Synthesis of indole alkaloid (-)-corynantheidol and formal synthesis of (-)-corynantheidine via one-pot asymmetric azaelectrocyclization

Article abstract of DOI:10.1016/j.tetlet.2009.05.045

The highly efficient asymmetric total synthesis of indole alkaloid, (-)-corynantheidol, containing a 2,4,5-trisubstituted piperidine core, was achieved using a new version of the one-pot azaelectrocyclization reaction. The formal synthesis of (-)-corynant

Full text of DOI:10.1016/j.tetlet.2009.05.045

Tetrahedron Letters 50 (2009) 4482–4484
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of indole alkaloid (ꢀ)-corynantheidol and formal synthesis
of (ꢀ)-corynantheidine via one-pot asymmetric azaelectrocyclization
*
Yanwu Li, Toyoharu Kobayashi, Shigeo Katsumura
Department of Chemistry and Open Research Center on Organic Tool Molecules, School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly efficient asymmetric total synthesis of indole alkaloid, (ꢀ)-corynantheidol, containing a 2,4,5-
trisubstituted piperidine core, was achieved using a new version of the one-pot azaelectrocyclization
reaction. The formal synthesis of (ꢀ)-corynantheidine was also achieved using the common synthetic
intermediate for these corynantheines.
Received 6 April 2009
Revised 13 May 2009
Accepted 18 May 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Corynantheidol
Synthesis
One-pot
Azaelectrocyclization
Piperidine
Corynantheines, which are the family of indole alkaloids related
to yohimbine and known as ring E seco equivalents (Fig. 1),1 have a
characteristic tetracyclic skeleton possessing three asymmetric
centers, and several total syntheses of these alkaloids have been re-
ported.2 A few total syntheses of corynantheidol (1), which was
isolated from Mitragyna parvifolia (Roxb.) Korth. (Rubiaceae) in
1973,3 have been realized,4 and a number of partial and total syn-
theses of corynantheidine (2), which was isolated from the African
plant Psudocinchona Africana5 and whose structure was deter-
mined in 1955,6 were reported.7 However, in these syntheses, only
two approaches were enantioselective.8 Meyers and co-workers
completed the synthesis of (ꢀ)-corynantheidol (1) using b-carbo-
line formamidine via the intramolecular Blaise reaction, and also
performed the formal synthesis of (ꢀ)-corynantheidine (2).8a Cook
and co-workers achieved the total syntheses of (ꢀ)-corynantheidol
(1) and (ꢀ)-corynantheidine (2) in 2000 using the asymmetric Pic-
tet–Spengler reaction in a key bond-forming step.8b
N
N
N
H
N
H
H
H
H
H
OH
(-)-corynantheidol
OMe
MeO2C
(-)-corynantheidine
1
2
Figure 1. The structures of the corynantheine family of alkaloids.
(Fig. 2).10 In addition, based on this protocol, the stereoselective
syntheses of chiral 2,4,6-trisubstituted piperidines and an
Recently, we realized the highly stereoselective asymmetric 6p-
azaelectrocyclization of the conformationally flexible linear 1-
azatrienes using 7-isopropyl-cis-aminoindanol, and the substituted
chiral tetrahydropyridine derivatives were successfully obtained in
high yields and selectivities.9 Furthermore, in order to develop the
asymmetric 6p-azaelectrocyclization as a new strategy for alkaloid
synthesis, we reported a unique one-pot protocol, which led to the
facile and stereoselective preparation of the chiral tetracyclic 2,4-
disubstituted 1,2,5,6-tetrahydropyridine derivative (R1 = H)
* Corresponding author. Tel.: +81 79 565 8314; fax: +81 79 565 9077.
E-mail address: katsumura@kwansei.ac.jp (S. Katsumura).
