7
release of methane). The resulting biphasic sy
A
ste
C
m
C
w
E
as
P
a
T
llo
E
w
D
ed MAth
N
e r
U
es
S
id
C
ue
R
w
I
as purified by column chromatography on silica
P
T
to warm to room temperature and stirred additionally for 1 h. The
organic layer was separated; the aqueous layer was extracted with
diethyl ether (3 × 60 mL). The combined organic layers were
rinsed with brine, dried over Na SO , and filtered. The solvents
gel (petroleum ether/EtOAc = 60:1 to 20:1) to give ketone 18c as
a colorless oil (0.275 g, 80%). TLC: R 0.56 (petroleum
f
ether/EtOAc 10:1). [α]ꢁ +14.8 (с 2.78, CHCl ). H NMR (500
ꢁ
1
ꢀ
3
MHz, CDCl ): δ = 5.85-5.75 (m, 1H), 5.04-4.99 (m, 1H), 4.97-
2
4
3
were removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (petroleum
ether/EtOAc = 5:1 to 2:1) to give ketone 18a as white crystals
4.92 (m, 1H), 4.03 (dd, J = 11.9, 2.6 Hz, 1H), 3.94 (td, J = 11.9,
2.7 Hz, 1H), 3.84 (ddd, J = 11.5, 5.5, 1.9 Hz, 1H), 2.59 (t, J = 7.2
Hz, 2H), 2.32-2.25 (m, 2H), 1.66-1.56 (m, 1H), 1.40 (s, 3H),
1
3
(
3.08 g, 94%). The enantiomeric excess for 18a was up to 98% as
1.34-1.29 (m, 1H), 1.32 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H).
С
1
29
determined from H spectra by using (+)-Eu(hfc) shift reagent.
TLC: R 0.36 (petroleum ether/EtOAc 4:1). [α] +3.82 (с 1.16,
CHCl ). M.p. 59.2-60.7 °С. H NMR (400 MHz, CDCl ): δ =
NMR (125 MHz, CDCl ): δ = 214.1, 137.9, 115.0, 98.5, 74.2,
3
3
ꢁ
ꢆ
60.1, 50.7, 37.0, 30.0, 27.8, 25.4, 21.2, 19.1 (× 2). IR (film): ν
f
ꢀ
1
3081, 2994, 1705, 1641, 1381, 1370, 1198, 1106, 949. HRMS
3
3
+
+
4
3
1
.03 (dd, J = 11.6, 2.5 Hz, 1H), 3.96 (td, J = 11.9, 2.8 Hz, 1H),
.85 (dd, J = 5.3, 1.8 Hz, 1H), 2.15 (s, 3H), 1.68-1.56 (m, 1H),
.42 (s, 3H), 1.36-1.31 (m, 1H), 1.33 (s, 3H), 1.12 (s, 3H), 1.06
(ESI): MNa , found 263.1617. [C H O Na] requires 263.1623.
14 24 3
13
(s, 3H). С NMR (100 MHz, CDCl ): δ = 213.3, 98.5, 73.9, 60.1,
3
Acknowledgments
5
1
1.0, 29.9, 26.0, 25.4, 21.2, 19.1 (× 2). IR (film): ν 2994, 2969,
+
705, 1381, 1370, 1220, 1172, 1107, 970. HRMS (ESI): MNa ,
+
This work was supported by the Ministry of Education of
Republic of Belarus.
found 223.1314. [C H O Na] requires 223.1310.
11
20
3
4
1
.15. (S)-2-(2,2-Dimethyl-1,3-dioxan-4-yl)-2-methylpentan-3-one
11b
8b
A solution of nitrile 19 (0.200 g, 1.09 mmol) in absolute
References and notes
diethyl ether (4 mL) was added drop-wise to a solution of
ethyllithium {freshly prepared according to Negishi protocol
from 1.56 M t-BuLi solution in pentane (4.65 mL, 7.25 mmol),
ethyl iodide (0.538 g, 3.45 mmol), and absolute diethyl ether (4
mL)} under argon atmosphere at 0 °C. The reaction mixture was
stirred for 2 h at the same temperature and quenched by drop-
30
1. Altmann, K.-H.; Höfle, G.; Müller, R.; Mulzer, J.; Prantz, K. In
The Epothilones: An Outstanding Family of Anti-Tumor Agents.
In Progress in the Chemistry of Organic Natural Products;
Kinghorn, A. D., Falk, H., Kobayashi, J., Ed.; Springer: Vienna,
2
009; Vol. 90, 260 p.
2.
(a) Gerth, K.; Bedorf, N.; Höfle, G.; Irschitk, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560-563. (b) Höfle,
G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem. Int. Ed. 1996, 35, 1567-1569.
(a) Su, D.-S.; Balog, A.; Meng, D.; Bertinato, P.; Danishefsky, S.
J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew.
Chem. Int. Ed. Engl. 1997, 36, 2093-2096. (b) Giannakakou, P.;
Gussio, Rick.; Nogales, E.; Downing, K. H.; Zaharevitz, D.;
Bollbuck, B.; Poy, G.; Sackett, D.; Nicolaou, K. C.; Fojo, T.
Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 2904-2909. (с) Altmann,
K.-H.; Gertscha, J. Nat. Prod. Rep. 2007, 24, 327-357.
wise addition of saturated NH Cl solution (11 mL) (warning:
4
strong foaming due to release of ethane). The resulting biphasic
system was allowed to warm to room temperature and rapidly
stirred for 24 h (TLC-control). The organic layer was separated;
the aqueous layer was extracted with diethyl ether (3 × 5 mL).
