First total synthesis and absolute configuration of the styryl lactone gonioheptolide A

Article abstract of DOI:10.1055/s-2007-990862

Efficient asymmetric syntheses of both naturally occurring and non-naturally occurring enantiomers of gonioheptolide A are reported. The absolute configuration of (+)-gonioheptolide A was established by NOESY, Mosher ester analysis, and comparison with the specific rotation of the isolated (+)-gonioheptolide A. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990862

3512
PAPER
First Total Synthesis and Absolute Configuration of the Styryl Lactone
Gonioheptolide A
Styryl Lactone
h
Goniohepto
u
lide
A
chi Gupta,a,1 Murali Rajagopalan,b,2 Mamoun M. Alhamadsheh,a,1 L. M. Viranga Tillekeratne,a
Richard A. Hudson*a,b
a
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo,
2801 West Bancroft St., Toledo, OH 43606, USA
Department of Chemistry, College of Arts and Sciences, University of Toledo, 2801 West Bancroft St., Toledo, OH 43606, USA
Fax +1(419)5307946; E-mail: Richard.hudson@utoledo.edu
b
Received 21 April 2007; revised 3 July 2007
Abstract: Efficient asymmetric syntheses of both naturally occur-
ring and non-naturally occurring enantiomers of gonioheptolide A
are reported. The absolute configuration of (+)-gonioheptolide A
was established by NOESY, Mosher ester analysis, and comparison
with the specific rotation of the isolated (+)-gonioheptolide A.
H
OH
O
O
OH
H
O
O
HO
OMe
HO
O
OH
Key words: gonioheptolide A, styryl lactones, natural products,
antitumor agents, stereoselective synthesis
gonioheptolide A (1)
(–)-goniofupyrone (2)
Figure 1
Gonioheptolide A (1, Figure 1) is representative of the
styryl lactones, a structurally interesting, synthetically
challenging and biologically important group of natural
products derived from the plant family Annonaceae indig-
enous to Asia.3 Considerable prior effort has focused on
the isolation, characterization,4 and synthesis of many dif-
ferent styryl lactones.5 A number of total syntheses of dif-
ferent styryl lactones have also appeared.6
eventual cell death.10 Clearly, analogues with enhanced
selective cytotoxicity would be desirable.
Since the absolute configuration of (–)-goniofupyrone
was established,6g it was assumed that (+)-gonioheptolide
A,7 the naturally occurring isomer, had the absolute con-
figuration shown as 1 in Figure 1. However, no experi-
mental evidence establishing that absolute configuration
has been reported. Here, we report a stereospecific synthe-
sis of both enantiomers of gonioheptolide A allowing for
simultaneous determination of the absolute configura-
tions.
Gonioheptolide A has five contiguous stereocenters start-
ing from a benzylic carbon and leading toward a carboxy
terminal methyl ester. While racemic gonioheptolide A
has been prepared by semi-synthesis from ( )-goniofupy-
rone,7 no stereospecific total synthesis or semi-synthesis
from other styryl lactones of known configuration has es-
tablished the absolute configuration of gonioheptolide A
unambiguously.
Our general approach to the synthesis of gonioheptolide is
shown in Scheme 1. Introduction of the terminal phenyl as
the (E)-styrene in 5 subsequent to the selective elaboration
of L-(+)-tartrate as the monobenzyl derivative 4 facilitated
Sharpless asymmetric epoxidation to give intermediate 6.
Subsequent intramolecular cyclization of 6 was followed
with conversion into 7 and final elaboration of 7 into 1
(Scheme 1).
In addition to determining the absolute configuration of
the natural product, a total stereoselective synthesis of go-
nioheptolide A could also provide an approach to the syn-
thesis of any or all of its possible stereoisomers, and
potentially to the stereoselective synthesis of other impor-
tant styryl lactones,8 as well as many non-naturally occur-
ring analogues. Since they have considerable selective
cytotoxic activity toward many cancer cell lines,9 a versa-
tile, general route to other styryl lactones as well as gonio-
heptolide A would further provide an enriched diversity of
styryl lactones not available from natural sources, leading
toward a more thoroughly defined structure–activity rela-
tionship. The styryl lactones act by stimulating apoptosis
through an intrinsic-pathway-activation of caspases, caus-
ing a cascade of proteolytic activity, cell damage, and
In the first phase of our syntheses of 1 through intermedi-
ate 7 we prepared 5 as shown in Scheme 2. Conversion of
3 into 4 involved well-known reactions,11 that have previ-
ously been applied in the stereoselective synthesis of
monosaccharides.12 Swern oxidation of 4 gave the known
aldehyde intermediate 8.12 Subsequent Wittig alkenation
gave a mixture of isomers that could be readily
isomerized13 to give the purified (E)-styryl isomer 9 in a
good overall yield of 65% over two steps. Efficient re-
moval of the ketal under acidic conditions gave interme-
diate 5 in excellent overall yield of 16% over the seven-
step process.
