An efficient synthesis of the C27-C45 fragment of lagunamide A, a cyclodepsipeptide with potent cytotoxic and antimalarial properties

Article abstract of DOI:10.1016/j.tetasy.2013.11.020

An efficient and stereoselective synthesis of the entire C27-C45 moiety of lagunamide A has been achieved from 1-[(4S)-4-benzyl-2-thioxothiazolidin-3-yl] propan-1-one in six steps with 22% overall yield. The key step in the synthesis is an asymmetric acetal aldol reaction featuring the enantioselective addition of a chiral thiazolidinethione-derived titanium enolate to an acetal to establish the stereochemistry at C39.

Full text of DOI:10.1016/j.tetasy.2013.11.020

Tetrahedron: Asymmetry 25 (2014) 187–192
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient synthesis of the C27–C45 fragment of lagunamide A, a
cyclodepsipeptide with potent cytotoxic and antimalarial properties
Hui-Ming Liu a, Chieh-Yu Chang b, Ya-Chi Lai c, Mei-Due Yang c, Ching-Yao Chang d,
⇑
a Department of Safety, Health and Environmental Engineering, Hungkuang University, Shalu, Taichung 433, Taiwan, ROC
b Department of Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan, ROC
c Department of Clinical Nutrition, China Medical University Hospital, Taichung 404, Taiwan, ROC
d Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 October 2013
Accepted 28 November 2013
An efficient and stereoselective synthesis of the entire C27–C45 moiety of lagunamide A has been
achieved from 1-[(4S)-4-benzyl-2-thioxothiazolidin-3-yl]propan-1-one in six steps with 22% overall
yield. The key step in the synthesis is an asymmetric acetal aldol reaction featuring the enantioselective
addition of a chiral thiazolidinethione-derived titanium enolate to an acetal to establish the stereochem-
istry at C39.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
0.91 lM, respectively, when tested against Plasmodium falciparum.
Tan et al. have reported that lagunamide A possesses a 26-mem-
Cyclodepsipeptide natural products often display remarkable
biological activities along with their complex molecular scaffolds,
making them interesting targets for chemical synthesis.1 Laguna-
mides A and B were first isolated from the marine cyanobacterium
Lyngbya majuscule, collected from Pulau Hantu Besar (Singapore).2
These cyclodepsipeptides showed highly potent inhibitory activity
against P383 murine leukemia cell lines with IC50 values of 6.4 and
20.5 nM, respectively. Furthermore, lagunamides A and B exhibited
significant antimalarial properties with IC50 values of 0.19 and
bered macrocycle and eleven stereogenic centers, which consists
of a novel polyketide moiety, an a-hydroxy acid unit, two L-amino
acids, and three N-methyl amino acid residues. In 2012, the first
successful synthesis of lagunamide A was achieved by Dai et al.3
Six diastereomers of lagunamide A were synthesized, and analysis
of their NMR spectra led to a correction of the stereochemistry at
C7 and C39 to the (S)- and (R)-configurations, respectively
(Fig. 1). More recently, Wei et al. have prepared lagunamide A
(3.0%, 20 steps) and its analogues from commercially available
O
O
7
N
O
R
N
O
N
N
H
N
N
H
O
O
N
O
O
O
N
O
O
O
O
HN
HN
OH
O
OH
O
O
39
O
O
lagunamide A (revised by Dai et al.)
lagunamide A, R=
lagunamide B, R=
(published by Tan et al.)
Figure 1. The structures of lagunamides A and B.
⇑
Corresponding author. Tel.: +886 (4)23323456; fax: +886 (4)23316699.
E-mail address: cychang@asia.edu.tw (C.-Y. Chang).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.020

188
H.-M. Liu et al. / Tetrahedron: Asymmetry 25 (2014) 187–192
(S)-2-methylbutanol.4 Our retrosynthetic approach to lagunamide
A, as shown in Scheme 1, features a disconnection of the macrocy-
cle to polypeptide moiety 1 and unsaturated carboxyl derivative 2.
