Carvone hydrochloride in the synthesis of thiazole-containing C 11-C21-block of epithilones gem-dimethylcyclopropane analogs

Article abstract of DOI:10.1134/S1070428010020089

Starting with R-(-)-carvone hydrochloride a synthesis was developed of the key chiral block for the epothilones gem-dimethylcyclopropane analog.

Full text of DOI:10.1134/S1070428010020089

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 2, pp. 191−197. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.K. Selezneva, F.A. Gimalova, R.F. Valeev, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 2, pp. 198−204.
Carvone Hydrochloride in the Synthesis
of Thiazole-Containing C11-C21-Block
of Epithilones gem-Dimethylcyclopropane Analogs
N. K. Selezneva, F. A. Gimalova, R. F. Valeev, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences,
Ufa, 450054 Russia
e-mail: bioreg@anrb.ru
Received April 13, 2009
Abstract—Starting with R-(–)-carvone hydrochloride a synthesis was developed of the key chiral block for the
epothilones gem-dimethylcyclopropane analog.
DOI: 10.1134/S1070428010020089
epoxycyclopropane derivative II [7] we planned to use
in the synthesis of a chiral block III, the precursor of
epothilones gem-dimethylcyclo-propane analogs IV [8].
The preparation of structures III we presumed to perform
by the nucleophilic opening of the epoxy ring followed by
the cleavage of α-ketol V effected by Pb(OAc)4 and
fusion of the thiazole fragment by Wittig–Horner
procedure (Scheme 1).
Nowadays epothilones and their analogs attract exclu-
sive interest as the most promising class of compounds
with the taxol-like mechanism of anticancer action [1–
3].Among modified substances more stable and less toxic
carbaanalogs of epothilone are prominent, where the
epoxy ring is replaced by a cyclopropane cycle [4, 5]. In
this respect we are interested in the synthesis of new
gem-dimethylcyclopropane analogs of epothilones. The
previously obtained from carvone hydrochloride (I) [6]
However our numerous attempts at the regioselective
Scheme 1.
OH
O
O
O
Nu_
O
O
Nu
H2O2
HCl
H
Et2O
aqueous NaOH
H
H
H
Cl
I
V
d-carvon
II
S
N
S
OR
HO
N
CO2Me
O
H
H
O
OH
O
III
IV
191

SELEZNEVAet al.
192
opening of the epoxy ring in compound II with versatile
O-, N-nucleophiles (aqueous NaOH; BnONa–BnOH,
80°C; NaN3, DMF, NH4Cl, 80°C; BnNH2, 20°C) did not
result in the preparatively plausible process with regard
to selectivity and yield of reaction products V. Therefore
we decided to proceed from preliminary opened diol forms
of compound II, in particular, from compound VI obtained
by dihydroxylation of carvone derivative I with OsO4
(catalyst)–morpholine N-oxide [9]. In this event also the
attempts on intramolecular cyclization of compound VI
even under controlled mild conditions led prevailingly to
side reactions of retroaldol cleavage etc. giving a mixture
of products. Monoacetate VII in the deprotonation with
LDA under the indicated conditions did not afford the
cyclization product, and t-BuOK reacted both with
compound VII and monosilyl derivative VIII analogously
to diol VI yielding an intractable mixture of substances.
The attempt to involve into the cyclization with the help
of t-BuOK directly compound I instead of the expected
caren-2-one led to the formation in a high yield of
eucarvone (IX) (Scheme 2).
and t-BuOK led to the formation of cyclopropane
derivative XI and enone XII respectively. As seen, in the
experiment with the hydroperoxide anion a good yield of
compound XI was obtained (80%) (Scheme 3).
The next important stage of the synthesis was the
hydrolysis of the acetonide protection in compound XI.
Under the standard hydrolysis conditions of the acetonide
group (aqueous mineral acids, organic solvent, heating)
the three-carbon ring suffered destruction providing
several compounds. A more unambiguous result was
obtained by methanolysis of compound XI assisted by
montmorilonite resin K-10 affording in 75% yield
transformed diol XIII. At the use of acetone as solvent
enone XII was obtained (Scheme 4).
