Stereoselective total synthesis of dodoneine

Article abstract of DOI:10.1002/hlca.200900478

A simple and highly efficient stereoselective total synthesis of dodoneine (1), a naturally occurring bioactive 5,6-dihydro-2H-pyran-2-one, was achieved. The synthesis involved Keck's asymmetric allylation, iodine-induced electrophilic cyclization, and Gr

Full text of DOI:10.1002/hlca.200900478

1960
Helvetica Chimica Acta – Vol. 93 (2010)
Stereoselective Total Synthesis of Dodoneine
by Baggu Chinnababu, Sudina Purushotham Reddy, Chitturi Bhujanga Rao, Karuturi Rajesh, and
Yenamandra Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad 500007, India (phone: þ 91-40-27193167; fax: þ 91-40-27160512; e-mail: luchem@iict.res.in)
A simple and highly efficient stereoselective total synthesis of dodoneine (1), a naturally occurring
bioactive 5,6-dihydro-2H-pyran-2-one, was achieved. The synthesis involved Keckꢀs asymmetric
allylation, iodine-induced electrophilic cyclization, and Grubbsꢀ catalyzed ring-closing metathesis as
key steps.
Introduction. – The 6-substituted 5,6-dihydro-2H-pyran-2-one A, an a,b-unsatu-
rated d-lactone, is an important structural subunit in many biologically promising
natural products. This unit is of interest for a wide variety of biological activities, such as
insect-growth inhibitors and insect antifeedent, cytotoxic activities, and antifungal and
antitumor properties [1]. The pyran units are widely distributed in all parts including
leaves, stems, flowers and fruits of the plant families Lamiaceae, Piperaceae,
Lauraceae, and Annonaceae (for a recent review on the synthesis of naturally
occurring representatives of the pyran-containing compound class, see [2]). Dodoneine
(¼(6R)-5,6-dihydro-6-[(2S)-2-hydroxy-4-(4-hydroxyphenyl)butyl]-2H-pyran-2-one;
1), a member of this group, has been isolated from Tapinanthus dodoneifolius, a
parasitic medicinal plant that grows on the Sheanut trees in Loumbila, West Africa [3].
The structure of 1 was determined from spectroscopic data and X-ray diffraction
analysis of a crystalline derivative. Considering the structure as well as its activity and in
continuation of our interest in the synthesis of biologically active natural products [4],
we report herein an efficient alternative way for the stereoselective synthesis of 1.
While our work on the synthesis of 1 was in progress, four different syntheses of this
molecule have appeared [5].
Our planned approach to dodoneine (1) involves Grubbsꢀ catalyzed ring-closing
metathesis, an asymmetric allylation, and a diastereoselective iodolactonization as the
chirality-inducing steps starting from 4-hydroxybenzaldehyde (Scheme 1).
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 93 (2010)
1961
Scheme 1. Retrosynthetic Approach to Dodoneine (1)
Results and Discussion. – The retrosynthetic analysis of dodoneine (1) (Scheme 1)
suggested to start the synthesis with commercially available 4-hydroxybenzaldehyde
(2), which was protected with BnBr to yield the corresponding benzyl ether. The benzyl
ether was subjected to C2 homologation with ethyl (triphenylphosphoranylidene)ace-
tate to afford an a,b-unsaturated ester, which on reduction with LiAlH4 afforded
alcohol 3 (Scheme 2). The saturated alcohol 3 was oxidized with 2-iodoxybenzoic acid
(IBX) in DMSO to afford the corresponding aldehyde 4, which was subjected to the
catalytic asymmetric allylation with an allylstannane developed by Keck and co-
workers [6] to furnish the homoallylic alcohol 5 in 79% yield with an excellent
enantioselectivity of 94.7% ee (see Exper. Part). The homoallylic alcohol 5 was treated
with di(tert-butyl) dicarbonate ((Boc)2O) in the presence of DMAP in MeCN [7] to
afford the homoallylic tert-butyl carbonate 6, which was subjected to the diastereo-
selective iodolactonization [8] with I2 in dry MeCN at ꢀ 208 to furnish the cyclic
iodocarbonate 7 in 82% yield as a single diastereoisomer (as determined by 1H-NMR
analysis). Iodocarbonate 7, upon exposure to basic MeOH solution [8], gave the
desired ꢃsynꢀ-epoxy alcohol 8 in 86% yield. The epoxy alcohol 8 was protected with
tBuMe2SiCl/1H-imidazole to afford (tert-butyl)dimethylsilyl ether 9. Now, the terminal
oxirane moiety of 9 was opened with CH2¼CHMgBr to provide a diastereoisomer
mixture (ꢃsynꢀ/ꢃantiꢀ 43 :57 by 1H-NMR analysis) of homoallylic alcohols. The required
ꢃsynꢀ-alcohol 10 was separated by CC, and its structure was determined by spectro-
scopic analysis of the corresponding acetonide B, in the 13C-NMR spectrum of which
two Me groups and the quaternary C-atom appeared at d(C) 20.3, 30.4, and 97.8 [9].
