First stereoselective total synthesis of naturally occurring (6 R)-6-(4-Oxopentyl)-5,6-dihydro-2 H -pyran-2-one and Its (6 S)-enantiomer

Article abstract of DOI:10.1055/s-0031-1289643

(6R)-6-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one, a naturally occurring ,-unsaturated -lactone, and its (6S)-enantiomer have been synthesized stereoselectively starting from pentane-1,5-diol. The synthesis involves Maruoka asymmetric allylation and ring-cl

Full text of DOI:10.1055/s-0031-1289643

PAPER
469
First Stereoselective Total Synthesis of Naturally Occurring
(6R)-6-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one and Its (6S)-Enantiomer1
6
-(
R
)
-(4-Oxopenty
i
l)-5,6-d
g
ihydro-2
H
-p
a
yran-2-onembar Balaji Shinde, Boddu Shashi Kanth, Malampati Srilatha, Biswanath Das*
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 10 October 2011; revised 21 November 2011
The synthesis of (6R)-6-(4-oxopentyl)-5,6-dihydro-2H-
pyran-2-one [(R)-1] was initiated by converting pentane-
1,5-diol (4) into monobenzyl ether 5 by treatment with
benzyl bromide and potassium hydroxide (Scheme 2).
The primary hydroxy group of 5 was oxidized with pyri-
dinium chlorochromate to the corresponding aldehyde 6,
which was immediately treated with methylmagnesium
iodide to form the racemic alcohol 7. The hydroxy group
of 7 was protected as its TBDPS ether by treatment with
tert-butyldiphenylsilyl chloride in the presence of imida-
zole and a catalytic amount of 4-(dimethylamino)pyridine
to afford 8; the benzyl group 8 was deprotected by hydro-
genation in the presence of palladium on carbon to furnish
the alcohol 9. This alcohol 9 was oxidized with pyridini-
um chlorochromate to give the aldehyde 10, which subse-
quently underwent Maruoka asymmetric allylation,7
using the titanium complex (S,S)-I (Figure 2) and allyl-
tributyltin to generate the homoallylic alcohol (R)-3.
Compound (R)-3 was esterified with acryloyl chloride in
the presence of triethylamine and a catalytic amount of 4-
(dimethylamino)pyridine to produce the acrylate ester
(R)-11. Deprotection of the TBDPS ether group of (R)-11
by treatment with tetrabutylammonium fluoride generated
the alcohol (R)-2, which was oxidized with pyridinium
chlorochromate to the corresponding ketone (R)-12. The
13C NMR spectrum of (R)-3 showed that some of the sig-
nals were split, indicating that the compound is a diaste-
reomeric mixture; the diastereomers were not separated
because at a later stage one of the chiral center is de-
stroyed. Compounds (R)-11 and (R)-2 were also diaste-
reomeric mixtures (as indicated by their 13C NMR
spectra), but compound (R)-12 was a single isomer. The
Abstract: (6R)-6-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one,
a
naturally occurring a,b-unsaturated d-lactone, and its (6S)-enan-
tiomer have been synthesized stereoselectively starting from pen-
tane-1,5-diol. The synthesis involves Maruoka asymmetric
allylation and ring-closing metathesis as the key steps.
Key words: lactones, (6R)-6-(4-oxopent-2-enyl)-5,6-dihydro-2H-
pyran-2-one, (6S)-6-(4-oxopent-2-enyl)-5,6-dihydro-2H-pyran-2-
one, ring-closing metathesis, stereoselective synthesis
6-Substituted 5,6-dihydro-2H-pyran-2-ones exhibit vari-
ous important biological properties including cytotoxic,
antifungal, and antibacterial activity;2 the synthesis of
these compounds is an attractive target to organic chem-
ists.3 (6R)-6-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one
[(R)-1] (Figure 1), a member of this class of compounds,
was isolated from Piper reticulatum (Piperaceae).4 The
total synthesis of this compound has not yet been reported
though several related compounds have recently been
synthesized.5 In continuation of our work6 on the stereo-
selective construction of bioactive natural products, we
report here the first synthesis of this compound (R)-1 and
its (6S)-isomer (S)-1.