The difficulties found on the way to ketol V both from
compounds VI–VIII (the formation in basic media of
the products of α- and β-ketol decomposition and their
subsequent transformations) and from acetonide XI
(lability of the cyclopropane ring under the conditions of
acid hydrolysis of acetals) forced us to develop alternative
routes to the target structures III. In particular, we
decided first “neutralize” the highly reactive ketol frag-
ment in the substrates by first olifination by Wittig reaction
with a thiazole-containing phosphonate and only
afterwards begin to build up the cyclopropane fragment
of molecule III. To this end the monosilylated ketodiol
VIII was treated with lead tetraacetate in a mixture
benzene–methanol [10] to obtain methyl ester XIV. The
Therefore we decided to work with completely
protected derivative of diol VI. Although compound VI
did not react with carbonylimidazole, the performance of
the acetonide protection was quite easy. Obtained
acetonide X proved to be more stable and less subject to
side reactions. The experiments on intramolecular
cyclization using LDA, the system NaOH–aqueous H2O2
Scheme 2.
OH
O
OH
O
O
OsO4 (catalyst)_N-morphline oxide
THF_H2O, 90%
t-BuOK, 0°C
71%
IX
Cl
Cl
VI
I
t-BuOK,
THF, _78°C
OH
O
OR
Ac2O_Py, ~70%
root temperature
t-BuOK, 0°C
Mixture of reaction products
or Et3SiCl_Py, 98%
or
2.5 equiv LDA, THF,
_78°C
0°C
Cl
VII, VIII
R =Ac (VII), SiEt3 (VIII).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010

CARVONE HYDROCHLORIDE IN THE SYNTHESIS OF THIAZOLE-CONTAINING C11−C21-BLOCK
193
Scheme 3.
O
OH
O
2
O
Im2CO
O
O
O
OH
O1
O
3a
6
Me2CO
4
5
7
MeC(OMe)2, TsOH (catalyst)
90%
THF, 65°C
Cl
VI
Cl
X
Cl
LDA, THF, _78°C
20°C, 20%
or H2O2_aqueous NaOH, 80%
t-BuOK, THF, 0°C, 35%
O
O
O
O
H
O
O
H
XI
XII
Scheme 4.
OH
O
O
OH
O
O
O
O
O
Me2CO, К-10, 20°C
MeOH, К-10, 20°C
H
H
MeO
XIII
XII
XI
condensation of the latter with the anion of phosphonate
XV in THF at –78°C we obtained olefin XVI that
underwent clear intramolecular cyclization into
cyclopropane derivative XVII at dehydrohalogenation by
treating with sodium hexamethyldisilazide in THF at –
78°C (Scheme 5).
Thus based on d-carvone we prepared the key C11–
C21-block for the synthesis of the gem-dimethylcyclo-
propane analog of epothilones.
respectively, internal reference TMS. The specific
rotation was measured on a polarimeter Perkin Elmer-
341. Mass spectra were taken on an instrument Shimadzu
LCMS-2010 under chemical ionization conditions under
atmospheric pressure and electrons energy 20 eV with
the registration of both positive and negative ions. The
mobile liquid phase a mixture MeOH–water, 50:50, flow
rate 0.03 or 0.05 ml/min.
(2R,3R,5R)-2,3-Dihydroxy-2-methyl-5-(1-chloro-
1-methylethyl)cyclohexan-1-one (VI). To a stirred
solution of 1.0 g (5.36 mmol) of chloride I in 10 ml of
a mixture acetone–water, 4:1, was added in succession
1 mg of OsO4 and 15 min later 1.5 g (11.11 mmol)of
morpholine N-oxide. The reaction mixture was stirred
for 8 h, acetone was distilled off, to the residue was added
a saturated solution of Na2SO3, the mixture was stirred
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer IR
Prestige-21 Shimadzu from thin films. 1H and 13C NMR
spectra were registered on a spectrometer Bruker AM-
300 at operating frequencies 300.13 and 75.47 MHz
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010

SELEZNEVAet al.