The alcohol 10 was then treated with acryloyl chloride (¼ prop-2-enoyl chloride) to
afford the diene ester 11 in 90% yield. Compound 11 was subjected to an intra-
molecular ring-closure metathesis reaction in the presence of the 1st generation
Grubbsꢀ catalyst to yield a,b-unsaturated lactone 12 in 82% yield [10]. The protecting
benzyl ether and (tert-butyl)dimethylsilyl ether moieties of 12 were removed with TiCl4
to afford dodoneine (1). The physical and spectroscopic data of the synthetic
dodoneine (1) were identical to those reported for natural dodoneine [3].

1962
Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
a) K2CO3, BnBr, DMF, 08 ! r.t., 6 h; 83%. b) Ph3PCHCOOEt, benzene, reflux, 2 h; 90%. c). LiAlH4,
THF, 808, 0.5 h; 80%. d) 2-Iodoxybenzoic acid, DMSO, CH2Cl2, 3 h; 90%. e) (R)-BINOL, 4-ꢄ molecular
sieves, (i-PrO)4Ti, allyltributylstannane, CH2Cl2, ꢀ 78 !ꢀ 208, 72 h; 79%. f) (Boc)2O, DMAP (¼ N,N-
dimethylpyridin-4-amine), MeCN, r.t., 5 h; 94%. g) I2, MeCN, ꢀ 208, 12 – 15 h; 82%. h) K2CO3, MeOH,
t
08 ! r.t., 2 h; 86%. i) BuMe2SiCl, 1H-imidazole, CH2Cl2, r.t., 4.5 h; 88%. j) CH2¼CHMgBr, Et2O, 08,
1.5 h; 76%. k) Acryloyl chloride, Et3N, 08 ! r.t., 1 h; 90%. l) Grubbsꢀ first generation catalyst, CH2Cl2,
508, 28 h; 82%. m) TiCl4, CH2Cl2, 08, 2 h; 82%.
In conclusion, an efficient and straightforward total synthesis of dodoneine (1) was
achieved. The Keck asymmetric allylation of aldehyde 4 for the introduction of chirality
and the subsequent diastereoselective I2-induced electrophilic cyclization constitute the

Helvetica Chimica Acta – Vol. 93 (2010)
1963
key reactions for the construction of the ꢃsynꢀ-1,3-diol moiety. The synthetic strategy
described here has a significant potential for the synthesis of a variety of other
biologically important substituted 1,3-diol-containing natural products.
The authors thank the Ministry of Earth Sciences (MoES) and the Council of Scientific and
Industrial Research (CSIR), New Delhi, for financial assistance, and the director of the IICT.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros and were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under N2. Org. solns. were dried
(Na2SO4) and concentrated below 408. Column chromatography (CC): silica gel (Acmeꢀs 60 – 120 mesh).
HPLC: Eurocel 01 (250 ꢁ 4.6 mm, particle size 5 mm); mobile phase hexane/i-PrOH 90 :10; flow rate
1.0 ml/min; detection with a photo-diode array. Optical rotations: Horiba high-sensitive polarimeter
SEPA-300; at 258. IR Spectra: Perkin-Elmer-IR-683 spectrophotometer with NaCl optics; ˜n in cmꢀ1. 1H-
(200 and 300 MHz) and 13C-NMR (50 and 75 MHz) Spectra: Varian-Gemini-FT-200 and Bruker-Avance-
300 instrument; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Agilent-Technologies
instrument, 1100 series (Agilent ChemStation software); in m/z (rel. %).
