Total synthesis and cytotoxicity of (+)- and (-)-goniodiol and 6-epi-goniodiol. Construction of α,β-unsaturated lactones by ring-closing metathesis

Article abstract of DOI:10.1246/bcsj.80.387

(+)-Goniodiol, a potent and selective cytotoxin, and (-)-6-epi-goniodiol, as well as their enantiomers, have been synthesized starting from cinnamyl alcohol. The key steps of the synthesis were Sharpless asymmetric epoxidation and cyclization of an acrylate derivative using ring-closing metathesis reaction. The cytotoxicity of both enantiomers of goniodiol and 6-epi-goniodiol against HL-60 cells was examined.

Full text of DOI:10.1246/bcsj.80.387

ꢀ 2007 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 80, No. 2, 387–394 (2007)
387
Total Synthesis and Cytotoxicity of (+)- and (À)-Goniodiol
and 6-epi-Goniodiol. Construction of ꢀ,ꢁ-Unsaturated
Lactones by Ring-Closing Metathesis
Katsuyuki Nakashima, Naoki Kikuchi, Daisuke Shirayama, Takuo Miki, Kazuhiro Ando,
Masakazu Sono, Shinya Suzuki, Masaki Kawase, Masuo Kondoh, Masao Sato, and Motoo Tori
ꢀ
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514
Received July 18, 2006; E-mail: tori@ph.bunri-u.ac.jp
(+)-Goniodiol, a potent and selective cytotoxin, and (ꢁ)-6-epi-goniodiol, as well as their enantiomers, have been
synthesized starting from cinnamyl alcohol. The key steps of the synthesis were Sharpless asymmetric epoxidation and
cyclization of an acrylate derivative using ring-closing metathesis reaction. The cytotoxicity of both enantiomers of
goniodiol and 6-epi-goniodiol against HL-60 cells was examined.
(+)-Goniodiol (1) was isolated from the leaves and twigs
of Goniothalamus sesquipedalis (Annonaceae)1,2 and from
the stem bark of Goniothalamus giganteus (Annonaceae),3 as
a potent and selective cytotoxic compound against human lung
carcinoma A-549 (ED50 = 0.12 mg mLꢁ1)2 and P-388 murine
leukemia cells (IC50 = 4.56 mg mLꢁ1).4 Because of the unique
structural features and potent biological activities, several
groups have accomplished the synthesis of these com-
O
O
OH
OH
O
O
OH
(-)-6-epi-Goniodiol (2)
OH
(+)-Goniodiol (1)
pounds.5–9 Honda and co-workers constructed the ꢀ-lactone
4
PCy3
´
moiety using ring enlargement of furylmethanol. Vatele and
Mes
N
N
Mes
Ph
Ph
co-workers5 used the Ghosez method.10 Recently, we have
communicated the synthesis of ꢁ,ꢂ-unsaturated lactones from
acrylate derivatives using Grubbs’ reagents 3 and 4.11 This
methodology can be applied to the synthesis of 1 and 6-epi-
goniodiol (2),9,12 and at the same time we are intrested in
the biological activities of these compounds. During our work,
unfortunately, we became to know that a similar synthetic
work was published in 2002 and 2003.9 However, we studied
the selectivity of ring-opening of the epoxide and also the
stereochemistry at the 6-position, and a biological study about
both enantiomers of goniodiol and 6-epi-goniodiol was also
carried out. Now, we report the details of the total synthesis
of both (+)- and (ꢁ)-1 and 2 starting from cinnamyl alcohol
(5), as well as their biological activities (Chart 1).
Cl
Cl
Ru
Cl
Cl
Ru
PCy3
PCy3
4
3
Chart 1.
(3.5:1.0) in 58% overall yield. The stereochemistry of the alco-
hols was determined by the NMR spectrum, because the di-
methyl groups of alcohol 96 appeared at ꢀ ¼ 27:0 and 24.5
(ꢀꢀ ¼ 2:5) in the 13C NMR spectrum. On the other hand,
the dimethyl groups of alcohol 106 appeared at ꢀ ¼ 27:1 and
27.0 (ꢀꢀ ¼ 0:1) in the 13C NMR spectrum.14 From the above
results, the structure of alcohol 9 should be anti-form and that
of alcohol 10, syn-form.6 These isomers were presumably pro-
duced due to the SN1 mechanism, because it is at the benzylic
position. Therefore, epoxide 66 was treated with benzoic acid
in the presence of Ti(OiPr)4 in CH2Cl2 to yield a benzoate
11 as the sole product in 83% yield.15 After protection of the
primary alcohol with TBDPS, benzoate 12 was hydrolyzed
with Cs2CO3 in MeOH:H2O (8:1) followed by protection of
the diol with acetonide to afford compound 146 in 89% yield
in three steps. Deprotection of the silyl ether and Dess–Martin
oxidation gave aldehyde 156,9,16 in 65% yield (2 steps). The re-
sults of allylation of this aldehyde are summarized in Table 1.
The best result was obtained using Grignard reagent in ether to
give in 71% yield in the ratio of 3:7 in favor of 16b.9 There-
fore, we next studied the oxidation–reduction methodology.
