(EtOAc–MeOH, 9 : 1) afforded the alcohol 14 as a colourless oil
(161 mg, 75%). Rf = 0.40 (EtOAc–MeOH, 9 : 1); mmax/cm−1
(CHCl3 film) 3382, 2360, 1695, 1453, 1205, 1080, 700; dH
(400 MHz, CDCl3) 1.18–1.25 (6H, m, CH3, CH2CH3), 2.88–
2.95 (2H, m, C(3)H, CHMe), 3.46 (1H, m, CHHOH), 3.54
(1H, m, C(4)H), 3.63–3.68 (2H, m, CHHOH, C(2)H), 4.17
(2H, m, CO2CH2CH3), 4.36–4.52, 4.79 (4H, m, CH2Ph), 6.92
(1H, s, NH), 7.10–7.40 (10H, m, ArH); dC (400 MHz, CDCl3)
13.8 (CH3), 15.0 (OCH2CH3), 38.8, 42.4 (C(3), CHMe), 48.5,
49.8 (CH2Ph), 52.8 (C(4)), 58.1 (C(2)), 62.2 (OCH2CH3),
64.6 (CH2OH), 126.2, 127.6, 127.9, 128.1, 128.7, 129.1, 129.8
(ArCH), 136.1, 136.8 (ArC), 170.67, 173.4, 175.4 (CO2Et,
CONH2 and C(5)); m/z (ESI+) 461(M + Na+ 100), 439 (M +
H+, 40%); HMRS (M + H+) 439.2232; C25H31N2O5 requires
439.2233.
with the synthesis of 3b. Flash column chromatography (DCM–
MeOH, 98 : 2) afforded the mixture 17a and 18a as a pale
yellow solid (95 mg, 58%). Rf = 0.45 (DCM–MeOH, 98 : 2); dH
(400 MHz, CDCl3) major compound 2.91 (1H, m, C(7)H), 3.09–
3.20 (2H, m, C(6)H, C(7)H), 3.52 (1H, m, C(4)Hendo), 4.25 (1H,
m, C(4)Hexo), 4.32 (1H, m, C(5)H), 6.35 (1H, s, C(2)H), 7.30–
7.45 (5H, m, ArH), dC (400 MHz, CDCl3) major compound:
28.6 (C(6)), 38.1 (C(7)), 61.6 (C(5)), 69.9 (C(4)), 87.8 (C(2)),
118.5 (CN), 125.9, 128.6, 129.1 (ArCH), 137.0, (ArC), 173.4
(C(8)); minor compound: 25.6 (C(6)), 37.0 (C(7)), 58.7 (C(5)),
68.0 (C(4)), 88.3 (C(2)), 117.6 (CN), 125.9, 128.6, 129.0 (ArCH),
137.6, (ArC), 174.2 (C(8)).
(2R, 5S, 6S)-6-(N-Benzyloxycarbonyl-2-aminomethyl)-8-oxo-
2-phenyl-1-aza-3-oxa-bicyclo[3.3.0]octane (17b) and (2R, 5S,
6R)-6-(N-benzyloxycarbonyl-2-aminomethyl)-8-oxo-2-phenyl-1-
aza-3-oxa-bicyclo[3.3.0]octane (18b)
(2S, 3S, 4S, 1ꢀS)-3-(1-Dibenzylcarbamoyl-ethyl)-5-oxo-pyrroli-
dine-2,4-dicarboxylic acid 4-ethyl ester 2-methyl ester (15)
By analogy with the synthesis of 7, the mixture of nitriles 17a
and 18a (85 mg, 0.37 mmol), CoCl2.H2O (176 mg, 0.74 mmol)
and NaBH4 (140 mg, 3.7 mmol) in EtOH (10 ml) gave an amine
which as used in the next step without further purification. The
crude amine, benzoyloxycarbonyl chloride (79 ll, 0.55 mmol)
and Et3N (103 ll, 0.74 mmol) in THF (6.5 ml), followed by
