Stereoselective synthesis of (S,E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-(tritylthio)hept-4-enoate

Article abstract of DOI:10.2174/157017811794557868

(S E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-(tritylthio)hept-4-enoate was synthesized from commercially available L-malic acid by the Julia-Kocienski olefination coupling method. This method provides a concise synthetic strategy for (S,E) -3-hydroxy-7-mercaptohept-4-enoic acid.

Full text of DOI:10.2174/157017811794557868

66
Letters in Organic Chemistry, 2011, 8, 66-69
Stereoselective Synthesis of (S,E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-
(tritylthio)hept-4-enoate
Zhiyi Yaoa, Xin Zengb, Wei Yic and Sheng Jiang*,b
aCollege of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, P. R. China
bKey Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of
Sciences, Guangzhou, P. R. China
cNovo Nordisk Pharmaceuticals Sci. & Tech. Co. Ltd, Beijing, P. R. China
Received October 12, 2010: Revised December 14, 2010: Accepted December 20, 2010
Abstract: (S,E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-(tritylthio)hept-4-enoate was synthesized from commercially
available L-malic acid by the Julia-Kocienski olefination coupling method. This method provides a concise synthetic
strategy for (S,E) -3-hydroxy-7-mercaptohept-4-enoic acid.
Keywords: (S,E)-3-hydroxy-7-mercaptohept-4-enoic acid, Julia-Kocienski olefination coupling, L-malic acid.
INTRODUCTION
and 8, which were synthesized from propane-1,3-diol and L-
malic acid, respectively [15]. The crucial olefination
coupling of 7 and 8 proceeded smoothly to yield the desired
product 9 as a mixture of E/Z stereoisomers (E/Z
approximately.8:1, as determined by H-NMR) with a yield
of 80%.
Inhibition of histone deacetylase (HDAC) activity has
been clinically validated as a novel therapeutic strategy for
the treatment of cancer [1]. To date, natural products, such as
largazole, spiruchostatins A and B, and the depsipeptides
FR901375 and K228, have been reported to have potent
HDAC-inhibitory activity [2-6]. All these natural products
have a common motif, (S,E)-3-hydroxy-7-mercaptohept-4-
enoic acid (Fig. 1), which is essential for their HDAC-
inhibitory activity. (S,E)-3-hydroxy-7-mercaptohept-4-enoic
acid contains a seven-carbon framework with four functional
groups and a chiral center. Although the preparation of (S)-3-
hydroxy-7-mercaptohept-4-enoic acid has been reported
during the total synthesis of natural products by several
groups [7-15], it is nonetheless worthwhile to develop a
more concise route.
1
At this point, we assumed that the steric structure of
aldehyde 7 was the key factor for olefination. To verify this
idea, we reversed the coupling partners, preparing aldehyde
20 by the monoprotection of propane-1,3-diol and Swern
oxidation.
Our new synthesis route is outlined in Scheme 2.
Treatment of L-malic acid with SOCl2 in methanol gave its
dimethyl ester 11, which was then reduced by borane–
dimethylsulfide (BH3–Me2S). The diol 12 was sequentially
silylated by tert-butyl TBSCl to generate 13 in 90% yield.
The ester group of 13 was saponified by KOH, and then
coupled with 2-(trimethylsilyl) ethanol to provide the 2-
(trimethylsilyl)ethyl (TSE)-protected acid 15, which gave
alcohol 16 after selective removal of the t-butyldimethylsilyl
(TBS)-protecting group on the primary alcohol. The
Mitsunobu method was used for the formation of tetrazole
18, which was then treated by m-CPBA to yield the sulfone
19. Using NaHMDS as the base, the olefination coupling
process generated compound 21 (E/Z approximately 4:1, as
Recently, we have published an efficient method for the
total synthesis of largazole, in which a new approach for the
synthesis of 3-hydroxy-7-mercaptohept-4-enoic acid was
also developed [15]. This approach involved the production
of (S,E)-3-hydroxy-7-mercaptohept-4-enoic acid by Julia-
Kocienski olefination. The olefination led to geometric
isomers with chirality at C5 and the E/Z ratio being 8:1,
moreover, the derivatives with trans geometry had better
biological activity. Therefore, we proceeded to develop an
improved strategy, which would produce a more favorable
E/Z ratio during the synthesis of (S,E)-3-hydroxy-7-
mercaptohept-4-enoic acid.
