A catalytic enantioselective route to cis- and trans-3,4,4,5-tetrasubstituted cyclohexanones; remarkable chiral catalyst control in sequential catalytic 1,4-additions to cyclohexadienones

Article abstract of DOI:10.1016/S0040-4020(01)00071-0

Asymmetric copper-phosphoramidite catalysed conjugate addition of Et₂Zn to easily accessible, nearly enantiomerically pure cyclohexenones 2 and 4 was performed. Depending on the enantiomer of the chiral phosphoramidite used, the cis- or trans-3,4,4,5-tetrasubstituted cyclohexanones 5 and 6 could be formed selectively. Surprisingly, there is no directing effect of the 5-ethyl- or 4-alkoxy-substituents and the stereochemical outcome is only governed by the configuration of the chiral ligand.

Full text of DOI:10.1016/S0040-4020(01)00071-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2485±2489
A catalytic enantioselective route to cis- and trans-3,4,4,5-
tetrasubstituted cyclohexanones; remarkable chiral catalyst
control in sequential catalytic 1,4-additions to cyclohexadienones
Rosalinde Imbos, Adriaan J. Minnaard and Ben L. Feringap
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Dedicated to Professor H. Kagan
Received 31 May 2000; revised 1 August 2000; accepted 3 August 2000
AbstractÐAsymmetric copper-phosphoramidite catalysed conjugate addition of Et2Zn to easily accessible, nearly enantiomerically pure
cyclohexenones 2 and 4 was performed. Depending on the enantiomer of the chiral phosphoramidite used, the cis- or trans-3,4,4,5-
tetrasubstituted cyclohexanones 5 and 6 could be formed selectively. Surprisingly, there is no directing effect of the 5-ethyl- or 4-alkoxy-
substituents and the stereochemical outcome is only governed by the con®guration of the chiral ligand. q 2001 Published by Elsevier
Science Ltd.
1. Introduction
The stereochemistry of the conjugate addition of organo-
cuprates to cyclic substituted enones has been studied
intensively8 and a possible transition state involving trihapto
Optically active multi-substituted cyclic alkanones are
attractive chiral building blocks, as they contain structural
features prominent in several classes of natural compounds.1
These chiral cycloalkanones are generally synthesised from
enantiomerically pure cycloalkenones, which in turn are
usually obtained by either a classical or an enzymatic reso-
lution2 or multistep synthetic routes from chiral building
blocks.3 Formation of multiple stereocenters, by conjugate
addition of organometallic reagents to chiral cyclic enones,
is governed by kinetic control,4 which has stereochemical
consequences, i.e. products are mostly trans-disubstituted.5
p
(d-p3 ) coordination9 has been proposed (Fig. 1). In the
transition state leading to the cis-product an unfavourable
interaction between the R and Me substituents takes place,
resulting in predominant formation of the trans-adduct.
Scheme 1.
As was already discovered in the 1960's, the conjugate
addition of MeMgCl to (racemic) 5-methyl-2-cyclohexe-
none affords a mixture of two diastereomeric products in a
trans/cis ratio of 95:5 (Scheme 1).6 The diastereoselectivity
has been explained not only in terms of steric hindrance but
also in terms of difference in the energy of the transition
state.6
For 3,5-disubstituted cyclohexanones the trans-product is
higher in energy (one of the substituents is always axial)
than the cis (all-equatorial), but nonetheless almost exclu-
sively the trans product is formed.7
Keywords: conjugate addition; phosphoramidites; chiral cyclohexanones;
asymmetric catalysis.
p
Corresponding author. Tel.: 131-50-3634278; fax: 131-50-3634296;
e-mail: feringa@chem.rug.nl
Figure 1.
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020(01)00071-0

