Syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A

Article abstract of DOI:10.1021/jo048365f

(Chemical Equation Presented) Total syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A were achieved via a samarium diiodide-promoted reductive deamination reaction, followed by simultaneous recyclization of a proline deri

Full text of DOI:10.1021/jo048365f

Syntheses of (+)-Cytisine, (-)-Kuraramine, (-)-Isokuraramine, and
(-)-Jussiaeiine A
Toshio Honda,* Rie Takahashi, and Hidenori Namiki
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received September 15, 2004
Total syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A were
achieved via a samarium diiodide-promoted reductive deamination reaction, followed by simulta-
neous recyclization of a proline derivative to give the corresponding δ-lactam derivative, as a key
step.
Introduction
Naturally occurring lupine alkaloids, which have a
wide range of structural and stereochemical features,
continue to provide challenging synthetic targets.1 Among
them, (-)-cytisine (1)2 has received special attention3 and
several synthetic methods have been developed,4 since
it has been shown to be an important probe in nicotinic
acetylcholine receptor research5 and shows high affinity
at neuronal nicotinic receptors.6
FIGURE 1. Structure of dipiperidine alkaloids.
(+)-Kuraramine (2) and (+)-jussiaeiine A (3), isolated
are dipiperidine-type alkaloids with two chiral centers
at the 3 and 5 positions of the piperidine ring, and are
known to be oxidative metabolites of N-methylcytisine.
Another dipiperidine-type alkaloid, (+)-isokuraramine
(4)9 was also isolated from the fresh flowers of Sophora
flavescens as a minor constituent, and its structure was
determined to be the diastereoisomer of (+)-kuraramine
by spectroscopic methods.9 However, little attention has
been focused on the chiral synthesis of these alkaloids
(Figure 1).
Thus, we planned to establish a novel synthetic route
to these alkaloids, including cytisine, via a common
synthetic intermediate. The key feature of our synthesis
is based on a samarium diiodide-promoted reductive
from Sophora flavescens7 and Ulex jussiaei,8 respectively,
(1) (a) Ohmiya, S.; Saito, K.; Murakoshi, I. Lupine Alkaloids. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1995; Vol.
47, pp 1-114. (b) El-Shazly, A.; Sarg, T.; Ateya, A.; Witte, E. A.; Wink,
M. Pharmazie 1996, 51, 768.
(2) (a) Partheil, A. Arch. Pharm. (Weinheim, Ger.) 1894, 232, 161.
(b) Ing, H. R. J. Chem. Soc. 1932, 2778. (c) Leonard, N. J. In The
Alkaloids; Manske, R. H. F., Holmes, H. L., Eds.; Academic Press: New
York, 1953; Vol. 3, pp 119-199. (d) El-Shazly, A.; Sarg, T.; Ateya, A.;
Witte, E. A.; Wink, M. Pharmazie 1996, 51, 768.
(3) (a) van Tamelen, E. E.; Baran, J. S. J. Am. Chem. Soc. 1955, 77,
4944. (b) van Tamelen, E. E.; Baran, J. S. J. Am. Chem. Soc. 1956, 78,
2913. (c) van Tamelen, E. E.; Baran, J. S. J. Am. Chem. Soc. 1958, 80,
4659. (d) Bohlmann, F.; English, A.; Ottawa, N.; Sander, H.; Weise,
W. Chem. Ber. 1956, 89, 792. (e) Govindachari, T. R.; Rajadurai, S.;
Subramanian, M.; Thyagarajan, B. S. J. Chem. Soc. 1957, 3839.
(4) For recent synthesis of racemic cytisine, see: (a) Nshimyumu-
kiza, P.; Cahard, D.; Rouden, J.; Lasne, M.-C.; Plaquevent, J.-C.
Tetrahedron Lett. 2001, 42, 7787. (b) O’Neill, B. T.; Yohannes, D.;
Bundesmann, M. W.; Arnold, E. P. Org. Lett. 2000, 2, 4201. (c) Coe, J.
W. Org. Lett. 2000, 2, 4205. (d) Botuha, C.; Galley, C. M. S.; Gallagher,
T. Org. Biomol. Chem. 2004, 2, 1825 and references therein. For chiral
synthesis of (-)-cytisine, see: (e) Danieli, B.; Lesma, G.; Passarella,
D.; Sacchetti, A.; Silvani, A.; Virdis, A. Org. Lett. 2004, 6, 493.
(5) (a) Barlow, R. B.; McLeod, L. J. Br. J. Pharmacol. 1969, 35, 161.
(b) McDonald, I. A.; Cosford, N.; Vernier, J.-M. Annual Reports in
Medicinal Chemistry; Academic Press: New York, 1994; Vol. 30, pp
41-50. (c) Schmitt, J. D.; Bencherif, M. Annual Reports in Medicinal
Chemistry; Academic Press: New York, 2000; Vol. 35, pp 41-52.
(6) (a) Pabreza, L. A.; Dhawan, S.; Keller, K. J. Mol. Pharmacol.
1991, 39, 9. (b) Hall, M.; Zerbe, L.; Leonard, S.; Freedman, R. Brain
Res. 1993, 600, 127. (c) Happe, H. K.; Peters, J. L.; Bergman, D. A.;
Murrin, L. C. Neuroscience 1994, 62, 929.
(7) Murakoshi, I.; Kidoguchi, E.; Haginiwa, J.; Ohmiya, S.; Higash-
iyama, K.; Otomasu, H. Phytochemistry 1981, 20, 1407. Kuraramine
was isolated as an amorphous solid.
(8) Ma´ximo, P.; Lourenc¸o, A. J. Nat. Prod. 2000, 63, 201.
