Catalytic asymmetric syntheses of (?)-oudemanisin A and its diastereomer

Article abstract of DOI:10.1016/j.tetasy.2017.06.002

The first asymmetric catalytic synthesis of (?)-oudemanisin A 1a and its diastereomer 1b has been achieved. The key steps of our strategy involved the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed by Trost's ProPhenol ligand, chemoselective oxidation of the olefinic diol, base-induced ring opening of the lactone, and acylation–alkylation of the ester.

Full text of DOI:10.1016/j.tetasy.2017.06.002

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric syntheses of (À)-oudemanisin A and its
diastereomer
Yun Zhou, Qinghua Bian, Pengfei Yang, Lifeng Wang, Shuoning Li, Xiao Sun, Mingan Wang, Min Wang,
⇑
Jiangchun Zhong
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric catalytic synthesis of (À)-oudemanisin A 1a and its diastereomer 1b has been
achieved. The key steps of our strategy involved the asymmetric alkynylation of an unsaturated aliphatic
aldehyde catalyzed by Trost’s ProPhenol ligand, chemoselective oxidation of the olefinic diol, base-
induced ring opening of the lactone, and acylation–alkylation of the ester.
Received 10 April 2017
Revised 17 May 2017
Accepted 31 May 2017
Available online xxxx
Ó 2017 Published by Elsevier Ltd.
1. Introduction
Me
OMe
Me
OMe
(S)
(S)
(S)
(R)
Mushrooms have received considerable attention as a source of
bioactive compounds, such as strobilurins, oudemansins,1a
sterostreins,1b terreumols,1c Laxitextines1d and xerucitrinic acids.1e
These secondary metabolites possess various biological activities,
including antitumour, antifungal, antimalarial and antibacterial
activities.1 (À)-Oudemanisin A 1a (Fig. 1) has gained special inter-
est because it exhibits strong antifungal properties against Candida
albicans BMSY 212, Sporobolomyces salmonicolor SBUG 549, Penicil-
lium notatum JP 36,2 and Cladosporium sphaerospermum.3 In addi-
tion, (À)-oudemanisin A has shown antimalarial4 and cytotoxic
activities against UACC-62 (human melanoma cells), MCF-7
(human breast cancer), TK-10 (human renal carcinoma),3 KB (oral
human epidermoid carcinoma), and NCI-H187 (human small-cell
lung cancer) cells.4
OMe COOMe
OMe COOMe
1a
1b
Figure 1. The structures of (À)-oudemanisin A 1a and its diastereomer 1b.
The significant biological activities and the interesting struc-
tural features of (À)-oudemanisin A, in addition to the potential
biological activities of its diastereomer prompted us to search for
more efficient and convenient synthetic strategies. Herein, we have
accomplished the total syntheses of (À)-oudemanisin A and its
diastereomer via an asymmetric catalytic method.
2. Results and discussion
(À)-Oudemanisin A 1a was first isolated from cultures of Stro-
bilurus tenacellus in 1979. Its structure and the relative configura-
tion were elucidated by spectroscopic and X-ray analysis.5 The
original synthesis of (À)-oudemanisin A was achieved via reduc-
tion of the b-keto ester with baker’s yeast (Saccharomyces cere-
visiae) and its absolute configuration was assigned as (3R,4S).6
Shortly thereafter, there were several formal syntheses reported,
and the main strategies involved the microbiological asymmetric
reduction of the prochiral b-keto ester,7 the lipase-catalyzed
hydrolysis of an acetate,8 the derivation from the chiral pool mate-
rial (+)-carvone,9 and the enantioselective [2,3]-Wittig rearrange-
ment of crotyloxyacetaldehyde-SAEP-hydrazone.10
The retrosynthetic analysis of (À)-oudemanisin A 1a is shown in
Figure 2. The target molecule 1a was expected to be obtained via
acylation–alkylation of ester 11a. A base-induced ring opening of
lactone 10a, followed by etherification and esterification could give
ester 11a. The key intermediate lactone 10a could be formed by
chemoselective oxidation of olefinic diol 9, which could be synthe-
sized through two hydroboration–oxidations, Dess-Martin oxida-
tion, olefination and reduction from enynic alcohol 3. The chiral
secondary alcohol in 3 could be introduced using Trost’s ProPhenol
ligand catalyzed enantioselective alkynylzinc addition to olefinic
aldehyde 2.
