Stereoselective synthesis of (+)-goniodiol, (+)-goniotriol, (-)-goniofupyrone, and (+)-altholactone using a catalytic asymmetric hetero-Diels-Alder/allylboration approach

Article abstract of DOI:10.1002/ejoc.200800535

The stereoselective total synthesis of several members of the styryllactone family was achieved efficiently from common intermediate 8, prepared by a catalytic asymmetric inverse-electron-demand hetero-Diels-Alder/allylboration sequence. The transformatio

Full text of DOI:10.1002/ejoc.200800535

FULL PAPER
DOI: 10.1002/ejoc.200800535
Stereoselective Synthesis of (+)-Goniodiol, (+)-Goniotriol, (–)-Goniofupyrone,
and (+)-Altholactone Using a Catalytic Asymmetric
Hetero-Diels–Alder/Allylboration Approach
Annaïck Favre,[a] François Carreaux,*[a] Michael Deligny,[a][‡] and Bertrand Carboni[a]
Keywords: Lactones / Total synthesis / Asymmetric catalysis / Cycloaddition / Boron
The stereoselective total synthesis of several members of the
styryllactone family was achieved efficiently from common
intermediate 8, prepared by a catalytic asymmetric inverse-
electron-demand hetero-Diels–Alder/allylboration sequence.
The transformation of 8 into α,β-unsaturated lactone led to
the preparation of (+)-goniodiol (1) in a reduced number of
steps. The epoxidation reaction was used to generate the re-
maining stereogenic centers on the lactone moiety of 8, and
these intermediates were then elaborated into (+)-goniotriol
(2), (–)-goniofupyrone (3), and (+)-altholactone (4) by an
isomerization or cyclization step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
bered lactone moiety have attracted, in recent years, con-
siderable attention from synthetic chemists.[8] Different ap-
proaches have been used for the formation of the 5,6-dihy-
dropyran-2-one ring, including the two major routes re-
ported to date for this class of compounds: Cyclization of
substituted δ-hydroxy acid derivatives and ring-closing me-
tathesis.[9] In addition, the stereochemical centers adjacent
to the pyranyl ring system can be created by using chiral
starting products[10] or by stoichiometric and catalytic
asymmetric reactions.[11] Herein, we report a concise, ster-
eoselective route to bioactive styryllactones, namely, (+)-
goniodiol (1),[12] (+)-goniotriol (2), (–)-goniofupyrone (3),
and (+)-altholactone (4) by using a tandem reaction suit-
able for the preparation of various stereoisomers and the
design of analogues.[13]
In the course of our program directed towards the devel-
opment of new multicomponent reactions involving an al-
lylboration reaction,[14] we and others have simultaneously
described a general approach for the asymmetric synthesis
of α-hydroxyalkyldihydropyrans.[15] The first step of the se-
quence was the formation of cyclic allylboronate 7 obtained
from ethyl vinyl ether and boroacrolein pinacolate by using
Introduction
In the inventory of plants used in traditional medicine
in Asia, the Goniothalamus species (Annonaceae) are well
represented. Thus, extracts of seeds of Goniothalamus amu-
yon have been employed for the treatment of edema and
rheumatism.[1] Other general applications include their use
as painkillers[2] and mosquito repellents.[3] Taking into ac-
count their medicinal properties, these plants are considered
a potential source of biologically active compounds. The
phytochemical study of the genus Goniothalamus was inten-
sified when, in 1972, Geran et al. showed that the ethanolic
extract of stem bark of Goniothalamus giganteus Hook. f. &
Thomas was very toxic to mice during a P-388 in vivo anti-
leukemic screening.[4] Investigations of this extract, reported
by McLaughlin and co-workers, led to the discovery of two
major classes of compounds with biologically interesting
properties that include annonaceous acetogenins[5] and sty-
ryllactones.[6] To date, more than 30 bioactive molecules be-
longing to the styryllactone family are listed from various
Goniothalamus species.[7]
Styryllactones can be divided into two main groups ac- a catalytic enantioselective inverse-electron-demand hetero-
cording to the size of the lactone ring (γ- and δ-lactones). [4+2] cycloaddition reaction. Boronate 7 was then treated
Owing to their significant cytotoxicity against several hu- with an aldehyde in a second step (Figure 1). We have also
man tumor cell lines, styryllactones comprising a six-mem- shown that it was possible to create three contiguous asym-
metric centers in a highly stereoselective manner when a
chiral aldehyde is used in the allylboration step.[16] On the
[a] Sciences Chimiques de Rennes, Ingéniérie Chimique et Molé-
basis of these preliminary results, we envisioned that this
cules pour le Vivant, UMR CNRS 6226,
strategy should be adaptable for the synthesis of several bi-
oactive styryllactones by using common intermediate 8,
which can be prepared from a conveniently protected alde-
hyde derived from (R)-mandelic acid.
Campus de Beaulieu, 35042 Rennes Cedex, France
Fax: +33-2-23236227
E-mail: francois.carreaux@univ-rennes1.fr
[‡] Current address: UCB Pharma, Chemin du Foriest,
1420 Braine l’Alleud, Belgium
4900
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4900–4907

Synthesis of (+)-Goniodiol and its Derivatives
Scheme 1. IEDHDA/allylboration strategy applied to styryllactones synthesis.
Figure 1. Catalytic inverse-electron-demand hetero-Diels–Alder
(IEDHDA)/allylboration sequence.
Oxidation of ethyl lactol 8 followed by migration of the
Scheme 2. Reagents and conditions: (a) MeOH, p-TsOH
double bond would lead to the α,β-unsaturated δ-lactone
skeleton of (+)-goniodiol (1), as depicted in Scheme 1. Con-
cerning the elaboration of goniotriol (2), goniofupyrone (3),
and altholactone (4), the installation of an additional hy-
droxy group with a definite configuration should be real-
ized by exploiting the oxidation products of the endocyclic
double bond of 8.
(0.01 equiv.), reflux, 3 h, quantitative yield; (b) tBuPh2SiCl
(1.5 equiv.), imidazole (2 equiv.), DMAP (0.05 equiv.), CH2Cl2,
room temp., 12 h, 93%; (c) iBu2AlH (1.1 equiv.), Et2O, –78 °C,
0.5 h, 83%; (d) 5 (0.01 equiv.), 4 Å molecular sieves, room temp.,
2 h, 85%; (e) 6 (1 equiv.), 70 °C, 10 h, 65%.
this is the first example of an allylboration reaction involv-
ing a chiral γ-alkoxyallylboronate and a functionalized α-
chiral aldehyde to be reported in the literature.
Results and Discussion
Synthesis of (+)-Goniodiol (1)
Synthesis of the key building block 8 required the prepa-
ration of the (R)-(tert-butyldiphenylsilyloxy)phenylacetalde-
(+)-Goniodiol (1) was first isolated from the leaves and
hyde (6) in three steps from (R)-mandelic acid.[17] After an twigs of Goniothalamus sesquipedalis[3] and was found to
esterification reaction followed by the protection of the hy- have a significant and selective cytotoxicity against human
droxy group with tert-butyldiphenylsilyl chloride, the re- lung carcinoma cell line A-459 (ED50 = 0.122 µgmL–1)[6d]
sulting methyl mandelate was efficiently reduced with iBu2- and P-388 murine leukemia cells (IC50 = 4.56 mgmL–1).[10e]
AlH at –78 °C to give expected aldehyde 6 in 77% overall As mentioned earlier in our general synthetic plan, we envi-
yield (Scheme 2). Treatment of commercially available ethyl sioned that the synthesis of 1 could be feasible from 8 by
vinyl ether with 3-boronoacrolein pinacolate[18] in the pres- using only a few synthetic transformations.
ence of Jacobsen’s tridentate [(Schiff base)chromium(III)]
complex[19] 5 resulted in the formation of product 7 in good 8 in lactone. However, under the conditions described by
yield (85%) and high enantioselectivity (96%ee).
