Synthesis of γ-lactones from cycloocta-1,5-diene - Starting materials for natural-product synthesis

Article abstract of DOI:10.1002/ejoc.200400219

The bislactones rac-tetrahydro-2,2′-bifuranyl -5,5′-dione (rac-12) and its diastereomer meso-25 were prepared from endo-5-hydroxy-9- oxabicyclo [4.2.1]nonan-2-one (endo-10) and endo-6-hydroxy-9-oxabicyclo[3.3.1] nonan-2-one (endo-11) or exo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (exo-23), respectively, under the conditions of a Baeyer-Villiger oxidation with trifluoroperacetic acid. The latter compounds were obtained by O-heterocylization of cis,cis-cycloocta-1,5-diene (1) by either reaction with peracids followed by hydrolysis and Jones oxidation or ruthenium tetraoxide oxidation, respectively. The optically active bislactone (R,R)-(-)-12 was prepared in a similar manner from (1S,5R,6R)-(+)-10 and (1R,5R,6R)-(+)-11, which, in turn, were obtained by lipase-catalyzed asymmetric acetylation of the corresponding diols meso-2 and rac-3 and subsequent Jones oxidation of the formed hydroxy esters (1S,2S,5R,6R)-(+)-4 and (1R,2R,5R,6R)-(+)-5. Since the regioisomeric hydroxy-9-oxa-bicyclo[4.2.1]- and -[3.3.1]nonan-2-ones (1S,5R,6R)-(+)-10 and (1R,5R,6R)-(+)-11 yielded the same bislactone [(R,R)-(-)-12] it is presumed that the sequence proceeds via open-chain intermediates. Applying this strategy to the enantiopure acetoxy ketones (1S,5R,6R)-(+)-8 and (1R,5R,6R)-(+)-9, followed by Kolbe electrolysis of the formed (R,R)-5-acetoxy-7-carboxyheptan-4-olide [(R,R)-27], (R,R)-5-acetoxydecan- 4-olide [(R,R)-29] was accessible in a five-step synthesis. The absolute configuration of (+)-8 was determined by X-ray analysis of the dithiepane derivative 14. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400219

FULL PAPER
Synthesis of γ-Lactones from Cycloocta-1,5-diene ؊ Starting Materials for
Natural-Product Synthesis
Sandra Behr,[a] Klaus Hegemann,[a] Holger Schimanski,[a] Roland Fröhlich,[a] and
Günter Haufe*[a]
Keywords: Alkenes / Cyclization / Lactones / Natural products / Oxygen heterocycles
The bislactones rac-tetrahydro-2,2Ј-bifuranyl-5,5Ј-dione
(rac-12) and its diastereomer meso-25 were prepared from
endo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (endo-10)
and endo-6-hydroxy-9-oxabicyclo[3.3.1]nonan-2-one (endo-
11) or exo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (exo-
23), respectively, under the conditions of a Baeyer−Villiger
oxidation with trifluoroperacetic acid. The latter compounds
the formed hydroxy esters (1S,2S,5R,6R)-(+)-4 and
(1R,2R,5R,6R)-(+)-5. Since the regioisomeric hydroxy-9-oxa-
bicyclo[4.2.1]- and -[3.3.1]nonan-2-ones (1S,5R,6R)-(+)-10
and (1R,5R,6R)-(+)-11 yielded the same bislactone [(R,R)-(−)-
12] it is presumed that the sequence proceeds via open-chain
intermediates. Applying this strategy to the enantiopure
acetoxy ketones (1S,5R,6R)-(+)-8 and (1R,5R,6R)-(+)-9, fol-
were obtained by O-heterocylization of cis,cis-cycloocta-1,5- lowed by Kolbe electrolysis of the formed (R,R)-5-acetoxy-
diene (1) by either reaction with peracids followed by hydro-
lysis and Jones oxidation or ruthenium tetraoxide oxidation,
respectively. The optically active bislactone (R,R)-(−)-12 was
prepared in a similar manner from (1S,5R,6R)-(+)-10 and
(1R,5R,6R)-(+)-11, which, in turn, were obtained by lipase-
catalyzed asymmetric acetylation of the corresponding diols
meso-2 and rac-3 and subsequent Jones oxidation of
7-carboxyheptan-4-olide [(R,R)-27], (R,R)-5-acetoxydecan-4-
olide [(R,R)-29] was accessible in a five-step synthesis. The
absolute configuration of (+)-8 was determined by X-ray ana-
lysis of the dithiepane derivative 14.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
which has been known for several years.[11Ϫ14] According
to these procedures the diene 1 was transformed into a mix-
ture of skeletal isomers of 9-oxabicyclononanediols 2 and
3, which were then separated by simultaneous desymmetri-
zation of meso-2 and kinetic resolution of rac-3 using Can-
dida rugosa lipase generating enantiopure monoacetates 4
and 5.[15,16]
In general, γ-butyrolactones are versatile starting materi-
als in synthetic organic chemistry since countless com-
pounds containing this function show interesting biological
activities. Many publications deal with the synthesis of 5-
hydroxy-γ-heptadecalactone (muricatacin, obtained from
the seeds of Annona muricata),[1Ϫ3] which is a potent cyto-
toxic agent on different tumor cell lines.[4] 5-Hydroxy-γ-de-
calactone, a lower homologue of muricatacin, was assumed
to be the autoregulatory factor (L-factor) of the antibiotic-
producing Gram-positive actinomycete Streptomyces
griseus.[5] Although this effect was subsequently contra-
dicted,[6] great efforts were made to synthesize this enantio-
pure target molecule.[7Ϫ10]
In this paper we describe a new approach to the bislac-
tones 12 and meso-25 and compounds 27, 28 and 29 con-
taining a single γ-butyrolactone ring. These compounds can
serve as starting materials for the above-mentioned type of
natural products and other biologically active compounds.
The sequence starts with an O-heterocylization reaction of
cis,cis-cycloocta-1,5-diene (1) using peracids, a reaction
Results and Discussion
At the beginning of our investigation the known pro-
cedures[13,14,16] for the O-heterocylization of cycloocta-1,5-
diene (1) were improved. Using commercially available 40%
peracetic acid (Wofasteril), followed by neutral workup,
30% of a 41:59 mixture of two racemic bicyclic skeletal iso-
meric monoacetates 4 and 5 as well as 63% of a 63:37 mix-
ture containing the diols 2 and 3 was isolated (Scheme 1).
[a]
Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster
Corrensstr. 40, 48149 Münster, Germany
Fax: ϩ 49-251-83-39772
E-mail: haufe@uni-muenster.de
Scheme 1. Synthesis of racemic monoacetates 4 and 5 as well as
diols 2 and 3 by transannular O-heterocyclization
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Synthesis of γ-Lactones from Cycloocta-1,5-diene
FULL PAPER
In contrast, workup at pH 10 gave a 45:55 mixture of in high yield and without affecting the enantiopurity
meso-2 and rac-3 in 92% yield. In the past these diols were (Scheme 3).
known to be produced in 65Ϫ70% yield using performic
acid, generated in situ from formic acid and 30% hydrogen
peroxide.[14,16]
Since these mixtures are difficult to separate, compounds
2 and 3 were used together for the next step. The lipase-
catalyzed kinetic resolution of rac-3 and the desym-
metrization of meso-2 by acetylation with vinyl acetate
gave different ratios of (1S,2S,5R,6R)-(ϩ)-5-acetoxy-
9-oxabicyclo[4.2.1]nonan-2-ol [(1S,2S,5R,6R)-(ϩ)-4] and
(1R,2R,5R,6R)-(ϩ)-6-acetoxy-9-oxabicyclo-[3.3.1]nonan-2-
ol [(1R,2R,5R,6R)-(ϩ)-5] with different enantiomeric purity
depending on the applied lipase and rate of conversion
(Scheme 2).[15,16]
Scheme 3. Reaction sequence leading to bislactone 12
The absolute configuration of compound (ϩ)-4 could not
be determined directly or from simple derivatives formed at
the hydroxyl function.[16] Thus, we first tried benzylation of
compound (ϩ)-10 with sodium hydride as the base, but this
reaction led to the tricyclic acetal 13 by transannular
nucleophilic attack of the intermediary alkoxide at the car-
bonyl group. The pure product 13 was isolated chromato-
graphically as an oily compound (Scheme 4).