(9) Murakoshi, I.; Kidoguchi, E.; Haginiwa, J.; Ohmiya, S.; Higash-
iyama, K.; Otomasu, H. Phytochemistry 1982, 21, 2379. The optical
rotation has not yet been reported, due to the small amount available.
10.1021/jo048365f CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/15/2004
J. Org. Chem. 2005, 70, 499-504
499

Honda et al.
Again, the physicochemical properties of ent-2 were
identical with those reported in the literature, except for
the sign of optical rotation14 {ent-2: mp 78-80 °C, [R]D
-3.6 (c 2.1, EtOH); lit.7 [R]D +8.4 (c 0.52, EtOH)}.
The same treatment of the diastereoisomeric compound
17 gave isokuraramine ent-4 as an amorphous solid, [R]D
-93.0 (c 2.1, EtOH).9
FIGURE 2. Reductive deamination of R-aminocarbonyl com-
pounds.
To achieve the total synthesis of (+)-cytisine from the
common intermediate 13 through the formation of a
carbon-nitrogen bond, as shown in Scheme 4, N-benzy-
lation of 13 and subsequent ethoxycarbonylation of 18
with ethyl chlorocarbonate in the presence of LDA were
carried out to provide a mixture of diastereoisomeric
â-ketoesters (19 and 20) in a ratio of ca. 1:1.
deamination reaction of an R-amino ester, recently
developed by us, as depicted in Figure 2.10
On the basis of a retrosynthetic analysis of these
alkaloids as depicted in Scheme 1, we decided to exploit
a readily available 4R-hydroxy-L-proline derivative as a
starting material to synthesize the enantiomers of the
aforementioned natural products, since the use of the
antipodal starting material, D-hydroxyproline,11 should
lead to the synthesis of natural products if this synthetic
strategy can be established.
Although the attempted isomerization of the mixture
to the thermodynamically more stable 3,5-cis-compound
under various reaction conditions, such as basic treat-
ment of a mixture of 19 and 20 with lithium diisopropyl-
amide in THF, sodium hydride in appropriate solvents,
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in benzene,
did not improve the ratio, reduction of the mixture with
LiAlH4 gave the primary alcohols 21 and 22, in respective
yields of 48% and 43%. Finally, mesylation of 21 followed
by thermal cyclization of the mesylate yielded the tricyclic
compound 23. Debenzylation of 23 under the hydro-
genolysis conditions furnished ent-1, whose spectroscopic
data were identical with those reported in the literature15
except for the sign of optical rotation {ent-1: mp 152-
153 °C, [R]D +113.5 (c 0.3, EtOH); lit.16 mp 152-153 °C,
lit.15 [R]D -110 (c 0.5, EtOH), lit.4e [R]D -114 (c 1, EtOH)}.
In summary, we have established novel and facile
syntheses of dipiperidine-type lupine alkaloids, including
cytisine. Although these syntheses give the antipodal
forms of the natural products, we believe that the
strategy developed here should be a useful tool for finding
new drugs that are biologically related to cytisine.
Results and Discussion
Thus, 4-hydroxy-L-proline methyl ester 5 was con-
verted to the corresponding triflate 8 in three steps.
Treatment of 8 with 2-tributylstannyl-6-methoxypyridine
9 in the presence of a palladium catalyst12 afforded the
coupling product 10 in 88% yield. Hydrogenation of 10
over 10% palladium-charcoal in MeOH gave 11, stereo-
selectively. After the Boc group was removed, samarium
diiodide-promoted reductive deamination of the resulting
12, followed by simultaneous cyclization of the resulting
δ-amino ester, was carried out in THF-HMPA in the
presence of methanol as a proton source to give the
desired common intermediate, the δ-lactam 13, in 78%
yield.10 (Scheme 2)
N-Methylation of 13 with iodomethane and sodium
hydride in THF-HMPA furnished the corresponding
N-methylpiperidone 14, which was further converted into
hydroxymethyl derivative as follows.
Treatment of the amide 14 with ethyl chlorocarbonate
in the presence of LDA in THF gave an inseparable
mixture of diastereomers (15 and 16), in a ratio of ca.
1:1. Reduction of the amide and ester functions of the
mixture with LiAlH4 in THF afforded the amino alcohols
ent-3 and 17 in respective yields of 50% and 46%. The
spectroscopic data of ent-3 obtained here were identical
with those reported for (+)-jussiaeiine A (Scheme 3).
Moreover, the sign of the optical rotation of the synthetic
compound corresponded to that of the antipode {ent-3,
[R]D -5.2 (c 0.5, CHCl3); lit.8 [R]D +3.3 (c 0.26, CHCl3)}.
Therefore, we were able to establish the first enantiose-
lective synthesis of (-)-jussiaeiine A. Jussiaeiine A (ent-
3) was converted into (-)-kuraramine (ent-2) by treat-
ment with iodotrimethylsilane in refluxing acetonitrile.13
Experimental Section
Methyl (2S)-N-tert-Butoxycarbonyl-4-[2′-(6′-methoxy-
pyridyl)]-2,5-dihydropyrrole-2-carboxylate (10). To a
stirred solution of vinyl triflate (8) (2.12 g, 5.65 mmol) and
pyridyl(tributyl)stannane (9) (2.70 g, 6.78 mmol) in THF (30
mL) were successively added tetrakis(triphenylphosphine)-
palladium(0) (327 mg, 0.283 mmol), lithium chloride (288 mg,
6.78 mmol), and copper(I) iodide (1.29 g, 6.78 mmol) at room
temperature under argon. The mixture was heated at 65 °C
for 4 h. After being cooled to room temperature, the mixture
was diluted with Et2O and the organic layer was washed with
5% NH4OH. The aqueous layer was extracted with Et2O. The
combined ethereal layer was washed with brine and dried over
Na2SO4. Evaporation of the solvent gave a residue, which was
subjected to silica gel column chromatography. Elution with
hexanes-Et2O (3:2) afforded the coupling product (10) (1.66
g, 88%) as an inseparable mixture of rotational isomers. [R]25
D
-135 (c 1.0, CHCl3); IR (cm-1) 1755, 1709, 1470, 1433, 1400,
(10) (a) Honda, T.; Ishikawa,F. Chem. Commun. 1999, 1065. (b)
Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925. (c) Katoh, M.; Matsune,
R.; Nagase, H.; Honda, T. Tetrahedron Lett. 2004, 45, 6221.