4-(Benzyloxy)benzaldehyde. To a soln. of aldehyde 2 (10.0 g, 81.88 mmol) and K2CO3 (33.86 g,
245.6 mmol) in dry DMF (70 ml) at 08 was added BnBr (90.21 mmol, 10.9 ml) under N2, and the mixture
was stirred overnight. After completion of the reaction (TLC), it was quenched with H2O (50 ml) and
50% AcOEt/hexane (60 ml) at 08 and then extracted with AcOEt (3 ꢁ 50 ml). The combined org. extract
was washed with brine, dried (Na2SO4), and concentrated, and the residue purified by CC (AcOEt/
hexane 1:1): pure 4-(benzyloxy)benzaldehyde (14.41 g, 83%). White solid. IR (neat): 2956, 1741, 1681,
1510, 1251. 1H-NMR (200 MHz): 9.84 (s, 1 H); 7.80 (d, J ¼ 8.7, 2 H); 7.43 – 7.35 (m, 5 H); 7.08 (d, J ¼ 8.7,
2 H); 5.02 (s, 2 H). 13C-NMR (50 MHz): 199.6; 163.7; 133.5; 132.1; 129.9; 128.6; 128.0; 127.5; 114.7; 69.9.
ESI-MS: 235 ([M þ Na]þ).
Ethyl (2E)-3-[4-(Benzyloxy)phenyl]prop-2-enoate. To a stirred soln. of 4-(benzyloxy)benzaldehyde
(5.0 g, 23.58 mmol) in dry benzene (50 ml) was added ethyl (triphenylphosphoranylidene)acetate
(10.66 g, 30.65 mmol), and the mixture was refluxed for 2 h. After completion of the reaction (TLC), the
mixture was diluted with H2O (40 ml) and extracted with AcOEt (3 ꢁ 25 ml), and the combined extract
was concentrated. The residue was purified by CC (AcOEt/hexane 2 :8): pure ethyl (2E)-3-[4-
(benzyloxy)phenyl]prop-2-enoate (5.9 g, 90%). Colorless solid. IR (neat): 1710, 1650, 1565, 1510, 1243,
943. 1H-NMR (200 MHz): 7.61 (d, J ¼ 16.1, 1 H); 7.43 – 7.22 (m, 7 H); 6.88 (d, J ¼ 8.7, 2 H); 6.25 (d, J ¼
16.1, 1 H); 5.08 (s, 2 H); 4.20 (q, J ¼ 7.2, 2 H); 1.28 (t, J ¼ 7.2, 3 H). 13C-NMR (50 MHz): 166.27; 160.2;
143.8; 136.2; 129.4; 128.3; 127.8; 127.1; 115.6; 114.9; 69.7; 59.9; 14.2. ESI-MS: 305 ([M þ Na]þ).
3-[4-(Benzyloxy)phenyl]propan-1-ol (3). To a stirred soln. of LiAlH4 (0.269 g, 7.09 mmol) in dry
THF was added ethyl (E)-3-[4-(benzyloxy)phenyl]prop-2-enoate (2 g, 7.09 mmol) at 08 under N2 and
refluxed for 0.5 h. After completion of the reaction (TLC), the mixture was diluted with H2O (50 ml) at
08 and extracted with AcOEt (2 ꢁ 15 ml). The combined org. extract was washed with brine, dried
(Na2SO4), and concentrated, and the residue purified by CC (hexane/AcOEt 3 :7): pure 3 (1.33 g, 80%).
1
Colorless crystalline solid. IR (neat): 3432, 1612, 1509, 1249. H-NMR (200 MHz): 7.43 – 7.35 (m, 5 H);
7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 5.01 (s, 2 H); 3.65 (t, J ¼ 7.1, 2 H); 2.62 (t, J ¼ 7.1, 2 H); 2.08 (br.
s, 1 H); 1.98 – 1.81 (m, 2 H).13C-NMR (50 MHz): 157.8; 136.6; 134.5; 129.2; 128.7; 128.0; 127.1; 114.3;
70.0; 62.3; 33.3; 19.6. ESI-MS: 265 ([M þ Na]þ).
