Formal synthesis of epibatidine

Article abstract of DOI:10.3987/COM-05-10407

A straightforward formal synthesis of epibatidine has been established starting from trans-(2S,4R)-4-hydroxyproline.

Full text of DOI:10.3987/COM-05-10407

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HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1705 - 1711
Received, 24th March, 2005, Accepted, 27th April, 2005, Published online, 28th April, 2005
FORMAL SYNTHESIS OF EPIBATIDINE
Meng-Yang Chang* and Hua-Ping Chen
Department of Applied Chemistry, National University of Kaohsiung, Kaohsiung
811, Taiwan
Abstract—A straightforward formal synthesis of epibatidine has been established
starting from trans-(2S,4R)-4-hydroxyproline.
1. INTRODUCTION
In view of structural framework of trans-(2S,4R)-4-hydroxyproline (1), it possesses three functional
groups that can be easily modified, including 1-amino, 2-carboxylate and 4-hydroxy groups.1 The
skeleton represents out the significant feature for producing a series of different carbon framework2 using
an efficient modification. Here we report a straightforward formal synthesis of epibatidine (2) has been
established starting from trans-(2S,4R)-4-hydroxyproline (1) as shown in Figure 1.
Figure 1.
H
N
Ts
N
HO
N
Cl
CO2H
N
H
O
trans-4-hydroxyproline (1)
(+)-3
(+)-epibatidine (2)
Epibatidine was first isolated from the skin extract of the Ecuadorian poison frog Epipedobates tricolor
by Daly and co-workers in 1992.3a Subsequently, it was reported containing extremely higher potency as
an analgesic approximately 200 times more potent then morphine.3c-3d Because of its scarcity and
interesting biological activities, more than sixty synthetic reports have published.3e-3mm Compound (3)
was already chosen as a key intermediate for synthesizing epibatidine in the literature.3p,3x-3y
2. RESULTS AND DISCUSSION
In Scheme 1, N-Ts-proline methyl ester was readily obtained from trans-4-hydroxyproline (1) in two
o
steps, i.e. methylation with thionyl chloride and methanol in -78 C and N-tosylate protection with
p-toluenesulfonyl chloride and triethylamine in an ice bath. Next, N-Ts-proline methyl ester was silylated

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with t-butyldimethylsilyl chloride and imidazole to give O-TBS-proline ester. Reduction of
O-TBS-proline ester with sodium borohydride in the presence of lithium chloride furnished alcohol (4).
Thus, synthesis of alcohol (4) was achieved in four steps from trans-4-hydroxyproline (1) in 90% overall
yield with only once purification.
Scheme 1. Formal synthesis of epibatidine (2).
HO
TBSO
1) SOCl2, MeOH
1) Swern ox., THF
2) TsCl, Et3N, DCM
CO2H
N S
N
2) Ph3P=CH2, DCM
(two steps 88%)
3) TBSCl, Im., DMF
4) NaBH4, LiCl, MeOH
(four steps 90%)
H
Ts
OH
4
1
Ts
N
TBSO
1) 9-BBN, THF
then H2O2, NaOH
O
TBAF, THF
N
Ts
N
Ts
2) LDA, TsCl, THF
(two steps 77%)
then PCC, DCM
(two steps 85%)
O
5
6
3
With alcohol (4) in hand, alcohol (4) was transformed into olefin (5) by Swern oxidation and Wittig
olefination protocol. Ketone (6) was obtained by desilyation of compound (5) with tetrabutylammonium
fluoride followed by oxidation of the resulting alcohol with pyridinium chlorochromate and Celite under
the one-pot condition. Chain extension to the olefin (6) was achieved by hydroboration with
9-borabicyclo[3.3.1]nonane to provide the alcohol.4a-4b Finally, exposure of the corresponding alcohol to
p-toluenesulfonyl chloride and lithium diisopropylamide caused simultaneous tosylation and cyclization,5
1
providing the bicyclic ketone (3). The H-NMR spectral data was in accordance with the reported in the
literature.3p,3y During the intramolecular ring closure process, the fused azabicyco[3.2.0]heptane
framework was not observed under this basic condition.
3. CONCLUSION
In summary, we have developed
a
straightforward approach for synthesizing the
7-azabicyclo[2.2.1]heptane ring system (3) and applied this route to the formal synthesis of epibatidine
(2) in nine steps provided 51% overall yield.
4. EXPERIMENTAL
General. Dichloromethane (DCM) and tetrahydrofuran (THF) were distilled prior to use from a deep-blue
solution of sodium-benzophenone ketyl. All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were routinely carried out under an atmosphere of

