Stereoselective and facile total synthesis of (+)-goniodiol, a styryllactone from carbohydrates

Article abstract of DOI:10.1016/j.tetasy.2010.08.017

The stereoselective synthesis of (+)-goniodiol, a cytotoxic styryllactone, has been accomplished in 10 steps starting from inexpensive and readily available d-manitol and δ-gluconolactone involving the direct and straightforward reaction conditions of Gri

Full text of DOI:10.1016/j.tetasy.2010.08.017

Tetrahedron: Asymmetry 21 (2010) 2443–2447
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective and facile total synthesis of (+)-goniodiol, a styryllactone
from carbohydrates
⇑
Jhillu Singh Yadav , Saibal Das, Anand Kumar Mishra
Division of Organic Chemistry-1, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2010
Accepted 21 August 2010
The stereoselective synthesis of (+)-goniodiol, a cytotoxic styryllactone, has been accomplished in 10
steps starting from inexpensive and readily available D-manitol and d-gluconolactone involving the direct
and straightforward reaction conditions of Grignard addition, chain elongation, and hydroboration, thus
making the synthesis simple and convenient.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
O
Asian trees of genus Goniothalamus have been a source of di-
verse families and classes of compounds possessing important
and interesting biological properties.1 In the past, powdered leaves
of Goniothalumus have been used as traditional medicines in North
Malaysia in the region of Manipur (India) as an abortificant during
labor pain,2 with more than 30 bioactives having been listed1b so
far. Numerous bioactive styryllactones have been isolated from
Goniothalamus species3 and are reported to be useful in the treat-
ment of endema and rheumatism.4 They also possess significant
cytotoxicity against several human tumors.1c These are natural
heterocyclic compounds with potential cytotoxicity including
anti-fungal, anti-tumor, and anti-biotic properties.5 Other applica-
tion includes their use as pain killers and mosquito repellants.6
(+)-Goniodiol 1 is a styryldihydropyrone obtained from Gonio-
thalamus sesquipedalis, a shrub growing abundantly in the state
of Manipur, situated in the north-eastern region of India;2 it was
first isolated in 1985 from the petroleum ether extract of the leaves
and twigs,2 and later on from the ethanolic extract of stem bark of
Goniothalamus gigantus,7 reported to show selective and significant
cytotoxicity against human lung carcinoma cell lines A-549
OH
O
H
H
H
OH
1
Figure 1. A styryllactone, (+)-goniodiol.
Chiron approaches,15 Jacobsen’s kinetic resolution along with
epoxidation and dihydroxylations from cinnamyl alcohol,16 and
regioselective mono-dihydroxylations followed by Red-Al reduc-
tion.17 In a continuation of our efforts toward convenient synthesis
of (+)-goniodiol, we herein report a facile stereoselective approach
utilizing straightforward reaction conditions from the easily avail-
able carbohydrates, D-mannitol and d-gluconolactone, in 10 steps
via a key intermediate 3 with 16% overall yield.
2. Results and discussions
As depicted in the retrosynthetic analysis (Scheme 1), the
desired compound (+)-goniodiol
compound 2 by means of acid catalyzed lactonization. Then, com-
pound 2 can be envisaged from the key intermediate 3 by utilizing
selective hydroboration followed by chain elongation. Next, the
(ED50 = 0.122
cells (IC50 = 4.56
l
g mlꢀ1),8 HL-60 cells,9 and P-388 murine leukemia
1 could be obtained from
l
g mlꢀ1),10 making it an important molecule to
study further (Fig. 1).
In 1992, Honda et al.11 accomplished the first synthesis of
(+)-goniodiol in 15 steps, by generating oxygenated lactones via
furan oxidation thereby establishing and securing its absolute con-
figuration. Afterward, many research groups showed significant
interest and achieved its synthesis9,12 using different strategies13
via different intermediates.14 Recently, we have demonstrated four
synthetic routes for its total synthesis and their analogs using
key intermediate 3 could be obtained from either D-mannitol or
d-gluconolactone via an easy reaction sequence. The approach
was based on the fact that the two desired stereogenic centers in
the target compound 1 could be obtained from the pattern dis-
played in
diastereoselectively.
