Formal syntheses of dihydrocorynantheine and isorhynchophylline via proline catalyzed Mannich-Michael reaction

Article abstract of DOI:10.3987/COM-09-11828

Proline catalyzed Mannich-Michael reaction of 3-ethyl-3-buten-2-one with 9-tosyl-3,4-dihydro-β-carboline proceeded in a highly stereoselective manner. The reaction was applied to formal syntheses of dihydrocorynantheine and isorhynchophylline. The Japan I

Full text of DOI:10.3987/COM-09-11828

HETEROCYCLES, Vol. 81, No. 8, 2010
1791
HETEROCYCLES, Vol. 81, No. 8, 2010, pp. 1791 - 1798. © The Japan Institute of Heterocyclic Chemistry
Received, 7th September, 2009, Accepted, 23rd June, 2010, Published online, 24th June, 2010
DOI: 10.3987/COM-09-11828
FORMAL SYNTHESES OF DIHYDROCORYNANTHEINE AND
ISORHYNCHOPHYLLINE VIA PROLINE CATALYZED
MANNICH-MICHAEL REACTION
Kazuhiro Nagata, Hitomi Ishikawa, Ayako Tanaka, Michiko Miyazaki,
Takuya Kanemitsu, and Takashi Itoh*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: itoh-t@pharm.showa-u.ac.jp
Abstract – Proline catalyzed Mannich-Michael reaction of 3-ethyl-3-buten-2-one
with 9-tosyl-3,4-dihydro-β-carboline proceeded in a highly stereoselective manner.
The reaction was applied to formal syntheses of dihydrocorynantheine and
isorhynchophylline.
INTRODUCTION
We have been investigating asymmetric addition reactions to cyclic imines and their application to the
syntheses of indole alkaloids.1 In the study, we have found a highly enantioselective addition of ketones
to 9-tosyl-3,4-dihydro-β-carboline using proline catalyst.2 1-Substituted-β-carbolines thus obtained
would be viable precursors for the synthesis of corynanthe-type indole alkaloids and biogenetically
related oxindole alkaloids. Dihydrocorynantheine (1) and isorhynchophylline (2) were selected as target
molecules for evaluating the availability of the above mentioned reaction. Dihydrocorynantheine was first
isolated from the bark of Pseudocinchona africana A. Chev.3 as early as 1938, but few examples of the
asymmetric synthesis were reported.4 In the case of isorhynchophylline, which is also an old alkaloid
from Uncaria rhynchophylla Miq.,5 no enantioselective synthesis was reported. Thus we have
N
20
N
N
15
H
20
OMe
H
H
O
15
N
O
H
O
OMe
O
O
dihydrocorynantheine (1)
isorhynchophylline (2)
Figure 1. Target indole alkaloids for synthesis

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HETEROCYCLES, Vol. 81, No. 8, 2010
investigated an application of our method to the syntheses of these alkaloids. In this paper, these results
are described.
RESULTS AND DISCUSSION
The synthesis of dihydrocorynantheine (1) was commenced with the compound 3 which was prepared
from the enantioselective Mannich-Michael reaction catalyzed by (R)-proline2 (Scheme 1). Since
removal of N-9 tosyl group at a later stage of the synthesis was revealed to be difficult, elimination of
tosyl group was to be carried out firstly. After protection of carbonyl group by 1,3- propanediol to give
compound 4, removal of tosyl group was performed using Red-Al, and then the acetal was cleaved to give
5 as a mixture of epimer at C(20). The structures of the both isomers were determined by comparison of
1H and 13C NMR data with reported ones.6 This epimerization was of no consequence because the chiral
center returned to the original configuration in the next step. Thus, without a separation of the epimers,
the resulting ketones 5 were subjected to a Horner-Wadsworth-Emmons reaction with trimethyl
phosphonoacetate to afford compound 6 in 84% yield.7 A. I. Meyers et al. reported that treatment of
either 5 or its epimer at C(20) with 10% KOH gave the 10:1 equilibrium mixture of 5 and its epimer at
C(20).6 Thus, in the basic conditions of Horner-Wadsworth-Emmons reaction, the epimer was
considered to isomerize to thermodynamically more stable compound 5. Stereochemistry of E/Z
configuration was determined by NOE observations (Figure 2). Hydrogenation with Wilkinson’s
catalyst under medium pressure gave 7 in 60 % yield. The synthesis of dihydrocorynantheine
(R)-proline
(30 mol %)
O
1,3-propanediol, TsOH
toluene, reflux, 4 h
N
N
O
+
N
N
N
DMSO, 20oC
N
H
H
Ts
Ts
4
Ts
O
O
y. 85%, 99% ee
3
y. 90%
1) Red-Al, toluene
reflux, 4 h
N
N
N
(MeO)2POCH2CO2Me, NaH
benzene, reflux, 2 h
N
H
H
H
H
20
2) 1 N HCl, dioxane
reflux, 4 h
O
y. 77%
O
5
6
84%
O
5:C(20)-epimer = 3:2
H2, 5 bar
Wilkinson's cat.
N
N
N
N
H
H
H
H
MeOH, rt, 5 h
O
OMe
O
60%
7
O
O
a single isomer
dihydrocorynantheine (1)
Scheme 1. Asymmetric synthesis of dihydrocorynantheine (1)