Results and Discussion
The Sharpless asymmetric epoxidation13 of cinnamyl alco-
hol (5) provided 2,3-epoxyalcohol 66,13 in 95% yield. The
enantio excess of 6 (in the case of (+)-dietyl tartrate (DET))
was determined by GC as 93.8% ee (Fig. 1). The reaction
of alcohol 6 with tert-butyldiphenylchlorosilane (TBDPSCl)
and triethylamine in the presence of N,N-dimethylaminopyri-
dine (DMAP) provided the silyl ether 76 in 99% yield. Cleav-
age of the oxirane ring of 7 with p-toluenesulfonic acid in
THF–H2O (5:1) afforded a mixture of diol 8 in 66% yield. Pro-
tection of the diol 8 with 2,2-dimethoxypropane in the pres-
ence of p-toluenesulfonic acid followed by deprotection with
tetrabutylammonium fluoride provided alcohols 96 and 106
Published on the web February 13, 2007; doi:10.1246/bcsj.80.387

388 Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
Synthesis of Goniodiol and Its 6-Epimer
TBDPSCl
Et3N, DMAP
(+)-DET
Ti(OiPr)4
OTBDPS
O
OH
OH
O
99%
O
TBHP, MS4A
6
5
7
95%, 93.8% ee
OH
TsOH
THF-H2O
O
1) dimethoxypropane
TsOH, acetone
O
O
OTBDPS
+
2) TBAF, THF
OH
66%
OH
OH
9
45%
10
8
13%
TBDPS-Cl
DMAP
OBz
OBz
Benzoic acid
Ti(OiPr)4
Cs2CO3
OH
OTBDPS
6
CH2Cl2
rt, 2 h
MeOH:H2O (8:1)
rt, 2 h
CH2Cl2
rt, 3 h
OH
OH
12
11
quant.
83%
MeO
OMe
OH
1) TBAF, THF
O
O
68%
rt
OTBDPS
OTBDPS
2) Dess-Martin oxd.
CH2Cl2, rt, 3 h
TsOH
acetone
rt, overnight
OH
14
13
96%
89% (3 steps)
O
O
O
O
Tabel 1
O
O
+
solvent
-78 °C
CHO
OH
OH
15
16a
16b
O
O
Table 2
solvent, -78 °C
Dess-Martin
16a
+ 16b
O
97 %
17
Fig. 1. Preparation of alcohols 16a and 16b from cinnamyl alcohol (5).
Table 1. Allylation of Aldehyde 15
Ratio/% (GC-MS)
Entry
Reagent
MgBr
MgBr
Solvent
Time/h
Yields/%
16a
16b
62
15
1
2
3
THF
Et2O
THF
6
2
4
67
71
15
38
30
63
70
37
58
(-)-Icp2B
O
B
O
4
5
CH2Cl2
MeOH
3
6
68
—
42
30
Sn
38
17
A mixture of 16a9 and 16b9 was oxidized with Dess–Martin
periodinane and ketone 17 was reduced, whose results are list-
ed in Table 2. In Entry 6, when LiBEt3H was used in THF,
compound 16a9 was obtained as a major product in the ratio
of 73:27 in 85% yield. Thus, this method turned out to com-
pensate the selectivity of both compounds.
acryloyl chloride to give acrylates 18a9 and 18b9 in 47 and
18% (isolation yields), respectively (Fig. 2). After separation
with column chromatography, acrylate 18a9 was treated with
5 mol % of Grubbs’ reagent 3 in CH2Cl2 (5 mM) to provide
ꢁ,ꢂ-unsaturated lactone 19a9 in 90% yield. It is worth men-
tioning that Ti(OiPr)4 was not necessary in this reaction, al-
though many reports pointed out that the use of Ti(OiPr)4
A mixture of alcohols 16a9 and 16b9 was treated with

K. Nakashima et al.
Table 2. Reduction of Ketone 17
Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
389
Ratio/% (GC-MS)
Entry
Reagent
Solvent
Time/h
Yield/%
16a
16b
17
1
2
3
4
5
6
7
8
L-Selectride
DIBAL
Zn(BH4)2
LAH
NaBH4
LiBEt3H
LiBH4
LiBH4 + LiBr
THF
THF
Et2O
Et2O
Et2O
THF
THF
THF
2.5
2
2.5
1
1
1
77
quant.
—
50
75
85
77
84
60
42
21
72
52
73
73
70
40
58
17
28
48
27
27
30
58
1
4
O
O
O
O
O
O
COCl
+
O
O
iPr2NEt
OH
CH2Cl2
0 °C, 2.5 h
O
O
16
18b
18a
O
O
O
O
a) FeCl3 on SiO2
CHCl3
OH
3 (5 mol%)
90%
18a
CH2Cl2 (5 mM)
reflux, overnight
O
b) Montmorillonite KSF
CH2Cl2, rt
OH
O
19a
90%
71%
(+)-Goniodiol (1)
O
O
O
a) FeCl3 on SiO2
CHCl3
3 (5 mol%)
OH
O
18b
96%
CH2Cl2 (5 mM)
reflux, overnight
O
b) Montmorillonite KSF
CH2Cl2, rt
OH
(-)-6-epi-Goniodiol (2)
O
76%
92%
19b
Fig. 2. Synthesis of goniodiol (1) and 6-epi-goniodiol (2).
was essential for cyclization reactions.17 Similarly, acrylate
18b9 was treated with 5 mol % of Grubbs’ reagent 3 in CH2Cl2
(5 mM) to provide ꢁ,ꢂ-unsaturated lactone 19b9 in 92% yield.
