A short-step synthesis of trans-whisky lactone by an asymmetric Michael reaction

Article abstract of DOI:10.1016/S0957-4166(98)00080-9

trans-Whisky lactone 6 was synthesized enantioselectively in only six steps from readily available 2-trimethylsilyloxyfurans and 3-crotonoyl-1,3- oxazolidin-2-one using an asymmetric Michael reaction as the key step.

Full text of DOI:10.1016/S0957-4166(98)00080-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1165–1170
A short-step synthesis of trans-whisky lactone by an asymmetric
Michael reaction
Hisashi Nishikori,a Katsuji Ito b and Tsutomu Katsuki a,∗
aDepartment of Chemistry, Faculty of Science, Kyushu University 33, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
bDepartment of Chemistry, Fukuoka University of Education, Akama, Munakata, Fukuoka 811-4192, Japan
Received 21 January 1998; accepted 13 February 1998
Abstract
trans-Whisky lactone 6 was synthesized enantioselectively in only six steps from readily available 2-
trimethylsilyloxyfurans and 3-crotonoyl-1,3-oxazolidin-2-one using an asymmetric Michael reaction as the key
step. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Multi-substituted γ-lactone substructures exist in many natural products and asymmetric syntheses of
γ-lactones or their synthetic equivalents have received considerable attention.1 Recently, highly enantios-
elective Lewis acid catalyzed asymmetric Michael reactions have been reported2 and we expected that an
asymmetric Michael reaction between the anion 1 bearing a protected hydroxy group and enoate 2 would
provide a useful method for the synthesis of chiral γ-lactones (Eq. 1). However, anion 1 is a strong base
and vitiates the Lewis acid catalyst. Therefore, an equivalent of 1 which is not basic but nucleophilic
is required to perform this type of Michael reaction successfully in the presence of chiral Lewis acid
catalyst.
(1)
∗
Corresponding author. E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00080-9

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2. Results and discussion
It has been reported that 2-trimethylsilyloxyfurans react with various electrophiles including enoates,
to give the corresponding C4-substituted butenolides.3 This suggests that 2-trimethylsilyloxyfurans
are good candidates for equivalents of 1. Thus, we examined chiral Lewis acid promoted Michael
additions of 2-trimethylsilyloxyfuran to oxazolidinone enoates and found that scandium–BINOL 3 or
copper–bis(oxazoline) complex 4 serve as efficient catalysts for the present purpose.4 Catalyst 3 shows
high anti- and moderate enantioface selectivity, while complex 4 shows good anti- and high enantioface
selectivity (Scheme 1). Advantages of using 2-trimethylsilyloxyfurans as nucleophiles are twofold: (i)
they directly provide an acylated hydroxy group which can be readily cleaved under hydrolytic or
reductive conditions; (ii) the resulting butenolide moiety can be further functionalized in various ways.
Recrystallization of the obtained Michael adduct 5 gave enantiopure anti-adduct anti-5 as a single isomer.
Scheme 1.
To demonstrate the efficiency of the present reaction for the synthesis of γ-lactone derivatives, we
examined the enantiospecific conversion of Michael adduct anti-5 to trans-whisky lactone, (3S,4R)-3-
methyloctan-4-olide 6. trans-Whisky lactone is found along with cis-whisky lactone in many liquors
such as whisky, brandy and wine stored in oak barrels, because they are extracted from the barrels while
maturing.5,6
The necessary one-carbon elongation for the present conversion seemed to be executed by direct
nucleophilic addition to saturated γ-lactone 7 or by its reduction and subsequent nucleophilic addition.
Contrary to our expectation, treatment of compound 7 with methyllithium or with reducing agents such as
lithium aluminum hydride or diisobutylaluminum hydride (DIBAL-H) gave complex mixtures, because
the two functional groups (butenolide and imido groups) had similar reactivity toward these nucleophiles
(Scheme 2). The reduction of anti-5 with DIBAL-H also gave a complex mixture.
Scheme 2.

