A versatile access to enantiomerically pure 5-substituted 4-hydroxycyclohex-2-enones: An advanced hemisecalonic acid a model

Article abstract of DOI:10.1055/s-2007-983761

A convenient route for the versatile preparation of 5-substituted 4-hydroxycyclohex-2-enones via the addition of an organocuprate to a cyclohex-2-enone is reported. These compounds are important intermediates in our synthetic studies towards the mycotoxin

Full text of DOI:10.1055/s-2007-983761

PAPER
2175
A Versatile Access to Enantiomerically Pure 5-Substituted
4-Hydroxycyclohex-2-enones: An Advanced Hemisecalonic Acid A Model
Versatile
A
ccess to
l
E
nant
r
iomerica
i
lly Pur
k
e
5-Substitut
e
ed 4-Hydroxycyc
K
lohex-2-enones . Ohnemüller, Carl F. Nising, Arantxa Encinas, Stefan Bräse*
Institute for Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Received 19 February 2007; revised 23 April 2007
Two articles reporting the synthesis of fairly similar com-
pounds have been published by the groups of Maycock4
and Matsuo.5 Both made use of the same strategy, the con-
jugate addition of an organocuprate to the building block
6 accessible via a procedure developed by both Trost and
Danishefsky.6,7 Independently, both groups reported that
they isolated the product of the addition together with sig-
nificant, but strongly varying, amounts of the cyclohex-
enone formed by elimination of acetone from the product
of conjugate addition.
Abstract: A convenient route for the versatile preparation of 5-sub-
stituted 4-hydroxycyclohex-2-enones via the addition of an organo-
cuprate to a cyclohex-2-enone is reported. These compounds are
important intermediates in our synthetic studies towards the myco-
toxin secalonic acid A.
Keywords: stereoselective synthesis, cyclohexenone, Michael
addition, domino reaction, natural products
Mycotoxins are both an increasing threat for humankind
and a challenge for synthetic chemists due to their biolog-
ical activity and demanding molecular architecture. Aim-
ing at the total synthesis of the challenging secalonic acids
11 by use of the domino oxa-Michael addition–aldol con-
densation as the key step of our synthetic strategy,2 we
found that this reaction could not be realized using a cy-
clohexenone building block carrying a substituent at C3 4
(Scheme 1).3 Therefore, the complexity of the building
block had to be reduced from the 3,4,5-trisubstituted cy-
clohex-2-enones 4 to the simpler, but sterically less hin-
dered, 4,5-substituted cyclohex-2-enones, such as 4-
hydroxy-4-methylcyclohex-2-enone (5a).
When attempting to utilize this reaction for the addition of
a methylcuprate using the conditions described in the lit-
erature,5 we also found that the product was contaminated
with the corresponding elimination product (Table 1). As
the elimination product is identical with the target mole-
cule, 4-hydroxy-5-methylcyclohex-2-enone (5a), a more
thorough investigation of its mode of formation was con-
ducted.
A change of the temperature profile of the conjugate addi-
tion reaction shows that the elimination takes place if the
reaction is conducted above –40 °C (Table 1, entries 1, 2);
for any temperature below, no cyclohexenone 5a was
formed (Table 1, entries 3, 4). However, lower tempera-
A flexible and reliable pathway for the stereoselective
preparation of this compound was required.
HO
CO2Me
Me
O
OH
O
OH
OH
biaryl coupling
OH
O
OH
O
Me
MeO2C
secalonic acid A–G (1a–g)
OH
O
OH
O
OPG O
X
X
domino oxa-Michael addition–
aldol condensation
+
O
Me
R
Me
OH
MeO2C
OH
OH
4
(R = CH2OPG)
hemisecalonic acid (2)
3
5a (R = H)
Scheme 1 Retrosynthesis of the secalonic acids 1
SYNTHESIS 2007, No. 14, pp 2175–2185
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983761; Art ID: T03407SS
© Georg Thieme Verlag Stuttgart · New York

2176
U. K. Ohnemüller et al.
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Table 2 Ratio of Addition Product 7a to Addition/Elimination
Product 5a Depending on the Workup Conditions
Table 1 Effect of Temperature Variation on the Conjugate Addition
of Me2CuMgBr·SMe2
O
O
O
O
O
O
Me2CuMgBr⋅SMe2
Me2CuMgBr⋅SMe2
elimination
elimination
THF, Me2S,
–50 °C
THF, Me2S
O
O
Me
Me
O
Me
O
Me
O
O
O
O
OH
OH
6
6
5a
7a
5a
7a
Entry
Temp (°C) Time (h)
Yield (%)
Entry
Workup
Yield (%)
Overall
conditionsa
r.t., 10 min
r.t., 2 h
7a
44
31
15
0
5a
yield (%)
7a
5a
6
1
2
3
4
–20
–40
–60
–50
1
1
57
59
56
73
1
2
3
4
traces 44
6
10
23
10
41
38
10
1
0
r.t., 15 h
14
0
40 °C, 2 d
a Temperature and time of stirring after addition of sat. NH4Cl soln.
tures need to be compensated for by a prolonged reaction
time; the conditions described in Table 1, entry 4 resulted
in the highest yield (73%) of the 1,4-addition product
without any detectable amount of 5a. Furthermore, the re-
moval of copper salts after quenching, which could not be
fully realized following the procedure published by
Matsuo,5 could be accomplished by addition of saturated
ammonium chloride solution followed by bubbling air
through the reaction mixture; this accelerated the oxida-
tion to copper(II) significantly.
transforms into hydroquinone, due to the basic conditions,
and 8 is formed by conjugate addition of hydroquinone to
the substrate. This unexpected reaction outcome depicts a
remarkable example for a nonreversible oxa-Michael
addition.
Table 3 Conjugate Addition of Various Nucleophiles to 6
O
O
A 6:1 ratio of the initially formed 7a and the cyclohex-
enone 5a was found for both reactions conducted at higher
temperatures. Attempts to alter this ratio by modification
of the workup conditions were not successful: prolonged
stirring after the addition of saturated ammonium chloride
solution resulted in an alteration of the ratio to up to 1:1.5
(Table 2, entry 3), but gave only a moderate overall yield.
R2CuMgBr⋅SMe2
THF, Me2S,
–50 °C, 14 h
up to 73%
R
O
O
O
O
6
7
Entry
R
Product
7a
Yield (%) Side product (%)
The scope and limitations of the addition reaction were in-
vestigated by reacting 6 with cuprates of variable size and
stability (Table 3).
1
2
3
4
5
6
7
8
Me
Et
73
66
40a
0
–
7b
–
For any of the addition reactions performed, the diastereo-
selectivity was >99:1 in favor of anti addition. In all cases,
the nucleophile had attacked from the side of 6 that does
not contain the oxygen substituent on C4. This observa-
tion is consistent with the result found by Maycock and
with the conjugate addition of cuprates to a very similar
system reported in the literature that also showed anti dia-
stereoselectivity.8 By using functionalized Knochel-type
cuprates, this procedure should also allow the synthesis of
higher functionalized cyclohexenones.9 This issue is cur-
rently under investigation in our group.
Pr
7c
24 (5c)
i-Pr
7d
–
CH2-t-Bu
7e
7f
28
n.d.b
4
–
CH=CH2
–
CH2CH=CH2 7g
Ph 7h
4 (8)c
27
–
a Overall yield of the addition reaction was 64%; reaction was con-
ducted at –20 °C.
b The yield was not determined because 7f is unstable towards column
chromatography.
Interestingly, the unusual side product 8 (Figure 1) was
isolated from the addition of allylcuprate to 6 (Table 3,
entry 7). Instead of reacting with the allylcuprate, which
seems to decompose rapidly, the cyclohexenone 6 slowly
c Compound 8 was formed by conjugate addition of hydroquinone, a
degradation product of 6 under basic conditions.
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

PAPER
Versatile Access to Enantiomerically Pure 5-Substituted 4-Hydroxycyclohex-2-enones
2177
O
O
lane and chlorotriisopropylsilane for the transformation of
7a (49% and 47%; entries 1, 2), are not comparable to the
yield reported for the unsubstituted system (87%, R = H).7
The installation of less bulky protecting groups was im-
possible if the protection reaction proceeded by an SN2
mechanism, as it is necessary for an allylation or benzyla-
tion reaction (Table 4, entries 3, 4). Yet, the esterification
to the 4-bromobenzoic acid ester 15 could be realized in
23% yield (Table 4, entry 5), whereas only traces of the
corresponding acetate 16 were isolated from the reaction
with acetic acid anhydride (Table 4, entry 6).
OH
OTBDMS
O
Me
O
O
O
O
O
8
9
10
Figure 1 Unexpected side products of the conjugate addition and
the elimination step
As the direct transformation of the addition products 7 to
the building block 5 resulted in only very low yields due
to the high solubility of the unprotected 5-substituted 4-
hydroxycyclohex-2-enones 5 in water, the introduction of
an additional step was required to render this reaction
more efficient.7 When the elimination step was performed
in the presence of tert-butylchlorodimethylsilane, the si-
lyl-protected derivatives of 7 could be isolated in satisfy-
ing yields (Table 4, entry 1).
After altering the reaction conditions to 1,8-diazabicy-
clo[5.4.0]undec-7-ene (1.5 equiv) and tert-butylchlorodi-
methylsilane (1.3 equiv), the tert-butyldimethylsilyl-
protected cyclohex-2-enone 11a could be isolated in a
very satisfying 93% yield (Table 4, entry 7). The opti-
mized elimination/protection procedure was applied to
the transformation of the cyclohexanones 7a–c,f–h to the
corresponding unsaturated compounds (Table 4, entries
8–12). A significant decrease in yield with increasing size
of the substituent at C5 was observed, showing that the
protection reaction is also sensitive to sterical hindrance
near the reaction site on the cyclic system.
Table 4, entries 1–6 summarize the outcome of the elimi-
nation/protection reaction resulting when the conditions
reported by Danishefsky [DBU (1.12 equiv), TBDMSCl
(1.07 equiv), benzene, heat, 3 h; DBU (0.28 equiv), heat,
2.5 h] were applied.7 Even the results obtained using the
standard protecting reagents tert-butylchlorodimethylsi-
The vinylated derivative 7f could only be isolated in 9%
yield (Table 4, entry 10) as it tends to undergo a Claisen
Table 4 Elimination and Simultaneous Protection
O
O
DBU (1.5 equiv),
PG–X (1.3 equiv)
R
C6H6, ∆, 6 h
up to 93%
O
R
O
OPG
7
11
Entry
1
Substrate
7a
R
PG-X
Product
11a
12
Yield (%)
49a
47a
0a
Me
Me
Me
Me
Me
Me
Me
Et
TBDMSCl
TIPSCl
2
7a
3
7a
H2C=CHCH2Br
BnBr
13
4
7a
14
0a
5
7a
4-BrC6H4COCl
Ac2O
15
23a
tracea
93
6
7a
16
7
7a
TBDMSCl
TBDMSCl
TBDMSCl
TBDMSCl
TBDMSCl
TBDMSCl
11a
11b
11c
11f
11g
11h
8
7b
74
9
7c
Pr
67
10
11
12
7f
CH=CH2
CH2CH=CH2
Ph
9b
7g
55
7h
11
a These experiments were performed under the conditions reported by Danishefsky.
b Yield after two steps (see also Table 3, entry 6).