In the subsequent conversion of 5 into 1 we first followed
the route in Scheme 3 showing the seven step conversion
of 5 into 13, the C3 epimer of 1. As predicted by the
SYNTHESIS 2007, No. 22, pp 3512–3518
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990862; Art ID: M02807SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

PAPER
Styryl Lactone Gonioheptolide A
3513
OH
OBn
HO
HO2C
HO
CO2H
OH
OBn
O
O
OH
5
4
3
OH
O
H
O
1
OBn
O
H
OH
TBSO
OTBS
7
6
Scheme 1 General approach for the preparation of gonioheptolide A
Sharpless model,14 using (+)-diethyl tartrate as the chiral ing the secondary hydroxys, removing the benzyl group,
ligand in epoxidation gave the desired threo-epoxide 6 in and subsequently oxidizing the primary alcohol product to
87% yield. No attempts were made at this stage to deter- the aldehyde 7 using Dess–Martin periodinane. In the sec-
mine the level of diastereoselectivity. The intramolecular ond step, selective debenzylation required the use of min-
cyclization of 6 under acidic conditions led to the forma- imal amounts of catalyst, since excessive quantities led to
tion of dihydroxytetrahydrofuran 10 in a 5-endo fashion. ring opening due to hydrogenolysis of the secondary ben-
This reaction occurred in high yield and with great selec- zylic ether. By addition of the palladium catalyst portion-
tivity. Acid-catalyzed stereospecific conversion of b-hy- wise and performing the hydrogenolysis at atmospheric
droxy epoxides to hydroxytetrahydrofurans as well as the pressure and room temperature, these byproducts could be
cyclization of epoxy esters to lactones are also well- suppressed at optimal conditions and 11 was obtained in
known and have been employed elsewhere in the synthe- 91% yield. Compound 11 was subsequently converted
sis of other styryl lactones.5b,6d,6m,8a,15
into 7 in 75% yield.
The conversion of 10 into 7, a key intermediate in the last Finally, a stereoselective aldol reaction was carried out
stage of the synthesis of 1, was carried out by first protect- under kinetically controlled conditions using the lithium
enolate of methyl acetate. Predominantly the undesired
anti-Felkin–Anh stereoisomer 12 was obtained under
O
OBn
these conditions with excellent diastereoselectivity
(>96% de). The absolute configuration at the hydroxy car-
bon was observed to be S as confirmed by Mosher ester
analysis (Figure 2).16 Mild desilylation using tris(dimeth-
ylamino)sulfonium difluorotrimethylsilicate (TASF)17
gave compound 13, which was the C3 epimer of the target
molecule 1.
H
c
a
b
O
O
3
4
8
OBn
d
5
O
O
Alternative introduction of the aldol ester earlier in the
synthesis led to difficulties that were insurmountable. In-
termediate 9 was converted into aldol 14. However, when
the ketal was removed the stable lactone 15 was formed
(Scheme 4). Thus, we chose to stage the aldol chemistry
at the end of the overall sequence in the synthesis reported
here.
9
Scheme 2 Reagents and conditions: (a) (i) 2,2-dimethoxypropane,
MeOH, cyclohexane, TsOH, reflux, 85%; (ii) LiAlH4, THF, reflux,
60%; (iii) NaH, BnBr, THF, 0 °C to r.t., 63%; (b) Swern oxidation,
–78 °C, 70%; (c) (i) BnP+Ph3Br–, n-BuLi, THF, –40 °C; (ii) AIBN,
PhSH, benzene, 80 °C, 76% (2 steps); (d) TFA, H2O, 0 °C to r.t., 95%.
H
O
H
d
c
O
b
a
OH
OH
6
5
OBn
TBSO
HO
OTBS
OH
11
10
H
O
O
OH
H
O
O
f
e
OMe
7
HO
OMe
OH
TBSO
13
[α]D20 –6
OTBS
12
Scheme 3 Reagents and conditions: (a) (+)-DET, Ti(Oi-Pr)4, t-BuOOH, MS 4 Å, CH2Cl2, –20 °C, 87%; (b) CSA, CH2Cl2, r.t., 85%; (c) (i)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 88%; (ii) H2, Pd/C, MeOH, r.t., 91%; (d) DMP, CH2Cl2, 0 °C to r.t., 75%; (e) MeOAc, LDA, –78 °C, THF,
81%; (f) TASF, DMF, r.t., 90%.
Synthesis 2007, No. 22, 3512–3518 © Thieme Stuttgart · New York

3514
S. Gupta et al.
PAPER
OMTPA
O
1
HO
3
O
+0.002
–0.105
H
H
+0.026 O
H
O
1'
O
OMe
2'
5'
H
+0.125
H
2
4'
+0.032
–0.031
–0.001
3'
TBSO
OTBS
HO
H
H
OH
12
Figure 3
Figure 2
O
(–)-tartaric acid (17) (Scheme 6). In comparison to the
strategy shown in Schemes 2, 3, and 5 for (–)-goniohep-
tolide A, we used (–)-diethyl tartrate in the Sharpless ep-
oxidation instead of (+)-diethyl tartrate, and the (R)-2-
methyl-1,3,2-oxazaborolidine catalyst in place of the cor-
responding (S)-isomer to synthesize (+)-gonioheptolide A
(18). Since the specific rotation of synthesized goniohep-
tolide A was +5, there was little doubt that the absolute
configuration of the naturally occurring (+)-goniohep-
tolide A (18) is opposite to the one proposed earlier (1,
Figure 1).3b,7
OH
OH
O
HO
O
OMe
H+
O
O
15
14
Scheme 4
Mitsunobu inversion18 was attempted on intermediate 12.
This approach failed presumably due to the presence of
the bulky tert-butyldimethylsilyl at C3 in the tetrahydro-
furan ring. An alternative approach shown in Scheme 5
employed stereospecific reduction of the reoxidized aldol
hydroxy using the Corey–Bakshi–Shibata (CBS)19 re-
agent (S)-2-methyl-1,3,2-oxazaborolidine as a chiral cata-
lyst. As predicted by the model for this reduction, the
desired (R)-alcohol 16 was obtained in good yield with
excellent diastereoselectivity (>98% by Mosher ester
analysis). Subsequent desilylation using tris(dimethyl-
amino)sulfonium difluorotrimethylsilicate led to the for-
mation of (–)-goniofupyrone (2) along with small
amounts of the (–)-enantiomer of gonioheptolide A. Con-
version of 16 to (–)-gonioheptolide A in 70% yield was
accomplished in two steps. (–)-Gonioheptolide A was
identical (NMR, NOESY) to the natural product except
for the reported specific rotation of +5.3b,7 The observed
specific rotation of –5 and not +5 suggested initially that
the configurations of all stereocenters were opposite to
those shown in (–)-gonioheptolide A (1, Figure 1) for the
reported naturally occurring isomer.
