Synthesis of 4-hydroxy-5-methyl- and 4-hydroxy-6-methylcyclohexenones by PdII-catalyzed oxidation and lipase-catalyzed hydrolysis

Article abstract of DOI:10.1002/ejoc.201200704

A short route for the syntheses of methyl-substituted hydroxycyclohexenones, which are building blocks for various natural products, is presented. Both oxygen atoms were introduced as acetates by a palladium(II)-catalyzed 1,4-addition to a 1,3-diene. The

Full text of DOI:10.1002/ejoc.201200704

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201200704
Synthesis of 4-Hydroxy-5-methyl- and 4-Hydroxy-6-methylcyclohexenones by
PdII-Catalyzed Oxidation and Lipase-Catalyzed Hydrolysis
Anne C. Meister,[a] Martin Nieger,[b] and Stefan Bräse*[a]
Dedicated to Professor Jan-Erling Bäckvall on the occasion of his 65th birthday
Keywords: Synthetic methods / Enzyme catalysis / Regioselectivity / Homogeneous catalysis / Palladium / Natural
products / Cyclohexenones
A short route for the syntheses of methyl-substituted hy-
droxycyclohexenones, which are building blocks for various
hydroxy-5-methylcyclohexene and its 6-methyl regioisomer
as a separable mixture. The target compounds 4-hydroxy-5-
natural products, is presented. Both oxygen atoms were in- methylcyclohex-2-enone and 4-hydroxy-6-methylcyclohex-
troduced as acetates by a palladium(II)-catalyzed 1,4-ad-
dition to a 1,3-diene. The distinction between the two acet-
oxy groups was achieved by regioselective monohydrolysis
with lipase from Candida rugosa, which gave 1-acetoxy-4-
2-enone could then be obtained as diastereomeric mixtures
in good overall yields and with moderate enantiomeric ex-
cesses (31–67%).
Introduction
The 1,4-dioxo-2-methylcyclohexene ring is a structural
motif that is present in a large number of natural products.
In particular, several xanthones, such as secalonic acids A–
G (1a–g),[1] the ergochrysins,[2] ergoflavin,[3] monodictysins
B (2) and C,[4] blennolides A and B,[5] the phomoxanth-
ones,[6] and leptosphaerins G and F,[7] contain such a sub-
structure (Figure 1). Furthermore, small natural products,
such as the ampelomines,[8] epoxydine A (3),[9] gabosine
O,[10] or dihydroepiepoformin (4),[10] are accessible from
either 4-hydroxy-5-methylcyclohex-2-enone (5) or 4-hy-
droxy-6-methylcyclohex-2-enone (6).
The literature describes many syntheses of 5 and 6: in
2006, the first enantioselective seven-step synthesis of trans-
5 was reported by Bräse et al.[11] In 2002, Carreño et al.
presented an eight-step synthesis of enantiomerically pure
TBDMS-protected cis-6 (TBDMS = tert-butyldimethyl-
silyl), followed shortly afterwards by another eight-step syn-
thesis of the other enantiomer.[12] Shan and O’Doherty syn-
thesized trans-6 in 10 steps from the chiral pool substance,
Figure 1. Selected natural products that may be accessible from cy-
clohexenone building block 5 or 6. The structural motifs in 1–4
that are represented by the building blocks are printed in grey.
d-quinic acid, as well as Boc-protected cis-6 (Boc = tert-
butoxycarbonyl) in 9 steps from the same starting mate-
rial.[13] A diastereoselective eight-step synthesis of PMB-
protected cis-5 (PMB = para-methoxybenzyl) has been re-
ported by Piers et al.,[14] and a mixture of cis-6 and trans-6
has been synthesized by Edwards et al. in six steps.[15]
All the methods described above require long syntheses
and are only able to produce one of the desired regioiso-
mers. In this paper, a practical method to obtain both re-
gioisomers 5 and 6 in only six steps is presented.
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-6084-8581
E-mail: Braese@kit.edu
Homepage: http://www.ioc.kit.edu/braese/
[b] Laboratory of Inorganic Chemistry, Department of Chemistry,
University of Helsinki,
P. O. Box 55, 00014 University of Helsinki, Finland
E-mail: Martin.Nieger@helsinki.fi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200704.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
A. C. Meister, M. Nieger, S. Bräse
FULL PAPER
It would be advantageous to introduce both of the oxy- sible regioisomers (i.e., 5 and 6) were obtained in low yield.
gen functionalities of the target molecules at the same time Regioselective monoprotection of diol 10 was attempted,
(Scheme 1). There are many methods to realize this,[16–23] but with the sterically demanding tert-butyldiphenylsilyl
but they are usually restricted to symmetrical substrates or chloride, only a mixture of regioisomers 11a and 11b was
substrates with a rather low degree of substitution. The pal- obtained.
ladium(II)-catalyzed 1,4-addition developed by Bäckvall et
al.,[24] being a more general method, was chosen for the
synthesis of unsymmetrical dioxo species 8. Compound 8
was then converted into 4-hydroxy-5-methylcyclohex-2-en-
one (5) or 4-hydroxy-6-methylcyclohex-2-enone (6) by a
three-step synthesis, using a lipase-catalyzed hydrolysis as
the key step.
Scheme 3. Attempts to differentiate the two oxygen functionalities.
Only major isomers are shown. Reagents and conditions:
a) K2CO3, MeOH, room temp., 3 d; b) potassium tert-butoxide,
DMSO, room temp.; or sodium 2,6-di-tert-butyl-4-methylphenol-
ate, THF, room temp.; or sodium 2,6-di-tert-butylphenolate, THF,
Scheme 1. PdII-catalyzed oxidation to give 8, a precursor for either
5 or 6. Only major isomers are shown.
These compounds can be key intermediates for the total
syntheses of the above-mentioned natural products. As re- room temp.; or sodium 2,4-di-tert-butylphenolate, THF, room
temp.; c) DMP, CH2Cl2, room temp., 3 h; or pyridinium chloro-
chromate (PCC), CH2Cl2, acetone, room temp., 30 min;
d) TBDPSCl, imidazole, 4-(dimethylamino)pyridine (DMAP)
(15 mol-%), DMF, room temp., 1 h.
gards the secalonic acids 1a–g, the first steps towards their
total synthesis were carried out, starting from cyclohex-
enone building block 5 (Scheme 8).
A selective palladium(0)-catalyzed mono-transesterifica-
Results and Discussion
tion of 8 was tried, using benzoic acid and the “Trost” li-
gand,[27] but this transformation was not successful either
(not shown).
Further palladium(II)-catalyzed oxidations of 7 were car-
ried out to obtain different 1,4-functionalized products (see
Scheme 4). Both the monochloro- (13 and 14) and the
monobromo compounds 15 and 16 were obtained as in-
As mentioned above, diacetate 8, obtained by the pro-
cedure described by Bäckvall et al.,[24] was used to synthe-
size the desired cyclohexenones 5 and 6. Starting from com-
mercially available 4-methylcyclohex-1-ene (9), diene 7 was
available in good yield by a sequence of bromination and
elimination. Oxidation under Bäckvall’s conditions with
catalytic amounts of palladium(II) acetate provided 8 in
good yield as a diastereomeric mixture (Scheme 2). The
major diastereomers were those in which the two acetate
groups were arranged trans to each other.