D-mannitol with the remaining center being created
Accordingly, the synthesis of the key intermediate 3 was started
from
D-mannitol (Scheme 2) and d-gluconolactone (Scheme 3). Diol
⇑
Corresponding author. Tel.: +91 40 2716 3030; fax: +91 40 2716 0387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
4 was prepared in two steps18 and was converted to olefin 5 using
0957-4166/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2010.08.017

2444
J. S. Yadav et al. / Tetrahedron: Asymmetry 21 (2010) 2443–2447
O
OH OH
O
O
O
O
PPTS, MeOH
HO
HO
5 Steps
OH
O
OH
O
Ph
HO
rt, 12h
81%
ref 15c
64% overall
OH
OH OH
O
OTBDPS
OH
OH
D-Mannitol
δ-gluconolactone
9
1
O
Ph
OTBDPS
Acid catalysed
O
O
Lactonization
HO
PPh3, imidazole
I2, Toluene
110 C, 3h
81%
O
HO
Ph
Ph
3
Chain
O
OTBDPS
O
OTBDPS
º
O
O
Elongation
TBDPSO
O
HO
HO
10
3
Ph
O
CO2Me
OH
Scheme 3. Synthesis of key intermediate 3 from d-gluconolactone.
OH
δ-gluconolactone
2
for the preparation of key intermediate 3 (Scheme 3), where com-
pound 9 was obtained using the protocol already described earlier
in five sequential steps in 65% overall yield.15c Then after selective
deprotection of the terminal acetonide, diol 10 was transformed
into an olefin, thus furnishing the key intermediate 3 in 81% yield.
With the key intermediate 3 in hand (Scheme 4), selective hyd-
roboration using dicyclohexylborane exclusively provided the
homologated primary alcohol 11 after oxidative workup.20 Further
oxidation of alcohol 11 to its corresponding aldehyde15b and chain
elongation utilizing the Still–Gennari reagent,21 [(F3CCH2O)2-
Scheme 1. Retrosynthesis for (+)-goniodiol.
PPh3, Imidazole,
I2, Toluene,
HO
O
HO
2 steps
ref 18
15% overall
O
D-Mannitol
º
110 C, 3h,
O
O
O
80%
4
i) NaIO4,
sat. NaHCO3
DCM, rt, 5h
POCH2CO2Me], furnished the corresponding Z-isomeric a,b-unsat-
O
urated ester 2 in 77% yield along with trace amounts of the E-
isomer, which was separated by column chromatography. The Z-
geometry of ester 2 was confirmed by 1H NMR resonance of the
loefinic protons at d 5.68 ppm as a triplet of the doublet with a cou-
pling constant of J = 11.3 and 2.2 Hz and d 6.0 ppm as a multiplet.
Ester 2 was then subjected to acidic conditions hoping to achieve
the deprotection of both acetonide and silyl ether in single step fol-
lowed by in situ lactonization using 1 M HCl in MeOH. Unfortu-
nately none of the desired compound was obtained; thus several
conditions (Table 1) using several reagents were examined. Entries
1, 2, and 4 furnished the cyclized compound 12 along with unre-
acted ester 2.
PPTS, MeOH
O
OH
rt, 12h,
75%
O
O
O
O
OH
ii) PhMgBr, THF,
º
º
-5 C - 0 C
then rt, 12h
5
6
74% in two steps
O
O
Ph
OH
Ph
OH
+
O
8
7
Major-isomer
Minor-isomer
O
TBDPSCl, DMAP
imidazole, DCM
Ph
OTBDPS
Cy2BH, THF
O
º
O
O
0 C - rt, 3h,
º
0 C - rt, 6h,
97%
Ph
HO
Ph
3
then
O
OTBDPS
O
OTBDPS
Scheme 2. Synthesis of key intermediate 3 from
D-mannitol.
H2O2, NaOH
º
0 C - rt, 2h
87%
3
11
triphenylphosphine conditions.19b The terminal acetonide moiety
of olefin 5 was subjected to selective hydrolysis to furnish diol 6
in a satisfactory yield of 75%. Diol 6 was carried forward for
in situ cleavage of the terminal diols to furnish the corresponding
aldehyde, which subsequently underwent phenyl Grignard reac-
tion. The mixture of alcohols obtained was purified by column
chromatography to afford the desired alcohol 7 as the major prod-
uct (49.6%) along with the minor product 8 (24.8%).15b The stereo-
chemistry of the separated carbinols 7 and 8 was confirmed by
comparing the analytical data reported by Gracza et al. and Agra-
wal et al.19 At this point, carbinol 7, obtained as the major isomer,
was used in the synthesis of (+)-goniodiol after protecting its sec-
ondary alcohol as a silyl ether to produce the key intermediate 3 in
an excellent 97% yield. Moreover, the carbinol 8 obtained in the
process could be utilized for the synthesis of 8-epi-goniodiol. It is
noteworthy that better diastereoselectivities and yields were
obtained, when d-gluconolactone was used as the starting material
TBDPSO
Ph
O
TFA/H2O
IBX, DMSO, THF, rt, 7h
(4:1)
CO2Me
DCM, rt,
5 - 12h
99%
O
(F3CCH2O)2POCH2CO2Me
2
º
NaH, THF, -78 C, 30 min
77%
TFA/H2O (10:1)
rt, 5h
56%
O
O
OH
O
TBDPSO
O
HF/pyridine
rt, 48h
52%
OH
OH
12
1
Scheme 4. Total synthesis of (+)-goniodiol.

