Synthesis of epothilones molecule fragment (15R)-C13-C 21 from D-mannitol

Article abstract of DOI:10.1134/S1070428010110175

Efficient synthesis of an epothilone molecules fragment (15R)-C ¹³-C²¹ was carried out from D-mannitol through its conversion into methyl 2,3-O-cyclohexylidene-D-glycerate followed by the cyclopropanation of the ester group with ethy

Full text of DOI:10.1134/S1070428010110175

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 11, pp. 1702−1708. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.N. Kovalenko, N.A. Sokolov, O. G. Kulinkovich, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 11, pp. 1694−1700.
Synthesis of Epothilones Molecule Fragment (15R)-C13–C21
from D-Mannitol
V. N. Kovalenko, N. A. Sokolov, and O. G. Kulinkovich
Belorussian State University, Minsk, 220030 Belarus
e-mail: o.k ulinkovich@gmail.com
Received May 25, 2010
Abstract—Efficient synthesis of an epothilone molecules fragment (15R)-C13–C21 was carried out from D-mannitol
through its conversion into methyl 2,3-O-cyclohexylidene-D-glycerate followed by the cyclopropanation of the
ester group with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide and the transformation of
the obtained cyclopropanol into the corresponding 2-substituted allyl bromide. The coupling of the latter catalyzed
by copper with 2-methylthiazolyl-4-magnesium bromide, the shift of a double carbon-carbon bond in the product
obtained into the position, conjugated with the thiazole ring, and the common transformation of the protected
1,2-diol function afforded the target compound in 15% yield.
DOI: 10.1134/S1070428010110175
First compounds from the series of epothilones were
isolated from extracts of mixobacterium Sorangium cel-
lulosum [1], and they attracted a considerable attention
as a promising initial material for developing antitumor
agents [2]. Some of these compounds, among them ep-
othilone B (I) at present is under clinical tests, and its
15-azaanalog II is the active substance of the antitumor
drug with the commercial name Ixempra [3, 4]. The most
efficient strategies of the synthesis of epothilones and
their analogs are based on the macrocycle formation by
lactonization or olefin metathesis and on the use as the
key intermediates thiazole-containing C13–C21 epothilone
fragments (S)-(III) and (S)-(IV) [5, 6].
In the course of the development of cyclopropanol
procedures for the syntheses of naturally existing biologi-
cally active compounds [7–9] we found efficient ways to
the synthesis of compound (S)-(III) from L-malic acid
[10], and compounds (S)-(IV) and (R)-(IV), from methyl
2,3-O-isopropylidene-D-glycerate prepared in its turn
from D-mannitol [11]. Here we report on the conver-
sion of the latter into the C13–C21 epothilone fragment
(R)-(III), a promising intermediate for the epothilone
Scheme 1.
O
O
12
S
S
13
21
8
15
15
7
HO
HO
N
N
6
3
NH
O
O
O
O
O
OH
OH
15-aza epothilone B Ixempra (II)
Epothilone B (I)
TBS
OH
O
O
TBS
OH
13
N
N
S
N
N
S
15
21
S
S
(S)-III
(S)-IV
(R)-III
(R)-IV
TBS = SiMe2Bu-t.
1702

SYNTHESIS OF EPOTHILONES MOLECULE FRAGMENT (15R)-C13–C21
1703
synthesis through the stage of the hydroxy group substitu-
tion with the reversal of the streochemical configuration
of the atom C15 [12] (Scheme 1).
the cationic cyclopropyl-allyl rearrangement induced
by magnesium bromide [16]. The coupling catalyzed
with copper of allyl bromide IX with 2-methylthiazolyl-
4-magnesium bromide (XI) prepared from 4-bromo-
2-methylthiazole (X) [10] proceeded cleanly to yield
compound XII (Scheme 2). The published procedure of
preparation of compound X by methylation with dimethyl
sulfate of 4-bromothiazolyl-2-lithium obtained by the
reaction of halogen-lithium exchange [17] from the avail-
able 2,4-dibromothiazole was essentially improved by the
workup of the reaction mixture with aqueous ammonia
and the purification of the monomethylated product X by
the distillation in a vacuum. The use of the described in
the original procedure treatment of the reaction mixture
with water did not completely eliminate the excess of
the methylating agent, and the purification of 4-bromo-
2-methylthiazole (X) by column chromatography on
silica gel did not separate the target product from the
simultaneously formed 2,5-dimethylthiazol due to the
similar chromatographic mobility of these substances.
