Synthesis of enantiomerically pure (-)-wine lactone based on a palladium-catalyzed enantioselective allylic substitution

Article abstract of DOI:10.1002/(SICI)1099-0690(200002)2000:3<419::AID-EJOC419>3.0.CO;2-N

The first enantioselective synthesis of enantiomerically pure (-)-wine lactone, (-)-1a, a fragrance constituent of various white wines, and its epimer (+)-1b, was carried out. The key steps are allylic substitution of (±)-2-cyclohexen-1-yl acetate (2) wit

Full text of DOI:10.1002/(SICI)1099-0690(200002)2000:3<419::AID-EJOC419>3.0.CO;2-N

FULL PAPER
Synthesis of Enantiomerically Pure (–)-Wine Lactone Based on a Palladium-
Catalyzed Enantioselective Allylic Substitution
E. J. Bergner[a] and Günter Helmchen*[a]
Keywords: Asymmetric synthesis / Natural products / Palladium / Wine lactone / Allylic substitution
The first enantioselective synthesis of enantiomerically pure
acid L2 as catalyst, subsequent decarboxylation, iodolacton-
(–)-wine lactone, (–)-1a, a fragrance constituent of various
ization and elimination, furnishing enantiomerically pure bi-
white wines, and its epimer (+)-1b, was carried out. The key cyclic lactone (+)-7 in 47% overall yield. The diastereoselec-
steps are allylic substitution of (±)-2-cyclohexen-1-yl acetate
(2) with dimethylmalonate using palladium complexes of
phosphanyldihydrooxazol L1 or of the phosphanylcarboxylic
tive introduction of methyl groups by SN2’-type substitution
with an organocopper compound and by enolate alkylation
gave lactone (–)-1a in 43% overall yield from (+)-7.
Introduction
cemic 1a and its endo-C-3-epimer 1b (cf. Scheme 5) by
Claisen rearrangement from 2-cyclohexenol derivatives.[5]
In 1975 Southwell identified a group of bicyclic terpenoid
lactones[1] in the urine of koala animals. One of these lac-
tones was assigned the constitution A [3a,4,5,7a-tetrahydro- Results and Discussion
3,6-dimethylbenzofuran-2(3H)-one]. In 1997 Guth identi-
We now report the first enantio- and in all steps highly
fied one of the stereoisomers with constitution A in white
wine types Gewürztraminer and Scheurebe as an important
flavor component.[2] He then synthesized all the eight ste-
reoisomers and compared their odor threshold values which
differed considerably.[3] The compound with the highest
odor activity was the lactone (–)-1a, which was found to
be identical to the natural product and was named ‘‘wine
lactone.’’ The absolute configuration of wine lactone was
assigned by spectroscopic comparison with the synthetic
stereoisomers. The odor of (–)-1a is described as sweet,
woody and coconut-like with an odor threshold as low as
0.02 pg/L of air; the odor activity of the enantiomer, (ϩ)-
1a, displaying a threshold value of Ͼ1 µg/L of air, is lower
by a factor of Ͼ108. Recently wine lactone was also found
in orange juice and black pepper.[4]
diastereoselective synthesis of enantiomerically pure (–)-
wine lactone and its C-3-epimer. The retrosynthetic analysis
of our synthesis is displayed in Scheme 1. Enantioselectivity
was provided by asymmetric palladium-catalyzed allylic
substitution of 2-cyclohexen-1-yl acetate with dimethylma-
lonate, diastereoselectivity by iodolactonization and enol-
ate alkylation.
Scheme 1. Retrosynthetic analysis
For the enantioselective palladium-catalyzed alkylation[6]
of racemic 2-cyclohexen-1-yl acetate (2)[7] with alkali metal
dimethylmalonates we made use of the chiral ligands L1
and L2 which are particularly well suited for applications
to cyclic substrates (Scheme 2).[8]
With the P,N-chelate L1 as ligand, the reaction of sub-
strate 2 with sodium dimethylmalonate at –20 °C in DMF
as solvent had previously yielded the ester (ϩ)-3 with 93%
ee.[8a] In THF as solvent the ee of the product was only
85%, although the reaction was faster than in DMF.
Lowering the amount of catalyst from 1 mol-% to 0.1
mol-%, as is desirable for preparative applications, gave (ϩ)-
3 with 82% ee (88% yield). Fortunately, a high degree of
enantioselectivity is not required for the alkylation as the
iodolactone (–)-6 (see below), an intermediate in the route
to wine lactone, can be obtained enantiomerically pure by
simple recrystallization. In previous work, the alkylation of
Starting from (ϩ)- and (–)-limonene, Guth prepared the
eight stereoisomers with constitution A as mixtures of dias-
tereomers and separated these by chromatography. Prior to
the discovery of wine lactone, a diastereoselective route was
developed in 1981 by Bartlett and Pizzo who prepared ra-
[a]
Organisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Fax: (internat.) ϩ49-6221/544-205
E-mail: en4@ix.urz.uni-heidelberg.de
Eur. J. Org. Chem. 2000, 419Ϫ423
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0203Ϫ0419 $ 17.50ϩ.50/0
419

E. J. Bergner, G. Helmchen
FULL PAPER
mixture of regioisomers (ϩ)-8a/8b:8c ϭ 55:45 (1H NMR)
via SN2’ or SN2 attack, respectively. The ratio of the ste-
reoisomers 8a and 8b could not be determined directly be-
1
cause of overlapping signals in the H NMR spectrum. In-
direct assessment was carried out with the subsequently
formed iodolactones 9 (see below). As anticipated, an or-
ganocopper compound prepared from MeMgCl and
CuBr Me2S complex in a mixture of THF and Me2S as
solvent furnished exclusively the products of SN2’ attack;
an anti-syn selectivity of (ϩ)-8a:8b ϭ 92:8 was obtained.
