Stereoselective synthesis of the non-lactonic portion of (Z)-cryptofolione and approaches towards its conversion to (Z)-cryptofolione

Article abstract of DOI:10.1002/hlca.201400242

The stereoselective synthesis of the non-lactonic part of the natural G₂ checkpoint inhibitor, (Z)-cryptofolione, has been accomplished. Butane-1,4-diol was used as the starting material, and the stereogenic centers were generated through L-proline-catalyzed α-aminoxylation and Maruoka asymmetric allylation. We attempted to convert this non-lactonic moiety to (Z)-cryptofolione via olefin cross-metathesis reaction, but by this approach another naturally occurring lactonic compound, goniothalamin, was obtained.

Full text of DOI:10.1002/hlca.201400242

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Stereoselective Synthesis of the Non-Lactonic Portion of (Z)-Cryptofolione
and Approaches towards Its Conversion to (Z)-Cryptofolione1)
by Siddavatam Nagendraa), Vanka Krishna Reddyb), and Biswanath Das*a)
a) Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500 007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
b) Department of Chemistry, Sri Krishnadevaraya University, Anantapur-515055, India
The stereoselective synthesis of the non-lactonic part of the natural G2 checkpoint inhibitor, (Z)-
cryptofolione, has been accomplished. Butane-1,4-diol was used as the starting material, and the
stereogenic centers were generated through l-proline-catalyzed a-aminoxylation and Maruoka
asymmetric allylation. We attempted to convert this non-lactonic moiety to (Z)-cryptofolione via olefin
cross-metathesis reaction, but by this approach another naturally occurring lactonic compound,
goniothalamin, was obtained.
Introduction. – (Z)-Cryptofolione (1) was isolated from the crude extract of
Cryptocarya conncina, a plant of the laurel family [1]. The molecule contains an a,b-
unsaturated d-lactone ring, along with two more olefinic C¼C bonds (one with (E)- and
the other with (Z)-configuration), as well as two OH groups of opposite configuration
(one at C(4’) in b- and the other at C(6’) in a-orientation). Compound 1 possesses G2
checkpoint inhibition capacity in human breast carcinoma MCF-7 cells and is more
active than its (E)-isomer [1]. However, in spite of its interesting structural features
and significant biological properties, the total synthesis of (Z)-cryptofolione 1 has not
yet been accomplished. In recent years, several natural products containing the d-
lactone moiety such as (þ)-goniothalamin [2a][2b], (þ)-cryptocaryalactone [2c], (þ)-
cryptofolione [2d], and (þ)-strictifolione [2e] (Fig. 1) have been synthesized. In a
common approach of their synthesis, two olefinic fragments of the compounds are
prepared, and these two fragments are coupled by olefin cross-metathesis reaction
using Grubbsꢀ catalyst [2d][2e]. Continuing our work [3] on the construction of natural
bioactive compounds, we attempted to synthesize (Z)-cryptofolione (1) by this
approach. We prepared the olefinic fragment 2 of the target molecule 1. However, the
attempted cross-metathesis reaction of 2 with the known ethenyl compound 3 occurred
with the (Z)-configured C¼C bond of the former but not with the terminal CH¼CH2
group, leading to the formation of another natural lactonic compound. Herein, we
report the stereoselective synthesis of the non-lactonic moiety 2 of (Z)-cryptofolione
(1), and our attempts to convert it to the natural compound 1 (Scheme 1).
1
)
Part 84 in the series, ꢂSynthetic Studies on Natural Productsꢀ.
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Figure. Structures of natural products containing d-lactone moieties
Scheme 1. Retrosynthetic Analysis of 1 and 2
Results and Discussion. – The retrosynthetic analysis (Scheme 1) of 2 indicates that
it can be synthesized from the alkyne 4, which in turn can be prepared from the
propargyl alcohol 5 derived from butane-1,4-diol (6).
