FELLUGA ET AL.
Scheme 1. Formation of optically active a-ketols from (S)-(ꢀ)-1-phenylethylimine 2 and nitroolefins 3a–d.
products were separated on column chromatography, using light petro-
leum–ethyl acetate in 5:1 ratio as the eluent.
3.97 (dt, J1 =J2 = 11.3 Hz, J3 =5.7Hz, 1H, C-4), 3.22 (dd, J1 = 19.6 Hz,
J2 = 10.6 Hz, 1H, H-5 cis to Ph), 3.09 (bs, 1H, OH), 2.92 (dd, J1 = 19.6 Hz,
J2 = 10.0 Hz, 1H, H-5 trans to Ph), 1.53 (s, 1H, CH3); 13C NMR (100 MHz,
CDCl3) d, ppm: 212.5 (s, CO), 134.4 (s, Ph), 129.2 (2d, Ph), 128.5 (d, Ph),
127.1 (2d, Ph), 96.0 (d, C-3), 80.5 (s, C-2), 40.7 (d, C-4), 35.2 (t, C-5), 22.6
(1R,3aR,6aR)-(+)-1-Hydroxy-1-methyl-6a-nitrohexahydro-1H-pentalen-2-one
[(+)-5a].50 [a]D25 = +32 (c 0.25, CH3OH), 90% e.e.; CD (0.0082 M, CH3OH),
Δe308 = +0.974; Δe265 = ꢀ0.319; high-resolution gas chromatography
(HRGC) (b-cyclodextrin, 150 ꢁC): (+)-5a, 30.4 min, (ꢀ)-5a, 31.1 min.
(1S,3aR,6aR)-(+)-1-Hydroxy-1-methyl-6a-nitrohexahydro-1H-pentalen-2-
one [(+)-6a].50 [a]D25 = +23.5 (c 0.8, CH3OH), 89% e.e. CD (0.0078 M,
CH3OH), Δe305 = +1.01; Δe252 = ꢀ0.48; HRGC (b-cyclodextrin, 150 ꢁC):
(ꢀ)-6a, 45.4 min, (+)-6a, 46.7 min.
+
•
(q, CH3). MS (70 eV): 235 (M , <1), 187 (5, M–OH–NO), 160 (11), 159
(12, 187–CO), 147 (71), 145 (35), 131 (46), 129 (100), 117 (42), 103 (14), 91
(15), 77 (13); Anal. calc. for C12H13NO4: C, 61.27, H, 5.57, N, 5.95. Found:
C, 60.99, H, 5.52, N, 5.67. [a]2D5 =ꢀ45.0 (c, 0.04 CHCl3), 71% e.e.; HPLC (flow
rate, 1 ml/min, pressure 34 bar): (+)-7c, 19.40 min, (ꢀ)-7c, 20.85 min.
(2R,3R,4R)-(+)-2-Hydroxy-2,3-dimethyl-3-nitro-4-phenylcyclopentanone
[(+)-5d].47 Rf 0.75 (eluent: ethyl acetate-light petroleum gradient from 15:85 to
(1R,3aR,7aR)-(+)-1-Hydroxy-1-methyl-7a-nitrooctahydro-2H-inden-2-one
[(+)-5b].48 [a]D25 = +114 (c 0.33, CH3OH), 92% e.e. CD (0.0155M, CH3OH),
Δe310 = +2.39; Δe274 = ꢀ0.41. HRGC (b-cyclodextrin, 150ꢁC): (+)-5b,
96.7 min, (ꢀ)-5b, 100.7min.
1
20:80): M.p. 172–173 ꢁC. H NMR (400 MHz, CDCl3) d, ppm: 7.35 (m, 3H,
Ph), 7.17 (m, 2H, Ph), 3.88 (dd, J1 =11.0Hz, J2 = 9.9 Hz, 1H, H-4), 3.11, 2.96
(part AB of an ABX system, JAB =19.2Hz, JAX = 11.0 Hz, JBX = 9.9Hz, 2H, 2
H-5), 1.60 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) d,
ppm: 209.4 s, 134.2 (s), 129.0 (2d), 128.6 (d), 128.2 (2d), 99.2 (s), 79.8 (s),
48.6 (d), 38.0 (t), 15.9 (q), 14.0 (q); [a]2D5 = +25 (c 0.1, CHCl3), 71% e.e.; CD
(c 0.004, CHCl3): e304 +1.657; e273 ꢀ0.319; e248 +0.756. HRGC (b-cyclodextrin,
150 ꢁC): (+)-5d, 249.1min, (ꢀ)-5d, 254.8 min.
(1S,3aR,7aR)-(+)-1-Hydroxy-1-methyl-7a-nitrooctahydro-2H-inden-2-one
[(+)-6b].48 [a]D25 = +60 (c 0.18, CH3OH), >99% e.e. CD (0.0084 M,
CH3OH), Δe306 = +2.30; Δe272 = ꢀ0.40. HRGC (b-cyclodextrin, 150 ꢁC):
(ꢀ)-6b, 50.7 min, (+)-6b, 52.3 min.
