Synthesis of the northern fragment of an epothilone D analogue from (-)-carvone

Article abstract of DOI:10.1016/j.tet.2012.06.020

A simple and effective synthesis of the chiral thiazole-containing fragment of an epothilone D analogue from (-)-carvone is described.

Full text of DOI:10.1016/j.tet.2012.06.020

Tetrahedron 68 (2012) 6868e6872
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Synthesis of the northern fragment of an epothilone D analogue from (ꢀ)-carvone
*
Ruslan F. Valeev , Radmir F. Bikzhanov, Niyaz Z. Yagafarov, Mansur S. Miftakhov
Institute of Organic Chemistry, Ufa Research Centre, Russian Academy of Sciences, Prospect Oktyabrya, 71, 450054 Ufa, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2012
Received in revised form 17 May 2012
Accepted 6 June 2012
A simple and effective synthesis of the chiral thiazole-containing fragment of an epothilone D analogue
from (ꢀ)-carvone is described.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 15 June 2012
Keywords:
Epothilones
Thiazole-containing fragment
Carvone
Rubottom methodology
Oxidative cleavage
Wittig olefination
1. Introduction
2. Results and discussion
Among microtubule stabilizing natural products (taxol, dis-
codermolide, dictyostatin),1e4 the epothilones (Epo)5 are one of the
most perspective candidates for a new antitumour agents. Six Epo
derivatives are now at various stages of clinical assay,6 including the
Epo B lactam analogue ixabepilone,7 which received FDA approval
for the treatment of patients with locally advanced or metastatic
breast cancer in 2007. The main shortcomings of the natural Epo for
practical application are poor metabolic and chemical stability,
toxicity and lipophilicity. The poor metabolic stability of Epo is
expressed in a rapid in vivo lactone ring hydrolysis, the chemical
instability is due to the epoxide-containing side chain (nucleophilic
(ꢀ)-Carvone is considered as a very convenient chiral starting
compound for the synthesis of 4. It has a trisubstituted cis-double
bond, the correct stereochemistry at the chiral centre, the iso-
propylidene moiety as a methyl ketone equivalent and the keto
group suitable for the chemoselective oxidative cleavage.
To transform (ꢀ)-carvone into
for the oxidative ring cleavage, Rubottom methodology was used
(transformation of a ketone into an -hydroxy ketone via silyl enol
ether formation, followed by epoxidation and rearrangement).10
a-hydroxy ketones 10a,b suitable
a
a
-
Hydroxylation of ketones of the carvone series was reported pre-
viously.11 The acetonide 7, derived from epoxide 612 was converted
into TMS-enol ester 8 followed by m-CPBA oxidation, which yielded
ring opening) and the ‘southern’ b-hydroxy ester fragment (dehy-
dratation reactions and possible allylic ester transformations).
Accordingly, we concentrated on the synthesis of a novel Epo D
lactam analogue 3, in which the epoxide functional group is absent
(toxicity reduction) and the methylene unit is isosterically dis-
placed in the C15eC3 fragment (chemical stabilization). Danishefsky
and co-workers previously reported the synthesis of 12,13-desoxy
analogue of 18 and a lactam analogue 2, which exhibited in-
creased microtubulin stabilizing and advanced anticancer activity
in comparison with natural Epo B 1. Therefore, a new Epo derivative
3 is also of interest to SAR assay development.9 This paper describes
the synthesis of the thiazole-containing fragment 4 from the in-
expensive natural terpene (ꢀ)-carvone 5 Scheme 1.
the TMS-protected a-hydroxy ketone 9. Deprotection of the
TMSeether gave a mixture of isomeric hydroxy ketones 10a and
10b in a ratio of 10:1 (epimers at the hydroxyl-carrying centre). At
the same time, the diastereomeric ratio (3:2) established during the
formation of epoxide 6 was found to be unchanged by 13C NMR
spectroscopic analysis Scheme 2.