HETEROCYCLES, Vol. 81, No. 8, 2010
1793
from 7 was already reported using condensation reaction with methyl formate followed by methylation
with diazomethane.4, 8 Therefore, a new synthetic route to dihydrocorynantheine was established.
We then investigated the synthesis of isorhynchophylline (Scheme 2). Rhynchophylline and
isorhynchophylline, which have spiro[pyrrolidine-3,3’-oxindole] ring system, have been used as
ingredients of folk medicines, and exhibit antipyretic and hypotensive activities.9 Moreover, these
alkaloids possess a protective effect against glutamate-induced neuronal death.10 Although there are two
examples for the total synthesis of rhynchophylline and isorhynchophylline,11, 12 enantioselective
synthesis has not yet been reported. It was considered that the key step for the synthesis of
rhynchophylline and/or isorhynchophylline was oxidative transformation of tetrahydro-β–carboline into
oxindole to construct the spiro[pyrrolidine-3,3’-oxindole] ring system. Finch and Taylor reported the
oxidative transformation of dihydrocorynantheine to rhynchophylline,13 but the yield was low.
Recently, Martin et. al. reported the transformation of an ethyl ester of compound 7 into corresponding
oxindole, but products obtained were a mixture of epimers with the selectivity of 42:33, and these
compounds were led to rhynchophylline and isorhynchophylline, respectively, in a racemic synthesis.12
Since the stereoselectivity in the oxidative transformation was considered to depend on the conformation
of CD ring,14 we examined conversion of tetrahydro-β-carboline skeleton to the spiro-
[pyrrolidine-3,3’-oxindole] ring in early stages of the synthesis. When compound 5 was allowed to react
with NBS,14, 15 oxindole 8 was obtained in 80 % yield as a single diastereomer. Although stereospecific
construction of spiro[pyrrolidine-3,3’-oxindole] ring was achieved in the reaction, following
Horner-Wadsworth-Emmons reaction was unsuccessful to give compound 9. Thus, oxidative
N
NBS
7
N
O
H
O
N
H
N
H
THF/AcOH/H2O
0oC, 30 min
O
H
5
y. 80%
8
(MeO)2POCH2CO2Me
NaH
benzene
N
O
N
NBS
N
H
O
7
OMe
N
H
H
O
N
H
THF/AcOH/H2O
0oC, 30 min
H
N
H
O
6
O
9
O
O
isorhynchophylline (2)
O
57%
Scheme 2. Asymmetric synthesis of isorhynchophylline (2)