We focused on the generation of the syn-1,3-diol portion of 2 and
built the stereogenic centers of this subunit from readily available
thiazolidinethione 5 and (S)-1,1-dimethoxy-2-methylbutane 6.
ing diol 11 was re-protected by treatment with 2,2-dimethoxypro-
pane (Scheme 3). The 13C NMR chemical shifts of the acetonide
methyl groups and the ketal carbon were 19.5, 30.1, and
97.6 ppm, respectively. These values are characteristics of syn-
1,3-diol acetonides (19.4 0.21, 30.0 0.15, and 98.1 0.83) and
are clearly distinguishable from those observed for anti-1,3-diol
acetonides (24.6 0.76, 24.6 0.76, and 100.6 0.25).11
The next step in our route was the olefin cross-metathesis of 9a
with methyl methacrylate catalyzed by a Grubbs catalyst (1st or
2nd generation).5,12 However, the reaction in CH2Cl2 at ambient
temperature or at reflux resulted in the formation of a complex
mixture of products. Fortunately, protection of the free hydroxyl
group of 9a with tert-butyldimethylsilyl trifluoromethanesulfonate
(TBSOTf) afforded olefin 13 in excellent yield (94%),13 and olefin 13
underwent cross-metathesis with methyl methacrylate in CH2Cl2
at 50 °C over 16 h to produce the desired alkene 14 in 59% yield.14
The 1H NMR singlets for the methyl groups were observed at d 3.32
and 3.74 ppm, and suggested the presence of a methoxy group and
a methyl ester group, respectively. NOESY analysis was used to
determine the stereochemistry of alkene 14. An NOE was observed
between H-35/CH2-36, but no NOE was observed between H-35/
CH3-43, thus establishing the E-geometry of the double bond.
The methyl ester of 14 was converted into a carboxyl group by
saponification in an alkaline/THF solution for 3 days and then the
unsaturated carboxylic acid 15 was obtained in 97% yield.
2. Results and discussion
The reaction of (S)-2-methylbutanal 74,5 with methanol and cat-
alytic p-toluenesulfonic acid (p-TsOH) gave chiral acetal 6 as a col-
orless liquid in 78% yield.6 Following the conditions described by
Crimmins6 and Urpí,7 the acetal aldol reaction of dimethyl acetal
6 with thiazolidinethione 5 provided the methylated aldol adduct
8 in an 82:18 diastereomeric ratio and 62% yield after purification.
Reductive cleavage of the chiral auxiliary with diisobutylalumin-
ium hydride (DIBAL-H) afforded the corresponding aldehyde,8
which decomposed during chromatographic purification. A two-
step sequence involving reduction (DIBAL-H, CH2Cl2, ꢀ84 °C) and
Grignard addition (allylmagnesium chloride, THF, 0 °C) produced
the desired adduct 9a and its diastereomer 9b in 99% yield in a
2:3 ratio. This stereoselectivity can be explained using the transi-
tion state model proposed by Felkin et al.9 The inversion of config-
uration at the C37 hydroxy group in 9b was performed through
Dess–Martin periodinane (DMP) oxidation of 9b to yield ketone
10 (74%), followed by stereoselective reduction to afford alcohols
The amino group of
hydroxyl group with retention of configuration,15 and esterifica-
tion of the resulting -hydroxy carboxylic acid 16 gave methyl
D-allo-isoleucine was then diazotized to a
9a and 9b (a/b = 8/1) in 95% yield (Scheme 2).
a
a-
The stereochemistry of 9a was confirmed by examining the
spectra of the corresponding acetonide 12, which was synthesized
in 85% yield over two steps. The methyl ether was deprotected
with iodotrimethylsilane (TMSI) generated in situ,10 and the result-
hydroxy ester 17, obtained in 70% yield over two steps. The final
assembly of the C27–C45 fragment of lagunamide A was accom-
plished by condensation of alcohol 17 with unsaturated carboxylic
O
N
O
N
N
H
O
N
O
O
O
NHFmoc
OtBu
N
O
N
N
H
1
O
O
N
O
O
O
+
1
HN
27
OH
O
H3CO
O
O
OTBS OCH3
O
O
43
44
45
revised lagunamide A
2
O
OTBS OCH3
OH
OCH3
+
HO
O
3
4
S
O
OCH3
S
N
+
H3CO
Bn
6
5
Scheme 1. Retrosynthesis of the C27–C45 fragment of lagunamide A.