O
O
O 1
6
O
O 1
6
O
4
4
(R)-1
(S)-1
Figure 1
The retrosynthetic analysis (Scheme 1) suggested that ring-closing metathesis8 of (R)-12 was efficiently accom-
(R)-1 and (S)-1 can be prepared from the olefinic esters plished by using Grubbs’ first-generation (Grubbs I) cata-
lyst to afford the a,b-unsaturated d-lactone (R)-1, whose
(R)-2 and (S)-2, respectively, which can be obtained from
pentane-1,5-diol (4) via the allylic alcohols (R)-3 [for (R)- optical and spectral properties were found to be identical
1] and (S)-3 [for(S)-1].
O
O
O1
6
O
OTBDPS
OH
4
O
4
OH
4
HO
OH
1
1
(R)-1
(S)-1
(R)-2
(S)-2
(R)-3
(S)-3
4
Scheme 1 Retrosynthetic analysis of 6-(4-oxopentyl)-5,6-dihydropyran-2-one
SYNTHESIS 2012, 44, 469–473
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.12.2011
DOI: 10.1055/s-0031-1289643; Art ID: Z96711SS
© Georg Thieme Verlag Stuttgart · New York

470
D. B. Shinde et al.
PAPER
OR2
b
c
R1O
OH
R1O
R1O
7 R1 = Bn, R2 = H
O
4 R1 = H
6 R1 = Bn
a
5 R1 = Bn
d
8 R1 = Bn, R2 = TBDPS
9 R1 = H, R2 = TBDPS
e
OTBDPS
OH
OTBDPS
g
h
f
O
10
(R)-3
(S)-3
O
O
O
O
OR2
O
j
O
O
O
k
(R)-11 R2 = TBDPS
(S)-11 R2 = TBDPS
(R)- 2 R2 = H
(R)-1
(S)-1
(R)-12
(S)-12
i
i
(S)-2 R2 = H
Scheme 2 Synthesis of 6-(4-oxopentyl)-5,6-dihydro-2H-pyran-2-ones (R)-1 and (S)-1. Reagents and conditions: (a) BnBr, KOH, r.t., 1 h,
80%; (b) PCC, Celite, CH2Cl2, r.t., 1 h, 95%; (c) Mg, MeI, anhyd Et2O, 0 °C to r.t., 2 h, 92%; (d) TBDPSCl, Et3N, DMAP, CH2Cl2, 0 °C to r.t.,
2 h, 95%; (e) H2, Pd/C, EtOAc, 10 h, 97%; (f) PCC, Celite, CH2Cl2, r.t., 1 h, 94%, (g) [(S,S)-I, 10 mol%, for (R)-3], [(R,R)-I, 10 mol%, for (S)-
3], Bu3SnCH2CH=CH2, CH2Cl2, –15 °C to 0 °C, 15 h, 84%; (h) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 3 h, 88%; (i) TBAF, anhyd
THF, 0 °C to r.t., 3 h, 80%; (j) PCC, Celite, CH2Cl2, r.t., 1 h, 90%; (k) Grubbs I catalyst (10 mol%), CH2Cl2, 50 °C, 24 h, 86%.
to those reported for naturally occurring (6R)-6-(4-oxo- of the enantiomeric homoallylic alcohol (R)-3 into the nat-
pentyl)-5,6-dihydro-2H-pyran-2-one.4
ural lactone (R)-1 [i.e., acrylation with acryloyl chloride
to form (S)-11 and deprotection of the TBDPS ether to the
alcohol (S)-2, followed by oxidation to ketone (S)-12 and
finally ring-closing metathesis8 to generate (S)-1].
