Synthesis of the thiazole-containing C11-C21-block of a gem-dimethylcyclopropane derivative of epothilones

Article abstract of DOI:10.1016/j.mencom.2009.09.004

The synthesis of key chiral block for a gem-dimethylcyclopropane analogue of epothilones from R-carvone has been developed.

Full text of DOI:10.1016/j.mencom.2009.09.004

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 248–249
Synthesis of the thiazole-containing C11–C21-block of
a gem-dimethylcyclopropane derivative of epothilones
Natal’ya K. Selezneva, Fanuza A. Gimalova, Ruslan F. Valeev and Mansur S. Miftakhov*
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa,
Russian Federation. Fax: +7 347 235 6066; e-mail: bioreg@anrb.ru
DOI: 10.1016/j.mencom.2009.09.004
The synthesis of key chiral block for a gem-dimethylcyclopropane analogue of epothilones from R-carvone has been developed.
Currently, epothilones and, especially, their analogues are con-
sidered high-activity clinically acceptable anticancer drugs with
Taxol-like (tubulin-polymerising) mechanism of action.1–3 An
H
S
H
extremely fruitful approach to epothilones modification involves
HO
N
isosteric replacement, in particular, replacement of the epoxy
moiety, which is responsible for chemical lability and high
toxicity, with a cyclopropane moiety.4–10 We also intended
to synthesize a new gem-dimethylcyclopropane analogue of
epothilone A 1. This paper describes the synthesis of a key pre-
cursor, namely, thiazole-containing segment 2,† from d-carvone
(Scheme 1) (cf. ref. 11).
Chlorocyclohexenone 3, which is readily accessible from
d-carvone,12 was the starting compound. It is evident that
functionalization of compound 3 enables chemo rational ‘move-
ment’ towards block 2. The dihydroxylation of the double
bond of compound 3 via a ketodiol followed by its selective
oxidative cleavage allows one to generate an α-ketol system
suitable for olefination with a thiazole-containing phospho-
O
O
OH
O
1
S
O
N
OSiEt3
H
H
CO2Me
d-carvone
2
Scheme 1
†
NMR spectra were recorded on a Bruker AM-300 spectrometer at
300 (1H) and 75.47 MHz (13C), using TMS as the internal standard.
IR spectra were recorded on an IR Prestige-21 Fourier Transform Shimadzu
spectrophotometer from samples prepared as thin films or dispersed in
Nujol. Mass spectra were recorded on a Shimadzu LCMS-2010 spectro-
meter. Optical rotations were measured at 25 °C on a Perkin–Elmer 341
polarimeter. Commercial R-(–)-carvone (ee 98%, Aldrich), and syn-
thesized12 (5R)-5-(1-chloro-1-methylethyl)-2-methylcyclohex-2-en-1-one
3 with [a]D20 –42.4 (c 1.1, CHCl3) were used.
nate. Afterwards, a cyclopropane moiety in the products can be
created by intramolecular 1,3-SN2-replacement of chlorine with
carboxyenolates in the Me2Cl-containing centre (Scheme 2).