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dry nitrogen with magnetic stirring. Extract was dried with anhydrous magnesium sulfate before
concentration in vacuo. Crude products were purified using preparative TLC or column chromatography
on silica gel. All reported temperatures were uncorrected.
(2S,4R)-1-(4-Methylphenylsulfonyl)-2-hydroxylmethyl-4-(t-butyldimethylsilyloxy)pyrrolidine (4).
Thionyl chloride (2.5 g, 21.0 mmol) was added to a stirred solution of trans-4-hydroxyproline (1) (1.31 g,
10.0 mmol) in methanol (20 mL) at –78 oC for 10 min. The mixture was stirred in an ice bath for 30 min
then at rt for 30 min, followed by reflux for 3 h. Concentration in vacuo followed by azotropic removal of
water using benzene (50 mL) gave methyl 4-hydroxyproline hydrochloride (1.81 g, 100%). Triethylamine
(3.1 g, 30.6 mmol) and p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) were added to a solution of the
resulting product (1.81 g) in dichloromethane (40 mL) in an ice bath. After stirring at the same
temperature for 10 h, the mixture was concentrated in vacuo. Ethyl acetate (40 mL) was added to the
residue, and the solution was washed with 0.1 N aqueous hydrogen chloride solution (10 mL), saturated
sodium bicarbonate solution and brine, dried, filtered, then concentrated in vacuo to yield
N-toluenesulfonyl methyl 4-hydroxyprolinate (2.93 g, 98%). Without further purification,
t-butyldimethylsilyl chloride (1.51 g, 10.0 mmol) and imidazole (1.0 g, 14.7 mmol) were added to a
solution of the resulting product (2.93 g, 9.8 mmol) in dimethylforamide (15 mL) at rt. After stirring at
the same temperature for 2 h, the mixture was concentrated in vacuo. Ethyl acetate (40 mL) was added to
the residue, and the solution was washed with 0.1 N aqueous hydrogen chloride solution (10 mL),
saturated sodium bicarbonate solution and brine, dried, filtered, then concentrated in vacuo to give the
methyl N-toluenesulfonyl-4-[O-t-butyldimethylsilyloxy]prolinate (3.93 g, 97%). Without further
purification, lithium chloride (1.22 g, 28.8 mmol) and sodium borohydride (1.09 g, 28.8 mmol) were
added to a solution of the crude product (3.93 g) in methanol (30 mL) at rt. After stirring at the same
temperature for 12 h, the mixture was concentrated in vacuo. Ethyl acetate (60 mL) was added to the
residue, and the solution was washed with 0.1 N aqueous hydrogen chloride solution (10 mL), saturated
sodium bicarbonate solution and brine, dried, filtered, then concentrated in vacuo. Recrystallization from
hexane and ethyl acetate (ca. 2:1) yielded the products (4). The residue was purified by column
o
chromatography (hexane/ethyl acetate=2/1) to yield compound (4) (3.47 g, 95%). mp = 87-89 C
(hexane/ethyl acetate); [α]22D –18.12o (c 0.13, CHCl3); IR (CHCl3) 3500, 2930, 2800, 1600 cm-1; EI-MS:
C18H31NO4SSi m/z (%) = 91 (100), 142 (17), 155 (23), 328 (22), 385 (M+, 1); HRMS (EI, M+) calcd for
1
C18H31NO4SSi 385.1743, found 385.1745; H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 2H), 7.30
(d, J = 8.1 Hz, 2H), 4.26 (br s, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.69-3.61 (m, 3H), 3.22 (d, J = 10.8 Hz,
1H), 3.04 (br s, 1H), 2.42 (s, 3H), 1.95-1.86 (m, 1H), 1.77-1.74 (m, 1H), 0.70 (s, 9H), -0.08 (s, 3H), -0.10
(s, 3H); Anal. Calcd for C18H31NO4SSi C, 56.07; H, 8.10; N, 3.63. Found C, 56.01; H, 8.19; N, 3.78. The
total yield of four steps was 90%.