J. S. Yadav et al. / Tetrahedron: Asymmetry 21 (2010) 2443–2447
2445
Table 1
Acidic conditions examined on ester 2
Entry
Reagent/solvent
Time (h)
Temp (°C)
Isolated yield (%)
2
12
1
1
2
3
4
5
6
PTSA/MeOH
12
12
4
5–12
12
5
rt
rt
50
rt
rt
rt
20
9
100
—
—
—
80
70
—
99
—
—
—
—
—
50
56
HCl (3% in MeOH)
CH3CO2H (50% in H2O)
TFA/H2O (4:1)/DCM
Concd HCl/MeOH
TFA/H2O (10:1)
—
When ester 2 was exposed to TFA/H2O (4:1) in DCM, the lacton-
ized compound 12 was obtained as the sole product (entry 4),
which was then treated with HF/pyridine complex for the depro-
tection of silyl ether to furnish the final compound, (+)-goniodiol
1. However, target compound (+)-goniodiol 1 was also achieved di-
rectly from ester 2 using the same TFA/H2O (10:1) when no solvent
was used in addition. The spectroscopic data of the thus synthe-
sized (+)-goniodiol 1 were in agreement with the natural product.8
4.3. (R)-1-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)
ethane-1,2-diol (6)
To a stirred solution of 5 (2 g, 8.7 mmol) in MeOH (25 ml) at 0 °C
was added PPTS (6.60 g, 26.2 mmol) and stirred for 12 h at rt. The
reaction mixture, after it was cooled to 0 °C, was quenched by
saturated aqueous NaHCO3 (15 mL), and the solvents were evapo-
rated under reduced pressure, extracted with ethyl acetate
(3 ꢁ 30 mL), washed with brine, and placed over anhydrous Na2SO4
and evaporated under reduced pressure. The crude residue was
chromatographed to obtain the desired product 6 (1.2 g, 75%) as a
yellow oil. 1H NMR (CDCl3, 300 MHz): d 1.40 (s, 3H), 1.42 (s, 3H),
2.25 (br s, 1H), 2.65 (br s, 1H), 3.61–3.74 (m, 3H), 3.76–3.83
(m, 1H), 4.35–4.40 (m, 1H), 5.22 (d, J = 10.07 Hz, 1H), 5.37–5.44
(m, 1H), 5.82–5.93 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 26.8, 26.9,
63.4, 71.9, 79.2, 81.1, 109.3, 118.8, 135.8; IR (KBr): mmax 3401,
2988, 2933, 1644, 1378, 1054, 874 cmꢀ1. HRMS calcd for C9H16O4
3. Conclusion
In conclusion, a facile and stereoselective synthesis of the cyto-
toxic styryllactone, (+)-goniodiol, has been achieved starting from
inexpensive and readily available starting materials. The synthesis
involves direct and straightforward reaction conditions such as
aryl Grignard addition, chain elongation with a Still–Ginnari re-
agent, and hydroboration, which makes this synthetic route simple
and convenient.
[M+Na]+ 211.0946. Found: 211.0954, ½a 2D8
¼ þ6:9 (c 0.58, CH2Cl2)
ꢂ
{literature value; ½a D22
ꢂ
¼ þ4:4 (c 0.21, CH2Cl2)}.19a
4. Experimental
4.1. General
4.4. (S)-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)
(phenyl)methanol (7) and (R)-((4R,5R)-2,2-dimethyl-5-vinyl-
1,3-dioxolan-4-yl)(phenyl)methanol (8)
IR spectra were recorded on a Perkin–Elmer FT-IR 240-c spec-
trophotometer using KBr optics. 1H and 13C NMR spectra were
respectively recorded on Gemini-200 and Varian Bruker-300 spec-
trometer in CDCl3 using TMS as internal standard. Mass spectra
were recorded on a Finnigan MAT 1020 mass spectrometer operat-
ing at 70 eV. The optical rotations were measured on a Jasco Dip
360 Digital polarimeter.
A solution of diol 6 (3 g, 15.9 mmol) in DCM (20 ml) containing
aqueous saturated NaHCO3 (3 ml) was treated with NaIO4 (6.81 g,
31.8 mmol) portionwise at 0 °C and stirred at a temperature below
20 °C for 5 h. Solid Na2SO4 (8 g) was added, and the mixture was
stirred for an additional 15 min, filtered, washed with DCM
(250 ml), and the solvent was evaporated to afford the correspond-
ing aldehyde, which was then immediately used for the next step.
To a solution of Grignard reagent [prepared in situ from Mg (0.53 g,
22.0 mmol) and phenylbromide (3.45 g, 22.0 mmol) in THF (20 m)]
at ꢀ5 °C was added a solution of the crude aldehyde in THF (5 ml).