194
Scheme 5.
OH
MeO
O
O
O
OSiEt3
Pb(OAc)4
MeOH_C6H6
88%
OSiEt3
Cl
Cl
VIII
XIV
N
S
N
S
S
PO(OMe)2
MeO
O
MeO
H
O
HMDS_Na, THF
_78oC, ~40%
N
XV
BuLi, THF, _78îC, 45%
H
OSiEt3
XVI
OSiEt3
XVII
Cl
for 30 min, then the products were extracted into
EtOAc, the extract was dried with MgSO4 and
evaporated. The solid residue was recrystallized from
a mixture petroleum ether–ethyl acetate to obtain 0.97 g
(82%) of compound VI. Colorless crystals, mp 96–97°C,
[α]D20 +43.4° (C 1.335, CHCl3). IR spectrum, ν, cm–1:
3427, 2924, 2852, 1722, 1458, 1386, 1369, 1260, 1240,
CH3CO), 2.21 m (3H each, CH, CH2), 2.74 m (2H,
C6H2), 3.76 s (1H, OH), 5.34 br.s (1H, OCH). 13C NMR
spectrum (CDCl3), δ, ppm: 20.94 (CH3), 23.44 (CH3CO),
29.33 (C4), 31.10 and 31.22 (gem-CH3), 38.99 (C6), 45.55
(C5), 74.50 (C2), 76.56 (C1'), 77.18 (C1), 169.74 (CH3CO),
210.95 (C=O).
(2R,3R,5R)-2-Hydroxy-2-methyl-3-triethyl-
silyloxy-5-(1-chloro-1-methylethyl)cyclohexan-1-
one (VIII). To a stirred solution of 0.3 g (1.36 mmol) of
diol VI in 3 ml of pyridine was added 0.36 ml (2.04 mmol)
of Et3SiCl, and the stirring was carried out till complete
consumption of the initial compound (~2 h, TLC
monitoring). Then , the solvent was evaporated, the
resudue was subjected to column chromatography on
silica gel (eluent EtOAc–petroleum ether, 1:5). Yield 0.45
g (98%). Colorless oily fluid, [α]D20 –7.2° (C 1.55, CHCl3).
1H NMR spectrum (CDCl3), δ, ppm: 0.56 q (6H, CH2Si,
J 7.96 Hz), 0.89 t (9H, CH3, J 7.96 Hz), 1.36 s (3H each,
CH3), 1.54 s and 1.57 s (3H each each, gem-CH3), 2.03
m (2H, C4H2), 2.36 m (1H, CH), 2.60 d (1H, J 3.5 Hz)
and 2.67 d.d (1H, C6H2, J 13.9, 2J 15.0 Hz), 3.51 s (1H,
OH), 4.02 t (1H, OCH, J 2.9 Hz). 13C NMR spectrum
(CDCl3), δ, ppm: 4.70 (SiCH2), 6.72 (CH3), 22.52 (CH3),
31.19 and 31.24 (gem-CH3), 32.11 (C4), 39.10 (C6), 45.17
(C5), 73.10 (C1'), 77.64 (C3), 78.44 (C2), 212.42 (C=O).
1
1141, 1085, 1047, 883, 567. H NMR spectrum (CDCl3),
δ, ppm: 1.47 s (3H each, CH3), 1.58 s and 1.63 s (3H
each each, gem-CH3), 2.03 t (1H, J 12.8 Hz) and 2.30 m
(1H, C4H2), 2.43 m (1H, CH), 2.67–2.70 m (2H, C6H2),
2.98 br.s (1H, OH), 4.07 t (1H, OCH, J 2.7 Hz), 4.21 s
(1H, OH). 13C NMR spectrum (CDCl3), δ, ppm: 23.08
(CH3), 29.34 (C4), 31.16 and 31.45 (gem-CH3), 38.55
(C6), 44.75 (C5), 74.22 (C1'), 75.03 (C3), 78.13 (C2),
212.95 (C=O).