The above approach was implemented as follows: carvone
derivative 3 was oxidized with the OsO4 cat.–NMO system13 to
give ketodiol 4‡ and, subsequently, monosilyl derivative 5.§ After
that, ketol 5 was converted to methyl ester 6¶ by treatment with
lead tetraacetate in a benzene–methanol mixture.14
Methyl (1R,3R)-2,2-dimethyl-3-{(2R,3E)-3-methyl-4-(2-methylthiazol-
4-yl)-2-[(triethylsilyl)oxy]but-3-en-1-yl}cyclopropanecarboxylate 2. A
2 M solution of HMDS–Na in THF (0.06 ml, 0.12 mmol) was added
dropwise at –78 °C to a solution of ester 8 (0.03 g, 0.065 mmol) in THF
(2 ml) and the reaction mixture was stirred for 1.5 h at the same tempe-
rature. The mixture was warmed to room temperature and decomposed
by adding a saturated NH4Cl solution. THF was evaporated and the
aqueous layer was extracted with EtOAc. The combined organic extracts
were dried with MgSO4 and the solvent was evaporated. The reaction
product was purified by column chromatography on silica gel using
EtOAc–light petroleum (1:9) as the eluent. Yield ~40%, colourless oil;
[a]D20 –165.0 (c 0.867, CHCl3). 1H NMR (CDCl3) d: 0.60 (q, 6H, CH2Si,
J 7.76 Hz), 0.95 (t, 9H, Me, J 7.76 Hz), 1.12 (s, 3H) and 1.19 (s, 3H,
gem-Me), 1.45 (ddd, 1H, 3-CH, J 6.7, 6.5 and 7.0 Hz), 1.62 (ddd, 1H,
1'-CH2, J 5.7, 7.0 and 14.0 Hz), 1.71 (d, 1H, 1-CH, J 7.0 Hz), 1.74
(ddd, 1H, 1'-CH2, J 6.2, 6.5 and 14.0 Hz), 2.0 (s, 3H, Me), 2.71 (s, 3H,
Methiazole), 3.61 (s, 3H, OMe), 4.18 (dd, 1H, OCH, J 6.2 and 5.7 Hz),
6.47 (s, 1H, =CH), 6.92 (s, 1H, =CHthiazole). 13C NMR, d: 4.76 (SiCH2),
6.87 (Me), 13.98 (Me), 19.20 (Methiazole), 20.79 and 21.51 (gem-Me),
27.32 (2-C), 30.53 (1-C), 32.49 (3-C), 35.84 (1'-C), 51.21 (OMe), 78.39
(2'-C), 115.09 (=CHthiazole), 118.79 (4'-C), 141.99 (3'-C), 153.08 (4-Cthiazole),
164.29 (2-Cthiazole), 173.13 (CO2Me). MS (CIAD), m/z: 424 [MH]+, 292
[MH – HOSiEt3]+.
Condensation of 6 with the anion of phosphonate 715 in THF
at –78 °C gave olefin 8,†† which underwent smooth intramolecular
cyclization to target cyclopropane 2 upon deprotonation with
sodium hexamethyldisilazide in THF at –78 °C.
‡
(2R,3R,5R)-5-(1-Chloro-1-methylethyl)-2,3-dihydroxy-2-methylcyclo-
hexan-1-one 4. OsO4 (1 mg) and then (15 min later) N-methylmor-
pholine N-oxide (NMO) (1.5 g, 11.11 mmol) were successively added
with stirring to a solution of chloride 1 (1.0 g, 5.36 mmol) in an acetone–
water mixture (4:1, 10 ml). The reaction mixture was stirred for 8 h;
acetone was evaporated; saturated Na2SO3 solution was added to the
residue, the mixture was stirred for 30 min, and reaction products were
extracted with EtOAc, dried with MgSO4, and concentrated. The solid
residue was recrystallized from a light petroleum–ethyl acetate mixture
(10:1). Yield 82% (0.97 g), white crystals, mp 96–97 °C. [a]D20 +43.4
(c 1.335, CHCl3). IR (n/cm–1): 3427, 2924, 2852, 1722, 1458, 1386,
1369, 1260, 1240, 1141, 1085, 1047, 883, 567. 1H NMR (CDCl3) d: 1.47
(s, 3H, Me), 1.58 and 1.63 (2s, 6H, gem-Me), 2.03 (t, 1H, J 12.8 Hz)
and 2.30 (m, 1H, 4-CH2), 2.43 (m, 1H, 5-CH), 2.67–2.70 (m, 2H, 6-CH2),
2.98 (br. s, 1H, OH), 4.07 (t, 1H, OCH, J 2.7 Hz), 4.21 (s, 1H, OH).
13C NMR, d: 23.08 (Me), 29.34 (4-C), 31.16 and 31.45 (gem-Me), 38.55
(6-C), 44.75 (5-C), 74.22 (C–Cl), 75.03 (3-C), 78.13 (2-C), 212.95 (C=O).
– 248 –
© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 248–249
This study was supported by the Federal Agency for Science
OH
and Innovations and the RF President Grant Council (project
no. NSh-1725.2008.3) and by the Programme 18P for funda-
mental studies of the Russian Academy of Sciences ‘Develop-
ment of Methods for Synthesising Chemical Compounds and
Creating New Materials’.