Scheme 2. Synthesis of a mixture of enantiopure monoacetates 4
and 5 by lipase-catalyzed esterification
Additionally, the diacetates meso-6 and (1R,2R,5R,6R)-
(ϩ)-7 were produced, which were easily separated from the
monoacetates by column chromatography. The remaining
diols meso-2 (traces) and the enantiopure (1S,2S,5S,6S)-
(Ϫ)-3 were separated from the product mixture by crystalli-
zation. Using the most selective enzyme (Candida rugosa
lipase) compounds (Ϫ)-3 (14% yield) and (ϩ)-7 (10% yield)
were isolated as pure isomers with Ͼ98% ee each. Addition-
ally, an 80:20 mixture of the monoesters (ϩ)-4 (Ͼ98% ee)
and (ϩ)-5 (80% ee) was isolated with 40% yield.[15] The
Scheme 4. Derivatizations of hydroxy ketone 10
absolute configuration of the products of lipase-catalyzed
acetylation of meso-2 and rac-3, except for compound (ϩ)-
4, has already been described.[16] The absolute configura-
tion of (ϩ)-4 was determined indirectly (vide infra).
Consequently, we tried to protect the carbonyl group and
to determine the absolute configuration after eventual deri-
In the next step Jones’ reagent was used to oxidize the vatization of the remaining OH function. Therefore, similar
free hydroxyl function of the enantiopure monoacetates to a known protocol,[17] we treated the ketone (ϩ)-10 [con-
(1S,2S,5R,6R)-(ϩ)-4 and (1R,2R,5R,6R)-(ϩ)-5 to form the taminated with 30% of (ϩ)-11] with propane-1,3-thiol in
acetoxy ketones (1S,5R,6R)-(ϩ)-8 and (1R,5R,6R)-(ϩ)-9. the presence of BF3·diethyl ether, but we did not get the
Hydrolysis with methanolic potassium hydroxide gave the expected 1,3-dithiolane. Instead, the solid dithiepane 14 and
hydroxy ketones (1S,5R,6R)-(ϩ)-10 and (1R,5R,6R)-(ϩ)-11 its skeletal isomer were formed as a 72:28 mixture by inter-
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S. Behr, K. Hegemann, H. Schimanski, R. Fröhlich, G. Haufe
FULL PAPER
mediary skeletal rearrangement (Scheme 4). A similar re-
arrangement was observed earlier by Mann et al.[18] By
careful crystallization single crystals of the major product
11-hydroxy-14-oxa-2,6-dithiatricyclo[8.3.1.01,7]tetradecane
(14) were grown. These crystals were suitable to determine
the absolute configuration to be (1S,7R,10R,11R) by X-ray
structural analysis (Figure 1).
Table 1. BaeyerϪVilliger oxidation of different mixtures of 10 and
11; comparison of yield and enantiomeric excess of product 12
Reactant ratio (ee)[a]
(1S,5R,6R)-(ϩ)-10 (1R,5R,6R)-(ϩ)-11 [ee found][b] (ee calcd.)[c]
Yield (R,R)-(Ϫ)-12
1
2
3
4
5
81 (Ͼ98%)
81 (Ͼ98%)
56 (Ͼ98%)
37 (Ͼ98%)
59 (rac)
19 (60%)
19 (30%)[d]
44 (83%)
63 (Ͼ98%)
41 (rac)
78 [95%] (92%)
78 [80%] (75%)
74 [93%] (93%)
72 [Ͼ98%] (Ͼ98%)
75 [rac]
[a]
According to enantiopurity of acetates 4 and 5, measured by
chiral GC (BetadexTM 120, 165 °C, isothermic).
Measured by
[b]
chiral GC (BetadexTM 120, 165 °C, isothermic). [c] Expected ee with
[d]
complete conversion of both 10 and 11 presumed.
(1S,5S,6S)-
(Ϫ)-11, prepared by lipase-catalyzed hydrolysis of rac-7.[16]
However, according to the different ratio and enantio-
meric purity of the skeletal isomers 10 and 11 (Table 1, en-
tries 1Ϫ4) used in the BaeyerϪVilliger oxidation it is pre-
sumed that the 9-oxabicyclo[3.3.1]nonan-2-one system 11
also generates the bislactone 12. Isomerization of the
hydroxy ketones can be excluded under these conditions.
Entries 3Ϫ5 in Table 1 show that the yield of 12 exceeds the
portion of [4.2.1]bicyclic hydroxy ketone 10 in the mixture
Figure 1. X-ray structure of (1S,7R,10R,11R)-11-hydroxy-14-oxa-
2,6-dithiatricyclo[8.3.1.01,7]tetradecane (1S,7R,10R,11R)-(14)
Since no reaction occurred at carbons number 10 and 11 of starting materials. In addition, the enantiomeric excess
during the SN2-type skeletal rearrangement, the configura- of 12 becomes lower with decreasing ee of ketone 11 (En-
tion of the original acetoxy alcohol is (1S,2S,5R,6R)-4 tries 1Ϫ3, Table 1). Furthermore no comparative δ-bislac-
(Scheme 3).
tone 15 (Scheme 5) was observed.
Continuing the synthetic sequence, BaeyerϪVilliger oxi-
Thus, the following mechanism is proposed. First the bi-
dation[19] of the acetoxy ketones (1S,5R,6R)-(ϩ)-8 and cyclic lactones 16 and 17 are formed, which are not stable
(1R,5R,6R)-(ϩ)-9 and of the hydroxy ketones (1S,5R,6R)- in the acidic medium and undergo ring opening and sub-
(ϩ)-10 and (1R,5R,6R)-(ϩ)-11 was planned. Normally per- sequent oxidation of the intermediate lactols under the oxi-
acids or hydrogen peroxide are used for such oxidations. dative conditions to give γ- and δ-lactono hydroxy acids
However, all attempts to react the acetoxy ketones 8 and 9 18 and 19. Since no δ-lactone was found as a product a
by ‘‘classical’’ reagents such as 32% peracetic acid or m- translactonization might occur via an open-chain inter-
chloroperbenzoic acid failed. These reagents seem to be too mediate 20, which, under the reaction conditions, forms the
weak for BaeyerϪVilliger oxidation of the mentioned ke- stable bislactone 12 exclusively. In some reactions with a
tones, which are deactivated due to the adjacent ether func- smaller excess of the peracid, the lactololactol 21 was
tionality. Trifluoroperacetic acid (TFPAA) has been de- formed in 14Ϫ16% yield. This observation supports the
scribed as a strong oxidizing agent in BaeyerϪVilliger oxi- presumed mechanism. Thus, this five-step procedure pro-
dation. However, starting with trifluoroacetic acid and 90% vides enantiopure (R,R)-(Ϫ)-12 from bulk cis,cis-cycloocta-
hydrogen peroxide[20] would provide an extensive safety 1,5-diene (1) in 26% overall yield.
