From p-benzoquinone to cyclohexane chirons: First asymmetric synthesis of (+)-rengyolone and (+)- and (-)-menisdaurilide

Article abstract of DOI:10.1016/S0957-4166(03)00357-4

Starting from a common, easily available, enantiopure monoketal of p-benzoquinone, the synthesis of a large number of cyclohexane chirons has been achieved. The first synthesis of (+)-rengyolone and (+)- and (-)-menisdaurilide has been performed from one of these new building blocks. The wide variety of functional groups of this series of chirons makes them useful for subsequent synthetic processes.

Full text of DOI:10.1016/S0957-4166(03)00357-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2021–2032
From p-benzoquinone to cyclohexane chirons: first asymmetric
synthesis of (+)-rengyolone and (+)- and (−)-menisdaurilide
Felix Busque´, Mariona Canto´, Pedro de March,* Marta Figueredo, Josep Font and
Sonia Rodr´ıguez
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
Received 4 April 2003; accepted 11 April 2003
Abstract—Starting from a common, easily available, enantiopure monoketal of p-benzoquinone, the synthesis of a large number
of cyclohexane chirons has been achieved. The first synthesis of (+)-rengyolone and (+)- and (−)-menisdaurilide has been
performed from one of these new building blocks. The wide variety of functional groups of this series of chirons makes them
useful for subsequent synthetic processes. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
‘rengyo’ in oriental medicine and used for its anti-
inflammatory, diuretic and antidotal properties. Simul-
taneously, Italian researchers2 isolated compound 1
from the leaves of Halleria lucida, a plant used for
magical purposes and in folk medicine in Southern
Africa, and gave it the name halleridone. Afterwards,
rengyolone, the name that first appeared in the litera-
ture and which will be used in this paper, has been
extracted also from other plants3 and three Japanese
patents claim the anticancer activity of 1 and its esters.4
Benzofuranone 2 was first reported in the literature in
1978 as a product of the acid hydrolysis of menisdau-
rin, a nitrile glucoside isolated from Menispermum dau-
ricum.5 Later on, lactone 2 has been also isolated from
several other plants6 and its absolute configuration has
been unequivocally established.6c,d Menisdaurilide is
also the aglycon of phyllanthurinolactone, a bioactive
substance that folds together the leaves of the plant
Phyllanthus urinaria in the daytime, a phenomenon
called nyctinasty.7
Nature synthesizes a large number of products which
contain a densely functionalized cyclohexane subunit
that accommodates several stereocenters in its struc-
ture. Rengyolone, ( )-1, and menisdaurilide, (−)-2, are
two representative examples of such natural products
(Fig. 1). The benzofuranone 1 was simultaneously iso-
lated in 1984 by two research groups. Endo and
Hikino1 named it rengyolone, because they isolated it
from the fruit of the plant Forsythia suspensa, named
Nature also biosynthesizes a series of polyoxygenated
cyclohexanes like phyllostine,8 a phytotoxic compound,
or bromoxone,9 aranorosin,10 the manumycins,11 and
fumagillin and its analogues,12 all of them presenting
interesting antitumor activity (Fig. 2).
Therefore, it is not surprising that many methodologies
for the synthesis of cyclohexane chirons had been devel-
oped during the last decade. Some of these efforts
include the work by Hudlicky’s group,13 who have
described the successful preparation of a large number
Figure 1.
* Corresponding author. Tel.: 34-935811258; fax: 34-935811265;
e-mail: pere.demarch@uab.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00357-4

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F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
diols, e.g. 8, was considered a suitable approach for our
purpose.18 The usefulness of C2-symmetric diols as chi-
ral auxiliaries for asymmetric induction has been
demonstrated during the last years by a substantial
number of publications.9c,19 Chiral auxiliaries with C2-
symmetry usually provide higher levels of stereochemi-
cal control than those lacking symmetry as they present
the main advantage of reducing the number of possible
competing transition states. Owing to their C2-symme-
try, in monoketal 8 both faces of the remaining car-
bonyl group and both carbonꢀcarbon double bonds are
equivalent. Another important feature is that all six
carbon atoms of the cyclohexane ring are function-
alised. Monoketal (+)-8 can be prepared in gram-scale
from p-benzoquinone and (R,R)-hydrobenzoin in a sin-
gle step.18a In recent papers, we have already described
the utility of these enantiopure monoketals in several
diastereoselective transformations,20 including an
efficient synthesis of (S)-4-hydroxy-2-cyclohexen-1-one.
We report now the straightforward synthesis of several
new enantiopure polyfunctionalised cyclohexanes with
the structure of 1,4-dioxa[4.5]decane, starting from
monoketal 8. The value of these new chirons for bioac-
tive product synthesis is demonstrated by completing
the first synthesis of (+)-rengyolone and (+)- and (−)-
menisdaurilide.21
Figure 2.
of enantiopure cyclohexadiene-1,2-diols, 3, (Fig. 3) by
enzymatic oxidation of the aromatic compounds.
Ogasawara14 has synthesized several non racemic Diels–
Alder cycloadducts, 4, derived from p-benzoquinone.
The cyclohexenone 5 has been described by Sato.15
Enders16 has achieved the asymmetric synthesis of sev-
eral substituted 1,4-cyclohexanedione derivatives, 6,
and Taber has described the cyclohexenone 7,17 and
used it as an intermediate in a synthesis of fumagillin.12c
Most of these authors have demonstrated the versatility
of these cyclohexanes as chiral building blocks by per-
forming also the syntheses of other natural products in
enantiopure form.
2. Results and discussion
2.1. Synthesis of new cyclohexane chirons
With the aim of preparing a new set of cyclohexane
chirons, we have systematically explored the modifica-
tion of the CꢀC double bonds and the carbonyl group
of 8. Epoxidation, bromination, and iodination reac-
tions have been performed, because many cyclohexane
natural products present the oxygen or halogen atoms
as substituents. Considering that the cyclohexane ring
may present different degrees of unsaturation, several
reduction processes of 8 have also been studied.
Finally, we have investigated the formation of new CꢀC
bonds at the carbonyl carbon atom and its a-position,
since several interesting natural products present side
chains at these positions.
Reaction of ketal 8 with an excess of hydrogen peroxide
in the presence of a catalytic amount of sodium hydrox-
ide at room temperature afforded the cis-bisepoxide
(+)-9 as a white solid in 95% yield (Scheme 1).
Figure 3.
A few years ago, we started a research project, focused
on the development of a new class of cyclohexane
chirons. As other authors,9c,14 we visualized the inex-
pensive p-benzoquinone as an appropriate starting
material and we conceived a new approach in order to
convert this achiral, highly symmetric molecule, pre-
senting two pairs of equivalent functional groups, into
a useful chiron. The formation of enantiopure monoke-
tals of p-benzoquinone derived from C2-symmetric 1,2-
Scheme 1. Reagents and conditions: (a) exc. H2O2, NaOH
cat., MeOH, rt, 1 day, 95%; (b) NaBH4, MeOH, 0°C, 10 min,
81%.

F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2023
The presence in the 13C NMR spectrum of eight non-
aromatic signals reveals the loss of symmetry in the
molecule and hence evidences that the epoxides are in a
We reasoned that the formation of phenol 14 could be
favored by traces of acid present in the solvents. Thus,
a third essay in toluene provided the desired cyclohex-
anone 12 in 95% yield. A different preparation of 12,
starting from 1,4-cyclohexanediol was recently
described by Konopelski23 in relation with the synthesis
of anticancer chemotherapeutic agents, but we believe
that our new access to 12 competes advantageously.
The structural assignment of bisketal 13 relies on the
presence of a quadruplet at l 3.49 and a triplet at l
1
cis-relationship. The H NMR spectrum of 9 displays
four different signals for the oxirane protons, all of
them showing a multiplicity of double doublet. This
pattern discloses the existence of long range coupling
constants between the pairs of protons H-7/H-9 and
H-6/H-10, indicative of a boat conformation for the
cyclohexane ring with the oxirane oxygen atoms occu-
pying axial positions, as in the case of the natural
product aranorosin.10b The exclusive formation of cis
bisepoxides in the oxidation of p-benzoquinone ketals
was already documented in the literature.22 The advan-
tage of using a C2-symmetric chiral auxiliary becomes
apparent here, where a unique diastereoisomer of the
cis-bisepoxide is possible.
1
1.18 in the H NMR and the two acetal signals at l
109.5 and 99.2 in its 13C NMR. The 1H NMR spectrum
of 14 shows two doublets at l 6.71 and 6.60, which are
characteristic for an electron rich p-disubstituted ben-
zene ring.
When ketone 8 was subjected to NaBH4 reduction in
methylene chloride–methanol solution (1:1), the new
bisallylic alcohol (+)-15 was isolated in 87% yield as a
white solid. The absorptions at l 99.4 and 62.4 in its
13C NMR spectrum demonstrate the presence of the
ketal group and the allylic alcohol, respectively.
