Building blocks for (C15-C3)-modified epothilone D analogs

Article abstract of DOI:10.1134/S1070428014100170

A promising potentially biologically active structure have been designed by isosteric rearrangement of the C¹⁵-C³ fragment of epothilone D, and building blocks necessary for its assembly have been synthesized.

Full text of DOI:10.1134/S1070428014100170

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 10, pp. 1511–1519. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © R.F. Valeev, R.F. Bikzhanov, M.S. Miftakhov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 10,
pp. 1523–1531.
Building Blocks for (C15–C3)-Modified Epothilone D Analogs
R. F. Valeev, R. F. Bikzhanov, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received March 14, 2014
Abstract—A promising potentially biologically active structure have been designed by isosteric rearrangement
of the C15–C3 fragment of epothilone D, and building blocks necessary for its assembly have been synthesized.
DOI: 10.1134/S1070428014100170
An important landmark in the chemotherapy of
cancer was the discovery of taxol and implementation
of tubulin-polymerizing antineoplastics (taxotere,
paclitaxel) in medical practice [1, 2]. Later, a number
of other natural compounds have been found to exhibit
analogous effect (discodermolide, sarcodictyins,
laulimalide, epothilones, etc.). Epothilones occupy
a particular place in this series [3–5]. They are essen-
tially more advantageous than taxol due to their very
low sensitivity to P-glycoprotein efflux pump, activity
against cancer cells overexpressing P-glycoprotein and
other taxol-resistant cancer cell lines, and insensitivity
toward some taxol-inactivating tubulin mutations
[6–8]. Furthermore, the synthesis of epothilones is
simpler than the synthesis of taxol. Among natural
compounds with taxol-like mechanism of anticancer
effect, epothilones are those for which total syntheses
have been developed and structure–activity relation-
ships have been studied in detail [9–15].
bilized by the C1=O···HO–C2 hydrogen bond, and
elimination of the C2-hydroxy group is impossible).
Such isosteric rearrangement of the C15–C3 fragment of
natural epothilone I has not been reported. This struc-
tural modification should affect the stability of the
resulting compounds and change their conformation
upon binding to tubulin, so that their biological activity
should change. The above considerations determined
the choice of compounds II and III as target structures.
Compound III is an isostere of epothilone D (I), which
is important from the viewpoint of estimation of the
effect of modification of the C15–C3 fragment on the
biological activity of epothilones.
We have developed a retrosynthetic scheme which
implies preparation of key building blocks V–VII
starting from commercially available γ-butyrolactone
Me
10
S
Me
21
The main drawbacks of the use of epothilones in
practice are their metabolic instability related to fast
opening of the lactone ring in vivo with loss of activity
and chemical instability due to opening of the epoxide
ring by the action of nucleophiles, dehydration of the
α-hydroxy carbonyl fragment, and possible trans-
formations of the allylic alcohol fragment.
We previously planned to synthesize new metaboli-
cally and chemically more stable epothilone D (I)
analogs, compounds II and III [16] with isosterically
displaced methylene unit in the C15–C3 fragment. We
presumed that, unlike readily hydrolyzable in vivo
macrolide I, its analogs II and III contain more stable
lactam and lactone fragments, respectively (the
C1=O carbonyl group is sterically hindered and is sta-
Me
OH
Me
15
Me
Me
3
N
Me
O
O
1
O
OH
I
Me
O
9
S
Me
16
21
Me
OH
Me
Me
Me
N
14
Me
3
1
15
2
X
OH
O
II, III
II, X = NH; III, X = O.
1511

VALEEV et al.
1512
Scheme 1.
Me
Me
O
COOMe
S
Me
Me
N
Me
CH2
OH
IV
(R)-(–)-Carvone
N
N
Me
O
O
N
O
N
O
S
S
Me
Julia-Kocienski
Ph
20
10
O
Me
OH
Me
Me
N
Me
O
Me
X
Me
t-BuMe2SiO
OH
II, III
V
γ-Butyrolactone
Amidation
Aldol condensation
O
H
N
O
Me
Me
HO
Me
O
OH
O
O
O
Me
t-BuPh2SiO
Me
Me
Ph
Me
VI
VII
(R)-(–)-Pantolactone
and (R)-(–)-pantolactone (Scheme 1). The synthesis of
thiazolyl-substituted block IV from R-(–)-carvone was
reported by us previously [17].
stituted oxazolidinone XI was synthesized from
L-valine methyl ester hydrochloride (X) according to
[19] (Scheme 2).
Sulfone V was synthesized from commercial γ-bu-
tyrolactone. The main problem was to introduce
a methyl group into the 2-position of γ-butyrolactone
with asymmetric induction. Insofar as direct alkylation
methods did not ensure high enantioselectivity, we
tried a roundabout way following the tested Evans
oxazolidinone procedure [18]. Required acid chloride
IX was prepared by standard methods from γ-butyro-
lactone through γ-bromobutyric acid (VIII), and sub-
Lithium derivative of XI was acylated with acid
chloride IX, and N-(4-bromobutyryl)oxazolidinone
XII thus obtained was brought into reaction with
1-phenyl-1H-tetrazole-5-thiol (XIII) [20]. The result-
ing compound XIV was treated with hexamethyldi-
silazane sodium salt to generate enolate which was
alkylated with methyl iodide at –78°C. This alkylation
step was characterized by high stereoselectivity, and
the purity of XV attained 98% (according to the
Scheme 2.