risk, which can be easily avoided by preparing trifluoroper-
In order to amplify the variety of stereochemical infor-
acetic acid in situ from trifluoroacetic acid and sodium per- mation in intermediates of natural-product syntheses we did
carbonate (Na2CO3·1.5H2O2).[21] According to this proto- not confine ourselves to application of peracids in O-hetero-
col an 81:19 mixture of the hydroxy ketones (1S,5R,6R)- cyclization reactions. In due course we also used transition-
(ϩ)-10 and (1R,5R,6R)-(ϩ)-11 was transformed into bislac- metal-catalyzed oxidative cyclizations. For oxidation of
tone (R,R)-(Ϫ)-12 in 78% yield in the presence of six equiv- open-chain 1,5-dienes to form cis-2,5-disubstituted tetra-
alents of trifluoroperacetic acid generated in situ (Table 1, hydrofurans potassium permanganate,[22] ruthenium tetra-
entry 1). From the isolated yield it remained unclear oxide,[23,24] perruthenate[25] or osmium tetraoxide[26] have
whether (R,R)-(Ϫ)-12 is formed exclusively from been applied in the literature. Using catalytic amounts of
(1S,5R,6R)-(ϩ)-10 or also from (1R,5R,6R)-(ϩ)-11, al- RuCl3 hydrate and excess sodium periodate as oxidant
though the slightly decreased enantiomeric excess of (R,R)- cis,cis-cycloocta-1,5-diene (1) was converted into a 6:85:9
(Ϫ)-12 (95% ee) might indicate that both (1S,5R,6R)-(ϩ)- mixture
10 (Ͼ98% ee) and (1R,5R,6R)-(ϩ)-11 (60% ee) might have (exo,exo-22),
of
exo,exo-9-oxabicyclo[4.2.1]nonane-2,5-diol
exo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-5-
been oxidized to 12. Unfortunately, we were not able to one (exo-23) and 9-oxabicyclo[4.2.1]nonane-2,5-dione (24;
isolate optically active (1R,5R,6R)-(ϩ)-11 as a pure skel- Scheme 6). The major product was isolated in 53% yield
etal isomer.
after complete conversion of 1 in the presence of four equiv-
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Synthesis of γ-Lactones from Cycloocta-1,5-diene
FULL PAPER
these conditions. The relative stereochemistry of the prod-
ucts was assigned by spectroscopic data and a mechanism
proposed.[23]
For comparison, permanganate was applied to oxidize
cis,cis-cycloocta-1,5-diene (1) under the conditions men-
tioned in the literature, except that a lower temperature (0
°C) was used.[22] After 1.5 hours conversion reached just
52% (GC) and diketone 24 was identified as the main prod-
uct (75%) by GC. Desired compounds exo,exo-22 and exo-
23 were detected as side products in only 14% and 11%
yields, respectively. Due to the fact that the conversion was
not complete at this point, the mixture was just analyzed
by GC and no further attempts at optimization were made.
Under the conditions described above, the hydroxy ke-
tone exo-23 underwent BaeyerϪVilliger oxidation giving
the bislactone meso-25 in 57% yield. The lactololactol 26
was identified as a minor product in ratios of 2Ϫ25%
(Scheme 7). Jones oxidation of the crude product mixture
of another run of BaeyerϪVilliger oxidation (meso-25:26 ϭ
75:25, GC) gave the pure bislactone meso-25 in 68% yield.
Thus, this three-step procedure provided meso-25 from bulk
cis,cis-cycloocta-1,5-diene (1) in 36% overall yield.
Scheme 5. Presumed mechanism of BaeyerϪVilliger oxidation of
hydroxy ketones endo-10 and endo-11 leading to 12 as the major
product
Scheme 7. BaeyerϪVilliger oxidation of exo-23 and subsequent
Jones oxidation
In principle there are other syntheses known in which
either the stereochemistry of the bislactones 12 and 25 and
corresponding monolactones is provided already in the
starting material, for example - and -gulono-1,4-lactone,
-mannono-1,4-lactone[27Ϫ29] or -tartric acid and -man-
nitol,[30] or in which conventional asymmetric steps are
used, for example the Sharpless bishydroxylation of γ-un-
saturated mono-esters[31] and diesters.[32,33] Our approach,
however, also gives the possibility of preparing enantiopure
or racemic 12 and meso-bislactone 25 as well as enantiopure
monolactones by minimal modifications of the workup
conditions. Therefore, we applied Jones oxidation directly
to a 74:26 mixture of monoacetates (1S,2S,5R,6R)-(ϩ)-4
(Ͼ98% ee) and (1R,2R,5R,6R)-(ϩ)-5 (80% ee) which gave
acetoxy ketones (1S,5R,6R)-(ϩ)-8 and (1R,5R,6R)-(ϩ)-9 in
good yield. These were treated with a threefold excess of
trifluoroperacetic acid, leading to almost enantiopure
(R,R)-5-acetoxy-7-carboxyheptane-4-olide [(R,R)-27] in
35% yield after aqueous workup of the acidic reaction mix-
ture and continuous extraction with dichloromethane
(Scheme 8). When the reaction mixture was quenched with
methanol, continuous extraction gave the methyl ester
[(R,R)-(Ϫ)-28] in 61% yield[34,35] When using saturated so-
dium hydrogencarbonate solution for workup the bislac-
Scheme 6. RuO4 oxidation of diene 1
alents of sodium periodate in a mixture of water, aceto-
nitrile and acetone (v/v/v ϭ 1:1:1, Table 2, entry 3). No 9-
oxabicyclo[3.3.1]nonane derivative was observed under
Table 2. Oxidative cyclization of 1 using catalytic amounts of RuCl3
hydrate and four equivalents of NaIO4
Solvent mixture
Product ratio[a]
Yield
(total volume in mL)[b] exo,exo-22 exo-23 24 exo-23
1
2
3
4
A 1:2:1 (25)
A 1:1:1.5 (35)
B 1:1:1 (30)
C 1:1 (20)
6
10
2
85
68
72
68
9
44[c]
22 50[d]
26 53[d]
25 47[d]
7
[a]
[b]
Determined by GC. A: water/ethyl acetate/acetone; B: water/
[c]
acetonitrile/acetone; C: water/acetonitrile; per 1 mmol of 1.
Aqueous workup with sat. sodium thiosulfate solution, then con-
tinuous extraction with ethyl acetate for three days. [d] Filtration of
precipitate, then continuous extraction with ethyl acetate for three
days.
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S. Behr, K. Hegemann, H. Schimanski, R. Fröhlich, G. Haufe
FULL PAPER
tone [(R,R)-(Ϫ)-12 was again isolated in 76% yield after or transition metal oxidants like RuO4 — the relative
column chromatography. No other product was isolated. stereochemistry of the 9-oxabicyclononanone, the starting
The mechanism presumed to operate for hydroxy ketones material for BaeyerϪVilliger oxidation, can be chosen. En-
endo-10 and endo-11 (Scheme 6) should also be valid for the antiopure compounds were achieved by lipase-catalysed
acetoxy ketones 8 and 9 and will also be useful for the syn- simultaneous desymmetrization and kinetic resolution, as
thesis of other derivatives of 10 and 11 containing a pro- reported recently.[15]
tected OH group.
