Formal synthesis of aspidospermidine via the intramolecular cascade transannular cyclization

Article abstract of DOI:10.1055/s-0033-1338447

A formal synthesis of aspidospermidine is reported through a novel preparation of Stork's penultimate tricyclic ketone intermediate. The key steps of the synthesis consist of an intramolecular cascade transannular cyclization, triggered by the removal of Boc group, which simultaneously forms the C, D, and E rings of aspidospermidine and conveniently setting up the quaternary stereocenter via decarboxylative alkylation reaction of the β-keto ester. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338447

LETTER
▌1303
letter
Formal Synthesis of Aspidospermidine via the Intramolecular Cascade Trans-
annular Cyclization
Synthesis of Aspidospermidine
Jiu-Zhong Huang,a,b Xiao-Ke Jie,a,c Kun Wei,a Hongbin Zhang,b Min-Cai Wang,c Yu-Rong Yang*a
a
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences,
Kunming 650201, P. R. of China
Fax +86(871)5223179; E-mail: yangyurong@mail.kib.ac.cn
b
Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan University, Kunming 650091, P. R. of China
c
Chemistry Department, Zhengzhou University, Zhengzhou 450052, P. R. of China
Received: 28.02.2013; Accepted after revision: 30.03.2013
many others have reported the formal syntheses based on
Abstract: A formal synthesis of aspidospermidine is reported
Stork’s tricyclic ketone. In addition, the diasteromer of 5a
through a novel preparation of Stork’s penultimate tricyclic ketone
could be used in the preparation of aspido-
intermediate. The key steps of the synthesis consist of an intramo-
lecular cascade transannular cyclization, triggered by the removal
spermidine.3c,g,4j,n
of Boc group, which simultaneously forms the C, D, and E rings of
aspidospermidine and conveniently setting up the quaternary stereo-
center via decarboxylative alkylation reaction of the β-keto ester.
N
D
N
E
Key words: alkaloid, total synthesis, palladium, cross-coupling,
cyclization
H
H
H
C
A
B
N
N
H
Ac
H
OMe
The Aspidosperma alkaloids have received much atten-
tion from the synthetic community due to their structural
complexity and interesting biological activities. To date,
over 250 alkaloids in this family have been isolated1 and
many of them incorporate the core exemplified by aspido-
spermidine (1, Figure 1). Unlike the more complicated
vinblastine and vincristine, which are frontline drugs in
cancer therapy,2 aspidospermidine is not of pharmacolog-
ical interest and is lacking in sensitive functional groups.
Also for this reason, 1 has often been used as an attractive
target for the development of new routes to these alka-
loids, thereby culminating in a cornucopia of synthetic
studies in the literature.3,4 A pioneering work in this area,
Stork and Dolfini first synthesized the alkaloids aspido-
spermine (2) and quebrachamine (3) nearly 50 years ago.5
In their classic synthesis, a late-stage Fischer indole syn-
thesis to introduce the indole moiety onto a tricyclic
ketone intermediate 5a was successfully adopted. More-
over, this work established that all of the stereocenters in
the final target were responsive to a single, nonepimeriz-
able quaternary center in ketone 5 (Scheme 1). Since then,
aspidospermidine (1)
aspidospermine (2)
N
N
OAc
OH
H CO2Me
Me
H
N
N
H
MeO
quebrachamine (3)
vindoline (4)
O
N
N
H
H
H
O
O
5a
6
Figure 1 Natural products, intermediate ketone 5a, and tetracyclic
unnatural alkaloid 6
+N
N
N
PhNHNH2
H
AcOH
H
LAH
H
1
N
N
O
5
H
7
Scheme 1
SYNLETT 2013, 24, 1303–1306
Advanced online publication: 08.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338447; Art ID: ST-2013-W0185-L
© Georg Thieme Verlag Stuttgart · New York

1304
J.-Z. Huang et al.
