Simple stereoselective synthesis of unsaturated lactone intermediates and their conversion into natural dihydropyranones and their enantiomers#

Article abstract of DOI:10.2174/1570178611310050003

The stereoselective synthesis of the unsaturated lactone intermediates, (S) - and (R)-2-(6-oxo-3, 6-dihydro-2Hpyran-2-yl) acetaldehydes has been accomplished from propane 1,3 diol employing Maruoka asymmetric allylation and ring closing metathesis reaction. The intermediates were converted into two natural dihydropyranones, 6 (R)-4-oxopent-2-enyl 5,6-dihydro-2H-pyran-2-one and (R)- rugulactone and their enantiomers through Wittig olefination.

Full text of DOI:10.2174/1570178611310050003

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Letters in Organic Chemistry, 2013, 10, 317-323
317
Simple Stereoselective Synthesis of Unsaturated Lactone Intermediates
and Their Conversion into Natural Dihydropyranones and Their
Enantiomers#
Digambar Balaji Shindea, Boddu Shashi Kantha, Avula Satyakumara, V.T. Kambleb and Biswanath Dasa*
aNatural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India;
bOrganic Chemistry Research Laboratory, School of Chemical Sciences, SRTMU, Nanded-431606, Maharashtra, India
Received January 31, 2013: Revised April 08, 2013: Accepted April 22, 2013
Abstract: The stereoselective synthesis of the unsaturated lactone intermediates, (S) - and (R)-2-(6-oxo-3, 6-dihydro-2H-
pyran-2-yl) acetaldehydes has been accomplished from propane 1,3 diol employing Maruoka asymmetric allylation and
ring closing metathesis reaction. The intermediates were converted into two natural dihydropyranones, 6 (R)-4-oxopent-2-
enyl 5,6-dihydro-2H-pyran-2-one and (R)- rugulactone and their enantiomers through Wittig olefination.
Keywords: Lactone intermediates, Wittig olefination, maruoka asymmetric allylation, 6 -(R)-4-oxopent-2-enyl 5,6-dihydro-
2H-pyran-2-one, (R)- rugulactone, enantiomer.
INTRODUCTION
and 7a respectively which can be produced from propane 1,3
diol (9) via the allylic alcohols 8 (for 1) and 8a (for 1a).
The compounds containing 5,6-dihydro-2H-pyran-2-one
unit have been isolated from plants and marine organisms
[1]. These compounds are known to possess a broad range of
biological activities including cytotoxic, antibacterial and
antifungal properties [2]. They act as excellent Michael ac-
ceptors for nucleophilic amino acid residues of the natural
receptor [3]. Due to interesting structural pattern and impor-
tant biological activities these compounds are attractive tar-
get to the total synthesis [4].
The synthesis of 1 was initiated with propane 1,3-diol (9)
which was converted into monobenzyl ether 10 by using
benzyl bromide and KOH [12] (Scheme 2). The primary
hydroxy group of 10 was oxidized with pyridinium chloro-
chromate (PCC) to the corresponding aldehyde which was
converted [13] to the homoallyl alcohol 8 with a high enanti-
oselectivity (ee 97%) through Maruoka allylation [14] using
allyl (tributyl) tin and titanium complex (S, S-1). Compound
8 was esterified with acryloyl chloride in the presence of
triethyl amine and catalytic amount of DMAP to give the
acryloyl ester 7. The ring closing metathesis [15] (RCM) of
7 was successfully accomplished by using Grubbs 1st genera-
tion catalyst to produce the unsaturated lactone 11. The de-
benzylation of 11 was achieved [16] by treatment with tita-
nium tetrachloride (TiCl4) to furnish the alcohol 12. This
alcohol 12 was then oxidized with iodobenzoic acid (IBX) to
form the corresponding aldehyde 1 which was directly used
for further conversion into natural dihydropyranones.
As a part of our ongoing program [5] on the synthesis of
naturally occurring bioactive compounds we realized to dis-
cover a simple synthesis of an intermediate 1 [(S)-2-(6-oxo-
3,6-dihydro-2H-pyran-2-yl)acetaldehyde] which can be con-
verted into different natural dihydropyranone derivatives
such as dodoneine [6] (2), 6 (R)-[4-oxopent-2-enyl] 5,6-
dihydro-2H-pyran-2-one [7] (3), (R)- rugulactone [8] (4), (-)-
tarconanthus lactone [9] (5), and (6S)-5,6-dihydro-6-[(2R)-2-
hydroxy-6-phenylhexyl]-2H-pyran-2-one [10] (6) and others
(Fig. 1). The enantiomer 1a of the intermediate 1 can gener-
ate the enantiomers of these natural products. Here we report
a simple synthesis of the intermediates 1 and 1a and their
conversion into naturally occurring dihydropyranones 3 and
4 and their enantiomeric analogs. Compound 3 was isolated
[7] from Piper reticulactum while compound 4 from Crypto-
carya rugulosa [8]. The latter inhibits constituents NF-ꢀB
activity in human lymphoma cell lines [11].
The C-6 enantiomer 1a of the intermediate 1 was also
synthesized from the compound 10 prepared from propane
1,3-diol (9) (Scheme 2). Oxidation of the compound 10 to
the corresponding aldehyde was achieved using pyridinium
chlorochromate (PCC) and the aldehyde was then converted
[13] to the homoallyl alcohol 8a with high enantioselectivity
(ee 97%) through Maruoka allylation [14] using allyl (tribu-
tyl) tin and titanium complex (R, R-1). The subsequent con-
version of this homoallylic alcohol 8a into the intermediate
1a was completed by following the same sequence of reac-
tion as carried out above for conversion of the enantiomeric
homoallylic alcohol 8 into the intermediate 1 (i.e., acrylation
with acryloyl chloride to form 10a, and ring closing metathe-
sis [15] to produce 11a followed by debenzylation [16] to
give alcohol 12a and finally oxidation to generate 1a).
