An expedient stereoselective synthesis of the antifungal agent (6 S)-6-[(2 R)-2-hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one

Article abstract of DOI:10.1055/s-0030-1260214

An efficient and straightforward stereoselective synthesis of (6S)-6-[(2R)-2-hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one is described. The chiral centers were generated by Sharpless asymmetric epoxidation followed by regioselective epoxide ring open

Full text of DOI:10.1055/s-0030-1260214

PAPER
3271
An Expedient Stereoselective Synthesis of the Antifungal Agent
(6S)-6-[(2R)-2-Hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one
(
6
S
)-6-[(2
R
)-2-H
y
.
droxy-6-phen
V
ylhexyl]-5,6-dihy
e
dro-2
H
-pyr
n
an-2-one kat Narsaiah,* Ramesh S. Ghogare
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: vnakkirala2001@yahoo.com
Received 20 June 2011; revised 22 July 2011
This work is dedicated to Dr J. S. Yadav on the occasion of his 60th birthday
Grignard conditions.3 As part of our research program on
the synthesis of biologically active molecules,4 we report
an enantioselective synthesis of 1 based on the Sharpless
asymmetric epoxidation protocol.
Abstract: An efficient and straightforward stereoselective synthe-
sis of (6S)-6-[(2R)-2-hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyr-
an-2-one is described. The chiral centers were generated by
Sharpless asymmetric epoxidation followed by regioselective ep-
oxide ring opening with Red-Al to afford 1,3-diols, exclusively. All
the reactions were very clean and the products were obtained in very
good yields.
A retrosynthetic analysis (Scheme 1) suggested that the
key steps would be the Sharpless asymmetric epoxidation
of an allylic alcohol derived from aldehyde 2 and regiose-
lective ring opening of epoxide 4 with Red-Al [sodium di-
hydrobis(2-methoxyethoxy)aluminate].
Keywords: Wittig reactions, epoxidations, diols, pyrans
Our synthetic strategy began with a Wittig two-carbon ex-
tension of 5-phenylpentanal (2) in benzene5 to give ethyl
(2E)-7-phenylhept-2-enoate in 90% yield. The product
was subjected to mixed hydride reduction with lithium
aluminum hydride and aluminum trichloride in anhydrous
tetrahydrofuran at 0 °C to give (2E)-7-phenylhept-2-en-1-
ol (3) in 75% yield.6 Allylic alcohol 3 was subjected to
Sharpless asymmetric epoxidation with titanium tetraiso-
propoxide and diethyl (–)-tartrate at –20 °C in the pres-
ence of powdered molecular sieves to give the chiral
epoxy alcohol 4 in 90% yield and excellent enantioselec-
tivity.7 The epoxide ring in 4 was regioselectively cleaved
by treatment with Red-Al at 0 °C.8 This reaction was very
clean and was completed within three hours to give the
1,3-diol 5 exclusively. Treatment of diol 5 with pivaloyl
chloride in the presence of pyridine in dichloromethane
resulted in selective protection of the primary alcohol
group.9 Derivatization of the secondary alcohol with tert-
butyl(dimethyl)silyl chloride in the presence of imidazole
in dichloromethane gave the pivalate 610 in 95% yield.
The pivaloyl group in 6 was selectively removed by treat-
ment with diisobutylaluminum dihydride (DIBAL-H) at
–78 °C.11 The resulting primary alcohol 7 was subjected
to Swern oxidation12 with oxalyl chloride and dimethyl
sulfoxide, and the resulting aldehyde was, without purifi-
cation, subjected to a Wittig reaction to give the chain-
extended ester 8 in 90% yield. Ester 8 was reduced with
Natural products containing pyrone moieties exhibit a va-
riety of pharmacological properties, including antifungal,
antitumor, antibacterial, and antigrowth effects. The
broad range of biological activities reported for this class
of compounds has been ascribed to their inherent tenden-
cy to act as good Michael acceptors. Because of their bio-
logical importance, the synthesis of naturally occurring
pyrones has been the subject of intense research.1 The nat-
ural product (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phe-
nylhexyl]-2H-pyran-2-one (1) was isolated from the
evergreen tree Ravensara crassifolia and has been report-
ed to act as an antifungal agent against the phytopathogen-
ic fungus Cladosporium cucumerinum.2
An earlier synthesis of 1 involved Keck allylation, ring-
closing metathesis, olefin cross-metathesis, vinyl-
Grignard reaction, asymmetric allylation, Prins cyclization,
and regioselective ring opening of an epoxide under
O
OH
O
1