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(2S,4R)-1-(4-Methylphenylsulfonyl)-2-vinyl-4-(t-butyldimethylsilyloxy)pyrrolidine (5).
A stirred solution of oxalyl chloride (400 mg, 3.15 mmol) in dichloromethane (20 mL) was mixed with
o
o
dimethyl sulfoxide (400 mg, 5.1 mmol) at –78 C. The solution was warmed to –40 C for 15 min and
recooled to –78 oC, and then a solution of alcohol (4) (1.0 g, 2.6 mmol) in dichloromethane (10 mL) was
added dropwise for 90 min followed by excess triethylamine (4 mL, 28.5 mmol) for 30 min. The reaction
mixture was warmed to rt and poured into saturated aqueous ammonium chloride solution (2 mL), and
concentrated. The residue was diluted with water (15 mL) and extracted with ethyl acetate (3 x 30 mL).
The organic layer was washed with brine and water, dried, filtered and concentrated to produce crude
aldehyde (950 mg, 2.48 mmol). To a stirred solution of methyltriphenylphosphonium iodide (10.0 g, 4.0
o
mmol) in dry tetrahydrofuran (40 mL) was added n-butyllithium (2.0 mL, 1.6 M, 3.2 mmol) at –78 C.
The orange red colored mixture was stirred at –78 oC for 1 h. The aldehyde product (950 mg, 2.48 mmol)
was added to the reaction mixture at –78 oC via a syringe and the mixture was further stirred at –78 oC for
8 h. The reaction was quenched with aqueous saturated ammonium chloride (10 mL) and the mixture was
extracted with ether (3 x 50 mL) and the combined organic layers were washed with brine (2 x 20 mL),
dried, filtered and evaporated. Purification on silica gel (hexane/ethyl acetate = 15/1) afforded compound
o
(5) (871 mg, two steps 88% from compound (4)) as a colorless solid. mp = 81-83 C (hexane/ethyl
acetate); [α]21 –54.25o (c 0.1, CHCl3); EI-MS: C19H31NO3SSi m/z (%) = 91 (100), 149 (15), 155 (15),
D
270 (18), 324 (12), 381 (M+, 1); HRMS (EI, M+) calcd for C19H31NO3SSi 381.1794, found 381.1796; 1H
NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.91 (ddd, J = 7.5, 10.5,
17.0 Hz, 1H), 5.21 (d, J = 17.0 Hz, 1H), 5.13 (d, J = 10.5 Hz, 1H), 4.26-4.23 (m, 1H), 4.02 (dd, J = 7.5,
14.5 Hz, 1H), 3.65 (dd, J = 5.0, 11.0 Hz, 1H), 3.18 (dd, J = 1.5, 11.0 Hz, 1H), 2.41 (s, 3H), 1.85-1.75 (m,
13
2H), 0.72 (s, 9H), -0.07 (s, 6H); C NMR (125 MHz, CDCl3) δ 143.19, 139.12, 134.30, 129.48 (2x),
127.73 (2x), 115.26, 69.48, 61.17, 57.58, 42.57, 25.55 (3x), 21.45, 17.81, -4.99, -5.08; Anal. Calcd for
C19H31NO3SSi C, 59.80; H, 8.19; N, 3.67. Found C, 60.03; H, 8.33; N, 3.45.
(2S)-1-(4-Methylphenylsulfonyl)-2-vinylpyrrolidin-4-one (6).
A solution of tetra-n-butylammonium fluoride (1.2 mL, 1.0 M, 1.2 mmol) in tetrahydrofuran (3 mL) was
added to a solution of compound (5) (381 mg, 1.0 mmol) in tetrahydrofuran (3 mL) at rt for 1 h. A
mixture of dichloromethane (20 mL), pyridinium chlorochromate (1.08 g, 5.0 mmol) and Celite (1.0 g)
was added to the stirring reaction. After being stirred at rt for 10 h, the mixture was filtered through a
short silica gel column. The filtrate was dried, filtered and evaporated. Purification on silica gel
(hexane/ethyl acetate = 5/1) yielded compound (6) (225 mg, two steps 85% from compound (5)) as a
o
colorless solid. mp = 110-112 C (hexane/ethyl acetate); [α]22 +56.50o (c 0.14, CHCl3); EI-MS:
D
C13H15NO3S m/z (%) = 91 (100), 155 (4), 265 (M+, 1); HRMS (EI, M+) calcd for C13H15NO3S 265.0773,
1
found 265.0774; H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.81

