Asymmetric Carbocycle and Heterocycle Synthesis
J . Org. Chem., Vol. 63, No. 5, 1998 1625
170.4; IR (neat) 3403, 1615 cm-1; HRMS (EI) calcd for C24H29
NO3 379.2147, found 379.2136.
-
NO3Cl 366.1836, found 366.1833. For 37Cl calcd 368.1807,
found 368.1815.
r-Ben zyl-â-br om oeth yl La cta m 5. To a stirred solution
of hydroxy lactam 4 (95 mg, 0.25 mmol) in 5.0 mL of CH2Cl2
at 0 °C was added triphenylphosphine (99 mg, 0.38 mmol),
followed by N-bromosuccinimide (67 mg, 0.38 mmol). The
mixture was stirred for 60 min and then diluted with CH2Cl2
(15 mL) and washed with water (20 mL). The phases were
separated, and the organic phase washed with brine (20 mL),
dried (MgSO4), and concentrated. The residue was purified
by flash chromatography (1:1 hexanes-ethyl acetate) to give
â-Iod op r op yl la cta m 8a was obtained from 1,3-diiodopro-
pane and 7 in 31% yield as a colorless oil: [R]23D +21.2 (c 1.34,
CHCl3); 1H NMR (CDCl3) δ 1.49 (m, 3H), 1.58 (s, 3H), 1.87
(app quint, J ) 7.5 Hz, 2H), 2.01 (m, 2H), 2.20 (m, 1H), 2.64
(app q, J ) 11.1 Hz, 1H), 3.18 (t, J ) 6.9 Hz, 2H), 3.35 (s, 3H),
3.58 (dd, J ) 3.0, 10.5 Hz, 1H), 3.78 (dd, J ) 5.4, 10.2 Hz,
1H), 4.04 (m, 1H), 5.23 (d, J ) 7.8 Hz, 1H), 7.32 (m, 5H); 13C
NMR (CDCl3) δ 5.97, 24.54, 28.97, 30.54, 37.24, 37.87, 42.21,
59.25, 63.25, 70.50, 78.21, 93.40, 126.6, 128.3, 128.6, 139.1,
168.8; IR (neat) 1649 cm-1; HRMS (FAB, M + H) calcd for
C19H26NO3I 444.1036, found 444.1032.
93 mg (84%) of bromo lactam 5 as a colorless oil: [R]23 +58.8
D
1
(c 1.74, CHCl3); H NMR (CDCl3) δ 0.79 (d, J ) 7.0 Hz, 3H),
0.85 (s, 3H), 1.30 (app t, J ) 12.6 Hz, 1H), 1.71 (m, 1H), 2.07
(m, 3H), 2.40 (m, 1H), 2.85 (dd, J ) 4.2, 13.5 Hz, 1H), 3.42 (m,
3H), 4.81 (quint, J ) 7.2 Hz, 1H), 5.00 (d, J ) 5.7 Hz, 1H),
7.25 (m, 10 H); 13C NMR (CDCl3) δ 15.57, 27.25, 29.73, 30.60,
36.28, 37.69, 39.39, 48.17, 54.88, 79.41, 91.93, 126.0, 126.8,
127.7, 128.2, 128.3, 130.3, 136.6, 137.8, 169.8; IR (neat) 1642
â-Ch lor op r op yl la cta m 8b was obtained from 1-chloro-3-
iodopropane and 7 in 49% yield as a pale yellow oil: [R]23
D
1
+22.7 (c 1.78, CHCl3); H NMR (CDCl3) δ 1.51 (m, 3H), 1.58
(s, 3H), 1.82, (app quint, J ) 7.2 Hz, 2H), 1.98 (app t, J ) 10.2
Hz, 1H), 2.02 (m, 1H), 2.21 (m, 1H), 2.65 (app q, J ) 11.4 Hz,
1H), 3.35 (s, 3H), 3.54 (t, J ) 6.6 Hz, 2H), 3.58 (dd, J ) 3.0,
10.2 Hz, 1H), 3.78 (dd, J ) 5.4, 10.5 Hz, 1H), 4.04 (m, 1H),
5.23 (d, J ) 7.8 Hz, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) δ
24.46, 29.18, 29.66, 33.64, 37.81, 42.13, 44.67, 59.18, 63.18,
70.46, 78.17, 93.35, 126.6, 128.3, 128.5, 139.1, 168.7; IR (neat)
cm-1
.
Cyclobu ta n e-F u sed Tr icyclic La cta m 6. To a stirred
solution of diisopropylamine (0.05 mL, 0.36 mmol) in 1.0 mL
of THF at 0 °C was added n-butyllithium (2.30 M solution in
hexanes, 0.14 mL, 0.32 mmol), followed by HMPA (0.06 mL,
0.34 mmol). The mixture was stirred at 0 °C for 15 min and
then transferred dropwise via cannula to a stirred solution of
bromo lactam 5 (93 mg, 0.21 mmol) in 1.0 mL of THF at 0 °C.