Treatment of 9 with sodium borohydride gave the
diastereoisomeric alcohols (+)-10 and (+)-11 in 54% and
27% yield, respectively, as solids. Besides the four oxi-
1
rane protons, the H NMR spectra of both alcohols
show two doublets at l :4.5 and 2.7, assignable to the
H-8 and the hydroxyl proton, respectively. The stereo-
chemical assignment of the less polar and major isomer
10 relies on the NOE observed on two of the oxirane
protons upon irradiation of H-8. The same experiment
was negative for its diastereoisomer 11.
Sodium borohydride reduction of the carbonyl group
of ketal 12 delivered the alcohol (+)-16 as a solid in
91% yield. The C2-symmetry of the chiral auxiliary
prevents the formation of a new stereogenic center at
C-8 and hence the existence of diastereoisomeric prod-
ucts. Nevertheless, in alcohol (+)-16 the molecular sym-
metry is lost causing the appearance of a different
doublet at l 4.75 and 4.71 for each dioxolane proton.
Compound 16 is an intermediate in the above men-
tioned Konopelski’s synthesis of 12.23
Next, we studied the reduction processes of the dienone
system of 8. The hydrogenation of 8 using Pd over
charcoal in ethanol was very fast, the starting substrate
being consumed in 15 min, and purification of the
crude material afforded three new compounds identified
as (+)-12, (+)-13, and (+)-14 in 15, 36 and 39% yield,
respectively (Scheme 2). The same reaction performed
in ethyl acetate to avoid the incorporation of the sol-
vent furnished only compounds 12 (59%) and 14 (16%).
We also explored the incorporation of chlorine and
bromine atoms into the cyclohexane moiety of ketal 8,
which had a double interest. Firstly, some bioactive
cyclohexanes present a vinylic halogen atom in their
structure and, secondly, a vinylic halide is an appropri-
ate precursor for the introduction of side chains
through well established CꢀC coupling reactions.24
Treatment of 8 with an excess of bromine in methylene
chloride followed by addition of triethylamine afforded
the bromo derivatives (+)-17 and (+)-18 as white solids
in 73 and 24% yield, respectively (Fig. 4). Using 0.53
equivalents of bromine the monoreaction product 17
was the main product, isolated in 86% yield considering
the recovered acetal 8. The NMR spectra of 18 were
very simple, according to the high symmetry of the
1
molecule, while the H NMR spectrum of 17 showed
three olefinic absorptions at l 7.39, 6.97 and 6.40,
corresponding to H-6, H-10 and H-9, respectively. The
iodination reaction was performed with an excess of
iodine in carbon tetrachloride as solvent and in the
presence of pyridine. The mono- and direaction prod-
ucts, (+)-19 and (+)-20, respectively, were isolated as
white solids in ca. 50% yield each. The olefinic protons
of 19 resonate at l 7.70, 6.96 and 6.41.
Once the reduction and oxidation reactions of the
dienone system of 8 had been thoroughly investigated,
our next goal was the attachment of carbon chains to
the cyclohexane skeleton. Some natural products con-
Scheme 2. Reagents and conditions: (a) H2, Pd/C, toluene, 15
min, 95%; (b) NaBH4, MeOH/CH2Cl2 1/1, 0°C, 30 min, 87%;
(c) NaBH4, MeOH, 0°C, 15 min, 91%.

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F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2.2. Synthesis of (+)-rengyolone
None of the samples of rengyolone isolated from natu-
ral sources present a significant value of specific rota-
tion and it is therefore accepted that the natural
compound occurs as a racemate. The proposed biosyn-
thetic pathway involves spontaneous closure of the
achiral quinol 24 (Scheme 3) formed by the enzymatic
hydrolysis of the glucoside cornoside.3d,27 Nevertheless,
in 1997 a Chinese group published the isolation of six
new compounds from Clerodendrum indicum, one of
them with identical structure and relative stereochem-
istry to rengyolone.28 This compound was named
cleroindicin F and the authors reported a specific rota-
tion of [h]2D0 −2.74 (c 0.016, MeOH). Moreover, since
rengyolone had only been synthesized in racemic
form,27,29 the actual specific rotation of the pure enan-
tiomers was unknown.
Figure 4.
tain a hydroxymethyl group or longer chains at the
a-carbonyl position of a cyclohexenone. For this reason
we decided to attempt the reaction of ketal 8 with
formaldehyde. The incorporation of a hydroxymethyl
group would additionally open several synthetic alter-
natives to enlarge this side chain. The reaction between
8 and an excess of aqueous formaldehyde in the pres-
ence of 4-dimethylaminopyridine (DMAP)25 afforded
the mono- and dihydroxymethyl derivatives, (+)-21 and
(+)-22, in 25 and 51% isolated yield, respectively. The
1H NMR spectrum of 21 discloses two deshielded pro-
tons at l 7.00–6.90 (H-6 and H-10) and a third one at
l 6.26 (H-9). That of 22, according to the symmetry of
the molecule, shows only three singlets at l 6.95, 4.94
and 4.45 due to the olefinic, benzylic and methylene
protons, respectively, along with the aromatic signals.
In the 13C NMR spectra of 21 and 22 the hydroxy-
methyl groups display resonances at l 60.2 and 57.1,
respectively.
Scheme 3.
We envisaged hydroxyester 23 as a suitable precursor to
intend an asymmetric synthesis of rengyolone, through
a biomimetic strategy consisting in the preparation of a
chiral equivalent of the postulated biogenetic intermedi-
ate 24 (Scheme 4). The reduction of 23 with lithium
aluminum hydride furnished a complex mixture of
ketone 8, unreacted 23, phenol 14, and the desired diol
(+)-25 in a ratio 1:3:1:5. Fortunately, a second attempt
with lithium borohydride afforded the diol 25 as a solid
in 94% yield.
Compounds 17, 19 and 21 are p-benzoquinone deriva-
tives in which both pairs of functional groups initially
equivalent have been differentiated, and hence may be
particularly
useful
for
further
synthetic
transformations.
Considering the structure of rengyolone and menisdau-
rilide, we then directed our efforts to link a C2-chain to
the carbonyl group of 8. Wittig-type reactions were
originally attempted, but all our trials to condense 8
with phosphonates derived from ethyl acetate or acetic
acid failed. However, treatment of 8 with ethyl iodoac-
etate in the presence of indium powder26 led to the
isolation of the new ester (+)-23 in 94% yield as a
colorless oil. Both olefinic protons of compound 23
resonate at l 6.3–6.1, according to the loss of conjuga-
tion, and the incorporation of the acetate unit is confirm-
ed by the presence of the ethoxy group (l 4.17 and
Scheme 4. Reagents and conditions: (a) LiBH4, THF, 0°C, 4
days, 94%; (b) Hg(CF3COO)2, DME, rt, 2 h, then NaBH4, 1.2
M NaOH, rt, 5 min, 78%; (c) montmorillonite K-10, CH2Cl2,
rt, 1 day, 45%.
1
1.26) and a singlet at l 2.63 in the H NMR spectrum
and the absorption at 1731 cm−1 in the IR spectrum.

F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2025
The next transformation consisted in the cyclization to
the benzofuran skeleton through an intramolecular
addition of the primary alcohol to the olefin. In princi-
ple, this process could give rise to up to four
diastereoisomers, but we expected only the formation of
the cis fused isomers according to reported precedents
in related ring closing reactions leading to the forma-
tion of benzofurans.27,29 Thus, treatment of 25 with
mercuric trifluoroacetate followed by reduction with
sodium borohydride30 afforded a ca. 2:1 mixture of
cyclic ethers 26 and 27 in 78% yield. Repeated column
chromatography led to the isolation of the less polar
1
and major isomer 26 as a solid in 52% yield. Its H
NMR spectrum shows two olefin protons at l 6.05 (d)
and 5.91 (dd). The last signal attributed to H-5 because
of the long range coupling constant with one H-7. The
formation of the furan ring is also evidenced by the
signal of H-7a at l 4.26 (dd). The NOESY spectrum of
26 was not conclusive to determine its stereochemistry,
but an X-ray crystallographic analysis confirmed the cis
stereochemistry of the ring fusion and also revealed
that the absolute configuration of the new stereogenic
centers (3a and 7a) was S.21b
The minor isomer 27 was obtained with a 92% purity
and was characterized by its NMR data. Removal of
the chiral auxiliary from compound 26 using montmo-
rillonite K-1011b,22b yielded 45% of (+)-1 as a colorless
oil that crystallized on standing, whose NMR data
match those reported for ( )-1.1,2,3c,29a This synthetic
(+)-rengyolone showed a specific rotation [h]2D0 +48.6 (c
0.3 MeOH) and an enantiomeric excess of 85%, deter-
mined by CGC and NMR analysis assisted by the
perdeuterated Pirkle alcohol31 as chiral shift reagent.