Grieco et al.,[22] the expected product was not obtained, and
At first we considered the direct oxidation of ethyl lactol
Allylation of 6 with cyclic allylboronate 7 was performed only products resulting from a cyclization reaction due to
without solvent at 70 °C for 10 h to give dihydropyran 8 as the presence of the unprotected hydroxy group in the start-
a unique stereoisomer (Ͼ95%dr) in 65% yield,[20] which is ing material, which acts as an internal nucleophile during
acceptable taking into account the high stereoselectivity of the reaction, were obtained.[23] We thus decided to protect
this reaction.[21] Note that, to the best of our knowledge, the alcohol function and compound 8 was converted into
Eur. J. Org. Chem. 2008, 4900–4907
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4901

A. Favre, F. Carreaux, M. Deligny, B. Carboni
FULL PAPER
benzyl ether 9 in 84% yield by using standard conditions with DBU smoothly opened the epoxide ring to give allylic
(Scheme 3). The one-pot conversion of 9 into the corre- alcohol 13 in 60% overall yield from 10. The assignment of
sponding lactone 10 by using the m-CPBA/BF3·OEt2 sys- the relative configuration of the two stereogenic centers in
tem was effected very cleanly in 90% yield. No product aris- the δ-lactone ring of 13 was based on the coupling constant
ing from the epoxidation of the double bond was detected J5,6 = 10.4 Hz, which indicates the equatorial nature of the
by 1H NMR spectroscopy. Isomerization of the β,γ-unsatu- hydroxy group.[24] Mitsunobu reaction of 13 with p-nitro-
rated lactone 10 to the corresponding α,β-unsaturated lac- benzoic acid, triphenylphosphane, and diethyl azodicarbox-
tone was achieved by using a catalytic amount of DBU at ylate (DEAD) furnished p-nitrobenzoate 14 in 76% yield,
room temperature to afford 11 in 91% yield. Finally, suc- which was subsequently hydrolyzed with 1% aqueous po-
cessive deprotection of the different protecting groups pres- tassium carbonate to provide 15 in 53% yield with an in-
ent in 11, TBDPS and benzyl ethers, delivered synthetic (+)- verted stereochemistry at the allylic position (J5,6 = 3.2 Hz).
goniodiol (1) in 39% yield for the two-step sequence.
Desilylation of 15 with HF·pyridine followed by deben-
zylation with TiCl4 led to (+)-goniotriol (2) in 65% yield
for the last two steps.
Scheme 3. Reagents and conditions: (a) NaH (1.3 equiv.), BnBr
(1.5 equiv.), Bu4N+I– (0.1 equiv.), THF, room temp., 3 h, 84%; (b)
m-CPBA (1.5 equiv.), BF3·OEt2 (1.5 equiv.), CH2Cl2, 0 °C to room
temp., 14 h, 90%; (c) DBU (0.01 equiv.), THF, room temp., 18 h,
91%; (d) HF/pyridine, room temp., 48 h; (e) TiCl4 (2 equiv.),
CH2Cl2, room temp., 1 h, 39% from 11.
Scheme 5. Reagents and conditions: (a) m-CPBA (2.8 equiv.),
CH2Cl2, room temp., 5 d; (b) DBU (2.9 equiv.), CH2Cl2, 0 °C to
room temp., 36 h, 60% from 10; (c) PPh3 (3 equiv.), DEAD
(3 equiv.), p-NO2C6H4CO2H (3 equiv.), toluene, room temp., 18 h,
76%; (d) 1% K2CO3, MeOH, 0 °C to room temp., 12 h, 53%; (e)
HF/pyridine, room temp., 48 h; (f) TiCl4 (2 equiv.), CH2Cl2, room
temp., 2 h, 65% from 15.
Synthesis of (+)-Goniotriol (2)
(+)-Goniotriol (2), a highly oxygenated styryllactone, has
been, in particular, isolated from the stem bark of Goni-
othalamus giganteus, and it showed some activity in the
brine shrimp lethality test (BST) and potato disc assay (PD)
and mild activity towards human tumor cells.[6b] We
planned to introduce the missing hydroxy group onto the
lactone moiety of the advanced intermediate 10 by using an
epoxidation/isomerization sequence followed by a reaction
with inversion of configuration at C-5, as depicted in
Scheme 4.
Synthesis of (–)-Goniofupyrone (3) and (+)-Altholactone (4)
(–)-Goniofupyrone (3) and (+)-altholactone (4), which
have in common a bicyclic skeleton, were first isolated from
[6e]
the stem bark of Goniothalamus giganteus
and from the
bark of an unnamed Polyalthia (Annonaceae) species,
respectively.[25] (+)-Altholactone is known to possess antitu-
mor activity against P-388 murine leukemia in vivo at
45 mgkg–1 as well as some cytotoxic activity (in vitro).[6a,10i]
Owing to its biological importance, 4 has attracted the at-
tention of several synthetic groups, in contrast to (–)-goni-
ofupyrone (3).[26] Our strategy for the construction of the
tetrahydrofuran ring with the desired four chiral centers
present in these two natural products was based on an
epoxidation reaction of the olefinic double bond of 8 fol-
lowed by an intramolecular cyclization, as described in
Scheme 6.
Scheme 4. Retrosynthesis of (+)-goniotriol 2.
Accordingly, α,β-unsaturated lactone 10 was treated with
In the first step, the oxidation of 8 with m-CPBA in
m-CPBA in CH2Cl2 to afford the expected epoxide with CH2Cl2 led to the formation of the expected epoxide 16
complete conversion after 5 d. NMR spectroscopic analysis with a good level of diastereoselectivity (dr 9:1) and in 69%
(1H, 13C) of the residue indicated the formation of a single yield (Scheme 7). After separation of the two isomers by
diastereomer. Owing to the instability of 12 on silica gel, column chromatography, major epoxide 16 was subjected
the stereochemistry of the epoxidation reaction could not to treatment with nBu4NF at 50 °C for 24 h. Under these
be determined at this stage of the synthesis but was assigned conditions, cyclized product 17, which results from desi-
after the following step on the basis of the stereochemistry lylation of 16 with concomitant ring closure, was obtained
of the isomerization product (Scheme 5). Treatment of 12 in 70% yield (J5,6 = 2.8 Hz). Conversion of 17 into lactone
4902
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4900–4907

Synthesis of (+)-Goniodiol and its Derivatives
pared in 27, 12, 35, and 25% overall yields, respectively.
This new approach successfully supplements the methodol-
ogies already described in the literature for the synthesis of
this family of compounds. Moreover, by taking into ac-
count the availability of both isomers of mandelic acid and
the chromium(III) complex, this strategy should be appli-
cable to the synthesis of different stereoisomers. Application
of this methodology to the preparation of other natural
products is underway in the laboratory.
Scheme 6. Retrosynthesis of (–)-goniofupyrone (3) and (+)-altho-
lactone (4).
Experimental Section
18 was cleanly carried out with m-CPBA in the presence of
BF3·OEt2 in 90% yield. Finally, removal of the benzyl
group with SnCl4 provided (–)-goniofupyrone (3) in 80%
yield.
General Remarks: The catalyst was prepared according to Jacob-
sen’s procedure.[19] 3-Boroacrolein pinacolate was prepared accord-
ing to the published procedure.[18] Reactions were performed in
oven-dried glassware under an atmosphere of argon. Tetra-
hydrofuran (THF) was distilled from deep-blue solutions of so-
dium/benzophenone ketyl prior to use. CH2Cl2 was distilled from
CaH2. Unless otherwise stated, all reagents were used as received.