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

2178
U. K. Ohnemüller et al.
PAPER
rearrangement to the phenylacetaldehyde 10 (Figure 1).
However, due to the instability of this compound, neither
its yield nor its complete characterization could be as-
signed.
Table 5 Effect of Variation of the Proton Source on the Deprotec-
tion Step
O
Most interestingly, a very small amount of a side product
was isolated and identified as the cyclohexanone 9 with a
conjugated, but exocyclic, double bond (Figure 1). This
compound is formed when the deprotonation does not ab-
stract a proton from C2 but C6 of the saturated cyclohex-
anone 7a. The enolate thus formed cannot eliminate
acetone, but instead it is consumed by an aldol condensa-
tion reaction with acetone liberated by molecules that are
pursuing the intended reaction course. As the formation of
the condensation product 9 was only observed for the me-
thyl-substituted compound 7a, the conclusion can be de-
rived that the presence of any larger substituent at C5 most
probably prevents the deprotonation at C6 of 7, and cer-
tainly averts the subsequent aldol condensation.
Me
OTBDMS
11a
TBAF, additive
THF, r.t., 60 h
0–85%
O
O
O
O
O
H
H
+
+
Me
Me
Me
H
HO
18
HO
OH
OH
Me
Me
OH
OH
5a
17
As we have already reported, cyclohexenones with a large
substituent at C4 are not suitable for the key domino oxa-
Michael–addition aldol reaction planned for the total syn-
thesis of the secalonic acids 1.3 Therefore, the preliminary
deprotection of the cyclohexenone building block 11 is es-
sential. Initially experiments with 11a using standard con-
ditions (TBAF, THF, r.t.), resulted in the formation of the
dimers 17 and 18 instead of the target molecule 5a
(Table 5).
Entry
Additive
Equiv of
additive
Product
Yield (%)
1
2
3
–
–
17
18
37
MeOH
MeOH
25
5
traces
5a
18
36
traces
4
5
PhOH
AcOH
5
5
5a
5a
traces
75
The formation of dimer 17 (Table 5, entry 1) is accom-
plished by the dimerization of the primarily formed alco-
holate of 5a, which cannot be protonated immediately
under the aprotic deprotection conditions. The alcoholate
is presumed to form an epoxy enolate and to undergo stan-
dard Michael addition to another cyclohexenone moiety.
Regeneration of the cyclohexenone by a proton shift with
subsequent protonation upon workup results in 17. Ep-
oxide opening by addition of water instead led to 18.
ed or unprotected 5-substituted 4-hydroxycyclohex-2-
enones.
Finally, these unprotected 5-substituted 4-hydroxycyclo-
hex-2-enones 5 were employed as building blocks for the
domino oxa-Michael addition–aldol2,3 condensation to-
gether with 5-methoxysalicylaldehyde (19) to give access
The addition of a proton source seemed the easiest way to
shorten the lifespan of the alcoholate of 5a. The applica-
tion of methanol in varying amounts led to the formation
of byproduct 18, a hydrate of 17 whose stereochemistry
could not be elucidated completely. The best result for
methanol as additive was 36% of the desired product 5a
contaminated with 18 (Table 5, entries 2, 3). Adding the
more acidic phenol as proton source merely resulted in the
isolation of traces of 5a, showing that the alcoholate could
still dimerize before being protonated (Table 5, entry 4).
Only the presence of acetic acid allowed the isolation of
5a in a satisfying 75% yield (Table 5, entry 5). The need
for nonaqueous workup conditions was recently also ad-
dressed by Kishi et al.10
Table 6 Deprotection of Variably Substituted 4-Hydroxycyclohex-
2-enones 11
O
O
1) TBAF (1.0 equiv)
AcOH (5.0 equiv)
THF, r.t., 24 h
2) TBAF (0.25 equiv)
r.t., 24 h
R
R
OTBDMS
OH
82% to quant.
11
5
Entry
Substrate
R
Product
5a
Yield (%)
1
2
3
4
11a
11b
11c
11h
Me
Et
Pr
Ph
75
The general applicability of this procedure was investigat-
ed by using these conditions for the deprotection of vari-
ably substituted cyclohexenones of type 11 (Table 6). All
substrates could be transformed in good to excellent
yields.
5b
99.5
70
5c
5h
93
The method described above is generally applicable to the
stereoselective synthesis of a large variety of silyl-protect-
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

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Versatile Access to Enantiomerically Pure 5-Substituted 4-Hydroxycyclohex-2-enones
2179
and with ‘–’ for negative signals, respectively. IR spectra were re-
corded using the Bruker FTIR device IFS 88. EI-MS and EI-HRMS
spectra were recorded on a Finnigan MAT 90 instrument; elemental
analyses were performed using a Heraeus CHN-O-Rapid device.
Specific rotations [a]D were determined using the Perkin-Elmer
device Polarimeter 241.
to tetrahydroxanthenones cores 20 with excellent yields
(Table 7). All compounds were obtained as mixture of dia-
stereomers at the 4a-position, in some cases as separable
mixture. However, we developed a route to 4a-substituted
tetrahydroxanthenones by addition of cuprates generating
a new stereogenic center at the 4a-position, thus this ob-
stacle is not a drawback. Finally, the xanthone 20a can be
considered as an advanced enantiomerically pure hemi-
secalonic acid A model.1 To our knowledge, this is the
first synthesis of such an advanced model compound.
20
1,4-Addition of Copper Nucleophiles to 6; General Procedure A
CuBr·SMe2 (1.30 equiv) was completely dissolved in Me2S (2.00
mL/mmol CuBr·SMe2) and then diluted with THF (4.00 mL/mmol
CuBr·SMe2. At –30 to –20 °C, this soln was then slowly added to a
1 M soln of the corresponding alkyl or aryl Grignard reagent in THF
(2.60 equiv). The mixture was stirred at –20 °C for 1 h and then it
was cooled to –50 °C and treated with a soln of 6 (1.00 equiv) in
THF (2.00 mL/mmol 6) by dropwise addition and then stirred at
–50 °C for 14 h. Sat. aq NH4Cl soln was added and the mixture was
brought up to r.t. Oxidation of residual copper(I) species was ac-
complished by conducting a stream of air through the reaction slur-
ry for 30 min. The aqueous phase was then separated and extracted
several times with EtOAc. The combined organic phases were freed
from copper by washing with 10% aq NH4Cl, dried (Na2SO4), and
filtered. After removal of the solvent, the crude product was puri-
fied by flash column chromatography (silica gel, cyclohexane–
EtOAc).
Table 7 Application of the Substituted 4-Hydroxycyclohex-2-
enones 5 to the Domino Oxa-Michael–Aldol Condensation
O
MeO
CHO
OH
+
R
OH
19
5a–c
N-methylimidazole
dioxane–H2O (1:2)
)))), 48 h
5-Alkyl/aryl-4-(trialkylsiloxy)cyclohex-2-enones 11; General
Procedure B
Compound 7 (1.00 equiv) was dissolved in benzene (4.00 mL/mmol
7) and treated with a trialkylsilyl chloride (1.30 equiv). DBU (1.50
equiv) was added and the mixture was heated to 100 °C for 5–7 h.
The mixture was cooled to r.t., diluted with Et2O, and washed with
H2O (2 ×), 1 M HCl (2 ×), and sat. aq NaHCO3 soln (2 ×). The soln
was dried (Na2SO4) and filtered, the solvent was removed, and the
crude product was purified by flash column chromatography (silica
gel, cyclohexane–EtOAc).
O
O
MeO
MeO
+
O
R
O
R
H
H
OH
OH
trans-20a–c
cis-20a–c
Entry
Substrate
R
Product
Ratio
cis/trans
Yield (%)
Deprotection of 5-Alkyl/aryl-4-(trialkylsiloxy)cyclohex-2-
enones 11; General Procedure C
The 5-alkyl- or 5-aryl-4-(trialkylsiloxy)cyclohex-2-enone (1.00
equiv) was dissolved in THF (4.00 mL/mmol cyclohexenone deriv-
ative) and treated with AcOH (5.00 equiv) followed by the addition
of 1 M TBAF in THF (1.00 equiv). The mixture was stirred at r.t.
for 24 h and then another portion of TBAF soln (0.25 equiv) was
added and stirring was continued at r.t. for an additional 24 h. The
solvent was removed in vacuo with a minimum pressure of 100
mbar at 40 °C. The residue was purified by flash column chroma-
tography (silica gel, cyclohexane–EtOAc).
1
2
3
5a
5b
5c
Me
Et
20a
20b
20c
1.5:1
1:1.2
1.3:1
62
82
82
Pr
In summary, we developed a robust route to enantiomeri-
cally pure 4,5-disubstituted cyclohex-2-enones suitable as
building blocks in the total synthesis of mycotoxins with
the xanthone skeleton. As a first attempt, we have synthe-
sized tetrahydroxanthenone derivatives employing the
domino oxa-Michael addition–aldol condensation with
excellent yields.
Tetrahydroxanthones 20; General Procedure D
Argon was passed through H2O (1.2 mL/mmol) for 15 min with si-
multaneous sonication. N-Methylimidazole (0.50 equiv), 5-meth-
oxysalicylaldehyde (19, 1.00 equiv) and the corresponding 5-
substituted 4-hydroxycyclohex-2-enone 5 (2.00 equiv) were then
suspended in the degassed solvent and treated with ultrasound for
48 h. After this time, H2O was added and the mixture was extracted
several times with EtOAc. The resulting combined organic phases
were dried (Na2SO4), and filtered. After removal of the solvent, the
crude product was purified by flash column chromatography (silica
gel, cyclohexane–EtOAc).
Substrates were purchased from commercial sources and used with-
out further purification. Column chromatography was performed
using Macherey-Nagel silica gel 60 (230–400 mesh) under flash
conditions. For TLC, aluminum foil layered with silica gel with flu-
orescence indicator (silica gel 60 F254) produced by Merck were em-
ployed. Melting points were determined using a Laboratory Devices
Inc. MelTemp II device. 1H and 13C NMR spectra were recorded on
a Bruker AM400 (400 MHz/100 MHz) or Bruker DRX500 (500
MHz/125 MHz) instrument using CDCl3 as the solvent and residual
CHCl3/CDCl3 as shift reference [d (CHCl3) = 7.28 /d
(CDCl3) = 77.00]. NMR signals that are labeled with an asterix (*)
are interchangeable within their corresponding numbers. 13C signals
are labeled with ‘+’ for positive signals in the DEPT 135 spectrum
(3R,4S,5R)-3,4-(Isopropylidenedioxy)-5-methylcyclohexanone
(7a)
Following general procedure A. Scale: 6 (500 mg, 2.97 mmol).
Chromatography (cyclohexane–EtOAc, 5:1) gave a colorless oil;
yield: 402 mg (73%); Rf = 0.47 (cyclohexane–EtOAc, 2:1).
[a]D20 –36.93 (c 1.61, CHCl3).
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2180
U. K. Ohnemüller et al.
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IR (KBr): 2985 (m, n C–H), 2935 (m, n C–H), 2908 (m, n C–H),
1719 (s, n C=O), 1381 (m, d C–H), 1211 (m), 1049 cm–1 (s, n C–O).
MS (EI): m/z (%) = 212 (1) [M+], 197 (59) [(M – CH3)+], 155 (100)
[(M – C3H5O)+], 137 (32), 109 (20), 95 (29), 67 (18), 43 (21)
[(C2H3O)+].