OH
Cl
HBr
SOCl2
Br
Br
70%
O
O
O
O
VIII
IX
O
Me
Me
[19]
HN
· HCl
Me
OMe
O
H2N
Me Me Me
O
X
XI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

BUILDING BLOCKS FOR (C15–C3)-MODIFIED EPOTHILONE D ANALOGS
1513
Scheme 3.
N
N
N
, Na2CO3
Me2CO
O
O
N
O
O
O
HS
Ph
Br
S
N
HN
IX, BuLi, THF
XIII
N
N
O
O
N
N
Me
O
81%
86%
N
N
Me
Me
Ph
Me
Me
Me Me Me
Me
Me
Me
Me
XI
XII
XIV
O
O
N
Me
Me
N
N
Me
Me
NaN(SiMe3)2, MeI
THF, –60°C, 4 h
N
N
LiAlH4, THF, 5°C
89%
N
OH
N
N
S
S
89%
Ph
Me
Ph
O
Me
XV
Me
XVI
Me
(NH4)6Mo7O24·4H2O
N
N
t-BuMe2SiCl, imidazole
DMAP, CH2Cl2, 8 h
N
N
N
H2O2, EtOH, 8 h
N
N
OH
OSiMe2Bu-t
85%
96%
N
S
S
O
O
O
O
Ph
Ph
XVII
V
1H NMR data). Removal of the chiral fragment from
XV via reduction with LiAlH4 gave sulfide XVI which
was oxidized to sulfone XVII, and the hydroxy group
in the latter was protected by silylation with tert-butyl-
chloro(dimethyl)silane to obtain target building block
V (Scheme 3).
Commercial (R)-(–)-pantolactone containing gemi-
nal methyl groups and properly oriented hydroxy
group was an appropriate starting compounds for the
synthesis of blocks VI and VII, which are necessary
for assembling the polypropionate fragment of epo-
thilone molecule.
with amines taking into account that amide function
can act as temporary protection of the carboxy group.
By treatment of pantolactone with liquid ammonia we
obtained amide XVIII which was converted in suc-
cession to acetal XIX, acid XX, and amido ester XXI
(Scheme 4). However, the condensation of ester XXI
with ethylmagnesium bromide gave no expected com-
pound XXII.
In order to synthesize a more reactive substrate for
the condensation with EtMgBr, compound XVIII was
converted into orthogonally substituted amide XXIV
(Scheme 5) which was protected at the NH2 group by
treatment with Boc2O. Selective hydrolysis of tert-
butyl(dimethyl)silyl ether XXV was expected to pro-
duce the corresponding primary alcohol which we
Chemodifferentiated ring opening of pantolactone
to ω-hydroxy acid is inconvenient because of revers-
ibility of the reaction. Therefore, we tried ring opening
Scheme 4.
O
O
Me
Me
O
PhCH(OMe)2
TsOH, PhH
HO
Me
O
Me
Me
NH3
H2N
OH
O
H2N
O
OH
Me
Ph
XVIII
XIX
O
O
O
O
Me
Me
Me
O
Me
O
Me
O
Me
RuCl3, NaIO4
OH
OMe
EtMgBr, THF
MeCN–CCl4–H2O, 4 h
CH2N2, Et2O
93%
H2N
Ph
H2N
Ph
H2N
Me
92%
O
O
OH
O
XX
XXI
XXII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

VALEEV et al.
1514
Scheme 5.
O
O
O
Me
Me
Me
Me
Me
Me
t-BuMe2SiCl, DMAP
t-BuPh2SiCl, DMAP
OSiMe2Bu-t
OSiMe2Bu-t
imidazole, CH2Cl2
imidazole, CH2Cl2
H2N
H2N
Boc
H2N
94%
92%
OH
XVIII
OH
OH
OSiPh2Bu-t
XXIII
XXIV
O
O
Me
t-BuPh2SiO
Me
Boc2O, DMAP, MeCN
93%
CSA, MeOH–CH2Cl2, 0°C
68%
OSiMe2Bu-t
O
N
H
Me
Me
OSiPh2Bu-t
XXV
XXVI
O
O
(1) CSA, MeOH–CH2Cl2, 0°C
(2) TEMPO, PhI(OAc)2, CH2Cl2
t-BuPh2SiO
t-BuPh2SiO
PDC, CH2Cl2
71%
NH
OH
NH
(1) 68%; (2) 78%
Me
Me
Me
Me
O
VI
XXVII
CSA stands for camphorsulfonic acid, and TEMPO, for 2,2,6,6-tetramethylpiperidine 1-oxyl.
Scheme 6.
O
Me
Me
PhCH(OMe)2
HO
Me
Me
Me
LiAlH4, THF
88%
TsOH, PhH, 2 h
O
OH
OH
O
HO
94%
O
OH
Me
(R)-Pantolactone
Me
Ph
XXVIII
XXIX
Me
Me
Me
Me
Me
EtMgBr, Et2O
–78°C, 1 h
PDC, CH2Cl2, 12 h
PCC, CH2Cl2, 12 h
92%
O
O
O
CHO
67%
87%
O
O
Me
O
Me
HO
XXXI
O
Ph
Ph
Ph
XXX
VII
planned to oxidize to aldehyde and react the latter with
EtMgBr. However, the hydrolysis of XXV gave
lactone XXVI. By selective hydrolysis of unprotected
amido ester XXIV we obtained primary alcohol whose
mild oxidation afforded cyclic aminal VI, and com-
pound VI was oxidized with pyridinium dichromate
(PDC) to lactam XXVII. Unfortunately, neither
compound XXVI nor XXVII reacted with EtMgBr.