D-Mannitol was by the known procedure converted
into biscyclohexylidene derivative VI [13], whose vicinal
diol fragment was subjected to destructive oxidation by
the method used with the corresponding isopropylidene
analog [14] to obtain the known methyl 2,3-O-cyclo-
hexylidene-D-glycerate (VII) (Scheme 2) that had been
previously prepared from compound VI through its oxida-
tion into the corresponding aldehyde [15]. The reaction of
ester VII with ethylmagnesium bromide in the presence
of an equimolar amount of titanium(IV) isopropoxide
resulted in a good yield of cyclopropanol VIII, whereas
the yield of the cyclopropanation product from the iso-
propylidene derivative of the D-methyl glycerate under
similar conditions did not exceed 60% [11]. The attempts
to carry out the cyclopropanation of compound VII in the
presence of catalytic quantities of titanium(IV) isopropox-
ide led to significantly lower yields of compound VIII.
The boiling of the solution of disubstituted olefin XII
in tert-butanol in the presence of potassium tert-butylate
led to the shift of the disubstituted double bond into the
position conjugated with the thiazole ring and to the
formation with a high stereoselectivity of trisubstituted
(E)-olefin XIII [10]. In the latter the acid hydrolysis of
the acetal moiety followed by selective tosylation of the
Analogously to the previously described protocol of
the synthesis of the fragments C13–C21 of the epothilone
molecules (S)-(III), (S)-(IV), and (R)-(IV) [10, 11] the
substituted cyclopropanol VIII was further converted
into the corresponding methanesufonate which was
transformed into 2-substituted allyl bromide IX through
Scheme 2.
(1) KIO4, MeOH_H2O
(2) Br2, MeOH_H2O
Cyclohexanone,
BF3, HC(OEt)3
OH
O
O
O
D-mannitol
O
O
66% [13]
O
CO2Me
OH
VI
V
VII
(1) MsCl, Et3N
(2) MgBr2
O
O
O
O
Br
OH
Br
O
EtMgBr, Ti(OPr-i)4
IX
VIII
O
N
S
(1) BuLi, _78°C
(2) CuI, MgBr2
S
S
MgBr
XII
N
N
XI
X
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

KOVALENKO et al.
1704
primary hydroxy group in the arising 1,2-diol gave mono-
sulfonate XIV that by the treatment with sodium cyanide
in dimethyl sulfoxide was converted into β-hydroxynitrile
XV. In the course of the latter process in the reaction
mixture alongside substrate XIV and compound XV was
also detected oxirane derivative XVI, probably the direct
precursor of nitrile XV.
EXPERIMENTAL
1H and 13C NMR spectra were registered on a spec-
trometer BrukerAC 400 at operating frequencies 400 and
100 MHz respectively from solutions in deuterochloro-
form. IR spectra were recorded on a spectrophotometer
Bruker Vertex 70 from solutions of samples in tetrachloro-
methane. The melting points were measured in capillaries
on anApotec instrument. The chromatographic isolation
of individual compounds was performed on silica gel
(70–230 mesh). All solvents before use were dried by
conventiol methods and distilled.
The optical purity of secondary alcohol XV was
1
estimated from the H NMR spectrum of the product
of its acylation with Mosher’s (S)-acid [18]. In the
1H NMR spectrum of Mosher ester XVII the signal
of the methine proton was observed at δ 5.68 ppm, the
proton signals from methoxy and methyl groups, at
δ 3.65 and 1.98 ppm. No signals were detected from the
minor diastereomer at δ 5.76, 3.53, and 2.17ppm indicat-
ing that compound XV was obtained with ee >99%. The
expected chemical shifts of the proton signals belonging
to the minor diastereomer were determined from the
1H NMR spectrum of the ester prepared from the second-
ary alcohol XV and racemic Mosher’s acid. The silylation
of compound XV followed by the reduction of the formed
product with diisobutylalumunum hydride resulted in the
target aldehyde (R)-(III) in the yield 15% with respect to
D-mannitol (V) (Scheme 3).
The protocol of the synthesis of the fragment C13–C21
of epothilones molecule (R)-(III) is distinguished from
the previously developed procedures for preparation of
the fragment C13–C21 of epothilones molecules (S)-(III),
(S)-(IV) and (R)-(IV) from the derivatives of chiral
α-hydroxycarboxylic acids [10, 11] by the lesser number
of stages and larger overall yield of the target compound.