Figure 1 (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-
pyran-2-one (1)
OTBS
O
O
O
OH
OH
H
10
4
2
Scheme 1
SYNTHESIS 2011, No. 20, pp 3271–3276
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1260214; Art ID: Z61911SS
© Georg Thieme Verlag Stuttgart · New York

3272
A. V. Narsaiah, R. S. Ghogare
PAPER
O
O
c
a, b
d
H
OH
OH
2
3
4
OH
OTBS
OTBS
g
e, f
h, i
OH
OPiv
OH
5
6
7
OTBS
OTBS
OTBS
O
O
j
k
l
OH
OH
OEt
OH
9
10
8
OTBS OH
OTBS OTBS
OTBS OTBS
OTBS OTBS
p, q
o
m, n
OPiv
OH
12
13
11
14
r
1
CO2Me
Scheme 2 Reagents and conditions: (a) Ph3P=CHCO2Et, benzene, 2 h, 90%; (b) LAH, AlCl3, anhyd THF, 0 °C to r.t., 3 h, 75%; (c) Ti(Oi-Pr)4,
(–)-DET, –20 °C, CH2Cl2, 12 h, 90%; (d) Red-Al, anhyd THF, 0 °C, 3 h, 90%; (e) PivCl, pyridine, CH2Cl2, r.t., 3 h, 95%; (f) TBSCl, imidazole,
CH2Cl2, r.t., 1 h, 95%; (g) DIBAL-H, THF, –78 °C, 30 min, 90%; (h) Swern oxidation, –78 °C, 2 h. 90%; (i) Ph3P=CHCO2Et, benzene, 2 h,
90%; (j) LAH, AlCl3, anhyd THF, 0 °C to r.t. °C, 75%; (k) Ti(Oi-Pr)4, (–)-DET, –20 °C, CH2Cl2, 12 h, 90%; (l) Red-Al, anhyd THF, 0 °C, 3 h,
90%; (m) PivCl, pyridine, CH2Cl2, r.t., 3 h, 95%; (n) TBSCl, imidazole, CH2Cl2, r.t., 1 h, 95%; (o) DIBAL-H, THF, –78 °C, 30 min, 90%; (p)
Swern oxidation, –78 °C, 2 h. 90%; (q) (F3CCH2O)2P(O)CH2CO2Me, NaH, anhyd THF, 75%; (r) TsOH, MeOH, r.t., 30 min, 90%.
lithium aluminum hydride and aluminum trichloride in NMR, IR, and mass spectroscopy and optical rotation
anhydrous tetrahydrofuran at 0 °C to room temperature to measurements, and by comparison with literature reports.
give the allylic alcohol 9 in 75% yield.
In conclusion, we successfully performed a stereoselec-
The allylic alcohol was subjected to a second Sharpless tive synthesis of 1 by using the Sharpless asymmetric ep-
asymmetric epoxidation to give the epoxy alcohol 10 in oxidation protocol as a source of chirality. All the
90% yield and excellent selectivity. The product 10 was reactions were clean, and the products were all obtained in
reduced with Red-Al in anhydrous tetrahydrofuran to give very good yields.
the corresponding 1,3-diol 11 in 90% yield. The 1,3-diol
was selectively esterified with pivaloyl chloride in the
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro-
photometer. 1H NMR spectra were recorded on a Bruker 300 MHz,
spectrometer in CDCl3 with TMS as internal standard. Mass spectra
were recorded on a Finnigan MAT 1020 mass spectrometer operat-
ing at 70 eV.
presence of pyridine to protect the primary hydroxy
group, and then silylated with tert-butyl(dimethyl)silyl
chloride in the presence of imidazole to protect the sec-
ondary alcohol; both reactions occurred in very good
yields. The pivaloyl group was selectively removed from
the protected diol 12 by treatment with DIBAL-H in tet-
rahydrofuran at –78 °C to give the silylated derivative 13
in 90% yield. The primary alcohol group in 13 was sub-
jected to oxidation under Swern conditions using oxalyl
chloride to give the corresponding aldehyde, which was
treated with methyl-2-[bis(2,2,2-trifluoroethoxy)phos-
phoryl]acetate to give the Z-olefin 14 in a very good yield.
Finally, the olefin 14 was treated with 4-toluenesulfonic
acid in methanol at room temperature to remove the silyl
protecting group and cyclize the compound to give the tar-
get molecule (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phe-
nylhexyl]-2H-pyran-2-one (1) in a very good yield. All
the products were characterized by means of 1H NMR, 13C
Ethyl (2E)-7-Phenylhept-2-enoate
Wittig ylide Ph3P=CHCO2Et (12.5 g, 3.7 mmol) was added to a
stirred soln of 5-phenylpentanal (2; 5 g, 3.08 mmol) in benzene (50
mL). The mixture was then refluxed for 2 h until the reaction was
complete (TLC). The solvent was then removed under reduced
pressure, and the residue was extracted with EtOAc (2 × 50 mL).
The organic layer was washed with brine, dried (Na2SO4), and con-
centrated under reduced pressure. The crude product was purified
by column chromatography [silica gel (60–120 mesh), EtOAc–
hexane (1:9)] to give a colorless liquid; yield: 6.4 g (90%).
IR (neat): 3026, 2982, 2932, 2858, 1719, 1653, 1495, 1454, 1368,
1309, 1268, 1148, 1096, 1042, 980, 851, 747, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.30 (t, J = 6.5 Hz, 3 H), 1.48–1.58
(m, 2 H), 1.62–1.73 (m, 2 H), 2.50 (q, J = 7.5 Hz, 2 H), 2.62 (t,
J = 7.5 Hz, 2 H), 4.18 (q, J = 6.5 Hz, 2 H), 5.80 (d, J = 15.9 Hz, 1
H), 6.85–6.95 (m, 1 H), 7.10–7.30 (m, 5 H).
