M. Asano et al. / Bioorg. Med. Chem. 21 (2013) 5725–5737
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dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (n-Hexane/
EtOAc = 98:2 ? 34:66) to give 7 (190 mg, 86%) as colorless oil.
(Method B: 9c ? 7)
room temperature for 18 h, the mixture was partitioned between
water (30 mL) and EtOAc (70 mL). The organic layer was dried over
MgSO4, concentrated in vacuo and the residue was purified by col-
umn chromatography (n-Hexane/EtOAc = 98:2 ? 34:66) to give 8c
(1.06 g, 75%) as pale yellow solid.
To a solution of 9c (240 mg, 0.810 mmol) in MeOH (4.0 mL)
was added 28% sodium methoxide methanol solution (50 mg),
and the reaction mixture was stirred at 60 °C for 18 h. The mix-
ture was concentrated in vacuo, and the residue was purified by
column chromatography (n-Hexane/EtOAc = 98:2 ? 34:66) to
give 7 (149 mg, 62%) as colorless oil.1H-NMR (300 MHz, CDCl3)
d 0.05 (1H, dt, J = 8.1, 6.0 Hz), 0.77ꢀ0.90 (1H, m), 1.26ꢀ1.38
(1H, m), 1.38ꢀ1.50 (9H, m), 1.48ꢀ1.69 (1H, m), 1.75ꢀ1.95 (2H,
m), 2.51 (1H, ddd, J = 11.1, 4.3, 2.2 Hz), 2.60ꢀ2.90 (2H, m),
3.50ꢀ3.64 (1H, m), 3.69ꢀ3.81 (3H, m), 3.81ꢀ4.07 (1H, m),
4.54ꢀ4.82 (1H, m).
1H NMR (300 MHz, CDCl3) d 0.32ꢀ0.50 (2H, m), 1.33ꢀ1.63 (11H,
m), 2.35ꢀ2.51 (1H, m), 2.72ꢀ2.97 (2H, m), 3.05ꢀ3.16 (1H, m),
3.28ꢀ3.51 (1H, m), 3.55ꢀ3.86 (4H, m), 3.86ꢀ4.01 (1H, m),
4.34ꢀ4.54 (1H, m).
4.14. Methyl(1aS,4R,6aR,7aS)-5-benzyloctahydro-1H-
cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4-carboxylate (9a) and
methyl (1aS,4S,6aR,7aS)-5-benzyloctahydro-1H-
cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4-carboxylate (9b)
To a solution of 5c (700 mg, 2.31 mmol) in EtOAc (10 mL) was
added 4 M HCl in EtOAc (30 mL, 120 mmol), and the reaction mix-
ture was stirred at room temperature for 3 h. The reaction mixture
was concentrated in vacuo, the precipitated solid was collected by
filtration, and dissolved in toluene (30 mL). To the solution were
added methyl 2,3-dibromopropionate (512 mg, 2.08 mmol) and
triethylamine (4.62 mL, 33.15 mmol), and the reaction mixture
was stirred at 90 °C for 18 h. The mixture was partitioned between
water (50 mL) and EtOAc (50 mL), and the organic layer was dried
over MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (n-Hexane/EtOAc = 75:25 ? 0:100) to
give 9a (45 mg, 8%, pale yellow oil) and 9b (290 mg, 49%, colorless
oil).