(2R,3R,4R)-(+)-2-Hydroxy-2-methyl-3-nitro-4-phenylcyclopentanone [(+)-
5c].47 13C NMR (67.8 MHz, CD3OD) d, ppm: 210.8 (s, CO), 140.5 (s,
Ph), 129.9 (2d, Ph), 128.6 (2d, Ph), 128.5 (d, Ph), 95.8 (d, C-3), 77.9 (s,
C-2), 43.6 (t, C-5), 42.2 (d, C-4), 20.2 (q, CH3); [a]2D5 = +133.6 (c, 0.1
CHCl3), 99% e.e. [lit.49 [a]D25 = +134.0 (c 0.1, CHCl3), 99% e.e.]; UV
(1.45 ꢂ 10ꢀ4 M, CH3OH), nm, 212.0 (e, 8090), 224.0 (e, 2772); CD
(0.006 M, CH3OH), Δe312 = +2.2; Δe276 = ꢀ1.2; Δe232 = +1.8).
(2S,3R,4R)-(+)-2-Hydroxy-2,3-dimethyl-3-nitro-4-phenylcyclopentanone
[(+)-6d]. Rf 0.25 (eluent: ethyl acetate-light petroleum gradient 15:85 to
20:80); M.p. 149ꢁC; 1H NMR d, ppm: 7.35 (m, 3H, Ph), 7.17 (m, 2H, Ph),
3.57 (t, J = 10.4 Hz, 1H, H-4), 3.11 (dd, J1 = 10.4 Hz, J2 = 19.6 Hz, 1H, H-5 cis
to Ph), 2.91 (dd, J1 = 10.4 Hz, J2 = 19.6 Hz, 1H, H-5 trans to Ph), 1.63 (s, 3H,
CH3), 1.41 (s, 3H, CH3); 13C NMR (100MHz, CDCl3): 209.4 s, 134.2 (s),
129.0 (2d), 128.6 (d), 128.2 (2d), 99.2 (s), 79.8 (s), 48.6 (d), 38.0 (t), 15.9
(q), 14.0 (q); [a]2D5 = ꢀ43.4 (c 0.65, CHCl3), [a]2D5 = ꢀ59.4 (c 0.325, CH3OH),
89% e.e.; CD (c 0.013, CHCl3): e297 +2.370; e257 ꢀ2.266; e233 –1.139; HRGC (b-
cyclodextrin, 150 ꢁC): (+)-6d, 181.8 min, (ꢀ)-6d, 185.0 min.
High performance liquid chromatograms (flow rate, 1 ml/min, pres-
sure 34 bar): (+)-5c, 7.31 min, (ꢀ)-5c, 7.68 min.
With the use of (R)-(+)-1-phenylethylamine as the catalyst (20 mol%),
ketol (ꢀ)-5c was isolated, [a]2D5 = ꢀ134.0 (c 0.1, CHCl3), 99% e.e. CD
(0.01 M, CH3OH), Δe312 = ꢀ2.2; Δe276 = +1.2; Δe232 = ꢀ1.8).
With the use of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroa-
cetic acid (2PMP/TFA) as the catalyst (20 mol%), ketol (+)-5c was iso-
lated, [a]2D5 = +91.6 (c, 0.1 CHCl3), 68% e.e.
(2R,3R,4R)-(+)-4-(3-bromophenyl)-2-hydroxy-2-methyl-3-nitrocyclopentanone
[(+)-8)]. Ketol (+)-8 was isolated from the reaction catalyzed by (S)-(ꢀ)-1-
phenylethylamine as a white crystalline solid, m.p. 131–132 ꢁC, from n-hep-
tane–ethyl acetate; Rf: 0.57, eluent: light petroleum–ethyl acetate 6:1; IR
(nujol) 3428 (OH), 1595, 651 (Ar), 1759 (CO), 1557, 1382, 1364, 1356 cmꢀ1
(2S,3R,4R)-(+)-2-Hydroxy-2-methyl-4-phenyl-3-nitrocyclopentanone [(+)-6c].
