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

Article abstract of DOI:10.1055/s-2007-990928

An enantioselective route for the synthesis of (6S)-5,6-dihydro-6-[(2R)-2- hydroxy-6-phenylhexyl]-2H-pyran-2-one is reported. The synthesis is based on epoxide ring opening with a Grignard reagent and stereoselective reduction employing catecholborane as

Full text of DOI:10.1055/s-2007-990928

3886
PAPER
Enantioselective Total Synthesis of the Antifungal Agent (6S)-5,6-Dihydro-6-
[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one1
Enantioselective
T
o
otal Synthesi
w
s
of
a
n
A
ntifungal
r
A
gent avaram Sabitha,* Chitti Srinivas, Kadari Sudhakar, Manne Rajkumar, Chittapragada Maruthi, Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: sabitha@iictnet.org
Received 29 May 2007; revised 28 June 2007
hydroxy-6-phenylhexyl]-2H-pyran-2-one are a few ex-
amples among natural products with the 6-substituted 5,6-
dihydro-2H-pyran-2-one moiety (Figure 1).
Abstract: An enantioselective route for the synthesis of (6S)-5,6-
dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is re-
ported. The synthesis is based on epoxide ring opening with a Grig-
nard reagent and stereoselective reduction employing
catecholborane as key reactions.
(6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-
2H-pyran-2-one (1), which was isolated by Hostettmann
and co-workers2 in 2001 from Ravensara crassifolia, ex-
hibits an antifungal activity against the phytopathogenic
fungus Cladosporium cucumerinum in a bioautographic
TLC assay. Its structure contains an a,b-unsaturated d-
lactone moiety with a fixed syn-1,3-diol system. These
structural features are also present in several other biolog-
ically active natural products, which are responsible for a
wide variety of biological activities.3 To date, a single
report4 outlining a ring-closing-metathesis approach has
appeared in the literature for the synthesis of 1.
Key words: 6-substituted 5,6-dihydro-2H-pyran-2-ones, cate-
cholborane, antifungal activity
Significant biological activities such as antifungal, anti-
feedant, antibacterial, and antitumour activity, as well as
structural uniqueness, make lactones attractive targets to
venture their total synthesis. Massoialactones, 7-epi-go-
niodiol, (+)-goniothalamin, (–)-tarchonanthuslactone,
(+)-kavain, (+)-dihydrokavain, (–)-argentilactone, (+)-
cryptocarya diacetate, and (6S)-5,6-dihydro-6-[(2R)-2-
O
O
O
OMe
O
O
O
OMe
(R)-(+)-kavain
(S)-(+)-dihydrokavain
O
O
(R)-(+)-goniothalamin
O
O
O
2
3
4
O
6
1
OAc OAc
R
(R)-(–)-massoialactone
5
(+)-cryptocarya diacetate
O
O
O
O
HO
HO
O
O
O
(S)-(+)-massoialactone
OH
O
Ph
(–)-tarchonanthuslactone
OH
7-epi-goniodiol
Figure 1
SYNTHESIS 2007, No. 24, pp 3886–3890
x
x.
x
x
.
2
0
0
7
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-990928; Art ID: Z13207SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Total Synthesis of an Antifungal Agent
3887
O
5
2
OH
2'
O
6
1
OH OH
O
6'
4'
4
Ph
Ph
OEt
1
2
OH
O
OBn
Ph
OBn
3
4
Scheme 1 Retrosynthetic plan for (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one
Recently, we reported the synthesis of several bioactive
a
O
lactones.5 In a continuation of our studies, we became in-
+
OBn
Ph
MgBr
terested in the synthesis of 1. The synthesis is based on ep-
oxide ring opening with a Grignard reagent and
stereoselective reduction using catecholborane as key re-
actions to fix the syn-1,3-diol system (Scheme 1).