Since the value of the specific rotation measured for our
sample of (+)-1 with 85% ee is much higher than that
reported for cleroindicin F ([h]2D0 −2.74),28 it is clear that
the last compound should be identified as racemic
rengyolone.
Scheme 5. Reagents and conditions: (a) KOH, H2O/EtOH, rt,
5 h, 84%; (b) CF3COOH, CHCl3, rt, 2 days, 60% of 29 and
28% of 30 or Hg(CF3COO)2, CH2Cl2, rt, 1 day, 30% of 29
and 45% of 30; (c) SOCl2, py, rt, 30 min, 84%; (d) montmoril-
lonite K-10, CH2Cl2, reflux, 6 days, 49%; (e) NaBH4,
CeCl3·7H2O, EtOH, 0°C, 30 min, 74%; (f) SOCl2, py, rt, 15
min, 89%; (g) montmorillonite K-10, CH2Cl2, reflux, 1 day,
65%; (h) NaBH4, CeCl3·7H2O, EtOH, 0°C, 30 min, 63%.
2.3. Synthesis of (+)- and (−)-menisdaurilide
The synthesis of menisdaurilide was continued indepen-
dently from each diastereoisomer. Dehydration of the
tertiary alcohol of 29 was unsuccessful in both acid and
basic media, but treatment with thionyl chloride,34
To the best of our knowledge, there is only one
reported synthesis of 2 and it is prepared as the race-
mate.32 Our synthesis of (+)- and (−)-2 is depicted in
Scheme 5. Potassium hydroxide mediated saponifica-
tion of 23 provided the hydroxy acid (+)-28 as a white
solid in 84% yield.
1
afforded (−)-31 as a white solid in 84% yield. Its H
NMR spectrum shows three signals in the olefin region
at l 6.74 (d), 6.31 (dd) and 5.92 (dd) that correspond to
H-5, H-4, and H-3, respectively. The IR spectrum
shows the characteristic absorptions of an a,b-buteno-
lide at 1785 and 1758 cm−1. Removal of the acetal was
performed as above by treatment of 31 with montmoril-
lonite K-10. This reaction furnished 49% yield of the
benzofuranone (−)-32, which spectroscopic data are
identical to those reported for racemic 32.32b Finally,
(+)-menisdaurilide ([h]2D0=+27.6 (c 0.6, MeOH)) was
prepared in 74% yield by reduction of the ketone
function of (−)-32 using Luche’s reagent, as previously
described for the synthesis of ( )-2.32 In a similar way,
the levorotatory natural isomer of 2 was synthesized
from lactone 30. Dehydration of 30 afforded (+)-33 as
a solid in 89% yield. Removal of the chiral auxiliary
provided a 65% yield of the solid benzofuranone (+)-32
which upon reduction afforded a sample of crystalline
g-Lactonisation was achieved by intramolecular addi-
tion of the carboxylic acid to the olefin promoted either
by trifluoroacetic acid or mercuric trifluoroacetate.33
Under both conditions, the cis fused, crystalline lac-
tones (+)-29 and (+)-30 were exclusively produced in 60
and 28 or 30 and 45% yields, respectively. The forma-
tion of the lactone is secured by the presence of signals
at 1774 and 1785 cm−1 in the IR spectrum of 29 and 30,
respectively. The less polar diastereoisomer 29 could be
isolated in pure form, while 30 was contaminated with
ca. 7% of 29, according to NMR analysis. Although the
configuration of the new stereocenters could not be
determined by spectroscopic analysis, it was established
by chemical correlation (vide infra).

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F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
(−)-2 in 63% yield ([h]2D0 −20.0 (c 0.4, MeOH)). The
specific rotation values previously reported for (−)-2,
isolated from natural sources oscilate in the range
between −27.3 and −31.4.5,6
(2.4 mL, 23.3 mmol) was added. A 0.06 M aqueous
solution of NaOH (1.6 mL, 0.10 mmol) was added
dropwise and the resulting solution was left at room
temperature for 1 day. Water was added (5 mL) and
the solution was extracted with methylene chloride.
Flash chromatography of the oily crude material (304
mg) using hexane/ethyl acetate (4:1) as eluent afforded
(+)-9 as a white solid (210 mg, 0.62 mmol, 95%): mp
116–117°C (ether/pentane); [h]2D0=+44.1 (c 1.2, CHCl3);
IR (KBr) 3037, 2924, 1715, 1455, 1138, 998, 934, 766,
702 cm−1; 1H NMR l 7.50–7.20 (m, 10H), 5.08 (d,
J=8.8 Hz, 1H), 4.95 (d, J=8.8 Hz, 1H), 3.83 (t, J=3.7
Hz, 1H), 3.74 (t, J=3.7 Hz, 1H), 3.58 (dd, J=3.7, 2.6
Hz, 1H), 3.50 (dd, J=3.7, 2.6 Hz, 1H); 13C NMR l
197.4, 134.5, 134.3, 129.2, 129.0, 128.8, 128.7, 126.6,
126.5, 101.4, 86.8, 86.0, 60.8, 60.0, 55.3, 55.2; MS m/z
337 (M++1, 1), 173 (21), 167 (34), 165 (22), 156 (26),
145 (26), 131 (39), 105 (100), 96 (21), 91 (53), 89 (23), 79
(30), 77 (50), 68 (22). Anal. calcd for C20H16O5: C,
71.00; H, 5.36. Found: C, 71.04; H, 5.05.
The spectral data of both (+)-2 and (−)-2 matched
exactly those of ( )-2.6b–d,32b The enantiomeric purity of
our synthetic samples was determined by NMR analysis
assisted by the perdeuterated Pirkle alcohol.31 The mea-
sured ee of (+)-2 was >98% and that of (−)-2 80%,
values in accordance with the specific rotations experi-
mentally observed.
3. Conclusions
In conclusion we have described a straightforward and
efficient access to the first enantiopure bisepoxide of a
p-benzoquinone monoketal and the preparation of sev-
eral new cyclohexane chirons with a wide variety of
functional groups which are useful for further synthetic
elaborations. Considering the low cost and easy accessi-
bility of the starting materials, p-benzoquinone and
enantiopure hydrobenzoin, this set of enantiopure
cyclohexanes can become valuable chirons for bioactive
product synthesis. As an application, we have accom-
plished the first synthesis of (+)-rengyolone, and (+)-
and (−)-menisdaurilide from the common cyclohexane
building block (+)-23 in 22, 15 and 14% overall yields,
respectively. Enantioselective syntheses of other natural
products from chiral building blocks derived from p-
benzoquinone monoketals are currently under
development.
4.3. (2R,3R,6R,7R,8R,9S,10S)-6,7:9,10-Diepoxy-2,3-
diphenyl-1,4-dioxaspiro[4.5]decan-8-ol, (+)-10, and its
(2R,3R,6R,7R,8S,9S,10S)-isomer, (+)-11
To a solution of (+)-9 (86 mg, 0.26 mmol) in methanol
(3 mL) at 0°C, NaBH4 (8 mg, 0.21 mmol) was added in
small portions. The mixture was allowed to react for 10
min. The solvent was removed and water was added (2
mL); the mixture was neutralized with saturated
aqueous NH4Cl and was extracted with methylene chlo-
ride. Flash chromatography of the oily crude material
(109 mg) using CH2Cl2/ether (25:1) as eluent afforded
the following fractions: (i) 48 mg (0.14 mmol, 54%) of
(+)-10 as a white solid; and (ii) 23 mg (0.07 mmol, 27%)
of (+)-11 as a white solid. (+)-10: mp 215–217°C
(CH2Cl2/pentane); [h]2D0=+20.4 (c 0.8, CHCl3); IR
(KBr) 3543, 3473, 3065, 3037, 2994, 2896, 1497, 1455,
1258, 1145, 1124, 1072, 1008, 970, 878, 766, 702 cm−1;
1H NMR l 7.40–7.10 (m, 10H), 5.04 (d, J=8.8 Hz,
1H), 4.83 (d, J=8.8 Hz, 1H), 4.58 (d, J=9.5 Hz, 1H),
3.47 (m, 2H), 3.34 (m, 1H), 3.25 (m, 1H), 2.85 (d,
J=9.5 Hz, 1H); 13C NMR l 134.9, 129.1, 128.73,
128.68, 128.5, 126.7, 126.5, 102.0, 86.7, 85.6, 60.8, 55.8,
55.6, 53.9, 53.4; MS m/z (CI/NH3) 356 (M++18, 100),
214 (30), 197 (38). Anal. calcd for C20H18O5: C, 71.00;
H, 5.36. Found: C, 71.22; H, 5.30. (+)-11: mp 213–
215°C (CH2Cl2/pentane); [h]2D0=+8.9 (c 0.9, CHCl3); IR
(KBr) 3431, 3194, 3030, 2891, 1494, 1453, 1391, 1261,
4. Experimental
4.1. General
Reaction mixtures were stirred magnetically. The
organic extracts were dried over anhydrous sodium
sulfate. Reaction solutions were concentrated using a
rotary evaporator at 5–10 Torr. Flash chromatogra-
phies were performed using Merck silica gel (230–400
mesh). (R,R)-Hydrobenzoin was prepared according to
a previously described method.35 Infrared spectra were
1
recorded on a Nicolet 5 ZDX spectrophotometer. H
and 13C NMR spectra were recorded on a Bruker
AC-250-WB instrument at 250 and 62.5 MHz, respec-
tively, in CDCl3 solutions. Mass spectra were per-
formed on a Hewlett-Packard 5985B instrument using
electron impact at 70 eV; only peaks with higher inten-
sity than 20% are reported, unless they belong to
molecular ions or to significant fragments. Alterna-
tively, chemical ionization with ammonia has been
used. CGC was performed using a capillary column of
FS-Lipodex B (25 m×0.25 mm) from Macherey-Nagel.
