A Diels-Alder/retro-Diels-Alder approach for the enantioselective synthesis of microbial butenolides

Article abstract of DOI:10.1002/ejoc.201200991

Several volatile lactones have been identified from the endophytic fungus Geniculosporium sp. isolated from the rockrose Cistus monspeliensis, commonly known as Montpelier cistus. The fungal volatiles were collected from agar-plate cultures by using a closed-loop stripping apparatus and the headspace extracts were analysed by GC-MS. Structures for these lactones were proposed from their mass spectral data. The suggested structures were verified by synthesis of reference compounds through a Diels-Alder/retro-Diels-Alder approach. This synthetic method was also successfully applied in the synthesis of butenolides that are signalling molecules from streptomycetes. For the enantioselective synthesis of these butenolides a modified route including an enantioselective Diels-Alder reaction was used.

Full text of DOI:10.1002/ejoc.201200991

FULL PAPER
DOI: 10.1002/ejoc.201200991
A Diels–Alder/Retro-Diels–Alder Approach for the Enantioselective Synthesis
of Microbial Butenolides
Christian A. Citron,[a] Susanne M. Wickel,[a] Barbara Schulz,[b] Siegfried Draeger,[b] and
Jeroen S. Dickschat*[a]
Keywords: Synthetic methods / Diels–Alder reaction / Natural products / Lactones
Several volatile lactones have been identified from the endo-
phytic fungus Geniculosporium sp. isolated from the rockrose
Cistus monspeliensis, commonly known as Montpelier cistus.
The fungal volatiles were collected from agar-plate cultures
by using a closed-loop stripping apparatus and the head-
space extracts were analysed by GC–MS. Structures for these
lactones were proposed from their mass spectral data. The
suggested structures were verified by synthesis of reference
compounds through Diels–Alder/retro-Diels–Alder ap-
a
proach. This synthetic method was also successfully applied
in the synthesis of butenolides that are signalling molecules
from streptomycetes. For the enantioselective synthesis of
these butenolides a modified route including an enantio-
selective Diels–Alder reaction was used.
autoinducers or quorum-sensing molecules with varying N-
acyl chains. These species-specific compounds are synthe-
sised and excreted by Gram-negative bacteria involved in
cell-to-cell communication.[9] Some brominated butenol-
ides, including 8 and 9 from the macroalga Delisea pulchra
can interfere with bacterial quorum-sensing systems by
blocking the acyl homoserine lactone receptor.[10] In con-
trast, streptomycetes use butenolides, such as 2-(1-hy-
droxyalkyl) derivatives 10 and 11 or butanolide 12 Ϫ also
known as A factor Ϫ and its biosynthetic precursor 13, as
quorum-sensing signals.[11–13] A group of structurally re-
lated lactones with unknown biological functions was iden-
tified from a marine streptomycete including unusual enol
lactone 14 with β,γ-unsaturation.[14] This selection of com-
pounds demonstrates the high structural variability and the
diverse biological activities of naturally occurring five-mem-
bered lactones.
Recent investigations by us and other groups demon-
strate that microorganisms can emit structurally diverse
compounds from all kinds of substance classes.[15–25] We
have frequently identified lactones as major constituents of
the volatile fractions of various bacteria, e.g. algicidal lact-
ones 15–19 from the marine bacterium Ruegeria pomeroyi
DSS-3[26] or blastmycinone (20) and several structurally re-
lated butanolides from streptomycetes.[27] Because head-
space extractions usually do not provide sufficient material
for NMR spectroscopic characterisation of the volatiles re-
leased from agar plate cultures, the extracts can only be
analysed by GC–MS. For unambiguous compound identifi-
cation synthetic references are required, and therefore ro-
bust and flexible methods for the synthesis of lactones are
required. Several of the lactones in Figure 1 are chiral, and
frequently only one of the enantiomers exhibits bioactivity,
thus requiring enantioselective approaches. Here we report
Introduction
Lactones are a large class of natural products with im-
portant biological activities. The basic system represented
by the five-membered lactone 4-butanolide (1) Ϫ also called
γ-butyrolactone Ϫ is a prodrug, which upon ring opening
by the addition of water yields γ-hydroxybutyric acid (2,
GHB, Figure 1). In low doses, GHB has a stimulating, anxi-
olytic, antidepressive, or aphrodisiacal effect by binding to
the GHB receptor. However, in higher concentrations the
γ-aminobutyric acid (GABAB) receptor is activated re-
sulting in strong sedative to narcotic activity and ultimately
deep coma or death.[1,2] Some of its derivatives exhibit inter-
esting flavour properties such as a fruity aroma from do-
decan-4-olide (3) or a woody or coconut-like aroma from
cis- and trans-3-methyloctan-4-olide (4), also termed whis-
key lactones or oak lactones, respectively.[3,4] The but-
anolides buibuilactone (5) and japonilure (6) which contain
an unsaturated side-chain are used as pheromones by the
cupreous chafer, Anomala cuprea, and the Japanese beetle,
Popillia japonica.[5,6] Interestingly, 5 is also a volatile re-
leased by marine bacteria.[7] Some natural butanolides are
derived from amino acids, such as the N-acyl homoserine
lactones (HSL). Representatives of this class, e.g. N-butyryl
HSL (7) from Pseudomonas aeruginosa,[8] form a group of
[a] Institut für Organische Chemie, Technische Universität
Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Fax: +49-531-3915272
E-mail: j.dickschat@tu-bs.de
Homepage: http://www.oc.tu-bs.de/dickschat/startseite_de.html
[b] Institut für Mikrobiologie, Technische Universität
Braunschweig,
Spielmannstraße 7, 38106 Braunschweig, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200991.
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Enantioselective Synthesis of Microbial Butenolides
e.g. C9H16O2 and a base peak at m/z = 112 in agreement
with the structure of a 2-butyl-methylbut-2-enolide or a 2-
butylpent-2-enolide. For these structures the formation of
the even ion at m/z = 112 is easily explained by a McLaf-
ferty rearrangement (Scheme 1). The suggested 2-butyl-3-
methylbut-2-enolide structure was further supported by
previous isolation of this compound from the fungus
Hypoxylon serpens[30] and other endophytic fungi for which
the mass spectrum was reported.[31] Compounds B and C
exhibited very similar mass spectra suggesting these com-
pounds are structurally closely related isomers, e.g. dia-
stereoisomers. Their molecular ions were detected at m/z =
156, corresponding e.g. to C9H18O2, and prominent frag-
ment ions were observed at m/z = 100 and 85 arising from
a McLafferty rearrangement and subsequent cleavage of a
methyl group (Scheme 1). Therefore, the structures of cis-
and trans-2-butyl-3-methylbutanolide, both formal re-
duction products of A, were suggested, but it was imposs-
ible to assign the structure of a particular diastereoisomer.
To prove the proposed molecular structures, synthesis of all
three compounds was performed.
Figure 1. A selection of naturally occurring butanolides and but-
enolides.
on the identification of volatile lactones from the endo-
phytic fungus Geniculosporium sp. 9910 that was isolated
from Cistus monspeliensis. We report their synthesis by
using a Diels–Alder/retro-Diels–Alder approach and devel-
opment of this approach into an enantioselective method
for the synthesis of the butenolide signalling molecules 10
and 11 from Streptomyces antibioticus, by using a recently
published enantioselective Diels–Alder reaction.[28]
Results and Discussion
The endophytic fungus Geniculosporium sp. 9910 at-
tracted our attention because of a strong minty odour that
was released from agar-plate cultures. The volatiles emitted
from these agar-plate cultures were collected on charcoal by
a closed-loop stripping apparatus (CLSA),[29] extracted
with dichloromethane, and the extracts analysed by GC–
MS. A total ion chromatogram of a representative extract
is shown in Figure 2 (a). The headspace extracts were com-
posed of major compound A along with minor metabolites
B and C and a few unidentified oxygenated sesquiterpenes.
None of these compounds were part of our mass spectro-
scopic database, and therefore, structural proposals had to
be made by interpretation of the mass spectroscopic data.
The mass spectrum of A (Figure 2, b) exhibited a molecular
Figure 2. a) Total ion chromatogram of a representative headspace
extract from Geniculosporium sp. 9910, b) mass spectrum of the
ion at m/z = 154 corresponding to a molecular formula of main compound A, c) mass spectrum of the minor compound B.
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FULL PAPER
Scheme 1. MS fragmentation mechanisms of a) compound A and
b) compound B explaining the formation of the most abundant
fragment ions observed.
Scheme 2. Synthesis of volatiles from Geniculosporium sp. and re-
lated 2,3-disubstituted but-2-enolides and butanolides.
