Stereoselective total synthesis of (+)-cryptofolione and (+)-goniothalamin

Article abstract of DOI:10.1016/j.tetasy.2011.06.029

The stereoselective total synthesis of two naturally occurring α-pyrone derivatives (+)-cryptofolione and (+)-goniothalamin has been accomplished via a common intermediate. The synthetic sequence involves the asymmetric reduction of a propargyl ketone and olefin cross-metathesis as the key reactions.

Full text of DOI:10.1016/j.tetasy.2011.06.029

Tetrahedron: Asymmetry 22 (2011) 1249–1254
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of (+)-cryptofolione and (+)-goniothalamin q
⇑
Biswanath Das , Siddavatam Nagendra, Cheruku Ravindra Reddy
Organic Chemistry 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:
The stereoselective total synthesis of two naturally occurring a-pyrone derivatives (+)-cryptofolione and
Received 9 June 2011
Accepted 27 June 2011
Available online 4 August 2011
(+)-goniothalamin has been accomplished via a common intermediate. The synthetic sequence involves
the asymmetric reduction of a propargyl ketone and olefin cross-metathesis as the key reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
alcohol 5 which in turn can be prepared from phenyl acetylene 6
and propane 1,3-diol 7.
Naturally occurring
a
-pyrone derivatives exhibit various impor-
The present synthesis of (+)-cryptofolione 1 was initiated
(Scheme 2) by protecting one of the hydroxyl groups of propane-
1,3-diol 7 by treatment with PMB-Br in THF to yield the PMB ether
8. Compound 8 was subjected to oxidation with PCC followed by
reaction with phenyl acetylene 6 using n-BuLi in THF to form the
propargyl alcohol 9. The free hydroxyl group of this alcohol was
oxidized with IBX in DMSO to produce the propargyl ketone 10.
The asymmetric reduction11 of 10 was accomplished with
BH3ꢀMe2S in the presence of (R)-2-methyl-CBS-oxazaborolidine as
a catalyst to generate the chiral propargyl alcohol 5 (ee 97%) with
tant biological properties, such as cytotoxic, antiviral, and antibac-
terial activities.1 (+)-Cryptofolione 1, a member of this group, was
isolated from different Cryptocarya species.2 The compound was
found to be active against the trypomastigots of Trypanosoma cruzi
reducing their number by 77% at 250
another related -pyrone derivative, was isolated from the genus
l
g/ml.3 (+)-Goniothalamin 2,
a
Cryptocarya4 and Goniothalamus.5 The compound displayed an
in vitro cytotoxic effect by inducing apoptosis on different cancer
cell lines, such as breast carcinoma, ovarian carcinoma, and leuke-
mia.6 The synthesis of both of these compounds (+)-cryptofolione
17 and (+)-goniothalamin 28 has recently become an attractive tar-
get to organic chemists. The stereoisomers of cryptofolione O-ben-
zyl ethers have also been synthesized.9 In continuation of our
an
a-OH group.
The reduction of alcohol 5 with lithium aluminium hydride in
THF afforded the chiral allylic alcohol 11 in high yield. The hydroxyl
group of 11 was acetylated and the PMB ether group of the product
12 was deprotected with DDQ in CH2Cl2–H2O (4:1) to furnish com-
pound 13. This acetate derivative underwent oxidation with IBX in
DMSO and the resulting aldehyde was subjected to Maruoka allyla-
tion12 with the Binol complex (S,S)-I and allyl tributyltin. The reac-
tion mixture was purified to give the desired fragment 3 and to
remove its minor diastereoisomer (3%). The 1,3-anti relationship
of the hydroxyl and acetoxy group in 3 was established by analysis
of the 13C NMR spectrum13 of the corresponding acetonide 16
(Scheme 3) prepared via the dihydroxy compound 15. The spec-
trum showed that the methyl groups of the acetonide appeared at
d 25.6 and 24.9 and the quaternary carbon at d 100.5.
work10 on the construction of natural
a-pyrones we have synthe-
sized 1 and 2 with a convenient approach through a common inter-
mediate.
O
O
OH
OH
O
O
1
2
24.9
25.6
2. Results and discussion
100.5 ppm
O
O
The retrosynthetic analysis (Scheme 1) suggested that (+)-cryp-
tofolione 1 could be prepared from intermediates 3 and 4 by olefin
cross-metathesis. Compound 3 can be obtained from the propargyl
Compound 3 was subsequently coupled (Scheme 1) with 4 by
olefin cross-metathesis reaction14 using Grubb’s second generation
catalyst. Compound 4 was previously prepared by us starting from
q
Part 48 in the series, ‘synthetic studies on natural products’.
Corresponding author.
E-mail address: biswanathdas@yahoo.com (B. Das).
⇑
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.029

1250
B. Das et al. / Tetrahedron: Asymmetry 22 (2011) 1249–1254
O
O
OAc OH
OH
OH
O
O
+
1
4
3
OH
OPMB
+
HO
OH
5
7
6
Scheme 1.