Our strategy began with the synthesis of chiral lactones 10a and
10b (Scheme 1). In the presence of triphenylphosphine oxide, the
asymmetric addition between methacrolein 2 and alkynylzinc
⇑
Corresponding author. Tel.: +86 010 62731356; fax: +86 010 62820325.
E-mail address: zhong@cau.edu.cn (J. Zhong).
http://dx.doi.org/10.1016/j.tetasy.2017.06.002
0957-4166/Ó 2017 Published by Elsevier Ltd.
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2
Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
2,2,6,6-tetramethyl-1-piperidinyloxy/[bis(acetoxy)iodo]benzene
Me
OMe
Me
(TEMPO/BAIB) system gave the desired lactones 10a and 10b as a
1:3 mixtures, which were easily separated by silica gel column
chromatography.17 The diastereomeric ratio was determined by
HPLC with a Venusil XBP-Si column. The stereochemistry of lac-
tone 10b at C-3 was assigned as (R) by the NOE effect observed
between H-4 and the hydrogens of the methyl at C-3.18 Therefore,
the absolute configuration of 10b was (3R,4R,5E), and stereo-
chemistries of its C-3 epimer 10a was (3S,4R,5E).
(S)
(S)
(S)
(R)
OMe COOMe
1a
OMe COOMe
11a
O
OH
O
(R)
Ph
(R)
Ph
(S)
HO
As with key intermediate lactones 10a and 10b, the synthesis of
the target molecules (À)-oudemanisin A 1a and its diastereomer
1b was studied (Scheme 2). A base-induced ring opening of lactone
10a resulted in the formation of the corresponding hydroxyl acid,19
which was applied to the etherification with MeI/NaH20 and a sub-
sequent esterification with MeI/K2CO3.21 Ester 11a was obtained
smoothly in 63% yield over three steps. Acylation of ester 11a with
N-formylimidazole followed by O-alkylation of the resultingb-for-
myl ester with dimethyl sulfate furnished (À)-oudemanisin A 1a
in 46% yield over two steps.22 The NMR spectrum and specific rota-
9
10a
OH
O
Ph
(
)
R
Ph
3
2
Figure 2. Retrosynthetic analysis of (À)-oudemanisin A 1a.
tion of 1a {[
natural (À)-oudemanisin A {[
a
]
18.5 = À18.3 (c 0.5, CHCl3)} were consistent with the
D
22
a
]
578 = À20 (c 0.03, EtOH)}.5 Using
, Me Zn
Ph
OH
2
the similar procedure of 1a, the diastereomer of (À)-oudemanisin
A 1b was synthesized from lactone 10b, and its structure was char-
acterized by 1H NMR, 13C NMR and HRMS spectra.
(S,S)-ProPhenol
TBDPSCl, imidazole
(R)
O
P(O)Ph3, toluene, -20 oC
93% yield, 96% ee
4-DMAP, DCM, rt
92% yield
Ph
2
3
OTBDPS
Dess-Martin
periodinane
OTBDPS
(1) KOH, dioxane, rt
(2) NaH, MeI, THF, rt
O
9-BBN, THF, rt
Me
O
(R)
(R)
(R)
DCM, rt
then NaOH, H2O2
95% yield
(S)
Ph
Ph
(R)
(3) K2CO3, MeI, DMF, rt
60% yield, 3 steps
83% yield
Ph
(S)
4
5
HO
OMe COOMe
10a
11a
1a
MePPh3Br
n-BuLi, THF
-78oC to rt
86% yield
OTBDPS
OTBDPS
9-BBN, THF, rt
(1) N-formylimidazole, LDA, THF, -78oC
Me
OMe
(R)
(R)
then NaOH, H2O2
82% yield
(S)
Ph
(2) K2CO3, Me2SO2, acetone, rt
46% yield, 2 steps
(S)
Ph
O
7
6
OMe COOMe
OTBDPS
OH
LiAlH4, THF, 0 oC to reflux
70% yield
O
OMe
Me
(R)
(R)
Ph
O
(S)
HO
HO
Ph
(R)
8
9
(R)
(R)
Ph
O
OMe COOMe
O
O
1b
10b
PhI(OAc)2, TEMPO
O
(R)
DCM, rt
Ph
(R)
(R)
(S)
Ph
Scheme 2. Synthesis of (À)-oudemanisin A 1a and its diastereomer 1b.