The synthesis was carried out by using a Diels–Alder/
retro-Diels–Alder approach starting from citraconic anhy-
dride (22, Scheme 2), similarly to published routes to but-
enolides through a retro-Diels–Alder reaction.[32,33] The
The successful application of the Diels–Alder/retro-
Diels–Alder reaction with cyclopentadiene (21) resulted in Diels–Alder route to butenolides 29 and 30 prompted us to
adduct 23 that was subsequently reduced with LiAlH4 to further develop this method for the synthesis of butenolides
give diol 24. Ley oxidation with tetrapropylammonium per- with different alkylation patterns, because these compounds
ruthenate (TPAP) and N-methylmorpholine N-oxide were detected in the headspace extracts from other microor-
(NMO) resulted in regioisomeric lactones 25 and 26 in a 1:1 ganisms. For the synthesis of butenolides with a 2,4,4-tri-
mixture. Because the lactones were inseparable by column alkylation pattern a modified route was used (Scheme 3).
chromatography, the mixture was used in the next step with- The Diels–Alder reaction of 21 with maleic anhydride (32)
out purification. Deprotonation with lithium diisoprop- gave adduct 33 that was reduced to lactone 34 with NaBH4.
ylamide (LDA) followed by alkylation with butyl iodide re- The reaction with methylmagnesium iodide yielded diol 35
sulted in the transformation of 25 into 27, whereas re- that served as the precursor for lactone 36 by TPAP/NMO
gioisomeric lactone 26 did not react and was separable from oxidation. α-Alkylation with methyl iodide gave 37 that was
target compound 27. This alkylation step proved to be more smoothly converted into 39 in o-dichlorobenzene at reflux
efficient with alkyl iodides than with alkyl bromides as temperatures. Similarly, the retro-Diels–Alder reaction of 36
demonstrated by the lower yield in the alkylation of 25 to yielded 38 that was obtained in lower yields owing to its
ethyl derivative 28. Heating alkylation products 27 and 28 volatility causing losses during compound purification.
to reflux in o-dichlorobenzene for 24 h caused an efficient Synthetic compound 38 was recently identified as a volatile
retro-Diels–Alder reaction with nearly quantitative yields of released by the actinobacterium Thermomonospora curv-
butenolides 29 and 30. Subsequent catalytic hydrogenation ata.[15]
of 29 with a Pd catalyst on Al2O3 gave butanolide cis-31
The synthesis of a butenolide with a 3,4,4-trialkylation
with high diastereoselectivity that was isomerised to trans- pattern was planned by using the same Diels–Alder/retro-
31 by treatment with NaOMe in methanol. All three lact- Diels–Alder method. Starting from 23, NaBH4 reduction
ones were identical with respect to their mass spectra and gave 26 with high regioselectivity (Scheme 4). However, this
GC retention times to the compounds released by Geniculo- molecule failed to react to give 40 in a Grignard reaction
sporium. Principal component A was identified as butenol- with methylmagnesium iodide, even in the presence of addi-
ide 29, the first eluting saturated lactone C was trans-31, tives such as cerium(III) chloride. The further planned steps
and the second eluting lactone B was its diastereoisomer in the synthesis of 42 included Ley oxidation of 40 to give
cis-31. Both cis- and trans-31 are new natural products.
lactone 41 and its retro-Diels–Alder reaction to 42. In con-
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Enantioselective Synthesis of Microbial Butenolides
cules by using (–)-menthol as a chiral auxiliary was pre-
viously presented by Séquin and co-workers.[36,37] Recently,
an enantioselective Diels–Alder reaction of citraconic anhy-
dride with cyclopentadiene by using a chiral oxazaborolid-
ine catalyst was reported,[28] thus opening up the possibility
of an enantioselective synthesis of 25 as required for the
preparation of (–)-10 and (–)-11 (Scheme 5). Because both
enantiomers of the oxazaborolidine catalyst are commer-
cially available, both of the enantiomers of 10 and 11 could
be prepared. The Diels–Alder adduct (+)-23 was obtained
with an enantiomeric excess of 52% ee (original report:
92% ee)[28] as determined by GC analysis on a chiral sta-
tionary phase (Figure 3, a and b) and transformed into en-
antiomerically enriched 25 in analogy to the conversion of
racemic 23 (Scheme 2). The subsequent deprotonation of
enantiomerically enriched (+)-25 with LDA and addition of
isobutyraldehyde yielded 43 as a single diastereoisomer that
upon boiling in o-dichlorobenzene (b.p. 179 °C) resulted in
(–)-10 by retro-Diels–Alder reaction. Analysis of the prod-
uct by GC on a chiral stationary phase established an enan-
tiomeric excess for (–)-10 of 56% ee (Figure 3, c and d) and
is in the same range as for Diels–Alder adduct (+)-23. The
high diastereoselectivity in the reaction of 25 with isobutyr-
aldehyde can be rationalised by the proposed six-membered
transition-state assembly shown in Scheme 6. The ester
enolate of 25 is attacked by the aldehyde from the convex
face. For steric reasons the aldehyde hydrogen points
towards the bridging methylene unit of the norbornene sys-
tem and the large alkyl group points away from it. Conse-
quently, in the reaction with the major enantiomer of 25
the aldehyde is attacked from the Re face. The resulting
stereochemistry at the newly formed secondary alcohol is a
(S)-configuration (for R = alkyl).
Scheme 3. Synthesis of 2,4,4-trisubstituted but-2-enolides.
clusion, the synthesis of 3,4,4-trisubstituted butenolides is
not possible through this route, thus demonstrating its
limitations. An alternative route for the synthesis of com-
pound 42 was presented by Jäger and co-workers.[34]
Scheme 4. Planned synthesis of 3,4,4-trisubstituted but-2-enolide
42.
Chiral aminoanthracenes have been adopted in a Diels–
Alder/retro-Diels–Alder sequence for the enantioselective
synthesis of lactams and butenolides.[35] In a similar ap-
proach we investigated the possibility of lactone 25 acting
as a template in the enantioselective synthesis of lactones.
However, because chiral compounds cis- and trans-31 from
Geniculosporium sp. 9910 in our approach were made
through achiral butenolide 29, we choose bioactive butenol-
ide signalling molecules (–)-10 and (–)-11 from Streptomy-
ces antibioticus Tü 99 to apply our method for an enantiose-
Scheme 5. Enantioselective synthesis of signalling compounds (–)-
lective synthesis. An enantioselective route to these mole- 10 and (–)-11 from Streptomyces antibioticus.
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C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger, J. S. Dickschat
FULL PAPER
two diastereoisomers, the first with a (1S,2S)-configured 1-
hydroxy-2-methylbutyl side-chain in the reaction with the
major enantiomer of 25, and the second with a (1R,2S)-
configured side-chain in the reaction with its minor
enantiomer. The retro-Diels Alder reaction of 44 conse-
quently resulted in a mixture of diastereoisomeric butenol-
ides, (1S,2S)-11 and (1R,2S)-11, with a diastereoisomeric
excess of 45% de (Figure 3, f), reflecting the enantiomeric
excess as observed for Diels–Alder adduct 23. The reaction
sequence to (1SR,2S)-11 was also performed from racemic
25 that was treated with (S)-2-methylbutyraldehyde. Ob-
tained product 44 was subjected to a retro-Diels–Alder re-
action to result in the formation of a 1:1 mixture of dia-
stereoisomers of 11 (Figure 3, e).
The synthesis of 2,3-disubstituted butanolides such as 31
could also be rationalised e.g. through a copper-catalysed
1,4-addition to the stem compound butenolide followed by
direct trapping of the enolate with an alkyl iodide. However,
such a double alkylation of butenolide has never been re-
ported and failed in our hands, and only a few reports exist
for such an approach starting from γ-substituted butenolide
derivatives.[38–41] Another drawback of such an approach
would be that butenolide is expensive and prone to poly-
merisation, whereas the compounds used in our method
(maleic or citraconic anhydride) are cheap and stable. An
alternative approach to chiral α-substituted butenolides that
was recently applied in the synthesis of abyssomycins in-
cludes α-metallation of a butenolide with tBuLi followed by
direct addition to an α-chiral aldehyde.[42] This procedure
shows low diastereoselectivity, whereas our method pro-
ceeds with very high diastereoselectivity, as can be seen by
the formation of the two enantiomers of 10 with an enan-
tiomeric excess of 56% ee, or by the formation of the two
diastereoisomers of 11 with a diastereoisomeric excess of
45% de. In both cases the enantiomeric excess of Diels–
Alder adduct (+)-23 (52% ee) is reflected within the limits
of measuring accuracy. A higher enantiomeric excess of tar-
get compound 10 (or a higher diastereoisomeric excess of
11) would be obtainable by the Diels–Alder/retro-Diels–
Alder methodology, if the enantioselectivity of the Diels–
Alder reaction to (+)-23 could be improved. Although re-
ported much higher, repeated trials to increase the enantio-
selectivity in the synthesis of (+)-23 following the published
procedure always resulted in an enantiomeric excess for 23
in the range of ca. 50% ee in our hands.
Figure 3. Gas chromatograms of a) (rac)-23 and b) enantiomer-
ically enriched (+)-23 on a chiral Lipodex G capillary column, c)
(rac)-10 and d) enantiomerically enriched (–)-10 on a chiral Hydro-
dex capillary column, and e) (1SR,2S)-11 obtained from (rac)-23
and f) from enantiomerically enriched (+)-23 on a chiral Hydrodex
capillary column. For separation of the two diastereoisomers of 11
a chiral GC column was used, because no separation could be
1
achieved on a HP5-MS capillary column. H and 13C NMR spec-
troscopic analyses showed that the two peaks in chromatograms e)
and f) represent different diastereoisomers and not a pair of
enantiomers.
Conclusions
Three volatile lactones were found in the headspace ex-
tracts of the endophytic fungus Geniculosporium sp. and
identified by synthesis of reference compounds 2-butyl-3-
methylbut-2-en-4-olide (29) and the saturated counterparts
cis- and trans-2-butyl-3-methylbutan-4-olide (31). For the
Scheme 6. Suggested six-membered transition state assembly for
the reaction of the ester enolate of 25 with aldehydes.