The mixture was allowed to warm from 0 °C to room temperature
slowly and after 12 h quenched with aqueous saturated NH4Cl.
Extraction with Et2O (3 ꢁ 20 mL), then a brine wash, dried over
Na2SO4, and removal of the solvent followed by purification gave
an enantiomerically pure yellow viscous liquid 7 and 8 (2.7 g,
74.4% yield including both isomers in two steps). Compound 7:
1H NMR (CDCl3, 300 MHz): d 1.42 (s, 3H), 1.46 (s, 3H), 2.67 (br s,
1H), 3.86 (dd, J = 8.30 Hz, and J = 5.28 Hz, 1H), 4.26–4.32 (m, 1H),
4.57 (d, J = 4.532 Hz, 1H), 4.97–5.02 (m, 1H), 5.06–5.14 (m, 1H),
5.34–5.47 (m, 1H), 7.23–7.35 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d 27, 74, 79, 84.4, 109.7, 118.1, 126.8, 128.2, 128.4, 134.7, 139.9;
IR (KBr): mmax 3456, 2987, 2924, 2855, 1454, 1376, 1248, 1217,
1052, 927, 881, 703 cmꢀ1. HRMS calcd for C14H18O3 [M+Na]+
4.2. (4S,4’R,5R)-2,2,2’,2’-Tetramethyl-5-vinyl-4,4’-bi(1,3-
dioxolane) (5)
To a solution of diol 4 (10 g, 38.1 mmol) in dry toluene (400 ml)
was added triphenylphosphine (40 g, 152.6 mmol) followed by
imidazole (10.4 g, 152.6 mmol) and stirred vigorously. To the
resulting solution was added iodine (29 g, 114.5 mmol) and the
mixture was refluxed at 110 °C for 3 h. The reaction mixture, after
being returned to room temperature, was decanted into excess sat-
urated aqueous Na2S2O3 (100 ml) and saturated aqueous NaHCO3
(100 ml) in a separating funnel. The residue in the reaction flask
was extracted with EtOAc (3 ꢁ 100 ml). These organic extracts
were combined with the material in the separating funnel and sha-
ken until the iodine was consumed. The organic phase was washed
with H2O (1 ꢁ 100 ml), dried and concentrated. The crude residue
was chromatographed to obtain 5 (7 g, 80.4%) as a viscous liquid.
1H NMR (CDCl3, 300 MHz): d 1.31 (s, 3H), 1.35, 1.40 (2s, 9H), 3.60
(t, J = 7.55 Hz, 1H), 3.84–3.94 (m, 1H), 4.00–4.09 (m, 2H), 4.31
(t, J = 6.79 Hz, 1H), 5.16 (d, J = 10.57 Hz, 1H), 5.38 (d, J = 17.37 Hz,
1H), 5.82–5.95 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 25.1, 26.5,
26.8, 66.9, 76.6, 80.3, 81.0, 109.2, 109.5, 117.0, 135.8; IR (KBr): mmax
2988, 2935, 2883, 1375, 1249, 1065, 925, 847 cmꢀ1. HRMS calcd
257.1153. Found: 257.1156, ½a D28
¼ þ4:8 (c 0.21, CH2Cl2). Com-
ꢂ
pound 8: 1H NMR (CDCl3, 300 MHz): d 1.40 (s, 3H), 1.45 (s, 3H),
2.47 (br s, 1H), 3.93 (dd, J = 8.30 Hz, and J = 3.77 Hz, 1H), 4.34–
4.40 (m, 1H), 4.81 (d, J = 10.57 Hz, 1H), 4.94 (d, J = 17.37 Hz, 1H),
5.00 (d, J = 3.77 Hz, 1H), 5.08–5.21 (m, 1H), 7.23–7.37 (m, 5H);
13C NMR (CDCl3, 75 MHz): d 26.9, 71.6, 76.8, 84.1, 109.2, 116.8,
125.9, 127.8, 128.2, 135.6, 138.5; IR (KBr): mmax 3460, 2988, 2927,
for C12H20O4 [M+Na]+ 251.1259. Found: 251.1256, ½a 2D8
¼ ꢀ6:0
ꢂ
(c 2.98, CHCl3).