Scheme 2. Synthesis of diene 7 and oxidation according to Bäckvall
et al.[24] Only the major isomer of 8 is shown. Reagents and condi-
tions: a) Br2, CHCl3, 0 °C;[25] b) KOH, triethylene glycol, 180 °C;[26]
c) Pd(OAc)2 (5 mol-%), p-benzoquinone (28 mol-%), MnO2,
LiOAc·2H2O, HOAc, pentane, room temp., 3 d.
The two acetate groups had then to be distinguished.
First, selective monohydrolysis at the 1-position was at-
tempted (Scheme 3). The acetate at this position is less steri-
cally hindered, so sterically hindered bases should provide
alcohol 12. Unfortunately, no reaction occurred, probably
due to excessive steric bulk. However, hydrolysis of both
acetate groups could be achieved with potassium carbonate
to give 10. Regioselective mono-oxidation of 10 was then
Scheme 4. Palladium(II)-catalyzed 1,4-additions. Only major iso-
mers are shown. Reagents and conditions: a) Pd(OAc)2 (8 mol-%),
LiCl, LiOAc·2H2O, p-benzoquinone, HOAc, room temp., 1 d;[29]
b) Pd(OAc)2 (5 mol-%), LiBr, LiOAc·2H2O, p-benzoquinone,
HOAc, EtOAc, room temp., 4 d; c) Pd(OAc)2 (5 mol-%), benzoic
acid, p-benzoquinone, acetone, room temp., 3 d; d) trimethylamine
attempted, but only inseparable mixtures of the two pos- N-oxide, DMSO/CH2Cl2 (1:1), room temp., 1 d.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
Methyl-Substituted 4-Hydroxycyclohexenones
separable regioisomeric mixtures. Nevertheless, the bromo lysis of the residual acetate group could not be achieved
compounds were oxidized under Kornblum’s conditions,[28] using common bases, such as sodium methoxide, potassium
and gave a mixture of regioisomers 19 and 20. Unfortu- carbonate, or lithium hydroxide (in catalytic or stoichiomet-
nately, it was not possible to separate these compounds ric amounts). Apparently, the substrate or the product de-
either. Dibenzoate 17, available by palladium(II)-catalyzed compose under basic conditions. As lipases are known to be
reaction with benzoic acid, could only be obtained in low effective catalysts for acetate hydrolysis under mild, neutral
yields, and it was not possible to achieve its monohydro- conditions, lipase from wheat germ was chosen for the re-
lysis.
maining hydrolysis. To our delight, with this procedure, cy-
In view of the unselective, low-yielding reactions shown clohexenone 5 was obtained in good yield as a mixture of
above, attention was focused on enzyme-catalyzed hydroly- cis/trans diastereomers (2.1:1.0).
sis. It has been demonstrated that lipases are good catalysts
The diastereomers could not be separated at any stage
for the regioselective monohydrolysis of molecules with (12, 19 or 5) by column chromatography or by HPLC. The
multiple acetate groups,[30] so 18 different lipases were separation of the cis and trans isomers of 5 was then at-
tested on diacetate 8. The lipase from Candida rugosa was tempted by their conversion into different esters or ethers,
found to be the most suitable for the monohydrolysis of 8 but again, only inseparable mixtures were obtained. These
(Scheme 5). Two separable regioisomers [3.2 (12): 1.0 (21)] experiments are described in the Supporting Information
were obtained, and the minor regioisomer (i.e., 21) crys-
Due to lack of separation by chromatographic methods
tallized in an enantiomerically pure form, allowing the de- using chirally modified columns (HPLC and GC), the enan-
termination of its relative stereochemistry (Figure 2).
tiomeric excesses of 12, 19, and 5 could not be determined.
For cyclohexenone 5, the ee values were measured after
conversion into the corresponding (S)-(+)-Mosher esters
(Scheme 5). For cis-5 and trans-5, they were 61% and 67%,
respectively.
The minor regioisomer obtained from the monohydro-
lysis (i.e., 21; four diastereomers; 6.5:3.5:2.6:1.0), was con-
verted into cyclohexenone 20 under the same conditions as
those used for regioisomer 12 (Scheme 6). Compound 20
was formed as a mixture of two diastereomers (cis/trans =
1.0:1.0). This diastereomeric mixture was then, as above,
hydrolyzed with lipase from wheat germ to give cyclohex-
enone 6 (cis/trans = 1.7:1.0). Again, the diastereomers of
21, 20, and 6 were inseparable, and their ee values could
not be determined with chirally modified GC or HPLC col-
umns.
Scheme 5. Synthesis of cyclohexenone 5 and determination of its
ee value. Only major isomers are shown. Reagents and conditions:
a) lipase from Candida rugosa, phosphate buffer (pH = 7), room
temp., 23 h; b) DMP, CH2Cl2, room temp., 4 h; c) lipase from
wheat germ, phosphate buffer (pH = 7), room temp., 4 d;
d) DMAP, triethylamine, (S)-(+)-Mosher chloride, CH2Cl2 (abs.),
50 min, room temp.
Scheme 6. Synthesis of cyclohexenone 6 and determination of its
ee value. Only major isomers are shown. Reagents and conditions:
a) DMP, CH2Cl2, room temp., 4 h; b) lipase from wheat germ,
phosphate buffer (pH = 7), room temp., 4 d; c) DMAP, triethyl-
amine, (S)-(+)-Mosher chloride, CH2Cl2 (abs.), 50 min, room temp.
Figure 2. Molecular structure of 21 (displacement parameters are
drawn at the 50% probability level).
In the same manner as for cyclohexenone 5, the ee values
The major regioisomer (i.e., 12), which was obtained as for cyclohexenone 6 were determined after conversion into
a mixture of four diastereomers (5.1:2.1:1.0:1.0), was trans- the (S)-(+)-Mosher esters. Four diastereomers were ob-
formed into the desired cyclohexenone 5 in two steps. First, tained in quantitative yield, and the ee values of compounds
oxidation of the alcohol group was performed with Dess– cis-6 and trans-6 were 37% and 31%, respectively.
Martin periodinane (DMP), and gave cyclohexenone 19 as
The conversion of monoacetate 21 into cyclohexenone 5
a mixture of two diastereomers (cis/trans = 1.9:1.0). Hydro- could be achieved by a protection–deprotection sequence
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
A. C. Meister, M. Nieger, S. Bräse
FULL PAPER
(Scheme 7): the free alcohol functionality in 21 was pro- total synthesis of the above-mentioned secalonic acids (1),
tected as a silyl ether [TBDMS or tert-butyldiphenylsilyl ergochrysins, ergoflavin, monodictysins B (2b) and C,
(TBDPS)], then the acetate was hydrolyzed with lithium hy- blennolides A and B, phomoxanthones, and leptosphaerins
droxide, and finally, the so-formed alcohol was oxidized G and F.
with DMP. Deprotection of the silyl ether was carried out
with tetrabutylammonium fluoride (TBAF)/HOAc to give
cyclohexenone 5 in 64% overall yield for TBDMS as pro-
tecting group, and in 39% overall yield for TBDPS, which
is probably due to the higher steric demand of the TBDPS
group.