Following an alternative version of pantolactone
decyclization, we synthesized known triol XXVIII
[21] (Scheme 6). The subsequent transformation
sequence XXVIII → XXXI involved no essential dif-
ficulties, and the oxidation of alcohol XXXI with pyri-
dinium chlorochromate (PCC) afforded ketone VII in
a good yield.
for the assembly of target structures II and III.
Coupling of this blocks and final steps of the synthesis
of epothilone D isosteres will be reported elsewhere.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from thin films (neat) or Nujol mulls. The
1H and 13C NMR spectra were measured on a Bruker
AM-300 spectrometer at 300 and 75.47 MHz, respec-
tively, using CDCl3 as solvent and tetramethylsilane as
internal reference. The mass spectra were obtained on
a Shimadzu LCMS-2010 EV instrument; samples were
introduced as solutions in ethanol. The optical rota-
tions were measured on a Perkin Elmer 241 MS polar-
imeter. Analytical thin-layer chromatography was
performed on Sorbfil plates (Russia). Silica gel
(Lancaster, UK) was used for column chromatography.
In summary, starting from accessible initial com-
pounds we have synthesized building blocks necessary
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

BUILDING BLOCKS FOR (C15–C3)-MODIFIED EPOTHILONE D ANALOGS
1515
5-{(3S)-4-[tert-Butyl(dimethyl)silyloxy]-3-
methylbutanesulfonyl}-1-phenyl-1H-tetrazole (V).
tert-Butyl(chloro)dimethylsilane, 1.0 g (6.6 mmol),
was added at room temperature to a solution of 1.30 g
(4.4 mmol) of alcohol XVII, 0.66 g (9.7 mmol) of
imidazole, and 0.27 g (2.2 mmol) of 4-(dimethyl-
amino)pyridine in 25 mL of methylene chloride. The
mixture was stirred until the initial compound disap-
peared (~4 h, TLC) and evaporated, and the residue
was purified by silica gel column chromatography
using petroleum ether–ethyl acetate (15:1) as eluent.
Yield 1.7 g (96%), colorless oily liquid, [α]D20 = –5.4°
(c = 1.73, CH2Cl2). IR spectrum, ν, cm–1: 3445, 2957,
2929, 2898, 2857, 1472, 1344, 1258, 1154, 1097.
1H NMR spectrum, δ, ppm: 0.03 s [6H, Si(CH3)2],
0.87 s (9H, t-Bu), 0.93 d (3H, CH3, J = 7.0 Hz), 1.77–
1.86 m (2H, 2-H, 3-H), 2.02–2.08 m (1H, 2-H), 3.39–
3.44 m and 3.52–3.57 m (1H each, 4-H), 3.79–3.84 m
(2H, CH2SO2), 7.57–7.69 m (5H, Ph). 13C NMR spec-
trum, δC, ppm: 3.0, 16.3 18.2, 25.6, 25.9, 34.7, 54.5,
66.6, 125.1, 129.7, 131.4, 133.1, 153.5. Mass spectrum
(APCI), m/z (Irel, %): 409 (16), [M – H]–, 339 (84), 325
(100), 311 (64).
127.8, 130.0, 132.8, 135.9, 175.2. Mass spectrum:
m/z 385 [M + H]+.
2-Methyl-2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]-
pentan-3-one (VII). A solution of 0.065 g (0.3 mmol)
of compound XXXI in 2 mL of anhydrous methylene
chloride was added in one portion to a suspension of
0.05 g (0.2 mmol) of pyridinium chlorochromate in
4 mL of anhydrous methylene chloride under stirring
at 0°C. The mixture was stirred for 12 h at room tem-
perature and filtered through a thin layer of silica gel,
and the sorbent was washed with methylene chloride
(5×7 mL). The combined extracts were dried over
MgSO4 and evaporated, and the residue was purified
by silica gel chromatography using ethyl acetate–
petroleum ether (1:3) as eluent. Yield 0.046 g (92%),
oily material (a mixture of diastereoisomers at a ratio
1
of 3:1). H NMR spectrum, δ, ppm: 1.00 s (3H, CH3),
1.03 m (3H, CH3, J = 14.9 Hz), 1.14 s (3H, CH3),
2.63–2.69 m (2H, 3-H), 3.68–3.71 m (2H, CH2O),
4.02 s (1H, CHO), 5.52 s (1H, CHPh), 7.38–7.56 m
(5H, Ph). 13C NMR spectrum, δC, ppm: 7.71, 18.9,
21.2, 33.1, 49.3, 66.5, 87.0, 107.2, 126.3, 127.5, 128.6,
136.1, 212.3. Mass spectrum: m/z 249 [M + H]+.
