Asymmetric total synthesis of an iboga-type indole alkaloid, voacangalactone, newly isolated from Voacanga africana

Article abstract of DOI:10.1021/ol3027945

A new hexacyclic iboga-type indole alkaloid, voacangalactone (1), was isolated from Voacanga africana, and its structure including the absolute configuration was established by asymmetric total synthesis involving such key steps as the asymmetric Diels-Alder reaction using an aminodiene and the construction of an isoquinuclidine ring and an indole skeleton.

Full text of DOI:10.1021/ol3027945

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5800–5803
Asymmetric Total Synthesis of an Iboga-Type
Indole Alkaloid, Voacangalactone, Newly
Isolated from Voacanga africana
Masaya Harada, Ken Nunettsu Asaba, Masumi Iwai, Noriyuki Kogure, Mariko Kitajima,
and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8675, Japan
htakayam@p.chiba-u.ac.jp
Received December 15, 2012
ABSTRACT
A new hexacyclic iboga-type indole alkaloid, voacangalactone (1), was isolated from Voacanga africana, and its structure including the absolute
configuration was established by asymmetric total synthesis involving such key steps as the asymmetric DielsꢀAlder reaction using an
aminodiene and the construction of an isoquinuclidine ring and an indole skeleton.
Voacanga africana belonging to Apocynaceae has been
used as a traditional medicine in Africa. Both root bark
and seeds are a rich source of monoterpenoid indole
alkaloids having unique structures and biological activ-
ities. Recently, we found two iboga-type alkaloids that
showed cannabinoid CB1 receptor antagonistic activity
from V. africana root bark.1 These are the first examples of
natural alkaloids having cannabinoid CB1 receptor antag-
Figure 1. Structures of voacangalactone (1) and voacangine (2).
onistic activity. We also reported that iboga-type alkaloids
isolated from V. africana inhibited capsaicin-induced con-
traction in the mouse rectum possibly via inhibition of a
transient receptor potential vanilloid type 1 (TRPV1)-
mediated pathway.2 Further investigation of the crude
baseofthisplant hasled totheisolation ofanew hexacyclic
iboga-type alkaloid: voacangalactone (Figure 1). Herein
we report the structure determination based on spectro-
scopic analyses and asymmetric total synthesis.
The crude base obtained from the root bark of V.
africana was purified by repeated chromatography to
afford new alkaloid 1 (0.013% yield based on the crude
base). Compound 1, named voacangalactone, was found
to have the molecular formula C21H24N2O3 from HREI-
1
MS [m/z 352.1788 (Mþ)]. The H and 13C NMR spectra
were similar to those of voacangine (2) except for the
presence of signals for an oxygenated quaternary carbon
at C-20 and the absence of signals for a methyl group at the
carbomethoxyfunction, a structure commontoiboga-type
alkaloids (Table 1). 2D NMR correlations indicated that
compound 1 had a voacangine skeleton with a lactone
(1) Kitajima, M.; Iwai, M.; Kikura-Hanajiri, R.; Goda, Y.; Iida, M.;
Yabushita, H.; Takayama, H. Bioorg. Med. Chem. Lett. 2011, 21, 1962–
1964.
(2) Lo, M. W.; Matsumoto, K.; Iwai, M.; Tashima, K.; Kitajima, M.;
Horie, S.; Takayama, H. J. Nat. Med. 2011, 65, 157–165.
r
10.1021/ol3027945
Published on Web 11/06/2012
2012 American Chemical Society