Our synthesis was initiated by protection of one OH group of butane-1,4-diol (6) by
treatment with 4-methoxybenzyl bromide (PMB-Br) and NaH to form the PMB ether
7 (Scheme 2). The latter was oxidized with pyridinium chlorochromate (PCC), and the
aldehyde obtained was subjected to asymmetric aminoxylation [4] using l-proline and
PhNO, followed by addition of the Ohira-Bestmann reagent 8 and K2CO3 to furnish the
chiral propargyl alcohol 5 (ee 96%, determined by chiral HPLC) [5]. The alcohol 5 was
treated with PhI in the presence of CuI, Ph3P, and Pd/C to form the alkyne 9 [6]. The
free OH group of 9 was protected as (tBu)Ph2Si (TBDPS) ether (10), and the PMB-
ether group of the latter was deprotected to afford the alcohol 11. The latter was
oxidized with 2-iodoxybenzoic acid (IBX), and the corresponding aldehyde was
subjected to asymmetric Maruoka allylation [7] with allyl(tributyl)tin and the bis{[(S)-
binaphthoxy](isopropoxy)titanium} oxide complex A to afford the chiral homoallylic
alcohol 12 (de 97%). Thus, both stereogenic centers present in 2 have been created.
Next, the TBDPS-ether group of 12 was deprotected to furnish the diol 4. Finally, the
selective hydrogenation [8] of the CꢀC bond of 4 with (AcO)2Ni, NaBH4, and ethane-
1,2-amine under H2 yielded the non-lactonic part 2 of (Z)-cryptofolione 1.

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Scheme 2. Stereoselective Synthesis of the Non-Lactonic Moiety 2 of 1
a) NaH, 4-Methoxybenzyl bromide (PMB-Br), THF, 08 to r.t., 3 h; 87%. b) 1) Pyridium chlorochromate
(PCC), CH2Cl2, r.t., 1.5 h. 2) l-proline, nitrosobenzene (PhNO), À 208, 24 h. 3) K2CO3, 8, 67% (over
three steps); ee 96%. c) 10% Pd/C, Ph3P, CuI, K2CO3, PhI, 1,2-dimethoxyethane (DME)/H2O 3 :1, 858,
5 h; 89%. d) 1H-Imidazole, (tBu)Ph2SiCl (TBDPS-Cl), 4-(dimethylamino)pyridine (DMAP), CH2Cl2,
08 to r.t., 6 h; 88%. e) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O 8 :2, 08 to r.t.,
3 h; 85%. f) 1) 2-Iodoxybenzoic acid (IBX), DMSO, CH2Cl2, 08 to r.t., 1.5 h; 92%. 2) (S,S)-I,
Allyl(tributyl)stannane, CH2Cl2, 08, 18 h; 74% (de 97%). g) Bu4NF, THF, 08 to r.t., 5 h; 78%. h)
(AcO)2Ni, NaBH4, NH2(CH2)2NH2, H2, EtOH, r.t.; 76%.
The 1,3-anti-relationship of the two OH groups of 2 was established by analysis of
the 13C-NMR spectrum [9] of the corresponding acetonide 13 prepared from 2
(Scheme 3). The spectrum exhibited the Me signals of the acetonide at 25.8 and 25.2,
and that of the quaternary C-atom at 100.2 ppm.
Next, we attempted to convert the fragment 2 to the natural (Z)-cryptofolione 1 by
olefin cross-metathesis reaction [10] with the olefinic lactone 3 [11] using Grubbsꢀ 2nd-
generation catalyst, G2, under different conditions. However, we did not obtain
compound 1. Interestingly, the cross-metathesis reaction occurred with the internal
(Z)-configured C¼C bond of 2 (Scheme 4) to generate another naturally occurring
lactonic compound, goniothalamin 14 [12].
Scheme 3. Preparation of Acetonide 13 from 2

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Scheme 4. Olefin Cross-Metathesis Reaction of 2 and 3
We also tried to carry out the olefinic cross-metathesis reaction with the acetonide
13, derived from 2, and the olefinic lactone 3 using G2. However, in this case the
lactonic dimer 15 was the only product obtained (Scheme 5).
Scheme 5. Olefin Cross-Metathesis Reaction of 13 and 3
In conclusion, we have developed a stereoselective synthesis of the non-lactonic
moiety of the natural (Z)-cryptofolione (1) and attempted, unsuccessfully, to convert it
to 1. One of the approaches afforded another natural compound, goniothalamin 14.
The authors thank UGC and CSIR, New Delhi, for financial assistance.
