Total Synthesis of the Nonenolide Xyolide Using a Regioselective Nucleophilic Epoxide Opening Approach

Article abstract of DOI:10.1055/s-0034-1380780

The total synthesis of the nonenolide xyolide is described as a convergent synthesis in 16 steps from the commercially available starting material butane-1,4-diol. The key reactions involved are: Sharpless asymmetric epoxidation, Pinnick oxidation, acid-mediated nucleophilic regioselective epoxide ring opening, Steglich esterification, and ring-closing metathesis.

Full text of DOI:10.1055/s-0034-1380780

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2129–2137
paper
2129
S. B. Wadavrao et al.
Paper
Synthesis
Total Synthesis of the Nonenolide Xyolide Using a Regioselective
Nucleophilic Epoxide Opening Approach
Sachin B. Wadavrao
Ramesh S. Ghogare
A. Venkat Narsaiah*
O
esterification
O
butane-1,4-diol
HO
O
OH
OPMB
O
O
O
Organic and Biomolecular Chemistry Division, Indian Institute
of Chemical Technology, Hyderabad-500007, Telangana, India
vnakkirala@iict.res.in
OH OTBS
RCM
octanal
OH
OH
xyolide
OTBS
regioselective epoxide
ring opening
Received: 10.11.2014
Accepted after revision: 20.04.2015
Published online: 19.06.2015
invasive weeds.5 Xyolide is a newly identified 10-mem-
bered-ring lactone isolated as a secondary fungal metabo-
lite from the Amazonian endophytic fungus Xylaria fejeensis
and it shows good inhibitory activity against the growth of
Pythium ultimum, an oomcyete plant pathogen with
MIC = 425 μM.6 The structural fascination and biological ac-
tivity of xyolide has attracted synthetic chemists and led to
its synthesis by different routes.7
As part of our regular research program on the synthesis
of biologically active natural and synthetic compounds,8
herein we wish to report, our synthetic strategy for the ste-
reoselective total synthesis of the nonenolide xyolide utiliz-
ing regioselective 2,3-epoxy ring opening, Steglich esterifi-
cation, and ring-closing metathesis methods as shown in
Scheme 1.
DOI: 10.1055/s-0034-1380780; Art ID: ss-2014-n0687-op
Abstract The total synthesis of the nonenolide xyolide is described as
a convergent synthesis in 16 steps from the commercially available
starting material butane-1,4-diol. The key reactions involved are:
Sharpless asymmetric epoxidation, Pinnick oxidation, acid-mediated
nucleophilic regioselective epoxide ring opening, Steglich esterification,
and ring-closing metathesis.
Key words natural product, xyolide, Sharpless epoxidation, regiose-
lective ring opening, ring-closing metathesis
Ten-membered lactones (Figure 1) are abundant and
represent the core of many natural products and display a
wide range of pharmacological properties, such as antibac-
terial, antifungal, antiviral, and anticancer activity.1 Micro-
carpalide2 and achaetolide3 shows antimicrofillament ac-
tivity, phomol shows antibacterial and antifungal activity,4
and stagonolide A and herbarumins inhibit the growth of
As shown in the retrosynthetic analysis, our synthetic
strategy started from commercially available butane-1,4-
diol for the acid fragment 10 (Scheme 2) and octanal for the
hydroxyalkene fragment 18 (Scheme 3). Butane-1,4-diol
was selectively monoprotected using tert-butyl(chloro)di-
C5H11
C6H13
C6H13
O
O
O
O
OH
O
OH
O
HO
O
OH
HO
OH
OH
O
OH
HO
O
xyolide (1)
microcarpalide
achaetolide
C4H9
O
O
O
O
O
O
HO
OH
OH
OH
O
O
OH
O
O
O
HO
OH
OH
OH
herbarumin I
herbarumin II
phomol
stagonolide A
Figure 1 Naturally occurring nonenolides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2129–2137

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Synthesis
ed ethyl (E)-6-(tert-butyldimethylsiloxy)hex-2-enoate (3)
in 92% (two steps). Reduction of the obtained ester 3 was
carried out using diisobutylaluminum hydride12 to give (E)-
6-(tert-butyldimethylsiloxy)hex-2-en-1-ol (4) in 95% yield,
which was subjected to Sharpless asymmetric epoxida-
tion13 with (–)-diethyl tartrate, titanium(IV) isopropoxide,
and tert-butyl hydroperoxide to give enantiopure epoxide 5
in 78% yield. Conversion of the free alcohol into the iodo
group was achieved using molecular iodine, imidazole, and
triphenylphosphine in diethyl ether–acetonitrile (3:1) at
0 °C to obtain tert-butyl{3-[(2S,3R)-3-(iodomethyl)oxiran-
2-yl]propoxy}dimethylsilane (6) in 78%. Compound 6 was
converted into secondary allylic alcohol 7 (80% yield) using
activated zinc in ethanol at reflux for four hours.14 Protec-
tion of the hydroxy group in compound 7 with a 4-meth-
oxybenzyl imidate15 produced the PMB-protected com-
pound 8 in 85% yield.