(3R)-3-[tert-Butyl(diphenyl)silyloxy]-5-hydroxy-
4,4-dimethylpyrrolidin-2-one (VI). Camphorsulfonic
acid, 0.23 g (1.0 mmol), was added at 0°C to a solution
of 0.5 g (1.0 mmol) of compound XXIV in 40 mL of
methanol–methylene chloride (1:1). The mixture was
stirred until the initial compound disappeared (TLC)
and treated with a saturated solution of sodium hydro-
gen carbonate, the organic layer was separated, the
aqueous layer was extracted with diethyl ether
(3×10 mL), and the extracts were combined with the
organic phase, dried over MgSO4, filtered, and evap-
orated. The residue was dissolved in methylene
chloride, 0.64 g (2.0 mmol) of (diacetoxy-λ3-iodanyl)-
benzene and 0.01 g of 2,2,6,6-tetramethylpiperidine
1-oxyl were added, and the mixture was stirred at 20°C
until the initial compound disappeared (TLC). The
mixture was evaporated, and the residue was subjected
to silica gel chromatography using petroleum ether–
ethyl acetate (8:1) as eluent. Yield 0.2 g (78%), yellow
oily liquid (a mixture of diastereoisomers at a ratio of
3:1). Given below are spectral data for the major
stereoisomer. IR spectrum, ν, cm–1: 3461, 3244, 2957,
(4S)-4-Isopropyl-5,5-dimethyloxazolidin-2-one
(XI) was synthesized according to the procedure de-
scribed in [19]. Colorless needles, mp 86–87°C, [α]D20 =
1
+26.5° (c = 2.62, CHCl3). H NMR spectrum, δ, ppm:
0.85 d and 0.94 d (3H each, CH3, J = 6.4 Hz), 1.31 s
and 1.41 s (3H each, CH3), 1.72–1.79 m (1H, CHCH3),
3.12 d (1H, CHN, J = 8.4 Hz), 7.27 br.s (1H, NH).
(4S)-3-(4-Bromo-1-oxobutyl)-4-isopropyl-5,5-di-
methyl-1,3-oxazolidin-2-one (XII). A solution of
0.5 g (3.18 mmol) of oxazolidinone XI in 5 mL of
THF was cooled to –80°C, 3.2 mL (6.37 mmol) of
a 2 N solution of butyllithium in hexane was added
under stirring, and the mixture was stirred for 15 min
while slowly adding a solution of 2.4 g (12.7 mmol) of
acid chloride IX [22] in 5 mL of THF. The mixture
was stirred for 1 h, allowed to warm up to –60°C, and
quenched by slowly adding 0.5 mL of aqueous THF.
The mixture was then adjusted to room temperature
and treated with a saturated solution of ammonium
chloride, the organic phase was separated, and the
aqueous phase was extracted with ethyl acetate (2×
10 mL). The extracts were combined with the organic
phase, dried over MgSO4, filtered, and evaporated, and
the residue was purified by silica gel column chroma-
tography using ethyl acetate–petroleum ether (1:3) as
eluent. Yield 0.5 g (81%), yellow viscous liquid.
[α]D20 = +29.3° (c = 3.94, CH2Cl2). IR spectrum, ν,
1
2928, 2957, 1727, 1112, 702, 503. H NMR spectrum,
δ, ppm: 1.00 s (3H, CH3), 1.06 s (3H, CH3), 1.09 s
(9H, t-Bu), 3.79 d (1H, CHOH, J = 10.8 Hz), 4.45 s
(1H, CHOSi), 5.47 br.s (1H, NH), 7.42–7.46 m (6H,
SiPh2), 7.66 d (4H, SiPh2, J = 6.3 Hz). 13C NMR spec-
trum, δC, ppm: 16.9, 18.1, 18.4, 26.2, 43.5, 82.8, 94.4,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

VALEEV et al.
1516
1
cm–1: 2971, 2933, 2880, 1774, 1701. H NMR spec-
trum, δ, ppm: 0.94 d and 1.01 d (3H each, CH3, J =
7.0 Hz), 1.38 s and 1.50 s (3H each, CH3), 2.11–2.15 m
(1H, CH), 2.20–2.25 m (2H, 3′-H), 3.05–3.18 m (2H,
2′-H), 3.49 t (2H, 4′-H, J = 6.7 Hz), 4.13 d (1H, 4-H,
J = 3.1 Hz). 13C NMR spectrum, δC, ppm: 17.1, 21.4,
21.6, 27.3, 28.9, 29.6, 32.7, 33.9, 66.4, 83.0, 153.5,
172.5. Mass spectrum, m/z (Irel, %): 307 (20) [M + H]+,
227 (100).
J = 7.0 Hz), 1.31 d (3H, CH3, J = 6.7 Hz), 1.36 s and
1.48 s (3H each, CH3), 1.89–1.94 m (1H, 3′-H), 2.11–
2.15 m (1H, CH), 2.29–2.33 m (1H, 3′-H), 3.34–
3.37 m and 3.43–3.48 m (1H each, 4′-H), 3.88–3.91 m
(1H, 2′-H), 4.17 d (1H, 4-H, J = 3.1 Hz), 7.51–7.55 m
(5H, Ph). 13C NMR spectrum, δC, ppm: 16.9, 18.5,
21.4, 21.6, 28.8, 29.6, 31.0, 31.9, 37.1, 66.1, 82.8,
124.0, 129.8, 130.2, 133.7, 153.0, 154.5, 176.4. Mass
spectrum: m/z 418 [M + H]+.