2446
J. S. Yadav et al. / Tetrahedron: Asymmetry 21 (2010) 2443–2447
1454, 1376, 1248, 1216, 1054, 704 cmꢀ1. ½a D28
ꢂ
¼ þ15:1 (c 0.2,
was stirred for 2 h at room temperature. Aqueous NH4Cl was added
and the reaction mixture was extracted with EtOAc (2 ꢁ 30 ml). The
combined organic layers were dried over anhydrous Na2SO4 and con-
centrated in vacuo. The residue was purified by column chromatogra-
phy to afford compound 11 (1.8 g, 86.7%) as a green liquid. 1H NMR
(CDCl3, 300 MHz): d 1.04 (s, 9H), 1.08 (s, 3H), 1.22–1.36 (m, 5H),
2.01 (br s, 1H), 3.36–3.49 (m, 2H), 3.59–3.69 (m, 1H), 3.77–3.86 (m,
1H), 4.66 (d, J = 6.2 Hz, 1H), 7.11–7.43 (m,13H), 7.69–7.76 (m, 2H);
13C NMR (CDCl3, 75 MHz): d 19.3, 26.5, 26.9, 27.1, 35.0, 60.0, 76.8,
84.2, 108.6, 127.3, 127.8, 129.4, 129.5, 133.2, 133.6, 135.9, 136.1,
139.7; IR (KBr): mmax 3449, 2932, 2890, 1590, 1375, 1215, 1108,
1062, 701 cmꢀ1. HRMS calcd for C30H38O4Si [M+Na]+ 513.2437.
CH2Cl2) {literature value; ½a D22
ꢂ
¼ þ14:4 (c 0.25, CH2Cl2)}.19a
4.5. tert-Butyl((S)-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-di oxolan-
4-yl)(phenyl)methoxy)diphenylsilane (3)
To a solution of alcohol 7 (4 g, 17.0 mmol) in anhydrous CH2Cl2
(30 ml) at 0 °C were added TBDPSCl (5.63 g, 20.4 mmol), DMAP
(cat.), and imidazole (3.48 g, 51.2 mmol) successively and the mix-
ture was stirred for 5 h at 25 °C. The reaction mixture was
quenched by adding H2O (20 ml) and then extracted with CH2Cl2
(2 ꢁ 50 ml). The organic extracts were washed with brine solution,
dried over Na2SO4, and removal of the solvent followed by purifica-
tion gave a yellow viscous liquid compound 3 (7.8 g, 96.7%). From
compound 10: To a solution of diol 10 (2 g, 3.9 mmol) in dry tolu-
ene (25 ml) was added triphenylphosphine (4.14 g, 11.8 mmol) fol-
lowed by imidazole (1.07 g, 15.7 mmol) and stirred vigorously. To
the resulting solution was added iodine (3.0 g, 11.8 mmol) and the
mixture was refluxed at 110 °C for 3 h. The reaction mixture, after
being returned to room temperature, was decanted into excess sat-
urated aqueous Na2S2O3 (100 ml) and saturated aqueous NaHCO3
(15 ml) in a separating funnel. The residue in the reaction flask
was extracted with EtOAc (3 ꢁ 20 ml). These extracts were com-
bined with the material in the separating funnel and shaken until
the iodine was consumed. The organic phase was washed with
H2O (1 ꢁ 20 ml), dried, and concentrated. The crude residue was
chromatographed to obtain 3, (1.5 g, 80.64%) as a yellow viscous
liquid. 1H NMR (CDCl3, 300 MHz): d 1.03 (s, 9H), 1.15(s, 3H), 1.31
(s, 3H), 3.83–3.97 (m, 2H), 4.68 (d, J = 6.04 Hz, 1H), 4.77–4.88
(m, 2H), 5.14–5.27 (m, 1H), 7.12–7.20 (m, 5H), 7.23–7.42
(m, 8H), 7.71 (d, J = 6.78 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d 19.3, 26.6, 26.9, 34.4, 76.7, 78.1, 84.6, 108.8, 116.7, 127.2,
127.3, 127.6, 127.7, 129.3, 129.5, 133.4, 133.7, 135.4, 135.9,
136.1, 139.7; IR (KBr): mmax 3056, 2934, 2859, 1654, 1591, 1373,
1231, 1112, 1056, 699 cmꢀ1. HRMS calcd for C30H36O3Si [M+Na]+
Found: 513.2431, ½a D28
¼ þ45:3 (c 1, CH3OH).
ꢂ
4.8. (Z)-Methyl4-((4R,5S)-5-((S)-(tert-butyldiphenylsilyl
oxy)(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-
enoate (2)
To a stirred solution of IBX (0.86 g, 3.0 mmol) in DMSO (5 ml) at
25 °C was added dropwise a solution of compound 10 (1.0 g,
2.0 mmol) in THF (12 ml). The resulting mixture was stirred at
25 °C for 7 h. Then the solid obtained was filtered and washed with
ether (10 ml). The filtrate was extracted with ether, washed with
water, brine and dried over Na2SO4 and then concentrated under
reduced pressure to afford the crude aldehyde, which was immedi-
ately used for the next reaction without further purification. To a
stirred solution of O,O’-bis-(2,2,2 trifluoroethyl)(methoxycarbonyl-
methyl) phosphonate (0.88 g, 2.7 mmol) in dry THF (10 ml) at 0 °C
was added NaH (0.097 g, 4.0 mmol) and stirred for 30 min at 0 °C.