O
PMBO
OH
O
O
O
O
O
O
OTBS
H13C6
H13C6
OH
OH
OTBS
1
19
O
OH OTBS
OTBS
HO
+
OPMB
18
12
10
O
O
OH
TBSO
OH
5
octanal
butane-1,4-diol
Desilylation of compound 8 with 10-camphorsulfonic
acid in dichloromethane produced primary alcohol 9 in 90%
yield, which was subjected to Swern oxidation followed by
Pinnick oxidation16 using sodium chlorite under buffer con-
ditions to afford (S)-4-(4-methoxybenzyloxy)hex-5-enoic
acid (10) in 75% yield (after two steps).17
Scheme 1 Retrosynthesis of xyolide
methylsilane in the presence of imidazole in dichlorometh-
ane to give 4-(tert-butyldimethylsiloxy)butan-1-ol (2)9 in
95% yield. Swern oxidation10 of compound 2 followed by C2
Wittig11 olefination in benzene at room temperature afford-
i) Swern oxidation
OEt
DIBAL-H, CH2Cl2
–78 °C, 1 h, 95%
TBSCl, imidazole
OH
TBSO
TBSO
butane-1,4-diol
DMAP, CH2Cl2
O
ii) Ph3P=CHCO2Et
benzene, 2 h, 92%
3
2
0 °C to r.t.,1 h, 95%
I2, imidazole, Ph3P
Et2O–MeCN (3:1)
(–)-DET, Ti(Oi-Pr)4
TBHP, CH2Cl2
O
O
Zn, EtOH
reflux, 4 h, 80%
OH
I
OH
TBSO
TBSO
TBSO
–20 °C, 4 h, 78%
0 °C to r.t., 2 h, 78%
4
5
6
i) Swern oxidation
CSA, CH2Cl2
PMB-(C=NH)-CCl3, Et2O
10
TBSO
TBSO
HO
ii) NaClO2, NaHPO4⋅2H2O
t-BuOH-2-methylbut-2-ene
(3:1), 0.5 h, 75%
0 °C, 1 h, 90%
CSA, cyclohexane, 4 h, 85%
OH
OPMB
OPMB
9
7
8
Scheme 2 Synthesis of fragment 10
(+)-DET, Ti(Oi-Pr)4
TBHP, CH2Cl2
1. Ph3P=CH-CO2Et
benzene, 2 h
O
PhCOOH,Ti(Oi-Pr)4
octanal
OH
OH
2. DIBAL-H, CH2Cl2
–20 °C, 4 h, 78%
CH2Cl2, 0 °C, 1 h, 88%
12
–78 °C, 1 h, 90%
11
TBSCl, imidazole
DMAP, CH2Cl2
OBz
OBz
OBz
CSA (0.1 equiv)
OTBS
OH
OH
MeOH–CH2Cl2 (1:3)
2 h, 87%
0 °C, r.t., 1 h, 95%
OH
OTBS
OTBS
13
14
15
TBSCl, imidazole
DMAP, CH2Cl2
OBz OTBS
OBz OH
OTBS
OH OTBS
OTBS
K2CO3, MeOH
0 °C, r.t., 2 h, 92%
1. Swern oxidation
2. CH2=CHMgBr
0 °C, r.t., 1 h, 95%
OTBS
THF, 0 °C, 2 h, 85%
17
16
18
Scheme 3 Synthesis of fragment 18
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Synthesis
Synthesis of segment 18 began from commercially
available octanal, which was subjected to C2 Wittig fol-
lowed by reduction with diisobutylaluminum hydride to af-
ford (E)-dec-2-en-1-ol (11) in 95% yield. Sharpless asym-
metric epoxidation of allylic alcohol 11 was performed us-
ing (+)-diethyl tartrate, titanium(IV) isopropoxide, and tert-
butyl hydroperoxide in dichloromethane to give enantio-
pure [(2R,3R)-3-heptyloxiran-2-yl]methanol (12) in 78%
yield with 95% ee. The treatment of chiral epoxide 12 with
acid-mediated nucleophilic regioselective 2,3-ring opening
in presence of benzoic acid and titanium(IV) isopropoxide
gave (2S,3R)-3-(benzoyloxy)decane-1,2-diol (13) in 88%
yield as a single isomer,18 which was confirmed by 1H NMR
spectroscopy. This regioselective ring-opening protocol
serve as the key synthetic intermediate in this approach.
Thus, obtained diol benzoate 13 was subjected to protec-
tion with tert-butyl(chloro)dimethylsilane in the presence
of imidazole in dichloromethane to give, (2S,3R)-1,2-
bis(tert-butyldimethylsiloxy)decan-3-yl benzoate (14) in
95% yield.
Selective desilylation of compound 14 was carried out
using 10-camphorsulfonic acid in a mixture of methanol–
dichloromethane (1:3) solvent to afford (2S,3R)-3-(benzoyl-
oxy)-2-(tert-butyldimethylsiloxy)decan-1-ol (15) in 87%
yield. The obtained alcohol 15 was oxidized under Swern
conditions to give the corresponding aldehyde, which was
directly subjected to Grignard reaction with 1 M vinylmag-
nesium bromide in tetrahydrofuran in anhydrous tetrahy-
drofuran to produce the secondary allyl alcohol 16 as a
mixture of anti/syn diastereomers (9:1). The major diaste-
reomer was separated by column chromatography to give
pure anti isomer (3S,4S,5R)-5-(benzoyloxy)-4-(tert-butyldi-
methylsiloxy)dodec-1-en-3-ol (16) (85% yield in two steps).
The TBS protection of alcohol 16 with tert-butyl(chloro)di-
methylsilane, imidazole, and a catalytic amount of 4-(di-
methylamino)pyridine gave silyl ether 17 in 95% yield.
Treatment of compound 17 with potassium carbonate in
methanol resulted in deprotection of the benzoyl group to
give (3S,4R,5R)-3,4-bis(tert-butyldimethylsiloxy)dodec-1-
en-5-ol (18) in 92% yield.
The coupling of fragments 10 and 18 (Scheme 4) was
successfully performed using the Steglich protocol19 in the
presence of N,N′-dicyclohexyldicarbodiimide and 4-(di-
methylamino)pyridine in dichloromethane to give ester 19
in 75% yield. Deprotection of the PMB group was carried
out with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a
mixture of water–dichloromethane (1:19) solvent to afford
the diene ester in 80% yield; Ring-closing metathesis reac-
tion with this compound using Grubbs’ second-generation
catalyst20 (10 mol%) afforded the 10-membered lactone 20
as the sole product (E-isomer) in 82% yield. Compound 20
was subjected to esterification with succinic anhydride21
using pyridine with 4-(dimethylamino)pyridine as the cata-
lyst in dichloromethane to give acid 21 (91%), which on
desilylation with 2 M hydrochloric acid gave xyolide (1) in
73% yield. The spectroscopic data and optical rotation of
synthetic compound 1 are comparable with that in the lit-
erature, which is good agreement with the reported xyo-
lide.1
In conclusion, the stereoselective total synthesis of xyo-
lide is accomplished in 16 steps from readily available bu-
tane-1,4-diol. The main feature of the synthesis includes
the construction of a chiral fragment by using Sharpless
asymmetric epoxidation, acid-mediated nucleophilic regio-
selective epoxide opening, and ring-closing metathesis.
All reagents were purchased from commercial sources and were used
without additional purification. All reactions were performed under
an inert atmosphere unless otherwise noted. THF was freshly distilled
over Na/benzophenone ketyl. Petroleum ether refers to the fraction
boiling in the 60–80 °C range. Column chromatography was per-
formed on silica gel (Acme grade 60–120 mesh). All reactions were
monitored by TLC to completion; TLC plates (Merck precoated silica
gel 60 F 254 plates) were made visible with UV light, in an I2 chamber
PMBO
OH
1. DDQ
H2O/CH2Cl2 (1:19)
0 °C to r.t., 1 h, 80%
O
O
OTBS
DCC, DMAP
O
O
+
10
18
CH2Cl2, 0 °C to r.t.
3 h, 75%
2. Grubbs II, CH2Cl2
reflux, 12 h, 62%
OTBS
OTBS
19
OTBS
20
O
OH
O
O
N
N
Mes
Mes
Ph
succinic anhydride
DMAP, py, CH2Cl2
O
O
Cl
2 M HCl
THF, 4 h, 73%
Ru
1
Cl
0 °C to r.t., 12 h, 91%
OTBS
PCy3
Grubbs-II
OTBS
21
Scheme 4 Synthesis of xyolide 1
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Synthesis
or with phosphomolybdic acid spray. Melting points were recorded
using a Buchi M-560 melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin-Elmer FT-IR 240-c spectrophotom-
eter. 1H NMR spectra were recorded on Bruker-300 MHz, spectrome-
ter in CDCl3 using TMS as internal standard. Mass spectra were re-
corded on a Finnigan MAT 1020 mass spectrometer operating at 70
eV. Optical rotations were measured on Rudolph Autopol IV polarim-
eter at 25 °C.
um potassium tartrate and the mixture stirred for 2 h. The mixture
was passed through a bed of Celite. The filtrate was extracted with
CH2Cl2 (2 × 20 mL) and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, EtOAc–hexane
2:8) to obtain allylic alcohol 4 as a colorless liquid; yield: 5.6 g (95%).