OH
H
O
O
HO2C
HO
CO2H
OH
OMe
HO
OH
D-(–)-tartaric acid
(+)-gonioheptolide A
17
18
Scheme 6
In conclusion, we have established the absolute configu-
ration of the natural isomer of gonioheptolide A by syn-
thesizing both isomers of gonioheptolide A. The synthetic
strategy proved applicable for the synthesis of different
isomers of gonioheptolide A and intermediates in the syn-
thesis could be useful in the asymmetric synthesis of other
styryl lactones.
All reactions were carried out under N2 atmosphere using anhyd sol-
vents and conditions, unless otherwise noted. THF and Et2O were
distilled under N2 from Na–benzophenone. The solvents used were
ACS grade from Fisher. Reagents were purchased from Aldrich and
Acros, and used without further purification. Reactions were moni-
tored by TLC carried out on 0.20 mm Polygram SIL silica gel plates
(Art.-Nr. 805 023) with fluorescent indicator UV254 using UV light
and 15% H2SO4–MeOH and heat as visualizing agents. Normal-
phase flash column chromatography was carried out using Davisil
silica gel (100–200 mesh, Fisher). NMR spectra were recorded on
Varian INOVA 600 and Varian VXRS-400 instruments and cali-
brated using residual undeuterated solvent as an internal reference.
Optical rotations were recorded on an AUTOPOL III 589/546 pola-
rimeter. HRMS were recorded on a Micromass LCT Electrospray
mass spectrometer performed at the Mass Spectrometry & Prote-
omics Facility (The Ohio State University).
NOESY of (–)-gonioheptolide A (1) showed strong NOE
signals between the C2¢ and C3¢, C2¢ and C5¢ protons in
the furan ring (Figure 3). This also confirmed the threo
stereochemistry of the epoxide 6.
We also synthesized the (+)-isomer of gonioheptolide A
in an analogous process to that shown starting from
OH
H
O
O
a
b
12
OMe
TBSO
OTBS
16
c
(–)-gonioheptolide A (1)
[α]D20 –5
2
Mosher Ester; General Procedure
To a stirred soln of alcohol (1 equiv), DMAP (0.5 equiv), and Et3N
(3 equiv) in CH2Cl2 was added (+)-(S)- or (–)-(R)-a-methoxy-a-(tri-
fluoromethyl)phenylacetyl chloride (MTPACl) (3 equiv) at r.t. The
resulting mixture was stirred overnight. The soln was diluted with
EtOAc and washed with H2O, dried, and concentrated in vacuo. Pu-
Scheme 5 Reagents and conditions: (a) (i) DMP, CH2Cl2, r.t., 80%;
(ii) (S)-2-methyl-1,3,2-oxazaborolidine, BH3–THF, THF, r.t., 83%;
(b) TASF, DMF, r.t.; (c) MeOH, THF, H2SO4, r.t., 70% (2 steps).
Synthesis 2007, No. 22, 3512–3518 © Thieme Stuttgart · New York

PAPER
Styryl Lactone Gonioheptolide A
3515
rification by column chromatography (silica gel) furnished the
Mosher ester. Note: It should be noted that (R)- or (S)-MTPA esters
are obtained from (S)- or (R)-MTPACl, respectively.
to give 9 as a pale yellow oil (0.7 g, 76% over 2 steps); Rf = 0.66 (sil-
ica gel, 25% EtOAc–hexanes).
[a]D20 –34.55 (c 1.1, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.25–7.38 (m, 10 H), 6.62 (d,
J = 15.6 Hz, 1 H), 6.16 (dd, J = 6.5, 15.6 Hz, 1 H), 4.61 (q, J = 11.5
Hz, 2 H), 4.42 (t, J = 12 Hz, 1 H), 3.98–4.02 (m, 1 H), 3.69–3.60 (m,
2 H), 1.47 (br s, 6 H).
13C NMR (100 MHz, CDCl3): d = 138.3, 136.5, 133.9, 128.8, 128.6,
128.2, 127.9, 127.9, 126.9, 126.5, 80.5, 79.5, 73.8, 69.7, 27.3, 27.2.
[(4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methanol (4)
2,3-O-Isopropylidene-L-threitol was synthesized from (+)-tartaric
acid 3 as reported earlier.11 To a cooled suspension (0 °C) of NaH
(0.541 g, 22.5 mmol) in THF (8 mL) was added dropwise 2,3-O-iso-
propylidene-L-threitol (2.0 g, 12.34 mmol) in THF (6 mL). The
mixture was stirred at 0 °C for 1 h after which BnBr (2.1 g, 12.2
mmol) was added and the mixture was warmed to r.t. and stirred for
6 h. The reaction was then quenched with sat. NH4Cl soln and ex-
tracted with Et2O. The combined organic extracts were dried (anhyd
Na2SO4), concentrated, and purified by flash chromatography (sili-
ca gel, 3–20% EtOAc–hexanes) to give 4 (1.9 g, 63%) as a colorless
oil; Rf = 0.24 (silica gel, 25% EtOAc–hexanes).
1H NMR (600 MHz, CDCl3): d = 7.35–7.25 (m, 5 H), 4.57 (s, 2 H),
4.06–4.02 (m, 1 H), 3.94–3.91 (m, 1 H), 3.74–3.72 (m, 1 H), 3.68–
3.65 (m, 2 H), 3.56–3.53 (m, 1 H), 1.41 (d, J = 3.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 137.9, 128.7, 128.1, 127.9, 109.6,
79.8, 76.8, 73.9, 70.6, 62.6, 27.2, 27.2.
HRMS: m/z [M + Na]+ calcd for C21H24NaO3: 347.1623; found:
347.1633.