H.-M. Liu et al. / Tetrahedron: Asymmetry 25 (2014) 187–192
189
O
OCH3
a
ref. 4, 5
(S)-2-methylbutanol
H3CO
7
6
S
S
O
O
OCH3
OCH3
X
Y
b
c
S
N
S
N
Bn
Bn
9a: X=H, Y=OH
9b: X=OH, Y=H
10: X=Y=O
8
5
e
d
Scheme 2. Reagents and conditions: (a) CH3OH, p-TsOH, rt, 24 h, 78%; (b) TiCl4, DIPEA, CH2Cl2, 0 °C, 1 h, then SnCl4, 6, ꢀ84 °C to 0 °C, 62%; (c) (i) DIBAL-H, CH2Cl2, ꢀ84 °C,
10 min, (ii) allylmagnesium chloride, THF, 0 °C, 1 h, 99% (9a/9b = 2/3) over two steps; (d) Dess–Martin periodinane, CH2Cl2, 0 °C, 30 min, 74%; (e) NaBH4, CH3OH, 0 °C, 15 min,
95% (9a/9b = 8/1).
OCH3
OH
OH
H
OH
O
O
a
b
9a
11
12
Scheme 3. Reagents and conditions: (a) TMSCl, NaI, CH3CN, rt; (b) 2,2-dimethoxypropane, p-TsOH, rt, 4 h, 85% over two steps.
OH
OCH3
O
OTBS
OCH3
OTBS
OCH3
a
b
H3CO
13
14
9a
O
OTBS OCH3
c
H3CO
O
HO
OCH3
OTBS
O
e
O
15
2
OH
OH
d
ref. 15
O
OH
D-allo-isoleusine
O
O
17
16
Scheme 4. Reagents and conditions: (a) TBSOTf, Et3N, CH2Cl2, 0 °C, 1 h, 94%; (b) methyl methacrylate, Grubbs catalyst 2nd generation, CH2Cl2, reflux, 16 h. 59%; (c) KOH(aq)
THF, rt, 3 d, 97%; (d) CH3OH, p-TsOH, reflux, 16 h, 70% (from -allo-isoleucine); (e) 17, DCC, DMAP, CH2Cl2, rt, 22 h, 87%.
,
D
acid 15 using 1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimeth-
ylamino)pyridine (DMAP) in CH2Cl2 to provide the desired frag-
ment 2 in 87% purified yield (Scheme 4).
pursuing the synthesis of other members of the lagunamide family
and their analogues. The results of this study will be reported in
due course.
3. Conclusion
4. Experimental
4.1. General
In conclusion, we have reported a convenient and efficient route
for the stereoselective synthesis of the C27–C45 fragment of lagu-
namide A, which shows potent cytotoxic and antimalarial proper-
ties in vitro. The synthetic sequence is based on an enantioselective
acetal aldol reaction to construct the C39 stereocenter and olefin
cross-metathesis to build the E alkene skeleton. We are actively
Starting materials were obtained from commercial suppliers and
were used without further purification unless otherwise stated. All
reactions were performed in flame-dried apparatus under an atmo-
sphere of nitrogen at room temperature unless otherwise stated.

190
H.-M. Liu et al. / Tetrahedron: Asymmetry 25 (2014) 187–192
CH2Cl2 and THF were distilled under nitrogen. Flash chromatogra-
phy was carried out using Merck silica gel 60, 70–230 mesh ASTM.
Optical rotations were measured on a Rudolph research analytical
Autopol IV polarimeter. NMR spectra were recorded on a Varian
Mercury 400 or Varian INOVA 600 spectrometer. Chemical shifts
are reported as the d value in ppm relative to TMS (d = 0), which
was used as the internal standard in CDCl3 for 1H NMR spectra
and the center peak of CDCl3 (d = 77.0 ppm) was used as an internal
standard in 13C NMR spectra. Mass spectra were collected on a Finn-
igan/Thermo Quest MAT 95XL, Finnigan LCQ ion-trap or Thermo
Scientific LTQ Orbitrap hybrid FTMS mass spectrometer.