IR (neat): 3355, 2928, 2856, 1468, 1254, 1219, 1100, 968, 836, 773
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.70 (q, J = 5.4 Hz, 2 H), 4.10 (d, J = 5.4
Hz, 2 H), 3.62 (t, J = 6.4 Hz, 2 H), 2.05–2.15 (m, 2 H), 1.55–1.68 (m, 2
H), 0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 132.8, 129.0, 63.7, 62.4, 32.1, 30.8, 28.4,
25.8, –5.3.
4-(tert-Butyldimethylsiloxy)butan-1-ol (2)
To a stirred solution of butane-1,4-diol (3 mL, 33.3 mmol) in anhy-
drous CH2Cl2 (30 mL) was added imidazole (2.73 g, 66.6 mmol) at 0 °C
and the mixture was stirred for 30 min. TBSCl (5 g, 33.3 mmol) dis-
solved in CH2Cl2 (20 mL) was added and the mixture was stirred at r.t.
for 1 h (TLC monitoring). The mixture was quenched with sat. NH4Cl
solution and extracted with CH2Cl2 (2 × 30 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, EtOAc–hexane, 2:8) to afford TBS ether 2 as a colorless syrup;
yield: 6.4 g (95%).
HRMS: m/z [M + H]+ calcd for C12H27O2Si: 231.1774; found: 231.1785.
{(2S,3S)-3-[3-(tert-Butyldimethylsiloxy)propyl]oxiran-2-yl}meth-
anol (5)
To a stirred mixture of molecular sieves powder (4 Å, 5.5 g) and Ti(Oi-Pr)4
(0.85 mL, 2.8 mmol) in CH2Cl2 (15 mL) at –20 °C was added (–)-DET
(0.6 mL, 3.5 mmol) dissolved in CH2Cl2 (2 mL) and the mixture was
stirred for 15 min. Then 3 M TBHP in toluene (15.9 mL, 47.8 mmol)
was added. After 30 min, a solution of allylic alcohol 4 (5.5 g, 23.9
mmol) dissolved in CH2Cl2 (8 mL) was added. The resulting mixture
was stirred at –20 °C for 4 h and then quenched with H2O (17 mL) fol-
lowed by 20% NaOH solution (5.7 mL). The mixture was stirred at r.t.
for 45 min, and it was filtered and the filtrate was extracted with
CH2Cl2 (3 × 25 mL). The combined organic layers were washed with
brine, dried (Na2SO4), filtered, and concentrated. The residual oil was
purified by column chromatography (hexanes–EtOAc, 1.5: 8.5) to give
chiral epoxy alcohol 5 as a colorless liquid; yield: 4.5 g (78%).
IR (neat): 3682, 3611, 3339, 3017, 2930, 2858, 1424, 1265, 1219,
1091, 1025, 942, 860, 784 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.72 (t, J = 6.5 Hz, 2 H), 3.62 (t, J = 6.5
Hz, 2 H), 1.53–1.64 (m, 4 H), 0.90 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 63.3, 62.8, 30.2, 29.9, 25.9, 25.5, 18.3,
–3.5.
MS (ESI): m/z = 205 [M + H]+.
Ethyl (E)-6-(tert-Butyldimethylsiloxy)hex-2-enoate (3)
To a stirred solution of oxalyl chloride (5.5 g, 44.1 mmol) in anhy-
drous CH2Cl2 (40 mL) at –78 °C was added DMSO (6.9 g, 88.2 mmol)
over 20 min and the mixture was stirred for an additional 15 min. Al-
cohol 2 (6 g, 29.4 mol) dissolved in CH2Cl2 (10 mL) was added and the
mixture was stirred for 30 min. Et3N (20.4 mL, 147 mmol) was added
dropwise and the mixture was stirred at r.t. for 1 h (TLC monitoring).
The mixture was quenched with water and the aqueous phase was
extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo to give
the aldehyde which was used in the next step.
[α]D25 +0.2 (c 0.5, CHCl3).
IR (neat): 3441, 2927, 2856, 1692, 1467, 1253, 1219, 1096, 835, 773
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.87–3.92 (m, 1 H), 3.60–3.71 (m, 3 H),
2.90–3.10 (m, 2 H), 1.60–1.72 (m, 4 H), 0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 62.5, 61.6, 58.4, 55.8, 29.0, 28.1, 25.9,
18.3, –5.3.
HRMS: m/z [M + H]+ calcd for C12H27O3Si: 247.1724; found: 247.1737.
The aldehyde was dissolved in benzene (60 mL), the Wittig ylide (12.4
g, 35.2 mmol) was added at r.t. and the mixture was stirred for 2 h
(TLC monitoring). The solvent was evaporated and the residue was
purified by column chromatography (silica gel, EtOAc–hexane, 1:9) to
afford unsaturated ester 3 as a colorless liquid; yield: 7.3 g (92%).
tert-Butyl{3-[(2S,3R)-3-(iodomethyl)oxiran-2-yl]propoxy}dimeth-
ylsilane (6)
To a solution of epoxy alcohol 5 (4.5 g, 18.2 mmol) in Et2O–MeCN
(3:1, 40 mL) was added Ph3P (4.8 g, 18.2 mmol) followed by imidazole
(1.5 g, 21.9 mmol) at 0 °C and the mixture was stirred for 10 min.
Then I2 (4.6 g, 18.2 mmol) was added at 0 °C and the mixture was
stirred for 2 h at r.t. (TLC monitoring). The mixture was quenched
with sat. Na2S2O3 (15 mL) and extracted with EtOAc (3 × 20 mL). The
organic layers were washed with brine and dried (Na2SO4). The sol-
vent was evaporated and residue was purified by column chromatog-
raphy (silica gel, EtOAc–hexane, 0.5:9.5) to afford epoxy iodo 6 as a
colorless liquid; yield: 5 g (78%).
IR (neat): 2929, 2855, 1717, 1653, 1368, 1317, 1268, 1213, 1040, 980,
771 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.9 (dt, J = 15.8, 6.9 Hz, 1 H), 5.82 (d,
J = 15.4 Hz, 1 H), 4.19 (q, J = 6.4 Hz, 2 H), 3.62 (t, J = 6.5 Hz, 2 H), 2.28
(q, J = 6.5 Hz, 2 H), 1.60–1.71 (m, 2 H), 1.28 (t, J = 6.4 Hz, 3 H), 0.88 (s,
9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.6, 148.3, 121.7, 61.9, 60.2, 30.8,
28.4, 25.8, 25.6, 14.2, –3.6.
[α]D25 +3.2 (c 0.5, CHCl3).