H
91% yield, dr 1:3
C
H
NOE
H
10a
10b
H
3. Conclusion
Scheme 1. Synthesis of chiral lactones 10a and 10b.
In conclusion, the first asymmetric catalytic synthesis of (À)-
oudemanisin A 1a and its diastereomer 1b has been carried out.
This approach included the asymmetric alkynylation of an unsatu-
rated aliphatic aldehyde catalyzed by Trost’s ProPhenol ligand,
chemoselective oxidation of olefinic diol, base-induced ring open-
ing of lactone, and acylation–alkylation of ester. Furthermore, (À)-
oudemanisin A and its diastereomer synthesized herein are poten-
tially valuable for the development of antitumor and antifungal
drugs.
reagent, prepared in situ from phenylacetylene and dimethylzinc,
with (S,S)-ProPhenol ligand as catalyst, afforded enynic alcohol 3
in 93% yield and with 96% ee.11 According to the governing prece-
dents of Trost’s enantioselective alkynylation of unsaturated alde-
hydes,11a the absolute configuration of enynic alcohol 3 was
assigned as (R). The secondary alcohol in enynic alcohol 3 was
protected with tert-butyldiphenylsilyl chloride (TBDPSCl) to
obtain TBDPS-protected enynic alcohol 4 in 92% yield.12 Subse-
quent hydroboration-oxidation with 9-BBN and H2O2 converted
TBDPS-protected enynic alcohol 4 into mono-TBDPS-protected
4. Experimental
4.1. General
acetylenic diol
5
as
a
mixture of C-2 epimers almost
quantitatively.13
Acetylenic aldehyde 6 was obtained via Dess-Martin oxidation
of mono-TBDPS-protected acetylenic diol 5,14 followed by olefina-
tion of acetylenic aldehyde 6 with methyl triphenylphosphonium
bromide and n-BuLi to provide TBDPS-protected enynic alcohol 7
in 86% yield.15 The hydroboration–oxidation13 and reduction with
All reactions were performed under an argon atmosphere
unless otherwise stated, and solvents were distilled and dried fol-
lowing the standard procedures. Unless otherwise mentioned, all
commercially available reagents were used directly. Enantiomeric
excess (ee) and diastereomeric ratio (dr) were determined on an
Agilent 1200 HPLC system with a Daicel Chiralcel OJ-H column or
a Venusil XBP-Si column, and n-hexane/2-propanol as the eluent.
16
LiAlH4 were carried out sequentially, to furnish olefinic diol 9.
Finally, the chemoselective oxidation of olefinic diol 9 with
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Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Optical rotations were measured on
Polarimeter. NMR spectra were obtained on
a
PERKIN ELEMER 341
Bruker DP-
(50.04 mL, 0.5 M in THF, 25.02 mmol, 3 equiv) at room tempera-
ture under an argon atmosphere. The resulting mixture was stirred
for 12 h, and NaOH solution (16.68 mL mL, 3 M, 50.04 mmol,
6 equiv) was then added at 0 °C. After stirring for 30 min, the mix-
ture was cooled to À20 °C, and H2O2 solution (16.68 mL, 30%) was
added slowly. The reaction was maintained for 3 h at room tem-
perature, and then quenched with saturated aqueous NH4Cl
(30 mL). The organic layer was separated and the aqueous layer
was extracted with Et2O (3 Â 50 mL). The combined organic phases
were washed with brine (30 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to obtain a crude prod-
uct. The crude product was purified by silica gel chromatography
(petroleum ether/ethyl acetate 5:1) to give mono-TBDPS-protected
a
X300 MHz spectrometer. Chemical shifts (d) were reported in
ppm downfield from internal tetramethylsilane (TMS) for 1H
NMR (dH = 0.00 ppm) and CDCl3 for 13C NMR (dC = 77.00 ppm).
High resolution mass spectra (HRMS) were conducted on a Waters
LCT Premier instrument with electrospray ionization (ESI) as the
source.
