Stereoselective first total synthesis of (R)-rugulactone

Article abstract of DOI:10.1016/j.tetasy.2009.09.016

A simple and highly efficient stereoselective synthetic route has been developed for the synthesis of (R)-rugulactone, a 6-arylalkyl-5,6-dihydro-2H-pyran-2-one, from readily available substrates such as 1,3-propanediol and 3-phenyl-1-propanal employing Ke

Full text of DOI:10.1016/j.tetasy.2009.09.016

Tetrahedron: Asymmetry 20 (2009) 2315–2319
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective first total synthesis of (R)-rugulactone
*
D. Kumar Reddy, V. Shekhar, T. Srikhanth Reddy, S. Purushotham Reddy, Y. Venkateswarlu
Natural Products Laboratory, Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and highly efficient stereoselective synthetic route has been developed for the synthesis of (R)-
rugulactone, a 6-arylalkyl-5,6-dihydro-2H-pyran-2-one, from readily available substrates such as 1,3-
propanediol and 3-phenyl-1-propanal employing Keck’s asymmetric allylation and cross metathesis as
key steps.
Received 25 June 2009
Accepted 22 September 2009
Available online 29 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
compounds 2 and 3. The key fragment 2 was prepared via Still–
Gennari modification of the Horner–Emmons reaction from 8,
6-Arylalkyl-5,6-dihydro-2H-pyran-2-ones are important struc-
tural features of the genus of Cryptocarya of Lauraceae family,
lacking a substituent at C-4.1 Due to the Michael acceptor proper-
which could be readily prepared via Keck’s asymmetric allylation
route from the easily available 1,3-propanediol 6. The vinyl ketone
3 in turn was prepared from 3-phenyl-1-propanal 4.
ties of the
a,b-unsaturated
a-pyrones toward amino acid residues
of receptors, these
a
-pyrone molecules possess interesting biolog-
2. Results and discussion
ical activities such as antitumor, anti-inflammatory, antibacterial,
antiviral, and antifungal activities.2 The arylalkyl-substituted
As outlined in Scheme 1, the 1,3-propanediol 6 was selectively
protected with benzyl bromide5 to mono benzyl ether 7. The pri-
mary alcohol in 7 was oxidized using iodoxybenzoic acid (IBX) in
DMSO to afford the corresponding aldehyde, which was subjected
to the catalytic asymmetric allyl stannation developed by Keck
et al.6 to furnish the homoallylic alcohol 8 in 80% yield with an
excellent enantioselectivity of 97.5% ee (determined by chiral
HPLC).7 The spectroscopic and analytical data8 were in good agree-
ment with the literature values. The absolute stereochemistry of
the newly generated stereogenic center in compound 8 bearing
the hydroxyl group was determined by preparing the MPTA esters
by a modified Mosher’s method,9 and were found to have an (R)-
configuration (Fig. 1). The negative chemical shift difference to
the left side of the MTPA plane and the positive chemical shift dif-
ferences to the right side of the MTPA plane indicated that the hy-
droxyl stereochemistry had an (R)-configuration (Fig. 1).
The secondary hydroxyl group in 8 was protected as its TPS
ether using TPSCl and imidazole in dry DCM to yield 9. Next, the
benzyl group in compound 9 was removed using lithium napht-
halenide (LN)10 to yield primary alcohol 10 in 81%. The primary
alcohol in compound 10 was oxidized using IBX in DMSO to yield
the aldehyde which was subjected to Still–Gennari modification of
the Horner–Emmons olefination reaction11 to afford unsaturated
ester 11 with a Z/E ratio of 95:05 in 80% yield. Compound 11 upon
a
,b-unsaturated d-lactones are ubiquitous metabolites of the ever-
green trees of Cryptocarya genus which are well known for their
legendary medicinal properties.2 Recently, a 6-arylalkyl-5, 6-dihy-
dro-2H-pyran-2-one, (R)-rugulactone 1 was isolated from the
dichloromethane extract of Cryptocarya rugulosa by Cardellina
et al.3 The structure was established via NMR and HRMS studies
and the absolute configuration was determined by a CD spectrum.
Biological assays of (R)-rugulactone found it to inhibit the nuclear
factor-
j
B (NF-
j
B) activation pathway that is active in many types
of cancers, exhibiting up to fivefold induction of I
jB at 25
l
m/mL.3
In a continuation of our interest in the synthesis of biologically
active natural products,4 we planned to synthesize compound 1.