The mixture of 10a and 10b was then subjected to oxidative
cleavage by the action of lead tetraacetate13 in MeOH/C6H6 and the
crude product was reduced using Luche conditions14
(NaBH4eCeCl3). This reaction sequence gave the acetonide ester
12 in a good yield (88%). Acetonide ester deprotection followed by
oxidative cleavage according to the procedure described above
produced b-hydroxy ketone 14 Scheme 3.
The thiazole-containing phosphonium and phosphonate re-
agents 15aec were tested in the Wittig olefination reaction of
* Corresponding author. E-mail address: rusl0@yandex.ru (R.F. Valeev).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.020

R.F. Valeev et al. / Tetrahedron 68 (2012) 6868e6872
6869
O
1
S
S
OH
15
X
OH
N
O
N
2
3
N
H
O
O
O
OH
OH
OH
3
1, X=O
2, X=NH
O
S
N
OTBS
5
4
Scheme 1. Retrosynthetic analysis of the nothern fragment of the Epo D analogue 4.
hydroxy ketone 14. It was found that ylides 15a and 15b had low
activity in the olefination reaction while 15c smoothly reacted with
ketone 14 producing the (E)-olefin15 16 in high yield. Subsequent
hydroxyl protection and DIBAL-H reduction reactions afforded the
target alcohol 4 Scheme 4 Table 1.
grade and used without further purification unless otherwise in-
dicated. All reactions were carried in oven-dried glassware. TLC was
performed using Sorbfil STC-1A 110 mm layer, silica gel 5e17 pre-
coated foil plates. Column chromatography was carried out using
210e280 mesh silica gel. Optical rotations were measured using the
sodium D line at 589 nm on a Perkin Elmer, Model 241 MC polar-
imeter. IR (infrared spectra) was recorded on
a Shimadzu
3. Conclusion
IRPrestige-21 spectrometer as a Nujol mull or as neat thin films on
KBr plates. 1H and 13C NMR spectra were obtained using a Bruker
AM-300 (300 MHz for 1H and 75.47 MHz for 13C) as solutions in
CDCl3 (Aldrich Chemical Company; spectra grade). Mass spectra
were recorded on Shimadzu LCMS QP-2010EV (APCI) spectrometer.
Elemental analyses were carried on a Euro EA 3000 CHNS-analyzer.
We have developed a synthesis of an Epo D analogue fragment
from the known (ꢀ)-carvone. The prepared fragment will be used
for the total synthesis of a novel Epo D analogue in our future
investigations.
4. Experimental
4.1. General
4.2. (5R,40RS)-2-Methyl-5-(20,2040-trimethyl-10,30-dioxolan-40-
yl)cyclohex-2-en-1-one (7)
Solvents were purified and dried before used by standard pro-
cedures. Reagents were generally the best quality commercial
To a stirred solution of 612 (7.00 g, 42.2 mmol) in dry acetone
(60 mL) was added BF3$Et2O (9.53 g, 84.3 mmol) under Ar at room
O
TMSO
O
c
a
b
O
O
O
O
O
6
7
8
O
O
O
d
+
TMSO
HO
O
HO
O
O
O
O
O
9
10 a
10 b
dr 10 : 1
a) BF3 OEt2, Me2CO, rt, 1 h, 93%; b) LDA, TMSCl, THF, - 78 oC, 1 h, quant.; c)
m-CPBA, 1 M aq. NaHCO3, CH2Cl2, 10 oC, 2 h, 93%; d) TBAF, THF, 0-10 oC, 20 min, 83%.
Scheme 2. Synthesis of hydroxy ketones 10a,b via the Rubottom reaction.

6870
R.F. Valeev et al. / Tetrahedron 68 (2012) 6868e6872
O
MeO2C
MeO2C
HO
c
b
a
HO
O
O
O
O
O
O
O
10 a, b
11
12
CO2Me
MeO2C
HO
d
O
OH
OH
OH
13
14
o
a) Pb(OAc)4, MeOH-C6H6 (1:1), 0 C to rt, 20 min, 92%; b) NaBH4, CeCl3 7H2O, MeOH, 5
oC to rt, 1 h, 96%; c) 1% aq. HCl, THF, 50 oC, 5 h, 85%; d) Pb(OAc)4, MeOH-C6H6 (1:1), 0 oC
to rt, 20 min, 96%.