(4S)-4-Isopropyl-5,5-dimethyl-3-[1-oxo-4-(1-phe-
nyl-1H-tetrazole-5-sulfonyl)butyl]-1,3-oxazolidin-
2-one (XIV). Compound XIII, 0.06 g (0.34 mmol),
was dissolved in 5 mL of acetone, 0.06 g (0.6 mmol)
of sodium carbonate was added under stirring, the
mixture was stirred for 10 min, and a solution of 0.08 g
(0.26 mmol) of bromide XII in 2 mL of acetone was
slowly added. The mixture was stirred for 12 h,
filtered, and evaporated, and the residue was purified
by silica gel column chromatography using ethyl
acetate–petroleum ether (1:3) as eluent. Yield 0.1 g
(86%), colorless viscous liquid, [α]D20 = +21.8° (c =
2.49, CH2Cl2). IR spectrum, ν, cm–1: 2976, 2934, 2879,
(2S)-2-Methyl-4-(1-phenyl-1H-tetrazole-5-sul-
fonyl)butan-1-ol (XVI). A solution of 0.022 g
(0.58 mmol) of LiAlH4 in THF was added dropwise
under stirring at ~5°C to a solution of 0.2 g
(0.48 mmol) of compound XV in 5 mL of THF. The
mixture was stirred for 2 h at room temperature,
aqueous THF (1:1) was added, the mixture was stirred
for 5 min at ~5°C, the organic layer was separated, and
the aqueous layer was extracted with diethyl ether
(3×10 mL). The combined extracts were dried over
MgSO4, filtered, and evaporated. The residue, 0.11 g
(89%), was a yellow viscous liquid which was used in
further synthesis without chromatographic purification.
1
1768, 1736, 1701. H NMR spectrum, δ, ppm: 0.93 d
(2S)-2-Methyl-4-(1-phenyl-1H-tetrazole-5-sul-
fonyl)butan-1-ol (XVII). A solution of 0.05 g
(0.04 mmol) of (NH4)6Mo7O24·4H2O in 0.4 mL of
47% hydrogen peroxide was added dropwise under
stirring at ~0°C to a solution of 0.05 g (0.19 mmol) of
compound XVI in 3 mL of ethanol. The mixture was
stirred for 12 h at room temperature and treated with
brine, the organic layer was separated, and the aqueous
layer was extracted with diethyl ether (3×10 mL). The
combined extracts were dried over MgSO4, filtered,
and evaporated. The residue, 0.05 g (85%), was a light
yellow viscous liquid which was used in further syn-
thesis without chromatographic purification.
and 1.01 d (3H each, CH3, J = 7.0 Hz), 1.38 s and
1.50 s (3H each, CH3), 2.11–2.15 m (1H, CH), 2.21–
2.26 m (2H, 3′-H), 3.05–3.18 m (2H, 2′-H), 3.47–
3.50 m (2H, 4′-H), 4.13 d (1H, 4-H, J = 3.1 Hz), 7.53–
7.57 m (5H, Ph). 13C NMR spectrum, δC, ppm: 17.0,
21.4, 23.9, 28.8, 29.5, 32.4, 34.0, 66.3, 83.0, 123.9,
129.8, 130.1, 133.6, 153.5, 154.1, 172.4. Mass spec-
trum: m/z 404 [M + H]+.
(4S,2′S)-4-Isopropyl-5,5-dimethyl-3-[2-methyl-
1-oxo-4-(1-phenyl-1H-tetrazole-5-sulfonyl)butyl]-
1,3-oxazolidin-2-one (XV). A solution of 0.1 g
(0.25 mmol) of compound XIV in 5 mL of THF was
cooled to –78°C, 0.5 mL (0.5 mmol) of a 1 M solution
of hexamethyldisilazane sodium salt in THF was
added dropwise under stirring, the mixture was stirred
for 30 min, and 0.15 mL (2.5 mmol) of methyl iodide
was added. The mixture was stirred for 1 h at –78°C
and for 12 h at –30°C, a saturated solution of am-
monium chloride was added, the organic phase was
separated, and the aqueous phase was extracted with
ethyl acetate (3×10 mL). The combined extracts were
dried over MgSO4, filtered, and evaporated, and the
residue was purified by silica gel column chromatog-
raphy using ethyl acetate–petroleum ether (1:5) as
eluent. Yield 0.09 g (89%), colorless viscous liquid,
[α]D20 = +37.8° (c = 1.95, CH2Cl2). IR spectrum, ν, cm–1:
(4R)-5,5-Dimethyl-2-phenyl-1,3-dioxane-
4-carboxamide (XIX). Compound XVIII [23], 0.06 g
(0.41 mmol), was dissolved in 5 mL of benzene,
0.09 mL (0.62 mmol) of (dimethoxymethyl)benzene
and a catalytic amount of p-toluenesulfonic acid were
added, and the mixture was stirred for 30 min at room
temperature, and evaporated. The residue was subject-
ed to silica gel column chromatography using petro-
leum ether–ethyl acetate as eluent to isolate 0.07 g
(70%) of oily acetal XIX as a 10:1 mixture of dia-
stereoisomers with respect to the acetal chiral center.
Major (2R,4R)-isomer. IR spectrum, ν, cm–1: 3486,
1
3290, 3207, 2957, 2931, 2895, 2858, 1691. H NMR
1
2971, 2931, 2878, 2853, 1772, 1730, 1698. H NMR
spectrum, δ, ppm: 1.12 s and 1.21 s (3H each, CH3),
3.70 d and 3.75 d (1H each, CH2, J = 11.6 Hz), 4.13 s
spectrum, δ, ppm: 0.92 d and 0.98 d (3H each, CH3,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

BUILDING BLOCKS FOR (C15–C3)-MODIFIED EPOTHILONE D ANALOGS
1517
(1H, CHO), 5.54 s (1H, CHPh), 5.62 br.s and 6.46 br.s
(1H each, NH2), 7.40–7.52 m (5H, Ph). 13C NMR
spectrum, δC, ppm: 19.2, 21.8, 33.1, 78.5, 84.0, 101.4,
126.2, 128.4, 129.3, 137.8. 171.8. Mass spectrum:
m/z 236 [M + H]+.