The solution was stirred for 30 min at 0 °C and then warmed
to ambient temperature and stirred 6 h. The mixture was
partitioned between ether (10 mL) and saturated NH4Cl (aq,
10 mL), and the phases were separated. The organic phase
was dried (MgSO4) and concentrated. The residue was purified
by flash chromatography (2:1 hexanes-ethyl acetate) to yield
52 mg (69%) of tricyclic lactam 6 as a colorless oil: [R]23D +125
1647 cm-1
.
â-Iod obu tyl la cta m 8c was obtained from 1,4-diiodobutane
and 7 in 37% yield as a colorless oil: [R]23 +26.4 (c 1.66,
D
CHCl3); 1H NMR (CDCl3) δ 1.44 (m, 5H), 1.59 (s, 3H), 1.82
(m, 2H), 1.99 (m, 2H), 2.21 (m, 1H), 2.65 (app q, J ) 11.1 Hz,
1H), 3.18 (t, J ) 6.6 Hz, 2H), 3.35 (s, 3H), 3.59 (dd, J ) 3.0,
10.5 Hz, 1H), 3.78 (dd, J ) 5.1, 10.2 Hz, 1H), 4.04 (m, 1H),
5.23 (d, J ) 7.8 Hz, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) δ
6.43, 24.45, 27.40, 29.40, 33.13, 35.23, 37.85, 42.12, 59.15,
63.10, 70.47, 78.14, 93.37, 126.5, 128.2, 128.4, 139.1, 168.9;
IR (neat) 1647 cm-1; HRMS (FAB, M + H) calcd for C20H28
NO3I 458.1192, found 458.1195.
-
1
(c 1.35, CHCl3); H NMR (CDCl3) δ 0.51 (s, 3H), 0.74 (d, J )
6.7 Hz, 3H), 1.46 (m, 1H), 1.76 (app t, J ) 12.0 Hz, 1H), 2.11
(m, 2H), 2.35 (m, 3H), 2.89 (d, J ) 12.9 Hz, 1H), 3.46 (d, J )
13.2 Hz, 1H), 4.79 (quint, J ) 6.9 Hz, 1H), 5.04 (d, J ) 5.7 Hz,
1H), 7.24 (m, 10H); 13C NMR (CDCl3) δ 15.46, 20.79, 26.29,
30.12, 31.47, 40.95, 42.58, 46.19, 54.15, 79.10, 92.79, 126.1,
126.7, 127.6, 128.2, 130.1, 136.6, 137.7, 172.5; IR (neat) 1637
cm-1; HRMS (EI) calcd for C24H27NO2 361.2042, found 361.2039.
A significant amount of starting bromo lactam 5 (17 mg, 18%)
was also recovered.
â-Iod op en tyl la cta m 8e was obtained from 1,5-diiodopen-
tane and 7 in 47% yield as a pale yellow oil: [R]23 +21.1 (c
D
1
1.40, CHCl3); H NMR (CDCl3) δ 1.45 (m, 7H), 1.59, (s, 3H),
1.82 (m, 2H), 1.98 (m, 2H), 2.20 (m, 1H), 2.64 (app q, J ) 11.1
Hz, 1H), 3.18 (t, J ) 6.9 Hz, 2H), 3.35 (s, 3H), 3.59 (dd, J )
3.0, 10.5 Hz, 1H), 3.78 (dd, J ) 5.4, 10.5 Hz, 1H), 4.04 (m,
1H), 5.23 (d, J ) 7.8 Hz, 1H), 7.32 (m, 5H); 13C NMR (CDCl3)
δ 6.77, 24.49, 25.46, 29.45, 30.30, 33.18, 36.17, 37.94, 42.19,
59.19, 63.15, 70.54, 78.18, 93.46, 126.6, 128.2, 128.5, 139.2,
169.1; IR (neat) 1648 cm-1. Anal. Calcd for C21H30NO3I: C,
53.51; H, 6.42. Found: C, 53.38; H, 6.45.
Gen er a l P r oced u r e for Alk yla tion of Cya n o En a m in es
7 w ith r,ω-Dih a lid es (Meth od A). â-Ch lor obu tyl La cta m
8d . To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.22
mL, 1.33 mmol) in 3.5 mL of THF at -78 °C was added
n-butyllithium (2.30 M solution in hexanes, 0.56 mL, 1.28
mmol) followed by HMPA (0.22 mL, 1.28 mmol). The solution
was stirred for 5 min at -78 °C, warmed to 0 °C, stirred 1.5
min, and then cooled to -78 °C, at which time cyano enamine
71 (0.28 g, 0.99 mmol) in 1.5 mL of THF was added dropwise
over 1 min. The solution was stirred at -78 °C for 20 min,
and 1-chloro-4-iodobutane (0.24 mL, 1.97 mmol) was added
dropwise. The mixture was stirred for 6 h at -78 °C and
quenched with saturated NaHCO3 (10 mL). The mixture was
diluted with ether (15 mL), and the phases were separated.