Figure 3. Molecular structure of the racemic diastereomer 26a (dis-
placement parameters are drawn at the 50% probability level).
Although the separation of the diastereomers of cyclo-
hexenones 5 or 6 was not possible, their diastereomeric mix-
tures can be used directly to create larger scaffolds, the dia-
stereomers of which can then be easily separated.
Conclusions
Scheme 7. Conversion of monoacetate 21 into cyclohexenone 5.
Only major isomers are shown. Reagents and conditions:
In this paper, a short and practical synthesis of enantio-
merically enriched 4-hydroxy-5-methylcyclohex-2-enone (5;
a) DMAP (15 mol-%), imidazole, TBDMSCl, DMF (abs.), room
temp., 20 h; b) LiOH, THF/water (2:1), room temp., 20 h; c) DMP,
61–67% ee) and 4-hydroxy-6-methylcyclohex-2-enone (6;
31–37% ee) is reported. Both cyclohexenones could be ob-
tained in six steps from commercially available cyclohexene
9. The key step for their synthesis was a lipase-catalyzed
monohydrolysis of diacetate 8, which provided the precur-
CH2Cl2, room temp., 4 h; d) TBAF, HOAc, THF, room temp., 13 d;
e) DMAP (15 mol-%), imidazole, TBDPSCl, DMF (abs.), room
temp., 20 h; f) LiOH, THF/water (1:1), room temp., 23 h; g) DMP,
CH2Cl2, room temp., 4 h; h) TBAF, HOAc, THF, room temp., 4 d.
Starting from the mixture of cis- and trans-cyclohex- sors for both 5 and 6. Diacetate 8 is readily available from
enone 5, a first attempt towards the total synthesis of the the corresponding diene (i.e., 10) by palladium(II)-catalyzed
secalonic acids 1a–g was made. Using a strategy similar to oxidation according to Bäckvall’s method.
that used for the total synthesis of blennolide C,[31] cyclo-
Cyclohexenones 5 and 6 are substructures of many small
hexenone 5 was treated with 6-methoxysalicylaldehyde to natural products, e.g., epoxydine A (3) or the ampelomines.
give xanthene 26 as a mixture of four diastereomers Therefore, 5 and 6 may be promising precursors for many
(Scheme 8). This time, all four diastereomers could be sepa- total syntheses.
rated by column chromatography. The stereochemistry of
Although the diastereomers of 5 and 6 were inseparable,
26a was confirmed by crystal structure analysis (Figure 3). the diastereomeric mixture of 5 could be used to build up
Xanthenes 26a–d are promising key intermediates for the xanthene scaffold 26 in one step. The diastereomers ob-
Scheme 8. Synthesis of xanthenes 26a–d. Reagents and conditions: a) 6-methoxysalicylaldehyde, N-methylimidazole, dioxane/water (1:2),
60 °C, 3 d, 48%.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
Methyl-Substituted 4-Hydroxycyclohexenones
CHCH3, CH2), 2.03 (s, 3 H, COCH3), 4.05 (dd, 3J = 3J = 4.3 Hz, 1
tained from this reaction were separable, and represent
interesting key compounds for the total synthesis of xan-
thenone natural products, such as the secalonic acids (1).
3
3
4
H, CHOH), 5.25 (ddd, J = 8.2, J = J = 4.1 Hz, 1 H, CHOAc),
3
3
5.84 (mc, 1 H, HC=), 6.05 (dd, J = 9.9, J = 4.5 Hz, 1 H, HC=)
ppm.
Rf (21; mixture of diastereomers; cyclohexane/ethyl acetate = 1:1)
1
= 0.57. H NMR (diastereomer 21a; 400 MHz, CDCl3): δ = 0.98
(d, J = 7.0 Hz, 3 H, CHCH3), 1.56 (mc, 1 H, CH2), 1.69–1.81 (m,
Experimental Section
3
General Remarks: NMR spectra were recorded with a Bruker
Avance 300, a Bruker AM 400, or a Bruker Avance 600 spectrome-
ter, in solution. Chemical shifts are expressed in parts per million
(ppm, δ) downfield from tetramethylsilane (TMS), and are refer-
enced to residual solvent peaks. All coupling constants (J) are abso-
lute values and are expressed in Hertz (Hz). The descriptions of
signals include: s = singlet, d = doublet, m = multiplet, mc = cen-
tered multiplet, br. s = broad singlet, dd = doublet of doublets, ddd
= doublet of doublet of doublets, etc. The spectra were analyzed
according to first order approximations. Solvents, reagents and
chemicals were purchased from Aldrich, ABCR, Acros, and May-
bridge. All solvents, reagents, and chemicals were used as pur-
chased, unless stated otherwise.
1 H, CH2), 1.98 (s, 3 H, COCH3), 2.00–2.05 (m, 1 H, CHCH3),
3
3
3
3
4.00 (dd, J = J = 4.2 Hz, 1 H, CHOH), 5.19 (ddd, J = J = 8.3,
4J = 4.1 Hz, 1 H, CHOAc), 5.82 (dddd, 3J = 9.9, 3J = 4.4 Hz,
other coupling constants could not be measured because of signal
3
3
4
overlap, 1 H, HC=), 6.01 (ddd, J = 9.9, J = 4.6, J = 0.6 Hz, 1
1
H, HC=) ppm. H NMR (diastereomer 21b; 400 MHz, CDCl3): δ
= 1.05 (d, J = 6.5 Hz, 3 H, CHCH3), 1.32 (ddd, J = 22.8, J =
12.1, J = 9.9 Hz, 1 H, CH2), 1.52–1.60 (m, 1 H, CH2), 1.98 (s, 3
3
2
3
3
H, COCH3), 2.00–2.05 (m, 1 H, CHCH3), 3.79 (mc, 1 H, CHOH),
3
5.34 (mc, 1 H, CHOAc), 5.58 (dddd, 3J = 10.2, J = 4J = 3.9, 4J
= 2.0 Hz, 1 H, HC=), 5.73–5.77 (m, 1 H, HC=) ppm. 1H NMR
3
(diastereomer 21c; 400 MHz, CDCl3): δ = 1.02 (d, J = 6.5 Hz, 3
H, CHCH3), 1.47–1.52 (m, 1 H, CH2), 1.69–1.81 (m, 2 H, CH2,
CHCH3), 1.98 (s, 3 H, COCH3), 3.66 (mc, 1 H, CHOH), 5.11 (mc,
Note: In the Exp. Section, only Rf values and 1H NMR spectro-
scopic data are given. For full compound characterization, see the
Supporting Information
3
3
1 H, CHOAc), 5.70–5.75 (m, 1 H, HC=), 5.88 (dd, J = 10.0, J =
1.9 Hz, 1 H, HC=) ppm. 1H NMR (diastereomer 21d; 400 MHz,
CDCl3): δ = 0.99 (d, J = 6.8 Hz, 3 H, CHCH3), 1.44–1.47 (m, 1
3
Monoacetates 12a–d and 21a–d: Lipase from Candida rugosa
(255 mg, 2.0 units/mg, 120 units/mmol substrate) was added to a
suspension of 850 mg 1,4-diacetoxy-5-methylcyclohex-2-ene (mix-
ture of four diastereomers, 4.00 mmol, 1.00 equiv.) in 47 mL phos-
phate buffer (0.1 m, pH 7), at room temp. After stirring at room
temp. for 23 h, half-saturated sodium chloride solution (50 mL)
was added, and the resulting mixture was extracted with ethyl acet-
ate (4ϫ150 mL). The combined organic extracts were dried with
sodium sulfate and filtered, and the solvent was removed in vacuo.