The (6S)-enantiomer (S)-1 of the natural lactone (R)-1 was
also synthesized from 9, which was prepared from pen-
tane 1,5-diol (4) (Scheme 2). Compound 9 was oxidized
with pyridinium chlorochromate to the corresponding al- In conclusion, we have developed the first stereoselective
dehyde 10, which was then subjected to Maruoka asym- total synthesis of the naturally occurring lactone, (6R)-(4-
metric allylation7 using titanium complex (R,R)-I oxopentyl)-5,6-dihydro-2H-pyran-2-one and its (6S)-
(Figure 2) and allyltributyltin to form the homoallylic al- enantiomer involving some simple steps including
cohol (S)-3. The subsequent conversion of this homoallyl- Maruoka asymmetric allylation and ring-closing metathe-
ic alcohol (S)-3 into (S)-1 was completed by following a sis.
similar sequence of reactions to that used for conversion
O
O
Oi-Pr
i-PrO
O
O
Ti
Ti
O
O
O
O
Ti
O
O
Ti
i-PrO
Oi-Pr
(S,S)-I
(R,R)-I
PCy3
Ru
Cl
Cl
Ph
PCy
Grubbs I catalyst
Figure 2
Synthesis 2012, 44, 469–473
© Thieme Stuttgart · New York

PAPER
6-(R)-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one
471
TLC used silica gel F254 plates and the spots were examined under
UV light and then developed by an iodine vapor. Column chroma-
tography was performed with silica gel (BDH 100–200 mesh). Sol-
vents were purified according to standard procedures. The spectra
were recorded with the following instruments; IR: Perkin-Elmer
RX FT-IR spectrophotometer; NMR: Varian Gemini 200 MHz (1H)
and 50 MHz (13C) spectrometer; ESIMS: VG-Autospec micromass.
Organic extracts were dried over anhyd Na2SO4. Optical rotations
were measured with Jasco DIP 300 digital polarimeter at 25 °C.
[6-(Benzyloxy)hexan-2-yloxy)tert-butyldiphenylsilane (8)
To a stirred soln of 7 (2.40 g, 11.54 mmol) in anhyd CH2Cl2 (25 mL)
were added imidazole (1.57 g, 23.08 mmol), cat. DMAP (0.14 g,
1.15 mmol), and TBDPSCl (3.81 g, 13.85 mmol) at 0 °C to r.t. The
mixture was stirred for 2 h and then diluted with CH2Cl2 (25 mL).
The organic layer was washed with brine (35 mL), and dried (anhyd
Na2SO4). Evaporation of the solvent under reduced pressure fol-
lowed by column chromatography (EtOAc–hexane, 1:9) afforded 8
(4.89 g, 95%) as a yellowish liquid.
IR: 1461, 1428, 1368, 1108 cm–1.
5-(Benzyloxy)pentan-1-ol (5)
1H NMR (200 MHz, CDCl3): d = 7.70–7.61 (m, 4 H), 7.39–7.19 (m,
11 H), 4.43 (s, 2 H), 3.82 (m, 1 H), 3.35 (t, J = 7.0 Hz, 2 H), 1.53–
1.22 (m, 6 H), 1.02 (s, 12 H).
13C NMR (50 MHz, CDCl3): d = 138.7, 135.9, 134.9, 134.4, 129.5,
129.4, 128.3, 127.6, 127.5, 127.4, 72.8, 70.3, 69.5, 39.3, 29.8, 27.2,
23.3, 21.9, 19.4.
To pentane-1,5-diol (4, 2.00 g, 19.23 mmol) was added KOH pellets
(1.08 g, 19.23 mmol) and the mixture was stirred for 5 min. BnBr
(1.64 g, 14.43 mmol) was added in one portion and the mixture was
stirred for 1 h at r.t. When the reaction was complete (TLC), it was
quenched with cold H2O, and the mixture was extracted with EtOAc
(3 × 50 mL). The organic layer was dried (anhyd Na2SO4). Evapo-
ration of the solvents and purification of the residue by column
chromatography (EtOAc–hexane, 3:7) gave pure 5 (2.98 g, 80%) as
a colorless liquid.
MS (ESI): m/z = 469 [M + Na]+.
Anal. Calcd for C29H38O2Si: C, 77.98; H, 8.57; Si, 6.29. Found: C,
78.01; H, 8.62; Si, 6.23%.