To the best of our knowledge, the synthesis of 1 has not been
reported in the literature and hence we herein report an efficient
stereoselective first total synthesis of (R)-rugulactone 1.
O
O
O
1
Our synthetic approach to (R)-rugulactone is outlined in Scheme 1,
which involves Grubb’s cross metathesis reaction between
treatment with 3% HCl in MeOH afforded 6-allyl-5,6-dihydro-a-
pyrone 2 in 78% yield (Scheme 2).
a
The fragment 5-phenyl-pent-1-en-3-ol 3 was prepared from
phenyl-1-propanal 4. Compound 4 was reacted with vinyl magne-
sium bromide to yield allyl alcohol 5,12 which on oxidation with
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.016

2316
D. K. Reddy et al. / Tetrahedron: Asymmetry 20 (2009) 2315–2319
O
O
O
O
O
O
+
3
2
1
O
OTPS
H
BnO
8
4
HO
OH
6
Scheme 1.
4. Experimental
4.1. General
-0.32
H
-0.28
-0.09
OMTPA
-0.02
H
0.16
0.1
(R)
O
-0.11
0.08
H
The reactions were carried out under N2 in anhydrous solvents
such as CH2Cl2, THF, and EtOAc. All reactions were monitored by
TLC (silica-coated plates and visualized under UV light). Yields re-
fer to material after chromatography and which is spectroscopi-
cally (1H, 13C NMR) homogeneous. Air-sensitive reagents were
transferred by a syringe or a double-ended needle. Evaporation of
solvents was performed at reduced pressure on a Buchi rotary
evaporator. 1H and 13C NMR spectra were recorded in CDCl3 solu-
tion on a Varian Gemini 200 and Brucker Avance 300 spectrome-
ters. Chemical shifts (d) are reported relative to TMS (d = 0.0) as
an internal standard. Mass spectra were obtained on MS-EI, MS-
ESI, and HRMS mass spectrometers. Column chromatography was
performed on silica gel (60–120 mesh) supplied by Acme Chemical
Co., India. TLC was performed on Merck 60 F-254 silica gel plates.
IR (FT-IR) spectra were recorded either on KBr pellets or neat as
thin film. Optical rotations were recorded on JASCO DIP–360 digital
polarimeter at 25 °C.
Figure 1. Determination of the absolute configuration and
and (R)-MTPA ester derivatives of 8 (
d = dS ꢁ dR).
D
d values for the (S)-
D
IBX in DMSO afforded vinyl ketone 3 in good yield.13 Finally,
compounds 2 and 3 in a 1:3 ratio were subjected to cross metath-
esis using second generation Grubb’s catalyst (5 mol %)14 in dichlo-
romethane under reflux conditions to yield desired (R)-rugulactone
1 in 74% yield (Scheme 3). The 1H and 13C NMR spectra of synthetic
compound 1 are in good agreement with those of the natural (R)-
rugulactone and as a result we are able to report for the first time
the specific rotation of 1 as ½a D25
¼ ꢁ61:9 (c 0.5, CHCl3).
ꢀ
3. Conclusion
In conclusion, the asymmetric synthesis of (R)-rugulactone has
been achieved from commercially available inexpensive 1,3-pro-
pane diol 6 and 3-phenyl-1-propanal 4 by the successful utilization
of the Keck’s asymmetric allylation and Grubb’s cross metathesis
reaction.
4.1.1. 3-(Benzyloxy)propane-1-ol 75
To a solution of 1,3-propanediol 6 (2 g, 26.31 mmol) in dry THF
(50 mL) was added sodium hydride (605 mg, 26.30 mmol) at 0 °C,
OTPS
OH
c
a
b
BnO
BnO
OH
BnO
HO
OH
9
8
6
7
O
OTPS
OTPS
f
O
d
e
MeO
HO
O
11
10
2
Scheme 2. Reagents and conditions: (a) BnBr, NaH, TBAI, THF. 0 °C to rt, 2 h, 85%; (b) (i) IBX, dry DMSO; dry CH2Cl2, 5 h, 88%, (ii) (R)-BINOL, 4 Å MS, Ti(OiPr)4, allyl-
tributylstannane, CH2Cl2, ꢁ78 °C to ꢁ20 °C, 80%; (c) TBDPSCl, imidazole, dry CH2Cl2, 4 h, 95%; (d) Li in naphthalene, ꢁ20 °C, 3 h, 81%; (e) (i) IBX, dry DMSO, dry CH2Cl2, 5 h,
85%, (ii) MeO2CCH2P(O)(OCH2CF3)2, NaH, dry THF, ꢁ78 °C, 2 h, 76%; and (f) 3% HCl in MeOH 30 min, 78%.

