A highly stereoselective divergent synthesis of bicyclic models of photoreactive sesquiterpene lactones

Article abstract of DOI:10.1002/ejoc.200600611

Sesquiterpene lactones are natural stereochemically pure compounds, which show a number of biological activities. In order to study the reactivity of sesquiterpene lactones in biological systems, we describe herein the asymmetric synthesis of a simple mod

Full text of DOI:10.1002/ejoc.200600611

FULL PAPER
DOI: 10.1002/ejoc.200600611
A Highly Stereoselective Divergent Synthesis of Bicyclic Models of
Photoreactive Sesquiterpene Lactones
Sébastien Fuchs,[a] Valérie Berl,*[a] and Jean-Pierre Lepoittevin[a]
Keywords: α-Methylene-γ-butyrolactones / Asymmetric synthesis / Palladium / Allylic substitution / Enantioselectivity /
Diastereoselectivity
Sesquiterpene lactones are natural stereochemically pure
compounds, which show a number of biological activities. In
order to study the reactivity of sesquiterpene lactones in bio-
logical systems, we describe herein the asymmetric synthesis
Enantioselectivity was obtained by asymmetric palladium-
catalyzed allylic substitution, and diastereoselectivity was
achieved by iodolactonization. This strategy afforded the dif-
ferent lactones with an enantiomeric excess of Ͼ98%.
of
a simple model, the α-methylene-hexahydrobenzofu-
ranone 1, which includes the α-methylene-γ-butyrolactone
moiety and presents all the different possible ring junctions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tis, one of the most extreme forms of photosensitivity,
which may develop after sensitization to sesquiterpene lac-
tones.[9]
Introduction
The α-methylene-γ-butyrolactone ring system is of great
interest and significance since this cyclic template is found
in many highly bioactive molecules and especially in sesqui-
terpene lactones (Figure 1). Sesquiterpene lactones are nat-
ural products, reported to have considerable biological ac-
tivities as allergenic agents,[1] growth inhibitors[2] and anti-
bacterial,[3] antiinflammatory[4] and antitumor agents.[5]
Previous work has shown that α,β-unsaturated carbonyl
systems such as an α-methylene-γ-butyrolactone, an α,β-un-
saturated cyclopentenone or a conjugated ester was re-
quired for significant activity. Indeed these structures have
been shown to react with nucleophiles, especially cysteine
sulfhydryl groups, by a Michael-type addition.[6] While the
cyclopentenone moiety reacts readily with glutathion
(GSH) and plays an important role in detoxification, the α-
methylene-γ-lactone seems to be very important in pharma-
cological activity.[1,5,6] More recently, we have shown that
α-methylene-γ-butyrolactones have an interesting photore-
activity potential and can form intramolecular photoad-
ducts with psoralens[7] and intra or intermolecular pho-
toadducts with thymine.[8] The intermolecular photochemi-
cal reaction gives [2+2] photocycloadducts involving the
5,6-double bond of the thymine and the exomethylenic un-
saturated bond of the lactone. This high photoreactivity of
sesquiterpene lactones towards thymine could explane ob-
served phototoxic reactions such as chronic actinic dermati-
Figure 1. Example of natural sesquiterpene lactones and structures
of the 4 models 1.
Sesquiterpene lactones are stereochemically pure com-
pounds, which present a cis or trans ring junction at the α-
methylene-γ-butyrolactone ring (Figure 1). The importance
of the ring junction has already been demonstrated for al-
lergic contact dermatitis[10] and is suspected in the photore-
activity of these molecules with DNA. In order to study the
reactivity of sesquiterpene lactones in biological systems, we
have developed a simple model, the α-methylene-hexahy-
dro-benzofuranone 1, which includes the α-methylene-γ-bu-
tyrolactone moiety and represents all the different possible
ring junctions (Figure 1). There are a number of synthetic
approaches to α-methylene-γ-butyrolactones, but few of
them are asymmetric.[11] A simple approach, used for many
years for the synthesis of α-methylene-γ-butyrolactones, has
been the synthesis of pure optically active lactones followed
[a] Laboratoire de Dermatochimie associé au CNRS, Université
Louis Pasteur, Clinique Dermatologique, CHU,
67091 Strasbourg Cedex, France
Fax: +33-3-88610414
E-Mail: vberl@chimie.u-strasbg.fr
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S. Fuchs, V. Berl, J.-P. Lepoittevin
FULL PAPER
by the introduction of the α-methylene moiety. Among the
different reports regarding the synthesis of optically active
lactones 2, the most efficient strategies are: i) the asymmet-
ric Baeyer–Villiger oxidation of cyclic ketones, which results
in a mixture of normal and abnormal lactones,[12] ii) the
biological reduction of γ- and δ-keto acids and their es-
ters[13] and iii) the enantioselective C–H bond insertion cat-
alyzed by rhodium(II).[14] Unfortunately, even if these stra-
tegies led to lactone 2 with the desired enantioselectivity
and diastereoselectivity, none of them gave access to the
four enantiomers in their pure form.
We describe herein an efficient divergent synthesis of the
four stereoisomers of 1 with high enantiomeric excess. The
key step of this strategy is based on a palladium-catalyzed
allylic asymmetric alkylation, followed by a directed iodo-
lactonization.
Results and Discussion
Scheme 2. Synthesis of the cis ring-junction models 1a and 1b. Rea-
gents and conditions: (a) NBS, AIBN, CCl4, ∆, 3 h; (b)
CH3COOH, NEt3, acetone, room temp., 14 h; (c) (C3H5PdCl)2,
(R,R)-10a or (S,S)-10b, CH2Cl2, NaCH(COOCH3)2, THAB, room
temp., 6 d; (d) NaCN, DMSO, ∆, overnight; (e) I2, KI, NaHCO3,
H2O, room temp., overnight; (f) nBu3SnH, AIBN, THF, ∆, 40 min.
(g)[11a] LDA, (SePh)2, HMPA, THF, –78 °C, 1 h, then –40 °C, 3 h;
(h)[11a] LDA, MeI, HMPA, THF, ether, –78–0 °C, 12 h; (i)[11a]
H2O2, CH3COOH, 0 °C, 40 min.
For the synthesis of 1, we used a divergent strategy as
described in the retrosynthetic analysis (Scheme 1). The
trans ring junction at the γ-butyrolactone ring is therefore
obtained from the cis one. The α-methylenation of the lac-
tone ring was performed in the last steps.
gand have been described with dicyclohexylcarbodiimide
(DCC) or 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide
(EDCI) as the coupling reagent. The literature reports
highly variable yields ranging from 30–90%, and a purifica-
tion by column chromatography on silica is generally neces-
sary. In our hands, when the reaction was conducted under
the conditions described by Trost and coworkers,[17] with
DCC as the coupling reagent and catalytic amounts of 4-
(dimethylamino)pyridine (DMAP), only poor yields were
obtained (41%), and a purification by column chromatog-
Scheme 1. Retrosynthetic scheme.
