TREA

Epothilone minor constituents

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Information

  • Patent Grant
  • 6624310
  • Patent Number
    6,624,310
  • Date Filed
    Wednesday, March 21, 2001
    24 years ago
  • Date Issued
    Tuesday, September 23, 2003
    22 years ago
Information
Abstract
The invention relates to compounds which are obtained by fermenting DSM 6773, especially epothilones A1, A2, A8, A9, B10, C1, C2, C3, C4, C5, C6, C7, C8, C9, D1, D2, D5, G1, G2, H1, H2, I1, I2, I3, I4, I5, I6 and K and trans-epothilones C1 and C2.
Description




The invention concerns compounds which in the present context are designated epothilone side components, viz. compounds 5 to 13 and 16 to 39. These compounds can be produced by fermenting DSM 6773 in accordance to DE 41 38 042.8.




Characterizing data of the compounds according to the invention will be compiled as follows.




Production: The processing of a raw epothilone mixture, which has been produced by fermenting DSM 6773 in a 900 l fermentor, can be drawn schematically from

FIGS. 1

to


2


.











Activities: cf. table 1













































Epothilone A




(1)




R


1


= H; R = H






Epothilone B




(2)




R


1


= H; R = Me






Epothilone E




(3)




R


1


= OH, R = H






Epothilone F




(4)




R


1


= OH; R = Me














































Epothilone A


1






(5)




R


1


= H; R


2


, R


8


= Me






Epothilone A


2






(6)




R


2


= H; R


1


, R


8


= Me






Epothilone A


8






(7)




R


8


= H; R


1


, R


2


= Me






Epothilone A


9






(8)




R


1


= CH


2


OH; R


2


, R


8


= Me













































Epothilone B


10






(9)














































Epothilone G


1






(10)




R = H






Epothilone G


2






(11)




R = Me














































Epothilone H


1






(12)




R = H






Epothilone H


2






(13)




R = Me














































Epothilone C




(14)




R


1


, R


2


, R


3


, R


4


= Me; R = H






Epothilone D




(15)




R


1


, R


2


, R


3


, R


4


, R = Me






Epothilone C


1






(16)




R


1


= H; R


2


, R


3


, R


4


= Me; R = H






Epothilone D


1






(17)




R


1


= H; R


2


, R


3


, R


4


= Me; R = Me






Epothilone C


2






(18)




R


2


= H; R


1


, R


3


, R


4


= Me; R = H






Epothilone D


2






(19)




R


2


= H; R


1


, R


3


, R


4


= Me; R = Me






Epothilone C


3






(20)




R


3


= H; R


1


, R


2


, R


4


= Me; R = H






Epothilone C


4






(21)




R


4


= H; R


1


, R


2


, R


3


= Me; R = H














































Epothilone C


5






(22)




R = H






Epothilone D


5






(23)




R = Me













































Epothilone C


6






(24)














































Epothilone C


7






(25)




R


7


= OH; R


8


= Me






Epothilone C


8






(26)




R


8


, R


7


= H






Epothilone C


9






(27)




R


6


= CH


2


OH; R


7


= H














































trans-Epothilone C


1






(28)




R


1


= H; R


2


= Me






trans-Epothilone C


2






(29)




R


2


= H; R


1


= Me














































Epothilone I


1






(30)




R, R


3


= H; R


1


, R


2


= Me






Epothilone I


2






(31)




R = H; R


1


, R


2


, R


3


= Me






Epothilone I


3






(32)




R


1


, R


2


, R


3


, R = Me






Epothilone I


4






(33)




R


2


, R = H; R


1


, R


3


= Me






Epothilone I


5






(34)




R


2


= H; R


1


, R


3


R = Me






Epothilone I


6






(35)




R


1


= H; R


2


, R


3


, R = Me













































Epothilone K




(36)














































(37)
















































(38)




R = H







(39)




R = Me















Epothilone A


1


(5): colorless amorphous solid; [α]


D




22


−69 (c 0.1, MeOH); UV (MeOH) λ


max


nm (ε) 208 (19600), 247 (13600); IR (KBr) ν


max


3437, 2959, 2931, 2876, 1732, 1710, 1455, 1259, 978 cm


−1


;


1


NMR (CDCl


3


, 400 MHz) δ 6.95 (1H, s, H-19), 6.60 (1H, bs, H-17), 5.68 (1H, dd, J=4.4, 4.0 Hz, H-15), 4.12 (1H, m, H-3), 3.71 (1H, m, H-7), 3.52 (1H, bs, 7-OH), 3.37 (1H, bd, J=7.5 Hz, 3-OH), 3.21 (1H, dq, J=7.7, 7.0 Hz, H-4), 3.02 (1H, ddd, J=9.2, 4.5, 2.8 Hz, H-13), 2.87 (1H, ddd, J=8.3, 4.5, 3.7 Hz, H-12), 2.78 (1H, dd, J=16.8, 4.3 Hz, H-2a), 2.70 (3H, s, H-21), 2.66 (1H, dq, J=3.9, 7.0 Hz, H-6), 2.65 (1H, dd, J=16.8, 5.2 Hz, H-2b), 2.16 (1H, ddd, J=15.4, 4.4, 2.8 Hz, H-14a), 2.12 (3H, bs, H-27), 1.91 (1H, ddd, J=15.4, 9.2, 4.0 Hz, H-14b), 1.63 (1H, m, H-10a), 1.62 (2H, m, H-11), 1.59 (1H, m, H-9a), 1.52 (1H, m, H-10b), 1.39 (1H, m, H-8), 1.35 (1H, m, H-9b), 1.211 (3H, d, J=7.0 Hz, H-23), 1.207 (3H, d, J=7.0 Hz, H-24), 0.89 (3H, d, J=6.9 Hz, H-25); EIMS m/z 479 [M]


+


(21), 322 (31), 306 (65), 304 (47), 168 (45), 166 (73), 164 (100), 151 (30), 140 (35); HREIMS m/z 479.2317 (calcd. for C


27


H


41


NO


5


S, 479.2342).




Epothilone A


2


(6): colorless amorphous solid; [α]


D




22


+12.0 (c 1.0, MeOH); UV(MeOH) λ


max


nm (ε) 210 (15100), 248 (15500); IR (KBr) ν


max


3438, 2963, 2929, 2875, 1734, 1706, 1458, 1262, 981 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.98 (1H, s, H-19), 6.63 (1H, bs, H-17), 5.40 (1H, dd, J=8.3, 3.4 Hz, H-15), 4.26 (1H, ddd, J=8.5, 4.8, 4.7 Hz, H-3), 3.85 (1H, dd, J=7.9, 2.6 Hz, H-7), 3.54 (1H, bs, 3-OH), 3.09 (1H, dq, J=4.8, 7.0 Hz, H-4), 3.01 (1H, ddd, J=8.3, 4.8, 4.6 Hz, H-13), 2.98 (1H, dq, J=7.9,7.0 Hz, H-6), 2.89 (1H, ddd, J=6.7, 4.6, 4.4 Hz, H-12), 2.68 (3H, s, H-21), 2.60 (1H, dd, J=15.1, 8.5 Hz, H-2a), 2.52 (1H, bs, 7-OH), 2.50 (1H, dd, J=15.1, 4.7 Hz, H-2b), 2.18 (1H, ddd, J=15.0, 4.8, 3.4 Hz, H-14a), 2.11 (3H, d, J=1.3 Hz, H-27), 1.82 (1H, ddd, J=15.0, 8.3, 8.1 Hz, H-14b), 1.63 (1H, m, H-8), 1.61 (2H, m, H-11a and H-10a), 1.46 (1H, m, H-11b), 1.39 (2H, m, H-9), 1.31 (1H, m, H-10b), 1.22 (3H, d, J=7.0 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-22), 1.01 (3H, d, J=6.9 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 216.2 (s, C-5), 170.1 (s, C-1), 164.9 (s, C-20), 152.0 (s, C-18), 137.0 (s, C-16), 120.3 (d, C-17), 116.5 (d, C-19), 76.7 (d, C-15), 75.6 (d, C-7), 69.1 (d, C-3), 57.1 (d, C-12), 54.3 (d, C-13), 50.3 (d, C-4), 49.6 (d, C-6), 39.4 (t, C-2), 35.5 (d, C-8), 32.2 (t, C-14), 29.6 (t, C-9), 27.6 (t, C-11), 23.9 (t, C-10), 19.2 (q, C-21), 18.0 (q, C-25), 15.6 (q, C-27), 13.9 (q, C-24), 12.4 (q, C-22); EIMS m/z 479 [M]


+


(18), 322 (38), 306 (78), 304 (59), 168 (48), 166 (96), 164 (100), 151 (33), 140 (38); HREIMS m/z 479.2318 (calcd. for C


27


H


41


NO


5


S, 479.2342).




Epothilone A


8


(7): colorless amorphous solid; [α]


D




22


−76.2 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 210 (15300), 248 (15500); IR (KBr) ν


max


3440, 2967, 2932, 2876, 1736, 1691, 1467, 1252, 979 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.95 (1H, s, H-19), 6.64 (1H, dd, J=15.6, 0.9 Hz, H-17), 6.52 (1H, dd, J=15.6, 6.6 Hz, H-16), 5.68 (1H, dddd, J=7.8, 6.6, 3.2, 0.9 Hz, H-15), 4.11 (1H, ddd, J=10.1, 6.6, 3.5 Hz, H-3), 3.78 (1H, ddd, J=5.2, 3.2, 3.2 Hz, H-7), 3.66 (1H, d, J=6.6 Hz, 3-OH), 3.23 (1H, dq, J=5.2, 6.9 Hz, H-6), 3.08 (1H, ddd, J=7.3, 5.5, 4.1 Hz, H-13), 2.90(1H, ddd, J=6.6, 4.6, 4.1 Hz, H-12), 2.69 (3H, s, H-21), 2.52 (1H, dd, J=14.7, 10.1 Hz, H-2a), 2.44 (1H, bd, J=3.2 Hz, 7-OH), 2.41 (1H, dd, J=14.7, 3.5 Hz, H-2b), 2.10 (1H ddd, J=15.0, 5.5, 3.2 Hz, H-14a), 1.90 (1H, ddd, J=15.0, 7.8, 7.3 Hz, H-14b), 1.71 (1H, m, H-8), 1.65 (1H, m, H-11a), 1.50 (1H, m, H-10a), 1.47 (1H, m, H-11b), 1.40 (2H, m, H-9), 1.39 (1H, m, H-10b), 1.33 (3H, s, H-23), 1.16 (3H, d, J=6.9 Hz, H-24), 1.08 (3H, s, H-22), 0.98 (3H, d, J=7.0 Hz, H-25);


13


C NMR (CDCl


3


, 75 MHz) δ 220.3 (s, C-5), 170.7 (s, C-1), 166.5 (s, C-20), 152.2 (s, C-18), 128.4 (d, C-16), 125.9 (d, C-17), 116.4 (d, C-19), 75.0 (d, C-7), 73.6 (d, C-3), 72.7 (d, C-15), 57.3 (d, C-12), 54.1 (d, C-13), 52.6 (s, C-4), 43.8 (d, C-6), 38.9 (t, C-2), 36.3 (d, C-8), 32.5 (t, C-14), 30.3 (t, C-9), 26.7 (t, C-11), 24.0 (t, C-10), 21.3 (q, C-23), 21.0 (q, C-22), 19.3 (q, C-21), 17.1 (q, C-25), 14.5 (q, C-24); EIMS m/z 479 [M]


+


XXX; HRDCIMS m/z 480.2401 (calcd. for C


25


H


38


NO


6


S, 480.2401).




