E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
2761
J = 3.0, 5.7 Hz, 1H, H-6), 6.22 (dd, J = 3.0, 5.8 Hz, 1H,
H-5), 3.35 (br, 1H, H-1), 3.09 (br, 1H, H-4, H-4 of major
diastereomer), 2.36 (dd, J = 3.4, 13.2 Hz, 1H, H-3exo),
2.24 (dd, J = 2.7, 13.2 Hz, 1H, H-3endo), 1.92–1.96 (br
d J = 9.7, 2H, H-7); 13C NMR (CDCl3) d (major diaste-
reomer) 140 (C-6), 132 (C-5), 122 (CN), 55.6 (C-1), 48.8
(C-4), 45.9 (C-7), 43.1 (C-3), 22.8 (C-2) (minor diastereo-
mer) 142 (C-6), 133 (C-5), 121 (CN), 56.3 (C-1), 47.2 (C-
4), 47.1 (C-7), 42.8 (C-3), 24.8 (C-2). The 1H NMR
matches the literature spectrum;26 IR (KBr) 3071,
2990, 2946, 2869, 2235, 1712, 1336, 1269, 766,
725 cmꢀ1; MS (EI): m/z (rel. intensity) 154 (M+Å 11%),
117 (M+Å-HCl, 4%), 91 (M+Å-HClCN, 15%), 66 (retro
Diels–Alder, 100%).
4.2.4. 2-Chlorobicyclo[2.2.1]heptane-exo-2-carboxamide
5. Hydrogenation of 2-chlorobicyclo[2.2.1]hept-5-ene-
exo-2-carboxamide 4 98% yield. H NMR d 6.24 (br s,
1
1H, NH), 5.40 (br s, 1H, NH), 2.82 (ddd, J = 2.8, 4.5,
13.6 Hz, 1H, H-3endo), 2.60 (br d, J = 4.0 Hz 1H, H-1),
2.31 (br t, J = 4.4 Hz, 1H, H-4), 2.13 (m, J = 3.0, 9.2,
12.4 Hz, 1H, H-6endo), 1.78 (br d, J = 10.2 Hz, 1H, H-
7A), 1.62 (m, Jꢁ4 and 8-8.7, 12.3 Hz, 1H, H-6exo), 1.53
(br d, J = 13.5 Hz, 1H, H-5exo), 1.49 (m, 1H, H-3exo),
1.38 (m, J = 3.4, 10.2, 1H, H-7B), 1.34 (m, J = 2.3, 8.9,
11.3, 1H, H-5endo). 13C NMR d 174.9 (C-amide), 75.7
(C-2), 49.0 (C-1), 44.8 (C-4), 38.2, 36.8, 28.3, 25.2. IR
(KBr) 3406, 3295, 3181, 2957, 2873, 1662, 1608, 1386,
769, 589 cmꢀ1; MS 174 (M+Å, 31%), 138 (M+ÅꢀCl,
30%), 129 (18%), 106 (100%), 93 (38%), 67 (30%).
20
4.2.2. 2-Chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxam-
ide, 4. A solution of 3 (240 mg, 1.56 mmol) in DMSO
(10 mL) and 3 equiv of 0.5 M aqueous NaOH was stir-
red at 50 ꢁC for 4 h. The reaction mixture was diluted
with water (10 mL) and neutralized with concentrated
HCl. The product was extracted into EtOAc
(3 · 10 mL) and dried over Na2SO4. Concentration in
vacuo gave a light yellow solid. Purification by column
chromatography on silica gel with hexane–EtOAc (gra-
dient, starting at 6:1 and ending at 2:1) gave 4 (192 mg,
71% yield, white crystalline, 1:9 endo/exo carboxamide).
The exo-amide diastereomer was purified further by col-
umn chromatography. Found; Mp 112–114 ꢁC (lit. 114–
115 ꢁC),26 GC Rt (SPB 5) 22.2 min (RI 1354); UV–vis
(kmax = 204 nm, emax = 6000 Mꢀ1 cmꢀ1, EtOH 95%);
1H NMR d 6.46 (br, 1H, NH), 6.40 (dd, J = 3.0,
5.6 Hz; 1H, H-6), 6.22 (dd, J = 3.0, 5.6 Hz; 1H, H-5),
5.54 (br, 1H, NH), 3.24 (m, 1H, H-1), 2.98 (m, 1H, H-
4), 2.86 (dd, J 3.7, 12.9 Hz; 1H, H-3endo), 1.89 (br d,
J = 9.1 Hz, 1H, H-7A), 1.57 (br d, J = 8.9 Hz, 1H, H-
7B), 1.50 (dd, J = 3.6, 12.9 Hz; 1H, H-3exo); 13C NMR
d 175.3 (C-amide), 139.4 (C-5), 134.9 (C-6), 74.7 (C-2),
54.3 (C-1), 48.4 (C-4), 42.7 (C-3), 42.3 (C-7); IR (KBr)
3413, 3282, 3188, 2977, 1662, 1604, 1383; MS (EI) 172
(M+Å+1, 40%), 136 (M+Å-Cl, 9%), 106 (79%), 91 (53%),
66 (100%). Anal. Calcd for C8H10OCl: C, 55.8; H,
5.81; N, 8.14. Found: C, 56.1; H, 5.90; N, 8.01.