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R. Imbos et al. / Tetrahedron 57 (2001) 2485±2489
Scheme 2.
Scheme 4.
Recently, Sato et al. reported on the conjugate addition of
cuprates to 5-(tert-butyldimethylsiloxy)-2-cyclohexenone
(5-(TBSO)-2-cyclohexenone).10 Conjugate addition of a
higher order cyanocuprate yields the trans-product, whereas
conjugate addition of a lower order cuprate affords the
cis-product in a d.e. of 99% (Scheme 2). The unexpected
cis-selectivity is proposed to be due to the ability of the
alkoxy-moiety to coordinate to the lower-order cuprate.
However, conjugate addition of a lower order cuprate to
4-TBSO-2-cyclohexenone afforded the trans-product in
97%, indicating that the selectivity is also highly dependent
on the position of the alkoxy group on the cyclohexenone
ring.
yield and with an e.e. of 97%, using only 2 mol% of chiral
catalyst and 1.1 equiv. of diethylzinc (Scheme 3). 3-Ethyl-
4-methoxy-4-methylcyclohexenone 4 is formed as a syn/
anti (90/10) mixture of both diastereoisomers, where the
3-ethyl group in the major isomer is syn to the alkoxy
moiety. The excellent syn-selectivity was subscribed to a
coordinating effect of the MeO-moiety. The syn-diastereo-
isomer can be obtained, after column chromatography, in
55% yield and with an e.e. of 97%.
Cyclohexenones 2 and 4 can be subjected to a second conju-
gate addition, using the same conditions as depicted in
Scheme 3. In contrast to the planar and rigid cyclohexa-
dienones the conjugate addition products (cyclohexenones)
are ¯exible and are therefore expected to show different
reactivity and selectivity in the second copper-phosphor-
amidite catalysed asymmetric 1,4-addition of Et2Zn.
To the best of our knowledge, until now the work on conju-
gate additions to 5-substituted cyclohexenones to yield 3,5-
disubstituted cyclohexanones has focussed on stoichio-
metric chemistry using various organometallic reagents.
The challenge for us was to develop a catalytic version of
these reactions and to obtain stereocontrol exclusively via
the use of a chiral catalyst. In this way, possibly the cis and
trans diastereoisomers can selectively be formed, simply by
choosing the appropriate catalyst.
The key question was: is the stereochemistry of the second
addition in¯uenced by the presence of the asymmetric
centre in the cyclohexenone or is it controlled by the chiral
catalyst?12 The results of these experiments might give us
valuable information on the behaviour of the chiral phos-
phoramidite catalyst and the mechanism involved in our
copper-catalysed conjugate additions.
Recently, we developed a highly ef®cient catalytic route to
enantiomerically pure cyclohexenones,11 using the Cu-
phosphoramidite catalysed asymmetric conjugate addition
of dialkylzinc reagents to cyclohexadienones. For instance,
3-ethyl-4,4-dimethoxycyclohexenone 2 is obtained in 76%
Furthermore, it is important to know whether the cis- and
trans-disubstituted products can be formed selectively.
2. Results and discussion
2.1. Conjugate addition to ethyl-cyclohexenone-acetal 2
Conjugate addition of Et2Zn to 4,4-dimethoxycyclohexa-
dienone 1 using the in situ prepared catalyst from
Cu(OTf)2 and the (S,R,R) enantiomer of Lp-1 (1:2 ratio,
2 mol%) yielded the product 2 in 97% e.e. and 76% yield
(Scheme 3). After work-up and puri®cation, a second conju-
gate addition of Et2Zn using the same enantiomer of the
catalyst gave the 3,5-disubstituted cyclohexanone 5 in a
trans/cis ratio of 96:4 in 77% isolated yield, which is in
²
accordance with expectation (Scheme 4). Using the same
enantiomer of 2 as substrate and using the enantiomer of
²
Unfortunately, we were not able to determine the e.e's of the diadducts.
However, it may be deduced from the enantioselectivity in the ®rst step
that trans-5a will have an e.e. of 97% (cis is meso).
Scheme 3.

