Epothilone Analogues
2783±2800
analogue 57a (6.4 mg, 66%). 57a: Rf 0.57 (100% EtOAc); [a]2D2 À81.3
(c 1.0, CHCl3); IR (thin film): nÄmax 3421, 2929, 1735, 1684, 1601, 1460,
J 7.7 Hz, 1H, ArH), 6.99 (d, J 7.7 Hz, 1H, ArH), 6.56 (s, 1H,
CH CCH3), 5.84 (brs, 1H, CHOH), 5.29 (dd, J 10.3, 1.0 Hz, 1H,
1
1260, 1055 cmÀ1; H NMR (600 MHz, CDCl3): d 8.51 (d, J 4.0 Hz, 1H,
CH2CH(O)), 4.46 (dd, J 11.4, 1.8 Hz, 1H, CHOH), 3.72 (dd, J 5.9,
2.6 Hz, 1H, CHOH), 3.25 (dq, J 13.6, 2.6 Hz, 1H, CH3CHC(O)), 3.02
(brs, 1H, OH), 2.77 (dd, 9.2, 2.6 Hz, 1H, CH-epoxide), 2.50 (s, 3H, ArCH3),
2.49 (dd, J 12.8, 11.4 Hz, 1H, CH2C(O)), 2.24 ± 2.18 (m, 2H,
ArH), 7.68 (dd, J 7.9, 7.9 Hz, 1H, ArH), 7.26 (d, J 7.9 Hz, 1H, ArH), 7.14
(dd, J 7.5, 4.8 Hz, 1H, ArH), 6.61 (s, 1H, CH CCH3), 5.37 (dd, J 7.5,
0.8 Hz, 1H, CH2CH(O)), 5.12 ± 5.16 (brs, 1H, CHOH), 4.34 (bd, J
11.7 Hz, 1H, CHOH), 3.75 ± 3.72 (m, 1H, CHOH), 3.29 ± 3.24 (m, 1H,
CH3CHC(O)), 2.86 (brs, 1H, OH), 2.80 (dd, J 7.0, 7.0 Hz, 1H, CH-
epoxide), 2.52 (dd, J 14.9, 10.9 Hz, 1H, CH2C(O)), 2.40 (dd, J 14.9,
C CHCH2CH(O), CH2C(O)), 1.99 (s, 3H, CH CCH3), 1.40 (s, 3H,
(CH3)-epoxide), 1.86 ± 1.66 (m, 2H), 1.61 ± 1.54 (m, 2H), 1.52 ± 1.46 (m,
2H), 1.36 ± 1.30 (m, 1H), 1.27 (s, 3H, C(CH3)2), 1.14 (d, J 6.6 Hz, 3H,
CH3CHC(O)), 1.07 (s, 3H, C(CH3)2), 0.98 (d, J 7.0 Hz, 3H, CH3CH);
13C NMR (125.7 MHz, CDCl3): d 220.8, 170.7, 157.9, 154.5, 141.5, 136.9,
124.8, 121.4, 120.7, 72.8, 71.0, 62.6, 61.9, 54.4, 39.9, 36.1, 33.4, 32.6, 30.9, 29.7,
27.8, 22.9, 22.4, 21.3, 17.5, 16.1, 13.6; MALDI HRMS (DHB): m/z: 502.3176
2.6 Hz, 1H, CH2C(O)), 2.19 ± 2.04 (m, 1H, C CHCH2CH(O)), 2.05 (s, 3H,
CH CCH3), 1.92 ± 1.85 (m, 1H, C CHCH2CH(O)), 1.78 ± 1.70 (m, 1H),
1.64 ± 1.58 (m, 1H), 1.54 ± 1.40 (m, 3H), 1.37 (s, 3H, (CH3)-epoxide), 1.34 ±
1.28 (m, 1H), 1.26 ± 1.22 (m, 1H), 1.27 (s, 3H, C(CH3)2), 1.14 (d, J 7.0 Hz,
3H, CH3CHC(O)), 1.06 (s, 3H, C(CH3)2), 0.98 (d, J 7.0 Hz, 3H, CH3CH);
13C NMR (150.9 MHz, CDCl3): d 221.5, 171.5, 156.4, 149.9, 141.9, 137.4,
126.21, 124.8, 122.5, 77.3, 72.7, 62.9, 62.7, 61.2, 54.6, 43.7, 40.4, 37.1, 33.2, 32.3,
31.6, 23.4, 22.8, 22.7, 21.9, 17.7, 16.4, 15.0; MALDI HRMS (DHB): m/z:
[MH] calcd for C29H43NO6 502.3169. 57 f: (52%); Rf 0.23 (100%
EtOAc); [a]2D2 À11 (c 0.4, CHCl3); IR (thin film): nÄmax 3463, 2927,
1736, 1684, 1451, 1252, 1065, 977, 734 cmÀ1 1H NMR (600 MHz, CDCl3):
;
d 8.51 (m, 2H, ArH), 7.58 (d, J 7.9 Hz, 1H, ArH), 7.27 (m, 1H, ArH),
510.2830 [MNa] calcd for C28H41NO6 510.2832.