1
1151, 1128, 1066, 1021, 996, 941, 770, 702 cm−1; H
NMR l 7.40–7.20 (m, 10H), 5.06 (d, J=8.6 Hz, 1H),
4.90 (d, J=8.6 Hz, 1H), 4.36 (br d, J=10.2 Hz, 1H),
3.63 (m, 1H), 3.58 (m, 1H), 3.50 (m, 2H), 2.50 (br d,
J=10.2 Hz, 1H); 13C NMR l 135.0, 134.7, 129.1, 128.8,
128.7, 128.6, 126.8, 126.5, 101.8, 86.8, 85.7, 63.9, 58.0,
57.4, 56.3, 56.1; MS m/z (CI/NH3) 356 (M++18, 100),
339 (M++1, 6).
4.2. (2R,3R,6R,7S,9R,10S)-6,7:9,10-Diepoxy-2,3-
diphenyl-1,4-dioxaspiro-[4.5]decan-8-one, (+)-9
4.4. (2R,3R)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decan-8-
one, (+)-12
To a solution of (+)-8 (201 mg, 0.66 mmol) in methanol
(35 mL), a 30% aqueous solution of hydrogen peroxide
(a) A suspension of (+)-8 (101 mg, 0.33 mmol) and
palladium (10%) on activated carbon (32 mg) in ethanol

F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2027
(10 mL) and ethyl acetate (2 mL) was reduced with
hydrogen at room temperature and atmospheric pres-
sure for 15 min. The mixture was filtered through Celite
and the solvent was removed. Flash chromatography of
the oily crude material (110 mg) using hexane/ether
(5:1) as eluent afforded the following fractions: (i) 47
mg (0.12 mmol, 36%) of (2R,3R)-8,8-diethoxy-2,3-
diphenyl-1,4-dioxaspiro[4.5]decane, (+)-13, as a color-
less oil; (ii) 15 mg (0.05 mmol, 15%) of (+)-12,23 as a
colorless oil; and (iii) 40 mg (0.13 mmol, 39%) of
4-[(1R,2R)-2-hydroxy-1,2-diphenylethoxy]phenol, (+)-
14, as a white solid. (b) A suspension of (+)-8 (100 mg,
0.33 mmol) and palladium (10%) on activated carbon
(32 mg) in ethyl acetate (2 mL) was reduced with
hydrogen at room temperature and atmospheric pres-
sure for 15 min. The mixture was filtered through Celite
and the solvent was removed. Flash chromatography of
the oily crude material (76 mg) using hexane/ether (2:1)
as eluent afforded the following fractions: (i) 60 mg
(0.19 mmol, 59%) of (+)-1223 as a colorless oil; and (ii)
16 mg (0.05 mmol, 16%) of (+)-14 as a white solid. (c)
A suspension of (+)-8 (200 mg, 0.66 mmol) and palla-
dium (10%) on activated carbon (66 mg) in toluene (5
mL) was reduced with hydrogen at room temperature
and atmospheric pressure for 15 min. The mixture was
filtered through Celite and the solvent was removed.
Flash chromatography of the oily crude material (222
mg) using hexane/ether (2:1) as eluent afforded the
following fractions: (i) 194 mg (0.63 mmol, 95%) of
(+)-12;23 and (ii) 10 mg (0.03 mmol, 5%) of (+)-14.
(+)-12: [h]2D0=+38.4 (c 1.3, CHCl3); IR (KBr) 3066,
3033, 2959, 2898, 1718, 1452, 1266, 1131, 1098, 1026,
was allowed to react at the same temperature for 30
min. The solvent was removed, water (10 mL) was
added and the mixture was acidified with aqueous 5%
HCl. Extraction with CH2Cl2 afforded an oily crude
material (303 mg) that was purified by flash chromatog-
raphy using hexane/ethyl acetate (4:1) as eluent to yield
263 mg (0.86 mmol, 87%) of (+)-15 as a white solid: mp
104–106°C (ether/pentane); [h]2D0=+24.4 (c 2.1, CHCl3);
IR (KBr) 3472, 3036, 2894, 1496, 1458, 1399, 1251,
1
1196, 1112, 1032, 1006, 960, 775, 703 cm−1; H NMR l
7.45–7.25 (m, 6H), 7.25–7.10 (m, 4H), 6.28 (m, 2H),
6.17 (m, 2H), 4.85 (s, 2H), 4.49 (br d, J=9.5 Hz, 1H),
2.21 (d, J=9.5 Hz, 1H); 13C NMR l 136.0, 133.4,
128.5, 128.2, 126.7, 126.6, 99.4, 85.6, 85.5, 62.4; MS
m/z (CI/NH3) 324 (M++18, 21), 214 (100), 197 (76).
Anal. calcd for C20H18O3: C, 78.41; H, 5.92. Found: C,
78.41; H, 6.05.
4.6. (2R,3R)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decan-8-ol,
(+)-16
To a solution of (+)-12 (134 mg, 0.43 mmol) in
methanol (10 mL) at 0°C, NaBH4 (17 mg, 0.43 mmol)
was added in small portions. The mixture was allowed
to react at 0°C for 15 min. The solvent was removed,
water (2 mL) was added and the mixture was acidified
with aqueous 5% HCl. Extraction with CH2Cl2
afforded an oily crude material (134 mg) that was
purified by flash chromatography using hexane/ether
(1:1) as eluent to yield 122 mg (0.39 mmol, 91%) of
(+)-1623 as a white solid: mp 80–83°C (ether/pentane);
[h]2D0=+44.4 (c 1.2, CHCl3); IR (KBr) 3286, 2954, 2932,
1
934, 759, 702 cm−1; H NMR l 7.25–7.10 (m, 10H),
4.81 (s, 2H), 2.62 (br t, J=6.9 Hz, 4H), 2.29 (m, 4H);
13C NMR l 209.9, 136.1, 128.5, 126.6, 107.8, 85.4, 38.0,
35.2; MS m/z (CI/NH3) 326 (M++18, 100), 309 (M++1,
13), 103 (31), 86 (25). Anal. calcd for C20H20O3: C,
77.90; H, 6.54. Found: C, 78.19; H, 6.61. (+)-13: [h]2D0=
+18.5 (c 0.3, CHCl3); IR (film) 3066, 3036, 2971, 2930,
1
2876, 1453, 1368, 1127, 1034, 938, 764, 702 cm−1; H
NMR l 7.40–7.10 (m, 10H), 4.75 (d, J=8.6 Hz, 1H),
4.71 (d, J=8.6 Hz, 1H), 3.87 (br s, 1H), 2.25–1.70 (m,
9H); 13C NMR l 136.8, 128.4, 128.3, 126.7, 126.7,
109.1, 85.2, 68.1, 33.1, 32.9, 32.0, 31.8; MS m/z (CI/
NH3) 311 (M++1, 6), 214 (100). Anal. calcd for
C20H22O3: C, 77.39; H, 7.14. Found: C, 77.20; H, 7.21.