The residue was purified by column chromatography (silica gel,
cyclohexane/ethyl acetate, 10:1) to obtain monoacetate 12 (295 mg,
1.73 mmol, 43%) as a greenish oil. The four diastereomers (12a–d:
5.1:2.1:1.0:1.0) could not be separated. Monoacetate 21 (the re-
gioisomer) was also obtained from the column chromatography
(64.7 mg, 0.380 mmol, 9.5%) as reddish crystals. Neither could
these four diastereomers (21a–d: 6.5:3.5:2.6:1.0) be separated. An
inseparable fraction containing the two regioisomers (78 mg,
0.458 mmol, 11%) was also obtained as a yellow oil.
H, CH2), 1.69–1.81 (m, 2 H, CH2, CHCH3), 1.99 (s, 3 H, COCH3),
3.88 (dd, 3J = 3J = 3.9 Hz, 1 H, CHOH), 5.22–5.24 (m, 1 H,
3
CHOAc), 5.70–5.75 (m, 1 H, HC=), 5.94 (ddd, 3J = 10.0, J = 4.8,
4J = 2.0 Hz, 1 H, HC=) ppm.
Cyclohexenones cis-19, trans-19: DMP solution (0.48 m in dichloro-
methane, 10.8 mL. 5.20 mmol, 1.00 equiv.) was added to a solution
of monoacetate 12 (mixture of 4 diastereomers; 885 mg, 5.20 mmol,
1.00 equiv.) in dichloromethane (46 mL) at room temp. The white
suspension was stirred for 2 h at room temp., then further DMP
solution (0.48 m in dichloromethane, 5.4 mL, 2.60 mmol,
0.500 equiv.) was added. After stirring for a further 2 h, the reac-
tion mixture was poured into a solution of sodium thiosulfate (6 g)
and sodium hydrogen carbonate (6 g) in water (80 mL), and the
biphasic system was stirred until the organic phase became clear.
The phases were separated and the aqueous phase was extracted
with ethyl acetate (3ϫ120 mL). The combined organic extracts
were dried with sodium sulfate and filtered, and the solvents were
evaporated. The residue was purified by column chromatography
(silica gel, cyclohexane/ethyl acetate = 10:1 + 3% triethylamine) to
give the product as two inseparable diastereomers (cis-19/trans-19
= 1.9:1.0; 805 mg, 4.79 mmol, 92%) as a yellow oil.
Rf (12; mixture of diastereomers; cyclohexane/ethyl acetate = 1:1)
= 0.49. – 1H NMR (diastereomer 12a; 400 MHz, CDCl3): δ = 0.95
(d, 3J = 7.0 Hz, 3 H, CHCH3), 1.63 (ddd, 2J = 13.9, 3J = 3J =
3.4 Hz, 1 H, CH2), 1.81–1.89 (m, 1 H, CH2), 2.04 (s, 3 H, COCH3),
2.23 (mc, 1 H, CHCH3), 4.25 (ddd, 3J = 3J = 3J = 4.1 Hz, 1 H,
Rf (mixture of diastereomers; cyclohexane/ethyl acetate = 3:1) =
0.46. 1H NMR (cis-19; 300 MHz, CDCl3): δ = 1.03 (d, 3J = 6.6 Hz,
3 H, CHCH3), 2.10 (s, 3 H, COCH3), 2.44–2.52 (m, 3 H, CH2,
CHCH3), 5.45 (ddd, 3J = 3J = 4.0, 4J = 1.0 Hz, 1 H, CHOAc), 6.05
3
3
3
CHOH), 5.17 (dd, J = J = 4.2 Hz, 1 H, CHOAc), 5.88 (dd, J =
9.9, 3J = 4.4 Hz, 1 H, HC=), 5.98 (dd, 3J = 10.0, 3J = 4.1 Hz, 1 H,
HC=) ppm. 1H NMR (diastereomer 12b; 400 MHz, CDCl3): δ =
3
4
3
3
(dd, J = 10.2, J = 0.9 Hz, 1 H, HC=), 6.83 (dd, J = 10.2, J =
3
2
3
3
0.99 (d, J = 6.8 Hz, 3 H, CHCH3), 1.33 (ddd, J = J = 12.9, J
= 9.8 Hz, 1 H, CH2), 1.81–1.89 (m, 1 H, CHCH3), 2.06 (s, 3 H,
COCH3), 2.08–2.11 (m, 1 H, CH2), 4.33 (mc, 1 H, CHOH), 5.05
(mc, 1 H, CHOAc), 5.60 (ddd, 3J = 10.2, 3J = 4J = 2.0 Hz, 1 H,
HC=), 5.80 (dddd, 3J = 10.1, 3J = 4J = 3.5, 4J = 1.8 Hz, 1 H, HC=)
1
4.2 Hz, 1 H, HC=) ppm. H NMR (trans-19; 300 MHz, CDCl3): δ
3
= 1.05 (d, J = 6.5 Hz, 3 H, CHCH3), 2.13 (s, 3 H, COCH3), 2.24
(dd, 2J = 28.4, 3J = 15.4 Hz, 1 H, CH2), 2.28–2.38 (m, 1 H,
2
3
4
CHCH3), 2.57 (ddd, J = 15.7, J = 3.1, J = 0.9 Hz, 1 H, CH2),
5.32 (ddd, J = 9.0, J = J = 2.1 Hz, 1 H, CHOAc), 6.00 (ddd, J
= 10.3, J = 2.0, J = 1.1 Hz, 1 H, HC=), 6.73 (dd, J = 10.2, J
= 2.2 Hz, 1 H, HC=) ppm.