HETEROCYCLES, Vol. 65, No. 7, 2005
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(ddd, J = 6.0, 10.0, 17.5 Hz, 1H), 5.28 (d, J = 17.5 Hz, 1H), 5.21 (d, J = 10.0 Hz, 1H), 4.60-4.56 (m, 1H),
3.73 (d, J = 18.5 Hz, 1H), 3.66 (d, J = 18.5 Hz, 1H), 2.49 (dd, J = 9.0, 18.5 Hz, 1H), 2.45 (s, 3H), 2.34
13
(dd, J = 4.0, 18.5 Hz, 1H); C NMR (125 MHz, CDCl3) δ 208.29, 144.30, 135.88, 134.31, 129.96 (2x),
127.60 (2x), 117.12, 59.34, 53.27, 43.38, 21.45; Anal. Calcd for C13H15NO3S C, 58.85; H, 5.70; N, 5.28.
Found C, 59.11; H, 5.98; N, 5.38.
(1S,4R)-7-(4-Methylphenylsulfonyl)-7-azabicyclo[2.2.1]heptan-2-one (3).
To a stirred solution of olefin (6) (133 mg, 0.5 mmol) in tetrahydrofuran (20 mL) was added
9-borabicyclo[3.3.1]nonane (0.5 M in THF, 2 mL, 2.0 mmol) via syringe under nitrogen system. The
mixture was heated at reflux for 2 h. Oxidation was carried out by dropwise addition of a solution of 4.5
mL of 35% hydrogen peroxide/0.5 N sodium hydroxide/water (vol: 4:4:1). The mixture was held an
additional 1 h at reflux temperature and the mixture was extracted with ether (3 x 50 mL) and the
combined organic layers were washed with brine (2 x 20 mL), dried, filtered and evaporated to yield the
crude product alcohol (127 mg, 0.45 mmol). Without further purification, a solution of lithium
diisopropylamide (1.0 M in THF, 1.2 mL, 1.2 mmol) in tetrahydrofuran (5 mL) was added to a solution of
the crude resulting alcohol (127 mg, 0.45 mmol) in tetrahydrofuran (10 mL) at -78 oC. p-Toluenesulfonyl
chloride (115 mg, 0.6 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise at -78 oC . The
mixture was stirred at 0 °C for 30 min and then stirred at 25 °C for 10 h. The reaction was quenched with
aqueous saturated ammonium chloride (1 mL) and the mixture was extracted with ether (3 x 50 mL) and
the combined organic layers were washed with brine (2 x 20 mL), dried, filtered and evaporated.
Purification on silica gel (hexane/ethyl acetate = 3/1) afforded compound (3) (102 mg, two steps 77%
from compound (6)) as a colorless solid. mp = 134-136 oC (hexane/ethyl acetate); [α]22D +52.55o (c 0.05,
CHCl3); IR (CHCl3) 1760, 1150 cm-1; EI-MS: C13H15NO3S m/z (%) = 91 (100), 105 (36), 145 (19), 155
1
(13), 237 (11), 265 (M+, 1); HRMS (EI, M+) calcd for C13H15NO3S 265.0773, found 265.0773; H NMR
(500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.59 (t, J = 5.0 Hz, 1H), 4.10 (d, J
= 5.0 Hz, 1H), 2.44 (s, 3H), 2.40 (dd, J = 6.0, 18.0 Hz, 1H), 2.18-2.06 (m, 2H), 1.93 (d, J = 18.0 Hz, 1H),
1.67-1.57 (m, 2H); Anal. Calcd for C13H15NO3S C, 58.85; H, 5.70; N, 5.28. Found C, 59.93; H, 5.88; N,
5.49. The 1H-NMR spectral data were in accordance with the reported in the literature 3p and 3y.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC 93-2113-M-390-004 &
94-2113-M-390-001) of the Republic of China for financial support.
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