Most reactions were monitored by TLC on precoated silica plates
(Merck 60 F254, 0.25 mm). Silica gel 60F254 was used for column
flash chromatography. Deactivated silica gel refers to silica gel
washed with triethylamine prior to use. Melting points (uncor-
rected) were measured with a Kofler melting point apparatus.
NMR spectra were recorded in CDCl3 with a 300 MHz spectrome-
ter operating in the Fourier transform mode. 1H NMR spectro-
scopic data are presented as follows: chemical shift, multiplicity,
coupling constant, integration. The following abbreviations are
used: s, singlet; br. s, broad singlet; d, doublet; t, triplet; q, quartet;
dq, doublet of quartets; dd, doublet of doublets; ddd, doublet of
doublets of doublets; m, multiplet. 13C NMR spectra were obtained
with broadband proton decoupling. Chemical shifts were recorded
relative to the internal tetramethylsilane (TMS) reference signal.
Optical rotations were measured by using a 1-mL cell with a 1-dm
path length at 23 °C with a Perkin-Elmer 341 digital polarimeter,
and the concentration is expressed in gdL–1. High-resolution mass
spectra (HRMS) were recorded at the Centre Régional de Mesures
Physiques de l’Ouest. Enantiomeric excesses were determined by
gas chromatography performed by using a Varian CP3380 GC unit
equipped with a capillary chiral column (Varian WCOT Fused
Silica 25mϫ0.25 mm coated CP Chirasil-dex CB DF = 0.25).
Chromatography conditions: carrier gas, argon; injection tempera-
ture, 200 °C; detector temperature, 250 °C.
Scheme 7. Reagents and conditions: (a) m-CPBA (2.3 equiv.),
CH2Cl2, room temp., 12 h, 69%; (b) TBAF (1.5 equiv.), THF,
50 °C, 24 h, 70%; (c) m-CPBA (4 equiv.), BF3·OEt2 (4 equiv.),
CH2Cl2, 0 °C to room temp., 12 h, 90%; (d) SnCl4 (2 equiv.),
CH2Cl2, 40 °C, 10 h, 80%.
Concerning the synthesis of (+)-altholactone (4), the
double bond was generated by a dehydration reaction of 18
(Scheme 8). By using a catalytic amount of p-toluenesul-
fonic acid (pTSA) in toluene at 85 °C for 5 h, α,β-unsatu-
rated lactone 19 was obtained in 73% yield. The last step
of the synthesis was the deprotection of the benzyl ether
using SnCl4, which gave the product in 78% yield. Synthetic
altholactone (4) was identical to the natural compound by
comparison with spectral and physical data.
(1S,2R)-2-{[tert-Butyl(diphenyl)silyl]oxy}-1-[(2R,6S)-6-ethoxy-5,6-
dihydro-2H-pyran-2-yl]-2-phenylethanol (8): Catalyst 5 (9.60 mg,
0.020 mmol) and powdered BaO (400 mg) were added to a mixture
of boronoacrolein pinacolate (364 mg, 2.00 mmol) and ethyl vinyl
ether (1.90 mL, 20.0 mmol) in an oven-dried round-bottomed flask
(10 mL) containing a stirring bar. After stirring for 1.5 h at room
temperature, the ethyl vinyl ether was evaporated in vacuo, and
cycloadduct 7 was distilled by using a Kugelrohr apparatus (b.p.
90–95 °C/0.01 Torr, 430 mg, 85%, 96%ee). Allylboration with (R)-
[(tert-butyldiphenylsilyl)oxy](phenyl)acetaldehyde (6; 637 mg,
1.7 mmol) was carried out at 70 °C for 10 h without solvent and
then diluted with EtOAc. The solution was stirred for 30 min with
an aqueous saturated solution of NaHCO3. After this time, the
organic layer was separated and the aqueous layer was extracted
with EtOAc (3ϫ20 mL). The combined organic extract was dried
with MgSO4 and concentrated. Purification by flash column
chromatography (deactivated silica gel, cyclohexane/EtOAc, 95:5)
Scheme 8. Reagents and conditions: (a) p-TsOH (0.3 equiv.), tolu-
ene, 85 °C, 5 h, 73%; (b) SnCl4 (2 equiv.), CH2Cl2, 40 °C, 24 h,
78%.
Conclusions
In this paper we have demonstrated that the hetero-Di-
els–Alder/allylboration sequence is an appropriate strategy
for the synthesis of several bioactive styryllactones. From
common advanced intermediate 8, (+)-goniodiol, (+)-goni-
otriol, (–)-goniofupyrone, and (+)-altholactone were pre- led to pure product 8 (555 mg, 65%) as a white solid. M.p. 139–
Eur. J. Org. Chem. 2008, 4900–4907
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4903

A. Favre, F. Carreaux, M. Deligny, B. Carboni
FULL PAPER
141 °C. [α]2D3 = +39.3 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.02 (s, 9 H), 1.18 (t, J = 7.1 Hz, 3 H), 2.13–2.24 (m,
2 H), 2.47 (d, J = 7.9 Hz, 1 H), 3.30 (dq, J = 9.5, 7.1 Hz, 1 H),
3.72 (dq, J = 9.5, 7.1 Hz, 1 H), 3.78 (dt, J = 7.8, 2.6 Hz, 1 H), 4.63
The mixture was quenched with a saturated aqueous NH4Cl solu-
tion (2 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ϫ5 mL). The combined organic layer was
dried with MgSO4 and concentrated. Purification of the residue by
(dd, J = 6.1, 4.6 Hz, 1 H), 4.70–4.77 (m, 1 H), 4.82 (d, J = 7.6 Hz, silica gel chromatography (cyclohexane/EtOAc, 9:1) gave 11
1 H), 5.58–5.70 (m, 1 H), 5.73–5.89 (m, 1 H), 7.12–7.50 (m, 13
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.5, 19.8, 27.4, 31.2,
64.6, 73.5, 76.3, 77.3, 98.4, 124.9, 127.6, 127.8, 127.9, 128.2, 128.4,
129.8, 133.7, 134.4, 136.4, 136.5, 141.7 ppm. HRMS (EI): calcd.
for C25H23O3Si [M – HOC2H5 – tBu]+ 399.1417; found 399.1410.
(82 mg, 91%) as a colorless oil. [α]2D3 = +45.9 (c = 1.82, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.06 (s, 9 H), 2.00 (ddd, J = 18.1,
6.2, 3.7, 1 H), 2.42 (m, 1 H), 3.58 (dd, J = 7.8, 2.5 Hz, 1 H), 3.90
(d, J = 18.4 Hz, 1 H), 3.95 (d, J = 18.4 Hz, 1 H), 4.76 (dt, J = 12.6,
3.0 Hz, 1 H), 5.11 (d, J = 7.8 Hz, 1 H), 5.89 (dd, J = 9.8, 2.4 Hz,
1 H), 6.75 (ddd, J = 9.8, 6.2, 2.1 Hz, 1 H), 7.01 (m, 2 H), 7.19–
7.68 (m, 18 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4, 26.1,
27.1, 74.1, 74.5, 76.3, 83.9, 121.1, 127.3, 127.5, 127.6, 127.7, 127.8,
127.9, 128.0, 128.1, 128.2, 129.5, 129.7, 133.1, 133.5, 135.9, 136.0,
137.6, 141.3, 163.5 ppm. HRMS (ESI): calcd. for C36H38O4SiNa
585.2437; found 585.2434.
({(1R,2S)-2-(Benzyloxy)-2-[(2R,6S)-6-ethoxy-5,6-dihydro-2H-pyr-
an-2-yl]-1-phenylethyl}oxy)(tert-butyl)diphenylsilane (9): A solution
of alcohol 8 (300 mg, 0.58 mmol) in THF (12 mL) was added to a
suspension of NaH (60 % dispersion in mineral oil, 46.4 mg,
1.16 mmol) in THF (18 mL) at 0 °C under an atmosphere of argon.