The aqueous phase was extracted with ether (15 mL), and the
combined organic phases concentrated. To the crude chloro-
cyano enamine were added THF (15 mL) and 1 N HCl (aq)
(15 mL), and the mixture was stirred at ambient temperature
24 h. The mixture was concentrated, the residue was ex-
tracted with ether (3 × 15 mL), and the combined organic
phases were dried (MgSO4) and concentrated. Flash chroma-
tography of the residue (1:1 hexanes-ethyl acetate) provided
â-Ch lor op en tyl la cta m 8f was obtained from 1-chloro-5-
iodopentane and 7 in 48% yield as a colorless oil: [R]23D +23.2
(c 1.18, CHCl3); 1H NMR (CDCl3) δ 1.43 (m, 7H), 1.58 (s, 3H),
1.76 (m, 2H), 1.97 (m, 2H), 2.19 (m, 1H), 2.63 (app q, J ) 11.4
Hz, 1H), 3.34 (s, 3H), 3.51 (t, J ) 6.6 Hz, 2H), 3.58 (dd, J )
3.0, 10.5 Hz, 1H), 3.78 (dd, J ) 5.4, 10.2 Hz, 1H), 4.04 (m,
1H), 5.22 (d, J ) 8.1 Hz, 1H), 7.31 (m, 5H); 13C NMR (CDCl3)
δ 24.48, 25.84, 26.74, 29.48, 32.35, 36.23, 37.96, 42.22, 44.83,
59.19, 63.16, 70.56, 78.20, 93.47, 126.6, 128.2, 128.5, 139.2,
169.1; IR (neat) 1647 cm-1
.
â-Iod oh exyl la cta m 8g was obtained from 1,6-diiodohex-
ane and 7 in 50% yield as a colorless oil: [R]23 +18.5 (c 1.95,
D
CHCl3); 1H NMR (CDCl3) δ 1.43 (m, 9H), 1.58 (s, 3H), 1.81
(m, 2H), 1.98 (m, 2H), 2.19 (m, 1H), 2.64 (m, 1H), 3.17 (t, J )
6.9 Hz, 2H), 3.35 (s, 3H), 3.59 (dd, J ) 3.3, 10.2 Hz, 1H), 3.78
(dd, J ) 5.4, 10.2 Hz, 1H), 4.04 (m, 1H), 5.22 (d, J ) 8.1 Hz,
1H), 7.32 (m, 5H); 13C NMR (CDCl3) δ 6.88, 24.46, 26.32, 28.39,
29.49, 30.24, 33.27, 36.26, 37.96, 42.21, 59.16, 63.10, 70.53,
78.15, 93.44, 126.5, 128.2, 128.4, 139.2, 169.1; IR (neat) 1648
cm-1
.
0.19 g (53%) of â-chlorobutyl lactam 8d as a colorless oil: [R]23
â-Ch lor obu ten yl la cta m 8h was obtained from cis-1,4-
D
1
+23.9 (c 1.19, CHCl3); H NMR (CDCl3) δ 1.45 (m, 5H), 1.58
dichloro-2-butene and 7 in 49% yield as a pale yellow oil: [R]23
D
(s, 3H), 1.69 (m, 2H), 1.99 (m, 2H), 2.21 (m, 1H), 2.65 (app q,
J ) 11.1 Hz, 1H), 3.35 (s, 3H), 3.53 (t, J ) 6.6 Hz, 2H), 3.59
(dd, J ) 3.3, 10.2 Hz, 1H), 3.78 (dd, J ) 5.4, 10.2 Hz, 1H),
5.23 (d, J ) 7.8 Hz, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) δ
23.76, 24.37, 29.39, 32.28, 35.50, 37.76, 42.03, 44.55, 59.06,
63.04, 70.44, 78.08, 93.31, 126.4, 128.1, 128.3, 139.1, 168.8;
+27.2 (c 1.42, CHCl3); 1H NMR (CDCl3) δ 1.53 (app t, J ) 12.3
Hz, 1H), 1.58 (s, 3H), 2.12 (m, 5H), 2.65 (dd, J ) 4.5, 16.5 Hz,
1H), 3.35 (s, 3H), 3.58 (dd, J ) 3.0, 10.5 Hz, 1H), 3.78 (dd, J
) 5.4, 10.5 Hz, 1H), 4.04 (m, 1H), 4.06 (d, J ) 8.1 Hz, 2H),
5.23 (d, J ) 7.8 Hz, 1H), 5.61 (ddd, J ) 7.5, 10.8 Hz, J ) 15.0
Hz, 1H), 5.78 (ddd, J ) 8.1, 10.8, 15.9 Hz, 1H), 7.32 (m, 5H);
13C NMR (CDCl3) δ 24.45, 29.78, 33.39, 37.52, 38.81, 41.74,
IR (neat) 1647 cm-1; HRMS (FAB, M + H) calcd for C20H28
-