representative Akuammiline alkaloids and their comꢀ
mon carbazole carboxylate skeleton
14
15
(Ar = 2-NO2C6H4)
Figure 3. Retrosynthetic analysis for (ꢀ)ꢀvincorine (5)
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With this idea in mind, we proposed a retrosynthetic analyꢀ
sis for (ꢀ)ꢀvincorine as shown in Figure 3. Disconnection of
the N4ꢀC21 bond of (ꢀ)ꢀvincorine would give rise to aminal
intermediate 11, which could be derived from carbazole carꢀ
boxylate 12. The latter could be accessed from 13 via the type
II oxidative coupling pathway, while olefin 13 could be conꢀ
structed via an organocatalyzed Michael addition12 of aldeꢀ
hyde 15 to alkylidene malonate 14 and subsequent transforꢀ
mations.
OꢀTMS protected diphenylprolinol 19 in MeCN at 0 C for 3
days. In this case, the desired Michael adduct 20 were isolated
with 75% yield as a diastereomeric mixture in a ratio of 5:1.
After failing to increase diastereoselectivity by changing solꢀ
vents, reaction temperatures and catalysts, we decided to use
this mixture for further conversion. Accordingly, oxidation of
the aryl selenide part in 20 followed by Et3Nꢀmediated elimiꢀ
nation produced olefin 21 as a mixture of Eꢀ and Zꢀisomers.
The ratio was about 1.7:1, which could be enhanced to 30:1 by
exposing on UV light (360 nm) for 16 hours. Noteworthy is
that using both bases and acids as catalysts for this isomerizaꢀ
tion failed to give any satisfactory results. Unfortunately, the
ee value of 21 was only 64% (enantiomer ratio was about
82:18) as determined by chiral HPLC. This probably origiꢀ
nates from moderate diastereoselectivity at the C15 position
during the formation of 20. Next, reduction of the aldehyde 21
and protection the resultant alcohol with TBS delivered 22 in
84% yield. Finally, selective removal of the Boc protecting
group in indole part15 was achieved by treatment with silica
gel at low pressure to furnish 13 with 73% yield.
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Scheme 1
Boc
H
N
N
CO2Et
a, b
c, d
71%
81%
MeO
NHBoc
MeO
MeO
NH2
16
17
MeO2C
Boc
CO2Me
Boc
N
e, f
g
N
OH
NHBoc
77%
MeO
75%
NHBoc
18
14
MeO2C
Boc
CO2Me
MeO2C
Boc
CO2Me
CHO
With the diester 13 in hand, we attempted the crucial intraꢀ
molecular oxidative coupling (Scheme 2). Deprotonation of 13
with two equivalent LHMDS, followed by adding a solution of
iodine at ꢀ78 oC only gave the desired coupling product 23 in a
low yield (<10%).10a Since most of the starting material was
recovered in this case, we decided to improve the yield by inꢀ
creasing reaction temperature at oxidative coupling step. Forꢀ
tunately, when coupling reaction was carried at ꢀ40 oC, 23 was
isolated in 67% yield as a single isomer. At a higher temperaꢀ
ture the reaction yield dropped dramatically. Other oxidants
such as NIS, Cu(II) salts and Fe(III) salts11a,11d were found to
be less effective for this transformation.