OH
O
OPMB
OPMB
b
6
d
HO
OH
OPMB
O
c
7
R=H
a
9
10
8
R=PMB
e
OH
OR
OAc
OPMB
OR1
i
f
O
5
R=H, R1=PMB
11
g
12 R=Ac, R1=PMB
j
h
R=Ac, R1=H
13
O
OR
OH
O
OAc OH
4
k
14
1
R=Ac
R=H
3
l
Scheme 2. Reagents and conditions: (a) NaH, PMB-Br, TBAI, THF, 0 °C to rt, 3 h, 90%; (b) PCC, DCM, Celite, rt, 1.5 h, 92%; (c) 6, n-BuLi, THF, 0 °C, 2 h, 89%; (d) IBX, DMSO, DCM,
0 °C to rt, 4 h, 88%; (e) (R)-(Me)-CBS (1.0 M in toluene), THF, BH3ꢀMe2S, ꢁ20 °C, 2 h, 70%, ee 97%; (f) LAH, THF, 0 °C to rt, 2 h, 89%; (g) Ac2O, Et3N, DMAP, DCM, 0 °C to rt, 45 min,
91%; (h) DDQ, DCM/H2O-8:2, 2.5 h, 83%; (i) IBX, DMSO, DCM, 0 °C to rt, 1.5 h, 92%; (j) (S,S)-I, allyl tributyl stannane, DCM, 0 °C, 18 h, 74%, (97:3, anti/syn ratio); (k) Grubb’s II
catalyst (0.01 mmol), DCM, 50 °C, 3 h, 71%; (l) 10% HCl, CH3CN–H2O, 6 h, 72%.
OR OH
O
O
b
3
R=Ac
R=H
a
16
15
Scheme 3. Reagents and conditions: (a) K2CO3, methanol, rt, 30 min, 84%; (b) 2,2-DMP, acetone, p-TSA, 3 h, 89%.

B. Das et al. / Tetrahedron: Asymmetry 22 (2011) 1249–1254
1251
L
-ascorbic acid.10c The coupling reaction afforded the
a-pyranone
zyl groups of the products were unsuccessful.9 In our present
method, the protecting group (acetate) was easily removed to gen-
erate the target molecule 1.
derivative 14 whose acetate group was hydrolyzed to produce
the target molecule (+)-cryptofolione 1. The spectroscopic data of
1 were identical to those reported earlier.7
The intermediate 13 (Scheme 2) was subsequently utilized for
the synthesis of another a-pyranone derivative, (+)-goniothalamin
2 (Scheme 4). The former was oxidized with IBX in DMSO to give the
corresponding aldehyde, which was subjected to Still–Gennari–
Wittig reaction with (CF3CH2O)2P(O)CH2COOMe to afford the
iPrO
O
Ti
O
O
O
O
a,b-unsaturated ester 17. The acetate group of this ester was hydro-
Ti
lyzed with methanolic K2CO3 and the resulting product 18 was
cyclized with methanol and PPTS to produce (+)-goniothalamin.
Another alternative approach for the synthesis of 2 was the cou-
pling of styrene 19 with 4 (Scheme 5) by olefin cross-metathesis
reaction using a Grubb’s second generation catalyst. The spectro-
scopic data of 2 prepared by both methods (Schemes 4 and 5) were
in good agreement with those reported earlier.8
iPrO
(S,S)-I
N
N
Cl
3. Conclusion
In conclusion, the stereoselective total synthesis of (+)-crypto-
folione and (+)-goniothalamin has been achieved via a common
intermediate. The synthesis employed the reduction of a propargyl
ketone and olefin cross-metathesis as the key steps.
Ru
Cl
Ph
P(Cy)3
Grubbs' Catalyst
4. Experimental
4.1. General
(II generation)
The Maruoka allylation using a Ti-Binol complex and the ring
closing metathesis were used previously in an approach for the
synthesis of cryptofolione 1.7c This method involved the addition
of a complex silyloxydiene with trans-cinnamaldehyde. The yield
of the metathesis reaction in this method was 58%. The synthesis
of the stereoisomers of cryptofolione-O-benzyl ethers also utilized
the metathesis reaction, but several attempts to deprotect the ben-
Silica gel F254 plates were used for thin layer chromatography
(TLC) in which the spots were examined under UV light and then
developed by an iodine vapor. Column chromatography was per-
formed with silica gel (BDH 100–200 mesh). Solvents were purified
according to standard procedures. The spectra were recorded with
OAc
OAc
b
a
O
OH
13
O
O
OAc
d
COOMe
17
18
R=Ac
R=H
2
c
Scheme 4. Reagents and conditions: (a) IBX, DMSO, DCM, 0 °C to rt, 4 h, 92%; (b) NaH, (CF3CH2O)2P(O)CH2COOMe, THF, 0 °C to ꢁ78 °C, 1 h, 84%; (c) K2CO3, methanol, rt,
30 min, 70%; (d) MeOH, PPTS, 0 °C to rt, 6 h, 76%.