Scheme 3. Oxidative cleavage of hydroxy ketones 10a,b and synthesis of the desired compound 14.
temperature. The reaction was monitored by TLC (20% ethyl ace-
tate/petroleum ether) and after stirring for 1 h, NaHCO3 was added
following, which the solution was concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (50 mL),
washed with water (40 mL), dried over MgSO4 and concentrated.
Purification of the product by column chromatography (10% ethyl
acetate/petroleum ether) afforded 7 (8.78 g, 93%, a mixture of di-
astereoisomers at C40 in a ratio of 3/2) as a light yellow oil; [Found:
C, 69.4; H, 8.7. C13H20O3 requires C, 69.64; H, 8.93%]; Rf (20% ethyl
acetate/petroleum ether) 0.53; nmax (Nujol mull) 2934, 2876, 1676,
4.3. Trimethyl (3R,40RS)-{[6-methyl-3-(20,20,40-trimethyl-10,30-
dioxolan-40-yl)cyclohexa-1,5-dien-1-yl]oxy}silane (8)
A solution of diisopropylamine (9.37 mL, 67.0 mmol) in tetra-
hydrofuran (40 mL) was cooled to ꢀ78 ꢁC, a 2.0 M solution of n-
butyllithium in hexane (33.5 mL, 67.0 mmol) was added dropwise
under stirring, the mixture was stirred for 30 min at ꢀ10 ꢁC and
cooled to ꢀ78 ꢁC, and a solution of compound 7 (7.50 g, 33.5 mmol)
in tetrahydrofuran (10 mL) was added dropwise. The mixture was
allowed to warm up to ꢀ40 ꢁC, stirred for 40 min at that temper-
ature, and cooled to ꢀ78 ꢁC, chloro(trimethyl)silane (8.50 mL,
67.0 mmol) was added dropwise. The mixture was stirred for 1 h at
ꢀ70 ꢁC until the initial compound disappeared and was then
treated with a saturated aqueous solution of sodium chloride. The
organic phase was separated, the aqueous phase was extracted
with methylene chloride (2ꢂ30 mL), and the extracts were com-
bined with the organic phase, dried over MgSO4, filtered, and
evaporated to provide 8 (9.91 g, quant.) as a yellow oil. The product
was used in the next step without chromatographic purification.
1379, 1369, 1250, 1211, 1059, 733 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3):
1.27 (1.8H, s, CMe), 1.30 (1.2H, s, CMe), 1.38 (3H, s, OCMe), 1.41 (3H, s,
OCMe), 1.79 (3H, s,]CMe), 2.18e2.26 (3H, m,]CHCH, CH2CH,
CHC]O), 2.44e2.66 (2H, m,]CHCH, CHC]O), 3.71 (0.4H, d, J
2.0 Hz, OCH), 3.73 (0.6H, d, J 2.0 Hz, OCH), 3.88e3.93 (1H, m, OCH),
6.73e6.75 (0.4H, m,]CH), 6.78e6.80 (0.6H, m,]CH); dC (75 MHz,
CDCl3/CHCl3) 15.5, 21.8, 22.6, 26.5, 26.8, 27.2, 27.7, 39.4, 40.2, 43.3,
43.5, 72.1, 72.4, 81.6, 81.8, 109.3, 135.1, 135.3, 144.2, 144.8, 199.0,
199.6; m/z (APCI) 225 (18, MHþ), 167 (100), 149 (52%).
CO2Me
b
S
CO2Me
a
N
O
CH2OH
CH2OH
16
14
OH
S
CO2Me
S
c
N
N
OTBS
OTBS
4
17
a) i. 15c, NaHMDS, THF, - 78 oC, 1 h; ii. 14, - 78 to - 30 oC, 12 h, 86%; b) TBSCl, imidazole,
DMAP, CH2Cl2, rt, 4 h, 96%; c) DIBAL-H, CH2Cl2, - 78 to - 30 oC, 1 h, 80%.