(3S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol (5). To a stirred soln. of iodoxybenzoic acid (2.5 g,
9.15 mmol) in dry DMSO (8 ml) was added a soln. of 3 (1.5 g, 6.19 mmol) in dry CH2Cl2 (35 ml) at r.t.
and stirred for 5 h. After completion of the reaction, the mixture was filtered, diluted with H2O (25 ml),
and extracted with CH2Cl2 (2 ꢁ 30 ml). The combined org. layer was washed with brine (20 ml), dried
(Na2SO4), and concentrated, and the residue purified by CC (hexane/AcOEt 1:9): (1.33 g, 90%) of 4.
Colorless solid.

1964
Helvetica Chimica Acta – Vol. 93 (2010)
Separately, a mixture of (R)-BINOL (0.31 g, 1.1 mmol) and (i-PrO)4Ti (0.15 g, 0.55 mmol) in CH2Cl2
(30 ml) in the presence of 4-ꢄ molecular sieves (2.6 g) was stirred under reflux. After 1 h, the mixture
was cooled to r.t., 4 (1.3 g, 5.54 mmol) was added, and the resulting mixture was stirred for 10 min. Then,
the mixture was cooled to ꢀ 788, allyltributylstannane (2.3 g, 7.2 mmol) was added, and stirring was
continued at ꢀ 208 for 72 h. After completion of the reaction (TLC), the reaction was quenched with sat.
NaHCO3 soln. (5 ml), stirred for an additional 45 min, and extracted with CH2Cl2 (40 ml). The org. phase
was washed with H2O (15 ml), dried (Na2SO4), and concentrated and the residue purified by CC
(AcOEt/hexane 2 :8): 5 (1.20 g, 79%). Colorless solid. HPLC (Chiralpack IB (250 ꢁ 4.6 mm, 5 mm),
hexane/i-PrOH 95 :5, flow rate 1 ml/min, UV/VIS detector): 94.69% ee. [a]2D5 ¼ ꢀ16 (c ¼ 1.8, CHCl3). IR
(neat): 3441, 2924, 2856, 1610, 1509, 1457, 1378, 1236, 1174, 1020. 1H-NMR (CDCl3, 300 MHz): 7.43 – 7.29
(m, 5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 5.88 – 5.07 (m, 1 H); 5.19 – 5.07 (m, 1 H); 5.02 (s,
2 H); 3.69 – 3.58 (m, 1 H); 2.81 – 2.56 (m, 2 H); 2.36 – 2.09 (m, 2 H); 1.79 – 1.68 (m, 2 H); 1.64 – 1.52 (br. s,
1 H). 13C-NMR (75 MHz): 157.05; 137.2; 134.2; 129.3; 128.5; 127.8; 127.4; 118.3; 114.8; 69.99; 69.77; 42.2;
38.70; 31.18. HR-ESI-MS: 300.1957 ([M þ NH4]þ, C19H26NO2þ ; calc. 300.1958).
Carbonic Acid (1S)-1-{2-[4-(Benzyloxy)phenyl]ethyl}but-3-en-1-yl tert-Butyl Ester (6). To a soln. of
5 (1.23 g, 4.36 mmol) in MeCN (40 ml) were added (Boc)2O (1.42 g, 6.54 mmol) and DMAP (0.53 g,
4.36 mmol), and the mixture was stirred for 5 h. After completion of the reaction (TLC), the solvent was
evaporated, the residue dissolved in CH2Cl2 (30 ml), the org. phase washed with 5% HCl soln. (3 ꢁ
20 ml), dried (Na2SO4), and concentrated, and the crude product purified by CC (silica gel, hexane/
AcOEt 9 :1): 6 (1.56 g, 94%). Colorless oil. [a]2D5 ¼ ꢀ8 (c ¼ 2, CHCl3). IR (neat): 2923, 2854 1736, 1636,
1368, 1510, 1459, 1369, 1277, 1165. 1H-NMR (CDCl3, 300 MHz): 7.43 – 7.35 (m, 5 H); 7.08 (d, J ¼ 8.7, 2 H);
6.88 (d, J ¼ 8.7, 2 H); 5.84 – 5.72 (m, 1 H); 5.06 (d, J ¼ 8.8, 1 H); 5.02 (s, 2 H); 4.74 – 4.68 (m, 1 H); 2.74 –
2.53 (m, 2 H); 2.37 (t, J ¼ 6.8, 2 H); 1.95 – 1.78 (m, 2 H); 1.5 (s, 9 H). 13C-NMR (75 MHz): 159.6; 154.7;
133.4; 129.3; 128.5; 127.8; 127.4; 118.0; 114.8; 85.9; 75.8; 70.0; 38.9; 35.7; 30.8; 27.9. ESI-MS: 405.21 ([M þ
Na]þ).