To the reaction mixture, the above mentioned aldehyde 11 dis-
solved in dry THF (4 ml) was added and stirred for 30 min at
ꢀ78 °C. The reaction mixture was quenched with saturated NH4Cl
solution (3 ml) and stirred at room temperature for 10 min. The
layers were separated and the aqueous layer was extracted with
EtOAc (2 ꢁ 10 ml). The combined organic layers were washed with
brine (2 ꢁ 15 ml), dried over Na2SO4, and concentrated in vacuo
followed by purification by column chromatography to afford the
(Z)-olefinic ester 2 (0.85 g, 76.9% yield, overall two steps) as a green
liquid. 1H NMR (CDCl3, 300 MHz): d 1.04 (s, 9H), 1.06 (s, 3H), 1.28
(s, 3H), 2.32–2.54 (m, 2H), 3.60–3.68 (m, 4H), 3.77–3.83 (m, 1H),
4.69 (d, J = 6.0 Hz, 1H), 5.68 (td, J = 11.3, 2.3, 2.3 Hz, 1H), 6.00–
6.09 (m, 1H), 7.12–7.41 (m, 12H), 7.69–7.73 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 19.3, 26.6, 27.0, 27.2, 32.4, 50.9, 75.9, 76.6,
83.7, 108.5, 120.6, 127.2, 127.3, 127.4, 127.7, 127.8, 129.4, 129.5,
133.3, 133.6, 135.9, 136.1, 139.8, 145.2, 166.3; IR (KBr): mmax
2934, 2893, 1724, 1647, 1433, 1374, 1176, 1108, 1066, 827,
702 cmꢀ1. HRMS calcd for C33H40O5Si [M+Na]+ 567.2542. Found:
495.2331. Found: 495.2309, ½a D28
¼ þ47:0 (c 1, CH3OH).
ꢂ
4.6. (R)-1-((4R,5S)-5-((S)-(tert-Butyldiphenylsilyloxy)
(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-
diol (10)
To a stirred solution of 9 (2 g, 3.6 mmol) in MeOH (25 mL) at 0 °C
was added PPTS (4.59 g, 18.2 mmol) and stirred for 12 h at room
temperature. The reaction mixture after reaching 0 °C was quenched
by saturated aqueous NaHCO3 (15 ml) and evaporated under re-
duced pressure, then extracted with ethyl acetate (3 ꢁ 30 ml),
washed with brine, dried over anhydrous Na2SO4, and evaporated
under reduced pressure. The crude residue was chromatographed
to give diol 10 (1.5 g, 81.1%) as a green viscous liquid. 1H NMR (CDCl3,
300 MHz): 0.9 (s, 3H), 1.08 (s, 9H), 1.23 (s, 3H), 3.38–3.65 (m, 5H),
4.95 (d, J = 4.53 Hz), 7.15–7.44 (m, 13H), 7.64–7.68 (m, 2H); 13C
NMR (CDCl3, 75 MHz): d 19.9, 26.3, 26.9, 63.5, 72.2, 75.4, 77.2,
82.6, 108.9, 127.3, 127.6, 129.8, 129.9, 132.0, 132.7, 135.8, 135.9,
138.4; IR (KBr): mmax 701, 1065, 1110, 1212, 1244, 1377, 1458,
2933, 3068, 3422 cmꢀ1. HRMS calcd for C30H38O3Si [M+Na]+
567.2557, ½a 2D8
¼ þ50:9 (c 1, CH3OH).
ꢂ
4.9. (R)-6-((1S,2R)-2-(tert-Butyldiphenylsilyloxy)-1-hy droxy-2-
phenylethyl)-5,6-dihydropyran-2-one (12)
To a stirred solution of 2 (100 mg, 0.18 mmol) in CH2Cl2 (6.0 ml)
was added a mixture of water (0.25 ml) and TFA (1 ml). The reac-
tion mixture was stirred at room temperature for 6 h. The reaction
mixture was quenched with solid NaHCO3, extracted with DCM,
washed with brine, dried over anhydrous Na2SO4, and evaporated
under reduced pressure to provide the lactonized product 12
(0.085 g, 98.8%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): d 1.04
(s, 9H), 1.96–2.08 (m, 1H), 2.61 (br s, 1H), 2.72–2.85 (m, 1H),
3.65–3.72 (m, 1H), 3.83–3.92 (m, 1H), 5.03 (d, J = 8.30, 1H), 5.83–
5.89 (m, 1H), 6.71–6.80 (m, 1H), 7.14–7.44 (m, 12H), 7.62–7.68
(m, 3H); 13C NMR (CDCl3, 75 MHz): d 19.3, 26.0, 27.0, 75.7, 120.7,
127.2, 127.4, 127.7, 127.9, 128.2, 129.6, 129.8, 132.7, 133.2,
135.7, 135.8, 139.8, 145.3, 163.5; IR (KBr): mmax 3455, 2930, 1724,
1425, 1385, 1249, 1111, 1076, 819, 702 cmꢀ1. HRMS calcd for
529.2386. Found: 529.2380. ½a D28
¼ þ39:0 (c 1, CHCl3).