HRMS (EI): m/z [M – CH3]+ calcd for (C11H17O3): 197.1178; found:
197.1172.
1H NMR (500 MHz, CDCl3): d = 1.10 (d, 3J = 7.2 Hz, 3 H, 5-CH3),
2
1.35 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 2.04 (dd, J = 17.0 Hz,
3J = 8.8 Hz, 1 H, H6a), 2.17–2.26 (m, 1 H, H5), 2.41 (dd, 2J = 17.0
Hz, 3J = 4.4 Hz, 1 H, H6b), 2.57 (dd, 2J = 16.9 Hz, 3J = 5.0 Hz, 1 H,
2
3
H2a), 2.69 (dd, J = 16.8 Hz, J = 5.5 Hz, 1 H, H2b), 4.13 (dd,
3J = 6.6 Hz, 3J = 6.6 Hz, 1 H, H4), 4.61 (ddd, 3J = 6.9 Hz, 3J = 5.3
Hz, 3J = 5.3 Hz, 1 H, H3).
(3R,4S,5R)-3,4-(Isopropylidenedioxy)-5-neopentylcyclo-
hexanone (7e)
Neopentylmagnesium bromide was prepared by the dropwise addi-
tion of a soln of neopentyl bromide (0.876 g, 5.80 mmol, 2.60
equiv) in THF (800 mL) to thermally and mechanically activated Mg
shavings (141 mg, 5.80 mmol, 2.60 equiv) suspended in THF (5.80
mL). To ensure complete consumption of the magnesium shavings,
1,2-dibromoethane (0.129 mL, 0.691 mmol, 0.31 equiv) was added
and the mixture was heated to 65 °C for 14 h. The greyish green soln
was diluted with THF (5.00 mL) and was added dropwise to a soln
of CuBr·SMe2 (596 mg, 2.90 mmol, 1.30 equiv) in Me2S (4.50 mL)
and THF (9.00 mL) according to general procedure A. After 2 h stir-
ring at –20 °C, a greyish brown suspension had formed, which was
cooled down to –50 °C. A soln of the unsaturated acetonide 6 (375
mg, 2.23 mmol, 1.00 equiv) in THF (4.50 mL) was slowly added.
The mixture was stirred at –50 °C for 14 h followed by the workup
procedure described in general procedure A. Chromatography (cy-
clohexane–EtOAc, 9:1) gave a colorless oil; yield: 151 mg (28%);
colorless oil; Rf = 0.34 (cyclohexane–EtOAc, 9:1).
13C NMR (125 MHz, CDCl3): d = 17.1 (+, 5-CH3), 23.8 (+, CH3),
26.6 (+, CH3), 32.4 (+, C5), 41.8 (–, C2), 42.0 (–, C6), 72.5 (+, C3),
78.2 (+, C4), 107.7 (Cq, C8), 207.3 (Cq, C1).
MS (ESI): m/z (%) = 185 (37) [(M + H)+], 169 (100) [(M – CH3)+],
127 (99) [(C7H11O2)+], 109 (49) [(C6H9O)+], 97 (35), 85 (78), 81
(39), 59 (49), 43 (69) [(C2H3O)+].
HRMS (EI): m/z [M + H]+ calcd for C10H17O3: 185.1178; found:
185.1176.
(3R,4S,5R)-5-Ethyl-3,4-(isopropylidenedioxy)cyclohexanone
(7b)
Following general procedure A. Scale: 6 (1.00 g, 5.95 mmol). Chro-
matography (cyclohexane–EtOAc, 5:1) gave a colorless oil; yield:
775 mg (66%); Rf = 0.29 (cyclohexane–EtOAc, 5:1).
[a]D20 –24.25 (c 1.04, CHCl3).
[a]D20 +54.54 (c 5.58, CHCl3).
IR (KBr): 2965 (m, n C–H), 2936 (m, n C–H), 1719 (s, n C=O),
1382 (m, d C–H), 1055 cm–1 (m, n C–O).
IR (KBr): 2958 (m, n C–H), 2910 (m, n C–H), 2868 (m, n C–H),
1704 (s, n C=O), 1062 cm–1 (m, n C–O).
1H NMR (500 MHz, CDCl3): d = 0.98 (t, 3J = 7.4 Hz, 3 H, 2¢-CH3),
1.23–1.33 (m, 1 H, H1¢a), 1.37 (s, 3 H, CH3), 1.49 (s, 3 H, CH3),
1.57–1.68 (m, 1 H, H1¢b), 1.99–2.10 (m, 2 H, H5, H6a), 2.54–2.60
1H NMR [400 MHz, CDCl3 (spectrum shows contamination by hy-
droquinone, d = 6.80)]: d = 0.93 [s, 9 H, C(CH3)3], 1.09 (dd,
2J = 13.9 Hz, 3J = 5.5 Hz, 1 H, H1¢a), 1.34 (dd, 2J = 13.9 Hz, 3J = 4.1
Hz, 1 H, H1¢b), 1.37 [s, 3 H, C(CH3)2], 1.48 [s, 3 H, C(CH3)2], 2.14
3
(m, 1 H, H6b), 2.61–2.68 (m, 2 H, 2 H2), 4.16 (dd, J = 6.0 Hz,
3J = 6.0 Hz, 1 H, H4), 4.51–4.57 (m, 1 H, H3).
2
3
4
(ddd, J = 17.3 Hz, J = 5.0 Hz, J = 1.1 Hz, 1 H, H6a), 2.16–2.23
(m, 1 H, H5), 2.50 (dd, 2J = 17.6 Hz, 3J = 4.7 Hz, 1 H, H2a), 2.63–
2.71 (m, 2 H, H2b, H6b), 4.19 (ddd, 3J = 7.2 Hz, 3J = 3.6 Hz, 4J = 1.1
Hz, 1 H, H4), 4.62 (ddd, 3J = 7.2 Hz, 3J = 4.7 Hz, 3J = 3.4 Hz, 1 H,
H3).
13C NMR (125 MHz, CDCl3): d = 11.5 (+, C2¢), 24.4 [+, C(CH3)2],
24.9 (–, C1¢), 27.0 [+, C(CH3)2], 39.1 (+, C5), 39.7 (–, C6), 42.0
(–, C2), 72.3 (+, C3), 76.7 (+, C4), 108.3 [Cq, C(CH3)2], 209.1 (Cq,
C1).
MS (EI): m/z (%) = 198 (1) [M+], 183 (77) [(M – CH3)+], 141 (100)
[(C8H13O2)+], 123 (51) [(C8H11O)+], 95 (71) [(C6H7O)+], 81 (35), 43
(63) [(C2H3O)+].
13C NMR [100 MHz, CDCl3 (spectrum shows contamination by hy-
droquinone, d = 136.5)]: d = 24.0 (+, CH3), 26.5 (+, CH3), 29.2 [+,
C(CH3)3], 31.5 [Cq, C(CH3)3], 33.4 (+, C5), 41.8 (–, C2)*, 41.9 (–,
C6)*, 45.5 (–, C1¢), 72.1 (+, C3), 77.6 (+, C4), 108.1 [Cq, C(CH3)2],
209.5 (Cq, C1).
HRMS (EI): m/z [M]+ calcd for (C11H18O3): 198.1256; found:
198.1254.
MS (EI): m/z (%) = 240 (34) [M+], 225 (83) [(M – CH3)+], 183 (41)
[(M – C4H9)+], 165 (26), 125 (55), 109 (28), 100 (32), 85 (33), 71
(45), 57 (100) [(C4H9)+], 43 (37) [(C2H3O)+].
HRMS (EI): m/z [M]+ calcd for (C14H24O3): 240.1725; found:
240.1728.
(3R,4S,5R)-3,4-(Isopropylidenedioxy)-5-propylcyclohexanone
(7c)
Following general procedure A. Scale: 6 (1.07 g, 6.37 mmol). Chro-
matography (cyclohexane–EtOAc, 5:1) gave a light-brown oil;
yield: 535 mg (40%); Rf = 0.34 (cyclohexane–EtOAc, 5:1). Addi-
tionally, 236 mg (24%) of 5c were isolated.
(3R,4S,5R)-5-Allyl-3,4-(isopropylidenedioxy)cyclohexanone
(7g)
[a]D20 –22.30 (c 4.73, CHCl3).
IR (KBr): 2959 (m, n C–H), 2933 (m, n C–H), 2874 (w, n C–H),
Following general procedure A. Scale: 6 (1.50 g, 8.92 mmol). Chro-
matography (cyclohexane–EtOAc, 5:1) gave a brown oil; yield: 80
mg (4%); Rf = 0.49 (cyclohexane–EtOAc, 2:1). The analytical data
are in accordance with those reported in the literature.8 Additional-
ly, starting material 6 (228 mg, 15%) and 811 (87 mg, 4%) were iso-
lated.
1719 (s, n C=O), 1381 (m, d C–H), 1056 cm–1 (m, n C–O).
1H NMR (500 MHz, CDCl3): d = 0.93 (t, 3J = 7.2 Hz, 3 H, 3¢-CH3),
1.17–1.27 (m, 1 H, H1¢a), 1.29–1.56 (m, 3 H, H1¢b, 2 H2¢), 1.37 (s,
3 H, CH3), 1.49 (s, 3 H, CH3), 2.05 (dd, 2J = 16.9 Hz, 3J = 7.6 Hz, 1
H, H6a), 2.08–2.16 (m, 1 H, H5), 2.57 (dd, 2J = 16.9 Hz, 3J = 4.1 Hz,
1 H, H6b), 2.58–2.68 (m, 2 H, 2 H2), 4.15 (dd, 3J = 6.0 Hz, 3J = 6.0
Hz, 1 H, H4), 4.51–4.56 (m, 1 H, H3).
13C NMR (125 MHz, CDCl3): d = 14.0 (+, C3¢), 20.2 (–, C2¢), 24.3
(+, CH3), 27.0 (+, CH3), 34.3 (–, C1¢), 37.2 (+, C5), 40.1 (–, C6),
41.9 (–, C2), 72.3 (+, C3), 76.9 (+, C4), 108.3 [Cq, C(CH3)2], 209.1
(Cq, C1).
[a]D20 +19.45 (c 1.83, CHCl3)
IR (KBr): 3077 (vw, n C=C–H), 2987 (w, n C–H), 2916 (w, n C–H),
1719 (s, n C=O), 1382 (m, d C–H), 1045 cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.50 (s, 3 H,
CH3), 1.98–2.05 (m, 1 H, H1¢a), 2.05 (dd, 2J = 17.3 Hz, 3J = 8.4 Hz,
1 H, H6a), 2.16–2.25 (m, 1 H, H5), 2.31–2.40 (m, 1 H, H1¢b), 2.56
2
3
2
(dd, J = 17.3 Hz, J = 4.5 Hz, 1 H, H6b), 2.64 (dd, J = 17.1 Hz,
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

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Versatile Access to Enantiomerically Pure 5-Substituted 4-Hydroxycyclohex-2-enones
2181
2
3
3J = 5.4 Hz, 1 H, H2a), 2.69 (dd, J = 17.1 Hz, J = 5.2 Hz, 1 H,
H2b), 4.16 (dd, 3J = 6.6 Hz, 3J = 6.3 Hz, 1 H, H4), 4.54 (ddd,
3J = 6.6 Hz, 3J = 5.4 Hz, 3J = 5.2 Hz, 1 H, H3), 5.05–5.13 (m, 2 H,
2 H3¢), 5.76 (dddd, 3J = 16.9 Hz, 3J = 10.3 Hz, 3J = 7.5 Hz, 3J = 6.6
Hz, 1 H, H2¢).