Scheme 4. Synthesis of the target compound 4.

R.F. Valeev et al. / Tetrahedron 68 (2012) 6868e6872
6871
Table 1
1.8 Hz, CHOH), 4.08 (0.6H, d, J 1.8 Hz, CHOH), 6.66e6.67 (0.6H, m,]
CH), 6.76e6.77 (0.4H, m,]CH); dC (75 MHz, CDCl3/CHCl3) 13.9, 15.2,
19.6, 20.3, 20.6, 24.2, 26.2, 26.8, 27.1, 27.4, 52.7, 54.1, 72.0, 74.8, 75.9,
81.4, 82.3, 111.4, 113.1, 135.2, 136.8, 144.9, 146.4, 199.8, 200.3.
The testing of thiazole-containing phosphonium and phosphoranium reagents
15aec in the Wittig olefination reaction of 14
S
X
N
4.5. Methyl (2Z,5R,40RS)-2-methyl-6-oxo-5-(20,20,40-trimethyl-
10,30-dioxolan-40-yl)hex-2-enoate (11)
15
Lead tetraacetate (13.0 g, 29.3 mmol) was added with stirring at
Entry
a
X
Yield of 16, %
0
ꢁC to a solution of the isomeric mixture of 10a and 10b (5.40 g,
22.5 mmol) in methanolebenzene (1:1, 40 mL), the mixture was
stirred for 20 min at room temperature, ethylene glycol (0.42 g,
6.77 mmol) and water (30 mL) were added, and the mixture was
stirred for 10 min and treated with ether (40 mL). The extract was
dried over MgSO4, filtered, and evaporated to provide 11 (5.59 g,
92%) as a yellow oil. The product was used in the next step without
chromatographic purification.
O
20
P(OMe)2
b
c
PþPh3Clꢀ
53
86
P
þBu3Clꢀ
4.4. (40RS,5R,6RS)-2-Methyl-5-(20,20,40-trimethyl-10,30-
dioxolan-40-yl)-6-[(trimethylsilyl)oxy]cyclohex-2-en-1-one (9)
4.6. Methyl (2Z,5R,40RS)-6-hydroxy-2-methyl-5-(20,20,40-
trimethyl-10,30-dioxolan-40-yl)hex-2-enoate (12)
Crude compound 8 (9.91 g, 33.5 mmol) was dissolved in methy-
lene chloride (40 mL), a 1 M aqueous solution of NaHCO3 (33 mL) was
added, and 70% m-chloroperoxybenzoic acid (10.7 g, 43.5 mmol) was
added in three portions (at 15-min intervals) under stirring at 10 ꢁC.
The mixture was stirred for 2 h at 10 ꢁC then a saturated aqueous
solution of Na2S2O3 was added, the mixture was stirred for 15 min,
and the organic phase was separated, washed with a saturated
aqueous solution of NaHCO3, dried over MgSO4, filtered, and evap-
orated to provide 9 (9.71 g, 93%) as a yellow oil. The product was used
in the next step without chromatographic purification.
Compound 11 (5.59 g, 20.7 mmol) was dissolved in methanol
(30 mL), CeCl3$7H2O (7.71 g, 20.7 mmol) was added with stirring,
the mixture was cooled to 5 ꢁC, NaBH4 (0.79 g, 20.7 mmol) was
added, then the mixture was stirred for 1 h at room temperature.
The mixture was then treated with water (60 mL), stirred for
15 min, saturated with sodium chloride, then extracted with ethyl
acetate (3ꢂ30 mL), dried over MgSO4, filtered, and evaporated.