Epothilone A


9


(δ): colorless amorphous solid; [α]


D




22


−37.6 (c 0.5, MeOH); UV (MeOH) λ


max


nm (ε) 211 (15500), 253 (14100); IR (KBr) ν


max


3423, 2965, 2932, 2877, 1736, 1690, 1463, 1249, 1014, 979 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.10 (1H, s, H-19), 6.72 (1H, dd, J=10.7, 4.3 Hz, 27-OH), 6.60 (1H, bs, H-17), 5.69 (1H, dd, J=11.6, 2.0 Hz, H-15), 5.59 (1H, d, J=6.6 Hz, 3-OH), 4.49 (1H, ddd, J=12.9, 4.3, 1.2 Hz, H-27a), 4.27 (1H, ddd, J=11.6, 6.6, 2.9 Hz, H-3), 4.11 (1H, ddd, J=12.9, 10.7, 1.0 Hz, H-27b), 3.71 (1H, ddd, J=4.8, 3.0, 2.8 Hz, H-7), 3.17 (1H, dq, J=3.0, 6.8 Hz, H-6), 3.04 (1H, ddd, J=9.7, 3.6, 2.2 Hz, H-13), 2.93 (1H, bs, 7-OH), 2.91 (1H, ddd, J=9.7, 3.6, 2.7 Hz, H-12), 2.72 (3H, s, H-21), 2.48 (1H, dd, J=14.2, 11.6 Hz, H-2a), 2.11 (1H, dd, J=14.2, 2.9 Hz, H-2b), 2.03 (1H, ddd, J=14.7, 2.2, 2.0 Hz, H-14a), 1.86 (1H, m, H-11a), 1.85 (1H, m, H-14b), 1.79 (1H, m, H-8), 1.52 (1H, m, H-10a), 1.37 (3H, m, H-9 and H-10b), 1.37 (3H, s, H-23), 1.36 (1H, m, H-11b), 1.19 (3H, d, J=6.8 Hz, H-24), 1.02 (3H, d, J=7.1 Hz, H-25), 1.00 (3H, s, H-22);


13


C NMR (CDCl


3


, 75 MHz) δ 220.5 (s, C-5), 170.2 (s, C-1), 167.5 (s, C-20), 150.7 (s, C-18), 138.9 (s, C-16), 125.2 (d, C-17), 119.5 (d, C-19), 76.7 (d, C-15), 73.4 (d, C-7), 70.4 (d, C-3), 57.7 (d, C-12), 57.2 (t, C-27), 55.3 (d, C-13), 54.2 (s, C-4), 41.3 (d, C-6), 40.7 (t, C-2), 37.5 (d, C-8), 31.8 (t, C-14), 31.2 (t, C-9), 28.0 (t, C-11), 23.7 (q, C-23), 23.2 (t, C-10), 19.2 (q, C-21), 16.8 (q, C-22), 15.8 (q, C-25), 13.5 (q, C-24); EIMS m/z 509 [M]


+


(9), 491 (4), 322 (28), 321 (25), 180 (45), 167 (40), 166 (100), 165 (49), 154 (47), 138 (33); HREIMS m/z 509.2467 (calcd. for C


26


H


39


NO


7


S, 509.2447).




Epothilone B


10


(9): colorless amorphous solid; [α]


22


−27 (c 0.15, MeOH); UV (MeOH) λ


max


nm (ε) 212 (15800), 247 (12500); IR (KBr) ν


max


3434, 2962, 2930, 2876, 2858, 1733, 1692, 1461, 1259, 1052, 981 cm


−1


;


1


H NMR (CDCl


3


, 600 MHz) δ 6.99 (1H, s, H-19), 6.60 (1H, bs, H-17), 5.42 (1H, dd, J=8.0, 3.0 Hz, H-15), 4.25 (1H, ddd, J=9.5, 6.3, 2.8 Hz, H-3), 4.23(1H, bs, 3-OH), 3.77 (1H, ddd, J=4.0, 3.9, 3.8 Hz, H-7), 3.30 (1H, dq, J=4.0, 6.9 Hz, H-6), 3.01 (2H, q, J=7.6 Hz, H-21), 2.81 (1H, dd, J=7.7, 4.6 Hz, H-13), 2.68 (1H, bs, 7-OH), 2.54 (1H, dd, J=13.9, 9.5 Hz, H-2a), 2.36 (1H, dd, J=13.9, 2.8 Hz, H-2b), 2.11 (1H, ddd, J=15.3, 4.6, 3.0 Hz, H-14a), 2.09 (3H, s, H-27), 1.91 (1H, ddd, J=15.3, 8.0, 7.7 Hz, H-14b), 1.74 (1H, m, H-8), 1.73 (1H, m, H-11a), 1.51 (1H, m, H-10a), 1.41 (1H, m, H-11b), 1.39 (3H, t, J=7.6 Hz, H-28), 1.38 (3H, m, H-9 and H-10b), 1.37 (3H, s, H-23), 1.28 (3H, s, H-26), 1.17 (3H, d, J=6.9 Hz, H-24), 1.09 (3H, s, H-22), 1.01 (3H, d, J=7.0 Hz, H-25); EIMS m/z 521 [M]


+


(22), 449 (7), 350 (18), 334 (57), 248 (16), 234 (27), 196 (41), 182 (59), 180 (96), 178 (100), 166 (44), 154 (44); HREIMS m/z 521.2808 (calcd. for C


28


H


43


NO


6


S, 521.2811).




Epothilone G


1


(10): colorless amorphous solid; [α]


D




22


−39.7 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 203 (15200), 236 (15100); IR (KBr) ν


max


3456, 2962, 2933, 2876, 1736, 1691, 1585, 1466, 1262, 980 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.47(1H, s, H-19), 6.33 (1H, bs, H-17), 5.42 (1H, dd, J=8.3, 2.9 Hz, H-15), 4.11 (1H, ddd, J=10.1, 6.1, 3.4 Hz, H-3), 3.78 (1H, bddd, J=5.2, 3.5, 3.5 Hz, H-7), 3.63 (1H, bd, J=6.1 Hz, 3-OH), 3.21 (1H, dq, J=5.2, 7.0 Hz, H-6), 3.00 (1H, ddd, J=7.7, 4.8, 4.2 Hz, H-13), 2.88 (1H, ddd, J=7.1, 4.2, 4.2 Hz, H-12), 2.53 (1H, dd, J=14.8, 10.1 Hz, H-2a), 2.51 (1H, bd, J=3.5 Hz, 7-OH), 2.43 (1H, dd, J=14.8, 3.4 Hz, H-2b), 2.43 (3H, s, H-21), 2.07 (1H, ddd, J=15.1, 4.8, 2.9 Hz, H-14a), 1.99 (3H, d, J=1.3 Hz, H-27), 1.86 (1H, ddd, J=15.1, 8.3, 7.7 Hz, H-14b), 1.71 (1H, m, H-8), 1.69 (1H, m, H-11a), 1.53 (1H, m, H-10a), 1.42 (1H, m, H-11b), 1.40 (3H, m, H-9 and H-10b), 1.34 (3H, s, H-23), 1.16 (3H, d, J=7.0 Hz, H-24), 1.09 (3H, s, H-22), 0.99 (3H, d, J=6.9 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 220.1 (s, C-5), 170.5 (s, C-1), 161.0 (s, C-20), 137.4 (s, C-18), 136.7 (s, C-16), 135.9 (d, C-19), 116.4 (d, C-17), 76.4 (d, C-15), 74.9 (d, C-7), 73.7 (d, C-3), 57.4 (d, C-12), 54.4 (d, C-13), 52.6 (s, C-4), 43.8 (d, C-6), 38.8 (t, C-2), 36.2 (d, C-8), 31.4 (t, C-14), 30.4 (t, C-9), 27.0 (t, C-11), 23.9 (t, C-10), 21.3 (q, C-23), 21.2 (q, C-22), 17.2 (q, C-25), 15.8 (q, C-27), 14.4 (q, C-24), 13.8 (q, C-21); EIMS m/z 477 [M]


+


(4), 405 (7), 290 (40), 152 (39), 150 (100), 148 (23), 124 (23); HREIMS m/z 477.2684 (calcd. for C


26


H


39


NO


7


, 477.2727)




Epothilone G


2


(11): colorless amorphous solid; [α]