Experimental Section
General Remarks: All reagents and solvents were obtained from
commercial sources and used as received, unless otherwise speci-
fied. Tetrahydrofuran was dried by distillation over sodium benzo-
phenone. Products were separated by column chromatography (sil-
ica gel 60, Merck 0.063Ϫ0.200 mm, 70Ϫ230 mesh). The compo-
sition of the crude reaction products and the conversions of sub-
strates were monitored by GC using quartz capillary columns: 25 m
ϫ 0.33 mm ϫ 0.52 µm HP-1 (HewlettϪPackard) and 30 m ϫ
0.32 mm ϫ 0.25 µm SPB-1TM (Supelco). Enantiomeric excesses (ee)
were determined by GC: 30 m ϫ 0.25 mm ϫ 0.25 µm chiral Beta-
DexTM 120 (Supelco), isothermic (165 °C). Optical rotations were
determined at λ ϭ 589 nm (sodium D-line). 1H NMR (400.1 MHz
or 300.1 MHz) and 13C NMR (100.6 MHz or 75.5 MHz) were re-
corded in CDCl3. Chemical shifts are reported as δ values (ppm)
relative to TMS as internal standard. The multiplicities of 13C sig-
nals were determined by the DEPT pulse sequence. The assignment
of the 1H and 13C signals is based on 2D NMR spectra (1H,1H-
Scheme 8. BaeyerϪVilliger oxidation of acetoxy ketones 8 and 9
leading either to bislactone 12, lactono acid 27 or methyl ester 28
1
COSY or H,13C-HECTOR). Signals of inseparable mixtures were
assigned to the respective compounds using 1D-TOCSY difference
spectra. Mass spectra (electron impact ionisation, 70 eV) were re-
corded by GC/MS coupling. Elementary analyses were carried out
by the ‘‘Mikroanalytisches Laboratorium, Organische Chemie’’,
University of Münster. The X-ray data set was collected with a
four-circle diffractometer. Programs used: data collection EX-
PRESS (Nonius B.V., 1994), data reduction MolEN (K. Fair,
EnrafϪNonius B.V., 1990), structure solution SHELXS-97,[36]
structure refinement SHELXL-97,[37] graphics SCHAKAL.[38]
In an additional step (R,R)-27 was transformed into
(R,R)-5-acetoxydecan-4-olide (R,R)-29 (Scheme 9), the O-
acetyl derivative of the already mentioned 5-hydroxy-γ-de-
calactone. Kolbe electrolysis of (R,R)-5-acetoxy-7-carboxy-
heptane-4-olide (R,R)-27 and butanoic acid gave (R,R)-29
in 10% yield after purification by column chromatography.
The application of other co-acids might give access to other
biologically active lactones.
(1S,5R,6R)-(؉)-5-Hydroxy-9-oxabicyclo[4.2.1]nonane-2-one (endo-
10) and (1R,5R,6R)-(؉)-6-Hydroxy-9-oxabicyclo[3.3.1]nonane-2-
one (endo-11): According to known procedures for corresponding
racemic compounds[13] an 81:19 mixture of acetates (1S,2S,5R,6R)-
(ϩ)-4 (Ͼ98% ee) and (1R,2R,5R,6R)-(ϩ)-5 (60% ee) (1.19 g,
5.94 mmol)[15] was dissolved in acetone (50 mL). At 0 °C Jones’
reagent (2.5 mL portion, made from 26.0 g of CrO3, 23 mL of
concd. H2SO4 and 77 mL of H2O) was added slowly. The mixture
was warmed up to room temperature and stirred for 1 h. Excess
oxidant was destroyed with 2-propanol (13 mL) at 0 °C, and then
the mixture was treated with water (30 mL) to dissolve the precipi-
tate and extracted with dichloromethane (5 ϫ 25 mL). The com-
bined organic layer was dried over MgSO4 and concentrated in
vacuo. The crude residue was then dissolved in methanol (30 mL)
and treated slowly with 2  methanolic KOH (25 mL) at room tem-
perature. After stirring for three more hours, water (20 mL) was
added and the mixture was neutralized with 4  HCl. After evapor-
ation of methanol to the greatest possible extent, the aqueous resi-
due was extracted continuously with ethyl acetate for three days.
The combined organic phases were dried over MgSO4 and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, cyclohexane/ethyl acetate, 1:1) to give (1S,5R,6R)-
(ϩ)-10 (Ͼ98% ee) and (1R,5R,6R)-(ϩ)-11 (60% ee) as a colorless
oil with an unchanged ratio of the skeletal isomers (81:19, GC).
Scheme 9. Kolbe electrolysis of lactono acid (R,R)-27 and but-
anoic acid
Conclusion
Herein we have reported BaeyerϪVilliger oxidations of
9-oxabicyclononan-2-ones, which were readily accessible by
transannular O-heterocyclizations of cycloocta-1,5-diene (1)
with in-situ-generated trifluoroperacetic acid as the key
step. Depending on the workup conditions either the corre-
sponding bislactones or functionalized γ-butyrolactones
were synthesized in moderate to good yields. Both series of
compounds are useful intermediates in synthesis since the
stereochemistry is easily controllable. Dependent upon the
reagent used for the oxidation of 1 — either peracetic acid Yield: 0.78 g (84% over two steps). Previously spectroscopic data
3888  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 3884Ϫ3892

Synthesis of γ-Lactones from Cycloocta-1,5-diene
FULL PAPER
were just partially described.[13] 1H NMR (400 MHz, CDCl3): δ ϭ (t, 12-CH2 [14]), 28.8 (t, 5-CH2 [15]), 28.0 (t, 8-CH2 [14]), 27.8 (t,
4.55Ϫ4.62 (m, 1 H [10], 6-CH), 4.38 (dd, J ϭ 10.1, 2.0 Hz, 1 H, 13-CH2 [15]), 26.5 (t, 12-CH2 [15]), 26.3 (t, 9-CH2 [15]), 24.7 (t, 8-
[10], 1-CH), 4.22Ϫ4.30 (m, 1 H [11], 5-CH), 4.05 (dt, J ϭ 11.1, CH2 [15]), 22.6 (2 t, 4-CH2 [14], 4-CH2 [15]) ppm. GC-MS (70 eV,
4.7 Hz, 1 H [10], 5-CH), 4.00Ϫ4.07 (m, 1 H [11], 1-CH), 3.92 (dt, Ion Trap): m/z (%) ϭ 248 (9) [Mϩ ϩ 2], 247 (15) [Mϩ ϩ 1], 246
J ϭ 12.3, 4.9 Hz, 1 H [11], 6-CH), 2.88 (dt, J ϭ 14.0, 2.4 Hz, 1 H (100) [Mϩ], 244 (4), 171 (6), 153 (9), 134 (31) [247 Ϫ C6H9O2], 133
[10], exo-3-CH), 2.73Ϫ2.86 (m, 1 H [11], exo-3-CH), 1.35Ϫ2.42 (m, (6) [Mϩ Ϫ C6H9O2], 119 (36) [Mϩ Ϫ C7H11O2], 106 (65) [C3H6S2ϩ],
7 H [10], endo-3-CH, 4-CH2, 7-CH2, 8-CH2; 7 H [11], endo-3-CH,
97 (10), 85 (18) [C5H9Oϩ], 71 (33) [C4H7Oϩ], 81 (17), 72 (22)
4-CH2, 7-CH2, 8-CH2) ppm. 13C NMR (400 MHz, CDCl3): δ ϭ [C4H8Oϩ], 71 (100) [C4H7Oϩ], 67 (34) [95 Ϫ C2H4], 66 (7), 58 (10),
219.4 (s, [10], 2-CϭO), 218.2 (s, [11], 2-CϭO), 85.5 (d, [10], 6-CH),
84.2 (d, [10], 1-CH), 78.4 (d, [11], 5-CH), 73.3 (d, [10], 5-CH), 71.4
(d, [11], 1-CH), 69.1 (d, [11], 6-CH), 38.3 (t, [10], 3-CH2), 35.8 (t,
[11], 3-CH2), 32.4 (t, [10], 8-CH2), 28.5 (t, [11], 7-CH2), 28.1 (t, [10],
7-CH2), 26.1 (t, [11], 8-CH2), 23.8 (t, [10], 4-CH2), 20.1 (t, [11], 4-
CH2) ppm.
55 (20), [C4H7ϩ], 45 (18), 41 (32) [C3H5ϩ].