NOEs were observed between one of the methyl groups of the
acetonide and two oxymethine protons at C-7 and C-8 posi-
tions of 19a9 and 19b,9 supporting the results by 13C NMR ex-
periment described above. However, the stereochemistry of the
6-position was not determined at this stage. Deprotection of
In order to test the possibility, we synthesized the precursors
2117a and 2417a from aldehyde 20 (Fig. 3). Attempted cycliza-
tion of 2117a or 2417a using 3 did not work at all, although these
reactions were reported.17a,20 However, when new-generation
catalyst 4 (20 mol %) was used, lactones 2217a and 2317a were
obtained in 41 and 50% yields. Similarly, compound 2417a af-
forded 2517a,20 and 2617a,20 in 42 and 50% yields on treatment
of 24 with 4 in CH2Cl2. Therefore, the choice of the catalyst, 3
or 4, may depend upon the functionality of the substrates. The
reason why 21 and 24 did not cyclize into lactones using 3 is
not clear now. However, the presence of the acetonide moiety
nearby both the olefins might have impeded the reaction. The
stereochemistry of compounds 22, 23, 25, and 26 was deter-
mined by NOESY spectra. The methyl group of the acetonide
at ꢀ ¼ 1:30 in compound 23 had NOEs into H-5, H-6, and H-
7ꢂ, and the one at ꢀ ¼ 1:37 had NOE into H-7ꢁ. On the other
hand, the methyl group at ꢀ ¼ 1:35 in compound 22 had NOE
into H-6ꢂ, and the one at ꢀ ¼ 1:47 had NOE into H-5. There-
fore, compound 22 should have 5S,6R configuration, and 23
must be 5R,6R, respectively. The methyl group at ꢀ ¼ 1:36
in compound 25 had NOEs into H-7ꢂ and H-8ꢂ, and the
one at ꢀ ¼ 1:42 had NOEs into H-6 and H-8ꢁ. While in the
18
lactone 19a9 with FeCl3 on silica-gel in CHCl3 provided
goniodiol [1, ½ꢁꢂD þ72:4 (c 0.68, CHCl3), lit. þ75:8 (CHCl3),2
þ72:1 (CHCl3)9] in 90% yield. The spectral data of 1 was
completely identical with those of the natural product reported
in the literature.2,3,9 Similarly, lactone 19b9 provided 6-epi-
goniodiol [2, ½ꢁꢂD ꢁ40:1 (c 2.8, CHCl3), lit. ꢁ47:4 (CHCl3)9]
in 96% yield. The yields of deprotection of acetonide using
FeCl3 on silica-gel18 varied depending on the grade of the re-
agent prepared. Thus, we have found that Montmorillonite
19
KSF in CH2Cl2 worked constantly to afford 1 in 71% and
2 in 76% yield, respectively. Ring-closing metathesis reaction
of 18a9 and 18b9 smoothly proceeded using Grubbs’ catalyst 3
as described above. These results well agreed with our previ-
ous report on simpler ꢁ,ꢂ-unsaturated lactones.11

390 Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
Synthesis of Goniodiol and Its 6-Epimer
O
O
1)
O
O
4
MgBr
THF
O
O
(20 mol%)
O
O
O
H
O
H
CHO
O
O
CH2Cl2
(10 mM)
2)
COCl
20
H
+
O
H
O
H
Et3N, DMAP
CH2Cl2
21 (47%)
22 (41%)
23 (50%)
O
O
O
1)
4
O
O
MgBr
(20 mol%)
O
O
O
THF
H
20
+
O
CH2Cl2
(10 mM)
O
2)
COCl
Et3N, DMAP
CH2Cl2
H
O
H
O
26 (49%)
25 (42%)
24 (19%)
Fig. 3. Preparation of ꢁ,ꢂ-unsaturated lactones.
O
O
O
1
1
1
1
O
O
O
5
H
H
O
H
H
O
5
7
H
O
H
O
H
H
H
H
7
6
6
5
5
O
6
8
7
8
O
6
7
H
O
H
H
H
H
H
O
O
O
H
H
22
23
25
26
Fig. 4. Selected NOEs detected for compounds 22, 23, 25, and 26.
120
100
80
60
40
20
0
the conformation of 1a, whose population was 57%. On the
other hand, the global minimum conformation of (ꢁ)-6-epi-
goniodiol (2) was 2a, whose population was 89%. Their con-
formations were expressed with CPK models (Fig. 7). In the
case of 1a, the hydrophilic functions, namely, four oxygen
atoms, were exposed outside of the molecule in one side. How-
ever, in the case of 2a, oxygen atoms randomly exist in the
molecule. We suspect that this difference in conformation
might be the main reason for the biological activity. Therefore,
we further synthesized the enantiomers of (+)-1 and (ꢁ)-2
(specific rotations of (ꢁ)-goniodiol (1e) and (+)-6-epi-gonio-
diol (2e) as well as compounds on the way to them were de-
scribed in the Experimental). The values of cytotoxic activity
of (ꢁ)-1e and (+)-2e were almost the same as those of (+)-1
and (ꢁ)-2, respectively. The results are shown in Fig. 6. Thus,
the absolute configuration did not affect the biological activity.
The conformations are presumably important for displaying
biological activities.
0.1
1
10
100
1000
µ M
Fig. 5. Cytotoxicity of (+)-goniodiol (1) ( ) and (ꢁ)-6-
epi-goniodiol (2) ( ) against HL-60 cells.
case of compound 26, the methyl group at ꢀ ¼ 1:38 had NOEs
into H-7ꢂ and H-8ꢂ, and the one at ꢀ ¼ 1:46 had NOE into
H-8ꢁ. Therefore, compound 25 was established as 6S,7R and
26 as 6R,7R, respectively (Fig. 4).
Experimental
General. All reactions were carried out under argon atmo-
sphere. Anhydrous solvents were purchased from Kanto Chemical
Co., Inc. Reagents were purchased at the highest commercial qual-
ity and used without further purification. The IR spectra were
measured on a JASCO FT/IR 500 spectrophotometer. 1H and
13C NMR spectra were recorded on a Varian Unity 600, a JEOL
ECP-400, or a Varian Gemini 200 spectrometer. The solvent used
for NMR spectra was CDCl3 unless otherwise stated. MS spectra
were measured on a JEOL JMS 700 MStation spectrometer.