Compound (+)-6c was isolated from the reaction catalyzed by (S)-(+)-1-
2PMP/TFA as a white crystalline solid, m.p. 142–143 ꢁC, from n-heptane-
ethyl acetate; Rf: 0.31, eluent: light petroleum–ethyl acetate 3:1; IR (nujol)
3506 (OH), 1755 (CO), 1600, 1590, 698, 675 cmꢀ1 (Ph), 1546, 1365 (NO2);
1H NMR (400MHz, CDCl3) d, ppm: 7.35 (m, 5H, Ph), 5.20 (d, J= 10.1 Hz,
1H, H-3), 4.03 (dt, J1 = J2 = 11.3 Hz, J3 = 10.1 Hz, 1H, H-4), 3.16 (dd,
J1 = 9.9 Hz, J2 = 19.8Hz, 1H, H-5 trans to Ph), 3.05 (1H, bs, OH), 2.67 (dd,
J1 = 11.3Hz, J2 = 19.8 Hz, 1H, H-5 cis to Ph), 1.37 (s, 1H, CH3); 13C NMR
(100 MHz, CDCl3) d, ppm: 210.4 (s, CO), 137.5 (s, Ph), 129.3 (2d, Ph),
128.3 (d, Ph), 127.2 (2d, Ph), 96.3 (d, C-3), 80.4 (s, C-2), 41.4 (t, C-5), 39.8
1
(NO2). H NMR (400 MHz, CDCl3) d, ppm: 7.45 (m, 2H, o- to Br ArH), d
7.25 (m, 2H, ArH), 4.85 (d, J = 9.5 Hz, 1H, H-3), 4.33 (dt, J1 = J2 = 11.4Hz,
J3 = 9.5 Hz, 1H, H-4), 3.17 (dd, J1 = 9.5 Hz, J2 = 19.4 Hz, 1H, H-5 trans to Ph),
2.60 (dd, J1 = 11.4Hz, J2 = 19.4Hz, 1H, H-5 cis to Ph), 2.53 (bs, 1H, OH),
1.57 (s, 3H, CH3); 13C NMR (100MHz, CDCl3) d, ppm: 207.9 (s, CO),
140.1 (s), 131.5 (d, Ar), 130.8 (d, Ar), 130.2 (d, Ar), 126.7 (d, Ar), 123.3 (s,
Ar), 94.3 (d, C-3), 41.5 (d, C-4), 40.5 (t, C-5), 21.2 (q, CH3); 13C NMR
(100 MHz, CD3OD) d, ppm: 210.1 (s, CO), 143.3 (s), 131.9 (d, Ar), 131.7
(d, Ar), 131.6 (d, Ar), 127.7 (d, Ar), 123.7 (s, Ar), 95.3 (d, C-3), 77.8 (s, C-
2), 43.5 (d, C-4), 42.0 (t, C-5), 20.0 (q, CH3); MS (70 eV): 285, 283 (0.5, M
–30), 227, 225 (100), 211, 209 (30), 197, 195 (9), 145 (60), 128 (35). Anal. calc.
for C12H12NO4Br: C, 45.88, H, 3.85, N, 4.46. Found: C, 46.46, H, 3.91, N, 4.33;
[a]2D5 = +103.3 (c, 0.18, CHCl3), 90% e.e.; CD (0.0025 M, CH3OH), e310 = +2.6;
e277 = ꢀ1.8; e232 = +1.6. HPLC (flow rate, 1 ml/min, pressure 29bar): (+)-8,
8.20min, (ꢀ)-8, 8.94 min.
(d, C-4), 19.7 (q, CH3). MS (70 eV): 235 (M+ , <1), 187 (5, M–OH–NO),
•
160 (10), 159 (14, 187–CO), 147 (72), 145 (35), 131 (46), 129 (100), 117
(42), 103 (14), 91 (15), 77 (13); Anal. calc. for C12H13NO4: C, 61.27, H,
5.57, N, 5.95. Found: C, 60.44, H, 5.41, N, 5.53; [a]2D5 = +22.2 (c, 0.22 CHCl3),
81% e.e.; HPLC (flow rate, 1 ml/min, pressure 30bar): (+)-6c, 8.59 min, (ꢀ)-
6c, 9.22 min.
(2S,3S,4R)-(ꢀ)-2-Hydroxy-2-methyl-4-phenyl-3-nitrocyclopentanone [(ꢀ)-7c].
Compound (ꢀ)-7c was isolated from the reaction catalyzed by 2PMP/TFA
as a pale yellow solid, m.p. 127–128 ꢁC, from n-heptane-ethyl acetate; Rf:
0.12, eluent: light petroleum–ethyl acetate 3:1; IR (nujol) 3414 (OH), 1754
(CO), 1601, 1590, 700, 670 (Ph), 1552, 1365 cmꢀ1 (NO2); 1H NMR
(400 MHz, CDCl3) d, ppm: 7.30 (m, 5H, Ph), 5.18 (d, J= 5.7 Hz, 1H, C-3),
(R)-(ꢀ)-2-Methyl-3-nitro-4-phenylcyclopent-2-en-1-one [(ꢀ)-9)] The crude
mixture of ketols obtained from the reaction between diacetyl and b-
nitrostyrene, catalyzed by (S)-(ꢀ)-1-phenylethylamine, was acetylated in
chloroform with acetic anhydride (25 eq.), in the presence of catalytic
amounts of p-toluenesulfonic acid (PTSA), at 0 ꢁC. The mixture was
stirred at room temperature for 24 h. The reaction mixture was washed
Chirality DOI 10.1002/chir