flash column chromatography (petrol(40/60)–EtOAc, 30 : 70)
afforded 17b as a pale yellow solid (76 mg, 56% over two
steps) and 18b as a pale yellow solid (10 mg, 8% over two
steps); mmax/cm−1 (CHCl3 film) 3451, 3019,1710, 1514, 1215, 755;
17b: Rf = 0.27 (petrol(40/60)–EtOAc, 30 : 70); dH (400 MHz,
CDCl3) 1.91–2.02 (1H, m, C(6)H), 2.16 (1H, dd, J 16.6 and
9.3, C(7)Hexo), 2.27 (1H, dd, J 16.6 and 7.6, C(7)Hendo), 2.80–
2.87 (2H, m, CH2NH), 3.16 (1H, t, J 7.8, C(4)Hendo), 3.49–
3.57 (1H, m, C(5)H), 3.83 (1H, t, J 7.8, C(4)Hexo), 5.02 (1H,
br, NH), 5.12 (2H, s, CH2Ph), 6.58 (1H, s, C(2)H), 7.13–7.33
(8H, m, ArH), 7.53 (2H, m, ArH); dC (400 MHz, CDCl3)
37.9 (C(7)), 39.7 (C(6)), 44.1 (CH2), 62.5 (C(5)), 67.0 (CH2Ph),
71.1 (C(4), 87.6 (C(2)), 126.7,128.8,128.8, 128.9 (ArCH), 137.4
(ArC), 139.9 (ArC), 156.8 (HNCO), 176.8 (C(8)); 18b; Rf =
0.36 (petrol(40/60)–EtOAc, 30 : 70); dH (400 MHz, CDCl3) 1.88
(1H, dd, J 17.2 and 6.6, C(7)Hendo), 2.07–2.17 (1H, m, C(6)H),
2.25 (1H, dd, J 17.2 and 9.2, C(7)Hexo), 2.54 (2H, m, CHHNH),
2.88 (2H, m, CHHNH), 3.18 (1H, m, C(4)Hendo), 3.40 (1H, m,
C(5)H), 3.59 (1H, m, C(4)Hexo), 4.30 (1H, br, NH), 5.15 (2H, s,
CH2Ph), 6.60 (1H, s, C(2)H), 7.13–7.29 (6H, m, ArH), 7.38 (2H,
m, ArH), 7.51 (2H, m, ArH).
Lactam 14 (40 mg, 0.09 mmol) was treated with PDC (159 mg,
0.46 mmol) in DMF (2 ml), and then diazomethane in
Et2O. Flash column chromatography (EtOAc–MeOH, 98 : 2)
afforded 15 as a colourless oil (23 mg, 54%). Rf = 0.55 (EtOAc–
MeOH, 98 : 2); [a]D23 −4.0 (c 1.3 in CHCl3); mmax/cm−1 (CHCl3
film) 2980, 2360, 1714, 1639, 1437, 1209, 1029, 700; dH (400MHz,
CDCl3) 1.23 (3H, d, J 7.1, CH3), 1.30 (3H, t, J 7.1, CH2CH3),
3.13 (1H, q, J 6.8, CHMe), 3.29 (1H, d, J 6.6, 5.7, C(3)H), 3.73
(3H, s, CO2CH3), 3.82 (1H, d, J 6.6, C(4)H), 4.10 (1H, d, J
5.7, C(2)H), 4.24 (2H, m, CO2CH2CH3), 4.50–4.54, 4.70–4.74
(4H, m, CH2Ph), 6.54 (1H, m, NH), 7.14–7.40 (10H, m, ArH); dC
(400 MHz, CDCl3) 14.1 (OCH2CH3), 15.8 (CH3), 37.4 (CHMe),
45.1 (C(3)), 48.4, 49.8 (CH2Ph), 51.5 (C(4)), 52.7 (CO2CH3),
56.8 (C(2)), 61.9 (OCH2CH3), 126.3, 127.6, 128.2, 128.7, 129.1
(ArCH), 136.2, 137.1 (ArC), 169.4, 171.3, 171.5, 174.7 (CO2Me,
CO2Et, CONH2 and C(5)); m/z (ESI+) 489(M + Na+ 100);
HMRS (M + H+) 467.2185; C26H31N2O6 requires 467.2182.