(2R,3R,5R)-2-Hydroxy-2-methyl-3-oxo-5-(1-
chloro-1-methylethyl)cyclohexyl acetate (VII). To
a stirred solution of 0.1 g (0.45 mmol) of diol VI in 2 ml
of pyridine was added 0.45 ml (4.40 mmol) of acetic
anhydride, and the stirring was carried out till complete
consumption of the initial compound (TLC monitoring).
Then 5 ml of ice water was added, the product was
extracted into CHCl3, the extract was dried with MgSO4,
the solvent was evaporated, the reaction product was
subjected to column chromatography on SiO2 (eluent
EtOAc–petroleum ether, 1:2). Yield 0.08 g (67%).
Colorless oily fluid, [α]D20 +0.2° (C 0.97, CHCl3). 1H NMR
spectrum (CDCl3), δ, ppm: 1.47 s (3H each, CH3), 1.59
s and 1.60 s (3H each each, gem-CH3), 2.03 s (3H each,
2,6,6-Trimethylcyclohepta-2,4-dien-1-one (IX).
To a solution of 0.3 g (1.6 mmol) of chloride I in 10 ml of
anhydrous THF at 0°C was added 0.27 g (2.40 mmol) of
t-BuOK. The reaction mixture was stirred for ~4 h (TLC
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CARVONE HYDROCHLORIDE IN THE SYNTHESIS OF THIAZOLE-CONTAINING C11−C21-BLOCK
195
monitoring), then it was decomposed by adding a
saturated solution of NH4Cl, the reaction product was
extracted into chloroform, the extract was dried with
MgSO4, and evaporated, the residue was subjected to
column chromatography on SiO2 (eluent EtOAc–
petroleum ether, 1 : 3) to obtain 0.17 g (71%) of eucarvone
(IX). Colorless oily fluid. IR spectrum, ν, cm–1: 3019,
2959, 2926, 2868, 1647, 1458, 1420, 1364, 1260, 1238,
1179, 1119, 866, 810, 731. 1H NMR spectrum (CDCl3),
δ, ppm: 1.06 C (6H, gem-CH3), 1.92 s (3H each, CH3),
2.65 s (2H, C7H2), 5.77 d.d (1H, =C4H, J 8.1, 11.5 Hz),
5.97 d (1H, =C3H each, J 11.7 Hz), 6.48 d.d 1H, =C5H,
J 1.2, 8.1 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 19.92
(CH3), 26.93 (gem-CH3), 33.14 (C6), 54.13 (C7), 122.13
(C4), 133.92 (C3), 138.39 (C2), 148.85 (C5), 200.06
(C=O). Mass spectrum, m/z: 151 [M + H]+, 123 [M +
H–C2H4]+, 107, 192 [M + H + CH3CN]+, 149 [M – H]–,
165, 181 [M – H + CH3OH]–.
(XI). a. To a stirred solution of 0.07 ml (0.99 mmol) of
diisopropylamine in 5 ml of anhydrous THF at–78°C
under an argon atmosphere was added dropwise 0.65 ml
of 2.0 N BuLi solution. The reaction mixture was stirred
for 15 min at –78°C, then it was warmed to –10°C and
stirred over 15 min, then it was cooled to–78°C, and 0.1 g
(0.38 mmol) of acetonide X in 2 ml of anhydrous THF
was added dropwise, the mixture was stirred for 30 min
at –78°C, then it was warmed to 0°C and stirred for 2 h.