O
O
OH
OsO4 cat.–NMO
THF–H2O, 90%
Et3SiCl–Py
98%
Cl
Cl
References
3
4
1
2
3
4
5
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OH
O
OSiEt3
MeO
O
Pb(OAc)4
O
MeOH–C6H6
88%
OSiEt3
Cl
Cl
5
6
N
S
S
6
7
MeO
O
PO(OMe)2
N
7
n-BuLi, THF, –78 °C
45%
OSiEt3
8
9
Cl
8
K. C. Nicolaou, H. Vallberg, P. N. King, F. Roschangar, Y. He,
D. Vourloumis and C. G. Nicolaou, Chem. Eur. J., 1997, 3, 1957.
N
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D. Vourloumis and C. G. Nicolaou, Chem. Eur. J., 1997, 3, 1971.
11 F. A. Gimalova, N. K. Selezneva, L. S. Khasanova, Kh. F. Sagitdinova
and M. S. Miftakhov, Zh. Org. Khim., 2008, 44, 1630 (Russ. J. Org.
Chem., 2008, 44, 1606).
S
MeO
H
HMDS–Na, THF
–78 °C, 40%
O
H
OSiEt3
12 J. Wolinsky, J. J. Hamsher and R. O. Hutchins, J. Org. Chem., 1970,
2
35, 207.
Scheme 2
13 V. VanRheenen, R. C. Kelly and D. Y. Cha, Tetrahedron Lett., 1976,
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§
14 E. Baer, J. Am. Chem. Soc., 1942, 64, 1416.
15 N. Nakajima and M. Ubukata, Heterocycles, 2004, 64, 333.
(2R,3R,5R)-5-(1-Chloro-1-methylethyl)-2-hydroxy-2-methyl-3-[(triethyl-
silyl)oxy]cyclohexanone 5. Et3SiCl (0.36 ml, 2.04 mmol) was added
with stirring to a solution of diol 4 (0.3 g, 1.36 mmol) in pyridine
(3 ml). The reaction mixture was stirred until the starting compound was
consumed (~2 h, TLC monitoring). The solution was then concentrated
and the residue was separated on a column with silica gel using EtOAc–
light petroleum (1:5) as the eluent. Yield 98% (0.45 g), colourless oil.
[a]D20 –7.2 (c 1.55, CHCl3). 1H NMR (CDCl3) d: 0.56 (q, 6H, CH2Si,
J 7.96 Hz), 0.89 (t, 9H, Me, J 7.96 Hz), 1.36 (s, 3H, Me), 1.54 and 1.57
(2s, 2×3H, gem-Me), 2.03 (m, 2H, 4-CH2), 2.36 (m, 1H, 5-CH), 2.60
(d, 1H, J 3.5 Hz) and 2.67 (d, 1H, 6-CH2, J 13.9 Hz, 2J 15.0 Hz), 3.51 (s,
1H, OH), 4.02 (t, 1H, OCH, J 2.9 Hz). 13C NMR, d: 4.70 (SiCH2), 6.72
(Me), 22.52 (Me), 31.19 and 31.24 (gem-Me), 32.11 (4-C), 39.10 (6-C),
45.17 (5-C), 73.10 (C–Cl), 77.64 (3-C), 78.44 (2-C), 212.42 (C=O).
Received: 20th March 2009; Com. 09/3301
†† Methyl (3R,5R,6E)-3-(1-chloro-1-methylethyl)-6-methyl-7-(2-methyl-
thiazol-4-yl)-5-[(triethylsilyl)oxy]hept-6-enoate 8. A 3 N solution of n-BuLi
in hexane (0.3 ml, 9.0 mmol) was added at –78 °C with stirring under
argon to a solution of phosphonate 7 (0.09 g, 0.41 mmol) in dry THF
(5 ml). The reaction mixture was stirred for 30 min, then a solution of
ketone 6 (0.1 g, 0.27 mmol) in THF (5 ml) was added dropwise at –78 °C.