Figure 2. Synthesis of chiral tetrahydropyridines using one-pot asymmetric
azaelectrocyclization protocol.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.045

Y. Li et al. / Tetrahedron Letters 50 (2009) 4482–4484
4483
compound (–)-5 was first accomplished in preference to the con-
struction of the C ring. Thus, reduction of both the ester group
and the aminoacetal moiety with diisobutylaluminum hydride (DI-
BAL-H) at ꢀ78 °C provided the corresponding diol (ꢀ)-6 in 74%
yield. The primary hydroxy group of (ꢀ)-6 was selectively con-
verted into the corresponding carbonate by the reaction with ethyl
chloroformate. The successful one-carbon elongation was achieved
by the CO insertion using a catalytic amount of Pd(OAc)2 and Ph3P
in EtOH under a carbon monoxide atmosphere to produce the cor-
responding ethyl ester (ꢀ)-7 in 64% yield in two steps. Elimination
of the indanol moiety of (–)-7, which was a chiral nitrogen source
and a protecting group at the tetrahydropyridine nitrogen, was
achieved by the established procedure.10 Thus, the ethyl ester
(ꢀ)-7 was oxidized with lead tetraacetate in the presence of n-pro-
pylamine at ꢀ50 °C to afford the tetrahydropyridine derivative
(ꢀ)-8 in 75% yield. With the key intermediate (ꢀ)-8 in hand, the
remaining objectives were the construction of the tetracyclic ring
system and stereoselective reduction of the double bond in the
piperidine ring. After several trials, we achieved the construction
of the tetracyclic ring system using the Bosch’s Pummerer cycliza-
tion sequence.15 Thus, the sulfoxide (ꢀ)-9 was prepared in 82%
yield as a 1:1 mixture of diastereomers by the alkylation of amine
(ꢀ)-8 with phenyl vinyl sulfoxide in methanol under reflux. Treat-
ment of the sulfoxide (ꢀ)-9 with trimethylsilyl triflate in the pres-
ence of diisopropylethylamine at room temperature for 30 min
provided the expected tetracyclic sulfide (ꢀ)-10 in 84% yield.
Next was the removal of the resulting thiophenyl group and
the phenylsulfonyl group at the nitrogen of the indole. After sev-
eral trials, we found that the Birch reduction was extremely effec-
tive for this removal. The treatment of (–)-10 in liquid NH3 and
THF with lithium successfully produced the alcohol (ꢀ)-11 in
70% yield resulting from the reduction of the ethyl ester group
in addition to removal of both the thiophenyl and phenylsulfonyl
groups. Thus, three functional groups were nicely reduced by one
operation. In order to achieve the stereoselective reduction of the
double bond in the tetrahydropyridine ring, we attempted the
catalytic hydrogenation using several catalysts, such as Pd-C,
Ra-Ni, and Rh(PPh3)3Cl. Among them, we found that platinum
dioxide was most suitable for this purpose. The synthesis of
(ꢀ)-corynantheidol (1) was achieved by the hydrogenation of
(ꢀ)-11 in the presence of a catalytic amount of platinum dioxide
in MeOH in 96% yield as a single diastereomer. The optical rota-
tion and the spectral (1H and 13C NMR) data of the synthesized
(ꢀ)-corynantheidol (1) were in good correspondence with those
published in the literatures.8a,b,16
Scheme 1. One-pot azaelectrocyclization. Reagents and conditions: (a) 3, (ꢀ)-a,
MS5A, 1,4-dioxane, 80 °C, 30 min then 4, Pd2(dba)3, trifurylphosphine, LiCl, reflux,
11 h, 77%.
indolizidine alkaloid, (ꢀ)-dendroprime, were achieved.11 More-
over, we also realized a new version of the one-pot procedure for
the synthesis of 2,4,5-trisubstituted 2,5-chiral 1,2,5,6-tetrahydro-
pyridines (R1 = Et) (Fig. 2) by the further developed one-pot asym-
metric azaelectrocyclization using tetrasubstituted vinyl iodide
having a t-butyl ester group (R2 = t-Bu) (Fig. 2).12
In this Letter, the highly stereocontrolled asymmetric total syn-
thesis of (ꢀ)-corynantheidol (1) and formal synthesis of (ꢀ)-cory-
nantheidine (2) are described as a demonstration of a new
version of the one-pot asymmetric azaelectrocyclization protocol
using tetrasubstituted vinyl iodide 3 through the intermediates
of (ꢀ)-5 and (ꢀ)-8 (Schemes 1 and 2).
According to the established reaction conditions described in
the previous Letter,12 the tetrasubstituted vinyl iodide 3,13 amino-
indanol derivative (ꢀ)-a, and MS5A were mixed in 1,4-dioxane,
and the mixture was heated at 80 °C for 30 min. After checking
the consumption of 3 by TLC, the indolyl vinyl stannane 4, which
was prepared from 1-benzenesulfonyl-2-formylindole14 by a se-
quence of the Cory-Fucks alkyne synthesis, base treatment
(LiHMDS and then BuLi in THF, ꢀ78 °C), and hydrostanylation with
tributyltin hydride (AIBN in benzene, reflux) in 53% yield for three
steps, was added, and the resulting mixture was refluxed in the
presence of a catalytic amount of Pd2(dba)3, trifurylphosphine,
and LiCl (Scheme 1). The desired tetracyclic aminoacetal (ꢀ)-5
was obtained in 77% yield as a single diastereomer. Thus four
new bonds were created by controlling the stereochemistry at
three asymmetric centers in a single operation.