6.56 (s, 1H, CH CCH3), 5.49 (dd, J 6.6, 3.7 Hz, 1H, CH2CH(O)), 4.10 ±
3.97 (brs, 1H, CHOH), 3.81 ± 3.78 (brs, 1H, CHOH), 3.60 ± 3.55 (brs, 1H,
CHOH), 3.34 ± 3.28 (m, 1H, CH3CHC(O)), 2.82 (dd, J 6.6, 6.6 Hz, 1H,
CH-epoxide), 2.57 (dd, J 14.5, 9.6 Hz, 1H, CH2C(O)), 2.49 ± 2.44 (m, 2H,
A similar procedure was employed to prepare the pyridine analogues 57b ±
g. 57b: (66%); Rf 0.34 (100% EtOAc); [a]2D2 À35.0 (c 0.3, CHCl3);
IR (thin film): nÄmax 3442, 2925, 1732, 1688, 1589, 1462, 1435, 1380, 1260,
OH, CH2C(O)), 2.10 ± 2.05 (m, 1H, C CHCH2CH(O)), 2.02 ± 1.80 (m, 1H,
1075, 739, 692 cmÀ1
;
1H NMR (500 MHz, CDCl3): d 8.37 (d, J 4.8 Hz,
C CHCH2CH(O)), 1.92 (s, 3H, CH CCH3), 1.75 ± 1.66 (m, 2H), 1.65 ± 1.55
(m, 4H), 1.36 (s, 3H, (CH3)-epoxide), 1.30 (s, 3H, C(CH3)2), 1.17 (d, J
7.0 Hz, 3H, CH3CHC(O)), 1.10 (s, 3H, C(CH3)2), 1.00 (d, J 7.0 Hz, 3H,
CH3CH); 13C NMR (150.9 MHz, CDCl3): d 220.6, 170.5, 150.1, 147.9,
136.0, 123.6, 74.5, 73.9, 61.1, 60.4, 52.3, 51.7, 43.7, 39.0, 36.4, 31.8, 31.6, 30.7,
1H, ArH), 7.53 (d, J 7.4 Hz, 1H, ArH), 7.13 (dd, J 7.7, 4.5 Hz, 1H, ArH),
6.64 (s, 1H, CH CCH3), 5.49 (dd, J 9.6, 2.2 Hz, 1H, CH2CH(O)), 4.28
(dd, J 11.0, 2.6 Hz, 1H, CHOH), 3.74 (m, 1H, CHOH), 3.23 (dq, J 6.6,
3.3 Hz, 1H, CH3CHC(O)), 2.91 (brs, 1H, OH), 2.84 (dd, J 8.4, 3.3 Hz,
1H, CH-epoxide), 2.49 (dd, J 13.5, 11.0, 1H, CH2C(O)), 2.28 (d, J
3.0 Hz, 1H, CH2C(O)), 2.26 (s, 3H, ArCH3), 2.23 ± 2.16 (m, 2H,
29.7, 22.9, 31.3, 21.0, 20.8, 17.3, 14.2, 14.2; ESI (DHB): m/z: 510 [MNa]
calcd for C28H41NO6 510. 57g: (73%); Rf 0.20 (100% EtOAc); [a]D22
C CHCH2CH(O)), 1.84 (s, 3H, CH CCH3), 1.80 ± 1.72 (m, 3H), 1.68 ±
1.58 (m, 3H), 1.34 (s, 3H, (CH3)-epoxide), 1.29 (s, 3H, C(CH3)2), 1.13 (d,
J 7.0 Hz, 3H, CH3CHC(O)), 1.07 (s, 3H, C(CH3)2), 1.00 (d, J 7.0 Hz,
3H, CH3CH); 13C NMR (125.7 MHz, CDCl3): d 220.7, 170.9, 154.6, 146.1,