RESULTS AND DISCUSSION
Our retrosynthetic study (Scheme 1) depicts that the
compounds 1 and 1a can be prepared from olefinic esters 7
*Address correspondence to this author at the Natural Product Chemistry
Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-
500007, India; Tel: +91 40 27191234; Fax: +91 40 27193198;
E-mail: biswanathdas@yahoo.com
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

318 Letters in Organic Chemistry, 2013, Vol. 10, No. 5
Shinde et al.
O
O
O
OH
O
O
2
OH
3
O
O
O
O
O
1
O
O
O
OH
4
6
O
O
O
OH
5
OH
OH
Fig. (1). Structures of naturally occurring dihydropyranones.
O
O
1
O
3
O
1
HO
OH
1
4
OBn
3
OBn
6
O
9
1
: 6 (S)
1a : 6 (R)
7
: 3 (S)
7a : 3 (R)
8
: 3 (S)
8a : 3 (R)
Scheme 1. Retrosynthetic analysis of 1 and 1a.
The intermediates 1 and 1a were then separately sub-
ond report [18a] of the total synthesis of 3 (Scheme 3). For
preparation of the other natural product dihydropyranone
derivative, rugulactone 4 and its enantiomer 4a the 1-
triphenylphosphoranylidene -4-phenylbutan-2-one (17) was
synthesized from bromomethylbenzene (13) (Scheme 4).
jected to Wittig olefination [17] with 1-
triphenylphosphoranylidene -2-propanone (commercially
available) to afford the natural dihydropyranones, 6- (R)-[4-
oxopent-2-enyl] 5, 6-dihydro-2H-pyran-2-one (3) and its
enantiomer (3a) respectively in good yields. This is the sec-
The latter was treated with acetyl acetone (14) using
OH
a
b
c
HO
OH
HO
O
OBn
OBn
8
: 3 (S)
10
9
8a : 3 (R)
O
O
O
e
f
O
d
O
O
O
OH
OBn
OiPr
OBn
O
12 : 6 (S)
12a : 6 (R)
1
: 6 (S)
7
: 3 (S)
11 : 6 (S)
11a : 6 (R)
1a : 6 (R)
7a : 3 (R)
PCy3
O
O
OiPr
Ti
Cl
Ti
O
O
Ru
O
O
O
O
Ti
Ti
Ph
iPrO
iPrO
Cl
O
O
PCy3
Grubbs'1st generation catalyst
(R, R)-1
(S, S)-1
Scheme 2. Synthesis of 1 and 1a.
Reagents, conditions and yields: a) BnBr, KOH r.t., 1 h, 80%, b) i. PCC, Celite, CH2Cl2, r.t., 1 h, 95 %, ii. [(S,S)-1, 10 mol %, for 8],
[(R,R)-1, 10 mol %, for 8a], Bu3SnCH2-CH=CH2, CH2Cl2, -15 °C to 0 °C, 15 h, 82 %, c) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to
r.t., 30 min 96%, d) Grubbs’ 1st generation catalyst, CH2Cl2, 50 °C, 24 h, 85% e) TiCl4, CH2Cl2, 0 °C to r.t., 1 h, 89%, f) IBX, DMSO, r.t., 5
h.

Simple Stereoselective Synthesis of Unsaturated Lactone Intermediates
Letters in Organic Chemistry, 2013, Vol. 10, No. 5
319
O
O
O
O
O
O
O
j
i
O
O
3
: 6 (R)
1
: 6 (S)
4
: 6 (R)
3a : 6 (S)
1a : 6 (R)
4a : 6 (S)
Scheme 3. Synthesis of 3, 3a, 4 and 4a.
Reagents, conditions and yields: i) CH3COCH=PPh3, C6H6, reflux, 10 h, 80 %, j) PhCH2CH2COCH=PPh3, C6H6, reflux, 14 h, 72 %.
O
O
O
PPh3
Br
O
O
ref 18
Br
g, h
ref 18
+
16
17
15
13
14
Scheme 4. Synthesis of 17.
Reagents, conditions and yields: g) PPh3, benzene, reflux, 85% 24 h; h) 1 % NaOH, CH2Cl2, r.t., 1 h, 78%.
methanolic K2CO3 to afford the keto compound 15 which on
bromination with bromine in MeOH produced bromo com-
pound 16 [19]. The bromo compound 16 was subsequently
treated with triphenylphosphine (PPh3) to yield the required
1-triphenylphosphoranylidene -4-phenylbutan-2-one (17)
[20]. The intermediate 1 and 1a were then separately treated
with the phosphorane 17 to yield rugulactone (4) (Scheme 3)
and its enantiomer (4a) respectively. The synthesis of rugu-
lactone was reported earlier [13-18] but the present method
constitutes an easy access to this molecule.
ganic layer was separated, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by using column
chromatography (ethyl acetate / hexane, 3: 7) to afford pure
3-(benzyloxy)propan-1-ol (10) (7.07 g, 80%) as a colorless
1
liquid. IR: 3410, 1493, 1465, 1363, 1210 cm-1; H NMR
(CDCl3, 200 MHz): ꢁ 7.38-7.22 (5H, m), 4.48 (2H, s), 3.69
(2H, t, J = 7.0 Hz), 3.58 (2H, t, J = 7.0 Hz), 2.96 (1H, brs),
1.89-1.78 (2H, m); 13C NMR (CDCl3, 50 MHz): ꢁ 138.0,
128.0, 127.2, 72.8, 67.9, 59.9, 32.1; EIMS: m/z 167 [M+H]+..