(11) D-Hydroxyproline is a known compound, see: (a) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5256.
(b) Schch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry 2002, 13, 1973.
(c) Sagawa, Y.; Kimura, T.; Fujikawa, T.; Noguchi, K.; Ohtake, N.
Bioorg. Med. Chem. Lett. 2003, 13, 57.
(12) Koskinen, A. M. P.; Schwerdtfeger, J.; Edmonds, M. Tetrahe-
dron Lett. 1997, 38, 5399.
(13) (a) Gonza´lez, C.; Guilia´n, E.; Castedo, L. Tetrahedron 1999, 55,
5195. (b) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2000,
2, 3421. (c) Baldwin, J. E.; Adlington, R. M.; Conte, A.; Irtapati, N. R.;
Marquez, R.; Pritchard, G. J. Org. Lett. 2002, 4, 2125.
1
1368, 1346, 1329, 1273, 1257, 1202, 1176 and 1126; H NMR
δ 1.46 (5.85H, s), 1.53 (3.15H, s), 3.76 (1.95H, s), 3.77 (1.05H,
s), 3.92 (1.95H, s), 3.94 (1.05H, s), 4.58-4.71 (2H, m), 5.15-
(14) Although the value of the optical rotation of ent-2 was slightly
lower than that in the literature, we believe that our synthetic
compound is optically pure, since the intermediate 10 was successfully
transformed into cytisine with the correct optical rotation.
(15) Wang, Y.-H.; Li, J.-S.; Kubo, H.; Higashiyama, K.; Komiya, H.;
Ohmiya, S. Chem. Pharm. Bull. 1999, 47, 1308.
(16) Normatov, M.; Abduazimov, K. A.; Yunusov, S. Y. Dokl. Akad.
Nauk USSR 1962, 19, 45.
500 J. Org. Chem., Vol. 70, No. 2, 2005

Synthesis of Naturally Occurring Lupine Alkaloids
SCHEME 1. Retrosynthetic Route for Dipiperidine Alkaloids
SCHEME 2. Preparation of the Key δ-Lactama
a Reagents and conditions: (a) (Boc)2O, Et3N, CH2Cl2, rt (quant.); (b) (COCl)2, DMSO, Et3N, CH2Cl2, -40 °C to rt (91%); (c) LiHMDS,
N-(5-chloro-2-pyridyl)triflimide, THF, -78 to -20 °C (89%); (d) Pd(PPh3)4, LiCl, CuI, 2-tributylstannyl-6-methoxypyridine (9), THF, 65
°C (88%); (e) H2, Pd/C, MeOH, rt (quant.); (f) TFA, CH2Cl2, 0 °C (quant.); (g) SmI2, THF-HMPA, MeOH, 0 °C to rt (78%); (h) NaH, MeI,
THF-HMPA, 0 °C to rt (quant.); (i) LDA, ClCO2Et, THF, -78 °C (quant.).
Anal. Calcd for C17H22N2O5: C, 61.06; H, 6.63; N, 8.38.
Found: C, 60.81; H, 6.62; N, 8.23.
SCHEME 3. Synthesis of ent-Jussiaeiine A,
ent-Kuraramine, and ent-Isokuraraminea
Methyl (2S,4S)-2-N-tert-Butoxycarbonyl-4-[2′-(6′-meth-
oxypyridyl)]pyrrolidine-2-carboxylate (11). A solution of
compound 10 (100 mg, 0.315 mmol) in MeOH (1.6 mL)
containing 10% palladium-carbon (10 mg) was stirred at room
temperature under an atmospheric pressure of hydrogen for
2 h. After the insoluble material was removed by filtration
through a pad of Celite, the filtrate was concentrated to give
a residue, which was subjected to silica gel column chroma-
tography. Elution with hexanes-EtOAc (4:1) afforded the
reduction product (11) (101 mg, 100%) as an inseparable
mixture of rotational isomers. [R]24 -20.7 (c 1.0, CHCl3); IR
D
(cm-1) 1753, 1703, 1603, 1590, 1579, 1468, 1439, 1402, 1366,
1290, 1260, 1200, 1179, 1160, 1119, and 1136; 1H NMR δ 1.43
(6.03H, s), 1.47 (2.97H, s), 2.34 (1H, ddd, J ) 9.6, 11.0, and
12.4 Hz), 2.62 (1H, ddd, J ) 6.9, 7.4, and 12.4 Hz), 3.41 (1H,
dddd, J ) 6.9, 7.4, 10.4, and 11.0 Hz), 3.64 (0.33H, dd, J )
10.4 and 10.9 Hz), 3.67 (0.67H, dd, J ) 10.4 and 10.9 Hz),
3.74 (2.01H, s), 3.76 (0.99H, s), 3.90 (2.01H, s), 3.91 (0.99H,
s), 4.03 (1H, dd, J ) 7.4 and 10.9 Hz), 4.34 (0.67H, dd, J ) 7.4
and 9.6 Hz), 4.41 (0.33H, dd, J ) 7.4 and 9.6 Hz), 6.60 (1H,
dd, J ) 0.5 and 8.2 Hz), 6.73 (0.67H, br d, J ) 7.3 Hz), 6.76
(0.33H, br d, J ) 7.3 Hz), 7.49 (1H, dd, J ) 7.3 and 8.2 Hz);
13C NMR δ up 35.8, 36.6, 51.3, 80.1, down 28.3, 28.4, 44.5,
45.3, 51.9, 52.1, 53.2, 59.1, 59.3, 109.0, 114.6, 138.8; HRMS
m/z (EI) calcd for C17H24N2O5 (M+) 336.1685, found 336.1683.
a Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt (50%
for ent-3; 46% for 17); (b) TMSCl, NaI, MeCN, reflux (83% for ent-
2; quant. for ent-4).
5.17 (0.65H, m), 5.21-5.25 (0.35H, m), 6.67 (1H, d, J ) 8.2
Hz), 7.42 (1H, d, J ) 7.4 Hz), 7.55 (1H, dd, J ) 7.4 and 8.2
Hz); 13C NMR δ up 52.6, 52.9, 80.2, 141.6 148.3, 148.4, 153.3,
153.8, 163.3, 170.4, 170.8, down 28.1, 28.3, 52.1, 52.2, 53.0,
66.9, 67.3, 110.6, 110.8, 113.3, 121.1, 121.5, 138.7; HRMS m/z
(EI) calcd for C17H23N2O5 (M+ + 1) 335.1607, found 335.1610.
J. Org. Chem, Vol. 70, No. 2, 2005 501

Honda et al.
SCHEME 4. Synthesis of ent-Cytisinea
with brine, and dried over Na2SO4. Evaporation of the solvent
gave a residue, which was purified by column chromatography
on silica gel with EtOAc-MeOH (10:1) as an eluent to afford
the δ-lactam (13) (204 mg, 78%) as crystals. [R]27 -42.5 (c
D
1.0, CHCl3); mp 130-131 °C (colorless prisms from hexane-
CH2Cl2); IR (cm-1) 1668, 1600, 1580, 1496, 1468, 1439, 1414,
1316, 1285, 1036, 808, and 775; 1H NMR δ 2.11-2.25 (2H, m),
2.42-2.60 (2H, m), 3.55-3.68 (2H, m), 3.91 (3H, s), 5.90 (1H,
br s), 6.62 (1H, d, J ) 8.2 Hz), 6.78 (1H, d, J ) 7.3 Hz), 7.52
(1H, dd, J ) 7.3 and 8.2 Hz); 13C NMR δ up 26.6, 30.8, 46.7,
158.6, 163.6, 172.1, down 40.6, 53.1, 108.8, 114.1, 139.0; HRMS
m/z (EI) calcd for C11H14N2O2 (M+) 206.1055, found 206.1078.
Anal. Calcd for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58.
Found: C, 63.81; H, 6.83; N, 13.42.
5(S)-[2′-(6-Methoxypyridyl)]-N-methyl-2-piperidone (14).
To a mixture of lactam 13 (406 mg, 1.97 mmol) and sodium
hydride (60% in oil) (118 mg, 2.96 mmol) in dry THF (10 mL)
containing hexamethylphosphoric triamide (0.514 mL, 2.96
mmol) was added iodomethane (0.514 mL, 2.37 mmol) at 0 °C,
and the resulting mixture was stirred for 90 min at room
temperature. The mixture was treated with saturated NH4Cl
solution and extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. Evaporation of the
solvent gave a residue, which was subjected to column chro-
matography on silica gel. Elution with CHCl3-MeOH (25:1,
v/v) gave the N-methyl compound 14 (433 mg, 99%) as a
colorless solid: [R]26 -37.3 (c 1.0, CHCl3); mp 48-50 °C
D
a Reagents and conditions: (a) NaH, BnBr, THF-HMPA, THF,
0 °C to rt (quant.); (b) LDA, ClCO2Et, THF, -78 °C (quant.); (c)
LiAlH4, THF, 0 °C to rt (48% for 19; 43% for 20 from 13); (d) MsCl,
Et3N, CH2Cl2, 0 °C, then toluene, reflux (89% from 21); (e) H2,
Pd(OH)2, ammonium formate, MeOH, reflux (81%).
(colorless prisms from Et2O-hexane); IR (cm-1) 1640, 1600,
1578, 1466, 1286, and 1130; 1H NMR δ 2.09-2.18 (2H, m),
2.47-2.55 (2H, m), 3.00 (3H, s), 3.17 (1H, m), 3.46-3.67 (2H,
m), 3.91 (3H, s), 6.62 (1H, d, J ) 8.2 Hz), 6.76 (1H, d, J ) 7.2
Hz), 7.52 (1H, dd, J ) 7.2 and 8.2 Hz); 13C NMR δ up 27.1,
31.4, 54.2, 158.6, 163.7, 169.6, down 34.7, 41.2, 53.2, 108.8,
114.1, 139.0; HRMS m/z (EI) calcd for C12H16N2O2 (M+)
220.1212, found 220.1215. Anal. Calcd for C12H16N2O2: C,
65.43; H, 7.32; N, 12.72. Found: C, 65.49; H, 7.33; N, 12.68.
Anal. Calcd for C17H24N2O5: C, 60.70; H, 7.19; N, 8.21.
Found: C, 60.47; H, 7.27; N, 8.21.