Iodolactonization under standard conditions gave a 92:8
mixture (GC) of the diastereomers (–)-9a and 9b in 95%
yield (Scheme 5). The major diastereomer (–)-9a was ob-
tained in a pure form by recrystallization. Dehydrohalo-
genation with DBU gave the lactone (ϩ)-10 in excellent
yield; the original 92:8 mixture of (–)-9a and 9b gave rise to
an inseparable mixture of (ϩ)-10 with 9b which does not
undergo the elimination.
Scheme 2. Reagents and conditions: (a) procedure 1: 0.1 mol-% of
[C3H5PdCl]2, 0.12 mol-% of L1, THF, NaCH(COOCH3)2, 5 °C
(88%, 82% ee); procedure 2: 3.0 mol-% of [C3H5PdCl]2, 9.0 mol-%
of L2, THF, LiCH(COOCH3)2, room temp. (91%, 95% ee)
2 with lithium dimethylmalonate in THF as solvent was
also carried out with the enantiomer of L2 as ligand which
induced formation of the product with 98% ee.[9] For the
present work a sample of L2 with an ee of only 92% was
available; due to a nonlinear effect,[10] this nevertheless in-
duced the formation of (ϩ)-3 with 95% ee (yield 91%) in
the Pd-catalyzed reaction of acetate 2 with lithium di-
methylmalonate.
The alkylated malonate (ϩ)-3 was subjected to a Krap-
cho decarbomethoxylation (Scheme 3)[11] and the resulting
ester was saponified. Subsequent iodolactonization gave
(–)-6.[12] The enantiomeric purity of this compound could
be raised to Ͼ 99.9% ee by recrystallization.[13] The yields
of (–)-6 were 66 and 82% when the ee of the starting mat-
erial (ϩ)-5 was 82 and 95%, respectively. Elimination of HI
from (–)-6 by treatment with DBU gave the unsaturated lac-
tone (ϩ)-7 in excellent yield.
Scheme 4. Regioselectivity in reactions with organocopper com-
pounds
Scheme 3. Reagents and conditions: (a) NaCl, H2O, DMSO,
160 °C (74%); (b) NaOH, 120 °C (95%); (c) KI, I2, NaHCO3, H2O
(82%, Ͼ 99.9% ee); (d) DBU, THF, reflux (82–91%)
Scheme 5. Reagents and conditions: (a) KI, I2, NaHCO3, H2O/
THF, room temp. (95%, dr ϭ 92:8; after recrystallization: 60%, dr
Ͼ 99:1); (b) DBU, THF, reflux (92%); (c) LDA, MeI, THF, –78 °C
(79–90%); (d) LDA, THF, then H2C(COOtBu)2, –78 °C (61–74%)
The methyl group at C-6 was introduced by reaction of
(ϩ)-7 with a methyl copper compound (Scheme 4). This
type of reaction was previously studied by Curran et al.
Finally, alkylation of (ϩ)-10 according to the procedure
and Grieco et al. with analogous five-membered bicyclic of Bartlett and Pizzo[5] gave (–)-1a. The epimeric lactone
lactones.[14] It was reported that reactions with organo- (ϩ)-1b was prepared from (–)-1a by deprotonation and sub-
copper compounds prepared from organolithium com- sequent reprotonation (Scheme 5). The diastereoselectivity
pounds proceeded with low degrees of regioselectivity due was strongly dependent on the acid used for protonation.
to competing SN2’ and SN2 reactions. High selectivity in Thus, after deprotonation with LDA treatment of the res-
favor of the SN2’-mode was obtained with organocopper ultant lithium enolate with CH3COOH gave a 3:1 ratio of
reagents ‘‘RCu/MgBr2’’ derived from Grignard compounds, (–)-1a and (ϩ)-1b. In order to increase the likelihood of
in combination with stoichiometric amounts of CuBr Me2S. direct C-protonation relative to O-protonation, di-tert-butyl
Our own results with (ϩ)-7 corroborate these generaliza- malonate[15] was used as the CH-acid; this procedure indeed
tions. Thus, reaction of (ϩ)-7 with a reagent prepared from furnished the epi-wine lactone (ϩ)-1b with a diastereoselec-
methyllithium and CuBr in diethyl ether at –20 °C gave a tivity of Ͼ 99:1.