For the chiral amide ½a ¼ ꢀ25 (c 1.0, CHCl3); Rt
D
20
(Cyclosil B) 19.3 min, and ½a ¼ þ25 (c 0.9, CHCl3);
D
Rt (CycloSil B) 18.9 min.
To facilitate the assignment of the 1H NMR spectrumof
5, racemic 4 (28.7 mg, 0.17 mmol) was deuterated as de-
scribed above to give 5,6-D2-5 27.2 mg (93%); 1H NMR
d 6.21 (br, 1H, NH), 5.30 (br, 1H, NH), 2.83 (ddd, J <2,
J = 4.5, 13.6 Hz), 2.60 (br, 1H, H-1), 2.31 (br, 1H, H-4),
2.15 (dm, 1H, H-6endo), 1.77 (br d, J = 10.2 Hz, 1H, H-
7A), 1.50 (ddd, J = 2.1, 3.3, 13.6 Hz, 1H, H-3exo), 1.36
(br d, J = 10.2, 1H, H-7B), 1.33 (br d, J = 8.9, 1H, H-
5endo); IR (KBr) 3423, 3181, 2967, 2926, 2161 (C-D
str.), 1648, 1373, 779, 588 cmꢀ1. MS 176 (M+Å, 100%),
140 (M+Å-Cl, 28%), 131 (12%), 108 (16%), 106 (50%),
95 (17%), 93 (16%), 67 (13%). Additions of electrophiles
and nucleophiles, halogens or hydrogen to the bicy-
clo[2.2.1]hept-5-ene systemare known to proceed exclu-
sively fromthe exo face.40,41 In this case, the signals
corresponding to H-5exo and H-6exo in compound 5 dis-
appeared in the spectrumof compound 5,6 D2–5, which
facilitated assignment of the spectrum of 5.
4.2.5. ( )-Bicyclo[2.2.1]hept-5-ene-2-one 2. a-Chloro-
nitrile 3 (0.93 g, 6.0 mmol) was placed in a round-bottom
flask, fitted with a condenser, dissolved in a minimum
volume of ether, DMSO (15 mL) and 2.5 M NaOH
(10 mL). The mixture was maintained at 70 ꢁC ca. 4 h.
The product was extracted into freshly distilled ether
(2 · 15 mL), washed with brine (15 mL), and dried over
Na2SO4. The solvent was removed by fractional distilla-
tion to give bicyclo[2.2.1]hept-5-ene-2-one 2 (0.286 g,
44% yield). Similarly, 2-chlorobicyclo[2.2.1]hept-5-ene-
exo-2-carboxamide 4 was converted to ( )-2 in 83%
Pure 2-chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxam-
ide 4 was then subjected to chromatographic resolution
on a medium-pressure liquid chromatograph equipped
with an MCTA column. This gave the (ꢀ) (1S,2S,4S)-
20
enantiomer first; ½a ¼ ꢀ60 (c 0.6, CHCl3) Rt (Cyclosil
D
B) 16.3 min, (Chiracel) 13.5 min, followed by the (+)
20
1
(1R,2R,4R)-enantiomer; ½a ¼ þ60 (c 0.4, CHCl3) Rt
yield. H NMR d 6.52 (dd, J = 2.8, 5.6 Hz, 1H, H-6),
D
(Cyclosyl B) 16.8 min, (Chiracel) 16.4 min. A typical
separation profile for a large-scale MCTA separation
is shown in Figure 1.
6.06 (m, 1H, H-5), 3.14 (br s, 1H, H-1), 2.95 (m, 1H,
H-4), 2.15 (m, J = 9.2 Hz, 1H, H-7), 1.96–1.88 (m,
J = 9.2, 16.5 Hz, 2H, H-7 and H-3), 1.79 (dd, J = 4.5,
16.5 Hz, 1H, H-3). 13C NMR d 216 (C-2), 143 (C-6),
131 (C-5), 56 (C-1), 51 (C-4), 40, 37; IR 3477 (ꢁtwice
C@O stretch), 3067, 2970, 2936, 1749, 1326, 1125,
709 cmꢀ1; GC Rt (SPB 5) 10.2 min (RI 931); MS m/z
108 (M+Å 48%), 91 (M+Å-OH, 3.8%), 77 (5%), 66 (100%).
4.2.3. Typical hydrogenation of the bicyclo[2.2.1]hept-5-
ene compounds 4 or 2. A solution of the compound in
hexane and a catalytic amount of palladium on charcoal
were placed in a 6 mL vial, fitted with a stirbar, a screw-
cap and a rubber septum. The vial was sealed, pressur-
ized with hydrogen, and the reaction mixture stirred
for ca. for 4 h. The crude product was passed through
a short silica gel column and concentrated in vacuo to
give a reduced compound.
4.2.6. (+)-Bicyclo[2.2.1]hept-5-en-2-one (+)-2 from
(+)-2-chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxamide
(+)-4. Compound (+)-4 (10 mg, 0.059 mmol) was
placed in a flask with a condenser. DMSO (1 mL) and