Silica-gel BW-300 (200–400 mesh, Fuji Silycia) was used for
column chromatography, and silica-gel 60F254 plate (0.25 mm,
Merck) were used for TLC.
The biological activity of the synthesized compounds was
tested using HL-60 cell by WST-8 assay.21 Cytotoxicity (IC50)
of (+)-goniodiol (1) was shown to be 40 mM in HL-60 cells.
However, (ꢁ)-6-epi-goniodiol (2) has no cytotoxicity in HL-
60 cells (IC50 > 200 mM). It is worth mentioning that two
structurally closely related compounds, 1 and 2, showed com-
pletely different activities against HL-60 cells (Fig. 5). This is
presumably because both compounds adopt different confor-
mations. Therefore, we next studied their conformations by
calculation of the steric energies. Calculation of the global
minimum of (+)-goniodiol (1) by CONFLEX22 resulted in
Synthesis of 3-Benzoyloxy-3-phenylpropane-1,2-diol (11).
To a stirred solution of epoxide 66 (5.0 g, 33.3 mmol) in CH2Cl2

K. Nakashima et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
391
120
100
80
19.2 (C), 26.8 (CH3), 64.1 (CH2), 73.6 (CH), 75.8 (CH), 127.4
(CH), 127.8 (CH), 128.3 (CH), 128.4 (C), 129.7 (CH), 129.8 (C),
129.9 (CH), 130.0 (CH), 132.8 (CH), 135.5 (CH), 137.3 (C), 165.2
(CO); MS (CI) m=z 511 ½M þ Hꢂþ, 493, 453, 433, 389, 353, 311
(base), 269, 253, 233, 199, 191, 105, 91; HRMS (CI) Found m=z
511.2306 ½M þ Hꢂþ C32H35O4Si requires 511.2304.
Synthesis of 3-t-Butyldiphenylsilyloxy-1-phenylpropane-1,2-
diol (13). A solution of benzoate 12 (117.6 mg, 0.231 mmol) in
MeOH:H2O (8:1, 10 mL) was treated with Cs2CO3 (76 mg, 0.234
mmol, 1.0 equiv) at rt for 3 h. Sat. NH4Cl solution was added and
the mixture was extracted with ether. The organic layer was wash-
ed with brine, dried over MgSO4, and evaporated to give a residue.
The residue was purified by silica-gel column chromatography
(hexane–EtOAc, in gradient) to afford diol 136 (50.9 mg, 54%).
Synthesis of 4-(t-Butyldiphenylsilyloxy)methyl-2,2-dimeth-
yl-5-phenyl-1,3-dioxolane (14). A solution of diol 13 (725.1 mg,
1.79 mmol) in acetone (50 mL) was treated with 2,2-dimethoxy-
propane (0.44 mL, 3.57 mmol, 2.0 equiv) and TsOH (92 mg) at rt
overnight. Sat. aqueous NaHCO3 solution was added and the mix-
ture was extracted with ether. The organic layer was washed with
brine, dried over MgSO4, and evaporated to give a residue. The
residue was purified by silica-gel column chromatography (hex-
60
40
20
0
0.1
1
10
100
1000
µ
M
Fig. 6. Cytotoxicity of (ꢁ)-goniodiol (1e) ( ) and (+)-6-
epi-goniodiol (2e) ( ) against HL-60 cells.
18:5
ane–EtOAc, in gradient) to afford 146 (737.4 mg, 92%). ½ꢁꢂD
19
ꢁ48:7 (c 1.19, CHCl3). ent-14; ½ꢁꢂD þ49:8 (c 1.36, CHCl3).
Synthesis of (4S,5R)-(2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-
yl)methanol (9). A solution of acetonide 14 (594.6 mg, 1.33
mmol) in THF (50 mL) was treated with TBAF (1 M THF solun.,
2.67 mL, 2.67 mmol, 2.0 equiv) at rt overnight. The solvent was
evaporated and the residue was extracted with ether. The organic
layer was washed with brine, dried over MgSO4, and evaporated
to give a residue. The residue was purified by silica-gel column
chromatography (hexane–EtOAc, in gradient) to afford 96 (202.8
mg, 68%).
1a
2a
(+)-goniodiol (1)
(-)-6-epi-goniodiol (2)
Fig. 7. Most stable conformation of (+)-goniodiol (1) and
(ꢁ)-6-epi-goniodiol (2) displayed by CPK model.
Synthesis of 2,2-Dimethyl-5-phenyl-1,3-dioxolane-4-carbal-
dehyde (15). A solution of alcohol 9 (87.8 mg, 0.422 mmol) in
CH2Cl2 (10 mL) was treated with Dess–Martin reagent (363 mg,
0.856 mmol, 2.0 equiv) and NaHCO3 (111 mg, 1.33 mmol, 3.1
equiv) at rt for 1.5 h. A 25% sodium thiosulfate aqueous solution
and then sat. NaHCO3 aqueous solution were added and the mix-
ture was extracted with ether. The organic layer was washed with
brine, dried over MgSO4, and evaporated to give aldehyde 156,9
(83.5 mg, 96%).