After 15 min, benzyl bromide (86 µL, 0.70 mmol) and Bu4N+I–
(22 mg, 0.058 mmol) were added to the solution. The mixture was
stirred at room temperature for 3 h. After this period, water (6 mL)
was added and the layers were separated. The aqueous layer was
extracted with Et2O (3ϫ30 mL). The combined organic extract
was dried with MgSO4 and concentrated. Purification of the resi-
due by deactivated silica gel chromatography (cyclohexane/EtOAc,
99:1) afforded 9 (288 mg, 84%) as a colorless oil. [α]2D3 = +64.0 (c
(6R)-6-[(1R,2R)-1,2-Dihydroxy-2-phenylethyl]-5,6-dihydro-2H-pyr-
an-2-one [(+)-Goniodiol (1)]: The HF·pyridine complex (0.1 mL)
was added to a room-temperature solution of silyl ether 11 (60 mg,
0.11 mmol) in CH3CN (1 mL). After stirring for 2 d, the reaction
mixture was quenched with saturated aqueous NaHCO3 (1 mL)
and extracted with EtOAc (3ϫ5 mL). The combined organic layer
was dried with MgSO4 and concentrated. The residual oil was dis-
solved in CH2Cl2 (1 mL) and TiCl4 (1.0  CH2Cl2 solution;
0.22 mL, 0.22 mmol) was added to the solution. The reaction mix-
1
= 0.32, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.02 (s, 9 H),
1.15 (t, J = 7.0 Hz, 3 H), 2.09–2.19 (m, 2 H), 3.21 (dq, J = 9.1,
7.0 Hz, 1 H), 3.73 (dq, J = 9.1, 7.0 Hz, 1 H), 3.78 (m, 1 H), 4.24 ture was stirred at room temperature for 1 h, diluted with saturated
(d, J = 11.1 Hz, 1 H), 4.35 (d, J = 11.1 Hz, 1 H), 4.53 (dd, J = 5.0, aqueous NaHCO3 solution, and extracted with CH2Cl2 (3ϫ3 mL).
3.3 Hz, 1 H), 4.56 (br. s, 1 H), 5.04 (d, J = 6.6 Hz, 1 H), 5.50 (d, J
The combined organic layer was washed with water and brine,
= 10.1 Hz, 1 H), 5.65 (m, 1 H), 7.02 (m, 2 H), 7.16–7.38 (m, 14 H), dried with MgSO4, and concentrated. The residue was purified by
7.46 (d, J = 7.9 Hz, 2 H), 7.62 (d, J = 7.9 Hz, 2 H) ppm. 13C NMR silica gel chromatography (cyclohexane/EtOAc, 1:1) to afford (+)-
(75 MHz, CDCl3): δ = 15.1, 19.4, 27.1, 31.4, 63.8, 74.4, 74.6, 75.0,
84.9, 98.7, 124.4, 127.1, 127.2, 127.3, 127.4, 127.5, 127.7, 127.9,
1 (10 mg, 39%) as a colorless oil. [α]2D3 = +74.1 (c = 0.20, CHCl3)
[ref.[6d] [α]2D2 = +74.4 (c = 0.3, CHCl3)]. 1H NMR (300 MHz,
128.1, 128.6, 129.4, 129.5, 133.3, 134.0, 136.0, 136.1, 138.5, CDCl3): δ = 2.22 (dddd, J = 18.4, 6.4, 3.8, 0.5 Hz, 1 H), 2.27 (br.
141.2 ppm. HRMS (ESI): calcd. for C38H44O4SiNa 615.2907;
found 615.2902.
s, 1 H), 2.55 (s, 1 H), 2.82 (dddd, J = 18.4, 12.8, 2.5, 2.0 Hz, 1 H),
3.71 (m, 1 H), 4.82 (ddd, J = 12.8, 3.8, 2.0 Hz, 1 H), 4.98 (d, J =
7.3 Hz, 1 H), 6.05 (ddd, J = 9.8, 2.9, 1.0 Hz, 1 H), 6.95 (ddd, J =
9.8, 6.4, 2.2 Hz, 1 H), 7.30–7.48 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.1, 73.8, 75.2, 77.2, 120.7, 126.4, 128.4, 128.8, 140.7,
146.0, 163.8 ppm. HRMS (ESI): calcd. for C13H14O4Na 257.0790;
found 257.0795.
(6R)-6-[(1S,2R)-1-(Benzyloxy)-2-{[tert-butyl(diphenyl)silyl]oxy}-2-
phenylethyl]-3,6-dihydro-2H-pyran-2-one (10): m-CPBA (45 mg,
0.26 mmol) followed by BF3·OEt2 (25.1 µL, 0.20 mmol) were added
to a stirred solution of ethyl lactol 9 (120 mg, 0.20 mmol) in
CH2Cl2 (6 mL) at 0 °C under an atmosphere of argon. The re-
sulting mixture was warmed to room temperature and stirred for
20 h. The mixture was quenched with saturated aqueous Na2S2O3
solution (2 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (3ϫ10 mL). The combined organic
layer was dried with MgSO4 and concentrated. The residue was
purified by silica gel chromatography (cyclohexane/EtOAc, 9:1) to
afford lactone 10 (102 mg, 90%) as a colorless oil. [α]2D3 = +100.0
(5R,6R)-6-[(1S,2R)-1-(Benzyloxy)-2-{[tert-butyl(diphenyl)silyl]oxy}-
2-phenylethyl]-5-hydroxy-5,6-dihydro-2H-pyran-2-one (13): m-
CPBA (78 mg, 0.45 mmol) was added to a solution of lactone 10
(90 mg, 0.16 mmol) in CH2Cl2 (10 mL) at 0 °C under an atmo-
sphere of argon. The resulting mixture was warmed to room tem-
perature and stirred for 5 d. The mixture was washed with a satu-
rated aqueous NaHCO3 solution (3 mL). The aqueous layer was
(c = 0.34, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.05 (s, 9 extracted with CH2Cl2 (3ϫ10 mL) and the combined organic layer
H), 2.86–2.88 (m, 2 H), 3.57 (dd, J = 8.6, 1.2 Hz, 1 H), 3.61 (d, J was dried with MgSO4 and concentrated. Crude epoxide 12 was
= 10.2 Hz, 1 H), 3.96 (d, J = 10.2 Hz, 1 H), 4.97 (d, J = 8.6 Hz, 1 subjected to the next reaction without further purification. 1H
H), 5.40 (m, 1 H), 5.83–5.86 (m, 2 H), 6.83–6.85 (m, 2 H), 7.14– NMR (300 MHz, CDCl3): δ = 1.07 (s, 9 H), 2.66 (d, J = 18.2 Hz,
7.41 (m, 14 H), 7.45 (dd, J = 7.9, 1.4 Hz, 2 H), 7.62 (dd, J = 7.9,
1.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.5, 27.1,
30.8, 74.3, 75.2, 77.7, 85.1, 123.7, 124.1, 127.3, 127.5, 127.6, 127.7,
127.8, 127.9, 128.0, 128.1, 129.5, 129.6, 133.3, 133.4, 136.0, 136.1,
137.5, 141.4, 167.0 ppm. HRMS (ESI): calcd. for C36H38O4SiNa
585.2437; found 585.2433.