IR: 3417, 1635, 1453, 1362, 1209, 1098 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.25 (m, 5 H), 4.46 (s, 2 H),
5-(tert-Butyldiphenylsiloxy)hexan-1-ol (9)
3.58 (t, J = 7.0 Hz, 2 H), 3.44 (t, J = 7.0 Hz, 2 H), 1.66–1.39 (m, 6
A soln of 8 (4.60 g, 10.31 mmol) in EtOAc (45 mL) was mixed with
Pd/C (10% mol) and stirred for 10 h under a H2 atmosphere (3.8
bars). The catalyst was removed by filtration and the solvent was
evaporated to give a residue that was purified by column chroma-
tography (EtOAc–hexane, 4:6) to afford pure 9 (3.56 g, 97%) as
pale-yellow liquid.
H).
13C NMR (50 MHz, CDCl3): d = 138.5, 128.4, 127.6, 127.5, 72.9,
70.3, 62.8, 32.5, 29.5, 22.2.
MS (ESI): m/z = 195 [M + H]+, 222 [M + Na]+.
Anal. Calcd for C12H18O2: C, 74.18; H, 9.35. Found: C, 74.22; H,
9.40.
IR: 3450, 1460, 1427, 1366, 1107 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.72–7.62 (m, 4 H), 7.44–7.32 (m,
6 H), 3.83 (m, 1 H), 3.51 (t, J = 7.0 Hz, 2 H), 1.56–1.24 (m, 6 H),
1.08 (s, 12 H).
13C NMR (50 MHz, CDCl3): d = 136.1, 136.0, 134.9, 134.5, 129.5,
129.4, 127.8, 127.7, 69.5, 39.0, 32.8, 27.0, 23.1, 21.2, 19.3.
6-(Benzyloxy)hexan-2-ol (7)
To a stirred suspension of Celite (5.00 g) in CH2Cl2 (20 mL) was
added a soln of 5 (2.80 g, 14.44 mmol) in CH2Cl2 (30 mL) at r.t. To
this suspension PCC (4.65 g, 21.65 mmol) was added at r.t. After 1
h, the mixture was filtered off through a Celite pad. The filtrate was
concentrated under reduced pressure and the residue was purified
by column chromatography (EtOAc–hexane, 1:9). The purified al-
dehyde 6 (2.63 g, 95%) was directly subjected to Grignard reaction.
MS (ESI): m/z = 379 [M + Na]+.
Anal. Calcd for C22H32O2Si: C, 74.10; H, 9.05; Si, 7.88. Found: C,
74.14; H, 9.08; Si, 7.93.
The Grignard reagent was made by slow addition of MeI (4.81 g,
33.85 mmol) to small pieces of Mg metal (0.82 g, 33.85 mmol) in a
2-necked round-bottom flask containing anhyd Et2O (30 mL). The
flask was fitted with a reflux condenser. The mixture was stirred un-
til the soln became ash color. The soln of aldehyde 6 (2.60 g, 13.54
mmol) in anhyd Et2O (20 mL) was added dropwise to the freshly
prepared Grignard reagent at 0 °C. The mixture was stirred for 2 h
at 0 °C to r.t. and the reaction was quenched with aq sat. NH4Cl soln
(25 mL). The aqueous layer was extracted with Et2O (3 × 25 mL)
and the combined organic layers were washed with brine soln (20
mL), dried (anhyd Na2SO4), and concentrated in vacuo. The residue
was purified by column chromatography (EtOAc–hexane, 2:8) to
afford 7 (2.56 g, 92%) as a colorless liquid.
5-(tert-Butyldiphenylsiloxy)hexanal (10)
To a stirred suspension of Celite (2.00 g) in CH2Cl2 (20 mL) was
added a soln of 9 (1.50 g, 4.21 mmol) in CH2Cl2 (20 mL) at r.t. To
this suspension PCC (1.36 g, 6.32 mmol) was added r.t. After 1 h,
the mixture was filtered off through a Celite pad. The filtrate was
concentrated under reduced pressure and the residue was purified
by column chromatography (EtOAc–hexane, 1:9) to give purified
10 (1.40 g, 94%) as a pale-yellow liquid.