X-ray Crystallographic Study: Careful recrystallization from ace-
tone gave single crystals of 14 suitable for X-ray structural analysis:
formula C11H18O2S2, M ϭ 246.37, colorless crystal 0.30 ϫ 0.25 ϫ
3
˚
˚
0.10 mm, a ϭ 15.420(2), c ϭ 9.686(1) A, V ϭ 1994.5(4) A , ρcalcd. ϭ
1.231 g cmϪ3, µ ϭ 34.74 cmϪ1, empirical absorption correction by
ψ-scan data (0.422 Յ T Յ 0.723), Z ϭ 6, hexagonal, space group
1-Benzyloxy-9,10-dioxatricyclo[4.2.1.12,5]decane (13): A suspension
of a 60% sodium hydride (0.11 g, 2.8 mmol) in mineral oil was ad-
ded under argon to a 70:30 mixture of (1S,5R,6R)-5-hydroxy-9-
oxabicyclo[4.2.1]nonan-2-one (10) and (1R,5R,6R)-6-hydroxy-9-
˚
P61 (no. 169), λ ϭ 1.54178 A, T ϭ 223 K, ω/2θ scans, 1600 reflec-
tions collected (Ϫh, Ϫk, Ϫl), [(sinθ)/λ] ϭ 0.62 AϪ1, 1439 indepen-
˚
dent (Rint ϭ 0.048) and 1366 observed reflections [I Ն 2 σ(I)], 137
oxabicyclo[3.3.1]-nonan-2-on (11) (0.40 g, 2 mmol) in 40 mL of abs. refined parameters, R ϭ 0.061, wR2 ϭ 0.183, max. residual electron
density 1.20 (Ϫ0.31) e·AϪ3, remaining electron density is located
˚
THF. The reaction mixture was refluxed for 30 min and then benzyl
bromide (0.34 g, 2 mmol) in 2 mL of abs. THF was added over a around 0,0,z and cannot be assigned in a chemically meaningful
period of 20 min and refluxed for 18 hours. The reaction mixture
was then poured into 50 mL of water and extracted with ethyl acet-
ate (3 ϫ 50 mL). The combined organic layer was dried over mag-
nesium sulfate and the solvent was removed in vacuo. The remain-
ing residue was purified by column chromatography (cyclohexane/
ethyl acetate, 1:1) to give 13 as an oil. Yield: 0.24 g (49%). 1H NMR
(300 MHz, CDCl3): δ ϭ 7.21Ϫ7.38 (m, 5 H, 14-CH, 14Ј-CH, 15-
way, Flack parameter 0.08(4), hydrogens calculated and refined as
riding atoms.
CCDC-233051 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: ϩ 44-1223-336-033; E-mail:
CH, 15Ј-CH, 16-CH), 4.55Ϫ4.80 (m, 2 H, 12-CH2), 3.91Ϫ4.06 (m, deposit@ccdc.cam.ac.uk].
3 H, 2-CH, 5-CH, 6-CH), 1.72Ϫ2.38 (m, 8 H, 3-CH2, 4-CH2, 7-
CH2, 8-CH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 138.5 (s, 13-
C), 128.3 (2d, 15-CH, 15Ј-CH), 127.4 (d, 16-CH), 127.3 (2d, 14-
CH, 14Ј-CH), 108.0 (s, 1-C), 81.8 (d, 2-CH), 79.4 (d, 6-CH), 79.1
(d, 5-CH), 63.7 (t, 12-CH2), 27.6 (2t, 4-CH2, 7-CH2), 27.3 (t, 8-
CH2), 26.1 (t, 3-CH2) ppm. GC-MS (70 eV): m/z (%) ϭ 246 (0.4)
[Mϩ], 200 (0.6), 156 (12) [Mϩ Ϫ C7H6], 155 (96) [Mϩ Ϫ C7H7], 138
(4), 137 (2) [155 Ϫ H2O], 111 (78) [137 Ϫ C2H2], 99 (6), 92 (11), 91
(100) [Mϩ Ϫ C8H11O3], 85 (12) [111 Ϫ C2H2], 81 (16), 67 (4), 65
(11), 57 (4), 55 (14), 41 (6). C15H18O3 (246.3): calcd. C 73.15, H
7.37; found C 73.22, H 7.55.
exo-5-Hydroxy-9-oxabicyclo[4.2.1]nonane-2-one (exo-23). a) Oxi-
dation by RuO4: NaIO4 (21.4 g, 0.1 mol) was dissolved in water
(250 mL) in a 1-L flask and a catalytic amount of RuCl3·xH2O
dissolved in acetone (250 mL) was added. Diene 1 (2.71 g, 3.07 mL,
25 mmol) was dissolved in acetonitrile (250 mL) and added to the
ruthenium tetraoxide solution within 45 min. After stirring for an
additional 40 min the slurry was filtered and the remaining solution
was extracted continuously with ethyl acetate. The organic layer
was washed with brine (50 mL), dried over MgSO4 and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel with a mixture of cyclohexane/ethyl acetate (2:1)
to give exo-23 as a colorless oil. Yield: 2.06 g (53%). 1H NMR
Synthesis of (1S,7R,10R,11R)-11-Hydroxy-14-oxa-2,6-dithiatri-
cyclo[8.3.1.01,7]tetradecane (14): Propane-1,3-dithiol (0.32 g, (400 MHz, CDCl3): δ ϭ 4.61 (m, 1 H, 6-CH), 4.40 (dd, J ϭ 9.4,
3.0 mmol) was added dropwise at room temperature to a 70:30 mix-
ture of (1S,5R,6R)-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (10) 1 H, 3-CH or 3Ј-CH), 2.85 (br. s, 1 H, -OH), 2.22Ϫ2.32 (m, 1 H,
and (1R,5R,6R)-6-hydroxy-9-oxabicyclo[3.3.1]nonan-2-one (11) 8-CH or 8Ј-CH), 2.11Ϫ2.18 (m, 2 H, 3-CH or 3Ј-CH, 7-CH or 7Ј-
(0.45 g, 2.9 mmol) in 30 mL of dry dichloromethane. Then, five CH), 2.02Ϫ2.09 (m, 1 H, 8-CH or 8Ј-CH), 1.88Ϫ1.96 (m, 1 H, 4-
2.6 Hz, 1 H, 1-CH), 3.80 (m, 1 H, 5-CH), 3.23 (dt, J ϭ 13.9, 2.9 Hz,
drops of BF3·Et2O were added and the mixture was stirred for 4 h.
Subsequently the solvent was removed in vacuo and the crude
product was purified by column chromatography (cyclohexane/
CH or 4Ј-CH), 1.73-1.82 (m, 1 H, 4-CH or 4Ј-CH), 1.54Ϫ1.63 (m,
1 H, 7-CH or 7Ј-CH) ppm. 13C NMR (400 MHz, CDCl3): δ ϭ
217.4 (s, 2-CϭO) 83.9 (d, 6-CH), 83.6 (d, 1-CH), 71.4 (d, 5-CH),
ethyl acetate, 1:1). A 72:28 mixture of 14 and 15 remained as a 35.2 (t, 3-CH2), 29.8 (t, 8-CH2), 25.9 (t, 4-CH2), 25.5 (t, 7-CH2)
solid. Yield: 0.52 g (72%). [α]2D0 ϭ Ϫ10.1 (c ϭ 1.03, chloroform). ppm. GC-MS (70 eV, Ion Trap): m/z (%) ϭ 156 (5) [Mϩ], 138 (5)
1H NMR (400 MHz, CDCl3): δ ϭ 4.70Ϫ4.73 (m, 1 H [15], 10-CH), [Mϩ Ϫ H2O], 128 (6) [Mϩ Ϫ CO], 113 (5) [Mϩ Ϫ 43], 110 (8)
4.41Ϫ4.45 (m, 1 H [15], 11-CH), 4.04Ϫ4.12 (m, 1 H [14], 11-CH), [138 Ϫ CO or 128 Ϫ H2O], 100 (16) [128 Ϫ CO or C2H4], 95 (6),
3.95Ϫ4.00 (m, 1 H [14], 10-CH), 3.10Ϫ3.16 (m, 1 H [14], 7-CH; 1 85 (33) [113 Ϫ CO or C2H4], 84 (21), 83 (18), 82 (21) [110 Ϫ CO or
H [15], 7-CH), 2.65Ϫ3.01 (m, 5 H [14], 3-CH2, 8-CH2, endo- or C2H4], 81 (22), 72 (30) [100 Ϫ CO or C2H4], 71 (100), 67 (36), 57
exo-13-CH2; 4 H [15], 9-CH2, 12-CH2), 1.71Ϫ2.47 (m, 9 H [14], 4- (47) [85 Ϫ CO or C2H4], 55 (28) [85 Ϫ CH2O], 44 (60) [72 Ϫ CO or
CH2, 5-CH2, 9-CH2, 12-CH2, endo- or exo-13-CH2; 10 H [15], 3- C2H4], 43 (46), 41 (46), 39 (18). C8H12O3 (156.2): calcd. C 61.52,
CH2, 4-CH2, 5-CH2, 8-CH2, 13-CH2) ppm. 13C NMR (100 MHz, H 7.74; found C 61.05, H 7.49.