(S)-1-(benzyloxy)hex-5-en-3-ol (8)
CONCLUSION
A solution of compound 10 (3.00 g, 18.07 mmol) in
DCM (40 mL) was added slowly to a suspension of celite
(6.00 g) in DCM (30 mL) at room temperature. To this sus-
pension pyridinium chlorochromate (PCC) (5.76 g, 26.76
mmol) was added at 0 °C and the reaction was kept at room
temperature where the reaction was stirred for 1 h. Celite pad
filtration followed by concentration of the filtrate provided a
residue that was purified by column chromatography (1:9).
The purified aldehyde (2.82 g, 95%) was directly subjected
to allylation.
In conclusion, we have developed a simple stereoselec-
tive synthesis of two isomeric ꢀ, ꢁ-unsaturated ꢂ-lactone
intermediates and converted them into two naturally occur-
ring dihydropyranones, 6- (R)-[4-oxopent-2-enyl] 5,6-
dihydro-2H-pyran-2-one and (R)- rugulactone and their
enantiomers. The present synthetic method can also be util-
ized for the preparation of several other related bioactive
natural dihydropyranones.
Ti(OiPr)4 (0.65 g, 2.29 mmol) was added to a solution of
TiCl4 (0.14 g, 0.76 mmol) in DCM (15 mL) at 0 °C under N2
environment and the mixture was warmed to room tempera-
ture and stirred for 1.5 h. Silver (I) oxide (0.35 g, 1.52
mmol) was then added and the reaction was stirred for 6 h
prohibiting direct light. Later DCM (40 mL) followed by (S)-
BINOL (0.86 g, 3.05 mmol) were added to reaction mixture
at room temperature and the reaction was allowed to stir for
2.5 h to give the chiral bis-Ti(IV) oxide (S, S)-1. The result-
ing complex was cooled to -15 oC to which aldehyde (2.50 g,
15.24 mmol) followed by allyltributyltin (6.58 g, 19.81
mmol) were added. The reaction was allowed to warm to 0
oC and was further stirred for 15 h. The reaction was
quenched by adding saturated aqueous NaHCO3 (50 mL) and
the mixture was extracted with EtOAc (3 ꢀ 30 mL). The
combined organic layer were separated and dried over anhy-
drous Na2SO4. Solvent was evaporated under reduced pres-
sure and the crude product was purified by column chroma-
tography (ethyl acetate / hexane, 1: 9) to afford pure (S)-1-
(benzyloxy) hex-5-en-3-ol (8) (2.57 g, 82 %, ee 97%) as a
colorless liquid. The optical rotation of the compound was
EXPERIMENTAL
General Procedures
The spectra were recorded with the following instru-
ments; IR: Perkin Elmer RX1 FT-IR spectrophotometers.
NMR: Varian Gemini 200 MHz, Bruker 300 MHz (1H) and
50 MHz (13C) spectrometer; ESI-MS; VG-Autospec micro-
mass. Optical rotations were recorded on Jasco Dip 360 digi-
tal polarimeter. The column chromatography was performed
using silica gel (BDH 100-200 Mesh) and TLC with silica
gel GF254 precoated plates.
3-(benzyloxy)propan-1-ol (10)
Propane 1,3-diol (9) (4.00 g, 52.63 mmol) and KOH pel-
lets (3.03 g, 52.63 mmol) were stirred for 5 min. Benzyl
bromide (4.50 g, 26.32 mmol) was added in one portion and
the resulting mixture was stirred at room temperature for 1 h.
After completion of the reaction as indicated by TLC, cold
water (10 mL) was added in the reaction mixture and mix-
ture was extracted with ethyl acetate (3 ꢀ 100 mL). The or-

320 Letters in Organic Chemistry, 2013, Vol. 10, No. 5
Shinde et al.
1
[ꢀ]D32 = - 2.6 (c = 1.0, CHCl3); IR: 3444, 1640, 1492, 1451,
CHCl3); IR: 1713, 1640, 1492, 1451, 1363, 1207 cm-1; H
1
1363, 1207 cm-1; H NMR (CDCl3, 200 MHz): ꢁ 7.38-7.22
NMR (CDCl3, 200 MHz): ꢁ 7.32-7.19 (5H, m), 6.38 (1H, d,
J = 16.0 Hz ), 6.03 (1H, m), 5.80-5.71 (2H, m), 5.15 (1H,
m), 5.04 (1H, m), 4.42 (2H, s), 4.10 (1H, m), 3.51-3.42 (2H,
m), 2.41-2.31 (2H, m), 1.92-1.80 (2H, m); 13C NMR (CDCl3,
50 MHz): ꢁ 185.0, 157.9, 152.8, 150.0, 148.1, 147.8, 146.8,
137.3, 92.2, 90.0, 85.9, 58.1, 53.0; ESIMS: m/z 261
[M+H]+..