Anal. Calcd for C13H24O2Si: C, 64.95; H, 10.06. Found: C, 65.12;
H, 10.14.
(4S,5R)-4-(tert-Butyldimethylsiloxy)-5-ethylcyclohex-2-enone
(11b)
Following general procedure B. Scale: 7b (700 mg, 3.53 mmol).
Chromatography (cyclohexane–EtOAc, 9:1) gave a light yellow oil;
yield: 662 mg (74%); Rf = 0.35 (cyclohexane–EtOAc, 9:1).
13C NMR (100 MHz, CDCl3): d = 24.5 (+, CH3), 27.1 (+, CH3), 36.3
(–, C1¢), 37.2 (+, C5), 39.9 (–, C6), 42.2 (–, C2), 72.2 (+, C3), 76.3
(+, C4), 108.5 [Cq, C(CH3)2], 117.6 (–, C3¢), 134.9 (+, C2¢), 208.7
(Cq, C1).
MS (EI): m/z (%) = 210 (10) [M+], 195 (100) [(M – CH3)+], 153 (80)
[(M – C3H5O)+], 135 (30), 107 (52), 93 (82), 79 (27), 43 (56)
[(C2H3O)+].
IR (KBr): 3041 (m, n C=C–H), 2959 (m, n C–H), 2931 (m, n C–H),
2885 (w, n C–H), 2858 (m, n C–H), 1689 (s, n C=O), 1092 cm–1 (m,
n C–O).
[a]D20 –198.00 (c 0.20, CHCl3).
HRMS (EI): m/z [M]+ calcd for (C12H18O3): 210.1256; found:
210.1251.
1H NMR (400 MHz, CDCl3): d = 0.14 (s, 3 H, SiCH3), 0.15 (s, 3 H,
SiCH3), 0.92 (t, 3J = 7.5 Hz, 3 H, 2¢-CH3), 0.94 [s, 9 H, SiC(CH3)3],
2
3
1.19–1.31 (m, 1 H, H1¢a), 1.82 (dqd, J = 13.4 Hz, J = 7.6 Hz,
(3R,4S,5S)-3,4-(Isopropylidenedioxy)-5-phenylcyclohexanone
(7h)
Following general procedure A. Scale: 6 (850 mg, 5.05 mmol).
Chromatography (cyclohexane–EtOAc, 5:1) gave a light-yellow
oil; yield: 334 mg (27%); Rf = 0.24 (cyclohexane–EtOAc, 5:1).
3J = 3.4 Hz, 1 H, H1¢b), 1.95–2.04 (m, 1 H, H5), 2.07 (dd, 2J = 15.5
3
2
3
Hz, J = 12.7 Hz, 1 H, H6a), 2.64 (ddd, J = 15.5 Hz, J = 2.6 Hz,
4J = 1.5 Hz, 1 H, H6b), 4.21 (ddd, 3J = 8.4 Hz, 3J = 2.0 Hz, 4J = 1.5
Hz, 1 H, H4), 5.93 (ddd, 3J = 10.2 Hz, 3J = 2.0 Hz, 4J = 1.2 Hz, 1 H,
H2), 6.81 (dd, 3J = 10.2 Hz, 4J = 2.1 Hz, 1 H, H3).
[a]D20 –56.96 (c 10.7, CHCl3).
13C NMR (100 MHz, CDCl3): d = –4.7 (+, SiCH3), –4.3 (+, SiCH3),
10.5 (+, C2¢), 13.0 [Cq, SiC(CH3)3], 24.4 (–, C1¢), 25.8 [+,
SiC(CH3)3], 40.6 (–, C6), 45.6 (+, C5), 71.6 (+, C4), 128.4 (+, C2),
154.1 (+, C3), 199.4 (Cq, C1).
MS (EI): m/z (%) = 254 (1) [M+], 239 (3) [(M – CH3)+], 197 (79)
[(M – C4H9)+], 179 (13) [(M – C2H7OSi)+], 155 (16), 105 (17), 75
(100) [(C2H7OSi)+].
IR (KBr): 3062 (vw, n C=C–H), 3030 (w, n Car–H), 2987 (m, n C–
H), 2935 (w, n C–H), 1719 (s, n C=O), 1381 (s, d C–H), 1047 cm–1
(s, n C–O).
1H NMR (500 MHz, CDCl3): d = 1.39 (s, 3 H, CH3), 1.55 (s, 3 H,
2
3
CH3), 2.63 (dd, J = 17.8 Hz, J = 8.9 Hz, 1 H, H6a), 2.67 (dd,
2J = 17.0 Hz, 3J = 4.9 Hz, 1 H, H2a), 2.74 (dd, 2J = 17.0 Hz, 3J = 4.4
Hz, 1 H, H2b), 2.76 (dd, 2J = 17.8 Hz, 3J = 4.7 Hz, 1 H, H6b), 3.43
(ddd, 3J = 8.9 Hz, 3J = 4.7 Hz, 3J = 4.7 Hz, 1 H, H5), 4.60–4.66 (m,
2 H, H3, H4), 7.24–7.30 (m, 3 H, H2¢, H4¢, H6¢), 7.37 (dd, 3J = 7.6
Hz, 3J = 7.6 Hz, 2 H, H3¢, H5¢).
HRMS (EI): m/z [M]+ calcd for (C14H26O2Si): 254.1702; found:
254.1700.
(4S,5R)-4-(tert-Butyldimethylsiloxy)-5-propylcyclohex-2-enone
(11c)
Following general procedure B. Scale: 7c (332 mg, 1.56 mmol).
Chromatography (cyclohexane–EtOAc, 9:1) gave a colorless oil;
yield: 281 mg (67%); Rf = 0.39 (cyclohexane–EtOAc, 9:1).
13C NMR (125 MHz, CDCl3): d = 24.3 (+, CH3), 27.0 (+, CH3), 40.9
(–, C6), 42.3 (–, C2), 42.6 (+, C5), 72.4 (+, C3)*, 77.7 (+, C4)*,
108.6 [Cq, C(CH3)2], 127.1 (+, C4¢), 127.4 (+, C2¢, C6¢), 128.8 (+,
C3¢, C5¢), 140.0 (Cq, C1¢), 208.5 (Cq, C1).
MS (EI): m/z (%) = 246 (81) [M+], 231 (62) [(M – CH3)+], 189 (21)
[(M – C3H6O)+], 171 (26), 143 (35), 131 (72), 129 (67), 104 (100),
[(C8H8)+], 43 (54) [(C2H3O)+].
[a]D20 –409.23 (c 0.79, CHCl3).
FT-IR (film on KBr): 3041 (vw, n C=C–H), 2957 (m, n C–H), 2932
(m, n C–H), 2897 (w, n C–H), 2858 (m, n C–H), 1688 (s, n C=O),
1094 cm–1 (w, n C–O).
HRMS (EI): m/z [M]+ calcd for (C15H18O3): 246.1256; found:
246.1259.
1H NMR (400 MHz, CDCl3): d = 0.14 (s, 3 H, SiCH3), 0.15 (s, 3 H,
SiCH3), 0.90–0.95 [m, 12 H, 3¢-CH3, SiC(CH3)3], 1.15–1.32 (m, 2
H, H1¢a, H2¢a), 1.36–1.49 (m, 1 H, H2¢b), 1.66–1.77 (m, 1 H, H1¢b),
2.02–2.13 (m, 2 H, H5, H6a), 2.58–2.68 (m, 1 H, H6b), 4.16–4.21
(m, 1 H, H4), 5.87 (ddd, 3J = 10.2 Hz, 4J = 1.3 Hz, 4J = 1.3 Hz, 1 H,
H2), 6.80 (dd, 3J = 10.2 Hz, 3J = 2.1 Hz, 1 H, H3).
13C NMR (100 MHz, CDCl3): d = –4.8 (+, SiCH3), –4.3 (+, SiCH3),
14.1 (+, C3¢), 18.0 [Cq, SiC(CH3)3], 19.2 (–, C2¢), 25.7 [+,
SiC(CH3)3], 4.0 (–, C1¢), 41.1 (–, C6), 43.8 (–, C5), 71.7 (–, C4),
128.4 (–, C2), 153.9 (–, C3), 199.3 (Cq, C1).
(4S,5R)-4-(tert-Butyldimethylsiloxy)-5-methylcyclohex-2-enone
(11a)
Following general procedure B. Scale: 7a (1.38 g, 7.50 mmol).
Chromatography (cyclohexane–EtOAc, 9:1) gave a light-yellow
oil; yield: 1.67 g (93%); Rf = 0.46 (cyclohexane–EtOAc, 9:1).
[a]D20 –157.44 (c 0.80, CHCl3).
IR (KBr): 3041 (m, n C=C–H), 2956 (m, n C–H), 2930 (w, n C–H),
2894 (w, n C–H), 2858 (m, n C–H), 1687 cm–1 (s, n C=O).
MS (EI): m/z (%) = 268 (1) [M+], 253 (3) [(M – CH3)+], 211 (100)
1H NMR (600 MHz, CDCl3): d = 0.12 (s, 3 H, SiCH3), 0.13 (s, 3 H,
SiCH3), 0.93 [s, 9 H, Si-C(CH3)3], 1.08 (d, 3J = 6.1 Hz, 3 H, 5-CH3),
2.08–2.19 (m, 2 H, H5, H6a), 2.50 (d, 3J = 13.0 Hz, 1 H, H6b), 4.10
(d, 3J = 8.7 Hz, 1 H, H4), 5.91 (d, 3J = 10.2 Hz, 1 H, H2), 6.78 (dd,
3J = 10.2 Hz, 3J = 1.7 Hz, 1 H, H3).
[(M – C4H9)+], 155 (9), 75 (39) [(C2H7OSi)+].
HRMS (EI): m/z [M]+ calcd for (C15H28O2Si): 268.1859; found:
268.1856.
(4S,5S)-4-(tert-Butyldimethylsiloxy)-5-vinylcyclohex-2-enone
(11f)
13C NMR (150 MHz, CDCl3): d = –4.8 (+, SiCH3), –4.4 (+, SiCH3),
18.0 [Cq, Si-C(CH3)3], 18.5 (+,5-CH3), 25.8 [+, Si-C(CH3)3], 39.4
(+, C5), 44.1 (–, C6), 73.5 (+, C4), 128.6 (+, C2), 154.2 (+, C3),
199.1 (Cq, C1).
Divinylcuprate was prepared according to general procedure A and
added to the unsaturated acetonide 6 (100 mg, 595 mmol). The
workup was conducted by addition of sat. aq NH4Cl soln (5 mL), fil-
tration and washing of the filter cake with EtOAc (20 mL). The or-
ganic phase was separated and the solvents removed. The residue
was dissolved in H2O and extracted with EtOAc (4 × 10 mL). The
combined organic phases were washed with 10% aq NH4Cl (2 × 10
MS (EI): m/z (%) = 240 (11) [M+], 225 (87) [(M – CH3)+], 183 (100)
[(M – C4H9)+], 165 (17) [(M – C2H7OSi)+], 75 (74) [(C2H7OSi)+].
HRMS (EI): m/z [M – C4H9]+ calcd for (C9H15O2Si): 183.0841;
found: 183.0844.
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

2182
U. K. Ohnemüller et al.
PAPER
mL), H2O (10 mL), and brine (10 mL), dried (Na2SO4), and filtered.