141.7, 138.3, 132.2, 124.8, 122.2, 71.5, 62.1, 61.8, 54.0, 41.9, 39.8, 36.3, 33.1,
31.9, 30.8, 29.7, 22.5, 22.2, 21.7, 17.7, 17.5, 16.8, 15.2, 14.2; MALDI HRMS
À27 (c 0.4, CHCl3); IR (thin film): nÄmax 3451, 2950, 2919, 1733, 1687,
1457, 1247, 1063, 987, 797 cmÀ1; 1H NMR (600 MHz, CDCl3): d 8.56 (brs,
2H, ArH), 7.15 (d, J 2.4 Hz, 2H, ArH), 6.53 (s, 1H, CH CCH3), 5.47 (dd,
J 6.2, 3.7 Hz, 1H, CH2CH(O)), 4.13 ± 3.97 (brs, 1H, CHOH), 3.82 ± 3.77
(brs, 1H, CHOH), 3.75 ± 3.65 (brs, 1H, CHOH), 3.35 ± 3.28 (m, 1H,
CH3CHC(O)), 2.81 (dd, J 6.2, 6.2 Hz, 1H, CH-epoxide), 2.58 (dd, J
14.3, 9.5 Hz, 1H, CH2C(O)), 2.51 ± 2.44 (m, 2H, OH, CH2C(O)), 2.10 ± 2.04
(DHB): m/z: 502.3174 [MH] calcd for C29H43NO6 502.3169. 57c: (68%);
Rf 0.71 (100% EtOAc); [a]2D2 À77.5 (c 1.3, CHCl3); IR (thin film):
(m, 1H, C CHCH2CH(O)), 2.02 ± 1.96 (m, 1H, C CHCH2CH(O)), 1.93 (s,
nÄmax 3441, 2930, 1735, 1682, 1600, 1460, 1376, 1260, 1148, 1054 cmÀ1
;
3H, CH CCH3), 1.74 ± 1.66 (m, 2H), 1.65 ± 1.56 (m, 4H), 1.36 (s, 3H,
1H NMR (600 MHz, CDCl3): d 8.35 (d, J 4.8 Hz, 1H, ArH), 7.08 (s, 1H,
(CH3)-epoxide), 1.30 (s, 3H, C(CH3)2), 1.17 (d, J 7.0 Hz, 3H,
CH3CHC(O)), 1.10 (s, 3H, C(CH3)2), 1.01 (d, J 7.0 Hz, 3H, CH3CH);
13C NMR (150.9 MHz, CDCl3): d 220.5, 170.5, 149.7, 144.5, 139.1, 124.8,
123.7, 74.8, 73.7, 61.1, 60.4, 53.4, 52.4, 43.7, 39.0, 36.4, 31.8, 31.6, 30.7, 27.8,
ArH), 6.95 (d, J 4.8 Hz, 1H, ArH), 6.56 (s, 1H, CH CCH3), 5.38 (brs,
1H, CHOH), 5.35 (dd, J 9.6, 1.8 Hz, 1H, CH2CH(O)), 4.38 ± 4.32 (m, 1H,
CHOH), 3.74 ± 3.70 (m, 1H, CHOH), 3.29 ± 3.24 (m, 1H, CH3CHC(O)),
2.92 (brs, 1H, OH), 2.78 (dd, J 8.8, 3.5 Hz, 1H, CH-epoxide), 2.49 (dd,
J 13.2, 11.0 Hz, 1H, CH2C(O)), 2.35 (s, 3H, ArCH3), 2.31 (m, 1H), 2.25
(dd, J 13.2, 2.6 Hz, 1H, CH2C(O)), 2.20 ± 2.14 (m, 1H,
26.8, 22.8, 21.2, 21.0, 20.8, 17.3, 14.9, 14.2; ESI (DHB): m/z: 510 [MNa]
calcd for C28H41NO6 510.