(4S,6S)-4-{2-[4-(Benzyloxy)phenyl]ethyl}-6-(iodomethyl)-1,3-dioxan-2-one (7). To a stirred soln. of
6 (1.54 g, 4.03 mmol) in dry MeCN (25 ml) was added I2 (2.04 g, 8.06 mmol) at ꢀ 408 and stirred for 10 h.
After completion of the reaction (TLC), aq. Na2S2O3 soln. (50 ml) followed by aq. NaHCO3 soln. (40 ml)
were added. The mixture was then extracted with AcOEt (3 ꢁ 30 ml), the extract washed with H2O
(15 ml), dried (Na2SO4), and concentrated, and the residue purified by CC (AcOEt/hexane 3 :7): pure 7
(1.49 g, 82%). Colorless oil. [a]2D5 ¼ ꢀ10 (c ¼ 1, CHCl3). IR (neat): 3029, 2923, 2854, 1746, 1610, 1510,
1455, 1383, 1238, 1177, 1106. 1H-NMR (300 MHz): 7.43 – 7.34 (m, 5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼
8.7, 2 H); 5.02 (s, 2 H); 4.64 – 4.53 (m, 1 H); 4.50 – 4.29 (m, 1 H); 3.48 – 3.34 (m, 1 H); 3.29 – 3.17 (m, 1 H);
2.84 – 2.59 (m, 1 H); 2.39 – 2.30 (m, 1 H); 1.97 – 1.53 (m, 4 H). 13C-NMR (75 MHz): 177.8; 156.9; 137.91;
131.8; 128.9; 128.1; 127.5; 127.0; 114.6; 75.0; 74.7; 69.6; 36.1; 31.4; 29.6; 3.88. HR-ESI-MS: 470.0826
([M þ NH4]þ, C20H25INOþ4 ; calc. 470.0823).
(2S)-4-[4-(Benzyloxy)phenyl]-1-[(2S)-oxiran-2-yl]butan-2-ol (¼(aS,2S)-a-{2-[4-(Benzyloxy)phe-
nyl]ethyl}oxirane-2-ethanol; 8). To a stirred soln. of 7 (1.49 g, 3.29 mmol) in MeOH (25 ml) was added
K2CO3 (2.2 g, 16.03 mmol) at 08. The mixture was then warmed and stirred at r.t. for 2 h. After
completion of the reaction (TLC), aq. NaHCO3 soln. (40 ml) was added, and the mixture was extracted
with AcOEt (3 ꢁ 25 ml). The combined org. phase was dried (Na2SO4), the solvent evaporated, and the
residue purified by CC (AcOEt/hexane 4 :6): 8 (0.84 g, 86%). Colorless oil. [a]2D5 ¼ ꢀ13 (c ¼ 0.9, CHCl3).
IR (neat): 3429, 2927, 2856, 1611, 1510, 1460, 1379, 1244, 1174, 1076. 1H-NMR (300 MHz): 7.43 – 7.34 (m,
5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 5.02 (s, 2 H); 4.00 – 3.81 (m, 1 H); 2.68 – 2.40 (m, 5 H);
1.93 – 1.53 (m, 4 H).13C-NMR (75 MHz): 157.0; 137.2; 129.9; 128.5; 127.8; 127.4; 114.8; 70.0; 49.8; 47.7;
40.2; 40.0; 30.4. ESI-MS: 321.04 ([M þ Na]þ).