IR: 3450, 1460, 1427, 1366, 1107 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.61 (s, 1 H), 7.68–7.60 (m, 4 H),
7.44–7.30 (m, 6 H), 3.84 (m, 1 H), 2.25 (t, J = 7.0 Hz, 2 H), 1.67–
1.55 (m, 2 H), 1.50–1.38 (m, 2 H), 1.08 (s, 12 H).
13C NMR (50 MHz, CDCl3): d = 202.2, 136.0, 135.9, 134.9, 134.7,
130.1, 130.0, 128.2, 128.1, 69.4, 44.6, 39.2, 27.1, 23.2, 19.9, 18.4.
IR: 3367, 1642, 1453, 1360, 1215, 1091 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.35–7.25 (m, 5 H), 4.46 (s, 2 H),
3.75 (m, 1 H), 3.46 (t, J = 7.0 Hz, 2 H), 1.68–1.41 (m, 6 H), 1.16 (d,
J = 7.0 Hz, 3 H).
MS (ESI): m/z = 377 [M + Na]+
13C NMR (50 MHz, CDCl3): d = 138.5, 128.3, 127.6, 127.5, 72.9,
70.2, 67.9, 39.1, 29.7, 23.6, 22.5.
(R)-8-(tert-Butyldiphenylsiloxy)non-1-en-4-ol [(R)-3]; Typical
Procedure
To a stirred soln of TiCl4 (0.10 g, 0.34 mmol) in CH2Cl2 (10 mL)
was added dried Ti(Oi-Pr)4 (0.03 g, 0.19 mmol) at 0 °C under a N2
atmosphere and the mixture was allowed to warm to r.t. After 1.5 h,
Ag2O (0.08 g, 0.34 mmol) was added and the reaction was contin-
ued for 6 h under exclusion of direct light. The mixture was diluted
with CH2Cl2 (20 mL), treated with (S)-BINOL (0.19 g, 0.68 mmol)
at r.t. for 2.5 h to furnish the chiral bis-Ti(IV) oxide (S,S)-I. This
MS (ESI): m/z = 209 [M + H]+, 231 [M + Na]+.
Anal. Calcd for C13H20O2: C, 74.94; H, 9.65. Found: C, 74.99; H,
9.74.
© Thieme Stuttgart · New York
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472
D. B. Shinde et al.
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(R)-8-Hydroxynon-1-en-4-yl Acrylate [(R)-2]; Typical Proce-
complex was cooled to –15 °C and treated sequentially with 10
(1.20 g, 3.40 mmol) and allyltributyltin (1.46 g, 4.42 mmol) at the
same temperature. The mixture was allowed to warm to 0 °C and
stirred for 15 h. The mixture was quenched with sat. aq NaHCO3 (50
mL) and extracted with EtOAc (3 × 20 mL). The combined organic
extracts were dried (anhyd Na2SO4). Evaporation of the solvents
and purification of the residue by column chromatography (EtOAc–
hexane, 2:8) gave pure (R)-3 (1.12 g, 84%) as a colorless liquid;
[a]D32 +3.36 (c 0.6, CHCl3).
dure
To a soln of (R)-11 (0.80 g, 1.77 mmol) in anhyd THF (10 mL) was
added 1 M TBAF in THF (3.55 mL, 3.55 mmol) dropwise at 0 °C
and the mixture was stirred for 3 h. H2O (20 mL) was added and the
mixture was extracted with EtOAc (3 × 20 mL). The organic ex-
tracts were washed with brine (30 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. Evaporation of the solvents and purification
of the residue by column chromatography (EtOAc–hexane, 3:7)
gave pure (R)-2 (1.12 g, 80%) as a colorless liquid; [a]D32 +21.75 (c
0.4, CHCl3).
IR: 3382, 1466, 1428, 1108, cm–1.
1H NMR (200 MHz, CDCl3): d = 7.71–7.59 (m, 4 H), 7.41–7.28 (m,
6 H), 5.72 (m, 1 H), 5.14–5.03 (m, 2 H), 3.82 (m, 1 H), 3.50 (m, 1
H), 2.25–1.98 (m, 2 H), 1.52–1.22 (m, 6 H), 1.04 (m, 12 H).