Table 1. 1H and 13C NMR Data for Natural Voacangalactone
(1) (in CDCl3)
Scheme 1. Retrosynthetic Analysis
voacangalactone (1)
1Ha
13Cb
2
3
137.1
50.3
3.24ꢀ3.20 (overlapped)
3.09 (br-d, 9.9)
5
6
3.33 (br-ddd, 14.5, 3.1, 3.1)
3.24ꢀ3.20 (overlapped)
3.42 (ddd 16.5, 12.9, 3.1)
2.72 (br-d, 16.5)
54.2
20.1
7
109.7
128.7
100.0
154.2
111.7
112.0
129.4
26.2
8
9
6.93 (d, 2.0)
10
11
12
13
14
15
6.82 (dd, 8.5, 2.0)
7.24 (d, 8.5)
2.24 (br-s)
2.07ꢀ2.03 (overlapped)
1.81 (d, 14.6)
35.9
16
17
45.8
37.5
elongate the carbon chain, DIBAL reduction of the methyl
ester group of diene 15, and finally TBS protection of the
resultant primary alcohol afforded iodoalkene 10. Chiral
aminodiene 8, the substrate for the diastereoselective
DielsꢀAlder reaction, was obtained in 81% yield by the
copper-mediated amino coupling of prepared iodoalkene
10 with oxazolidinone 9 by applying Buchwald’s condition
(CuI, DMEDA, CsCO3, THF).4
2.31 (ddd, 14.2, 3.1, 3.1)
2.07ꢀ2.03 (overlapped)
1.02 (3H, dd, 7.4, 7.4)
1.98 (dq, 14.8, 7.4)
18
7.3
19
1.80 (dq, 14.8, 7.4)
29.4
88.1
20
21
3.51 (s)
65.6
10-OMe
CO
3.86 (3H, s)
56.1
178.1
Then, we attempted the diastereoselective DielsꢀAlder
reaction of chiral aminodiene 8 with highly reactive 1,1-
disubstituted alkene 75 that was prepared from dimethyl
malonate. The reaction of aminodiene 8 with 7 in CH2Cl2
at room temperature proceeded smoothly to form desired
cyclohexene derivative 6 in 97% yield as the sole product.
The relative and absolute configurations of 6 were deter-
mined by X-ray crystallographic analysis.6
The high diastereoselectivity of the DielsꢀAlder reac-
tion could be explained as follows. The attack of alkene 7
occurred from the less-hindered face of the anti structure of
aminodiene 8, which was more stable than the syn con-
former, induced by the stabilizing interaction between the
dipoles of dienyl and oxazolidinone moieties7 (Figure 2).
Next, we turned our attention to the construction of an
isoquinuclidine core in the iboga-type skeleton (Scheme 3).
Reductive cleavage of the oxazolidinone ring of 6 under
conventional conditions [Pd(OH)2/C, H2] afforded 16.
However, expected amine 17 could not be obtained even
under heated or high-pressure conditions. After several
attempts, we successfully synthesized 17 through a one-pot
operation from 6, i.e., reductive cleavage of oxazolidinone,
NH
9.48 (br-s)
a 600 MHz. b 150 MHz.
moiety consisting of C-16, C(O), O, C-20, and C-21. To the
best of our knowledge, this is the first example of natural
iboga-type alkaloids having such a function. Then, we
attempted the total synthesis of voacangalactone to reveal
its relative and absolute configurations.
Our synthetic plan for voacangalactone (1) is shown in
Scheme 1. The indole moiety of the target compound could
beconstructedat thelaststage by transformation of alkyne
derivative 4, which could be obtained from a key inter-
mediate, such as 5 having an isoquinuclidine core common
to iboga-type indole alkaloids. Chiral isoquinuclidine 5
could be formed via the diastereoselective DielsꢀAlder
reaction of 1,1-disubstituted alkene 7 and chiral aminodiene
8 having a chiral auxiliary, the latter of which could be
synthesized by copper-mediated amino coupling of iodoalk-
ene 10 and commercially available oxazolidinone 9.
We initially prepared iodoalkene 10 from diethyl ethyl-
malonate (11) in seven steps (Scheme 2). The introduction
of a diiodomethyl group into 11, hydrolysis and decarbox-
ylation of 12, LAH reduction of carboxylic acid, and
MnO2 oxidation of the resultant allylic alcohol gave
known aldehyde 14.3 Wittig reaction of aldehyde 14 to
(4) Jiang, L.; Job, J. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667–3669.
(5) Bachman, G. B.; Tanner, H. A. J. Org. Chem. 1939, 4, 493–501.
Freshly prepared alkene 7 (CH2Cl2 solution) was used for the
DielsꢀAlder reaction since 7 was quite unstable and easily polymerized.
(6) See the Supporting Information.
(3) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990
47–65.
(7) Robitte, R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-B
rynaert, J. J. Org. Chem. 2003, 68, 9809–9812.
Org. Lett., Vol. 14, No. 22, 2012
5801