1 H), 2.83 (d, J = 18.2 Hz, 1 H), 3.17–3.19 (m, 2 H), 3.69 (d, J =
10.6 Hz, 1 H), 3.72 (d, J = 8.9 Hz, 1 H), 3.78 (d, J = 10.6 Hz, 1
H), 4.92 (d, J = 8.9 Hz, 1 H), 5.29 (m, 1 H), 6.87–6.88 (m, 2 H),
7.15–7.34 (m, 14 H), 7.50 (dd, J = 7.9, 1.4 Hz, 2 H), 7.60 (dd, J =
7.9, 1.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.5, 27.0,
31.9, 49.9, 50.7, 74.5, 74.6, 83.0, 127.3, 127.5, 127.8, 127.9, 128.0,
128.2, 128.3, 128.4, 129.5, 129.7, 132.9, 133.2, 136.0, 136.1, 136.7,
140.9, 166.3 ppm.
(6R)-6-[(1S,2R)-1-(Benzyloxy)-2-{[tert-butyl(diphenyl)silyl]oxy}-2-
phenylethyl]-5,6-dihydro-2H-pyran-2-one (11): DBU (2 drops) was
added dropwise to a solution of lactone 10 (90 mg, 0.16 mmol) in
THF (10 mL) at 0 °C under an atmosphere of argon. The resulting
solution was warmed to room temperature and stirred for 18 h.
DBU (69 µL, 0.46 mmol) was added dropwise to a solution of the
above epoxide in CH2Cl2 (4.5 mL) at 0 °C under an atmosphere of
argon. The resulting solution was warmed to room temperature
4904
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4900–4907

Synthesis of (+)-Goniodiol and its Derivatives
and stirred for 24 h. The mixture was quenched with a saturated
aqueous NH4Cl solution (1 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3ϫ4 mL). The com-
bined organic layer was dried with MgSO4 and concentrated. Puri-
fication of the residue by silica gel chromatography (cyclohexane/
EtOAc, 9:1) gave alcohol 13 (56 mg, 60% from 10) as a colorless
oil. [α]2D3 = –12.5 (c = 0.52, CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ = 1.02 (s, 9 H), 2.06 (br. s, 1 H), 3.47 (d, J = 11.7 Hz, 1 H), 3.81
(dd, J = 8.4, 1.6 Hz, 1 H), 3.99 (d, J = 11.7 Hz, 1 H), 4.19 (m, 1
H), 4.46 (dd, J = 10.4, 1.6 Hz, 1 H), 5.10 (d, J = 8.4 Hz, 1 H), 5.73
(dd, J = 9.9, 2.2 Hz, 1 H), 6.59 (dd, J = 9.9, 1.7 Hz, 1 H), 7.07–
7.10 (m, 2 H), 7.21–7.40 (m, 14 H), 7.48 (dd, J = 8.0, 1.3 Hz, 2 H),
7.62 (dd, J = 8.0, 1.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 19.4, 27.1, 62.5, 73.2, 73.7, 78.8, 80.0, 119.7, 127.3, 127.5, 127.9,
128.0, 128.1, 128.4, 128.6, 128.9, 129.5, 129.7, 135.9, 136.1, 137.4,
141.6, 149.5, 162.1 ppm. HRMS (ESI): calcd. for C36H38O5SiNa
601.2386; found 601.2389.
ether 15 (25 mg, 0.043 mmol) in CH3CN (2 mL). After stirring for
2 d, the reaction mixture was quenched with a saturated aqueous
NaHCO3 solution (1 mL) and extracted with EtOAc (3ϫ5 mL).
The combined organic layer was dried with MgSO4 and concen-
trated. The residual oil was dissolved in CH2Cl2 (1 mL) and TiCl4
(1.0  CH2Cl2 solution; 86 µL, 0.086 mmol) was added to the solu-
tion. The reaction mixture was stirred at room temperature for 2 h,
diluted with a saturated NaHCO3 solution, and extracted with
CH2Cl2 (3ϫ3 mL). The combined organic layer was washed with
water and brine, dried with MgSO4, and concentrated. The residue
was purified by silica gel chromatography (cyclohexane/EtOAc, 2:8)
to afford (+)-2 (7.2 mg, 65%) as a white solid. M.p. 168–170 °C.
[α]2D3 = +117 (c = 0.10, MeOH) [ref.[6b] m.p. 170 °C, [α]2D5 = +121.0
(MeOH)]. 1H NMR (300 MHz, CDCl3): δ = 4.18 (dd, J = 7.9,
3.9 Hz, 1 H), 4.43 (dd, J = 5.4, 2.7 Hz, 1 H), 4.59 (dd, J = 3.9,
2.7 Hz, 1 H), 4.73 (d, J = 7.9 Hz, 1 H), 6.08 (d, J = 9.9 Hz, 1 H),
7.02 (dd, J = 9.9, 5.4 Hz, 1 H), 7.22–7.50 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 63.5, 73.9, 75.5, 80.3, 123.0, 128.7, 128.9,
129.2, 143.3, 146.4, 166.0 ppm. HRMS (ESI): calcd. for
C13H14O5Na 273.0739; found 273.0742.
(5S,6R)-6-[(1S,2R)-1-(Benzyloxy)-2-{[tert-butyl(diphenyl)silyl]oxy}-
2-phenylethyl]-5-[(p-nitrobenzoyl)oxy]-5,6-dihydro-2H-pyran-2-one
(14): DEAD (33 µL, 0.21 mmol) was added to a solution of alcohol
13 (40 mg, 0.068 mmol), triphenylphosphane (55 mg, 0.21 mmol),
and p-nitrobenzoic acid (35 mg, 0.21 mmol) in dry toluene (2 mL)
under an atmosphere of argon. The resulting mixture was stirred
for 15 h at room temperature. After addition of water (0.5 mL) and
separation of the layers, the aqueous layer was extracted with
EtOAc (3ϫ4 mL). The combined organic layer was washed with a
saturated aqueous NaHCO3 solution (2 mL) and water (2 mL),
dried with MgSO4, and concentrated. The residue was purified by
chromatography over silica gel (cyclohexane/EtOAc, 8:2) to furnish
p-nitrobenzoate 14 (38.2 mg, 76%) as a colorless oil. [α]2D3 = +63.6
(c = 0.44, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.05 (s, 9
H), 4.16 (dd, J = 6.6, 3.8 Hz, 1 H), 4.58 (d, J = 11.2 Hz, 1 H),
4.70–4.72 (m, 2 H), 5.00 (d, J = 3.8 Hz, 1 H), 5.44 (dd, J = 5.8,
2.5 Hz, 1 H), 6.17 (d, J = 9.6 Hz, 1 H), 6.93–7.07 (m, 6 H), 7.20–
7.39 (m, 13 H), 7.60 (d, J = 6.8 Hz, 2 H), 7.83 (d, J = 8.8 Hz, 2
H), 8.09 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 19.3, 27.0, 64.0, 74.7, 75.8, 78.6, 82.4, 123.3, 125.5, 127.1, 127.4,
127.6, 127.8, 128.0, 128.2, 129.8, 129.9, 130.7, 132.6, 133.0, 133.6,
135.9, 136.0, 137.9, 139.2, 139.7, 150.6, 162.0, 163.2 ppm. HRMS
(ESI): calcd. for C43H41NO8SiNa 750.2499; found 750.2498.