Purification of the product by column chromatography (30% ethyl
acetate/petroleum ether) afforded 12 (5.41 g, 96%, a mixture of
diastereoisomers at C40 in a ratio of 3/2) as a colourless oil; [Found:
C, 61.7; H, 8.7. C14H24O5 requires C, 61.76; H, 8.82%]; Rf (30% ethyl
acetate/petroleum ether) 0.22; nmax (Nujol mull) 3449, 2957, 2938,
4.4.1. (5R,6S,40RS)-6-Hydroxy-2-methyl-5-(20,20,40-trimethyl-10,30-di-
oxolan-40-yl)cyclohex-2-en-1-one (10a) (a mixture of di-
astereoisomers at C4 in a ratio of 3/2). A solution of compound 9
0
1717, 1456, 1432, 1356, 1321 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 1.31
(9.71 g, 31.1 mmol) in tetrahydrofuran (30 mL) was cooled to 0 ꢁC,
a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran
(31 mL, 31.1 mmol) was added dropwise under stirring, and the
mixture was stirred for 20 min at 10 ꢁC and treated with a saturated
solution of sodium chloride. The organic phase was separated and
the aqueous phase was extracted with methylene chloride
(2ꢂ30mL), theextracts were combinedwith theorganicphase, dried
over MgSO4, filtered, and evaporated. Purification of the product by
column chromatography (15% ethyl acetate/petroleum ether) affor-
ded a mixture of 10a and 10b in a ratio of 10/1 (6.20 g, 83%) as a light
yellow oil; [Found: C, 64.8; H, 8.2. C13H20O4 requires C, 65.0; H,
8.33%]; Rf (20% ethyl acetate/petroleum ether) 0.19; nmax (Nujol mull)
(3H, s, OCMe), 1.38 (3H, s, OCMe), 1.33 (1.2H, s, CMe), 1.42 (1.8H, s,
CMe), 1.79e1.83 (1H, m, CH2CH), 1.90 (3H, s,]CMe), 2.40e2.52 (1H,
m,]CHCH), 2.63e2.74 (1H, m,]CHCH), 3.60e3.64 (1H, m, CHOH),
3.72e3.83 (5H, m, CO2Me, OCH, CHOH), 3.95 (0.4H, d, J¼8.6 Hz,
OCH), 3.99 (0.6H, d, J¼8.6 Hz, OCH), 5.90e6.01 (1H, m,]CH); dC
(75 MHz, CDCl3/CHCl3) 20.5, 21.8, 23.6, 26.6, 27.1, 26.8, 27.6, 48.4,
48.9, 51.4, 62.0, 62.2, 72.6, 73.7, 83.5, 84.2, 108.9, 109.1, 128.0, 128.5,
141.2, 142.1, 186.3; m/z (APCI) 273 (12, MHþ), 215 (100), 197 (41%).
4.7. Methyl (2Z,5R,6RS)-6,7-dihydroxy-5-(hydroxymethyl)-
2,6-dimethylhept-2-enoate (13)
3468, 2982, 2934, 2884, 1678, 1377, 1254, 1213, 1055, 870 cmꢀ1
; dH
To a stirred solution of 12 (4.80 g, 17.6 mmol) in tetrahydrofuran
(20 mL) was added 1% aqueous HCl (7 mL) at room temperature.
The mixture was heated to 50 ꢁC and after stirring for 5 h, NaHCO3
and MgSO4 were added, the tetrahydrofuran was decanted, and the
remaining white precipitate was washed with ethyl acetate
(3ꢂ30 mL). The combined organic phase was evaporated and the
resulting light yellow oil was purified by column chromatography
(ethyl acetate) to provide 13 (3.48 g, 85%, a mixture of di-
astereoisomers at C6 in a ratio of 3/2) as a colourless oil; [Found: C,
56.7; H, 8.5. C11H20O5 requires C, 56.90; H, 8.62%]; Rf (ethyl acetate)
0.23; nmax (Nujol mull) 3401, 3381, 2953, 1713, 1454, 1435, 1246,
(300 MHz, CDCl3/CHCl3) 1.26 (1.2H, s, CMe),1.29 (1.2H, s, OCMe),1.33
(1.8H, s, CMe), 1.36 (1.2H, s, OCMe), 1.37 (1.8H, s, OCMe), 1.40 (1.8H, s,
OCMe), 1.77 (3H, s,]CMe), 2.13e2.25 (2H, m,]CHCH, CH2CH),
2.38e2.44 (1H, m,]CHCH), 3.72e3.74 (1H, m, OCH), 3.82e3.91 (1H,
m, OCH), 4.01 (0.4H, d, J 9.5 Hz, CHOH), 4.12 (0.6H, d, J 9.5 Hz, CHOH),
6.66e6.67 (0.6H, m,]CH), 6.76e6.77 (0.4H, m,]CH); dC (75 MHz,
CDCl3/CHCl3) 13.9, 15.2, 19.6, 24.2, 26.2, 26.6, 26.8, 27.0, 27.1, 27.4,
48.8, 50.2, 71.8, 74.3, 76.6, 81.4, 82.3, 108.1, 109.6, 132.5, 133.0, 144.4,
146.4, 199.8, 200.3; m/z (APCI) 241 (21, MHþ), 183 (100), 165 (63%).