Methyl 2,3-O-cyclohexylidene-D-glycerate (VII).
To a solution of 40.0 g (0.116 mol) of cyclohexylidene
derivatives of D-mannitol VI [13] in 300 ml of methanol
was added at vigorous stirring 750 ml of water, 2.0 g
(0.02 mol) of KHCO3, and 32.0 g (0.14 mol) of KIO4. The
mixture was stirred for 3 h at room temperature, there-
after 50.0 g (0.59 mol) of NaHCO3 was added and then
dropwise 14.8 ml (0.29 mol) of bromine was added. Then
the reaction mixture was treated with saturated water solu-
tion of Na2SO3, filtered, the precipitate was washed with
dichloromethane (2×100 ml), water layer was extracted
with the same solvent (3×100 ml). The combined organic
solutions were dried with Na2SO4, the solvent was dis-
tilled off at a reduced pressure, the residue was distilled in
a vacuum [bp 82–83°C (1 mm Hg)]. Yield 35.3 g (76%),
[α]D 19.5° (c 6.8, CHCl3) {[α]D 18.99° (c1.0, MeOH)
[15]}. The spectral characteristics of compound obtained
were consistent with the published data [15].
1-{(2R)-1,4-Dioxaspiro[4.5]dec-2-yl}cyclopropanol
Scheme 3.
OH
(1) HCl, H2O, THF
(2) p-TsCl, Py
O
TsO
N
S
t-BuOK, t-BuOH
O
N
S
XII
XIII
XIV
(1) t-BuMe2SiCl, Im
(2) (i-Bu)2AlH
(R)-III
OH
O
NaCN, DMSO
NC
N
S
N
S
O
F3C
MeO
O
F3C
, Py
Cl
MeO Ph
O
Ph
NC
XVI
XV
N
S
XVII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SYNTHESIS OF EPOTHILONES MOLECULE FRAGMENT (15R)-C13–C21
1705
1
(VIII). To a solution of 35.3 g (0.176 mol) of ester VII
and 50.0 g (0.176 mol) of titanium(IV) isoropoxide in
250 ml of THF under an argon atmosphere was added
within 3 h while stirring a solution of ethylmagnesium
bromide prepared from 20.5 g (0.84 mol) of magnesium
and 87.0 g (0.80mol) of ethyl bromide in 500 ml of THF.
The solvent was distilled off at a reduced pressure, the
reaction mixture was diluted with 300 ml of dichloro-
methane, and it was treated at cooling with 100 ml of
saturated water solution of NH4Cl. The precipitate was
filtered off, washed with dichloromethane (3 × 150 ml),
the filtrate was dried with Na2SO4, the solvent was dis-
tilled off at a reduced pressure, the residue was distilled
in a vacuum [bp 86–88°C (1 mm Hg)]. Yield 25.0 g
(72%), [α]D 4.0° (c5.5, CHCl3). IR spectrum, ν, cm–1:
1645 (C=C). H NMR spectrum, δ, ppm: 1.38–1.68 m
[10H, (CH2)5], 3.74–3.78 m (1H, OCH2), 3.90–4.06 m
(2H, CH2Br), 4.21 d.d (1H, OCH2, J1 8.2, J2 6.4 Hz),
4.64–4.68 m (1H, OCH), 5.35 br.s (1H, CH2=), 5.40 br.s
(1H, CH2=). 13C NMR spectrum, δ, ppm: 23.8 (CH2), 23.9
(CH2), 25.1 (CH2), 31.9 (CH2), 35.2 (CH2), 35.9 (CH2),
68.9 (CH2), 76.3 (CH), 109.9 (C), 117.0 (CH2), 143.3 (C).
Found, %: C 50.75; H 6.60. C11H17BrO2. Calculated, %:
C50.59; H 6.56.
4-Bromo-2-methylthiazole (X). To a solution of
30.0 g (0.123 mol) of 2,4-dibromothiazole in 400 ml of
ether at –78°C under argon was added dropwise 115 ml
(133 mmol) of 1.16 M solution of butyllithium in hexane.