Synthesis 2011, No. 20, 3271–3276 © Thieme Stuttgart · New York

PAPER
(6S)-6-[(2R)-2-Hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one
3273
MS (EI, 70 eV): m/z = 255 [M + Na], 233 [M+], 196, 177, 155, 150,
121.
1H NMR (300 MHz, CDCl3): d = 1.25–1.72 (m, 8 H), 2.61 (t, J = 7.0
Hz, 2 H), 2.95 (br s, 1 H), 3.70–3.89 (m 3 H), 7.10–7.25 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.4, 128.3, 128.2, 125.6, 71.9,
61.5, 38.1, 37.5, 35.8, 31.4, 25.1.
(2E)-7-Phenylhept-2-en-1-ol (3)
A suspension of AlCl3 (3.27 g, 2.45 mmol) in anhyd THF (30 mL)
was added to a stirred mixture of LAH (2.05 g, 5.4 mmol) in anhyd
THF (20 mL) at 0 °C, and the mixture was stirred for 15 min. A soln
of ethyl (2E)-7-phenylhept-2-enoate (5.7 g, 2.45 mmol) in anhyd
THF (50 mL) was then slowly added and the resulting mixture was
stirred for 3 h at 0 °C to r.t. until the reaction was complete (TLC).
The reaction was quenched by adding crushed ice. EtOAc (100 mL)
was added and the mixture was stirred well then filtered. The filtrate
was washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. The crude product was purified by column chroma-
tography [silica gel (60–120 mesh), EtOAc–hexane (2:8)] to give a
colorless liquid; yield: 3.5 g (75%).
MS (EI, 70 eV): m/z = 231 [M + Na], 186, 173, 131, 123, 117, 105.
(3R)-3-Hydroxy-7-phenylheptyl Pivalate
Pyridine (1.25 mL, 1.5 mmol) and PivCl (1.82 mL, 0.68 mmol)
were successively added to a stirred mixture of diol 5 (2.63 g, 1.26
mmol) and CH2Cl2 (30 mL) at 0 °C, and the resulting mixture was
stirred at 0 °C to r.t. for 3 h until the reaction was complete (TLC).
The mixture was then neutralized by adding 1 M HCl and extracted
with CH2Cl2 (2 × 20 mL). The combined organic layer was washed
with brine, dried (Na2SO4), and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
[silica gel (60–120 mesh), EtOAc–hexane (2:8)] to give a colorless
liquid; yield: 3.5 g (95%).
IR (neat): 3361, 3026, 2929, 2856, 1669, 1603, 1495, 1454, 1088,
970, 745, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38–1.48 (m, 2 H), 1.58–1.66 (m,
2 H), 2.08 (q, J = 7.5 Hz, 2 H), 2.60 (t, J = 7.5 Hz, 2 H), 4.05 (t,
J = 7.5 Hz, 2 H), 5.52–5.72 (m, 2 H), 7.05–7.30 (m, 5 H).
MS (EI, 70 eV): m/z = 208 [M + 18], 190 [M+], 173, 161, 145, 131,
118, 105, 91.
IR (neat): 3443, 3064, 3027, 2932, 2858, 1730, 1639, 1463, 1365,
1285, 1254, 1157, 1101, 1066, 1011, 939, 837, 805, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (s, 9 H), 1.27–1.81 (m, 8 H),
2.60 (t, J = 7.0 Hz, 2 H), 3.58 (br s, 1 H), 4.04–4.12 (m, 1 H), 4.28–
4.37 (m, 1 H), 7.09–7.11 (m, 3 H), 7.19–7.24 (m, 2 H).
MS (EI, 70 eV): m/z = 315 [M + Na], 293 [M+], 275, 173, 131, 117,
103.
[(2R,3R)-3-(4-Phenylbutyl)oxiran-2-yl]methanol (4)
Ti(Oi-Pr)4 (0.9 mL, 0.3 mmol) and (–)-DET (0.68 mL, 0.39 mmol)
were added to constantly stirred mixture of 4-Å MS (4 g) in anhyd
CH2Cl2 (30 mL) at –20 °C. After 20 min, a soln of enol 3 (3 g, 1.5
mmol) in CH2Cl2 (20 mL) at –20 °C was added and the mixture was
stirred for 30 min. t-BuOOH (2.2 mL, 2.25 mmol) and the resulting
mixture was stirred at –20 °C for 12 h until the reaction was com-
plete (TLC). The reaction was then quenched with H2O [13.5 mL,
20 times the weight of Ti(Oi-Pr)4 used in the reaction] at 0 °C and
the mixture was stirred for 10 min. 30% aq NaOH (3 mL) was added
and stirring was continued for 45 min at r.t. The mixture was then
extracted with CH2Cl2 (2 × 20 mL) and the combined organic layers
were washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. The crude product was purified by column chroma-
tography [silica gel (60–120 mesh), EtOAc–hexane (2:8)] to give a
colorless liquid; yield: 2.9 g (90%); [a]D27 +16.6 (c 1.5, CHCl3).