(E,2S,3S)-1-(Benzyloxy)-5-phenylpent-4-ene-2,3-diol (5)
To a cooled (0 °C) soln of 9 (0.5 g, 1.54 mmol) in CH2Cl2 (38 mL)
was added 90% TFA in H2O (3 mL) and the mixture was stirred at
0 °C for 1 h. The mixture was diluted with CH2Cl2, washed with
H2O, sat. aq Na2CO3 soln, and again with H2O. The organic layer
was dried (anhyd Na2SO4), filtered, and concentrated. The crude
product was purified by flash column chromatography (silica gel,
10–50% EtOAc–hexanes) to give 5 (0.42 g, 95%) as a white solid;
Rf = 0.51 (silica gel, 66% EtOAc–hexanes).
[a]D20 –25.25 (c 0.8, CHCl3).
HRMS: m/z [M + Na]+ calcd for C14H20NaO4: 275.1259; found:
1H NMR (600 MHz, CDCl3): d = 7.36–7.27 (m, 10 H), 6.64 (d,
J = 16.2 Hz, 1 H), 6.19 (dd, J = 6.5, 16.2 Hz, 1 H), 4.55 (q, J = 11.4
Hz, 2 H), 4.36–4.33 (m, 1 H), 3.78–3.75 (m, 1 H), 3.67–3.58 (m, 2
H).
275.1262.
(4R,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde (8)12
To 2 M oxalyl chloride in CH2Cl2 (5.1 mL, 10.2 mmol ) at –78 °C
was added DMSO (1.63 g, 20.9 mmol) dropwise. After 10 min of
stirring at –78 °C, 4 (1.29 g, 5.10 mmol) in CH2Cl2 (16 mL) was
added dropwise and the resulting soln was stirred for 1 h. Et3N (4.3
mL, 30.6 mmol) was added and the mixture was stirred at –78 °C
for 30 min and then warmed to r.t. for 30 min. The mixture was
quenched with H2O and extracted with CH2Cl2. The combined or-
ganic extracts were dried (anhyd Na2SO4), concentrated, and puri-
fied by flash chromatography (silica gel, 9–16% EtOAc–hexanes)
to give 8 (0.9 g, 70%) as a pale yellow oil; TLC as a streak (silica
gel, 50% hexanes–EtOAc).
1H NMR (600 MHz, CDCl3): d = 9.75 (s, 1 H), 7.35–7.2 (m, 5 H),
4.59 (s, 2 H), 4.26–4.21 (m, 2 H), 3.68–3.62 (m, 2 H), 1.48 (s, 3 H),
1.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 200.9, 137.9, 128.7, 128.1, 127.9,
111.9, 82.3, 76.4, 73.8, 70.1, 27.1, 26.4.
13C NMR (100 MHz, CDCl3): d = 137.8, 136.6, 132.8, 128.8, 128.7,
128.2, 128.1, 128.0, 126.8, 73.9, 73.7, 73.5, 71.7.
HRMS: m/z [M + Na]+ calcd for C18H20NaO3: 307.1310; found:
347.1308.
(1R,2S)-3-(Benzyloxy)-1-[(2S,3S)-3-phenyloxiran-2-yl]pro-
pane-1,2-diol (6)
Activated, powdered 4 Å molecular sieves (38 mg) and anhyd
CH2Cl2 (10 mL) were placed in a 50-mL flame-dried flask. (+)-DET
(218 mg, 1.05 mmol) was added to the above slurry and the mixture
was cooled to –20 °C. Ti(Oi-Pr)4 (1.0 mL, 3.38 mmol) and anhyd
3.6 M t-BuOOH in CH2Cl2 (0.59 mL, 2.1 mmol) were added drop-
wise and the mixture was stirred at –20 °C for 40 min. A predried
(4 Å MS) soln of 5 (200 mg, 0.704 mmol) in CH2Cl2 (8 mL) was
added to it dropwise and the mixture was stirred at –20 °C for 7 h.
The reaction was quenched by adding it to a cooled (0 °C) soln of
FeSO4·7H2O (0.33 g per mmol of allylic alcohol) and tartaric acid
(0.1 g per mmol of allylic alcohol) in H2O (1 mL per mmol of allylic
alcohol) and stirred for 10 min without a cooling bath. The aqueous
layer was extracted with Et2O and the combined organic extracts
were stirred over 30% NaOH in brine (1 mL per mmol of allylic al-
cohol) at 0 °C for 1 h. The aqueous layer was again extracted with
Et2O and the combined organic extracts were dried (anhyd Na2SO4),
filtered, and concentrated. The crude product was purified by flash
column chromatography (silica gel, 50% EtOAc–hexanes) to give 6
(183 mg, 87%) as a white crystalline solid; Rf = 0.50 (silica gel,
66% EtOAc–hexanes).
HRMS: m/z [M + Na]+ calcd for C14H18NaO4: 273.1103; found:
273.1090.