1
2883, 1451, 1374, 1261, 1126, 1054, 982, 700 cm−1; H
NMR l 7.35–7.12 (m, 10H), 4.73 (s, 2H), 3.49 (q,
J=7.3 Hz, 4H), 1.99 (s, 8H), 1.18 (t, J=7.3 Hz, 6H);
13C NMR l 136.9, 128.4, 128.2, 126.6, 109.5, 99.2, 85.1,
55.4, 32.9, 30.6, 15.5; MS m/z (CI/NH3) 337 (M+−EtO,
76), 141 (100). Anal. calcd for C24H30O4: C, 75.36; H,
7.91. Found: C, 75.29; H, 8.01. (+)-14: mp 154–155°C
(CH2Cl2); [h]2D0=+13.3 (c 0.5, acetone); IR (KBr) 3571,
3522, 3058, 3030, 2889, 1511, 1230, 1166, 1026, 780, 702
4.7. Bromination reaction of (+)-8
(a) To a solution of (+)-8 (100 mg, 0.33 mmol) at 0°C,
a 0.1 M solution of bromine in CH2Cl2 (5 mL, 0.50
mmol) was added. The mixture was allowed to react at
0°C for 15 min and triethylamine (95 mL, 0.66 mmol)
was added. After 1 h at room temperature, ether was
added and the mixture was washed successively with
water, 1 M HCl, saturated aqueous NaHCO3 and
saturated aqueous NaCl. Flash chromatography of the
oily crude material (129 mg) using hexane/CH2Cl2 (3:2)
as eluent afforded the following fractions: (i) 35 mg
(0.08 mmol, 24%) of (2R,3R)-7,9-dibromo-2,3-
diphenyl-1,4-dioxaspiro[4.5]deca-6,9-dien-8-one, (+)-18,
as a white solid; and (ii) 93 mg (0.24 mmol, 73%) of
(2R,3R)-7-bromo-2,3-diphenyl-1,4-dioxaspiro[4.5]deca-
6,9-dien-8-one, (+)-17, as a white solid. (b) To a solu-
tion of (+)-8 (298 mg, 0.98 mmol) in CH2Cl2 (2 mL) at
0°C, a 0.089 M solution of bromine in CH2Cl2 (6 mL,
0.54 mmol) was added. The mixture was allowed to
1
cm−1; H NMR l 7.30–6.93 (m, 10H), 6.71 (d, J=8.8
Hz, 2H), 6.60 (d, J=8.8 Hz, 2H), 4.95 (d, J=7.9 Hz,
1H), 4.86 (d, J=7.9 Hz, 1H), 4.62 (s, 1H), 3.40 (s, 1H);
13C NMR l 151.7, 150.1, 138.6, 137.3, 128.1, 128.0,
127.9, 127.4, 126.9, 117.6, 116.0, 86.6, 78.7; MS m/z
(CI/NH3) 324 (M++18, 42), 306 (M+, 2), 289 (26), 214
(100), 197 (45). Anal. calcd for C20H18O3: C, 78.41; H,
5.92. Found: C, 78.37; H, 6.01.
4.5. (2R,3R)-2,3-Diphenyl-1,4-dioxaspiro[4.5]deca-6,9-
dien-8-ol, (+)-15
To a solution of (+)-8 (300 mg, 0.99 mmol) in methanol
(2.5 mL) and CH2Cl2 (2.5 mL) at 0°C, NaBH4 (38 mg,
0.97 mmol) was added in small portions. The mixture

2028
F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
react at 0°C for 15 min and triethylamine (102 mL, 0.75
mmol) was added. After 1 h at room temperature, ether
was added and the mixture was washed successively
with water, 1 M HCl, saturated aqueous NaHCO3 and
saturated aqueous NaCl. Flash chromatography of the
oily crude material (329 mg) using hexane/CH2Cl2 (3:2)
as eluent afforded the following fractions: (i) 12 mg
(0.026 mmol, 3%) of (+)-18 as a white solid; (ii) 182 mg
(0.47 mmol, 49%) of (+)-17 as a white solid; and (iii)
129 mg (43%) of starting (+)-8. Considering the recov-
ered material, the yield of (+)-17 is 86%. (+)-17: mp
119–121°C (CH2Cl2/pentane); [h]2D0=+49.2 (c 1.0,
CH2Cl2); IR (KBr) 3034, 2923, 2854, 1683, 1610, 1454,
1327, 1274, 1208, 1127, 1011, 987, 951, 816, 767, 699
(s, 2H), 7.40–7.30 (m, 6H), 7.25–7.10 (m, 4H), 4.91 (s,
2H); 13C NMR l 152.7, 134.2, 129.2, 128.8, 126.6,
101.4, 99.6, 86.0; MS m/z (CI/NH3) 574 (M++18, 0.2),
557 (M++1, 0.6), 214 (100), 197 (47), 196 (47). Anal.
calcd for C20H14I2O3: C, 43.19; H, 2.54. Found: C,
43.29; H, 2.51.
4.9. Reaction between (+)-8 and formaldehyde
A solution of (+)-8 (207 mg, 0.68 mmol), 4-dimethyl-
aminopyridine (29 mg, 0.24 mmol) and 35–40%
aqueous formaldehyde (175 mL, 2.3 mmol) in THF (4
mL) was heated at the reflux temperature for 7 days in
a vessel under nitrogen atmosphere provided with a
balloon. The solvent was removed and the oily crude
material (354 mg) was purified by flash chromatogra-
phy using CH2Cl2/ether (9:1) as eluent affording the
following fractions: (i) 14 mg (7%) of starting (+)-8; (ii)
54 mg (0.16 mmol, 24%) of (2R,3R)-7-hydroxymethyl-
2,3-diphenyl-1,4-dioxaspiro[4.5]deca-6,9-dien-8-one, (+)-
21, as a colorless oil; and (iii) 117 mg (0.32 mmol, 47%)
of (2R,3R) - 7,9 - di(hydroxymethyl) - 2,3 - diphenyl - 1,4-
dioxaspiro[4.5]deca-6,9-dien-8-one, (+)-22, as a white
solid. Considering the recovered starting material, the
yields of (+)-21 and (+)-22 are 25% and 51%, respec-
1
cm−1; H NMR l 7.39 (d, J=2.9 Hz, 1H), 7.37–7.30
(m, 6H), 7.27–7.15 (m, 4H), 6.97 (dd, J=10.0, 2.9 Hz,
1H), 6.40 (d, J=10.0 Hz, 1H), 4.93 (s, 2H); 13C NMR
l 177.8, 144.2, 144.0, 134.6, 129.0, 128.8, 127.6, 126.6,
125.6, 100.1, 86.1, 86.0; MS m/z (CI/NH3) 402–400
(M++18, 43, 44), 214 (100). Anal. calcd for C20H15BrO3:
C, 62.68; H, 3.95. Found: C, 62.83; H, 3.92. (+)-18: mp
192–195°C (CH2Cl2/pentane); [h]2D0=+36.0 (c 1.3,
CH2Cl2); IR (KBr) 3056, 3037, 2922, 1694, 1604, 1452,
1
1310, 1261, 1126, 1003, 758, 700 cm−1; H NMR l 7.38
(s, 2H), 7.37–7.30 (m, 6H), 7.25–7.15 (m, 4H), 4.91 (s,
2H); 13C NMR l 171.7, 144.6, 134.1, 129.2, 128.8,
126.6, 123.2, 101.0, 86.1; MS m/z (CI/NH3) 482-480-
478 (M++18, 2, 3, 2), 214 (100). Anal. calcd for
C20H14Br2O3: C, 51.98; H, 3.05. Found: C, 51.82; H,
3.13.
1
tively. (+)-21: [h]D20=+56.0 (c 2.0, CHCl3); H NMR l
7.40–7.28 (m, 6H:Har), 7.27–7.17 (m, 4H), 7.00–6.90 (m,
2H), 6.26 (d, J=9.7 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H),
4.92 (d, J=8.7 Hz, 1H), 4.44 (d, J=1.3 Hz, 2H); 13C
NMR l 185.8, 144.1, 138.4, 138.0, 135.0, 134.9, 129.0,
128.9, 128.87, 128.83, 128.6, 126.7, 126.6, 99.0, 86.0,
85.8, 60.2; MS m/z (CI/NH3) 352 (M++18, 1), 335
(M++1, 13), 317 (60), 228 (100), 214 (38), 197 (45), 91
(28); HRMS (FAB) calcd for (M+1)+ C21H19O4:
335.1282. Found: 335.1274. (+)-22: mp 204–206°C
(THF/pentane); [h]2D0=+65.2 (c 0.7, THF); IR (KBr)
3347 (br), 3067, 3041, 2907, 2880, 1691, 1654, 1454,
1308, 1186, 1088, 1024, 994, 977, 910, 751, 697 cm−1; 1H
NMR l 7.40–7.30 (m, 6H), 7.25–7.15 (m, 4H), 6.95 (s,
4.8. Iodination reaction of (+)-8
To a solution of (+)-8 (101 mg, 0.33 mmol) in CCl4 (2
mL) and pyridine (1 mL) at 0°C, iodine (200 mg, 0.78
mmol) was added. The mixture was allowed to react at
room temperature for 3 h. Ether (10 mL) was added
and the mixture was washed successively with water, 1
M HCl, water (twice), and 20% aqueous Na2S2O3.