1096, 837. 1H NMR spectrum (CDCl3), δ, ppm: 0.08 s
[6H, Si(CH3)2], 0.90 s (9H, t-Bu), 0.94 s and 1.02 s
(3H each, CH3), 3.48 d and 3.58 d (1H each, CH2, J =
11.6 Hz), 4.02 s (1H, CHOH), 5.94 br.s and 6.80 br.s
(1H each, NH2). 13C NMR spectrum, δC, ppm: 5.7,
18.1, 20.0, 21.4, 25.7, 38.3, 73.1, 78.8, 175.2. Mass
spectrum, m/z (Irel, %): 284 (100), 262 (60) [M + H]+.
(1R)-1-Amino-4-methoxy-3,3-dimethyl-1,4-dioxo-
butan-2-yl benzoate (XXI). Compound XIX, 0.37 g
(0.15 mmol), was dissolved in a mixture of 30 mL of
acetonitrile, 30 mL of carbon tetrachloride, and 15 mL
of water, 0.04 g (0.15 mmol) of RuCl3·H2O and 1.6 g
(7.5 mmol) of NaIO4 were added in succession, and
the mixture was stirred for 4 h at room temperature.
The mixture was then diluted with an equal volume of
water, the organic phase was separated, the aqueous
phase was extracted with ethyl acetate (3×100 mL),
and the extracts were combined with the organic
phase, dried over Na2SO4, filtered, and evaporated to
isolate 0.37 g (92%) of acid XX as an oily liquid which
was subjected to methylation without additional
purification.
(2R)-4-[tert-Butyl(dimethyl)silyloxy]-2-[tert-
butyl(diphenyl)silyloxy]-3,3-dimethylbutanamide
(XXIV). tert-Butyl(chloro)diphenylsilane, 0.6 g
(2.2 mmol), was added at room temperature to a solu-
tion of 0.52 g (1.99 mmol) of compound XXIII, 0.43 g
(6.4 mmol) of imidazole, and 0.12 g (0.99 mmol) of
DMAP in 20 mL of methylene chloride. The mixture
was stirred until the initial compound disappeared
(~4 h, TLC) and evaporated, and the residue was puri-
fied by silica gel column chromatography using petro-
leum ether–ethyl acetate (3:1) as eluent. Yield 0.92 g
(92%), colorless oily liquid, [α]D20 = +7.7° (c = 1.93,
CH2Cl2). IR spectrum, ν, cm–1: 3486, 3290, 3207,
1
2957, 2931, 2858, 1691, 1112, 838, 702. H NMR
Acid XX, 0.2 g (0.8 mmol), was dissolved in 10 mL
of diethyl ether, 0.07 mL (1.6 mmol) of a diazo-
methane solution was added at room temperature, and
the mixture was stirred until the initial compound dis-
appeared (TLC). The mixture was evaporated, and the
residue was purified by silica gel column chromatog-
raphy using petroleum ether–ethyl acetate (3:1) as
eluent. Yield of ester XXI 0.21 g (93%), colorless oily
liquid, [α]D20 = +18.2° (c = 0.68, CH2Cl2). IR spectrum,
ν, cm–1: 3491, 3292, 3210, 2956, 2931, 2895, 2851,
spectrum, δ, ppm: 0.05 s [6H, Si(CH3)2], 0.83 s (9H,
t-Bu), 0.86 s and 0.89 s (3H each, CH3), 1.12 s (9H,
t-Bu), 3.23 d and 3.41 d (1H each, CH2, J = 11.6 Hz),
4.14 s (1H, CHO), 5.56 br.s and 6.10 br.s (1H each,
NH2), 7.34–7.41 m (6H, SiPh2) 7.65–7.70 m (4H,
SiPh2). 13C NMR spectrum, δC, ppm: 5.53, 18.2, 18.3,
19.7, 20.8, 25.9, 27.2, 40.3, 69.1, 79.0, 127.7, 130.0,
132.9, 135.9, 174.3. Mass spectrum: m/z 501 [M + H]+.
3-[tert-Butyl(diphenyl)silyloxy]-4,4-dimethyldi-
hydrofuran-2(3H)-one (XXVI). Di-tert-butyl dicar-
bonate, 0.22 g (0.98 mmol), was added at room tem-
perature to a solution of 0.38 g (0.76 mmol) of amide
XXIV and 0.10 g (0.84 mmol) of DMAP in 20 mL of
acetonitrile. The mixture was stirred until the initial
compound disappeared (TLC) and evaporated. The
residue was 0.43 g (93%) of oily carbamate XXV. It
was subjected to hydrolysis without purification.
A solution of 0.4 g (0.67 mmol) of compound XXV
in 20 mL of methanol–methylene chloride (1:1) was
cooled to 0°C, 0.15 g (0.67 mmol) of camphorsulfonic
acid was added, and the mixture was stirred until the
initial compound disappeared (TLC). The mixture was
treated with a saturated solution of sodium hydrogen
carbonate, the organic phase was separated, the aque-
ous phase was extracted with diethyl ether (3×10 mL),
the extracts were combined with the organic phase,
dried over MgSO4, filtered, and evaporated, and the
residue was purified by silica gel chromatography on
silica gel using petroleum ether–ethyl acetate (20:1) as
1
1689. H NMR spectrum, δ, ppm: 1.35 s and 1.38 s
(3H each, CH3), 3.69 s (3H, OCH3), 5.73 br.s (1H,
CHO), 6.11 br.s (2H, NH2), 7.46–7.61 m (3H, Ph),
8.06 d (2H, Ph, J = 8.0 Hz). 13C NMR spectrum, δC,
ppm: 22.2, 23.5, 41.4, 55.7, 83.0, 128.1, 129.2, 129.9,
134.2, 161.7, 171.2, 173.2. Mass spectrum: m/z 280
[M + H]+.