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1167
It is well known that esters are less reactive toward nucleophiles than lactones, due to the anomeric
effect. Thus, we examined the selective conversion of the imido group to an acid or ester group but usual
hydrolysis (LiOH or NaOH) or alcoholysis (K2CO3–MeOH) again gave complex mixtures. However,
titanium alkoxide mediated alcoholysis7 seemed to be a promising method for this conversion, because
the imido group was expected to serve as a bidentate ligand and to coordinate to the titanium ion in
preference to the lactone. As expected, treatment of anti-5 with titanium tetraisopropoxide in 2-propanol
selectively converted the imido group into the desired isopropyl ester 8 (Scheme 3), leaving the lactone
group intact. The conversion of compound 8 into trans-whisky lactone 6 was completed in four steps.
Compound 8 was hydrogenated in the presence of Pd/C to give γ-lactone 9. DIBAL-H reduction of 9
in THF at −78°C occurred selectively at the lactone moiety, giving the corresponding lactol 10, and the
reduction of the isopropyl ester group was not observed under the present conditions. Lactol 10 was then
subjected to Wittig reaction. The direct Wittig product, γ-hydroxy ester, was not isolated but it cyclized
in situ to give γ-lactone 11 as a sole product. Hydrogenation of the terminal olefin in 11 in the presence
of Pd/C gave trans-whisky lactone 6. The specific rotation of 6 was [α]2D5 +82.1 (c 0.68, MeOH) [lit.6h
[α]2D3 +79.5 (c 1.0, MeOH)].
Scheme 3.
In conclusion, we were able to show that the Michael addition products of 2-trimethylsiloxyfuran to
enoates are useful synthetic precursors of γ-lactones by performing a short step synthesis of trans-whisky
lactone. This demonstrates the high utility of the present asymmetric Michael reaction because various
γ-lactone sub-structures exist in many natural products.
3. Experimental
All melting points are uncorrected. NMR spectra were recorded at 270 MHz on a JEOL EX-270
instrument. Signals are expressed as ppm downfield from tetramethylsilane used as an internal standard
(δ value in CDCl3) unless otherwise described. IR spectra were obtained with a SHIMADZU FTIR-
8600 instrument. Optical rotation was measured with a JASCO DIP-360 automatic digital polarimeter.
High resolution mass spectra (HRMS) were recorded on a JEOL JMS-SX/SX 102A instrument. Column
chromatography was conducted on silica gel BW-820-MH, 70–200 mesh ASTM, available from Fuji

