General method for deprotonations
32.34 (CH2Ph), 36.30 (C(6)), 48.34 (C(7)), 58.30 (C(5)), 69.90
(C(4)), 94.39 (C(2)), 123.94, 125.10, 125.22, 128.56, 130.12,
To a solution of LDA (1.3 equiv., generated from diisoprop-
ylamine and n-butyllithium in dry THF) was added lactam 2d
(1.3–2.5 mmol) dropwise over 5 min and the solution left to
stir for a further 15 min. The electrophile (0.9–1.1 equiv.) (see
Table 1) was then added and the reaction left stirring at Ϫ78 ЊC
until TLC analysis indicated completion. The reaction mixture
was then warmed to rt and quenched with distilled water and
partitioned with DCM (30 cm3). The aqueous layer was
extracted with EtOAc and the combined organics washed with
brine, then dried (MgSO4). Solvent removal in vacuo and puri-
fication by flash column chromatography gave the products, as
indicated below.
143.02 (ArCH), 146.98, 147.53 (ArC), 173.00 (C᎐O); m/z (CIϩ)
᎐
353 (M ϩ Hϩ, 8%), 323 (50), 218 (100), 203 (40).
(؉)-(2R,5S,7S)-7-{[1-(tert-Butyloxycarbonyl)-3-indolyl]-
methyl}-2-methyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-
one 8c and (؉)-(2R,5S,7R)-7-{[1-(tert-butyloxycarbonyl)-3-
indolyl]methyl}-2-methyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]-
octan-8-one 7c. exo-Diastereomer 7c: (20 mg, 22%); Rf 0.47
(50:50 petrol–EtOAc); [α]D20 ϩ67.8 (c, 1.0 in CHCl3); νmax (film)/
cmϪ1 1371 (s), 1453 (s), 1692 (s), 1731 (s); δH(200 MHz, CDCl3)
1.70 (9H, s, C(CH3)3), 1.98 (3H, s, CH3), 1.90–2.20 (2H, m,
C(6)H), 2.95–3.40 (3H, m, C(7)H and ArCH2), 3.56–3.60 (1H,
m, C(4)H), 3.80–4.16 (2H, m, C(4)H and C(5)H), 7.24–7.67
(9H, m, ArH), 8.10–8.14 (1H, m, ArH); δC(50.3 MHz, CDCl3)
25.75 (CH3), 26.74 (ArCH2), 28.14 (C(CH3)3), 28.97 (C(6)),
47.98 (C(7)), 59.26 (C(5)), 70.13 (C(4)), 83.80 (C(CH3)3), 94.57
(C(2)), 115.47 (Indole CH), 117.89 (Indole C), 119.37, 122.73,
123.76, 124.78 (Indole CH), 125.14, 127.87, 128.29 (PhCH),
(؉)-(2R,5S,7S)-2-Methyl-2-phenyl-7-(phenylmethyl)-1-aza-
3-oxabicyclo[3.3.0]octan-8-one 8a and (؉)-(2R,5S,7R)-2-
methyl-2-phenyl-7-(phenylmethyl)-1-aza-3-oxabicyclo[3.3.0]-
octan-8-one 7a. exo-Diastereomer 7a: white crystalline solid
(0.12 g, 17%); mp 108–110 ЊC; Rf 0.3 (50:50 petrol–EtOAc); [α]D20
ϩ39.0 (c, 1.0 in CHCl3); found: C, 77.85; H, 6.85; N, 4.98.
C20H21NO2 requires C, 78.1; H, 6.9; N, 4.6%; νmax (film)/cmϪ1
1691 (s); δH(200 MHz, CDCl3) 1.89–2.08 (2H, m, C(6)H2), 1.97
(3H, s, CH3), 2.92–2.99 (2H, m, PhCH2), 3.08–3.15 (1H, m,
C(7)H), 3.51–3.56 (1H, m, C(4)Hendo), 3.62–3.68 (m, 1H,
C(5)H), 3.94–4.00 (1H, dd, J 7.5, 6.0 Hz, C(4)Hexo), 7.22–7.45
(10H, m, ArH); δC(125.8 MHz, CDCl3) 25.66 (CH3), 28.36
(CH2Ph), 37.17 (C(6)), 49.44 (C(7)), 59.16 (C(5)), 70.19 (C(4)),
125.25, 126.83, 128.09, 128.44, 128.71, 129.42 (ArCH); m/z
(CIϩ) 308 (M ϩ Hϩ, 100%), 188 (55).