Obtention of the cis Ring-Junction γ-Butyrolactone
Enantioselectivity was obtained by the asymmetric palla- raphy on silica was necessary. More recently, Lloyd-Jones
dium-catalyzed allylic substitution of acetate 4 with di- and Stephen[18] described a modification of the Trost pro-
methyl malonate, and diastereoselectivity was achieved by cedure with EDCI, a water-soluble carbodiimide, instead of
iodolactonization. The precursor of the palladium-cata- DCC in the presence of a catalytic amount of DMAP to
lyzed reaction was synthesized from cyclohexene in two afford the expected ligand in 55% yield. This methodology
steps: a Wohl–Ziegler allylic bromination according to a applied on the 2 chiral diamines in the presence of catalytic
known procedure[15] followed by a substitution of the bro- or stoichiometric amounts of DMAP resulted in the forma-
mide by acetate (Scheme 2).
tion of ligand (R,R)-10a and ligand (S,S)-10b in similar
Recently, efficient systems have been developed to per- yields (55%). However, we observed that the order of ad-
form allylic alkylations.[16] The flow of new ligands has dition of the reagents also had much influence. In the pro-
never stopped, and a dramatic enhancement of enantio- cedure described by Trost and coworkers, the coupling
selectivity has been observed as a result. We chose Trost’s agent DCC or EDCI was added to the reaction mixture
bidentate ligand, because its C2-symmetry gives a rigid last. Indeed, if the EDCI is added to the mixture of acid
complex resulting in good enantioselectivities on cyclic sub- and DMAP before the addition of the amine, the reaction
strates. This ligand is commercially available, but it can also resulted in the formation of ligand (R,R)-10a and ligand
be easily synthesized by a peptidic coupling reaction be- (S,S)-10b in 74% and 64% yield, respectively, after
tween o-diphenylphosphinylbenzoic acid and chiral recrystallisation, and no further purification by chromatog-
diaminocyclohexanes. Different ways of obtaining this li- raphy was necessary (Scheme 3).
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Stereoselective Synthesis of Photoreactive Sesquiterpene Lactones
FULL PAPER
the iodolactone 7a with a perfect diastereospecificity (94%
ee). The enantiomeric purity of this compound could be
raised to ee Ͼ 98% by recrystallisation, as described pre-
viously.[22] A hydrodeiodination of 7a in the presence of
Bu3SnH led to the enantiomerically pure lactone
(3aR,7aR)-2a in quantitative yield. The enantiomeric purity
was supported by [α]2D0 values and by the absence of the
1
signal due to the undesired enantiomer in the 300 MHz H
NMR spectrum in the presence of a europium chiral shift
reagent. The major drawback of this reaction is the excess
of hydride needed to increase both the rate and the yield of
the reaction, resulting in a more difficult separation of the
product from tin residues. A solution to this problem was
the use of the simple work-up procedure described by Berge
and Roberts.[23] We thus obtained the lactone (3aR,7aR)-2a
in 95% yield, and no further purification was necessary.
With the same procedure, the cis ring-junction γ-butyro-
lactone (3aS,7aS)-2b was obtained with the same enantio-
selectivity and similar yields with the (S,S)-10b enantiomer
as the chiral ligand in the allylic alkylation catalyzed by
palladium.
Lactones (3aR,7aR)-2a and (3aS,7aS)-2b were then con-
verted into their corresponding α-methylene-γ-butyrolac-
tones 1a and 1b, according to the procedure described by
Grieco and coworkers,[11a] (i.e. by α-selenylation, methyl-
ation with MeI and oxidation leading to a β-syn elimi-
nation). The α-selenylation step gave a mixture of 2 dia-
stereomers in a 8:2 ratio, which was used without separation
to give the α-methylene-γ-butyrolactone 1a or 1b in good
yields.
Scheme 3. Synthesis of ligand (R,R)-10a. Reagents and conditions:
EDCI, DMAP, CH2Cl2, room temp., overnight.
The allylic acetate 4 was transformed into the diester (S)-
5a by treatment with NaCH(CO2Me)2 in the presence of a
catalytic amount of (π-allylPdCl)2 and ligand (R,R)-10a
with high enantioselectivity. The limited solubility of the
sodium salt of dimethyl malonate led to the use of tetraalk-
ylammonium salts (THAB).[19] As shown in Table 1, con-
version and enantiomeric excess are highly dependent on
the number of equiv. and the addition mode of the reagents.
Upon decreasing the amount of sodium dimethyl malonate
and THAB, the ee varied from 82% to 88% (Table 1, Entry
2). The enantioselectivity was improved by reversing the ad-
dition order of the two solutions, but the conversion was
low (Table 1, Entry 3). Finally, by doubling the quantities
of ligand and catalyst, while maintaining the number of
equiv. of dimethyl malonate, we succeeded in substantially
improving the conversion to 86%, while preserving good
enantioselectivity (Table 1, Entry 4). A similar study in the
presence of ligand (S,S)-10b afforded the enantiomer (R)-
5b with the same results. Enantioselectivities were deter-
mined by NMR spectroscopy with the Eu(hfc)3 shift rea-
gent, and absolute configurations were determined by com-
parison to optical rotations reported in the literature.[20]
Obtention of the γ-Butyrolactone with trans Ring Junction
Table 1. Asymmetric allylic alkylation of acetate 4 with dimethyl
malonate (DMM) afforded (S)-5a.[a]
In order to benefit from the good enantioselectivities ob-
tained in the synthesis of the cis-configured lactones, we
decided to convert lactones (3aR,7aR)-2a and (3aS,7aS)-2b
into the trans-configured lactones (3aR,7aS)-2c and
(3aS,7aR)-2d, respectively. This could be done by ring open-
ing of the cis-configured lactone, followed by inversion of
the oxygenated stereogenic centre and recyclisation. While
the isomerization of lactone 2 with a trans ring junction
into a lactone with a cis ring junction is well known in the
literature,[24] the opposite isomerization (i.e. obtention of
the trans lactone starting from the cis lactone) was never
reported. This is probably due to the great stability of lac-
tones with a cis ring junction, compared to their open-ring
α-hydroxyester or α-hydroxy acid forms. We solved this
problem as described in Scheme 4.