D




22


−22.6 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 202 (21500), 236 (14800); IR (KBr) ν


max


3456, 2965, 2934, 2877, 1737, 1690, 1586, 1464, 1250,980 cm


−1


,


1


H NMR (CDCl


3


, 400 MHz) δ 7.48 (1H, s, H-19), 6.33 (1H, bs, H-17), 5.43 (1H, dd, J=7.1, 3.6 Hz, H-15), 4.12 (1H, ddd, J=9.9, 6.4, 3.4 Hz, H-3), 3.77 (1H, ddd, J=4.7, 4.4, 4.1 Hz, H-7), 3.83 (1H, bd, J=6.4 Hz, 3-OH), 3.30 (1H, dq, J=4.7, 6.9 Hz, H-6), 2.78 (1H, dd, J=7.0, 5.4 Hz, H-13), 2.54 (1H, dd, J=14.3, 9.9 Hz, H-2a), 2.51 (1H, bd, J=4.1 Hz, 7-OH), 2.44 (3H, s, H-21), 2.40 (1H, dd, J=14.3, 3.4 Hz, H-2b), 2.03 (1H, ddd, J=15.2, 5.4, 3.6 Hz, H-14a), 2.00 (3H, d, J=1.3 Hz, H-27), 1.92 (1H, ddd, J=15.1, 7.1, 7.0 Hz, H-14b), 1.71 (1H, m, H-8), 1.68 (1H, m, H-11a), 1.51 (1H, m, H-10a), 1.42 (1H, m, H-11b), 1.39 (3H, m, H-9 and H-10b), 1.35 (3H, s, H-23), 1.26 (3H, s, H-26), 1.16 (3H, d, J=6.9 Hz, H-24), 1.07 (3H, s, H-22), 0.99 (3H, d, J=7.0 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 220.7 (s, C-5), 170.5 (s, C-1), 161.0 (s, C-20), 137.4 (s, C-18), 136.5 (s, C-16), 135.9 (d, C-19), 116.3 (d, C-17), 76.6 (d, C-15), 74.6 (d, C-7), 73.5 (d, C-3), 61.3 (s, C-12), 61.1 (d, C-13), 52.7 (s, C-4), 43.4 (d, C-6), 39.0 (t, C-2), 36.5 (d, C-8), 32.0 (t, C-11), 31.8 (t, C-14), 30.8 (t, C-10), 22.9 (q, C-26), 21.0 (q, C-23), 20.8 (q, C-22), 17.2 (q, C-25), 15.9 (q, C-27), 14.1 (q, C-24), 13.8 (q, C-21); EIMS m/z491[M]


+


(21), 419 (6), 320 (18), 304 (39), 166 (42), 152 (57), 150 (100), 149 (44), 148 (58), 124 (35), 109 (33); HREIMS m/z 491.2878 (calcd. for C


27


H


41


NO


7


, 491.2883).




Epothilone H


1


(12): colorless amorphous solid; [α]


D




22


−84.2 (c 0.2, MeOH); UV (MeOH) λ


max


nm (ε) 203 (19600), 237 (12000); IR (KBr) ν


max


3436, 2933, 2880, 2860, 1734, 1688, 1585, 1251, 1007 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.47 (1H, s, H-19), 6.31 (1H, bs, H-17), 5.43 (1H, ddd, J=10.6, 10.2, 4.5 Hz, H-12), 5.36 (1H, dddd, J=10.6, 9.6, 5.0, 1.3 Hz, H-13), 5.30 (1H, dd, J=9.9, 2.0 Hz, H-15), 4.16 (1H, ddd, J=11.2, 5.3, 2.8 Hz, H-3), 3.73 (1H, ddd, J=3.9, 2.5, 2.3 Hz, H-7), 3.12 (1H, dq, J=2.3, 6.9 Hz, H-6), 2.92 (1H, d, J=2.5 Hz, 7-OH), 2.91 (1H, d, J=5.3 Hz, 7-OH), 2.66 (1H, ddd, J=15.1, 9.9, 9.6 Hz, H-14a), 2.50 (1H, dd, J=15.4, 11.2 Hz, H-2a), 2.43 (3H, s, H-21), 2.37 (1H, dd, J=15.4, 2.8 Hz, H-2b), 2.23 (1H, m, H-14b), 2.18 (1H, m, H-11a), 2.01 (1H, m, H-11b), 2.08 (3H, d, J=1.3 Hz, H-27), 1.74 (1H, m, H-8), 1.65 (1H, m, H-10a), 1.33 (1H, m, H-9a), 1.31 (3H, s, H-23), 1.19 (1H, m, H-10b), 1.18 (1H, m, H-9b), 1.17 (3H d, J=6.9 Hz, H-24), 1.08 (3H, s, H-22), 0.99 (3H, d, J=7.1 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 461 [M]


+


(6), 310 (5), 274 (10), 273 (7), 171 (63), 152 (100), 148 (18), 111 (15); HREIMS m/z 461.2743 (calcd. for C


26


H


39


NO


6


, 461.2777).




Epothilone H


2


(13): colorless amorphous solid; [α]


D




22


−44.4 (c 0.25, MeOH); UV (MeOH) λ


max


nm (ε) 203 (14500), 236 (12200); IR (KBr) ν


max


3436, 2967, 2935, 2880, 1734, 1690, 1586, 1251, 1007 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.46 (1H, s, H-19), 6.30 (1H, bs, H-17), 5.23 (1H, dd, J=9.8, 2.1 Hz, H-15), 5.12 (1H, dd, J=10.1, 5.3 Hz, H-13), 4.20 (1H, ddd, J=10.8, 5.7, 2.9 Hz, H-3), 3.71 (1H, ddd, J=3.8, 2.6, 2.6 Hz, H-7), 3.14 (1H, dq, J=2.6, 6.9 Hz, H-6), 2.93 (d, J=5.7 Hz, 3-OH), 2.90 (1H, bd, J=2.6 Hz, 7-OH), 2.62 (1H, ddd, J=15.1, 9.8, 9.8 Hz, H-14a), 2.46 (1H, dd, J=15.1, 10.8 Hz, H-2a), 2.43 (3H, s, H-21), 2.3 (1H, dd, J=15.1, 2.9 Hz, H-2b), 2.29 (1H, m, H-11a), 2.19 (1H, bd, J=15.1 Hz, H-14b), 1.97 (3H, d, J=1.3 Hz, H-27), 1.87 (1H, m, H-11b), 1.73 (1H, m, H-8), 1.67 (1H, m, H-10a), 1.65 (3H, bs, H-26), 1.32 (3H, s, H-23), 1.26 (2H, m, H-9), 1.24 (1H, m, H-10b), 1.18 (3H, d, J=6.9 Hz, H-24), 1.07 (3H, s, H-22), 1.00 (3H, d, J=7.0 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz), δ 220.6 (s, C-5), 170.3 (s, C-1), 161.0 (s, C-20), 138.6 (s, C-12), 138.4 (s, C-16), 137.5 (s, C-18), 135.6 (d, C-19), 120.8 (d, C-13), 115.8 (d, C-17), 78.9 (d, C-15), 74.3 (d, C-7), 72.7 (d, C-3), 53.3 (s, C-4) 42.0 (d, C-6), 39.6 (t, C-2), 38.6 (d, C-8), 32.4 (t, C-14), 31.9 (t, C-9), 31.6 (t, C-11), 25.6 (t, C-10), 23.0 (q, C-26), 22.8 (q, C-23), 18.8 (q, C-22), 16.1 (q, C-27), 15.9 (q, C-25), 13.8 (q, C-21), 13.6 (q, C-24), EIMS m/z 475 [M]


+


(11), 288 (9), 287 (5), 188(7), 171 (32), 152 (100), 111 (10); HREIMS m/z 475.2913 (calcd. for C


27


H


41


NO


6


, 475.2934).




Epothilone C


1


(16): colorless amorphous solid; [α]


D




22


−114.0 (c 10.0, MeOH); UV (MeOH) λ


max


nm (ε) 211 (16500), 248 (12500); IR (KBr) ν


max


3440, 2933, 2877, 2858, 1730, 1708, 1457, 1244,981 cm


1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.96 (1H, s, H-19), 6.56 (1H, bs, H-17), 5.47 (1H, dd, J=9.2, 3.0 Hz, H-15), 5.43 (1H, m, H-12), 5.40 (1H, m, H-13), 4.40 (1H, ddd, J=6.2, 6.1, 6.1 Hz, H-3), 3.69 (1H, dd, J=5.7, 3.6 Hz, H-7), 3.01 (1H, dq, J=5.7, 6.9 Hz, H-6), 3.01 (1H, bs, 3-OH), 2.84 (1H, dq, J=5.2, 7.0 Hz, H-4), 2.68 (3H, s, H-21), 2.66 (1H, ddd, J=16.4, 9.2, 7.3 Hz, H-14a), 2.64 (1H, dd, J=15.9, 7.1 Hz, H-2a), 2.54 (1H, dd, J=15.9, 6.1 Hz, H-2b), 2.38 (1H, bd, J=16.4 Hz, H-14b), 2.35 (1H, bs, 7-OH), 2.07 (3H, bs, H-27), 2.03 (2H, m, H-11), 1.62 (1H, m, H-10a), 1.53 (1H, m, H-8), 1.35 (1H, m, H-9a), 1.22 (1H, m, H-9b), 1.19 (3H, d, J=6.9 H, H-24), 1.14 (3H, d, J=6.9 Hz, H-23), 1.10 (1H, m, H-10b), 0.95 (3H, d, J=6.9 Hz, H-25),


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(5), 324 (8), 290 (8), 204 (7), 168 (100), 164 (15), 139 (36); HREIMS m/z 463.2381 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone D


1


(17): colorless amorphous solid; [α]