13C NMR (50 MHz, CDCl3): d = 136.0, 135.9, 134.9, 134.8, 134.5,
129.4, 127.5, 127.4, 118.9, 70.4, 69.5, 69.4*, 42.0, 41.9*, 39.4,
39.3*, 36.8, 36.7*, 27.2, 23.5, 23.4*, 21.4, 21.3*, 19.4; * signal for
the diastereomer.
IR: 3448, 1713, 1632, 1412, 1201 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.39 (dd, J = 14.0, 2.0 Hz, 1 H),
6.06 (m, 1 H), 5.85–5.66 (m, 2 H), 5.10–4.93 (m, 3 H), 3.70 (m, 1
H), 2.33 (t, J = 7.0 Hz, 2 H), 1.64–1.24 (m, 6 H), 1.14 (d, J = 7.0 Hz,
3 H).
13C NMR (50 MHz, CDCl3): d = 166.2, 133.3, 130.6, 128.5, 117.9,
73.5, 68.1, 68.0*, 39.1, 39.0, 38.9* , 33.8, 23.5, 23.4*, 21.9; * signal
for the diastereomer.
MS (ESI): m/z = 397 [M + H]+, 419 [M + Na]+.
Anal. Calcd for C25H36O2Si: C, 75.70; H, 9.15. Found: C, 75.74; H,
9.17.
MS (ESI): m/z = 235 [M + Na]+.
Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C, 67.93; H,
9.54.
(S)-8-(tert-Butyldiphenylsiloxy)non-1-en-4-ol [(S)-3]
Following the typical procedure for (R)-3 using TiCl4 (0.10 g, 0.34
mmol) in CH2Cl2 (10 mL), dried Ti(Oi-Pr)4 (0.03 g, 0.19 mmol),
Ag2O (0.08 g, 0.34 mmol), CH2Cl2 (20 mL), and (R)-BINOL (0.19
g, 0.68 mmol) to give chiral bis-Ti(IV) oxide (R,R)-I, which was re-
acted with 10 (1.20 g, 3.40 mmol) and allyltributyltin (1.46 g, 4.42
mmol) and purified in the same manner to give (S)-3 (1.12 g, 84%)
as a colorless liquid; [a]D32 –3.17 (c 0.6, CHCl3). Spectral data (1H,
13C NMR and MS) were identical to those of (R)-3.
(S)-8-Hydroxynon-1-en-4-yl Acrylate [(S)-2]
Following the typical procedure for (R)-2 using (S)-11 (0.80 g, 1.77
mmol), THF (10 mL), and 1 M TBAF in THF (3.55 mL, 3.55 mmol)
gave pure (S)-2 (1.12 g, 80%) as a colorless liquid; [a]D32 –21.58 (c
0.4, CHCl3). Spectral data (1H, 13C NMR and MS) were identical to
those of (R)-2.
(R)-8-Oxonon-1-en-4-yl Acrylate [(R)-12]; Typical Procedure
To a stirred suspension of Celite (1.00 g) in CH2Cl2 (5 mL) was add-
ed a soln of (R)-2 (0.25 g, 1.18 mmol) in CH2Cl2 (10 mL) at r.t. To
this suspension PCC (0.51 g, 2.36 mmol) was added at 0 °C and the
mixture was warmed to r.t. After 1 h, the mixture was filtered off
through a Celite pad. The filtrate was concentrated under reduced
pressure and the residue was purified by column chromatography
(EtOAc–hexane, 2:8) to give (R)-12 (0.22 g, 90%) as a colorless liq-
uid; [a]D32 +15.12 (c 1.25, CHCl3).