420
Eur. J. Org. Chem. 2000, 419Ϫ423

Synthesis of Enantiomerically Pure (Ϫ)-Wine Lactone Based
FULL PAPER
ester (1.32 g, 10.0 mmol) in dry THF (15 mL) at –40 °C. After re-
moval of the cooling bath, the reaction mixture was stirred at room
temperature for 10 min. The resultant suspension was then added
to solution A. After stirring for 1 h at room temperature satd.
NH4Cl solution (30 mL) was added and the mixture was extracted
with diethyl ether. The organic layer was washed with water, dried
over Na2SO4 and the solvents were removed in vacuo to give an
oil which was subjected to flash chromatography on silica gel
(35 ϫ 5 cm) using petroleum ether/ethyl acetate (97:3) as eluent.
Malonate (ϩ)-3 (0.96 g, 91%) was obtained as a colorless oil. The
ee of 95% was determined by GC analysis as described above.
Conclusion
In conclusion, our route based on the asymmetric allylic
alkylation allows wine lactone and its C-3-epimer to be con-
veniently prepared. As the Pd-catalyzed allylic substitution
can provide enantiomers with equal facility, the four ste-
reoisomers with constitution A possessing a cis-configura-
tion of the bicyclic ring system are accessible via this route
in an enantiomerically pure form.
Methyl (؉)-(S)-(Cyclohex-2-enyl)acetate [(؉)-4]: A mixture of
NaCl (3.30 g, 56.7 mmol), water (13 mL, 0.7 mol), (ϩ)-3 (10.9 g,
52.0 mmol, ee ϭ 82%) and DMSO (80 mL) was heated at 160 °C
for 24 h. After cooling, the mixture was diluted with water
(300 mL) and extracted with diethyl ether. The organic layer was
dried over Na2SO4. The solvent was then removed and the residue
was purified by flash chromatography on silica gel (40 ϫ 3.5 cm)
using petroleum ether/ethyl acetate (97:3) as eluent to give (ϩ)-4
(5.9 g, 74%) as a colorless liquid. – [α]2D0 ϭ ϩ50.9 (c ϭ 4.0,
Experimental Section
General Methods: Reactions in dry solvents were carried out un-
der an argon atmosphere. – Melting points and boiling points are
uncorrected. – TLC: Machery-Nagel Polygram Sil G/UV precoated
sheets, treatment with I2 and/or aqueous KMnO4 solution for visu-
alization. – For flash chromatography ICN Kieselgel S (0.032–
0.063 mm) was used. – 1H and 13C NMR spectra were recorded on
a Bruker AC 300 spectrometer [300.13 MHz (1H), 75.46 MHz
(13C), CDCl3]. – Optical rotations were determined with a Perkin–
Elmer 241 Polarimeter. – Gas chromatography was carried out on
a Hewlett–Packard HP 5890 A instrument equipped with a Chrom-
pack Permethyl β-CD (50 m ϫ 0.25 mm) column. – CuBr Me2S
was purchased from Fluka. CuI was purchased from Aldrich. –
Ligand L2 was liberated from L2 BH3 directly prior to use by heat-
ing a solution of L2 BH3 and 1.1 equiv. of DABCO in dry toluene
(2 mL per mmol) at reflux for 3 h followed by removal of the solv-
ent in vacuo.
1
CHCl3). – H NMR (CDCl3): δ ϭ1.18–1.29 (m, 1 H, CH2), 1.45–
1.61 (m, 1 H, CH2), 1.63–1.71 (m, 1 H, CH2), 1.72–1.83 (m, 1 H,
CH2), 1.91–1.98 (m, 2 H, CH2), 2.22 (dd, J ϭ 14.8 Hz, J ϭ 8.1 Hz,
1 H, CH2CϭO), 2.29 (dd, J ϭ 14.8 Hz, J ϭ 6.8 Hz, 1 H, CH2Cϭ
O), 2.50–2.60 (m, 1 H, HCϭCHCH), 3.64 (s, 3 H, OCH3), 5.50
(dd, J ϭ 10.1 Hz, J ϭ 2.0 Hz, 1 H, HCϭCHCH), 5.65–5.71 (m, 1
H, HCϭCHCH). – 13C NMR: δ ϭ 20.7 (t, CH2), 25.8 (t, CH2),
28.6 (t, CH2), 32.0 (d, HCϭCHCH), 40.4 (t, CHCϭO), 51.1 (q,
OCH3), 127.9 (d, HCϭCHCH), 129.8 (d, HCϭCHCH), 172.9 (s,
CϭO). – C9H14O2 (154.209): calcd. C 70.09, H 9.15; found C 70.16,
H 9.21.
Dimethyl (؉)-(R)-2-(Cyclohex-2-enyl)malonate [(؉)-3]. – Proced-
ure 1: A solution of [(η3-C3H5)PdCl]2 (11 mg, 30 µmol) and L1
(43 mg, 73 µmol) in dry THF (30 mL) was stirred at room temper-
ature for 20 min under an argon atmosphere, then cooled to 5 °C,
and (±)-2-cyclohexen-1-yl acetate (8.4 g, 60 mmol) was added to
give solution A. – Sodium hydride (2.16 g, 90.0 mmol, 95%) was
suspended in dry THF (150 mL) and malonic acid dimethyl ester
(15.8 g, 120 mmol) was added. Upon stirring at room temperature
a clear, colorless solution resulted which was added to solution A.