22


D−118.6 (c 0.5, MeOH); UV (MeOH) λ


max


nm (ε) 208 (18300), 249 (11900); IR (KBr) ν


max


3439, 2965, 2934, 2877, 1729, 1707, 1456, 1250, 980 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.98 (1H, s, H-19), 6.56 (1H, bs, H-17), 5.51 (1H, dd, J=9.5, 3.4 Hz, H-15), 5.16 (1H, dd, J=8.0, 4.2 Hz, H-13), 4.42 (1H, ddd, J=7.1, 6.3, 5.5 Hz, H-3), 3.70 (1H, dd, J=6.5, 2.9 Hz, H-7), 3.07 (1H, dq, J=6.5, 6.9 Hz, H-6), 2.95 (1H, dq, J=4.7, 7.0 Hz, H-4), 2.71 (3H, s, H-21), 2.69 (1H, dd, J=16.0, 6.3 Hz, H-2a), 2.64 (1H, m, H-14a), 2.59 (1H, dd, J=16.0, 7.1 Hz, H-2b), 2.46 (1H, bs, 3-OH), 2.38 (1H, bd, J=16.0 Hz, H-14b), 2.19 (1H, ddd, J=13.3, 8.6, 5.7 Hz, H-11a), 2.10 (3H, d, J=1.4 Hz, H-27), 2.02 (1H, bs, 7-OH), 1.91 (1H, ddd, J=13.3, 6.0, 6.0 Hz, H-11b), 1.68 (1H, m, H-10a), 1.66 (3H, bs, H-26), 1.53 (1H, m, H-8), 1.37 (1H, m, H-9a), 1.26 (1H, m, H-9b), 1.24 (3H, d, J=6.9 Hz, H-24), 1.19 (1H, m, H-10b), 1.14 (3H, d, J=7.0, H-23), 0.99 (3H, d, J=6.9 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 217.0 (s, C-5), 169.7 (s, C-1), 165.0 (s, C-20), 152.2 (s, C-18), 138.5 (s, C-12), 137.7 (s, C-16), 120.7 (d, C-13), 120.1 (d, C-17), 116.3 (d, C-19), 78.8 (d, C-15), 77.2 (d, C-7), 67.7 (d, C-3), 52.1 (d, C4), 46.5 (d, C-6), 40.6 (t, C-2), 37.6 (d, C-8), 32.3 (t, C-14), 31.8 (t, C-11), 29.5 (t, C-9), 25.5 (t, C-10), 23.1 (q, C-26), 19.2 (q, C-21), 15.5 (q, C-27), 16.6 (q, C-25), 14.5 (q, C-24), 9.7 (q, C-23); EIMS m/z 477 [M]


+


(13), 304 (19), 303 (31), 218 (40), 204 (41) 168 (100), 164 (45), 157 (25), 139 (18); HREIMS m/z 477.2544 (calcd. for C


26


H


39


NO


5


S, 477.2549).




Epothilone C


2


(18): colorless amorphous solid; [α]


D




22


−11.6 (c 10.0, MeOH); UV (MeOH) λ


max


nm (ε) 212 (15500), 249 (12100); IR (KBr) ν


max


3428, 2962, 2929, 2877, 2859, 1734, 1705, 1460, 1251, 982 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.99 (1H, s, H-19), 6.66 (1H, bs, H-17), 5.55 (1H, ddd, J=10.4, 9.2, 6.1 Hz, H-12), 5.38 (1H, ddd, J=10.4, 9.3, 6.2 Hz, H-13), 5.22 (1H, dd, J=8.8, 2.8 Hz, H-15), 4.42 (1H, dddd, J=9.4, 5.6, 4.2, 4.1 Hz, H-3), 3.93 (1H, d, J=5.6 Hz, 3-OH), 3.86 (1H, m, H-7), 3.15 (1H, bs, 7-OH), 3.12 (1H, dq, J=4.2, 7.0 Hz, H-4), 3.00 (1H, dq, J=6.9, 7.0 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, dddd, J=15.1, 9.3, 8.8, 0.8 Hz, H-14a), 2.58 (1H, dd, J=15.4, 9.4 Hz, H-2a), 2.38 (1H, dd, J=15.4, 4.1 Hz, H-2b), 2.31 (1H, ddd, J=15.1, 6.2, 2.8 Hz, H-14b), 2.08 (3H, d, J=1.3 Hz, H-27), 2.15 (1H, m, H-11a), 2.04 (1H, m, H-11b), 1.71 (1H, m, H-8), 1.59 (1H, m, H-10a), 1.43 (1H, m, H-9a), 1.31 (1H, m, H-9b), 1.26 (3H, d, J=7.0 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-23), 1.11 (1H, m, H-10b), 1.00 (3H, d, J=6.9 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(7), 324 (7), 306 (8), 290 (17), 168 (100), 164 (14), 139 (27); HREIMS m/z 463.2392 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone D


2


(19): colorless amorphous sold; [α]


D




22


−12.5 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 210 (15400), 248 (11200); IR (KBr) ν


max


3436, 2965, 2930, 2877, 1732, 1705, 1458, 1253, 980 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.97 (1H, s, H-19), 6.56 (1H, bs, H-17), 5.18 (1H, dd, J=7.9, 4.9 Hz, H-15), 5.18 (1H, ddd, J=9.6, 5.4, 1.0 Hz, H-13), 4.27 (1H, m, H-3), 3.88 (1H, dd, J=5.6, 4.6 Hz, H-7), 3.19 (1H, bs, 3-OH), 3.07 (1H, dq, J=4.3, 7.0 Hz, H-4), 2.95 (1H, dq, J=5.6, 7.0 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, dd, J=14.9, 7.8 Hz, H-2a), 2.56 (1H, ddd, J=14.7, 9.6, 7.9 Hz, H-14a), 2.43 (1H, dd, J=14.9, 5.6 Hz, H-2b), 2.38 (1H, bs, 7-OH), 2.26 (1H, ddd, J=14.5, 5.4, 4.9 Hz, H-14b), 2.19 (1H, ddd, J=13.0, 10.4, 5.4 Hz, H-11a), 2.10 (3H, d, J=1.4 Hz, H-27), 1.95 (1H, ddd, J=13.0, 10.3, 5.3 Hz, H-11b), 1.72 (1H, m, H-S), 1.68 (3H, bs, H-26), 1.61 (1H, m, H-10a), 1.39 (2H, m, H-9), 1.21 (1H, m, H-10b), 1.19 (3H, d, J=6.9 Hz, H-24), 1.17 (3H, d, J=7.0, H-22), 1.00 (3H, d, J=6.9 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 216.8 (s, C-5), 170.4 (s, C-1), 164.9 (s, C-20), 152.3 (s, C-18), 139.8 (s, C-12), 137.5 (s, C-16), 120.5 (d, C-17), 119.2 (d, C-13), 116.3 (d, C-19), 80.0 (d, C-15), 74.3 (d, C-7), 69.7 (d, C-3), 48.6 (d, C-4), 48.4 (d, C-6), 39.9 (t, C-2), 36.6 (d, C-8), 32.2 (t, C-14), 32.7 (t, C-11), 30.9 (t, C-9), 26.0 (t, C-10), 23.6 (q, C-26), 19.2 (q, C-21), 15.4 (q, C-27), 17.1 (q, C-25), 12.4 (q, C-24), 12.7 (q, C-23); EIMS m/z 477 [M]


+


(22), 304 (19), 303 (17), 218 (22), 204 (25), 168 (100), 164 (28), 157 (31), 139 (21); HREIMS m/z 477.2545 (calcd. for C


26


H


39


NO


5


S, 477.2549).




Epothilone C


3


(20): colorless amorphous solid; [α]


22




D


−62.1 (c 5.0, MeOH); UV (MeOH) λ


max


nm (ε) 212 (16200), 248 (12300); IR (KBr) ν


max


3432, 2928, 2878, 2858, 1736, 1698, 1252, 1040 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.95 (1H, s, H-19), 6.56 (1H, bs, H-17), 5.44 (1H, ddd, J=10.9, 10.3, 5.4 Hz, H-12), 5.33 (1H, ddd, J=10.9, 9.3, 4.6 Hz, H-13), 5.23 (1H, dd, J=9.5, 2.2 Hz, H-15), 4.36 (1H, ddd, J=11.3, 5.6, 2.3 Hz, H-3), 4.04 (1H, d, J=5.6 Hz, 3-OH), 3.93 (1H, ddd, J=9.5, 2.3, 1.4 Hz, H-7), 3.56 (1H, bd, J=2.3 Hz, 7-OH), 2.70 (1H, dd, J=18.0, 1.4 Hz, H-6a), 2.67 (3H, s, H-21), 2.61 (1H, ddd, J=15.3, 9.5, 9.3 Hz, H-14a), 2.38 (1H, dd, J=14.3, 11.3 Hz, H-2a), 2.36 (1H, dd, J=18.0, 9.5 Hz, H-6b), 2.28 (1H, bd, J=15.3 Hz, H-14b), 2.12 (1H, m, H-11a), 2.06 (1H, dd, J=14.3, 2.3 Hz, H-2b), 2.03 (3H, d, J=1.3 Hz, H-27), 1.96 (1H, m, H-11b), 1.75 (1H, m, H-8), 1.54 (1H, m, H-10a), 1.26 (1H, m, H-9a), 1.25 (3H, s, H-23), 1.17 (1H, m, H-10b), 1.15 (1H, m, H-9b), 1.03 (3H, s, H-22), 0.91 (3H, d, J=6.8 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(28), 290 (14), 168 (100), 164 (36), 157 (44), 151 (25); HREIMS m/z 463.2379 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone C


4


(21): colorless amorphous solid; [α]


D




22


−75.6 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 212 (17200), 248 (12500); IR (KBr) ν


max


3434, 2974, 2932, 2859, 1735, 1686, 1252, 1046 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.96 (1H, s, H-19), 6.60 (1H, bs, H-17), 5.43 (1H, m, H-12), 5.40 (1H, m, H-13), 5.26 (1H, dd, J=9.6, 2.3 Hz, H-15), 4.41 (1H, ddd, J=11.4, 5.8, 2.5 Hz, H-3), 3.78 (1H, m, H-7), 3.70 (1H, bs, 3-OH), 3.46 (1H, d, J=0.9 Hz, 7-OH), 3.01 (1H, dq, J=0.5, 7.0 Hz, H-6), 2.69 (3H, s, H-21), 2.66 (1H, ddd, J=15.3, 9.6, 8.8 Hz, H-14a), 2.47 (1H, dd, J=14.5, 11.4 Hz, H-2a), 2.29 (1H, m, H-14b), 2.25 (1H, dd, J=14.5, 2.5 Hz, H-2b), 2.24 (1H, m, H-11a), 2.07 (3H, d, J=1.4 Hz, H-27), 1.96 (1H, m, H-11b), 1.51 (2H, m, H-8), 1.44 (2H, m, H-10), 1.37 (2H, m, H-9), 1.32 (3H, s, H-23), 1.17 (3H, d, J=7.0 Hz, H-24), 1.07 (3H, s, H-22);


13


C NMR see Table 1; EIMS m/z 463 [M]


+


(7), 276 (15), 171 (33), 168 (100), 164 (23), 151 (22), 111 (13); HREIMS m/z 463.2373 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone C


5


(22): colorless amorphous solid; [α]