4.2. (R)-2-Methyl-5-phenylpent-1-en-4-yn-3-ol 3
To
a solution of (S,S)-ProPhenol ligand (1.28 g, 2 mmol,
0.2 equiv) and triphenylphosphine oxide (1.12 g, 4 mmol,
0.4 equiv) in toluene (50 mL) was added phenyl acetylene (3.06 g,
30 mmol, 3 equiv) at 0 °C under an argon atmosphere. A solution
of Me2Zn (25 mL, 1.2 M in toluene, 30 mmol, 3 equiv) was then
added slowly via syringe at the same temperature. After the result-
ing mixture was stirring for 1.5 h at 0 °C, the mixture was cooled to
À20 °C. Methacrolein 2 (0.70 g, 10 mmol, 1 equiv) was added
slowly via syringe, and the reaction mixture was maintained at
À20 °C for 48 h. The reaction was quenched with water (20 mL)
and filtered through a Celite pad. The organic layer was separated
and the aqueous layer was extracted with Et2O (3 Â 50 mL). The
combined organic phases were washed with brine (50 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure
to afford a crude product. The crude product was purified by silica
gel column chromatography (petroleum ether/ethyl acetate 10:1)
to give enynic alcohol 3 (1.60 g, 93% yield, 96% ee) as a yellow
oil. Enantiomeric excess was determined by HPLC with a Daicel
Chiralcel OJ-H column (7% 2-propanol in n-hexane, 1.0 mL/min,
acetylenic diol 5 (3.57 g, 95% yield) as a yellow oil. [a]
18.5 = +146.6
D
(c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.85–7.78 (m, 4H), 7.47–
7.12 (m, 11H), 4.74–4.67 (m, 1H), 3.85–3.72 (m, 2H), 2.14–2.04 (m,
1H), 1.47 (br s, 1H), 1.15 (s, 9H), 1.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 136.1, 135.9, 133.6, 133.1, 131.4, 129.8, 129.5, 128.1,
128.0, 127.7, 127.4, 122.7, 88.9, 86.6, 67.6, 65.4, 42.6, 27.0, 19.4,
12.8; HRMS (ESI) m/z 429.2230 [M+H]+ (calcd for C28H33O2Si,
429.2244).
4.5. (2RS,3R)-3-(tert-Butyldiphenylsilyloxy)-2-methyl-5-phenyl-
pent-4-ynal 6
To
a solution of Dess-Martin regent (3.53 g, 8.31 mmol,
1.4 equiv) in dry DCM (20 mL) was added mono-TBDPS-protected
acetylenic diol 5 (2.55 g, 5.94 mmol, 1 equiv) at 0 °C under an
argon atmosphere. The reaction mixture was warmed to room
temperature and stirred for 3 h. After cooling to 0 °C, NaOH solu-
tion (15%, 80 mL) was added slowly. The organic layer was sepa-
rated and the aqueous layer was extracted with DCM
(3 Â 60 mL). The combined organic phases were washed with brine
(50 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure to obtain a crude product. The crude product
was purified by silica gel chromatography (petroleum ether/ethyl
acetate 20:1) to afford acetylenic aldehyde 6 (2.11 g, 83% yield)
254 nm); minor (S)-enantiomer tr = 17.63 min, major (R)-enan-
18.5
tiomer tr = 14.69 min.
[a
]
D
À13.1 (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.49–7.46 (m, 2H), 7.34–7.28 (m, 3H), 5.28 (s,
1H), 5.06 (s, 1H), 5.09 (s, 1H), 2.62 (br s, 1H), 1.96 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 144.0, 131.6, 128.4, 128.2, 122.4, 112.4,
88.1, 85.7, 66.6, 18.1; HRMS (ESI) m/z 173.0962 [M+H]+ (calcd for
C12H13O, 173.0961).
as a yellow oil. [a]
18.5 = +137.2 (c 3.2, CHCl3); 1H NMR (300 MHz,
D
4.3. (R)-3-(tert-Butyldiphenylsilyloxy)-2-methyl-5-phenylpent-
1-en-4-yne 4
CDCl3) d 9.95–9.90 (m, 1H), 7.78–7.72 (m, 5H), 7.44–7.10 (m,
10H), 4.89–4.81 (m, 1H), 2.78–2.65 (m, 1H), 1.25–1.08 (m, 12H);
13C NMR (75 MHz, CDCl3) d 203.4, 202.9, 136.09, 136.05, 135.95,
135.91, 134.8, 133.3, 132.8, 132.2, 131.5, 131.4, 130.0, 129.9,
129.7, 129.66, 129.62, 128.6, 128.4, 128.12, 128.09, 127.77,
127.73, 127.70, 127.5, 127.4, 87.8, 87.5, 65.0, 64.9, 53.2, 52.6,
26.9, 26.6, 19.4, 19.3, 10.4, 9.5; HRMS (ESI) m/z 427.2071 [M+H]+
(calcd for C28H31O2Si, 427.2088).