endo-Diastereomer 8a: yellow oil (0.34 g, 47%); Rf 0.6 (50:50
petrol–EtOAc); [α]D20 ϩ210.8 (c, 1.0 in CHCl3); νmax (film)/cmϪ1
1696 (s); δH(500 MHz, CDCl3) 1.50–1.57 (1H, m, C(6)Hendo),
1.98 (3H, s, CH3), 2.22–2.27 (1H, m, C(6)Hexo), 2.76 (1H, dd,
J 14.0 Hz, JЈ 10.0 Hz, PhCHH), 3.11–3.17 (1H, m, C(7)H),
3.32 (1H, dd, J 14.0 Hz, JЈ 4.0 Hz, PhCHH), 3.51 (1H, m,
C(4)Hendo), 3.91–3.96 (1H, m, C(5)H), 4.03–4.06 (1H, m,
C(4)Hexo), 7.22–7.40 (2H, m, ArH), 7.53–7.54 (8H, m, ArH);
δC(125.8 MHz, CDCl3) 25.88 (CH3), 32.11 (CH2Ph), 36.55
(C(6)), 48.90 (C(7)), 58.39 (C(5)), 70.08 (C(4)), 125.29, 126.60,
128.17, 128.53, 128.74, 129.18 (ArCH); m/z (CIϩ) 308
(M ϩ Hϩ, 15%), 138 (30), 121 (95), 105 (100); HRMS 308.1651
(found), 308.1651 (calc. for C20H22NO2).
130.64, 135.66 (Indole C), 143.38 (PhC), 149.97 (C᎐O(Boc)),
᎐
175.70 (lactam C᎐O); m/z (CIϩ) 447.0 (M ϩ Hϩ, 20%), 391.1
᎐
(30), 347 (90); HRMS 447.2284 (found), 447.2284 (calc. for
C27H31N2O4).
endo-Diastereomer 8c: (0.050 g, 55%); Rf 0.61 (50:50 petrol–
EtOAc); [α]D20 ϩ116.6 (c, 1.0 in CHCl3); νmax (film)/cmϪ1 1371 (s),
1452 (s), 1693 (s), 1730 (s); δH(200 MHz, CDCl3) 1.50–1.70 (1H,
m, C6(H)endo), 1.80 (9H, s, C(CH3)3), 2.00 (3H, s, CH3), 2.25–
2.40 (1H, m, C6(H)exo), 2.75–2.90 (1H, m, ArCH), 3.20–3.45
(3H, m, ArCH and C-7(H)), 3.50–3.52 (1H, m, C-4(H)), 3.80–
4.20 (2H, m, C-4(H) and C-5(H)), 7.25–7.60 (8H, m, ArH),
8.13–8.17 (1H, m, ArH); δC(50.3 MHz, CDCl3) 25.60 (C(7)),
25.92 (CH3), 28.14 (C(CH3)3), 32.00 (C(6)), 47.32 (C(7)), 58.39
(C(5)), 70.07 (C(4)), 83.61 (C(CH3)3), 94.26 (C(2)), 115.50
(Indole CH), 118.11 (Indole C), 119.16, 122.74, 123.57, 124.70
(Indole CH), 125.31, 128.05, 128.56 (PhCH), 130.84, 135.73
(Indole C), 143.41 (PhC), 149.97 (C᎐O), 173.94 (lactam C᎐O);
᎐
᎐
m/z (CIϩ) 447 (M ϩ Hϩ, 20%), 347 (100), 190 (60), 145 (90);
HRMS 447.2284 (found), 447.2284 (calc. for C27H31N2O4).
(؉)-(2R,5S,7S)-2,7-Dimethyl-2-phenyl-1-aza-3-oxabicyclo-
[3.3.0]octan-8-one 8d and (؉)-(2R,5S,7R)-2,7-dimethyl-2-
phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-one 7d. exo-Diastereo-
mer 7d: yellow oil (10 mg, 3%); Rf 0.3 (50:50 40–60 petrol–
EtOAc); [α]D20 ϩ160 (c, 0.5 in CHCl3); δH(200 MHz, CDCl3) 1.34
(3H, d, J 7.4 Hz, CH3), 1.84–2.18 (2H, m, C(6)H2), 1.97 (3H, s,
CH3), 2.79–2.88 (1H, m, C(7)H), 3.55–3.70 (1H, m, C(4)H),
4.06–4.17 (2H, m, C(4)H and C(5)H), 7.29–7.53 (m, 5H, ArH);
m/z (CIϩ) 232 (M ϩ Hϩ, 20%), 121 (90), 105 (100); HRMS
232.1338 (found), 232.1338 (calc. for C14H18NO2).