Methyl (2S,4S)-4-[2′-(6′-Methoxypyridyl)]pyrrolidine-
2-carboxylate (12). To a stirred solution of 11 (50.0 mg, 0.149
mmol) in CH2Cl2 (0.7 mL) was added trifluoroacetic acid (0.23
mL, 2.98 mmol) at 0 °C under argon, and the resulting solution
was stirred for 2 h at room temperature. After the mixture
was concentrated, the residue was treated with saturated
aqueous NaHCO3 solution and extracted with CH2Cl2. The
extract was dried over Na2SO4. Evaporation of the solvent gave
a residue, which was subjected to silica gel column chroma-
tography. Elution with CHCl3-MeOH (20:1) afforded the
3-Ethoxycarbonyl-5(S)-[2′-(6′-methoxypyridyl)]-N-meth-
yl-2-piperidones 15 and 16. To a solution of the N-methyl
compound 14 (200 mg, 0.909 mmol) in dry THF (4.5 mL) in
the presence of lithium diisopropylamide [prepared from
diisopropylamine (0.64 mL, 4.55 mmol) and n-butyllithium
(1.58 M hexane solution) (3.00 mL, 4.55 mmol)] was added
ethyl chloroformate (0.130 mL, 1.36 mmol) at -78 °C under
argon, and the solution was stirred for 1 h at the same
temperature. The mixture was treated with saturated NH4Cl
solution and extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. Evaporation of the
solvent gave a residue, which was subjected to column chro-
matography on silica gel. Elution with hexanes-EtOAc (1:3,
v/v) gave an inseparable mixture of the esters 15 and 16 (433
mg, 99%) as a colorless oil: IR (cm-1) 1739, 1650, 1600, 1578,
1468, 1292, 1266, 1186, 1156, and 1032; 1H NMR δ 1.30 (1.5H,
t, J ) 7.1 Hz), 1.31 (1.5H, t, J ) 7.1 Hz), 2.28-2.60 (2H, m),
3.00 (1.5H, s), 3.03 (1.5H, s), 3.14-3.26 (0.5H, m), 3.40-3.76
(3.5H, m), 3.90 (1.5H, s), 3.92 (1.5H, s), 4.15-4.33 (2H, m),
6.62 (0.5H, d, J ) 8.2 Hz), 6.63 (0.5H, d, J ) 8.2 Hz), 6.76
(0.5H, d, J ) 7.3 Hz), 6.77 (0.5H, d, J ) 7.3 Hz), 7.52 (0.5H,
dd, J ) 7.1 and 8.2 Hz), 7.53 (0.5H, dd, J ) 7.3 and 8.2 Hz);
13C NMR δ up 30.3, 30.9, 54.0, 54.4, 61.3, 61.4, 157.5, 157.8,
163.8, 165.7, 170.9, 171.3, down 14.1, 35.0, 35.1, 37.7, 40.6,
47.4, 49.6, 53.2, 53.3, 109.0, 109.3, 114.1, 114.4, 139.1; HRMS
m/z (EI) calcd.for C15H20N2O4 (M+) 292.1423, found 292.1421.
amine 12 (35.0 mg, 100%) as a colorless oil. [R]23 -40.4 (c
D
1.0, CHCl3); IR (cm-1) 1740, 1600, 1579, 1469, 1438, 1418,
1280, 1260, 1210, 1135 and 805; 1H NMR δ 2.19 (1H, ddd, J )
7.7, 7.9 and 12.9 Hz), 2.32 (1H, br s), 2.58 (1H, td, J ) 8.2 and
12.9 Hz), 3.24-3.27 (2H, m), 3.31-3.47 (1H, m), 3.75 (3H, s),
3.90 (3H, s), 3.90-3.95 (1H, m), 6.56 (1H, dd, J ) 0.7 and 8.2
Hz), 6.70 (1H, br d, J ) 7.2 Hz), 7.45 (1H, dd, J ) 7.2 and 8.2
Hz); 13C NMR δ up 35.1, 50.5, 155.6, 164.2, 169.4, down 43.9,
53.4, 58.6, 100.5, 110.1, 115.1, 139.5; HRMS m/z (EI) calcd for
C12H16N2O3 (M+) 236.1161, found 236.1147.
5(S)-[2′-(6′-Methoxypyridyl)]-2-piperidone (13). A 0.2 M
THF solution of samarium diiodide was prepared as follows.