Epothilone stannane 58: To a solution of vinyl iodide 19 (42.5 mg,
0.079 mmol, 1.0 equiv) and diisopropylethylamine (3 mL, 0.016 mmol,
0.2 equiv) in toluene (0.8 mL) was added [Pd(PPh3)4] (9 mg, 0.008 mmol,
0.1 equiv) followed by hexamethylditin (107 mL, 0.396 mmol, 5.0 equiv).
The reaction mixture was heated at 858C for 30 min with monitoring by
TLC (50% EtOAc in hexanes) every 5 min, then quickly filtered through
silica gel and the filtrate concentrated under reduced pressure. Flash
column chromatography (silica gel pre-treated with Et3N, 17 to 50%
EtOAc in hexanes) provided stannane 58 (29.0 mg, 64%). 58: Rf 0.59
(50% EtOAc in hexanes); [a]D22 À2.5 (c 0.3, CHCl3); IR (thin film):
nÄmax 3471, 2961, 2922, 2845, 2363, 1734, 1691, 1623, 1459, 1377, 1296, 1257,
1151, 1093, 1031, 978, 881, 800 cmÀ1; 1H NMR (500 MHz, CDCl3): d 5.88
C CHCH2CH(O)), 2.02 (s, 3H, CH CCH3), 1.88 (s, 3H, (CH3)-epoxide),
1.78 ± 1.70 (m, 2H), 1.64 ± 1.56 (m, 1H), 1.54 ± 1.40 (m, 3H), 1.32 ± 1.28 (m,
1H), 1.26 (s, 3H, C(CH3)2), 1.13 (d, J 6.6 Hz, 3H, CH(CH3), 1.05 (s, 3H,
C(CH3)2), 0.97 (d, J 7.0 Hz, 3H, CH3CH); 13C NMR (150.9 MHz, CDCl3):
d 220.7, 170.7, 155.2, 148.7, 147.8, 140.8, 125.1, 124.7, 122.6, 76.3, 71.5, 62.2,
61.7, 60.3, 53.9, 39.6, 36.1, 32.9, 32.3, 30.7, 22.5, 22.1, 21.7, 21.1, 20.9, 17.7, 16.8,
15.8, 14.1; MALDI HRMS (DHB): m/z: 524.2983 [MNa] calcd for
C29H43NO6 524.2988. 57d: (71%), Rf 0.60 (100% EtOAc); [a]2D2 À66.0
(c 1.9, CHCl3); IR (thin film): nÄmax 3412, 2961, 2917, 1732, 1682, 1600,
1456, 1374, 1259, 1154, 1044, 1006, 973, 796, 670 cmÀ1; 1H NMR (500 MHz,
CDCl3): d 8.34 (s, 1H, ArH), 7.48 (dd, J 6.5, 1.8 Hz, 1H, ArH), 7.16 (d,
J 6.5 Hz, 1H, ArH), 6.58 (s, 1H, CH CCH3), 5.36 (dd, J 7.6, 1.5 Hz, 1H,
(s, 1H, CH CCH3), 5.33 (dd, J 6.1, 3.9 Hz, 1H, CH2CH(O)), 4.05 (ddd,
CH2CH(O)), 4.34 (dd, J 9.5, 2.2 Hz, 1H, CHOH), 3.72 (dd, J 4.4,
4.4 Hz, 1H, CHOH), 3.25 (q, J 5.5 Hz, 1H, CH3CHC(O)), 2.79 (dd, J