Scheme 2
Scheme 3
Scheme 4
To construct an indole moiety in voacangalactone (1),
we conducted the transformation of 5 into alkyne deriva-
tive 4 (Scheme 4). Following Reding and Fukuyama’s
procedures,8 5 was converted into carboxylic acid 20 by
alkaline hydrolysis and subsequent iodolactonization.
Next, we attempted the transformation of carboxylic acid
20 into alcohol 22. Several reaction conditions were ex-
amined for the selective reduction of the carboxylic residue
of 20, but desired alcohol 22 was obtained in low yields.
The best result was obtained with a stepwise method, i.e.,
conversion of 20 into lactol 21 by reduction with an excess
Figure 2. Possible mechanism in the diastereoselective Dielsꢀ
Alder reaction.
decarboxylation of 16 by treatment with CSA under Ar
atmosphere, and a second reductive cleavage of the NꢀC
bond under H2 atmosphere. Cbz protection of the amine
residue in 17 afforded 18 in 90% overall yield from 6. The
primary alcohol in 18 was then converted into O-mesyl
group to produce 19, which was treated with Cs2CO3 in
DMF to give isoquinuclidine derivative 5.
amount of BH3 S(CH3)2 and the subsequent selective
3
oxidation of the lactol hydroxyl group with iodine, afford-
ing desired 22 in 77% yield from 20. Deiodination of 22
proceeded in a quantitative yield by refluxing with AIBN
(8) Reding, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973–976.
Org. Lett., Vol. 14, No. 22, 2012
5802

reaction following Utimoto’s method11 (NaAuCl4 2H2O
in EtOH) (Scheme 5).
3
Scheme 5
To accomplish the asymmetric total synthesis of voa-
cangalactone (1), we attempted to construct a seven-mem-
bered C-ring. Side chain extension at the indole β-position
in 3 was achieved by treatment with (COCl)2 and metha-
nolysis of the resulting carboxylic chloride. Deprotection
of the Cbz group in 26 by treatment with TMSCl/NaI in
MeCN produced the desired secondary amine that was
spontaneously cyclized to 27 in 89% yield. At the final
stage, the two carbonyl groups in 27 were simultaneously
reduced with an excess amount of BH3 THF to furnish
3
26
target alkaloid 1 in 56% yield. Synthetic 1 ([R]D ꢀ34.2
(c 0.12, MeOH)) was completely identical in all respects
1
(mass, UV, IR, H and 13C NMR, CD) with natural
voacangalactone. Therefore, the structure of voacangalac-
tone including the absolute configuration was established
to be formula 1.
In conclusion, we have succeeded in the asymmetric
total synthesis of the new alkaloid, voacangalactone (1),
isolated from Voacanga africana, which enabled us to
determine its structure including its absolute configura-
tion. The synthesis involved the preparation of optically
active isoquinuclidine derivative 5, a key intermediate for
the syntheses of iboga-type alkaloids, via the diastereose-
lective DielsꢀAlder reaction. Further synthetic study of
this class of alkaloids is under investigation in our
laboratory.
and nBu3SnH in benzene to afford 23, and 23 was con-
verted into desired alkyne derivative 4 by DMP oxidation
and successive SeyferthꢀGilbert homologation using the
OhiraꢀBestmann reagent in 98% yield.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Japan
Society for the Promotion of Science and a Grant-in-Aid
from the Ministry of Health, Labour and Welfare of
Japan.
The Sonogashira cross coupling of 4 and iodoaniline
derivative 249 proceeded in 60% yield by treatment with
Pd(PPh3)4, CuSO4, and sodium ascorbate in Et3N/DMF
(1/1),10 and resulting compound 25 was transformed into
indole 3 in 84% yield by the Au-catalyzed cyclization
Supporting Information Available. Experimental pro-
1
cedure, copies of H and 13C NMR spectral data for
compounds 3ꢀ6, 8, 10, 15, 18ꢀ20, 22, 23, 25ꢀ27 and
synthetic voacangalactone (1), and crystallographic data
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117–122.
(10) Bag, S. S.; Kundu, R.; Das, M. J. Org. Chem. 2011, 76, 2332–
2337.
(11) (a) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett.
1988, 29, 1799–1802. (b) Nakajima, R.; Ogino, T.; Yokoshima, S.;
Fukuyama, T. J. Am. Chem. Soc. 2010, 132, 1236–1237.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5803