Flash chromatography of the solid crude material (188
mg) using hexane/ether (15:1) as eluent afforded the
following fractions: (i) 77 mg (0.14 mmol, 42%) of
(2R,3R)-7,9-diiodo-2,3-diphenyl-1,4-dioxaspiro[4.5]deca-
6,9-dien-8-one, (+)-20, as a white solid; (ii) 64 mg (0.15
mmol, 45%) of (2R,3R)-7-iodo-2,3-diphenyl-1,4-dioxas-
piro[4.5]deca-6,9-dien-8-one, (+)-19, as a white solid;
and (iii) 13 mg (13%) of starting (+)-8. Considering the
recovered material, the yield of (+)-20 is 48% and that
of (+)-19 is 52%. (+)-19: mp 130–131°C; [h]2D0=+45.0 (c
1.7, CHCl3); IR (KBr) 3037, 2917, 1680, 1602, 1455,
1
2H), 4.94 (s, 2H), 4.45 (br s, 4H); H NMR (d6-DMSO)
l 7.40 (br s, 10H), 7.08 (s, 2H), 5.21 (t, J=5.5 Hz, 2H),
5.18 (s, 2H), 4.25 (d, J=5.5 Hz, 4H); 13C NMR l
186.4, 139.1, 138.0, 134.9, 128.9, 128.7, 126.7, 99.2,
85.9, 60.3; 13C NMR (d6-DMSO) l 185.0, 138.8, 138.0,
135.1, 128.8, 128.5, 127.3, 99.1, 84.5, 57.1; MS m/z
(CI/NH3) 382 (M++18, 1), 365 (M++1, 3), 317 (44), 258
(22), 214 (100), 197 (20). Anal. calcd for C22H20O5: C,
72.51; H, 5.53. Found: C, 72.30; H, 5.51.
4.10. Ethyl 2-[(2R,3R)-8-hydroxy-2,3-diphenyl-1,4-dioxa-
spiro[4.5]deca-6,9-dien-8-yl]acetate, (+)-23
1
1321, 1279, 1124, 1029, 1005, 815, 759, 695 cm−1; H
To a suspension of recently opened 99.99% indium
powder (0.57 g, 4.93 mmol) in freshly distilled DMF (6
mL) under nitrogen atmosphere, ethyl iodoacetate (0.78
mL, 6.57 mmol) was added dropwise over 5 min. The
resulting hot solution was allowed to cool down to
room temperature and stirred for 30 min. Ketal (+)-8
(1.00 g, 3.29 mmol) was added in portions over 5 min
and the solution stirred at the same temperature for 5
h. Then it was added to a stirred mixture of ethyl
acetate (100 mL) and water (10 mL) and stirring was
maintained for 15 min. The supernatant liquid was
decanted and the remaining gelatinous solid was
NMR l 7.70 (d, J=2.9 Hz, 1H), 7.40–7.27 (m, 6H),
7.25–7.15 (m, 4H), 6.96 (dd, J=9.9, 2.9 Hz, 1H), 6.41
(d, J=9.9 Hz, 1H), 4.93 (d, J=8.8 Hz, 1H), 4.89 (d,
J=8.8 Hz, 1H); 13C NMR l 178.6, 152.2, 144.0, 134.5,
129.0, 128.7, 126.6, 126.3, 105.5, 99.8, 86.0, 85.9; MS
m/z (CI/NH3) 448 (M++18, 7), 431 (M++1, 4), 324 (74),
214 (100), 200 (46), 197 (98), 169 (40), 141 (45). Anal.
calcd for C20H15IO3: C, 55.83; H, 3.51. Found: C,
55.87; H, 3.55. (+)-20: mp 233–236°C (CH2Cl2/pen-
tane); [h]2D0=+28.3 (c 0.6, CHCl3); IR (KBr) 3037, 2924,
1
1680, 1314, 1124, 998, 752, 702 cm−1; H NMR l 7.78

F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2029
washed with ethyl acetate (2×20 mL). The joined
organic phases were mixed with water (30 mL) and
stirred vigorously for 20 min. The aqueous phase was
again washed with ethyl acetate (25 mL). Flash chro-
matography of the oily crude material (1.93 g) using
hexane/ethyl acetate (4:1) as eluent afforded (+)-23
(1.21 g, 3.08 mmol, 94%) as a colorless oil: [h]2D0=+11.8
(c 3.7, CHCl3); IR (film) 3452 (br), 3034, 2981, 1731,
white solid; and (iii) 23 mg of an unidentified solid
material. Repeated chromatography allowed the isola-
tion of 60 mg (0.17 mmol, 52%) of (+)-26: mp 64–66°C
(ether/pentane); [h]D20=+2.4 (c 1.7, CHCl3); IR (KBr)
3403 (br), 3033, 2957, 2929, 2886, 1453, 1396, 1190,
1
1140, 1092, 1049, 1019, 980, 760, 698 cm−1; H NMR l
7.30–7.26 (m, 6H), 7.23–7.15 (m, 4H), 6.05 (d, J=10.0
Hz, 1H), 5.91 (dd, J=10.0, 1.5 Hz, 1H), 4.77 (d, J=8.4
Hz, 1H:H), 4.68 (d, J=8.4 Hz, 1H), 4.26 (dd, J=11.3,
5.5 Hz, 1H), 4.19–4.08 (m, 2H), 2.46 (ddd, J=13.2, 5.5,
1.5 Hz, 1H), 2.25 (s, 1H), 2.15–1.97 (m, 3H); 13C NMR
l 135.9, 133.1, 129.0, 128.54, 128.51, 128.45, 126.9,
126.63, 126.57, 106.4, 85.42, 85.36, 83.4, 78.0, 67.7,
40.4, 38.2; MS m/z (CI/NH3) 368 (M++18, 12), 351
(M++1, 20), 214 (100), 172 (66). 27 (ca. 92:8 mixture of
1
1454, 1412, 1202, 1162, 1117, 1015, 699 cm−1; H NMR
l 7.40–7.27 (m, 6H), 7.25–7.15 (m, 4H), 6.26 (d, J=
10.2 Hz, 2H), 6.13 (m, 2H), 4.86 (d, J=8.0 Hz, 1H),
4.81 (d, J=8.0 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 3.62
(br s, 1H), 2.63 (s, 2H), 1.26 (t, J=7.3 Hz, 3H); 13C
NMR l 171.3, 136.0, 135.32, 135.26, 128.5, 128.4,
128.1, 128.0, 127.8, 127.35, 127.29, 126.8, 126.5, 99.3,
85.6, 85.5, 66.1, 60.9, 44.8, 14.1; MS m/z (CI/NH3) 393
(M++1, 4), 214 (100), 199 (27), 197 (78). Anal. calcd for
C24H24O5: C, 73.45; H, 6.16. Found: C, 72.97; H, 6.45.
1
27 and 26): H NMR l 7.35–7.26 (m, 6H), 7.23–7.15
(m, 4H), 6.00 (s, 2H), 4.81 (d, J=8.5 Hz, 1H), 4.75 (d,
J=8.5 Hz, 1H), 4.32 (dd, J=9.5, 5.0 Hz, 1H), 4.11 (dd,
J=8.5, 6.7 Hz, 1H), 4.09 (dd, J=8.5, 4.7 Hz, 1H), 2.51
(dd, J=13.6, 5.0 Hz, 1H), 2.18–2.04 (m, 3H), 1.87 (s,
1H); 13C NMR l 136.2, 136.1, 133.4, 129.8, 128.54,
128.47, 128.43, 126.7, 105.8, 85.5, 85.4, 82.6, 77.2, 67.4,
40.0, 38.7; MS m/z (CI/NH3) 368 (M++18, 6), 351
(M++1, 20), 214 (100), 172 (58). Mixture of 26 and 27.
Anal. calcd for C22H22O4: C, 75.41; H, 6.33. Found: C,
75.34; H, 6.38.
4.11. (2R,3R)-8-(2-Hydroxy)ethyl-2,3-diphenyl-1,4-dioxa-
spiro[4.5]deca-6,9-dien-8-ol, (+)-25
To a solution of (+)-23 (200 mg, 0.51 mmol) in anhy-
drous THF (2 mL) at 0°C, a 2 M solution of LiBH4 in
THF (250 mL, 0.50 mmol) was added. The mixture was
allowed to react at the same temperature for 4 d. A few
drops of water were added, the mixture was filtered
through Celite and the solvent was removed. Flash
chromatography of the solid crude material (179 mg)
using hexane/ethyl acetate (2:1) as eluent afforded the
following fractions: (i) 10 mg (0.03 mmol, 6%) of
(+)-15; and (ii) 167 mg (0.48 mmol, 94%) of (+)-25 as a
white solid: mp 41–43°C (ethyl acetate/hexane); [h]2D0=
+14.2 (c 2.5, CHCl3); IR (KBr) 3386 (br), 3033, 2888,
1496, 1454, 1411, 1201, 1119, 1076, 1040, 1015, 965, 699
cm−1; 1H NMR l 7.40–7.25 (m, 6H), 7.25–7.10 (m, 4H),
6.24 (d, J=10.2 Hz, 2H), 6.19–6.08 (m, 2H), 4.86 (d,
J=8.5 Hz, 1H), 4.81 (d, J=8.5 Hz, 1H), 3.80 (q, J:5.7
Hz, 2H), 2.34 (t, J=5.7 Hz, 1H), 2.28 (br s, 1H), 1.94
(t, J=5.8 Hz, 2H); 13C NMR l 136.8, 136.7, 135.9,
128.5, 127.5, 127.4, 126.7, 126.6, 99.5, 85.7, 85.5, 68.2,
59.3, 42.0; MS m/z (CI/NH3) 351 (M++1, 1), 315 (11),
199 (84), 155 (20), 137 (100); HRMS (FAB) calcd for
(M+1)+ C22H23O4: 351.1596. Found: 351.1593.