(2 ꢁ 50 mL). The combined organic phases were dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
to afford a mixture containing the crude aldehyde (2.95 g). The
crude aldehyde mixture was dissolved in THF (50 mL), and
allylmagnesium chloride (2 M, 11 mL, 3 equiv) was added drop-
wise at 0 °C. After 1 h, the reaction was quenched by the addition
of saturated ammonium chloride solution and extracted with
EtOAc (2 ꢁ 50 mL). The combined organic phases were dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
to give a crude product mixture (3.45 g). The crude product was
purified by flash column chromatography eluting with hexane/
EtOAc (10:1) to give a diastereomeric mixture (1.47 g, 99%, 9a/
9b = 2/3). The diastereomers were separated by flash column chro-
matography eluting with hexane/EtOAc (20:1) to give 9a (0.58 g,
39%) as a colorless liquid and diastereomer 9b (0.88 g, 59%) as a
4.2. (S)-1,1-Dimethoxy-2-methylbutane 6
To a solution of aldehyde 7 (7.74 g, 90 mmol) in methanol
(20 mL) was added p-TsOH (20 mg). After 24 h, the reaction was
quenched by the addition of saturated sodium bicarbonate solution
and extracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic
phases were dried over anhydrous magnesium sulfate, filtered,
and concentrated under reduced pressure in an ice bath. The prod-
uct was isolated by Kugelrohr distillation (60 mmHg, 90 °C) to give
colorless liquid. Compound 9a: ½a D25
ꢂ
¼ ꢀ16:0 (c 1.09, CHCl3); 1H
NMR (400 MHz, CDCl3) d 6.01–5.93 (m, 1H). 5.16–5.09 (m, 2H),
3.74–3.70 (m, 1H), 3.48 (s, 3H), 3.02 (dd, J = 8.4 Hz, 2.4 Hz, 1H),
2.41–2.37 (m, 1H), 2.17–2.10, (m, 1H), 1.83–1.74 (m, 1H),
1.55–1.42 (m, 2H), 1.35–1.26 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.89
(d, J = 6.8 Hz, 3H), 0.82 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 135.9, 117.0, 90.4, 73.5, 61.1, 41.4, 38.5, 38.3, 27.8, 14.0,
13.3, 12.4; MS (APCI): m/z 201 [M+H]+; HRMS (APCI): m/z calcd
for [C12H25O2+H]+ 201.1849, found 201.1854. Compound 9b:
6 (9.27 g, 78%) as a colorless liquid. ½a D25
¼ ꢀ0:55 (c 1.28, CHCl3);
ꢂ
1H NMR (400 MHz, CDCl3) d 4.04 (d, J = 6.8 Hz, 1H), 3.35 (s, 6H),
1.70–1.51 (m, 2H), 1.18–1.07 (m, 1H), 0.92–0.88 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 108.8, 53.5, 37.3, 24.6, 13.9, 11.3; MS
(ESI): m/z 133 [M+H]+; HRMS (ESI): m/z calcd for [C7H16O2+H]+
133.1223, found 133.0678.
½
a 2D5
ꢂ
¼ þ0:4 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3)
d
5.88–5.79 (m, 1H), 5.14–5.06 (m, 2H), 4.00–3.97 (m, 1H), 3.50 (s,
3H), 3.02 (t, J = 5.6 Hz, 1H), 2.35–2.28 (m, 1H), 2.18–2.11 (m, 1H),
1.77–1.66 (m, 2H), 1.48–1.40 (m, 1H), 1.20–1.13 (m, 1H), 0.97 (d,
J = 7.2 Hz 3H), 0.94 (d, J = 6.8 Hz 3H), 0.91 (t, J = 7.6 Hz 3H); 13C
NMR (100 MHz, CDCl3) d 135.8, 117.0, 90.5, 70.6, 61.8, 39.6, 38.1,
37.6, 26.8, 14.4, 11.7, 11.3; MS (APCI): m/z 201 [M+H]+; HRMS
(APCI): m/z calcd for [C12H25O2+H]+ 201.1849, found 201.1854.