15
h, i
94%
MeO
N
CHO
N
MeO
20
21
SeAr
NHBoc
NHBoc
j, k
84%
Ar = 2-NO2C6H4
Ph
Ph
OTMS
N
H
19
MeO2C
CO2Me
OTBS
R
N
MeO
Scheme 2
NHBoc
22: R = Boc
13: R = H
l, 74%
Reagents and conditions: a) (Boc)2O, cat. DMAP, CH2Cl2; b)
Pd(OAc)2, ethyl acrylate, tꢀBuO2Bz, 1,4ꢀdioxane/AcOH, 70 oC; c)
Pd/C, H2 (1 atm), THF/MeOH; d) DibalꢀH, THF, ꢀ78 to ꢀ40 oC; e)
IBX, ethyl acetate, reflux; f) dimethyl malonate, cat. proline,
o
DMSO, r.t.; g) cat. 19, 15, CH3CN, 0 C, 3 days; h) m-CPBA,
THF, ꢀ78 oC to r.t., Et3N workup; i) UV light (360 nm); j) NaBH4,
MeOH, ꢀ78 to 0 oC; k) TBSCl, imidazole, DMF; l) silica gel, 70
oC, 0.2ꢀ0.3 mmHg
Our synthesis started from the preparation of the oxidative
coupling precursor 13 as outlined in Scheme 1. After protecꢀ
tion of commercially available 5ꢀmethoxyꢀtryptamine 16 with
(Boc)2O, the resultant 1,3,5ꢀtrisubstituted indole was subjected
to direct CꢀH functionalization via a palladiumꢀcatalyzed
alkenylation13 to afford 1,2,3,5ꢀtetrasubstituted indole 17 in
71% overall yield. Hydrogenation of the CꢀC double bond of
17 and subsequent reduction the ester group with DibalꢀH
provided alcohol 18. Oxidation of 18 with IBX gave an aldeꢀ
hyde, which was condensed with dimethyl malonate14 to proꢀ
duce the alkylidene malonate 14. According to our proposed
retrosynthetic analysis, we planned to introduce a side chain
via organocatalyzed Michael addition of the aldehyde 15 to
14.12 This seemed to be a challenging work because both aldeꢀ
hyde and Michael acceptor are much more complicated than
those reported by Córdova and coworkers.12a After some exꢀ
perimentations, we were pleased to find that the best results
could be obtained by treating 14 and 15 under the catalysis of
Reagents and conditions: a) LHMDS, I2, THF, ꢀ40 oC to r.t.; b)
KCN, H2O, DMF, 100 C; c) Ph3PCl2, CH2Cl2; d) TMSOTf, 2,6ꢀ
lutidine, CH2Cl2, r.t.; e) K2CO3, KI, CH3CN, 60 C; f) 37% aq.
o
o
HCHO, NaBH3CN, CH3CN, AcOH.
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Experimental procedures and compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
7
Corresponding Author
8
9
madw@mail.sioc.ac.cn
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12
13
ACKNOWLEDGMENT
The authors are grateful to National Basic Research Program of
China (973 Program, grant 2010CB833200), Chinese Academy of
Sciences and the National Natural Science Foundation of China
(grant 21132008 & 20921091) for their financial support.
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Figure 4. The favored conformation during the oxidative coupling
The stereochemical outcome during the formation of 23
could be explained through two chairlike transitionꢀstates as
depicted in Figure 4. In the transitionꢀstate B, the strong repulꢀ
sion between the axial ester group and the indole moiety preꢀ
vents path b. Thus, the coupling reaction undergoes through
the transitionꢀstate A to create the quaternary carbon center
and set the desired stereochemistry.
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ring. Accordingly, removal of one methyl ester at the C16 poꢀ
sition under Krapcho’s reaction conditions16 gave 11 in 65%
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material. Next, the TBS protected hydroxyl group in 11 was
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with the assistance of KI to provide 25, whose structure was
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25 with HCHO and NaBH3CN to furnish (ꢀ)ꢀvincorine (5) in
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diastereoselectivity in the organocatalyzed Michael addition,
23.6
the optical rotation ([α]D
= ꢀ93.1, c = 0.65, EtOH) of our
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8877.
synthetic vincorine was somewhat lower than that reported for
natural product ([α]D20.0 = ꢀ139, c = 1.0, EtOH).4b
In conclusion, we have developed an efficient approach for
synthesizing (ꢀ)ꢀvincorine. This protocol allows the assembly
of the target molecule through 18 steps from the commercially
available 5ꢀmethoxytryptamine with an overall yield of 5%.
The key elements in this synthesis include using two newlyꢀ
developed reactions, namely a Pdꢀcatalyzed direct CꢀH funcꢀ
tionalization of indole derivatives and an organocatalyzed
asymmetric Michael addition of aldehydes to alkylidene maꢀ
lonates, as well as an intramolecular oxidative coupling beꢀ
tween indole and malonate moieties. The completion of (ꢀ)ꢀ
vincorine synthesis also demonstrated the versatility of these
new methodologies in natural product synthesis. Obviously,
such synthetic strategy is also promising for assembling other
Akuammilineꢀtype alkaloids. Investigations to prove this hyꢀ
pothesis are actively pursued and the results will be reported in
due course.
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(12) For organocatalytic conjugate addition of aldehydes to alkyliꢀ
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E.; Bonneau, C.; Córdova, A. Adv. Synth. Catal. 2008, 350, 657. (b)
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ASSOCIATED CONTENT
Supporting Information.
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(14) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Gianotti, M.;
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(17) Aizpurua, J. M.; CossIo, F. P.; Palomo, C. J. Org. Chem.
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(18) CCDC 874147 contains the supplementary crystallographic
data for the compound 25. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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