(5H, m), 5.79 (1H, m), 5.11-5.02 (2H, m), 4.50 (2H, s), 3.82
(1H, m), 3.73-3.54 (2H, m), 2.71 (1H, brs), 2.21 (2H, t, J =
7.0 Hz ), 1.77-1.66 (2H, m); 13C NMR (CDCl3, 50 MHz): ꢁ
138.1, 135.0, 128.4, 127.9, 127.8, 118.0, 73.5, 70.5, 69.0,
42.2, 36.0; ESIMS: m/z 229 [M+Na]+..
(R)-1-(benzyloxy)hex-5-en-3-ol (8a)
(R)-1-(benzyloxy) hex-5-en-3-yl acrylate (7a)
A solution of compound 10 (3.00 g, 18.07 mmol) in
DCM (40 mL) was added slowly to a suspension of celite
(6.00 g) in DCM (30 mL) at room temperature. To this sus-
pension pyridinium chlorochromate (PCC) (5.76 g, 26.76
mmol) was added at 0 °C and the reaction was kept at room
temperature where the reaction was stirred for 1 h. Celite pad
filtration followed by concentration of the filtrate provided a
residue that was purified by column chromatography (1:9).
The purified aldehyde (2.82 g, 95%) was directly subjected
to allylation.
Et3N (1.96 g, 19.42 mmol) and DMAP (0.12 g, 0.97
mmol) were added slowly to a solution of compound 8a
(2.00 g, 9.71 mmol) in DCM (20 mL) at 0 °C and the mix-
ture was stirred for 10 min. Acryloyl chloride (1.05 g, 11.65
mmol) was added and the reaction was brought to room tem-
perature and stirred for 3 h. After the completion of reaction,
water (20 mL) was added and the mixture was extracted with
DCM (3 ꢂ 30 mL). The organic layer was washed with brine
(15 mL), dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the gummy mixture
was purified by using column chromatography (ethyl ace-
tate/hexane, 1:9) which afforded pure (R)-1-(benzyloxy) hex-
5-en-3-yl acrylate (7a) (2.42 g, 96%) as a yellow liquid. The
Ti(OiPr)4 (0.65 g, 2.29 mmol) was added to a solution of
TiCl4 (0.14 g, 0.76 mmol) in DCM (15 mL) at 0 °C under N2
environment and the mixture was warmed to room tempera-
ture and stirred for 1.5 h. Silver (I) oxide (0.35 g, 1.52
mmol) was then added and the reaction was stirred for 6 h
prohibiting direct light. Later DCM (40 mL) followed by
(R)-BINOL (0.86 g, 3.05 mmol) were added to reaction mix-
ture at room temperature and the reaction was allowed to stir
for 2.5 h to give the chiral bis-Ti(IV) oxide (R, R)-1. The
32
optical rotation of compound was [ꢀ]D = + 22.1 (c = 0.7,
CHCl3). The spectral data (proton NMR, carbon NMR and
MS) of 7a were found to be identical as those of 7.
(S)-6-(2-(benzyloxy)ethyl)-5,6-dihydropyran-2-one (11)
o
resulting complex was cooled to -15 C to which aldehyde
A solution of compound 7 (2.00 g, 7.69 mmol) dissolved
in DCM (150 mL) was added slowly to a solution of Grubbs’
catalyst (1st generation, 5 mol %) in dry DCM (100 mL) and
was stirred at 55 °C for 12 h. After completion of the reac-
tion, the contents were cooled and the solvent was evapo-
rated under reduced pressure. The resulting crude residue
was subjected to column chromatography (ethyl ace-
tate/hexane, 2:8) to give pure (S)-6-(2-(benzyloxy)ethyl)-5,6-
dihydropyran-2-one (11) (1.47 g, 85%) as a colorless liquid.
(2.50 g, 15.24 mmol) followed by allyltributyltin (6.58 g,
19.81 mmol) were added. The reaction was allowed to warm
to 0 o C and was further stirred for 15 h. The reaction was
quenched by adding saturated aqueous NaHCO3 (50 mL) and
the mixture was extracted with EtOAc (3 ꢂ 30 mL). The
combined organic layers were separated and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product was purified by column
chromatography (ethyl acetate / hexane, 1: 9) to afford pure
(R)-1-(benzyloxy) hex-5-en-3-ol (8a) (2.57 g, 82 %, ee 97%)
as a colorless liquid. The optical rotation of the compound
was [ꢀ]D32 = + 2.4 (c = 1.0, CHCl3). The spectral data (proton
NMR, carbon NMR and MS) of 8a were found to be identi-
cal as those of 8.
32
The optical rotation of compound was [ꢀ]D = - 32.6 (c =
1.0, CHCl3); IR: 1715, 1640, 1492, 1451, 1363, 1207 cm-1;
1H NMR (CDCl3, 200 MHz): ꢁ 7.38-7.20 (5H, m), 6.83 (1H,
m ), 5.99 (1H, d, J = 9.0 Hz), 4.51 (1H, d, J = 12.0 Hz), 4.43
(1H, d, J = 12.0 Hz), 3.72-3.55 (2H, m), 2.60-2.27 (2H, m),
2.10-1.83 (2H, m); 13C NMR (CDCl3, 50 MHz): ꢁ163.6,
144.3, 128.2, 127.5, 123.9, 121.8, 74.9, 72.8, 65.3, 35.2,
29.8; ESIMS: m/z 255 [M+Na]+..