5
4
OTBS
OH
b
Ph
OR
Ph
OBn
3
The synthesis of 1 began with the known epoxide 4
(Scheme 2).6 Upon treatment with (3-phenylpropyl)mag-
nesium bromide (5) in the presence of a catalytic amount
of copper(I) iodide in tetrahydrofuran at 0 °C, epoxide 4
furnished the secondary alcohol 3 in 86% yield. The sec-
ondary hydroxy group of 3 was protected as its tert-bu-
tyldimethylsilyl ether 6 in 95% yield, and the benzyl
group was removed using Pd/C (10%) in ethyl acetate to
afford the free primary hydroxy compound 7 in 87%
yield. Oxidation of alcohol 7 using 2-iodoxybenzoic acid
(IBX) in dimethyl sulfoxide provided the corresponding
aldehyde 8 in 94% yield. Next, the aldehyde 8 was con-
verted into the d-silyloxy-b-oxo ester 9 in 83% yield by
treatment with ethyl diazoacetate in the presence of a cat-
alytic amount of tin(II) chloride, as reported in our earlier
communication.5f Then, the second stereogenic center
with the required stereochemistry was established using
catecholborane. Accordingly, the silyl group was depro-
tected in 85% yield and stereoselective reduction of the
resulting acyclic b-hydroxy ketone employing 2.5 equiv-
alents of catecholborane7 resulted in the syn-1,3-dihy-
droxy ester 2 in 96% yield with high diastereoselectivity.
The 1,3-diol moiety of 2 was protected as the acetonide 10
in 90% yield, and its stereochemistry was confirmed by
analyzing the 13C NMR spectroscopic data.
6, R = Bn
7, R = H
c
OTBS
OTBS O
O
d
e
CHO
( )3
( )3
Ph
Ph
OEt
9
8
OH OH
O
f, g
h
Ph
OEt
2
O
OMe
O
O
O
O
j
R
Ph
Ph
12
10, R = COOEt
11, R = CHO
i
k
1
Scheme 2 Reagents and conditions: a) CuI, THF, 0 °C to r.t., 2 h,
86%; b) TBDMSCl, imidazole, CH2Cl2, DMAP, 0 °C, 2 h, 95%; c)
H2, Pd/C, EtOAc, r.t., 6 h, 87%; d) IBX, DMSO, 0 °C to r.t., 2 h, 94%;
e) N2CHCO2Et, anhyd SnCl2, CH2Cl2, 0 °C to r.t., 40 min, 83%; f)
TBAF, THF, 2 h, 85%; g) catecholborane, THF, –10 °C, 5 h, 96%; h)
2,2-dimethoxypropane, PPTS, 90%; i) DIBAL-H, CH2Cl2, –78 °C,
1 h, 70%; j) (CF3CH2O)2P(O)CH2CO2Me, NaH, THF, –78 °C, 2 h,
80%; k) PTSA, benzene, r.t., 1 h, 73%.
The ester 10 was converted into aldehyde 11 using di-
isobutylaluminum hydride in 70% yield and subsequently
subjected to Still–Gennari condensation with bis(2,2,2-
trifluoroethyl) (methoxycarbonylmethyl)phosphonate in
tetrahydrofuran at –78 °C to afford the Z-olefinic ester 12
in 80% yield. Treatment of 12 with p-toluenesulfonic acid
in benzene at room temperature finally gave the target
molecule 1 in 73% yield. The physical and spectroscopic
data of the synthetic sample 1 were in good agreement
with the reported data of the natural product.
phenylhexyl]-2H-pyran-2-one (1) employing a Grignard
reaction and stereoselective reduction of a b-hydroxy ke-
tone as key steps.
Reactions were conducted under a N2 atmosphere using anhydrous
solvents such as CH2Cl2, THF, benzene, and EtOAc. All reactions
were monitored by TLC using silica-coated plates (Merck 60 F-
254) with visualization under UV light. Light petroleum ether of the
distillation range 60–80 °C was used. Yields refer to chromatog-
raphically and spectroscopically (1H, 13C NMR) homogeneous ma-
terial. Air-sensitive reagents were transferred by syringe or with a
double-ended needle. Evaporation of solvents was performed under
In summary, we have accomplished the enantioselective
total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-
Synthesis 2007, No. 24, 3886–3890 © Thieme Stuttgart · New York

3888
G. Sabitha et al.
PAPER
reduced pressure using a Buchi rotary evaporator. 1H NMR spectra
were recorded in CDCl3 on Varian FT-200 MHz (Gemini) and
Bruker UXNMR FT-300 MHz (Avance) instruments. Chemical
shift values are reported in parts per million (d) relative to tetra-
methylsilane (d 0.0) as an internal standard. Mass spectra were re-
corded under electron impact at 70 eV on a LC/MSD (Agilent
Technologies) instrument. Column chromatography was performed
on silica gel (60–120 mesh) supplied by Acme Chemical Co., India.