O
O
O
Grubb's II catalyst
(0.01 mmol)
O
+
CH2Cl2
50ºC, 4h, 70%
4
2
19
Scheme 5.

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B. Das et al. / Tetrahedron: Asymmetry 22 (2011) 1249–1254
the following instruments; IR: Perkin–Elmer RX FT-IR spectropho-
tometer; NMR: Varian Gemini 200 MHz (1H) and 50 MHz (13C)
spectrometer; ESIMS: VG-Autospec micromass. Organic extracts
were dried over anhydrous Na2SO4. Optical rotations were mea-
sured with a JASCO DIP 300 digital polarimeter at 25 °C.
6.85 (2H, d, J = 8.0 Hz), 4.49 (2H, S), 3.86 (2H, t, J = 7.0 Hz), 3.78
(3H, s), 2.93 (2H, t, J = 7.0 Hz); 13C NMR (50 MHz): d 185.9,
159.5, 133.2, 132.1, 130.9, 130.0, 129.1, 128.2, 120.1, 114.0, 91.2,
87.9, 73.0, 64.3, 55.5, 45.2; ESIMS: m/z 295 [M+H]+; HRESIMS:
Calcd for
C
19H18O3Na m/z 317.1168 [M+Na]+, Found m/z
317.1153 [M+Na]+.
4.1.1. 3-(4-Methoxybenzyloxy) propan-1-ol 8
Propane-1,3-diol (5.0 g, 65.78 mmol) was taken in 50 mL of dry
THF. Next, NaH (60% dispersion in mineral oil, 2.49 g, 65.78 mmol)
was added in portions at 0 °C. The reaction mixture was stirred at
0 °C for 30 min. Tetrabutylammonium iodide (TBAI) (1.6 g,
0.66 mmol) was added to it followed by the addition of 4-meth-
oxybenzylbromide (13.2 g, 65.78 mmol) in THF (50 mL). The reac-
tion mixture was stirred for a further 2 h at room temperature.
Ice water (15 mL) was added carefully to the reaction mixture to
quench any excess of NaH. The reaction mixture was extracted
with EtOAc (50 mL). The organic layer was washed with water
(15 mL) and brine (20 mL). Evaporation and purification by means
of silica gel chromatography (EtOAc/hexane = 20:80) afforded
4.1.4. (R)-5-(4-Methoxybenzyloxy)-1-phenylpent-1-yn-3-ol 5
A 1 M solution of (R)-(Me)-CBS in toluene (4.29 mL, 4.08 mmol)
under a static atmosphere of N2 was dissolved in anhydrous THF.
To this solution was added BH3ꢀSMe2 (5.1 mL, 5 M in THF,
20.4 mmol) and the mixture was cooled to ꢁ20 °C. Then a solution
of propargyl ketone 9 (6 g, 20.4 mmol) in anhydrous THF was
added slowly via syringe and the mixture was stirred at ꢁ20 °C
for 2 h. The reaction was quenched with MeOH (20 mL) at the same
temperature and allowed to warm to 25 °C. The solvent was re-
moved under reduced pressure and the residue was purified by
column chromatography (ethyl acetate/hexane = 18:82) to afford
pure chiral alcohol
¼ þ50:5 (c 1.5, CHCl3); IR:
1247 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.40–7.16 (7H, m), 6.82,
5
as
a
pale brown oil (4.2 g, 70%).
compound 8 (11.6 g, 90%) as a colorless liquid. IR:
m
3393, 1613,
½
a 2D5
ꢃ
m
3425, 1612, 1513, 1443,
1513, 1462, 1248 cmꢁ1 1H NMR (200 MHz, CDCl3): 7.22 (2H, d,
;
;
J = 8.0 Hz), 6.83 (2H, d, J = 8.0 Hz), 4.41 (2H, s), 3.79 (3H, s), 3.70
(2H, d, J = 7.0 Hz), 3.56 (2H, d, J = 7.0 Hz), 2.52 (1H, br s), 1.86–
1.74 (2H, m); 13C NMR (50 MHz): d; ESIMS: m/z 197 [M+H]+, Anal.
Calcd for C11H16O3: C, 67.35; H, 8.16. Found: C, 67.46; H, 8.11.
(2H, d, J = 8.0 Hz), 4.78 (1H, m), 4.49 (2H, s), 3.88 (1H, m), 3.75
(3H, s), 3.67 (1H, m), 2.11 (1H, m), 1.99 (1H, m); 13C NMR
(50 MHz): d 159.2, 132.0, 129.9, 129.5, 128.7, 123.0, 113.9, 89.5,
84.8, 73.0, 67.2, 62.0, 55.1, 37.0; ESIMS: m/z 319 [M+Na]+; HRE-
SIMS: Calcd for C19H20O3Na m/z 319.1325 [M+Na]+, Found m/z
319.1316 [M+Na]+.