Similarly, the reaction of enantiomerically enriched 25 synthesis of these compounds a Diels–Alder/retro-Diels–
with (S)-2-methylbutyraldehyde resulted in 44 as precursor Alder approach starting from cyclopentadiene and citra-
for (–)-11 by retro-Diels–Alder reaction. The reaction to 44 conic anhydride was developed. The Diels–Alder adduct
proceeded with high diastereoselectivity, thus resulting in was reductively converted into regioisomeric lactones 25
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Enantioselective Synthesis of Microbial Butenolides
were recorded with a Varian Cary 100 Bio, and IR spectra were
recorded with a Bruker Tensor 27 ATR (attenuated total reflec-
tance). Specific rotations were measured with a Dr. Kernchen Pro-
pol Digital Automatic Polarimeter. GC–MS analyses were carried
out with a HP 6890 gas chromatograph connected to a HP 5973
inert mass detector fitted with a BPX-5 fused silica capillary col-
umn (25 m, 0.25 mm i. d., 0.25 μm film). Instrumental parameters
were (1) inlet pressure, 77.1 kPa, He 23.3 mLmin–1, (2) injection
volume, 2 μL, (3) transfer line, 300 °C, and (4) electron energy
70 eV. The GC was programmed as follows: 5 min at 50 °C increas-
and 26. Subsequent α-alkylation of 25 and retro-Diels–
Alder reaction resulted in 2,3-dialkylbutenolides. A modifi-
cation of this approach by using maleic anhydride was also
successfully applied in the synthesis of 2,4,4-trimethylbut-2-
en-4-olide (39). A recently published enantioselective Diels–
Alder reaction of cyclopentadiene and citraconic anhy-
dride[28] was used for the stereoselective synthesis of but-
enolide signalling molecules from Streptomyces antibioticus.
As a key step the enolate of enantiomerically enriched lact-
one 25 was alkylated with aldehydes in a highly diastereo- ing at 10 °C min–1 to 320 °C, and operated in split mode (20:1, 60 s
valve time). The carrier gas was He at 1 mLmin–1. Retention in-
selective reaction. A suggested transition state assembly for
dices (I) were determined from a homologous series of n-alkanes
this step shows that the high rigidity of lactone 25 serves in
(C8–C38).
an efficient transfer of the stereochemical information to
the newly formed stereogenic centre of the secondary (–)-(S)-3-(1-Hydroxy-2-methylpropyl)-4-methylfuran-2(5H)-one [(–)-
10]: Compound 43 (169 mg, 0.7 mmol, 1.0 equiv.) obtained from
enantiomerically enriched 25 was dissolved in o-dichlorobenzene
(5 mL) and heated to reflux for 1 d. After cooling to room tempera-
ture the complete reaction mixture was loaded onto a silica gel
column. Column chromatography (eluant gradient from 100%
pentane to 100% diethyl ether) yielded (–)-10 (102 mg, 0.6 mmol,
86%, 56% ee) as a pale yellow oil. [α]2D5.0 = –34.3 (c = 1.2, CH2Cl2).
Rf = 0.21 (pentane/diethyl ether, 1:1). GC (BPX-5): I = 1485. 1H
alcohol function.
Experimental Section
Strain and Culture Conditions: Geniculosporium sp. 9910 was iso-
lated from the leaves of Cistus monspeliensis collected near Arles
(France) in October 2008. Identification of the fungus was accord-
ing to its morphology.[43] The fungus was cultured on Kartoffel-
Möhre medium[44] in glass petri dishes to avoid contamination with
plasticisers. After inoculation the fungus was grown for 21 d at
20 °C.
2
NMR (400 MHz, CDCl3, TMS): δ = 4.71 (br. d, JH,H = 7.3 Hz, 1
2
H, CH2), 4.65 (br. d, JH,H = 7.3 Hz, 1 H, CH2), 4.15 (br. s, 1 H,
3
CH), 3.14 (br. d, JH,H = 5.0 Hz, 1 H, OH), 2.09 (s, 3 H, CH3),
3
1
2.08–1.99 (m, 1 H, CH), 1.04 (d, JH,H = 6.7, JC,H = 125.7 Hz, 3
3
1
H, CH3), 0.84 (d, JH,H = 6.8, JC,H = 125.4 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 174.5 (CO), 158.7 (Cq), 127.7
(Cq), 73.0 (CH), 72.6 (CH2), 34.1 (CH), 19.1 (CH3), 18.7 (CH3),
12.7 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 170 (Ͻ1) [M]+, 152
(4), 127 (100), 110 (31), 99 (35), 82 (34), 67 (10), 53 (21). IR (ATR):
Analytical Methods: The volatiles emitted by Geniculosporium sp.
9910 were collected with a modified CLSA.[29] The agar plates were
placed in a small chamber as part of a closed apparatus with a
circulating air stream that was passed over the agar plates and then
through a charcoal filter (Chromtech GmbH, Idstein, Precision
Char Coal Filter 5 mg) for 18–24 h. The charcoal filter was eluted
with analytically pure dichloromethane (40–50 μL), the extract was
directly analysed by GC–MS and stored at –80 °C. GC–MS analy-
ses were carried out with an Agilent 7890A connected with an Ag-
ilent 5975C inert mass detector fitted with a HP-5 fused silica capil-
lary column (30 m, 0.25 mm i. d., 0.25 μm film, Agilent). GC con-
ditions were as follows: inlet pressure 77.1 kPa, He 23.3 mLmin–1,
injection volume 1.5 μL, transfer line 300 °C, electron energy 70 eV.
The operation mode was splitless (60 s valve time) and the carrier
gas was He at 1.2 mLmin–1. The GC was programmed as follows:
5 min at 50 °C increasing with 5 °C min–1 to 320 °C. Retention in-
dices (I) were determined from a homologous series of n-alkanes
(C8–C32).
ν = 3457 (br.), 2966 (w), 1728 (s), 1091 (m), 916 (w) cm–1. UV/
˜
Vis (CH2Cl2): λmax (ε, Lmol–1 cm–1) = 229 (2746) nm. The same
procedure was used for the conversion of (rac)-43 into (rac)-10. The
spectroscopic data of the product was the same as above.
3-[(1S,2S)-1-Hydroxy-2-methylbutyl]-4-methylfuran-2(5H)-one
[(1S,2S)-11] and 3-[(1R,2S)-1-Hydroxy-2-methylbutyl]-4-methyl-
furan-2(5H)-one [(1R,2S)-11]: The diastereoisomeric mixture of
(1S,2S)-44 and (1R,2S)-44 (81 mg, 0.32 mmol, 1.0 equiv.) obtained
from enantiomerically enriched 25 was dissolved in o-dichloro-
benzene (5 mL) and heated to reflux for 1 d. After cooling to room
temperature the complete reaction mixture was loaded onto a silica
gel column. Column chromatography (eluant gradient from 100%
pentane to 100% diethyl ether) yielded a mixture of (1S,2S)-11 and
(1R,2S)-11 (52 mg, 0.28 mmol, 87%, 45% de) as a pale yellow li-
quid. [α]2D1.4 = –18.0 (c = 0.5, CH2Cl2). Rf = 0.23 (pentane/diethyl
ether, 1:1). GC (BPX-5): I = 1584. 1H NMR (400 MHz, CDCl3,
TMS): δ = 4.73–4.62 (m, 2 H, CH2 of both diastereoisomers), 4.29
General Synthetic Methods: Chemicals were purchased from Acros
Organics (Geel, Belgium) or Sigma Aldrich Chemie GmbH (Stein-
heim, Germany) and used without further purification. All non-
aqueous reactions were performed under an inert atmosphere (N2)
in flame-dried flasks. Solvents were purified by distillation and
dried according to standard methods. For all general procedures,
the relative amounts of the reagents are given as equivalents refer-
ring to the molar ratios of the compounds, and the relative
amounts of solvents are given as final concentrations of the trans-
formed starting material (set to 1.0 equiv.). Thin-layer chromatog-
raphy was performed with 0.2 mm precoated plastic sheets Poly-
gram Sil G/UV254 (Machery-Nagel). Column chromatography was
3
3
(d, JH,H = 7.0 Hz, 1 H, CH of minor diast.), 4.20 (d, JH,H
=
8.3 Hz, 1 H, CH of major diast.), 2.98 (br. s, 1 H, OH of both
diast.), 2.08 (s, 3 H, CH3 of minor diast.), 2.07 (s, 3 H, CH3 of
major diast.), 1.88–1.74 (m, 2 H, CH2 and CH of major diast., 1
H, CH of minor diast.), 1.42–1.34 (m, 1 H, CH2 of minor diast.),
1.26–1.18 (m, 1 H, CH2 of major diast.), 1.12–1.03 (m, 1 H, CH2
of minor diast.), 1.01 (d, 3JH,H = 6.7 Hz, 3 H, CH3 of minor diast.),
3
3
0.94 (t, JH,H = 7.5 Hz, 3 H, CH3 of major diast.), 0.91 (t, JH,H
=
3
7.3 Hz, 3 H, CH3 of minor diast.), 0.79 (d, JH,H = 6.8 Hz, 3 H,
CH3 of major diast.) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.26/174.29 (CO of main/minor diastereoisomer), 158.04/158.01
(Cq), 127.6 (Cq of both diastereoisomers), 72.8 (CH2), 71.2/71.1
(CH), 40.1/40.5 (CH), 24.8/25.6 (CH2), 15.1/14.4 (CH3), 12.50/
12.48 (CH3), 11.0/11.5 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 184
1
carried out with Merck silica gel 60 (70–200 mesh). H NMR and
13C NMR spectra were recorded on Bruker DRX-400 (400 MHz),
AV III-400 (400 MHz) or AV II-600 (600 MHz) spectrometers, and
were referenced against TMS (δ = 0.00 ppm) for 1H NMR and
CDCl3 (δ = 77.16 ppm) for 13C NMR spectroscopy. UV spectra
Eur. J. Org. Chem. 2012, 6636–6646
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6641

C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger, J. S. Dickschat
FULL PAPER
(Ͻ1) [M]+, 166 (5), 127 (100), 110 (49), 99 (36), 82 (41), 67 (20), 53
(rac)-23, compound (–)-24 was prepared from (+)-23. The spectro-
(41), 41 (74). IR (ATR): ν = 3451 (br.), 2964 (w), 1728 (s), 1452 scopic data for (–)-24 were in agreement with those of (rac)-24.