The synthesis of (ꢀ)-corynantheidol (1) from compound (ꢀ)-5
is shown in Scheme 2. In order to optimize the efficiency of the
synthesis, we selected the synthetic route in which the one-carbon
elongation at the four position of the tetrahydropyridine nucleus of
Scheme 2. Total synthesis of (ꢀ)-corynantheidol. Reagents and conditions: (a) DIBAL-H, CH2Cl2, ꢀ78 °C, 15 min, 74%; (b) ClCO2Et, pyridine, THF, ꢀ20 °C, 15 min, then rt,
30 min, 88%; (c) Pd(OAc)2, Ph3P, CO, EtOH, 50 °C, 18 h, 88%; (d) Pb(OAc)4, n-PrNH2, CHCl3, ꢀ50 °C, 30 min, 75%; (e) PhS(O)CH@CH2, MeOH, reflux, 27 h, 82%; (f) TMSOTf, DIPEA,
CH2Cl2, rt, 30 min, 84%; (g) Li, NH3, THF, ꢀ78 °C then ꢀ33 °C, 70%; (h) H2, PtO2, MeOH, rt, 30 min, 96%.

4484
Y. Li et al. / Tetrahedron Letters 50 (2009) 4482–4484
work was also supported by the Maching Fund Subsidy for Private
University of Japan. T.K. is grateful to the JSPS for a Research Fel-
lowship for Young Scientist.
References and notes
1. Isolation: Kerner, P.; Schwyzer, R.; Flan, A. Helv. Chim. Acta 1952, 35, 851;
Structure determination: Prelog, V.; Janot, M. M.; Goumelen, E. E.; Katz, T. J. J.
Am. Chem. Soc. 1957, 79, 6426.
2. (a)For a review on the various total synthesese of the corynantheine series, see:
Total Synthesis of Natural products; Apsimon, J. A., Ed.; Wiley: New York, 1977;
Vol. 3, pp 315–344; (b) Lounasmaa, M.; Tolvanen, A. The Corynantheine-
Heteroyohimbine Group. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.;
John Wiley & Sons Ltd: Chichester, UK, 1994; pp 58–147; (c) Takayama, H.
Chem. Pharm. Bull. 2004, 52, 916–928; d The syntheses of dihydrocorynantheol,
see: (i) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006,
8, 1533–1535. (ii) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006, 71,
6547. (iii) Amat, M.; Gomez-Esque, A.; Escolano, C.; Santos, M. M. M.; Molins,
E.; Bosch, J. J. Org. Chem. 2009, 74, 1205.
3. (a) Shellard, E. J.; Houghton, P. J. Planta Med. 1973, 24, 13; (b) Vamvacas, C.;
Phillipsborn, W. V.; Schlittler, E.; Schmid, H.; Karrer, P. Helv. Chim. Acta 1957,
40, 1793.
4. (a) Imanishi, T.; Inoue, M.; Wada, Y.; Hanaoka, M. Chem. Pharm. Bull. 1982, 30,
1925; (b) Lounasmaa, M.; Jokela, R.; Tirkkonen, B.; Miettinen, J.; Halonen, M.
Heterocycles 1992, 34, 321.
5. Janot, M.-M.; Goutarel, R. C. R. Acad. Sci. 1944, 218, 852.
6. Janot, M.-M.; Goutarel, R.; Le Hir, A.; Tsatsas, G.; Prelog, V. Helv. Chim. Acta
1955, 38, 1073.
Scheme 3. Reagents and conditions: (a) Ba(OH)2, H2O, THF/MeOH (2:1), 50 °C,
30 min, 100%; (b) Li, NH3, THF, ꢀ78 °C then ꢀ33 °C, 84%; (c) thionyl chloride, MeOH,
reflux, 1 h, 60%, (d) H2, PtO2, MeOH, rt, 30 min, 72%.
7. (a) Weisbach, J. A.; Kirkpatrick, J. L.; Williams, K. R.; Anderson, E. L.; Yim, N. C.;
Douglas, B. Tetrahedron Lett. 1965, 3457; (b) Wenkert, E.; Dave, K. G.; Lewis, R.