4.3. (2R,3R,4S)-1-[(40S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-
methoxy-2,4-dimethylhexan-1-one 8
A solution of thiazolidinethione 5 (3.98 g, 15 mmol) in anhy-
drous CH2Cl2 (100 mL) was cooled to 0 °C, and neat TiCl4 (2.1 mL,
19.5 mmol, 1.3 equiv) then added dropwise, resulting in the forma-
tion of an orange slurry. After stirring for 5 min, DIEA (3.4 mL,
19.5 mmol, 1.3 equiv) was added dropwise. The resulting dark
solution was stirred at 0 °C for 1 h, and then cooled to ꢀ84 °C for
another 15 min. Neat SnCl4 (3.5 mL, 30 mmol, 2 equiv) and acetal
6 (3.96 g, 30 mmol, 2 equiv) were added dropwise. After the addi-
tion was completed, the solution was stirred at ꢀ84 °C for an addi-
tional 30 min, and then slowly warmed to 0 °C over 4 h. The
reaction was quenched by the addition of saturated ammonium
chloride solution and extracted with CH2Cl2 (3 ꢁ 50 mL). The com-
bined organic phases were dried over anhydrous magnesium sul-
fate, filtered, and concentrated in vacuo to afford a yellow
mixture (6.92 g). The crude product was purified by flash column
chromatography eluting with hexane/EtOAc (30:1) to give 8
4.5. (5R,6R,7S)-6-Methoxy-5,7-dimethylnon-1-en-4-one 10
To a solution of alcohol 9b (1.94 g, 9.7 mmol) in CH2Cl2
(100 mL) was cooled to 0 °C, and DMP (6.20 g, 1.5 equiv) was
added portionwise. After 5 min at 0 °C, the reaction solution was
stirred at ambient temperature for another 30 min. The reaction
was quenched with saturated sodium sulfite solution and
extracted with CH2Cl2 (3 ꢁ 50 mL). The combined organic phases
were dried over anhydrous magnesium sulfate, filtered, and con-
centrated in vacuo to afford a colorless mixture (4.02 g). The crude
product was purified by flash column chromatography eluting
with hexane/EtOAc (20:1) to give ketone 10 (1.42 g, 74%) as a
colorless liquid.
½
a 2D5
ꢂ
¼ ꢀ68:65 (c 0.96, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.00–5.91 (m, 1H), 5.19–5.11 (m, 2H), 3.29 (s,
3H), 3.35–3.28 (m, 3H), 2.90–2.83 (m, 1H), 1.50–1.45 (m, 2H),
1.36–1.28 (m, 1H), 0.96–0.93 (m, 6H), 0.87 (d, J = 6.8 Hz, 3H); 13C
NMR (150 MHz, CDCl3) d 212.7, 130.7, 118.5, 86.7, 60.9, 49.0,
48.0, 36.9, 27.2, 13.8, 12.5, 12.3; MS (EI): m/z 198 [M]+; HRMS
(EI): m/z calcd for [C12H22O2]+ 198.1620, found 198.1630.
(3.39 g, 62%) as a yellow liquid. ½a D25
ꢂ
¼ ꢀ27:8 (c 1.22, CHCl3); 1H
NMR (400 MHz, CDCl3) d 7.37–7.26 (m, 5H), 5.52–5.47 (m, 1H),
5.13–5.05 (m, 1H), 3.65–3.45 (m, 1H), 3.42 (s, 3H), 3.37–3.31 (m,
1H), 3.19–3.14 (m, 1H), 3.09–3.03 (m, 1H), 2.85–2.82 (m,1H),
1.61–1.51 (m, 2H), 1.42–1.26 (m,1H), 1.08 (d, J = 6.8 Hz, 3H), 1.00
(t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 201.4, 177.7, 137.0, 129.6, 129.1, 127.4, 87.0, 68.9, 61.3, 42.1,
37.7, 37.1, 31.4, 27.8, 15.3, 13.3, 12.7; MS (EI): m/z 365 [M]+; HRMS
(EI): m/z calcd for [C19H27NO2S2]+ 365.1484, found 365.1479.
4.6. Synthesis of 9a and 9b from ketone 10
A solution of ketone 10 (1.42 g, 7.2 mmol) in methanol (50 mL)
was cooled to 0 °C, and NaBH4 (0.38 g, 10 mmol, 5.5 equiv) was
added portionwise. After 15 min, the reaction was quenched by
the addition of NaOH solution (2 M, 20 mL), concentrated in vacuo
to remove the methanol, and extracted with EtOAc (3 ꢁ 50 mL).