˜
(w), 1040 (s), 789 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε, Lmol–1 cm–1) [α]2D4.9 = –5.8 (c = 3.3, CH2Cl2).
= 230 (2737) nm. The same procedure was used for the conversion
(3aR*,4S*,7R*,7aS*)-3a-Methyl-3a,4,7,7a-tetrahydro-4,7-methano-
of the 1:1 mixture (1SR,2S)-44 into (1SR,2S)-10. The spectroscopic
isobenzofuran-1(3H)-one [(rac)-25] and (3aR*,4S*,7R*,7aS*)-7a-
data of the product was the same as above.
Methyl-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one
(3aR*,4S*,7R*,7aS*)-3a-Methyl-3a,4,7,7a-tetrahydro-4,7-methano-
isobenzofuran-1,3-dione [(rac)-23]: To as solution of citraconic an-
hydride (22, 14.7 g, 150 mmol, 1.0 equiv.) in chloroform (90 mL)
was added freshly distilled cyclopentadiene (21, 10.9 g, 165 mmol,
1.1 equiv.) at 0 °C. The reaction mixture was stirred overnight at
room temperature and light was excluded. After evaporation of the
solvent under reduced pressure and recrystallization from methanol
(rac)-23 (24.6 g, 138 mmol, 92%) was obtained as a colourless so-
lid; m.p. 137 °C. Rf = 0.18 (hexane/ethyl acetate, 5:1). GC (BPX-
5): I = 1431. 1H NMR (400 MHz, CDCl3, TMS): δ = 6.39 (dd,
[(rac)-26]: To a solution of (rac)-24 (4.6 g. 27 mmol, 1.0 equiv.) in
absolute CH2Cl2 (75 mL) was added molecular sieves (4 Å, 11.5 g),
NMO (4.6 g, 35 mmol, 1.3 equiv.), and TPAP (477 mg, 1.3 mmol,
0.05 equiv.). The reaction mixture was stirred overnight at room
temperature. The mixture was filtered and concentrated under re-
duced pressure. Column chromatography on silica gel (hexane/ethyl
acetate, 2:1) yielded a mixture of regioisomeric lactones (rac)-25
and (rac)-26 that were inseparable by column chromatography (1:1,
2.92 g, 17.8 mmol, 66%); m.p. 128 °C. Regioisomer (rac)-25: Rf =
1
0.39 (hexane/ethyl acetate, 2:1). GC (BPX-5): I = 1416. H NMR
3
3JH,H = 6.0, 3.0 Hz, 1 H, CH), 6.29 (dd, JH,H = 5.8, 2.9 Hz, 1 H,
3
4
(400 MHz, CDCl3, TMS): δ = 6.36 (dd, JH,H = 5.8, JH,H
=
3
3.1 Hz, 1 H, CH), 6.29 (dd, 3JH,H = 5.8, 4JH,H = 3.0 Hz, 1 H, CH),
3.92 (d, JH,H = 9.7 Hz, 1 H, CH2), 3.89 (d, JH,H = 9.7 Hz, 1 H,
CH2), 3.31–3.29 (m, 1 H, CH), 2.78 (d, JH,H = 4.6 Hz, 1 H, CH),
CH), 3.47–3.44 (m, 1 H, CH), 3.13 (d, JH,H = 4.6 Hz, 1 H, CH),
2
3
2
2
3.04–3.03 (m, 1 H, CH), 1.84 (dt, JH,H = 9.4, JH,H = 1.7 Hz, 1
2
3
3
H, CH2), 1.80 (dt, JH,H = 9.3, JH,H = 1.5 Hz, 1 H, CH2), 1.62 (s,
3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.9 (CO),
170.9 (CO), 137.3 (CH), 135.3 (CH), 53.8 (Cq), 53.5 (CH), 52.0
(CH), 50.8 (CH2), 46.7 (CH), 21.3 (CH3) ppm. MS (EI, 70 eV): m/z
(%) = 178 (Ͻ1) [M]+, 133 (1), 119 (2), 106 (6), 91 (25), 77 (9), 66
2.74–2.73 (m, 1 H, CH), 1.76–1.72 (m, 2 H, CH2), 1.43 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 178.1 (CO), 136.9
(CH), 136.2 (CH), 77.0 (CH2), 55.4 (CH), 52.3 (CH), 50.3 (CH2),
46.9 (Cq), 46.1 (CH), 26.3 (CH3) ppm. MS (EI, 70 eV): m/z (%) =
164 (Ͻ1) [M]+, 105 (3), 99 (14), 91 (11), 77 (6), 66 (100), 51 (7), 39
(100), 51 (9), 39 (24). IR (ATR): ν = 3079 (w), 2989 (w), 1850
˜
(m), 1769 (s), 1458 (w), 1218 (m), 1165 (m), 1014 (s), 895 (s), 739
(19). IR (ATR): ν = 3066 (w), 2982 (w), 1746 (s), 1455 (w), 1389
˜
(s) cm–1.
(m), 1234 (m), 1115 (s), 986 (s), 728 (s), 703 (s) cm–1. Regioisomer
Enantioselective Synthesis of (+)-(3aR,4S,7R,7aS)-3a-Methyl- (rac)-26: Rf = 0.39 (hexane/ethyl acetate, 2:1). GC (BPX-5): I =
3
3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione [(+)-23]:
This compound was prepared from citraconic anhydride (2.8 g,
25.0 mmol) as reported previously (3.74 g, 21.0 mmol, 84%). The
spectroscopic data of (+)-23 were in agreement with those of (rac)-
23. [α]2D4.9 = +4.9 (c = 3.1, CH2Cl2). The enantiomeric excess was
determined by chiral GC analysis (52% ee).
1451. 1H NMR (400 MHz, CDCl3, TMS): δ = 6.33 (dd, JH,H
=
=
4
3
4
5.7, JH,H = 3.0 Hz, 1 H, CH), 6.26 (dd, JH,H = 5.8, JH,H
3.0 Hz, 1 H, CH), 4.27 (dd, 2JH,H = 9.8, 3JH,H = 8.7 Hz, 1 H, CH2),
3.75 (dd, 2JH,H = 9.8, 3JH,H = 3.1 Hz, 1 H, CH2), 3.05–3.03 (m, 1 H,
CH), 2.85–2.83 (m, 1 H, CH), 2.65 (ddd, 3JH,H = 8.8, 4.0, 3.1 Hz, 1
4
H, CH), 1.69 (q, JH,H = 1.6 Hz, 2 H, CH2), 1.51 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.9 (CO), 138.2
(CH), 134.1 (CH), 68.8 (CH2), 53.6 (Cq), 51.9 (CH), 49.6 (CH2),
47.7 (CH), 46.7 (CH), 22.5 (CH3) ppm. MS (EI, 70 eV): m/z (%) =
164 (Ͻ1) [M]+, 103 (4), 99 (17), 91 (21), 77 (21), 66 (100), 51 (21),
[(1S*,2R*,3S*,4R*)-2-Methylbicyclo[2.2.1]hept-5-ene-2,3-diyl]di-
methanol [(rac)-24]: LiAlH4 (1.6 g, 41.6 mmol, 1.3 equiv.) was sus-
pended in absolute THF (80 mL) and the suspension was cooled
to 0 °C. A solution of (rac)-23 (5.81 g, 32 mmol, 1.0 equiv.) in abso-
lute THF (20 mL) was added dropwise. The reaction mixture was
heated to reflux for 2 h and after cooling to 0 °C quenched with
HCl (6 m). The aqueous layer was extracted three times with diethyl
ether, the combined organic layers were dried with MgSO4 and
concentrated under reduced pressure. Recrystallisation (hexane/
ethyl acetate, 1:1) gave (rac)-24 (4.6 g, 27 mmol, 88%) as a colour-
less solid; m.p. 138 °C. Rf = 0.18 (hexane/ethyl acetate, 1:1). GC
(BPX-5, MSTFA): I = = 1509. 1H NMR (400 MHz, CDCl3, TMS):
39 (63). IR (ATR): ν = 3066 (w), 2982 (w), 1746 (s), 1455 (w), 1389
˜
(m), 1234 (m), 1115 (s), 986 (s), 728 (s), 703, (s) cm–1. HRMS:
+
calcd. for C10H12O2 164.08318; found 164.08441.