(3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-7-phenylheptyl Pivalate
(6)
Imidazole (3.25 g, 4.7 mmol) and TBSCl (2.15 g, 1.43 mmol) were
added to a stirred soln of (3R)-3-hydroxy-7-phenylheptyl pivalate
(3.5 g, 1.19 mmol) in anhyd CH2Cl2 (40 mL) at 0 °C, and the mix-
ture was stirred for 5 min at 0 °C. A catalytic amount of DMAP was
then added and stirring was continued further for 1 h at r.t. until the
reaction was complete (TLC). Crushed ice was added, and the mix-
ture was extracted with CH2Cl2 (2 × 30 mL). The organic extracts
were washed with brine, dried (Na2SO4), and concentrated under
vacuum. The crude product was purified by column chromatogra-
phy [silica gel (60–120 mesh), EtOAc–hexane (1:9)] to give a col-
orless liquid; yield: 4.62 g (95%); [a]D27 +9.2 (c 1.5, CHCl3).
IR (neat): 3063, 3027, 2930, 2856, 1730, 1639, 1463, 1256, 1064,
1035, 836, 803, 744, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.30 (s, 6 H), 1.05 (s, 9 H), 1.38
(s, 9 H), 1.50–1.95 (m, 8 H), 2.80 (t, J = 7.5 Hz, 2 H), 3.90–3.99 (m,
1 H), 4.20–4.40 (m, 2 H), 7.28–7.45 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 178.4, 142.5, 128.3, 128.2, 125.6,
68.9, 61.6, 37.3, 35.9, 35.8, 31.6, 27.2, 25.8, 24.7, 18.1, –4.4, –4.7.
IR (neat): 3423, 3025, 2924, 2854, 1603, 1458, 1029, 898, 746, 699
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.44–1.62 (m, 4 H), 1.65–1.71 (m,
2 H), 2.62 (t, J = 7.0 Hz, 2 H), 2.85–2.95 (m, 2 H), 3.56–3.61 (m, 1
H), 3.86 (dd, J = 3.5, 9.0 Hz, 1 H), 7.11–7.25 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.3, 128.3, 128.2, 125.6, 61.5,
58.5, 55.8, 35.7, 31.3, 31.0, 25.5.
MS (EI, 70 eV): m/z = 429 [M + Na], 407 [M+], 275, 173, 131, 103.
MS (EI, 70 eV): m/z = 229 [M + Na], 206 [M+], 185, 171, 149, 133,
(3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-7-phenylheptan-1-ol (7)
1 M DIBAL-H (13 mL, 1.1 mmol) was added to a stirred soln of si-
lylated compound 6 (4.5 g, 1.1 mmol) in anhyd THF (50 mL) at
–78 °C, and the mixture was stirred for 30 min until the reaction was
complete (TLC). The reaction was quenched by adding few drops
of MeOH, and the mixture was stirred for 10 min. Sat. aq Rochelle’s
salt was added and stirring was continued for 4 h. The solvent THF
was removed under reduced pressure and the residue was extracted
with EtOAc (2 × 20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated under vacu-
um. The crude product was purified by column chromatography
[silica gel (60–120 mesh), EtOAc–hexane (2:8)] to give a colorless
liquid; yield: 3.2 g (90%); [a]D27 +7.3 (c 1.5, CHCl3).
105, 102, 91.
(3R)-7-Phenylheptane-1,3-diol (5)
A 65% soln of Red-Al in toluene (5.25 mL, 1.7 mmol) was slowly
added to a stirred soln of epoxide 4 (2.9 g, 1.4 mmol) in anhyd THF
(30 mL) at 0 °C, and the mixture was stirred for 3 h at 0 °C until the
reaction was complete (TLC). The reaction was quenched by add-
ing sat. aq sodium potassium tartrate. The mixture was stirred for 30
min then extracted with EtOAc (2 × 25 mL). The combined organic
layers was washed with brine, dried (Na2SO4), and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography [silica gel (60–120 mesh), EtOAc–hexane (3:7)] to
give a colorless liquid; yield: 2.63 g (90%); [a]D27 +13.5 (c 1.5,
CHCl3).
IR (neat): 3406, 3063, 3027, 2930, 2856, 1605, 1463, 1370, 1256,
1064, 1035, 836, 803, 755, 744, 699 cm–1.
IR (neat): 3369, 3085, 3062, 3026, 2926, 2855, 1944, 1603, 1495,
1453, 1331, 1150, 1058, 868, 801, 746, 698 cm–1.
Synthesis 2011, No. 20, 3271–3276 © Thieme Stuttgart · New York

3274
A. V. Narsaiah, R. S. Ghogare
PAPER
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.28–
1.40 (m, 2 H), 1.50–1.82 (m, 6 H), 2.60 (t, J = 7.5 Hz, 2 H), 3.60–
3.68 (m, 1 H), 3.70–3.80 (m, 1 H), 3.85–3.95 (m, 1 H), 7.10–7.28
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.6, 128.3, 128.2, 125.6, 71.9,
63.8, 40.2, 36.7, 35.9, 31.6, 25.9, 25.1, 18.1, –4.4, –4.5.
MS (EI, 70 eV): m/z = 366 [M + 18], 349 [M+], 279, 263, 217, 191,
151, 145.