MS (ESI): m/z = 273 [M + H]+.
IR (neat): 2928, 2856, 1692, 1467, 1253, 1219, 1096, 835, 773 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.62–3.72 (m, 2 H), 3.20–3.30 (m, 1 H),
2.95–3.10 (m, 2 H), 2.70–2.80 (m, 1 H), 1.60–1.72 (m, 4 H), 0.88 (s, 9
H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 62.3, 58.3, 28.9, 28.2, 25.8, 18.2, 4.9,
–5.3.
(E)-6-(tert-Butyldimethylsiloxy)hex-2-en-1-ol (4)
To a stirred solution of unsaturated ester 3 (7.2 g, 25.7 mmol) in anhy-
drous CH2Cl2 (50 mL) at –78 °C was added 25% DIBAL-H in toluene
(29.2 mL, 51.5 mmol) slowly over 15 min. The mixture was stirred at
this temperature for 1 h, cooled to 0 °C, and quenched with sat. sodi-
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HRMS: m/z [M + H]+ calcd for C12H26O2ISi: 357.0741; found: 357.0761.
(S)-6-(tert-Butyldimethylsiloxy)hex-1-en-3-ol (7)
were washed with brine, dried (Na2SO4), and evaporated. The crude
alcohol was purified by column chromatography (silica gel, EtOAc–
hexane, 2:8) to afford primary alcohol 9 as a colorless liquid; yield:
1.8 g (90%).
To a stirred solution of epoxy iodo 6 (5 g, 14 mmol) in EtOH (20 mL)
was added activated Zn dust (9.1 g, 140 mmol) and the mixture was
stirred at reflux for 4 h. After complete consumption of the starting
material, the mixture was passed through a Celite bed. The filtrate
was concentrated and the residue was purified by column chromatog-
raphy (silica gel, EtOAc–hexane, 2:8) to afford allylic alcohol 7 as a
colorless liquid; yield: 2.7 g (80%).
[α]D25 –22.4 (c 0.4, CHCl3).
IR (neat): 3393, 2923, 2854, 1611, 1512, 1462, 1300, 1246, 1174,
1055, 772 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 7.0 Hz, 2 H), 6.88 (d, J = 7.0
Hz, 2 H), 5.72–5.82 (m, 1 H), 5.20–5.30 (m, 2 H), 4.53 (d, J = 11.2 Hz, 1
H), 4.28 (d, J = 11.2 Hz, 1 H), 3.80 (s, 3 H), 3.74–3.78 (m, 1 H), 3.59 (t,
J = 6.5 Hz, 2 H), 1.18–1.96 (m, 4 H).
[α]D25 +1.4 (c 0.5, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 159.1, 138.7, 130.4, 129.4, 117.6, 113.7,
80.0, 69.8, 62.8, 55.2, 32.2, 28.7.
IR (neat): 3392, 2926, 2855, 1467, 1387, 1361, 1253, 1099, 991, 920,
834 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.84–5.91 (m, 1 H), 5.24 (dd, J = 17.2,
1.3 Hz, 1 H), 5.10 (dd, J = 17.2, 1.3 Hz, 1 H), 4.10–4.18 (m, 1 H), 3.67 (t,
J = 7.0 Hz, 2 H), 2.75 (br. s, 1 H), 1.52–1.56 (m, 4 H), 0.88 (s, 9 H), 0.03
(s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 141.2, 114.2, 72.6, 63.3, 34.4, 28.7, 25.9,
25.6, –5.3.
HRMS: m/z [M + Na]+ calcd for C14H20O3Na: 259.1304; found:
259.1317.
(S)-4-(4-Methoxybenzyloxy)hex-5-enoic Acid (10)
To a stirred solution of oxalyl chloride (1 mL, 10.8 mmol) in anhy-
drous CH2Cl2 (40 mL) at –78 °C was added DMSO (1.6 mL, 21.6 mmol)
over 20 min. The resulting mixture was stirred for an additional 15
min. Alcohol 9 (1.7 g, 7.2 mmol) dissolved in CH2Cl2 (10 mL) was add-
ed slowly and the mixture was stirred for 30 min. To this mixture was
added Et3N (5 mL, 136 mmol) and the mixture was stirred at r.t. for 1
h (TLC monitoring). The mixture was quenched with water and the
aqueous phase was extracted with CH2Cl2 (2 × 20 mL). The combined
organic layers were washed with brine, dried (anhyd Na2SO4), and
concentrated in vacuo to give the aldehyde.
HRMS: m/z [M + H]+ calcd for C12H27O2Si: 231.1774; found: 231.1785.
tert-Butyl{[(S)-4-(4-methoxybenzyloxy)hex-5-en-1-yl]oxy}di-
methylsilane (8)
To a stirred solution of 4-methoxybenzyl alcohol (3.5 g, 25.3 mmol) in
Et2O (20 mL) was added a suspension of NaH (0.2 g, 60%, 5 mmol) dis-
solved in Et2O (20 mL) at r.t. The resulting mixture was stirred for 30
min and cooled to 0 °C, to this was added trichloroacetonitrile (1.93
mL, 1.2 mmol) slowly and stirring was continued at r.t. for 6 h. The
solvent was evaporated to give an orange syrup, which was dissolved
in anhyd hexane (50 mL) containing a few drops of MeOH. This sus-
pension was shaken vigorously and filtered on Celite bed; filtrate was
concentrated to afford the imidate.
To a stirred mixture of the aldehyde (1.6 g, 4.9 mmol) in t-BuOH–2-
methylbut-2-ene (3:1, 20 mL) at 0 °C was added a solution of NaClO2
(1.2 g, 9.9 mmol) and NaH2PO4 (2.1 g, 9.9 mmol) dissolved in the min-
imum quantity of water. Stirring was continued for 30 min at r.t. (TLC
monitoring). The mixture was diluted with H2O (20 mL) and t-BuOH
was removed under reduced pressure; the aqueous layer was extract-
ed with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated under reduced pressure
to give the crude acid, which was purified by column chromatography
(hexane–EtOAc, 7:3) to afford acid 10 as a colorless liquid; yield: 1.3 g
(75%).
The above imidate (6.1 g, 21.7 mmol) was taken up in cyclohexane
(30 mL) and added to a solution of alcohol 7 (2.5 g, 10.8 mmol) dis-
solved in CH2Cl2 (15 mL). The resulting mixture was cooled to 0 °C and
CSA (0.25 g, 2.17 mmol) was added and the mixture was stirred at r.t.
for 4 h to give a white precipitate of trichloroacetamide. The solution
was filtered off, and washed with CH2Cl2. The filtrate was washed
with sat. NaHCO3 and brine. The solvent was evaporated and the resi-
due was purified by column chromatography (silica gel, EtOAc–hex-
ane, 1: 9) to give PMB ether 8 as a pale yellow liquid; yield: 3.2 g
(85%).
[α]D25 –22.0 (c 0.5, CHCl3) [Lit.17a [α]D25 –27.4 (c 0.1, CHCl3)].