(3aR*,4S*,7R*,7aS*)-7a-Butyl-3a-methyl-3a,4,7,7a-tetra-hydro-
4,7-methanoisobenzofuran-1(3H)-one [(rac)-27]: Diisopropyl-amine
(1.49 g, 14.8 mmol, 1.5 equiv.) was dissolved in THF (80 mL) and
a solution of n-butyllithium (1.6 m in hexane, 9.3 mL, 14.8 mmol,
1.5 equiv.) was added dropwise at 0 °C. The reaction mixture was
stirred for 1 h at 0 °C and then cooled to –78 °C. A solution of a
1:1 mixture of compounds (rac)-25 and (rac)-26 [1.62 g, 9.83 mmol,
1.0 equiv.; the mixture contains ca. 5.9 mmol of (rac)-25] in THF
(10 mL) was added and stirred for a further 2 h at –78 °C. Butyl
iodide (3.24 g, 17.7 mmol, 1.8 equiv.) was added dropwise and stir-
ring was continued overnight while the reaction warmed to room
temperature. The reaction was quenched by the addition of a satu-
rated solution of NH4Cl (100 mL) and extracted three times with
diethyl ether. The combined organic layers were dried with MgSO4
and concentrated under reduced pressure. Column chromatography
on silica gel (pentane/diethyl ether, 1:1) yielded (rac)-27 (1.15 g,
5.24 mmol, 88%) as a colourless oil. Rf = 0.63 (pentane/diethyl
ether, 1:1). GC (BPX-5): I = 1742. 1H NMR (400 MHz, CDCl3,
3
3
δ = 6.12 (dd, JH,H = 5.8, 3.0 Hz, 1 H, CH), 6.03 (dd, JH,H = 5.8,
3.0 Hz, 1 H, CH), 4.13 (br. s, 2 H, 2ϫ OH), 3.62 (dd, 2JH,H = 11.3,
2
3JH,H = 3.9 Hz, 1 H, CH2), 3.56 (d, JH,H = 11.0 Hz, 1 H, CH2),
2
2
3.34 (d, JH,H = 10.4 Hz, 1 H, CH2), 3.29 (d, JH,H = 11.2 Hz, 1
H, CH2), 2.70 (br. s, 1 H, CH), 2.33 (br. s, 1 H, CH), 2.06 (dt,
3
3
2JH,H = 11.2, JH,H = 3.6 Hz, 1 H, CH2), 1.71 (dt, JH,H = 8.6,
3JH,H = 1.5 Hz, 1 H, CH2), 1.37 (dt, JH,H = 8.6, JH,H = 1.8 Hz,
1 H, CH), 1.31 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 136.3 (CH), 133.9 (CH), 67.6 (CH2), 64.5 (CH2), 53.3 (CH),
52.8 (CH), 47.4 (CH2), 46.8 (CH), 46.6 (Cq), 26.8 (CH3) ppm. MS
(EI, 70 eV): m/z (%) = 312 (Ͻ1) [M]+, 297 (1), 245 (18), 222 (8),
209 (30), 191 (5), 156 (37), 143 (59), 132 (21), 119 (11), 103 (11),
3
3
91 (12), 73 (100), 45 (10). IR (ATR): ν = 3244 (br.), 3063 (w), 2965
˜
2
(m), 1487 (w), 1335 (w), 1081 (w), 1028 (s), 1009 (m), 813 (m), 729
TMS): δ = 6.30 (m, 2 H, 2ϫ CH), 3.89 (d, JH,H = 9.6 Hz, 1 H,
(s) cm–1.
2
CH2), 3.76 (d, JH,H = 10.7 Hz, 1 H, CH2), 2.89–2.87 (m, 1 H,
[(1S,2R,3S,4R)-2-Methylbicyclo[2.2.1]hept-5-ene-2,3-diyl]dimeth- CH), 2.64–2.63 (m, 1 H, CH), 1.87–1.76 (m, 2 H, 2ϫ CH2), 1.65
anol [(–)-24]: By using the same procedure as for the synthesis of
(ddd, 2JH,H = 14.1, 3JH,H = 11.1, 4.4 Hz, 1 H, CH2), 1.57 (dt, 2JH,H
6642
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6636–6646

Enantioselective Synthesis of Microbial Butenolides
4
= 9.1, JH,H = 1.6 Hz, 1 H, CH2), 1.51–1.38 (m, 2 H, 2ϫ CH2), Column chromatography (eluant gradient from 100% hexane to
3
1.33 (sext, JH,H = 6.9 Hz, 2 H, CH2), 1.31 (s, 3 H, CH3), 0.92 (t, 100% ethyl acetate) yielded 30 (671 mg, 5.32 mmol, 92%) as a pale
3JH,H = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
yellow oil. Rf = 0.47 (hexane/ethyl acetate, 1:1). GC (BPX-5): I =
= 180.3 (CO), 138.2 (CH), 135.4 (CH), 76.0 (CH2), 58.9 (Cq), 54.6
1212. 1H NMR (400 MHz, CDCl3, TMS): δ = 4.61 (q, 4JH,H = 1.0,
(CH), 52.4 (CH), 48.4 (Cq), 47.9 (CH2), 33.1 (CH2), 28.3 (CH2), 1JC,H = 150.2 Hz, 2 H, CH2), 2.29 (q, JH,H = 7.7 Hz, 2 H, CH2),
3
1
3
23.4 (CH2), 22.9 (CH3), 13.8 (CH3) ppm. MS (EI, 70 eV): m/z (%)
2.03 (br. s, JC,H = 128.1 Hz, 3 H, CH3), 1.09 (t, JH,H = 7.6 Hz, 3
= 220 (Ͻ1) [M]+, 155 (100), 109 (8), 91 (14), 66 (95), 41 (16). IR
H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.8 (CO), 155.9
(ATR): ν = 3470 (br.), 2960 (w), 1732 (s), 1160 (w), 1027 (w), 710, (Cq), 128.5 (Cq), 72.3 (CH2), 16.6 (CH2), 12.5 (CH3), 11.9
˜
+
(m) cm–1. HRMS: calcd. for C14H20O2 220.14578; found (CH3) ppm. MS (EI, 70 eV): m/z (%) = 126 (83) [M]+, 111 (24), 97
220.14745.
(78), 83 (15), 69 (76), 53 (34), 41 (100). IR (ATR): ν = 2973 (w),
˜
1738 (s), 1451 (w), 1340 (w), 1091 (m), 1033 (s), 915 (w) cm–1. UV/
(3aR*,4S*,7R*,7aS*)-7a-Ethyl-3a-methyl-3a,4,7,7a-tetra-hydro-
4,7-methanoisobenzofuran-1(3H)-one [(rac)-28]: Diisopropyl-amine
Vis (CH2Cl2): λmax (ε, Lmol–1 cm–1) = 231 (1787) nm.
(2.14 g, 21 mmol, 1.1 equiv.) was dissolved in absolute THF cis-3-Butyl-4-methyldihydrofuran-2(3H)-one (cis-31): To a solution
(30 mL) and a solution of n-butyllithium (1.6 m in hexane, 12.9 mL,
21 mmol, 1.1 equiv.) was added dropwise at 0 °C. The mixture was
stirred for 1 h at 0 °C and then cooled to –78 °C. A solution of a
1:1 mixture of compounds (rac)-25 and (rac)-26 [3.07 g, 18.7 mmol,
1.0 equiv.; the mixture contains ca. 9.5 mmol of (rac)-25] in abso-
lute THF (6 mL) was added and stirred for a further 2 h at –78 °C.
Ethyl bromide (2.37 g, 21 mmol, 1.1 equiv.) was added dropwise
and stirring was continued overnight while the reaction mixture
warmed to room temperature. The reaction was quenched with
water and extracted three times with diethyl ether. The combined
organic layers were dried with MgSO4 and concentrated under re-
duced pressure. Column chromatography on silica gel (hexane/ethyl
acetate, 2:1) yielded (rac)-38 [1.24 g, 6.5 mmol, 68% based on (rac)-
25] as a colourless oil. Rf = 0.57 (hexane/ethyl acetate, 2:1). GC
of 29 (230 mg, 1.5 mmol, 1.0 equiv.) in methanol (10 mL) was
added Pd/AlOx (10%, 160 mg, 0.15 mmol, 0.1 equiv.). The mixture
was stirred under an atmosphere of H2 (40 bar) for 24 h at 60 °C.
After cooling to room temperature, filtration and concentration un-
der reduced pressure, cis-31 (131 mg, 0.84 mmol, 56%) was ob-
tained as colourless oil. Rf = 0.85 (hexane/ethyl acetate, 1:1). GC
(BPX-5): I = 1330. GC (HP-5): I = 1312. 1H NMR (400 MHz,
2
3
CDCl3, TMS): δ = 4.26 (dd, JH,H = 8.9, JH,H = 5.4 Hz, 1 H,
2
3
CH2), 3.96 (dd, JH,H = 8.9, JH,H = 2.1 Hz, 1 H, CH2), 2.67–2.58
(m, 1 H, CH), 2.55–2.49 (m, 1 H, CH), 1.81–1.72 (m, 1 H, CH2),
3
1.48–1.33 (m, 5 H, 3ϫ CH2), 1.02 (d, JH,H = 7.1 Hz, 3 H, CH3),
3
0.93 (t, JH,H = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 178.8 (CO), 73.2 (CH2), 43.7 (CH), 33.1 (CH), 29.7
(CH2), 24.5 (CH2), 22.6 (CH2), 13.8 (CH3), 13.4 (CH3) ppm. MS
(EI, 70 eV): m/z (%) = 156 (Ͻ1) [M]+, 141 (4), 113 (12), 100 (55),
1
(BPX-5): I = 1417. H NMR (400 MHz, CDCl3, TMS): δ = 6.32–
2
6.28 (m, 2 H, 2ϫ CH), 3.90 (d, JH,H = 9.7 Hz, 1 H, CH2), 3.76 85 (100), 69 (24), 55 (33), 41 (55). IR (ATR): ν = 2959 (w), 2935
˜
2
(d, JH,H = 9.6 Hz, 1 H, CH2), 2.90–2.88 (m, 1 H, CH), 2.64–2.62 (w), 1767 (s), 1460 (w), 1166 (m), 986 (m) cm–1.