3
3
4
3
1
ppm. H NMR (diastereomer 12c; 400 MHz, CDCl3): δ = 0.96 (d,
4
5
3
3
coupling constant could not be measured because of signal overlap,
2
3
3
3 H, CHCH3), 1.49 (ddd, J = 23.1, J = 12.9, J = 10.2 Hz, 1 H,
CH2), 1.81–1.89 (m, 2 H, CH2, CHCH3), 2.07 (s, 3 H, COCH3),
Cyclohexenones cis-5, trans-5: Lipase from wheat germ (92 mg, 826
units, 9 units/mg) was added to an emulsion of cyclohexenone 19
[mixture of 2 diastereomers (cis-19/trans-19 = 1.9:1.0); 702 mg,
4.17 mmol, 1.00 equiv.] in phosphate buffer (0.1 m, pH 7, 65 mL),
and the mixture was stirred for 23 h. After this time, the same
4.20 (ddd, 3J = 3J = 7.8, J = 4.0 Hz, 1 H, CHOH), 4.92 (mc, 1 H,
CHOAc), 5.71 (dd, J = 10.0, J = 2.3 Hz, 1 H, HC=), 5.91–5.95
(m, 1 H, HC=) ppm. 1H NMR (diastereomer 12d; 400 MHz,
CDCl3): δ = 1.03 (d, 3J = 7.0 Hz, 3 H, CHCH3), 1.81–1.89 (m, 3 H,
4
3
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
A. C. Meister, M. Nieger, S. Bräse
FULL PAPER
amount again of lipase was added. After 3 more days, saturated
sodium chloride solution (130 mL) was added, and the mixture was
extracted with ethyl acetate (5ϫ100 mL). After drying with sodium
sulfate, filtration, and evaporation of the solvent, the residue was
purified by column chromatography (silica gel, cyclohexane/ethyl
acetate = 1:2 + 3% triethylamine). The product was obtained as a
Cyclohexenones cis-20, trans-20: DMP solution (0.48 m in dichloro-
methane, 2.66 mL, 1.27 mmol, 1.00 equiv.) was added to a solution
of monoacetate 21 (mixture of 4 diastereomers; 217 mg, 1.27 mmol,
1.00 equiv.) in dichloromethane (12 mL), at room temp. The white
suspension was stirred for 2 h at room temp. Then further DMP
solution (0.48 m in dichloromethane, 1.33 mL, 0.637 mmol,
0.500 equiv.) was added. After stirring for a further 2 h, the reac-
tion mixture was poured into a solution of sodium thiosulfate (2 g)
and sodium hydrogen carbonate (2 g) in water (25 mL), and the
biphasic system was stirred until the organic phase became clear.
The phases were separated and the aqueous phase was extracted
with ethyl acetate (3ϫ40 mL). The combined organic extracts were
dried with sodium sulfate and filtered, and the solvents were evapo-
rated. The residue was purified by column chromatography (silica
gel, cyclohexane/ethyl acetate = 10:1 + 3% triethylamine) to give
the product as two inseparable diastereomers (cis-20/trans-20 =
1.0:1.0; 200 mg, 1.19 mmol, 93%) as a yellow liquid.
mixture of diastereomers (cis-5/trans-5
= 2.1:1.0; 464 mg,
3.68 mmol, 88%) as a yellowish oil.
Rf (mixture of diastereomers; cyclohexane/ethyl acetate = 1:1) =
1
3
0.26. H NMR (cis-5; 300 MHz, CDCl3): δ = 1.09 (d, J = 6.6 Hz,
3 H, CH3), 1.75 (br. s, 1 H, OH), 2.37–2.54 (m, 3 H, CHCH3,
3
CH2), 4.46 (mc, 1 H, CHOH), 6.01 (d, J = 10.3 Hz, 1 H, CH=),
6.88 (dd, 3J = 10.1, 3J = 4.0 Hz, 1 H, CH=) ppm. 1H NMR (trans-
5; 300 MHz, CDCl3): δ = 1.17 (d, 3J = 6.1 Hz, 3 H, CH3), 1.75 (br.
s, 1 H, OH), 2.06–2.21 (m, 2 H, CHCH3, CH2), 2.37–2.54 (m, 1 H,
CH2), 4.16 (mc, 1 H, CHOH), 5.96 (mc, 1 H, CH=), 6.91 (dd, 3J =
3
10.4, J = 1.9 Hz, 1 H, CH=) ppm.
Rf (mixture of diastereomers; cyclohexane/ethyl acetate = 3:1) =
0.45. 1H NMR (cis-20; 400 MHz, CDCl3): δ = 1.15 (d, 3J = 5.4 Hz,
3 H, CHCH3), 1.80 (mc, 1 H, CH2), 2.10 (s, 3 H, COCH3), 2.35–
2.41 (m, 1 H, CH2), 2.43–2.51 (m, 1 H, CHCH3), 5.66 (mc, 1 H,
Xanthenes 26a–d: N-Methylimidazole (105 μL, 108 mg, 1.31 mmol,
0.500 equiv.), 6-methoxysalicylaldehyde (400 mg, 2.63 mmol,
1.00 equiv.) and cyclohexenone 5 [mixture of two diastereomers
(cis-5/trans-5 = 1.3:1.0), 365 mg, 2.89 mmol, 1.10 equiv.] were
added to a degassed dioxane/water mixture (1:2, 4.5 mL), and the
mixture was stirred for 3 d at 60 °C. Water (6 mL) was added, and
the mixture was extracted with ethyl acetate (4ϫ20 mL). The com-
bined organic extracts were dried with sodium sulfate, the solvent
was removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, cyclohexane/ethyl acetate =
6:1). The product was obtained as four separable diastereomers:
26a (89 mg, 13%); 26b (102 mg, 15%); 26c (77 mg, 11%); and 26d
(59 mg, 9%).
3
4
CHOAc), 6.02 (dd, J = 10.4, J = 2.4 Hz, 1 H, CH=), 6.75 (ddd,
3
4
1
3J = 10.4, J = J = 2.0 Hz, 1 H, CH=) ppm. H NMR (trans-20;
3
400 MHz, CDCl3): δ = 1.17 (d, J = 5.8 Hz, 3 H, CHCH3), 2.00–
2.07 (m, 1 H, CH2), 2.09 (s, 3 H, COCH3), 2.20 (mc, 1 H, CH2),
3
3
3
2.74 (mc, 1 H, CHCH3), 5.46 (ddd, J = J = 8.8, J = 4.4 Hz, 1
H, CHOAc), 6.04 (dd, 3J = 10.2, 4J = 0.8 Hz, 1 H, CH=), 6.81
(ddd, J = 10.2, J = 4.3, J = 0.8 Hz, 1 H, CH=) ppm.
3
3
4
Cyclohexenones cis-6, trans-6: Lipase from wheat germ (14 mg, 128
units, 9 units/mg) was added to an emulsion of cyclohexenone 20
(mixture of 2 diastereomers cis-20/trans-20 = 1.0:1.0; 109 mg,
0.648 mmol, 1.00 equiv.) in phosphate buffer (pH 7, 0.1 m, 11 mL),
and the mixture was stirred for 23 h. Then the same amount again
of lipase was added. After 3 more days, saturated sodium chloride
solution (20 mL) was added, and the mixture was extracted with
ethyl acetate (5ϫ20 mL). After drying with sodium sulfate, fil-
tration, and evaporation of the solvent, the residue was purified by
column chromatography (silica gel, cyclohexane/ethyl acetate = 1:2
+ 3% triethylamine). The product was obtained as a mixture of
diastereomers (cis-6/trans-6 = 1.7:1.0; 62 mg, 0.491 mmol, 76%) as
a yellowish oil.