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Silysia Chemical Ltd. Solvents were dried and distilled shortly before use. Reactions were carried out
under an atmosphere of nitrogen or argon if necessary.
3.1. 3-[(3S,20S)-3-(20,50-Dihydro-50-oxo-20-furyl)butanoyl]-1,3-oxazolidin-2-one anti-5
The Michael reaction of 2-trimethylsilyloxyfuran and 3-crotonoyl-1,3-oxazolidin-2-one using catalyst
4 gave compound 5 of 95% ee together with a small amount of syn-isomer, according to the reported
procedure.4b Crude 6 was recrystallized from hexane–AcOEt to give enantiomerically pure anti-5 as a
single isomer in 58% yield.
3.2. (4S,5S)-6-Isopropoxycarbonyl-5-methyl-2-hexen-4-olide 8
To a solution of anti-5 (498 mg, 2.1 mmol) in i-PrOH (10 ml) was added titanium tetraisopropoxide
(1.2 ml, 4.2 mmol) at room temperature. After being heated at 80°C for 2 h, the mixture was cooled to
room temperature and quenched with 2 N HCl (10 ml). After vigorous stirring for 1 h, the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and evaporated. The residue
was chromatographed on silica gel (hexane:AcOEt=7:3) to afford unsaturated γ-lactone 8 (424 mg, 96%
yield) as a colorless oil. [α]2D6 +23.3 (c 0.38, CHCl3); 1H NMR (270 MHz): δ 7.49 (dd, J=1.6 and 5.9 Hz,
1H), 6.15 (dd, J=2.3 and 5.9 Hz, 1H), 4.96–5.05 (m, 2H), 2.41 (dd, J=5.3 and 17.1 Hz, 1H), 2.45–2.40
(m, 1H), 2.21 (dd, J=9.2 and 17.1 Hz, 1H), 1.24 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 1.10 (d,
J=6.6 Hz, 3H); IR (neat): 2979, 2937, 1755, 1728, 1375, 1263, 1165, 1107, 993, 968, 822 cm−1. Found:
C, 62.30; H, 7.63%. Calcd for C11H16O4: C, 62.24; H, 7.60%.
3.3. (4R,5S)-6-Isopropoxycarbonyl-5-methylhexan-4-olide 9
A solution of lactone 8 (400 mg 1.9 mmol) in AcOEt (20 ml) containing 10% Pd–C (80 mg) was
stirred under H2 (1 atm) at room temperature overnight. The catalyst was removed by filtration through
a pad of Celite, and the filtrate was concentrated under reduced pressure to afford γ-lactone 9 (382 mg,
1
95% yield) as a colorless oil. [α]2D6 −31.2 (c 1.23, CHCl3); H NMR (270 MHz): δ 5.03 (hept, J=6.3
Hz, 1H), 4.29 (dt, J=6.3 and 8.3 Hz, 1H), 2.66–2.52 (m, 3H), 2.36–2.14 (m, 3H), 1.99–1.84 (m, 1H),
1.24 (d, J=6.3 Hz, 6H), 0.99 (d, J=6.6 Hz, 3H); IR (neat): 2980, 2937, 1778, 1728, 1460, 1421, 1375,
1265, 1184, 1109, 1022, 972, 916 cm−1. Found: C, 61.67; H, 8.46%. Calcd for C11H18O4: C, 61.66; H,
8.47%.
3.4. (3S,4R)-3-Methyl-7-octen-4-olide 11
To a solution of γ-lactone 9 (352 mg, 1.6 mmol) in THF (8 ml) was added diisobutylaluminum hydride
(1.76 ml, 0.93 mol dm−3 in hexane) at −78°C. After being stirred for 2 h, the mixture was quenched with
MeOH and gradually raised to room temperature. To the mixture was added saturated aqueous potassium
sodium tartrate (2 ml). After vigorous stirring for 1 h, the organic layer was removed and the aqueous
layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4
and concentrated. Silica gel chromatography of the residue (hexane:AcOEt=7:3) afforded lactol 10 (332
mg, 94% yield), which was immediately used for the next reaction.
To a suspension of methyltriphenylphosphonium iodide (185 mg, 0.46 mmol) in THF (4.5 ml) and
HMPA (0.5 ml) was added potassium hexamethyldisilazide (0.85 ml, 0.5 mol dm−3 in toluene) at
room temperature. After being stirred for 10 min, the yellow solution was cooled to −78°C and to this

H. Nishikori et al. / Tetrahedron: Asymmetry 9 (1998) 1165–1170
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solution was added the above lactol 10 (71 mg, 0.33 mmol) in THF (1.0 ml). The reaction mixture
was allowed to warm to room temperature and quenched with saturated aqueous NH4Cl. The organic
layer was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layers
were dried over anhydrous MgSO4 and concentrated. The residue was chromatographed on silica gel
(hexane:AcOEt=8:2) to afford γ-lactone 11 (37 mg, 73% yield). [α]2D6 +69.6 (c 0.71, CHCl3); 1H NMR
(270 MHz): δ 5.81 (ddt, J=6.6, 10.2 and 16.8 Hz, 1H), 5.05 (dd, J=1.3 and 16.8 Hz, 1H), 5.01 (dd, J=1.3
and 10.2 Hz, 1H), 4.03 (dt, J=4.0 and 7.6 Hz, 1H), 2.74–2.61 (m, 1H), 2.34–2.13 (m, 4H), 1.82–1.58 (m,
2H), 1.13 (d, J=6.3, 3H); IR (neat): 2980, 2937, 1778, 1728, 1460, 1421, 1375, 1246, 1209, 1171, 993,
937, 916 cm−1. Found: C, 70.48; H, 9.34%. Calcd for C9H14O2: C, 70.09; H, 9.15%.
3.5. trans-Whisky lactone 6
A solution of γ-lactone 10 (30 mg 0.19 mmol) in AcOEt (3 ml) containing 10% Pd–C (8 mg) was
stirred under H2 (1 atm) at room temperature overnight. The mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure to afford trans-whisky lactone 6 (28 mg, 93%
yield) as a colorless oil. [α]2D6 +82.1 (c 0.68, CHCl3). Its spectroscopic data (1H NMR and IR) were the
same as the reported ones in all respects.6h
Acknowledgements
Financial support from the Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan and from Japan Tobacco Co. Ltd. are gratefully acknowledged.
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