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HETEROCYCLES, Vol. 81, No. 8, 2010
transformation of 6 into compound 9 with NBS was investigated. The result was that a single
diastereomer was isolated in 57% yield. Configurations at C(7) position of compound 8 and 9 were
determined by NOE spectroscopic experiments (Figure 2). Since compound 9 had been converted into
isorhynchophylline in three steps,11 a formal synthesis of isorhynchophylline was accomplished.
In summary, we have established a new synthetic
H
H
H
route to the synthesis of dihydrocorynantheine and
achieved first formal synthesis of
H
N
H
H
H
H
Me
N
N
H
H
H
H
a
H
H
H
O
H
H
isorhynchophylline as an optically active form.
These results show the usefulness of proline
O
N
H
O
H
H
O
6
8
catalyzed
Mannich-Michael
reaction
of
H
H
H
H
9-tosyl-3,4-dihydro-β-carboline. The application
of the method to the synthesis of other alkaloids is
now under investigation.
H
H
H
H
N
H
H
N
O
H
H
O
O
9
Figure 2. Differential NOE data of compounds 6, 8, and 9
EXPERIMENTAL
General. Unless otherwise specified, reagents were purchased from commercial suppliers and used
without further purification. NBS was recrystallized from H2O prior to use. Dehydrated toluene, benzene,
DMSO, THF, and MeOH were purchased from commercial suppliers. Moisture sensitive reactions were
carried out under an atmosphere of Ar. 1H and 13C NMR spectra ware recorded on a 500 MHz (125 MHz
for 13C) or a 400 MHz (100 MHz for 13C)spectrometer. All melting points are uncorrected.
Synthesis of compound 4
To a solution of 3 (40 mg, 94 μmol) in toluene was added 1,3-propanediol (69 μL, 0.94 mmol) and
p-TsOH ·H2O (3.6 mg, 19 μmol). The solution was refluxed for 1 hour using Dean-Stark apparatus. After
cooling to room temperature, saturated aqueous NaHCO3 sol. was added and extracted with AcOEt. The
combined organic layers were dried over MgSO4 and evaporated off. The residue was purified by
chromatography on silica gel (CH2Cl2:AcOEt=10:1→8:1) to give compound 4 (39 mg) in 86% yield: pale
yellow amorphous; [α]17D +174.03 (c 0.98, CHCl3); 1H-NMR (500 MHz CDCl3) δ: 0.95 (3H, t, J=7.4 Hz),
1.12 (1H, septed, J=7.4 Hz), 1.41 (1H, d, J=13.2 Hz), 1.48 (1H, t, J=12.7 Hz), 1.64-1.70 (1H, m),
1.96-2.08 (2H, m), 2.27 (3H, s), 2.71 (2H, brs), 2.77 (1H, dd, J=10.9 Hz, 4.6 Hz), 2.97 (1H, t, J=12.6 Hz),