Ethyl (7R)-3,4-Anhydro-6-O-benzyl-7-O-[tert-butyl(diphenyl)silyl]-
2-deoxy-7-C-phenyl-α-D-talo-heptopyranoside (16): m-CPBA
(97 mg, 0.56 mmol) was added to a solution of ethyl lactol 8
(150 mg, 0.25 mmol) in CH2Cl2 (5 mL) at 0 °C under an atmo-
sphere of argon. The resulting mixture was warmed to room tem-
perature and stirred for 12 h. The mixture was washed with a satu-
rated aqueous NaHCO3 solution (3 mL). The aqueous layer was
extracted with CH2Cl2 (3ϫ10 mL) and the combined organic layer
was dried with MgSO4 and concentrated. Purification of the resi-
due by deactivated silica gel chromatography (cyclohexane/EtOAc,
9:1) afforded 16 (107 mg, 69%) as a colorless oil. [α]2D3 = +18.7 (c
1
= 0.40, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.05 (s, 9 H),
1.13 (t, J = 7.0 Hz, 3 H), 1.73 (ddd, J = 14.2, 9.3, 1.7 Hz, 1 H),
2.14 (ddd, J = 14.2, 2.1, 2.1 Hz, 1 H), 2.57 (d, J = 4.4 Hz, 1 H),
2.93 (m, 1 H), 3.17 (dq, J = 9.4, 7.0 Hz, 1 H), 3.61 (dq, J = 9.4,
7.0 Hz, 1 H), 3.95 (dd, J = 4.9, 4.9 Hz, 1 H), 4.18 (d, J = 4.4 Hz,
1 H), 4.31 (d, J = 11.8 Hz, 1 H), 4.34 (dd, J = 9.3, 2.7 Hz, 1 H),
4.53 (d, J = 11.8 Hz, 1 H), 5.12 (d, J = 5.5 Hz, 1 H), 7.12–7.49 (m,
18 H), 7.66 (dd, J = 7.8, 1.4 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 15.1, 19.3, 26.9, 27.1, 31.3, 52.9, 53.5, 64.4, 73.9, 74.3,
74.9, 83.3, 96.9, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 128.2,
128.9, 129.5, 129.6, 133.2, 133.9, 135.9, 136.0, 138.5, 140.6 ppm.
HRMS (ESI): calcd. for C38H44O5SiNa 631.2856; found 631.2858.
(5S,6R)-6-[(1S,2R)-1-(Benzyloxy)-2-{[tert-butyl(diphenyl)silyl]oxy}-
2-phenylethyl]-5-hydroxy-5,6-dihydro-2H-pyran-2-one (15): A 1%
K2CO3 solution (1.54 mL) was added to a solution of p-nitrobenzo-
ate 14 (30 mg, 0.04 mmol) in THF (2.6 mL) at 0 °C. The solution
was stirred at room temperature for 12 h, diluted with water, and
extracted with EtOAc (3ϫ3 mL). The combined organic layer was
dried with MgSO4 and concentrated. Purification of the residue by
silica gel chromatography (cyclohexane/EtOAc, 7:3) gave alcohol
15 (14 mg, 53%) as a colorless oil. [α]2D3 = +11.1 (c = 0.18, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.03 (s, 9 H), 2.91 (br. s, 1 H),
3.93, (d, J = 10.3 Hz, 1 H), 4.01 (dd, J = 6.8, 3.8 Hz, 1 H), 4.25
(m, 1 H), 4.33 (d, J = 10.3 Hz, 1 H), 4.50 (dd, J = 3.2, 3.2 Hz, 1
H), 5.11 (d, J = 6.8 Hz, 1 H), 5.96 (d, J = 9.6 Hz, 1 H), 6.81 (dd,
J = 9.6, 5.7 Hz, 1 H), 7.03–7.06 (m, 2 H), 7.21–7.37 (m, 16 H),
7.63–7.66 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4,
27.1, 62.5, 74.5, 74.7, 77.2, 83.7, 122.7, 127.4, 127.7, 127.8, 128.0,
128.1, 128.2, 128.3, 128.4, 129.7, 129.8, 135.9, 136.0, 137.2, 140.5,
143.5, 162.1 ppm. HRMS (ESI): calcd. for C36H38O5SiNa
601.2386; found 601.2389.
Ethyl (7R)-4,7-Anhydro-6-O-benzyl-2-deoxy-7-phenyl-α-D-ido-hep-
topyranoside (17): A 1.0  solution of TBAF (220 µL, 0.22 mmol)
was added to a solution of epoxide 16 (90 mg, 0.15 mmol) in THF
(4.5 mL) at 0 °C under an atmosphere of argon. The resulting solu-
tion was stirred at 50 °C for 24 h. The reaction was quenched with
CH2Cl2 (10 mL) and a saturated aqueous NH4Cl solution (10 mL).
The phases were separated and the aqueous layer extracted with
CH2Cl2 (3ϫ10 mL). The combined organic layer was dried with
MgSO4 and concentrated, and the crude product was purified by
silica gel chromatography (cyclohexane/EtOAc, 8:2) to give 17
(37.8 mg, 70%) as a colorless oil. [α]2D3 = +85.3 (c = 0.34, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 7.0 Hz, 3 H), 1.70
(br. s, 1 H), 1.84–1.88 (m, 2 H), 3.56 (dq, J = 9.1, 7.0 Hz, 1 H),
3.87 (dd, J = 2.5, 2.5 Hz, 1 H), 3.94 (dq, J = 9.1, 7.0 Hz, 1 H), 4.02
(d, J = 3.7 Hz, 1 H), 4.37 (d, J = 2.5 Hz, 1 H), 4.42 (m, 1 H), 4.58
(d, J = 11.6 Hz, 1 H), 4.63 (d, J = 11.6 Hz, 1 H), 4.82 (d, J =
3.7 Hz, 1 H), 4.86 (d, J = 2.0 Hz, 1 H), 7.28–7.39 (m, 8 H), 7.45–
7.49 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.3, 34.6,
64.3, 66.4, 72.3, 78.0, 78.5, 86.8, 91.0, 96.7, 126.9, 127.7, 127.8,
(5S,6R)-6-[(1R,2R)-1,2-Dihydroxy-2-phenylethyl]-5-hydroxy-5,6-di-
hydro-2H-pyran-2-one [(+)-Goniotriol (2)]: The HF·pyridine com-
plex (0.17 mL) was added to a room-temperature solution of silyl
Eur. J. Org. Chem. 2008, 4900–4907
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4905

A. Favre, F. Carreaux, M. Deligny, B. Carboni
FULL PAPER
127.9, 128.5, 137.6, 140.0 ppm. HRMS (ESI): calcd. for
C22H26O5Na 393.1678; found 393.1677.
mixture was heated at 40 °C for 24 h. After cooling, the reaction
was quenched with a saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2 (3ϫ2 mL) and the com-
bined organic layer was washed with water, dried with MgSO4, and
concentrated to dryness. The residue was purified by silica gel
chromatography (cyclohexane/EtOAc, 1:1) to afford (+)-4 (5.6 mg,
78%) as a white solid. M.p. 108–110 °C. [α]2D3 = +181.4 (c = 0.10,
EtOH) [lit.:[6a] m.p. 110 °C, [α]D = +184.7 (EtOH)]. 1H NMR
(300 MHz, CDCl3): δ = 2.48 (br. s, 1 H), 4.49 (dd, J = 5.6, 2.4 Hz,
1 H), 4.68 (dd, J = 5.1, 5.1 Hz, 1 H), 4.76 (d, J = 5.6 Hz, 1 H),
4.97 (dd, J = 5.4, 2.4 Hz, 1 H), 6.26 (d, J = 9.9 Hz, 1 H), 7.02 (dd,
J = 9.9, 4.9 Hz, 1 H), 7.30–7.38 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 68.2, 83.7, 86.0, 86.2, 123.8, 126.1, 128.4, 128.7, 138.0,
140.2, 161.1 ppm. HRMS (ESI): calcd. for C13H12O4Na 255.0633;
found 255.0634.