4.1.2. 5-(4-Methoxybenzyloxy)-1-phenylpent-1-yn-3-ol 9
To a stirred solution of 8 (8 g, 40.81 mmol) in dry CH2Cl2
(70 mL) was added Celite (50 g) and PCC (16.98 g, 61.21 mmol) at
0 °C and the reaction was stirred for 1.5 h at room temperature.
The reaction was diluted with ether (45 mL) and then passed
through a silica gel column and eluted with ethyl acetate/hexane
(10:90) to afford the corresponding aldehyde (7.28 g, 92%) as a col-
orless liquid.
To a solution (3.39 mL, 30.92 mmol) of phenyl acetylene in
50 ml of dry THF at 0 °C was added (19.3 mL, 30.92 mmol) of
n-BuLi (1.6 M in hexane). After 30 min, the aldehyde (6 g,
30.92 mmol) was added dropwise. After being stirred for 2 h, the
reaction was quenched with 25 mL of saturated NH4Cl solution
and extracted with EtOAc (3 ꢂ 35 mL). The combined organic ex-
tracts were washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue upon purification
by column chromatography (ethylacetate/hexane = 15:85) affor-
4.1.5. (R,E)-5-(4-Methoxybenzyloxy)-1-phenylpent-1-en-3-ol 11
To a stirred solution of LiAlH4 (0.535 g, 14.16 mmol) in dry THF
(5 mL) under N2 was added 7 (3.5 g, 11.82 mmol) dissolved in THF
(25 mL) at 0 °C. After stirring for 2 h, the reaction mixture was
quenched with a saturated Na2SO4 solution at 0 °C and filtered.
The residue was washed with EtOAc (45 mL) and the EtOAc layer
was concentrated under reduced pressure. The crude product
was purified by column chromatography (EtOAc/n-hexane—
19:81) to obtain 11 (3.115 g, 89%) as
¼ þ4:65 (c 1.75, CHCl3); IR: 3420, 1612, 1511, 1453,
1249 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.35–7.11 (7H. m), 6.81
a pale yellow oil;
½
a 2D5
ꢃ
m
;
(2H, d, J = 8.0 Hz), 6.54 (1H, d, J = 18.0 Hz), 6.15 (1H, dd, J = 18.0,
6.0 Hz), 4.49–4.37 (3H, m), 3.78 (3H, s), 3.69–3.54 (2H, m), 1.90–
1.79 (2H, m); 13C NMR (50 MHz): d 159.2, 137.0, 132.0, 130.1,
130.0, 129.6, 128.4, 128.2, 127.1, 126.8, 113.9, 73.1, 71.8, 67.9,
55.2, 36.2; ESIMS: m/z 321 [M+Na]+; HRESIMS: Calcd for
ded pure 5-(4-methoxybenzyloxy)-1-phenylpent-1-yn-3-ol
(8.14 g 89%) as a colorless liquid; IR: 3425, 1612, 1513, 1443,
1247 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.40–7.16 (7H, m), 6.82,
9
m
C
19H22O3Na m/z 321.1466 [M+Na]+, Found m/z 217.0508 [M+Na]+.
;
(2H, d, J = 8.0 Hz), 4.78 (1H, m), 4.49 (2H, s), 3.88 (1H, m), 3.75
(3H, s), 3.67 (1H, m), 2.11 (1H, m), 1.99 (1H, m); 13C NMR
(50 MHz): d 159.2, 132.0, 129.9, 129.5, 128.7, 123.0, 113.9, 89.5,
84.8, 73.0, 67.2, 62.0, 55.1, 37.0 ESIMS: m/z 319 [M+Na]+; HRESIMS:
Calcd for C19H20O3 m/z 319.1325 [M+Na]+, Found m/z 319.1310
[M+Na]+.
