Synthesis of a chiral building block for the C6?C9fragment of epothilones

Article abstract of DOI:10.1134/S1070428016060208

A procedure has been developed for the synthesis of a new chiral building block for epothilone analogs starting from L-malic acid.

Full text of DOI:10.1134/S1070428016060208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 6, pp. 883–886. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © R.F. Valeev, A.M. Davletbaev, R.F. Talipov, M.S. Miftakhov, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 6,
pp. 896–898.
Synthesis of a Chiral Building Block
for the C6‒C9 Fragment of Epothilones
R. F. Valeeva, A. M. Davletbaevb, R. F. Talipovb, and M. S. Miftakhova*
a Institute of Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
b Bashkir State University, ul. Zaki Validi 32, Ufa, 450074 Bashkortostan, Russia
Received April 13, 2016
Abstract—A procedure has been developed for the synthesis of a new chiral building block for epothilone
analogs starting from L-malic acid.
DOI: 10.1134/S1070428016060208
Much attention is given to the preparation of
individual isomers of chiral building blocks (synthons)
for directed synthesis [1]. While developing a synthetic
approach to epothilone D analogs 1 [2, 3] through key
acyclic precursor 2, it was necessary to obtain building
block 3 containing S-configured CHMe fragment. We
planned to use compound 3 for the construction of the
C6‒C9 fragment of epothilone 1 molecule (Scheme 1).
smoothly obtained in 89% yield by heating diester 6
with NaBH4 in EtOH [6]. Selective protection of
vicinal hydroxy groups in 7 was achieved by acetaliza-
tion with acetone according to [7]. Swern oxidation of
primary alcohol 8 gave aldehyde 9 which was sub-
jected to Corey–Fuchs olefination [8]. Geminal di-
bromide 10 thus obtained was treated in succession
with butyllithium and chloro(trimethyl)silane. The
resulting compound 3 was separated from minor dia-
stereoisomer by column chromatography on silica gel.
The diastereoisomeric purity of 3 was 99% (GLC).
We have developed a simple and efficient synthesis
of individual diastereoisomer 3 starting from L-malic
acid (4) (Scheme 2). The alkylation of diester 5
derived from L-malic acid (4) [4] gave a mixture of
diastereoisomers at a ratio of 6:1 (GLC) in favor of the
desired isomer 6 [5], which could not be separated by
silica gel chromatography. Thew reduction of 6 with
LiAlH4, (i-Bu)2AlH, or BH3 ·THF afforded triol 7 in
very poor yield (10‒20%), whereas compound 7 was
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
1
trometer from thin films or Nujol mulls. The H and
13C NMR spectra were measured on a Bruker AM-300
spectrometer at 300 and 75.47 MHz, respectively,
Scheme 1.
Intramolecular
cyclization
Me3Si
9
Me
Me
O
CH
X
9
S
S
Me
Me
21
21
Me
10
Me
S
Me
6
OH
Me
6
OH
Me
Me
Me
Me
N
N
O
Me
O
Me
O
O
1
1
Me
X
X
Me
O
Me
OH
OH
1
2
3
1, X = O, NH; 2, X = O, I.
883