The mixture was stirred for 1 h at –78°C, then 35 ml
(0.37 mol) of dimethyl sulfate in 30 ml of ether was
added, the mixture was stirred for 0.5 h at –78°C and
warmed to room temperature withinj 2 h. To the reaction
mixture 200 ml of 20% water solution of ammonia was
added, and the two-phase system was vigorously stirred
for 1 h. The organic layer was separated, the water layer
was extracted with ether (3×50 ml), the combined organic
solvents were washed with brine, dried with Na2SO4, the
solvent was distilled off at a reduced pressure, the residue
was distilled in a vacuum [bp 88–89°C (16mm Hg)]. Yield
17.5 g (80%). The spectral characteristics of compound
obtained were consistent with the published data [17].
1
3584 (OH), 3091 (CH cyclopropane). H NMR spec-
trum, δ, ppm: 0.48–0.45 m (1H, CH2 cyclopropane),
0.59–0.69 m (1H, CH2 cyclopropane), 0.81–0.91 m (2H,
CH2 cyclopropane), 1.27–1.71 m [10H, (CH2)5], 2.48 br.s
(1H, OH), 3.69–3.73 m (1H, OCH), 3.98–4.05 m (2H,
OCH2). 13C NMR spectrum, δ, ppm: 9.4 (CH2), 12.5
(CH2), 23.7 (CH2), 23.9 (CH2), 25.1 (CH2), 34.9 (CH2),
36.0 (CH2), 53.9(C), 65.4 (CH2), 80.4 (CH), 109.8 (C).
Found, %: C 66.80; H 9.23. C11H18O3. Calculated, %:
C66.64; H 9.15.
3-Bromo-2-{(2S)-1,4-dioxaspiro[4.5]dec-2-yl}-
prop-1-ene (IX). To a solution of 24.5 g (0.124 mol) of
tertiary cyclopropanol VIII and 42.0 ml (0.30 mol) of
triethylamine in 200 ml of ethyl ether was added at stirring
and cooling with ice a solution of 15.5 ml (0.20 mol) of
methanesulfonyl chloride in 50 ml of ether. The reaction
mixture was warmed to room temperature within 2 h, it
was treated with 150 ml of saturated water solution of
NaHCO3, the organic layer was separated, the water layer
was extracted with ether (3×50 ml), the combined organic
solvents were washed with brine and dried with Na2SO4.
The solvent was distilled off at a reduced pressure, to the
residue was added 250 ml of chloroform and a solution
of magnesium bromide prepared from 11.0 g (0.45 mol)
of magnesium and 81.0 g (0.43 mol) of dibromoethane
in 250 ml of ether. The mixture was boiled at stirring for
2.5–3 h, cooled, washed with 300 ml of saturated water
solution of NaHCO3, the organic layer was separated,
the water layer was extracted with ether (2×100 ml).
The combined organic solvents were washed with brine
and dried with Na2SO4. The solvent was distilled off at
a reduced pressure, the residue was distilled in a vacuum
[bp 90–93°C (1mm Hg)]. Yield 23.5 g (73%), [α]D 14.3°
(c 4.2, CHCl3). IR spectrum, ν, cm–1: 3095 (CH olefin),
4-(2-{(2S)-1,4-Dioxaspiro[4.5]dec-2-yl}prop-2-en-
1-yl)-2-methylthiazole (XII). To a solution of 17.6 g
(99 mmol) of 4-bromo-2-methylthiazole (X) in 100 ml
of ether at –78°C under argon was added dropwise
while stirring 80 ml (93 mmol) of 1.16 M solution of
butyllithium in hexane. The mixture was stirred for 1 h
at –78°C, then 0.35 g (1.83 mmol) of copper iodide was
added, the mixture was warmed to –40°C, and an ether
solution was added of magnesium bromide prepared from
3.10 g (128 mmol) of magnesium and 22.6 g (120 mmol)
of dibromoethane in 90 ml of ether. The mixture was
warmed at stirring to 0°C, then 17.6 g (67 mmol) of
2-substituted allyl bromide IX in 80 ml of ether was
added, and the mixture was warmed to the room tem-
perature. The reaction mixture was treated with 150 ml of
the saturated water solution of NH4Cl, the organic layer
was separated, the water layer was extracted with ether
(3×75 ml). The combined organic solvents were washed
with saturated solution of NaHCO3 and with brine, dried
with Na2SO4, the solvent was distilled off at a reduced
pressure, the residue was distilled in a vacuum [bp
132–134°C (1mm Hg)]. Yield 17.3 г (92%), [α]D 11.3°
(c 5.5, CHCl3). IR spectrum, ν, cm–1: 3090 (CH olefin),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

KOVALENKO et al.