Optical rotations were measured with a JASCO DIP-370 Polarime-
ter at 25 °C.
(2 × 50 mL), and the filtrate was concentrated under reduced pres-
sure and purified by silica gel column chromatography (petroleum
ether–EtOAc, 6:4) to afford compound 7 (3.4 g, 87%) as a colorless
liquid.
[a]D25 +35.0 (c 0.001, CHCl3).
IR (neat): 3445, 2925, 2854, 1457, 1381, 1256, 1021, 765 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.04 (m, 5 H), 4.04–3.58 (m,
3 H), 2.60 (t, J = 7.5 Hz, 2 H), 1.93–1.04 (m, 8 H), 0.90 (s, 9 H),
0.01 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 142.5, 128.4, 128.2, 125.6, 71.7,
60.2, 37.8, 36.7, 35.9, 31.5, 25.8, 25.0, 17.9, –4.4, –4.7.
(3R)-1-(Benzyloxy)-7-phenylheptan-3-ol (3)
To a suspension of Mg (1.3 g, 56.11 mmol) in anhyd THF (20 mL),
3-phenylpropyl bromide (11.17 g, 56.11 mmol) was added dropwise
under a N2 atmosphere at 0 °C. The mixture was allowed to stir for
ca. 1 h at r.t. A catalytic amount of CuI was then added at 0 °C to
the suspension of Grignard reagent, which was allowed to stir at the
same temperature for ca. 0.5 h. Epoxide 4 (5.0 g, 28.05 mmol) in an-
hyd THF (15 mL) was added dropwise at 0 °C and the mixture was
stirred at r.t. for ca. 0.5 h. After completion of the reaction, the re-
action mixture was quenched with sat. aq NH4Cl (20 mL) and ex-
tracted with EtOAc (3 × 50 mL). The organic layer was washed with
brine (40 mL), dried (anhyd Na2SO4), and concentrated under re-
duced pressure; purification by silica gel column chromatography
(petroleum ether–EtOAc, 7:3) afforded 3 (7.2 g, 86%) as a viscous
liquid.
LC/MS: m/z = 345 [M+ + Na].
Anal. Calcd for C19H34O2Si: C, 70.75; H, 10.62. Found: C, 69.19;
H, 9.75.
(3R)-3-[tert-Butyl(dimethyl)silyloxy]-7-phenylheptanal (8)
To an ice-cooled soln of IBX (4.42 g, 15.80 mmol) in DMSO (4.5
mL, 63.22 mmol) was added a soln of alcohol 7 (3.4 g, 10.53 mmol)
in anhyd CH2Cl2 (10 mL). The mixture was stirred at r.t. for 2 h and
then filtered through a Celite® pad and washed with Et2O (2 × 50
mL). The combined organic filtrates were washed with H2O (40
mL) and brine (40 mL), dried (anhyd Na2SO4), and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography (petroleum ether–EtOAc, 9:1) to afford aldehyde 8
(3.2 g, 94%) as a viscous liquid.
[a]D25 +6.3 (c 0.015, CHCl3).
IR (neat): 2925, 2854, 1726, 1629, 1457, 1256, 1021, 765 cm–1.
IR (neat): 3435, 3061, 3027, 2930, 2856, 1721, 1602, 1494, 1454,
1363, 1267, 1206, 1094, 1028, 798, 741 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.43–7.07 (m, 10 H), 4.52 (s, 2 H),
3.85–3.55 (m, 3 H), 2.62 (t, J = 7.8 Hz, 2 H), 1.77–1.31 (m, 8 H).
1H NMR (200 MHz, CDCl3): d = 9.76 (s, 1 H), 7.36–7.01 (m, 5 H),
4.28–4.05 (m, 1 H), 2.60 (t, J = 7.3 Hz, 2 H), 2.52–2.40 (m, 2 H),
1.93–1.45 (m, 6 H), 0.86 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 202.1, 142.3, 128.4, 128.3, 125.7,
68.1, 50.8, 37.7, 35.8, 31.4, 25.7, 24.8, 17.9, –4.4, –4.7.
13C NMR (75 MHz, CDCl3): d = 142.7, 137.9, 128.4, 128.2, 127.7,
127.6, 125.6, 96.1, 73.3, 72.3, 69.2, 37.3, 36.4, 35.9, 31.5, 25.2.