[(2R,3R)-3-((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-6-phenyl-
hexyl)oxiran-2-yl]methanol (10)
Ti(Oi-Pr)4 (0.25 mL, 0.08 mmol) and (–)-DET (0.13 mL, 0.1 mmol)
were added successively to a constantly stirred mixture of powdered
4 Å MS (2 g) in CH2Cl2 (20 mL) at –20 °C, and the mixture was
stirred for 20 min. A soln of enoate 9 (1.6 g, 0.43 mmol) in CH2Cl2
(20 mL) at –20 °C was added followed, after 30 min, by t-BuOOH
(0.6 mL, 0.65 mmol). The mixture was stirred at –20 °C for 12 h un-
til the reaction was complete (TLC). The reaction was quenched
with H2O (5 mL), and the mixture was stirred for 10 min. 30% aq
NaOH (1.5 mL) was added, and the mixture was stirred for 45 min
at r.t. then extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The crude product was purified by
column chromatography [silica gel (60–120 mesh), EtOAc–hexane
(3:7)] to give a colorless liquid; yield: 1.5 g (90%); [a]D26 –4.32 (c
1.5, CHCl3).
MS (EI, 70 eV): m/z = 323 [M+], 279, 257, 191, 173, 147, 133, 131,
117, 102.
Ethyl (2E,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-9-phenylnon-
2-enoate (8)
Oxalyl chloride (1.25 mL, 1.5 mmol) was added to a stirred mixture
of DMSO (2 mL) and CH2Cl2 (10 mL) at –78 °C. A soln of alcohol
7 (3.2 g, 1 mmol) in CH2Cl2 (10 mL) was then added, and mixture
was stirred at –78 °C for 2 h. Et3N was added (7 mL, 5 mmol), and
the mixture was stirred for 45 min at –78 °C until the reaction was
complete (TLC). The mixture was then allowed to warm to 0 °C,
sat. aq NH4Cl was added, and the mixture was stirred well. The mix-
ture was extracted with CH2Cl2 (2 × 20 mL) and the combined or-
ganic extracts were washed with brine, dried (Na2SO4), and
concentrated under vacuum to give the aldehyde (yield: 3 g, 95%),
which was used for next reaction without purification.
IR (neat): 3431, 3062, 3026, 2931, 2857, 1603, 1494, 1464, 1367,
1254, 1070, 941, 835, 775, 745, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.24–
1.38 (m, 2 H), 1.44–1.74 (m, 6 H), 2.59 (t, J = 7.5 Hz, 2 H), 2.79–
2.85 (m, 1 H), 2.97–3.03 (m, 1 H), 3.51–3.59 (m, 1 H), 3.77–3.89
(m, 2 H), 7.07–7.25 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.4, 128.3, 128.2, 125.6, 69.9,
61.9, 59.1, 53.1, 37.6, 36.9, 31.5, 25.5, 24.6, 18.0, –4.5, –4.6.
MS (EI, 70 eV): m/z = 229 [M + Na], 365, 206 [M+], 357, 344, 279,
239, 193, 171.
The aldehyde (3 g, 0.93 mmol) was dissolved in benzene (30 mL)
and Ph3P=CHCO2Et (4.75 g, 1.4 mmol) was added. The resulting
mixture was refluxed for 2 h until the reaction was complete (TLC).
The solvent was removed under reduced pressure and the residue
was extracted with EtOAc (2 × 20 mL). The organic layer was
washed with brine, dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy [silica gel (60–120 mesh), EtOAc–hexane (1:9)] to give a col-
orless liquid; yield: 3.2 g (85%); [a]D25 –13.7 (c 1, CHCl3).
IR (neat): 3027, 2933, 2857, 1722, 1656, 1463, 1367, 1318, 1259,
1174, 1096, 1043, 898, 937, 836, 775, 746 cm–1.
(3S,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-9-phenylnonane-1,3-
diol (11)
A 65% soln of Red-Al in toluene (1.5 mL, 0.49 mmol) was slowly
added to a stirred mixture of epoxide 10 (1.5 g, 0.41 mmol) in anhyd
THF (20 mL) at 0 °C and the mixture was stirred for 4 h at 0 °C until
the reaction was complete (TLC). The reaction was quenched by ad-
dition of sat. aq Rochelle’s salt, and the mixture was stirred for 30
min then extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The crude product was purified by column
chromatography [silica gel (60–120 mesh), EtOAc–hexane (3:7)] to
give a colorless liquid; yield: 1.35 g (90%); [a]D27 –9.45 (c 1.5,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.28
(t, J = 7.5 Hz, 3 H), 1.31–1.48 (m, 4 H), 1.56–1.63 (m, 2 H), 2.26–
2.33 (m, 2 H), 2.59 (t, J = 7.5 Hz, 2 H), 3.71–3.77 (m, 1 H), 4.17 (q,
J = 7.5 Hz, 2 H), 5.78 (d, J = 15.9 Hz, 1 H), 6.82–6.95 (m, 1 H),
7.09–7.25 (m, 5 H).
MS (EI, 70 eV): m/z = 391 [M+], 279, 206, 259, 219, 193, 156, 128.