(180 mL) was added benzoic acid (4.48 g, 1.1 equiv) and
Ti(iPrO)4 (10.42 mL, 1.1 equiv), successively and the mixture was
stirred for 3 h at rt. After addition of 15% aqueous tartaric acid
solution, the mixture was extracted with ethyl acetate. The organic
solution was washed with brine, dried over MgSO4, and evaporat-
ed to give a residue. The residue was purified by silica-gel column
chromatography (hexane–EtOAc, in gradient) to afford benzoate
18
11 (7.54 g, 83%). 11; ½ꢁꢂD þ23:8 (c 1.18, CHCl3); FT-IR: 3400
1
cmꢁ1; H NMR (200 MHz) ꢀ 3.15 (2H, –OH), 3.64 (2H, m), 4.03
Allylation of 2,2-Dimethyl-5-phenyl-1,3-dioxolane-4-carbal-
dehyde (15). Entry 1: To a stirred solution of aldehyde 15 (170.4
mg, 0.819 mmol) in THF (34 mL) was added allylmagnesium bro-
mide (1 M Et2O solun.; 4.13 mL, 4.13 mmol, 5.0 equiv) at ꢁ78 ꢃC
and the mixture was stirred for 6 h. Sat. NH4Cl aqueous solution
was added and the mixture was extracted with ether. The organic
layer was washed with brine, dried over MgSO4, and evaporated
to give a residue. The residue was purified by silica-gel column
chromatography (hexane–EtOAc, in gradient) to afford 16a9 and
16b9 (38:62, 137.0 mg, 67%). Entry 2: Similarly, aldehyde 15
(21.1 mg, 0.102 mmol) in Et2O (5 mL) was treated with allylmag-
nesium bromide (1 M Et2O soln., 0.50 mL, 0.50 mmol, 5.0 equiv)
at ꢁ78 ꢃC for 2 h to afford 16a and 16b (30:70, 18.0 mg, 71%).
Entry 3: Aldehyde 15 (58.9 mg, 0.290 mol) in CH2Cl2 (5 mL)
was treated with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaboralane
(0.16 mL, 0.871 mmol, 3.0 equiv) at ꢁ78 ꢃC for 3 h to afford 16a
and 16b (42:58, 48.6 mg, 68%). Entry 4: Aldehyde 15 (20.9 mg,
0.101 mmol) in MeOH (5 mL) was treated with tetraallyltin
(0.01 mL, 0.0412 mmol, 0.4 equiv) at rt for 6 h to afford a mixture
of 16a, 16b, and 15 (30:38:17, 25.0 mg).
(1H, m), 5.93 (1H, d, J ¼ 7:0 Hz), 7.43 (8H, m), 8.03 (2H, d,
J ¼ 7:0 Hz); 13C NMR (50 MHz) ꢀ 62.7 (CH2), 74.0 (CH), 76.0
(CH), 127.3 (CH), 128.5 (CH), 128.6 (CH, C), 128.7 (CH), 129.8
(CH), 133.4 (CH), 137.1 (C), 165.9 (CO); MS (CI) m=z 273
½M þ Hꢂþ, 212, 181, 151 (base), 133, 105, 58, 56; HRMS (CI)
Found m=z 273.1121 ½M þ Hꢂþ C16H17O4 requires 273.1127.
18
ent-11; ½ꢁꢂD ꢁ25:4 (c 1.01, CHCl3).
Synthesis of 1-Benzoyloxy-3-t-butyldiphenylsilyloxy-1-phen-
ylpropan-2-ol (12). A solution of diol 11 (6.1 g, 25.4 mmol) in
DMF (82 mL) was treated with imidazole (2.6 g, 1.5 equiv) and
TBDPSCl (7.92 mL, 1.2 equiv) at rt for 3 h. Water was added
and the mixture was extracted with ether. The organic solution
was washed with brine, dried over MgSO4, and evaporated to give
a residue. The residue was purified by silica-gel column chroma-
tography (hexane–EtOAc, in gradient) to afford 12 (13.0 g, quant.).
1
12; FT-IR: 3500, 1720 cmꢁ1; H NMR (300 MHz) ꢀ 1.06 (9H, s),
2.48 (1H, d, J ¼ 5:7 Hz), 3.81 (1H, dd, J ¼ 10:5, 4.2 Hz), 3.87
(1H, dd, J ¼ 10:5, 5.4 Hz), 4.17 (1H, m), 6.05 (1H, d, J ¼ 6:9 Hz),
7.35 (14H, m), 7.67 (4H, m), 7.98 (2H, m); 13C NMR (50 MHz) ꢀ

392 Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
Synthesis of Goniodiol and Its 6-Epimer
1-(2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl)-3-buten-1-one
(17). A solution of alcohol 16 (162.7 mg, 0.656 mmol) in CH2Cl2
(25 mL) was treated with Dess–Martin reagent (557 mg, 1.31
mmol, 2.0 equiv) and NaHCO3 (165 mg, 1.97 mmol, 3.0 equiv)
at rt overnight. A 25% aqueous sodium thiosulfate solution and
sat. NaHCO3 aqueous solution were added. The mixture was ex-
tracted with ether and the organic layer was washed with brine,
dried over MgSO4, and evaporated to yield ketone 17 (157.1 mg,
(6R)-6-[(4S,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5,6-
dihydro-2H-pyran-2-one (19a). A solution of Grubbs’ reagent
(3, 92.2 mg, 0.11 mmol) in degassed CH2Cl2 (10 mL) was added
to a solution of diene 18a9 (170 mg, 0.56 mmol) in degassed
CH2Cl2 (100 mL). The mixture was stirred overnight at room tem-
perature. The solvent was removed under reduced pressure, and the
residue was purified by silica-gel column chromatography (elution
20
with CH2Cl2) to yield lactone 19a9 (134 mg, 87%). ½ꢁꢂD ꢁ65:8 (c
17
1
97%); FT-IR: 1720, 1640 cmꢁ1; H NMR (200 MHz) ꢀ 1.50 (3H,
1.40, CHCl3). ent-19a; ½ꢁꢂD þ79:2 (c 1.30, CHCl3).