The combined organic layers were rinsed with brine, dried over
Na SO , and filtered. The solvents were removed under reduced
3
.
2
4
pressure, and the residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc = 50:1 to
4
5
.
.
Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal,
L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods C. M. Cancer Res.
1995, 55, 2325-2333.
(a) Smit, W. M.; Šufliarsky, J.; Werner, T. L.; Dizon, D. S.;
Wagnerová, M.; Hirte, H. W.; Spirtos, N. M.; Oza, A.; Dirix, L.;
El-Hashimy, M.; Acharyya, S.; Tan, E. Y.; Weber, D.; Schellens,
J. H. M. Clinical Ovarian & Other Gynecologic Cancer 2014, 5,
2
0
{
0:1) to give ketone 18b as a colorless oil (0.21 g, 90%). TLC: R
f
ꢁꢇ
.79 (petroleum ether/EtOAc 4:1). [α] +13.2 (с 1.02, CHCl )
ꢀ
3
11b
ꢁꢁ
1
Lit. [α] +13.5 (с 0.465, CHCl )}. H NMR (500 MHz,
ꢀ
3
CDCl ): δ = 4.03 (dd, J = 11.5, 2.2 Hz, 1H), 3.94 (td, J = 11.9,
3
2
7
1
.6 Hz, 1H), 3.85 (ddd, J = 11.5, 5.3, 1.6 Hz, 1H), 2.50 (q, J =
.1 Hz, 2H), 1.66-1.56 (m, 1H), 1.40 (s, 3H), 1.33-1.29 (m, 1H),
.32 (s, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H).
5
3-59. (b) Ceresa, C.; Avan, A.; Giovannetti, E.; Geldof, A. A.;
Avan, A.; Cavaletti, G.; Peters, G. J. J. Anticancer Res. 2014, 34,
17-523.
1
3
5
С NMR (125 MHz, CDCl ): δ = 215.6, 98.5, 74.1, 60.2, 50.7,
3
6
.
(a) Hunt, J. T. Mol. Cancer Ther. 2009, 8, 275-281. (b) Rak
Tkaczuk, K. H. Breast Cancer: Basic and Clinical Research 2011,
3
1
1.9, 29.9, 25.5, 21.2, 19.3, 19.1, 8.0. IR (film): ν 2990, 1707,
+
380, 1198, 970. HRMS (ESI): MNa , found 237.1469.
5
, 1-14.
+
[
C H O Na] requires 237.1467.
12
22
3
7. (7) (a) Alexander, E. J.; Rosa, E.; Bolos, J.; Castaner, R. Drugs
Fut. 2008, 33, 496-506. (b) DeConti, R. C.; Algazi, A. P.;
Andrews, S.; Urbas, P.; Born, O.; Stoeckigt, D.; Floren,
L.; Hwang, J.; Weber, J.; Sondak, V. K.; Daud, A. I. Br. J. Cancer
4
.16. (S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methylhept-6-en-3-
11b
one 18c
2
010, 103, 1548-1553. (c) Rustin, G.; Reed, N.; Jayson, G. C.;
A solution of nitrile 19 (0.263 g, 1.44 mmol) in absolute
diethyl ether (5.5 mL) was added drop-wise to a solution of
Ledermann, J. A.; Adams, M.; Perren, T.; Poole, C.; Lind, M.;
Persic, M.; Essapen, S.; Gore, M.; Calvert, H.; Stredder, C.;
Wagner, A.; Giurescu, M.; Kaye S. Ann. Oncol. 2011, 22, 2411-
2416. (d) Beer, T. M.; Smith, D. C.; Hussain, A.; Alonso,
M.; Wang, J.; Giurescu, M.; Roth, K.; Wang, Y. Br. J. Cancer
homoallyllithium {freshly prepared
according to Negishi
30
protocol from 1.56 M t-BuLi solution in pentane (6.40 mL, 9.98
31
mmol), homoallyl iodide (0.872 g, 4.79 mmol), and absolute
diethyl ether (5.3 mL)} under argon atmosphere at 0 °C. The
reaction mixture was stirred for 2 h at the same temperature and
2
012, 107, 808-813.
8
.
For reviews on the SAR of the epothilones synthetic analogues,
see (a) Altmann, K.-H.; Memmert, K. Epothilones as lead
structures for new anticancer drugs – pharmacology, fermentation,
and structure-activity-relationships. In Natural Compounds as
Drugs; Petersen, F.; Amstutz, R., Ed.; Birkhäuser: Basel, 2008;
Vol. 66, 275-334. (b) Klar, U.; Krause, W. Current Cancer
Therapy Reviews 2011, 7, 10-36. (c) Forli, S. Current Topics in
Medicinal Chemistry 2014, 14, 2312-2321.
quenched by drop-wise addition of saturated NH Cl solution (15
4
mL) and acetic acid (0.2 mL). The resulting biphasic system was
allowed to warm to room temperature and rapidly stirred for 24 h
TLC-control). The organic layer was separated; the aqueous
(
layer was extracted with diethyl ether (3 × 8 mL). The combined
organic layers were rinsed with brine, dried over Na SO , and
2
4
filtered. The solvents were removed under reduced pressure, and