4.1.6. (R,E)-5-(4-Methoxybenzyloxy)-1-phenylpent-1-en-3-yl
acetate 12
To a stirred solution of compound 11 (3 g, 10.06 mmol) in dry
CH2Cl2 (25 mL) was added Et3N (4.2 mL, 30.2 mmol) followed by
acetic anhydride (1.8 mL, 20.13 mmol) and DMAP (0.12 g,
1.06 mmol) at 0 °C. The reaction mixture was continuously stirred
for 45 min and then diluted with CH2Cl2 (5 mL). The organic layer
was washed with brine (25 mL), and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure followed by col-
umn chromatography (ethylacetate/hexane = 5:95) afforded ace-
4.1.3. 5-(4-Methoxybenzyloxy)-1-phenylpent-1-yn-3-one 10
To an ice-cold solution of IBX (15.12 g, 54.05 mmol) in DMSO
(30 mL), was added a solution of 9 (8 g, 27.02 mmol) in anhydrous
CH2Cl2 (70 mL) and the reaction mixture was stirred at 25 °C for
4 h. The mixture was diluted with CH2Cl2 (20 mL), stirred for
4 h, filtered through a Celite pad, and the pad was washed with
CH2Cl2 (10 mL) The combined filtrates were washed with H2O
(5 mL), dried over anhydrous Na2SO4, and concentrate under re-
duced pressure and the residue was purified by column chroma-
tography (ethyl acetate/hexane = 2:48) to afford the pure
tate 12 (2.7 g, 91%) as a colorless liquid; ½a D25
ꢃ
¼ þ24:6 (c 0.8,
CHCl3); IR:
m ;
1735, 1612, 1511, 1453 cmꢁ1 1H NMR (200 MHz,
CDCl3): d 7.38–7.20 (7H, m), 6.86 (2H, d, J = 8.0 Hz), 6.60 (1H, d,
J = 18.0 Hz), 6.12 (IH, dd, J = 18.0, 8.0 Hz), 5.59 (1H, m), 4.42 (2H,
s), 3.79 (3H, s), 3.49 (2H, t, J = 7.0 Hz), 2.10–1.88 (5H, m); 13C
NMR (50 MHz): d 170.2, 159.1, 132.2, 130.1, 129.0, 128.1, 127.8,
126.9, 126.1, 125.8, 113.9, 72.9, 72.1, 65.3, 55.0, 34.8, 31.2; ESIMS:
m/z 363 [M+Na]+; HRESIMS: Calcd for C21H24O4Na m/z 363.1571
[M+Na]+, Found m/z 363.1572 [M+Na]+.
propargyl ketone 10 as a pale yellow liquid (7.1 g, 88%). IR:
1670, 1611, 1512, 1248 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.55
(2H, d, J = 8.0 Hz), 7.48–7.34 (3H, m), 7.28 (2H, d, J = 8.0 Hz),
m
;

B. Das et al. / Tetrahedron: Asymmetry 22 (2011) 1249–1254
1253
4.1.7. (R,E)-5-Hydroxy-1-phenylpent-1-en-3-yl acetate 13
To a stirred solution of compound 12 (2 g, 5.88 mmol) in
CH2Cl2/H2O (8:2) was added DDQ at 0 °C (1.44 g, 6.47 mmol) and
stirred for 2.5 h. The solution was quenched with solid NaHCO3
(100 mg) at 0 °C, filtered through a Celite pad, and washed with
CH2Cl2 (10 mL). Concentration of the residue under reduced pres-
sure followed by purification by column chromatography (ethyl
acetate/hexane = 25:75) pure compound 13 (1.032 g, 83%) as a pale
(1H, m), 6.61 (1H, d, J = 18.0 Hz), 6.15 (1H, d, 18.0, 8.0 Hz), 6.02
(1H, d, J = 8.0 Hz), 5.88 (1H, m), 5.75–5.60 (2H, m), 4.88 (1H, m),
3.62 (1H, m), 2.48–2.32 (3H, m), 2.29–2.20 (2H, m), 2.12 (3H, s),
1.80–1.62 (2H, m); 13C NMR (50 MHz): d 170.2, 164.3, 145.1,
136.8, 132.1, 131.1, 130.2, 130.1, 128.6, 127.7, 126.5, 121.3, 76.7,
70.5, 68.2, 42.2, 40.4, 29.5, 22.3; ESIMS: m/z 379 [M+Na]+; Anal.
Calcd for C21H24O5: C, 70.79; H, 6.74. Found: C, 70.68; H, 6.77.
yellow oil; ½a 2D5
ꢃ
¼ þ17:3 (c 1.15, CHCl3); IR:
m
3430, 1732, 1449,
4.1.10. 6-[(1E,4R,6S,7E)-4,6-Dihydroxy-8-phenylocta-1,7-dien-1-
yl]-5,6-dihydro-2H-pyran-2-one [(+)-cryptofolione)] 1
1372, 1242 cmꢁ1
;
1H NMR (200 MHz, CDCl3): 7.39–7.21 (5H, m),
6.62, (1H, d, J = 18.0 Hz), 6.15 (1H, dd, J = 18.0, 8.0 Hz), 5.62 (1H,
m), 3.72–3.55 (2H, m), 2.11 (3H, s), 1.98–1.85 (2H, m); 13C NMR
(50 MHz): 171.2, 136.1, 132.8, 128.5, 128.0, 126.9, 126.1, 72.1,
58.3, 37.8, 21.1; ESIMS: m/z 243 [M+Na]+; Anal. Calcd for
An aqueous 10% soln of HCl (2 mL) was added to a stirred solu-
tion of 14 (0.12 g, 0.38 mmol) in MeCN (5 mL) at 0 °C, and the mix-
ture was stirred at 0 °C for 6 h. The reaction was quenched with
solid NaHCO3 (150 mg) and the mixture was filtered. The filtrate
was concentrated under reduced pressure, and the crude product
was purified by column chromatography (EtOAc/hexane, 60:40)
to afford (+)-cryptofolione 1 (74 mg, 72%) as a colorless oil. The
spectroscopic properties of the compound were similar to those re-
C13H16O3: C, 70.91; H, 7.27. Found: C, 70.83; H, 7.32.