After stirring for 7 d at 5 °C satd. NH4Cl solution (100 mL) was
added and the mixture was extracted with diethyl ether. The or-
ganic layer was washed with water, dried over Na2SO4, and the
solvents removed in vacuo. Flash chromatography on silica gel
(35 ϫ 5 cm) using petroleum ether/ethyl acetate 97:3 as eluent gave
(ϩ)-3 (11.2 g, 88%) as a colorless oil. An ee of 82% was determined
by GC analysis on a Chrompack Permethyl β-CD column at 110
(؉)-(S)-Cyclohex-2-enylacetic Acid [(؉)-5]: An emulsion of (ϩ)-
4 (5.4 g, 35 mmol, 82% ee) in 1  NaOH (50 mL) was vigorously
stirred and heated at reflux for 1 h. After cooling to room temper-
ature, the solution was acidified with 6  HCl and extracted with
ethyl acetate. The organic layer was dried over Na2SO4 and concen-
trated in vacuo to yield (ϩ)-5 (4.7 g, 95%) as a slightly yellow oil. –
[α]2D7 ϭ ϩ54.2 (c ϭ 2.9, CHCl3, 82% ee). – ref.[17]: [α]2D7 ϭ ϩ65.0
1
(c ϭ 2.7, CHCl3, 84% ee). – H NMR (CDCl3): δ ϭ 1.22–1.34 (m,
1 H, CH2), 1.47–1.61 (m, 1 H, CH2), 1.63–1.74 (m, 1 H, CH2),
1.79–1.89 (m, 1 H, CH2), 1.93–2.09 (m, 2 H, CH2), 2.27 (dd, J ϭ
15.3 Hz, J ϭ 8.1 Hz, 1 H, CH2CϭO), 2.35 (dd, J ϭ 15.3 Hz, J ϭ
8.1 Hz, 1 H, CH2CϭO), 2.58 (m, 1 H, HCϭCHCH), 5.54 (dd, J ϭ
10.1 Hz, J ϭ 2.0 Hz, 1 H, HCϭCHCH), 5.67–5.74 (m, 1 H, HCϭ
CHCH), 11.4 (br. s, 1 H, COOH). – 13C NMR: δ ϭ 20.7 (t, CH2),
24.8 (t, CH2), 28.5 (t, CH2), 31.8 (d, HCϭCHCH), 40.4 (t, CH2Cϭ
O), 123.2 (d, HCϭCHCH), 129.6 (d, HCϭCHCH), 179.3 (s,
COOH).
°C, tR[(–)-(S)-3] ϭ 36.9 min, tR[(ϩ)-(R)-3] ϭ 37.9 min. – [α]2D0
ϭ
ϩ38.5 (c ϭ 3.4, CHCl3). – ref.[16]: [α]2D2 ϭ –15.6 (c ϭ 2.6, CHCl3,
50% ee). – 1H NMR (CDCl3): δ ϭ 1.27–1.36 (m, 1 H, CH2), 1.48–
(–)-(3aS,7R,7aR)-Hexahydro-7-iodo-benzo[b]furan-2-one [(–)-6]:
1.65 (m, 1 H, CH2), 1.68–1.73 (m, 2 H, CH2), 1.93–2.00 (m, 2 H, A solution of iodine (16.2 g, 63.6 mmol) and KI (32.3 g, 195 mmol)
CH2), 2.85 (mc, 1 H, CϭCCH), 3.24 [d, J ϭ 9.5 Hz, 1 H, in water (60 mL) was added to a solution of (ϩ)-5 (4.50 g,
CH(COOCH3)2], 3.68 (s, 6 H, OCH3), 5.47 (dd, J ϭ 10.1 Hz, J ϭ 32.3 mmol, 82% ee) and NaHCO3 in water (170 mL). The resulting
2.0 Hz, 1 H, HCϭCHCH), 5.72 (mc, 1 H, HCϭCHCH). – 13C mixture was stirred for 5 h at room temperature. A satd. aqueous
NMR: δ ϭ 20.8 (t, CH2), 24.8 (t, CH2), 26.6 (t, CH2), 35.3 (d, Cϭ
Na2S2O3 solution was then added until the reaction mixture be-
C–CH), 52.2 (q, OCH3), 56.8 [d, CH(COOCH3)2], 127.3 (d, CϭC– came colorless. The mixture was extracted four times with diethyl
CH), 129.5 (d, CϭC-CH), 168.6 (s, CϭO).