The combined organic phases were dried over anhydrous magne-
sium sulfate, filtered, and concentrated in vacuo to yield a colorless
mixture (1.47 g). The crude product was purified by flash column
chromatography eluting with hexane/EtOAc (10:1) to give a diaste-
reomeric mixture (1.37 g, 95%, 9a/9b = 8/1).
4.4. (4S,5S,6R,7S)-6-Methoxy-5,7-dimethylnon-1-en-4-ol 9a and
diastereomer 9b
A
solution of thiazolidinethione 8 (2.67 g, 7.4 mmol) in
anhydrous CH2Cl2 (75 mL) was cooled to ꢀ84 °C, and DIBAL-H
(20%, 11.3 mL, 1.5 equiv) then slowly added dropwise. The result-
ing solution was stirred for 10 min, quenched by the addition of
saturated ammonium chloride solution and extracted with CH2Cl2

H.-M. Liu et al. / Tetrahedron: Asymmetry 25 (2014) 187–192
191
4.7. (4S,5S,6R)-4-Allyl-2,2,5-trimethyl-6-[(10S)-1-methylpropyl]-
1,3-dioxane 12
2.91 (dd, J = 9.6 Hz, 2.0 Hz, 1H), 2.31–2.27 (m, 2H), 1.85 (s, 3H),
1.90–1.84 (m, 1H), 1.55–1.42 (m, 2H), 1.38–1.31 (m, 1H), 0.94 (t,
J = 7.2 Hz, 3H), 0.87 (s, 9 H), 0.87–0.83 (m, 6H), 0.04 (s, 3H), 0.02
(s, 3H); 13C NMR (100 MHz, CDCl3) d 168.8, 141.4, 128.3, 86.8,
72.4, 60.9, 51.7, 42.6, 37.8, 31.9, 27.9, 26.0, 18.2, 12.9, 12.8, 12.5,
11.2, ꢀ4.3, ꢀ4.5; MS (APCI): m/z 387 [M+H]+; HRMS (APCI): m/z
calcd for [C21H43O4Si+H]+ 387.2925, found 387.2931.
To a solution of alcohol 9a (0.075 g, 0.38 mmol) and NaI (0.17 g,
1.14 mmol, 3 equiv) in anhydrous CH3CN (5 mL) was added TMSCl
(0.15 mL, 1.18 mmol, 3.1 equiv) dropwise, and the solution was
stirred at room temperature for 30 min, and monitored by thin-
layer chromatography (TLC). The reaction was quenched with
H2O and extracted with EtOAc (3 ꢁ 50 mL). The combined organic
phases were washed with saturated sodium sulfite solution, dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to afford crude diol 11 (0.081 g). Crude diol 11 and p-TsOH
(3 mg) were dissolved in 2,2-dimethoxypropane (2 mL), and then
stirred at ambient temperature for 4 h. The reaction mixture was
diluted with EtOAc (20 mL), and washed with saturated aqueous
solution of NaHCO3 (10 mL), and then brine (5 mL). After drying
over anhydrous magnesium sulfate, it was filtered and concen-
trated in vacuo to afford a colorless mixture (0.103 g). The crude
product was purified by flash column chromatography eluting
with hexane/EtOAc (100:1) to afford acetal 12 (0.072 g, 85%) as a
4.10. (E)-(5S,6R,7R,8S)-5-[tert-Butyl(dimethyl)silyl]oxy-7-methoxy-
2,6,8-trimethyl-dec-2-enoic acid 15
To a solution of ester 14 (0.25 g, 0.65 mmol) in THF (5 mL) and
water (2 mL) was added KOH (0.5 g) at 0 °C. The resulting solution
was stirred magnetically at room temperature for 3 d, and the reac-
tion was monitored by thin-layer chromatography (TLC). The reac-
tion solution was acidified with dilute hydrochloric acid to pH 2,
and extracted with ethyl acetate (3 ꢁ 20 mL). The combined organ-
ic phases were dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo to yield a crude mixture (2.84 g). The
crude product was purified by flash column chromatography elut-
ing with hexane/EtOAc (5:1) to afford carboxylic acid 15 (0.23 g,
colorless liquid ½a D25
ꢂ
¼ þ8:0 (c 0.81, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
5.96–5.87 (m, 1H), 5.09–5.02 (m, 2H), 3.54–3.43
97%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ26:7 (c 1.24, CHCl3); 1H NMR
(m, 2H), 2.42–2.37 (m, 1H), 2.22–2.15 (m, 1H), 1.39 (s, 3H), 1.34
(s, 3H), 1.55–1.26 (m, 4H), 0.87 (t, J = 7.4 Hz, 3H), 0.83 (d,
J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d 135.3, 116.1, 97.6, 75.2, 74.3, 37.6, 35.0, 34.8, 30.1, 26.7, 19.5,
12.3, 12.0, 11.6; MS (APCI): m/z 227 [M+H]+; HRMS (APCI): m/z
calcd for [C14H27O2+H]+ 227.2006, found 227.2001.