4.4.2. (5R,6R,40RS)-6-Hydroxy-2-methyl-5-(20,20,40-trimethyl-10,30-
1209, 1136, 1049 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 1.17 (1.2H, s,
dioxolan-40-yl)cyclohex-2-en-1-one (10b) (a mixture of di-
CMe), 1.19 (1.8H, s, CMe), 1.80e1.87 (1H, m, CH2CH), 1.89 (1.8H, s,]
CMe), 1.91 (1.2H, s,]CMe), 2.23e2.36 (1H, m,]CHCH), 2.41e2.46
(1H, m,]CHCH), 3.54e3.64 (1H, m, CCHOH), 3.72 (1.2H, s, CO2Me),
3.74 (1.8H, s, CO2Me), 3.75e3.85 (3H, m, CH2OH, CCHOH),
5.87e5.99 (1H, m,]CH); dC (75 MHz, CDCl3/CHCl3) 20.6, 21.1, 24.1,
26.5, 26.7, 45.6, 48.4, 51.8, 52.0, 60.0, 62.1, 66.6, 68.5, 74.0, 76.0,
128.7, 128.8, 141.9, 141.9, 176.6; m/z (APCI) 277 (81), 261 (100), 231
(13, [MꢀH]ꢀ), 173 (30%).
astereoisomers at C4 in a ratio of 3/2). Rf (20% ethyl acetate/petro-
0
leum ether) 0.19; nmax (Nujol mull) 3468, 2982, 2934, 2884, 1678,
1377, 1254, 1213, 1055, 870 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 1.26
(1.2H, s, CMe), 1.29 (1.2H, s, OCMe), 1.33 (1.8H, s, CMe), 1.36 (1.2H, s,
OCMe), 1.37 (1.8H, s, OCMe), 1.40 (1.8H, s, OCMe), 1.71 (3H, s,]CMe),
2.13e2.25 (2H, m,]CHCH, CH2CH), 2.60e2.66 (1H, m,]CHCH),
3.64e3.66 (1H, m, OCH), 3.82e3.91 (1H, m, OCH), 4.05 (0.4H, d, J

6872
R.F. Valeev et al. / Tetrahedron 68 (2012) 6868e6872
4.8. Methyl (2Z,5R)-5-(hydroxymethyl)-2-methyl-6-oxohept-
2-enoate (14)
2.64e2.72 (1H, m,]CHCH), 2.74 (3H, s, N]CMe), 2.79e2.87 (1H, m,
CH2CH), 3.61e3.74 (2H, m, CH2OSi), 3.76 (3H, s, CO2Me), 6.00 (1H, t,
J 7.0 Hz,]CH), 6.41 (1H, s,]CH), 6.91 (1H, s,]CHS); dC (75 MHz,
CDCl3/CHCl3) -5.5, 16.2, 18.1, 19.0, 20.6, 25.8, 29.8, 51.1, 52.2, 65.7,
114.6, 120.7, 127.2, 140.5, 141.6, 153.2, 164.1, 168.3; m/z (APCI) 410
(16, MHþ), 310 (100), 296 (10%).