ꢂ
4.7. 2-((4R,5S)-5-((S)-(tert-Butyldiphenylsilyloxy)(phenyl)
methyl)-2,2-dimethyl-1,3 dioxolan-4-yl)ethanol (11)
To a stirred solution of alkene 3 (2.0 g, 4.2 mmol) in dry THF
(20 mL) at 0 °C, dicyclohexylborane (10.48 mL, 5.2 mmol, 0.5 M in
THF) was added slowly. The mixture was stirred at room temperature
for 12 h. Then it was cooled to 0 °C and treated with aqueous NaOH
(21.1 ml, 21.1 mmol, 1 M aqueous solution) followed by H2O2
(1.43 ml, 21.2 mmol, 50% aqueous solution). The reaction mixture

J. S. Yadav et al. / Tetrahedron: Asymmetry 21 (2010) 2443–2447
2447
C29H32O4Si [M+Na]+ 495.1967. Found: 495.1955, ½a 2D8
¼ þ20:5
ꢂ
2. Talapatra, S. K.; Basu, D.; Deb, T.; Goswami, S.; Talapatra, B. Indian J. Chem., Sect.
B 1985, 24, 29–34.
3. (a) Fang, X. P.; Anderson, J. E.; Qiu, X. X.; Kozlowski, J. F.; Chang, C. J.;
McLaughlin, J. L. Tetrahedron 1993, 49, 1563; (b) Wang, S.; Zhang, Y. J.; Chen, R.
Y.; Yu, D. Q. J. Nat. Prod. 2002, 65, 835.
(c 0.75, CH3OH).
4.10. (R)-6-((1R,2R)-1,2-Dihydroxy-2-phenylethyl)-5,6-di
hydropyran-2-one (1)
4. Kan, W. S. Pharmaceutical Botany; National Research Institute of Chinese
Medicine: Taipei, 1979. p 247.
5. (a) Mu, Q.; Tang, W. D.; Liu, R. Y.; Li, C. M.; Lou, L. G.; Sun, H. D. Planta Med.
2003, 69, 826; (b) Pihie, A. H.; Stanslas, J.; Din, L. B. Anticancer Res. 1998, 18,
1739.
6. (a) Sam, T. W.; Yeu, C. S.; Matsieh, S.; Gan, E. K.; Razak, D.; Mohamed, A. L.
Tetrahedron Lett. 1987, 28, 1541; (b) Goh, S. H.; Ee, G. C.; Chuah, C. H.; Wei, C.
Aust. J. Chem. 1995, 48, 199.
7. Geran, R. I.; Greenberg, N. H.; MacDonald, M. M.; Schumacher, A. M.; Abbott, B.
J. Cancer Chemother. Rep. 1972, 3, 1–103.
8. Fang, X. P.; Anderson, J. E.; Chang, C. J.; McLaughlin, J. L.; Fanwick, P. E. J. Nat.
Prod. 1991, 54, 1034–1043.
To the HF/pyridine complex (0.1 ml) was added a room temper-
ature solution of silyl ether 12 (60 mg, 0.1 mmol) in CH3CN (1 ml).
After stirring for 48 h, the reaction mixture was quenched with sat-
urated aqueous NaHCO3 (1 ml) and extracted with EtOAc
(3 ꢁ 5 ml). The combined organic layer was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by silica gel
chromatography to furnish compound 1 (15 mg, 51.7%) as a color-
less oil.
9. Nakashima, K.; Kikuchi, N.; Shirayama, D.; Miki, T.; Ando, K.; Sono, M.; Suzuki,
S.; Kawase, M.; Kondoh, M.; Sato, M.; Tori, M. Bull. Chem. Soc. Jpn. 2007, 80,
387–394.
4.11. Typical procedure to obtain compound 1 from compound
2 in one step
10. Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55, 2493–2514.
11. Tsuhiki, M.; Kanai, K.; Honda, T. J. Chem. Soc., Chem. Commun. 1992, 1640–1641.
12. (a) Prasad, K. R.; Gholap, S. L. Tetrahedron Lett. 2007, 48, 4679–4682; (b)
Yoshida, T.; Yamauchi, S.; Tago, R.; Maruyama, M.; Akiyama, K.; Sugahara, T.;
Kishida, T.; Koba, Y. Biosci. Biotechnol. Biochem. 2008, 72, 2342–2352.