IR (neat): 3459, 3074, 2954, 2854, 1706, 1611, 1512, 1421, 1246,
1174, 1034, 929, 851, 736 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 7.5 Hz, 2 H), 6.89 (d, J = 7.5
Hz, 2 H), 5.68–5.80 (m, 1 H), 5.25–5.32 (m, 2 H), 4.53 (d, J = 11.2 Hz, 1
H), 4.28 (d, J = 11.2 Hz, 1 H), 3.79 (s, 3 H), 3.76–3.78 (m, 1 H), 2.5 (t,
J = 7.2 Hz, 2 H), 1.18–1.96 (m 2 H).
[α]D25 –19.3 (c 0.45, CHCl3).
IR (neat): 2952, 2925, 2854, 1626, 1512, 1464, 1247, 1173, 1093, 833,
773 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 179.2, 159.1, 138.1, 130.4, 129.3, 117.6,
113.7, 78.8, 69.8, 55.2, 30.1, 30.0.
HRMS: m/z [M + Na]+ calcd for C14H18O4Na: 273.1097; found:
273.1110.
1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 7.0 Hz, 2 H), 6.88 (d, J = 7.0
Hz, 2 H), 5.69–5.77 (m, 1 H), 5.23–5.29 (m, 2 H), 4.54 (d, J = 11.2 Hz, 1
H), 4.28 (d, J = 11.2 Hz, 1 H), 3.79 (s, 3 H), 3.74–3.78 (m, 1 H), 3.59–
3.63 (m, 2 H), 1.18–1.96 (m, 4 H), 0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 158.9, 139.1, 130.8, 129.3, 116.9, 113.6,
80.0, 69.8, 63.0, 55.2, 31.7, 28.6, 25.9, –5.3.
(E)-Dec-2-en-1-ol (11)
HRMS: m/z [M + H]+ calcd for C20H35O3Si: 351.2350; found: 351.2370.
To a stirred mixture of octanal (2 g, 15.6 mmol) in benzene (60 mL)
was added the Wittig ylide (10.9 g, 31.2 mmol) at r.t. and the mixture
was stirred for 1 h (TLC monitoring). The solvent was evaporated and
the residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:9) to afford the unsaturated ester as white solid.
Thus obtained ester (2.8 g, 14.14 mmol) was dissolved in anhydrous
CH2Cl2 (30 mL) at –78 °C and to this was added 25% DIBAL-H in tolu-
ene (16 mL, 28.28 mmol) slowly over 15 min. The mixture was stirred
(S)-4-(4-Methoxybenzyloxy)hex-5-en-1-ol (9)
To a stirred solution of 8 (3 g, 8.5 mmol) in anhydrous CH2Cl2 (25 mL)
was added CSA (0.55 g, 1.7 mmol) and the mixture was stirred at 0 °C
for 1 h (TLC monitoring). The mixture was quenched with sat. NaHCO3
and extracted with CH2Cl2 (2 × 15 mL). The combined organic layers
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S. B. Wadavrao et al.
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Synthesis
at this temperature for 2 h, cooled to 0 °C, quenched with sat. sodium
potassium tartrate (15 mL), and stirred for 2 h. The mixture was
passed through bed of Celite and the filtrate was extracted with
CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel, EtOAc–hexane 2:8) to
give allylic alcohol 11 as a as colorless liquid; yield: 2.2 g (90%, 2
steps).
1H NMR (300 MHz, CDCl3): δ = 8.03–8.12 (m, 2 H), 7.52–7.62 (m, 1 H),
7.41–7.48 (m, 2 H), 5.05–5.14 (m, 1 H), 3.69–3.78 (m, 2 H), 3.60–3.66
(m, 1 H), 1.75–1.93 (m, 2 H), 1.18–1.39 (m, 10 H), 0.88 (t, J = 7.0 Hz, 3
H).
13C NMR (75 MHz, CDCl3): δ = 167.3, 133.3, 129.7, 128.4, 74.9, 73.0,
62.4, 31.7, 30.7, 29.3, 29.0, 25.4, 22.5, 14.1.
HRMS: m/z [M + H]+ calcd for C17H27O4: 295.1903; found: 295.1896.
IR (neat): 3355, 2928, 2856, 1696, 1552, 1219, 1100, 968, 772 cm–1
1H NMR (300 MHz, CDCl3): δ = 5.60–5.73 (m, 2 H), 4.09 (d, J = 6.2 Hz, 2
H), 2.01–2.07 (m, 2 H), 1.22–1.41 (m, 10 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 133.6, 128.7, 63.8, 32.2, 31.8, 29.1, 22.6,
14.0.
.
(2S,3R)-1,2-Bis(tert-butyldimethylsiloxy)decan-3-yl Benzoate (14)
To a stirred solution of diol 13 (2 g, 6.8 mmol) in anhydrous CH2Cl2
(20 mL) at 0 °C was added imidazole (1 g, 14.9 mmol) and the mixture
was stirred for 15 min. TBSCl (2 g, 13.6 mmol) dissolved in anhydrous
CH2Cl2 (5 mL) was added followed by DMAP (cat.) and the mixture
was stirred for 1 h at r.t. (TLC monitoring). Water was added to the
mixture and it was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were washed with brine and dried (Na2SO4), the sol-
vent was evaporated, and the residue was purified by column chro-
matography (silica gel, EtOAc–hexane, 0.5:9.5) to afford TBS ether 14
as a colorless liquid; yield: 3.37 g (95%).
MS (ESI): m/z = 157 [M + H]+.
[(2S,3S)-3-Heptyloxiran-2-yl]methanol (12)
To a stirred mixture of molecular sieves powder (4 Å, 2 g) and Ti(Oi-Pr)4
(0.43 mL, 1.5 mmol) in CH2Cl2 (15 mL) at –20 °C was added (+)-DET
(0.4 mL, 1.9 mmol) dissolved in CH2Cl2 (2 mL) and the mixture was
stirred for 15 min. Then 3 M TBHP in toluene (9.2 mL, 25.6 mmol) was
added and the mixture was stirred for 30 min. To this mixture, allylic
alcohol 11 (2 g, 12.8 mmol) dissolved in CH2Cl2 (10 mL) was added
slowly. The resulting mixture was stirred at –20 °C for 4 h and then
quenched with H2O (8.7 mL) followed by the addition of 20% NaOH
solution (3 mL). The mixture was stirred at r.t. for 45 min, then it was
filtered and the filtrate was extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography
(EtOAc–hexanes, 1:9) to give chiral epoxy alcohol 12 as a colorless liq-
uid; yield: 1.72 g (78%); 95% ee [Chiral HPLC (Gilson, Chiralpak IC col-
umn, 250 × 4.6 mm, hexane–i-PrOH, 95:5, flow rate 1.5 mL/min,
25 °C, λmax = 210 nm)].
[α]D25 +5.7 (c 0.5, CHCl3).