(2R)-4-[tert-Butyl(dimethyl)silyloxy]-2-hydroxy-
3,3-dimethylbutanamide (XXIII). tert-Butyl(chloro)-
dimethylsilane, 0.1 g (0.68 mmol), was added at room
temperature to a solution of 0.1 g (0.68 mmol) of com-
pound XVIII, 0.15 g (2.18 mmol) of imidazole, and
0.04 g (0.34 mmol) of DMAP in 15 mL of methylene
chloride. The mixture was stirred until the initial com-
pound disappeared (~4 h, TLC) and evaporated, and
the residue was purified by silica gel column chroma-
tography using petroleum ether–ethyl acetate (3:1) as
eluent. Yield 0.17 g (94%), colorless oily liquid,
[α]D20 = +29.7° (c = 2.00, CH2Cl2). IR spectrum, ν,
cm–1: 3478, 3397, 3350, 3319, 2954, 2930, 2859, 1667,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

VALEEV et al.
1518
eluent. Yield 0.17 g (68%), light yellow viscous liquid,
2-Methyl-2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]-
propan-1-ol (XXIX). Compound XXVIII, 0.6 g
(4.5 mmol), was dissolved in 10 mL of benzene, 1.03 g
(6.75 mmol) of (dimethoxymethyl)benzene and a cata-
lytic amount of p-toluenesulfonic acid were added, and
the mixture was stirred for 2 h at room temperature.
The mixture was evaporated, and the residue was
purified by silica gel column chromatography using
petroleum ether–ethyl acetate (3:1) as eluent. Yield
0.94 g (94%), oily substance (a mixture of diastereo-
isomers at a ratio of 3:1). IR spectrum, ν, cm–1: 3300,
[α]D20 = +12.3° (c = 0.84, CH2Cl2). IR spectrum, ν, cm–1:
1
2957, 2928, 2857, 1719, 1112, 703. H NMR spec-
trum, δ, ppm: 0.74 s and 1.13 s (3H each, CH3), 1.15 s
(9H, t-Bu), 3.70 d and 3.89 d (1H each, CH2, J =
8.8 Hz), 4.04 s (1H, CHOSi), 7.37–7.43 m (6H, SiPh2),
7.73 d.d (4H, SiPh2, J = 6.5 Hz). 13C NMR spectrum,
δC, ppm: 20.2, 21.3, 22.9, 27.0, 42.1, 79.3, 89.5, 127.9,
129.0, 131.8, 135.8, 177.2. Mass spectrum: m/z 370
[M + H]+.
(4R)-4-[tert-Butyl(diphenyl)silyloxy]-3,3-dimeth-
ylpyrrolidine-2,5-dione (XXVII). A solution of 0.2 g
(0.5 mmol) of compound VI in 2 mL of anhydrous
methylene chloride was added in one portion under
stirring at 0°C to a suspension of 0.14 g (0.75 mmol)
of pyridinium dichromate in 4 mL of anhydrous
methylene chloride. The mixture was stirred for 12 h at
room temperature and filtered through a thin layer of
silica gel, the precipitate was washed on a filter with
methylene chloride (5×7 mL), the washings were
combined, dried over MgSO4, and evaporated, and the
residue was subjected to silica gel chromatography
using ethyl acetate–petroleum ether (1:3) as eluent.
Yield 0.14 g (71%), oily material, [α]D20 = +28.3° (c =
0.51, CH2Cl2). IR spectrum, ν, cm–1: 3244, 2957, 2928,
1
1670, 1465, 1380, 1280. H NMR spectrum, δ, ppm:
0.84 s and 0.88 s (3H each, CH3), 3.41 d and 3.43 d
(1H each, 1-H, J = 11.0 Hz), 3.52 d and 3.71 d (1H
each, 5-H, J = 7.3 Hz), 3.75–3.78 m (1H, 4-H), 5.49 s
(1H, CHPh), 7.35–7.50 m (5H, Ph). 13C NMR spec-
trum, δC, ppm: 21.8, 23.9, 35.3, 64.5, 68.9, 85.7, 104.3,
126.8, 127.9, 128.5, 136.1. Mass spectrum: m/z 223
[M + H]+.
2-Methyl-2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]-
propanal (XXX). A solution of 0.51 g (1.35 mmol) of
compound XIX in 2 mL of anhydrous methylene
chloride was added in one portion to a suspension of
0.2 g (0.9 mmol) of pyridinium dichromate in 4 mL of
anhydrous methylene chloride under stirring at 0°C.
The mixture was stirred for 12 h at room temperature
and filtered through a thin layer of silica gel, the pre-
cipitate was washed on a filter with methylene chloride
(5×7 mL), and the combined washings were dried over
MgSO4 and evaporated. The residue was purified by
silica gel chromatography using ethyl acetate–petro-
leum ether (1:3) as eluent. Yield 0.13 g (67%), oily
material (a mixture of diastereoisomers at a ratio of
3:1). IR spectrum, ν, cm–1: 1730, 1480, 1390, 1270,
1
2857, 1727, 1112, 702, 503. H NMR spectrum, δ,
ppm: 0.82 s (3H, CH3), 1.14 s (9H, t-Bu), 1.24 s (3H,
CH3), 4.29 s (1H, CHOSi), 7.37–7.46 m (6H, SiPh2),
7.71 d.d and 7.80 d.d (2H each, SiPh2, J = 6.5 Hz).