Then 2–3 ml of saturated NH4Cl solution was added, the
mixture was stirred for 10 min, THF was evaporated,
and the residue was treated with CHCl3 (3 × 5 ml). The
combined organic solutions were washed with brine, dried
with MgSO4, and evaporated. The residue was subjected
to column chromatography on SiO2 (eluent EtOAc–
petroleum ether, 1 : 4). Yield 0.02 g (23%).
b. To a stirred solution of 0.06 g (0.23 mmol) of
acetonide X in 2 ml of anhydrous MeOH at 0°C was
added dropwise 0.18 ml of 47% H2O2 solution, then was
slowly added 0.22 ml of 4 N NaOH solution. The reaction
mixture was warmed to room temperature and stirred
for 8 h. Then 3 ml of H2O was added, the reaction product
was extracted into CH2Cl2, the extract was dried with
MgSO4, and evaporated. The residue was subjected to
column chromatography on SiO2 (eluent EtOAc–
petroleum ether, 1 : 3). Yield 0.04 g (80%). Colorless oily
(3aR,6R,7aR)-2,2,3a-Trimethyl-6-(1-chloro-1-
methylethyl)tetrahydro-1,3-benzodioxol-4(3aH)-
one (X). To a solution of 0.4 g (1.8 mmol) of diol VI and
0.4 ml (3.37 mmol) of dimethoxypropane in 5 ml of
anhydrous acetone was added 30 mg of TsOH. The
reaction mixture was stirred till complete consumption
of the initial compound (~15 h, TLC monitoring), then
0.1 g of anhydrous NaHCO3 was added, the stirring was
continued for 15 min, the solution was filtered, and acetone
was distilled off. The residue was diluted with CH2Cl2,
the solution obtained was washed with brine, dried with
MgSO4, and evaporated. The solid residue was recrystal-
lized from a mixture EtOAc–petroleum ether, 1:10, to
obtain 0.38 g (80%) of acetonide X. Colorless crystals,
mp 98–100°C, [α]D20 +4.4° (C 1.43, CHCl3). IR spectrum,
ν, cm–1: 2995, 2960, 2932, 2914, 2852, 1724, 1462, 1394,
1368, 1294, 1267, 1240, 1227, 1205, 1171, 1142, 1111, 1056,
1031, 995, 931, 885, 835, 721, 711, 596, 569, 514. 1H NMR
spectrum (CDCl3), δ, ppm: 1.37 s, 1.38 s (3H eacheach,
CMe2), 1.40 s (3H each, CH3), 1.59 C, 1.63 s (3H
eacheach, gem-CH3), 1.96 d.t.d (1H, J 2.87, 2.65, 2.87,
11.9 Hz), 2.27 m (1H, C7H2), 2.45 m (1H, J 12.8,
13.7 Hz), 2.69 d.t (1H, C5H2, J 2.88, 13.9 Hz), 2.48 m
(1H, C6H), 4.19 t (1H, OCH, J 2.65 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 19.42 (CH3), 26.69, 26.97
(CMe2), 27.57 (C7), 30.98, 31.08 (gem-CH3), 41.48 (C5),
43.87 (C6), 72.26 (C1'), 80.82 (C7a), 82.04 (C3a), 108.48
(C2), 211.05 (C=O). Found, %: C 59.38; H 7.86; Cl 13.70.
C13H21ClO3. Calculated, %: C 59.88; H 8.12; Cl 13.60.
fluid, [α]D20 –323.2° (C 1.02, CHCl3). H NMR spectrum
1
(CDCl3), δ, ppm: 0.95 s, 1.27 s ( 3H each, gem-CH3),
1.16 s (3H each, CH3), 1.35 s, 1.38 s (3H each, CMe2),
1.43 m (1H, CH), 1.51 m (1H, CH), 1.57 m (1H), 2.48
d.d.d.d (1H, CH2, J 3.2, 3.5, 3.2, 3.2 Hz), 4.09 t (1H,
OCH, J 2.2 Hz). 13C NMR spectrum (CDCl3), δ, ppm:
17.18 (CH3), 18.63, 26.31 (gem-CH3), 19.15 (C5), 22.99
(C5a), 24.96 (C6), 27.78, 28.13 (CMe2), 31.83 (C4a), 80.03
(C3a), 81.06 (C6a), 109.42 (C2), 208.48 (C=O).