IR (neat): 2953, 2856, 2311, 1720, 1467, 1271, 1253, 1108, 834, 774,
709 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.03–8.12 (m, 2 H), 7.52–7.62 (m, 1 H),
7.41–7.48 (m, 2 H), 5.26–5.29 (m, 1 H), 3.95–3.99 (m, 1 H), 3.55–3.66
(m, 2 H), 1.77–1.87 (m, 1 H), 1.63–1.70 (m, 1 H), 1.18–1.42 (m, 10 H),
0.91 (s, 9 H), 0.89 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.06 (s, 6 H), 0.05 (s,
6 H).
13C NMR (75 MHz, CDCl3): δ = 166.1, 132.6, 129.6, 128.2, 75.8, 74.3,
64.8, 31.7, 29.5, 29.1, 28.3, 25.9, 25.7, 25.5, 22.6, 14.0, –4.8, –4.4, –5.5,
–5.4.
HRMS: m/z [M + H]+ calcd for C29H55O4Si2: 523.3633; found: 523.3604.
[α]D25 –31.4 (c 0.5, CHCl3) [Lit.13b,22 [α]D20 –36.5 (c 2.8, CHCl3).
(2S,3R)-3-(Benzoyloxy)-2-(tert-butyldimethylsiloxy)decan-1-ol
(15)
IR (neat): 3392, 2923, 2854, 1512, 1463, 1377, 1214, 1079, 1032, 880,
732 cm–1
.
To a stirred solution of 14 (3 g, 5.7 mmol) in MeOH–CH2Cl2 (1:3, 24
mL) was added CSA (0.13 g, 0.57 mmol) and the mixture was stirred
for 2 h. When the reaction was complete, water was added and the
mixture was extracted with CH2Cl2 (2 × 20 mL). The combined organic
extracts were washed with brine, dried (anhyd Na2SO4), and concen-
trated under reduced pressure. The residue was purified by using col-
umn chromatography (silica gel, EtOAc–hexane, 2:8) to afford alcohol
15 as a colorless liquid; yield: 2 g (87%).
1H NMR (300 MHz, CDCl3): δ = 3.91 (dd, J = 12.5, 2.4 Hz, 1 H), 3.62 (dd,
J = 12.5, 4.2 Hz, 1 H), 2.90–2.97 (m, 2 H), 1.54–1.61 (m, 2 H), 1.38–1.52
(m, 2 H), 1.23–1.37 (m, 8 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 61.7, 58.4, 56.0, 31.7, 31.5, 29.3, 29.1,
25.9, 22.6, 14.0.
MS (ESI): m/z = 195 [M + Na]+.
[α]D25 +3.5 (c 0.5, CHCl3).
(2S,3R)-3-(Benzoyloxy)decane-1,2-diol (13)
To a stirred solution of epoxy alcohol 12 (1.6 g, 9.3 mmol) in anhy-
drous CH2Cl2 (20 mL) was added Ti(Oi-Pr)4 (2.75 mL, 13.9 mmol) un-
der N2 at 0 °C. The mixture was stirred for 15 min, then benzoic acid
(1.7 mg, 13.9 mmol) was added and the stirring was continued for a
further 1 h at 0 °C (TLC monitoring). Aq 15% tartaric acid solution (25
mL) was added and stirring was continued until the distinct phases
were separated. The aqueous phase was extracted with CH2Cl2 (2 × 20
mL) and the combined organic phases were washed with sat. NaHCO3
solution and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (hexanes–EtOAc,
6:4) to yield diol 13 as a colorless oil; yield: 2.48 g (88%).
IR (neat): 3450, 2927, 2856, 1717, 1465, 1274, 1108, 1050, 834, 775
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.03–8.12 (m, 2 H), 7.52–7.62 (m, 1 H),
7.41–7.48 (m, 2 H), 5.26–5.29 (m, 1 H), 3.95–3.99 (m, 1 H), 3.55–3.66
(m, 2 H), 2.02–2.05 (m, 1 H), 1.70–1.80 (m, 2 H), 1.25–1.35 (m, 10 H),
0.93 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.10 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.3, 132.9, 129.6, 128.3, 75.1, 74.0,
63.3, 31.7, 29.9, 29.4, 29.1, 25.8, 25.5, 22.6, 14.0, –4.5, –4.7.
HRMS: m/z [M + H]+ calcd for C23H41O4Si: 409.2768; found: 409.2757.
[α]D25 +22.3 (c 0.5, CHCl3).
(3S,4S,5R)-5-(Benzoyloxy)-4-(tert-butyldimethylsiloxy)dodec-1-
en-3-ol (16)
IR (neat): 3457, 2923, 2854, 1738, 1512, 1454, 1244, 1108, 1079,
To a stirred solution of oxalyl chloride (0.7 mL, 7.3 mmol) in CH2Cl2
(40 mL) at –78 °C was added DMSO (1.14 mL, 14.7 mmol) over 20
min. The resulting mixture was stirred for an additional 15 min and
1032, 880, 731 cm–1
.
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then alcohol 15 (2 g, 4.9 mmol) dissolved in CH2Cl2 (10 mL) was add-
ed. The mixture was stirred for 30 min, and Et3N (3.4 mL, 24.5 mmol)
was added dropwise. The mixture was allowed to reach r.t. and stirred
for 3 h. When the reaction was complete, the mixture was quenched
with water and extracted with CH2Cl2 (2 × 15 mL). The combined or-
ganic layers were washed with brine, dried (anhyd Na2SO4), and con-
centrated in vacuo to obtained the aldehyde.
were washed with brine and dried (Na2SO4) and the solvent was
evaporated in vacuo. Residue was purified by column chromatogra-
phy (EtOAc–hexane, 1:9) to obtain the pure secondary alcohol 18 as a
colorless liquid; yield: 1.26 g (92%).
[α]D25 –2.5 (c 0.5, CHCl3).
IR (neat): 3350, 2955, 2856, 1601, 1467, 1275, 1253, 1107, 1071, 926,
833, 749 cm–1
.
To a stirred solution of the aldehyde (2 g, 4.9 mmol) in anhydrous THF
(20 mL) was added slowly 1 M vinylmagnesium bromide in THF (9.85
mL, 9.8 mmol) at 0 °C and the mixture was stirred for 2 h (TLC moni-
toring). The mixture was quenched with sat. NH4Cl and extracted
with EtOAc (2 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The residue was puri-
fied by column chromatography (silica gel, hexanes–EtOAc, 8:2) to
give chiral allyl alcohol 16 as a colorless liquid; yield: 1.75 g (85%).
1H NMR (300 MHz, CDCl3): δ = 5.84–5.93 (m, 1 H), 5.22 (dd, J = 17.2,
1.3 Hz, 1 H), 5.13 (dd, J = 10.3, 1.2 Hz, 1 H), 4.19–4.25 (m, 1 H), 3.65
(m, 1 H), 3.50–3.55 (m, 1 H), 1.50–1.55 (m, 2 H), 1.25–1.35 (m, 10 H),
0.90 (s, 9 H), 0.89 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.06 (s, 6 H), 0.05 (s,
6 H).
13C NMR (75 MHz, CDCl3): δ = 139.1, 115.9, 79.3, 76.7, 73.5, 32.6, 31.8,
29.6, 29.2, 26.0, 25.9, 22.6, 18.2, 18.1, 14.0, –3.7, –4.1, –4.5, –4.7.
