Synthesis of a 12,13-Diol-Acetonide Epothilone B Analog
FULL PAPER
0.06 (s, 3 H), 0.09 (s, 3 H), 0.60 (q, J = 8.0 Hz, 6 H), 0.85–1.47 (m,
19 H), 0.89 (s, 18 H), 0.94 (t, J = 7.8 Hz, 9 H), 1.19 (s, 3 H), 1.20
(s, 3 H), 1.39 (s, 3 H), 1.55–1.63 (m, 1 H), 1.73–1.88 (m, 1 H), 1.99
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stereomeric ratio was 5.8:1.1:1.0. Major Diasteromer 74: H NMR
(250 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.08 (s, 3 H), 0.62 (q, J =
8.0 Hz, 6 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.84–1.86 (m, 9 H), 0.89
(s, 9 H), 0.96 (t, J = 7.8 Hz, 9 H), 1.02 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 0.9 Hz, 3 H), 2.05–2.19 (m, 2 H), 2.70 (s, 3 H), 3.10 (mc, 1
(s, 3 H), 1.13 (s, 3 H), 1.16 (s, 3 H), 1.21 (s, 3 H), 1.39 (s, 3 H), H), 3.59 (dd, J = 10.0, 2.3 hz, 1 H), 3.75 (dd, J = 6.6, 1.8 Hz, 1 H),
1.99 (d, J = 1.1 Hz, 3 H), 2.02–2.17 (m, 2 H), 2.70 (s, 3 H), 3.20– 3.94 (dd, J = 7.3, 3.4 Hz, 1 H), 4.35 (dd, J = 8.4, 5.5 Hz, 1 H),
3.31 (m, 2 H), 3.46 (s, 1 H), 3.60 (dd, J = 9.8, 2.3 Hz, 1 H), 3.93
(dd, J = 7.1, 3.9 Hz, 1 H), 4.35 (dd, J = 8.4, 5.5 Hz, 1 H), 4.96–
5.08 (m, 2 H), 5.70–5.87 (m, 1 H), 6.48 (s, 1 H), 6.92 (s, 1 H) ppm.
4.92–5.07 (m, 2 H), 5.70–5.89 (m, 1 H), 6.48 (s, 1 H), 6.90 (s, 1
H) ppm. 13C NMR (63 MHz, CDCl3): δ = –4.94, –4.61, –3.79,
–3.67, 5.51, 7.03, 13.07, 15.20, 17.45, 18.17, 18.51, 18.80, 19.21,
13C NMR (100 MHz, CDCl3): δ = –4.94, –4.61, 5.46, 7.01, 9.71, 21.34, 22.19, 24.43, 25.85, 26.23, 26.71, 28.64, 31.50, 36.12, 39.03,
13.10, 15.27, 18.17, 19.21, 19.48, 21.17, 21.20, 22.76, 25.85, 26.73,
28.66, 33.38, 35.48, 36.20, 39.23, 39.59, 41.15, 54.28, 74.93, 76.97,
39.27, 39.59, 45.11, 53.76, 76.97, 77.05, 77.45, 78.59, 81.92, 106.55,
115.24, 116.49, 120.10, 136.66, 140.80, 153.12, 164.33, 218.40 ppm.
77.08, 78.91, 82.04, 106.53, 115.26, 116.92, 120.07, 136.13, 140.87, IR (Si, film): νmax = 2956, 2934, 2856, 1694, 1373, 1253, 1105, 986,
˜
153.09, 164.31, 222.47 ppm. IR (Si, film): νmax = 2957, 1684, 1461,
836, 775 m, 738, 610 cm–1. MS (FI = 7 kV, 3 mA, 135 °C): m/z =
˜
1375, 1252, 1180, 1104, 998, 738, 610 cm–1. MS (EI = 70 eV, 910 (30), 909 (28), 908 (100), 907 (31), 894 (2), 851 (4), 774 (3),
180 °C): m/z = 796 (Ͻ1), 795 (4), 794 (2) [M+], 793 (5), 510 (40), 653(5), 382 (2), 283 (2), 185 (14). [α]2D0 = –4.7 (c = 0.9, CHCl3).