(2E,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-9-phenylnon-2-en-1-
ol (9)
A suspension of AlCl3 (1 g, 0.73 mmol) in THF (15 mL) was added
to a stirred mixture of LAH (0.61 g, 1.6 mmol) and anhyd THF (10
mL) at 0 °C, and the mixture was stirred for 15 min at 0 °C. A soln
of enoate 8 (3 g, 0.73 mmol) in anhyd THF (30 mL) was then added
slowly, and the mixture was stirred at 0 °C to r.t. for 3 h until the
reaction was complete (TLC). The reaction was quenched by add-
ing crushed ice, EtOAc (60 mL) was added, and the mixture was
stirred well then filtered. The filtrate was washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified by column chromatography [silica gel (60–
120 mesh), EtOAc–hexane (2:8)] to give a colorless liquid; yield:
1.92 g (75%); [a]D26 –3.66 (c 1.6, CHCl3).
IR (neat): 3378, 3027, 2932, 2857, 1603, 1462, 1368, 1254, 1164,
937, 834, 776, 743, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.24–
1.36 (m, 2 H), 1.44–1.66 (m, 8 H), 2.60 (t, J = 7.5 Hz, 2 H), 2.90 (br
s, 1 H), 3.60 (br s, 1 H), 3.71–3.81 (m, 2 H), 3.87–4.01 (m, 2 H),
7.07–7.26 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.5, 128.3, 128.2, 125.6, 69.9,
61.6, 58.9, 53.0, 37.6, 36.9, 35.9, 31.5, 25.8, 24.7, 18.0, –4.5, –4.6.
MS (EI, 70 eV): m/z = 367 [M+], 356, 340, 309, 295, 279, 242, 217,
193, 113.
IR (neat): 3346, 3026, 2931, 2856, 1603, 1461, 1365, 1253, 1093,
1033, 934, 834, 774, 744, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.22–
1.46 (m, 4 H), 1.52–1.62 (m, 2 H), 2.12–2.18 (m, 2 H), 2.59 (t,
J = 7.5 Hz, 2 H), 3.60–3.69 (m, 1 H), 4.04 (d, J = 6.5 Hz, 2 H), 5.58–
5.64 (m, 2 H), 7.08–7.26 (m, 5 H).
(3S,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxy-9-phenyl-
nonyl Pivalate
Pyridine (0.35 mL, 0.4 mmol) and PivCl (0.5 mL, 0.38 mmol) were
added successively to a stirred soln of diol 11 (1.35 g, 0.36 mmol)
in CH2Cl2 (15 mL) at 0 °C. The mixture was stirred at 0 °C to r.t. for
3 h until the reaction was complete (TLC) and then neutralized with
1 M HCl and extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The crude product was purified by
13C NMR (75 MHz, CDCl3): d = 142.6, 131.2, 129.5, 128.4, 128.1,
125.6, 71.9, 63.8, 40.2, 36.7, 35.6, 31.6, 25.9, 25.1, 18.1, –4.3, –4.5.
Synthesis 2011, No. 20, 3271–3276 © Thieme Stuttgart · New York

PAPER
(6S)-6-[(2R)-2-Hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one
3275
column chromatography [silica gel (60–120 mesh), EtOAc–hexane
(2:8)] to give a colorless liquid; yield: 1.6 g (95%); [a]D23.8 –7.3 (c
1.5, CHCl3).
the mixture was stirred for 20 min. A soln of alcohol 13 (1 g, 0.2
mmol) in CH2Cl2 (5 mL) was added and stirring was again contin-
ued for 2 h at –78 °C. Et3N (1.4 mL, 1.04 mmol) was added and the
mixture was stirred at –78 °C for 45 min. The mixture was then al-
lowed to warm to 0 °C in an ice bath and the reaction was quenched
with sat. aq NH4Cl. The mixture was extracted with CH2Cl2 (2 × 15
mL) and the combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated under vacuum. The crude alde-
hyde that was obtained [yield; 0.95 g (95%)] was used in the next
step without purification.
IR (neat): 3451, 3027, 2933, 2858, 1725, 1636, 1465, 1366, 1286,
1254, 1160, 1068, 937, 834, 775, 743, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 6 H), 0.90 (s, 9 H), 1.20
(s, 9 H), 1.24–1.40 (m, 2 H), 1.46–1.72 (m, 8 H), 2.60 (t, J = 7.5 Hz,
2 H), 3.70–3.80 (m, 1 H), 3.85–3.95 (m, 1 H), 4.07–4.30 (m, 2 H),
7.07–7.27 (m, 5 H).
MS (EI, 70 eV): m/z = 451[M+], 433, 338, 319, 301, 263, 199, 157.
Methyl-2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (0.8 g,
0.26 mmol) was added to a stirred mixture of NaH (0.15 g, 0.6
mmol) and THF (10 mL) at 0 °C, and the resulting mixture was
stirred for 30 min. The mixture was then cooled to –78 °C and a soln
of the aldehyde in anhyd THF (5 mL) was added. The mixture was
stirred for 1 h at –78 °C until the reaction was complete (TLC). The
reaction was then quenched with sat. aq NH4Cl, and the mixture was
extracted with EtOAc (2 × 15 mL). The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated under
vacuum. The crude product was purified by column chromatogra-
phy [silica gel (60–120 mesh), EtOAc–hexane (1:9)] to give a col-
orless liquid; yield: 0.94 g (85%); [a]D27 –51.12 (c 0.5, CHCl3).