13C NMR spectrum, δC, ppm: 20.8, 21.2, 26.9, 29.7,
47.3, 77.7, 127.6, 130.1, 132.6, 136.3, 174.9, 180.1.
Mass spectrum: m/z 383 [M + H]+.
(2R)-3,3-Dimethylbutane-1,2,4-triol (XXVIII).
A solution of 2.70 g (15.7 mmol) of (R)-(–)-pantolac-
tone in 10 mL of THF was added dropwise under
stirring at 0°C to a suspension of 0.9 g (23.62 mmol)
of LiAlH4 in 30 mL of anhydrous THF. The mixture
was stirred for 4 h at room temperature, anhydrous
Na2SO4 was added, and 50% sulfuric acid was slowly
added to pH ~3. The mixture was stirred for 30 min
and neutralized by adding anhydrous sodium hydro-
gen carbonate, the precipitate was filtered off and
washed on a filter with ethyl acetate (5×20 mL), the
filtrate was evaporated, and the residue was dried
under reduced pressure on heating on a water bath.
1
1235, 1070. H NMR spectrum, δ, ppm: 1.03 s and
1.26 s (3H each, CH3), 3.71 d and 3.74 d (1H each,
5-H, J = 7.3 Hz), 3.95–3.97 m (1H, 4-H), 5.56 s (1H,
CHPh), 7.35–7.60 m (5H, Ph), 9.68 s (1H, CHO).
13C NMR spectrum, δC, ppm: 17.1, 18.3, 48.4, 65.4,
85.1, 105.6, 127.9, 128.1, 128.6, 137.2, 203.6. Mass
spectrum: m/z 221 [M + H]+.
2-Methyl-2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]-
pentan-3-ol (XXXI). A solution of 0.09 g (0.41 mmol)
of compound XXX in 10 mL of diethyl ether was
cooled to –78°C, a solution of ethylmagnesium
bromide prepared from 0.1 g of magnesium turnings
and 0.3 mL of ethyl bromide in 1 mL of diethyl ether
was slowly added under stirring, and the mixture was
stirred for 1 h and hydrolyzed with a saturated aqueous
solution of ammonium chloride. The organic phase
was separated, the aqueous phase was extracted with
Yield 2.4 g (88%), colorless oily liquid, [α]D20
=
–15.85° (c = 0.1, MeOH). IR spectrum, ν, cm–1: 3368,
3176, 3120, 1460, 1376, 1184, 1144, 1128, 1036, 1008,
816. Found, %: C 53.56; H 10.20. C6H14O3. Calculat-
ed, %: C 53.73; H 10.44.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

BUILDING BLOCKS FOR (C15–C3)-MODIFIED EPOTHILONE D ANALOGS
1519
7. Wolff, A., Technau, A., and Brandner, G., Int. J. Oncol.,
ethyl acetate (3×40 mL), the combined extracts were
dried over Na2SO4, filtered, and evaporated, and the
residue was purified by silica gel column chromatog-
raphy using petroleum ether–ethyl acetate (2:1) as
eluent. Yield 0.09 g (87%), oily material (a mixture of
diastereoisomers with respect to C*HOH at a ratio of
2:1). IR spectrum, ν, cm–1: 3321, 1478, 1385, 1270,
1997, vol. 11, p. 123.
8. Giannakakou, P., Sackett, D.L., Kang, Y.K., Zhan, Z.R.,
Buters, J.T.M., Fojo, T., and Poruchynsky, M.S., J. Biol.
Chem., 1997, vol. 272, p. 17118.
9. Nicolaou, K.C., Roschangar, F., and Vourloumis, D.,
Angew. Chem., Int. Ed., 1998, vol. 37, p. 2014.
1
10. Borzilleri, R.M. and Vite, G.D., Drugs Future, 2002,
1235, 1070. H NMR spectrum, δ, ppm: 0.86 s (3H,
vol. 27, p. 1149.
CH3), 1.00 t (3H, CH3, J = 14.9 Hz), 1.29 s (3H, CH3),
1.54–1.66 m (2H, 3-H), 3.43–3.44 m (1H, 2-H), 3.61 d
(1H, CH2O, J = 7.3 Hz), 3.63–3.69 m (1H, CHO),
3.71 d (1H, CH2O, J = 7.3 Hz), 5.56 s (1H, CHPh),
7.34–7.53 m (5H, Ph). Mass spectrum, m/z (Irel, %):
505 (21) [M + H]+, 475 (100).
11. Wartmann, M. and Altmann, K.H., Curr. Rev. Med.
Chem. Anticancer Agents, 2002, vol. 2, p. 123.
12. Altmann, K.H., Mini Rev. Med. Chem., 2003, vol. 3,
no. 2, p. 149.
13. Altmann, K.H., Org. Biomol. Chem., 2004, vol. 2,
p. 2137.
This study was performed using the equipment of
Khimiya Shared Use Center, Institute of Organic
Chemistry, Ufa Research Center, Russian Academy of
Sciences.
14. Altmann, K.H., Curr. Pharm. Des., 2005, vol. 11,
p. 1595.
15. Altmann, K.H., Pfeiffer, B., Arseniyadis, S., Pratt, B.A.,
and Nicolaou, K.C., ChemMedChem, 2007, vol. 2,
no. 4, p. 396.
16. Bikzhanov, R.F., Cand. Sci. (Chem.) Dissertation, Ufa,
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