10.2, 2.9 Hz, 1H, CH-epoxide), 2.50 (dd, J 10.9, 9.1, 1H, CH2C(O)), 2.31
(s, 3H, ArCH3), 2.27 (dd, J 11.3, 2.2 Hz, 1H, CH2C(O)), 2.16 (dt, J 12.8,
J 9.6, 6.3, 3.3 Hz, 1H, CHOH), 3.77 (dd, J 8.5, 4.4 Hz, 1H, CHOH),
3.65 (d, J 5.9 Hz, 1H, OH), 3.32 (dq, J 6.6, 5.2 Hz, 1H, CH3CHC(O)),
2.75 (dd, J 6.3, 6.3 Hz, 1H, CH-epoxide), 2.53 (dd, J 14.7, 9.6 Hz, 1H,
CH2C(O)), 2.50 (d, J 4.4 Hz, 1H, OH), 2.42 (dd, J 14.7, 3.7 Hz, 1H,
7.2 Hz, 1H, C CHCH2CH(O)), 2.01 (s, 3H, CH CCH3), 1.87 (dt, J 12.8,
CH2C(O)), 1.96 (ddd, J 15.1, 5.6, 4.2 Hz, 1H, C CHCH2CH(O)), 1.87
7.2 Hz, 1H, C CHCH2CH(O)), 1.73 (m, 2H), 1.59 (m, 2H), 1.45 (s, 3H,
(ddd, J 14.7, 7.0, 6.7 Hz, 1H), 1.84 (s, 3H, CH3C CH), 1.67 (m, 2H), 1.51
(CH3)-epoxide), 1.36 (s, 3H, C(CH3)2), 1.14 (d, J 5.5 Hz, 3H,
CH3CHC(O)), 1.05 (s, 3H, C(CH3)2), 0.98 (d, J 5.8 Hz, 3H, CH3CH);
13C NMR (125.7 MHz, CDCl3): d 220.7, 170.7, 152.6, 149.4, 140.2, 137.1,
131.2, 125.0, 123.4, 76.4, 71.6, 62.1, 61.7, 53.9, 42.0, 39.6, 36.2, 32.9, 32.3, 30.8,
29.6, 22.5, 22.1, 21.7, 18.1, 17.8, 16.8, 15.7, 14.1; MALDI-FTMS HRMS
(m, 1H), 1.43 (m, 2H), 1.35 (m, 2H), 1.34 (s, 3H, C(CH3)2), 1.27 (s, 3H),
1.16 (d, J 7.0 Hz, 3H, CH3CHC(O)), 1.08 (s, 3H, C(CH3)2), 0.99 (d, J
7.0 Hz, 3H, CH3CH), 0.18 (s, 9H, Sn(CH3)3); 13C NMR (125.7 MHz,
CDCl3): d 220.8, 170.7, 149.8, 125.9, 73.7, 61.2, 60.9, 52.2, 43.7, 39.0, 36.4,
31.7, 31.6, 29.7, 22.7, 21.4, 20.9, 17.3, 14.2, 1.0, À8.8; FAB HRMS (NBA/CsI):
(DHB): m/z: 502.3171 [MH] calcd for C29H43NO6 502.3169. 57e: (72%);
Rf 0.73 (100% EtOAc); [a]2D2 À56.0 (c 1.0, CHCl3); IR (thin film):
m/z: 707.1402 [MCs] calcd for C26H46O6Sn 707.1376.
nÄmax 3441, 2925, 1732, 1692, 1455, 1006, 1380, 1259, 1149, 1071 cmÀ1
;
Epothilone dimer 59: In a similar procedure as was employed for the
preparation of analogues 57a ± e, vinyl iodide 19 (2.7 mg, 0.005 mmol,
1H NMR (500 MHz, CDCl3): d 7.57 (dd, J 7.7, 7.7 Hz, 1H, ArH), 7.08 (d,
Chem. Eur. J. 2000, 6, No. 15
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