(4S,5S)-4-(Benzyloxymethyl)-2,2-dimethyl-5-[(E)-styryl]-1,3-
dioxolane (9)
To a soln of BnPh3PBr (1.46 g, 3.38 mmol) in anhyd THF (14.1 mL)
under N2 at –40 °C was added 2.5 M n-BuLi in hexanes (1.35 mL,
3.38 mmol). After stirring at –40 °C for 15 min, 8 (0.71 g, 2.82
mmol) in THF (5.64 mL) was added slowly to the mixture when the
orange color faded slowly. After stirring at r.t. for 4 h, the mixture
was poured into aq NH4Cl and extracted with Et2O. The combined
organic extracts were dried (Na2SO4) and concentrated to give an E/
Z mixture of alkene products, which was subsequently equilibrated
to the E-isomer as follows: To a soln of AIBN (119 mg, 8% by
weight) in anhyd benzene (10 mL), PhSH (0.26 mg, 16% by weight)
was added followed by the addition of the E/Z alkene mixture in
benzene. The mixture was refluxed at 80 °C and the reaction was
monitored by TLC. After 2 h the reaction was complete and the sol-
vent was removed under reduced pressure. The crude product was
purified by flash chromatography (silica gel, 2% EtOAc–hexanes)
[a]D20 –41.30 (c 0.4, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.34–7.29 (m, 10 H), 4.57 (q,
J = 11.4 Hz, 2 H), 3.97–3.94 (m, 1 H), 3.90–3.89 (m, 1 H), 3.85–
3.82 (m, 1 H), 3.69–3.63 (m, 2 H), 3.18–3.17 (m, 1 H), 2.66–2.64
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 137.8, 136.7, 128.8, 128.7, 128.6,
128.2, 128.1, 125.9, 73.9, 71.7, 71.5, 70.7, 63.1, 55.6.
HRMS: m/z [M + Na]+ calcd for C18H20NaO4: 323.1259; found:
323.1253.
Synthesis 2007, No. 22, 3512–3518 © Thieme Stuttgart · New York

3516
S. Gupta et al.
PAPER
(2R,3R,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)-5-phenyltet-
(2S,3S,4S,5R)-2-(Benzyloxymethyl)-5-phenyltetrahydrofuran-
3,4-diol (10)
rahydrofuran-2-carbaldehyde (7)
To a stirred soln of epoxide 6 (0.5 g, 1.67 mmol) in anhyd CH2Cl2
(8 mL) was added catalytic amount of 10-camphorsulfonic acid (37
mg, 0.16 mmol) and the soln was stirred for 4 h. The mixture was
neutralized with sat. aq NaHCO3 soln and extracted with EtOAc.
The combined organic extracts were dried (anhyd Na2SO4), concen-
trated, and purified by flash chromatography (silica gel, 1%
MeOH–CH2Cl2) to give 10 as a colorless oil (0.425 g, 85%);
Rf = 0.32 (silica gel, 66% EtOAc–hexanes).
Dess–Martin periodinane (164 mg, 0.39 mmol) was added to a soln
of 11 (121 mg, 0.28 mmol) in CH2Cl2 (0.6 mL) at 0 °C. The result-
ing mixture was stirred at r.t. for 30 min before it was subjected to
column chromatography (silica gel, 10% EtOAc–hexane) to give 7
as a colorless oil that was directly used in the next step.
1H NMR (600 MHz, CDCl3): d = 9.88 (d, J = 1.8 Hz, 1 H), 7.48–
7.27 (m, 5 H), 4.97 (s, 1 H), 4.53–4.52 (m, 1 H), 4.32 (dd, J = 1.2,
3.6 Hz, 1 H), 4.09 (d, J = 1.2 Hz, 1 H), 0.89 (s, 9 H), 0.68 (s, 9 H),
0.06 (d, J = 5.4 Hz, 6 H), –0.03 (s, 3 H), –0.17 (s, 3 H).
[a]D20 +3.8 (c 0.5, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.45 (d, J = 7.2 Hz, 1 H), 7.37–
7.27 (m, 9 H), 4.67–4.59 (m, 3 H), 4.34–4.29 (m, 2 H), 4.09–4.07
(m, 1 H), 3.98–3.89 (m, 2 H), 3.22 (d, J = 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 139.9, 137.6, 128.8, 128.7, 128.2,
128.1, 128.0, 126.5, 85.0, 84.9, 80.2, 78.5, 74.3, 69.8.
HRMS: m/z [M + Na]+ calcd for C18H20NaO4: 323.1259; found:
323.1279.
Methyl (S)-3-[(2S,3R,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)-
5-phenyltetrahydrofuran-2-yl]-3-hydroxypropanoate (12)
To a precooled soln of 1.8 M LDA in toluene (0.42 mL, 0.75 mmol)
at –78 °C was added excess methyl acetate (56 mg, 0.75 mmol). Af-
ter stirring at the same temperature for 30 min, aldehyde 7 (82 mg,
0.19 mmol) in THF (0.1 mL) was added dropwise to the mixture. It
was stirred at –78 °C for 30 min and then it was quenched with sat.
aq NH4Cl soln. The aqueous layer was extracted with EtOAc and
the combined organic extracts were dried (anhyd Na2SO4), concen-
trated, and purified by flash chromatography (silica gel, 6%
EtOAc–hexanes) to afford 12 (78 mg, 81%) as a colorless oil;
Rf = 0.38 (silica gel, 20% EtOAc–hexanes).
(2S,3R,4R,5R)-[3,4-Bis(tert-butyldimethylsiloxy)-5-phenyl-
tetrahydrofuran-2-yl]methanol (11)
To a soln of alcohol 10 (0.1 g, 0.33 mmol) in CH2Cl2 (3.3 mL) at 0
°C was added 2,6-lutidine (0.30 mL, 2.64 mmol). After stirring for
5 min at this temperature, TBSOTf (0.30 mL, 1.32 mmol) was add-
ed dropwise and the mixture was stirred at 0 °C for 20 min, after
which time no starting material was detected by TLC. Sat. aq NH4Cl
(3 mL) was added. The organic phase was separated, and the aque-
ous layer was extracted with CH2Cl2 (3 × 6 mL). The combined or-
ganic extracts were dried (anhyd Na2SO4), concentrated, and
purified by flash chromatography (silica gel, 2% EtOAc–hexanes)
to afford the bis(tert-butyldimethylsilyl) ether (0.155 g, 88%) as a
colorless oil; Rf = 0.74 (silica gel, 17% EtOAc–hexanes).