Entry
Molar equiv. of
(π-allylPdCl)2 ligand 10a DMM
Yield
[%]
ee[b]
[%]
THAB
1[c]
2[c]
3[d]
4[d]
0.025
0.025
0.025
0.05
0.05
0.05
0.05
0.1
2
1
1.3
1.3
2
1
1.3
1.3
50–60
50–60
10–50
86
82
88
94
94
[a] All reactions were performed at room temperature for 1 week.
[b] The enantioselectivity was determined by integration of the
NMR signals of the vinylic proton, upon titration with europium
chiral shift reagent (+)-Eu(hfc)3. [c] A solution of palladium, ligand
(R,R)-10a and acetate 4 was added dropwise to the nucleophile,
generated from dimethyl malonate, sodium hydride and THAB in
CH2Cl2. [d] Reversed addition: a solution of the nucleophile was
added dropwise to the reaction mixture.
cis-Configured lactones (3aR,7aR)-2a and (3aS,7aS)-2b
Decarboxylation of the alkyl malonate (S)-5a under con- were opened into their relatively stable hydroxy thioesters
ditions described by Krapcho (2 equiv. of NaCN, wet 11a and 11b, respectively, in good yields with a sulfur nu-
DMSO, 160 °C)[21] followed by a saponification step af- cleophile prepared from tert-butyl mercaptan and trimeth-
forded the monoacid (R)-6a in good yields. A modification ylaluminium.[25] A Mitsunobu reaction was then applied to
of this reaction, with 2.3 equiv. instead of 2 equiv. of NaCN the hydroxy thioester in the presence of 4-nitrobenzoic acid
in the presence of wet DMSO at 190 °C gave quantitatively (2 equiv.), PPh3 (2.25 equiv.) and diisopropyl azodicarbox-
the monoacid (R)-6a in one step. An iodolactonization, di- ylate (AIBN, 2.25 equiv.)[26] to afford the corresponding di-
rected by the first stereogenic centre, afforded quantitatively esters 12a and 12b, respectively, in good yields. Enantio-
Eur. J. Org. Chem. 2007, 1145–1152
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1147

S. Fuchs, V. Berl, J.-P. Lepoittevin
FULL PAPER
flash chromatography technique. Analytical TLC was performed
on pre-coated silica gel plates (Merck 60 F254). Melting points were
determined in capillary tubes with a Büchi Tottoli 510 apparatus
and are uncorrected. Elemental analyses were performed with a
Perkin–Elmer 240B instrument and were within Ϯ0.4% of calcu-
lated values in all cases. Optical rotations were determined with a
Perkin–Elmer 241 or a Perkin–Elmer 341 polarimeter at the sodium
D line (589 nm) and are reported as follows: [α]2D0 (c given in g/
100 mL, solvent). Infrared spectra were obtained with a Perkin–
Elmer FT-IR 1600 spectrometer; peaks are reported in reciprocal
1
centimetres. H and 13C NMR spectra were recorded with Bruker
AC200 [200.13 MHz (1H) and 50.32 MHz (13C)] or Avance 300
[300.13 MHz (1H) and 75.46 MHz (13C)] spectrometers in CDCl3,
unless otherwise specified. Chemical shifts are reported in ppm (δ)
with respect to TMS, and CHCl3 was used as the internal standard
(δ = 7.27 ppm). Multiplicities are indicated by s (singlet), d (doub-
let), t (triplet) and m (multiplet). 31P NMR spectra were recorded
with a Bruker AM-400 (162 MHz) spectrometer at ambient tem-
perature in CDCl3. All enantiomeric purities were determined by
1H NMR on a Bruker Avance 300, with the chiral shift reagent
Scheme 4. Synthesis of trans ring-junction models 1c and 1d. Rea-
gents and conditions: (a) AlMe3, tBuSH, CH2Cl2, room temp.,
overnight; (b) DIAD, PPh3, p-NO2C6H4COOH, THF, room temp.,
overnight; (c) NaOH, MeOH, room temp., overnight; (d) toluene,
∆, 30 min. (e)[11a] LDA, MeI, HMPA, THF, diethyl ether, –40 °C,
3 h; (f)[11a] LDA, (SePh)2, HMPA, THF, –78 °C, 1 h, then –40 °C,
1.5 h; (g)[11a] H2O2, CH3COOH, 0 °C, 40 min.
europium
tris[3-(heptafluoropropylhydroxymethylene)-(+)-cam-
phorate] [(+)-Eu(hfc)3] in C6D6.
3-Bromocyclohexene (3): To a suspension of AIBN (cat.) and N-
bromosuccinimide (NBS, 46.3 g, 0.26 mol) in tetrachloromethane
(150 mL), was added under argon, freshly distilled cyclohexene
(40 mL, 0.4 mol). The mixture was refluxed until the disappearance
of NBS. The mixture was then filtered, concentrated and distilled
under vacuum (63–64 °C, 15 mbar). The colourless liquid was
stored in the absence of light (30.1 g, 72% yield). 1H NMR
(200 MHz, CDCl3): δ = 5.95–5.76 (m, 2 H, 1-H, 2-H), 4.87–4.81
(m, 1 H, 3-H), 2.22–1.54 (m, 6 H, 3ϫCH2) ppm. 13C NMR
(50 MHz, CDCl3): δ = 131.1 (C-2), 129.0 (C-1), 49.0 (C-3), 32.8
(CH2), 24.7 (CH2), 18.9 (CH2) ppm.
selectivities were determined by NMR spectroscopy with
the Eu(hfc)3 shift reagent. The trans ring-junction lactones
(3aR,7aS)-2c and (3aS,7aR)-2d were obtained by saponifi-
cation (NaOH and MeOH), followed by an azeotropic dis-
tillation in toluene. In this step, the 4-nitrobenzoic acid ob-
tained from the saponification is used as an acid catalyst
for lactone formation.
Lactones (3aR,7aS)-2c and (3aS,7aR)-2d were then con-
verted into their corresponding α-methylene-γ-butyrolac-
tones 1c and 1d, respectively, according to the procedure
described by Grieco and coworkers.[11a] In the case of trans
ring-junction lactones, methylation with MeI is first real-
ised, followed by an α-selenylation in order to obtain exclu-
sively the exocyclic α-methylene group. Yields of these 2 re-
actions could be increased from 60% to 90% with a mixture
of THF and diethyl ether instead of THF alone.