{(1S)-3-[4-(Benzyloxy)phenyl]-1-{[(2S)-oxiran-2-yl]methyl}propoxy}(tert-butyl)dimethylsilane (9).
To a stirred soln. of 8 (0.9 g, 3.02 mmol) and 1H-imidazole (0.41 g, 6.04 mmol) in dry CH2Cl2 (20 ml) was
added tBuMe2SiCl (0.9 g, 6.04 mmol) slowly at 08, and the mixture was stirred for 5 h. After completion
of the reaction (TLC), the reaction was quenched with H2O (15 ml), the mixture extracted with CH2Cl2
(3 ꢁ 10 ml), the combined org. extract washed with brine, dried (Na2SO4), and concentrated, and the
residue purified by CC (AcOEt/hexane 1:9): pure 9 (1.09 g, 88%). Colorless oil. [a]2D5 ¼ ꢀ11.3 (c ¼ 0.7,
CHCl3). IR (neat): 3429, 2969, 2854, 1641, 1511, 1465, 1250, 1169, 1075. 1H-NMR (200 MHz): 7.44 – 7.34

Helvetica Chimica Acta – Vol. 93 (2010)
1965
(m, 5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 5.02 (s, 2 H); 4.03 – 3.83 (m, 1 H); 2.68 – 2.38 (m,
5 H); 1.93 – 1.53 (m, 4 H); 0.93 (s, 9 H); 0.06 (s, 6 H). 13C-NMR (75 MHz): 157.0; 137.2; 131.7; 129.2;
128.5; 127.8; 127.4; 114.8; 70.0; 49.8; 47.7; 40.2; 40.08; 30.48; 25.89; 18.09; ꢀ 4.36. ESI-MS: 435.6 ([M þ
Na]þ).
(4R,6S)-8-[4-(Benzyloxy)phenyl]-6-{[(tert-butyl)dimethylsilyl]oxy}oct-1-en-4-ol (10). To a soln. of
9 (0.860 g, 2.08 mmol) in dry Et2O (20 ml) at 08 was added slowly 2m CH2¼CHMgBr/Et2O (4.17 ml,
8.34 mmol) and stirred for 20 min under N2. After completion of the reaction (TLC), the reaction was
quenched with sat. NH4Cl soln. (20 ml) and extracted with AcOEt (2 ꢁ 10 ml). The combined org.
extract was washed with brine, dried (Na2SO4), and concentrated to afford a ꢃsynꢀ/ꢃantiꢀ 43 :57 alcohol
mixture in 76% yield, which was purified by CC (AcOEt/hexane 2 :8): pure 10 (ꢃsynꢀ-isomer; 0.4 g,
1
32.68%). Viscous liquid. [a]2D5 ¼ ꢀ0.8 (c ¼ 1, CHCl3). IR (neat): 1710, 1612, 1510, 1455, 1238. H-NMR
(200 MHz): 7.44 – 7.29 (m, 5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 6.12 (m, 1 H); 5.24 – 5.12 (m,
2 H); 5.02 (s, 2 H); 4.01 – 3.92 (m, 1 H); 3.89 – 3.76 (m, 1 H); 2.82 – 2.71 (m, 2 H); 2.18 – 2.04 (m, 2 H);
1.94 – 1.53 (m, 4 H); 0.92 (s, 9 H); 0.04 (s, 6 H). 13C-NMR (50 MHz): 157.0; 138.6; 135.0; 134.3; 129.5;
129.1; 128.5; 127.1; 119.9; 115.1; 74.5; 70.2; 69.4; 44.9; 39.6; 30.0; 25.8; 19.2; ꢀ 4.36. ESI-MS: 463 ([M þ
Na]þ).