509 (100) [aldehyde], 285 (8), 284 (44) [ketone]. HRMS: calcd. for
(4S,7R,8S,9S)-4,8-Bis(tert-butyldimethylsilyloxy)-12-{(4R,5R)-5-
C43H79NO6SSi2 [M+] 793.5167; found 793.5135. [α]2D0 = –6.8 (c =
[(S,E)-2-(tert-butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazol-4-
0.9, CHCl3). C43H79NO6SSi2 (794.32): calcd. C 65.02, H 10.02, N
yl)but-3-enyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}-5,5,7,9-tetramethyl-
1.76; S, 4.04; found C 64.94, H 10.33, N 1.74; S, 3.51. Minor Dia-
dodec-1-en-6-one (76): In analogy to the procedure above, aldol
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stereomer I: H NMR (250 MHz, CDCl3): δ = 0.03 (s, 3 H), 0.09
product 74 (52 mg, 0.066 mmol) in dry CH2Cl2 (5 mL) was treated
(s, 3 H), 0.60 (q, J = 7.5 Hz, 6 H), 0.90–1.68 (m, 23 H), 0.90 (s, 9
with 2,6-lutidine (60 µL) und 60 µL TBSOTf. After work-up and
H), 1.07 (s, 3 H), 1.14 (s, 6 H), 1.22 (s, 3 H), 1.40 (s, 3 H), 1.74–
concentration in vacuo the crude product 75 was dissolved in THF
1.88 (m, 1 H), 2.00 (d, J = 1.1 Hz, 3 H), 2.01–2.21 (m, 2 H), 2.70
(5 mL) and cooled to –18 °C. TBAF (80 µL, 1 in THF, 1.2 equiv.)
(s, 3 H), 3.22 (qd, J = 6.9, 2.1 Hz, 1 H), 3.40 (dd, J = 8.0, 1.6 Hz,
was added dropwise and the mixture was stirred for 80 min at
1 H), 3.49 (s, 1 H), 3.62 (dd, J = 9.8, 2.3 Hz, 1 H), 3.95 (dd, J =
–18 °C. After addition of satd. NH4Cl (5 mL), the aqueous phase
7.1, 4.1 Hz, 1 H), 4.36 (dd, J = 8.4, 5.2 Hz, 1 H), 4.98–5.08 (m, 2
was extracted with diethyl ether, and the combined organic phases
H), 5.68–5.87 (m, 1 H), 6.48 (s, 1 H), 6.91 (s, 1 H) ppm. 13C NMR
were washed with brine, dried with MgSO4 concentrated under re-
(63 MHz, CDCl3): δ = –4.94, –4.62, 5.47, 7.03, 10.69, 13.16, 15.47,
duced pressure. Purification by chromatography (hex/EE, 7:1) gave
18.16, 19.20, 19.77, 21.25, 21.30, 22.72, 25.84, 26.74, 28.64, 33.24,
compound 75 (6 mg) and the TES-deprotected product (44 mg).
35.42, 36.22, 39.23, 39.35, 41.40, 54.12, 75.02, 76.76, 76.93, 78.65,
The latter was dissolved in dry CH2Cl2 (5 mL) and treated with
81.90, 106.59, 115.28, 116.89, 120.05, 136.15, 140.84, 153.10,
80 µL 2,6-Lutidin und 80 µL TBSOTf. After 3 h at room temp.
164.41 ppm. IR (Si, film): νmax = 2956, 1458, 1375, 1255, 1107, 888,
˜
and standard work-up the product was purified by chromatography
(hex/EE, 10:1) to give compound 76 as a colorless oil (48 mg, 81%).