CDCl3): δ ϭ 87.9 (s, 1-C [14], 1-C [15]), 84.4 (d, 10-CH [15]), 81.2 exo,exo-2,5-Dihydroxy-9-oxabicyclo[4.2.1]nonane (22): 1H NMR
(d, 11-CH [15]), 73.2 (d, 10-CH [14]), 67.6 (d, 11-CH [14]), 54.2 (d,
7-CH2 [14], 7-CH2 [15]), 33.9 (t, 3-CH2 [14]), 33.7 (t, 3-CH2 [15]), (m, 2 H, 2-CH, 5-CH), 2.03Ϫ2.11 (m, 2 H, 7-CH or 7Ј-CH, 8-CH
32.7 (t, 5-CH2 [14]), 31.4 (t, 13-CH2 [14]), 29.7 (t, 9-CH2 [14]), 29.6 or 8Ј-CH), 1.83Ϫ1.92 (m, 2 H, 3-CH or 3Ј-CH, 4-CH or 4Ј-CH),
(400 MHz, [D4]methanol): δ ϭ 4.29 (m, 2 H, 1-CH, 6-CH), 3.60
Eur. J. Org. Chem. 2004, 3884Ϫ3892
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3889

S. Behr, K. Hegemann, H. Schimanski, R. Fröhlich, G. Haufe
FULL PAPER
1.58Ϫ1.71 (m, 4 H, 3-CH or 3Ј-CH, 4-CH or 4Ј-CH, 7-CH or 7Ј- (2) [C5H7O3ϩ], 87 (2), 86 (28), 85 (100) [C4H5O2ϩ], 57 (27)
CH, 8-CH or 8Ј-CH) ppm. 13C NMR (CDCl3): δ ϭ 85.9 (d, 1-CH, [85 Ϫ CO], 56 (7), 55 (5) [85 Ϫ CH2O], 42 (4), 41 (3), 39 (5).
6-CH), 76.8 (d, 2-CH, 5-CH), 29.2 (t, 7-CH2, 8-CH2), 27.8 (t, 3- In some cases 5Ј-hydroxytetrahydro-2,2Ј-bifuranyl-5-one (21) was
CH2, 4-CH2) ppm. GC-MS (70 eV, Ion Trap): m/z (%) ϭ 158 (0)
identified as a side-product of this reaction in 14Ϫ16% yield (GC).
[Mϩ], 140 (5) [Mϩ Ϫ H2O], 124 (6), 122 (5) [140 Ϫ H2O], 115 (3), 1H NMR (400 MHz, CDCl3): δ ϭ 5.57Ϫ5.58 (br. d, 1 H, cis- and
112 (28) [140 Ϫ CO or C2H4], 97 (23), 96 (32), 84 (84) [112 Ϫ CO trans-5Ј-CH), 4.50 (m, 1 H, 2-CH), 4.31 (m, 1 H, 2Ј-CH),
or C2H4], 79 (91), 71 (63), 68 (93), 67 (82), 57 (98) [C4H9ϩ], 55 (69),
44 (37), 43 (57), 42 (23), 41 (100), 39 (30).
2.61Ϫ2.72 (m, 2 H, 4-CH2), 2.20Ϫ2.33 (m, 2 H, 3-CH2), 2.08 (m,
2 H, 4Ј-CH2), 1.86 (m, 2 H, 3Ј-CH2) ppm. 13C NMR (CDCl3): δ ϭ
176.9 (s, 5-CϭO), 99.4 (d, 5Ј-C-OH), 81.8 (d, 2Ј-CH), 81.2 (d, 2-
9-Oxabicyclo[4.2.1]nonane-2,5-dione (24): 1H NMR (400 MHz,
CDCl3): δ ϭ 4.59 (m, 2 H, 1-CH, 6-CH), 2.95 (m, 2 H, 3-CH or CH), 32.9 (t, 4Ј-CH2), 28.0 (t, 4-CH2), 25.6 (t, 3-CH2), 24.9 (t, 3Ј-
3Ј-CH, 4-CH or 4Ј-CH), 2.38 (m, 2 H, 3-CH or 3Ј-CH, 4-CH or
4Ј-CH), 2.21Ϫ2.29 (m, 2 H, 7-CH or 7Ј-CH, 8-CH or 8Ј-CH),
CH2) ppm. GC-MS (70 eV, Ion Trap): m/z (%) ϭ 172 (1) [Mϩ], 154
(2) [Mϩ Ϫ H2O], 129 (2), 115 (9), 98 (11), 87 (100) [C4H7O2ϩ], 86
1.94Ϫ1.99 (m, 2 H, 7-CH or 7Ј-CH, 8-CH or 8Ј-CH) ppm. 13C (44), 85 (49) [C4H5O2ϩ], 69 (28) [87 Ϫ H2O], 57 (18) [85 Ϫ CO], 43
NMR (CDCl3): δ ϭ 212.0 (s, 2-CϭO, 5-CϭO) 85.2 (d, 1-CH, 6-
CH), 35.3 (t, 3-CH2, 4-CH2), 28.6 (t, 7-CH2, 8-CH2) ppm. GC-MS
(70 eV, Ion Trap): m/z (%) ϭ 154 (13) [Mϩ], 126 (56) [Mϩ Ϫ CO],
111 (14) [Mϩ Ϫ 43], 98 (85) [126 Ϫ CO or C2H4], 83 (42)
[111 Ϫ CO or C2H4], 70 (100) [98 Ϫ CO or C2H4], 69 (66), 56 (34),
55 (100) [83 Ϫ CO or C2H4], 54 (58), 42 (85) [70 Ϫ CO or C2H4],
41 (56), 39 (43). C8H10O3 (158.2): calcd. C 62.33, H 6.54; found C
61.97, H 6.58.
(25), 41 (21).
(2R,2ЈS)-Tetrahydro-2,2Ј-bifuranyl-5,5Ј-dione (meso-25): Hydroxy
ketone exo-23 (493 mg, 3.16 mmol) was transformed as described
above. The crude residue containing a mixture of meso-25 and 26
(75:25, GC) was dissolved in acetone (20 mL). At 0 °C Jones’ re-
agent (1 mL portion, made of 26.0 g of CrO3, 23 mL of concd.