D. K. Reddy et al. / Tetrahedron: Asymmetry 20 (2009) 2315–2319
2317
O
OH
O
b
a
H
3
4
5
O
O
O
O
O
c
O
+
2
1
3
Scheme 3. Reagents and conditions: (a) vinyl magnesium bromide, dry THF, 0 °C to rt, 1 h, 86%; (b) IBX, dry DMSO, dry CH2Cl2, 3 h, 90%; and (c) Grubb’s 2nd generation
catalyst (5 mol %), dry CH2Cl2, 40 °C, 12 h, 74%.
and the reaction mixture was stirred at room temperature for
30 min and again cooled to 0 °C. To this cooled solution were added
slowly benzyl bromide (4 g, 23.68 mmol) and tetra-N-butylammo-
nium iodide (cat.) and the reaction mixture was stirred for 2 h at
room temperature. After completion of the reaction as indicated
by TLC, the reaction was quenched with cold water, and the reac-
tion mixture was extracted into EtOAc (3 ꢂ 30 mL). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure to
yield crude compound 7 as an oil which was purified on silica
gel column chromatography using EtOAc–hexane (2:8) as eluent
to furnish the pure monobenzyl-protected alcohol 7 (3.71 g, 85%)
(300 MHz, CDCl3): d 7.37–7.26 (m, 5H), 5.91–5.76 (m, 1H), 5.15–
5.07 (m, 2H), 4.52 (br s, 2H), 3.93–3.83 (m, 1H), 3.68 (AB,
JAB = 5.2 Hz, 2H), 2.63 (br s, 1H), 2.25 (dt, J = 7.1 Hz, 1.4 Hz, 2H).
1.82–1.72 (m, 2H). 13C NMR (75 MHz, CDCl3): d 137.9, 134.8,
128.4, 127.7, 127.6, 117.5, 73.3, 70.3, 68.9, 41.9, and 35.8. EIMS:
m/z 206 [M]+.
4.1.3. [1-(2-Benzyloxy-ethyl)-but-3-enyloxy]-tert-butyl-diphen-
yl-silane 9
To a stirred cooled (0 °C) solution of compound 8 (2.5 g,
12.13 mmol) and imidazole (2.06 g, 30.25 mmol) in dry dichloro-
methane (30 mL) was added tert-butyldiphenylsilylchloride
(4.0 g, 14.55 mmol) dropwise. Stirring was then continued for
4 h. After completion of reaction, the reaction mixture was diluted
with water (20 mL) and extracted into dichloromethane
(3 ꢂ 30 mL). The combined organic layer was washed with brine
solution (10 mL), dried over anhyd Na2SO4, and concentrated
under vacuum to furnish the crude residue, which was purified
by column chromatography on silica gel eluting with AcOEt–hex-
ane (1:19) to afford the pure compound 9 (5.11 g, 95% yield):
as a colorless oil. IR (neat):
2401, 1952, 1702, 1496, 1455, 1363, 1216, 1099, 957, 932, 850,
and 771 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.33–7.27 (m, 5H),
m 3624, 3413, 3017, 2941, 2867,
;
4.50 (br s, 2H), 3.61 (t, J = 5.7 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.41
(br s 1H), 1.73–1.62 (m, 2H). 13C NMR (75 MHz, CDCl3): 137.9.
128.0, 127.3, 127.2, 72.5, 69.9, 61.7, 26.0. EIMS: m/z 166 [M]+.