ether, the organic layer was dried over Na2SO4 and concentrated
Procedure 2: A solution of L2, obtained by deprotection from
in vacuo to give (–)-6 (7.92 g, 92%, 82% ee). Recrystallization from
L2 BH3 (162 mg, 0.45 mmol) (see General Methods), and [(η3- ethyl acetate/diethyl ether yielded enantiomerically pure (–)-6
C3H5)PdCl]2 (27 mg, 74 µmol) in dry THF (3 mL) was stirred at
room temperature for 20 min under an argon atmosphere; then (±)-
2-cyclohexen-1-yl-acetate (0.70 g, 4.99 mmol) was added to give so-
lution A. – A 1.6  solution of nBuLi (5.0 mL, 8.0 mmol) in n-
hexane was added dropwise to a solution of malonic acid dimethyl
(5.64 g, 66%, Ͼ 99.9% ee)[18] as colorless crystals. – M.p. 95–96 °C,
ref.[13]: m.p. 96–96.5 °C. An ee of Ͼ 99.9% was determined by GC
analysis on a Chrompack Permethyl β-CD column at 155 °C,
tR[(ϩ)-6] ϭ 29.2 min, tR[(–)-6] ϭ 30.4 min. – [α]2D0 ϭ –53.4 (c ϭ
3.6, CH3OH). – ref.[13]: [α]2D2 ϭ –56.6 (c ϭ 0.4, CH3OH, Ͼ 99.9%
Eur. J. Org. Chem. 2000, 419Ϫ423
421

E. J. Bergner, G. Helmchen
FULL PAPER
1
ee). – H NMR (CDCl3): δ ϭ 1.23–1.36 (m, 1 H, CH2), 1.50–1.97 3 H, CH3), 1.20–1.39 (m, 3 H, CH2), 1.77–1.84 (m, 1 H, CH2), 2.22
(m, 5 H, CH2), 2.27 (dd, J ϭ 16.9 Hz, J ϭ 3.4 Hz, 1 H, CH2Cϭ
O), 2.57 (dd, J ϭ 16.9 Hz, J ϭ 6.8 Hz, 1 H, CH2CϭO), 2.73–2.83
(d, J ϭ 16.7 Hz, 1 H, CH2CϭO), 2.64 (dd, J ϭ 16.7 Hz, J ϭ
6.4 Hz, 1 H, CH2CϭO), 2.81 (dd, J ϭ 11.2, J ϭ 4.3 Hz, 1 H,
(m, 1 H, CHCH2CϭO), 4.59–4.61 (m, 1 H, CHI), 4.67–4.69 (m, 1 CHCH2CϭO), 4.71 (mc, 1 H, CHI), 4.81–4.83 (m, 1 H, CHO). –
H, CHO). – 13C NMR: δ ϭ 20.3 (t, CH2), 26.3 (t, CH2), 27.4 (d, 13C NMR: δ ϭ 23.5 (q, CH3), 27.6 (t, CH2), 28.1 (t, CH2), 30.3 (d,
CHI), 30.4 (t, CH2), 32.4 (d, CHCH2CϭO), 36.8 (t, CH2CϭO), CHCH3), 31.0 (d, CHCH2CϭO), 38.7 (t, CH2CϭO), 41.7 (d, CHI),
82.8 (d, CHO), 175.8 (s, CϭO).
83.8 (d, CHO), 176.1 (s, CϭO). – C9H13IO2 (280.10): calcd. C
38.59, H 4.68, I 45.31; found C 38.65, H 4.72, I 45.56.
(؉)-(3aS,7aR)-3a,4,5,7a-Tetrahydrobenzo[b]furan-2-one [(؉)-7]:
A solution of (–)-6 (2.93 g, 11.0 mmol, Ͼ 99.9% ee) and DBU
(2.01 g, 13.2 mmol) in dry THF (20 mL) was heated at reflux for
3 h. After cooling, 6  HCl (40 mL) was added and the mixture
was extracted repeatedly with ethyl acetate. The organic layer was
dried and concentrated in vacuo. Recrystallization of the residue
from ethyl acetate/n-hexane gave (ϩ)-7 (2.15 g, 82%) as colorless
plates. – M.p. 51–52 °C. – [α]2D0 ϭ ϩ103.6 (c ϭ 3.3, CHCl3). –
(؉)-(3aS,7aR)-2,3,3a,4,5,7a-Hexahydro-6-methylbenzofuran-
2(3H)-one [(؉)-10]: A solution of (–)-9a (1.78 g, 6.40 mmol, Ͼ
99.9% ee) and DBU (1.26 g, 8.20 mmol) in THF (20 mL) was
heated to reflux for 2 h. After cooling, 6  HCl (50 mL) was added
and the mixture was extracted with diethyl ether. The organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue was
crystallized from ethyl acetate/n-hexane to give (ϩ)-10 (0.89 g,
ref.[19]: [α]2D7 ϭ ϩ104.7 (c ϭ 1.0, CHCl3, Ͼ 95% ee). – 1H NMR 92%) as colorless crystals. – M.p. 45–47 ° C. – [α]2D0 ϭ ϩ63.2 (c ϭ
1
(CDCl3): δ ϭ 1.37–1.49 (m, 1 H, CH2), 1.66–1.76 (m, 1 H, CH2),
3.03, CHCl3). – H NMR (CDCl3): δ ϭ 1.42–1.53 (m, 1 H, CH2),
1.92–2.17 (m, 2 H, CH2), 2.28 (dd, J ϭ 17.0 Hz, J ϭ 3.8 Hz, 1 H, 1.67–1.76 (m, 1 H, CH2), 1.74 (s, CH3), 1.96–2.0 (m, 2 H,
CH2CϭO), 2.48–2.59 (m, 1 H, CHCH2CϭO), 2.68 (dd, J ϭ CH2CH2), 2.28 (dd, J ϭ 17.2 Hz, J ϭ 3.5 Hz, 1H, CH2CϭO), 2.43–
17.0 Hz, J ϭ 8.1 Hz, 1 H, CH2CϭO), 4.76 (m, 1 H, CHO), 5.80–
2.48 (m, 1 H, CHCH2CϭO), 2.68 (dd, J ϭ 17.2, J ϭ 8.0 Hz, 1 H,
5.86 (m, 1 H, HCϭCHCH), 6.00–6.16 (m, 1 H, HCϭCHCH). – CH2CϭO), 4.75–4.78 (m, 1 H, CHO), 5.57–5.60 (m, 1 H, ϭCH). –
13C NMR: δ ϭ 22.6 (t, CH2), 23.4 (t, CH2), 33.4 (d, CH-CH2Cϭ 13C NMR: δ ϭ 23.7 (q, CH3), 23.9 (t, CH2), 27.8 (t, CH2), 32.9 (d,
O), 35.0 (t, CH2CϭO), 75.4 (d, CHO), 123.1 (d, HCϭCHCH),
134.0 (d, HCϭCHCH), 176.4 (s, CϭO).