1
determined by H-NMR) at –78 °C in 35% yield. After the
selective removal of the primary TBS-protecting group, the
Mitsunobu reaction was carried out with TrtSH to give a
mixture of the cis and trans isomers of 23, which could then
be separated on a silica gel to provide the desired E-olefinic
23.
RESULTS AND DISCUSSION
As outlined in Scheme 1, we initially pursued the
synthesis of 1 through Julia-Kocienski olefination between 7
EXPERIMENTAL
Solvents were purified in a conventional manner. Thin-
layer chromatography was carried out on precoated GF254
plates (Qingdao, China). Flash-column chromatography was
conducted on silica gel (200–300 mesh, Qingdao, China).
*Address correspondence to these authors at the Key Laboratory of
Regenerative Biology, Guangzhou Institute of Biomedicine and Health,
CAS, Guangzhou, P. R. China; Tel: +86 18688888237; Fax: +86 20
32015299; E-mail: jiang_sheng@gibh.ac.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Stereoselective Synthesis of (S,E)-2-(trimethylsilyl)ethyl
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
67
OH
O
HS
OH
1: (S,E)-3-hydroxy-7-mercaptohept-4-enoic acid
R
OH
O
Me
Me
N
Me
O
Me
H
NH
O
NH
S
S
S
S
O
O
HN
HN
O
H
N
O
H
N
O
O
O
Me
O
Me
Me
2: spiruchostatin A (R=Me)
3: spiruchostatin B (R=Et)
4: FK228
O
Me
H
OH
N
O
N
S
O
H
S
N
O
NH
O
Me
Me
S
N
S
NH
O
O
O
O
H
N
O
S
N
H
O
Me
Me
6: largazole
5: FR901375
Fig. (1). Structures of (1) (S,E)-3-hydroxy-7-mercaptohept-4-enoic acid (2) spiruchostatin A, (3) spiruchostatin B, (4) FK228, (5) FR901375
and (6) Largazole.
OTBS
O
O
S
O
TBSO
O
Ph
N
TBSO
a
H
Si
+
N
TBSO
O
Si
O
O
N
N
9
8
7
Scheme 1. Preparation of (S)-2-(trimethylsilyl)ethyl 3,7-bis(tert-butyldimethylsilyloxy)hept-4-enoate, compound 9 (a) NaHMDS, THF, –78
°C, 80%.
Optical rotations were determined with
a
Perkin-
vacuum. Flash chromatography on silica gel(eluent:
heptane/EtOAc = 6/1, v/v) yielded 18 (12.36 g, 91%) as a
white solid. [ꢀ]23D = –11.5(c = 1.0, CHCl3). 1H-NMR (400
MHz, CDCl3): ꢀ 7.55 (m, 5H), 4.54 (m, 1H), 4.15 (m, 2H),
3.66 (dd, J = 13.6, 5.2, 1H ), 3.58 (dd, J = 12.8, 5.6, 1H ),
2.64 (dd, J = 15.2, 5.6, 1H), 2.57 (dd, J = 15.2, 5.6, 1H), 0.98
(t, J = 8.8, 2H), 0.85 (s, 9H) , 0.05(d, J = 8.8, 6H), 0.04 (s,
9H) ppm. 13C-NMR (100 MHz, CDCl3) : 130.1, 129.7,
123.9, 67.8, 62.8, 41.7, 40.0, 25.7, 17.9, 17.4, –1.6, –4.7, –
4.9 pm. MS (EI, m/z): 495 (M+ + 1).
Elmermodel241MC polarimeter. 1H-NMR and 13C-NMR
spectra were detected using a Bruker spectrometer, with
tetramethylsilane (TMS) as an internal standard, and the
chemical shifts were recorded in parts per million (ppm).