4.12. Methyl(1aR,4S,6aR,7aR)-5-benzyloctahydro-1H-
cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4-carboxylate (8a) and
methyl (1aR,4R,6aR,7aR)-5-benzyloctahydro-1H-
cyclopropa[4,5] pyrrolo[1,2-a]pyrazine-4-carboxylate (8b)
To a solution of 4c (5.14 g, 17.00 mmol) in EtOAc (50 mL) was
added 4 M HCl in EtOAc (50 mL), and the reaction mixture was stir-
red at room temperature for 18 h. The mixture was concentrated in
vacuo, and the residue was filtered through a column of Amber-
lystÒ A-21 (350 g, washed with methanol) with MeOH, and the fil-
trate was concentrated in vacuo to give 1-[(1R,3R,5R)-2-
azabicyclo[3.1.0]hex-3-yl]-N-benzylmethanamine 4A (2.76 g) as
dark-brown oil. The crude product was used without further puri-
fication for the next step. To a solution of the above crude product
(2.76 g) and triethylamine (5.78 mL, 41.2 mmol) in toluene
(100 mL) was added methyl 2,3-dibromopropioate (3.37 g,
13.7 mmol), and the reaction mixture was stirred at 90 °C for
18 h. The mixture was partitioned between water (150 mL) and
EtOAc (120 mL), and the organic layer was dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chro-
matography (n-Hexane/EtOAc = 98:2 ? 50:50) to give 8a
(810 mg, 21%, pale yellow oil) and 8b (1.38 g, 35%, pale yellow oil).
8a: 1H NMR (600 MHz, CDCl3) d 0.43ꢀ0.51 (1H, m), 0.57ꢀ0.63
(1H, m), 1.14ꢀ1.30 (1H, m), 1.32ꢀ1.40 (1H, m), 1.99ꢀ2.11 (1H,
m), 2.37ꢀ2.43 (1H, m), 2.49 (1H, dd, J = 11.0, 3.9 Hz), 2.70 (1H, t,
J = 11.0 Hz), 2.99 (1H, dd, J = 11.4, 4.0 Hz), 3.10ꢀ3.17 (1H, m),
3.33–3.41 (1H, m), 3.55 (1H, dd, J = 11.4, 2.2 Hz), 3.71 (3H, s),
3.85ꢀ3.96 (2H, m), 7.23 (1H, t, J = 6.8 Hz), 7.27ꢀ7.34 (4H, m).
13C NMR (151 MHz, CDCl3) d 15.2, 21.1, 32.8, 43.1, 51.2, 52.1,
52.3, 59.2, 60.0, 66.9, 126.9, 128.2 (2C), 128.6 (2C), 139.4, 173.1.
8b: 1H NMR (600 MHz, CDCl3) d 0.53ꢀ0.70 (2H, m), 1.34ꢀ1.43
(1H, m), 1.73 (1H, t, J = 11.2 Hz), 2.10 (1H, ddd, J = 13.1, 7.0,
6.7 Hz), 2.47ꢀ2.58 (1H, m), 2.65 (1H, dd, J = 11.4, 3.7 Hz), 2.99
(1H, t, J = 11.0 Hz), 3.17ꢀ3.26 (4H, m), 3.36 (1H, dd, J = 11.6,
3.5 Hz), 3.76 (3H, s), 3.82 (1H, d, J = 12.8 Hz), 7.22ꢀ7.27 (1H, m),
7.28ꢀ7.35 (4H, m).
9a: 1H NMR (600 MHz, CDCl3) d ꢀ0.04ꢀ0.07 (1H, m), 0.81ꢀ0.97
(1H, m), 1.25ꢀ1.34 (1H, m), 1.57 (1H, td, J = 11.5, 4.6 Hz), 1.77 (1H,
dd, J = 11.5, 6.1 Hz), 2.01ꢀ2.14 (1H, m), 2.58ꢀ2.71 (3H, m), 2.88
(1H, t, J = 10.1 Hz), 3.34ꢀ3.45 (1H, m), 3.48 (1H, br s), 3.73 (3H,
s), 3.83ꢀ4.00 (2H, m), 7.18ꢀ7.24 (1H, m), 7.29 (4H, d, J = 4.4 Hz).
13C NMR (151 MHz, CDCl3) d 1.7, 12.3, 29.9, 40.3, 51.2 (2C), 53.0,
55.8, 59.0, 60.3, 126.9, 128.2 (2C), 128.6 (2C), 139.4, 173.0.