Experimental Part
General. The solvents used were all of AR grade. TLC: Merck silica-gel 60 F254 plates. Column
chromatography (CC): silica gel (SiO2, 60 – 120 mesh; Qingdao Marine Chemical, P. R. China). Optical
rotations: JASCO DIP 360 digital polarimeter. NMR Spectra: Gemini 200-MHz spectrometer; in CDCl3;
d in ppm rel. to Me4Si as internal standard, J in Hz. ESI-MS: VG-Autospec micromass instrument; in m/z.
4-[(4-Methoxyphenyl)methoxy]butan-1-ol (7). Butane-1,4-diol (6; 5.0 g, 55.55 mmol) was taken in
50 ml of dry THF. NaH (60% dispersion in mineral oil; 2.49 g, 55.55 mmol) was added to it portionwise at
08. The mixture was stirred at 08 for 30 min. Bu4NI (1.6 g, 0.55 mmol) was added, followed by the addition
of 4-methoxybenzyl bromide (11.16 g, 55.55 mmol) in THF (50 ml). The mixture was stirred for a further
2 h at r.t. Ice-water (15 ml) was added carefully to the mixture to remove any excess of NaH. The mixture
was extracted with AcOEt (50 ml), and the org. layer was washed with H2O (15 ml) and brine (20 ml).
Evaporation of the solvent and purification of the residue by CC (AcOEt/hexane 20 :80) afforded 7

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(10.17 g, 87%). Colorless liquid. 1H-NMR (200 MHz, CDCl3): 7.28 (d, J ¼ 8.0, 2 H); 6.89 (d, J ¼ 8.0, 2 H);
4.47 (s, 2 H); 3.81 (s, 3 H); 3.67 (t, J ¼ 7.0, 2 H); 3.49 (t, J ¼ 7.0, 2 H); 1.73 – 1.62 (m, 4 H). 13C-NMR
(50 MHz, CDCl3): 159.0; 130.1; 129.2; 113.6; 72.5; 69.9; 62.3; 55.1; 29.8; 26.3. ESI-MS: 211 ([M þ H]þ).
Anal. calc. for C12H18O3 (210.28): C 68.54, H 8.63; found: C 68.63, H 8.67.
(3R)-5-[(4-Methoxyphenyl)methoxy]pent-1-yn-3-ol (5). To a stirred soln. of 7 (8.0 g, 37.91 mmol) in
dry CH2Cl2 (70 ml) were added Celite (50 g) and PCC (16.07 g, 56.85 mmol) at 08, and the mixture was
stirred for 1.5 h at r.t. The mixture was diluted with Et2O (45 ml) and subjected to CC (SiO2; AcOEt/
hexane 10 :90) to afford the corresponding aldehyde (7.04 g, 89%) as a colorless liquid, which was used
directly after flash chromatography (FC) for the next reaction.
The aldehyde (7.0 g, 33.49 mmol) was dissolved in MeCN (55 ml) and cooled to À 208. To this
mixture, l-proline (0.768 g, 6.68 mmol) was added, followed by addition of PhNO (3.47 g, 33.49 mmol).
The resulting mixture was stirred for 24 h, and, the solvent was evaporated. The residue was redissolved
in MeOH (60 ml). Next, the Ohira-Bestmann reagent (8; 236 mg, 1.23 mmol) in MeOH (8 ml) and
K2CO3 (3.46 g, 18.07 mmol) were added sequentially. The mixture was stirred for 8 h at 08. The reaction
was quenched by sat. NH4Cl (1 Â 10 ml), and the mixture was stirred for an additional 24 h at r.t. The org.
solvent was removed under reduced pressure, and the aq. layer was extracted with AcOEt (3 Â 10 ml).
The combined org. layers were washed with brine (10 ml), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The resulting residue was purified by CC (hexane/AcOEt 7:1) to give 5 (2.2 g,
67% for three conversions). Pale-yellow oil. [a]2D5 ¼ À8.9 (c ¼ 1.0, CHCl3). 1H-NMR (200 MHz, CDCl3):
7.22 (d, J ¼ 8.0, 2 H); 6.88 (d, J ¼ 8.0, 2 H); 4.63 – 4.61 (m, 1 H); 4.49 (d, J ¼ 12.0, 1 H); 4.42 (d, J ¼ 12.0,
1 H); 3.83 – 3.81 (m, 1 H); 3.81 (s, 3 H); 3.67 – 3.65 (m, 1 H); 3.11 – 3.09 (m, 1 H); 2.09 – 2.07 (m, 1 H);
1.93 – 1.91 (m, 1 H). 13C-NMR (50 MHz, CDCl3): 159.4; 130.0; 129.8; 113.9; 85.5; 73.1; 73.0; 67.7; 61.2;
55.1; 36.6. ESI-MS: 221 ([M þ H]þ). Anal. calc. for C13H16O3 (220.26): C 70.89, H 7.32; found: C 70.98, H
7.36.