CHCH2CϭO), 35.3 (t, CH2CϭO), 76.7 (d, CHO) 117.6 (s, ϭ
CCH3), 142.9 (d, HCϭ), 176.7 (s, CϭO).
(؉)-(2S,4R)- and (2S,4S)-(4-Methylcyclohex-2-enyl)acetic Acid
[(؉)-8a, 8b]: Under an argon atmosphere, a stirred suspension of
CuBr Me2S (5.20 g, 25.3 mmol) in a mixture of THF (50 mL) and
Me2S (20 mL) was cooled to –20 °C and a solution of CH3MgCl
(8.5 mL, 26 mmol, 3  in THF) was added dropwise. After stirring
for 1 h a solution of (ϩ)-7 (1.38 g, 10.0 mmol, Ͼ 99.9% ee) in THF
(8 mL) was added dropwise to the reaction mixture. The resulting
yellow suspension was allowed to warm to –10 °C and was stirred
for a further 12 h. Then 1  NaOH (100 mL) was added, the mix-
(–)-(3S,3aS,7aR)-3a,4,5,7a-Tetrahydro-3,6-dimethylbenzofuran-
2(3H)-one [(–)-1a]: Under an argon atmosphere, a solution of diiso-
propylamine (0.66 g, 6.50 mmol) in THF (20 mL) was cooled to –
78 °C and slowly treated with a solution of n-butyl lithium
(4.10 mL, 6.50 mmol, 1.6  in n-hexane). After stirring for 30 min
at –78 °C, a solution of (ϩ)-10 (0.72 g, 4.70 mmol, Ͼ 99.9% ee) in
THF (5 mL) was added to the reaction mixture over a period of
5 min. Stirring was continued for 30 min at –78 °C and then methyl
iodide (3.90 g, 27.5 mmol) was added. After stirring for a further
ture stirred for 2 h and extracted with diethyl ether (50 mL). The 1.5 h satd. NH4Cl solution (40 mL) was added, the resultant mix-
organic layer was discarded and the aqueous layer was acidified ture was allowed to warm to room temperature and was then ex-
with 6  HCl. After re-extraction with diethyl ether (3 ϫ 200 mL) tracted with diethyl ether. The organic layer was dried over Na2SO4
the organic layer was dried over Na2SO4 and concentrated in va-
cuo. Flash chromatography on silica gel (30 ϫ 4 cm) using petro-
leum ether/ethyl acetate 9:1 as eluent gave a 92:8 mixture of (ϩ)-
8a and 8b (1.74 g, 87%) as a colorless oil. – [α]2D0 ϭ ϩ130 (c ϭ 3.8,
and concentrated in vacuo. The residue was chromatographed on
silica gel (25 ϫ 5 cm) using petroleum ether/ethyl acetate (9:1) as
eluent to yield (–)-1a (0.63 g, 79%) as colorless crystals. – M.p. 48–
50 °C. – An ee of Ͼ 99.9% was determined by GC analysis on a
CHCl3). – 1H NMR (CDCl3): δ ϭ 0.94 (d, J ϭ 7.1 Hz, 3 H, CH3), Chrompack Permethyl β-CD column at 115 C; tR[(ϩ)-1a] ϭ
1.00–1.28 (m, 2 H, CH2), 1.77–1.91 (m, 2 H, CH2), 2.12 (mc, 1 H, 52.3 min, tR[(–)-1a] ϭ 54.5 min. – [α]2D0 ϭ –13.1 (c ϭ 3.0, CHCl3). –
CHCH3), 2.25 (dd, J ϭ 15.3 Hz, J ϭ 8.0 Hz, 1 H, CH2CϭO), 2.33
1H NMR (CDCl3): δ ϭ 1.23 (d, J ϭ 7.2 Hz, 3 H, HCCH3), 1.70
(dd, J ϭ 15.3 Hz, J ϭ 7.0 Hz, 1 H, CH2CϭO), 2.54 (mc, 1 H, (s, 3 H, HCϭCCH3), 1.72–2.01 (m, 4 H, CH2), 2.19–2.28 (m, 1 H,
CHCH2CϭO), 5.45–5.49 (m, 1 H, H3CCHCHϭCH), 5.52–5.56 CHCH–CH3), 2.34–2.44 (m, 1 H, CHCH3), 4.85–4.88 (m, 1 H,
(m, 1 H, H3CCHCHϭ), 10.8 (s, 1 H, COOH). – 13C NMR δ ϭ CHO), 5.47 (m, 1 H, CϭCH). – 13C NMR: δ ϭ 13.8 (q, HCCH3),
21.4 (q, CH3), 28.6 (t, CH2CH2), 30.2 (d, CHCH3), 30.6 (t, 22.1 (t, CH2), 23.4 (q, CϭCCH3), 25.7 (t, CH2), 37.6 (d, CHCH3),
CH2CH2), 128.7 (d, H3CCHCHϭCH), 134.5 (d, H3CCH–CHϭ), 40.1 (d, CHCHCH3), 75.2 (d, CHO), 118.6 (d, ϭCH), 140.5 (s,
178.8 (s, COOH).