4.1.2. (R)-6-(Benzyloxy)-1-hexen-4-ol 88
To a stirred solution of IBX (7.59 g, 27.07 mmol) in dry DMSO
(10 mL), a solution of 7 (3.0 g, 18 mmol) in dry DCM (50 mL) was
added at room temperature and stirred for 5 h at room tempera-
ture. After completion of the reaction as indicated by TLC, the mix-
ture was filtered, diluted with water (25 mL), and extracted into
DCM (2 ꢂ 50 mL). The combined organic layers were washed with
brine (20 mL), dried (Na2SO4), and evaporated to give crude alde-
hyde, which was purified on silica gel column using EtOAc–hexane
(1:9) to give pure aldehyde (2.6 g, 88%) as a colorless liquid. Sepa-
rately, a mixture of (R)-BINOL (0.443 g, 1.58 mmol) and Ti(OiPr)4
(0.50 g, 1.585 mmol) in CH2Cl2 (60 mL) in the presence of 4 Å
molecular sieves (MS) (4 g) was stirred at reflux. After 1 h, the reac-
tion mixture was cooled to room temperature and to it was added
the previously prepared aldehyde (2.6 g, 15.85 mmol) in dry DCM
and the resulting mixture was stirred for 10 min. The reaction mix-
ture was then cooled to ꢁ78 °C and allyl tributylstannane (6.29 g,
19.02 mmol) was added to the reaction mixture and the stirring
was continued at ꢁ20 °C for 36 h. After completion of the reaction
as noticed by TLC, the reaction was quenched with saturated NaH-
CO3 solution (10 mL) and the reaction mixture was stirred for an
additional 30 min and extracted into CH2Cl2 (40 mL). The organic
phase was washed with brine (30 mL), dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure to
give crude residue, which was purified over silica gel column chro-
matography using EtOAc–hexane (2:8) to afford homoallylic alco-
½
a 2D5
ꢀ
¼ ꢁ6:3 (c 1, CHCl3). IR (neat):
m 2961, 1645, 1621, 1489,
1461, 1349, 1353, 1217, 1097, 1024, 918 and 749. 1H NMR
(300 MHz, CDCl3): d 7.71–7.65 (m, 5H), 7.43–7.18 (m, 10H),
5.79–5.64 (m, 1H), 4.93 (m, 2H), 4.33 (br s, 2H), 3.96 (m, 1H),
3.48 (AB, JAB = 4.3 Hz, 2H), 2.25 (m, 2H), 1.82–1.77 (m, 2H), 1.05
(s, 9H) .13C NMR (75 Hz, CDCl3): 135.9, 134.5, 134.4, 129.5, 128.2,
127.5, 127.4, 127.4, 127.3, 117.0, 72.7, 70.3, 66.9, 41.5, 36.0, 27.0,
19.3. HRMS (ESI): m/z [M+Na]+ calcd for C29H36O2NaSi: 467.2382,
found: 467.2385.
4.1.4. 3-(tert-Butyl-diphenyl-silanyloxy)-hex-5-en-1-ol 10
To solution of naphthalene (14.41 g, 112.60 mmol) in dry THF
(20 mL) was added lithium metal (810 mg, 135.13 mmol). After
30 min, a dark green color developed which turned darker after
1.25 h. This solution was cooled to ꢁ25 °C and to this, a solution
of compound 9 (5 g, 11.26 mmol) in dry THF (3 mL) was added
by a cannula. The resulting mixture was stirred at ꢁ25 °C for 3 h.
After completion of the reaction as noticed by TLC, the reaction
was quenched with saturated aqueous ammonium chloride
(15 mL) and water (15 mL). The resulting solution was extracted
into ether (3 ꢂ 30 mL), washed with brine, and dried over Na2SO4.
The solvent was removed under reduced pressure to yield crude
compound 10 which was purified over silica gel column chroma-
tography using EtOAc–hexane (1:9) to afford primary alcohol 10
(3.22 g, 81%). ½a D25
ꢀ
¼ ꢁ23 (c 1, CHCl3): IR (neat):
m
3424, 2961,
.
hol 8 (2.61 g, 80%) as a clear liquid with ee >97%. ½a D25
ꢀ
¼ þ2:2 (c
1646, 1620, 1354, 1216, 1047, 1024, 919 and 747 cmꢁ1 1H NMR
1, CHCl3). IR (neat):
m
3444, 3069, 3030, 2921, 2862, 1640, 1492,
(300 MHz, CDCl3): d 7.76–7.65 (m, 4H), 7.46–7.34 (m, 6H), 5.66–
5.55 (m, 1H), 4.87 (m, 2H), 4.04–3.94 (m, 1H), 3.69–3.61 (m, 2H),
1451, 1363, 1207, 1096, 1025, 914 and 739 cmꢁ1
.