LC/MS: m/z = 359 [M+ + K].
LC/MS: m/z = 321 [M+ + Na].
Anal. Calcd for C19H32O2Si: C, 71.19; H, 10.06. Found: C, 71.10;
H, 9.35.
Anal. Calcd for C20H26O2: C, 80.50; H, 8.75. Found: C, 79.19; H,
8.35.
Ethyl (5R)-5-[tert-Butyl(dimethyl)silyloxy]-3-oxo-9-phenyl-
nonanoate (9)
{(1R)-1-[2-(Benzyloxy)ethyl]-5-phenylpentyloxy}(tert-bu-
tyl)dimethylsilane (6)
CH2Cl2 (15 mL) followed by ethyl diazoacetate (1.08 mL, 10.29
mmol) was added with stirring at 0 °C to anhyd SnCl2 (0.17 g, 0.93
mmol). To this suspension was slowly added a few drops of alde-
hyde 8 (3.0 g, 9.36 mmol) in anhyd CH2Cl2. When N2 evolution be-
gan the remaining soln of compound 8 was added dropwise over 10
min. After N2 evolution had stopped (30 min) the reaction was
transferred to a separatory funnel with sat. brine (30 mL) and ex-
tracted with Et2O (2 × 20 mL). The organic layers were combined
and dried (anhyd Na2SO4). The solvent was removed under reduced
pressure and the residue was purified by silica gel column chroma-
tography (petroleum ether–EtOAc, 5:0.5) to afford compound 9
(3.15 g, 83% yield) as a viscous liquid.
To a stirred soln of alcohol 3 (5.0 g, 16.75 mmol), imidazole (2.28
g, 33.51 mmol) and catalytic amounts of DMAP in anhyd CH2Cl2
(50 mL) was added TBDMSCl (3.78 g, 25.12 mmol) portionwise at
0 °C. The reaction mixture was stirred at the same temperature for
2 h and then quenched with H2O. The CH2Cl2 layer was separated
and the aqueous layer was extracted with additional CH2Cl2 (2 × 50
mL). The combined organic layers were washed with H2O (30 mL)
and brine (30 mL), and dried (anhyd Na2SO4). The solvent was re-
moved under reduced pressure and the residue was purified by silica
gel column chromatography (petroleum ether–EtOAc, 9.5:0.5) to
afford 6 (6.57 g, 95% yield) as a colorless liquid.
IR (neat): 2925, 2854, 1740, 1632, 1456, 1318, 1264, 1077, 897,
792, 698 cm–1.
[a]D25 –18.0 (c 0.01, CHCl3).
1H NMR (200 MHz, CDCl3): d = 7.43–7.01 (m, 10 H), 4.43 (s, 2 H),
3.88–3.70 (m, 1 H), 3.46 (t, J = 6.6 Hz, 2 H), 2.57 (t, J = 7.3 Hz, 2
H), 1.81–1.26 (m, 8 H), 0.84 (s, 9 H), 0.01 (s, 6 H).
IR (neat): 2928, 2855, 1744, 1719, 1633, 1463, 1379, 1252, 1149,
1094, 1033, 835, 772, 699 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.31–6.95 (m, 5 H), 4.29–4.04 (m,
3 H), 3.35 (s, 2 H), 2.75–2.38 (m, 4 H), 1.69–1.16 (m, 9 H), 0.81 (s,
9 H), 0.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 201.9, 167.3, 142.4, 128.4, 128.3,
125.6, 68.8, 68.4, 61.2, 50.8, 50.1, 39.3, 37.4, 35.8, 31.4, 29.8, 25.8,
24.6, 17.9, 14.1, –4.5.
LC/MS: m/z = 435 [M+ + Na].
Anal. Calcd for C26H40O2Si: C, 75.67; H, 9.77. Found: C, 74.60; H,
9.34.
(3R)-3-[tert-Butyl(dimethyl)silyloxy]-7-phenylheptan-1-ol (7)
To a soln of compound 6 (5.0 g, 12.11 mmol) in anhyd EtOAc (15
mL) was added a catalytic amount of 10% Pd/C and the reaction
mixture was stirred at r.t. under a H2 atmosphere for 6 h. Then the
reaction mixture was filtered, the solids were washed with EtOAc
LC/MS: m/z = 429 [M+ + Na].