2
(m, 1 H, CH), 1.90–1.72 (m, 3 H, 2ϫ CH2), 1.58 (dt, JH,H = 9.1,
trans-3-Butyl-4-methyldihydrofuran-2(3H)-one (trans-31): Sodium
(62 mg, 2.6 mmol, 3.0 equiv.) was dissolved in methanol (10 mL)
1
3JH,H = 1.6 Hz, 1 H, CH2), 1.32 (s, JC,H = 126.4 Hz, 3 H, CH3),
3
1.08 (t, JH,H = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
and cis-31 (133 mg, 0.85 mmol, 1.0 equiv.) was added. The reaction
CDCl3): δ = 180.2 (CO), 138.3 (CH), 135.5 (CH), 76.1 (CH2), 59.4
mixture was heated to reflux for 4 h. After cooling to room tem-
(Cq), 54.6 (CH), 53.9 (CH), 48.5 (Cq), 48.0 (CH2), 26.0 (CH2), 22.9
perature HCl (6 m) was added until the pH dropped to 1–2. The
(CH3), 10.7 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 192 (Ͻ1)
mixture was extracted three times with diethyl ether and dried with
[M]+, 115 (1), 99 (13), 91 (10), 77 (10), 66 (100), 51 (7), 39 (19). IR
MgSO4. The solvent was removed under reduced pressure. Column
(ATR): ν = 3065 (w), 2968 (m), 1753 (s), 1466 (w), 1381 (w), 1225
˜
chromatography on silica gel (pentane/diethyl ether) yielded trans-
31 (90 mg, 0.58 mmol, 67%) as a colourless liquid. Rf = 0.85 (hex-
ane/ethyl acetate, 1:1). GC (BPX-5): I = 1295. GC (HP-5): I = 1276.
+
(m), 1109 (m), 1029 (s), 707, (s) cm–1. HRMS: calcd. for C12H16O2
192.11448; found 192.11517.
2
3-Butyl-4-methylfuran-2(5H)-one (29): Compound (rac)-27 (1.15 g,
5.24 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (20 mL)
and heated to reflux for 1 d. After cooling to room temperature
the complete reaction mixture was loaded onto a silica gel column.
Column chromatography (eluant gradient from 100% hexane to
100% ethyl acetate) yielded 29 (778 mg, 5.0 mmol, 96%) as a pale
yellow oil. Rf = 0.36 (pentane/diethyl ether, 1:1). GC (BPX-5): I =
1H NMR (400 MHz, CDCl3, TMS): δ = 4.36 (dd, JH,H = 8.9,
2
3
3JH,H = 7.6 Hz, 1 H, CH2), 3.72 (t, JH,H = JH,H = 8.9 Hz, 1 H,
3
CH2), 2.38–2.28 (m, 1 H, CH), 2.10 (dt, JH,H = 9.7, 6.2 Hz, 1 H,
CH), 1.79–1.70 (m, 1 H, CH2), 1.63–1.53 (m, 1 H, CH2), 1.51–1.33
3
(m, 4 H, 2ϫ CH2), 1.16 (d, JH,H = 6.6 Hz, 3 H, CH3), 0.92 (t,
3JH,H = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 179.4 (CO), 72.5 (CH2), 46.7 (CH), 36.1 (CH), 28.9 (CH2), 28.7
(CH2), 22.7 (CH2), 16.9 (CH3), 13.8 (CH3) ppm. MS (EI, 70 eV):
m/z (%) = 156 (Ͻ1) [M]+, 141 (4), 113 (12), 100 (50), 85 (100), 69
1
1395. GC (HP-5): I = 1388. H NMR (400 MHz, CDCl3, TMS): δ
4
1
3
= 4.62 (q, JH,H = 1.0, JC,H = 150.2 Hz, 2 H, CH2), 2.26 (t, JH,H
1
= 7.5 Hz, 2 H, CH2), 2.03 (s, JC,H = 128.1 Hz, 3 H, CH3), 1.51– (19), 55 (34), 41 (55). IR (ATR): ν = 2959 (w), 2935 (w), 1767 (s),
˜
3
1.44 (m, 2 H, CH2), 1.36–1.28 (m, 2 H, CH2), 0.92 (t, JH,H = 7.3,
1JC,H = 124.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 175.0 (CO), 156.4 (Cq), 127.2 (Cq), 72.3 (CH2), 29.9 (CH2),
23.0 (CH2), 22.4 (CH2), 13.7 (CH3), 12.1 (CH3) ppm. MS (EI,
70 eV): m/z (%) = 154 (10) [M]+, 139 (15), 125 (17), 112 (100), 97
1460 (w), 1166 (m), 986 (m) cm–1.
(3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-4,7-methanoisobenzofuran-
1,3-dione (33): To a solution of maleic anhydride (32, 5.1 g,
51 mmol, 1.0 equiv.) in chloroform (90 mL) was added freshly dis-
tilled cyclopentadiene (21, 4.7 mL, 57 mmol, 1.1 equiv.) at 0 °C.
The reaction mixture was stirred at room temperature and under
exclusion of light for 5 h. After evaporation of the solvent under
reduced pressure and recrystallisation from methanol, compound
33 (13.8 g, 84 mmol, 81%) was obtained as a colourless solid; m.p.
162 °C. Rf = 0.18 (hexane/ethyl acetate, 5:1). GC (BPX-5): I = 1489.
(10), 83 (13), 67 (18). 55 (37), 39 (31). IR (ATR): ν = 2957 (w),
˜
2931 (w), 1741 (s), 1449 (w), 1087 (m), 1034 (s) cm–1. UV/Vis
(CH2Cl2): λmax (ε, Lmol–1 cm–1) = 231 (2339) nm.
3-Ethyl-4-methylfuran-2(5H)-one (30): Compound (rac)-28 (1.1 g,
5.8 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (20 mL)
and heated to reflux for 1 d. After cooling to room temperature
the complete reaction mixture was loaded onto a silica gel column.
4
1H NMR (400 MHz, CDCl3, TMS): δ = 6.31 (t, JH,H = 1.9 Hz, 2
H, 2ϫ CH), 3.60–3.58 (dd, 2 H, 2ϫ CH), 3.52–3.49 (m, 2 H, 2ϫ
Eur. J. Org. Chem. 2012, 6636–6646
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6643

C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger, J. S. Dickschat
27 mmol, 1.0 equiv.) and NMO (4.83 g, 37 mmol, 1.3 equiv.) were
FULL PAPER
CH), 1.79 (dt, JH,H = 9.1, JH,H = 1.7 Hz, 1 H, CH2), 1.60–1.56
2
3
(m, 1 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3 (2ϫ dissolved in absolute CH2Cl2 (75 mL). Molecular sieves (4 Å, 12 g)
CO), 135.5 (2 ϫ CH), 52.7 (CH2), 47.0 (2 ϫ CH), 46.1 (2 ϫ and TPAP (462 mg, 1.3 mmol, 0.05 equiv.) were added. The reac-
CH) ppm. MS (EI, 70 eV): m/z (%) = 164 (3) [M]+, 120 (7), 91 (59),
tion mixture was stirred overnight at room temperature, filtered,
66 (100), 51 (6), 39 (14). IR (ATR): ν = 3010 (w), 2982 (w), 1837 and concentrated under reduced pressure. Column chromatography
˜
(w), 1765 (s), 1336 (w), 1228 (m), 1080 (s), 902 (s), 843 (m), 730
on silica gel (hexane/ethyl acetate, 3:1) yielded (rac)-36 (2.1 g,
12 mmol, 46%) as a colourless solid; m.p. 65 °C. Rf = 0.36 (hexane/
ethyl acetate, 1:1). GC (BPX-5): I = 1533. 1H NMR (400 MHz,
CDCl3, TMS): δ = 6.26 (dd, 3JH,H = 5.1, 4JH,H = 2.5 Hz, 1 H, CH),
(s), 602 (s) cm–1.
(3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-4,7-methanoisobenzofuran-
1(3H)-one [(rac)-34]: NaBH4 (3.2 g, 84 mmol, 1.0 equiv.) was sus-
pended in absolute THF (20 mL) and cooled to 0 °C. A solution
of anhydride 33 (13.8 g, 84 mmol, 1.0 equiv.) in absolute THF
(120 mL) was added slowly, followed by stirring for 1 h at room
temperature. The reaction mixture was hydrolysed with HCl (6 m)
at 0 °C. The aqueous layer was extracted three times with CH2Cl2.
The combined organic layers were washed with brine, dried with
MgSO4, and concentrated under reduced pressure. Column
chromatography on silica gel (hexane/ethyl acetate, 2:1) yielded
(rac)-34 (6.5 g, 43.7 mmol, 52%) as a colourless solid; m.p. 120 °C.
Rf = 0.25 (hexane/ethyl acetate, 2:1). GC (BPX-5): I = 1480. 1H
NMR (400 MHz, CDCl3, TMS): δ = 6.31–6.27 (m, 2 H, 2ϫ CH),
3
4
3
6.23 (dd, JH,H = 5.7, JH,H = 2.9 Hz, 1 H, CH), 3.47 (dd, JH,H
8.9, JH,H = 5.1 Hz, 1 H, CH), 3.29–3.25 (m, 1 H, CH), 3.05–3.02
=
3
3
3
(m, 1 H, CH), 2.73 (dd, JH,H = 8.8, JH,H = 3.8 Hz, 1 H, CH),
2
3
2
1.63 (dt, JH,H = 8.4, JH,H = 1.7 Hz, 1 H, CH2), 1.42 (dt, JH,H
=
3
1
8.5, JH,H = 1.3 Hz, 1 H, CH2), 1.37 (s, JC,H = 126.9 Hz, 3 H,
CH3), 1.36 (s, JC,H = 126.9 Hz, 3 H, CH3) ppm. 13C NMR
1
(100 MHz, CDCl3): δ = 177.3 (CO), 135.9 (CH), 134.2 (CH), 83.9
(Cq), 52.6 (CH2), 51.6 (CH), 48.9 (CH), 45.2 (CH), 45.1 (CH), 32.3
(CH3), 23.6 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 178 (1) [M]+,
163 (2), 133 (2), 119 (4), 113 (42), 97 (12), 91 (22), 77 (5), 66 (100),
51 (3), 39 (8). IR (ATR): ν = 3067 (w), 2972 (w), 1748 (s), 1371
˜
2
3
2
(w), 1252 (m), 1128 (s), 960 (s), 811 (w), 724 (s), 661 (m) cm–1.