(؎)-2-Cyclohexen-1-yl Acetate (4): To a solution of 3-bromocy-
clohexene (3, 9.6 mL, 83 mmol) in acetone (150 mL), was added
under argon, acetic acid (95 mL, 1.7 mol, 20 equiv.) and then, cau-
tiously, triethylamine (160 mL, 1.2 mol). The mixture was stirred
for 14 h at room temperature, and saturated aqueous NaHCO3
(140 mL) was added. After concentration, the aqueous residue was
extracted with diethyl ether (4ϫ70 mL). The combined organic
layers were washed with water (2ϫ70 mL) and then brine
(1ϫ70 mL), dried with MgSO4 and concentrated. Purification by
distillation under vacuum (71–73 °C, 15 mbar) afforded a pale yel-
Conclusions
1
low oil (8.15 g, 70% yield). H NMR (200 MHz, CDCl3): δ = 6.0–
We have prepared the four isomers of 1 according to a
highly efficient procedure. The first stereogenic centre was
generated by a palladium-catalyzed asymmetric allylic alky-
lation with good enantioselectivity. The enantioselectivity
of the lactone has been increased to Ͼ98% by recrystalli-
sation after iodolactonization. Studies on the reactivity of
these models towards DNA are in progress.
5.92 (m, 1 H, 2Ј-H), 5.75–5.66 (m, 1 H, 3Ј-H), 5.31–5.22 (m, 1 H,
1Ј-H), 2.06 (s, 3 H, 2-H), 2.02–1.59 (m, 6 H, 3ϫCH2) ppm. 13C
NMR (50 MHz, CDCl3): δ = 170.7 (C=O), 132.6 (C-2Ј), 125.7 (C-
3Ј), 68.1 (C-1Ј), 28.3 (CH2), 24.9 (CH2), 21.4 (C-2), 18.9 (CH2)
ppm. IR (film): ν = 3032, 2940, 2867, 2835, 1700, 1240 cm–1.
˜
General Procedure for Palladium-Catalyzed Asymmetric Allylic
Alkylation: (Ϯ)-2-Cyclohexen-1-yl acetate (4, 1.68 g, 12 mmol) was
added to
a
solution of allylpalladium chloride dimer
[(C3H5PdCl)2, 0.22 g, 0.6 mmol, 0.05 equiv.] and chiral ligand 10
(0.83 g, 1.2 mmol, 0.1 equiv.) in dry CH2Cl2 (20 mL). This clear
yellow solution was stirred at room temperature for 30 min. In an-
other flask, sodium hydride (60% dispersion, 0.60 g, 14.9 mmol,
1.24 equiv.) and tetra-n-hexylammonium bromide (THAB, 6.48 g,
14.9 mmol, 1.24 equiv.) were suspended in dry CH2Cl2 (70 mL),
and freshly distilled dimethyl malonate (1.8 mL, 15.6 mmol,
1.3 equiv.) was added dropwise at room temperature. The resulting
viscous mixture was then added dropwise to the yellow solution
and stirred at room temperature for 6 d. The reaction mixture was
Experimental Section
All air- or moisture-sensitive reactions were conducted in flame-
dried glassware under an atmosphere of dry argon. All solvents
were reagent grade. Dried solvents were freshly distilled before use.
Tetrahydrofuran and diethyl ether were distilled from sodium
benzophenone. CH2Cl2 was dried with P2O5 before distillation. Di-
isopropylamine was refluxed 30 min over potassium hydroxide and
then distilled. Chromatographic purifications were conducted on
silica gel columns (Merck 60, 0.040–0.063 mm) according to the
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Stereoselective Synthesis of Photoreactive Sesquiterpene Lactones
FULL PAPER
concentrated in vacuo. Water (100 mL) was added, and the re-
sulting solution was extracted with diethyl ether (3ϫ100 mL). The
organic layer was washed with water (2ϫ50 mL), brine (50 mL),
dried with MgSO4 and concentrated in vacuo. Purification was car-
ried out by flash chromatography over silica gel (hexane/ethyl ace-
tate, 95:5).
troscopy with (+)-7a (15 mg) with (+)-Eu(hfc)3 (80 mg, 1.2 equiv.)
in C6D6; the (–)-enantiomer could not be detected. 1H NMR
(200 MHz, CDCl3): δ = 4.68 (dd, J1 = J2 = 4.4 Hz, 1 H, 7a-H),
4.58 (ddd, J1 = J2 = J3 = 4.3 Hz, 1 H, 7-H), 2.83–2.67 (m, 1 H, 3a-
H), 2.53 (B part of an ABX system, JAB = 16.8 Hz, JBX = 6.8 Hz,
1 H, 3-H), 2.24 (A of an ABX system, JAB = 16.8 Hz, JAX = 3.6 Hz,
1 H, 3-H), 1.96–1.18 (m, 6 H, 3ϫCH2) ppm. 13C NMR (50 MHz,
CDCl3): δ = 176.0 (C=O), 83.0 (C-7a), 36.9 (C-3), 32.6 (C-3a or
C-7), 30.7 (CH2), 27.7 (C-3a or C-7), 26.4 (CH2), 20.5 (CH2) ppm.
Dimethyl (–)-(S)-2-(Cyclohex-2-enyl)malonate (5a): The general
conditions with ligand (R,R)-10a gave (–)-5a as a colourless oil
(2.05 g, 80% yield). [α]2D0 = –43.5 (c = 1.9, CHCl3), ref.[20] [α]2D3
=
IR (nujol): ν = 2940, 2862, 1784, 1175 cm–1.
˜
–43.2 (c = 1.75, CHCl3, 99% ee), ref.[27] [α]2D2 = –15.6 (c = 2.6,
CHCl3, 50% ee); ee = 94% was determined by NMR spectroscopy
(–)-(3aS,7R,7aR)-Hexahydro-7-iodobenzofuran-2-one (7b): The
with (–)-5a (17 mg) with (+)-Eu(hfc)3 (70 mg, 0.7 equiv.) in C6D6. same procedure as for (+)-7a starting from (+)-6b (0.32 g,
1H NMR (200 MHz, CDCl3): δ = 5.83–5.73 (m, 1 H, 2Ј-H), 5.56– 2.29 mmol) gave (–)-7b, after recrystallisation, as colourless crystals
5.49 (m, 1 H, 3Ј-H), 3.74 (s, 6 H, 2ϫOCH3), 3.29 (d, J = 9.5 Hz, (0.49 g, 80% yield). M.p. 94–95 °C. [α]2D0 = –56.0 (c = 1.5, MeOH),
1 H, 2-H), 2.98–2.84 (m, 1 H, 1Ј-H), 2.05–1.98 (m, 2 H, 4Ј-H), ref.[28] [α]2D0 = –53.4 (c = 3.6, MeOH, 99.9% ee); ee Ն 98% was
1.84–1.26 (m, 4 H, 5ЈH and 6Ј-H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 168.9 (2ϫC=O), 129.7 (C-2Ј), 127.4 (C-3Ј), 56.9 (C-
2), 52.4 (2ϫMe), 35.4 (C-1Ј), 26.7 (CH2), 24.9 (CH2), 20.9 (CH2)
determined by NMR spectroscopy with (–)-7b (15 mg) with (+)-
Eu(hfc)3 (80 mg, 1.2 equiv.) in C6D6; the (+)-enantiomer could not
be detected.
ppm. IR (film): ν = 3024, 2951, 2840, 1735, 1250, 1150 cm–1.