(3R)-5-[(4-Methoxyphenyl)methoxy]-1-phenylpent-1-yn-3-ol (9). To a soln. of 5 (2.0 g, 9.09 mmol)
in DME (60 ml) were added H2O (20 ml), K2CO3 (3.10 g, 22.5 mmol), CuI (0.068 g, 0.36 mmol), Ph3P
(0.21 g, 0.92 mmol), and a cat. amount of 10% Pd/C. The resulting mixture was stirred at r.t. for 30 min,
then PhI was added, and the mixture warmed at 858 for 5 h. The mixture was cooled to r.t., filtered
through a Celite pad, washed with hot AcOEt (2 Â 25 ml). The soln. was diluted with H2O (50 ml) and
extracted with AcOEt (2 Â 50 ml). The org. phase was washed with brine (50 ml), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by CC to afford 9 (2.3 g, 89%). Pale-
yellow liquid. [a]2D5 ¼ þ49.2 (c ¼ 0.5, CHCl3). 1H-NMR (200 MHz, CDCl3): 7.40 – 7.18 (m, 7 H); 6.81 (d,
J ¼ 8.0, 2 H); 4.79 – 4.77 (m, 1 H); 4.48 (s, 2 H); 3.89 – 3.87 (m, 1 H); 3.78 (s, 3 H); 3.66 – 3.64 (m, 1 H);
2.98 (d, J ¼ 7.0, 1 H); 2.17 – 2.15 (m, 1 H); 1.99 – 1.97 (m, 1 H). 13C-NMR (50 MHz, CDCl3): 159.2; 132.0;
130.1; 129.8; 128.3; 128.1; 122.9; 114.1; 89.9; 85.0; 72.9; 67.1; 61.9; 55.2; 37.1. ESI-MS: 297 ([M þ H]þ).
Anal. calc. for C19H20O3 (296.36): C 77.0, H 6.80; found: C 77.14, H 6.91.
(tert-Butyl)({(3R)-5-[(4-methoxyphenyl)methoxy]-1-phenylpent-1-yn-3-yl}oxy)diphenylsilane (10).
1H-Imidazole (0.78 g, 11.4 mmol), DMAP (cat.), and TBDPSCl (2.5 g, 9.12 mmol) were added to a
stirred soln. of 9 (2.25 g, 7.6 mmol) in anh. CH2Cl2 (25 ml) at 08. Stirring was continued for 3 h, and then
the mixture was diluted with CH2Cl2 (15 ml). The org. layer was washed with brine (25 ml) and then dried
(Na2SO4). Evaporation of the solvent under reduced pressure, followed by CC (SiO2; AcOEt/hexane
10 :90) afforded 10 (3.57 g, 88%). Colorless liquid. [a]2D5 ¼ þ66.6 (c ¼ 1.0, CHCl3). 1H-NMR (200 MHz,
CDCl3): 7.74 (d, J ¼ 8.0, 2 H); 7.69 (d, J ¼ 8.0, 2 H); 7.40 – 7.23 (m, 7 H); 7.20 – 7.04 (m, 6 H); 6.72 (d, J ¼
8.0, 2 H); 5.75 (t, J ¼ 7.0, 1 H); 4.31 (s, 2 H); 3.73 (s, 3 H); 3.68 – 3.54 (m, 2 H); 2.14 – 1.98 (m, 2 H); 1.09 (s,
9 H). 13C-NMR (50 MHz, CDCl3): 159.2; 144.1; 136.1; 136.0; 131.2; 129.9; 129.4; 128.1; 127.8; 127.7;
123.0; 113.1; 90.5; 85.3; 72.6; 66.2; 62.0; 55.4; 38.7; 27.2; 19.1. ESI-MS: 535 ([M þ H]þ). Anal. calc. for
C35H38O3Si (534.26): C 78.61, H 7.16; found: C 78.51, H 7.20.