(S)-1-(benzyloxy)hex-5-en-3-yl acrylate (7)
Et3N (1.96 g, 19.42 mmol) and DMAP (0.12 g, 0.97
mmol) were added slowly to a solution of compound 8 (2.00
g, 9.71 mmol) in DCM (20 mL) at 0 °C and the mixture was
stirred for 10 min. Acryloyl chloride (1.05 g, 11.65 mmol)
was added and the reaction was brought to room temperature
and stirred for 3 h. After the completion of reaction, water
(20 mL) was added and the mixture was extracted with DCM
(3 ꢂ 30 mL). The organic layer was washed with brine (15
mL), dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the gummy mixture was
purified by using column chromatography (ethyl ace-
tate/hexane, 1:9) which afforded pure (S)-1-(benzyloxy) hex-
5-en-3-yl acrylate (7) (2.42 g, 96%) as a yellow liquid. The
(R)-6-(2-(benzyloxy)ethyl)-5,6-dihydropyran-2-one (11a)
A solution of compound 7a (2.00 g, 7.69 mmol) dis-
solved in DCM (150 mL) was added slowly to a solution of
Grubbs’ catalyst (1st generation, 5 mol %) in dry DCM (100
mL) and was stirred at 55 °C for 12 h. After the completion
of the reaction, the contents were cooled and the solvent was
evaporated under reduced pressure. The resulting crude resi-
due was subjected to column chromatography (ethyl ace-
tate/hexane, 2:8) to give pure (R)-6-(2-(benzyloxy)ethyl)-
5,6-dihydropyran-2-one (11a) (1.47 g, 85%) as a colorless
liquid. The optical rotation of compound was [ꢀ]D32 = + 31.9
(c = 1.0, CHCl3). The spectral data (Proton NMR, Carbon
32
optical rotation of compound was [ꢀ]D = - 22.6 (c = 0.7,

Simple Stereoselective Synthesis of Unsaturated Lactone Intermediates
Letters in Organic Chemistry, 2013, Vol. 10, No. 5
321
NMR and MS) of 11a were found to be identical as those of
11.
was stirred for 2 h. After completion ice cold water (2 mL)
was added and the mixture was extracted with DCM (3 x 10
mL). The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude product
was purified by using column chromatography with mobile
phase (ethyl acetate/hexane, 1:9). The purified aldehyde
(0.32 g, 80%) was directly subjected to further reaction.
(S)-6-(2-hydroxyethyl)-5,6-dihydropyran-2-one (12)
TiCl4 (1.63 mL, 8.62 mmol) was added to a solution of
11 (1.00 g, 4.31 mmol) in dry DCM (20 mL) under a N2 at-
mosphere at 0 °C and the content was stirred for 1 h at room
temperature. After completion, the reaction was quenched
with saturated aqueous NaHCO3 solution (20 mL). The mix-
ture was extracted into DCM (3 ꢂ 25 mL). The combined
organic layer was separated, washed with water (10 mL) and
brine (10 mL) and dried over anhydrous Na2SO4. The mix-
ture was concentrated under reduced pressure and the crude
product was purified by using to column chromatography
(ethyl acetate/hexane, 3:7) which afforded pure (S)-6-(2-
hydroxyethyl)-5,6-dihydropyran-2-one (12) (0.54 g, 89%) as
a colorless liquid. The optical rotation of compound was
[ꢀ]D32 = - 97.2 (c = 1.0, CHCl3); IR: 3444, 1705, 1640, 1492,
1451, 1363, 1207 cm-1; 1H NMR (CDCl3, 200 MHz): ꢁ 6.86
(1H, m ), 5.98 (1H, d, J = 9.0 Hz), 4.65 (1H, m), 3.84 (1H,
m), 3.75 (1H, m), 3.37 (1H, m) 2.43-2.31 (2H, m), 2.07-1.82
(2H, m); 13C NMR (CDCl3, 50 MHz): ꢁ 164.2, 144.9, 121.2,
75.0, 57.5, 36.2, 29.7; EIMS: m/z 143 [M+H]+..
1-triphenylphosphoranylidene -2-propanone (0.34 g, 1.08
mmol) was added to a solution of aldehyde 1 (0.10 g, 0.72
mmol) in benzene (10 mL) and the reaction content was re-
fluxed for 10 h. After cooling, the solvent was evaporated
under reduced pressure and the crude product (0.42 g, yellow
solid) was purified by using column chromatography (ethyl
acetate/hexane 1:8) to give (R, E)-6-(4-oxopent-2-enyl)-5,6-
dihydropyran-2-one (3) (0.10 g, 80%) as a colorless oil. The
25
optical rotation of compound was [ꢀ]D = - 40.5 (c = 1.2,
CHCl3); IR: 1718, 1670, 1635, 1433, 1363, 1247, 1096, 1025
cm-1. 1H NMR (CDCl3, 200 MHz): ꢁ 6.94-6.71 (2H, m), 6.18
(1H, d, J = 16.0 Hz), 6.05 (1H, d, J = 9.0 Hz), 4.60 (1H, m),
2.75-2.60 (2H, m), 2.42-2.34 (2H, m), 2.24 (3H, s); 13C
NMR (CDCl3, 50 MHz): ꢁ 198.6, 164.2, 144.9, 140.4, 134.8,
121.0, 75.8, 37.5, 29.6, 26.8; ESIMS: m/z 181 [M+H]+..
(S, E)-6-(4-oxopent-2-enyl)-5,6-dihydro-pyran-2-one (3a)
A solution of compound 12a (0.40 g, 2.82 mmol) in dry
DCM (5 mL) was slowly added to IBX (1.20 g, 2.82 mmol)
dissolved in dry DMSO (2.5 mL) at room temperature and
was stirred for 2 h. After completion, ice cold water (2 mL)
was added to the reaction and the mixture was extracted with
DCM (3 x 10 mL). The combined organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by using column chromatography
(ethyl acetate/hexane, 1:9). The purified aldehyde 1a (0.32 g,
80%) was directly subjected to further reaction.