To a solution of enynic alcohol 3 (1.58 g, 9.17 mmol, 1 equiv) in
dry DCM (20 mL) was added imidazole (1.25 g, 18.34 mmol,
2 equiv) and 4-DMAP (0.22 g, 1.83 mmol, 0.2 equiv) at 0 °C. The
resulting mixture was stirred for 10 min, TBPSCl (3.03 g,
11.01 mmol, 1.2 equiv) was then added slowly. After stirring over-
night at room temperature, the reaction was quenched with water
(15 mL). The organic layer was separated and the aqueous layer
was extracted with DCM (3 Â 30 mL). The combined organic
phases were washed with brine (30 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to furnish crude
product. The crude product was purified by silica gel column chro-
matography (petroleum ether/ethyl acetate 30:1) to afford TBDPS-
protected enynic alcohol 4 (3.46 g, 92% yield) as a yellow oil.
4.6. (3RS,4R)-4-(tert-Butyldiphenylsilyloxy)-3-methyl-6-phen-
ylhex -1-en-5-yne 7
To a suspension of methyl triphenylphosphonium bromide
(0.45 g, 1.25 mmol, 2.5 equiv) in THF (2 mL) was added slowly n-
BuLi (0.58 mL, 2.4 M in n-hexane, 1.4 mmol, 2.8 equiv) at 0 °C
under an argon atmosphere. The resulting mixture was warmed
to the room temperature and stirred for 2 h. After cooling to
À78 °C, a solution of acetylenic aldehyde 6 (0.21 g, 0.5 mmol,
1 equiv) in THF (1.5 mL) was added drop wise. The reaction mix-
ture was stirred overnight at the room temperature, and quenched
with water (2 mL). The organic layer was separated and the aque-
ous layer was extracted with EtOAc (3 Â 5 mL). The combined
organic phases were washed with brine (3 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to afford
a crude product. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate 80:1) to get
TBDPS-protected enynic alcohol 7 (0.183 g, 86% yield) as a yellow
[a]
18.5 = +145.1 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d 8.06–
D
7.92 (m, 4H), 7.60–7.37 (m, 11H), 5.29 (s, 1H), 5.18 (s, 1H), 5.08
(s, 1H), 2.12 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) d
144.3, 136.0, 135.8, 133.6, 131.5, 129.7, 129.6, 128.1, 127.6,
127.4, 122.9, 111.7, 89.2, 85.3, 68.1, 26.9, 19.4, 18.0; HRMS (ESI)
m/z 411.2122 [M+H]+ (calcd for C28H31OSi, 411.2139).
4.4. (2RS,3R)-3-(tert-Butyldiphenylsilyloxy)-2-methyl-5-phenyl-
pent-4-yn-1-ol 5
To a solution of TBDPS-protected enynic alcohol 4 (3.42 g,
8.34 mmol, 1 equiv) in dry THF (16 mL) was added slowly 9-BBN
oil. [a]
18.5 = +132.0 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3) d
D
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.06.002

4
Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7.85–7.76 (m, 4H), 7.44–7.26 (m, 11H), 6.09–5.81 (m, 1H), 5.09–
5.03 (m, 2H), 4.53–4.51 (m, 1H), 2.60–2.50 (m, 1H), 1.27–1.14
(m, 12H); 13C NMR (75 MHz, CDCl3) d 140.0, 139.9, 136.1, 136.0,
133.9, 133.6, 131.5, 131.4, 129.7, 129.5, 128.0, 127.9, 127.6,
127.3, 123.1, 115.3, 89.3, 89.0, 86.0, 68.4, 68.3, 44.9, 44.7, 27.0,
lactones 10a (27 mg) and 10b (81 mg), (total 108 mg, d.r. 1:3, 91%
yield) as a yellow oil. Diastereomeric ratio was determined by
HPLC with a Venusil XBP-Si column (10% 2-propanol in n-hexane,
1 mL/min, 230 nm); major 10b tr = 7.50 min, minor 10a tr = 8.84 -
min. 10a: [
a
]
D
18.5 = À11.6 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3)
19.4, 15.3, 14.7; HRMS (ESI) m/z 425.2276 [M+H]+ (calcd for C29
-
d 7.44–7.34 (m, 5H), 6.71 (d, J = 15.8 Hz, 1H), 6.19 (dd, J = 15.9,
6.9 Hz, 1H), 5.15 (t, J = 6.3 Hz, 1H), 2.85–2.70 (m, 2H), 2.36–2.28
(m, 1H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
176.5, 135.8, 133.6, 128.7, 128.3, 126.7, 123.1, 83.5, 36.5, 34.5,
14.9; HRMS (ESI) m/z 203.1069 [M+H]+ (calcd for C13H15O2,
H33OSi, 425.2295).