9b: 1H NMR (600 MHz, CDCl3) d ꢀ0.03ꢀ0.10 (1H, m), 0.84ꢀ0.92
(1H, m), 1.30ꢀ1.38 (1H, m), 1.53 (1H, td, J = 11.4, 4.4 Hz), 1.78 (1H,
dd, J = 11.4, 6.1 Hz), 1.88 (1H, t, J = 10.3 Hz), 2.04ꢀ2.13 (1H, m),
2.59 (1H, t, J = 10.3 Hz), 2.69 (1H, dt, J = 5.9, 2.6 Hz), 2.90 (1H, dd,
J = 10.3, 2.6 Hz), 3.24ꢀ3.29 (2H, m), 3.31 (1H, dd, J = 10.3, 3.7 Hz),
3.77 (3H, s), 3.80ꢀ3.87 (1H, m), 7.23ꢀ7.28 (1H, m), 7.29ꢀ7.34
(4H, m).
13C NMR (151 MHz, CDCl3) d 2.1, 12.1, 29.9, 40.0, 52.1, 53.0,
54.4, 54.6, 60.5, 65.2, 127.3, 128.2 (2C), 129.6 (2C), 137.0, 172.9.
4.15. 5-tert-Butyl 4-methyl (1aS,4R,6aR,7aS)-octahydro-5H-
cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4,5-dicarboxylate (9c)
A mixture of 9b (290 mg, 1.01 mmol) and 10% palladium on car-
bon (150 mg, 50% wet) in 5% HCl in MeOH (5.0 mL) was stirred at
room temperature for 8 h under hydrogen atmosphere (1 atm). The
mixture was filtered through a pad of CeliteÒ with MeOH, and the
filtrate was concentrated in vacuo. The residue was dissolved in
THF (10 mL), and to the solution were added satd NaHCO3
(10 mL) and Boc2O (218 mg, 1.0 mmol). The mixture was stirred
at room temperature for 18 h, and partitioned between water
(25 mL) and EtOAc (40 mL). The organic layer was dried over
MgSO4, and concentrated in vacuo. The residue was purified by col-
umn chromatography (n-Hexane/EtOAc = 97:3 ? 33:67) to give 9c
(240 mg, 80%) as colorless oil.
13C NMR (151 MHz, CDCl3) d 15.0, 20.0, 32.6, 43.2, 52.1 (2C),
56.0, 60.5 (2C), 64.2, 127.3, 128.2 (2C), 129.5 (2C), 137.0, 173.2.
4.13. 5-tert-Butyl 4-methyl (1aR,4R,6aR,7aR)-octahydro-5H-
cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4,5-dicarboxylate (8c)
A mixture of 8b (1.38 g, 4.75 mmol) and 10% palladium on car-
bon (500 mg, 50% wet) in 5% HCl in MeOH (20 mL) was stirred at
room temperature under hydrogen atmosphere (1 atm) for 5 h.
The reaction mixture was filtered through a pad of CeliteÒ with
MeOH, and the filtrate was concentrated in vacuo. The residue
was dissolved in THF (50 mL), and to the solution were added satd
NaHCO3 (50 mL) and Boc2O (1.04 g, 4.76 mmol). After stirring at
1H NMR (300 MHz, CDCl3) d 0.22ꢀ0.36 (1H, m), 0.77 (1H, dd,
J = 3.8, 2.6 Hz), 1.34ꢀ1.49 (10H, m), 1.72 (2H, d, J = 8.3 Hz), 2.48
(1H, br s), 2.53ꢀ2.66 (1H, m), 2.82ꢀ3.04 (2H, m), 3.36 (1H, dd,
J = 12.8, 4.7 Hz), 3.68 (1H, dd, J = 13.0, 3.6 Hz), 3.72ꢀ3.80 (3H, m),
4.39 (1H, br s).