G.; Sprague, P. W. J. Am. Chem. Soc. 1967, 89, 6741; (c) Szantay, C.; Barczai-Beke,
M. Chem. Ber. 1969, 102, 3693; (d) Brown, R. T.; Chapple, C. L.; Charalambides,
A. A. J. Chem. Soc., Chem. Commun. 1974, 756; (e) Van Tamelen, E. E.; Dorschel, C.
Bioorg. Chem. 1976, 5, 203; (f) Sakai, S.; Shinma, N. Chem. Pharm. Bull. 1978, 26,
2596; (g) Lounasmaa, M.; Jokela, R.; Laine, C.; Hanhinen, P. Tetrahedron Lett.
1995, 36, 8687.
8. (a) Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091; (b) Yu, S.; Berner, O.
M.; Cook, J. M. J. Am. Chem. Soc. 2000, 122, 7827.
9. (a) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660; (b) Tanaka, K.;
Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906.
10. Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.; Katsumura, S. Org. Lett.
2006, 8, 3809.
11. Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura, S. Org. Lett. 2006, 8, 3813.
12. The manuscript entitled ‘Efficient Synthetic Method of 2,4,5-Trisubstituted 2,5-
Chiral Tetrahydropyridines by One-pot Asymmetric Azaelectrocyclization
Protocol’ was accepted: Kobayashi, T.; Takeuchi, K.; Tsuchikawa, H.;
Katsumura, S. Chem. Commun. 2009. In the Letter, the structure including the
stereochemistry of the product produced by a new version of the one-pot
asymmetric azaelectrocyclization, was unambiguously determined by the X-
ray crystallographic analysis of the corresponding ethyl ester of a phenyl
derivative (Fig. 2, R1 = R2 = Et, R = Ph).
The formal synthesis of (ꢀ)-corynantheidine (2) from the inter-
mediate (ꢀ)-10 was also achieved (Scheme 3). After (ꢀ)-10 was
hydrolyzed with Ba(OH)2 in THF and MeOH, the Birch reduction
of the quantitatively produced (ꢀ)-12 provided the desired acid
(ꢀ)-13 in 84% yield resulting from the removal of the thiophenyl
and benzenesulfonyl groups without reduction of the carboxyl
group. Esterification of the obtained (ꢀ)-13 with thionyl chloride
in MeOH gave the corresponding ester (ꢀ)-14 in 60% yield. The cat-
alytic hydrogenation of the resulting (ꢀ)-14 with platinum dioxide
in MeOH successfully provided the Cook’s intermediate (ꢀ)-15 in
72% yield as a single diastereomer. The spectral characteristics of
the synthesized (ꢀ)-15 were in good agreement with those re-
ported by Cook and co-workers.8b According to the precedence
established by Cook and co-workers for the synthesis of corynant-
heidine 2, (ꢀ)-15 could be carried through to (ꢀ)-corynantheidine
(2) in two steps.
13. Tetrasubstituted vinyl iodide 3 was prepared as follows:
MgBr,
In summary, we achieved the asymmetric total synthesis of
(ꢀ)-corynantheidol (1) and the formal synthesis of (ꢀ)-corynant-
heidine (2) using the highly efficient and stereoselective one-pot
azaelectrocyclization protocol as the key step. Thus, the one-pot
CO2R
CuBr, I2
I
CO2R
I
CO2R
(Z)
(E)
3a : R = t-Bu
3b : R = t-Bu (Z : E = 1 : 0.7, 79%)
1) O3, Me2S
2) LiAl(OtBu)3H
and separation
of isomers
asymmetric 6p-azaelectrocyclization reaction developed by us
can be regarded as a powerful strategy for the synthesis of alka-
loids possessing a 2,4,5-trisubstituted piperidine core. Further
applications toward related natural alkaloids are currently being
pursued in our laboratory.
OHC
I
3 : R = t-Bu, 22% (3 steps)
CO2R
3) MnO2
14. Kuethe, J. T.; Davies, I.; Dormer, P. G.; Reamer, R. A.; Mather, D. J.; Reider, P. J.
Tetrahedron Lett. 2002, 43, 29.
15. Bennasar, M-L.; Zulaica, E.; Sufi, B. A.; Bosch, J. Tetrahedron 1996, 52, 8601;
(b) Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62,
3158.
Acknowledgments
This work was financially supported by a Grant-in-Aid for Sci-
ence Research on Priority Areas 16073222 from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. This
16. Synthesized; mp 188.6–189.8 °C,
½ ꢁ ꢀ86 (c 0.2, pyridine): lit; mp 189–
a D
½
191 °C,8a
½
a D
ꢁ
ꢀ93 (c 0.52, pyridine),8a
a D
ꢁ
ꢀ102 (c 0.62,pyridine).8b