Anal. Calcd for C23H38O4Si: C, 67.94; H, 9.42. Found: C, 68.62; H,
9.10.
Synthesis 2007, No. 24, 3886–3890 © Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of an Antifungal Agent
3889
Ethyl (5R)-5-Hydroxy-3-oxo-9-phenylnonanoate
2-[(4R,6R)-2,2-Dimethyl-6-(4-phenylbutyl)-1,3-dioxan-4-yl]ac-
etaldehyde (11)
To compound 9 (3.0 g, 7.37 mmol) in anhyd THF (10 mL) was add-
ed 1 M TBAF in THF (11.06 mL, 11.06 mmol) dropwise at 0 °C and
the mixture was stirred for 2 h. H2O (2 mL) was added and the mix-
ture was extracted with EtOAc (2 × 50 mL). The organic extracts
were washed with brine (30 mL) and dried (anhyd Na2SO4). Evap-
oration of the solvent afforded the d-hydroxy-b-oxo ester product
(1.83 g, 85%) as a liquid.
To a stirred soln of the acetonide-protected ester 10 (1.5 g, 4.48
mmol) in anhyd CH2Cl2 (10 mL) was added 1.4 M DIBAL-H in
hexane (3.84 mL, 5.38 mmol) dropwise over a 10-min period under
a N2 atmosphere at –78 °C. After stirring for 1 h at the same temper-
ature, anhyd MeOH (2 mL) was added and the reaction mixture was
allowed to warm to r.t. Sat. aq potassium sodium tartrate soln (10
mL) was added and the resulting mixture was stirred vigorously un-
til the two layers were separated. The organic layer was separated
and the aqueous layer was extracted with additional CH2Cl2 (2 × 40
mL). The combined organic layers were washed with H2O (30 mL)
and brine (30 mL), and dried (anhyd Na2SO4). Removal of the sol-
vent under reduced pressure and purification by column chromatog-
raphy (petroleum ether–EtOAc, 9:1) afforded the aldehyde 11 (0.91
g, 70% yield) as a viscous liquid.
IR (neat): 3446, 2988, 2930, 2364, 1737, 1631, 1455, 1379, 1260,
1027 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.37–7.02 (m, 5 H), 4.18 (q,
J = 7.09 Hz, 2 H), 4.09–3.96 (m, 1 H), 3.41 (s, 2 H), 2.90–2.48 (m,
4 H), 1.90–1.17 (m, 9 H).
LC/MS: m/z = 315 [M+ + Na].
Anal. Calcd for C17H24O4: C, 69.84; H, 8.27. Found: C, 68.79; H,
8.35.
IR (neat): 3328, 2958, 2346, 1702, 1623, 1425, 1379, 1027 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.02 (s, 1 H), 7.33–7.10 (m, 5 H),
4.34–4.19 (m, 1 H), 3.98–3.74 (m, 1 H), 2.56 (t, J = 7.5 Hz, 2 H),
2.52–2.27 (m, 2 H), 1.74–1.52 (m, 8 H), 1.33 (s, 3 H), 1.29 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 202.3, 143.1, 128.5, 128.3, 125.7,
109.2, 74.6, 69.5, 49.9, 41.3, 36.3, 31.3, 25.1, 24.4.
Ethyl (3R,5R)-3,5-Dihydroxy-9-phenylnonanoate (2)
A soln of ethyl (5R)-5-hydroxy-3-oxo-9-phenylnonanoate (1.8 g,
6.15 mmol) in anhyd THF was chilled in a MeOH–ice bath (–10 °C)
and charged with freshly distilled catecholborane (1.64 mL, 15.38
mmol). After 5 h, the reaction mixture was quenched by the addition
of anhyd MeOH (1 mL) and sat. aq potassium sodium tartrate soln
(2 mL). This mixture was allowed to stir at r.t. for 1 h, and the de-
sired product was isolated by silica gel column chromatography
(petroleum ether–EtOAc, 4:6) to afford the diol 2 (1.74 g, 96%) as
a liquid.
LC/MS: m/z = 313 [M+ + Na].
Anal. Calcd for C18H26O3: C, 74.45; H, 9.02. Found: C, 73.99; H,
8.89.