(3aR,7aR)-6-Isopropyl-2,2,3a-trimethyl-7,7a-
dihydro-1,3-benzodioxol-4-(3aH)-one (XII). To
a stirred solution of 0.1 g (0.38 mmol) of acetonide X in
2 ml of anhydrous THF was added 0.085 g (0.76 mmol)
of t-BuOK, and the mixture was stirred at room
temperature till complete consumption of the initial
compound (TLC monitoring). Then 2–3 ml of saturated
NH4Cl solution was added, the mixture was stirred for
10 min, THF was evaporated, and the residue was treated
with CHCl3 (3 × 5 ml). The combined organic solutions
were washed with brine, dried with MgSO4, and
evaporated. The residue was subjected to column
chromatography on SiO2 (eluent EtOAc–petroleum ether,
(3aR,6aR)-2,2,3a,5,5-Pentamethylhexahydro-
4H-cyclopropane[4,5]benzo[1,2-d]-1,3-dioxol-4-one
1 : 3). Yield 0.03 g (35%). Colorless oily fluid, [α]D20
–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010

SELEZNEVAet al.
196
(88%). Colorless oily fluid, [α]D20 +9.42° (C 3.81, CHCl3).
IR spectrum, ν, cm–1:
16.2° (C 0.905, CHCl3). IR spectrum, ν, cm–1: 2968, 2931,
2873, 1676, 1634, 1456, 1411, 1371, 1336, 1280, 1242,
1
1213, 1172, 1109, 1074, 991, 883, 844, 804, 514. H NMR
2955, 2912, 2878, 1735, 1717, 1458, 1435, 1415, 1373,
1352, 1294, 1240, 1194, 1159, 1113, 1105, 1011, 978, 889,
spectrum (CDCl3), δ, ppm: 1.14 d (6H, gem-CH3,
J 6.8 Hz), 1.28 s (3H each, CH3), 1.35 s, 1.38 s (3H
each, CMε2), 2.44 q (1H, CH, J 6.6, 6.8 Hz), 2.67 d.d.d.d
(1H, J 2.2, 2.4, 4.0, 2.3, 2.1, 4.0, 19.4 Hz), 2.79 d.d (1H,
C7H2, J 1.6, 19.4 Hz), 4.25 d.d (1H, OCH, J 1.8, 2.2,
4.0 Hz), 5.93 C (1H, =CH). 13C NMR spectrum (CDCl3),
δ, ppm: 13.85 (CH3), 15.13, 15.46 (gem-CH3), 21.52,
22.01 (CMε2), 23.76 (C7), 30.19 (CH), 73.28 (C7a), 74.67
(C3a), 103.00 (C2), 116.12 (C5), 161.02 (C6), 194.76
(C=O). Mass spectrum, m/z: 255 [M – H + MeOH]+,
225 [M + H]+, 167 [M + H – Me2CO]+, 165 [M – H –
Me2CO]–, 125 [M + H – Me2CO – CH2=CHCH3]+.
1
826, 743, 729, 594, 571, 516. H NMR spectrum (CDCl3),
δ, ppm: 0.58 q (6H, CH2Si, J 7.76 Hz), 0.93 t (9H, CH3,
J 7.74 Hz), 1.48 s and 1.53 s (3H each, gem-CH3), 2.15 s
(3H each, C7H3), 1.58 d.d (1H, J 6.41, 2.21 Hz),
2.00 d.d.d (1H, C4H2, J 2.21, 6.41, 2J 17.2 Hz), 2.24 m
(1H, CH), 2.36 d.d (1H, J 4.76, 15.93 Hz) and 2.60 d.d
(1H, C2H2, J 6.41, 15.92 Hz), 3.66 s (3H each, OCH3),
4.05 d.d (1H, OCH, J 6.6, 7.5 Hz). 13C NMR spectrum
(CDCl3), δ, ppm: 4.63 (SiCH2), 6.71 (CH3), 24.65 (C7H3),
30.11, 30.91 (gem-CH3), 36.55 (C4), 36.78 (C2), 43.22
(C3), 51.77 (OCH3), 73.93 (C1'), 77.89 (C5), 173.11
(CO2Mε), 211.15 (C=O).