4.13. (3aS,7aS)-3a-Hydroxy-3,3a,7,7a-tetrahydrobenzo-
furan-6(2H)-one, (+)-rengyolone, (+)-1
A mixture of (+)-26 (40 mg, 0.11 mmol) and montmo-
rillonite K-10 (200 mg) in CH2Cl2 (1 mL) was stirred at
room temperature for 22 h. The mixture was filtered
and the solvent was removed. Flash chromatography of
the crude material (30 mg) using hexane/ethyl acetate
(1:1) as eluent yielded the following fractions: (i) 16 mg
(0.07 mmol, 65%) of (R,R)-hydrobenzoin; and (ii) 8 mg
(0.05 mmol, 45%) of (+)-rengyolone, (+)-1, as a white
solid with ee (CGC and NMR)=85%: mp 60–62°C;
[h]2D0=+48.6 (c 0.3, MeOH); 1H NMR l 6.74 (dd,
J=10.2, 1.3 Hz, 1H), 6.00 (d, J=10.2 Hz, 1H), 4.22
(ddd, J=5.7, 4.7, 1.3 Hz, 1H), 4.06 (td, J:8.5, 6.5 Hz,
1H), 3.93 (td, J:8.5, 6.5 Hz, 1H), 2.76 (dd, J=16.9,
4.7 Hz, 1H), 2.58 (dd, J=16.9, 5.7 Hz, 1H), 2.32 (s,
1H), 2.31 (ddd, J=13.0, 8.5, 6.5 Hz, 1H), 2.18 (ddd,
J=13.0, 8.5, 6.5 Hz, 1H); 13C NMR l 196.5, 147.6,
128.9, 81.7, 75.8, 66.2, 40.2, 39.6.
4.12. (3aS,7aS,4%R,5%R)-4%,5%-Diphenyl-3,3a,7,7a-tetra-
hydrospiro[benzofuro-6(2H),2%-[1,3]dioxolan]-3a-ol, (+)-
26, and its (3aR,7aR,4%R,5%R)-isomer, 27
4.14. 2-[(2R,3R)-8-Hydroxy-2,3-diphenyl-1,4-dioxaspiro-
[4.5]deca-6,9-dien-8-yl]acetic acid, (+)-28
To a solution of (+)-25 (116 mg, 0.33 mmol) in dry
DME (6.5 mL) at room temperature, mercuric trifl-
uoroacetate (176 mg, 0.40 mmol) in dry DME (2.5 mL)
was added. The mixture was allowed to react at the
same temperature for 2 h. A solution of NaBH4 (41 mg,
1.05 mmol) in 1.2 M aqueous NaOH (2.6 mL) was
added and the reaction mixture was stirred at room
temperature for 5 min. The mixture was filtered, the
solid was washed with ether and the organic solution
was washed with water. Flash chromatography of the
oily crude material (118 mg) using hexane/ether (1:1) as
eluent yielded the following fractions: (i) 13 mg (0.04
mmol, 12%) of (+)-26 as a white solid; (ii) 77 mg (0.22
mmol, 66%) of a ca 1.5:1 mixture of (+)-26 and 27 as a
To a solution of (+)-23 (97 mg, 0.25 mmol) in ethanol
(1 mL), a 2.6 M aqueous solution of KOH (0.7 mL, 1.8
mmol) was added. The mixture was allowed to react at
room temperature for 5 h and 5% HCl was added until
pH=2. The solution was extracted with chloroform
and the organic phase was washed with water. Flash
chromatography of the oily crude material (82 mg)
using hexane/ethyl acetate (2:1) as eluent yielded 76 mg
(0.21 mmol, 84%) of (+)-28 as a white solid: mp 121–
123°C (ethyl acetate/hexane); [h]2D0=+14.8 (c 1.2,
CHCl3); IR (KBr) 3370, 3062, 3033, 1709, 1687, 1420,
1
1274, 1171, 1119, 1075, 1020, 994, 971, 697 cm−1; H

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F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
NMR l 7.40–7.26 (m, 6H), 7.23–7.15 (m, 4H), 6.25 (d,
J=10.4 Hz, 2H), 6.15 (m, 2H), 4.85 (d, J=8.7 Hz, 1H),
4.81 (d, J=10.4 Hz, 1H), 2.67 (s, 2H); 13C NMR l
174.7, 135.8, 134.9, 134.8, 128.6, 128.5, 128.4, 128.3,
126.8, 126.6, 99.1, 85.7, 85.5, 66.0, 44.6; MS m/z (CI/
NH3) 382 (M++18, 11), 214 (67), 199 (21), 198 (56), 197
(100). Anal. calcd for C22H20O5: C, 72.51; H, 5.53.
Found: C, 72.33; H, 5.54.
4.16. (7aS,4%R,5%R)-4%,5%-Diphenyl-7,7a-dihydrospiro-
[benzofuro-6(2H),2%-[1,3]dioxolan]-2-one, (−)-31
A solution of (+)-29 (176 mg, 0.48 mmol) and freshly
distilled thionyl chloride (98 mL, 1.35 mmol) in pyridine
(2 mL) was allowed to react at room temperature for 30
min. Ethyl acetate was added and the mixture was
washed successively with water, saturated aqueous
NaHCO3 and twice with water. Flash chromatography
of the oily crude material (167 mg) using hexane/ethyl
acetate (4:1) as eluent yielded 141 mg (0.41 mmol, 84%)
of (−)-31 as a white solid: mp 154–156°C (ethyl acetate/
hexane); [h]2D0=−96.6 (c 4.7, CHCl3); IR (KBr) 3033,
2958, 2924, 2897, 1785, 1758, 1199, 1095, 1058, 1020,
4.15. (3aS,7aS,4%R,5%R)-3a-Hydroxy-4%,5%-diphenyl-
3,3a,7,7a-tetrahydrospiro[benzofuro-6(2H),2%-
[1,3]dioxolan]-2-one, (+)-29, and its
(3aR,7aR,4%R,5%R)-isomer, (+)-30
1
(a) A solution of (+)-28 (271 mg, 0.74 mmol) and
trifluoroacetic acid (13 mL, 0.17 mmol) in chloroform
(14 mL) was allowed to react at room temperature for
2 days. The mixture was washed with water and
extracted with chloroform. Flash chromatography of
the oily crude material (280 mg) using hexane/ether
(1:1) as eluent yielded the following fractions: (i) 163
mg (0.45 mmol, 60%) of (+)-29 as a white solid; and (ii)
77 mg (0.21 mmol, 28%) of (+)-30 as a white solid
contaminated with ca. 7% of (+)-29 by NMR analysis.
(b) A solution of (+)-28 (40 mg, 0.11 mmol) and
mercuric trifluoroacetate (12 mg, 0.03 mmol) in CH2Cl2
(0.7 mL) was allowed to react at room temperature for
1 day. Saturated aqueous NaHCO3 (1 mL) was added
and after 5 min of stirring the mixture was extracted
with CH2Cl2. Flash chromatography of the crude mate-
rial (43 mg) using hexane/ether (1:1) as eluent yielded
the following fractions: (i) 12 mg (0.03 mmol, 30%) of
(+)-29 as a white solid; and (ii) 18 mg (0.05 mmol, 45%)
of (+)-30 as a white solid contaminated with ca. 7% of
(+)-29 by NMR analysis. (+)-29: mp 155–156°C (ether/
pentane); [h]2D0=+15.6 (c 1.0, CHCl3); IR (KBr) 3514
(br), 3036, 2978, 2902, 1774, 1295, 1174, 1092, 1053,
700 cm−1; H NMR l 7.37–7.26 (m, 6H), 7.23–7.10 (m,
4H), 6.74 (d, J=9.7 Hz, 1H), 6.31 (dd, J=9.7, 1.3 Hz,
1H), 5.92 (dd, J:1.8, 0.8 Hz, 1H), 5.24 (ddd, J=12.6,
5.2, 1.8 Hz, 1H), 4.85 (d, J=8.5 Hz, 1H), 4.77 (d,
J=8.5 Hz, 1H), 2.98 (dddd, J=12.0, 5.2, 1.3, 0.8 Hz,
1H), 2.17 (t, J:12.3 Hz, 1H); 13C NMR l 172.8, 161.8,
138.0, 135.1, 135.0, 128.8, 128.6, 126.7, 126.6, 121.8,
113.3, 105.6, 85.8, 85.2, 78.1, 41.8; MS m/z (CI/NH3)
364 (M++18, 72), 347 (M++1, 100). Anal. calcd for
C22H18O4: C, 76.29; H, 5.24. Found: C, 76.15; H, 5.14.
