Spiro â-Lactams as â-Turn Mimetics
J . Org. Chem., Vol. 66, No. 19, 2001 6337
F igu r e 4. Variation of NH proton chemical shifts (ppm) of 14 as a function of temperature (°C) from a sample measured in
DMSO-d6.
2H), 4.66 (d, J ) 12.0 Hz, 1H), 4.75 (d, J ) 12.5 Hz, 1H), 4.94
(d, J ) 12.0 Hz, 1H), 5.04 (d, J ) 12.5 Hz, 1H), 6.81 (m, 2H),
7.03 (m, 2H), 7.13-7.43 (m, 16H); 13C NMR (50 MHz, CDCl3)
δ 21.7, 22.4, 27.2, 33.9, 35.3, 46.8, 47.5, 66.0, 67.0, 72.0, 72.5,
78.0, 78.7, 126.2, 126.9, 127.0, 127.2, 127.3, 127.6, 127.8, 127.9,
134.2, 134.3, 135.4, 136.2, 153.2, 167.9, 168.3; IR (KBr) 1757,
1702 cm-1; HRMS Calcd for C21H22N2O3 350.1630. Found
350.1620. Anal. Calcd for C21H22N2O3 C, 71.98, H, 6.33, N, 7.99.
Found C, 71.64, H, 6.08, N, 8.14.
δ 1.89 (m, 2H), 2.04 (m, 2H), 2.28 (m, 2H), 2.46 (m, 2H), 3.52
(m, 4H), 3.75 (s, 3H), 3.79 (s, 3H), 4.49 (d, J ) 8.6 Hz, 1H),
4.55 (d, J ) 8.5 Hz, 1H), 5.02 (m, 2H), 5.31 (m, 2H), 6.15 (dd,
J ) 16 and 8.5 Hz, 1H), 6.52-6.84 (m, 7H), 7.02 (m, 2H), 7.24-
7.34 (m, 20H), 7.46 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 22.3,
23.0, 34.6, 35.8, 47.8, 48.3, 55.3, 55.4, 66.9, 67.7, 69.8, 70.3,
76.5, 76.8, 76.8, 77.1, 114.1, 118.3, 124.4, 125.5, 126.4, 126.5,
127.7, 127.8, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 131.3,
131.6, 135.4, 135.5, 135.8, 135.9, 136.4, 153.8, 154.3, 155.9,
156.0, 164.9, 165.0; IR (KBr) 1752, 1708 cm-1; HRMS Calcd
for C29H28N2O4 468.2049. Found 468.2027. Anal. Calcd for
(()-(3SR,4RS)-5-Ben zyloxyca r bon yl-2-(4-m eth oxyp h e-
n yl)-3-p h en yl-2,5-d ia za sp ir o[3,4]octa n -1-on e (8). Purified
through flash chromatography (33% EtOAc/hexanes), 734 mg
of 8, 83% yield. White solid, mp ) 144-146 °C. 1H and 13C
NMR show the presence of rotamers about the carbamate bond
C
29H28N2O4 C, 74.34, H, 6.02, N, 5.98. Found C, 74.64, H, 6.28,
N, 6.14.
(()-(3SR,4RS)-5-Ben zyloxyca r bon yl-2-m eth oxyca r bo-
n ylm eth ylen -3-ph en yl-2,5-diazaspir o[3,4]octan -1-on e (11).
1
in a 1:1 ratio. mp 144-146 °C; H NMR (200 MHz, CDCl3) δ
1.95-2.18 (m, 4H), 2.31-2.54 (m, 4H), 3.30-3.54 (m, 4H), 3.72
(s, 3H), 3.73 (s, 3H), 4.50 (d, J ) 12.3 Hz, 1H), 4.73 (d, J )
12.6 Hz, 1H), 4.69-5.02 (m, 3H), 5.03 (d, J ) 12.6 Hz, 1H),
6.77-6.87 (m, 6H), 7.00 (m, 2H), 7.14-7.41 (m, 20H); 13C NMR
(50 MHz, CDCl3) δ 21.8, 22.5, 34.3, 35.7, 47.0, 47.7, 55.0, 66.1,
67.1, 69.4, 70.0, 76.7, 77.4, 113.8, 118.1, 118.2, 126.5, 127.0,
127.3, 127.5, 127.8, 127.9, 130.7, 131.0, 133.1, 133.4, 135.1,
136.1, 153.1, 153.2, 155.6, 155.7, 164.6, 164.9; IR (KBr) 1751,
1695 cm-1; HRMS Calcd for C27H26N2O4 442.1892. Found
442.1892. Anal. Calcd for C27H26N2O4 C, 73.28, H, 5.92, N, 6.33.
Found C, 73.44, H, 5.78, N, 6.39.