Methyl (Z)-4-[(4S,6R)-2,2-Dimethyl-6-(4-phenylbutyl)-1,3-di-
oxan-4-yl]but-2-enoate (12)
IR (neat): 3434, 2978, 2924, 2364, 1743, 1626, 1449, 1370, 1264,
1037 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.30–7.05 (m, 5 H), 4.35–4.10 (m,
1 H), 4.13 (q, J = 7.3 Hz, 2 H), 3.98–3.76 (m, 1 H), 2.59 (t, J = 7.5
Hz, 2 H), 2.54–2.21 (m, 2 H), 1.74–1.52 (m, 8 H), 1.26 (t, J = 7.5
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.5, 142.5, 128.3, 128.2, 125.6,
72.0, 69.0, 60.7, 42.2, 41.7, 37.6, 35.8, 31.4, 25.0, 14.1.
LC/MS: m/z = 317 [M+ + Na].
Into a 50-mL round-bottom flask NaH (0.061 g, 2.58 mmol) was
taken and, to it, anhyd THF (4 mL) was added under a N2 atmo-
sphere. After 5 min, bis(2,2,2-trifluoroethyl) (methoxycarbonyl-
methyl)phosphonate (0.65 g, 2.06 mmol) in anhyd THF (2 mL) was
added dropwise at 0 °C, and the mixture was allowed to stir for 30
min. The mixture was cooled to –78 °C and aldehyde 11 (0.50 g,
1.72 mmol) in THF (1 mL) was added dropwise over a 10-min pe-
riod; the resulting mixture was stirred for 2 h at –78 °C. The reac-
tion mixture was quenched with sat. NH4Cl soln and the product
was extracted into Et2O (2 × 20 mL). The Et2O extracts were dried
(anhyd Na2SO4) and concentrated under reduced pressure (water
bath temperature should not exceed 30 °C) and the product was pu-
rified using silica gel column chromatography (petroleum ether–
EtOAc, 9.5:0.5) to afford the Z-olefinic ester 12 (0.48 g, 80% yield)
as a light yellow liquid.
[a]D25 –10.55 (c 0.5, CHCl3).
IR (neat): 2930, 2857, 1724, 1646, 1496, 1378, 1173, 1028 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–7.05 (m, 5 H), 6.47–6.23 (m,
1 H), 5.82 (d, J = 12.4 Hz, 1 H), 4.19–4.06 (m, 1 H), 3.97–3.79 (m,
1 H), 3.69 (s, 3 H), 2.59 (t, J = 7.5 Hz, 2 H), 2.50–2.20 (m, 2 H),
1.68–1.44 (m, 2 H), 1.44–1.21 (m, 12 H).
Anal. Calcd for C17H26O4: C, 69.36; H, 8.90. Found: C, 68.19; H,
8.13.
Ethyl 2-[(4R,6R)-2,2-Dimethyl-6-(4-phenylbutyl)-1,3-dioxan-4-
yl]acetate (10)
To a soln of diol 2 (1.5 g, 5.09 mmol) in anhyd acetone (10 mL),
2,2-dimethoxypropane (0.94 mL, 7.64 mmol) and PPTS (0.13 g,
0.51 mmol) were added. The mixture was stirred at r.t. for 12 h.
NaHCO3 was added to neutralize the PPTS and the mixture was fil-
tered. Removal of the solvent and purification by silica gel column
chromatography (petroleum ether–EtOAc, 9.5:0.5) afforded the ac-
etonide 10 (1.53 g, 90%) as a liquid.
[a]D25 –5.83 (c 1.2, CHCl3).
LC/MS: m/z = 369 [M+ + Na].
IR (neat): 2988, 2930, 2364, 1737, 1631, 1455, 1379, 1260, 1027
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30–7.05 (m, 5 H), 4.28–4.16 (m,
1 H), 4.12 (q, J = 7.5 Hz, 2 H), 3.83–3.66 (m, 1 H), 2.59 (t, J = 8.3
Hz, 2 H), 2.52–2.24 (m, 2 H), 1.68–1.44 (m, 8 H), 1.41 (s, 3 H), 1.33
(s, 3 H), 1.26 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.1, 142.6, 128.4, 128.3, 125.8,
98.7, 68.7, 66.0, 60.4, 41.5, 36.5, 36.2, 31.4, 30.9, 24.6, 19.7, 14.2.