˜
(+)-(3aR,7aR)-Hexahydrobenzofuran-2-one (2a): Tributyltin hy-
dride (Bu3SnH, 3.2 mL, 12 mmol, 1.6 equiv.) was added under ar-
gon to a solution of iodolactone (+)-7a (2.0 g, 7.52 mmol) and
AIBN (cat.) in THF (20 mL). The mixture was allowed to reflux
for 40 min and then concentrated. The residue was dissolved in
MeCN (40 mL) and washed with small fractions of hexane
(8ϫ10 mL). Evaporation of MeCN afforded a colourless oil (1.0 g,
95% yield) free of tin residues. [α]2D0 = +50.6 (c = 1.4, CHCl3),
ref.[30] [α]2D0 = +50.3 (c = 0.1, CHCl3, 100% ee); ee Ն 98% was
determined by NMR spectroscopy with (+)-2a (14 mg) with (+)-
Eu(hfc)3 (80 mg, 0.7 equiv.) in C6D6; the (–)-enantiomer could not
Dimethyl (+)-(R)-2-(Cyclohex-2-enyl)malonate (5b): The general
conditions with ligand (S,S)-10b gave (+)-5a as a colourless oil
(2.20 g, 86% yield). [α]2D0 = +43.1 (c = 1.9, CHCl3), ref.[28] [α]2D0
=
+38.5 (c = 3.4, CHCl3, 82% ee); ee = 94% was determined by
NMR spectroscopy with (+)-5b (32 mg) with (+)-Eu(hfc)3 (128 mg,
0.7 equiv.) in C6D6.
(–)-(R)-Cyclohex-2-enylacetic Acid (6a): To wet DMSO (75 mL)
were added sodium cyanide (95%, 9 g, 175 mmol, 2.3 equiv.) and
the diester (–)-5a (16.1 g, 76 mmol). The mixture was refluxed over-
night and then cooled to room temp., diluted with water (300 mL),
washed with pentane (1ϫ40 mL) and acidified to pH = 4 with
acetic acid. This aqueous phase was extracted with ethyl acetate
(3ϫ400 mL). The organic layer was washed with water (200 mL),
dried with MgSO4 and concentrated in vacuo to afford a brown
oil. Purification was accomplished by filtration through silica gel
(hexane/ethyl acetate, 65:35) to yield (–)-6a as a colourless oil
1
be detected. H NMR (200 MHz, CDCl3): δ = 4.51 (ddd, J1 = J2
= J3 = 4.1 Hz, 1 H, 7a-H), 2.60 (B part of an ABX system, JAB
=
16.5 Hz, JBX = 6.8 Hz, 1 H, 3-H), 2.46–2.30 (m, 1 H, 3a-H), 2.24
(A part of an ABX system, JAB = 16.5 Hz, JAX = 2.6 Hz, 1 H, 3-H),
1.96–1.18 (m, 8 H, 4ϫCH2) ppm. 13C NMR (50 MHz, CDCl3): δ
= 177.5 (C=O), 79.1 (C-7a), 37.4 (C-3), 34.8 (C-3a), 27.8 (CH2),
27.1 (CH ), 22.8 (CH ), 19.9 (CH ) ppm. IR (film): ν = 2934, 2858,
˜
(10.60 g, 99% yield). [α]2D0 = –59.5 (c = 2.6, CHCl3), ref.[29] [α]D
–46.9 (c = 0.9, CHCl3, 86% ee). 1H NMR (200 MHz, CDCl3): δ =
11.23 (sl, 1 H, COOH), 5.75–5.65 (m, 1 H, 3Ј-H), 5.53 (dd, J1
=
2
2
2
1777, 1174 cm–1.
=
(–)-(3aS,7aS)-Hexahydrobenzofuran-2-one (2b): The same pro-
10.1 Hz, J2 = 2.3 Hz, 1 H, 2Ј-H), 2.65–2.48 (m, 1 H, 1Ј-H), 2.35 (B cedure as for (+)-2a starting from (–)-7b (2.57 g, 9.64 mmol) gave
part of an ABX system, JAB = 15.2 Hz, JBX = 6.5 Hz, 1 H, 2-H), (–)-2b as a colourless oil (1.30 g, 96% yield). [α]2D0 = –51.7 (c = 0.5,
2.29 (A part of an ABX system, JAB = 15.2 Hz, JAX = 8.5 Hz, 1
H, 2-H), 2.00–1.20 (m, 6 H, 3ϫCH2) ppm. 13C NMR (50 MHz,
CDCl3): δ = 179.6 (C=O), 129.8 (C=C), 128.4 (C=C), 40.7 (C-2),
CHCl3), ref.[13b] [α]2D0 = –52.0 (c = 2.074, CHCl3, 97.2% ee, ref.[31]
[α]2D0 = –45.5 (c = 0.548, CHCl3, 100% ee); ee Ն 98% was deter-
mined by NMR spectroscopy with (–)-2b (5 mg) with (+)-Eu(hfc)3
32.1 (C-3Ј), 28.8 (CH ), 25.0 (CH ), 21.0 (CH ) ppm. IR (film): ν (40 mg, 1 equiv.) in C6D6; the (+)-enantiomer could not be de-
˜
2
2
2
= 3000, 3019, 2929, 1707, 1291 cm–1.
tected.
(+)-(S)-Cyclohex-2-enylacetic Acid (6b): The same procedure as for
α-Methylenation of Lactones with a cis Ring Junction [(+)-2a and
(–)-6a starting from (+)-5b (3.14 g, 14.8 mmol) gave (+)-6b as a [(–)-2b]: Lactones (+)-2a and (–)-2b (Ն98%) were transformed into
colourless oil (1.94 g, 94% yield). [α]2D0 = +59.4 (c = 2.6, CHCl3),
ref.[28] [α]2D7 = +54.2 (c = 2.9, CHCl3, 82% ee).
the corresponding α-methylene-γ-butyrolactones (+)-1a and (–)-1b
according to the procedure described by Grieco and coworkers:[11a]
an α-selenylation (purification by flash chromatography over silica
gel, pentane/diethyl ether (95:5), 70% yield), followed by methyl-
ation and oxidation (purification by flash chromatography over sil-
ica gel, hexane/ethyl acetate (85:15), 85% yield for the 2 steps).