After removal of the solvent, the crude product (40 mg, ca. 200
mmol) was directly used in the next transformation step correspond-
ing to general procedure B. The crude product, DBU (33.0 mg, 218
mmol, 1.07 equiv) and TBDMSCl (75.0 mg, 500 mmol, 2.45 equiv)
were dissolved in benzene (2 mL) and heated to 100 °C for 5.5 h.
The workup also followed general procedure C. Chromatography
(cyclohexane–EtOAc, 20:1, 1% Et3N) gave a colorless oil; yield: 13
mg (9%); Rf = 0.17 (cyclohexane–EtOAc, 20:1, 1% Et3N). The ana-
lytical data are in accordance with those reported in the literature as
far as they have been reported before.4
(4R,5S)-4-(tert-Butyldimethylsiloxy)-5-phenylcyclohex-2-enone
(11h)
Following general procedure B. Scale: 7h (250 mg, 1.02 mmol).
Chromatography (cyclohexane–EtOAc, 9:1) gave a colorless solid;
yield: 35 mg (11%); mp 74–75 °C; Rf = 0.26 (cyclohexane–EtOAc,
5:1).
[a]D20 –158.40 (c 0.50, CHCl3).
IR (KBr): 3032 (w, n C=C–H), 2951 (m, n C–H), 2929 (m, n C–H),
2896 (w, n C–H), 2855 (m, n C–H), 2817 (w, n C–H), 1682 (s, n
C=O), 1093 cm–1 (m, n C–O).
1H NMR (500 MHz, CDCl3): d = –0.48 (s, 3 H, SiCH3), –0.12 (s, 3
H, SiCH3), 0.77 [s, 9 H, SiC(CH3)3], 2.68 (dd, 2J = 16.5 Hz, 3J = 4.0
Hz, 1 H, H6a), 2.79 (dd, 3J = 16.5 Hz, 3J = 13.7 Hz, 1 H, H6b), 3.27
IR (KBr): 3081 (vw, n C=C–H), 3040 (vw, n C=C–H), 2955 (m, n
C–H), 2928 (s, n C–H), 2856 (m, n C–H), 1694 (m, n C=O), 1463
(w, n C=C), 1380 (w), 1252 (m), 1100 cm–1 (m n C–O).
3
3
3
(ddd, J = 13.7 Hz, J = 9.4 Hz, J = 4.0 Hz, 1 H, H5), 4.54 (ddd,
1H NMR (500 MHz, CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H,
SiCH3), 0.90 [s, 9 H, SiC(CH3)3], 2.32 (dd, 2J = 16.6 Hz, 3J = 12.6
Hz, 1 H, H6a), 2.57 (ddd, 2J = 16.6 Hz, 3J = 4.1 Hz, 4J = 0.9 Hz, 1
3J = 9.4 Hz, 3J = 1.8 Hz, 4J = 1.8 Hz, 1 H, H4), 6.04 (br d, 3J = 10.2
Hz, 1 H, H2), 6.86 (dd, 3J = 10.2 Hz, J = 1.8 Hz, 1 H, H3), 7.24–
3
7.30 (m, 3 H, H2¢, H4¢, H6¢), 7.35 (dd, 3J = 7.35 Hz, 3J = 7.3 Hz, 2
H, H3¢, H5¢).
3
3
H, H6b), 2.70–2.79 (m, 1 H, H5), 4.26 (ddd, J = 8.8 Hz, J = 2.0
Hz, 4J = 2.0 Hz, 1 H, H4), 5.10 (br d, 3J = 17.0 Hz, 1 H, H2¢a), 5.13
(br d, J = 10.6 Hz, 1 H, H2¢b), 5.81 (ddd, J = 17.0 Hz, J = 10.6
Hz, 3J = 7.5 Hz, 1 H, H1¢), 5.92 (br d, 3J = 10.2 Hz, 1 H, H2), 6.78
(dd, 3J = 10.1 Hz, 3J = 2.1 Hz, 1 H, H3).
13C NMR (125 MHz, CDCl3): d = –5.8 (+, SiCH3), –5.2 (+, SiCH3),
17.9 [Cq, SiC(CH3)3], 25.6 [+, SiC(CH3)3], 42.6 (–, C6), 50.7 (+,
C5), 73.0 (+, C4), 127.3 (+, C4¢), 128.2 (+, C2¢, C6¢), 128.4 (+, C2),
128.5 (+, C3¢, C5¢), 140.7 (Cq, C1¢), 153.9 (+, C3), 198.5 (Cq, C1).
3
3
3
13C NMR (125 MHz, CDCl3): d = –4.6 (+, SiCH3), –4.5 (+, SiCH3),
18.1 [Cq, SiC(CH3)3], 25.7 [+, SiC(CH3)3], 40.9 (–, C6), 48.2 (+,
C5), 71.4 (+, C4), 116.7 (–, C2¢), 128.5 (+, C2), 138.0 (+, C1¢),
153.4 (+, C3), 198.3 (Cq, C1).
MS (EI): m/z (%) = 302 (1) [M+], 287 (3) [(M – CH3)+], 245 (100)
[(M – C4H9)+], 198 (10), 75 (16) [(C2H7OSi)+].
HRMS (EI): m/z [M]+ calcd for (C18H26O2Si): 302.1702; found:
MS (EI): m/z (%) = 252 (1) [M+], 237 (2) [(M – CH3)+], 223 (4)
[(C13H23OSi)+], 209 (4) [(M – C2H3O)+], 195 (100) [(M – C4H9)+],
167 (20), 113 (30), 75 (87) [(C2H7OSi)+].
HRMS (EI): m/z [M]+ calcd for (C14H24O2Si): 252.1546; found:
252.1541.
302.1701.
(4S,5R)-4-Hydroxy-5-methylcyclohex-2-enone (5a)
Following general procedure C. Scale: 11a (1.47 g, 6.11 mmol).
Chromatography (cyclohexane–EtOAc, 1:1) gave a colorless oil;
yield: 578 mg (75%); Rf = 0.21 (cyclohexane–EtOAc, 1:1).
[a]D20 –135.71 (c 1.06, CHCl3).
(4S,5R)-5-Allyl-4-(tert-butyldimethylsiloxy)cyclohex-2-enone
(11g)
Following general procedure B. Scale: 7g (50.0 mg, 238 mmol).
Chromatography (cyclohexane–EtOAc, 9:1) gave a light yellow oil;
yield: 35 mg (55%); Rf = 0.39 (cyclohexane–EtOAc, 9:1). The ana-
lytical data are in accordance with those reported in the literature.4
IR (KBr): 3415 (m, n O–H), 2959 (w, n C–H), 2878 (w, n C–H),
1665 (m, n C=O), 1053 cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 1.18 (d, 3J = 6.1 Hz, 3 H, 5-CH3),
2.12–2.22 (m, 2 H, H5, H6a), 2.47 (br s, 1 H, OH), 2.53 (dd,
2J = 12.7 Hz, 3J = 1.2 Hz, 1 H, H6b), 4.14–4.19 (m, 1 H, H4), 5.97
[a]D20 –109.47 (c 1.13, CHCl3).
3
4
4
(ddd, J = 10.2 Hz, J = 2.3 Hz, J = 1.3 Hz, 1 H, H2), 6.92 (dd,
3J = 10.2 Hz, 3J = 2.0 Hz, 1 H, H3).
IR (KBr): 3078 (w, n C=C–H), 3041 (w, n C=C–H), 2957 (m, n
C–H), 2931 (w, n C–H), 2859 (m, n C–H), 1689 (s, n C=O), 1100
cm–1 (s, n C–O).
13C NMR (100 MHz, CDCl3): d = 18.1 (+, 5-CH3), 39.2 (+, C5),
44.0 (–, C6), 72.9 (+, C4), 129.0 (+, C2), 153.3 (+, C3), 199.2 (Cq,
C1).
1H NMR (400 MHz, CDCl3): d = 0.15 (s, 3 H, SiCH3), 0.16 (s, 3 H,
SiCH3), 0.95 [s, 9 H, SiC(CH3)3], 1.98 (ddd, 2J = 13.7 Hz, 3J = 8.5
Hz, 3J = 8.1 Hz, 1 H, H1¢a), 2.07 (dd, 2J = 15.8 Hz, 3J = 12.7 Hz, 1
H, H6¢a), 2.10–2.22 (m, 1 H, H5), 2.51–2.58 (m, 1 H, H1¢b), 2.62
(ddd, 2J = 15.8 Hz, 3J = 2.9 Hz, 4J = 1.3 Hz, 1 H, H6¢b), 4.23 (ddd,
3J = 8.5 Hz, 3J = 2.4 Hz, 3J = 2.0 Hz, 1 H, H4), 5.05–5.13 (m, 2 H,
2 H3¢), 5.73 (dddd, 3J = 16.7 Hz, 3J = 10.3 Hz, 3J = 8.1 Hz, 3J = 6.2
Hz, 1 H, H2¢), 5.94 (ddd, 3J = 10.2 Hz, 3J = 2.0 Hz, 4J = 1.3 Hz, 1
H, H2), 6.81 (dd, 3J = 10.2 Hz, 3J = 2.4 Hz, 1 H, H3).
13C NMR (100 MHz, CDCl3): d = –4.7 (+, SiCH3), –4.2 (+, SiCH3),
18.0 [Cq, SiC(CH3)3], 25.7 [+, SiC(CH3)3], 36.2 (–, C1¢), 40.9 (–,
C6), 43.7 (+, C5), 71.3 (+, C4), 117.6 (–, C3¢), 128.6 (+, C2), 134.9
(+, C2¢), 153.6 (+, C3), 199.0 (Cq, C1).
MS (EI): m/z (%) = 257 (15) [(M – CH3)+], 209 (81) [(M – C4H9)+],
191 (63) [(M – C2H7OSi)+], 167 (61), 151 (21) [(M – C6H15Si)+], 75
(100) [(C2H7OSi)+].
HRMS (EI): m/z [M – C4H9]+ calcd for (C11H17O2Si): 209.0998;
found: 209.1000.
MS (EI): m/z (%) = 126 (24) [M+], 109 (2) [(M – OH)+], 84 (100)
[(C4H4O2)+], 68 (28), 55 (52).
HRMS (EI): m/z [M]+ calcd for (C7H10O2): 126.0681; found:
126.0684.
(4S,5R)-5-Ethyl-4-hydroxycyclohex-2-enone (5b)
Following general procedure C. Scale: 11b (640 mg, 2.52 mmol).
Chromatography (cyclohexane–EtOAc, 1:1) gave a light yellow oil;
yield: 352 mg (99.5%); Rf = 0.25 (cyclohexane–EtOAc, 1:1).
[a]D20 –170.14 (c 0.71, CHCl3).
IR (KBr): 3413 (s, n O–H), 2965 (m, n C–H), 2936 (m, n C–H),
2879 (m, n C–H), 1680 (s, n C=O), 1058 cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 0.96 (t, 3J = 7.5 Hz, 3 H, 2¢-CH3),
1.32–1.44 (m, 1 H, H1¢a), 1.82–2.04 (m, 2 H, H1¢b, H5), 2.11 (dd,
3
2J = 16.2 Hz, J = 13.1 Hz, 1 H, H6a), 2.43 (br s, 1 H, OH), 2.62
(ddd, 2J = 16.2 Hz, 3J = 3.6 Hz, 4J = 1.0 Hz, 1 H, H6b), 5.24 (ddd,
3J = 9.2 Hz, 3J = 2.1 Hz, 4J = 2.1 Hz, 1 H, H4), 5.97 (ddd, 3J = 10.2
3
4
3
Hz, J = 2.2 Hz, J = 1.3 Hz, 1 H, H2), 6.92 (dd, J = 10.2 Hz,
3J = 2.1 Hz, 1 H, H3).