(R)-8-(tert-Butyldiphenylsiloxy)non-1-en-4-yl Acrylate [(R)-
11]; Typical Procedure
To a stirred soln of (R)-3 (1.00 g, 2.53 mmol) in anhyd CH2Cl2 (15
mL) were added, at 0 °C, Et3N (0.64 g, 6.33 mmol) and cat. DMAP
(0.03 g, 0.25 mmol). After 10 min, acryloyl chloride (0.27 g, 3.03
mmol) was added. The mixture was allowed to warm to r.t. and
stirred for 3 h. The mixture was diluted with H2O (20 mL) and ex-
tracted into CH2Cl2 (3 × 20 mL). The combined organic extracts
were washed with brine (10 mL), dried (anhyd Na2SO4), and con-
centrated in vacuo. The gummy mass was purified by column chro-
matography (EtOAc–hexane, 1:9) to afford pure (R)-11 (0.99 g,
88%) as a yellow liquid; [a]D32 +7.87 (c 1.5, CHCl3).
IR: 1719, 1639, 1407, 1196 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.39 (dd, J = 14.0, 2.0 Hz, 1 H),
6.07 (m, 1 H), 5.84–5.62 (m, 2 H), 5.11–5.01 (m, 2 H), 4.92 (m, 1
H), 2–48–2.36 (m, 2 H), 2.32 (t, J = 7.0 Hz, 2 H), 2.09 (s, 3 H),
1.62–1.52 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 208.7, 165.4, 134.9, 130.2, 127.8,
117.5, 73.1, 43.2, 38.4, 32.0, 26.6, 18.3.
IR: 3446, 2932, 2858, 1723, 1638, 1466, 1194, 1108, 1054 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.67–7.62 (m, 4 H), 7.40–7.30 (m,
6 H), 6.37 (dd, J = 8.0, 3.0 Hz, 1 H), 6.06 (m, 1 H), 5.79–5.66 (m, 2
H), 5.09–5.02 (m, 2 H), 4.92 (m, 1 H), 3.81 (m, 1 H), 2.28 (t, J = 7.0
Hz, 2 H), 1.52–1.26 (m, 6 H), 1.04 (s, 12 H).
MS (ESI): m/z = 233 [M + Na]+.
13C NMR (50 MHz, CDCl3): d = 165.8, 135.8, 135.7, 134.8, 134.4,
133.6, 130.3, 129.5, 129.4, 128.8, 127.5, 127.4, 117.6, 73.4, 69.3,
69.2*, 39.2, 39.1*, 38.5, 38.4*, 33.5, 27.0, 23.2, 23.1*, 21.1, 20.8*,
19.2; * signal for the diastereomer.
Anal. Calcd for C12H18O3: C, 68.54; H, 6.63. Found: C, 68.58; H,
6.66.
(S)-8-Oxonon-1-en-4-yl Acrylate [(S)-12]
Following the typical procedure for (R)-12 using Celite (1.00 g) in
CH2Cl2 (5 mL), (S)-2 (0.25 g, 1.18 mmol) in CH2Cl2 (10 mL), and
PCC (0.51 g, 2.36 mmol) gave (S)-12 (0.22 g, 90%) as a colorless
MS (ESI): m/z = 473 [M + Na]+.
Anal. Calcd for C28H38O3Si: C, 74.63; H, 8.51; Si, 6.23. Found: C,
74.66; H, 8.54; Si, 6.26.
32
liquid; [a]D –15.03 (c 1.25, CHCl3). Spectral data (1H, 13C NMR
and MS) were identical to those of (R)-12.
(S)-8-(tert-Butyldiphenylsiloxy)non-1-en-4-yl Acrylate [(S)-11]
Following the typical procedure for (R)-11 using (S)-3 (1.00 g, 2.53
mmol), CH2Cl2 (15 mL), Et3N (0.64 g, 6.33 mmol), cat. DMAP
(0.03g, 0.25 mmol), and acryloyl chloride (0.27 g, 3.03 mmol) gave
(6R)-6-(4-Oxopentyl)-5,6-dihydropyran-2-one [(R)-1]; Typical
Procedure
To a stirred soln of Grubbs I catalyst (10 mol%) in anhyd CH2Cl2
(100 mL) at 55 °C was added (R)-12 (100 mg, 0.48 mmol) dissolved
in CH2Cl2 (50 mL). The resulting mixture was heated for 14 h. After
completion of the reaction, the contents were cooled and the solvent
32
pure (S)-11 (0.99 g, 88%) as a yellow liquid; [a]D –7.66 (c 1.5,
CHCl3). Spectral data (1H, 13C NMR and MS) were identical to
those of (R)-11.