(+)-(3aR,7S,7aS)-Hexahydro-7-iodobenzofuran-2-one (7a): To aque-
ous NaHCO3 (0.2 , 80 mL, 16.9 mmol, 1.2 equiv.) containing the
acid (–)-6a (1.98 g, 14.1 mmol), were added a solution of I2 (3.94 g,
15.5 mmol, 1.1 equiv.) and KI (4.69 g, 28.2 mmol, 2 equiv.) in water
(20 mL). The mixture was stirred at room temperature overnight,
and then saturated aqueous Na2S2O3 (20 mL) was added. The
aqueous phase was extracted with CH2Cl2 (3ϫ20 mL). The or-
ganic layer was washed with water (15 mL), dried with MgSO4 and
concentrated. The clear orange solid (+)-7a was obtained with
good purity in a quantitative yield (3.70 g), which after recrystalli-
sation from ethyl acetate/hexane, gave enantiomerically pure (+)-5
(3aS,7aR)-3-(Phenylselenyl)hexahydrobenzofuran-2-one (8a) and
(3aR,7aS)-3-(Phenylselenyl)hexahydrobenzofuran-2-one (8b): Yellow
oil. (major isomer): 1H NMR (300 MHz, CDCl3): δ = 7.66–7.62
(m, 2 H, SePh), 7.31–7.25 (m, 3 H, SePh), 4.67 (ddd, J1 = J2 = J3
= 4.1 Hz, 1 H, 7a-H), 3.63 (d, J = 2.4 Hz, 1 H, 3-H), 2.34–2.24 (m,
1 H, 3a-H), 2.11–2.04 (m, 1 H), 1.79–1.14 (m, 7 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 175.8 (C=O), 135.1, 129.4, 128.8 and 127.2
(SePh), 77.5 (7a-C), 44.7 (3-C or 3a-C), 42.1 (3-C or 3a-C), 27.6
(CH2), 27.3 (CH2), 22.8 (CH2), 19.8 (CH2) ppm. (minor isomer):
as colourless crystals (2.93 g, 78% yield). M.p. 95–96 °C. [α]2D0
+55.7 (c = 1.2, MeOH); ee Ն 98% was determined by NMR spec-
=
Eur. J. Org. Chem. 2007, 1145–1152
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1149

S. Fuchs, V. Berl, J.-P. Lepoittevin
FULL PAPER
1H NMR (300 MHz, CDCl3): δ = 7.66–7.62 (m, 2 H, SePh), 7.31–
7.25 (m, 3 H, SePh), 4.48 (m, 1 H, 7a-H), 4.30 (d, J = 6.2 Hz, 1 H,
3-H), 2.51–2.41 (m, 1 H, 3a-H), 1.95–1.87 (m, 1 H), 1.79–1.14 (m,
7 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 134.0, 129.3 and 128.0
(SePh), 78.2 (C-7a), 49.7 (C-3 or C-3a), 39.6 (C-3 or C-3a), 27.7
(CH2), 25.3 (CH2), 23.4 (CH2), 19.4 (CH2) ppm (signals of quater-
nary C atoms were not visible).
2.5 equiv.) in dry CH2Cl2 (30 mL), was carefully added tert-butyl
mercaptan (1.7 mL, 14.9 mmol, 2.5 equiv.) at 0 °C under argon.
The mixture was stirred at 0 °C for 5 min and then warmed to
room temperature for 10 min. The cis-configured lactone 2 (0.84 g,
6.0 mmol) in CH2Cl2 (6 mL) was then added, and the mixture was
stirred at room temperature overnight. Quenching of the reaction
was performed by the addition of diethyl ether (50 mL), followed
by the careful addition of 10 % hydrochloric acid (35 mL). The
aqueous phase was extracted with diethyl ether (2ϫ20 mL), and
the organic layer was washed with saturated aqueous NaHCO3
(15 mL), water (15 mL) and brine (15 mL). Purification was per-
formed by flash chromatography over silica gel (pentane/diethyl
ether, 7:3) to yield the relatively stable hydroxy thioester 11 as a
white solid (1.24 g, 91% yield).
(3S,3aS,7aR)-3-Methyl-3-(phenylselenyl)hexahydrobenzofuran-2-one
(9a) and (3R,3aR,7aS)-3-Methyl-3-(phenylselenyl)hexahydrobenzo-
furan-2-one (9b): Orange oil. 1H NMR (200 MHz, CDCl3): δ =
7.71–7.53 (m, 2 H, SePh), 7.37–7.20 (m, 3 H, SePh), 4.56 (ddd, J1
= J2 = J3 = 5.8 Hz, 1 H, 7a-H), 2.43–2.29 (m, 1 H, 3a-H), 2.10–0.77
(m, 8 H), 1.45 (s, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ
= 178.7 (C=O), 138.0, 129.3, 128.9 and 126.2 (SePh), 76.6 (C-7a),
52.0 (C-3), 48.0 (C-3a), 28.5 (CH2), 25.9 (CH2), 23.8 (Me), 23.7
(CH2), 20.6 (CH2) ppm.
S-tert-Butyl (–)-(1ЈR,2ЈR)-2-(2Ј-Hydroxycyclohexyl)thioacetate
(11a): M.p. 46 °C. [α]2D0 = –6.7 (c = 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 3.87–3.84 (m, 1 H, 2Ј-H), 2.58 (B part of
an ABX system, JAB = 14.6 Hz, JBX = 7.5 Hz, 1 H, 2-H), 2.40 (A
part of an ABX system, JAB = 14.6 Hz, JAX = 6.8 Hz, 1 H, 2-H),
2.06–1.95 (m, 1 H, 1Ј-H), 1.84 (br. s, 1 H, OH), 1.75–1.20 (m, 8 H,
4ϫCH2), 1.44 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ
= 200.8 (C=O), 68.7 (C-2Ј), 48.0 [C(CH3)3], 47.0 (C-2), 39.2 (C-1Ј),
32.6 (CH2), 29.7 [C(CH3)3], 26.7 (CH2), 24.7 (CH2), 20.3 (CH2)
(+)-(3aR,7aR)-3-Methylene-cis-hexahydrobenzofuran-2(3H)-one
(1a): Colourless oil, ee Ն 98%. [α]2D0 = +71.9 (c = 1.8, CHCl3),
ref.[32] [α]2D5 = +63.3 (CHCl3, 90% ee). 1H NMR (200 MHz,
CDCl3): δ = 6.16 (d, J = 2.5 Hz, 1 H, 8-H), 5.49 (d, J = 2.5 Hz, 1
H, 8-H), 4.52 (ddd, J1 = J2 = J3 = 6.0 Hz, 1 H, 7a-H), 3.02–2.98
(m, 1 H, 3a-H), 1.92–1.19 (m, 8 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 170.3 (C=O), 139.2 (C-3), 119.0 (C-8), 76.2 (C-7a),
38.9 (C-3a), 28.2 (CH2), 25.6 (CH2), 20.5 (CH2), 19.8 (CH2) ppm.