7-Ethyloxycarbonyl-6-cyano-8-oxo-2-phenyl-1-aza-3-oxa-
bicyclo[3.3.0]octane (16)
To a solution of 5 (618 mg, 2.25 mmol) in EtOH (7 ml) at RT
was added KCN (176 mg, 2.7 mmol) dissolved in the minimal
amount of water. After stirring 1 h at RT, the mixture was
quenched with a solution of saturated ammonium chloride
(5 ml) and extracted with EtOAc (2 × 7 ml). The organic layer
was separated, dried over MgSO4, filtered and concentrated in
vacuo to give a purple oil. The crude material was purified by
flash column chromatography (petrol(40/60)–EtOAc, 3 : 2) to
afford 16 as a pale yellow oil and as a mixture of diastereomers
(528 mg, 78%). Rf = 0.45 (petrol(40/60)–EtOAc, 3 : 2); mmax/cm−1
(CHCl3 film) 2985, 2254, 1725, 1450, 1330, 1214, 1179, 908, 732;
dH (400 MHz, CDCl3) major compound: 1.33 (3H, t, J 7.2 Hz,
OCH2CH3), 3.73 (1H, m, C(6)H), 3.82 (1H, m, C(4)Hendo),
4.15 (1H, d, J 10.2Hz, C(7)H), 4.23–4.40 (4H, m, CH3CH2,
C(5)H and C(4)Hexo), 6.30 (1H, s, C(2)H), 7.30–7.41 (5H, m,
ArH); dC (400 MHz, CDCl3) major compound: 14.1 (CH3), 31.9
(C(6)), 55.2 (C(7)), 59.4 (C(5)), 62.9 (CH3CH2), 70.0 (C(4)),
87.9 (C(2)), 117.3 (CN), 125.9, 126.0, 128.6, 129.2 (ArCH),
136.7 (ArC)), 166.0 (CO2Et), 168.3 (C(8)); minor compound:
14.0 (CH3), 29.5, 33.4 (C(6)), 55.1, 55.6 (C(7)), 57.3, 61.2 (C(5)),
63.0, 63.2 (CH3CH2), 68.2–69.4 (C(4)), 87.8, 88.7 (C(2)), 116.0,
116.5 (CN), 125.9, 126.0, 126.6, 126.8, 128.4, 128.7, 129.0, 129.1
(ArCH), 136.3, 137.0 (ArC)), 165.8, 165.9 (CO2Et), 168.5, 169.1
(C(8)); m/z (CI+) 301 (M + H+, 100%); HMRS (M + H+)
301.1183; C16H17N2O4 requires 301.1188.
(2S, 3S)-3-(N-Benzyloxycarbonyl-2-aminomethyl)-2-
methyloxycarbonyl-5-oxo-pyrrolidine (19)
By analogy with the synthesis of 8, lactam 17b (170 mg, 0.46
mmol) and TFA (358 ll, 4.6 mmol) in DCM (4 ml), followed by
flash column chromatography (EtOAc–MeOH, 5 : 1) afforded
the alcohol as a pale yellow oil (56 mg, 44%). Rf = 0.31 (EtOAc–
MeOH, 4 : 1); [a]D22 = +32 (c 0.58 in CHCl3); mmax/cm−1 (CHCl3
film) 3330, 3019, 1691, 1215, 756; dH (400 MHz, CDCl3) 1.93–
2.01 (1H, m, C(3)H), 2.16–2.31 (1H, m, C(4)HH), 2.32–2.49
(1H, m, C(4)HH), 3.02–3.20 (1H, m, C(2)H), 3.29–3.42 (2H,
m, CH2NH), 3.57 (1H, br, CH2NH), 4.41 (2H, m, CH2OH),
5.00 (2H, s, CH2Ph), 6.09 (1H, br, NHC(O)), 7.09–7.35 (5H, m,
ArH); dC (400 MHz, CDCl3) 36.4 (C(3)), 43.9 (C(4)), 59.6 (C(2)),
60.4 (CH2), 64.4 (CH2OH), 66.7 (CH2Ph), 127.9, 128.1, 128.5
(ArCH), 136.4 (ArC), 157.2 (HNCOO), 178.8 (C(5)); m/z (CI)
294 (MH+, 100%), 311(40); HMRS 294.0978; (MH+, C14H16NO6
requires 294.0978).
This alcohol (50 mg, 0.18 mmol) was treated with PDC
(313 mg, 0.90 mmol) in DMF (3.5 ml), immediately followed by
diazomethane in Et2O. Flash column chromatography (EtOAc–
MeOH, 9 : 1) afforded 19 as a colourless oil (20 mg, 36%). Rf =
0.37 (EtOAc–MeOH, 9 : 1); mmax/cm−1 (CHCl3 film) 3435,
3018, 1708, 1215, 756; dH (400 MHz, CDCl3) 2.16 (1H, dd,
(2R, 5S, 6RS)-6-Cyano-8-oxo-2-phenyl-1-aza-3-oxa-
bicyclo[3.3.0]octane (17a, 18a)
A solution of nitrile 16 (223 mg, 0.74 mmol) and (Bu3Sn)2O
(756 lL, 1.48 mmol) in toluene (30 ml) was treated by analogy
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 7 2 – 2 8 8 2
2 8 7 9