(1R,3S)-5-[4-(Benzyloxy)phenyl]-3-{[(tert-butyl)dimethylsilyl]oxy}-1-(prop-2-en-1-yl)pentyl Prop-
2-enoate (11). To a stirred soln. of 10 (0.40 g, 0.90 mmol) in dry CH2Cl2 (20 ml) was added prop-2-enoyl
chloride (0.149 g, 1.65 mmol) and Et3N (0.22 g, 2.2 mmol) at 08. The mixture was allowed to warm to r.t.
and stirred for 4 h. After completion of the reaction (TLC), the mixture was diluted with H2O (15 ml)
and extracted with CH2Cl2 (2 ꢁ 10 ml). The combined org. extract was washed with brine, dried
(Na2SO4), and concentrated, and the residue purified by CC (AcOEt/hexane 2 :8): pure 11 (0.404 g,
90%). Colorless solid. [a]2D5 ¼ ꢀ7.3 (c ¼ 0.6, CHCl3). IR (neat): 2923, 2854, 1746, 1610, 1510, 1238, 1106.
1H-NMR (200 MHz): 7.43 – 7.29 (m, 5 H); 7.08 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼ 8.7, 2 H); 6.20 – 6.11 (m, 1 H);
6.03 – 5.86 (m, 1 H); 5.72 – 5.51 (m, 2 H); 5.20 – 5.06 (m, 3 H); 5.02 (s, 2 H); 4.64 – 4.52 (m, 1 H); 2.69 –
2.51 (m, 2 H); 2.40 – 2.29 (m, 2 H); 1.93 – 1.53 (m, 4 H); 0.92 (s, 9 H); 0.04 (s, 6 H). 13C-NMR (50 MHz):
169.5; 155.4; 137.4; 133.6; 132.5; 131.3; 130.3; 129.7; 128.8; 128.6; 127.9; 127.1; 118.3; 114.8; 75.0; 70.0;
69.6; 38.9; 35.7; 30.8; 25.8; 18.0; ꢀ 4.3. ESI-MS: 517 ([M þ Na]þ).
(6R)-6-{(2S)-4-[4-(Benzyloxy)phenyl]-2-{[(tert-butyl)dimethylsilyl]oxy}butyl}-5,6-dihydro-2H-py-
ran-2-one (12). To a stirred soln. of 1st generation Grubbsꢀ catalyst (5 mol-%) in dry CH2Cl2 (20 ml) at
558 was added 11 (0.3 g, 0.60 mmol) in CH2Cl2 (15 ml) and refluxed for 9 h. After completion of the
reaction (TLC), the mixture was cooled, the solvent evaporated, and the crude product purified by CC
(AcOEt/hexane 3 :7): pure 12 (0.232 g, 82%). Colorless solid. IR (neat): 2923, 2854, 1736, 1636, 1510,
1459, 1238, 1165, 916. 1H-NMR (200 MHz): 7.43 – 7.24 (m, 7 H); 7.01 (m, 1 H); 6.88 (d, J ¼ 8.7, 2 H); 6.00
(d, J ¼ 9.8, 1 H); 5.02 (s, 2 H); 4.65 – 4.54 (m, 1 H); 4.03 – 3.84 (m, 1 H); 286 – 2.63 (m, 2 H); 2.43 – 2.31
(m, 2 H); 1.93 – 1.53 (m, 4 H); 0.93 (s, 9 H); 0.05 (s, 6 H). ESI-MS: 489 ([M þ Na]þ).
(6R)-5,6-Dihydro-6-[(2S)-2-hydroxy-4-(4-hydroxyphenyl)butyl]-2H-pyran-2-one (1). To a stirred
soln. of 12 (0.20 g, 0.429 mmol) in dry CH2Cl2 (15 ml) under N2 at 08 was added TiCl4 (0.6 ml, 0.90 mmol),
and the mixture was stirred at r.t. for 2 h. After completion of the reaction (TLC), the reaction was
quenched with sat. aq. NaHCO3 soln. (10 ml) and the mixture extracted with CHCl3 (2 ꢁ 10 ml). The
combined org. layer was washed with H2O and brine, dried (Na2SO4), and concentrated, and the crude
residue purified by CC (AcOEt/hexane 3 :7): pure 1 (0.092 g, 82%). Colorless solid. [a]2D5 ¼ þ39.8 (c ¼
0.4, CHCl3) ([3]: [a]2D5 ¼ þ40.2 (c ¼ 0.4, CHCl3)). IR (neat): 3428, 2968, 2863, 1710, 1510, 1453, 1249.