Rf (26a; cyclohexane/ethyl acetate = 1:1) = 0.66. 1H NMR (dia-
stereomer 26a; 400 MHz, CDCl3): δ = 1.21 (d, 3J = 6.8 Hz, 3 H,
CHCH3), 2.01–2.10 (m, 1 H, CHCH3), 2.35 (dd, 2J = 18.1, 3J =
2
3
5.1 Hz, 1 H, CH2), 2.47 (br. s, 1 H, OH), 2.58 (dd, J = 18.1, J =
13.2 Hz, 1 H, CH2), 3.83 (s, 3 H, OCH3), 4.22 (mc, 1 H, CHOH),
4.94 (dd, 3J = 2.8, 4J = 2.8 Hz, 1 H, CHCHOH), 6.46 (d, 3J =
3
3
8.3 Hz, 1 H, CHAr), 6.51 (d, J = 8.3 Hz, 1 H, CHAr), 7.19 (dd, J
= 3J = 8.3 Hz, 1 H, CHAr), 7.84–7.85 (m, 1 H, =CH) ppm. Rf (26b;
cyclohexane/ethyl acetate = 1:1) = 0.50. 1H NMR (diastereomer
26b; 400 MHz, CDCl3): δ = 1.03 (d, 3J = 7.3 Hz, 3 H, CHCH3),
3
2.40–2.47 (m, 1 H, CHCH3), 2.52 (dd, 2J = 17.7, J = 3.0 Hz, 1 H,
2
3
CH2) 2.62 (dd, J = 17.7, J = 5.2 Hz, 1 H, CH2), 2.85 (br. s, 1 H,
OH), 3.84 (s, 3 H, OCH3), 4.36 (dd, 3J = 8.6, 3J = 4.2 Hz, 1 H,
CHOH), 4.82 (dd, 3J = 8.6, 4J = 2.3 Hz, 1 H, CHCHOH), 6.47 (d,
3J = 8.3 Hz, 1 H, CHAr), 6.56 (d, 3J = 8.3 Hz, 1 H, CHAr), 7.22
Rf (mixture of diastereomers; cyclohexane/ethyl acetate = 1:1) =
1
3
0.27. H NMR (cis-6; 400 MHz, CDCl3): δ = 1.13 (d, J = 6.5 Hz,
3 H, CH3), 1.72 (mc, 1 H, CH2), 2.32–2.40 (m, 2 H, CHCH3, CH2),
2.62 (br. s, 1 H, OH), 4.61–4.64 (m, 1 H, CHOH), 5.93 (d, 3J =
3
3
(dd, J = J = 8.3 Hz, 1 H, CHAr), 7.81–7.82 (m, 1 H, =CH) ppm.
Rf (26c cyclohexane/ethyl acetate = 1:1) = 0.55. 1H NMR (dia-
stereomer 26c; 400 MHz, CDCl3): δ = 1.18 (d, 3J = 6.4 Hz, 3 H,
CHCH3), 1.94–2.07 (m, 1 H, CHCH3), 2.20 (dd, 2J = 18.0, 3J =
13.1 Hz, 1 H, CH2) 2.63 (dd, 2J = 18.0, 3J = 4.4 Hz, 1 H, CH2),
2.82 (br. s, 1 H, OH), 3.84 (s, 3 H, OCH3), 3.89 (dd, 3J = 3J =
8.8 Hz, 1 H, CHOH), 4.75 (dd, 3J = 8.8, 4J = 2.3 Hz, 1 H,
3
3
4
10.1 Hz, 1 H, CH=), 6.88 (ddd, J = 10.1, J = J = 1.9 Hz, 1 H,
1
3
CH=) ppm. H NMR (trans-6; 300 MHz, CDCl3): δ = 1.15 (d, J
= 7.1 Hz, 3 H, CH3), 2.01–2.16 (m, 2 H, CH2), 2.62 (br. s, 1 H,
OH), 2.70–2.79 (m, 1 H, CHCH3), 4.53 (mc, 1 H, CHOH), 5.93 (d,
3J = 10.1 Hz, 1 H, CH=), 6.86 (dd, J = 10.1, 3J = 3.8 Hz, 1 H,
3
CH=) ppm.
CHCHOH), 6.47 (d, 3J = 8.3 Hz, 1 H, CHAr), 6.54 (d, 3J = 8.3 Hz, Crystal Structure Determinations: Single-crystal X-ray diffraction
1 H, CHAr), 7.21 (dd, J = 3J = 8.3 Hz, 1 H, CHAr), 7.80–7.81 (m, studies were carried out on a Nonius Kappa-CCD (21) or a
3
1 H, =CH) ppm. Rf (26d; cyclohexane/ethyl acetate = 1:1) = 0.58.
Bruker–Nonius APEXII (26a) diffractometer at 123(2) K using
Mo-Kα radiation (λ = 0.71073 Å). Direct Methods (SHELXS-97)
[32] were used for structure solution, and refinement was carried out
using SHELXL-97[32] (full-matrix least-squares on F2). Hydrogen
3
1H NMR (diastereomer 26d; 400 MHz, CDCl3): δ = 1.00 (d, J =
2
3
7.6 Hz, 3 H, CHCH3), 2.24 (dd, J = 17.8, J = 1.9 Hz, 1 H, CH2)
2
2.53–2.59 (m, 1 H, CHCH3), 2.77 (br. s, 1 H, OH), 3.00 (dd, J =
3
17.8, J = 6.1 Hz, 1 H, CH2), 3.84 (s, 3 H, OCH3), 4.28 (mc, 1 H, atoms were localized by difference electron density determination,
CHOH), 5.04 (mc, 1 H, CHCHOH), 6.48 (d, 3J = 8.3 Hz, 1 H, and refined using a riding model [H(O) free]. The absolute configu-
CHAr), 6.53 (d, 3J = 8.3 Hz, 1 H, CHAr), 7.20 (dd, 3J = 3J = 8.3 Hz,
1 H, CHAr), 7.85–7.86 (m, 1 H, =CH) ppm.
ration of 21 could not be determined reliably by refinement of
Flack’s x-parameter,[33] nor by using Bayesian statistics on Bijvoet
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
Methyl-Substituted 4-Hydroxycyclohexenones
differences (Hooft’s y-parameter).[34] The enantiomer was assigned
41, 2755–2757; b) M. C. Carreño, M. Pérez-Gonzalés, M. Rib-
agorda, Á. Somoza, A. Urbano, Chem. Commun. 2002, 3052–
3053; c) M. C. Carreño, Á. Somoza, M. Ribagorda, A. Ur-
bano, Chem. Eur. J. 2007, 13, 879–890.
M. Shan, G. A. O’Doherty, Org. Lett. 2008, 10, 3381–3384; M.
Shan, E. U. Sharif, G. A. O’Doherty, Angew. Chem. 2010, 122,
9682–9685; Angew. Chem. Int. Ed. 2010, 49, 9492–9495.
E. Piers, S. Caillé, G. Chen, Org. Lett. 2000, 2, 2483–2486.
M. G. Edwards, M. N. Kenworthy, R. R. A. Kitson, M. S.
Scott, R. J. K. Taylor, Angew. Chem. 2008, 120, 1961–1963; An-
gew. Chem. Int. Ed. 2008, 47, 1935–1937.
a) H. E. Burks, L. T. Kliman, J. P. Morken, J. Am. Chem. Soc.