(2R,3R)-2,3-Dihydroxy-2-methyl-5-(1-methoxy-
1-methylethyl)cyclohexan-1-one (XIII). To a solution
of 0.05 g (0.22 mmol) of compound XI in 2 ml of MeOH
was added 0.03 g of cation-exchanger K-10, and the
mixture was stirred for 24 h at room temperature. Then
the reaction mixture was filtered through a silica gel bed,
evaporated, the residue was subjected to column
chromatography on silica gel (eluent EtOAc–petroleum
ether, 1:3). Yield 0.03 g (75%). Colorless oily fluid, [α]D20
+38.6° (C 0.46, CHCl3). IR spectrum, ν, cm–1: 3458, 2972,
2933, 2829, 1715, 1458, 1427, 1383, 1366, 1304, 1249,
Methyl (3R,5R,6E)-6-methyl-7-(2-methyl-1,3-
thiazol-4-yl)-5-(triethylsiliyloxy)-3-(1-chloro-1-
methylethyl)hept-6-enoate (XVI). To a solution of
0.09 g (0.41 mmol) of phosphonate XV in 5 ml of
anhydrous THF at –78°C under an argon atmosphere
was added under stirring 0.3 ml (9.0 mmol) of 3 N solution
of BuLi in hexane. The reaction mixture was stirred for
30 min, then at –78°C was added dropwise a solution of
0.1 g (0.27 mmol) of ketone XIV in 5 ml of THF. The
reaction mixture was warmed to room temperature and
stirred over 2 h. Then a saturated NH4Cl solution was
added, THF was distilled off from the water layer, the
reaction products were extracted into EtOAc (3×10 ml),
the combined extracts were dried with MgSO4 and
evaporated. The residue was subjected to column
chromatography on silica gel (eluent EtOAc–petroleum
ether, 1 : 3). Yield 0.034 g (45%). Colorless oily fluid.
[α]D20 –13.3° (C 0.9, CHCl3). IR spectrum, ν, cm–1: 2953,
2912, 2875, 1732, 1458, 1436, 1414, 1361, 1238, 1165,
1
1168, 1149, 1128, 1047, 957, 854, 692, 590. H NMR
spectrum (CDCl3), δ, ppm: 1.19 s, 1.20 s (3H each, gem-
CH3), 1.38s (3H each, CH3), 1.64 m (1H, CH), 1.92 d.d
(1H, J 13.5, 12.8 Hz), 2.13 d (1H, CH2, J 12.8 Hz), 2.40–
2.60 m (2H, C6H2), 2.91 s (1H, OH), 3.22 s (3H each,
OCH3), 4.09 s (1H, OCH), 4.26 br.s (1H, OH). 13C NMR
spectrum (CDCl3), δ, ppm: 22.56 (CH3), 22.65, 23.33
(gem-CH3), 28.56 (C4), 37.72 (C6), 41.97 (C5H), 49.12
(OCH3), 74.96 (C1'), 75.95 (C3), 78.22 (C2), 214.17
(C=O).
1
1112, 1076, 1004, 974, 844, 741, 729, 686. H NMR
spectrum (CDCl3), δ, ppm: 0.59 q (6H, CH2Si, J 7.76
Hz), 0.94 t (9H, CH3, J 7.5 Hz), 1.51 s, 1.55 s (3H each,
gem-CH3), 1.55–1.72 m (1H, C4H2), 2.02 s (3H each,
CH3), 2.18–2.30 m (2H, C4H2, C3H), 2.47 d.d (1H, J
4.14 and 16.29 Hz), 2.63 d.d (1H, C2H2, J 7.98 and 16.29
Hz), 2.71 s (3H each, CH3thiazole), 3.66 C (3H each,
OCH3), 4.24 t (1H, OCH, J 6.7 Hz), 6.47 C (1H, =CH),
6.96 C (1H, =CHthiazole). 13C NMR spectrum (CDCl3),
δ, ppm: 4.74 (SiCH2), 6.84 (CH3), 13.36 (CH3), 19.17
(CH3thiazole), 30.35, 30.69 (gem-CH3), 37.05 (C4), 38.41
(C2), 44.08 (C3), 51.67 (OCH3), 74.47 (C1’), 78.21 (C5),
115.42 (C7), 120.24 (=CHthiazole), 141.19 (C6), 152.89
(C4thiazole), 164.32 (C2thiazole), 173.42 (CO2Me).