HRMS: m/z [M + H]+ calcd for C24H53O3Si2: 445.3527; found: 445.3513.
[α]D25 +5.5 (c 0.5, CHCl3).
IR (neat): 3450, 2927, 2856, 1717, 1568, 1453, 1320, 1274, 1106,
1053, 835, 774 cm–1
.
(3S,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)dodec-1-en-5-yl (S)-4-
(4-Methoxybenzyloxy)hex-5-enoate (19)
1H NMR (300 MHz, CDCl3): δ = 8.01–8.10 (m, 2 H), 7.52–7.62 (m, 1 H),
7.41–7.48 (m, 2 H), 5.90–6.05 (m, 1 H), 5.45 (d, J = 11.0 Hz, 1 H), 5.22–
5.27 (m, 1 H), 5.20 (d, J = 11.0 Hz, 1 H), 4.08–4.12 (m, 1 H), 3.95–4.02
(m, 1 H), 2.23 (br s, 1 H), 1.38–1.48 (m, 2 H), 1.10–1.40 (m, 10 H), 0.89
(s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.3, 136.4, 132.9, 129.6, 128.3, 116.5,
76.2, 75.5, 74.4, 31.7, 29.6, 29.2, 25.9, 25.5, 22.6, 14.0, –4.4.
To a stirred solution of acid 10 (0.33 g, 1.35 mmol) in CH2Cl2 (10 mL)
at 0 °C was added DCC (0.35 g, 1.6 mmol) in portions followed by
DMAP (cat.). The mixture was stirred for 15 min and then alcohol 18
(0.5 g, 1.1 mmol) dissolved in CH2Cl2 (10 mL) was added. The cooling
bath was removed and stirring was continued for 3 h (TLC monitor-
ing). The mixture was filtered and the solvent was removed under re-
duced pressure. The residue was purified by column chromatography
(silica gel, EtOAc–hexane, 0.5:9.5) to give ester 19 as a colorless liquid;
yield: 0.66 g (75%).
HRMS: m/z [M + H]+ calcd for C25H43O4Si: 435.2925; found: 435.2910.
[α]D25 +50.7 (c 0.5, CHCl3).
(3S,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)dodec-1-en-5-yl Ben-
zoate (17)
IR (neat): 3074, 2954, 2854, 1706, 1611, 1512, 1421, 1246, 1174,
To a stirred solution of allyl alcohol 16 (1.5 g, 3.5 mmol) in anhydrous
CH2Cl2 (10 mL) was added imidazole (0.36 g, 5.3 mmol) at 0 °C fol-
lowed by TBSCl (0.64 g, 4.2 mmol) dissolved in anhydrous CH2Cl2 (5
mL) and DMAP (cat.) and the mixture was stirred at r.t. for 1 h. After
complete consumption of the starting material (TLC monitoring), wa-
ter was added to the mixture and it was extracted with CH2Cl2 (2 × 10
mL). The combined organic layers were washed with brine and dried
(Na2SO4). The solvent was evaporated and the residue was purified by
column chromatography (silica gel, EtOAc–hexane, 0.5:9.5) to afford
TBS ether 17 as a colorless liquid; yield: 1.85 g (95%).
1034, 929, 770 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.20–7.30 (m, 2 H), 6.85–6.90 (m, 2 H),
5.68–5.85 (m, 2 H), 5.10–5.30 (m, 4 H), 4.51–4.53 (m, 2 H), 4.25–4.30
(m, 1 H), 3.95–4.0 (m, 1 H), 3.81 (s, 3 H), 3.75–3.80 (m, 1 H), 3.61–3.63
(m, 1 H), 2.31–2.48 (m, 2 H), 1.82–1.95 (m, 2 H), 1.57–1.62 (m, 2 H),
1.15–1.35 (m, 10 H), 0.92 (s, 9 H), 0.90 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H),
0.05 (s, 6 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 173.4, 159.0, 140.4, 138.7, 130.6, 130.1,
116.9, 115.0, 80.2, 78.0, 75.9, 72.2, 72.1, 56.5, 31.7, 31.5, 30.4, 29.6,
29.2, 28.7, 26.0, 25.9, 25.5, 22.6, 14.0, –3.8, –3.9, –4.4.
[α]D25 +4.2 (c 0.5, CHCl3).
HRMS: m/z [M + Na]+ calcd for C38H68O6NaSi2: 699.4452; found:
699.4484.
IR (neat): 2954, 2856, 1720, 1571, 1465, 1271, 1251, 1103, 1070, 925,
831, 774 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.04–8.10 (m, 2 H), 7.50–7.60 (m, 1 H),
7.41–7.48 (m, 2 H), 5.85–5.92 (m, 1 H), 5.30–5.36 (m, 1 H), 5.20 (d,
J = 11.0 Hz, 1 H), 5.17 (d, J = 11.0 Hz, 1 H), 4.08–1.12 (m, 1 H), 3.85–
3.90 (m, 1 H), 1.76–1.88 (m, 2 H), 1.20–1.40 (m, 10 H), 0.90 (s, 9 H),
0.89 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.06 (s, 6 H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.0, 138.4, 132.7, 130.5, 129.6, 128.2,
116.9, 77.8, 76.2, 75.8, 31.7, 29.6, 29.1, 28.9, 26.0, 25.9, 25.5, 22.6,
18.3, 18.2, 14.0, 3.8, –4.0, –4.5, –4.7.
(3S,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)dodec-1-en-5-yl (S)-4-
Hydroxyhex-5-enoate
To a stirred solution of ester 19 (0.6 g, 0.88 mmol) in CH2Cl2–H2O
(19:1, 20 mL) was added DDQ (0.3 g, 1.32 mmol) at 0 °C and the mix-
ture was stirred at r.t. for 1 h (TLC monitoring). The mixture was fil-
tered and the filtrate was washed with 5% NaHCO3 solution and then
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were
washed with water and brine, dried (Na2SO4), and evaporated. The
crude product was purified by column chromatography (silica gel,
EtOAc–hexane, 3:7) to afford the pure alcohol as a pale yellow syrup;
yield: 0.39 g (80%).
HRMS: m/z [M + H]+ calcd for C31H57O4Si2: 549.3789; found: 549.3773.
(3S,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)dodec-1-en-5-ol (18)
To a stirred solution of benzoate 17 (1.7 g, 3.1 mmol) in MeOH (20
mL) was added K2CO3 (0.85 g, 6.2 mmol) at 0 °C, and the mixture was
stirred for 2 h at r.t. (TLC monitoring). The mixture quenched by with
H2O (15 mL), and then MeOH was removed in vacuo and the residue
was extracted with EtOAc (2 × 10 mL). The combined organic phases
[α]D25 +62.3 (c 0.8, CHCl3).