H2SO4 and 77 mL of H2O) was added slowly. The mixture was
warmed up to room temperature and stirred for 1 h. Excess oxidant
was destroyed with 2-propanol (5 mL) at 0 °C. After dissolving
the precipitate in water (15 mL), the mixture was extracted with
dichloromethane (5 ϫ 25 mL). The combined organic layer was
dried over MgSO4 and concentrated in vacuo to give meso-25
(365 mg, 2.15 mmol, 68%). Spectroscopic data agree with pre-
viously published ones.[27]
A mixture of the cis- and trans-isomers of 5Ј-hydroxytetrahydro-
2,2Ј-bifuranyl-5-one (26) was identified as a side product of this
reaction in 2Ϫ25% yield (GC). H NMR (400 MHz, CDCl3): δ ϭ
5.62Ϫ5.76 (br. d, 2 H, cis- and trans-5Ј-CH), 4.49Ϫ4.57 (m, 2 H,
2-CH), 4.22Ϫ4.34 (m, 2 H, 2Ј-CH), 2.46Ϫ2.67 (m, 2 H, 4-CH2),
1.62Ϫ2.46 (m, 12 H, 3-CH2, 3Ј-CH2, 4Ј-CH2) ppm. 13C NMR
(CDCl3): δ ϭ 176.9, 176.7 (s, 5-CϭO), 106.2, 107.6 (d, 5Ј-C-OH),
80.4 (2d, 2-CH), 79.1, 78.9 (d, 2Ј-CH), 28.7, 28.6 (t, 4Ј-CH2), 27.9,
27.8 (t, 4-CH2), 24.9 (2t, 3Ј-CH2), 23.0, 22.8 (t, 3-CH2) ppm. GC-
b) Oxidation by KMnO4: KMnO4 (1.58 g, 10 mmol, 2.5 equiv.) was
dissolved in acetone (72 mL) and water (6 mL) and was then slowly
added to a solution of diene 1 (0.5 mL, 4 mmol) in acetone (2 mL)
at 0 °C. After stirring for 30 min the precipitate was filtered off and
acetone was removed almost completely in vacuo. The aqueous
layer was extracted with dichloromethane (3 ϫ 100 mL) and the
combined organic layers were dried over MgSO4 and concentrated
in vacuo. The residue was analysed by GC showing 48% of remain-
ing diene 1. The reaction products were identified as the diketone
24 (75%), the hydroxy ketone exo-23 and diol 22 (14% and 11%,
respectively).
1
General Procedure for the Baeyer؊Villiger Oxidation: The bicyclic
ketone (2.0 mmol) and trifluoroacetic acid (4 mL) were dissolved
in abs. dichloromethane (10 mL). Sodium percarbonate (1.32 g,
8.4 mmol) was then added in portions within one hour at 0 °C.
The heterogeneous mixture was warmed up to room temperature
and stirred vigorously for four hours. After addition of water
(15 mL) the two-phase mixture was stirred for an additional 18 h.
The mixture was then cautiously neutralized by addition of solid
and a saturated solution of sodium hydrogencarbonate. The aque-
ous phase was extracted continuously with dichloromethane for 3
d. The organic phase was then stirred over FeSO4 to destroy the
remaining peroxides, and then dried over MgSO4 and concentrated
in vacuo.
MS (70 eV, Ion Trap): m/z (%)
ϭ
172 (0) [Mϩ], 154 (4)
[Mϩ Ϫ H2O], 129 (3), 115 (7), 98 (8), 87 (100) [C4H7O2ϩ], 86 (43),
85 (58) [C4H5O2ϩ], 69 (35) [87 Ϫ H2O], 57 (16) [85 Ϫ CO], 43 (23),
41 (17).
(1S,5R,6R)-(؉)-5-Acetoxy-9-oxabicyclo[4.2.1]nonane-2-one (8) and
(1R,5R,6R)-6-(؉)-Acetoxy-9-oxabicyclo[3.3.1]nonane-2-one (9): Ac-
cording to known procedures for the corresponding racemic com-
pounds[13]
a 74:26 mixture of acetates (1S,2S,5R,6R)-(ϩ)-4
(Ͼ98% ee) and (1R,2R,5R,6R)-(ϩ)-5 (80% ee) (1.50 g, 7.5 mmol)[15]
was dissolved in acetone (150 mL). At 0 °C Jones’ reagent (5 mL
(2R,2ЈR)-(Ϫ)-Tetrahydro-2,2Ј-bifuranyl-5,5Ј-dione (12):
mixture of the hydroxy ketones (1S,5R,6R)-(ϩ)-10 (Ͼ98% ee) and
(1R,5R,6R)-(ϩ)11 (Ͼ98% ee) (312 mg, 2.0 mmol) was transformed for an additional hour the mixture was warmed up to room tem-
A
37:63 portion, made of 26.0 g of CrO3, 23 mL of concd. H2SO4 and
77 mL of H2O) was added slowly within one hour. After stirring
as described above. The residue was purified by column chromatog-
raphy (silica gel, cyclohexane/ethyl acetate, 1:2) as eluent to give
(2R,2ЈR)-(Ϫ)-12. Yield: 245 mg (72%). Spectroscopic data have
been reported previously.[27] [α]2D0 ϭ Ϫ78.5 (c ϭ 1.0, chloroform,
ref.[27] [α]2D0 ϭ Ϫ81, c ϭ 0.99, chloroform), Ͼ98% ee (chiral GC,
perature and stirred for 18 h. 2-Propanol (50 mL) was then added
to destroy excess oxidant. The precipitate was then dissolved in
water (50 mL), and the mixture was extracted with chloroform (4
ϫ 75 mL). The combined organic phases were washed with water
(2 ϫ 50 mL), dried over MgSO4 and concentrated in vacuo to give
Beta-DexTM 120). 1H NMR (400 MHz, CDCl3): δ ϭ 4.57Ϫ4.63 a 74:26 mixture of 8 and 9 as a yellowish oil. Yield: 1.20 g (81%).
(m, 2 H, 2-CH, 2Ј-CH), 2.69 (ddd, J ϭ 17.8, 10.1, 6.1 Hz, 2 H,
endo-4-CH, endo-4Ј-CH or exo-4-CH, exo-4Ј-CH), 2.54 (ddd, J ϭ
Spectroscopic data of the racemates have been partially reported.[13]
1H NMR (300 MHz, CDCl3): δ ϭ 5.15 (dt, J ϭ 11.4, 4.8 Hz, 1 H
17.8, 9.9, 7.7 Hz, 2 H, endo-4-CH, endo-4Ј-CH or exo-4-CH, exo- [8], 5-CH), 5.01 (dt, J ϭ 11.4, 4.8 Hz, 1 H [9], 6-CH), 4.57Ϫ4.71
4Ј-CH), 2.24Ϫ2.44 (m, 4 H, 3-CH2, 3Ј-CH2) ppm. 13C NMR (m, 1 H [8], 6-CH), 4.34Ϫ4.48 (m, 1 H [8], 1-CH, 1 H [9], 5-CH),
(CDCl3): δ ϭ 176.6 (s, 5-CϭO, 5Ј-CϭO), 80.1 (d, 2-CH, 2Ј-CH), 4.01Ϫ4.18 (m, 1 H [9], 1-CH), 2.71Ϫ2.96 (m, 1 H [8], exo-3-CH, 1
27.9 (t, 4-CH2, 4Ј-CH2), 23.9 (t, 3-CH2, 3Ј-CH2) ppm. GC-MS
H [9], exo-3-CH), 2.06 (s, 3 H [9], 12-CH3), 2.09 (s, 3 H [8], 12-
(70 eV, Ion Trap): m/z (%) ϭ 170 (2) [Mϩ], 142 (2) [Mϩ Ϫ CO], 115 CH3), 1.50Ϫ2.48 (m, 7 H [8], endo-3-CH, 4-CH2, 7-CH2, 8-CH2, 7
3890
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3884Ϫ3892

Synthesis of γ-Lactones from Cycloocta-1,5-diene
[9], endo-3-CH, 4-CH2, 7-CH2, 8-CH2) ppm. 13C NMR
FULL PAPER
with a stirrer and a platinum anode and cathode. In order to adjust
H
(300 MHz, CDCl3): δ ϭ 216.5 (s, 2-CϭO [8]), 215.3 (s, 2-CϭO [9]), 5% neutralization, 1  methanolic KOH (1.05 mL) was added. The
169.9 (s, 11-CϭO [9], 11-CϭO [8]), 83.7 (d, 1-CH [8]), 82.1 (d, 1- electrolysis was carried out at 25 °C with a current density of 0.1 A/
CH [9]), 79.6 (d, 6-CH [8]), 71.7 (d, 5-CH [8]), 69.8 (d, 5-CH [9]), cm2 for 23 min at a potential of 50 V. The reaction mixture was
66.3 (d, 6-CH [9]), 36.5 (t, 3-CH2 [8]), 30.7 (t, 4-CH2 [8]), 28.5 (t,
3-CH2 [9]), 26.4 (t, 7-CH2 [9]), 23.4 (t, 7-CH2 [8]), 23.2 (t, 8-CH2
added to water (50 mL) and the whole solution was extracted four
times with diethyl ether (each 50 mL). NaCl was then added to
[8]), 22.2 (t, 4-CH2 [9]), 21.7 (t, 8-CH2 [9]), 20.9 (2q, 12-CH3 [8], separate the layers. The combined organic layers were dried over
12-CH3 [9]) ppm.