To a stirred solution of Sm metal (1.15 g, 7.63 mmol) in THF
(16 mL) was slowly added a solution of diiodoethane (1.79 g,
6.37 mmol) in THF (16 mL) at ambient temperature under
argon, and the resulting dark blue solution was stirred for 30
min at the same temperature. The solution was cooled to 0
°C. HMPA (3 mL) was added and the whole was stirred for an
additional 15 min at the same temperature. To this solution
were added dry MeOH (0.129 mL, 3.18 mmol) and a solution
of 12 (300 mg, 1.27 mmol) in THF (3 mL) at the same
temperature, and the resulting mixture was stirred for 40 min
at ambient temperature. The mixture was treated with
saturated NaHCO3 solution (2 mL), Celite (10 g), and CHCl3-
MeOH (50 mL, 10/1, v/v). Insoluble materials were filtered off,
and the filtrate was treated with NaCl (5 g) and 20% NH4OH
solution (20 mL). The organic layer was separated, washed
(-)-Jussiaeiine A (ent-3) and (3S,5S)-3-Hydroxymeth-
yl-5-[2′-(6′-methoxypyridyl)]-N-methylpiperidine (17). To
a stirred suspension of lithium aluminum hydride (494 mg,
13.0 mmol) in THF (7 mL) was added a solution of the esters
15 and 16 (634 mg, 2.17 mmol) in THF (4 mL) at 0 °C, and
the resulting mixture was stirred for 12 h at room tempera-
ture. A 10% NaOH solution was carefully added to this mixture
and the insoluble material was filtered off by filtration through
a pad of Celite. The filtrate was concentrated to leave a
residue, which was purified by column chromatography on
502 J. Org. Chem., Vol. 70, No. 2, 2005

Synthesis of Naturally Occurring Lupine Alkaloids
silica gel with CHCl3-MeOH (50:1) as an eluent to afford
jussiaeiine A (ent-3) (257 mg, 50%) as a colorless oil. [R]27D -5.2
(c 0.5, CHCl3); IR (cm-1) 3360, 1600, 1590, 1578, 1466, 1440,
1416, 1317, 1292, 1270, 1070, 1037, and 1028; 1H NMR δ 1.25-
1.39 (1H, m), 1.66-1.75 (2H, m), 1.97-2.13 (2H, m), 2.35 (3H,
s), 2.92-3.09 (3H, m), 3.54 (1H, dd, J ) 6.8 and 10.7 Hz), 3.61
(1H, dd, J ) 5.6 and 10.7 Hz), 3.91 (3H, s), 6.56 (1H, d, J )
8.2 Hz), 6.73 (1H, d, J ) 7.3 Hz), 7.48 (1H, dd, J ) 7.3 and 8.2
Hz); 13C NMR δ up 32.6, 58.9, 61.1, 66.0, 160.7, 163.5, down
39.2, 43.7, 46.4, 53.1, 107.8, 114.1, 138.8; HRMS m/z (EI) calcd
for C13H20N2O2 (M+) 236.1525, found 236.1509.
J ) 4.2, 6.0, and 17.6 Hz), 3.11 (1H, dddd, J ) 5.0, 5.1, 9.9,
and 10.1 Hz), 3.43 (1H, ddd, J ) 1.2, 5.1, and 12.0 Hz), 3.54
(1H, dd, J ) 10.1 and 12.0 Hz), 3.85 (3H, s), 4.51 (1H, d, J )
14.6 Hz), 4.79 (1H, d, J ) 14.6 Hz), 6.58 (1H, d, J ) 8.2 Hz),
6.67 (1H, d, J ) 7.3 Hz), 7.72-7.35 (5H, m), 7.46 (1H, dd, J )
7.3 and 8.2 Hz); 13C NMR δ up 26.9, 31.6, 50.3, 51.6, 137.1,
158.5, 163.6, 169.5, down 41.3, 53.1, 108.7, 114.1, 127.3, 128.2,
128.5, 139.0; HRMS m/z (EI) calcd for C18H20N2O2 (M+)
296.1525, found 296.1526.
N-Benzyl-3-ethoxycarbonyl-5(S)-[2′-(6′-methoxypyri-
dyl)]-2-piperidone 19 and 20. Ethoxycarbonylation of 18 (70
mg, 0.237 mmol) was carried out by using the same procedure
as for the preparation of the mixture of 15 and 16 and gave
an inseparable mixture of 19 and 20 (368 mg, 99%) as a
Further elution with the same solvent system afforded
trans-alcohol 17 (238 mg, 46%) as a colorless oil. [R]27 +6.4
D
(c 1.0, CHCl3); IR (cm-1) 3370, 1600, 1578, 1466, 1440, 1414,
1
colorless oil: IR (cm-1) 1736, 1648, 1600, 1578, and 1468; H
1
1275, and 1039; H NMR δ 1.88-2.03 (3H, m), 2.27 (3H, s),
NMR δ 1.33 (3H, t, J ) 7.1 Hz), 2.35-2.61 (2H, m), 3.06-3.18
(0.5H, m), 3.34-3.68 (3.5H, m), 3.84 (1.5H, s), 3.87 (1.5H, s),
4.21-4.32 (2H, m), 4.37 (0.5H, d, J ) 14.7 Hz), 4.48 (0.5H, d,
J ) 14.7 Hz), 4.82 (0.5H, d, J ) 14.7 Hz), 4.98 (0.5H, d, J )
14.7 Hz), 6.58 (0.5H, d, J ) 8.3 Hz), 6.59 (0.5H, d, J ) 8.3
Hz), 6.66 (0.5H, d, J ) 7.2 Hz), 6.69 (0.5H, d, J ) 7.2 Hz),
7.28-7.36 (5H, m), 7.46 (1H, dd, J ) 7.2 and 8.3 Hz); 13C NMR
δ up 30.2, 30.8, 50.3, 50.5, 51.2, 51.8, 61.3, 61.4, 136.6, 136.7,
157.4, 157.7, 163.6, 163.7, 165.5, 165.7, 170.8, 171.3, down 14.1,
37.8, 40.5, 47.7, 49.7, 53.1, 53.2, 108.9, 109.1, 114.1, 114.4,
127.3, 127.4, 128.0, 128.1, 128.5, 128.6, 138.9, 139.0; HRMS
m/z (EI) calcd for C21H24N2O4 (M+) 368.1736, found 368.1716.
2.32-2.38 (2H, m), 2.89-2.99 (2H, m), 3.35-3.46 (1H, m), 3.85
(1H, dd, J ) 1.8 and 10.4 Hz), 3.92 (3H, s), 4.00 (1H, dd, J )
4.4 and 10.4 Hz), 6.56 (1H, d, J ) 8.2 Hz), 7.25 (1H, d, J ) 7.3
Hz), 7.48 (1H, dd, J ) 7.3 and 8.2 Hz); 13C NMR δ up 32.7,
58.8, 60.9, 68.2, 161.0, 163.5, down 34.6, 40.9, 46.5, 53.1, 107.8,
114.4, 138.7; HRMS m/z (EI) calcd for C13H20N2O2 (M+)
236.1525, found 236.1530.