IR (neat): 3462, 2927, 2856, 1778, 1741, 1640, 1372, 1242, 1168, 876,
722 cm–1
.
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1H NMR (300 MHz, CDCl3): δ = 5.75–5.90 (m, 2 H), 5.25–5.30 (m, 1 H),
5.10–5.20 (m, 4 H), 4.15–4.22 (m, 1 H), 3.95–4.03 (m, 1 H), 3.62–3.70
(m, 2 H), 2.40–2.50 (m, 2 H), 1.80–1.95 (m, 2 H), 1.60–1.70 (m, 2 H),
1.20–1.32 (m, 10 H), 0.92 (s, 9 H), 0.90 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H),
0.05 (s, 6 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 175.0, 174.0, 172.6, 133.4, 129.7, 79.5,
74.9, 73.0, 62.4, 31.7, 30.7, 29.3, 29.0, 25.4, 22.5, 14.0, –1.4, –1.9.
HRMS (ESI): m/z [M + H]+ calcd for C32H61O8Si2: 629.3826; found:
629.3818.
13C NMR (75 MHz, CDCl3): δ = 173.3, 140.3, 138.6, 116.9, 115.0, 77.9,
75.9, 75.1, 72.2, 72.1, 31.8, 31.5, 30.4, 29.6, 29.1, 28.7, 26.0, 25.8, 25.5,
22.6, 18.2, 14.0, –3.9, –4.0.
4-{[(5S,8S,9S,10R,E)-10-Heptyl-8,9-dihydroxy-2-oxo-3,4,5,8,9,10-
hexahydro-2H-oxecin-5-yl]oxy}4-oxobutanoic Acid (1)
To a stirred solution of acid 21 (230 mg, 0.37 mmol) in anhydrous THF
(5 ml) was added 2 M HCl (0.5 mL) at r.t. and the mixture was stirred
for 4 h (TLC monitoring). Then water and solvent were removed under
reduced pressure. The residue was extracted with EtOAc (2 × 10 mL)
and the combined organic layers were washed with NaHCO3 solution
and brine, dried (Na2SO4), and concentrated. The crude product was
purified by column chromatography (silica gel, EtOAc–hexane, 1:1) to
afford the target molecule xyolide 1 as a colorless syrup; yield: 100
mg (73%).
HRMS: m/z [M + H]+ calcd for C30H61O5Si2: 557.3979; found: 557.3992.
(5S,8S,9R,10R,E)-8,9-Bis(tert-butyldimethylsiloxy)-10-heptyl-5-
hydroxy-3,4,5,8,9,10-hexahydro-2H-oxecin-2-one (20)
A stirred solution of the diene compound (0.39 g, 0.7 mmol) in anhy-
drous CH2Cl2 (100 mL) was degassed for 20 min by argon bubbling.
Then Grubbs’ 2nd generation catalyst (0.057 mg, 0.07 mmol) was
added and the mixture was degassed for a further 15 min and then
refluxed for 12 h (TLC monitoring). The mixture was allowed to cool
to r.t. and the solvent was evaporated under reduced pressure. The
crude material was adsorbed on silica gel and purified by column
chromatography (silica gel, EtOAc–hexane, 9:1) to give lactone 20 as a
colorless liquid; yield: 0.23 g (62%).
[α]D25 +10.4 (c 0.7, CHCl3) [Lit.7c [α]D28 +10.1 (c 0.8, CHCl3)].
IR (neat): 3395, 2954, 2928, 2856, 1742, 1465, 1368, 1222, 1036, 834,
772 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.86 (dd, J = 15.2, 1.7 Hz, 1 H), 5.49 (dd,
J = 15.8, 1.9 Hz, 1 H), 5.04–5.12 (m, 1 H), 4.98 (m, 1 H), 4.45 (br s, 1 H),
3.50 (dd, J = 9.6, 1.9 Hz, 1 H), 2.50–2.62 (m, 4 H), 2.31–2.40 (m, 1 H),
1.95–2.10 (m, 3 H), 1.80–1.90 (m, 1 H), 1.50–1.60 (m, 1 H), 1.33–1.20
(m, 10 H), 0.87 (t, J = 6.7 Hz, 3 H).
[α]D25 +48.7 (c 1.0, CHCl3).
IR: 3456, 2925, 2851, 1737, 1394, 1247, 1215, 1173, 1096, 930, 830,
770 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.83 (dd, J = 15.6, 3.1 Hz, 1 H), 5.64 (dd,
J = 9.2, 1.9 Hz, 1 H), 5.20 (t, J = 7.5 Hz, 1 H), 4.15–4.22 (m, 1 H), 4.02 (t,
J = 7.5 Hz, 1 H), 3.65–3.70 (m, 2 H), 2.30–2.45 (m, 2 H), 1.82–1.95 (m,
2 H), 1.62–1.68 (m, 2 H), 1.20–1.32 (m, 10 H), 0.92 (s, 9 H), 0.90 (s, 9
H), 0.88 (t, J = 7.0 Hz, 3 H), 0.05 (s, 6 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 176.1, 174.5, 171.6, 132.8, 123.4, 74.8,
73.6, 72.6, 70.9, 31.8, 31.5, 31.2, 29.5, 29.4, 29.3, 29.1, 28.8, 24.6, 22.6,
14.0.
HRMS (ESI): m/z [M + NH4]+ calcd for C20H36O8N: 418.2435; found:
418.2459.
13C NMR (75 MHz, CDCl3): δ = 172.1, 134.4, 133.5, 80.5, 78.0, 73.8,
71.9, 34.5, 31.8, 31.5, 29.3, 29.1, 25.9, 22.6, 14.0, –1.9, –3.4.
HRMS (ESI): m/z [M + H]+ calcd for C28H57O5Si2: 529.3667; found:
529.3657.
Acknowledgement
S.B.W. and R.S.G. thank CSIR-New Delhi for providing a fellowship and
A.V.N. thanks CSIR-New Delhi for financial support as part of XII five
year plan under the title DENOVA (CSC-0205).
4-{[5S,8S,9R,10R,E)-8,9-Bis(tert-butyldimethylsiloxy)-10-heptyl-2-
oxo-3,4,5,8,9,10-hexahydro-2H-oxecin-5-yl]oxy}-4-oxobutanoic
Acid (21)
To a stirred solution of the lactone 20 (0.22 g, 0.41 mmol) in CH2Cl2 (2
mL) was added succinic anhydride (0.041 g, 0.41 mmol), pyridine (33
mg, 0.41 mmol) and DMAP (10 mg, 0.08 mmol) at 0 °C and the mix-
ture was stirred at r.t. for 12 h (TLC monitoring). The mixture was
poured into CH2Cl2 (20 mL) and phosphate buffer (pH 3.6) with vigor-
ous stirring. The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 10 mL). The combined extracts were dried
(Na2SO4) and concentrated to give the crude product, which was puri-
fied by chromatography (silica gel, benzene–acetone) to afford acid
21 as a colorless oil; yield: 238 mg (91%).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380780.
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