4.7. (3RS,4R)-4-(tert-Butyldiphenylsilyloxy)-3-methyl-6-phenyl-
hex-5-yn-1-ol 8
203.1067). 10b: [
a
]
18.5 = À16.8 (c 0.5, CHCl3); 1H NMR (300 MHz,
D
Following the similar procedure of synthesis of mono-TBDPS-
protected acetylenic diol 5, TBDPS-protected enynic alcohol 7
(0.321 mmol, 0.136 g, 1 equiv), 9-BBN (1.93 mL, 0.5 M in THF,
0.963 mmol, 3 equiv) and H2O2 (30%, 0.65 mL) afforded mono-
TBDPS-protected acetylenic diol 8 (0.122 g, 82% yield) as a yellow
CDCl3) d 7.43–7.23 (m, 5H), 6.70 (d, J = 15.9 Hz, 1H), 6.18 (dd,
J = 15.9, 7.3 Hz, 1H), 4.58 (t, J = 7.7 Hz, 1H), 2.96–2.64 (m, 1H),
2.41–2.23 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 176.0, 135.6, 133.8, 128.7, 128.4, 126.7, 125.2, 87.4,
37.3, 36.7, 16.5; HRMS (ESI) m/z 203.1071 [M+H]+ (calcd for
C13H15O2, 203.1067).
oil. [a]
18.5 = +129.6 (c 4.6, CHCl3); 1H NMR (300 MHz, CDCl3) d
D
7.87–7.78 (m, 4H), 7.51–7.22 (m, 11H), 4.58–4.55 (m, 1H), 3.69–
3.63 (m, 2H), 2.06–1.76 (m, 2H), 1.65–1.52 (m, 2H), 1.20–1.04
(m, 12H); 13C NMR (75 MHz, CDCl3) d 136.1, 136.0, 135.9, 135.8,
133.8, 133.5, 133.3, 131.4, 129.8, 129.7, 129.5, 129.4, 128.0,
127.9, 127.6, 127.5, 127.3, 122.9, 88.9, 88.8, 86.2, 86.0, 68.9, 68.4,
61.3, 60.7, 37.4, 36.9, 35.5, 35.4, 26.9, 26.8, 19.4, 19.3, 16.4, 15.0;
HRMS (ESI) m/z 443.2382 [M+H]+ (calcd for C29H35O2Si, 443.2400).
4.10. (3S,4R,E)-Methyl 4-methoxy-3-methyl-6-phenylhex-5-
enoate 11a
To a solution of lactone 10a (108.6 mg, 0.54 mmol, 1 equiv) in
dioxane (2 mL) was added KOH solution (5%, 1.8 mL) at room tem-
perature. After the reaction was maintained for 0.5 h at the same
temperature, HCl solution (1 M) was added until pH 4. The organic
layer was separated, and the aqueous layer was extracted with
Et2O (3 Â 8 mL). The combined organic phases were washed with
brine (5 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure to obtain the crude hydroxyl acid.
4.8. (3RS,4R,E)-3-Methyl-6-phenylhex-5-ene-1,4-diol 9
To a suspension of LiAlH4 (5.78 mmol, 0.22 g, 3.5 equiv) in THF
(10 mL) was added mono-TBDPS-protected acetylenic diol
8
(0.73 g, 1.65 mmol, 1 equiv) at 0 °C under an argon atmosphere.