(R)-6-(2-hydroxyethyl)-5, 6-dihydropyran-2-one (12a)
TiCl4 (1.63 mL, 8.62 mmol) was added to a solution of
11a (1.00 g, 4.31 mmol) in dry DCM (20 mL) under a N2
atmosphere at 0 °C and the content was stirred for 1 h at
room temperature. After completion, the reaction was
quenched with saturated aqueous NaHCO3 solution (20 mL).
The mixture was extracted into DCM (3 ꢂ 25 mL). The
combined organic layer was separated, washed with water
(10 mL) and brine (10 mL) and dried over anhydrous
Na2SO4. The mixture was concentrated under reduced pres-
sure and the crude product was purified by using column
chromatography (ethyl acetate/hexane, 3:7) which afforded
pure (R)-6-(2-hydroxyethyl)-5,6-dihydropyran-2-one (12a)
(0.54 g, 89%) as a colorless liquid. The optical rotation of
compound was [ꢀ]D32 = + 98.0 (c = 1.0, CHCl3). The spectral
data (Proton NMR, Carbon NMR and MS) of 12a were
found to be identical as those of 12.
1-triphenylphosphoranylidene -2-propanone (0.34 g, 1.08
mmol) was added to a solution of aldehyde 1a (0.10 g, 0.72
mmol) in benzene (10 mL) and the reaction content was re-
fluxed for 10 h. After cooling, the solvent was evaporated
under reduced pressure and the crude product (0.42 g, yellow
solid) was purified by using column chromatography (ethyl
acetate/hexane 1:8) to give (S, E)-6-(4-oxopent-2-enyl)-5,6-
dihydropyran-2-one (3a) (0.10 g, 80%) as a colorless oil.
25
The optical rotation of compound was [ꢀ]D = + 41.1 (c =
1-triphenylphosphoranylidene-4-phenyl-butan-2-one (17)
1.2, CHCl3). The spectral data (Proton NMR, Carbon NMR
The compound 16 (1.00 g, 4.40 mmol) was dissolved in
benzene (20 mL) to which a solution of triphenyl phosphine
(1.16 g, 4.40 mmol) in benzene (20 mL) was slowly added
dropwise. The reaction content was stirred for 48 h at room
temperature where by the oily precipitate became crystalline.
This salt was filtered and washed with hexane. A solution of
the salt in DCM (35 ml) was treated with 1 % NaOH (35
mL) to yield of 1-triphenylphosphoranylidene -4-
phenylbutan-2-one (17) (1.40 g, 78%) as a white solid. mp
132-135 oC.
and MS) of 3a were found to be identical as those of 3.
(R, E)-6-(4-oxo-6-phenylhex-2-enyl)-5,6-dihydropyran-2-
one [(R)-Rugulactone] (4)
Compound 12 (0.40 g, 2.82 mmol) dissolved in dry DCM
(5 mL) was slowly added to a solution of IBX (1.20 g, 2.82
mmol) in dry DMSO (2.5 mL) at room temperature and was
stirred for 2 h. After completion, ice cold water (2 mL) was
added to the reaction and the mixture extracted into DCM (3
x 10 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was
subjected to column chromatography (ethyl acetate/hexane,
1:9). The purified aldehyde 1 (0.32 g, 80%) was directly
subjected to further reaction.
(R, E)-6-(4-oxopent-2-enyl)-5,6-dihydro-pyran-2-one (3)
A solution of compound 12 (0.40 g, 2.82 mmol) in dry
DCM (5 mL) was slowly added to IBX (1.20 g, 2.82 mmol)
dissolved in dry DMSO (2.5 mL) at room temperature and

322 Letters in Organic Chemistry, 2013, Vol. 10, No. 5
Shinde et al.
ꢀ-pyrones and two bicyclic tetrahydro-ꢀ-pyrone derivatives from
Cryptocarya latifolia. Phytochemistry, 1995, 38, 1427-1430; c)
Cavasheiro, A. J.; Yoshida, M. 6-[ꢂ-Arylalkenyl]-5,6-dihydro-ꢀ-
pyrones from Cryptocarya moschata (Lauraceae). Phytochemistry,
2000, 53, 811-819.
a) Hoffmann, H. M. R.; Rabe, J. Synthesis and biological activity
of ꢀ-methylene-ꢁ-butyrolactones. Angew. Chem. Int. Ed. Engl.,
1985, 24, 94-110; b) Antonio, M. A.; de Carvalho, J. E.; Pillia, R.
A. (R)-Goniothalamin: total syntheses and cytotoxic activity
against cancer cell lines. Bioorg. Med. Chem., 2005, 13, 2927-
2933.
Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C.
M.; Hwang, I.; Swinkle, M. R.; Bonness, K. M.; Honkanen, R. E.;
Boger, D. L. Fundamental role of the fostriecin unsaturated lactone
and implications for selective protein phosphatase inhibition. J.
Am. Chem. Soc., 2003, 125, 15694-15695.
Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Stereoselective
syntheses of naturally occurring 5,6-dihydropyran-2-ones. Tetrahe-
dron, 2007, 63, 2929-2958.
a) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D. N.