Lead tetraacetate (7.94 g, 17.9 mmol) was added with stirring at
0
ꢁC to a solution of 13 (3.20 g, 13.8 mmol) in methanolebenzene
(1:1, 30 mL), the mixture was stirred for 20 min at room temper-
ature, ethylene glycol (0.25 g, 4.03 mmol) and water (20 mL) were
added, and the mixture was stirred for 10 min and then treated
with ethyl acetate. The organic phase was dried over MgSO4, fil-
tered, and evaporated, purification of the residue by column
chromatography (30% ethyl acetate/petroleum ether) afforded 14
(2.64 g, 96%) as a light yellow oil; [Found: C, 59.8; H, 7.8. C10H16O4
4.11. (2Z,5S,6E)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-
2,6-dimethyl-7-(20-methyl-10,30-thiazol-40-yl)hepta-2,6-dien-
1-ol (4)
requires C, 60.0; H, 8.0%]; Rf (ethyl acetate) 0.51; ½a D20
þ15.7, (c 0.8,
ꢃ
To a stirred solution of 17 (1.60 g, 3.91 mmol) in methylene
chloride (15 mL) at ꢀ78 ꢁC was added a 73% solution of DIBAL-H in
hexane (2.4 mL, 9.78 mmol), the reaction mixture was warmed to
ꢀ30 ꢁC and stirred for 1 h. A solution of MeOHeH2O (1:1, 30 mL) was
added dropwise, the mixture was allowed to warm to room tem-
perature and stirred for another 1 h. The white precipitate, which
formed was then filtered and washed with hot methylene chloride
(5ꢂ20 mL). The phases of the combined filtrate were separated, the
aqueous phase was saturated with NaCl and extracted with meth-
ylene chloride (3ꢂ20 mL). The combined organic phase was dried
over MgSO4, filtered and evaporated, the residue was purified by
column chromatography (20% ethyl acetate/petroleum ether) to
provide 4 (1.19 g, 80%) as a colourless oil; [Found: C, 62.8; H, 9.1; N,
3.5; S, 8.3. C20H35NO2SSi requires C, 62.99; H, 9.19; N, 3.67; S, 8.40%];
CH2Cl2); nmax (Nujol mull) 3412, 2953, 1718, 1701, 1458, 1437, 1264,
1244, 1204, 1132 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 1.89 (3H, s,]
CMe), 2.22 (3H, s, MeC]O), 2.23e2.24 (1H, m,]CHCH), 2.69e2.74
(2H, m,]CHCH, CH2CH), 3.73 (3H, s, CO2Me), 3.78 (2H, br s, CH2OH),
5.85e5.90 (1H, m,]CH); dC (75 MHz, CDCl3/CHCl3) 20.1, 26.9, 28.8,
51.1, 54.0, 61.5, 128.8, 139.0, 168.0, 210.6; m/z (APCI) 201 (32, MHþ),
183 (58), 139 (100), 109 (39%).