The reaction mixture was stirred for 0.5 h at the same temperature
and then refluxed overnight. After diluting with Et2O (10 mL),
MeOH (10 mL), water (6 mL), and NH4Cl solid (1 g) were added
sequentially. The resulting mixture was stirred for 3 h at room
temperature, followed by filtering through a Celite pad. The
organic layer was separated and the aqueous layer was extracted
with Et2O (3 Â 15 mL). The combined organic phases were washed
with brine (10 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure to give crude product. The crude
product was purified by silica gel chromatography (petroleum
ether/ethyl acetate 1:2) to afford olefinic diol 9 (0.24 g, 70% yield)
The crude hydroxyl acid was dissolved in THF (1 mL), and then
slowly added to a suspension of NaH (129 mg, 60% dispersion in
mineral oil, 5.4 mmol, 10 equiv) in THF (3 mL) at 0 °C under an
argon atmosphere. After the resulting mixture was stirred for 1 h
at room temperature, after which MeI (100 lL, 1.6 mmol, 3 equiv)
was added and stirred for another 0.5 h. The reaction mixture was
left overnight at room temperature, following by adding HCl solu-
tion (1 M) until pH 4. The organic layer was separated, and the
aqueous layer was extracted with Et2O (3 Â 10 mL). The combined
organic phases were washed with brine (8 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to afford
crude etherified hydroxyl acid.
as a yellow oil. [
a
]
D
18.5 = À3.4 (c 1.5, CHCl3); 1H NMR (300 MHz,
The crude etherified hydroxyl acid was dissolved in DMF (3 mL),
after which K2CO3 (112 mg, 0.81 mmol, 1.5 equiv) and MeI (68 lL,
CDCl3) d 7.40–7.20 (m, 5H), 6.61–6.54 (m, 1H), 6.30–6.18 (m,
1H), 4.27–4.03 (m, 1H), 3.81–3.62 (m, 2H), 3.32 (br s, 2H), 1.88–
1.73 (m, 2H), 1.63–1.58 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 136.8, 136.7, 131.3, 131.1, 130.1, 128.5, 128.4,
128.3, 127.6, 127.5, 126.4, 125.7, 77.2, 76.2, 60.9, 60.6, 37.1, 36.9,
36.0, 35.5, 16.6, 15.5; HRMS (ESI) m/z 207.1382 [M+H]+ (calcd for
1.1 mmol, 2 equiv) were added. After stirring overnight at room
temperature, the reaction was quenched with water (5 mL). The
organic layer was separated, and the aqueous layer was extracted
with EtOAc (3 Â 10 mL). The combined organic phases were
washed with water (3 Â 10 mL) and brine (10 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure to
afford crude product. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate 20:1) to obtain
ester 11a (80 mg, 60% yield over three steps) as a yellow oil.
C13H19O2, 207.1380).
4.9. (3S,4R,E)-4-Hydroxy-3-methyl-6-phenylhex-5-enoic acid
lactone 10a and (3R,4R,E)-4-hydroxy-3-methyl-6-phenylhex-5-
enoic acid lactone 10b
[a]
18.5 = +10.6 (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.41–
D
7.26 (m, 5H), 6.54 (d, J = 16.1 Hz, 1H), 6.05 (dd, J = 16.0, 7.9 Hz,
1H), 3.63 (s, 3H), 3.59 (dd, J = 7.8, 5.6 Hz, 1H), 3.31 (s, 3H), 2.54
(dd, J = 15.0, 5.4 Hz, 1H), 2.28 (dd, J = 13.0, 6.2 Hz, 1H), 2.15 (dd,
J = 14.9, 8.5 Hz, 1H), 1.00 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 173.5, 136.5, 133.4, 128.6, 127.8, 127.7, 126.5, 85.6,
56.7, 51.4, 37.5, 35.2, 15.6; HRMS (ESI) m/z 249.1475 [M+H]+ (calcd
for C15H21O3, 249.1485).
To a solution of olefinic diol 9 (0.12 g, 0.59 mmol, 1.0 equiv) in
DCM (6 mL) were added PhI(AcO)2 (0.95 g, 2.95 mmol, 5 equiv)
and TEMPO (18.44 mg, 0.12 mmol, 0.2 equiv) successively at room
temperature under an argon atmosphere. The reaction mixture
was stirred overnight at the same temperature, and quenched with
saturated aqueous Na2S2O3 (5 mL). The resulting mixture was
diluted with DCM (10 mL), and the organic layer was separated.