4.17. (7aR,4%R,5%R)-4%,5%-Diphenyl-7,7a-dihydrospiro-
[benzofuro-6(2H),2%-[1,3]dioxolan]-2-one, (+)-33
A solution of (+)-30 (166 mg, 0.46 mmol) and freshly
distilled thionyl chloride (94 mL, 1.29 mmol) in pyridine
(2 mL) was allowed to react at room temperature for 15
min. Ethyl acetate was added and the mixture was
washed successively with water, saturated aqueous
NaHCO3 and twice with water. Flash chromatography
of the solid crude material (192 mg) using hexane/ethyl
acetate (4:1) as eluent yielded 141 mg (0.41 mmol, 89%)
of (+)-33 as a white solid: mp 160–163°C (ethyl acetate/
hexane); [h]2D0=+222.8 (c 4.3, CHCl3); IR (KBr) 3062,
1
1014, 700 cm−1; H NMR l 7.40–7.26 (m, 6H), 7.24–
1
7.08 (m, 4H), 6.04 (dd, J=10.0, 1.2 Hz, 1H), 5.98 (d,
J=10.0 Hz, 1H), 4.80 (d, J=8.5 Hz, 1H), 4.73 (dd,
J=11.9, 5.4 Hz, 1H), 4.69 (d, J=8.5 Hz, 1H), 2.75 (d,
J=17.8 Hz, 1H), 2.69 (ddd, J=13.2, 5.4, 1.2 Hz, 1H),
2.66 (d, J=17.8 Hz, 1H), 2.51 (br s, 1H), 2.09 (dd,
J=13.2, 11.9 Hz, 1H); 13C NMR l 174.2, 135.4, 135.3,
131.2, 130.5, 128.8, 128.7, 128.6, 126.9, 126.5, 104.9,
85.64, 85.56, 83.9, 74.0, 40.9, 39.6; MS m/z (CI/NH3)
382 (M++18, 100), 214 (29), 197 (28). Anal. calcd for
C22H20O5: C, 72.51; H, 5.53. Found: C, 72.10; H, 5.43.
(+)-30 (ca. 93:7 mixture of 30 and 29): mp 103–106°C
(ether/pentane); [h]D20=+18.0 (c 1.0, CHCl3); IR (KBr)
3428 (br), 3034, 2926, 1785, 1178, 1130, 1057, 1025, 699
cm−1; 1H NMR l 7.40–7.26 (m, 6H), 7.23–7.10 (m, 4H),
6.04 (dd, J=10.0, 1.0 Hz, 1H), 5.89 (d, J=10.0 Hz,
1H), 4.81 (d, J=8.5 Hz, 1H), 4.79 (dd, J=10.5, 5.2 Hz,
1H), 4.73 (d, J=8.5 Hz, 1H), 3.20 (br s, 1H), 2.75 (d,
J=17.8 Hz, 1H), 2.68 (ddd, J=13.4, 5.2, 1.0 Hz, 1H),
2.64 (d, J=17.8 Hz, 1H), 2.13 (dd, J=13.4, 10.5 Hz,
1H); 13C NMR l 174.2, 135.5, 131.6, 130.8, 128.7,
128.62, 128.57, 128.51, 126.6, 126.5, 104.4, 85.6, 85.4,
83.2, 73.3, 41.3, 39.0; MS m/z (CI/NH3) 382 (M++18,
6), 364 (M+, 25), 214 (100), 172 (64), 112 (21), 78 (24),
74 (64). Anal. calcd for C22H20O5: C, 72.51; H, 5.53.
Found: C, 72.21; H, 5.45.
3031, 2924, 2900, 1784, 1757, 1195, 1031, 701 cm−1; H
NMR l 7.37–7.26 (m, 6H), 7.23–7.15 (m, 4H), 6.72 (d,
J=9.9 Hz, 1H), 6.43 (dd, J=9.9, 1.4 Hz, 1H), 5.92 (dd,
J:1.8, 1.0 Hz, 1H), 5.30 (ddd, J=12.7, 5.0, 1.8 Hz,
1H), 4.91 (d, J=8.6 Hz, 1H), 4.86 (d, J=8.6 Hz, 1H),
3.06 (dddd, J=11.8, 5.0, 1.4, 0.9 Hz, 1H), 2.16 (dd,
J=12.7, 11.8 Hz, 1H); 13C NMR l 172.7, 161.7, 138.5,
135.4, 135.2, 128.8, 128.7, 128.64, 128.58, 126.6, 126.4,
122.0, 113.4, 105.5, 86.1, 85.7, 77.7, 42.6; MS m/z
(CI/NH3) 364 (M++18, 100), 347 (M++1, 93). Anal.
calcd for C22H18O4: C, 76.29; H, 5.24. Found: C, 76.64;
H, 5.09.
4.18. (S)-6-Oxo-7,7a-dihydrobenzofuran-2(6H)-one, (−)-
32
A mixture of (−)-31 (127 mg, 0.37 mmol) and montmo-
rillonite K-10 (725 mg) in CH2Cl2 (3.5 mL) was heated
at the reflux temperature for 6 d. The mixture was
filtered and the solvent was removed. Flash chromatog-
raphy of the solid crude material (125 mg) using hex-
ane/ethyl acetate (4:1) as eluent afforded the following
fractions: (i) 65 mg of a mixture of 2-benzyl-2,4,5-
triphenyl-1,3-dioxolane and diphenylacetaldehyde, both
compounds derived from hydrobenzoin; (ii) 14 mg (0.04

F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
2031
mmol, 11%) of starting (−)-31; and (iii) 24 mg (0.16
References
mmol, 44%) of (−)-32 as a white solid. Considering the
recovered (−)-31 the yield of (−)-32 is 49%. (−)-32: mp
109–111°C (ethyl acetate/hexane) (lit.32b ( )-32: 104–
106°C (MeOH)); [h]D20=−207.4 (c 1.2, acetone); 1H
NMR l 7.51 (d, J=9.9 Hz, 1H), 6.32 (d, J=9.9 Hz,
1H), 6.19 (br s, 1H), 5.28 (ddd, J=12.2, 6.4, 2.0 Hz,
1H), 3.35 (dd, J=15.4, 6.4 Hz, 1H), 2.58 (dd, J=15.4,
12.2 Hz, 1H:H7).
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4.19. (R)-6-Oxo-7,7a-dihydrobenzofuran-2(6H)-one, (+)-
32
A mixture of (+)-33 (103 mg, 0.30 mmol) and montmo-
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the reflux temperature for 1 day. The mixture was
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MeOH); H NMR l 6.54 (dd, J=9.9, 2.5 Hz, 1H), 6.29
(dt, J=9.9, 1.7 Hz, 1H:H4), 5.79 (br s, 1H), 4.85 (ddd,
J=13.4, 4.9, 1.8 Hz, 1H), 4.62 (m, 1H), 2.89 (m, 1H),
2.23 (br d, J=6.4 Hz, 1H), 1.65 (ddd, J=13.4, 11.0,
10.4 Hz, 1H); 13C NMR l 173.5, 163.0, 143.6, 119.9,
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4.21.(6S,7aR)-6-Hydroxy-7,7a-dihydrobenzofuran-2(6H)-
one, (−)-menisdaurilide, (−)-2
Following the method described by Mori et al.,32b
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determined with the assistance of perdeuterated Pirkle
alcohol,31 in 63% yield: mp 106–108°C (CH2Cl2/pen-
tane) (lit.5 113°C, lit.6b 118–120°C, lit.6c 86°C, lit.6d
109–111°C); [h]20D −20.0 (c 0.4, MeOH) (lit.5 [h]2D0 −31.4
(c 1.00, MeOH), lit.6b [h]2D0=−28.9 (c 0.130, MeOH),
lit.6c [h]2D0 −30.6 (c 0.041, MeOH), lit.6d [h]2D0 −27.3 (c
0.307, MeOH)).
Acknowledgements
We gratefully acknowledge financial support of DGES
(project BQU2001-2600) and CIRIT (project 2001SGR
00178). We also thank Universitat Auto`noma de
Barcelona for a grant to S.R. and M.C. and the Gene-
ralitat de Catalunya for a grant to F.B.

2032
F. Busque´ et al. / Tetrahedron: Asymmetry 14 (2003) 2021–2032
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