Synthesis of Eight- and Nine-Membered Carbocycles
2923 2930
30 min.The reaction mixture was poured into brine and extracted with
Et2O.Drying, filtering, and concentration gave a crude residue that was
purified by flash chromatography (5 10% EtOAc/hexanes) to afford an
inseparable mixture of isomers (cis/trans ratio 80:20) of 23 (459 mg, 95%
yield) as a colorless oil. Rf 0.54 (20% EtOAc/hexanes); 1H NMR: d
5.97 5.44 (m, 1H), 5.20 4.87 (m, 2H), 3.06 (m, 0.8H), 2.64 1.85 (m,
7.2H), 1.65 (s, 3H), 1.62 1.36 (m, 2H), 1.16 (m, 1H); 13C NMR: d 212.9
(C), 211.9 (C), 133.0 (CH), 131.3 (CH), 119.5 (CH2), 118.5 (CH2), 78.8 (C),
76.9 (C), 76.8 (C), 76.7 (C), 76.5 (C), 76.4 (C), 46.3 (CH), 45.5 (CH), 41.1
(CH2), 40.7 (CH2), 40.0 (CH2), 39.8 (CH2), 33.8 (CH2), 33.7 (CH2), 21.6
(CH2), 21.4 (CH2), 20.0 (CH2), 18.8 (CH2), 3.26 (CH3), 3.25 (CH3).
(95 mg, 0.26 mmol) in MeOH (8 mL). After stirring for 5 min at room
temperature, the reaction mixture was poured into brine and then extracted
with Et2O.Drying, filtering, and concentration gave a crude residue that
was purified by flash chromatography (10 25% EtOAc/hexanes) to give
21 (78 mg, 76% yield) as a colorless oil. Rf 0.60 (60% EtOAc/hexanes);
1H NMR: d 7.51 7.30 (m, 5H), 4.19 (d, J 5.7 Hz, 1H), 3.72 (s, 3H),
3.17 2.85 (m, 4H), 2.60 2.39 (m, 4H), 2.32 2.17 (m, 1H), 1.98 (m, 1H),
1.83 (s, 3H), 1.71 (m, 3H); 13C NMR: d 207.1 (C), 178.6 (C), 178.1 (C),
175.8 (C), 134.8 (C), 132.3 (C), 129.0 (CH), 128.4 (CH), 126.7 (CH), 125.7
(C), 52.0 (CH3), 51.3 (CH), 41.9 (CH), 41.3 (CH2), 41.0 (CH), 39.2 (CH),
33.8 (CH2), 30.6 (CH2), 29.8 (CH2), 22.4 (CH2), 20.2 (CH3); MS (70 eV): m/
z (%): 395 (27) [M ], 317 (23), 159 (25), 105 (100); HRMS: m/z calcd for
C23H25NO5: 395.1733; found: 395.1725.
1-Hydroxy-3-isopropenylbicyclo[3.3.1]non-2-en-9-one (19): Catalyst
3
(60 mg, 0.07 mmol) was added to a solution of 18 (80:20 cis/trans mixture,
250 mg, 1.30 mmol) in CH2Cl2 (200 mL).The mixture was heated at reflux
for 3 h, and the solvent was then evaporated.The crude residue was
purified by flash chromatography (5 10% EtOAc/hexanes) to afford
unreacted trans-18 (45 mg) and 19 (193 mg, 97% yield) as a colorless oil.
(1S*,2S*,3R*,7S*,12S*)-1-Hydroxy-9-methyl-5-phenyl-5-azatetracyclo-
[10.4.1.02,1003,7]heptadec-9-ene-4,6,17-trione:
A mixture of 24 (70 mg,
0.34 mmol) and N-phenylmaleimide (117 mg, 0.68 mmol) in toluene
(14 mL) was heated at 1608C in a sealed tube for 4 h.The solvent was
evaporated and the residue was purified by flash chromatography (20
60% EtOAc/hexanes) to afford the Diels Alder adduct (86 mg, 67%
yield) as a viscous oil. Rf 0.44 (60% EtOAc/hexanes); 1H NMR: d
7.48 7.34 (m, 3H), 7.12 (m, 2H), 4.18 (s, 1H), 3.30 3.02 (m, 3H), 2.81 (m,
1H), 2.79 2.43 (m, 3H), 2.37 2.11 (m, 4H), 1.93 1.81 (m, 2H), 1.76 (s,
3H), 1.75 1.42 (m, 3H); 13C NM: d 212.4 (C), 178.5 (C), 177.2 (C), 131.7
(C), 130.9 (C), 130.5 (C), 128.9 (CH), 128.4 (CH), 126.2 (CH), 79.0 (C), 47.8
(CH), 45.3 (CH), 42.8 (CH2), 40.4 (CH), 36.0 (CH2), 35.6 (CH), 32.5 (CH2),
31.5 (CH2), 27.5 (CH2), 19.4 (CH3), 18.8 (CH2); MS (70 eV): m/z (%): 379
1
Rf 0.38 (20% EtOAc/hexanes); H NMR: d 5.66 (s, 1H), 5.10 (s, 1H),
5.01 (s, 1H), 4.82 (brs, 1H), 2.78 (m, 2H), 2.63 (m, 1H), 2.09 (m, 1H), 1.98
1.73 (m, 8H); 13C NMR: d 214.3 (C), 141.0 (C), 138.4 (C), 129.1 (CH),
113.3 (CH2), 75.6 (C), 44.0 (CH), 41.8 (CH2), 36.7 (CH2), 36.2 (CH2), 20.7
(CH3), 19.5 (CH2); MS (70 eV): m/z (%): 192 (39) [M ], 147 (61), 135 (100),
121 (29), 107 (28), 91 (52); HRMS: m/z calcd for C12H16O2: 192.1150;
found: 192.1141.