2009, 131, 9134–9135; b) S. L. Poe, J. P. Morken, Angew. Chem.
2011, 123, 4275; Angew. Chem. Int. Ed. 2011, 50, 4189–4192;
c) C. H. Schuster, B. Li, J. P. Morken, Angew. Chem. 2011, 123,
8052–8055; Angew. Chem. Int. Ed. 2011, 50, 7906–7909; d) R. J.
Ely, J. P. Morken, Org. Lett. 2010, 12, 4348–4351.
a) G. Stork, M. Isobe, J. Am. Chem. Soc. 1975, 97, 6260–6261;
b) H. Nakashima, M. Sato, T. Taniguchi, K. Ogasawara, Syn-
lett 1999, 1754–1756.
at random.
21:
Yellow,
C9H14O3,
M
=
170.20,
crystal
size
0.30ϫ0.12ϫ0.08 mm, orthorhombic, space group P212121 (no.
19): a = 5.2847(5) Å, b = 9.3366(11) Å, c = 17.6808(13) Å, V =
872.39(15) Å3, Z = 4, ρ(calcd.) = 1.296 Mgm–3, F(000) = 368, μ =
[13]
0.096 mm–1, 10714 reflections (2θmax = 55°), 1967 unique [Rint
=
[14]
[15]
0.037], 114 parameters, 1 restraint, R1 [IϾ2σ(I)] = 0.041, wR2 (all
data) = 0.088, GOOF = 1.06, largest diff. peak and hole 0.180/–
0.220 eÅ–3, x = –1.2(14), y = 0.1(5).
[16]
26a: Yellow, C15H16O4·H2O,
M
=
278.29, crystal size
0.25ϫ0.15ϫ0.10 mm, monoclinic, space group P21/c (no. 14): a =
9.5722(3) Å, b = 18.3352(9) Å, c = 8.0587(4) Å, β = 109.014(3)°, V
= 1337.20(10) Å3, Z = 4, ρ(calcd.) = 1.382 Mgm–3, F(000) = 592,
μ = 0.104 mm–1, 8768 reflections (2θmax = 55°), 3017 unique [Rint
= 0.036], 191 parameters, 4 restraints, R1 [IϾ2σ(I)] = 0.045, wR2
(all data) = 0.107, GOOF = 1.06, largest diff. peak and hole 0.302/–
0.209 eÅ–3.
[17]
[18]
[19]
[20]
[21]
[22]
S. Uemura, S.-i. Fukuzawa, M. Okano, Tetrahedron Lett. 1981,
22, 5331–5334.
J. Barluenga, J. Pérez-Prieto, G. Asensio, J. Chem. Soc. Perkin
Trans. 1 1984, 629–633.
S. Uemura, A. Tabata, M. Okano, K. Ichikawa, J. Chem. Soc.,
C 1970, 1630–1631.
CCDC-866127 (for 21) and -866128 (for 26a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and full analytical data for all com-
pounds are described in the Supporting Information
J.-i. Yoshida, T. Murata, S. Isoe, Tetrahedron Lett. 1987, 28,
211–214.
a) K. Gollnick, A. Griesbeck, Tetrahedron Lett. 1983, 24,
3303–3306; b) A. J. Pearson, Y.-S. Lai, W. Lu, A. A. Pinkerton,
J. Org. Chem. 1989, 54, 3882–3893; c) C. R. Johnson, J. L. Es-
ker, M. C. Van Zandt, J. Org. Chem. 1994, 59, 5854–5855; d)
S. Sano, T. Miwa, K. Hayashi, K. Nozaki, Y. Ozaki, Y. Nagao,
Tetrahedron Lett. 2001, 42, 4029–4031; e) A. G. Griesbeck,
T. T. El-Idreesy, A. Bartoschek, Adv. Synth. Catal. 2004, 346,
245–251; f) K. Feng, R.-Y. Zhang, L.-Z. Wu, B. Tu, M.-L.
Peng, L.-P. Zhang, D. Zhao, C.-H. Tung, J. Am. Chem. Soc.
2006, 128, 14685–14690; g) R. E. Ziegert, S. Bräse, Synlett
2006, 2119–2123.
Acknowledgments
We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) (BR 1750-12-1) for financial sup-
port.
[1] a) B. Franck, E.-M. Gottschalk, U. Ohnsorge, F. Hüper, Chem.
Ber. 1966, 99, 3842–3862; b) P. S. Steyn, Tetrahedron 1970, 26,
51–57; c) C. C. Howard, R. A. W. Johnstone, I. D. Entwistle, J.
Chem. Soc., Chem. Commun. 1973, 464; d) I. Kurobane, L. C.
Vining, G. McInnes, Tetrahedron Lett. 1978, 47, 4633–4636.
[2] B. Franck, G. Baumann, Chem. Ber. 1966, 99, 3863–3874.
[3] A. T. McPhail, G. A. Sim, J. D. M. Asher, J. M. Robertson, J. V.
Silverton, J. Chem. Soc. B 1966, 18–30.
[4] A. Krick, S. Kehraus, C. Gerhäuser, K. Klimo, M. Nieger, A.
Maier, H.-H. Fiebig, I. Atodiresei, G. Raabe, J. Fleischhauer,
G. M. König, J. Nat. Prod. 2007, 70, 353–360.
[5] W. Zhang, K. Krohn, Zia-Ullah, U. Flörke, G. Pescitelli, L.
Di Bari, S. Antus, T. Kurtán, J. Rheinheimer, S. Draeger, B.
Schulz, Chem. Eur. J. 2008, 14, 4913–4923.
[6] a) M. Isaka, A. Jaturapat, K. Rukseree, K. Danwisetkanjana,
M. Tanticharoen, Y. Thebtaranonth, J. Nat. Prod. 2001, 64,
1015–1018; b) B. Elsässer, K. Krohn, U. Flörke, N. Root, H.-
J. Aust, S. Draeger, B. Schulz, S. Antus, T. Kurtán, Eur. J. Org.
Chem. 2005, 4563–4570.
[7] J. Lin, S. Liu, B. Sun, S. Niu, E. Li, X. Liu, Y. Che, J. Nat.
Prod. 2010, 73, 905–910.
[8] H. Zhang, J. Xue, P. Wu, L. Xu, H. Xie, X. Wie, J. Nat. Prod.
2009, 72, 265–269.
[9] S. Qin, H. Hussain, B. Schulz, S. Draeger, K. Krohn, Helv.
Chim. Acta 2010, 93, 169–174.
[23]
[24]
S. Serra, A. Barakat, C. Fuganti, Tetrahedron: Asymmetry
2007, 18, 2573–2580.
a) J.-E. Bäckvall, S. E. Byström, R. E. Nordberg, J. Org. Chem.
1984, 49, 4619–4631. For further PdII-catalyzed 1,4-oxidations,
see: b) J.-E. Bäckvall, J. Vågberg, R. E. Nordberg, Tetrahedron
Lett. 1984, 25, 2717–2720; c) J.-E. Bäckvall, A. Gogoll, J.