(1S,5R,6S,8R,9R)-9-(Benzyloxy)-5-hydroxy-8-phenyl-2,7-dioxabicy-
clo[4.3.0]nonan-3-one (18): m-CPBA (56 mg, 0.32 mmol) followed
by BF3·OEt2 (42 µL, 0.32 mmol) were added to a solution of ethyl
lactol 17 (30 mg, 0.08 mmol) in CH2Cl2 (2.5 mL) at 0 °C under an
atmosphere of argon. The resulting mixture was warmed to room
temperature and stirred for 12 h. The mixture was washed with a
saturated aqueous NaHCO3 solution (1 mL). The aqueous layer
was extracted with CH2Cl2 (3ϫ5 mL) and the combined organic
layer was dried with MgSO4 and concentrated. The residue was
purified by silica gel chromatography (cyclohexane/EtOAc, 6:4) to
afford 18 (25 mg, 90%) as a colorless oil. [α]2D3 = +42.1 (c = 0.40,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 2.40 (br. s, 1 H), 2.70
(dd, J = 16.7, 5.3 Hz, 1 H), 2.94 (dd, J = 16.7, 3.6 Hz, 1 H), 4.11
(dd, J = 6.0, 1.7 Hz, 1 H), 4.34 (dd, J = 4.5, 4.5 Hz, 1 H), 4.48 (m,
1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.70 (d, J = 11.6 Hz, 1 H), 4.84
(d, J = 6.0 Hz, 1 H), 5.09 (dd, J = 4.5, 1.7 Hz, 1 H), 7.28–7.46 (m,
10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 35.2, 65.8, 72.6, 84.3,
84.9, 86.6, 90.4, 126.1, 127.8, 128.1, 128.4, 128.5, 128.7, 136.8,
138.1, 168.6 ppm. HRMS (ESI): calcd. for C20H20O5Na 363.1208;
found 363.1207.
Acknowledgments
We thank the University of Rennes 1 and the CNRS for their finan-
cial support. M.D. and A.F. also thank “le Ministère de la Recher-
che” for research fellowships.
(1S,5R,6S,8R,9R)-5,9-Dihydroxy-8-phenyl-2,7-dioxabicyclo[4.3.0]-
nonan-3-one [(–)-Goniofupyrone (3)]: SnCl4 (1.0  CH2Cl2 solution,
0.12 mL, 0.12 mmol) was added to a solution of benzyl ether 18
(20 mg, 0.059 mmol) in CH2Cl2 (1.5 mL) at room temperature. The
reaction mixture was heated at 40 °C for 10 h. After cooling, the
reaction was quenched with a saturated aqueous NaHCO3 solu-
tion. The aqueous layer was extracted with CH2Cl2 (3ϫ3 mL) and
the combined organic layer was washed with water, dried with
MgSO4, and concentrated to dryness. Chromatography of the resi-
due (cyclohexane/EtOAc, 3:7) gave (–)-3 (11.8 mg, 80%) as a color-
less oil. [α]2D3 = –6.2 (c = 0.10, CHCl3) [ref.[6e] [α]D = –5.0 (c = 0.10,
CHCl3)]. 1H NMR (300 MHz, CDCl3): δ = 2.65 (ddd, J = 16.6,
5.8, 1.0 Hz, 1 H), 2.78 (br. s, 1 H), 2.91 (dd, J = 16.6, 3.9 Hz, 1 H),
3.31 (br. s, 1 H), 4.29 (dd, J = 6.4, 2.4 Hz, 1 H), 4.36 (ddd, J = 5.4,
3.9, 1.0 Hz, 1 H), 4.44 (dt, J = 5.9, 3.9 Hz, 1 H), 4.70 (d, J = 6.4 Hz,
1 H), 4.96 (dd, J = 5.4, 2.4 Hz, 1 H), 7.28–7.36 (m, 5 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 35.1, 65.8, 76.4, 83.7, 85.7, 86.8,
126.0, 128.5, 128.7, 137.9, 169.3 ppm. HRMS (ESI): calcd. for
C13H14O5Na 273.0739; found 273.0740.
[1] Y. C. Wu, C. Y. Duh, F. R. Chang, G. Y. Chang, S. K. Wang,
J. J. Chang, D. R. McPhail, A. T. McPhail, K. H. Lee, J. Nat.
Prod. 1991, 54, 1077–1081, and references cited therein.
[2] T. W. Sam, C. S. Yeu, S. Matsjeh, E. K. Gan, D. Razak, A. L.
Mohamed, Tetrahedron Lett. 1987, 28, 2541–2544.
[3] S. K. Talapatra, D. Basu, T. Deb, S. Goswami, B. Talapatra,
Indian J. Chem., Sect. B 1985, 24, 29–34.
[4] R. I. Geran, N. H. Greenberg, M. M. Mac Donald, A. M.
Schumacher, B. J. Abbott, Cancer Chemother. Rep. 1972, 3, 1–
103.
[5] L. Zeng, Q. Ye, N. H. Oberlies, G. Shi, Z. M. Gu, K. He, J. L.
Mc Laughlin, Nat. Prod. Rep. 1996, 13, 275–306.
[6] a) A. A. E. El-Zayat, N. R. Ferrigni, T. G. McCloud, A. T. Mc-
Kenzie, S. R. Byrn, J. M. Cassady, C.-J. Chang, J. L. McLaugh-
lin, Tetrahedron Lett. 1985, 26, 955–956; b) A. Alkofahi, W.-W.
Ma, A. T. McKenzie, S. R. Byrn, J. L. McLaughlin, J. Nat.
Prod. 1989, 52, 1371–1373; c) X. P. Fang, J. E. Anderson, C. J.
Chang, P. E. Fanwick, J. L. McLaughlin, J. Chem. Soc. Perkin
Trans. 1 1990, 1655–1661; d) X. P. Fang, J. E. Anderson, C. J.
Chang, J. L. McLaughlin, P. E. Fanwick, J. Nat. Prod. 1991,
54, 1034–1043; e) X. P. Fang, J. E. Anderson, C. J. Chang, J. L.
McLaughlin, Tetrahedron 1991, 47, 9751–9758; f) X. P. Fang,
J. E. Anderson, X. X. Qui, J. F. Kozlowski, C. J. Chang, J. L.
McLaughlin, Tetrahedron 1993, 49, 1563–1570; g) C. Mukai,
H. Yamashita, S. Hirai, M. Hanaoka, J. L. McLaughlin, Chem.
Pharm. Bull. 1999, 47, 131–132.
[7] For publications on the cytotoxic activity and other bioactivit-
ies of styryllactones, see: a) M. A. Blazquez, A. Bermejo, M. C.
Zafra-Polo, D. Cortes, Phytochem. Anal. 1999, 10, 161–170; b)
H. B. Mereyala, M. Joe, Curr. Med. Chem. Anti-Cancer Agents
2001, 1, 293–300; c) P. Tuchinda, B. Munyoo, M. Pohmakotr,
P. Thinapong, S. Sophasan, T. Santisuk, V. Reutrakul, J. Nat.
Prod. 2006, 69, 1728–1733; d) Z. Tian, S. Chen, Y. Zhang, M.
Huang, L. Shi, F. Huang, C. Fong, M. Yang, P. Xiao, Phytome-
decine 2006, 13, 181–186.
(1S,6S,8R,9R)-9-(Benzyloxy)-8-phenyl-2,7-dioxabicyclo[4.3.0]non-4-
en-3-one (19): p-TsOH·H2O (4 mg, 0.02 mmol) was added to a solu-
tion of alcohol 18 (20 mg, 0.059 mmol) in toluene (2.5 mL). The
reaction mixture was stirred at 85 °C for 5 h, neutralized with a
saturated aqueous NaHCO3 solution, and extracted with CH2Cl2
(3ϫ5 mL). The combined organic layer was dried with MgSO4 and
concentrated. The residue was purified by silica gel chromatog-
raphy (cyclohexane/EtOAc, 6:4) to afford 19 (13.3 mg, 73%) as a
colorless oil. [α]2D3 = +151.9 (c = 0.53, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 4.26 (dd, J = 5.3, 1.4 Hz, 1 H), 4.59 (d, J = 5.1 Hz, 1
H), 4.64 (d, J = 11.6 Hz, 1 H), 4.68 (d, J = 11.6 Hz, 1 H), 4.87 (dd,
J = 5.3, 2.4 Hz, 1 H), 5.03 (dd, J = 4.7, 1.4 Hz, 1 H), 6.27 (d, J =
9.8 Hz, 1 H), 7.02 (dd, J = 9.8, 4.7 Hz, 1 H), 7.28–7.33 (m, 10
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 68.7, 72.8, 84.2, 85.3,
90.8, 124.3, 126.2, 127.8, 128.1, 128.3, 128.5, 128.6, 136.8, 138.2,
139.5, 160.9 ppm. HRMS (ESI): calcd. for C20H18O4Na 345.1103;
found 345.1102.