(-)-Isokuraramine (ent-4). A mixture of trans-alcohol 14
(75.0 mg, 0.318 mmol), chlorotrimethylsilane (0.403 mL, 3.18
mmol), sodium iodide (119 mg, 0.795 mmol), and dry acetoni-
trile (3.2 mL) was heated at reflux for 2 h. After being cooled
to room temperature, the mixture was treated with 20% NH4-
OH solution and concentrated to leave an aqueous layer. The
aqueous layer was extracted with CH3Cl-MeOH (10:1, v/v).
The extract was dried over Na2SO4. Evaporation of the solvent
gave a residue, which was subjected to silica gel column
chromatography. Elution with CHCl3-MeOH-NH4OH (6:1:
0.1) afforded isokuraramine (ent-4) (70.1 mg, 100%) as an
(3R,5S)-N-Benzyl-3-hydroxymethyl-5-[2′-(6′-methoxy-
pyridyl)]piperidine (21) and (3S,5S)-N-Benzyl-3-hydroxy-
methyl-5-[2′-(6′-methoxypyridyl)]piperidine (22). Reduc-
tion of the esters 19 and 20 (50 mg, 0.136 mmol) with lithium
aluminum hydride (30.9 mg, 0.815 mmol) was carried out by
using the same procedure as for the preparation of ent-3 and
17 and gave the cis-alcohol 21 (20.4 mg, 48%) and trans-alcohol
22 (18.3 mg, 43%), respectively.
amorphous solid. [R]29 -93.0 (c 2.1, EtOH); IR (cm-1) 3355,
D
1
1650, 1550, 1464, 1455, and 1050; H NMR δ 1.50-2.29 (5H,
21: [R]26D +22.7 (c 0.75, CHCl3); IR (cm-1) 3360, 1599, 1590,
m), 2.30 (3H, s), 2.63 (2H, br s), 3.03 (1H, br s), 3.53 (1H, dd,
J ) 5.1 and 11.4 Hz), 3.80 (1H, br s), 6.02 (1H, d, J ) 6.9 Hz),
6.42 (1H, d, J ) 9.2 Hz), 7.37 (1H, dd, J ) 6.9 and 9.2 Hz),
12.8 (1H, br s); 13C NMR δ up 32.0, 57.8, 57.9, 63.6, 152.3,
165.0, down 34.8, 35.6, 46.4, 103.7, 116.9, 141.9; HRMS m/z
(EI) calcd for C12H18N2O2 (M+) 222.1368, found 222.1343.
1
1578, 1466 and 1440, 1412, 1036; H NMR δ 1.26-1.42 (1H,
m), 1.57 (1H, br s), 1.72-1.80 (1H, m), 1.95-2.08 (2H, m),
2.12-2.20 (1H, m), 2.92-3.14 (3H, m), 3.48-3.60 (4H, m), 3.90
(3H, m), 6.54 (1H, d, J ) 8.1 Hz), 7.70 (1H, d, J ) 7.3 Hz),
7.22-7.35 (5H, m), 7.45 (1H, dd, J ) 7.3 and 8.1 Hz); 13C NMR
δ up 33.2, 56.6, 59.1, 63.3, 66.3, 138.0, 161.0, 163.4, down 39.0,
43.7, 53.1, 107.7, 114.1, 126.9, 128.1, 129.2, 138.7; HRMS m/z
(EI) calcd for C19H24N2O2 (M+) 312.1838, found 312.1849.
(-)-Kuraramine (ent-2). Kuraramine (ent-2) was obtained
from ent-3 (130 mg, 0.551 mmol), chlorotrimethylsilane (0.699
mL, 5.51 mmol), and sodium iodide (206 mg, 1.38 mmol) in
acetonitrile (5.5 mL) by the same procedure as for the
preparation of isokuraramine to give kuraramine ent-2 (101
mg, 83%) as crystals. [R]28D -3.6 (c 2.1, EtOH); mp 78-80 °C
(colorless needles from acetone-hexane); IR (cm-1) 3280, 1651,
1615, 1550, and 1457; 1H NMR δ 1.20-1.34 (1H, m), 1.8 (1H,
br t, J ) 11.0 Hz), 1.95-2.09 (3H, m), 2.34 (3H, s), 2.52 (1H,
br s), 2.84-2.95 (1H, m), 3.06 (2H, br d, J ) 11.0 Hz), 3.51-
3.60 (2H, m), 6.07 (1H, br d, J ) 6.9 Hz), 6.44 (1H, dd, J ) 0.8
and 9.1 Hz), 7.37 (1H, dd, J ) 6.9 and 9.1 Hz); 13C NMR δ up
31.6, 58.3, 60.1, 65.2, 150.9, 165.3, down 38.7, 39.7, 46.0, 103.7,
117.6, 141.8; HRMS m/z (EI) calcd for C12H18N2O2 (M+)
222.1368, found 222.1392.