H3CCϭ), 179.5 (s, CϭO). – C10H14O2 (166.22): calcd. C 72.26, H
8.49; found C 72.13, H 8.45.
(–)-(3aS,6R,7R,7aR)-3a,4,5,6,7,7a-Hexahydro-7-iodo-6-methyl-
benzofuran-2(3H)-one [(–)-9a]:
21.9 mmol) and KI (10.8 g, 65.1 mmol) in water (30 mL) was added
A
solution of iodine (5.55 g,
(؉)-(3R,3aS,7aR)-3a,4,5,7a-Tetrahydro-3,6-dimethylbenzofuran-
2(3H)-one [(؉)-1b]: Under an argon atmosphere, a solution of n-
to a well stirred mixture of (ϩ)-8a/8b (1.64 g, 10.6 mmol, Ͼ 99.9% butyl lithium (1.40 mL, 2.20 mmol, 1.6  in n-hexane) was added
ee), prepared as described above, THF (30 mL), NaHCO3 (2.7 g,
32.1 g) and water (30 mL). After stirring for 2 h at room temper-
ature, saturated aqueous Na2S2O3 solution was added to remove
the unreacted iodine. The mixture was extracted with diethyl ether
slowly to a cooled (–78 °C) solution of diisopropylamine (0.27 g,
2.70 mmol) in THF (30 mL). After stirring for 30 min at –78 °C a
solution of (–)-1a (0.30 g, 1.80 mmol) in THF (5 mL) was dropwise
added over a period of 5 min and the mixture was stirred for
(4 ϫ 150 mL), the organic layer dried over Na2SO4 and concen- 30 min. Di-tert-butylmalonate (0.58 g, 2.7 mmol) was then added
trated in vacuo to give a 92:8 mixture (GC) of (–)-9a and 9b (2.83 g, and the mixture stirred for a further 40 min at –78 °C. After this
95%) as a yellow solid. Recrystallization from ethyl acetate/n-hex- time satd. NH4Cl solution (30 mL) was added. The mixture was
ane gave pure trans-isomer (–)-9a (1.78 g, 60%) as colorless crys-
allowed to warm to room temperature and was then extracted with
diethyl ether. The organic layer was dried over Na2SO4 and concen-
tals. – M.p. 89–91 °C. – [α]2D0 ϭ –12.2 (c ϭ 3.0, CHCl3, Ͼ 99.9%
ee). – 1H NMR (CDCl3): δ ϭ 0.90–0.94 (m, 1 H, CHCH3), 0.93 (s, trated in vacuo. Flash chromatography on silica gel (25 ϫ 5 cm)
422
Eur. J. Org. Chem. 2000, 419Ϫ423

Synthesis of Enantiomerically Pure (Ϫ)-Wine Lactone Based
using petroleum ether/ethyl acetate (95:5) as eluent gave (ϩ)-1b
FULL PAPER
[6d]
5676. –
B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996,
[6e]
96, 395–422. –
576, 203–214.