4.1.8. (3R,5S,E)-5-Hydroxy-1-phenylocta-1,7-dien-3-yl acetate 3
To an ice-cold solution of IBX (2.3 g, 8.26 mmol) in DMSO
(8 mL) was added a solution of 13 (1 g, 4.13 mmol) in anhydrous
CH2Cl2 and the reaction mixture was stirred at 25 °C for 1.5 h.
The mixture was diluted with CH2Cl2 (5 mL), filtered through a
Celite pad, and the pad was washed with CH2Cl2. The combined fil-
trates were washed with H2O (10 mL), dried over anhydrous
Na2SO4, and the residue concentrated under reduced pressure to
afford the aldehyde, (0.91 g, 92%) which was used directly after
flash chromatography for the next reaction.
ported earlier.7 ½a D25
ꢃ
¼ þ45:6 (c 0.44, CHCl3) IR:
m 3442, 1711, 1639,
1384, 1252 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 7.38–7.14 (2–5H,
m), 6.83 (1H, m), 6.60 (1H, d, J = 16.0 Hz), 6.23 (1H, dd, J = 16.0,
7.0 Hz), 5.99 (1H, d, J = 8.0 Hz), 5.87 (1H, m), 5.62 (1H, dd,
J = 16.0, 7.0 Hz), 4.84 (1H, m), 4.60 (1H, m), 4.01, (1H, m), 3.24
(2H, br s), 2.42–2.33 (2H, m), 2.25 (2H, t, J = 7.0 Hz), 1.80–1.62
(2H, m); 13C NMR (50 MHz): d 164.2, 145.0, 136.6, 132.0, 131.1,
130.1, 130.0, 128.9, 127.9, 126.8, 121.5, 76.5, 70.3, 68.0, 42.1,
40.2, 29.7; ESIMS: m/z 337; HRESIMS: Calcd for C19H24O4Na m/z
337.1428 [M+Na]+, Found m/z 337.1415 [M+Na]+.
To a stirred solution of TiCl4 (0.03 g, 0.20 mmol) in CH2Cl2
(2 mL) was added dried Ti(OiPr)4 (0.17 g, 0.61 mmol) at 0 °C under
a nitrogen atmosphere and the mixture was allowed to warm to
room temperature. After 1 h, silver(I) oxide (0.09 g, 0.41 mmol)
was added at room temperature, and the mixture was stirred for
5 h under exclusion of direct light. The mixture was diluted with
CH2Cl2 (3 mL), and treated with (S)-BINOL (0.17 g, 0.53 mmol) at
room temperature for 2 h to furnish chiral bis-Ti (IV) oxide (S,S)-
I. The in situ generated (S,S)-I was cooled to ꢁ15 °C, and treated
sequentially with the aldehyde (0.9 g, 4.12 mmol) and allyltri-
nbutyltin (1.4 mL, 5.35 mmol) at the same temperature. The mix-
ture was allowed to warm to 0 °C and stirred for 18 h. The reaction
mixture was quenched with saturated aqueous NaHCO3 and ex-
tracted with ether (3 x 4 mL). The organic extracts were dried over
anhydrous Na2SO4. Evaporation of the solvents and purification of
the residue by column chromatography on silica gel (EtOAc/hex-
ane = 20:80) gave homoallyl alcohol 3 (0.357 g, 74%) as a pale yel-
4.1.11. (3R,5S,E)-1-Phenylocta-1,7-diene-3,5-diol 15
To a stirred solution of compound 3 (0.15 g, 0.57 mmol) in
CH3OH, was added K2CO3 (0.39 g, 2.88 mmol) at 25 °C and stirred
for 30 min. Then the solution was filtered and the filtrate concen-
trated in vacuo and purified by column chromatography (EtOAc/
hexane = 40:60) to afford compound 15 (0.105 g, 84%) as a pale
yellow oil. ½a 2D5
ꢃ
¼ þ36:4 (c 0.5, CHCl3); IR:
m 3414, 1642, 1446,
1252 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.38–7.15 (5H, m), 6.61
;
(1H, d, J = 18.0 Hz), 6.23 (1H, dd, J = 18.0, 8.0 Hz), 5.80 (1H, m),
5.18–5.10 (2H, m), 4.61 (1H, m), 4.01 (1H, m), 2.31–2.20 (2H, m),
1.81–1.72 (2H, m); 13C NMR (50 MHz): d 137.0, 134.2, 131.9,
130.0, 128.8, 127.9, 126.3, 118.5, 70.3, 68.0, 42.0; ESIMS: m/z 241
[M+Na]+; Anal. Calcd for C14H18O2: C, 77.06; H, 8.26. Found: C,
77.18; H, 8.21.