C9H12O2 (152.19): calcd. C 71.03, H 7.95; found C 71.42, H 8.12.
ppm. IR (CHCl ): ν = 3600–3300 (O-H), 2933, 2862, 1673 cm–1.
˜
3
C12H22O2S (230.37): calcd. C 62.57, H 9.62; found C 62.88, H 9.67.
S-tert-Butyl (+)-(1ЈS,2ЈS)-2-(2Ј-Hydroxycyclohexyl)thioacetate
(11b): [α]2D0 = +6.4 (c = 1.5, CHCl3). C12H22O2S (230.37): calcd. C
62.57, H 9.62; found C 62.79, H 9.67.
(–)-(3aS,7aS)-3-Methylene-cis-hexahydrobenzofuran-2(3H)-one
(1b): Colourless oil, ee Ն 98%. [α]2D0 = –69.6 (c = 1.9, CHCl3),
ref.[33] [α]2D5 = –46.4 (c = 0.07, CHCl3, 99% ee). C9H12O2 (152.19):
calcd. C 71.03, H 7.95; found C 71.06, H 8.12.
General Procedure for the Mitsunobu Reaction: DIAD (2.6 mL,
12.1 mmol, 2.25 equiv.) was added under argon to a solution of 11
(1.24 g, 5.38 mmol), PPh3 (3.18 g, 12.1 mmol, 2.25 equiv.) and p-
nitrobenzoic acid (1.8 g, 10.76 mmol, 2 equiv.) in THF (30 mL) at
–12 °C. The mixture was stirred at room temperature overnight,
and then silica gel was added. The crude was carefully concentrated
and the orange solid obtained was purified by flash chromatog-
raphy over silica gel (pentane/diethyl ether, 95:5) to yield 12 (1.43 g,
70% yield) as a white solid.
(+)-(1R,2R)-1,2-Bis[o-(diphenylphosphanyl)benzoylamino]cyclo-
hexane (10a): To a solution of 2-(diphenylphosphanyl)benzoic acid
(4.83 g, 15.78 mmol, 2.2 equiv.), DMAP (cat.) and EDCI (3.30 g,
17.19 mmol, 2.4 equiv.) in dry CH2Cl2 (50 mL), was added
(1R,2R)-trans-1,2-diaminocyclohexane (0.82 g, 7.17 mmol). The
mixture was stirred at room temperature overnight. Diethyl ether
(100 mL) was added, and the organic layer was washed with 10%
hydrochloric acid (3 ϫ 100 mL), water (1 ϫ 100 mL), saturated
aqueous NaHCO3 (3 ϫ 100 mL), water (1 ϫ 100 mL) and brine
(1ϫ100 mL), dried with MgSO4 and concentrated in vacuo. The
slightly brown solid (4.5 g, 92 % yield) was recrystallized from
MeCN to yield (1R,2R)-10a as a white solid (3.66 g, 74% yield).
(+)-(1S,2R)-2-(tert-Butylthiocarbonylmethyl)cyclohexyl p-Nitroben-
zoate [(+)-12a]: M.p. 79–81 °C. [α]2D0 = +58.8 (c = 3.0, CHCl3). H
1
NMR (300 MHz, C6D6): δ = 7.72–7.68 (m, 4 H Ar), 4.69 (ddd, J1
= J2 = 10.2 Hz, J3 = 4.2 Hz, 1 H, 1-H), 2.59 (B part of an ABX,
JAB = 14.5 Hz, JBX = 4.0 Hz, 1 H, 7-H), 2.32–2.12 (m, 1 H, 2-H),
2.16 (A part of an ABX system, JAB = 14.5 Hz, JAX = 8.3 Hz, 1
H, 7-H), 2.02–1.97 (m, 1 H), 1.81–1.77 (m, 1 H), 1.44–0.80 (m, 6
M.p. 136–139 °C. [α]2D4 = +55.6 (c = 2.3, CH2Cl2), ref.[34] [α]D
=
1
+55.1 (c = 2.85, CH2Cl2), ref.[18] [α]D = +61 (c = 2.3, CH2Cl2). H
NMR (200 MHz, CDCl3): δ = 7.58–7.48 (m, 2 H, 13-H and 13Ј-
H), 7.26–7.16 [m, 24 H, P(C6H5)2 and 11-H, 11Ј-H, 12-H, 12Ј-H], H), 1.26 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, C6D6): δ = 197.9
6.94–6.88 (m, 2 H, 10-H and 10Ј-H), 6.45 (bd, J = 7.3 Hz, 2 H,
NH), 3.87–3.70 (m, 2 H, 1-H and 2-H), 1.90–1.78 (m, 2 H, CH2),
1.70–1.58 (m, 2 H, CH2), 1.30–0.90 (m, 4 H, 2ϫCH2) ppm. 13C
(SCO), 163.7 (OCO), 150.0 (CNO2), 135.3 (CArCO), 130.3
(2ϫCH), 123.1 (2ϫCH), 77.4 (C-1), 47.6 [C(CH3)3], 47.5 (C-7),
39.3 (C-2), 31.5 (CH2), 30.5 (CH2), 29.3 [C(CH3)3], 24.7 (CH2),
NMR (50 MHz, CDCl3): δ = 169.2 (2 ϫ C=O), 140.7 (d, J = 24.0 (CH ) ppm. IR (CHCl ): ν = 3030, 2939, 2863, 1720, 1676,
˜
2
3
24.6 Hz, C-8 and C-8Ј), 137.7 (d, J = 13.1 Hz, C-9 and C-9Ј), 136.6
(d, J = 21.3 Hz, C), 134.2 (CH), 133.8 (d, J = 19.7 Hz, C-10 and
C-10Ј), 130.1 (CH) 128.7 (CH), 128.5 (CH), 128.4 (CH), 127.5
(CH), 53.8 (C-1 and C-2), 31.9 (C-3 and C-6), 24.6 (C-4 and C-5)
ppm. 31P NMR (162 MHz, CDCl3): –8.3 (s).
1530, 1365, 1275 cm–1. C19H25NO5S (379.47): calcd. C 60.14, H
6.64, N 3.69; found C 60.07, H 6.65, N 3.63.
