M. C. de la Torre, M. A. Sierra and E. lvaro
procedures and data for all the compounds obtained in this work are
given as the Supporting Information.
cooling bath was removed. The mixture was extracted with Et2O (2),
and the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography
(hexanes/AcOEt 20:1 ! 9:1) of the crude product provided 37 (mixture
of diastereoisomers) as a clear oil (119 mg, 51%). 1H NMR (300 MHz,
CDCl3): d=7.21 (d, J=8.5 Hz, 1H), 6.71 (dd, J=8.5, 2.7 Hz, 1H), 6.62
(d, J=2.7 Hz, 1H),5.63 (brs, 1H), 4.83 (brs, 1H), 3.77 (s, 3H), 2.84 (m,
2H), 2.46–1.32 (m, 18H), 1.30, 1.29 (s, 3H), 1.20, 1.17 (d, J=7.8 Hz in
both cases, 1H), 0.86 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=157.4 (C), 146.6, 145.5 (C), 137.9 (C), 132.5 (C), 126.3 (CH), 119.9,
119.4 (CH), 113.7 (CH), 111.4 (CH), 89.1, 88.8 (C), 84.9, 84.8 (C), 79.9,
79.8 (C), 65.3, 64.9 (CH), 55.2 (CH3), 49.4 (CH), 47.2, 47.1 (C), 43.5
(CH), 42.7, 42.6 (CH), 40.7, 40.6 (CH), 39.4 (CH), 39.0, 38.8 (CH2), 37.9,
37.8 (C), 33.0, 32.9 (CH2), 31.9, 31.8 (CH2), 31.0 (CH2), 29.8 (CH2), 27.7
(CH2), 26.4 (CH2), 26.1 (CH3), 22.8 (CH2), 21.2, 21.1 (CH3), 12.7 (CH3);
IR (film): nmax = 3434, 2932, 2202, 167, 1500, 1255, 744 cmꢀ1; MS (EI):
m/z (%): 460 (19) [M +], 442 (15) [M +ꢀH2O], 427 (13) [M +
ꢀH2OꢀCH3], 399 (9), 335 (7), 37 (14), 284 (24), 242 (46), 227 (70), 174
(67), 147 (58), 91 (28); elemental analysis calcd (%) for C31H40O3: C
80.83, H 8.75; found: C 80.94, H 8.67.
Hybrid 28 from 12 and N-methylreserpine (27): [Co2(CO)8] (72 mg,
0.17 mmol) was added to a solution of 12 (37 mg, 0.15 mmol) in CH2Cl2
(2 mL). The mixture was stirred at room temperature for 1 h, cooled to
ꢀ208C and then treated dropwise with BF3·OEt2 (38 mL, 0.30 mmol).
After 5 min of stirring, a CH2Cl2 solution of N-methylreserpine (95 mg,
0.15 mmol in 1 mL CH2Cl2) was added via cannula. The mixture was
kept at ꢀ208C for 20 h. After quenching with saturated aqueous
NaHCO3, the cooling bath was removed and the layers were separated.
The aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was purified by silica gel chromatog-
raphy (hexanes/AcOEt 3:2) to give 28 as a dark green oil (67 mg, 39%).
1H NMR (400 MHz, CDCl3): d=7.32 (s, 2H), 7.11 (s, 1H), 6.71 (s, 1H),
6.22 (brs, 1H), 5.05 (m, 1H), 4.44 (brs, 1H), 4.28 (d, J=9.2 Hz, 1H),
3.93 (s, 3H), 3.91 (s, 7H), 3.73 (s, 3H), 3.62 (s, 3H), 3.54 (t, J=5.5 Hz,
1H), 3.50 (s, 3H), 3.13–2.99 (m, 3H), 2.71 (dd, J=11.4, 4.8 Hz, 1H), 2.61
(t, J=11.5 Hz, 1H), 2.43–2.28 (m, 5H), 2.15 (m, 1H), 2.02 (m, 3H), 1.68
(d, J=14.3 Hz, 1H), 1.61 (d, J=9.9 Hz, 1H), 1.36 (s, 3H), 0.25 (m, 2H),
0.94 (s, 3H), 0.37 (s, 9H); 13C NMR (70 MHz, CDCl3): d=200.6 (6C),
172.6 (C), 165.4 (C), 154.3 (C), 153.0 (3C), 142.2 (C), 136.1 (C), 131.4
(C), 125.4 (C), 122.9 (CH), 119.9 (C), 78.8 (C), 76.7 (2CH), 70.2 (C), 91.2
(CH), 80.1 (C), 77.9 (CH), 77.7 (CH), 60.9 (CH3), 60.8 (CH3), 56.2
(2CH3), 55.7 (CH3), 55.4 (CH), 51.8 (CH), 51.6 (CH3, CH2), 49.4 (CH2),
47.7 (CH), 42.1 (CH), 41.0 (C), 34.7 (CH2), 33.8 (CH), 32.1 (CH3), 30.2
(CH2), 29.7 (CH2), 25.7 (CH3), 25.2 (CH2), 21.7 (CH3), 17.1 (CH2), 1.1
Chimera 38 from 37 and N-methylindole: [Co2(CO)8] (96 mg, 0.23 mmol)
was added to a solution of 37 (97 mg, 0.21 mmol) in CH2Cl2 (5.5 mL).