s), 1.80 (3H, s), 2.70 (1H, dd, J ¼ 18:4, 6.6 Hz), 2.87 (1H, dd, J ¼
18:4, 6.6 Hz), 4.75 (1H, d, J ¼ 17:4 Hz), 4.83 (1H, d, J ¼ 8:4 Hz),
4.96 (1H, d, J ¼ 9:8 Hz), 5.40 (1H, m), 5.48 (1H, d, J ¼ 8:4 Hz),
7.30 (5H, br s); 13C NMR (50 MHz) ꢀ 24.5 (CH3), 26.4 (CH3),
44.6 (CH2), 79.6 (CH), 84.0 (CH), 110.7 (C), 118.6 (CH2), 126.6
(CH ꢄ 2), 128.4 (CH ꢄ 3), 129.5 (CH), 135.8 (C), 206.5 (CO);
MS (CI) m=z 247 ½M þ Hꢂþ, 231, 189, 177, 141, 119, 89 (base);
HRMS (CI) Found m=z 247.1313 ½M þ Hꢂþ C15H19O3 requires
247.1334.
(6S)-6-[(4S,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5,6-
dihydro-2H-pyran-2-one (19b). A solution of Grubbs’ reagent
(3, 187.6 mg, 0.23 mmol) in degassed CH2Cl2 (30 mL) was added
to a solution of diene 18b9 (344 mg, 1.14 mmol) in degassed
CH2Cl2 (200 mL). The mixture was stirred overnight at room tem-
perature. The solvent was removed under reduced pressure, and the
residue was purified by silica-gel column chromatography (elution
20
with CH2Cl2) to yield lactone 19b9 (261 mg, 84%). ½ꢁꢂD ꢁ16:4
20
(c 2.00, CHCl3). ent-19b; ½ꢁꢂD þ26:5 (c 0.45, CHCl3).
Reduction of 1-(2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl)-3-
buten-1-one (17). Entry 1: A solution of ketone 17 (51.0 mg,
0.207 mmol) in THF (17 mL) was treated with L-selectride (1 M
THF soln., 0.42 mL, 0.415 mmol, 2.0 equiv) at ꢁ78 ꢃC for 2.5 h.
Water was added and the mixture was stirred for 2.5 h before con-
centration in vacuo. The mixture was extracted with ether and the
organic layer was washed with brine, dried (MgSO4), and evapo-
rated to give a residue. The residue was purified with silica-gel
column chromatography (hexane–EtOAc, in gradient) to afford
16a9 and 16b9 (60:40, 39.0 mg, 77%). Entry 2: Similarly, ketone
17 (47.5 mg, 0.193 mmol) in THF (3 mL) was treated with DIBAL
(1 M in toluene, 0.39 mL, 0.386 mmol, 2.0 equiv) to yield 16a and
16b (42:58, 55.9 mg, quant.). Entry 3: Ketone 17 (63.5 mg, 0.258
mmol) in Et2O (4 mL) gave 16a, 16b, and 17 (21:17:58, 21.4 mg)
with Zn(BH4)2 (4.65 mL, 2.32 mmol, 9.0 equiv). Entry 4: Ketone
17 (19.1 mg, 0.0776 mmol) was reduced with LiAlH4 (12.0 mg,
0.311 mmol, 4.0 equiv) to give 16a and 16b (72:28, 9.7 mg, 50%).
Entry 5: Ketone 17 (20.8 mg, 0.0846 mmol) in Et2O (4 mL) was
treated with NaBH4 (13.0 mg, 0.338 mmol, 4.0 equiv) to give 16a
and 16b (52:48, 15.8 mg, 75%). Entry 6: Ketone 17 (28.7 mg,
0.117 mmol) in THF (2 mL) was reduced with LiBHEt3 (1 M
THF soln., 0.02 mL, 0.175 mmol, 1.5 equiv) to give 16a and 16b
(73:27, 24.8 mg, 85%). Entry 7: Ketone 17 (25.4 mg, 0.103 mmol)
afforded 16a and 16b (73:27, 19.6 mg, 77%) with LiBH4 (10.0
mg, 0.413 mmol, 4.0 equiv) in Et2O (2 mL). Entry 8: Ketone 17
(7.5 mg, 0.0305 mmol) in THF (2 mL) was treated with LiBH4
(2.6 mg, 0.122 mmol, 4.0 equiv) and LiBr (3.9 mg, 0.0457 mmol,
1.5 equiv) in THF (2 mL) to give 16a and 16b (70:30, 6.4 mg,
84%).
(+)-Goniodiol (1). To a solution of lactone 19a9 (13.7 mg,
0.05 mmol) in CH2Cl2 (2 mL) was added Montmorillonite KSF
(68.5 mg), and the mixture was stirred overnight at room temper-
ature. The solvent was removed under reduced pressure, and the
residue was purified by silica-gel column chromatography (elution
with hexane–EtOAc; 0–50%) to yield goniodiol (1)7,9 (6.8 mg,
58%); Oil; ½ꢁꢂD þ72:4 (c 0.68, CHCl3); FT-IR 3460, 1730 cmꢁ1
;
1H NMR (200 MHz) ꢀ 2.18 (1H, ddd, J ¼ 18:5, 6.4, 3.8 Hz), 2.49
(1H, d, J ¼ 8:4 Hz), 2.79 (1H, ddt, J ¼ 18:5, 12.9, 2.7 Hz), 2.92
(1H, s), 3.72 (1H, br t, J ¼ 7:0 Hz), 4.80 (1H, ddd, J ¼ 12:9, 3.8,
2.3 Hz), 4.94 (1H, dd, J ¼ 7:1, 3.4 Hz), 5.99 (1H, dd, J ¼ 9:8,
2.7 Hz), 6.93 (1H, ddd, J ¼ 9:8, 6.4, 2.3 Hz), 7.30–7.43 (5H, m);
13C NMR (50 MHz) ꢀ 26.1 (CH2), 73.7 (CH), 75.1 (CH), 76.8
(CH), 120.6 (CH), 126.6 (CH), 128.3 (CH), 128.8 (CH), 140.8
(C), 146.2 (CH), 163.8 (CO); MS (CI) m=z 235 ½M þ Hꢂþ, 217
(base), 199, 171, 128, 107, 97, 41; HRMS (CI): Found m=z
235.0968 ½M þ Hꢂþ C13H15O4 requires 235.0970. ent-goniodiol
18
(1e); ½ꢁꢂD ꢁ80:5 (c 1.18, CHCl3).