(–)-(1R,2S)-2-(tert-Butylthiocarbonylmethyl)cyclohexyl p-Nitroben-
zoate [(–)-12b]: [α]2D0 = –57.7 (c = 1.3, CHCl3). C19H25NO5S
(379.47): calcd. C 60.14, H 6.64, N 3.69; found C 60.03, H 6.70, N
3.53.
(–)-(1S,2S)-1,2-Bis[o-(diphenylphosphanyl)benzoylamino]cyclo-
hexane (10b): The same procedure as for (+)-(1R,2R)-10a starting
from (1S,2S)-trans-1,2-diaminocyclohexane (0.80 g, 7.00 mmol)
gave the product as a white solid (3.09 g, 64% after recrystallisation
from MeCN). M.p. 134–136 °C.
(–)-(3aR,7aS)-Hexahydro-benzofuran-2-one (2c): To a solution of
(+)-12a (1.34 g, 3.52 mmol) in MeOH (100 mL) was added drop-
wise aqueous sodium hydroxide (1 , 14 mL, 14 mmol, 4 equiv.),
and the mixture was stirred overnight at room temperature. The
crude was concentrated, acidified with 10% hydrochloric acid, and
the aqueous layer was extracted several times with diethyl ether
General Procedure for the Opening of cis-Configured Lactones: To a
solution of trimethylaluminium (2  in toluene, 7.4 mL, 14.9 mmol,
1150
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1145–1152

Stereoselective Synthesis of Photoreactive Sesquiterpene Lactones
FULL PAPER
(15ϫ8 mL). After concentration of the combined organic layers,
the white solid was dissolved in toluene (400 mL). After 30 min of
azeotropic distillation, the mixture was cooled to room tempera-
ture, washed with saturated aqueous NaHCO3 (2ϫ 50 mL) and
brine (2ϫ20 mL), dried with MgSO4 and concentrated in vacuo.
The white solid (–)-2c was obtained with good purity (469 mg, 95%
yield) or could be further purified by flash chromatography over
silica gel (pentane/diethyl ether, 7:3, 82% yield). M.p. 30–32 °C.
[α]2D0 = –83.3 (c = 0.5, CHCl3), ref.[13b] [α]1D8 = –93 (c = 2.034,
CHCl3, 98.4% ee), ref.[24b] [α]2D3 = –77.6 (c = 4.6, CHCl3, pure). The
diastereomer could not be detected by NMR spectroscopy. 1H
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NMR (300 MHz, CDCl3): δ = 3.78 (ddd, J1 = J2 = 11 Hz, J3
3.8 Hz, 1 H, 7a-H), 2.50 (B part of an ABX system, JAB = 16.2 Hz,
JBX = 6.2 Hz, 1 H, 3-H), 2.22 (A part of an ABX system, JAB
=
=
16.2 Hz, JAX = 13.0 Hz, 1 H, 3-H), 2.00–1.20 (m, 9 H, 3a-H and 8
H cyclohexane) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.6
(C=O), 85.2 (C-7a), 44.8 (C-3a), 35.9 (C-3), 30.3 (CH2), 28.3 (CH2),
25.3 (CH2), 24.1 (CH2) ppm.
(+)-(3aS,7aR)-Hexahydro-benzofuran-2-one (2d): The same pro-
cedure as for (–)-2c starting from (–)-12b (1.36 g, 3.58 mmol) gave
(+)-2d as a white solid (409 mg, 82 % yield after purification).
[α]2D0 = +84.3 (c = 1.8, CHCl3), ref.[13b] [α]1D8 = +88 (c = 2.044,
CHCl3, 96.8% ee), ref.[24b] [α]2D3 = +78.5 (c = 2.9, CHCl3, pure).
The diastereomer could not be detected by NMR spectroscopy.
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α-Methylenation of Lactones with a trans Ring Junction [(–)-2c and
(+)-2d]: The lactones (–)-2c and (+)-2d (ee Ն 98%) were converted
into the corresponding α-methylene-γ-butyrolactones (–)-1c and
(+)-1d, respectively, according to the procedure described by Grieco
and coworkers:[11a] methylation [purification by flash chromatog-
raphy over silica gel, pentane/diethyl ether (90:10), 92% yield], fol-
lowed by an α-selenylation and direct oxidation [purification by
flash chromatography over silica gel, hexane/ethyl acetate (85:15),
70% yield for the 2 steps].
(3aR,7aS)-3-Methyl-hexahydrobenzofuran-2-one (13c) and
(3aS,7aR)-3-Methyl-hexahydrobenzofuran-2-one (13d): Colourless
1
oil. H NMR (300 MHz, CDCl3): δ = 3.96 (ddd, J1 = J2 = 11 Hz,
J3 = 3.8 Hz, 1 H, 7a-H), 2.62 (qd, J1 = J2 = 7.6 Hz, 1 H, 3-H),
2.26–2.22 (m, 1 H, 3a-H), 2.00–1.70 (m, 4 H, CH2 cyclohexane),
1.60–1.16 (m, 4 H, CH2 cyclohexane), 1.15 (d, J = 7.6 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 180.1 (C=O), 81.8
(C-7a), 47.3 (C-3a), 38.8 (C-3), 30.6 (CH2), 25.2 (CH2), 24.6 (CH2),
24.0 (CH2), 9.6 (C-8) ppm.
(–)-(3aR,7aS)-3-Methylene-trans-hexahydrobenzofuran-2(3H)-one
(1c): White solid. M.p. 60 °C, ee Ն 98%. [α]2D0 = –60.0 (c = 1.7,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 6.04 (d, J = 3.2 Hz, 1
H, 8-H), 5.36 (d, J = 3.2 Hz, 1 H, 8-H), 3.69 (ddd, J1 = J2
=
11.1 Hz, J3 = 3.5 Hz, 1 H, 7a-H), 2.44–2.34 (m, 1 H, 3a-H), 2.28–
2.21 (m, 1 H), 2.15–2.09 (m, 1 H), 1.98–1.82 (m, 2 H), 1.67–1.54
(m, 1 H), 1.44–1.29 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.6 (C=O), 139.6 (C-3), 117.1 (C-8), 83.1 (C-7a), 48.9 (C-3a),
30.5 (CH2), 25.8 (CH2), 24.9 (CH2), 24.0 (CH2). C9H12O2 (152.19):
calcd. C 71.03, H 7.95; found C 70.92, H 8.03.
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(+)-(3aS,7aR)-3-Methylene-trans-hexahydrobenzofuran-2(3H)-one
(1d): White solid. M.p. 61 °C, ee Ն 98%. [α]2D0 = +59.5 (c = 1.9,
CHCl3). C9H12O2 (152.19): calcd. C 71.03, H 7.95; found C 70.90,
H 8.15.
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