(400 MHz, CDCl3) d 7.04–6.99 (m, 1H), 4.08–4.03 (m, 1H), 3.40
(s, 3H), 2.91 (d, J = 9.2 Hz, 1H), 2.35–2.31 (m, 2H), 1.87 (s, 3H),
1.91–1.84 (m, 1H), 1.53–1.45 (m, 2H), 1.36–1.31 (m, 1H), 0.95 (t,
J = 7.2 Hz, 3H), 0.88 (s, 9 H), 0.87–0.84 (m, 6H), 0.04 (s, 3H), 0.03
(s, 3H); 13C NMR (100 MHz, CDCl3) d 173.6, 143.7, 128.0, 86.8,
72.2, 60.9, 42.6, 37.8, 32.2, 27.9, 26.0, 18.2, 12.9, 12.5, 12.4, 11.2,
ꢀ4.4, ꢀ4.5; MS (ESI): m/z 371 [MꢀH]ꢀ; HRMS (ESI): m/z calcd for
[C20H40O4SiꢀH]ꢀ 371.2612, found 371.2619.
4.8. (1S,2R,3R,4S)-1-Allyl-3-methoxy-2,4-dimethylhexoxy]-tert-
butyldimethylsilane 13
4.11. Methyl (2R,3S)-2-hydroxy-3-methylpentanoate 17
To a solution of alcohol 9a (0.68 g, 3.4 mmol) in anhydrous
CH2Cl2 (35 mL) was added triethylamine (1.4 mL, 10.3 mmol,
3 equiv) at 0 °C followed by the slow addition of TBSOTf (1.2 mL,
5.2 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for
10 min, and then stirred at room temperature for another 30 min.
The reaction was quenched by the addition of saturated ammonium
chloride solution and extracted with CH2Cl2 (2 ꢁ 50 mL). The com-
bined organic phases were dried over anhydrous magnesium sul-
fate, filtered, and concentrated in vacuo to afford a crude mixture
(2.42 g). The crude product was purified by flash column chroma-
tography eluting with hexane/EtOAc (150:1) to give 13 (1.01 g,
To a solution of (2R,3S)-2-hydroxy-3-methylpentanoic acid 16
(0.53 g, 4.0 mmol) and p-TsOH (10 mg) in methanol (15 mL) was
heated at reflux for 16 h. After cooling, the solution was concen-
trated in vacuo at 0 °C to afford a yellow mixture (0.64 g). The
crude product was purified by flash column chromatography elut-
ing with hexane/EtOAc (10:1) to give 17 (0.41 g, 70%) as a colorless
liquid ½a 2D5
ꢂ
¼ ꢀ16:2 (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3) d
4.20 (d, J = 3.2 Hz, 1H), 3.80 (s, 1H), 1.84–1.78 (m, 1H), 1.57–1.50
(m, 1H), 1.35–1.26 (m, 1H), 0.96 (t, J = 7.6 Hz, 3H), 0.82
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.8, 73.2, 52.3,
38.6, 26.0, 13.3, 11.8; MS (APCI): m/z 147 [M+H]+; HRMS (APCI):
m/z calcd for [C7H15O3+H]+ 147.1016, found 147.1009.