4.9. Methyl (2Z,5S,6E)-5-(hydroxymethyl)-2,6-dimethyl-7-(20-
methyl-10,30-thiazol-40-yl)hepta-2,6-dienoate (16)
A 1 M solution of NaHMDS in tetrahydrofuran (18.8 mL,
18.8 mmol) was added at ꢀ78 ꢁC with stirring under an argon at-
mosphere to a solution of tributylphosphonium reagent 15c (6.56 g,
18.8 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture
was stirred for 1 h, then a solution of ketone 14 (1.50 g, 7.50 mmol) in
tetrahydrofuran (5 mL) was added dropwise at ꢀ78 ꢁC. The reaction
mixture was stirred for 2 h at ꢀ78 ꢁC, warmed to ꢀ30 ꢁC and stirred
for another 12 h. A saturated aqueous solution of NH4Cl (50 mL) was
added, the layers were separated, the aqueous layer was extracted
with ethyl acetate (3ꢂ30 mL), the combined organic phase was
dried over MgSO4, filtered, and evaporated, purification of the res-
idue by column chromatography (30% ethyl acetate/petroleum
ether) afforded 16 (1.90 g, 86%) as a light yellow oil; [Found: C, 60.8;
H, 7.0; N, 4.7; S,10.8. C15H21NO3S requires C, 61.02; H, 7.12; N, 4.75; S,
Rf (25% ethyl acetate/petroleum ether) 0.19; ½a D20
ꢃ þ19.4, (c 2.17,
CH2Cl2); nmax (Nujol mull) 3433, 3053, 2980, 2927, 2856, 1265, 739,
704, 385 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 0.02 (6H, s, SiMe2), 0.87
(9H, s, SiCMe3), 1.77 (3H, s,]CMe), 1.94 (3H, s,]CMe), 2.20e2.39
(3H, m,]CHCH2, CH2CH), 2.67 (3H, s, N]CMe), 3.56e3.61 (1H, m,
CHOSi), 3.68e3.71 (1H, m, CHOSi), 4.00 (1H, d, J 12.0 Hz, CHOH), 4.18
(1H, d, J 12.0 Hz, CHOH), 5.23 (1H, t, J 7.0 Hz,]CH), 6.25 (1H, s,]CH),
6.83 (1H, s,]CHS); dC (75 MHz, CDCl3/CHCl3) -5.6, 17.2, 18.0, 18.8,
21.2, 26.3, 27.7, 51.4, 61.1, 65.1, 114.2, 119.9, 125.3, 135.9, 140.9, 152.7,
164.2; m/z (APCI) 382 (13, MHþ), 336 (100), 277 (16%).
Acknowledgements
10.85%]; Rf (50% ethyl acetate/petroleum ether) 0.22; ½a D20
ꢃ þ3.6, (c
1.7, CH2Cl2); nmax (Nujol mull) 3360, 3041, 2986, 1713, 1479, 1422,
This study was performed under financial support from the
Ministry of Education and Science of the Russian Federation (state
contract No 14.740.11.0367).
1242,1199 cmꢀ1
; dH (300 MHz, CDCl3/CHCl3) 1.88 (3H, s,]CMe), 2.02
(3H, s,]CMe), 2.43e2.50 (1H, m,]CHCH), 2.51e2.64 (1H, m,]
CHCH), 2.70 (3H, s, N]CMe), 2.72e2.83 (1H, m, CH2CH), 3.64e3.68
(2H, m, CH2OH), 3.73 (3H, s, CO2Me), 5.93 (1H, t, J 7.0 Hz,]CH), 6.40
(1H, s,]CH), 6.91 (1H, s,]CHS); dC (75 MHz, CDCl3/CHCl3) 16.0,19.1,
20.6, 29.7, 51.4, 52.0, 64.1,115.3,121.4,128.1,140.1,140.7,152.7,164.5,
168.2; m/z (APCI) 296 (12, MHþ), 277 (100), 219 (19%).
References and notes
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4.10. Methyl (2Z,5S,6E)-5-({[tert-butyl(dimethyl)silyl]oxy}
methyl)-2,6-dimethyl-7-(20-methyl-10,30-thiazol-40-yl)hepta-
2,6-dienoate (17)
3. Harris, C. R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434e8456.
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consumed (w4 h, TLC monitoring). The solution was then con-
centrated and the residue was purified by column chromatography
(6% ethyl acetate/petroleum ether) to provide 17 (2.0 g, 96%) as
a colourless oil; [Found: C, 61.5; H, 8.4; N, 3.3; S, 7.7. C21H35NO3SSi
requires C, 61.61; H, 8.56; N, 3.42; S, 7.82%]; Rf (10% ethyl acetate/
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petroleum ether) 0.18; ½a D20
ꢃ
þ1.3, (c 1.37, CH2Cl2); nmax (Nujol mull)
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2951, 2928, 2857, 1715, 1252, 1134, 1105, 837, 775, 368 cmꢀ1
;
dH
(300 MHz, CDCl3/CHCl3) 0.07 (6H, s, SiMe2), 0.91 (9H, s, SiCMe3),
1.91 (3H, s,]CMe), 2.02 (3H, s,]CMe), 2.43e2.52 (1H, m,]CHCH),