low liquid; ½a 2D5
ꢃ
¼ þ25:1 (c 0.15, CHCl3); IR:
m 3450, 1735, 1446,
1373, 1242 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 7.32–7.04 (5H,
4.1.12. (4S,6R,E)-4-Allyl-2,2-dimethyl-6-styryl-1,3-dioxane 16
To a stirred solution of compound 15 (0.07 g, 0.271 mmol) in
dry acetone (3 mL) under an N2 atmosphere at 0 °C was added p-
TSA (20 mg) followed by 2,2-dimetoxy propane. (0.4 mL,
0.325 mmol). The solution was stirred for 3 h, and then quenched
with solid NaHCO3 powder (30 mg) and filtered. The filtrate was
concentrated under reduced pressure and subjected to column
chromatography (EtOAc/hexane = 10:90) to afford pure compound
m), 6.54 (1H, d, J = 18.0 Hz), 5.10 (1H, dd, J = 18.0, 8.0 Hz), 5.72
(1H, m), 5.59 (1H, m), 5.10–4.93 (2H, m), 3.61 (1H, m), 2.32–2.15
(2H, m), 2.02 (3H, s), 1.81–1.62 (2H, m); 13C NMR (50 MHz): d
170.3, 137.0, 134.4, 132.2, 129.9, 128.8, 127.5, 126.4, 118.8, 70.3,
68.0, 46.0, 42.1, 21.1; ESIMS: m/z 283 [M+Na]+; HRESIMS: calcd
for
C
16H20O3Na m/z 283.1303 [M+Na]+, found m/z 283.1310
[M+Na]+.
16 (67 mg, 89%) as a colorless oil. ½a D25
ꢃ
¼ þ47:2 (c 1.0, CHCl3); IR:
m
4.1.9. (1E,3R,5S,7E)-5-Hydroxy-8-((R)-6-oxo-3,6-dihydro-2H-
pyran-2-yl)-1-phenylocta-1,7-dien-3-yl acetate 14
1643, 1605, 1445, 1271 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.36–
;
7.14 (5H, m), 6.51 (1H, d, J = 18.0 Hz), 6.17 (1H, dd, J = 18.0,
8.0 Hz), 5.80 (1H, m), 5.12–5.02 (2H, m), 4.48 (1H, m), 3.91 (1H,
m), 2.38–2.19 (2H, m), 1.89–1.72 (2H, m), 1.39 (6H, s); 13C NMR
(50 MHz): d 136.9, 134.5, 130.5, 129.9, 128.5, 127.4, 126.5, 117.2,
100.5, 68.1, 66.1, 40.2, 37.4, 25.5, 24.9; ESIMS: m/z 281 [M+Na]+;
Anal. Calcd for C17H22O2: C, 79.07; H, 8.53. Found: C, 79.23; H, 8.47.
A solution of compound 3 (0.15 g, 0.5769 mmol) and compound
4 (0.031 g, 0.28846 mmol) in dry CH2Cl2 (15 mL) was first bubbled
with an N2 flow, after which Grubb’s second generation catalyst
(5 mg, 0.01 mmol) was added at once and the resulting mixture
heated under N2 at 50 °C for 3 h. After cooling the solvent was
evaporated in vacuo. The residue upon purification by column
chromatography (ethyl acetate/hexane = 80:20) afforded pure
(1E,3R,5S,7E)-5-hydroxy-8-((R)-6-oxo-3,-dihydro-2H-pyran-2-yl)-
1-phenylocta-1,7-dien-3-yl acetate 14 (0.1479 g, 71%) as a color-
4.1.13. (5R,2Z,6E)-Methyl 5-acetoxy-7-phenylhepta-2,6-
dienoate 17
To an ice-cold solution of IBX (0.51 g, 0.18 mmol) in DMSO
(2 mL), was added a solution of 13 (0.2 g, 0.91 mmol) in anhydrous
CH2Cl2 and the reaction mixture was stirred at 25 °C for 3 h. The
less liquid. ½a 2D5
ꢃ
¼ þ7:7 (c 0.4, CHCl3); IR:
m 3447, 1720, 1378,
1244 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.39–7.20 (5H, m), 6.84
;

1254
B. Das et al. / Tetrahedron: Asymmetry 22 (2011) 1249–1254
mixture was diluted with CH2Cl2 (2 mL). The solution was stirred
for 4 h, filtered through a Celite pad, and the pad was washed with
CH2Cl2 (3 mL). The combined filtrates were washed with H2O
(4 mL), dried over anhydrous Na2SO4, and concentrated under re-
duced pressure to afford the aldehyde, (0.18 g, 92%) which was
used directly after flash chromatography for the next reaction.