G. Helmchen, J. Organomet. Chem. 1999,
(0.18 g, 61%) as colorless crystals. – M.p. 57–59 °C. – [α]2D0
ϭ
ϩ112 (c ϭ 3.0, CHCl3, Ͼ 99.9% ee). – 1H NMR (CDCl3): δ ϭ
1.12–1.17 (m, 1 H, CH2), 1.15 (d, J ϭ 7.2 Hz, 3 H, HCCH3), 1.64–
1.69 (m, 1 H, CH2), 1.76 (s, 3 H, HCϭCCH3), 1.95–1.99 (m, 2 H,
CH2), 2.28–2.35 (m, 1 H, CHCHCH3), 2.86 (dq, J ϭ 7.5 Hz, J ϭ
7.2 Hz, 1 H, HCCH3), 4.59–4.62 (m, 1 H, CHO), 5.63–5.65 (m, 1
H, CϭCH). – 13C NMR: δ ϭ 9.2 (q, HCCH3), 19.6 (t, CH2), 23.7
(q, CϭCCH3), 28.9 (t, CH2), 37.8 (d, CHCHCH3), 40.2 (d,
CHCH3), 74.6 (d, CHO), 117.0 (d, ϭCH), 144.0 (s, H3C–Cϭ),
178.8 (s, CϭO). – C10H14O2 (166.22): calcd. C 72.26, H 8.49; found
C 72.28, H 8.50.
[7]
2-Cyclohen-1-yl chloride or bromide as substrates gave mark-
edly lower enantioselectivity than the acetate.
[8] [8a]
S. Kudis, G. Helmchen, Angew. Chem. 1998, 110, 3210–
[8b]
3212; Angew. Chem. Int. Ed. 1998, 37, 3047–3050. –
Sennhenn, B. Gabler, G. Helmchen, Tetrahedron Lett. 1994, 35,
P.
[8c]
8595–8598. –
G. Helmchen, S. Kudis, P. Sennhenn, H.
Steinhagen, Pure Appl. Chem. 1997, 69, 513–518. – [8d] S. Kudis,
G. Helmchen, Tetrahedron 1998, 10449–10456. – [8e] S. Schleich,
G. Helmchen, Eur. J. Org. Chem. 1999, in press.
G. Knühl, P. Sennhenn, G. Helmchen, J. Chem. Soc., Chem.
Commun. 1995, 1845–1846.
[9]
[10]
G. Helmchen, A. Geiser, unpublished results.
[11] [11a] A. P. Krapcho, Synthesis 1982, 805–822. – [11b] A. P. Krap-
cho, Synthesis 1982, 893–914.
[12]
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 247) and the Fonds der Chemischen Industrie. We thank Mrs.
Olena Tverskoy for skillful technical assistance.
Alternatively, malonate (ϩ)-3 was saponified and the resultant
carboxylic acid decarboxylated by heating. This procedure
caused formation of substantial amounts of side products and
purification of the iodolactone was difficult.
[13]
The facility of purification of the iodolactone was independ-
ently found by us (ref.[7b]) and by the Scheffold group: T.
Troxler, R. Scheffold, Helv. Chim. Acta 1994, 77, 1193–1202.
[14] [14a] D. P. Curran, M.-H. Chen, D. Leszcweski, R. L. Elliot, D.
M. Rakiewiecz, J. Org. Chem. 1986, 51, 1612–1614. – [14b] P. A.
Grieco, C. V. Srinivasan, J. Org. Chem. 1981, 46, 2591–2593.
[1]
I. A. Southwell, Tetrahedron Lett. 1975, 24, 1885–1888.
[2] [2a]
B. Bonnländer, B. Baderschneider, M. Messerere, P. Win-
[2b]
terhalter, J. Agric. Food Chem. 1998, 46, 1474–1478. –
Guth, J. Agric. Food Chem. 1997, 45, 3022–3026.
H. Guth, Helv. Chim. Acta, 1996, 79, 1559–1571.
H.
[15]
The choice of this CH-acid was based on previous work of our
group: R. Wierzchowski, Dissertation, Universität Würzburg,
[3]
[4]
[4a] T. Jagella, W. Grosch, Z. Lebensm.-Unters. Forsch. A. 1999,
1985.
[4b]
[16]
209, 16–21. –
A. Hinterholzer, P. Schieberle, Flavour Fra-
A. Togni, Tetrahedron: Asymmetry 1991, 2, 683–690.
G. Buono, G. Pfeiffer, A. Mortreux, F. Petit, J. Chem. Soc.,
[17]
grance J. 1998, 13, 49–55.
[5]
P. A. Bartlett, C. F. Pizzo, J. Org. Chem. 1981, 46, 3896–3900.
Chem. Commun. 1980, 937–939.
[6] [6a]
[18]
C. G. Frost, J. Howarth, J. M. J. Williams, Tetrahedron
Using the same procedure (ϩ)-5 of 95% ee gave enantiomer-
[6b]
Asymmetry 1992, 3, 1089–1122. –
T. Hayashi, in: Catalytic
ically pure (–)-6 after recrystallization (yield: 82%).
[19]
Asymmetric Synthesis, (Ed.: I. Ojima), VCH, Weinheim, 1993,
E. Nagano, K. Mori, Biosci. Biotech. Biochem. 1992, 10,
[6c]
pp 325–365. –
T. Lübbers, P. Metz in Houben-Weyl E21,
1589–1591.
Stereoselective Synthesis (Eds.: G. Helmchen, R. W. Hoffmann,
J. Mulzer, E. Schaumann), 1995, pp. 2371–2473 and 5643–
Received September 16, 1999
[O99530]
Eur. J. Org. Chem. 2000, 419Ϫ423
423