(S)-2-(trimethylsilyl)ethyl 3-(tert-butyldimethylsilyloxy)-
4-(1-phenyl-1H-tetrazol-5-ylthio) butanoate (18)
DEAD (4.36 g, 25.0 mmol) was added dropwise to a
solution of 16 (8.355 g, 25.0 mmol) and Ph3P (6.55 g, 25.0
mmol) in anhydrous THF (125 mL) at 0 °C. The reaction
mixture was stirred at room temperature overnight, washed
with water (50 mL), and extracted with EtOAc (3 ꢀ 60 mL),
the combined organic phases were dried under anhydrous
Na2SO4 and the solvent was removed by evaporation under
(S)-2-(trimethylsilyl)ethyl 3-(tert-butyldimethylsilyloxy)-
4-(1-phenyl-1H-tetrazol-5-ylsulfonyl)butanoate (19)
Tetrazole 18 (4.94 g, 10.0 mmol) was dissovled in
CH2Cl2 (50 mL) and cooled to 0 °C. M-CPBA (77%, 2.35 g,

68
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
OH
Yao et al.
OH
O
O
O
OH
O
TBSO
OTBS
a
H3CO
b
c
HO
OCH3
OCH3
OH
OCH3
O
O
OH
13
10
12
11
O
TBSO
O
TBSO
OTBS
O
TBSO
g
Si
e
d
f
Si
O
OH
O
Ph
HS
N
OTBS
OH
O
N
17
16
15
N
14
N
TBSO
O
N
N
TBSO
N
N
O
i
Si
h
Si
N
O
N
S
O
O
S
N
N
TBSO
O
O
Ph
18
20
19
Ph
OTBS
OTBS
O
k
Si
j
TBSO
O
O
Si
HO
O
21
22
OH
O
Si
TrtS
23
Scheme 2. Preparation of (S,E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-(tritylthio)hept-4-enoate 23 (a) SOCl2/MeOH, reflux 92%; (b) borane
(BH3), Sodium borohydride (NaBH4), THF, rt, 89%; (c) tert-butyl dimethyl chlorosilane (TBSCl), imidazole, dimethyl formamide (DMF), rt,
92%; (d) KOH, THF/H2O;(e) dicyclohexylcarbodiimide (DCC), trimethylsily ethanol (TMSEOH), rt, 81% in two steps; (f) camphorsulfonic
acid (CSA), CHCl3/CH3OH, –10 °C, 80%; (g) Diethyl azodicarboxylate (DEAD), Ph3P, THF, rt, 91%; (h) m-chloroperbenzoic acid (m-
CPBA),CH2Cl2, rt, 85%; (i) sodium hexamethyldisilazane (NaHMDS), THF, –78 °C, 35%; (j) CSA, CHCl3/CH3OH, 0 °C, 89%; (k) 1.
triphenylmethyl thiol (TrtSH), DEAD, Ph3P, rt, 70%; 2. CSA, CHCl3/CH3OH, rt, 61%.
10.5 mmol) was added in small portions, and the resulting
mixture was stirred at room temperature overnight. The
reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure to give a yellow oil 19
(4.47 g, 85%), which was directly used in the next step
without further purification. [ꢀ]23D = –7.5 (c = 1.0, CHCl3).
1H-NMR (400 MHz, CDCl3): ꢀ 7.68–7.57 (m, 5H), 4.78 (m,
1H), 4.18–4.12 (m, 4H), 2.77 (dd, J = 13.6, 6.4, 1H), 2.57
(dd, J = 13.6, 5.2, 1H), 0.98 (t, J = 8.4, 2H), 0.82 (s, 9H) ,
0.07 (d, J = 7.2, 6H), 0.03 (s, 9H) ppm. 13C-NMR (100 MHz,
CDCl3) : 131.4, 129.6, 125.2, 64.1, 63.1, 61.8, 42.0, 29.6,
25.6, 17.8, 17.4, –1.59, –4.9, –5.0 ppm. MS (EI, m/z): 527
(M+ + 1).