The aqueous layer was extracted with DCM (3 Â 10 mL). The com-
bined organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure to
afford a crude product. The crude product was purified by silica
gel chromatography (petroleum ether/ethyl acetate 18:1) to obtain
4.11. (3R,4R,E)-Methyl 4-methoxy-3-methyl-6-phenylhex-5-
enoate 11b
Following the similar procedure of synthesis of ester 11a, lac-
tone 10b (108.6 mg, 0.54 mmol, 1 equiv) gave ester 11b (75 mg,
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.06.002

Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
56% yield over three steps) as a yellow oil. [a]
18.5 = +11.3 (c 1.0,
D
Acknowledgments
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.42–7.23 (m, 5H), 6.54 (d,
J = 16.0 Hz, 1H), 6.02 (dd, J = 16.0, 8.1 Hz, 1H), 3.67 (s, 3H), 3.48
(t, J = 7.5 Hz, 1H), 3.29 (s, 3H), 2.59–2.54 (m, 1H), 2.27–2.16 (m,
2H), 0.96 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.6,
136.5, 133.7, 128.6, 128.1, 127.8, 126.5, 86.3, 56.6, 51.4, 37.9,
35.4, 16.2; HRMS (ESI) m/z 249.1484 [M+H]+ (calcd for C15H21O3,
249.14852).
We appreciate the National Key Technology Research and
Development Program (No. 2015BAK45B01), National Training
Program of Innovation and Entrepreneurship for Undergraduates
(201510019142), and Beijing Training Program of Innovation and
Entrepreneurship
for
Undergraduates
(2015bj128
and
2015bj144) for the financial support.
4.12. (À)-Oudemanisin A 1a
A. Supplementary data
To a solution of ester 11a (41.8 mg, 0.17 mmol, 1 equiv) in dry
THF (6 mL) was added LDA (4.25 mL, 0.2 M in THF, 0.85 mmol,
3 equiv) at À78 °C under an argon atmosphere. The resulting mix-
ture was stirring for 20 min, after which N-formylimidazole
(4.8 mL, 0.26 M in THF, 1.24 mmol, 7.3 equiv) was slowly added.
After stirring for 30 min at the same temperature, the reaction
mixture was warmed to room temperature over 2 h. The reaction
was quenched with HCl (5 mL, 1 M) and diluted with Et2O
(10 mL). The organic layer was separated, and the aqueous layer
was extracted with Et2O (3 Â 10 mL). The combined organic phases
were washed with brine (10 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to obtain the crude
b-formyl ester.
The crude b-formyl ester was dissolved in acetone (20 mL), after
which K2CO3 (92 mg, 0.67 mmol, 3.9 equiv) and dimethyl sulfate
(0.37 mL, 5.1 mmol, 30 equiv) were added. The reaction mixture
was stirred for 12 h at room temperature and then quenched with
water (5 mL). The organic layer was separated and the aqueous
layer was extracted with Et2O (3 Â 15 mL). The combined organic
phases were washed with brine (8 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to afford crude
product. The crude product was purified by silica gel column chro-
matography (petroleum ether/ethyl acetate 20:1) to give (À)-
oudemanisin A 1a (22.7 mg, 46% yield over two steps) as a yellow
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.06.
002.
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oil. [
a
]
18.5 = À18.3 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.35–
D
7.19 (m, 5H), 7.18 (s, 1H), 6.41 (d, J = 15.9 Hz, 1H), 5.92 (dd, J = 15.9,
8.6 Hz, 1H), 3.96 (d, J = 9.1 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.32 (s,
3H), 3.00 (dq, J = 9.6, 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 168.2, 159.4, 137.1, 132.5, 129.7, 128.5, 127.4,
126.4, 112.4, 85.0, 61.3, 56.5, 50.9, 35.7, 15.7; HRMS (ESI) m/z
291.1590 [M+H]+ (calcd for C17H23O4, 291.1591).
15. Bleriot, Y.; Auberger, N.; Jagadeesh, Y.; Gauthier, C.; Prencipe, G.; Tran, A. T.;
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3-methyl-6-phenylhex-5-enoate 1b
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oil. [a]
18.5 +9.0 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.43–
D
7.22 (m, 6H), 6.59 (d, J = 15.9 Hz, 1H), 6.03 (dd, J = 15.9, 8.6 Hz,
1H), 4.02 (dd, J = 20.5, 11.4 Hz, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.23
(s, 3H), 3.02–2.97 (m, 1H), 1.07 (d, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 168.3, 159.2, 136.8, 133.8, 129.9, 128.5, 127.6,
126.5, 112.6, 84.3, 61.3, 56.4, 50.9, 35.2, 15.6; HRMS (ESI) m/z
291.1592 [M+H]+ (calcd for C17H23O4, 291.1591).
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.06.002