LC/MS: m/z = 357 [M+ + Na].
Anal. Calcd for C21H30O4: C, 72.80; H, 8.73. Found: C, 72.19; H,
8.35.
(6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-
2-one (1)
To a stirred soln of Z-olefinic ester 12 (0.2 g, 0.58 mmol) in benzene
(5 mL) was added a catalytic amount of PTSA under a N2 atmo-
sphere. The mixture was stirred at r.t. for 1 h and then the reaction
was quenched by the addition of solid NaHCO3. The mixture was
filtered and the solvent was removed under reduced pressure. The
residue was purified by column chromatography (petroleum ether–
EtOAc, 6:4) to afford 1 (0.115 g, 73%) as a solid.
Anal. Calcd for C20H30O4: C, 71.82; H, 9.04. Found: C, 70.61; H,
8.93.
[a]D25 –57.64 (c 0.65, CHCl3).
Synthesis 2007, No. 24, 3886–3890 © Thieme Stuttgart · New York

3890
G. Sabitha et al.
PAPER
(3) (a) Fujita, T.; Nishimura, H.; Kaburagi, K.; Mizutani, J.
IR (neat): 3449, 2926, 2361, 1714, 1639, 1496, 1378, 1173, 1032
cm–1.
1H NMR (200 MHz, CDCl3): d = 7.29–7.10 (m, 5 H), 6.91–6.83 (m,
1 H), 6.01 (dd, J = 2.1, 9.5 Hz, 1 H), 4.77–4.66 (m, 1 H), 4.05–3.93
(m, 1 H), 2.62 (t, J = 7.5 Hz, 2 H), 2.38–2.29 (m, 2 H), 1.84–1.69
(m, 2 H), 1.69–1.58 (m, 2 H), 1.54–1.39 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 164.1, 145.3, 142.1, 128.2, 128.1,
125.2, 121.2, 75.2, 66.7, 42.2, 37.3, 35.7, 31.2, 29.8, 25.1.
LC/MS: m/z = 297 [M+ + Na].
Phytochemistry 1994, 36, 23. (b) Nyandat, E.; Rwekika, E.;
Galeffi, C.; Palazzino, G.; Nicoletti, M. Phytochemistry
1993, 33, 1493. (c) Andrianaivoravelona, J. O.; Sahpaz, S.;
Terreaux, C.; Hostettmann, K.; Stoeckli-Evans, H.;
Rasolondramanitra, J. Phytochemistry 1999, 52, 265.
(d) Pereda-Miranda, R.; Garcia, M.; Delgado, G.
Phytochemistry 1990, 29, 2971.
(4) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy,
M. S. Tetrahedron Lett. 2004, 45, 9299.
(5) (a) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar, M.;
Yadav, J. S. Tetrahedron Lett. 2005, 46, 6567. (b) Sabitha,
G.; Narjis, F.; Swapna, R.; Yadav, J. S. Synthesis 2006,
2879. (c) Sabitha, G.; Reddy, E. V.; Yadagiri, K.; Yadav, J.
S. Synthesis 2006, 3270. (d) Sabitha, G.; Bhikshapathi, M.;
Yadav, J. S. Synth. Commun. 2007, 37, 561. (e) Sabitha, G.;
Bhaskar, V.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 8179.
(f) Sabitha, G.; Sudhakar, K.; Yadav, J. S. Tetrahedron Lett.
2006, 47, 8599. (g) Sabitha, G.; Swapna, R.; Reddy, E. V.;
Yadav, J. S. Synthesis 2006, 4242. (h) Sabitha, G.; Gopal,
P.; Yadav, J. S. Synth. Commun. 2007, 37, 1495.
Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 73.8; H,
8.63.
Acknowledgment
Ch.S. and K.S. thank UGC, New Delhi and M.R. and Ch.M. thank
CSIR, New Delhi for the award of fellowships.
References
(6) Simpson, T. J.; Smith, R. W.; Westaway, S. M.; Willis, C. L.
Tetrahedron Lett. 1997, 38, 5367.
(7) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190.
(1) IICT Communication No. 061205
(2) Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.;
Simonyi, M.; Antus, S.; Randriantsoa, A.; Hostettmann, K.
Helv. Chim. Acta 2001, 84, 3470.
Synthesis 2007, No. 24, 3886–3890 © Thieme Stuttgart · New York