(À)-6-epi-Goniodiol (2). To a solution of lactone 19b9 (79.1
mg, 0.29 mmol) in CH2Cl2 (10 mL) was added Montmorillonite
KSF (395.5 mg), and the mixture was stirred overnight at room
temperature. The solvent was removed under reduced pressure,
and the residue was purified by silica-gel column chromatography
(elution with hexane–EtOAc; 0–50%) to yield 6-epi-goniodiol
(2)9,12 (56.7 mg, 84%); ½ꢁꢂD ꢁ40:1 (c 2.8, CHCl3); FT-IR: 3400,
1
1700 cmꢁ1; H NMR (400 MHz) ꢀ 2.43–2.58 (3H, m), 2.71 (1H,
ddt, J ¼ 20:2, 11.4, 2.8 Hz), 4.18 (1H, td, J ¼ 5:7, 3.6 Hz), 4.38
(1H, dt, J ¼ 11:4, 5.7 Hz), 4.93 (1H, dd, J ¼ 5:7, 2.8 Hz), 6.00
(1H, ddd, J ¼ 9:7, 2.8, 1.1 Hz), 6.93 (1H, ddd, J ¼ 9:7, 6.2, 2.8
Hz), 7.33–7.43 (5H, m); 13C NMR (100 MHz) ꢀ 24.5 (CH2), 73.9
(CH), 74.8 (CH), 78.0 (CH), 120.8 (CH), 126.8 (CH), 128.5
(CH), 128.7 (CH), 139.6 (C), 145.9 (CH), 163.8 (CO); MS (CI)
m=z 235 ½M þ Hꢂþ, 217 (base), 173, 171, 128, 107, 97, 82; HRMS
(CI): Found m=z 235.0974 ½M þ Hꢂþ C13H15O4 requires 235.0970.
(1R)-1-[(4S,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-
3-enyl Acrylate (18a) and (1S)-1-[(4S,5R)-2,2-Dimethyl-5-phen-
yl-1,3-dioxolan-4-yl]but-3-enyl Acrylate (18b). To a solution of
alcohol 16 (1.0 g, 4.0 mmol) in CH2Cl2 (50 mL) were added N,N-
diisopropylethylamine (2.8 mL, 16.0 mmol), acryloyl chloride (0.8
mL, 9.8 mmol), and DMAP (100 mg) at 0 ꢃC. The mixture was
stirred for 5 h at 0 ꢃC. Water was added, and the mixture was ex-
tracted with CH2Cl2. The organic layer was washed with 1 M HCl,
saturated NaHCO3 and brine, dried (MgSO4), and was evaporated
to afford a residue, which was purified by silica-gel column chro-
matography (elution with hexane–EtOAc in gradient; 0–20%) to
18
ent-6-epi-goniodiol (2e); ½ꢁꢂD þ43:0 (c 0.64, CHCl3).
(5S)-5-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5H-furan-2-one
(22) and (5R)-5-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5H-fu-
ran-2-one (23). To a solution of aldehyde 20 (3.9 g, 30 mmol)
in THF (150 mL) was added vinylmagnesium bromide (1.0 M in
THF, 62 mL, 62 mmol) at ꢁ78 ꢃC, and the mixture was warmed to
room temperature overnight. Saturated NH4Cl was added, and the
solvent was removed. The residue was extracted with ether, and
the organic layer was washed with saturated NH4Cl and brine,
dried (MgSO4), and evaporated to afford a residue, which was pu-
23
yield 18a9 (254 mg, 21%) and 18b9 (424 mg, 35%). 18a: ½ꢁꢂD
30
ꢁ65:8 (c 1.00, CHCl3); 18b: ½ꢁꢂD þ0:93 (c 2.00, CHCl3). ent-
19
18
18a; ½ꢁꢂD þ98:1 (c 0.48, CHCl3); ent-18b; ½ꢁꢂD ꢁ7:7 (c 0.53,
CHCl3).