Chem. Soc., Chem. Commun. 1987, 1236–1238; d) J.-E.
Bäckvall, J. O. Vågberg, J. Org. Chem. 1988, 53, 5695–5699; e)
H. Grennberg, A. Gogoll, J.-E. Bäckvall, J. Org. Chem. 1991,
56, 5808–5811; f) H. Grennberg, S. Faizon, J.-E. Bäckvall, An-
gew. Chem. 1993, 105, 269–271; g) K. Bergstad, H. Grennberg,
J.-E. Bäckvall, Organometallics 1998, 17, 45–50; h) H. K. Cot-
ton, F. F. Huerta, J.-E. Bäckvall, Eur. J. Org. Chem. 2003,
2756–2763; i) R. C. Verboom, V. F. Slagt, J.-E. Bäckvall, Chem.
Commun. 2005, 1282–1284; j) B. W. Purse, L.-H. Tran, J. Piera,
B. Åkermark, J.-E. Bäckvall, Chem. Eur. J. 2008, 14, 7500–
7503.
[25]
[26]
[27]
G. Wickham, D. Young, W. Kitching, Organometallics 1988, 7,
1187–1195.
rd
Synthesis according to: Organikum, 23 ed., Wiley-VCH,
Weinheim, Germany, 2009, pp. 282–283.
a) B. M. Trost, L. S. Kallander, J. Org. Chem. 1999, 64, 5427–
5435; b) A. R. Yeager, G. K. Min, J. A. Porco Jr, S. E. Schaus,
Org. Lett. 2006, 8, 5065–5068.
a) N. Kornblum, J. W. Powers, G. J. Anderson, W. J. Jones,
H. O. Larson, O. Levand, W. M. Weaver, J. Am. Chem. Soc.
1957, 79, 6562; b) B. Boulin, B. Arreguy-San Miguel, B.
Delmond, Tetrahedron 1998, 54, 2752–2762.
a) J.-E. Bäckvall, J.-E. Nyström, R. E. Nordberg, J. Am. Chem.
Soc. 1985, 107, 3676–3686. Syntheses of bromo and benzoxy
species were performed according to: b) J.-E. Bäckvall, K. L.
[10] a) M. C. Carreño, E. Merino, M. Ribagorda, Á. Somoza, A.
Urbano, Org. Lett. 2005, 7, 1419–1422; b) M. C. Carreño, E.
Merino, M. Ribagorda, Á. Somoza, A. Urbano, Chem. Eur. J.
2007, 13, 1064–1077.
[11] U. K. Ohnemüller (née Schmid), C. F. Nising, M. Nieger, S.
Bräse, Eur. J. Org. Chem. 2006, 1535–1546.
[28]
[29]
[12] a) M. C. Carreño, M. Ribagorda, Á. Somoza, A. Urbano, An-
gew. Chem. 2002, 114, 2879–2881; Angew. Chem. Int. Ed. 2002,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
A. C. Meister, M. Nieger, S. Bräse
FULL PAPER
Granberg, R. B. Hopkins, Acta Chem. Scand. 1990, 44, 492–
499.
drolases, see: g) U. T. Bornscheuer, R. J. Kazlauskas, in: Hydro-
lases in Organic Synthesis: Regio- and Stereoselective Biotrans-
formations, Wiley-VCH, Weinheim, Germany, 1999. For over-
views about lipases and lipase-catalyzed reactions, see: h) C.-S.
Chen, C. J. Sih, Angew. Chem. 1989, 101, 711–724; i) R. D.
Schmid, R. Verger, Angew. Chem. 1998, 110, 1694; Angew.
Chem. Int. Ed. 1998, 37, 1608–1633. For hydrolysis and esterifi-
cation with lipases, see, for example: j) H. J. Gais, F. Theil, in:
Enzyme Catalysis in Organic Synthesis, 2nd ed., vol. 2 (Eds.: K.
Drauz, H. Waldmann), Wiley-VCH, Weinheim, Germany,
2002, pp. 335–578. For a review about chemoenzymatic reac-
tions, see: k) O. Pàmies, J.-E. Bäckvall, Chem. Rev. 2003, 103,
3247–3261.
[30] For reviews about biotransformations, see: a) W.-D. Fessner,
in: Asymmetric Synthesis with Chemical and Biological Meth-
ods, 1st ed. (Eds.: D. Enders, K.-E. Jaeger), Wiley-VCH,
Weinheim, Germany, 2007, pp. 351–375; b) G. Grogan, Annu.
Rep. Prog. Chem. Sect. B 2011, 107, 199–225. For reviews
about enzymes, see: c) E. Santaniello, P. Ferraboschi, P.
Grisenti, A. Manzocchi, Chem. Rev. 1992, 92, 1071–1140; d)
R. N. Perham, G. Michal, A. Jonke, A. H. T. Van Scheltinga,
C. Golker, S. Fukui, A. Tanaka, H. Uhlig, W. E. Goldstein,
H. A. Hagen, S. Pedersen, B. Poldermans, E. H. Reimerdes, W.
Leuchtenberger, U. Plocker, H. Waldmann, G. A. Whitesides,
G.-B. Kresse, K. Wulff, G. Henniger, L. Flohe, W. A. Gunzler,
C. Kessler, K. Aunstrup, in: Industrial Polymers Handbook, 1st
ed., vol. 3 (Ed.: E. S. Wilks), Wiley-VCH, Weinheim, Germany,
2001, pp. 1619–1915; e) M. N. Gupta, I. Roy, Eur. J. Biochem.
2004, 271, 2575–2583. For a review about enzymatic protecting
group techniques, see: f) D. Kadereit, H. Waldmann, Chem.
Rev. 2001, 101, 3367–3396. For detailed information about hy-
[31] E. M. C. Gérard, S. Bräse, Chem. Eur. J. 2008, 14, 8086–8089.
[32] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[33] H. D. Flack, Acta Crystallogr., Sect. A 1983, 39, 876–881.
[34] R. W. W. Hooft, L. H. Straver, A. L. Spek, J. Appl. Crystallogr.
2008, 41, 96–103.
Received: May 26, 2012
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20704
/KAP1
Date: 30-07-12 18:37:20
Pages: 9
Methyl-Substituted 4-Hydroxycyclohexenones
Building Blocks for Natural Products
A. C. Meister, M. Nieger,
S. Bräse* ........................................... 1–9
Synthesis of 4-Hydroxy-5-methyl- and 4-
Hydroxy-6-methylcyclohexenones by PdII-
Catalyzed Oxidation and Lipase-Catalyzed
Hydrolysis
Keywords: Synthetic methods / Enzyme ca-
talysis / Regioselectivity / Homogeneous
catalysis / Palladium / Natural
A six-step synthesis of enantiomerically en-
riched cyclohexenone building blocks for
natural products is presented. The key step
is a lipase-catalyzed, monohydrolysis of a
racemic diacetate, which provides two sep-
arable alcohols. Both can be converted into
the desired cyclohexenones within two
steps.
products / Cyclohexenones
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9