4.29 (dd, JH,H = 9.8, JH,H = 8.6 Hz, 1 H, CH), 3.80 (dd, JH,H
=
3
9.7, JH,H = 3.1 Hz, 1 H, CH), 3.35–3.32 (m, 1 H, CH), 3.27–3.23
(m, 1 H, CH), 3.15–3.07 (m, 2 H, 2ϫ CH), 1.65 (dt, JH,H = 8.6,
(3aS*,4R*,7S*,7aR*)-3,3,7a-Trimethyl-3a,4,7,7a-tetrahydro-4,7-
methanoisobenzofuran-1(3H)-one [(rac)-37]: Diisopropylamine
(700 mg, 7 mmol, 1.05 equiv.) was dissolved in absolute THF
(10 mL). A solution of n-butyllithium (1.6 m in hexane, 4.4 mL,
7 mmol, 1.05 equiv.) was added dropwise at 0 °C. The mixture was
stirred for 1 h at 0 °C and then cooled to –78 °C. A solution of
(rac)-36 (1.2 g, 6.7 mmol, 1.0 equiv.) in absolute THF (2 mL) was
added and the mixture was stirred for a further 2 h at –78 °C.
Methyl iodide (950 mg, 6.7 mmol, 1.0 equiv.) was added dropwise
and stirring was continued for 2.5 h while the reaction mixture
warmed to room temperature. The reaction was quenched with
water and extracted three times with diethyl ether. The combined
organic layers were dried with MgSO4 and concentrated under re-
duced pressure. Column chromatography on silica gel (hexane/ethyl
acetate, 3:1) yielded (rac)-37 (910 mg, 4.7 mmol, 71%) as a colour-
less liquid. Rf = 0.37 (hexane/ethyl acetate, 3:1). GC (BPX-5): I =
2
3JH,H = 1.6 Hz, 1 H, CH2), 1.47 (d, 2JH,H = 8.6 Hz, 1 H, CH2) ppm.
13C NMR (100 MHz, CDCl3): δ = 178.0 (CO), 136.7 (CH), 134.3
(CH), 70.2 (CH2), 51.7 (CH2), 47.5 (CH), 46.0 (CH), 45.7 (CH),
40.2 (CH) ppm. MS (EI, 70 eV): m/z (%) = 150 (1) [M]+, 105 (1),
91 (10), 85 (11), 77 (5), 66 (100), 51 (4), 39 (9). IR (ATR): ν = 3063
˜
(w), 2975 (w), 1752 (s), 1379 (m), 1176 (w), 1047 (m), 997 (s), 813
(m), 737 (s), 702 (s) cm–1.
2-[(1R,2S,3R,4S)-3-(Hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-yl]-
propan-2-ol [(rac)-35]: Magnesium turnings (2.3 g, 94 mmol,
2.4 equiv.) were covered with a small layer of absolute diethyl ether.
A solution of methyl iodide (13.5 g, 94 mmol, 2.4 equiv.) in diethyl
ether (50 mL) was added dropwise. After completion of the reac-
tion the mixture was cooled to 0 °C and a solution of (rac)-34
(6.4 g, 43 mmol, 1.0 equiv.) in diethyl ether (120 mL) was added
dropwise, followed by stirring of the reaction mixture for 1 h at
room temperature. The reaction mixture was quenched by the ad-
dition of a saturated solution of NH4Cl. The aqueous layer was
extracted three times with diethyl ether, the combined extracts were
dried with MgSO4, and concentrated under reduced pressure. Col-
umn chromatography on silica gel (hexane/ethyl acetate, 1:1)
yielded (rac)-35 (6.0 g, 33 mmol, 78%) as a colourless solid; m.p.
92 °C. Rf = 0.19 (hexane/ethyl acetate, 1:1). GC (BPX-5, MSTFA):
1
1530. H NMR (400 MHz, CDCl3, TMS): δ = 6.26–6.23 (m, 2 H,
2ϫ CH), 3.04–3.01 (m, 1 H, CH), 2.76–2.74 (m, 1 H, CH), 2.39
(d, 3JH,H = 3.9 Hz, 1 H, CH), 1.66 (dt, 2JH,H = 8.7, 3JH,H = 1.7 Hz,
2
3
1 H, CH2), 1.62 (dt, J = 8.8, JH,H = 1.5 Hz, 1 H, CH2), 1.60 (s,
3 H, CH3), 1.42 (s, 3 H, CH3), 1.34 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 180.3 (CO), 136.5 (CH), 135.0 (CH), 82.8
(Cq), 58.1 (CH), 55.8 (Cq), 52.4 (CH), 50.8 (CH2), 46.3 (CH), 32.3
(CH3), 23.7 (CH3), 23.6 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 192
(Ͻ1) [M]+, 134 (2), 127 (39), 109 (8), 91 (11), 77 (6), 66 (100), 51
1
3
I = 1668. H NMR (400 MHz, CDCl3, TMS): δ = 6.18 (dd, JH,H
4
3
4
= 5.9, JH,H = 2.9 Hz, 1 H, CH), 6.12 (dd, JH,H = 5.8, JH,H
=
(3), 39 (3). IR (ATR): ν = 3038 (w), 2971 (m), 1751 (s), 1464 (w),
˜
3.0 Hz, 1 H, CH), 4.28 (br. s, 2 H, 2ϫ OH), 3.71 (dd, 2JH,H = 11.5,
1310 (m), 1188 (m), 1072 (s), 940 (m), 719 (s) cm–1.
3JH,H = 5.0 Hz, 1 H, CH), 3.61 (dd, JH,H = 11.5, JH,H = 9.7 Hz,
2
3
3
1 H, CH), 2.86–2.79 (m, 2 H, CH2), 2.63 (ddt, JH,H = 4.9, 3.4,
5,5-Dimethylfuran-2(5H)-one (38): Compound (rac)-36 (900 mg,
5.1 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (20 mL)
and heated to reflux for 2 d. After cooling to room temperature
the complete reaction mixture was loaded onto a silica gel column.
Column chromatography (eluant gradient from 100% hexane to
100% ethyl acetate) gave 38 (300 mg, 2.7 mmol, 53%) as a colour-
less liquid. Rf = 0.19 (hexane/ethyl acetate, 3:1). GC (BPX-5): I =
9.5 Hz, 1 H, CH), 2.41 (dd, 3JH,H = 9.5, 3JH,H = 2.7 Hz, 1 H, CH),
3
4
3
1.42 (dt, JH,H = 8.1, JH,H = 2.0 Hz, 1 H, CH2), 1.37 (dt, JH,H
=
3
7.9, JH,H = 1.3 Hz, 1 H, CH2), 1.32 (s, 3 H, CH3), 1.16 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.1 (CH), 134.9
(CH), 73.5 (Cq), 63.6 (CH2), 54.5 (CH), 50.9 (CH2), 47.0 (CH),
46.9 (CH), 46.6 (CH), 32.7 (CH3), 28.5 (CH3) ppm. MS (EI, 70 eV):
m/z (%) = 326 (1) [M]+, 311 (1), 283 (1), 259 (14), 245 (7), 236 (6),
221 (8), 191 (41), 170 (29), 155 (14), 147 (28), 131 (100), 105 (6),
1
3
983. H NMR (400 MHz, CDCl3, TMS): δ = 7.45 (d, JH,H = 5.6,
1JC,H = 173.0 Hz, 1 H, CH), 5.99 (d, 3JH,H = 5.6, 1JC,H = 181.4 Hz,
1 H, CH), 1.50 (s, 1JC,H = 128.9 Hz, 6 H, 2ϫ CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.3 (CO), 161.3 (CH), 119.6 (CH), 86.5
(Cq), 25.2 (2ϫ CH3) ppm. MS (EI, 70 eV): m/z (%) = 112 (13)
91 (6), 81 (28), 73 (81), 66 (20). IR (ATR): ν = 3181 (br.), 3066
˜
(m), 2972 (m), 1484 (w), 1381 (m), 1169 (s), 1107 (m), 1035 (s), 905
(s), 715 (s) cm–1.
(3aS*,4R*,7S*,7aR*)-3,3-Dimethyl-3a,4,7,7a-tetrahydro-4,7-meth- [M]+, 97 (100), 69 (79), 54 (12), 43 (50). IR (ATR): ν = 3085 (w),
˜
anoisobenzofuran-1(3H)-one [(rac)-36]: Compound (rac)-35 (4.8 g, 2983 (w), 1741 (s), 1274 (m), 1196 (w), 1129 (s), 1070 (w), 961 (m),
6644
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6636–6646

Enantioselective Synthesis of Microbial Butenolides
943 (s), 818 (s), 698 (m) cm–1. UV/Vis (CH2Cl2): λmax (ε, THF (4 mL) was added and stirred for a further 2 h at –78 °C.
Lmol–1 cm–1) = 228 (341) nm.
Freshly prepared (S)-2-methylbutanal (310 mg, 3.6 mmol,
1.8 equiv.), obtained through oxidation of (S)-2-methylbutan-1-ol
with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl/NaOCl, was added
dropwise and stirring was continued overnight while the reaction
mixture warmed to room temperature. The reaction was quenched
with a saturated solution of NH4Cl and extracted three times with
diethyl ether. The combined organic layers were dried with MgSO4
and concentrated under reduced pressure. Column chromatography
on silica gel (pentane/diethyl ether, 1:1) yielded a diastereoisomeric
mixture of (1S,2S)-44 and (1R,2S)-44 (125 mg, 0.5 mmol, 50%,
48% de) as a colourless solid; m.p. 79 °C. [α]2D1.3 = +41.2 (c = 1.3,
3,5,5-Trimethylfuran-2(5H)-one (39): Compound (rac)-37 (910 mg,
4.7 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (20 mL)
and heated to reflux for 2 d. After cooling to room temperature
the complete reaction mixture was loaded onto a silica gel column.