(3R)-3-{[(tert-Butyl)(diphenyl)silyl]oxy}-5-phenylpent-4-yn-1-ol (11). To a stirred soln. of 10 (3.3 g,
6.17 mmol) in CH2Cl2/H2O 8 :2, DDQ was added at 08 (1.54 g, 6.79 mmol), and the mixture was stirred
for 2.5 h. The reaction was quenched with solid NaHCO3 at 08, and the mixture was filtered through
Celite pad and washed with CH2Cl2. Concentration of the mixture under reduced pressure, followed by
purification by CC (AcOEt/hexane 25 :75), afforded pure 11 (2.8 g, 85%). Pale-yellow oil. [a]2D5 ¼ þ84.3
(c ¼ 1.5, CHCl3). 1H-NMR (200 MHz, CDCl3): 7.80 (d, J ¼ 8.0, 2 H); 7.75 (d, J ¼ 8.0, 2 H); 7.48 – 7.32 (m,

Helvetica Chimica Acta – Vol. 98 (2015)
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6 H); 7.29 – 7.12 (m, 5 H); 4.80 (t, J ¼ 7.0, 1 H); 4.04 – 4.02 (m , 1 H); 3.88 – 3.86 (m, 1 H); 2.23 – 1.92 (m,
3 H); 1.10 (s, 9 H). 13C-NMR (50 MHz, CDCl3): 136.1; 135.9; 131.5; 130.1; 130.1; 128.1; 127.9; 127.8; 89.8;
86.0; 63.3; 60.0; 40.1; 27.0; 19.4. ESI-MS: 415 ([M þ H]þ). Anal. calc. for C27H30O2Si (414.61): C 78.22, H
7.29; found: C 78.26, H 7.31.
(4R,6R)-6-{[(1,1-Dimethylethyl)diphenylsilyl]oxy}-8-phenyloct-1-en-7-yn-4-ol (12). To an ice-cold
soln. of IBX (3.92 g, 14.5 mmol) in DMSO (5 ml) was added a soln. of 11 (2.71 g, 6.56 mmol) in anh.
CH2Cl2, and the mixture was stirred at 258 for 1.5 h. The mixture was diluted with CH2Cl2 (15 ml),
filtered through Celite pad, and the pad was washed with CH2Cl2. The combined filtrates were washed
with H2O (10 ml), dried (Na2SO4), and the residue was concentrated under reduced pressure to afford
the aldehyde (2.74 g, 92%), which was used directly after FC for the next reaction.
To a stirred soln. of TiCl4 (0.04 g, 0.33 mmol) in CH2Cl2 (5 ml) was added dried (iPrO)4Ti (0.281 g,
0.99 mmol) at 08 under N2, and the mixture was allowed to warm to r.t. After 1 h, Ag2O (0.152 g,
0.66 mmol) was added at r.t., 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 (0.377 g, 1.32 mmol) at r.t. for 2 h to
furnish A. The in situ generated A was cooled to À 158, and treated sequentially with aldehyde (2.74 g,
6.6 mmol) and (allyl)(tributyl)tin (2.7 ml, 8.5 mmol) at the same temp. The mixture was allowed to warm
to 08 and stirred for 18 h. The reaction was quenched with sat. aq. NaHCO3, and the mixture was
extracted with Et2O (3 Â 10 ml). The org. extracts were dried (Na2SO4). Evaporation of solvents and
purification of the residue by CC (SiO2; AcOEt/hexane 20 :80) gave 12 (2.2 g, 74%). Pale-yellow liquid.
1
[a]2D5 ¼ À12.4 (c ¼ 1.0, CHCl3). H-NMR (200 MHz, CDCl3): 7.79 (d, J ¼ 8.0, 2 H); 7.48 – 7.32 (m, 7 H);
7.28 – 7.19 (m, 2 H); 7.06 (d, J ¼ 8.0, 2 H); 5.84 – 5.82 (m, 1 H); 5.19 – 5.10 (m, 2 H); 4.80 (t, J ¼ 7.0, 1 H);
4.05 – 4.03 (m, 1 H); 2.34 – 2.25 (m, 3 H); 2.02 – 1.94 (m, 2 H); 1.10 (s, 9 H). 13C-NMR (50 MHz, CDCl3):
136.4; 136.2; 134.2; 129.7; 129.2; 127.7; 127.3; 127.1; 118.1; 89.9; 86.1; 68.8; 63.2; 44.5; 42.0; 26.9; 19.5. ESI-
MS: 455 ([M þ H]þ). Anal. calc. for C30H34O2Si (454.23): C 79.24, H 7.54; found: C 79.36, H 7.51.