(3S,5R)-3,5-Bis{[tert-butyl(dimethyl)silyl]oxy}-9-phenylnonyl
Pivalate (12)
Imidazole (0.92 g, 1.3 mmol) and TBSCl (0.6 g, 0.41 mmol) were
added to a stirred mixture of (3S,5R)-5-{[tert-butyl(dimethyl)si-
lyl]oxy}-3-hydroxy-9-phenylnonyl pivalate (1.6 g, 0.34 mmol) in
anhyd CH2Cl2 (20 mL) at 0 °C and the mixture was stirred for 5
min. A catalytic amount of DMAP was added and stirring was con-
tinued for a further for 1 h at r.t. until the reaction was complete
(TLC). Crushed ice was added and the mixture was extracted with
CH2Cl2 (2 × 10 mL). The organic extracts were washed with brine,
dried (Na2SO4), and concentrated under vacuum. The crude product
was purified by column chromatography [silica gel (60–120 mesh),
EtOAc–hexane (1:9)] to give a colorless liquid; yield: 1.9 g (95%);
[a]D23.8 –5.7 (c 1.5, CHCl3).
IR (neat): 2927, 2856, 1726, 1645, 1462, 1366, 1256, 1175, 1093,
1039, 834, 775, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.15 (s, 6 H), 0.20 (s, 6 H), 0.82
(s, 9 H), 0.90 (s, 9 H), 1.22–1.45 (m, 8 H), 2.58 (t, J = 7.5 Hz, 2 H),
2.65–2.76 (m, 1 H), 2.95–3.05 (m, 1 H), 3.70 (s, 3 H), 3.75–3.85 (m,
1 H), 3.95–4.01 (m, 1 H), 5.85 (d, J = 11.0 Hz, 1 H), 6.30–6.40 (m,
1 H), 7.10–7.30 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 166.7, 146.6, 142.6, 128.3, 128.2,
125.6, 120.6, 69.3, 68.5, 50.9, 44.5, 37.2, 36.0, 35.9, 31.7, 29.6,
25.9, 25.8, 24.7, 18.0, –4.3, –4.4, –4.5, –4.6.
IR (neat): 3027, 2929, 2857, 1731, 1466, 1364, 1284, 1254, 1156,
1103, 1065, 938, 836, 774, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 12 H), 0.85 (s, 9 H), 0.90
(s, 9 H), 1.18 (s, 9 H), 1.22–1.86 (m, 10 H), 2.58 (t, J = 7.5 Hz, 2 H),
3.66–3.91 (m, 2 H), 4.04–4.16 (m, 2 H), 7.07–7.27 (m, 5 H).
MS (EI, 70 eV): m/z = 565 [M+], 532, 433, 362, 301, 277, 240, 199,
171, 145.
MS (EI, 70 eV): m/z = 557 [M + Na], 535 [M+], 417, 403, 330, 288,
271, 196, 102.
(3S,5R)-3,5-Bis{[tert-butyl(dimethyl)silyl]oxy}-9-phenylnonan-
1-ol (13)
(6S)-6-[(2R)-2-Hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-
2-one (1)
A 1 M soln of DIBAL-H (4.2 mL, 0.36 mmol) was added to a stirred
soln of compound 12 (1.9 g, 0.33 mmol) in anhyd THF (20 mL) at
–78 °C and the mixture was stirred for 30 min until the reaction was
complete (TLC). The reaction was quenched by adding few drops
of MeOH and the mixture was stirred for 10 min. Sat. aq Rochelle’s
salt was added and stirring was continued for 4 h. The THF was re-
moved under reduced pressure and the residue was extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated under vacuum. The
crude product was purified by column chromatography [silica gel
(60–120 mesh), EtOAc–hexane (2:8)] to give a colorless liquid;
yield: 1.4 g (90%); [a]D23.8 –12.9 (c 1.5, CHCl3).
A catalytic amount of TsOH was added to a stirred soln of com-
pound 14 (0.9 g) in MeOH at r.t., and the mixture was stirred for 30
min until the reaction was complete (TLC). The reaction was
quenched with sat. aq NaHCO3 and the mixture was stirred for 30
min. The mixture was then filtered and the filter was washed with
MeOH. The soln was concentrated under reduced pressure to give a
crude product that was purified by column chromatography [silica
gel (60–120 mesh), EtOAc–hexane (3:7)] to give a pale yellow low-
melting solid; yield: 0.45 g (90%); mp 33–35 °C; [a]D20 –62.33 (c
0.65, CHCl3).
IR (neat): 3457, 2938, 2848, 1695, 1487, 1392, 1254, 835, 775, 700
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40–1.50 (m, 3 H), 1.55–1.70 (m,
3 H), 1.80–1.95 (m, 1 H), 2.30–2.40 (m, 3 H), 2.62 (t, J = 7.0 Hz, 3
H), 3.90–4.10 (m, 1 H), 4.65–4.85 (m, 1 H), 6.02 (dd, J = 1.5 & 9.5
Hz, 1 H), 6.85–6.95 (m, 1 H), 7.10–7.30 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 164.4, 145.4, 142.3, 128.2, 128.1,
125.5, 121.1, 74.9, 66.7, 42.2, 37.7, 35.7, 31.2, 29.8, 25.0.