N-Benzyl-5(S)-[2′-(6′-methoxypyridyl)]-2-piperidone
(18). To a mixture of the lactam 13 (215 mg, 1.04 mmol) and
sodium hydride (60% in oil) (50.1 mg, 1.25 mmol) in dry THF
(5 mL) containing hexamethylphosphoric triamide (0.272 mL,
1.57 mmol) was added benzyl bromide (0.186 mL, 1.57 mmol)
at 0 °C, and the resulting mixture was stirred for 90 min at
room temperature. The mixture was treated with saturated
NH4Cl solution and extracted with EtOAc. The organic layer
was washed with brine and dried over Na2SO4. Evaporation
of the solvent gave a residue, which was subjected to column
chromatography on silica gel. Elution with CHCl3-MeOH (25:
1, v/v) gave the N-benzyl compound 18 (309 mg, 99%) as a
colorless oil: [R]26D +5.6 (c 1.0, CHCl3); IR (cm-1) 1643, 1578,
1468, 1289, and 1031; 1H NMR δ 2.09 (1H, dddd, J ) 4.2, 5.0,
10.2, and 19.3 Hz), 2.18 (1H, dddd, J ) 6.0, 6.8, 9.9, and 19.3
Hz), 2.56 (1H, ddd, J ) 6.8, 10.2, and 17.6 Hz), 2.67 (1H, ddd,
22: [R]27D +43.7 (c 0.5, CHCl3); IR (cm-1) 3360, 1597, 1579,
1466, and 1037; 1H NMR δ 1.57 (1H, br s), 1.93-2.06 (3H, m),
2.31-2.47 (2H, m), 2.96-3.05 (2H, m), 3.38-3.49 (1H, m), 3.52
(2H, s), 3.85 (1H, dd, J ) 1.8 and 10.5 Hz), 3.90 (3H, s), 3.98
(1H, dd, J ) 4.0 and 10.5 Hz), 6.54 (1H, d, J ) 8.2 Hz), 6.75
(1H, d, J ) 7.3 Hz), 7.28-7.35 (5H, m), 7.46 (1H, dd, J ) 7.3
and 8.2 Hz); 13C NMR δ up 33.7, 57.1, 58.7, 63.4, 68.9, 137.8,
161.1, 163.4, down 34.5, 41.1, 53.1, 107.7, 114.6, 127.2, 128.3,
128.9, 138.7; HRMS m/z (EI) calcd for C19H24N2O2 (M+)
312.1838, found 312.1832.
(+)-N-Benzylcytisine (23). To a stirred solution of 21 (63.0
mg, 0.202 mmol) in CH2Cl2 (3.4 mL) in the presence of
triethylamine (56.3 µL, 0.404 mmol) was added methanesulfo-
nyl chloride (23.5 µL, 0.303 mmol) at 0 °C, and the resulting
mixture was stirred for 30 min at the same temperature. The
mixture was diluted with CH2Cl2 and washed with brine.
Evaporation of the solvent gave a residue, which was dissolved
in toluene (1.6 mL). The solution was heated at reflux for 3 h
and concentrated to leave a residue, which was purified by
column chromatography on silica gel with CHCl3-MeOH (10:
1) as an eluent to afford 23 (50.0 mg, 89%) as colorless crystals.
[R]26D +216 (c 0.42, CHCl3); mp 143-145 °C (colorless prisms
from CH2Cl2-hexane); IR (cm-1) 1654, 1570, 1546, and 1138;
1H NMR δ 1.76-1.84 (1H, m), 1.88-1.96 (1H, m), 2.29-2.47
(3H, m), 2.81-2.98 (3H, m), 3.38 (1H, d, J ) 13.7 Hz), 3.47
(1H, d, J ) 13.7 Hz), 3.89 (1H, dd, J ) 6.6 and 15.3 Hz), 4.11
(1H, d, J ) 15.3 Hz), 5.91 (1H, dd, J ) 1.5 and 6.9 Hz), 6.50
(1H, dd, J ) 1.5 and 9.1 Hz), 6.97-7.01 (2H, m), 7.16-7.31
J. Org. Chem, Vol. 70, No. 2, 2005 503

Honda et al.
(4H, m); 13C NMR δ up 25.9, 50.0, 59.9, 60.0, 62.0, 138.0, 151.4,
163.6, down 28.1, 35.5, 104.6, 116.5, 126.9, 128.1, 138.5; HRMS
m/z (EI) calcd for C18H20N2O (M+) 280.1576, found 280.1549.
(+)-Cytisine (ent-1). To a stirred solution of N-benzyl-
cytisine (23) (20.0 mg, 7.14 × 10-2 mmol) in MeOH (1.8 mL)
were added ammonium formate (90.1 mg, 1.43 mmol) and 20%
Pd(OH)2 on carbon (10.0 mg). The mixture was heated at reflux
under an atmospheric pressure of hydrogen for 1 h and then
cooled to room temperature. After filtration of the insoluble
material, the filtrate was concentrated to leave a residue,
which was purified by column chromatography on silica gel
with CHCl3-MeOH-NH4OH (7:1:0.1, v/v) as an eluent to
J ) 15.8 Hz), 6.00 (1H, dd, J ) 1.0 and 6.9 Hz), 6.46 (1H, dd,
J ) 1.0 and 9.1 Hz), 7.30 (1H, dd, J ) 6.9 and 9.1 Hz); 13C
NMR δ up 26.3, 49.7, 53.0, 53.9, 151.0, 163.6, down 27.7, 35.6,
104.9, 116.7, 138.7; HRMS m/z (EI) calcd for C11H14N2O (M+)
190.1106, found 190.1085.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology
of Japan.
Supporting Information Available: Experimental pro-
29
afford ent-1 (11 mg, 81%) as colorless crystals. [R]D +113.5
cedures and product characterization for new compounds and
(c 0.3, EtOH); mp 152-153 °C (colorless prisms from acetone);
1
selected H and 13C NMR spectra. This material is available
1
IR (cm-1) 3420, 1645, 1545 and 1156; H NMR δ 1.53 (1H, br
free of charge via the Internet at http://pubs.acs.org.
s), 1.95-1.97 (2H, m), 2.32 (1H, br s), 2.82-2.90 (1H, m), 2.97-
3.13 (4H, m), 3.90 (1H, dd, J ) 6.6 and 15.8 Hz), 4.13 (1H, d,
JO048365F
504 J. Org. Chem., Vol. 70, No. 2, 2005