MgSO4, the solvent was evaporated in vacuo and the residue was
purified by column chromatography (diethyl ether/pentane, 5:1).
Compound 29 was obtained as a yellow oil. Yield: 22 mg (10%).
1H NMR (300 MHz, CDCl3): δ ϭ 4.99 (ddd, J ϭ 10.3, 7.4, 4.1 Hz,
1 H, 5-CH), 4.58 (ddd, J ϭ 10.3, 6.4, 4.1 Hz, 1 H, 4-CH), 2.07 (s,
3 H, 12-CH3), 1.23-2.60 (m, 12 H, 2-CH2, 3-CH2, 6-CH2, 7-CH2,
8-CH2, 9-CH2), 0.85Ϫ0.96 (t, 3 H, 10-CH3) ppm. 13C NMR
(300 MHz, CDCl3): δ ϭ 176.5 (s, 1-CϭO), 170.4 (s, 11-CϭO), 79.8
(d, 4-CH), 74.3 (d, 5-CH), 31.4 (t, 8-CH2), 30.4 (t, 6-CH2), 28.1 (t,
2-CH2), 24.8 (t, 7-CH2), 23.9 (t, 9-CH2), 22.4 (t, 3-CH2), 20.9 (q,
12-CH3), 13.8 (q, 10-CH2) ppm. GC-MS (70 eV, Ion Trap): m/z
(R,R)-5-Acetoxy-7-carboxyheptane-4-olide (27): A 74:26 mixture of
bicyclic acetoxy ketones (1S,5R,6R)-(ϩ)-8 and (1R,5R,6R)-(ϩ)-9
(0.40 g, 2.00 mmol) was transformed as described above with tri-
fluoroacetic acid (7 mL) and sodium percarbonate (0.66 g,
4.2 mmol). Water (20 mL) was added after the reaction mixture
had been stirring for 18 h. After continuous extraction with di-
chloromethane (50 mL) the organic layer was extracted five times
with 0.1  NaHCO3 (each 30 mL). Then the aqueous layer was
acidified to pH 2 with 2  HCl and was extracted continuously
with dichloromethane (100 mL). The mixture was treated with
MgSO4 and concentrated in vacuo to give 25 as colorless oil. Yield:
0.16 g (35%). No other products were detected by GC. 1H NMR
(300 MHz, CDCl3): δ ϭ 5.01Ϫ5.10 (m, 1 H, 5-CH), 4.51Ϫ4.60 (m,
1 H, 4-CH), 2.09 (s, 3 H, 10-CH3), 1.68Ϫ2.72 (m, 8 H, 2-CH2, 3-
CH2, 6-CH2, 7-CH2) ppm. 13C NMR (300 MHz, CDCl3): δ ϭ
192.0 (s, 8-CϭO), 177.4 (s, 1-CϭO), 170.9 (s, 9-CϭO), 80.3 (d, 5-
CH), 73.1 (d, 4-CH), 28.0 (t, 7-CH2), 27.8 (t, 2-CH2), 25.4 (t, 6-
CH2), 23.7 (q, 10-CH3), 20.6 (t, 3-CH2) ppm. GC-MS (70 eV, Ion
Trap, as trimethylsilyl ester): m/z (%) ϭ 302 (0) [Mϩ], 287 (7)
[Mϩ Ϫ CH3], 246/245 (5/35) [287 Ϫ C2H2O], 227 (38)
[287 Ϫ C2H4O2], 217 (28) [245 Ϫ CO], 199 (15), 185 (13), 175 (63),
153 (10), 129 (8), 125(16), 117 (36), 111 (24), 98 (8), 86/85 (5/100)
[C4H5O2ϩ], 75 (75), 73 (42) [Si(CH3)3ϩ], 72 (4), 55 (20) [C4H7ϩ],
45 (8), 43 (48) [C2H3Oϩ].
(%)
ϭ Ϫ 1], 168 (3)
229/228 (3/39) [Mϩ], 227 (3) [Mϩ
[Mϩ Ϫ CH3CO2H], 150 (3) [168 Ϫ H2O], 125 (3), 111 (3), 95 (2),
85 (40) [C4H5O2ϩ], 67 (2), 55 (6) [C4H7ϩ], 43 (100) [C2H3Oϩ].
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
We wish to thank Prof. Dr. H.-J. Schäfer and Dr. S. Kratschmer
for their assistance with the Kolbe electrolyses.
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Beta-DexTM 120, after hydrolysis to (Ϫ)-12]. H NMR (400 MHz,
1
CDCl3): δ ϭ 5.07 (ddd, J ϭ 8.7, J ϭ 4.3, J ϭ 4.3 Hz, 1 H, 5-CH),
4.58 (ddd, J ϭ 7.7, J ϭ 6.5, J ϭ 4.3 Hz, 1 H, 4-CH), 3.64 (s, 3 H,
9-CH3), 2.51Ϫ2.55 (m, 2 H, 2-CH, 2-CHЈ), 2.39 (dd, J ϭ 7.7, J ϭ
3.4 Hz, 1 H, 7-CHЈ or 7-CH), 2.10 (s, 3 H, 11-CH3), 2.37 (dd, J ϭ
7.7, J ϭ 4.3 Hz, 1 H, 7-CH or 7-CHЈ), 2.28Ϫ2.35 (m, 1 H, 3-CHЈ
or 3-CH),1.90Ϫ2.13 (m, 3 H, 6-CH2, 3-CH or 3-CHЈ) ppm. 13C
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O), 170.4 (s, 10-CϭO), 80.0 (d, 4-CH), 73.1 (d, 5-CH), 51.8 (q, 9-
CH3), 29.6 (t, 7-CH2), 28.1 (t, 2-CH2), 25.8 (t, 6-CH2), 23.9 (t, 3-
CH2), 20.8 (q, 11-CH3) ppm. GC-MS (70 eV, Ion Trap): m/z (%) ϭ
244 (22) [Mϩ], 185 (16) [Mϩ Ϫ C2H3O2], 171 (5) [Mϩ Ϫ C3H5O2],
159 (23) [Mϩ Ϫ C4H5O2], 152 (14), 124 (17) [152 Ϫ CO], 97 (11),
85 (39) [C3H5O2ϩ], 43 (100) [C2H3Oϩ]. C11H16O6 (244.2): calcd. C
54.09, H 6.60; found C 53.88, H 6.87.
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Eur. J. Org. Chem. 2004, 3884Ϫ3892
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3891

S. Behr, K. Hegemann, H. Schimanski, R. Fröhlich, G. Haufe
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antiomerically enriched (S,S)-methyl ester (ϩ)-26. The enantio-
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acetylated rac-diols 2 and 3 (52%) followed by Jones oxidation
of the free hydroxyl group.
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3892
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3884Ϫ3892