13. (a) Mukai, C.; Cho, W. J.; Kim, I. J.; Kido, M.; Hanaoka, M. Tetrahedron 1991, 47,
3007–3036; (b) Surivet, J. P.; Volle, J. N.; Vatele, J. M. Tetrahedron: Asymmetry
1996, 7, 3305–3308; (c) Surivet, J. P.; Gore, J.; Vatele, J. M. Tetrahedron Lett.
1996, 37, 371–374; (d) Surivet, J. P.; Gore, J.; Vatele, J. M. Tetrahedron 1996, 52,
14877–14890; (e) Mukai, C.; Hirai, S.; Hanaoka, M. J. Org. Chem. 1997, 62,
6619–6626; (f) Surivet, J. P.; Vatele, J. M. Tetrahedron Lett. 1998, 39, 7299–
7300; (g) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1 1998,
3125–3126; (h) Harris, J. M.; O’Doherty, G. A. Tetrahedron 2001, 57, 5161–
5171; (i) Chen, J.; Lin, G. Q.; Wang, Z. M.; Liu, H. Q. Synlett 2002, 1265–1268; (j)
Banwell, M. G.; Coster, M. J.; Karunaratne, O. P.; Smith, J. A. J. Chem. Soc., Perkin
Trans. 2002, 1622–1624; (k) Banwell, M. G.; Coster, M. J.; Edwards, A. J.;
Karunaratne, O. P.; Smith, J. A.; Welling, L. L.; Willis, A. C. Aust. J. Chem. 2003, 56,
585–595; (l) Tate, E. W.; Dixon, D. J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 1698–
1706.
To compound 2 (50 mg, 0.09 mmol) was added a mixture of
water (0.1 ml) and TFA (1 ml). The reaction mixture was then stir-
red for next 5 h. The reaction mixture was quenched with solid
NaHCO3, extracted with DCM, washed with brine and dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The
residue was chromatographed to provide compound 1 (12 mg,
56%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): d 2.04–2.18
(m, 1H), 2.69–2.85 (m, 1H), 3.0 (br s, 1H), 3.64–3.72 (m, 1H),
4.70–4.78 (m, 1H), 4.91 (d, J = 7.5 Hz), 5.95 (dd, J = 9.8, 2.3 Hz,
1H), 6.8–6.9 (m, 1H), 7.27–7.42 (m, 5H); 13C NMR (CDCl3,
75 MHz): d 29.6, 75.1, 78.4, 120.8, 126.4, 128.1, 129.3, 140.3,
145.8, 164.0; IR (KBr): mmax 3451, 2986, 1719, 1645, 1440, 1375,
1210, 1058 cmꢀ1. HRMS calcd for C13H14O4 [M+H]+ 235.0970.
14. (a) Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2002, 67,
7547–7550; (b) Virolleaud, M. A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44,
8081–8084; (c) Deligny, M.; Carreaux, F.; Carboni, B. Synlett 2005, 1462–1464;
(d) Favre, A.; Carreaux, F.; Deligny, M.; Carboni, B. Eur. J. Org. Chem. 2008, 4900–
4907.
Found: 235.0968, ½a D28
¼ þ72:2 (c 0.68, CHCl3) {literature value;
ꢂ
½
a 2D2
ꢂ
¼ þ74:4 (c 0.3, CHCl3)}.8
15. (a) Yadav, J. S.; Madhavarao, B.; Rao, K. S.; Reddy, B. V. S. Synlett 2008, 1039–
1041; (b) Yadav, J. S.; Madhavarao, B.; Rao, K. S. Tetrahedron: Asymmetry 2009,
20, 1725–1730; (c) Yadav, J. S.; Madhavarao, B.; Rao, K. S. Synlett 2009, 3179–
3181.
16. Yadav, J. S.; Premalatha, K.; Harshavardhan, S. J.; Reddy, B. V. S. Tetrahedron Lett.
2008, 49, 6765–6767.
Acknowledgment
A.K.M. thanks CSIR, New Delhi, for the award of fellowships to
perform the research.
17. Sabitha, G.; Sudhakar, K.; Yadav, J. S. Synthesis 2007, 0385–0388.
18. Wiggins, L. J. Chem. Soc. 1946, 13–14.
19. (a) Babjek, M.; Kapitan, P.; Gracza, T. Tetrahedron 2005, 61, 2471; (b) Yadav, V.
K.; Agrawal, D. Chem. Commun. 2007, 5232–5234.
20. Kamal, A.; Reddy, P. V.; Prabhakar, S.; Suresh, P. Tetrahedron: Asymmetry 2009,
20, 1798–1801.
21. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
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