1-Hydroxy-3-isopropenylbicyclo[4.3.1]dec-3-en-10-one (24): Catalyst
3
(17 mg, 0.02 mmol) was added to a solution of 23 (80:20 mixture of cis/
trans isomers, 76 mg, 0.37 mmol) in CH2Cl2 (75 mL), and the reaction
mixture was heated at reflux for 5 h.The solvent was evaporated and the
residue was purified by flash chromatography (5 12% EtOAc/hexanes) to
afford 24 (48 mg, 79% yield) as a colorless oil. Rf 0.4 (20% EtOAc/
hexanes); 1H NMR: d 5.90 (t, J 7.2 Hz, 1H), 5.04 (s, 1H), 4.90 (s, 1H),
4.21 (brs, 1H), 2.96 (m, 2H), 2.87 2.56 (m, 2H), 2.48 2.19 (m, 3H), 2.05
1.86 (m, 2H), 1.83 (s, 3H), 1.80 1.67 (m, 2H); 13C NMR: d 211.9 (C),
143.3 (C), 143.2 (C), 124.8 (CH), 112.8 (CH2), 80.1 (C), 47.6 (CH), 42.9
(CH2), 36.9 (CH2), 33.0 (CH2), 28.1 (CH2), 21.0 (CH3), 19.4 (CH2); MS
(22) [M ], 361 (57), 333 (100), 185 (49), 175 (72), 159 (24), 105 (56); HRMS:
m/z calcd for C23H25NO4: 379.1784; found: 379.1779.
Methyl (3aS*,7S*,12aS*,12bR*)-5-methyl-1,3,11-trioxo-2-phenyl-1,2,3,
3a,4,6,7,8,9,10,11,12,12a,12b-tetradecahydrocyclonona[e]isoindole-7-car-
boxylate (25): Pb(OAc)4 (140 mg, 0.32 mmol) was added to a solution of
the above tetracycle (80 mg, 0.21 mmol) in MeOH (10 mL) and the
resulting solution stirred at room temperature for 5 min.The reaction
mixture was poured into brine and extracted with Et2O, dried, filtered, and
concentrated.The crude residue was purified by flash chromatography
(30 50% EtOAc/hexanes) to afford 25 (77 mg, 89% yield) as a white
solid. Rf 0.52 (60% EtOAc/hexanes); 1H NMR: d 7.46 7.38 (m, 3H),
7.24 7.20 (m, 2H), 3.58 (s, 3H), 3.49 (m, 1H), 3.26 3.18 (m, 3H), 3.02 (dd,
J 6.1, 15.7 Hz, 1H), 2.60 2.44 (m, 6H), 2.08 1.98 (m, 3H), 1.76 (s, 3H),
1.60 (m, 1H); 13C NMR: d 212.8 (C), 178.5 (C), 177.4 (C), 176.2 (C), 132.4
(C), 131.6 (C), 130.9 (C), 128.9 (CH), 128.5 (CH), 126.2 (CH), 79.3 (C), 51.7
(CH3), 45.2 (CH), 43.2 (CH), 43.0 (CH2), 40.3 (CH2), 39.9 (CH), 39.5 (CH),
35.4 (CH2), 30.5 (CH2), 23.6 (CH2), 19.6 (CH3); MS (70 eV): m/z (%): 409
(70 eV): m/z (%): 206 (6) [M ], 188 (88), 144(14), 131(18), 95(20), 85(35),
79(100); HRMS: m/z calcd for C13H18O2: 206.1307; found: 206.1311.
Diels Alder reactions and oxidative fragmentations. Synthesis of 21, 22
and 25
(1S*,2S*,3R*,7S*,12S*)-1-Hydroxy-9-methyl-5-phenyl-5-azatetracyclo-
[10.3.1.02,1003,7]hexadec-9-ene-4,6,16-trione (20): A solution of 19 (65 mg,
0.34 mmol) and N-phenylmaleimide (100 mg, 0.58 mmol) in toluene
(14 mL) was heated at 1558C in a sealed-tube for 5 h.The solvent was
evaporated and the residue was purified by flash chromatography (20
60% EtOAc/hexanes) to afford 20 (105 mg, 85% yield) as a white solid.