Column chromatography (eluant gradient from 100% hexane to
100% ethyl acetate) gave 39 (440 mg, 3.5 mmol, 74%) as a colour-
less liquid. Rf = 0.15 (hexane/ethyl acetate, 5:1). GC (BPX-5): I =
1080. 1H NMR (400 MHz, CDCl3, TMS): δ = 7.01 (q, 4JH,H = 1.7,
1JC,H = 170.1 Hz, 1 H, CH), 1.89 (d, 4JH,H = 1.7, 1JC,H = 128.8 Hz,
1
3 H, CH3), 1.45 (s, JC,H = 128.8 Hz, 6 H, 2ϫ CH3) ppm. 13C
CH2Cl2). Rf = 0.44 (pentane/diethyl ether, 1:1). GC (BPX-5): I =
NMR (100 MHz, CDCl3): δ = 173.6 (CO), 154.0 (CH), 128.1 (Cq),
84.1 (Cq), 25.6 (2ϫ CH3), 10.4 (CH3) ppm. MS (EI, 70 eV): m/z
(%) = 126 (33) [M]+, 111 (100), 83 (58), 67 (13), 55 (17), 43 (79).
3
1929. 1H NMR (400 MHz, CDCl3, TMS): δ = 6.37 (dd, JH,H
=
4
5.6, JH,H = 3.0 Hz, 1 H, CH of both diastereoisomers), 6.29 (dd,
3JH,H = 5.6, 4JH,H = 3.0 Hz, 1 H, CH of both diast.), 3.88 (d, 2JH,H
IR (ATR): ν = 3087 (w), 2982 (w), 1740 (s), 1296 (m), 1078 (s), 995
˜
2
= 9.3 Hz, 1 H, CH2 of both diast.), 3.80 (d, JH,H = 9.3 Hz, 1 H,
CH2 of both diast.), 3.69 (d, JH,H = 4.5 Hz, 1 H, CH of minor
diast.), 3.66 (d, JH,H = 6.0 Hz, 1 H, CH of major diast.), 3.12 (br.
(m), 962 (m), 888 (m), 762 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε,
3
Lmol–1 cm–1) = 228 (431) nm.
3
m, 1 H, CH of major diast.), 3.06 (br. m, 1 H, CH of minor diast.),
2.65 (br. m, 1 H, CH of both diast.), 2.31–2.17 (m, 1 H, CH of
both diast.), 2.04–1.86 (m, 2 H, CH2 and OH of both diast.), 1.76
(br. d, 2JH,H = 8.9 Hz, 1 H, CH2 of major diast.), 1.70 (br. d, 2JH,H
= 8.9 Hz, 1 H, CH2 of minor diast.), 1.61–1.56 (m, 1 H, CH2 of
both diast.), 1.51–1.38 (m, 1 H, CH2 of minor diast.), 1.435 (s, 3
H, CH3 of minor diast.), 1.431 (s, 3 H, CH3 of major diast.), 1.35–
(3aR,4S,7R,7aS)-7a-[(S)-1-Hydroxy-2-methylpropyl]-3a-methyl-
3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (43): Di-
isopropylamine (303 mg, 3 mmol, 1.5 equiv.) was dissolved in THF
(10 mL) and a solution of n-butyllithium (1.6 m in hexane, 1.9 mL,
3 mmol, 1.5 equiv.) was added dropwise at 0 °C. The mixture was
stirred for 1 h at 0 °C and then cooled to –78 °C. A solution of 25
(656 mg, 2 mmol, 1.0 equiv., the mixture contained ca. 1 mmol of
25) in THF (4 mL) was added and stirred for a further 2 h at
–78 °C. Isobutyraldehyde (259 mg, 3.6 mmol, 1.8 equiv.) was added
dropwise and stirring was continued overnight while the reaction
mixture warmed to room temperature. The reaction was quenched
with a saturated solution of NH4Cl and extracted three times with
diethyl ether. The combined organic layers were dried with MgSO4
and concentrated under reduced pressure. Column chromatography
on silica gel (pentane/diethyl ether, 1:1) yielded 43 (193 mg,
0.82 mmol, 82%) as a colourless solid; m.p. 108 °C. [α]2D5.0 = +53.5
(c = 1.2, CH2Cl2). Rf = 0.34 (pentane/diethyl ether, 1:1). GC (BPX-
5): I = 1836. 1H NMR (400 MHz, CDCl3, TMS): δ = 6.37 (dd,
3JH,H = 5.6, 4JH,H = 3.0 Hz, 1 H, CH), 6.29 (dd, 3JH,H = 5.7, 4JH,H
3
1.24 (m, 1 H, CH2 of major diast.), 1.08 (d, JH,H = 7.9 Hz, 3 H,
3
CH3 of minor diast.), 1.02 (d, JH,H = 6.7 Hz, 3 H, CH3 of major
3
diast.), 0.98 (t, JH,H = 7.4 Hz, 3 H, CH3 of major diast.), 0.97 (t,
3JH,H = 7.3 Hz, 3 H, CH3 of minor diast.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 179.0/178.9 (CO of main/minor dia-
stereoisomer), 138.0/137.9 (CH), 136.9 (CH of both diastereoiso-
mers), 77.0/74.7 (CH), 75.9 (CH2), 64.8/64.9 (Cq), 54.1/54.0 (CH),
49.8/50.0 (Cq), 49.0/48.7 (CH), 48.1/48.0 (CH2), 36.2/36.3 (CH),
24.2/29.6 (CH2), 23.25/23.28 (CH3), 18.8/14.0 (CH3), 11.6/11.7
(CH3) ppm. MS (EI, 70 eV): m/z (%) = 250 (Ͻ1) [M]+, 199 (5), 185
(11), 167 (88), 127 (49), 110 (11), 91 (21), 77 (16), 66 (100), 53 (10),
41 (22). IR (ATR): ν = IR (ATR): ν = 3470 (br.), 2693 (m), 1731
˜
˜
(s), 1136 (m), 1029 (s), 710 (m) cm–1. HRMS: calcd. for C10H17O3
+
2
= 3.2 Hz, 1 H, CH), 3.88 (d, JH,H = 9.3 Hz, 1 H, CH2), 3.80 (d,
([M – C5H5]+) 185.11722; found 185.11806. The same procedure
was used for the synthesis of a 1:1 mixture of the two diastereoiso-
mers (1SR,2S)-44 from (rac)-25 and (S)-2-methylbutanal. The spec-
troscopic data of the product were the same as above.
2JH,H = 9.3 Hz, 1 H, CH2), 3.61 (br. m, 1 H, CH), 3.14 (br. m, 1
3
3
H, CH), 2.65 (br. m, 1 H, CH), 2.50 (dsept, JH,H = 5.6, JH,H
=
2
6.8 Hz, 1 H, CH), 1.85 (br. m, 1 H, OH), 1.73 (dt, JH,H = 9.0,
3JH,H = 1.4 Hz, 1 H, CH2), 1.58 (dt, JH,H = 8.9, JH,H = 1.6 Hz,
2
3
3
1 H, CH2), 1.43 (s, 3 H, CH3), 1.09 (d, JH,H = 6.9 Hz, 3 H, CH3),
Supporting Information (see footnote on the first page of this arti-
1.05 (d, JH,H = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
3
1
cle): Copies of the H and 13C NMR spectra of all synthetic com-
CDCl3): δ = 178.9 (CO), 138.0 (CH), 136.9 (CH), 76.7 (CH), 75.9
(CH2), 64.8 (Cq), 54.0 (CH), 49.8 (Cq), 48.8 (CH), 48.0 (CH2), 29.8
(CH), 23.3 (CH3), 22.8 (CH3), 17.7 (CH3) ppm. MS (EI, 70 eV):
m/z (%) = 236 (Ͻ1) [M]+, 171 (5), 153 (4), 127 (2), 107 (9), 91 (3),
pounds.
Acknowledgments
77 (24), 66 (100), 53 (7), 39 (62). IR (ATR): ν = 3474 (br.), 2960
˜
(w), 1733 (s), 1390 (w), 1160 (m), 1030 (m), 1002 (m), 710 (m) cm–1.
Funding by the Deutsche Forschungsgemeinschaft (DFG) with an
Emmy-Noether grant (to J. S. D.) is gratefully acknowledged. We
thank Kathrin Meier for technical assistance, and J. S. D. thanks
Stefan Schulz for his support.
HRMS: calcd. for C14H18O2 ([M – H2O]+) 218.13013; found
+
218.13329.
(3aR,4S,7R,7aS)-7a-[(1S,2S)-1-Hydroxy-2-methylbutyl]-3a-methyl-
3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one [(1S,2S)-
44] and (3aR,4S,7R,7aS)-7a-[(1R,2S)-1-Hydroxy-2-methylbutyl]-3a-
methyl-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one
and [(1R,2S)-44]: Diisopropylamine (303 mg, 3 mmol, 1.5 equiv.)
was dissolved in THF (10 mL), and a solution of n-butyllithium
(1.6 m in hexane, 1.9 mL, 3 mmol, 1.5 equiv.) was added dropwise
at 0 °C. The mixture was stirred for 1 h at 0 °C and then cooled to
–78 °C. A solution of enantiomerically enriched 25 (656 mg,
2 mmol, 1.0 equiv., the mixture contained ca. 1 mmol of 25) in
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Eur. J. Org. Chem. 2012, 6636–6646
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6645

C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger, J. S. Dickschat
FULL PAPER
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Received: July 25, 2012
Published Online: October 9, 2012
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