1706
1
1651 (C=C). H NMR spectrum, δ, ppm: 1.37–1.69 m
[10H, (CH2)5], 2.67 s (3H, CH3 thiazole), 3.43–3.55 m
(2H, CH2C=CH2), 3.58–3.62 m (1H, OCH2), 4.00 d.d
(1H, OCH2, J1 8.1, J2 6.5 Hz), 4.53–4.57 m (1H, OCH),
4.90 br.s (1H, CH2C=CH2), 5.28 br.s (1H, CH2C=CH2),
was separated, the water layer was extracted with ether
(3 × 50 ml), the combined organic solutions were washed
with brine, dried with Na2SO4. The solvent was distilled
off at a reduced pressure, the residue was subjected to
column chromatography on silica gel (eluent petroleum
ether–ethyl acetate, 3 : 1). Yield 15.7 g (90%), [α]D 6.4°
(c 4.7, ethyl acetate). IR spectrum, ν, cm–1: 3613 (OH),
13
6.79 s (1H, CH thiazole). C NMR spectrum, δ, ppm:
19.1 (CH3), 23.8 (CH2), 23.9 (CH2), 25.1 (CH2),
34.3 (CH2), 35.2 (CH2), 35.9 (CH2), 68.5 (CH2), 77.9
(CH), 109.8 (C), 113.3 (CH2), 114.2 (CH), 144.6 (C),
153.7 (C), 165.6 (C). Found, %: C64.61; H 7.50.
C15H21NO2S. Calculated, %: C64.48; H 7.58.
1
1375 (SO2), 1178 (SO2). H NMR spectrum, δ, ppm:
1.91 s (3H, CH3C=CH), 2.41 s (3H, CH3C6H4), 2.67 (3H,
CH3 thiazole), 3.96 d.d (1H, CH2OTs, J1 10.2, J2 7.6 Hz),
4.11 d.d (1H, CH2OTs, J1 10.2, J2 3.7 Hz), 4.20 br.s (1H,
OH), 4.37 d.d (1H, CHOH, J1 7.6, J2 3.7 Hz), 6.57 br.s
(1H, CH3C=CH), 6.91 s (1H, CH thiazole), 7.28–7.30 m
(2H, C6H4), 7.75–7.77 m (2H, C6H4). 13C NMR spectrum,
δ, ppm: 14.9 (CH3), 18.9 (CH3), 21.5 (CH3), 72.3 (CH2),
74.2 (CH), 116.2 (CH), 120.8 (CH), 127.9 (2CH), 129.8
(2CH), 132.7 (C), 136.8 (C), 144.8 (C), 152.0 (C), 164.9
(C). Found, %: C54.50; H 5.46. C16H19NO4S2. Calcu-
lated, %: C54.37; H 5.42.
4-[(1E)-2-{(2S)-1,4-Dioxaspiro[4.5]dec-2-yl}-prop-
1-en-1-yl]-2-methylthiazole (XIII). Asolution of 15.8 g
(56.6 mmol) of compound XII and 9.0 g (80 mmol) of
potassium tert-butylate in 300 ml of tert-butanol was
boiled for 1 h. The solvent was distilled off at a reduced
pressure, the residue was diluted with water, the reaction
products were extracted into ether (5×80 ml). The com-
bined organic solutions were washed with the saturated
water solution of NaHCO3, dried with Na2SO4, the sol-
vent was distilled off at a reduced pressure, the residue
was subjected to column chromatography (silica gel,
eluent petroleum ether–ethyl acetate, 10:1). Yield 14.8 g
(94%), [α]D 2.0° (c5.0, CHCl3). IR spectrum, ν, cm–1:
(3S,4E)-3-Hydroxy-4-methyl-5-(2-methylthiazol-
4-yl)pent-4-enenitrile (XV) and 2-methyl-4-{(1E)-2-
[(2S)-oxiran-2-yl]prop-1-en-1-yl}thiazol (XVI). Amix-
ture of 10.0 g (28.3 mmol) of tosylate XIV and 10.0 g
(0.20 mol) of NaCN in 70 ml of dimethyl sulfoxide was
stirred for 10 h at 40°C. To the reaction mixture 100 ml
of water was added, the reaction products were extracted
into ethyl acetate (5 × 50 ml). The combined organic so-
lutions were washed with brine, dried with Na2SO4. The
solvent was distilled off at a reduced pressure, the residue