1H NMR (250 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.04 (s, 3 H), 0.05
(s, 6 H), 0.06 (s, 3 H), 0.09 (s, 3 H), 0.82–0.95 (m, 3 H), 0.89 (s, 9
H), 0.90 (s, 18 H), 0.99–1.47 (m, 13 H), 1.04 (s, 3 H), 1.05 (s, 3 H),
1.20 (s, 3 H), 1.40 (s, 3 H), 1.58–1.67 (m, 1 H), 1.74–1.87 (m, 1 H),
1.99 (d, J = 1.1, 3 H), 2.02–2.17 (m, 2 H), 2.70 (s, 3 H), 3.09 (m, 1
H), 3.69 (dd, J = 10.0, 2.3, 1 H), 3.77 (dd, J = 6.6, 1.8, 1 H), 3.97
(dd, J = 6.6, 4.1, 1 H), 4.35 (dd, J = 8.4, 5.5, 1 H), 4.93–5.04 (m,
2 H), 5.70–5.90 (m, 1 H), 6.48 (s, 1 H), 6.91 (s, 1 H). 13C NMR
(63 MHz, CDCl3): δ = –4.92, –4.56, –3.97, –3.77, –3.66, –3.31,
13.09, 15.31, 17.49, 18.18, 18.54, 19.23, 21.36, 22.11, 24.95, 25.86,
26.10, 26.24, 26.73, 28.65, 29.70, 31.50, 36.12, 39.02, 39.60, 45.07,
53.94, 76.28, 77.45, 78.58, 81.93, 106.56, 115.25, 116.29, 120.11,
817, 739, 611 cm–1. MS (FI = 7 kV, 3 mA, 130 °C): m/z = 794 (1)
[M+], 793 (6), 511 (14), 510 (31), 509 (100) [aldehyde], 285 (4), 284
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(40) [ketone], 255 (15), 243 (4). Minor Diastereomer II: H NMR
(250 MHz, CDCl3): δ = 0.03 (s, 3 H), 0.09 (s, 3 H), 0.61 (q, J =
7.3 Hz, 6 H), 0.91–1.69 (m, 23 H), 0.90 (s, 9 H), 1.07 (s, 3 H), 1.11
(s, 3 H), 1.17 (s, 3 H), 1.23 (s, 3 H), 1.41 (s, 3 H), 1.74–1.88 (m, 1
H), 2.00 (d, J = 1.1 Hz, 3 H), 2.03–2.17 (m, 2 H), 2.71 (s, 3 H),
3.20–3.36 (m, 3 H), 3.62 (dd, J = 9.8, 2.1 Hz, 1 H), 3.92 (dd, J =
7.3, 3.9 Hz, 1 H), 4.36 (dd, J = 8.5, 5.3 Hz, 1 H), 4.97–5.08 (m, 2
H), 5.70–5.88 (m, 1 H), 6.48 (s, 1 H), 6.91 (s, 1 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = –4.94, –4.61, 5.49, 7.03, 10.58, 13.13, 15.41,
18.17, 19.22, 19.41, 21.17, 21.39, 22.98, 25.85, 26.73, 28.64, 33.38,
35.50, 36.20, 39.24, 39.32, 41.53, 54.20, 75.10, 76.94, 77.05, 78.65,
81.91, 106.61, 115.28, 116.88, 120.06, 136.20, 140.84, 153.11,
136.78, 140.80, 153.13, 164.24, 218.47. IR (Si): ν = 2957 m, 2928 s,
˜
164.42 ppm. IR (Si, film): ν
= 2956, 1687, 1460, 1375, 1252,
˜
max
2856 s, 1695 m, 1472 m, 1374 m, 1256 m, 1216 w, 1180 w, 1106 s,
986 m, 886 w, 837 w, 775 m, 738 w, 671 w, 610 s. MS (FI = 7 kV,
1178, 1106, 976, 888, 837, 739, 610 cm–1. MS (FI = 7 kV, 3 mA,
130 °C): m/z = 795 (1), 794 (1) [M+], 793 (6), 511 (13), 510 (37),
509 (100) [aldehyde], 285 (6), 284 (44) [ketone], 255 (16), 243 (3).
2 mA, 150 °C): m/z = 912 (6), 911 (12), 910 (40), 909 (84), 908 (100)
20
[M], 897 (4), 851 (14) [M–tBu], 710 (2), 653 (4), 637 (3). [α]
+12.0 (c = 1.0, CHCl3).
=
365
(4S,7R,8S,9S)-8-(tert-Butyldimethylsilyloxy)-12-{(4R,5R)-5-[(S,E)-
2-(tert-butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazol-4-yl)but-
3-enyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}-5,5,7,9-tetramethyl-4-(tri-
ethylsilyloxy)dodec-1-en-6-one (75): Aldol adduct 74 (26 mg,
0.033 mmol) in CH2Cl2 (4 mL) was treated with 2,6-lutidine
(18 µL, 4 equiv.) and TBSOTf (18 µL, 2 equiv.). The mixture was
stirred for 3 h at room temp. and then quenched with satd. aq.
NaHCO3 (10 mL). The aqueous phase was extracted with diethyl
ether, and the combined organic phases were washed with brine,
dried with MgSO4 concentrated under reduced pressure. Column
chromatography (hex/EE, 10:1) gave 69 (28 mg, 94%) as a colorless
Acknowledgments
We thank Dr. J. W. Bats, Universität Frankfurt, for determining
the crystal structure of compound 53 and the Schering AG, Berlin,
for performing the biological tests with compound 7.
[1] a) G. Höfle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth,
H. Reichenbach, Angew. Chem. Int. Ed. Engl. 1996, 35, 1567;
b) H. Reichenbach, Wissenschaftlicher Bericht der GFB, 1996,
1
oil. H NMR (250 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.05 (s, 3 H),
Eur. J. Org. Chem. 2006, 3372–3394
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3393