MS (EI, 70 eV): m/z = 297 [M + Na], 275 [M+].
IR (neat): 3445, 3027, 2932, 2857, 1632, 1465, 1380, 1253, 1060,
939, 835, 774, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.15 (s, 6 H), 0.20 (s, 6 H), 0.90
(s, 9 H), 0.88 (s, 9 H), 1.22–1.90 (m, 10 H), 2.60 (t, J = 7.5 Hz, 2 H),
3.62–4.10 (m, 4 H), 7.05–7.25 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 142.5, 128.3, 128.2, 125.6, 69.9,
69.4, 60.2, 43.8, 37.6, 37.2, 35.9, 31.7, 25.8, 24.6, 17.9, –4.1, –4.4,
–4.5, –4.7.
MS (EI, 70 eV): m/z = 481 [M+], 451, 433, 403, 362, 349, 305, 279,
242, 217, 199.
Acknowledgment
Methyl (2Z,5S,7R)-5,7-Bis{[tert-butyl(dimethyl)silyl]oxy}-11-
phenylundec-2-enoate (14)
Oxalyl chloride (0.3 mL, 0.3 mmol) was added to a stirred mixture
of DMSO (0.25 mL, 0.31 mmol) and CH2Cl2 (5 mL) at –78 °C, and
R.S.G. is grateful to CSIR-New Delhi for the provision of a fel-
lowship.
Synthesis 2011, No. 20, 3271–3276 © Thieme Stuttgart · New York

3276
A. V. Narsaiah, R. S. Ghogare
PAPER
Kumar, J. K. Int. J. Ind. Chem. 2010, 1, 1. (d) Narsaiah, A.
V.; Narsimha, M.; Haritha, B. Org. Synth. Med. Chem. 2011,
1, 1. (e) Narsaiah, A. V.; Nagaiah, B. Synthesis 2010, 2705.
(f) Narsaiah, A. V.; Kumar, J. K. Synth. Commun. 2011, 41,
1603.
References
(1) (a) Hamamoto, T.; Seto, H.; Beppu, T. J. Antibiot. 1983, 36,
646. (b) Yoshida, M.; Nishikawa, M.; Nishi, K.; Abe, K.;
Horinouchi, S.; Beppu, T. Exp. Cell. Res. 1990, 187, 150.
(2) (a) Raoelison, G. E.; Terreaux, Ch.; Queiroz, E. F.; Zsila, F.;
Simonyi, M.; Antus, S.; Randriantsoa, A.; Hostettmann, K.
Helv. Chim. Acta 2001, 84, 3470. (b) Hewlett, N. M.; Hupp,
C. D.; Tepe, J. J. Synthesis 2009, 2825.
(3) (a) Chandrasekhar, S.; Narsimhulu, Ch.; Sultana, S.; Reddy,
M. S. Tetrahedron Lett. 2004, 45, 9299. (b) Sabitha, G.;
Srinivas, Ch.; Sudhakar, K.; Rajkumar, M.; Maruthi, Ch.;
Yadav, J. S. Synthesis 2007, 3886. (c) Krishna, P. R.;
Srinivas, R. Tetrahedron: Asymmetry 2007, 18, 2197.
(d) Das, B.; Narayana, K. L.; Krishnaiah, M.; Kumar, D. N.
Bioorg. Med. Chem. 2009, 19, 6396. (e) Lu, M. N.; Krishna,
A. S.; Rao, J. V.; Lu, Y. V. Tetrahedron 2009, 65, 2989.
(f) Yadav, J. S.; Kanth, D. C.; Rao, Y. G.; Ravindar, K.;
Reddy, B. V. S. Helv. Chim. Acta 2010, 93, 1432.
(5) (a) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318.
(b) Hoffmann, R. W. Angew. Chem. Int. Ed. 2001, 40, 1411.
(6) Eliel, E. L. Rec. Chem. Prog. 1961, 22, 129.
(7) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765. (b) Shibatomi, K. Synthesis 2010, 2679.
(c) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229.
(8) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719.
(9) Robins, M. J.; Hawrelak, S. D.; Kanai, T.; Siefer, J. M.;
Mengel, R. J. Org. Chem. 1979, 44, 1317.
(10) (a) Corey, E. J.; Lu, A. V. J. Am. Chem. Soc. 1972, 94, 6190.
(b) Ogilvie, K. K.; Iwacha, D. J. Tetrahedron Lett. 1973, 14,
317.
(11) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717.
(12) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(4) (a) Narsaiah, A. V.; Kumar, J. K. Synthesis 2010, 1989.
(b) Narsaiah, A. V.; Narsimha, P.; Navitha, G. Int. J. Appl.
Biol. Pharm. Technol. 2010, 1, 736. (c) Narsaiah, A. V.;
Synthesis 2011, No. 20, 3271–3276 © Thieme Stuttgart · New York