was subjected to column chromatography on silica gel
(eluent petroleum ether–ethyl acetate, 3 : 1–1 : 1). Yield
of compound XV 5.10 g (87%), mp 92–94°C, [α]D 13.8°
(c 2.1, ethyl acetate). IR spectrum, ν, cm–1: 3616 (OH),
1
3113 (CH olefin), 1664 (C=C). H NMR spectrum, δ,
ppm: 1.38–1.76 m [10H, (CH2)5], 2.03 s (3H, CH3C=CH),
2.70 s (3H, CH3 thiazole), 3.68–3.72 m (1H, OCH2),
4.14 d.d (1H, OCH2, J1 8.1, J2 6.7 Hz), 4.59–4.63 m
(1H, OCH), 6.62 br.s (1H, CH3C=CH), 6.96 s (1H, CH
thiazole). 13C NMR spectrum, δ, ppm: 14.1 (CH3), 19.2
(CH3), 23.8 (CH2), 23.9 (CH2), 25.1 (CH2), 35.1 (CH2),
35.9 (CH2), 68.2 (CH2), 80.6 (CH), 110.2 (C), 115.9 (CH),
120.0 (CH), 136.9 (C), 152.6 (C), 164.5 (C). Found, %:
C64.33; H 7.52. C15H21NO2S. Calculated, %: C64.48;
H 7.58.
1
2251 (C≡N). H NMR spectrum, δ, ppm: 2.00 s (3H,
CH3C=CH), 2.65 d (2H, CH2CN, J 6.4 Hz), 2.71 s (3H,
CH3 thiazole), 4.47 t (1H, CHOH, J 6.4 Hz), 4.62 br.s
(1H, OH), 6.66 br.s (1H, CH3C=CH), 6.97 s (1H, CH
thiazole). 13C NMR spectrum, δ, ppm: 14.0 (CH3), 18.9
(CH3), 24.7 (CH2), 72.6 (CH), 116.5 (CH), 117.7 (C),
120.2 (CH), 139.1 (C), 151.6 (C), 165.5 (C). Found, %:
C57.86; H 5.85. C10H12N2OS. Calculated, %: C57.67;
H 5.81.
(2S,3E)-2-Hydroxy-3-methyl-4-(2-methylthiazol-4-
yl)but-3-enyl 4-methylphenylsulfonate (XIV). A mix-
ture of 13.8 g (49.5 mmol) of compound XIII, 150 ml of
THF, and 50 ml of 3 M hydrochloric acid was stirred for
4 h at room temperature. To the mixture solid K2CO3 was
added to saturation, the organic layer was separated, the
products were extracted from the water layer into THF
(3×30 ml), the combined organic solutions were dried with
K2CO3, filtered, and evaporated at a reduced pressure.
The residue was dissolved in 80 ml of pyridine, cooled
to 0°C, and to the solution was added 11.0 g (58 mmol)
of p-toluenesulfonyl chloride. The mixture was kept for
5 h at 4–5°C, then diluted with 250 ml of ether and 100
ml oif saturated solution of NaHCO3. The organic layer
In the process carried out under the above described
conditions when 0.50 g (1.41 mmol) of tosylate XIV and
0.5 g (10 mmol) of NaCN in 5 ml of DMSO were taken
after 30 min at 40°C alongside nitrile XV [yield 0.05 g
(17%)] oxirane XVI was obtained [yield 0.19 g (74%).
1H NMR spectrum, δ, ppm: 1.92 s (3H, CH3C=CH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SYNTHESIS OF EPOTHILONES MOLECULE FRAGMENT (15R)-C13–C21
1707
methylthiazol-4-yl)-pent-4-enenitrile 145 mg (94%),
[α]D 10.5° (c1.0, CHCl3). IR spectrum, ν, cm–1: 2252
(C≡N). 1H NMR spectrum, δ, ppm: 0.05 s [3H, (CH3)2Si],
0.15 s [3H, (CH3)2Si], 0.92 s [9H, (CH3)3CSi], 2.06 s (3H,
CH3C=CH), 2.55 d.d (1H, CH2CN, J1 16.5, J2 5.0 Hz),
2.61 d.d (1H, CH2CN, J1 16.5, J2 7.5 Hz), 2.71 s (3H,
CH3 thiazole), 4.45 d.d (1H, CHOSi, J1 7.5, J2 5.0 Hz),
6.56 br.s (1H, CH3C=CH), 6.98 s (1H, CH thiazole).