1H-NMR (200 MHz): 7.08 (d, J ¼ 7.9, 2 H); 6.92 – 6.81 (m, 1 H); 6.77 (d, J ¼ 7.9, 2 H); 6.05 (d, J ¼ 9.9,
1 H); 4.96 (br. s, 1 H); 4.64 – 4.53 (m, 1 H); 4.12 – 3.88 (m, 1 H); 3.82 (br. s, 1 H); 2.77 – 2.59 (m, 2 H);
2.39 – 2.30 (m, 2 H); 2.00 – 1.70 (m, 4 H).13C-NMR (50 MHz): 165.3; 153.5; 145.6; 143.5; 131.3; 129.5;
129.7; 128.6; 120.9; 114.6; 75.4; 69.2; 44.5; 38.4; 30.9; 29.9. HR-MS: 285.1100 ([M þ Na]þ, C15H18O4Naþ;
calc. 285.1106).

1966
Helvetica Chimica Acta – Vol. 93 (2010)
REFERENCES
[1] S. E. Drewes, B. M. Schlapelo, M. M. Horn, R. Scott-Shaw, O. Sandor, Phytochemistry 1995, 38,
1427; J. Jodynis-Liebert, M. Murias, E. Bloszyk, Planta Med. 2000, 66, 199; R. Pereda-Miranda, M.
Fragoso-Serrano, C. M. Cerda-Garcia-Rojas, Tetrahedron 2001, 57, 47; M. Carda, F. Gonzalez, E.
Castillo, S. Rodriguez, J. Marco, Eur. J. Org. Chem. 2002, 2649; J. Murga, E. Falomir, J. Garcia-
Fortanet, M. Carda, J. A. Marco, Org. Lett. 2002, 4, 3447.
[2] J. A. Marco, M. Carda, J. Murga, E. Falomir, Tetrahedron 2007, 63, 2929.
[3] M. Ovedraogo, H. Carreyre, C. Vandelrouck, J. Bescound, G. Raymond, I.-P. Guissou, C. Cognard, F.
Becq, D. Potreau, A. Cousson, J. Marrot, J.-M. Coustard, J. Nat. Prod. 2007, 70, 2006.
[4] V. Suresh, J. J. P. Selvam, K. Rajesh, Y. Venkateswarlu, Tetrahedron: Asymmetry 2008, 19, 1509; V.
Suresh, K. Rajesh, J. J. P. Selvam, Y. Venkateswarlu, Tetrahedron Lett. 2008, 49, 7358.
[5] P. Alvarez-Bercedo, E. Falomir, J. Murga, M. Carda, J. A. Marco, Eur. J. Org. Chem. 2008, 4015; P.
Srihari, G. Rajender, R. S. Rao, J. S. Yadav, Tetrahedron Lett. 2008, 49, 5590; B. Das, K. Suneel, G.
Lakshmi, D. NandanKumar, Tetrahedron: Asymmetry 2009, 20, 1536; G. Sabitha, V. Bhaskar, S. S.
Sankara Reddy, J. S.Yadav, Synthesis 2009, 19, 3285.
[6] G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc. 1993, 115, 8467; G. E. Keck, D.
Krishnamurthy, M. C. Grier, J. Org. Chem. 1993, 58, 6543; N. Gogoi, J. Boruwa, N. C. Barua, Eur. J.
Org. Chem. 2006, 1722.
[7] L. F. Felpin, J. Lebreton, J. Org. Chem. 2002, 67, 9192.
[8] R. E. Taylor, M. Jin, Org. Lett. 2003, 5, 4959; J. J. W. Duan, A. B. Smith, J. Org. Chem. 1993, 58, 3703;
P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto, K. K. Jernstedt, J. Org. Chem. 1982, 47,
4013.
[9] S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31, 945; D. A. Evans, D. L. Rieger, J. R.
Gage, Tetrahedron Lett. 1990, 31, 7099.
[10] R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem. Res. 1995, 28, 446; R. H. Grubbs, Tetrahedron 2004,
60, 7117.
Received December 31, 2009