HETEROCYCLES, Vol. 81, No. 8, 2010
1795
3.19 (1H, m), 3.49 (1H, dd, J=13.7 Hz, 2.3 Hz), 3.79 (1H, dd, J=11.5 Hz, 3.4 Hz), 3.90 (1H, dd, J=12.0
Hz, 5.7 Hz), 4.16 (1H, td, J=13.2 Hz, 2.9 Hz), 4.41 (1H, d, J=10.9 Hz), 4.55 (1H, td, J=12.6 Hz, 2.3 Hz),
7.08 (1H, d, J=8.0 Hz), 7.21 (2H, td, J=7.4 Hz, 1.1 Hz), 7.25-7.30 (3H, m), 7.51 (2H, d, J=8.0 Hz), 8.12
(1H, d, J=8.0 Hz); 13C-NMR (125 MHz CDCl3) δ: 12.6, 18.1, 21.5, 22.2, 25.7, 31.1, 43.0, 44.9, 55.0 55.7,
59.3, 59.5, 98.1, 115.8, 118.4, 120.1, 124.0, 124.5, 126.4, 127.6, 129.5, 130.8, 134.0, 137.4, 144.6;
HR-FAB MS: Calcd for C27H33O4N2S [M+H]+: 481.2161. Found: 481.2137.
(3R,12bS)-Methyl (3-Ethyl-3,4,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-2-ylidene)acetate
(6)
To a solution of 4 (1.26 g, 2.6 mmol) in toluene (15 mL) was added Red-Al (3.6 mol/L in toluene 4.4 mL,
15.8 mmol) at room temperature, then the solution was refluxed for 3 h. 10% aqueous Rochelle salt
solution was added to the solution and extracted with AcOEt. The organic layer was dried over MgSO4,
and evaporated off. The residue was purified by chromatography on silica gel (CH2Cl2:AcOEt=2:1→3:2)
to give detosylated compound (753 mg). This compound was dissolved in dioxane (22 mL) and 1N aq.
HCl (4.5 mL) was added to the solution, and then the solution was refluxed for 1 h. Aqueous K2CO3
solution was added to the solution at 0 ºC, and the aqueous layer was extracted with AcOEt. The
combined organic layers were dried over MgSO4, and evaporated off. The residue was purified by
chromatography on silica gel (CHCl3:AcOEt= 4:1) to give 5 (533 mg) as a mixture of epimer at C(20)
(5:epimer=3:2). Part of this mixture (227 mg, 0.847 mmol) was dissolved in benzene (10 mL). This
solution was added to a benzene solution of NaH (60% in oil 169 mg, 4.23 mmol) and trimethyl
phosphonoacetate (635 μL, 4.23 mmol) and then refluxed for 2 h. After saturated aqueous NaHCO3
solution was added, the aqueous layer was extracted with AcOEt. The combined organic layers were
dried over MgSO4 and evaporated off. The residue was purified by chromatography on silica gel
(CHCl3:Et2O=5:1) to give compound 6 (231 mg) in 84 % yield; brown amorphous; [α]21 +60.0 (c 0.40,
D
1
CHCl3); H-NMR (400 MHz CDCl3) δ: 0.96 (3H, t, J=7.4 Hz), 1.43 (1H, septed, J=6.8 Hz), 1.77 (1H,
septed, J=6.8 Hz), 2.27-2.33 (2H, m), 2.65-2.70 (2H, m), 2.80 (1H, dt, J=6.6 Hz, 11.4 Hz), 2.94-3.06 (1H,
m), 3.12-3.18 (2H, m), 3.65 (1H, d, J=8.1 Hz), 3.73 (3H, s), 3.98 (1H, d, J=13.2 Hz), 5.69 (1H, s), 7.06
(1H, t, J=7.5 Hz), 7.12 (1H, d, J=7.2 Hz), 7.28 (1H, d, J=8.0 Hz), 7.45 (1H, d, J=7.5 Hz), 8.56 (1H, s);
13C-NMR (100 MHz CDCl3) δ: 11.7, 20.5, 22.4, 31.7, 45.9, 51.1, 51.7, 58.6, 59.5, 107.6, 111.0, 112.6,
118.0, 119.2, 121.2, 127.2, 133.7, 136.0, 161.9, 167.8; HR-FAB MS: Calcd for C20H24O2N2 [M+H]+:
325.1926. Found: 325.1916.
(3R,12bS)-Methyl (3-Ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-2-yl)acetate (7)
In the reactor, compound 6 (22 mg, 68 μmol) was dissolved in MeOH (5 mL) and chlorotris-
(triphenylphosphine)rhodium (I) (13 mg, 14 μmol) was added. The solution was stirred for 5 h under 5
bar H2 atmosphere at room temperature. The catalyst was removed by filtration through a plug of