[a]D20 +24.5 (c 0.6, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.34 (d, J = 7.2 Hz, 2 H), 7.26 (t,
J = 7.2 Hz, 2 H), 4.76 (s, 1 H), 4.45–4.40 (m, 1 H), 4.10 (d, J = 2.4
Hz, 1 H), 4.02 (s, 1 H), 3.98 (dd, J = 3.0, 8.4 Hz, 1 H), 3.72 (s, 3 H),
3.14 (d, J = 4.8 Hz, 1 H), 2.95 (dd, J = 3.0, 17.4 Hz, 1 H), 2.63 (dd,
J = 9.6, 17.4 Hz, 1 H), 0.89 (s, 9 H), 0.75 (s, 9 H), 0.07 (s, 3 H), 0.06
(d, J = 4.8 Hz, 6 H), –0.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.2, 141.1, 128.3, 127.4, 126.6,
89.8, 85.4, 84.1, 79.0, 65.9, 51.9, 38.9, 25.9, 25.8, 18.2, 18.1, –4.2,
–4.2, –4.5, –4.9.
[a]D20 +10.43 (c 0.7, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.38–7.18 (m, 10 H), 4.75 (s, 1 H),
4.60 (q, J = 12 Hz, 2 H), 4.37–4.35 (m, 1 H), 3.99–3.98 (m, 2 H),
3.80–3.77 (m, 2 H), 0.88 (s, 9 H), 0.75 (s, 9 H), 0.02 (s, 3 H), 0.01
(s, 3 H), –0.01 (s, 3 H), –0.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 141.1, 138.4, 128.6, 128.3, 128.2,
127.8, 127.3, 126.9, 89.4, 85.4, 81.4, 79.6, 73.8, 69.1, 25.9, 25.8,
18.2, 18.0, –4.2, –4.3, –4.5, –4.9.
HRMS: m/z [M + Na]+ calcd for C26H46NaO6Si2: 533.2731; found:
533.2738.
Methyl (S)-3-[(2S,3S,4S,5R)-3,4-Dihydroxy-5-phenyltetra-
hydrofuran-2-yl]-3-hydroxypropanoate (13)
To a soln of aldol product 12 (6 mg, 0.012 mmol) in DMF (0.1 mL)
was added dropwise a soln of TASF (8.1 mg, 0.029 mmol) in DMF
(0.1 mL). The resulting mixture was stirred overnight and diluted
with a phosphate buffer soln of pH 7. The organic phase was sepa-
rated and the aqueous layer was extracted with EtOAc. The com-
bined organic extracts were dried (anhyd Na2SO4), concentrated,
and purified by flash chromatography (5% MeOH–CH2Cl2) to af-
ford 13 (3 mg, 90%) as a white solid; Rf = 0.24 (silica gel, 10%
MeOH–CH2Cl2).
HRMS: m/z [M + Na]+ calcd for C30H48NaO4Si2: 551.2989; found:
551.2991.
This intermediate product (0.155 g, 0.29 mmol) was hydrogenated
over 5% Pd/C (8 mg) in MeOH (20 mL) at r.t. and H2 (1 bar). After
stirring for 30 min, another portion of 5% Pd/C (8 mg) was added
to the mixture. After stirring overnight the catalyst was filtered and
the filtrate was concentrated to give alcohol 11 (117 mg, 91%) as a
colorless oil; Rf = 0.33 (silica gel, 20% EtOAc–hexanes).
[a]D20 –6.0 (c 0.3, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.41–7.35 (m, 5 H), 4.62 (d, 1 H),
4.47–4.45 (m, 1 H), 4.40–4.39 (m, 1 H), 4.12–4.10 (m, 1 H), 3.99–
3.96 (m, 1 H), 3.72 (s, 3 H), 2.85 (dd, J = 3, 16.8 Hz, 1 H), 2.67 (dd,
J = 9, 16.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 173.5, 139.5, 129.1, 128.8, 128.3,
126.5, 85.8, 84.9, 81.4, 79.6, 68.1, 52.2, 38.0.
[a]D20 +3.67 (c 0.3, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.42 (d, J = 7.8 Hz, 2 H), 7.29 (m,
2 H), 7.23–7.21 (m, 1 H), 4.72 (d, J = 3 Hz, 1 H), 4.26–4.23 (m, 1
H), 4.10–4.09 (m, 1 H), 4.04–3.99 (m, 2 H), 3.91–3.87 (m, 1 H),
0.87 (s, 9 H), 0.79 (s, 9 H), 0.05 (s, 3 H), 0.01 (s, 3 H), –0.06 (s, 3
H), –0.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 140.7, 128.4, 127.7, 127.0, 88.2,
85.3, 81.7, 80.2, 62.8, 25.9, 25.8, 18.1, 18.0, –4.2, –4.4, –4.4, –4.8.
HRMS: m/z [M + Na]+ calcd for C14H18NaO6: 305.1001; found:
305.1001.
HRMS: m/z [M + Na]+ calcd for C23H42NaO4Si2: 461.2519; found:
461.2508.
Methyl (R)-3-[(2S,3R,4R,5R)-3,4-Bis(tert-butyldimethylsiloxy)-
5-phenyltetrahydrofuran-2-yl]-3-hydroxypropanoate (16)
Dess–Martin periodinane (93 mg, 0.22 mmol) was added to a soln
of 12 (80 mg, 0.16 mmol) in CH2Cl2 (3 mL) at 0 °C. The resulting
mixture was stirred at r.t. for 30 min before it was subjected to col-
umn chromatography (silica gel, 10% EtOAc–hexane) to give the
Synthesis 2007, No. 22, 3512–3518 © Thieme Stuttgart · New York

PAPER
Styryl Lactone Gonioheptolide A
3517
corresponding ketone (6.4 mg, 80%) as colorless oil, which was di-
rectly used in the next step. To a soln of the ketone (50 mg, 0.1
mmol) in THF (0.6 mL) was added 1 M (S)-2-methyl-1,3,2-ox-
azaborolidine in toluene (0.19 mL, 0.19 mmol) followed by addi-
tion of 1 M BH3 in THF soln (0.19 mL, 0.19 mmol) dropwise. The
resulting mixture was stirred at r.t. for 2 h after which it was cooled
to 0 °C and quenched by slow addition of H2O. The organic layer
was separated and the aqueous layer was extracted with EtOAc. The
combined organic extracts were dried (anhyd Na2SO4), concentrat-
ed, and purified by flash chromatography (silica gel, 6% EtOAc–
hexanes) to give the desired product 16 (42 mg, 83%) as a colorless
oil; Rf = 0.33 (silica gel, 20% EtOAc–hexanes).