13C NMR spectrum, δ, ppm: 4.8 (CH3), 5.2 (CH3), 13.5
(CH3), 18.1 (C), 19.2 (CH3), 25.6 (3CH3) 26.2 (CH2),74.5
(CH), 116.7 (CH), 117.6 (C), 120.5 (CH), 138.6 (C), 152.2
(C), 164.8 (C). Found, %: C59.41; H 8.15. C16H26N2OSSi.
Calculated, %: C59.58; H 8.12.
2.71 s (3H, CH3 thiazole), 2.79 d.d (1H, CH2 oxirane,
J1 5.2, J2 2.5 Hz), 2.94 d.d (1H, CH2 oxirane, J1 5.2,
J2 4.2 Hz), 3.48 d.d (1H, CH oxirane, J1 4.2, J2 2.5 Hz),
6.66 br.s (1H, CH3C=CH), 6.98 s (1H, CH thiazole).
Found, %: C59.75; H 6.15. C9H11NOS. Calculated, %:
C59.64; H 6.12.
Product of compound XV acylation with Mosher’s
(S)-acid (XVII). To a solution of 12 mg (0.058 mmol) of
compound XV in 0.5 ml of dichloromethane was added
50 mg (0.62 mmol) of pyridine and 30 mg (0.12 mmol)
of (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl
chloride. The mixture was kept for 12 h at room tem-
perature, then it was diluted with ether, washed with
saturated water solution of NaHCO3, dried with Na2SO4.
The solvent was distilled off at a reduced pressure, the
residue was subjected to column chromatography on silica
gel. Yield of (2R,3E)-3-methyl-4-(2-methylthiazol-4-
yl)-1-cyanobut-3-en-2-yl] (1S)-2-methoxy-2-phenyl-
3,3,3-fluoropropionate (XVII) 20 mg (90%). 1H NMR
spectrum, δ, ppm: 1.98 s (3H, CH3C=CH), 2.72 s (3H,
CH3 thiazole), 2.76 d.d (1H, CH2CN, J1 17.1, J2 4.6 Hz),
2.86 d.d (1H, CH2CN, J1 17.1, J2 8.4 Hz), 3.65 s (3H,
CH3O), 5.68 d.d [1H, CF3(OCH3)(Ph)CCO2CH, J1 8.4,
J2 4.6 Hz], 6.48 br.s (1H, CH3C=CH), 6.93 s (1H, CH
thiazole), 7.35–7.62 m (5H, C6H5).
(3R,4E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-5-
(2-methylthiazol-4-yl)pent-4-enal [(R)-III]. To a solu-
tion of 110 mg (0.34 mmol) silyl ether of compound XV
in 5 ml of toluene at –78°C was added dropwise 100 mg
(0.70 mmol) diisobutylaluminum hydride in 0.6 ml of
toluene. The mixture was stirred for 2 h at –78°C, diluted
with 0.5 ml methanol and 0.5 ml of 1 M water solution
of HCl, warmed to room temperature, 5 ml of water was
added, the organic layer was separated, the water layer
was extracted with ether (2 × 5 ml). The combined organic
solutions were dried with Na2SO4, the solvent was dis-
tilled off at a reduced pressure, the residue was subjected
to column chromatography on silica gel (eluent petroleum
ether–ethyl acetate, 20:1). Yield 100 mg (90%), [α]D 20.5°
(c 1.0, CHCl3). The spectral characteristics of compound
obtained were in agreement with those reported for the
aldehyde (S)-(III) [5].
Acylation of compound XV with racemic 2-methoxy-
2-phenyl-3,3,3-trifluoropropanoyl chloride was carried
out as described above. 1H NMR spectrum, δ, ppm: 1.98 s
(1.5H, CH3C=CH), 2.17 s (1.5H, CH3C=CH), 2.72 s
(3H, CH3 thiazole), 2.75–2.91 m (2H, CH2CN), 3.53 s
(1.5H, CH3O), 3.65 s (1.5H, CH3O), 5.68 d.d [0.5H,
CF3(OCH3)(Ph)CCO2CH, J1 8.4, J2 4.6 Hz], 5.76 d.d
[0.5H, CF3(OCH3)(Ph)CCO2CH, J1 6.7, J2 5.9 Hz],
6.48 br.s (1H, CH3C=CH), 6.93 s (1H, CH thiazole),
7.35–7.62 m (5H, C6H5).
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