D




22


−158.2 (c 0.5, MeOH); UV (MeOH) λ


max


nm (ε) 205 (19500), 247 (12700); IR (KBr) ν


max


3447, 2972, 2927, 1737, 1690, 1450, 1252, 1181, 936 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.93 (1H, s, H-19), 6.48 (1H, bs, H-17), 5.48 (1H, ddd, J=10.7, 6.2, 6.2 Hz, H-12), 5.39 (1H, m, H-13), 5.37 (1H, m, H-9), 5.34 (1H, dd, J=8.0, 2.3 Hz, H-15), 4.29 (1H, dd, J=6.0, 2.6 Hz, H-7), 4.09 (1H, ddd, J=10.8, 7.1, 2.9 Hz, H-3), 3.59 (1H, d, J=7.1 Hz, 3-OH), 3.17 (1H, dq, J=6.0, 6.9 Hz, H-6), 2.68 (3H, s, H-21), 2.54 (1H, ddd, J=15.2, 8.1, 8.0 Hz, H-14a), 2.44 (1H, bs, 7-OH), 2.42 (1H, dd, J=15.1, 2.9 Hz, H-2a), 2.41 (1H, ddd, J=15.2, 2.3, 2.3 Hz, H-14b), 2.34 (1H, dd, J=15.1, 10.8 Hz, H-2b), 2.20 (1H, m, H-10a), 2.18 (2H, m, H-11), 2.12 (1H, m, H-10b), 2.06 (3H, bs, H-27), 1.67 (3H, bs, H-25), 1.27 (3H, s, H-23), 1.21 (3H, d, J=6.9 Hz, H-24), 1.15 (3H, s, H-22);


13


C NMR, see Table 1; EIMS m/z 475 [M]


+


(6), 392 (7), 304 (6), 288 (33), 204 (76), 171 (19), 168 (100), 164 (12); HREIMS m/z 475.2380 (calcd. for C


26


H


37


NO


5


S, 475.2392).




Epothilone D


5


(23): colorless amorphous solid; [α]


D




22


−150 (c 0.2, MeOH); UV (MeOH) λ


max


nm (ε) 205 (23300), 248 (13600); IR (KBr) ν


max


3439, 2967, 2927, 1736, 1690, 1451, 1254, 1181, 987 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ; 6.94 (1H, s, H-19), 6.51 (1H, bs, H-17), 5.34 (1H, bs, H-9), 5.29 (1H, dd, J=8.0, 2.4 Hz, H-15), 5.16 (1H, dd, J=8.2, 6.2 Hz, H-13), 4.30 (1H, bd, J=4.9 Hz, H-7), 4.19 (1H, ddd, J=10.8, 7.6, 3.0 Hz, H-3), 3.68 (1H, d, J=7.6 Hz, 3-OH), 3.17 (1H, dq, J=4.9, 7.0 Hz, H-6), 2.69 (3H, s, H-21), 2.65 (1H, d, J=2.1 Hz, 7-OH), 2.56 (1H, ddd, J=16.2, 8.2, 8.0 Hz, H-14a), 2.40 (1H, dd, J=15.0, 3.0 Hz, H-2a), 2.39 (1H, bd, J=16.2 Hz, H-14b), 2.34 (1H, dd, J=15.0, 10.8 Hz, H-2b), 2.25 (2H, m, H-10a and H-11a), 2.20 (1H, m, H-10b), 2.17 (1H, m, H-11b), 2.05 (3H, d, J=1.0 Hz, H-27), 1.69 (3H, bs, H-25), 1.68 (3H, bs, H-26), 1.29 (3H, s, H-23), 1.23 (3H, d, J=7.0 Hz, H-24), 1.16 (3H, s, H-22);


13


C NMR, see Table 1; EIMS m/z 489 [M]


+


(4), 406 (4), 338 (7), 302 (13), 218 (35), 171 (10), 168 (100), 153 (20), 125 (10); HREIMS m/z 489.2536 (calcd. for C


27


H


39


NO


5


S, 489.2549).




Epothilone C


6


(24): colorless amorphous solid; [α]


D




22


−205.2 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 218 (24600), 237 (28800); IR (KBr) ν


max


3435, 2967, 2927, 2882, 1732, 1688, 1465, 1258, 988 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.97 (1H, s, H-19), 6.58 (1H, bs, H-17), 6.43 (1H, dd, 15.5, 10.8 Hz, H-11), 6.11 (1H, dd, J=10.8, 10.6 Hz, H-12), 5.75 (1H, ddd, J=15.5, 8.3, 5.6 Hz, H-10), 5.34 (1H, m, H-13), 5.34 (1H, dd, J=9.7, 2.4 Hz, H-15), 4.16 (1H, ddd, J=9.2, 4.9, 4.3 Hz, H-3), 3.74 (1H, ddd, J=2.2, 2.1, 1.7 Hz, H-7), 3.24 (1H, dq, J=2.1, 6.9 Hz, H-6), 3.06 (1H, d, J=2.2 Hz, 7-OH), 2.93 (1H, d, J=4.9 Hz, 3-OH), 2.78 (1H, dddd, J=14.1, 9.9 9.7, 0.7, H-14a), 2.71 (3H, s, H-21), 2.48 (1H, m, H-9a), 2.47 (1H, dd, J=15.5, 9.2 Hz, H-2a), 2.40 (1H, dd, J=15.5, 4.3 Hz, H-2b), 2.38 (1H, bdd, J=14.1, 7.8 Hz, H-14b), 2.11 (3)H, d, J=1.3 Hz, H-27), 1.96 (1H, m, H-8), 1.33 (3H, s, H-23), 1.11 (3H, d, J=6.9 Hz, H-24), 1.06 (3H, H-22), 1.05 (3H, d, J=6.8 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 475 [M]


+


(13), 387 (2), 316 (4), 288 (15), 230 (16), 204 (9), 171 (18), 168 (100), 164 (14), 151 (17); HREIMS m/z 475.2361 (calcd. for C


26


H


37


NO


5


S,


475.2392).






Epothilone C


7


(25): colorless amorphous solid; [α]


D




22


−XXX (c 2.0, MeOH); UV (MeOH) λ


max


nm (ε) XXX (XXX), XXX (XXX); IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.01 (1H, s, H-19), 6.66 (1H, bs, H-17), 559 (1H, ddd, J=11.1, 11.1, 3.8 Hz, H-12), 5.40 (1H, dd, J=11.1, 9.2, H-13), 5.03 (1H, d, J=9.3 Hz, H-15), 4.62 (1H, dd, J=9.3, 9.2 Hz, H-14), 4.18 (1H, bd, J=11.0 Hz, H-3), 3.72 (1H, bs, H-7), 3.20 (1H, bs, 3-OH), 3.09 (1H, dq, J=1.9, 6.8 Hz, H-6), 3.00 (1H, bs, 7-OH), 2.69 (3H, s, H-21), 2.47 (1H, dd, J=14.8, 11.0 Hz, H-2a), 2.32 (1H, dd, J=14.8, 2.6 Hz, H-2b), 2.27 (1H, m, H-11a), 2.19 (3H, bs, H-27), 2.13 (1H, m, H-11b), 1.76 ((H, m, H-8), 1.70 (1H, m, H-10a), 1.35 (1H, m, H-9a), 1.32 (3H, s, H-23), 1.23 (1H, m, H-9b), 1.21 (1H, m, H-10b), 1.18 (3H, d, J=6.8 Hz, H-24), 1.08 (3H, s, H-22), 1.00 (3H, d, J=6.9 Hz, H-25); EIMS m/z 493 [M]


+


XXX; HREIMS m/z 493.XXX (calcd. for C


26


H


39


NO


6


S, 493.2498).




Epothilone C


8


(26): colorless amorphous solid; [α]


D




22


−75.2 (c 2.5, MeOH); UV (MeOH) λ


max


nm (ε) 210 (16800), 248 (17800); IR (KBr) ν


max


3443, 2932, 2881, 1734, 1689, 1465, 1255, 1183, 976 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.93 (1H, s, H-19), 6.62 (1H, dd, J=15.6, 0.6 Hz, H-17), 6.49 (1H, dd, J=15.6, 6.6 Hz, H-16), 5.52 (1H, dddd, J=9.5, 6.6, 2.8, 0.6 Hz, H-15), 5.42 (1H, m, H-12), 5.41 (1H, m, H-13), 4.13 (1H, ddd, J=11.0, 5.3, 2.8 Hz, H-3), 3.69 (1H, ddd, J=3.7, 2.8, 2.5 Hz, H-7), 3.11 (1H, dq, J=2.5, 6.8 Hz, H-6), 2.95 (1H, d, J=5.3 Hz, 3-OH), 2.90 (1H, d, J=2.8 Hz, 7-OH), 2.69 (3H, s, H-21), 2.67 (1H, ddd, J=14.9, 9.5, 8.4 Hz, H-14a), 2.48 (1H, dd, J=15.6, 11.0 Hz, H-2a), 2.33 (1H, dd, J=15.6, 2.8 Hz, H-2b), 2.30 (1H, bd, J=14.9 Hz, H-14b), 2.14 (1H, m, H-11a), 2.03 (1H, m, H-11b), 1.71 (1H, m, H-8), 1.63 (1H, m, H-10a), 1.31 (1H, m, H-9a), 1.29 (3H, s, H-23), 1.17 (3H, d, J=6.8 Hz, H-24), 1.16 (1H, m, H-10b), 1.14 (1H, m, H-9b), 1.05 (3H, s, H-22), 0.97 (3H, d, J=7.1 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(21), 310 (10), 276 (21), 171 (83), 154 (100), 150 (27), 111 (18); HREIMS m/z 463.2382 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone C


9


(27): colorless amorphous solid; [α]