Methyl (3R,5R)-6-oxo-5-(triethylsilyloxy)-3-(1-
chloro-1-methylethyl)heptanoate (XIV). To a stirred
solution of 0.65 g (1.94 mmol) of compound VIII in 20 ml
of anhydrous mixture MeOH–benzene, 1 : 1, was added
3.46 g (7.77 mmol) of lead tetraacetate. The reaction
mixture was stirred for 15 min, then 3–4 drops of ethylene
glycol and 10 ml of water was added, and the mixture
was stirred for 10 min. The reaction product was extracted
into EtOAc, the combined organic extracts were dried
with MgSO4, the solvent was evaporated. The residue
was subjected to column chromatography on silica gel
(eluent EtOAc–petroleum ether, 1 : 5). Yield 0.62 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010

CARVONE HYDROCHLORIDE IN THE SYNTHESIS OF THIAZOLE-CONTAINING C11−C21-BLOCK
197
(C4thiazole), 164.29 (C2thiazole), 173.13 (CO2Me). Mass
Methyl (1R,3R)-2,2-dimethyl-3-[(2R,3E)-3-
methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-(triethyl-
silyloxy)but-3-en-1-yl]cyclopropane-carboxylate
(XVII). To a solution of 0.03 g (0.065 mmol) of ester
XVI in 2 ml of THF at –78°C was added dropwise
0.06 ml (0.12 mmol)of 2 M solution of sodium
hexamethyldisilazide in THF. The reaction mixture was
stirred at this temperature over 1.5 h, then it was warmed
to the room temperature, decomposed by adding a saturat-
ed NH4Cl solution, THF was distilled off, the reaction
products were extracted into EtOAc. The combined
extracts were dried with MgSO4 and evaporated. The
residue was subjected to column chromatography on silica
gel (eluent EtOAc–petroleum ether, 1 : 9). Yield 0.01 g
(36%). Colorless oily fluid, [α]D20 –165.0° (C 0.867,
CHCl3). 1H NMR spectrum (CDCl3), δ, ppm: 0.60 q
(6H, CH2Si, J 7.76 Hz), 0.95 t (9H, CH3, J 7.76 Hz),
spectrum, m/z: 424 [M + H]+, 292 [M + H – HOSiEt3]+.
The study was carried out under a financial support
of the Federal Agency on Science and Innovations and
of the Council of grants of the President of the Russian
Federation (project NSh-1725.2008.3).
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1.12 s, 1.19 s (3H each, gem-CH3), 1.45 d.d.d (1H, C3H each
,
J 6.7, 6.5, 7.0 Hz), 1.62 d.d.d (1H, C1'H2, J 5.7, 7.5,
2J 14.0 Hz), 1.71 m 1H, C1H, J 7.0 Hz), 1.74 d.d.d (1H,
C1'H2, J 6.2, 6.5, 14.0 Hz), 2.0 s (3H each, CH3), 2.71 s
(3H each, CH3thiazole), 3.61 s (3H each, OCH3), 4.18 d.d
(1H, OCH, J 6.2 and 5.7 Hz), 6.47 s (1H, =CH), 6.92 s
(1H, =CHthiazole). 13C NMR spectrum (CDCl3), δ, ppm:
4.76 (SiCH2), 6.87 (CH3), 13.98 (CH3), 19.20
(CH3thiazole), 20.79, 21.51 (gem-CH3), 27.32 (C2), 30.53
(C1), 32.48 (C3), 35.84 (C1'), 51.21 (OCH3), 78.39 (C2'),
115.09 (=CHthiazole), 118.79 (C4'), 141.99 (C3'), 153.08
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010