Stereoselective total synthesis of a potent natural antifungal com-
pound (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-
pyran-2-one. Biorg. Med. Chem. Lett.; 2009, 19, 6396-6398; b)
Das, B.; Satyalakshmi, G.; Suneel, K.; Shinde, D. B. Stereoselec-
tive total synthesis of the piperidine alkaloids, (+)-coniine, (+)-
pseudoconhydrine, and (+)-sedamine through a common interme-
diate. Tetrahedron Asymmetry, 2011, 22, 1000-1005.
Ovedraogo, M.; Carreyre, H.; Vandelrouck, C.; Bescound, J.;
Raymond, G.; Guissou, I.-P.; Cognard, C.; Becq, F.; Potreau, D.;
Cousson, A.; Marrot, J.; Coustard, J.-M. Structure elucidation of a
dihydropyranone from Tapinanthus dodoneifolius. J. Nat. Prod.,
2007, 70, 2006-2009.
Maxwell, A.; Dabideen, D.; Reynolds, W. F.; McLean, S. Two 6-
substituted 5,6-dihydropyran-2-ones from Piper reticulatum. J.
Nat. Prod., 1998, 61, 815-816.
Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L. M.;
McCloud, T. G.; Cardellina, J. H. II.; Shoemaker, R. H. Inhibitors
of the NF-kB activation pathway from Cryptocarya rugulosa. J.
Nat. Prod., 2009, 72, 336-339.
Bohlmann, F.; Suwita, A. Ein neues bisabolen-derivat und ein
neues dihydro kaffeesäure-derivat aus Tarchonanthus trilobus.
Phytochemistry, 1979, 18, 677-678.
Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.; Simonyi,
M.; Antus, S.; Randriantsoa, A.; Hostettmann, K. Absolute
configuration of two new 6-alkylated ꢀ-pyrones (2H-pyran-2-ones)
from Ravensara crassifolia. Helv. Chim. Acta, 2001, 84, 3470-
3476.
Berkowitz, B.; Huang, D.-B.; Chen-Park, F. E.; Sigler, P. B.;
Ghosh, G. The X-ray crystal structure of the NF-ꢃB p50·p65
heterodimer bound to the interferon ꢂ-ꢃB site. J. Bio. Chem., 2002,
277, 24694-24700.
a) Butler, C. L.; Clapp, M. J. The preparation of benzyloxyalkyl p-
toluenesulfonates. J. Am. Chem. Soc., 1938, 60, 1472-1473; b)
Crimmins, M. T.; Shamszad, M.; Anita, E.; Mattson, A, E. A
highly convergent approach toward (ꢄ)-brevenal. Org. lett., 2010,
12, 2614-2617.
Reddy, D. K.; Shekhar, V.; Reddy, T. S.; Reddy, S. P.; Venkates-
warlu, Y. Stereoselective first total synthesis of (R)-rugulactone.
Tetrahedron Asymmetry, 2009, 20, 2315-2319.
a) Hanawa, H.; Hashimoto, T.; Maruoka, K. Bis(((S)-
binaphthoxy)(isopropoxy)titanium) oxide as a 4-oxo-type chiral
Lewis Acid:ꢀ application to catalytic asymmetric allylation of alde-
hydes. J. Am. Chem. Soc., 2003, 125, 1708-1709; b) Das, B.;
Shinde, D. B.; Kanth, B. S.; Kamle, A.; Kumar, C. G. Total synthe-
sis of racemic and (R) and (S)-4-methoxyalkanoic acids and their
antifungal activity. Eur. J. Med. Chem., 2011, 46, 3124-3129.
Grubbs, R. H.; Miller, S. J.; fu, G. C. Ring-closing metathesis and
related processes in organic synthesis. Acc. Chem. Res., 1995, 28,
446-452.
Enders, D.; Dhulut, S.; Steinbusch, D.; Herrbach, A. Asymmetric
total synthesis of (ꢄ)-pironetin employing the SAMP/RAMP
hydrazone methodology. Chem. Eur. J., 2007, 13, 3942-3949.
Nakamura, S.; Inagaki, J.; Kudo, M.; Sugimoto, T.; Obara, K.;
Nakajima, M.; Hashimoto, S. Studies directed toward the total syn-
thesis of pinnatoxin A: synthesis of the 6,5,6-dispiroketal (BCD
1-triphenylphosphoranylidene -4-phenylbutan-2-one (17)
(0.41 g, 1.28 mmol) was added to a solution of aldehyde 1
(0.10 g, 0.72 mmol) in benzene (10 mL) and the reaction
content was refluxed for 14 h. After cooling, the solvent was
evaporated under reduced pressure and the crude product
(1.42 g, yellow solid) was purified using column chromatog-
raphy (ethyl acetate/hexane 1:8) to give (R, E)-6-(4-oxo-6-
phenylhex-2-enyl)-5,6-dihydropyran-2-one (rugulactone) (4)
(0.14 g, 72%) as a colorless oil. The optical rotation of the
[2]
[3]
25
compound was [ꢀ]D = - 34.2 (c = 1.0, CHCl3); IR: 1722,
1
1676, 1639, 1437, 1362, 1247 cm1; H NMR (CDCl3, 200
MHz): ꢁ 7.30-7.22 (2H, m),7.20-7.14 (3H, m), 6.85 (1H, m ),
6.79 (1H, m ), 6.19 (1H, d, J = 16.0 Hz), 6.04 (1H, d, J = 9.0
Hz), 4.55 (1H, m), 2.98-2.85 (4H, m), 2.71-2.57 (2H, m),
2.38-2.29 (2H, m); 13C NMR (CDCl3, 50 MHz): ꢁ 199.2,
165.2, 141.0, 140.8, 132.5, 130.6, 128.0, 127.8, 125.7, 119.2,
71.3, 40.8, 34.6, 35.8, 30.0; ESIMS: m/z 271 [M+H]+..