The mixture was stirred at room temperature for 1 h, cooled to ꢀ788C,
and treated with N-methylindole (17 mg, 0.84 mmol in 2 mL CH2Cl2) and
BF3·OEt2 (59 mL, 0.46 mmol) for 45 min at ꢀ788C. Then, the reaction
mixture was diluted with saturated aqueous NaHCO3 and warmed to
room temperature with stirring. The layers were separated, and the aque-
ous layer was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by silica gel chromatography (hex-
anes/AcOEt 50:1 ! 25:1) to provide 38 (181 mg, 78%) as dark green oil.
1H NMR (300 MHz, CDCl3): d=7.58 (d, J=7.8 Hz, 1H), 7.21–7.05 (m,
4H), 6.72 (d, J=2.4 Hz, 1H), 6.70 (s, 1H), 6.60 (m, 2H), 4.21 (brd, J=
8.8 Hz, 1H), 3.85 (t, J=5.4 Hz, 1H), 3.79 (s, 3H), 3.41 (s, 3H), 2.78–2.48
(m, 4H), 2.25–2.03 (m, 5H), 1.77–1.25 (m, 7H), 1.39 (s, 3H), 1.01 (s, 3H),
0.97 (s, 3H), 0.86 (m, 1H); 13C NMR (70 MHz, CDCl3): d=200.5 (6C),
158.1 (C), 157.5 (C), 137.9 (C), 137.0 (C), 132.6 (C), 126.7 (C), 126.3
(CH), 126.2 (CH), 123.4 (C), 121.5 (CH), 120.1 (CH), 119.3 (CH), 118.6
(CH), 113.7 (CH), 111.2 (CH), 79.4 (CH), 78.3 (C), 87.1 (C), 87.0 (C),
55.2 (CH3), 49.3 (CH), 49.1 (C), 46.0 (CH), 43.0 (CH2), 42.4 (CH), 41.7
(CH), 40.5 (C), 39.3 (CH), 34.3 (CH2), 34.2 (CH), 33.0 (CH2), 32.2 (CH3),
29.5 (CH2), 28.4 (CH2), 27.2 (CH2), 26.0 (CH2), 25.7 (CH3), 23.7 (CH2),
22.0 (CH3), 15.9 (CH3); IR (KBr): nmax = 3435, 2931, 2082, 2044, 2017,
1611, 1500, 1465, 1372, 1255, 736 cmꢀ1; elemental analysis calcd (%) for
C46H47NO8Co2: C 64.26, H 5.51; found: C 64.43, H 5.37.
(3CH3); IR (KBr): nmax
=
2081, 2043, 2014 cmꢀ1; elemental analysis
calcd (%) for C55H64N2O15SiCo2: C 57.99, H 5.66; found: C 57.54, H 5.43.
Compounds 30 and 31: [Co2(CO)8] (549 mg, 1.33 mmol) was added to a
solution of 12 (300 mg, 1.33 mmol) in CH2Cl2 (15 mL). The mixture was
stirred at room temperature for 1 h, cooled to ꢀ788C, and treated with
15 (707 mg, 1.22 mmol) and BF3·OEt2 (0.31 mL, 2.42 mmol in 7 mL
CH2Cl2). The temperature was allowed to warm from ꢀ78 to ꢀ208C, and
kept at ꢀ208C for 3.5 h. Then, the reaction mixture was diluted with sa-
turated aqueous NaHCO3 and warmed to room temperature with stir-
ring. The layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by silica gel chromatography (hexanes) to give 30–31 (1:2 mix-
ture of regioisomers) as a dark brown oil (706 mg, 53%). 30–31 could be
obtained separated.