D




22


−93.4 (c 1.0, MeOH); UV (MeOH) λ


max


nm (ε) 209 (15200), 254 (15700); IR (KBr) ν


max


3416, 2966, 2932, 1736, 1689, 1463, 1249, 1011 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 7.06 (1H, s, H-19), 6.65 (1H, bs, H-17), 6.56 (1H, dd, J=10.6, 4.4 Hz, 27-OH), 5.55 (1H, d, J=6.2 Hz, 3-OH), 5.52 (1H, dd, J=11.6, 2.0 Hz, H-15), 5.44 (1H, dddd, J=11.2, 10.7, 3.1, 1.7 Hz, H-12), 5.35 (1H, dddd, J=11.0, 10.7, 3.9, 1.7 Hz, H-13), 4.47 (1H, ddd, J=12.5, 4.4, 1.3 Hz, H-27a), 4.35 (1H, ddd, J=11.7, 6.2, 2.6 Hz, H-3), 4.20 (1H, ddd, J=12.5, 10.6, 0.9 Hz, H-27b), 3.63 (1H, ddd, J=4.6, 1.8, 0.9 Hz, H-7), 3.24 (1H, d, J=1.8 Hz, 7-OH), 3.13 (1H, dq, J=0.9, 6.8 Hz, H-6), 2.80 (1H, ddd, J=14.8, 11.6, 11.0 Hz, H-14a), 2.71 (3H, s, H-21), 2.40 (1H, dd, J=14.4, 11.7 Hz, H-2a), 2.24 (1H, m, H-11a), 2.06 (1H, dd, J=14.4, 2.6 Hz, H-2b), 2.01 (1H, ddd, J=14.8, 3.9, 2.0 Hz, H-14b), 2.00 (1H, m, H-11b), 1.77 (1H, m, H-8), 1.69 (1H, m, H-10a), 1.35 (1H, m, H-9a), 1.35 (3H, s, H-23), 1.19 (1H, m, H-10b), 1.19 (3H, d, J=6.8 Hz, H-24), 1.18 (1H, m, H-9b), 1.01 (3H, d, J=7.1 Hz, H-25), 0.98 (3H, s, H-22);


13


C NMR, see Table 1; EIMS m/z 493 [M]


+


(17), 306 (64), 184 (50), 171 (30), 167 (38), 166 (100), 138 (12); HREIMS m/z 493.2502 (calcd. for C


26


H


39


NO


6


S, 493.2498).




trans-Epothilone C


1


(28): colorless amorphous solid; [α]


D




22


−84 (c 0.2, MeOH); UV (MeOH) λ


max


nm (ε) 211 (17400), 248 (12900); IR (KBr) ν


max


3433, 2961, 2933, 2879, 1730, 1708, 1457, 1251, 975 cm


−1


;


1


H NMR (CDCl


3


, 600 MHz) δ 7.00 (1H, s, H-19), 6.64 (1H, bs, H-17), 5.45 (1H, ddd, J=15.2, 6.5, 6.5 Hz, H-12), 5.42 (1H, dd, J=6.4, 3.7 Hz, H-15), 5.35 (1H, dt, J=15.2, 7.1 Hz, H-13), 4.42 (1H, m, H-3), 3.58 (1H, ddd, J=8.1, 7.9, 2.8 Hz, H-7), 3.24 (1H, m, H-6), 3.14 (1H, dq, J=4.0, 6.9 Hz, H-6), 2.92 (1H, d, J=7.9 Hz, 7-OH), 2.71 (3H, s, H-21), 2.71 (2H, m, H-2), 2.53 (2H, m, H-14), 2.17 (1H, d, J=2.17 Hz, 3-OH), 2.11 (1H, m, H-11a), 2.06 (3H, bs, H-27), 1.93 (1H, m, H-11b), 1.68 (1H, m, H-9a), 1.65 (1H, m, H-10a), 1.33 (1H, m, H-8), 1.26 (3H, d, J=6.8 Hz, H-24), 1.16 (1H, m, H-10b), 1.12 (3H, d, J=6.9 Hz, H-22), 1.07 (1H, m, H-9b), 1.00 (3H, d, J=6.8 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(6), 290 (21), 289 (20), 204 (23), 194 (19), 190 (22), 168 (100), 164 (48), 157 (14), 152 (19), 151 (17), 139 (15), 111 (18), HREIMS m/z 463.2371 (calcd. for C


25


H


37


NO


5


S, 463.2392).




trans-Epothilone C


2


(29): colorless amorphous solid; [α]


D




22


−3 (c 1.5, MeOH); UV (MeOH) λ


max


nm (ε) 211 (15800), 248 (11900); IR (KBr) ν


max


3435, 2963, 2931, 2878, 1731, 1706, 1457, 1273, 979 cm


−1


;


1


H NMR (CDCl


3


, 600 MHz) δ 6.99 (1H, s, H-19), 6.57 (1H, bs, H-17), 5.56 (1H, ddd, J=15.1, 7.4, 7.0 Hz, H-12), 5.41 (1H, ddd, J=15.1, 7.0, 6.9 Hz, H-13), 5.41 (1H, dd, J=7.7, 2.8 Hz, H-15), 4.13 (1H, dddd, J=6.7, 6.2, 5.6, 5.1 Hz, H-3), 3.78 (1H, ddd, J=8.2, 6.5, 1.9 Hz, H-7), 3.18 (1H, d, J=5.6 Hz, 3-OH), 3.06 (1H, dq, J=8.2, 7.1 Hz, H-6), 2.98 (1H, dq, J=6.2, 7.0 Hz, H-4), 2.71 (3H, s, H-21), 2.64 (1H, dd, J=15.1, 6.7 Hz, H-2a), 2.54 (1H, dd, J=15.1, 5.1 Hz, H-2b), 2.44 (2H, m, H-14), 2.22 (1H, dddd, J=13.8, 7.0, 6.2, 2.9 Hz, H-11a), 2.10 (3H, d, J=1.1 Hz, H-27), 2.09 (1H, d, J=6.5 Hz, 7-OH), 1.88 (1H, dddd, J=13.8, 10.9, 7.4, 2.9 Hz, H-11b), 1.65 (1H, m, H-8), 1.63 (1H, m, H-10a), 1.56 (1H, dddd, J=12.7, 12.7, 3.9, 3.9 Hz, H-9a), 1.20 (3H, d, J=7.1 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-23), 1.13 (1H, m, H-10b), 1.04 (1H, m, H-9b), 1.01 (3H, d, J=7.0 Hz, H-25);


13


C NMR, see Table 1; EIMS m/z 463 [M]


+


(13), 290 (11), 190 (10), 168 (100), 164 (20), 157 (26), 139 (17); HREIMS m/z 463.2383 (calcd. for C


25


H


37


NO


5


S, 463.2392).




Epothilone I


1


(30): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.96 (1H, s, H-19), 6.54 (1H, bs, H-17), 5.49 (1H, ddd, J=10.3, 7.3, 7.3 Hz, H-12), 5.33 (1H, dd, J=8.3, 4.4 Hz, H-15), 5.31 (1H, m, H-13), 4.15 (1H, ddd, J=8.0, 5.0, 4.6 Hz, H-3), 3.80 (1H, m, H-7), 3.21 (1H, dq, J=6.0, 6.9 Hz, H-6), 2.89 (1H, d, J=5.0 Hz, 3-OH); 2.70 (3H, s, H-21), 2.65 (1H, ddd, J=15.8, 8.5, 8.3 Hz, H-14a), 2.42 (2H, m, H-2), 2.35 (1H, m, H-14b), 2.27 (1H, bd, J=3.3 Hz, 7-OH), 2.13 (1H, m, H-11a), 2.09 (3H, d, J=1.2 Hz, H-27), 2.00 (1H, m, H-11b), 1.72 (1H, m, H-8), 1.40 (2H, m, H-10


β


), 1.37 (1H, m, H-9


β


a), 1.36 (2H, m, H-9


α


), 1.32 (3H, s, H-23), 1.27 (3H, m, H-9


β


b and H-10


α


), 1.13 (3H, d, J=6.9 Hz, H-24), 1.09 (3H, s, H-22), 0.94 (3H, d, J=6.9 Hz, H-25);


13


C NMR (CDCl


3


, 75 MHz) δ 221.3 (s, C-5), 171.1 (s, C-1), 164.8 (s, C-20), 152.4 (s, C-18), 137.4 (s, C-16), 133.8 (d, C-12), 124.6 (d, C-13), 120.0 (d, C-17), 116.2 (d, C-19), 78.8 (d, C-15), 74.9 (d, C-7), 74.7 (d, C-3), 51.6 (s, C-4), 43.7 (d, C-6), 38.9 (t, C-2), 34.3 (d, C-8), 31.6 (t, C-14), 29.3 (t, C-9


α


), 28.6 (t, C-10


β


), 28.2 (t, C-10


α


), 26.6 (t, C-11), 24.8 (t, C-9


β


), 23.6 (q, C-22), 19.3 (q, C23), 19.3 (q, C-21), 16.5 (q, C-25), 15.5 (q, C-27), 13.7 (q, C-24); EIMS m/z 505 [M]


+


XXX; HREIMS m/z 505.XXX (calcd. for C


28


H


43


NO


5


S, 505.XXX).




Epothilone I


2


(31): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.95 (1H, s, H-19), 6.53 (1H, bs, H-17), 5.40 (1H, m, H-12), 5.38 (1H, dd, J=9.8, 3.3 Hz, H-15), 5.37 (1H, m, H-13), 4.21 (1H, ddd, J=8.6, 3.8, 3.6 Hz, H-3), 3.85 (1H, ddd, J=8.5, 5.8, 2.2 Hz, H-7), 3.18 (1H, dq, J=8.5, 7.0 Hz, H-6), 2.70 (3H, s, H-21), 2.65 (1H, ddd, J=15.2, 9.8, 9.0 Hz, H-14a), 2.51 (1H, d, J=3.6 Hz, 3-OH), 2.37 (2H, m, H-2), 2.32 (1H, bd, J=15.2 Hz, H-14b), 2.09 (3H, d, J=1.3 Hz, H-27), 2.07 (2H, m, H-11), 1.78 (1H, m, H-8), 1.65 (1H, d, J=5.8 Hz, 7-OH), 1.57 (1H, m, H-10


β


a), 1.44 (1H, m, H-10


α


a), 1.42 (1H, m, H-9


β


), 1.32 (3H, s, H-23), 1.21 (1H, m, H-10


β


b), 1.17 (3H, d, J=7.0 Hz, H-24), 1.13 (2H, m, H-9


α


), 1.06 (3H, s, H-22), 0.95 (3H, d, J=7.0 Hz, H-25


α


), 0.91 (3H, d, J=6.5 Hz, H-25


β


), 0.68 (1H, m, H-10


α


b);


13


C NMR (CDCl


3


, 100 MHz) δ 220.4 (s, C-5), 171.3 (s, C-1), XXX (s, C-20), 152.4 (s, C-18), 137.6 (s, C-16), 134.5 (d, C-12), 125.3 (d, C-13), 119.6 (d, C-17), 116.2 (d, C-19), 78.6 (d, C-15), 77.2 (d, C-7), 75.0 (d, C-3), 51.0 (s, C-4), 44.6 (d, C-6), 38.2 (t, C-2), 36.9 (t, C-9


α


), 34.5 (t, C-10


α


), 32.6 (d, C-8), 32.0 (t, C-14), 30.0 (d, C-9


β


), 27.4 (t, C-11), 26.6 (t, C-10


β


), 25.0 (q, C-22), 21.5 (q, C-25


β


), 19.3 (q, C-21), 17.9 (q, C-25


α


), 17.7 (q, C-23), 15.8 (q, C-24), 15.6 (q, C-27); EIMS m/z 519 [M]


+


XXX; HREIMS m/z 519.XXX (calcd. for C


29


H


45


NO


5


S, 519.XXX).