13C NMR (100 MHz, CDCl3): d = 173.5, 139.6, 128.8, 128.3, 126.3,
84.6, 84.2, 80.1, 68.1, 52.3, 37.7.
HRMS: m/z [M + Na]+ calcd for C14H18NaO6: 305.1001; found:
305.0989.
References
(1) Current address: Department of Chemistry, Portland State
University, Portland, OR, USA.
(2) Current address: Schering-Plough Corporation, NJ, USA.
(3) (a) Blazquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes,
D. Phytochem. Anal. 1999, 10, 161. (b) Fang, X.; Anderson,
J. E.; Qiu, X.; Kozlowski, J. F.; Chang, C.; McLaughlin, J.
L. Tetrahedron 1993, 49, 1563.
(4) (a) Bermejo, A.; Blazquez, M. A.; Rao, K. S.; Cortes, D.
Phytochem. Anal. 1999, 10, 127. (b) Bermejo, A.; Lora, M.
J.; Blazquez, M. A.; Rao, K. S.; Cortes, D.; Zafra-Polo, M.
C. Nat. Prod. Lett. 1995, 7, 117. (c) El-Zayat, A. A.;
Ferrigni, N. R.; McCloud, T. G.; McKenzie, A. T.; Byrn, S.
R.; Cassady, J. M.; Chang, C. J.; McLaughlin, J. L.
Tetrahedron Lett. 1985, 26, 955. (d) Fang, X. P.; Anderson,
J. E.; Chang, C. J.; McLaughlin, J. L. Tetrahedron 1991, 47,
9751.
[a]D20 +7.9 (c 0.3, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.44 (d, J = 7.8 Hz, 2 H), 7.29–
7.21 (m, 3 H), 4.72 (s, 1 H), 4.49–4.46 (m, 1 H), 4.12–4.11 (m, 1 H),
4.09–4.08 (m, 2 H), 3.71 (s, 3 H), 3.25 (s, 1 H), 2.71 (dd, J = 8.4,
15.6 Hz, 1 H), 2.62 (dd, J = 4.2, 15.6 Hz, 1 H), 0.87 (s, 9 H), 0.78
(s, 9 H), 0.08 (s, 3 H), 0.01 (s, 3 H), –0.08 (s, 3 H), –0.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.3, 140.5, 128.4, 127.8, 126.9,
87.3, 84.8, 82.3, 80.4, 68.1, 51.9, 38.3, 25.9, 25.8, 18.0, 17.9, –4.1,
–4.1, –4.4, –4.9.
HRMS: m/z [M + Na]+ calcd for C26H46NaO6Si2: 533.2731; found:
533.2747.
(5) (a) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
Tetrahedron 1999, 55, 2493. (b) Harris, J. M.; O’Doherty,
G. A. Org. Lett. 2000, 2, 2983.
(2R,3R,3aS,7R,7aS)-3,7-Dihydroxy-2-phenylhexahydro-5H-fu-
ro[3,2-b]pyran-5-one [(–)-Goniofupyrone, 2]
(6) (a) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron
Lett. 1987, 28, 3949. (b) Gillhouley, J. G.; Shing, T. K. M.
Chem. Commun. 1988, 976. (c) Tadano, K.; Ueno, Y.;
Ogawa, S. Chem. Lett. 1988, 111. (d) Kang, S. H.; Kim, W.
J. Tetrahedron Lett. 1989, 30, 5915. (e) Somfai, P.
Tetrahedron 1994, 50, 11315. (f) Mukai, C.; Hirai, S.;
Hanaoka, M. J. Org. Chem. 1997, 62, 6619. (g) Mukai, C.;
Hirai, S.; Kim, I. J.; Hanaoka, M. Tetrahedron Lett. 1996,
37, 5389. (h) Surivet, J. P.; Vatele, J. M. Tetrahedron 1999,
55, 13011. (i) Yang, Z. C.; Zhou, W. S. Heterocycles 1997,
45, 367. (j) Ye, J.; Bhatt, R. K.; Falck, J. R. Tetrahedron
Lett. 1993, 34, 8007. (k) Tate, E. W.; Dixon, D. J.; Ley, S.
V. Org. Biomol. Chem. 2006, 4, 1698. (l) Prasad, K. R.;
Gholap, S. L. J. Org. Chem. 2006, 71, 3643. (m) Reddy, L.
V.; Roy, A. D.; Roy, R.; Shaw, A. K. Chem. Commun. 2006,
3444.
(7) Mukai, C.; Yamashita, H.; Hirai, S.; Hanaoka, M.;
McLaughlin, J. L. Chem. Pharm. Bull. 1999, 47, 131.
(8) These may include the styryl butenolides and pyrones such
as goniothalamin. See related work in: (a) Harris, J. M.;
O’Doherty, G. A. Tetrahedron 2001, 57, 5161. (b) de
Fatima, A.; Kohn, L. K.; Antonio, M. A.; de Carvalho, J. E.;
Pilli, R. A. Bioorg. Med. Chem. 2005, 13, 2927.
(9) (a) Bermejo, A.; Tormo, J. R.; Cabedo, N.; Estornell, E.;
Figadere, B.; Cortes, D. J. Med. Chem. 1998, 41, 5158.