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

PAPER
Versatile Access to Enantiomerically Pure 5-Substituted 4-Hydroxycyclohex-2-enones
2183
13C NMR (100 MHz, CDCl3): d = 10.4 (+, C2¢), 24.5 (–, C1¢), 40.7
(–, C6), 45.4 (+, C5), 70.9 (+, C4), 128.8 (+, C2), 153.5 (+, C3),
199.4 (Cq, C1).
1H NMR (500 MHz, CDCl3): d = 1.08–1.20 [m, 24 H, 5-CH3,
2
3
Si(CH(CH3)2)3], 2.16 (dd, J = 16.0 Hz, J = 11.3 Hz, 1 H, H6a),
2
3
2.17–2.28 (m, 1 H, H5), 2.60 (dd, J = 16.0 Hz, J = 3.3 Hz, 1 H,
H6b), 4.28–4.32 (m, 1 H, H4), 5.94 (d, 3J = 10.4 Hz, 1 H, H2), 6.88
(dd, 3J = 10.4 Hz, 3J = 2.5 Hz, 1 H, H3).
MS (EI): m/z (%) = 140 (71) [M+], 98 (75) [(M – C2H2O)+], 84 (100)
[(C4H4O2)+].
13C NMR (125 MHz, CDCl3): d = 12.7 [+, Si(CH(CH3)2)3], 18.11
[+, Si(CH(CH3)(CH3))3], 18.13 [+, SiCH(CH3)(CH3)], 18.5 (+, 5-
CH3), 39.4 (+, C5), 43.6 (–, C6), 73.1 (+, C4), 128.6 (+, C2), 152.7
(+, C3), 199.2 (Cq, C1).
MS (EI): m/z (%) = 282 (1) [M+], 239 (100) [(M – C3H7)+], 165
(26), 103 (29), 75 (54).
HRMS (EI): m/z [M]+ calcd for (C8H12O2): 140.0837; found:
140.0839.
(4S,5R)-4-Hydroxy-5-propylcyclohex-2-enone (5c)
Following general procedure C. Scale: 11c (281 mg, 1.05 mmol).
Chromatography (cyclohexane–EtOAc, 1:1) gave a colorless oil;
yield: 113 mg (70%); Rf = 0.37 (cyclohexane–EtOAc, 1:1).
[a]D20 –157.11 (c 0.45, CHCl3).
HRMS (EI): m/z [M]+ calcd for (C16H30O2Si): 282.2015; found:
282.2012.
IR (KBr): 3420 (m, n O–H), 3037 (vw, n C=C–H), 2959 (m, n
C–H), 2933 (m, n C–H), 2873 (m, n C–H), 1677 (s, n C=O), 1053
cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 0.95 (t, 3J = 7.1 Hz, 3 H, 3¢-CH3),
1.21–1.38 (m, 2 H, H1¢a, H2¢a), 1.41–1.54 (m, 1 H, H2¢b), 1.73–1.84
(m, 1 H, H1¢b), 1.98–2.15 (m, 3 H, H5, H6a, OH), 2.60–2.66 (m, 1
H, H6b), 4.24 (ddd, 3J = 8.9 Hz, 3J = 1.9 Hz, 3J = 1.9 Hz, 1 H, H4),
5.97 (br d, 3J = 10.2 Hz, 1 H, H2), 6.92 (dd, 3J = 10.2 Hz, 3J = 6.1
Hz, 1 H, H3).
(4S,5R)-4-(4-Bromobenzoyloxy)-5-methylcyclohex-2-enone
(15)
Following general procedure B. Scale: 7a (82.0 mg, 445 mmol) and
4-bromobenzoyl chloride (294 mg, 1.34 mmol, 3.01 equiv) instead
of TBDMSCl. Chromatography (cyclohexane–EtOAc, 9:1) gave an
off-white solid; yield: 31 mg (23%); mp 108 °C; Rf = 0.48 (cyclo-
hexane–EtOAc, 5:1).
[a]D20 – 197.32 (c 1.10, CHCl3).
IR (KBr): 3104 (w, n C=C–H), 3089 (w, n C=C–H), 3059 (w, n
Car–H), 3041 (w, n Car–H), 2962 (m, n C–H), 2929 (m, n C–H), 2873
(m, n C–H), 2373 (vw), 2295 (vw), 2214 (vw), 1708 [s, n C=O
(RCO2R¢)], 1689 (s, n C=O), 1587 cm–1 (m, n C=C).
13C NMR (100 MHz, CDCl3): d = 14.1 (+, C3¢), 19.2 (–, C2¢), 34.1
(–, C1¢), 41.2 (–, C6), 43.8 (+, C5), 71.4 (+, C4), 128.9 (+, C2),
153.2 (+, C3), 199.2 (Cq, C1).
MS (EI): m/z (%) = 154 (50) [M+], 112 (66) [(M – C2H2O)+], 84
1H NMR (500 MHz, CDCl3): d = 1.11 (d, 3J = 6.6 Hz, 3 H, 5-CH3),
(100) [(C4H4O2)+].
2.30 (dd, 2J = 16.5 Hz, 3J = 12.7 Hz, 1 H, H6a), 2.54 (ddqd,
HRMS (EI): m/z [M]+ calcd for (C9H14O2): 154.0994; found:
154.0992.
3
3J = 12.7 Hz, J = 9.4 Hz, 3J = 6.6 Hz, 3J = 4.1 Hz, 1 H, H5), 2.63
2
3
3
(dd, J = 16.5 Hz, J = 4.1 Hz, 1 H, H6b), 5.57 (ddd, J = 9.4 Hz,
3J = 2.0 Hz, 4J = 1.5 Hz, 1 H, H4), 6.06 (dm, 3J = 10.1 Hz, 1 H, H2),
6.85 (dd, J = 10.1 Hz, J = 2.0 Hz, 1 H, H3), 7.58–7.61 (m, 2 H,
3
3
(4R,5S)-4-Hydroxy-5-phenylcyclohex-2-enone (5h)
Following general procedure C. Scale: 11h (143 mg, 473 mmol).
Chromatography (cyclohexane–EtOAc, 1:1) gave a colorless oil;
yield: 83 mg (93%); Rf = 0.27 (cyclohexane–EtOAc, 1:1).
[a]D20 –175.42 (c 0.12, CHCl3).
Har), 7.90–7.94 (m, 2 H, Har).
13C NMR (125 MHz, CDCl3): d = 18.1 (+, 5-CH3), 36.2 (+, C5),
43.8 (–, C6), 74.6 (+, C4), 128.4 (Cq, Car), 128.7 (Cq, Car), 130.5 (+,
C2), 131.3 (+, C2¢, C6¢)*, 131.9 (+, C3¢, C5¢)*, 148.1 (+, C3), 165.5
(Cq, RCO2R¢), 197.9 (Cq, C1).
MS (EI): m/z (%) = 310/308 (8/9) [M+], 185/183 (100/87)
[(C7H4BrO)+], 157/155 (15/16) [(C6H4Br)+], 124 (12), 108 (60)
[C7H8O)+], 80 (15).
IR (KBr): 3407 (m, n O–H), 3062 (w, n Car–H), 3031 (w, n Car–H),
2957 (w, n C–H), 2896 (w, n C–H), 1676 (s, n C=O), 1074 cm–1 (m,
n C–O).
1H NMR (500 MHz, CDCl3): d = 2.05 (br d, 3J = 3.8 Hz, 1 H, OH),
3
3
HRMS (EI): m/z [M]+ calcd for (C14H13BrO3): 310.0028; found:
310.0031.
2.66–2.76 (m, 2 H, 2 H6), 3.26 (ddd, J = 11.6 Hz, J = 10.0 Hz,
3J = 6.3 Hz, 1 H, H5), 4.66–4.72 (m, 1 H, H4), 6.08 (dd, 3J = 10.2
Hz, 3J = 2.0 Hz, 1 H, H2), 7.01 (dd, 3J = 10.2 Hz, 3J = 1.7 Hz, 1 H,
H3), 7.30–7.36 (m, 3 H, H2¢, H4¢, H6¢), 7.42 (dd, 3J = 7.4 Hz, 2 H,
H3¢, H5¢).
(4S,5R)-4-Hydroxy-2-[(1R,2S,3R)-2-hydroxy-3-methyl-5-oxo-
cyclohexyl]-5-methylcyclohex-2-enone (17)
13C NMR (125 MHz, CDCl3): d = 43.0 (–, C6), 50.7 (+, C5), 71.8
(+, C4), 127.7 (+, C2¢, C6¢), 127.9 (+, C4¢), 129.0 (+, C2), 129.2 (+,
C3¢, C5¢), 139.4 (Cq, C1¢), 152.1 (+, C3), 198.0 (Cq, C1).
MS (EI): m/z (%) = 188 (42) [M+], 146 (12) [(M – C2H2O)+], 104
(15), 84 (100) [(C4H4O2)+], 77 (12) [(C6H5)+], 55 (22), 43 (30)
[(C2H3O)+].
A soln of 11a (84.0 mg, 351 mmol, 1.00 equiv) in THF (2.00 mL)
was treated with a soln of 1 M TBAF in THF (351 mL, 351 mmol,
1.00 equiv) and stirred at r.t. for 1 h. The solvent was removed in
vacuo. Chromatography (cyclohexane–EtOAc, 1:1) gave a color-
less solid; yield: 16 mg (37%); Rf = 0.12 (cyclohexane–EtOAc,
1:1).
1H NMR (500 MHz, CDCl3): d = 1.06 (d, 3J = 7.2 Hz, 3 H, 3¢-CH3),
1.18 (d, 3J = 6.2 Hz, 3 H, 5-CH3), 2.00 (br s, 1 H, OH), 2.07–2.22
(m, 4 H, H5, H6a, H6¢a, H4¢a), 2.35–2.42 (m, 1 H, H3¢), 2.60 (dd,
2J = 15.7 Hz, 3J = 3.1 Hz, 1 H, H6b), 2.73 (dd, 2J = 13.4 Hz,
HRMS (EI): m/z [M]+ calcd for (C12H12O2): 188.0837; found:
188.0839.
(4S,5R)-5-Methyl-4-(triisopropylsiloxy)cyclohex-2-enone (12)
Following general procedure B. Scale: 7a (255 mg, 1.38 mmol) and
TIPSCl (285 mg, 1.48 mmol, 1.07 equiv) instead of TBDMSCl.
Chromatography (cyclohexane–EtOAc, 9:1) gave a colorless oil;
yield: 177 mg (47%); Rf = 0.35 (cyclohexane–EtOAc, 9:1).
2
3
3J = 12.5 Hz, 1 H, H6¢b), 2.81 (dd, J = 14.4 Hz, J = 6.1 Hz, 1 H,
H4¢b), 3.16 (br s, 1 H, OH), 3.39 (br d, 3J = 12.5 Hz, 1 H, H1¢), 3.76–
3.79 (m, 1 H, H2¢), 4.16 (br d, 3J = 7.3 Hz, 1 H, H4), 6.67 (s, 1 H,
H3).