The reaction mixture was warmed to room temperature and stirred for
another 2 h. A saturated solution of NH4Cl was added, THF was evaporated
from the aqueous layer, the reaction products were extracted with EtOAc
(3×10 ml), the combined extracts were dried with MgSO4, and the solvent
was evaporated. The product was purified in a column with SiO2 using
EtOAc–light petroleum (1:3) as the eluent. Yield 45% (0.03 g), colourless
oil. [a]D20 –13.3 (c 0.9, CHCl3). IR (n/cm–1): 2953, 2912, 2875, 1732,
1458, 1436, 1414, 1361, 1238, 1165, 1112, 1076, 1004, 974, 844, 741,
¶
Methyl (3R,5R)-3-(1-chloro-1-methylethyl)-6-oxo-5-[(triethylsilyl)oxy]-
heptanoate 6. Lead tetraacetate (3.46 g, 7.77 mmol) was added with
stirring to a solution of compound 5 (0.65 g, 1.94 mmol) in a dry MeOH–
benzene mixture (1:1, 20 ml). The reaction mixture was stirred for 15 min,
then ethylene glycol (3–4 drops) and water (10 ml) were added and the
mixture was stirred for another 10 min. The mixture was extracted with
EtOAc; the combined organic extracts were dried with MgSO4 and the
solvent was evaporated. The product was purified by column chromato-
graphy on silica gel using EtOAc–light petroleum (1:5) as the eluent.
Yield 88% (0.62 g), colourless oil. [a]D20 +9.42 (c 3.81, CHCl3). IR (n/cm–1):
2955, 2912, 2878, 1735, 1717, 1458, 1435, 1415, 1373, 1352, 1294, 1240,
1194, 1159, 1113, 1105, 1011, 978, 889, 826, 743, 729, 594, 571, 516.
1H NMR (CDCl3) d: 0.58 (q, 6H, CH2Si, J 7.76 Hz), 0.93 (t, 9H, Me,
J 7.74 Hz), 1.48 (s, 3H) and 1.53 (s, 3H, gem-Me), 2.15 (s, 3H, 7-Me),
1.58 (dd, 1H, J 6.40 and 2.20 Hz) and 2.00 (ddd, 1H, 4-CH2, J 2.20
and 6.40 Hz, 2J 17.2 Hz), 2.24 (m, 1H, 3-CH), 2.36 (dd, 1H, J 4.76 and
15.93 Hz) and 2.60 (dd, 1H, 2-CH2, J 6.41 and 15.92 Hz), 3.66 (s, 3H,
OMe), 4.05 (dd, 1H, OCH, J 6.6 and 7.5 Hz). 13C NMR, d: 4.63 (SiCH2),
6.71 (Me), 24.65 (7-Me), 30.11 and 30.91 (gem-Me), 36.55 (4-C), 36.78
(2-C), 43.22 (3-C), 51.77 (OMe), 73.93 (C–Cl), 77.89 (5-C), 173.11
(CO2Me), 211.15 (C=O).
1
729, 686. H NMR (CDCl3) d: 0.59 (q, 6H, CH2Si, J 7.76 Hz), 0.94 (t,
9H, Me, J 7.5 Hz), 1.51 (s, 3H) and 1.55 (s, 3H, gem-Me), 1.55–1.72
(overlapped m, 1H, 4-CH), 2.02 (s, 3H, 7-Me), 2.18–2.30 (m, 2H, 4-CH,
3-CH), 2.47 (dd, 1H, 2-CH2, J 4.14 and 16.29 Hz) and 2.63 (dd, 1H,
2-CH2, J 7.98 and 16.29 Hz), 2.71 (s, 3H, Methiazole), 3.66 (s, 3H, OMe),
4.24 (t, 1H, OCH, J 6.7 Hz), 6.47 (s, 1H, =CH), 6.96 (s, 1H, =CHthiazole).
13C NMR, d: 4.74 (SiCH2), 6.84 (Me), 13.36 (Me), 19.17 (Methiazole),
30.35 and 30.69 (gem-Me), 37.05 (4-C), 38.41 (2-C), 44.08 (3-C), 51.67
(OMe), 74.47 (C–Cl), 78.21 (5-C), 115.42 (7-C), 120.24 (=CHthiazole),
141.19 (6-C), 152.89 (4-Cthiazole), 164.32 (2-Cthiazole), 173.42 (CO2Me).
– 249 –