(3R,5R)-1-Phenyloct-7-en-1-yne-3,5-diol (4). To a stirred soln. of 12 (2.2 g, 4.43 mmol) in dry THF
(10 ml) at 08 was added Bu4NF (6.34 g, 5.76 mmol) dropwise. After completion of addition, the mixture
was kept at r.t. and stirred for 5 h. After completion (TLC), the reaction was quenched with sat.
(NH4)2CO3 soln. (3 ml), and the mixture was extracted into CH2Cl2 (2 Â 15 ml) and dried (Na2SO4). The
combined org. layer was concentrated in vacuo and subjected to CC (SiO2; hexane/AcOEt 6 :4) to afford
4 (0.81 g, 78%). Colorless liquid. [a]2D5 ¼ þ31.9 (c ¼ 1.5, CHCl3). 1H-NMR (200 MHz, CDCl3): 7.45 – 7.36
(m, 2 H); 7.31 – 7.22 (m, 3 H); 5.83 – 5.81 (m, 1 H); 5.18 – 5.07 (m, 2 H); 4.85 (t, J ¼ 7.0, 1 H); 4.23 – 4.21
(m, 1 H); 3.80 (br. s, 1 H); 2.92 (br. s, 1 H); 2.31 – 2.21 (m, 2 H); 1.91 – 1.82 (m, 2 H). 13C-NMR (50 MHz,
CDCl3): 134.1; 131.2; 128.7; 128.6; 122.8; 118.9; 89.9; 85.1; 68.3; 61.1; 42.2; 42.0. ESI-MS: 217 ([M þ H]þ).
Anal. calc. for C14H16O2 (216.28): C 77.75, H 7.46; found: C 77.86, H 7.49.
(1Z,3R,5S)-1-Phenylocta-1,7-diene-3,5-diol (2). To a stirred soln. of (AcO)2Ni (40 mg, 1.98 mmol) in
dry EtOH was added under H2 at r.t. NaBH4 (75 mg, 1.98 mmol) in EtOH and 3 drops of ethane-1,2-
diamine. To the resulting black mixture, 4 (0.65 g, 3.03 mmol) was added, and the mixture was stirred
under H2 until the reduction of the CꢀC group was completed (TLC). The reaction was quenched by
addition of active coal, and the mixture was filtered through Celite. Concentration of the filtrates in vacuo
1
and FC (SiO2) afforded 2 (0.498 g, 76%). Pale-yellow liquid. [a]2D5 ¼ þ38.2 (c ¼ 1.0, CHCl3). H-NMR
(200 MHz, CDCl3): 7.32 – 7.12 (m, 5 H); 6.41 (d, J ¼ 10.0, 1 H); 5.81 – 5.63 (m, 2 H); 5.10 – 5.00 (m, 2 H);
4.88 – 4.86 (m, 1 H); 3.93 – 3.91 (m, 1 H); 3.58 – 3.22 (br. s, 2 H); 2.22 – 2.14 (m, 2 H); 1.80 – 1.61 (m, 2 H).
13C-NMR (50 MHz, CDCl3): 136.4; 134.5; 134.1; 130.1; 128.8; 128.2; 127.2; 118.0; 68.1; 65.8; 42.1; 42.0.
ESI-MS: 219 ([M þ H]þ). Anal. calc. for C14H18O2 (218.29): C 77.03, H 8.31; found: C 77.18, H 8.29.