1
Data for 30 (minor isomer): H NMR (200 MHz, CDCl3): d=6.28 (d, J=
1.6 Hz, 2H), 5.82 (s, 2H), 3.83 (brd, J=8.4 Hz, 2H), 3.37 (t, J=5.9 Hz,
2H), 2.42–2.31 (m, 4H), 2.12–2.04 (m, 4H), 1.54–1.41 (d, J=7.1 Hz, 2H),
1.34 (s, 6H), 0.84 (s, 6H), 0.32 (s, 18H); 13C NMR (75 MHz, CDCl3): d=
200.4 (12C), 158.9 (2C), 149.5 (2C), 122.7 (2CH), 75.6 (2CH), 99.2 (2C),
80.0 (2C), 46.8 (2CH), 40.9 (2CH), 40.7 (2C7), 35.6 (2CH), 30.9 (2CH2),
27.8 (2CH2), 25.8 (2CH3), 21.8 (2CH3), 1.0 (6CH3); IR (KBr): nmax
=
2955, 2916, 2083, 2044, 2003, 1619, 1574, 1249, 838 cmꢀ1
.
Acknowledgements
Data for 31 (major isomer): 1H NMR (CDCl3, 200 MHz): d=6.25 (s,
1H), 5.96 (d, J=2.9 Hz, 1H), 5.79 (d, J=2.9 Hz, 1H), 5.53 (s, 1H), 4.77
(s, 1H), 3.81 (d, J=9.2 Hz, 1H), 3.39 (t, J=6.0 Hz, 1H), 2.57–2.25 (m,
7H), 2.11–2.04 (m, 2H), 1.55 (m, 1H), 1.34 (s, 3H), 1.28 (s, 3H), 1.23–
1.19 (m, 1H), 0.83 (s, 3H), 0.62 (s, 3H), 0.32 (s, 9H), 0.31 (s, 9H);
13C NMR (CDCl3, 75 MHz): d=200.8 (12C), 160.5 (C), 154.1 (C),149.7
(C), 146.8 (C), 123.7 (CH), 120.7 (CH), 111.5 (C), 77.6 (CH), 76.2 (CH),
99.2 (C), 80.5 (C), 79.3 (C), 53.4 (CH), 47.0 (CH), 45.0 (CH), 41.6 (CH),
41.4 (C), 40.6 (CH), 38.8 (C), 36.2 (CH), 32.7 (CH2), 31.7 (CH2), 31.3
(CH2), 27.9 (CH2), 26.7 (CH3), 26.1 (CH3), 22.2 (CH3), 21.0 (CH3), 1.6
Financial support by the Spanish Ministerio de Ciencia y Tecnología
(Grants CTQ2004-06250-C02-02/BQU (M.C.T.) and CTQ2004-06250-
C02-01/BQU (M.A.S.)) are gratefully acknowledged. E. lvaro thanks
the MEC (Spain) for an FPU-predoctoral fellowship.
[1] a) L. F. Tietze, H. P. Bell, S. Chandrasekhar, Angew. Chem. 2003,
115, 4128–4160; Angew. Chem. Int. Ed. 2003, 42, 3996–4028; b) G.
Mehta, V. Singh, Chem. Soc. Rev. 2002, 31, 324–334.
[2] a) J. Mann in Secondary Metabolism. Second Edition, Clarendon
Press, Oxford, 1987; b) J. McMurray, T. Begley in The Organic
Chemistry of Biologycal Pathways, Roberts & Company Publishers,
2005.
[3] M. D. Burke, S. L. Schreiber, Angew. Chem. 2003, 115, 48–60;
Angew. Chem. Int. Ed. 2004, 43, 46–58.
[4] Many of the new synthetic hybrids show promising activity, see for
example: P. Camps, R. El Achab, J. Morral, D. MuÇoz-Torrero, A.
(6CH3); IR (KBr): nmax
= 2917, 2084, 2044, 2013, 1625, 1598, 1249,
839 cmꢀ1
.
Compound 37: A solution of mestranol (157 mg, 0.51 mmol) in THF
(7 mL) at ꢀ788C was treated dropwise with a solution of nBuLi (0.8 mL,
1.1 mmol, 1.4m solution). The mixture was stirred for 30 min, and then
(1R)-(ꢀ)-myrtenal (0.12 mL, 0.77 mmol) was added dropwise via cannu-
la. The reaction was stirred for 4 h from ꢀ788C to RT. Subsequently, the
reaction mixture was quenched with saturated aqueous NH4Cl, and the
6410
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6403 – 6411