VALEEV et al.
884
Scheme 2.
O
O
Me
O
MeOH, H2SO4
reflux
Li(Pr-i)2, MeI
THF, –78°C
HO
MeO
MeO
OH
OMe
OMe
Me
O
OH
O
OH
O
OH
O
4
5
6
Me
Me
NaBH4, EtOH
70°C
Me2CO, TsOH
20°C
(COCl)2, DMSO
Et3N, CH2Cl2, –70°C
HO
HO
OH
Br
O
O
O
O
OH
Me
Me
Me
Me
7
8
9
Me
Me
CBr4, PPh3
CH2Cl2, 0°C
BuLi, Me3SiCl, THF
–78 to 20°C
Br
O
O
O
O
Me3Si
Me
Me
Me
Me
10
3
using CDCl3 as solvent and tetramethylsilane as
internal standard. The mass spectra were obtained on
a Shimadzu LCMS-2010 EV instrument. Analytical
TLC was performed on Sorbfil plates (Russia). Silica
gel (Lancaster, UK) was used for column chromatog-
raphy. The optical rotations were measured using
a Perkin-Elmer 241 MS polarimeter. The purity of
the isolated compounds was checked by GLC on
a Chrom 5 chromatograph.
3.12 br.s (1H, OH), 3.65 s (3H, OCH3), 3.76 s (3H,
OCH3), 4.25 d (1H, 2-H, J = 3.7 Hz). 13C NMR spec-
trum, δC, ppm: 13.0, 43.1, 51.9, 52.6, 72.4, 173.3,
173.6. Found, %: C 47.68; H 6.71. C7H12O5. Calculat-
ed, %: C 47.72; H 6.87.
(2S,3S)-3-Methylbutane-1,2,4-triol (7). A solution
of 5.1 g (29.0 mmol) of 6 in 20 mL of ethanol was
added dropwise under stirring to a solution of 2.2 g
(58.0 mmol) of NaBH4 in 50 mL of ethanol. The
mixture was stirred for 5 h at 70°C, cooled to 0°C,
acidified to pH ~2 with 35% aqueous HCl, and
filtered. The filtrate was diluted with 150 mL of
methanol and evaporated, the residue was dissolved in
methylene chloride, sodium hydrogen carbonate was
added to neutral reaction, and the solution was dried
over MgSO4 and evaporated under reduced pressure.
Yield 3.09 g (89%), light yellow liquid, de 86%
(GLC). IR spectrum, ν, cm–1: 3350, 2966, 2935, 2882,
Dimethyl (2S,3R)-2-hydroxy-3-methylbutane-
dioate (6). A solution of 18.7 mL (133 mmol) of
diisopropylamine in 100 mL of THF was cooled to
‒78°C, 39.7 mL (111 mmol) of a 2.8 N solution of
butyllithium in hexane was added dropwise under
stirring, and the mixture was stirred for 30 min at
‒10°C. The mixture was cooled to ‒78°C, a solution of
6.0 g (37.0 mmol) of diester 5 in 30 mL of THF was
added dropwise, and the mixture was allowed to warm
up to ‒20°C over a period of 45 min. The mixture was
cooled again to ‒78°C, 11.5 mL (185 mmol) of methyl
iodide was added dropwise, and the mixture was
stirred for 30 min at 0°C and treated with a 1 M solu-
tion of citric acid. The organic layer was separated,
the aqueous layer was extracted with ethyl acetate
(2×50 mL), the extracts were combined with the or-
ganic phase, dried over MgSO4, filtered, and evaporat-
ed, and the residue was subjected to silica gel chroma-
tography using petroleum ether–ethyl acetate (4:1) as
eluent. Yield 5.21 g (80%), light yellow liquid, de 86%
(GLC). IR spectrum, ν, cm–1: 3492, 2988, 2956, 1742,
1
1428, 1340, 1040. H NMR spectrum, δ, ppm: 0.87 d
(3H, CH3, J = 6.7 Hz), 1.81–1.91 m (1H, 3-H), 3.56–
3.68 m (2H, 1-H, 2-H), 3.72–3.79 m (2H, 4-H), 4.24–
4.34 m (1H, 1-H). 13C NMR spectrum, δC, ppm: 13.6,
37.2, 65.0, 67.2, 74.0. Found, %: C 49.81; H 10.11.
C5H12O3. Calculated, %: C 49.98; H 10.07.
(2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-
propan-1-ol (8). A catalytic amount of p-toluenesul-
fonic acid was added under stirring to a solution of
2.95 g (24.6 mmol) of 7 in 60 mL of acetone. The
mixture was stirred for 6 h at room temperature,
neutralized with sodium hydrogen carbonate, filtered,
and evaporated, and the residue was purified by silica
gel chromatography (petroleum ether–EtOAc, 5:1).
1
1439, 1212, 1143. H NMR spectrum, δ, ppm: 1.26 d
(3H, CH3, J = 6.7 Hz), 2.99–3.02 m (1H, 3-H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 6 2016