LETTER
As discussed above, we elected to intercept Stork’s inter-
mediate 5a (or its diastereomeric equivalent 5) to consti-
tute a formal synthesis of 1. Thus, our retrosynthesis of 5,
shown in Scheme 2, begins with the reduction of the inter-
nal double bond of a tricyclic vinylogous amide 8, which
in turn would be accessed from a key reaction of cascade
transannular cyclization of functionalized nine-membered
ring 9. The challenging all-carbon quaternary stereocenter
of the nine-membered ring 9 could be installed through an
enantioselective decarboxylative alkylation reaction of β-
keto ester 10, a powerful methodology developed by the
Stoltz group recently.7
D
H
N
E
N
N
H
C
H
O
A
B
N
H
O
H
aspidospermidine (1)
5
8
cascade
transannular
cyclization
Boc
N
O
O
O
Our synthesis commenced with β-keto ester 10, shown in
Scheme 3, which could be easily prepared in multigram
quantities in three steps from cheap adipic acid (see Sup-
porting Information). At the outset, we took on the race-
mic β-keto ester 10 to test the decarboxylative alkylation
reaction under the conditions of Pd(OAc)2/Ph3P, and the
transformation proceeded nicely to provide α-quaternary
cyclopentanone 11 in racemic form. Using this racemic
cyclopentanone as a linchpin, elongation of a nitrogen-
containing side chain on 11 was expected. To this end, we
first converted the ketone into its vinyl triflate 12 with
standard procedures in high yield, and then a highly effec-
tive Suzuki–Miyaura cross-coupling8 between this vinyl
triflate 12 and allylic carbamate derivative was enlisted to
yield diene 13. Selective hydroboration of the allylic po-
sition of 13 delivered the primary alcohol 14 uneventfully.
Iodination of the alcohol 14 followed by the treatment of
O
10
9
O
OR
Scheme 2 Retrosynthetic analysis of aspidopsermidine
In the context of our ongoing synthetic endeavor on the
complex polycyclic Lycopodium alkaloids,6 we first ob-
served an unusual intramolecular cascade cyclization
while attempting to initiate a plausibly biomimetic cycli-
zation approaching to lycojapodine A.6a Thus obtained
product 6 is unique in the tetracyclic skeleton in which the
left moiety of fused tricyclic vinylogous amide is similar
to ketone 5. Based on this observation, we conceived that
our cascade cyclization would be synthetically useful and
planed to showcase its utilities in the synthesis of Aspido-
sperma alkaloids.
O
O
O
OTf
Pd(OAc)2
KHMDS
O
Ph3P, THF
80%
PhNTf2
91%
( )-11
12
( )- 10
NHBoc
9-BBN,
DMF
Pd(dppf)Cl2
Cs2CO3, Ph3As
86%
NHBoc
NHBoc
NHBoc
I2, Ph3P
imidazole
9-BBN
91%
3 M NaOH, H2O2
OH
I
65%
13
15
14
t-BuOK
THF, 65%
Boc
Boc
NaIO4
RuCl3
N
N
H
N
N
TFA
61%
LAH
MeCN–H2O
87%
H
O
O
82%
O
ref. 4j
8
5b
O
OR
16
R = H 9a
CH2N2
90%
R = Me 9b
Scheme 3 Synthesis of ketone 5b
Synlett 2013, 24, 1303–1306
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Aspidospermidine
1305
H
N
+
N
N
8
9b
H
O
O
– Boc
O
OMe
O
OMe
19
18
17
Scheme 4
O
O
O
O
[Pd2(dba)3] (2.5 mol%)
O
PPh2
N
(S)-t-Bu-PHOX (6.25 mol%)
THF, r.t.
82%
(–)-11
( ) 10
86% ee
(S)-t-Bu-PHOX
Scheme 5
the iodide intermediate 15 with potassium tert-butoxide in Taken all together, in principle, here our route will consti-
THF, a cyclization occurred smoothly to close the nine- tute an enantioselective formal synthesis of 1.
membered ring 16. Eventually, the double bond of the cy-
clopentene ring inside of 16 was facilely cleaved by oxi-
In conclusion, a formal synthesis of aspidospermidine is
reported based on a novel synthesis of the pivotal tricyclic
ketone in which a cascade transannular cyclization plays
the key role; and decarboxylative alkylation reaction of β-
keto ester to set up the quaternary stereocenter was effi-
ciently adopted.
dation with RuCl3/NaIO4, furnishing two desired carbonyl
functional groups for the next cascade reaction.9 With the
oxidative cleavage product 9a in hand, we are poised for
the pivotal cascade cyclization. First, we heated the acid
compound 9a at 100 °C in AcOH–H2O (96:4) mixture;10
a trace of cyclized vinylogous amide 8 could be isolated.