Purified through flash chromatography (33% EtOAc/hexanes),
1
628 mg of 11, 77% yield. White solid, mp ) 95-97 °C. H and
13C NMR show the presence of rotamers about the carbamate
1
bond in a 1:1 ratio. H NMR (200 MHz, CDCl3) δ 1.9-2.1 (m,
4H), 2.37-2.53 (m, 4H), 3.23-3.47 (m, 4H), 3.48 (d, J ) 18.2
Hz, 1H), 3.70 (d, J ) 18.2 Hz, 1H), 3.70 (s, 6H), 4.43 (d, J )
18.2 Hz, 1H), 4.61-4.83 (m, 5H), 4.93 (d, J ) 12.5 Hz, 1H),
5.03 (d, J ) 12.5 Hz, 1H), 6.79 (m, 2H), 7.01 (m, 2H), 7.11-
7.35 (m, 16H); 13C NMR (50 MHz, CDCl3) δ 22.1, 22.7, 34.4,
35.8, 41.4, 41.5, 47.2, 47.9, 52.1, 52.2, 66.4, 67.4, 70.7, 71.2,
78.7, 79.4, 126.4, 127.1, 127.3, 127.5, 127.7, 128.00, 128.06,
128.12, 128.17, 134.1, 134.2, 135.6, 136.4, 153.4, 153.6, 168.3,
168.6, 169.1, 169.5; IR (KBr) 1781, 1750, 1702 cm-1; HRMS
calcd for C23H24N2O5 408.1685, found 408.1694. Anal. Calcd
for C23H24N2O5 C, 67.63; H, 5.92; N 6.86. Found: C, 67.54; H,
5.87; N, 6.99.
(()-(3SR,4SR)-5-Ben zyloxyca r bon yl-2-(4-m eth oxyp h e-
n yl)-3-(2-fu r yl)-2,5-d ia za sp ir o[3,4]octa n -1-on e (9). Purified
through flash chromatography (33% EtOAc/hexanes), 570 mg
of 9, 66% yield. Pale yelow solid, mp )118-120 °C. 1H and
13C NMR show the presence of rotamers about the carbamate
1
bond in a 1:1 ratio.; H NMR (200 MHz, CDCl3) δ 1.91-2.13
(()-(3SR,4RS)-5-(N-ter t-bu toxyca r bon yla m in oa cetyl)-
2-Met h oxyca r b on ylm et h ylen -3-p h en yl-2,5-d ia za sp ir o-
[3,4]octa n -1-on e (13). 2 mmol (816 mg) of 11 were dissolved
in a 3/1 mixture of EtOAc/methanol (16 mL) and transferred
via cannula to a flask under H2 (1 atm.) containing 50 mg of
10% Pd-C catalyst. The mixture was stirred overnight and
then the catalyst was filtered off on Celite. The organic layer
was concentrated in vacuo to afford 537 mg of a pale yellow
oil, which was employed without further purification. N-tert-
butoxycarbonylglycine (350 mg, 2 mmol), was dissolved in 4
mL of a 1:1 mixture of CHCl3 and toluene, 0.28 mL of NEt3 (2
mmol) was then added and the solution was cooled to -15 °C.
To this mixture was added 217 mg (2 mmol) of ethyl chloro-
formate and stirred at this temperature for 30 min. Then the
aforementioned crude oil was dissolved in 2 mL of CHCl3 and
added via cannula to the mixed anhydride previously formed.
The mixture was heated to 50 °C and stirred for 2h. The
solution was cooled to room temperature and washed with 5%
aqueous NaHCO3, 1M HCl and brine. The organic layer was
(m, 4H), 2.28-2.49 (m, 4H), 3.39-3.55 (m, 4H), 3.77 (s, 3H),
3.79 (s, 3H), 4.82 (d, J ) 12.1 Hz, 1H), 4.91 (d, J ) 12.5 Hz,
1H), 4.92 (s, 1H), 4.95 (s, 1H), 5.07 (d, J ) 12.1 Hz, 1H), 5.17
(d, J ) 12.5 Hz, 1H), 5.73 (d, J ) 3.3 Hz, 1H), 6.20 (m, 2H),
6.29 (d, J ) 3.3 Hz, 1H), 6.82 (m, 4 H), 7.18-7.34 (m, 16H);
13C NMR (50 MHz, CDCl3) δ 21.8, 22.7, 34.0, 35.4, 47.3, 47.9,
55.3, 63.9, 64.2, 66.7, 67.6, 77.1, 77.8, 109.0, 110.1, 110.2, 110.6,
114.0, 118.5, 127.7, 128.1, 128.2, 130.5, 130.8, 135.4, 136.5,
142.2, 142.7, 148.0, 148.1, 153.7, 156.0, 156.1, 164.5, 164.6;
IR (KBr) 1755, 1701 cm-1; HRMS Calcd for C25H24N2O5
432.1685. Found 432.1687. Anal. Calcd for C25H24N2O5 C,
69.43, H, 5.59, N, 6.48. Found C, 69.54, H, 5.78, N, 6.39.
(()-(3SR,4RS)-5-Ben zyloxyca r bon yl-2-(4-m eth oxyp h e-
n yl)-3-(2-p h en yleth ylen )-2,5-d ia za sp ir o[3,4]octa n -1-on e
(10). Purified through flash chromatography (33% EtOAc/
hexanes), 569 mg of 10, 63% yield. White solid, mp ) 142-
144 °C. 1H and 13C NMR show the presence of rotamers about
the carbamate bond in a 1:1 ratio. 1H NMR (200 MHz, CDCl3)