13C NMR (125 MHz, CDCl3): d = 17.8 (+, CH3), 17.9 (+, CH3), 36.2
(+, C1¢), 36.7 (+, C3¢), 38.7 (+, C5), 40.0 (–, C6¢), 43.0 (–, C4¢), 43.9
(–, C6), 71.5 (+, C2¢), 72.7 (+, C4), 137.8 (Cq, C2), 149.5 (+, C3),
198.6 (Cq, C1), 211.5 (Cq, C5¢).
IR (KBr): 3041 (vw, n C=C–H), 2945 (s, n C–H), 2892 (m, n C–H),
2867 (s, n C–H), 1686 cm–1 (s, n C=O).
[a]D20 –128.61 (c 0.76, CHCl3).
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

2184
U. K. Ohnemüller et al.
PAPER
MS (EI): m/z (%) = 252 (1) [M+], 234 (2) [(M – H2O)+], 169 (72)
[(C9H13O3)+], 153 (45), 127 (83) [(C7H11O2)+], 110 (100)
[(C7H10O)+], 81 (40), 55 (34), 43 (66) [(C2H3O)+].
HRMS (EI): m/z [M]+ calcd for (C14H20O4): 252.1362; found:
252.1360.
13C NMR (100 MHz, CDCl3): d = 17.3 (+, 3-CH3), 30.9 (+, C3),
45.7 (–, C2), 55.8 (+, OCH3), 76.1 (+, C4), 79.9 (+, C4a), 113.7 (+,
C8), 116.8 (+, C5), 118.5 (+, C6), 122.0 (Cq, Car), 128.5 (Cq, Car),
132.6 (+, C9), 149.1 (Cq, C9a), 154.7 (Cq, Car), 195.4 (Cq, C1).
MS (EI): m/z (%) = 260 (28) [M+], 203 (100) [(C13H15O2)+], 174
(29), 160 (22).
(1R,1¢R,4R,5S,5¢R,6R,6¢S)-5,6,6¢-Trihydroxy-4,5¢-dimethyl-
bicyclohexyl-2,3¢-dione (18)
HRMS (EI): m/z [M]+ calcd for (C15H16O4): 260.1049; found:
260.1042.
A soln of 11a (200 mg, 832 mmol, 1.00 equiv) in THF (4.00 mL)
was treated with MeOH (170 mL, 4.16 mmol, 5.00 equiv) and, sub-
sequently, with 1 M TBAF in THF (832 mL, 832 mmol, 1.00 equiv).
The mixture was stirred at r.t. for 48 h and then the solvent was re-
moved and the residue was purified by flash column chromatogra-
phy. Chromatography (cyclohexane–EtOAc, 1:1) gave a colorless
solid; yield: 31 mg (32%); Rf = 0.10 (cyclohexane–EtOAc, 1:1).
(3R,4S,4aR)-4-Hydroxy-7-methoxy-3-methyl-2,3,4,4a-tetra-
hydro-1H-xanthen-1-one (trans-20a)
The synthesis of trans-20a was realized in accordance to the proce-
dure described for cis-20a, yielding clean trans-20a as yellow-
brown oil (184 mg, 23%) and a cis/trans diastereomeric mixture
(8.5:1). Rf = 0.35 (cyclohexane–EtOAc, 2:1).
[a]D20 –140.33 (c 1.20, CHCl3).
[a]D20 +105.02 (c 1.45, CHCl3).
IR (KBr): 3483 (s, n O–H), 2957 (m, n C–H), 2875 (w, n C–H),
IR (KBr): 3467 (w, n O–H), 3039 (vw, n Car–H), 2958 (w, n C–H),
2909 (w, n C–H), 2839 (w, n OCH3), 1681 (m, n C=O), 1614 (m, n
C=C), 1570 (m, n Car=Car), 1233 (s, n Car–O–C), 1036 cm–1 (m, n
C–O).
1712 (vs, n C=O), 1067 cm–1 (s, n C–O).
1H NMR (400 MHz, CDCl3): d = 1.09 (d, 3J = 6.6 Hz, 3 H, 5¢-CH3),
1.17 (d, 3J = 6.4 Hz, 3 H, 4-CH3), 1.98 (dd, 2J = 17.0 Hz, 3J = 11.8
2
Hz, 1 H, H4¢a), 2.06–2.18 (m, 1 H, H5¢), 2.13 (dd, J = 13.8 Hz,
1H NMR (500 MHz, CDCl3): d = 1.03 (d, 3J = 7.6 Hz, 3 H, 3-CH3),
3J = 11.7 Hz, 1 H, H3a), 2.15–2.28 (m, 1 H, H4), 2.38 (dd, 2J = 15.9
Hz, 3J = 11.6 Hz, 1 H, H2¢a), 2.42 (dd 2J = 17.0 Hz, 3J = 3.6 Hz, 1
H, H4¢b), 2.45 (dd, 2J = 15.9 Hz, 3J = 6.8 Hz, 1 H, H2¢b), 2.52 (dd,
2J = 13.8 Hz, 3J = 3.4 Hz, 1 H, H3b), 2.60 (dd, 3J = 5.4 Hz, 3J = 2.2
3
2.28 (dd, 2J = 17.7 Hz, J = 1.6 Hz, 1 H, H2a), 2.55-2.63 (m, 1 H,
H3), 2.75 (br s, 1 H, OH), 3.04 (dd, 2J = 17.7 Hz, 3J = 6.2 Hz, 1 H,
H2b), 3.80 (s, 3 H, OCH3), 4.30 (dd, 3J = 3.7 Hz, 3J = 3.3 Hz, 1 H,
H4), 5.09 (dd, 3J = 3.3 Hz, 4J = 2.6 Hz, 1 H, H4a), 6.78 (d, 4J = 2.6
Hz, 1 H, H8), 6.85 (dd, 3J = 8.9 Hz, 4J = 2.6 Hz, 1 H, H6), 6.88 (d,
3J = 8.9 Hz, 1 H, H5), 7.45 (d, 4J = 2.62 Hz, 1 H, H9).
3
3
3
Hz, 1 H, H1), 3.35 (dddd, J = 11.6 Hz, J = 7.4 Hz, J = 6.8 Hz,
3J = 2.2 Hz, 1 H, H1¢), 3.75 (dd, 3J = 9.2 Hz, 3J = 3.4 Hz, 1 H, H5),
3.87 (dd, 3J = 7.7 Hz, 3J = 7.4 Hz, 1 H, H6¢), 4.57 (dd, 3J = 5.4 Hz,
3J = 3.4 Hz, 1 H, H6); the protons of the OH moieties could not be
detected.
13C NMR (125 MHz, CDCl3): d = 17.0 (+, 3-CH3), 30.6 (+, C3),
39.8 (–, C2), 55.8 (+, OCH3), 69.6 (+, C4), 74.8 (+, C4a), 113.7 (+,
C8), 117.0 (+, C5), 118.1 (+, C6), 122.2 (Cq, Car), 128.4 (Cq, Car),
132.3 (+, C9), 149.0 (Cq, C9a), 154.8 (Cq, Car), 197.4 (Cq, C1).
MS (EI): m/z (%) = 260 (14) [M+], 243 (1) [(M – OH)+], 232 (1),
203 (16) [(C13H15O2)+], 174 (5), 160 (4), 84 (38) [(C4H4O2)+], 69
(16), 56 (100) [(C3H4O)+], 43 (14) [(C2H3O)+].
13C NMR (100 MHz, CDCl3): d = 18.2 (+, 4-CH3), 18.9 (+, 5¢-CH3),
32.4 (+, C5¢), 33.7 (+, C4), 37.2 (+, C1¢), 40.7 (–, C2¢), 43.4 (–, C4¢),
45.8 (–, C3), 56.8 (+, C1), 74.1 (+, C5), 78.7 (+, C6), 82.2 (+, C6¢),
207.1 (Cq, C2)*, 210.2 (Cq, C3¢)*.
MS (EI): m/z (%) = 253 (10) [(M – OH)+], 234 (94) [(M – 2 H2O)+],
219 (21) [(C13H15O3)+], 143 (100) [(C7H11O3)+], 126 (53)
[(C7H10O2)+], 109 (73) [(C7H9O)+], 95 (63), 71 (47), 43 (78)
[(C2H3O)+].
HRMS (EI): m/z [M]+ calcd for (C15H16O4): 260.1049; found:
260.1052.
(3R,4S,4aR/S)-3-Ethyl-4-hydroxy-7-methoxy-2,3,4,4a-tetra-
hydro-1H-xanthen-1-one (cis/trans-20b)
Following general procedure D. Scale: 19 (163 mg, 1.07 mmol, 1.00
equiv), 5b (330 mg, 2.14 mmol, 2.00 equiv), N-methylimidazole
(43 mg, 535 mmol, 0.50 equiv). Chromatography (cyclohexane–
EtOAc, 5:1) gave a diastereomeric mixture cis/trans-20b (1:1.2);
yield: 242 mg (82%); Rf = 0.41 (cyclohexane–EtOAc, 2:1).
HRMS (EI): m/z [M – 2 H2O]+ calcd for (C14H18O3): 234.1256;
found: 234.1259.
(3R,4S,4aS)-4-Hydroxy-7-methoxy-3-methyl-2,3,4,4a-tetra-
hydro-1H-xanthen-1-one (cis-20a)
Following general procedure D. Scale: 19 (463 mg, 3.05 mmol, 1.00
equiv), 5a (770 mg, 6.09 mmol, 2.00 equiv), N-methylimidazole
(125 mg, 1.52 mmol, 0.50 equiv). Chromatography (cyclohexane–
EtOAc, 2:1) resulted in trans-20a (184 mg, 23%), a diastereomeric
mixture of cis/trans-20a (8.5:1, 226 mg, 28%), and cis-20a as a yel-
low solid (87 mg, 11%). The overall yield of diastereomers was
62%. Rf = 0.29 (cyclohexane–EtOAc 2:1).
IR (KBr): 3432 (s, n O–H), 3063 (vw, n Car–H), 2968 (m, n C–H),
2913 (m, n C–H), 2839 (m, n OCH3), 1682 (s, n C=O), 1615 (s, n
C=C), 1570 (s, n Car=Car), 1237 (s, n Car–O–C), 1034 cm–1 (m, n
C–O).
3
1H NMR (500 MHz, CDCl3, trans/cis 1.2:1): d = 0.98 (t, J = 7.5
Hz, 3 Hcis, cis-2¢-CH3), 1.02 (t, 3J = 7.3 Hz, 3 Htrans, trans-2¢-CH3),
1.18–1.29 (m, 1 Htrans, trans-H1¢a), 1.36–1.49 (m, 1 Hcis, 1 Htrans, cis-
H1¢a, trans-H1¢b), 1.83–1.92 (m, 1 Hcis, cis-H3), 1.93–2.02 (m, 1 H,
[a]D20 –135.33 (c 2.03, CHCl3).