K. Nakashima et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 2 (2007)
393
rified by silica-gel column chromatography (elution with hexane–
EtOAc in gradient; 0–50%) to yield alcohol (3.2 g, 68%). To a so-
lution of alcohol (3.2 g, 20 mmol) in CH2Cl2 (320 mL) was added
triethylamine (8.4 mL, 60 mmol), DMAP (320 mg), and acryloyl
chloride (3.25 mL, 40 mmol) at 0 ꢃC, and the mixture was stirred
for 4 h. Water was added, and the mixture was extracted with
CH2Cl2. The organic layer was washed with saturated NaHCO3,
water and brine, dried (MgSO4), and evaporated to afford a resi-
due, which was purified by silica-gel column chromatography
(elution with hexane–EtOAc in gradient; 0–20%) to yield ester
21 (3.0 g, 47%). A solution of catalyst 4 (2.4 g, 2.83 mmol) in de-
gassed CH2Cl2 (20 mL) was added to a solution of ester 21 (3.0 g,
14.2 mmol) in degassed CH2Cl2 (1.4 L). The mixture was stirred
for 2 days at room temperature. The solvent was removed under
reduced pressure, and the residue was purified by silica-gel col-
umn chromatography (elution with hexane–EtOAc in gradient;
0–50%) to yields lactone 22 (1.1 g, 41%) and lactone 23 (1.3 g,
50%); 22: FT-IR: 1765 cmꢁ1; 1H NMR (400 MHz) ꢀ 1.35 (3H, s),
1.47 (3H, s), 3.92 (1H, ddd, J ¼ 8:1, 6.2, 4.0 Hz), 4.10 (1H, dd,
J ¼ 9:2, 4.0 Hz), 4.16 (1H, dd, J ¼ 9:2, 6.2 Hz), 4.86 (1H, dd, J ¼
8:1, 1.8 Hz), 6.21 (1H, dd, J ¼ 5:9, 1.8 Hz), 7.64 (1H, dd, J ¼ 5:9,
1.8 Hz); 13C NMR (100 MHz) ꢀ 24.6 (CH3), 26.4 (CH3), 66.6
(CH2), 75.9 (CH), 82.9 (CH), 110.2 (C), 122.3 (CH), 154.8 (CH),
172.4 (C); MS (CI) m=z 185 ½M þ Hꢂþ (base), 169, 127, 101;
HRMS (CI) Found m=z 185.0785 ½M þ Hꢂþ C9H13O4 requires
(600 MHz) ꢀ 1.36 (3H, s), 1.42 (3H, s), 2.46 (1H, ddt, J ¼ 18:7,
11.0, 2.75 Hz), 2.62 (1H, dddd, J ¼ 18:7, 6.04, 4.12, 1.10 Hz),
4.05 (1H, td, J ¼ 7:14, 3.85 Hz), 4.15–4.20 (2H, m), 4.29 (1H,
ddd, J ¼ 11:0, 7.97, 4.12 Hz), 6.04 (1H, ddd, J ¼ 9:76, 2.74,
1.10 Hz), 6.93 (1H, ddd, J ¼ 9:76, 6.04, 2.74 Hz); 13C NMR
(50 MHz) ꢀ 24.9 (CH3), 26.1 (CH2), 26.6 (CH3), 66.9 (CH2), 76.0
(CH), 77.9 (CH), 109.9 (C), 121.3 (CH), 145.0 (CH), 163.1 (C);
MS (CI) m=z 199 ½M þ Hꢂþ (base), 141, 123, 89; HRMS (CI)
Found m=z 199.0977 ½M þ Hꢂþ C10H15O4 requires 199.0970;
22
26: ½ꢁꢂD þ131:9 (c 1.01, CHCl3); FT-IR: 1730 cmꢁ1
,
1H NMR
(600 MHz) ꢀ 1.38 (3H, s), 1.46 (3H, s), 2.36 (1H, dddd, J ¼ 18:4,
6.04, 4.12, 1.10 Hz), 2.54 (1H, ddt, J ¼ 18:4, 12.1, 2.47 Hz), 4.05
(1H, dd, J ¼ 8:79, 6.59 Hz), 4.09 (1H, dd, J ¼ 8:79, 6.59 Hz),
4.33 (1H, td, J ¼ 6:59, 4.12 Hz), 4.54 (1H, dt, J ¼ 12:1, 4.12 Hz),
6.04 (1H, ddd, J ¼ 9:89, 2.47, 1.10 Hz), 6.93 (1H, ddd, J ¼ 9:89,
6.04, 2.47 Hz); 13C NMR (50 MHz) ꢀ 24.9 (CH3), 25.0 (CH3),
26.0 (CH2), 64.7 (CH2), 75.6 (CH), 77.7 (CH), 110.1 (C), 121.2
(CH), 145.0 (CH), 163.5(C); MS (CI) m=z 199 ½M þ Hꢂþ (base),
183, 123, 101; HRMS (CI) Found m=z 199.0970 ½M þ Hꢂþ
C10H15O4 requires 199.0970.
Evalution of in vitro Cytotoxicity.21 Cytotoxicity against
HL-60 cells was assessed as follows: 1 ꢄ 104 cells seeded onto
96-well plate were incubated with the chemicals at the indicated
concentrations at 37 ꢃC for 24 h. Then, viability of the cells were
determined by WST-8 assay using cell counting kit-8 according
to the manufacturer’s instruction (Wako Pure Chemicals, Ltd.,
Osaka, Japan).
185.0814; 23: FT-IR: 1765 cmꢁ1 1H NMR (400 MHz) ꢀ 1.30
;
(3H, s), 1.37 (3H, s), 3.80 (1H, dd, J ¼ 8:8, 5.5 Hz), 4.06 (1H,
dd, J ¼ 8:8, 6.6 Hz), 4.37 (1H, ddd, J ¼ 6:6, 5.5, 3.7 Hz), 5.05
(1H, dt, J ¼ 3:7, 1.8 Hz), 6.18 (1H, dd, J ¼ 5:9, 1.8 Hz), 7.43
(1H, dd, J ¼ 5:9, 1.8 Hz); 13C NMR (100 MHz) ꢀ 24.8 (CH3),
25.7 (CH3), 64.6 (CH2), 74.0 (CH), 82.0 (CH), 110.2 (C), 123.0
(CH), 152.9 (CH), 172.5 (C); MS (CI) m=z 185 ½M þ Hꢂþ (base),
169, 127, 101; HRMS (CI) Found m=z 185.0783 ½M þ Hꢂþ
C9H13O4 requires 185.0813.
We thank Dr. Masami Tanaka and Miss Y. Okamoto
(Tokushima Bunri University) for measurement of 600 MHz
NMR and MS spectra, respectively.
References
(6S)-6-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5,6-dihydro-
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