heptane/EtOAc = 10/1, v/v) yielded 21 (0.85 g, 35%) as a
1
light yellow oil. [ꢀ]23 = –21.6 (c = 0.5, CHCl3). H-NMR
D
(400 MHZ, CDCl3): ꢀ 5.63 (dt, J = 15.6, 6.8, 1H), 5.49 (dd, J
= 15.6, 6.8, 1H ), 4.54 (dd, J = 12.4, 7.2, 1H), 4.14 (m, 2H),
3.61 (t, J = 6.8, 2H), 2.49 (dd, J = 14.4, 8.4, 1H), 2.38 (dd, J
= 14.4, 5.2, 1H), 2.22 (dd, J = 13.2, 6.4, 2H), 0.97 (dd, J =
8.4, 6.8, 2H) , 0.89 (s, 9H), 0.85 (s, 9H), 0.07–0.03 (m, 21H)
ppm. 13C-NMR (100 MHz, CDCl3): 171.3, 134.0, 127.7,
126.4 (minor), 70.7, 66.1 (minor), 62.8, 62.5, 44.2, 35.7,
31.5 (minor), 26.0, 18.3, 17.3, –1.5, –4.2, –5.0, –5.3 pm. MS
(EI, m/z): 489 (M+ + 1).
(S, E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-(tritylthio)hept-
4-enoate (23)
(S, E) 2-(trimethylsilyl)ethyl 3,7-bis(tert-butyldimethyl-
silyloxy)hept-4-enoate (21)
The compound 21 (0.49 g, 1.0 mmol) was dissolved in
CH2Cl2/MeOH (4/1 v/v, 45 mL), then, CSA (0.23 g, 1.0
mmol) in MeOH (1.5 ml) was added at –10 °C. The reaction
mixture was vigorously stirred at –10 °C for 6 h under N2
atmosphere, and then quenched with NaHCO3 solution (5
mL). The resulting solution was successively washed with
water(3 ꢁ 50mL) and brine (3 ꢁ 50mL). The organic phase
was dried under anhydrous Na2SO4 and concentrated, to
yield the oil 22. DEAD (0.17 g, 1.0 mmol) was added
dropwise to a solution of 22 (0.37 g, 1.0 mmol), TrtSH
(0.276 g, 1.0 mmol), and Ph3P (0.262 g, 1.0 mmol) in
NaHMDS (1.0 M in THF, 5.0 mL) was added slowly
with a syringe into the flask contained a solution of 19 (2.63
g, 5.0 mmol) and 20 (0.94 g, 5.0 mmol) in anhydrous THF
(25 mL). The reaction mixture was stirred for 2 h at –78 °C
and then quenched by adding NH4Cl solution (5 mL). The
aqueous phase was extracted with EtOAc (3ꢀꢀ 30 mL). The
combined organic phases were dried under anhydrous
Na2SO4, and the solvent was removed by evaporation under
vacuum. Flash chromatography on silica gel (eluent:

Stereoselective Synthesis of (S,E)-2-(trimethylsilyl)ethyl
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
69
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(m, 15H), 5.53 (m, 1H), 5.37 (dd, J = 15.2, 6.0, 1H), 4.38
(m, 1H), 4.14 (m, 2H), 4.15 (t, J = 8.9, 2H), 2.42 (m, 2H),
2.04 (m, 2H) , 0.94 (m, 2H), 0.03 (s, 9H) ppm. 13C-NMR
(100 MHz, CDCl3): 172.6, 145.1, 132.2, 130.3, 129.7, 128.0,
126.7, 68.7, 66.7, 63.2, 41.7, 31.6, 31.5, 17.5, –1.4 ppm. MS
(EI, m/z): 542 (M+ + Na).
[5]
[6]
CONCLUSION
In summary, (S,E)-2-(trimethylsilyl)ethyl 3-hydroxy-7-
(tritylthio)hept-4-enoate was synthesized from commercial
materials with an overall yield of 5%. This method may
potentially be applicable for the synthesis of other analogs
for structure–activity relationship studies. The application of
this methodology to the preparation of novel largazole or
other natural product analogs for biological evaluation is
under way and will be reported in due course.
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ACKNOWLEDGEMENT
[11]
[12]
This project was supported by the National Natural
Science Foundation (Grant No. 20802078, 20972160), the
National Basic Research Program of China (973 Program,
Grant No. 2009CB940900), the Guangdong Natural Science
Foundation (Grant No. 8151066302000008), and the NN-
CAS Research Foundation (Grant No. NNCAS-2008-8).
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Zeng, X.; Yin, B.; Hu, Z.; Liao, C.; Liu, J.; Li, S.; Li, Z.; Nicklaus,
M. C.; Zhou, G.; Jiang, S. Total synthesis and biological evaluation
of largazole and derivatives with promising selectivity for cancers
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