(4R,6S)-2,2-Dimethyl-4-[(Z)-2-phenylethenyl]-6-(prop-2-en-1-yl)-1,3-dioxane (13). To a stirred
soln. of 2 (0.25 g, 1.157 mmol) in dry acetone (3 ml) under N2 at 08 was added TsOH (20 mg) and 2,2-
dimethoxypropane (0.4 ml, 1.38 mmol). The soln. was stirred for 3 h, and the reaction was quenched with
solid NaHCO3 powder (30 mg). After filtration, the filtrate was concentrated under reduced pressure
and subjected to CC (AcOEt/hexane 10 :90) to afford pure 13 (0.245 mg, 83%). Colorless oil. [a]D25
¼
þ54.6 (c ¼ 1.0, CHCl3). 1H-NMR (200 MHz, CDCl3): 7.48 – 7.22 (m, 5 H); 6.59 (d, J ¼ 10.0, 1 H);
5.88 – 5.64 (m, 2 H); 5.15 – 5.02 (m, 2 H); 4.77 (q, J ¼ 7.0, 1 H); 3.98 – 3.96 (m, 1 H); 2.39 – 2.15 (m, 2 H);
1.76 (t, J ¼ 7.0, 2 H); 1.42 (s, 3 H); 1.38 (s, 3 H). 13C-NMR (50 MHz, CDCl3): 134.2; 132.1; 131.8; 128.8;

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128.2; 127.3; 116.9; 100.2; 64.0; 63.7; 40.2; 37.9; 25.8; 25.2. ESI-MS: 259 ([M þ H]þ). Anal. calc. for
C17H22O2 (258.36): C 74.97, H 7.40; found: C 74.89, H 7.43.
Goniothalamin (¼(6R)-5,6-Dihydro-6-[(E)-2-phenylethenyl]-2H-pyran-2-one; 14) [2a][2b][12]. A
soln. of 2 (0.10 g, 0.46 mmol) and 3 (0.025 g, 0.23 mmol) in dry CH2Cl2 (10 ml) was first bubbled with N2
flow, after which Grubbsꢀ 2nd-generation catalyst G2 (5 mg, 0.01 mmol) was added at once, and the
resulting mixture was heated under N2 at 508 for 3 h. After cooling, the solvent was evaporated in vacuo.
The residue on purification by CC (AcOEt/hexane 80 :20) afforded pure 14 (0.075 g, 82%). White solid.
1
[a]2D5 ¼ þ167.4 (c ¼ 1.3, CHCl3). H-NMR (200 MHz, CDCl3): 7.41 – 7.22 (m, 5 H); 6.92 – 6.90 (m, 1 H);
6.71 (d, J ¼ 10.0, 1 H); 6.23 (dd, J ¼ 15.0, 6.0, 1 H); 6.09 (d, J ¼ 10.0, 1 H); 5.08 (q, J ¼ 7.0, 1 H); 2.58 – 2.50
(m, 2 H). 13C-NMR (50 MHz, CDCl3): 164.2; 144.8; 136.0; 133.1; 128.3; 126.9; 125.9; 121.9; 78.0; 29.6.
ESI-MS: 201 ([M þ H]þ). Anal. calc. for C17H22O2 (200.23): C 74.97, H 7.40; found: C 74.85, H 7.43.
(6R,6’R)-6,6’-[(E)-Ethene-1,2-diyl]bis(5,6-dihydro-2H-pyran-2-one) (15). Through a soln. of 13
(0.015 g, 0.585 mmol) and 3 (0.026 g, 0.234 mmol) in dry CH2Cl2 (10 ml) was first bubbled N2, then G2
(5 mg, 0.01 mmol) was added at once, and the resulting mixture was heated under N2 at 508 for 4 h. After
cooling, the solvent was evaporated in vacuo. The residue on purification by CC (AcOEt/hexane, 5 :5)
1
afforded pure 15 (0.090 g, 70%). Colorless liquid. [a]2D5 ¼ À8.9 (c ¼ 0.5, CHCl3). H-NMR (200 MHz,
CDCl3): 6.92 – 6.83 (m, 2 H); 6.08 – 5.98 (m, 4 H); 5.01 – 4.90 (m, 2 H); 2.57 – 2.22 (m, 4 H). 13C-NMR
(50 MHz, CDCl3): 165.6; 143.3; 131.7; 129.0; 75.8; 19.3. ESI-MS: 221 ([M þ H]þ). Anal. calc. for
C12H22O4 (220.23): C 65.45, H 5.49; found: C 65.33, H 5.47.
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Received July 22, 2014