1H NMR

2318
D. K. Reddy et al. / Tetrahedron: Asymmetry 20 (2009) 2315–2319
2.35–2.23 (m, 1H), 2.23–2.11 (m, 1H), 1.95–1.75 (m, 1H), 1.70–1.60
(m, 1H), 1.06 (s, 9H). 13C NMR (75 MHz, CDCl3): d 135.9, 135.8,
129.8, 127.6, 127.5, 117.3, 71.6, 59.7, 41.0, 37.5, 27.0,19.2. HRMS
(ESI): m/z [M+Na]+ calcd for C22H30O2NaSi: 377.1912, found:
377.1921.
was continued for 1 h. After completion of the reaction as indicated
by TLC the reaction was quenched with saturated ammonium chlo-
ride solution, and the reaction mixture was extracted into diethyl
ether (3 ꢂ 50 mL). The combined organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure to
afford crude vinyl alcohol, which was purified over silica gel col-
umn chromatography using EtOAc–hexane (1:9) to afford pure
4.1.5. 5-(tert-Butyl-diphenyl-silanyloxy)-octa-2,7-dienoic acid
methyl ester 11
compound 3 as a clear liquid (1.038 mg, 86%). IR (neat):
m 3349,
To stirred solution of IBX (3.70 g, 13.22 mmol) in dry DMSO
(10 mL) was added a solution of 10 (3.12 g, 8.81 mmol) in DCM
(50 mL) at room temperature and stirred for 5 h at room tempera-
ture. After completion of the reaction, the mixture was filtered,
diluted with water (25 mL), and extracted into dichloromethane
(2 ꢂ 50 mL). The combined organic layer was washed with brine
(20 mL), dried (Na2SO4), and the solvent was removed under
reduced pressure to give the crude aldehyde, which was purified
on column chromatography using EtOAc–hexane (1:9) to give pure
aldehyde 10 (2.2 g, 9.56 mmol, 92%) as a colorless liquid. The alde-
hyde was used directly for the next reaction. To a cooled (0 °C) sus-
pension of NaH (358 mg, 14.94 mmol) in dry THF (10 mL) under a
N2 atmosphere was added bis-(2,2,2-trifluoromethyl)(methoxy
carbonyl methyl) phosphonate (2.37 g, 7.45 mmol) in dry THF
(10 mL) and was allowed to stir for 30 min. The reaction tempera-
ture was brought to ꢁ78 °C, then a solution of aldehyde 10 (2.63 g,
7.47 mmol) in dry THF (10 mL) was added dropwise over a period
of 10 min. The resulting mixture was stirred for 2 h at ꢁ78 °C. After
completion of the reaction, the reaction was quenched with satu-
rated NH4Cl and the reaction mixture was extracted into diethyl
ether (3 ꢂ 20 mL). The combined organic phase was dried over an-
hyd Na2SO4 and the solvent was evaporated under reduced pres-
sure to obtain the crude product, which was purified over silica
gel column chromatography using EtOAc–hexane (1:19) to afford
1604, 1498, 1455, 1428, 1403, 750 and 700 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 7.33–7.14 (m, 5H), 5.96–5.82 (m, 1H), 5.28–
5.10 (m, 2H), 4.13–4.07 (m, 1H), 2.7 (t, J = 7.2 Hz, 2H), 1.88–1.80
(m, 2H). 13C NMR (75 MHz, CDCl3): d 142.1, 140.9, 128.4, 125.8,
114.8, 72.6, 38.6, 31.7. EIMS: m/z = 162 [M]+.
4.1.8. 5-Phenyl-pent-1-en-3-one 313
To stirred solution of IBX (2.074 g, 7.4 mmol) in dry DMSO was
added a solution of 5 (800 mg, 4.92 mmol) in dichloromethane
(20 mL) at room temperature and stirred for 3 h at room tempera-
ture. After completion of the reaction, the mixture was filtered,
diluted with water (10 mL), and extracted into DCM (2 ꢂ 30 mL).
The combined organic layer was washed with brine (20 mL), dried
over anhyd Na2SO4, and evaporated to give crude vinyl ketone 3,
which was purified over silica gel column chromatography using
EtOAc–hexane (1:19) to afford pure vinyl ketone 3 (710 mg, 90%)
as a colorless liquid. IR (neat):
m
3061, 3027, 2925, 2856, 1709,
1605, 1495, 1450, 1403, 750 and 700 cmꢁ1
.