To a suspension of NaH (60% dispersion in mineral oil, 0.034 g,
0.90 mmol) under an N2 atmosphere in dry THF (2 mL) was added
bis-(2,2,2-trifluoroehtyl)(methoxy-carbonyl methyl) phosphonate
(0.3 mL, 0.99 mmol) at 0 °C. After the mixture was stirred for
30 min at the same temperature, the reaction mixture was cooled
to ꢁ78 °C, and then a solution of the aldehyde (0.18 g, 0.82 mmol)
in dry THF was added dropwise. After stirring for 1 h, the reaction
mixture was diluted with 5 mL of ether and quenched by the slow
addition of 2 mL of water. The reaction mixture was extracted with
ether (2 ꢂ 3 mL). The combined organic extracts were washed with
brine (5 mL), dried over anhydrous Na2SO4, and concentrated in va-
cuo. The residue upon purification by column chromatography
(ethyl acetate/hexane, 2:8) afforded pure (5R,2Z,6E)-methyl-5-
acetoxy-7-phenylhepta-2,6-dienoate 17 (0.16 g, 84%) as a colorless
purification by column chromatography (ethyl acetate/hexane,
5:5) afforded pure (+)-goniothalamin 2 (51 mg, 70%) as a white so-
lid. The spectroscopic data of 2 prepared by both methods were in
good agreement with those reported earlier.8
½
a 2D5
ꢃ
¼ þ167:8 (c
1.34, CHCl3); IR:
m
1719, 1651, 1381, 1243 cmꢁ1 1H NMR
;
(200 MHz, CDCl3): d 7.40–7.22 (5H, m), 6.91 (1H, m), 6.71 (1H,
dd, J = 18.0 Hz), 6.23 (1H, dd, J = 18.0, 6.0 Hz), 6.08 (1H, d,
J = 10.0 Hz), 5.09 (1H, m), 2.58–2.51 (2H, m) 13C NMR (50 MHz):
d 164.2, 144.8, 136.0, 133.1, 128.3, 126.9, 125.9, 121.9, 78.0, 29.6
ESIMS: m/z 223 (M+Na)+ Anal. Calcd for C13H12O2: C, 78.00; H,
6.00. Found: C, 78.21; H, 6.08.
Acknowledgments
The authors thank CSIR and UGC, New Delhi for financial
assistance.
References
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oil; ½a 2D5
ꢃ
¼ þ6:1 (c 1.45, CHCl3); IR:
m ;
1720, 1628, 1485, 1260 cmꢁ1
1H NMR (200 MHz, CDCl3): d 7.40–7.22 (5H, m), 6.62 (1H, d,
J = 16.0 Hz), 6.27 (1H, dd, J = 16.0, 7.0 Hz), 6.11 (1H, dd, J = 8.0,
5 Hz), 5.89 (1H, d, J = 8.0 Hz), 5.52 (1H, m), 3.72 (3H, s), 3.11 (2H,
t, J = 7.0 Hz), 2.08 (3H, s); 13C NMR (50 MHz): d 17.5, 166.8,
144.2, 133.1, 131.9, 129.1, 128.8, 127.9, 126.5, 122.0, 73.7, 51.2,
34.0, 21.1; ESIMS: m/z 297 (M+Na)+ Anal. Calcd for C16H18O4: C,
70.07; H, 6.57. Found: C, 70.18; H, 6.62.
4.1.14. (R,E)-6-Styryl-5,6-dihydropyran-2-one[(+)-goniothalmin]
2
To a stirred solution of compound 17 (0.15 g, 0.57 mmol) in
CH3OH, was added K2CO3 (0.302 g, 2.1 mmol) at 25 °C and stirred
for 30 min. Then the solution was filtered and the filtrate was con-
centrated in vacuo and purified by column chromatography
(EtOAc/hexane—15:85) to afford compound 18 (0.09 g, 76%) as a
colorless oil.
7. (a) Matsuoka, Y.; Aikawa, K.; Irie, R.; Katsuki, T. Heterocycles 2005, 66, 187; (b)
Sabitha, G.; Reddy, S. S. S.; Reddy, D. V. Synthesis 2010, 3453; (c) Kumar, R. N.;
Meshram, H. M. Tetrahedron Lett. 2011, 52, 1003.
8. (a) de Fatima, A.; Pilli, R. A. Arkivoc 2003, 118; (b) de Fathima, A.; Kohn, L. K.;
Antonio, M. A.; de Carvalho, J. E.; Pilli, R. A. Bioorg. Med. Chem. 2005, 13, 2927;
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4.1.14.1. Method A.
To a stirred solution of compound 18
(0.06 g, 0.25 mmol) in CH3OH at 0 °C was added pyridinium p-tol-
uene sulfonate (25 mg) and stirred for 6 h. The solution was
quenched with solid NaHCO3 powder (40 mg), filtered, and con-
centrated under reduced pressure and subjected to column chro-
matography (EtOAc/hexane = 5:5) to afford pure (+)-goniothalmin
2 (38 mg, 76%) as a white solid.
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4.1.14.2. Method B.
A solution of compound 19 (0.039 g,
0.018 mmol) and compound 4 (0.04 g, 0.37 mmol) in dry CH2Cl2
(5 mL) was first bubbled with an N2 flow, after which Grubb’s sec-
ond generation catalyst (5 mg, 0.01 mmol) was added at once and
the resulting mixture heated under N2 at 50 °C for 4 h. After
cooling the solvent was evaporated in vacuo. The residue upon