endo-Diastereomer 8d: yellow solid (0.15 g, 46%); mp 50–
55 ЊC; Rf 0.41 (50:50 petrol–EtOAc); [α]D20 ϩ238 (c, 1.0 in
CHCl3); found: C, 72.87; H, 7.63; N, 5.66. C14H17NO2 requires
C, 72.7; H, 7.4; N, 6.1%; νmax (film)/cmϪ1 1695 (s); δH(200 MHz,
CDCl3) 1.26 (3H, d, J 7.0 Hz, CH3), 1.48 (1H, dd, JЈ 12.0 Hz,
J 3.0 Hz, C(6)Hendo), 1.97 (3H, s, CH3), 2.40–2.52 (1H, m,
C(6)Hexo), 2.83–2.93 (1H, m, C(7)H), 3.63 (2H, t, J 7.0 Hz,
C(4)Hendo), 3.95–4.31 (2H, m, C(4)Hexo and C(5)H), 7.29–7.40
(4H, m, ArH), 7.51–7.55 (1H, m, ArH); δC(50.3 MHz, CDCl3)
16.0 (CH3), 26.0 (CH3), 35.0 (C(6)), 42.5 (C(7)), 59.0 (C(5)),
70.0 (C(4)), 94.0 (C(2)), 125.0, 128.0, 128.5 (ArCH), 143.0
(؉)-(2R,5S,7S)-2-Methyl-2-phenyl-7-(p-nitrophenylmethyl)-
1-aza-3-oxabicyclo[3.3.0]octan-8-one 8b and (؉)-(2R,5S,7R)-2-
methyl-2-phenyl-7-(p-nitrophenylmethyl)-1-aza-3-oxabicyclo-
[3.3.0]octan-8-one 7b. exo-Diastereomer 7b: colourless solid
(0.078 g, 24%), Rf 0.14 (2:1 petrol–EtOAc), mp 103–105 ЊC;
found: C, 67.96; H, 5.61; N, 7.87. C20H20N2O4 requires C,
68.18; H, 5.68; N, 7.95%; [α]D20 ϩ30.3 (c, 1.0 in CHCl3); νmax
(CHCl3)/cmϪ1 1694 (s), 1346 (s); δH(200 MHz, CDCl3) 1.96–
2.07 (2H, m, C(6)H2), 1.96 (3H, s, CH3), 3.07–3.17 (3H, m,
ArCH2, C(7)H), 3.52–3.61 (2H, m, C(4)H and C(5)H), 3.98–
4.03 (1H, m, C(4)H), 7.31–7.44 (7H, m, ArH), 8.02–8.08 (2H,
m, ArH); δC(50.3 MHz, CDCl3) 25.42 (CH3), 28.14 (CH2Ph),
37.13 (C(6)), 48.85 (C(7)), 59.00 (C(5)), 70.13 (C(4)), 94.16
(C(2)), 123.90, 125.06, 128.30, 128.46, 130.22 (ArCH), 143.11,
146.40, 147.11 (ArC), 173.96 (C᎐O); m/z (EIϩ) 353.2 (M ϩ Hϩ,
᎐
50%), 323.2 (30), 233.1 (100).
endo-Diastereomer 8b: colourless solid (0.19 g, 58%), Rf 0.56
(2:1 petrol–EtOAc); mp 93–95 ЊC; found: C, 67.9; H, 5.96;
N, 7.31. C20H20N2O4 requires C, 68.17; H, 5.72; N, 7.95%; [α]D20
ϩ152.7 (c, 1.0 in CHCl3); νmax (CHCl3)/cmϪ1 1347, 1696 (s);
δH(200 MHz, CDCl3) 1.44–1.61 (1H, m, C(6)Hendo), 1.97 (3H, s,
CH3), 2.22–2.35 (1H, m, C(6)Hexo), 2.84–2.96 (1H, dd, J 14.0,
9.0 Hz, ArCH), 3.14–3.23 (1H, m, C(7)Hexo), 3.34–3.43 (1H, dd,
J 14.0, 4.5 Hz, ArCH), 3.52–5.59 (1H, m, C(4)Hendo), 3.93–4.10
(2H, m, C(4)Hexo and C(5)Hexo), 7.28–7.54 (7H, m, ArH), 8.16–
8.21 (2H, d, J 8.5, ArH); δC(50.3 MHz, CDCl3) 25.82 (CH3),
(ArC), 175.0 (C᎐O).
᎐
(؉)-(2S,5S,7S)-7-Chloro-2-methyl-2-phenyl-1-aza-3-oxa-
bicyclo[3.3.0]octan-8-one 8e, (؉)-(2S,5S,7R)-7-chloro-2-methyl-
2-phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-one 7e, and (؉)-(2R,
5S)-7,7-dichloro-2-methyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]-
octan-8-one 9a. exo-Diastereomer 7e: colourless solid (21 mg,
9%); Rf 0.18 (4:1 petrol–EtOAc); mp 135–140 ЊC; [α]D20 ϩ142.6
(c, 1.0 CHCl3); νmax (CHCl3)/cmϪ1 1710; δH(200 MHz, CDCl3)
1980
J. Chem. Soc., Perkin Trans. 1, 2000, 1977–1982