[4]
[5]
(S, E)-6-(4-oxo-6-phenylhex-2-enyl)-5,6-dihydropyran-2-
one [(S)-Rugulactone] (4a)
Compound 12a (0.40 g, 2.82 mmol) dissolved in dry
DCM (5 mL) was slowly added to a solution of IBX (1.20 g,
2.82 mmol) in dry DMSO (2.5 mL) at room temperature and
was stirred for 2 h. After completion, ice cold water (2 mL)
was added to the reaction and the mixture extracted into
DCM (3 x 10 mL). The organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude product
was subjected to column chromatography (ethyl ace-
tate/hexane, 1:9). The purified aldehyde 1a (0.32 g, 80%)
was directly subjected to further reaction.
[6]
[7]
[8]
1-triphenylphosphoranylidene -4-phenylbutan-2-one (17)
(0.41 g, 1.28 mmol) was added to a solution of aldehyde 1a
(0.10 g, 0.72 mmol) in benzene (10 mL) and the reaction
content was refluxed for 14 h. After cooling, the solvent was
evaporated under reduced pressure, and the crude product
(1.42 g, yellow solid) was purified using column chromatog-
raphy (ethyl acetate/hexane 1:8) to give (S, E)-6-(4-oxo-6-
[9]
[10]
[11]
[12]
phenylhex-2-enyl)-5,6-dihydropyran-2-one
(rugulactone)
(4a) (0.14 g, 72%) as a colorless oil. The optical rotation of
25
the compound was [ꢀ]D = + 35.4 (c = 1.0, CHCl3). The
spectral data (Proton NMR, Carbon NMR and MS) of 4a
were found to be identical as those of 4.
CONFLICT OF INTEREST
[13]
[14]
The author(s) confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The authors thank CSIR and UGC, New Delhi for finan-
cial assistance.
[15]
[16]
[17]
REFERENCES
# Part 52 in the series, “Synthetic studies on natural
products”.
[1]
a) Rychnovsky, S. D. Total synthesis of bioactive marine macrol-
ides. Chem. Rev., 1995, 95, 2021-2040; b) Drewes, S. E.; Sehla-
pelo, B. M.; Horn, M. M.; Scott-Shaw, R.; Sandor, O. 5,6-Dihydro-

Simple Stereoselective Synthesis of Unsaturated Lactone Intermediates
Letters in Organic Chemistry, 2013, Vol. 10, No. 5
323
ring) system by double hemiketal formation/hetero-Michael addi-
tive total synthesis of (R)-rugulactone. Tetrahedron Lett., 2011, 52,
5133-5135; g) Mohapatra, D. K.; Karthik, P.; Yadav, J. S. Highly
concise and stereoselective total synthesis of (5R,7S)-kurzilactone.
Helv. Chim. Acta, 2012, 95, 1226-1230.
Roman, G.; Riley, J. G.; Vlahakis, J. Z.; Kinobe, R. T.; Brien, J. F.;
Nakatsub, K.; Szareka, W. A. Heme oxygenase inhibition by 2-
oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: effect of
halogen substitution in the phenyl ring. Bioorg. Med. Chem., 2007,
15, 3225-3234.
a) Szhntaya, C.; Kardos-B, Z.; Moldvai, I.; SzAntay Jr, C.; Eszter,
M- T.; Blasko, G. A practical enantioselective synthesis of epi-
batidine. Tetrahedron, 1996, 52, 11053-11062; b) Barco, A.; Ben-
etti, S.; Risi, C. D.; Marchetti, P.; Pollini, G. P.; Zanirato, V. 4-[(4-
Methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-
butanone and its dianion as versatile tools in organic synthesis.
Tetrahedron Lett., 1998, 39, 1973-1976.
tion strategy. Tetrahedron, 2002, 58, 10353-10374.
[18]
a) Mohapatra, D. K.; Das, P. P.; Reddy, D. S.; Yadav, J. S. First
total syntheses and absolute configuration of rugulactone and 6-
(R)-(4ꢀ-oxopent-2ꢀ-enyl)-5,6-dihydro-2H-pyran-2-one. Tetrahedron
Lett., 2009, 50, 5941-5944; b) Reddipalli, G.; Venkataiah, M.; Fad-
navis, N. W. Chemo-enzymatic synthesis of both enantiomers of
rugulactone. Tetrahedron Asymmetry, 2010, 21, 320-324; c) Cros,
F.; Pelotier, B.; Piva, O. Regioselective tandem ring closing/cross
metathesis of 1,5-hexadien-3-ol derivatives: application to the total
synthesis of rugulactone. Eur. J. Org. Chem., 2010, 5063-5070; d)
Allais, F. Aouhansou, M. Majira, A. Ducrot, P.-H. Asymmetric
total synthesis of rugulactone an ꢀ-pyrone from cryptocarya
rugulosa. Synthesis, 2010, 2787-2793; e) Bose, D.; Fernandez, E.;
Pietruszka, J. Stereoselective synthesis of both enantiomers of ru-
gulactone. J. Org. Chem., 2011, 76, 3463-3469; f) Goswami, A.;
Saikia, P.; Chaturvedi, D.; Barua, N. C. An improved stereoselec-
[19]
[20]