(b) Mereyala, H. B.; Joe, M. Curr. Med. Chem.: Anti-Cancer
Agents 2001, 1, 293. (c) Lan, Y. H.; Chang, F. R.; Yu, J. H.;
Yang, Y. L.; Chang, Y. L.; Lee, S. J.; Wu, Y. C. J. Nat. Prod.
2003, 66, 487.
(10) (a) Green, D. R.; Reed, J. C. Science 1998, 281, 1309.
(b) Inayat-Hussain, S. H.; Annuar, B. O.; Din, L. B.; Ali, A.
M.; Ross, D. Toxicol. Vitro 2003, 17, 433. (c) Li, P.;
Nijhawan, D.; Budihardjo, I.; Srinivasula, S. M.; Ahmad,
M.; Alnemri, E. S.; Wang, X. Cell 1997, 91, 479.
(d) Inayat-Hussain, S. H.; Osman, A. B.; Din, L. B.;
Taniguchi, N. Toxicol. Lett. 2002, 131, 153.
To a soln of 16 (5 mg, 0.01 mmol) in DMF (0.1 mL) was added
dropwise a soln of TASF (13.5 mg, 0.05 mmol) in DMF (0.1 mL).
The mixture was stirred overnight and diluted with a phosphate
buffer soln (pH 7). The organic phase was separated and the aque-
ous layer was extracted with EtOAc. The combined organic extracts
were dried (anhyd Na2SO4), concentrated, and purified by flash
chromatography (silica gel, 50% EtOAc–hexanes) to afford (–)-go-
niofupyrone (2) (2 mg, 82%).
[a]D20 –5.0 (c 0.2, CHCl3) [Lit.4d [a]D20 –5.0 (c 0.2, CHCl3)].
1H NMR (600 MHz, CDCl3): d = 7.37–7.30 (m, 5 H), 4.96 (dd,
J = 3, 5.4 Hz, 1 H), 4.70 (d, J = 6.6 Hz), 4.44 (dt, 1 H, J = 3.9, 5.9
Hz), 4.34 (br t, 1 H, J = 5.2 Hz), 4.28 (dd, J = 2.4, 6.6 Hz, 1 H), 2.90
(dd, J = 3.6, 16.8 Hz, 1 H), 2.67 (dd, J = 6, 16.8 Hz, 1 H), 2.54 (br
s, 1 H), 2.22 (br s, 1 H).
HRMS: m/z [M + Na]+ calcd for C13H14NaO5: 273.0739; found:
273.0762.
(–)-Methyl (R)-3-[(2S,3S,4S,5R)-3,4-Dihydroxy-5-phenyltetra-
hydrofuran-2-yl]-3-hydroxypropanoate [(–)-Gonioheptolide
A, 1]
To a soln of 16 (5 mg, 0.01 mmol) in DMF (0.1 mL) was added
dropwise a soln of TASF (13.5 mg, 0.05 mmol) in DMF (0.1 mL).
The mixture was stirred overnight and diluted with a buffer soln (pH
7). The organic phase was separated and the aqueous layer was ex-
tracted with EtOAc. The crude was dissolved in THF (0.3 mL) and
MeOH (0.3 mL) and a drop of concd H2SO4 was added.7 The reac-
tion was stirred at r.t. for 30 min, diluted with sat. aq soln of CaCO3,
and extracted with EtOAc. The solvent was evaporated and the
crude product was purified by flash chromatography (silica gel,
50% EtOAc–hexanes) to afford (–)-gonioheptolide A (1) (2 mg,
70%) as a white solid; Rf = 0.21 (silica gel, 25% EtOAc–hexanes).
[a]D20 –5.0 (c 0.3, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.46 (d, J = 7.8 Hz, 2 H), 7.36–
7.7.34 (m, 3 H), 4.59 (d, J = 6.6 Hz, 1 H), 4.47–4.43 (m, 1 H), 4.34
(dd, J = 4.8, 6.4 Hz, 1 H), 4.10–4.09 (m, 2 H), 3.71 (s, 3 H), 3.68 (d,
J = 4.8 Hz, 1 H), 3.62 (d, J = 7.8 Hz, 1 H), 2.88 (dd, J = 9, 16.8 Hz,
1 H), 2.64 (dd, J = 4.2, 16.8 Hz, 1 H).
(11) (a) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly,
S. B. Org. Synth. Coll. Vol. VIII; John Wiley & Sons:
London, 1993, 155. (b) Hungerbuehler, E.; Seebach, D.
Helv. Chim. Acta 1981, 64, 687.
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3518
S. Gupta et al.
PAPER
(15) (a) Su, Y. L.; Yang, C. S.; Teng, S. J.; Zhao, G.; Ding, Y.
(12) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265.
(13) Schwarz, M.; G raminski, G. F.; Waters, R. M. J. Org.
Chem. 1986, 51, 260.
(14) (a) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis,
Vol. 5; Morrison, J. D., Ed.; Academic Press: London, 1985,
247. (b) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune,
H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765.
Tetrahedron 2001, 57, 2147. (b) Peng, X.; Li, A.; Lu, J.;
Wang, Q.; Pan, X.; Chan, A. S. C. Tetrahedron 2002, 58,
6799. (c) Yadav, J. S.; Rajaiah, G.; Raju, A. K. Tetrahedron
Lett. 2003, 44, 5831. (d) Chen, J.; Lin, G. Q.; Liu, H. Q.
Tetrahedron Lett. 2004, 45, 8111.
(16) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512. (b) Dd [Dd = dS – dR] obtained from the (S)- and (R)-
MTPA esters of compound 12
(17) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.;
Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(18) Mitsunobu, O. Synthesis 1981, 1.
(19) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
Synthesis 2007, No. 22, 3512–3518 © Thieme Stuttgart · New York