FACILE SYNTHESIS OF PERAMIVIR
2645
was extracted with dichloromethane (3 ꢂ 40 ml). The combined organic layers were
washed with water and brine and dried over anhydrous Na SO . After filtration,
2
4
the filtrate was concentrated by rotary evaporator, and the residue was purified by
flash column chromatography using petroleum ether = ethyl acetate (10:1 to 9:1,
ꢁ
1
v:v) to give a white solid 4, 4.94 g, 68% yield; mp 108.5–110.2 C; H NMR
(
300 MHz, CDCl ), d5.57–5.59 (d, 1H, J ¼ 6.0 Hz, -CH), 5.19–5.22 (dd, 1H, J ¼ 9.0
3
and 1.5 Hz, -CH), 4.22 (m, 1H, -CH), 3.75 (s, 3H, -CH ), 3.56–3.59 (d, 1H,
3
J ¼ 9.0 Hz, -CH), 3.18–3.21 (d, 1H, J ¼ 7.5 Hz, -CH), 2.48–2.52 (m, 1H, -CH),
2
0
.03–2.11 (m, 2H, -CH ), 1.61–1.70 [m, 4H, (-CH ) ], 1.43 [s, 9H, (-CH ) ],
2 2 2 3 3
1
3
.91–0.94 (t, 3H, J ¼ 11.4 Hz, -CH ), 0.86–0.89 (t, 3H, J ¼ 11.4 Hz, -CH );
C
3
3
NMR (75 MHz, CDCl ) d175.2, 161.2, 155.0, 87.1, 79.6, 63.5, 55.7, 52.6, 52.2,
3
þ
4
0.6, 33.4, 28.4, 25.7, 24.0, 11.1, 10.8; MS: m=z, 377.4 [M þ Na] ; HRMS: m=z
þ
[
M þ H] calcd for C H N O 355.2228; found 355.2225.
1
8
31
2
5
Synthesis of (ꢀ)-Methyl (1S,2S,3R,4R)-3-[(1S)-1-(Acetylamino)-2-
ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentan
ecarboxylate (5)
NaBH (1.3 g, 34.5 mmol) was slowly added in batches to a solution of
4
compound 4 (4.9 g, 13.8 mmol), NiCl ꢃ 6H O (3.3 g, 13.9 mmol), and NaOH
2
2
(
28 mg, 0.07 mmol) in anhydrous methanol (60 ml) and stirred under a nitrogen
ꢁ
ꢁ
atmosphere at ꢀ5 C. The reaction mixture was stirred at 0 C for 2 h before
being concentrated in a rotary evaporator. To the resulting residue were added
ammonia solution (120 ml), NaNO (1 g, 14 mmol), and NH Cl (3 g, 56 mmol).
2
4
The solution was stirred at room temperature for 16 h. Upon completion, the
solution color turned blue and the white precipitate was separated. The precipi-
tate was filtered and dried in vacuo to give a white solid of amine intermediate,
4
.2 g, 85% yield.
Acetic anhydride (1.4 ml, 15 mmol) and dry triethylamine (1.0 ml, 7.5 mmol)
were added to this amine intermediate (2.7 g, 7.5 mmol) in dry dichloromethane
40 ml). The solution was stirred at room temperature for 6 h before being extracted
(
with dichloromethane (3 ꢂ 30 ml). The combined organic layers were washed with
water and brine and dried over anhydrous Na SO . After filtration, the filtrate
4
2
was concentrated by rotary evaporator, and the residue was purified by flash column
chromatography (silica, 5:1 v=v petroleum ether = acetone ! 3:1 v=v petroleum ether
=
1
4
acetone, gradient elution) to give 5 as a white solid, 2.75 g, 92% yield; mp
ꢁ
1
21.6–123.1 C; H NMR (300 MHz, CDCl ), d7.53–7.57 (d, 1H, J ¼ 9.9 Hz),
3
.75–4.78 (d, 1H, J ¼ 9.3 Hz), 4.24–4.26 (d, 1H, J ¼ 5.7 Hz), 4.12–4.18 (m, 1H,
-CH), 4.00–4.06 (m, 1H, -CH), 3.72 (s, 3H, -CH ), 2.81–2.86 (m, 1H, -CH),
3
2
1
0
.45–2.55 (ddd, 1H, J ¼ 8.7, 4.2 and 8.7 Hz, -CH), 2.09 (s, 3H, -CH ), 2.01 (m,
3
H, -CH), 1.66–1.75 (ddd, 1H, J ¼ 5.7, 5.4 and 5.7 Hz, -CH), 1.35–1.45 (m, 15H),
1
3
.78–0.89 [tt, 6H, J ¼ 14.1 and 14.4 Hz, (-CH ) ]; C NMR (75 MHz, CDCl )
3
2
3
d175.6, 171.7, 156.2, 80.2, 77.9, 52.3, 52.2, 50.5, 49.0, 48.2, 43.7, 33.5, 28.5, 23.4,
þ
þ
2
2.0, 21.4, 10.7, 10.2; MS: m=z, 401.4 [M þ H] , 423.7 [M þ Na] . HRMS: m=z
þ
[
M þ H] calcd. for C H N O 401.2646; found 401.2654.
2
0
37
2
6