SYNTHESIS OF A CHIRAL BUILDING BLOCK
885
Yield 3.38 g (86%), light yellow liquid, de 86%
(GLC). IR spectrum, ν, cm–1: 3398, 2986, 2936, 2880,
1380, 1371, 1216, 1063, 1043. H NMR spectrum, δ,
ppm: 0.82 d (3H, CH3, J = 7.0 Hz), 1.36 s and 1.41 s
[3H each, C(CH3)2], 1.81–1.89 m (1H, 2-H), 3.57–
3.75 m (4H, 1-H, 5′-H), 4.06–4.11 m (1H, 4′-H).
13C NMR spectrum, δC, ppm: 13.0, 25.7, 26.6, 39.2,
67.4, 68.7, 80.7, 109.4. Found, %: C 59.94; H 9.95.
C8H16O3. Calculated, %: C 59.97; H 10.07.
with the organic phase, dried over MgSO4, filtered, and
evaporated, and the residue was purified by silica gel
chromatography (petroleum ether–EtOAc, 10:1). Yield
3.38 g (85%), light yellow liquid, de 86% (GLC). IR
spectrum, ν, cm–1: 2985, 2933, 2875, 1438, 1197,
1
1
1120, 721, 695, 541. H NMR spectrum, δ, ppm:
1.01 d (3H, CH3, J = 7.0 Hz), 1.29 s and 1.36 s [3H
each, C(CH3)2], 2.54–2.60 m (1H, 2′-H), 3.54–3.56 m
(1H, 5-H), 3.91–3.99 m (2H, 4-H, 5-H), 6.32 d (1H,
Br2C=CH, J = 9.4 Hz). 13C NMR spectrum, δP, ppm:
15.6, 25.3, 26.3, 41.2, 67.2, 78.3, 90.2, 108.8, 139.5.
Found, %: C 34.51; H 4.44; Br 50.78. C9H14Br2O2.
Calculated, %: C 34.42; H 4.49; Br 50.89.
(2R)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-
propanal (9). A solution of 3.2 mL (37.5 mmol) of
oxalyl chloride in 60 mL of methylene chloride was
cooled to ‒60°C, a solution of 5.3 mL (75.0 mmol) of
dimethyl sulfoxide in 10 mL of methylene chloride
was added dropwise under stirring, and the mixture
was stirred for 10 min at ‒60°C. The mixture was
cooled to ‒78°C, a solution of 3.0 g (18.8 mmol)
of 8 in 10 mL of methylene chloride was added, the
mixture was stirred for 15 min at ‒60°C and cooled to
‒78°C, 13.0 mL (93.8 mmol) of triethylamine was
added, and the mixture was stirred for 10 min at
‒78°C. The mixture was then allowed to warm up to
room temperature, treated with water, and saturated
with sodium chloride, the organic layer was separated,
and the aqueous phase was extracted with methylene
chloride (2×50 mL). The extracts were combined with
the organic phase, dried over MgSO4, filtered, and
evaporated, and the residue was purified by silica gel
chromatography (petroleum ether–EtOAc, 5:1). Yield
2.28 g (77%), light yellow liquid, de 86% (GLC). IR
spectrum, ν, cm–1: 2986, 2938, 1729, 1381, 1371,
(4S)-2,2-Dimethyl-4-[(2S)-4-(trimethylsilyl)but-
3-yn-2-yl]-1,3-dioxolane (3). A solution of 3.0 g
(9.55 mmol) of 10 in 60 mL of THF was cooled to
‒78°C, 7.8 mL (22.0 mmol) of a 2.8 N solution of
butyllithium in hexane was added dropwise under
stirring, the mixture was stirred for 30 min at ‒30°C
and cooled to ‒78°C, and 2.4 mL (19.1 mmol) of
freshly distilled chloro(trimethyl)silane was added
dropwise. The mixture was allowed to warm up to 0°C
and neutralized with aqueous NaHCO3, the organic
layer was separated, and the aqueous phase was ex-
tracted with ethyl acetate (2×50 mL). The extracts
were combined with the organic phase, dried over
MgSO4, filtered, and evaporated, and the residue was
subjected to silica gel chromatography (petroleum
ether–EtOAc, 40:1). Yield 1.64 g (76%), colorless
liquid, [α]D20 = +8.0 (c = 0.23, CH2Cl2), de 99% (GLC).
IR spectrum, ν, cm–1: 2958, 2925, 2850, 1456, 1379,
1
1
1250, 1067, 844. H NMR spectrum, δ, ppm: 0.15 s
1214, 1162, 1062. H NMR spectrum, δ, ppm: 1.07 d
[9H, Si(CH3)3], 0.97 d (3H, CH3, J = 7.0 Hz), 1.37 s
and 1.44 s [3H each, C(CH3)2], 2.68–2.73 m (1H, 3-H),
3.82–3.87 m and 4.01–4.04 m (1H each, 5′-H), 4.11–
4.15 m (1H, 4′-H). 13C NMR spectrum, δC, ppm: 0.0,
16.0, 25.5, 26.3, 29.6, 66.7, 77.6, 81.5, 106.4, 109.8.
Mass spectrum: m/z 227 [M + H]+. Found, %: C 63.80;
H 9.84; Si 12.52. C9H14O2Si. Calculated, %: C 63.66;
H 9.80; Si 12.41. M 226.39.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-03-00 559_a) using the equipment of the
Khimiya Joint Center (Ufa Institute of Chemistry,
Russian Academy of Sciences).
(3H, CH3, J = 7.0 Hz), 1.35 s and 1.41 s [3H each,
C(CH3)2], 2.56–2.61 m (1H, 2-H), 3.64–3.73 m (2H,
5′-H), 4.10–4.14 m (1H, 4′-H), 9.77 s (1H, CHO).
13C NMR spectrum, δC, ppm: 9.9, 25.3, 26.5, 49.6,
67.4, 75.9, 109.9, 203.2. Found, %: C 60.80; H 8.79.
C8H14O3. Calculated, %: C 60.74; H 8.92.
(4S)-4-[(2S)-4,4-Dibromobut-3-en-2-yl]-2,2-di-
methyl-1,3-dioxolane (10). A solution of 16.6 g
(63.3 mmol) of triphenylphosphine in 40 mL of methy-
lene chloride was added dropwise under stirring to
a solution of 10.5 g (31.6 mmol) of carbon tetra-
bromide in 40 mL of methylene chloride, cooled to
0°C. The mixture was stirred for 10 min at 0°C, a solu-
tion of 2.0 g (12.7 mmol) of 9 in 20 mL of methylene
chloride was added, and the mixture was stirred for
15 min at 0°C and neutralized with a solution of
sodium hydrogen carbonate. The organic phase was
separated, the aqueous phase was extracted with meth-
ylene chloride (2×50 mL), the extracts were combined
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