Epothilone I


3


(32): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; TR (IKr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.95 (1H, s, H-19), 6.52 (1H, bs, H-17), 5.32 (1H, dd, J=9.1, 3.0 Hz, H-15), 5.08 (1H, dd, J=8.5, 3.9 Hz, H-13), 4.13 (1H, ddd, J=9.4, 4.3, 3.2 Hz, H-3), 3.81 (1H, m, H-7), 3.18 (1H, dq, J=6.8, 7.0 Hz, H-6), 2.83 (1H, d, J=4.3 Hz, 3-OH), 2.70 (3H, s, H-21), 2.61 (1H, ddd, J=15.8, 9.1, 8.5 Hz, H-14a), 2.43 (1H, dd, J=14.0, 3.2 Hz, H-2a), 2.38 (2H, dd, J=14.0, 9.4 Hz, H-2b), 2.30 (1H, bd, J=15.8 Hz, H-14b), 2.16 (1H, ddd, J=14.1, 8.3, 7.4 Hz, H-11a), 2.08 (3H, d, J=1.0 Hz, H-27), 1.99 (1H, d, J=4.7 Hz, 7-OH), 1.92 (1H, ddd, J=14.1, 6.3, 6.3 Hz, H-11b), 1.82 (1H, m, H-8), 1.67 (3H, s, H-26), 1.51 (1H, m, H-10


β


a), 1.40 (1H, m, H-9


β


), 1.33 (1H, m, H-10


β


b), 1.31 (3H, s, H-23), 1.27 (1H, m, H-10


α


a), 1.23 (1H, m, H-9


α


a), 1.16 (3H, d, J=7.0 Hz, H-24), 1.10 (1H, m, H-9


α


b), 1.07 (3H, s, H-22), 0.95 (3H, d, J=7.0 Hz, H-25


α


), 0.92 (3H, d, J=6.5 Hz, H-25


β


), 0.75 (1H, m, H-10


α


b); EIMS m/z 533 [M]


+


XXX; HREIMS m/z 533.XXX (calcd. for C


30


H


47


NO


5


S, 533.XXX).




Epothilone I


4


(33): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.95 (1H, s, H-19), 6.53 (1H, bs, H-17), 5.47 (1H, dt, J=11.1, 5.8 Hz, H-12), 5.33 (1H, ddd, J=9.2, 3.9, 0.5 Hz, H-15), 5.33 (1H, m, H-13), 4.09 (1H, dddd, J=9.6, 8.1, 4.5, 3.3 Hz, H-3), 3.83 (1H, m, (H-7), 3.57 (1H, bs, 3-OH), 2.89 (1H, dq, J=7.4, 7.1 Hz, H-6), 2.83 (1H, dq, J=8.1, 7.1 Hz, H-4), 2.70 (3H, s, H-21), 2.64 (1H, m, H-14a), 2.42 (1H, dd, J=14.2, 3.3 Hz, H-2a), 2.43 (1H, dd, J=14.2, 9.6 Hz, H-2b), 2.30 (1H, m, H-14b), 2.10(3H, d, J=1.3 Hz, H-27), 2.09 (2H, m, H-11), 1.81 (1H, m, H-8), 1.74 (1H, bd, J=5.6 Hz, 7-OH), 1.53 (1H, m, H-10


β


a), 1.49 (1H, m, H-9


β


), 1.47 (1H, m, H-10


α


a), 1.27 (1H, m, H-10


β


b), 1.24 (1H, m, H-9


α


a), 1.17 (3H, d, J=7.1 Hz, H-23), 1.14 (1H, m, H-9


α


b), 1.08 (3H, d, J=7.1 Hz, H-24), 0.97 (3H, d, J=6.9 Hz, H-25


α


), 0.91 (3H, d, J=6.5 Hz, H-25


β


), 0.79 (1H, m, H-10


α


b);


13


C NMR (CDCl


3


, 100 MHz) δ 217.0 (s, C-5), 170.8 (s, C-1), 164.8 (s, C-20), 152.4 (s, C-18), 137.1 (s, C-16), 134.6 (d, C-12), 124.7 (d, C-13), 120.2 (d, C-17), 116.4 (d, C-19), 78.7 (d, C-15), 76.4 (d, C-7), 71.3 (d, C-3), 50.7 (d, C-4), 50.1 (d, C-6), 40.7 (t, C-2), 38.5 (t, C-9


α


), 35.5 (t, C-10


α


), 33.4 (d, C-8), 31.8 (t, C-14), 30.0 (d, C-9


β


), 27.2 (t, C-11), 26.7 (t, C-10


β


), 21.4 (q, C-25


β


), 19.3 (q, C-21), 18.2 (q, C-25


α


), 15.4 (q, C-27), 14.4 (q, C-24), 13.1 (q, C-23); EIMS m/z 505 [M]


+


XXX; HREIMS m/z 505.XXX (calcd. for C


28


H


43


NO


5


S, 505.XXX).




Epothilone I


5


(34): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.97 (1H, s, H-19), 6.52 (1H, bs, H-17), 5.32 (1H, dd, J=7.1, 6.2 Hz, H-15), 5.03 (1H, dd, J=8.4, 5.0 Hz, H-13), 4.05 (1H, dddd, J=7.5, 7.2, 5.9, 4.6 Hz, H-3), 3.91 (1H, m, H-7), 3.17 (1H, d, J=5.9 Hz, 3-OH), 2.94 (1H, dq, J=7.2, 7.1 Hz, H-4), 2.87 (1H, dq, J=6.5, 6.9 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, dd, J=14.6, 4.6 Hz, H-2a), 2.60 (1H, m, H-14a), 2.53 (1H, dd, J=14.6, 7.5 Hz, H-2b), 2.31 (1H, m, H-14b), 2.10 (3H, d, J=1.1 Hz, H-27), 2.10 (1H, m, H-11a), 2.02 (1H, m, H-11b), 1.97 (1H, bd, J=5.6 Hz, 7-OH), 1.84 (1H, m, H-8), 1.66 (3H, s, H-26), 1.55 (1H, m, H-9


β


), 1.49 (1H, m, H-10


β


a), 1.39 (1H, m, H-10


β


b), 1.33 (1H, m, H-10


α


a), 1.31 (1H, m, H-9


α


a), 1.15 (3H, d, J=7.1 Hz, H-23), 1.12 (1H, m, H-9


α


b), 1.11 (3H, d, J=6.9 Hz, H-24), 0.97 (3H, d, J=6.9 Hz, H-25


α


), 0.94 (1H, m, H-10


α


b), 0.93 (3H, d, J=6.6 Hz, H-25


β


); EIMS m/z 519 [M]


+


XXX; HREIMS m/z 519.XXX (calcd. for C


29


H


45


NO


5


S, 519.XXX).




Epothilone I


6


(35): colorless amorphous solid; [α]


D




22


−XXX (c XXX, MeOH); UV (MeOH) λ


max


nm (ε) XXX; IR (KBr) ν


max


XXX cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.97 (1H, s, H-19), 6.52 (1H, bs, H-17), 5.24 (1H, dd, J=6.9, 6.9 Hz, H-15), 5.02 (1H, dd, J=8.8, 5.2 Hz, H-13), 4.22 (1H, tdd, J=6.1, 5.6, 4.8 Hz, H-3), 3.76 (1H, ddd, J=6.1, 5.7, 5.6 Hz, H-7), 3.13 (1H, d, J=5.6 Hz, 3-OH), 3.05 (1H, dq, J=4.8, 7.0 Hz, H-4), 2.79 (1H, dq, J=5.6, 6.9 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, m, H-14a), 2.57 (2H, d, J=6.1 Hz, H-2a), 2.30 (1H, m, H-14b), 2.08 (3H, d, J=1.0 Hz, H-27), 2.02 (2H, m, H-11), 1.73 (1H, d, J=6.1 Hz, 7-OH), 1.69 (1H, m, H-8), 1.66 (3H, s, H-26), XXX (H9


α


, H-9


β


, H-10


α


, H-10


β


), 1.21 (3H, d, J=7.0 Hz, H-22), 1.16 (3H, d, J=6.9 Hz, H-24), 0.94 (3H, d, J=6.9 Hz, H-25


α


), 0.91 (3H, d, J=6.4 Hz, H-25


β


); EIMS m/z 519 [M]


+


XXX; HREIMS m/z 519.XXX (calcd. for C


29


H


45


NO


5


S, 519.XXX).




Epothilone K (36): colorless amorphous solid; [α]


D




22


−7 (c 0.08, MeOH); UV (MeOH) λ


max


nm (ε) 212 (16700), 248 (12500); IR (KBr) ν


max


3431, 2963, 2927, 2856, 1731, 1712, 1262, 1093, 1021, 802 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.95 (1H, s, H-19), 6.51 (1H, bs, H-17), 5.49 (3H, m, H-15, H-13, and H-12), 4.04 (1H, dddd, J=7.9, 7.6, 6.9, 3.3 Hz, H-3), 3.36 (1H, dq, J=6.9, 6.8 Hz, H-6), 2.83 (1H, d, J=7.6 Hz, 3-OH), 2.75 (1H, ddd, J=16.1, 6.6, 3.4 Hz, H-14a), 2.74 (1H, dd, J=15.3, 3.3 Hz, H-2a), 2.71 (3H, s, H-21), 2.58 (2H, m, H-14b and H-8), 2.50 (1H, dd, J=15.3, 7.9 Hz, H-2b), 2.29 (1H, m, H-11a), 2.10 (1H, m, H-11b), 2.09 (3H, d, J=0.7 Hz, H-27), 1.78 (1H, m, H-9a), 1.65 (1H, m, H-10a), 1.48 (1H, m, H-10b), 1.18 (1H, m, H-9b), 1.15 (3H, d, J =6.8 Hz, H-22), 1.03 (3H, d, J=6.5 Hz, H-25); EIMS m/z 405 [M]


+ (


38), 317 (12), 260 (9), 232 (10), 204 (14), 190 (16), 168 (100), 164 (30), 151 (28); HREIMS m/z 405.XXX (calcd. for C


26


H


39


NO


5


S, 405.XXX).