Synthesis 2012, 44, 469–473
© Thieme Stuttgart · New York

PAPER
6-(R)-(4-Oxopentyl)-5,6-dihydro-2H-pyran-2-one
473
was removed under reduced pressure to yield a crude product,
which was purified by column chromatography (silica gel, EtOAc–
hexane, 2:8) to afford pure (R)-1 (75 mg, 86%) as a colorless liquid;
[a]D32 –89.05 (c 0.1, CHCl3).
References
(1) Part 52 in the series, ‘Synthetic Studies on Natural Products’.
(2) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94. (b) Sam, T. W.; Yeu, C. S.; Jodynis-
Liebert, J.; Murias, M.; Bloszyk, E. Planta Med. 2000, 66,
199. (c) Antonio, M. A.; de Carvalho, J. E.; Pillia, R. A.
Bioorg. Med. Chem. 2005, 13, 2927.
(3) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
2007, 63, 2929.
(4) Maxwell, A.; Dabideen, D.; Reynolds, W. F.; McLean, S.
IR: 1713, 1691, 1628, 1380, 1251 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.94, (m, 1 H), 5.99 (d, J = 10.0,
2.0 Hz, 1 H), 4.40 (m, 1 H), 2.49 (t, J = 7.0 Hz, 2 H), 2.38–2.25 (m,
2 H), 2.13 (s, 3 H), 1.81–160 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 208.4, 164.6, 144.9, 120.4, 76.8,
42.5, 33.8, 29.7, 28.8, 19.2.
J. Nat. Prod. 1998, 61, 815.
MS (ESI): m/z = 183 [M + H]+.
(5) (a) Kretschmer, M.; Menche, D. Synlett 2010, 2989.
(b) Yadav, J. S.; Pandurangam, T.; Reddy, V. V. B.; Reddy,
B. V. S. Synthesis 2010, 4300. (c) Ghosh, A. K.; Dawson, Z.
L. Synthesis 2009, 2992. (d) Shibahara, S.; Fujino, M.;
Tashiro, Y.; Okamoto, N.; Esumi, T.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Synthesis 2009, 2935.
(6) (a) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D.
N. Bioorg. Med. Chem. Lett. 2009, 19, 6396. (b) Das, B.;
Suneel, K.; Satyalakshmi, G. Tetrahedron: Asymmetry
2009, 20, 1536. (c) Das, B.; Veeranjaneyulu, B.;
Balasubramanyam, P.; Srilatha, M. Tetrahedron:
Asymmetry 2010, 21, 2762. (d) Das, B.; Nagendra, S.;
Reddy, C. R. Tetrahedron: Asymmetry 2011, 22, 1249.
(7) (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 1708. (b) Das, B.; Shinde, D. B.; Kanth, B.
S.; Kamle, A.; Kumar, C. G. Eur. J. Med. Chem. 2011, 46,
3124.
Anal. Calcd for C10H14O3: C, 65.90; H, 7.75. Found: C, 65.93; H,
7.79.
(6S)-6-(4-Oxopentyl)-5,6-dihydropyran-2-one [(S)-1]
Following the typical procedure for (R)-1 using Grubbs I catalyst
(10 mol%) in anhyd CH2Cl2 (100 mL) and (S)-12 (100 mg, 0.48
mmol) in CH2Cl2 (50 mL) gave pure (S)-1 (75 mg, 86%) as a color-
32
less liquid; [a]D +88.25 (c 0.1, CHCl3). Spectral data (1H, 13C
NMR and MS) were identical to those of (R)-1.
Acknowledgement
The authors thank CSIR and UGC, New Delhi for financial assi-
stance.
(8) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (c) Grubbs, R. H. Tetrahedron 2004, 60,
7117.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 469–473