[8] For a review on the synthesis of styryllactones up to 2004, see:
M. Mondon, J.-P. Gesson, Curr. Org. Synth. 2006, 3, 41–75.
[9] For a review concerning the synthetic methodologies for chiral
α-pyrones, see: J. A. Marco, M. Carda, J. Murga, E. Falomir,
Tetrahedron 2007, 63, 2929–2958.
[10] From mandelic acid, see: a) J.-P. Survivet, J.-M. Vatèle, Tetrahe-
dron 1999, 55, 13011–13028; from tartaric acid derivatives, see:
b) K. R. Prasad, S. L. Gholap, J. Org. Chem. 2008, 73, 2–11;
c) P. Somfai, Tetrahedron 1994, 50, 11315–11320; from glyceral-
dehyde derivatives, see: d) S. H. Kang, W. J. Kim, Tetrahedron
(1S,6S,8R,9R)-9-Hydroxy-8-phenyl-2,7-dioxabicyclo[4.3.0]non-4-en-
3-one [(+)-Altholactone (4)]: SnCl4 (1.0  CH2Cl2 solution, 62 µL,
0.062 mmol) was added to a solution of benzyl ether 19 (10 mg,
0.031 mmol) in CH2Cl2 (1 mL) at room temperature. The reaction
4906
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4900–4907

Synthesis of (+)-Goniodiol and its Derivatives
Lett. 1989, 30, 5915–5918; e) M. Tsubuki, K. Kanai, H. Na-
gase, T. Honda, Tetrahedron 1999, 55, 2493–2514; from com-
mercially available oxygenated lactones, see: f) T. K. M. Shing,
V. W.-F. Tai, J. Org. Chem. 1999, 64, 2140–2144, and references
cited therein; from glucose, see: g) G. S. C. Srikanth, U. M.
Krishna, G. K. Trivedi, Tetrahedron Lett. 2002, 43, 5471–5473;
h) J.-P. Gesson, J.-C. Jacquesy, M. Mondon, Tetrahedron 1989,
45, 2627–2640; from arabinose, see: i) Y. Ueno, K.-I. Tadano,
S. Ogawa, J. L. McLaughlin, A. Alkofahi, Bull. Chem. Soc. Jpn.
1989, 62, 2328–2337.
By alkoxyallylboration, see: a) P. V. Ramachandran, J. S. Chan-
dran, M. V. R. Reddy, J. Org. Chem. 2002, 67, 7547–7550; by
an anomeric rearrangement, see: b) E. W. Tate, D. J. Dixon,
S. V. Ley, Org. Biomol. Chem. 2006, 4, 1698–1706; by dihydrox-
ylation, see: c) J. Chen, G.-Q. Lin, Z.-M. Wang, H.-Q. Liu,
Synlett 2002, 1265–1268; d) M. G. Banwell, M. J. Coster, A. J.
Edwards, O. P. Karunaratne, J. A. Smith, L. L. Welling, A. C.
Willis, Aust. J. Chem. 2003, 56, 585–595, and references cited
therein; by epoxidation, see: e) Z.-C. Yang, W.-S. Zhou, Tetra-
hedron 1995, 51, 1429–1436; f) W.-P. Chen, S. M. Roberts, J.
Chem. Soc. Perkin Trans. 1 1999, 103–105; g) J. M. Harris,
G. A. O’Doherty, Tetrahedron 2001, 57, 5161–5171; h) J. S. Ya-
dav, A. K. Raju, P. P. Rao, G. Rajaiah, Tetrahedron: Asymmetry
2005, 16, 3283–3290; i) K. Nakashima, N. Kikuchi, D. Shiray-
ama, T. Miki, K. Ando, M. Sono, S. Suzuki, M. Kawase, M.
Kondoh, M. Sato, M. Tori, Bull. Chem. Soc. Jpn. 2007, 80,
387–394; by aldol reaction, see: j) C. Mukai, S. Hirai, M.
Hanaoka, J. Org. Chem. 1997, 62, 6619–6626; k) D. Enders, J.
Barbion, Chem. Eur. J. 2008, 14, 2842–2849.
[17] C. M. L. Delpiccolo, L. Méndez, M. A. Fraga, E. G. Mata, J.
Comb. Chem. 2005, 7, 331–344.
[18] C. Rasset-Deloge, P. Martinez-Fresneda, M. Vaultier, Bull. Soc.
Chim. Fr. 1992, 129, 285–290.
[19] K. Gademann, D. E. Chavez, E. N. Jacobsen, Angew. Chem.
2002, 114, 3185–3187; Angew. Chem. Int. Ed. 2002, 41, 3059–
3061.
[20] With an excess amount of aldehyde 6 (2 equiv.) the yield can
be enhanced to 78% when the reaction is warmed in toluene
at 70 °C for 48 h.
[21] A drop in the diastereoselectivity is observed (90% dr) under
the same conditions by using the enantiomer of aldehyde 6.
[22] P. A. Grieco, T. Oguri, Y. Yokoyama, Tetrahedron Lett. 1978,
19, 419–420.
[11]
[23]
[24] The relative stereochemistry of the C-5 and C-6 atoms in 12
was also confirmed by the synthesis of the stable vicinal diol
by using a catalytic amount of OsO4 and N-methylmorpholine
N-oxide as cooxidant. The reaction led to the formation of a
single diastereomer with a coupling constant of 9.1 Hz between
5-H and 6-H, which indicates that the dihydroxylation, like the
epoxidation, takes place from the sterically less-hindered face
of alkene 10.
[12]
[13]
Preliminary communication: M. Deligny, F. Carreaux, B. Car-
boni, Synlett 2005, 1462–1464.
F. Carreaux, A. Favre, B. Carboni, I. Rouaud, J. Boustie, Tetra-
hedron Lett. 2006, 47, 4545–4548.
[14] a) F. Carreaux, F. Possémé, B. Carboni, A. Arrieta, B. Lecea,
F. P. Cossio, J. Org. Chem. 2002, 67, 9153–9161; b) F. Possémé, [25] J. W. Loder, H. R. Nearn, Heterocycles 1977, 7, 113–118.
M. Deligny, F. Carreaux, B. Carboni, J. Org. Chem. 2007, 72,
[26] To the best of our knowledge, only two syntheses of 3 have
been described in the literature, including a hemisynthesis, see:
ref.[11j] and E. Peris, A. Cave, E. Estornell, M. C. Zafra-Polo,
B. Figadere, D. Cortes, A. Bermejo, Tetrahedron 2002, 58,
1335–1342.
984–989.
[15] a) M. Deligny, F. Carreaux, L. Toupet, B. Carboni, Adv. Synth.
Catal. 2003, 345, 1215–1219; b) X. Gao, D. G. Hall, J. Am.
Chem. Soc. 2003, 125, 9308–9309.
[16] X. Gao, D. G. Hall, M. Deligny, A. Favre, F. Carreaux, B. Car-
boni, Chem. Eur. J. 2006, 12, 3132–3142.
Received: June 3, 2008
Published Online: September 3, 2008
Eur. J. Org. Chem. 2008, 4900–4907
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4907