(37): colorless amorphous solid; [α]


D




22


−27.5 (c 0.4, MeOH); UV (MeOH) λ


max


nm (ε) 211 (16100), 247(12100); IR (KBr) ν


max


3431, 2967, 2929, 2875, 1704, 1462, 1381, 1010 cm


−1


;


1


H NMR (CDCl


3


, 400 MHz) δ 6.94 (1H, s, H-19), 6.55 (1H, bs, H-17), 5.56 (1H, dtt, J=10.8, 7.3, 1.4 Hz, H-12), 5.39 (1H, dtt, J=10.8, 7.3, 1.4 Hz, H-13), 4.17 (1H, t, J=6.6 Hz, H-15), 3.50 (1H, ddd, J=8.7, 2.6, 2.6 Hz, H-7), 3.10 (1H, d, J=2.6, 7-OH), 2.90 (1H, dq, J=2.6, 7.2 Hz, H-6), 2.77 (1H, sep, J=6.9 Hz, H-4), 2.70 (3H, s, H-21), 2.40 (2H, m, H-14), 2.07 (2H, m, H-11), 2.04 (3H, d, J=1.1 Hz, H-27), 1.78 (1H, bs, 15-OH), 1.74 (1H, m, H-9a), 1.50 (1H, m, H-8), 1.46 (1H, m, H-10a), 1.27 (1H, m, H-10b), 1.11 (1H, m, H-9b), 1.094 (3H, d, J=6.9 Hz, H-23), 1.089 (3H, d, J=6.9 Hz, H-22), 1.08 (3H, d, J=7.2 Hz, H-24), 0.82 (3H, d, J=6.7 Hz, H-25);


13


C NMR (CDCl


3


, 100 MHz) δ 220.5 (s, C-5), 164.6 (s, C-20), 152.9 (s, C-18), 141.5 (s, C-16), 133.4 (d, C-12), 125.0 (d, C-13), 119.2 (d, C-17), 115.6 (d, C-19), 77.2 (d, C-15), 74.9 (d, C-7), 44.9 (d, C-6), 40.0 (d, C-4), 35.5 (d, C-8), 33.5 (t, C-14), 32.3 (t, C-9), 27.9 (t, C-11), 26.9 (t, C-10), 19.2 (q, C-21), 18.6 (q, C-23), 18.1 (q, C-22), 15.6 (q, C-25), 14.4 (q, C-27), 9.3 (q, C-24); EIMS m/z 407 [M]


+


(0.1), 204 (0.8), 168 (100), 140 (3.4); HREIMS m/z 407.XXX (calcd. for C


23


H37NO


3


S, 407.XXX).




(38): colorless amorphous solid; [α]


22




D


+25.0 (c 0.5, MeOH); UV (MeOH) λ


max


nm (ε) 212 (17700), 247 (13400); IR (KBr) ν


max


3427, 2971, 2933, 2878, 2858, 1709, 1457, 1377, 1186, 1023 cm


−1


;


1


H NMR (CDCl


3


, 300 MHz) δ 6.95 (1H, s, H-19), 6.55 (1H, bs, H-17), 5.52 (1H, dtt, J=10.9, 7.2, 1.4 Hz, H-12), 5.39 (1H, dtt, J=10.9, 7.1, 1.2 Hz, H-13), 4.18 (1H, ddt, J=3.4, 0.4, 6.7 Hz, H-15), 2.71 (3H, s, H-21), 2.51 (1H, bq, J=6.8 Hz, H-8), 2.48 (1H, dq, J=17.7, 7.4 Hz, H-6a), 2.41 (1H, dq, J=17.7, 7.2 Hz, H-6b), 2.39 (2H, ddd, J=7.1, 6.7, 1.4 Hz, H-14), 2.06 (2H, ddt, 7.2, 1.2, 7.0 Hz, H-11), 2.05 (3H, d, J=1.4 Hz, H-27), 1.81 (1H, d, J=3.4 Hz, 15-OH), 1.66 (1H, m, H-9a), 1.32 (1H, m, H-9b), 1.31 (2H, m, H-10), 1.06 (3H, d, J=6.9 Hz, H-25), 1.04 (3H, dd, J=7.4, 7.2 Hz, H-24);


13


C NMR (CDCl


3


, 75 MHz) δ 215.3 (s, C-7), 164.6 (s, C-20), 152.9 (s, C-18), 141.5 (s, C-16), 132.7 (d, C-12), 125.3 (d, C-13), 119.2 (d, C-17), 115.6 (d, C-19), 77.2 (d, C-15), 46.0 (d, C-8), 34.3 (t, C-14), 33.5 (t, C-6), 32.7 (t, C-9), 27.5 (t, C-11), 27.3 (t, C-10), 19.2 (q, C-21), 16.5 (q, C-25), 14.4 (q, C-27), 7.8 (q, C-24); EIMS m/z 335 [M]


+


(2), 317 (4), 170 (27), 169 (67), 168 (100), 140 (20); HREIMS m/z 335.1912 (calcd. for C


19


H


29


NO


2


S, 335.1919).




(39): colorless amorphous solid; [α]


D




22


+26.4 (c 0.27, MeOH); UV (MeOE) λ


max


nm (ε) 203 (19100), 244 (12500); IR (KBr) ν


max


3430, 2970, 2934, 2877, 1710, 1458, 1377, 1184 cm


−1


;


1


H NMR(CDCl


3


, 400 MHz) δ 6.94 (1H, s, H-19), 6.55 (1H, bs, H-17), 5.17 (1H, t, J=7.3 Hz, H-13), 4.13 (1H, m, H-15), 2.70 (3H, s, H-21), 2.51 (1H, bq, J=6.8 Hz, H-8), 2.47 (1H, dq, J=17.7, 7.2 Hz, H-6a), 2.41 (1H, dq, J=17.7, 7.2 Hz, H-6b), 2.33 (2H, bdd, J=7.3, 6.8 Hz, H-14), 2.05 (3H, d, J=1.2 Hz, H-27), 2.03 (2H, m, H-11) 1.71 (1H, d, J=3.2 Hz, 15-OH), 1.69 (3H, d, J=1.3 Hz, H-26), 1.62 (1H, m, H-9a), 1.32 (3H, m, H-10 and H-9b), 1.06 (3H, d, J=6.9 Hz, H-25), 1.03 (3H, t, J=7.2 Hz, H-24); EIMS m/z 349 [M]


+


(0.7), 331 (1.7), 168 (100), 140 (5.1); HREIMS m/z 349.XXX (calcd. for C


20


H


31


NO


2


S, 349.XXX).












TAB. 1











Activity of epothilones and compounds (1) to (39) against






mouse fibroblasts (L929, IC 50/ng/ml)












Structural




Epothilone
















type




A


Y






B


Y






C


Y






D


Y






trans C


Y











Starting




(1) 4




(2) 1-2




(14) 50-100




(15) 20




—






epothilone






21-Hydroxy




(3) 10




(4) 1.5




—




—




—






(E&F)






Oxazoles




(10) 6




(11) 1




(12) 120




(13) 11




—






(G&H)






(R)-4-Des-




(5) 20




—




(16) 200




(17) 20




(28) 400






methyl (X


1


)






(S)-4-Des-




(6) 7




—




(10) 25-30




(19) 12




(29) 80






methyl (X


2


)






6-Desmethyl




—




—




(20) 1500




—




—






(X


3


)






8-Desmethyl




—




—




(21) 800




—




—






(X


4


)






8,9-Dehydro




—




—




(22) 1500




(23) 200




—






(X


5


)






10,11-Dehydro




—




—




(24) 120




—




—






(X


6


)






14-Hydroxy




—




—




(25)




—




—






(X


7


)






16-Desmethyl




(7) 20




—




(26) 250




—




—






(X


8


)






27-Hydroxy




(8) 100




—




(27) 200




—




—






(X


9


)






21-Methyl




—




(9) 1.5




—




—




—






(X


10


)






Compound




—




—




(36) 180






Compound




—




—




(37) 50




—




—






Compound




—




—




(38) 2000




(39) 500




—













Claims
  • 1. An Epothilone of the formula: wherein:for Epothilone A1 R1=H; R2, R8=Methyl; Epothilone A2 R2=H; R1, R8=Methyl; Epothilone A8 R8=H; R1, R2=Methyl; or Epothilone A9 R1=CH2OH; R2, R8=Methyl.
Priority Claims (1)
Number Date Country Kind
198 26 988 Jun 1998 DE
PCT Information
Filing Document Filing Date Country Kind
PCT/EP99/04244 WO 00
Publishing Document Publishing Date Country Kind
WO99/65913 12/23/1999 WO A
Foreign Referenced Citations (14)
Number Date Country
WO 9719086 May 1997 WO
WO 9808849 Mar 1998 WO
WO 9822461 May 1998 WO
WO 9825929 Jun 1998 WO
WO 9901124 Jan 1999 WO
WO 9902514 Jan 1999 WO
WO 9907692 Feb 1999 WO
WO 9927890 Jun 1999 WO
WO 9943653 Sep 1999 WO
WO 9954319 Oct 1999 WO
WO 0000485 Jan 2000 WO
WO 0031247 Jun 2000 WO
WO 0049012 Aug 2000 WO
WO 9825929 Nov 2002 WO
Non-Patent Literature Citations (1)
Entry
Nicolaou et al., 1998, “Chemical Biology of Epothilones”, Angew. Chem. Int. Ed. 37:2014-2045.