In the case of methyl ester 9b under the same conditions,
18% yield of the product was obtained. Then we took on
Synthesis of Vinylogous Amide 8
Methyl ester 9b (28 mg, 0.0789 mmol) was dissolved in TFA (1.5
the methyl ester 9b as the substrate for the optimization of mL) and then placed in a 90 °C oil bath. The resulting deep orange
reaction was stirred at 90 °C for 12 h. After the mixture was cooled
to r.t., to the residue was added 6 N NaOH to reach pH >7 and di-
luted with CHCl3 (3 mL), washed with brine, dried, and concentrat-
ed. The crude product was purified by flash column
reaction conditions. It is soon to find that in the presence
of pure AcOH heated at 110 °C, the yield can be enhanced
to 32%. Using TFA as solvent instead of AcOH at lower
temperature (90 °C), 61% yield of the product can be iso-
chromatography (CHCl3–MeOH, 100:1) to provide 9.8 mg of tri-
lated. This cascade process toward tricyclic vinylogous
amide 8 could be rationalized briefly as shown in Scheme
4.11 Cleavage of the Boc gives a secondary amine 17 that
cyclic ketone 8 (61%) as dark yellow oil.
IR (KBr): νmax = 3432, 2857, 1614, 1514, 1438, 1354, 1300, 1264,
1189, 923, 853, 702 cm–1. 1H NMR (600 MHz, CDCl3): δ = 3.60 (1
attacks the ketone to form enamine 18. The enamine 18 H, td, J = 10.8, 3.6 Hz), 3.30 (1 H, dd, J = 11.7, 6.0 Hz), 3.18 (1 H,
q, J = 10.8 Hz), 2.80 (2 H, m), 2.63 (1 H, m), 2.44 (1 H, m), 2.27 (1
continues to proceed an intramolecular nucleophilic sub-
stitution to yield tricyclic system 19, which is terminated
H, m), 1.60–2.00 (6 H, m), 1.54 (1 H, td, J = 13.2, 4.8 Hz), 1.13 (1
H, td, J = 13.8, 3.6 Hz), 0.89 (3 H, t, J = 7.8 Hz) ppm. 13C NMR
by deprotonation. Vinylogous amide 8 was first reported
(150 MHz, CDCl3): δ = 190.4, 175.3, 107.8, 54.1, 47.3, 35.2, 33.8,
by Banwell,4j and its internal double bond was reduced by
32.7, 28.8, 25.4, 24.2, 18.8, 8.1 ppm. HRMS (EI): m/z calcd for
C13H19NO [M]+: 205.1467; found: 205.1469.
the addition of lithium aluminium hydride to provide a tri-
cyclic ketone 5b. The stereochemistry of two methines of
ketone 5b was confirmed by the comparison with the data
of Banwell. According to the Fischer indole reaction in-
vestigated by previous groups, 5b could be led to aspido-
spermidine (vide ante).12 During the performance of this
work, the Stoltz group reported the enantioselective de-
carboxylative alkylation reaction of β-keto ester 10
(Scheme 5), an optical α-quaternary cyclopentanone (–)-
11 obtained in good yield and enantioselective excess.7
Acknowledgment
We thank the National Natural Science of China (No. 81102348,
21072200), Programs of ‘One Hundred Talented People’ and ‘We-
stern Light’ Joint Scholar of Chinese Academy of Sciences for fi-
nancial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
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J.-Z. Huang et al.
LETTER
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Synlett 2013, 24, 1303–1306
© Georg Thieme Verlag Stuttgart · New York