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HETEROCYCLES, Vol. 81, No. 8, 2010
alumina, and the filtrate was concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (CHCl3:Et2O=5:1→ 4:1) to give 7 in 60 % yield; pale yellow amorphous;
1H-NMR (400 MHz CDCl3) δ: 0.93 (3H, t, J =7.4), 1.17 (1H, septed, J =7.6), 1.37 (1H, q, J =12.0),
1.47-1.51 (1H, m), 1.59-1.64 (1H, m), 1.79-1.84 (1H, m), 2.09-2.15 (2H, m), 2.23 (1H, d, J =12.0), 2.60
(1H, dt, J =4.6, 11.5), 2.71 (1H, dt, J =3.4, 14.5), 2.97-3.03 (1H, m), 3.07-3.13 (2H, m), 3.24 (1H, d, J
=11.4), 3.73 (3H, s), 7.08 (1H, t, J =8.0), 7.13 (1H, t, J =6.9), 7.29 (1H, d, J =8.0), 7.46 (1H, d, J =7.5),
7.85 (1H, s); 13C-NMR (100 MHz CDCl3) δ: 11.0, 21.7, 23.5, 36.0, 37.3, 38.0, 41.6, 51.6, 53.1, 59.5, 60.1,
108.1, 110.7, 118.1, 119.3, 121.3, 127.3, 134.5, 136.0, 173.7; HR-FAB MS: Calcd for C20H27O2N2
[M+H]+: 327.2073. Found: 327.2101. This compound showed a tendency to turn dark after purification,
and varying of the value of specific rotation was observed during measurement. Thus the absolute
configuration was confirmed by deriving to dihydrocorynantheol according to a literature16 procedure.
Specific rotation of the dihydrocorynantheol thus obtained was [α]24 -9.03 (c 0.080, CHCl3); {lit.,16
D
[α]22D -14.2 (c 0.921, CHCl3)}.
Spirooxindole 8
To a solution of a single isomer 5 (70 mg, 0.26 mmol) in THF/H2O/AcOH=1/1/1 (6 mL) was added NBS
(51 mg, 0.29 mmol) at 0 ºC over 23 min, and the solution was stirred for 1 h. The reaction mixture was
made basic with saturated aqueous NaHCO3 solution and the aqueous layer was extracted with AcOEt.
The combined organic layers were dried over MgSO4 and evaporated off. The residue was purified by
chromatography on silica gel (AcOEt:hexane =5:1) to give compound 8 (60 mg) in 80% yield: pale
1
yellow amorphous; H-NMR (500 MHz CDCl3) δ: 0.94 (3H, t, J=7.4 Hz), 1.20-1.30 (1H, m), 1.76-1.82
(1H, m), 1.86-1.94 (1H, m), 2.43 (1H, t, J=12.0 Hz), 2.50-2.56 (1H, m), 2.65 (1H, dt, J=14.9 Hz, 2.3 Hz),
2.85 (2H, dd, J=14.3 Hz, 3.4 Hz), 2.92-3.06 (3H, m), 3.32 (1H, dd, J=10.9 Hz, 5.2 Hz), 3.90 (1H, dd,
J=11.5 Hz, 3.4 Hz), 7.31 (1H, t, J=7.4 Hz), 7.40 (1H, td, J=7.4 Hz, 1.1 Hz), 7.53 (1H, d, J=7.4 Hz), 7.63
13
(1H, d, J=7.4 Hz); C-NMR (125 MHz CDCl3) δ: 11.6, 19.3, 37.4, 42.5, 50.2, 51.2, 59.1, 59.7, 60.1,
121.8, 123.0, 127.0, 130.0, 140.8, 151.8, 178.5, 208.6; HR-FAB MS: Calcd for C17H21O2N2 [M+H]+:
285.1603. Found: 285.1598.
Spirooxindole 9
To a solution of compound 6 (28 mg, 87 μmol) in THF/H2O/AcOH=1/1/1 (3 mL) was added NBS (17 mg,
96 μmol) at 0 ºC over 15 min, and the solution was stirred for 1 h. The reaction mixture was diluted with
H2O, and K2CO3 was added to neutralize the solution. The aqueous solution was extracted with
ethyl acetate, and the combined organic layer were dried over MgSO4 and evaporated off. The residue
was purified by chromatography on silica gel (CHCl3:Et2O=4:1) to give compound 9 in 57% yield: pale
1
yellow amorphous; [α]24 +37.7 (c 0.61, CHCl3); H-NMR (400 MHz CDCl3) δ: 1.00 (3H, t, J =7.6),
D
1.31 (1H, septed, J =7.6), 1.68-1.83 (2H, m), 2.17 (1H, t, J =10.8), 2.26-2.32 (1H, m), 2.51 (1H, t, J

HETEROCYCLES, Vol. 81, No. 8, 2010
1797
=12.9), 2.61 (1H, td, J =2.2, 14.9), 2.86-2.89 (2H, m), 3.22 (1H, dd, J = 4.0, 10.4), 3.64 (1H, dd, J = 3.0,
11.4), 3.73 (3H, s), 4.41 (1H, dd, J = 3.0, 13.6), 5.72 (1H, s), 7.30 (1H, dd, J = 0.7, 7.4), 7.39 (1H, td, J =
1.2, 7.4), 7.50 (1H, dd, J = 0.7, 8.4), 7.65 (1H, d, J =7.8); 13C-NMR (100 MHz CDCl3) δ: 11.6, 21.7, 31.3,
37.8, 45.2, 50.4, 51.2, 60.1, 60.6, 61.3, 112.5, 121.7, 122.9, 126.7, 129.9, 140.8, 152.2, 160.1, 167.1,
179.0; HR-FAB MS: Calcd for C20H25O3N2 [M+H]+: 341.1865. Found: 341.1873.
ACKNOWLEDGEMENTS
This work was supported in part by Grants-in-Aid for Scientific Research and the High-Technology
Research Center Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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