1H NMR (300 MHz,
CDCl3): d 7.31–7.11 (m, 5H), 6.41–6.40 (m, 2H), 5.90–5.75 (m,
1H), 3.00–2.80 (m, 4H). 13C NMR (75 MHz, CDCl3): d 199.9, 141.0,
139.0136.4, 128.4, 128.3, 126.1, 41.1 and 28.7. EIMS: m/z 160 [M]+.
4.1.9. 6-(4-Oxo-6-phenyl-hex-2-enyl)-5,6-dihydro-pyran-2-one 1
A solution of compound 2 (200 mg, 1.449 mmol) and compound
3 (695 mg, 4.347 mmol) in DCM (100 mL) in 1:3 ratio was first
bubbled with a nitrogen flow, then Grubbs type II catalyst
(61.5 mg, 0.0725 mmol) was added at once and the resulting mix-
ture was heated under nitrogen at 40 °C for 12 h. After completion
of the reaction, the solvent was removed under reduced pressure
and the residue was purified over silica gel column chromatogra-
phy using AcOEt–hexane (2:8) to afford lactone 1 (289 mg, 74%)
(Z)-acrylate 11 (2.31 g, 76% yield) as a yellow oil. ½a D25
¼ þ13:6 (c
ꢀ
1, CHCl3). IR (neat):
m 3121, 2930, 2856, 1725, 1642, 1435, 1388,
1251, 1045, 918, 796, 742, 618 and 621 cmꢁ1
.
1H NMR (300 MHz,
CDCl3): 7.77–7.64 (m, 4H), 7.48–7.33 (m, 6H), 6.33 (dd,
d
J = 11.7 Hz, 7.5 Hz, 1H), 5.79 (dt, J = 11.7 Hz, 1.6 Hz, 1H), 5.76–
5.62 (m, 1H), 4.96 (m, 2H), 3.98–3.85 (m, 1H), 3.66 (s, 3H), 2.96–
2.84 (m, 1H), 2.82–2.71 (m, 1H), 2.19 (m, 2H), 1.08 (br s, 9H). 13C
NMR (75 MHz, CDCl3): d 166.1, 146.2, 135.7, 133.8, 134.0, 129.5,
127.4, 120.5, 117.2, 96.0, 72.0, 41.3, 35.3, 26.9, 19.2. HRMS (ESI):
m/z [M+Na]+ calcd for C22H30O2NaSi: 431.2018, found: 431.2020.
as a yellow oil. ½a D25
ꢀ
¼ ꢁ61:9 (c 0.5, CHCl3); IR (neat):
m 3077,
2922, 2854, 1720, 1644, 1430, 1387, 1249, 1158, 1042, 996, 921,
814 and 757 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.32–7.15 (m,
.
5H), 6.98–6.84 (m, 1H), 6.80 (dt, J = 16.0 Hz, 7.1 Hz, 1H), 6.20 (d,
J = 16.0 Hz, 1 H), 6.04 (d, J = 9.8 Hz, 1H), 4.54 (m, 1H), 3.02–2.83
(m, 4H), 2.73–2.58 (m, 2H), 2.40–2.31 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 199.0, 163.3, 144.5, 141.0, 140.0, 133.5, 128.5, 128.3,
126.1, 121.4, 76.1, 41.7, 37.5, 29.9, 28.9. HRMS (ESI): m/z
[M+NH4]+ calcd for C17H22NO3: 288.1594; found: 288.1593.
4.1.6. 6-Allyl-5, 6-dihydro-pyran-2-one 2
Ester 11 (2.2 g, 5.39 mmol) was taken in 3% HCl in methanol
solution (10 mL) and stirred for 30 min. After completion of the
reaction as indicated by TLC, the reaction was quenched with sat-
urated NaHCO3 and the reaction mixture was extracted into ethyl
acetate (3 ꢂ 25 mL). The combined organic extract was washed
with brine solution, dried over anhyd Na2SO4, and evaporated un-
der reduced pressure to give crude lactone 2, which was purified
over silica gel column chromatography using EtOAc–hexane (2:8)
to afford pure compound 2 as a clear liquid (580 mg 78%).