IR (KBr): 3398 (s, n O–H), 3023 (w, n Car–H), 2994 (m, n C=C–H),
2965 (m, n C–H), 2890 (m, n C–H), 2878 (m, n C–H), 2837 (m, n
OCH3), 2056 (vw), 1905 (vw), 1658 (s, n C=O), 1598 (s, n C=C),
1558 (s, n Car=Car), 1244 (s, n Car–O–C), 1032 cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 1.22 (d, 3J = 6.4 Hz, 3 H, 3-CH3),
1.96–2.09 (m, 1 H, H3), 2.24 (dd, 2J = 18.0 Hz, 3J = 13.2 Hz, 1 H,
H2a), 2.70 (br s, 1 H, OH), 2.67 (dd, 2J = 18.0 Hz, 3J = 4.5 Hz, 1 H,
H2b), 3.80 (s, 3 H, OCH3), 3.93 (dd, 3J = 10.8 Hz, 3J = 8.7 Hz, 1 H,
H4), 4.79 (dd, 3J = 8.7 Hz, 4J = 2.5 Hz, 1 H, H4a), 6.77 (d, 4J = 2.7
Hz, 1 H, H8), 6.875 (dd, 3J = 8.9 Hz, 4J = 2.76 Hz, 1 H, H6), 6.90
(d, 3J = 8.9 Hz, 1 H, H5), 7.45 (d, 4J = 2.62 Hz, 1 H, H9).
2
3
cis-H1¢b), 2.21 (dd, J = 18.0 Hz, J = 13.2 Hz, 1 Hcis, cis-H2a),
2
3
2.28–2.35 (m, 1 Htrans, trans-H3), 2.39 (dd, J = 17.8 Hz, J = 1.2
Hz, 1 Htrans, trans-H2a), 2.72 (dd, 2J = 18.0 Hz, 3J = 4.5 Hz, 1 Hcis,
cis-H2b), 2.79 (br s, 1 Hcis, 1 Htrans, cis-OH, trans-H), 2.99 (dd,
2J = 17.8 Hz, 3J = 6.2 Hz, 1 Htrans, trans-H2b), 3.79 (s, 3 Hcis, 3 Htrans
,
cis-OCH3, trans-OCH3), 4.00 (dd, 3J = 10.7 Hz, 3J = 8.8 Hz, 1 Hcis,
cis-H4), 4.38 (dd, 3J = 3.6 Hz, 3J = 3.6 Hz, 1 Htrans, trans-H4), 4.79
(dd, 3J = 8.8 Hz, 3J = 2.3 Hz, 1 Hcis, cis-H4a), 5.04 (dd, 3J = 2.8 Hz,
4J = 2.0 Hz, 1 Htrans, trans-H4a), 6.75–6.77 (m, 1 Hcis, 1 Htrans, cis-
Har, trans-Har), 6.80–6.90 (m, 2 Hcis, 2 Htrans, cis-Har, trans-Har), 7.39
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York

PAPER
Versatile Access to Enantiomerically Pure 5-Substituted 4-Hydroxycyclohex-2-enones
2185
(d, 3J = 2.3 Hz, 1 Hcis, cis-H9), 7.43 (d, 4J = 2.0 Hz, 1 Htrans, trans-
Car), 118.0 (+, Car), 118.4 (+, Car), 122.0 (Cq, Car), 122.2 (Cq, Car),
H9).
128.3 (Cq, Car), 128.4 (Cq, Car), 132.1 (+, trans-C9), 132.4 (+, cis-
C9), 148.9 (Cq, trans-C9a), 149.1 (Cq, cis-C9a), 154.66 (Cq, Car),
154.70 (Cq, Car), 195.7 (Cq, cis-C1), 197.5 (Cq, trans-C1).
13C NMR (125 MHz, CDCl3): d = 9.8 (+, cis-C2¢), 12.0 (+, trans-
C2¢), 23.4 (–, cis-C1¢), 24.5 (–, trans-C1¢), 36.4 (+, cis-C3), 37.8
(–, trans-C2), 37.8 (+, trans-C3), 42.2 (–, cis-C2), 55.7 (+, cis-
OCH3, trans-OCH3), 68.5 (+, trans-C4), 74.3 (+, cis-C4), 74.8 (+,
trans-C4a), 80.1 (+, cis-C4a), 113.6 (+, Car), 113.7 (+, Car), 116.8
(+, Car), 116.9 (+, Car), 118.0 (+, Car), 118.4 (+, Car), 122.0 (Cq,
Car)*, 122.2 (Cq, Car)*, 128.4 (Cq, cis-C9a)*, 128.4 (Cq, trans-
C9a)*, 132.2 (+, trans-C9), 132.5 (+, cis-C9), 148.9 (Cq, Car), 149.1
(Cq, Car), 154.67 (Cq, Car), 154.73 (Cq, Car), 195.8 (Cq, trans-C1)**,
197.4 (Cq, cis-C1)**.
MS (EI): m/z (%) = 288 (25) [M+], 203 (38) [(C12H11O3)+], 84 (64)
[(C4H4O2)+], 56 (100) [(C3H4O)+], 43 (21) [(C2H3O)+].
HRMS (EI): m/z [M]+ calcd for (C17H20O4): 288.1362; found:
288.1360.
Acknowledgment
We would like to thank the Fonds der chemischen Industrie, the
Klaus-Grohe-Stiftung (C.F.N.) and the Landesgraduiertenförde-
rung Baden-Württemberg (U.K.O.) for financial support.
MS (EI): m/z (%) = 274 (11) [M+], 203 (17) [(C12H11O3)+], 153 (11),
105 (13), 77 (20) [(C6H5O)+], 57 (12), 43 (100) [(C2H3O)+].
HRMS (EI): m/z [M]+ calcd for (C16H18O4): 274.1205; found:
274.1203.
References
(3R,4S,4aR/S)-4-Hydroxy-7-methoxy-3-propyl-2,3,4,4a-tetra-
hydro-1H-xanthen-1-one (cis/trans-20c)
(1) (a) Minio, Y.; Yunio, M.; Komei, M. Chem. Pharm. Bull.
1971, 19, 199. (b) Kraft, F. Arch. Pharm. (Weinheim, Ger.)
1906, 244, 336. (c) Jacobi, C. Arch. Pharm. (Weinheim,
Ger.) 1897, 39, 104. (d) Hale, M. E. Jr. Bryologist 1958, 61,
81. (e) Andersen, R.; Büchi, G.; Kobbe, B.; Demain, A. L. J.
Org. Chem. 1977, 42, 352. (f) Howard, C. C.; Johnstone, R.
A. W.; Entwistle, I. D. J. Chem. Soc., Chem. Commun. 1973,
464. (g) Howard, C. C.; Johnstone, R. A. W. J. Chem. Soc.,
Perkin Trans. 1 1973, 2440. (h) Franck, B.; Thiele, O. W.;
Reschke, T. Angew. Chem. 1961, 73, 494. (i) Franck, B.;
Thiele, O. W.; Reschke, T. Chem. Ber. 1962, 95, 1328.
(2) Lesch, B.; Bräse, S. Angew. Chem. Int. Ed. 2004, 43, 115;
Angew. Chem. 2004, 116, 118.
Following general procedure D. Scale: 19 (159 mg, 1.05 mmol, 1.00
equiv), 5c (324 mg, 2.10 mmol, 2.00 equiv), N-methylimidazole
(43.5 mg, 539 mmol, 0.50 equiv). Chromatography (cyclohexane–
EtOAc, 5:1) gave a diastereomeric mixture trans/cis (1.3:1) as a
yellow solid; yield: 246 mg (82%); Rf = 0.54 (cyclohexane–EtOAc,
2:1).
IR (KBr): 3451 (m, n O–H), 2959 (m, n C–H), 2930 (m, n C–H),
2872 (m, n OCH3), 1682 (m, n C=O), 1613 (m, n C=C), 1570 (s, n
Car=Car), 1236 (s, n Car–O–C), 1034 cm–1 (m, n C–O).
1H NMR (400 MHz, CDCl3): d = 0.92 (t, 3J = 7.2 Hz, 3 Htrans, trans-
3
3¢-CH3), 0.97 (t, J = 7.0 Hz, 3 Hcis, cis-3¢-CH3), 1.12–1.24 (m, 1
(3) Ohnemüller, U. K.; Nising, C. F.; Nieger, M.; Bräse, S. Eur.
Htrans, trans-H1¢a), 1.25–1.41 (m, 3 Hcis, 2 Htrans, 2 cis-H1¢, cis-H2¢a,
trans-H1¢b, trans-H2¢a), 1.43–1.55 (m, 1 Hcis, 1 Htrans, cis-H2¢b,
J. Org. Chem. 2006, 6, 1535.
(4) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Org Chem.
1997, 62, 3984.
(5) Matsuo, K.; Sugimura, W.; Shimizu, Y.; Nishiwaki, K.;
Kuwajima, H. Heterocycles 2000, 53, 1505.
(6) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332.
(7) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738.
(8) Kamenecka, T. M.; Overman, L. E. Tetrahedron Lett. 1994,
35, 4279.
(9) (a) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl.
1997, 36, 186; Angew. Chem. 1997, 109, 194. (b) Knochel,
P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (c) Krause, N.
Modern Organocopper Chemistry; Wiley-VCH: Weinheim,
2002.
(10) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723.
(11) Characterization details for this compound are available
from the authors.
2
trans-H2¢b), 1.85–1.98 (m, 1 Hcis, cis-H3), 2.18 (dd, J = 18.0 Hz,
2
3J = 13.1 Hz, 1 Hcis, cis-H2a), 2.36 (br d, J = 17.8 Hz, 1 Htrans
,
2
trans-H2a), 2.38–2.45 (m, 1 Htrans, trans-H3), 2.73 (dd, J = 18.0
Hz, 3J = 4.3 Hz, 1 Hcis, cis-H2b), 2.83–2.87 (m, 1 Hcis, 1 Htrans, cis-
OH, trans-OH), 2.99 (dd, 2J = 17.6 Hz, 3J = 6.0 Hz, 1 Htrans, trans-
H2b), 3.78 (s, 3 Hcis, 3 Htrans, cis-OCH3, trans-OCH3), 3.98 (dd,
3
3
3J = 9.3 Hz, J = 9.3 Hz, 1 Hcis, cis-H4), 4.35 (dd, J = 3.5 Hz,
3J = 3.5 Hz, 1 Htrans, trans-H4), 4.78 (dd, 3J = 8.6 Hz, 4J = 2.4 Hz, 1
3
4
Hcis, cis-H4a), 5.04 (dd, J = 2.7 Hz, J = 2.7 Hz, 1 Htrans, trans-
H4a), 6.74–6.76 (m, 1 Hcis, 1 Htrans, cis-H8, trans-H8), 6.81–6.90
(m, 2 Hcis, 2 Htrans, cis-H5, cis-H6, trans-H5, trans-H6), 7.38 (d,
4J = 2.3 Hz, 1 Hcis, cis-H9), 7.42 (d, 4J = 1.6 Hz, 1 Htrans, trans-H9).
13C NMR (125 MHz, CDCl3): d = 13.9 (+, trans-C3¢), 14.2 (+, cis-
C3¢), 18.9 (–, cis-C2¢), 20.4 (–, trans-C2¢), 33.0 (–, cis-C1¢), 33.6
(–, trans-C1¢), 35.2 (+, cis-C3), 35.6 (+, trans-C3), 38.1 (–, trans-
C2), 42.7 (–, cis-C2), 55.7 (+, cis-OCH3, trans-OCH3), 68.6 (+,
trans-C4), 74.7 (+, cis-C4), 74.9 (+, trans-C4a), 80.0 (+, cis-C4a),
113.59 (+, trans-C8), 113.64 (+, cis-C8), 116.8 (+, Car), 116.9 (+,
Synthesis 2007, No. 14, 2175–2185 © Thieme Stuttgart · New York