Rf 0.42 (75% EtOAc/hexanes); m.p. 988C; 1H NMR: d 7.38 7.17 (m,
3H), 6.97 (m, 2H), 4.38 (brs, 1H), 3.80 (dd, J 8.4, 4 Hz, 1H), 3.13 (t, J
7.5 Hz, 1H), 2.97 (s, 1H), 2.78 2.56 (m, 4H), 2.39 (m, 1H), 2.13 (d, J
8.4 Hz, 1H), 1.96 1.81 (m, 5H), 1.67 (s, 3H), 1.59 (m, 1H); 13C NMR: d
212.5 (C), 178.6 (C), 178.0 (C), 131.4 (C), 128.9 (CH), 128.5 (CH), 128.3 (C),
128.2 (C), 126.2 (CH), 77.2 (C), 53.1 (CH), 47.4 (CH2), 44.3 (CH), 42.3
(CH), 40.1 (CH), 36.8 (CH2), 34.6 (CH2), 32.6 (CH2), 19.2 (CH3).MS
(71) [M ], 332 (54), 183 (42), 159 (36), 119 (100), 105 (88); HRMS: m/z
calcd for C24H27NO5: 409.1889; found: 409.1877.
Acknowledgement
We thank the Spanish Ministries of Education and Culture (MEC) and
Science and Technology (MCyT) for financial support under projects
PB97-0524 and SAF2001-3120, respectively. J.R.R. thanks the MEC for a
predoctoral fellowship.
(70 eV): m/z (%): 365 (6) [M ], 337 (32), 254 (89), 174 (12), 91 (100), 77
(61); HRMS: m/z calcd for C22H23NO4: 365.1627; found: 365.1620.
(1S*,4S*,10S*,15S*)-7-Methyl-2-oxatetracyclo[6.6.1.11,1004,15]hexadec-7-
ene-3,16-dione (22): A solution of 19 (82 mg, 0.43 mmol) and methyl
acrylate (0.25 mL, 4.30 mmol) in toluene (9 mL) was heated at reflux for
50 h.The reaction mixture was concentrated, and the residue was purified
by flash chromatography to afford of an inseparable mixture of adducts
(18 mg) and 22 (58 mg, 55% yield) as a white solid. Rf 0.3 (40% EtOAc/
hexanes); m.p. 1418C; 1H NMR: d 3.36 (d, J 11 Hz, 1H), 3.15 (dd, J
11, 14.6 Hz, 1H), 2.95 (m, 1H), 2.82 (m, 1H), 2.25 (d, J 11 Hz, 1H), 2.20
1.96 (m, 3H), 1.88 1.77 (m, 6H), 1.63 (s, 3H), 1.59 (m, 1H); 13C NMR: d
210.0 (C), 176.9 (C), 131.9 (C), 120.2 (C), 88.7 (C), 45.5 (CH), 45.0 (CH),
39.8 (CH), 33.3 (CH2), 31.5 (CH2), 28.7 (CH2), 22.9 (CH2), 19.6 (CH3), 17.6
[1] a) T.Hudlicky, MG. .Natchus in
Organic Synthesis: Theory and
Applications, Vol. 2 (Ed.: T. Hudlicky), Jai Press, 1993, p. 1; b) J. B.
Hendrickson, ChemTech 1998, September, p.35; c) R.A. Sheldon,
ChemTech 1994, March, p.38; d) N.Hall, Science 1994, 266, 32.For a
discussion on atom-economy, see: e) B.M. Trost, Science 1991, 254,
1471; f) B.M.Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int.
Ed. Engl. 1995, 34, 259; g) A.F¸rstner, Chem. Eng. News 2001,
March 26, pp.180.
[2] a) P.A. Wender, B.L. Miller in
Organic Synthesis: Theory and
Applications, Vol. 2 (Ed.: T. Hudlicky), Jai Press, 1993, p.27; b) P.A.
Wender, S.T. Handy, D.L. Wright, Chem. Ind. 1997, 766; c) S.H.
Bertz, T.J.Sommer in Organic Synthesis: Theory and Applications,
Vol. 2 (Ed.: T. Hudlicky), Jai Press, 1993, p.67; d) L.F. Tietze, F.
Haunert in Stimulating Concepts in Chemistry; (Eds.: F. Vˆgtle, J. F.
Stoddart, M.Shibasaki), Wiley-VCH, Weinheim, 2000, pp.39.
(CH2).MS (70 eV): m/z (%): 246 (64) [M ], 218 (44), 173 (37), 131 (43), 113
(100); HRMS m/z calcd for C15H18O3: 246.1256; found: 246.1258.
Methyl (3aS*,7S*,11aS*,11bR*)-5-methyl-1,3,11-trioxo-2-phenyl-2,3,3a,
4,6,7,8,9,10,11,11a,11b-dodecahydro-1H-cycloocta[e]isoindole-7-carboxy-
late (21): Pb(OAc)4 (175 mg, 0.395 mmol) was added to a solution of 20
Chem. Eur. J. 2002, 8, No. 13
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0813-2929 $ 20.00+.50/0
2929