4.1.10. 7-Mosher’s ester derivative of 88,9
N,N1-Dicyclohexylcarbodiimide (DCC) (45 mg, 0.21 mmol), a
catalytic amount of 4-dimethylaminopyridine (DMAP), and CH2Cl2
(2 mL) taken under a nitrogen atmosphere were allowed to cool at
0 °C for 10 min after which a solution of homoallylic alcohol 8
(30 mg, 0.15 mmol) in CH2Cl2 (2 mL) was added. This was allowed
to stir for an additional 10 min, followed by the dropwise addition
½
a 2D5
ꢀ
¼ ꢁ115:8 (c 1, CHCl3). IR (neat):
m
3077, 2922, 2854, 1720,
1644, 1430, 1387, 1249, 1042 and 921 cmꢁ1
.
1H NMR (300 MHz,
CDCl3): d 6.92–6.85 (m, 1H), 6.03 (d, J = 9.8 Hz, 1H), 5.90–5.77
(m, 1H), 5.22–5.14 (m, 2H), 4.56–4.44 (m, 1H), 2.60–2.45 (m,
2H), 2.39–2.33 (m, 2H). 13C NMR (75 MHz, CDCl3): d 166.7, 144.9,
133.9, 121.3, 118.7, 76.3, 39.0, 28.6. HRMS (ESI): m/z [M+Na]+ calcd
for C8H10O2Na: 161.0573, found: 161.0568.
of (S)-a-methoxy-a-trifluoromethyl phenylacetic acid (34 mg,
0.15 mmol) in CH2Cl2 (2 mL). This reaction mixture was then stir-
red at 0 °C for 1 h and then at room temperature for 12 h. The reac-
tion mixture was diluted with CH2Cl2 (50 mL), washed with
saturated sodium bicarbonate solution (50 mL), dried over anhy-
drous Na2SO4, and evaporated to give crude (S)-Mosher’s ester of
8, which was purified over silica gel column chromatography using
EtOAc–hexane (1:19) to afford a colorless oil (S)-Mosher’s ester of
4.1.7. 5-Phenyl-pent-1-en-3-ol 512
To a cooled (0 °C) stirred solution of vinylmagnesium bromide
(1 M, 11.2 mL, 11.18 mmol) in THF was added dropwise 3-phe-
nyl-1-propanal 4 (1.0 g, 7.462 mmol) in THF (20 mL) and the reac-
tion temperature was brought to room temperature and stirring
8. (41 mg, 67%) ½a D25
¼ ꢁ47:1 (c 1, CHCl3); IR (neat): 2856, 1744,
ꢀ
1643, 1493, 1451, 1363, 1259, 1166, 1104, 1018, 992, 915, 735,

D. K. Reddy et al. / Tetrahedron: Asymmetry 20 (2009) 2315–2319
2319
695. 1H NMR (300 MHz, CDCl3): 7.58–7.46 (m, 2H), 7.40–7.24 (m,
8H), 5.84–5.69 (m, 1H), 5.38–5.28 (m, 1H), 5.14–5.04 (m, 2H),
4.35 (s, 2H), 3.52 (s, 3H), 3.31 (dd, J = 5.3 Hz, 2.7 Hz, 1H), 3.17
(dd, J = 5.3 Hz, 2.9 Hz, 1 Hz), 2.49–2.41 (m, 2H), 1.82–1.95 (m,
2H). 13C NMR (75 MHz, CDCl3): 165.6, 132.9, 129.4, 129.2, 128.5,
128.2, 128.1, 127.4, 126.8, 118.1, 84.4, 73.4, 72.9, 65.6, 56.5, 55.4,
49.8, 38.6, 33.5. ESIMS: m/z = 442 [M+Na]+. Similarly, the (R)-
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Mosher’s ester of
procedure.
8 was also prepared adopting the above
Acknowledgments
The authors D.K.R., V.S., T.S.R., and S.P. are thankful to CSIR, New
Delhi, India, for the financial support and to Dr. J. S. Yadav, Director,
Indian Institute of Chemical Technology (IICT), for his
encouragement.
7. Chiral HPLC conditions: column: eurocel 01(250 ꢂ 4.6 mm particle size 5
lm);
mobile phase hexane/isopropyl alcohol (90:10); flow rate: 1 mL/min;
detection: PDA (ee 97.5%).
8. (a) George, S.; Sudalai, A. Tetrahedron: Asymmetry 2007, 18, 975–981; (b)
Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819–4822.
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4092–4096; (b) Yoshido, W. Y.; Bryan, P. J.; Baker, B. J.; McClintock, J. B. J. Org.
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