94%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ28:9 (c 1.11, CHCl3); 1H NMR
(400 MHz, CDCl3) d 5.92–5.84 (m, 1H), 5.07–5.00 (m, 2H), 3.95–
3.92 (m, 1H), 3.40 (s, 3H), 2.92 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 2.24–
2.08 (m, 2H), 1.90–1.82 (m, 1H), 1.50–1.42 (m, 2H), 1.40–1.30 (m,
1H), 0.94 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H),
0.97 (d, J = 6.8 Hz, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) d
137.4, 116.0, 86.6, 73.2, 60.9, 42.5, 37.7, 37.1, 27.9, 26.1, 18.3,
12.7, 12.5, 11.0, ꢀ4.2, ꢀ4.3; MS (APCI): m/z 315 [M+H]+; HRMS
(APCI): m/z calcd for [C18H39O2Si+H]+ 315.2714, found 315.2720.
4.12. Synthesis of the C27–C45 fragment 2
To a cooled (ice bath) solution of carboxylic acid 15 (0.049 g,
0.13 mmol) and alcohol 17 (0.025 g, 0.17 mmol, 1.3 equiv) in anhy-
drous CH2Cl2 (10 mL) were added DCC (0.045 g, 0.22 mmol,
1.6 equiv) and DMAP (0.025 g, 0.2 mmol, 1.6 equiv). The mixture
was stirred at 0 °C for 5 min and then stirred at room temperature
for another 22 h. The reaction was quenched with saturated
ammonium chloride solution and was extracted with CH2Cl2
(3 ꢁ 20 mL). The combined organic phases were dried over anhy-
drous magnesium sulfate, filtered, and concentrated in vacuo to af-
ford a crude mixture (0.156 g). The crude product was purified by
flash column chromatography eluting with hexane/EtOAc (30:1) to
4.9. Methyl (E)-(5S,6R,7R,8S)-5-[tert-butyl(dimethyl)silyl]oxy-7-
methoxy-2,6,8-trimethyldec-2-enoate 14
To a solution of olefin 13 (0.63 g, 2 mmol) and methyl methac-
rylate (4.2 mL, 40 mmol, 20 equiv) in anhydrous CH2Cl2 (30 mL)
was added Grubbs catalyst 2nd generation (0.075 g, 5 mol %) while
flushing with N2 for 5 min. The mixture was then heated to 50 °C
for 16 h. After cooling to room temperature, the solvent was
removed in vacuo to obtain a yellow liquid (0.74 g). The crude
product was purified by flash column chromatography eluting
with hexane/EtOAc (100:1) to afford 14 (0.45 g, 59%) as a colorless
afford 2 (0.058 g, 87%) as a colorless liquid. ½a D25
¼ ꢀ19:1 (c 0.69,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3) d 6.97–6.93 (m, 1H), 5.07 (d,
J = 3.6 Hz, 1H), 4.08–4.03 (m, 1H), 3.74 (s, 3H), 3.40 (s, 3H), 2.91
(d, J = 9.2 Hz, 1H), 2.34–2.31 (m, 2H), 2.05–2.00 (m, 1H), 1.88 (s,
3H), 1.92–1.84 (m, 1H), 1.54–1.25 (m, 5H), 0.87 (s, 9H), 0.99–0.83
(m, 15H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.1, 167.8, 142.2, 128.1, 86.9, 75.1, 72.1, 61.0, 52.2, 42.7,
liquid. ½a 2D5
ꢂ
¼ ꢀ30:2 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3) d
6.89–6.85 (m, 1H), 4.05–4.01 (m, 1H), 3.74 (s, 3H), 3.39 (s, 3H),

192
H.-M. Liu et al. / Tetrahedron: Asymmetry 25 (2014) 187–192
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37.8, 37.0, 32.1, 27.9, 26.2, 26.1, 18.2, 14.8, 13.0, 12.8, 12.6, 11.8,
11.1, ꢀ4.3, ꢀ4.4; MS (APCI): m/z 501 [M+H]+; HRMS (APCI): m/z
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Acknowledgments
We would like to thank the National Science Council of the
Republic of China (NSC 100-2113-M-468-001) and Asia University
(101-asia-36) for financial support. We thank the Department of
Chemistry, National Chung-Hsing University, Taichung, Taiwan,
ROC for analysis of the NMR spectra.
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