R. Imbos et al. / Tetrahedron 57 (2001) 2485±2489
2487
Scheme 5.
Lp-1 (e.g. R,S,S), the products were formed in a trans/cis
ratio of 5:95 (yield 72%).
These results show that the chirality of the catalyst nearly
completely governs the stereochemical outcome of the
reaction and that there is apparently no interaction of the
catalytically active species with the 5-substituent of
the optically active cyclohexenone 2 (a 1,3-diaxial effect
plays no signi®cant role).
Scheme 6.
Lp-1, (i.e. R,S,S) afforded the cis-diadduct 6b with .98%
selectivity, as was expected. However, the conjugate
addition using the S,R,R enantiomer of Lp-1 afforded
the trans-diadduct 6a selectively (98% trans, 2% cis)
(Scheme 6).
²
This leads to the pleasant feature that the optically active
trans- and meso cis-di-adducts 5a and 5b can be made with
high selectivity and independently, simply by changing the
chirality of the ligand in the second conjugate addition step.
This means that in the second conjugate addition there is no
directing effect of the alkoxy moiety or the ethyl group at the
stereocenter at C-5. Again the stereocontrol in the second
addition is governed by the chirality of the catalyst and the
stereocenter already present in 4 as well as the alkoxy-
substituent plays a negligible role. Therefore, both the cis-
and trans-diadduct can be selectively made, depending on
the enantiomer of the chiral ligand used.
Conjugate addition of Et2Zn on racemic 5-ethyl-4,4-
dimethoxycyclohexenone using the (S,R,R)-enantiomer of
the catalyst afforded the product in a cis/trans ratio of
55:45 (Scheme 5) which is nearly the expected 1:1 ratio.
This provides additional support for the notion that the
stereocontrol is mainly governed by the chirality of the
catalyst and that the stereogenic centre already present
plays only a minor role.
2.3. Conjugate addition using a racemic ligand
2.2. Conjugate addition to ethyl-cyclohexenone ether 4
To further test the hypothesis that the stereoselectivity in the
conjugate addition depends only on the nature of the chiral
catalyst and not on the stereochemistry of the chiral cyclo-
hexenone, two more experiments were performed. Racemic
dimethylamine-substituted phosphoramidite (Lp-2) was
used as the ligand and conjugate additions of Et2Zn to
both enantiomerically pure and racemic 2 were performed.
We have shown that the copper-Lp-1 (S,R,R) catalysed
conjugate addition of diethylzinc to 4-methoxy-4-methyl-
cyclohexadienone 3 proceeds with a diastereomeric ratio
³,11a
of 90/10, where the major isomer is the syn-product 4.
(Scheme 3) The e.e. of the major isomer was 97%. The
diastereoselectivity was attributed to the syn-directing effect
of the alkoxy moiety.13
In both cases the diadduct 5 was obtained in a trans/cis ratio
of 70:30. The fact that in both cases the ratio is the same also
indicates that the 5-ethyl has no interaction with the cata-
lytic active species (Scheme 7).
Like 2, mono-adduct 4 still contains an enone functionality
and therefore may also be subjected to a second conjugate
addition, resulting in cyclohexanones with 3 consecutive
stereocenters. The question that arises in this case is: does
the alkoxy-moiety have a directing effect in the second
conjugate addition of diethylzinc or is it possible to synthe-
sise the trans- and cis-adducts 6a and 6b selectively and
independently?
Finally, a conjugate addition experiment using enantio-
merically pure syn-4 and racemic Lp-2 was performed.
The outcome was in accordance with expectation: the
product 6 was formed in a trans/cis ratio of 70:30, so in
this case an excess of trans-diadduct is formed. This means
that there indeed is no directing effect of the methoxy
moiety. Because the C-5 ethyl group in 4a also has no
directing effect (vide infra) and the racemic complexes are
much less reactive, the ratio must be mainly due to the steric
bulk of the methoxy group relative to the methyl group.
In order to perform these reactions and examine the stereo-
selectivity in the second catalytic 1,4-addition the syn-
mono-adduct 4a was separated from its diastereoisomer
by column chromatography and the single diastereoisomer
(100% syn) 4a was used as a starting material for the
following experiments.
3. Conclusion
A conjugate addition of Et2Zn to 4a using the enantiomer of
In the copper-Lp-1 catalysed conjugate addition of Et2Zn to
4,4,5-trisubstituted cyclohexenones a C-5 ethyl substituent
³
This means syn with respect to the methoxy substituent.

2488
R. Imbos et al. / Tetrahedron 57 (2001) 2485±2489
Scheme 7.
4.2. General procedure for the conjugate addition of
diethylzinc to 4,4-disubstituted-5-ethyl-cyclohex-2-
enone employing a chiral catalyst derived from
Cu(OTf)2 and a phosphoramidite
A solution of Cu(OTf)2 (0.010 mmol) and 0.023 mmol of a
phosphoramidite in 5 mL of freshly distilled toluene was
stirred under an argon atmosphere at ambient temperature
for 1 h. The mono-adduct (0.5 mmol) was added, the
mixture was cooled to 2208C and 1.1 equiv. of diethylzinc
in toluene (1.1 M) was added. Stirring was continued at
2208C for 16 h. Conversion was determined by TLC.
After complete conversion, the reaction mixture was poured
in 25 mL of 1 M NaOH and extracted three times with
diethyl ether (60 mL). The combined organic layers were
dried with brine (25 mL) and Na2SO4, ®ltered and evapo-
rated to yield the crude 1,4-adduct. The products were
puri®ed by column chromatography (hexane/EtOAcˆ9/1);
Figure 2.
has no effect on reactivity or selectivity. It also has been
shown that in contrast to the ®rst conjugate addition, there is
no directing effect of a 4-methoxy moiety during the second
conjugate addition. Therefore, only the stereochemistry of
the chiral ligand is of importance for the stereochemical
outcome of the reaction (Fig. 2).
The cis- or trans-diadducts can be synthesised in two steps
with high diastereoselectivity starting from prochiral
dienones, resulting in cyclohexanones with two or three
stereocenters and with high enantiomeric purity (up to
97%). The sequential catalytic 1,4-addition provides
¯exible methodology that is of importance for the synthesis
of natural products.
1
the cis/trans ratios were determined by H NMR.
4.2.1. trans-3,5-Diethyl-4,4-dimethoxycyclohexanone (5a).
Isolated yield 77%. 1H NMR d 0.84 (t, Jˆ7.3 Hz, 6H), 1.01
(m, 2H), 1.75 (m, 4H), 1.95 (m, 2H), 2.10 (dd, Jˆ5, 1 Hz,
2H), 3.26 (s, 6H). 13C NMR d 12.69 (q), 22.48 (t), 42.06 (d),
43.89 (q), 49.80 (q),101.46 (s), 211.34 (s). HRMS calcd for
C12H22O3 214.157, found 214.157.
4. Experimental
4.1. General
4.2.2. cis-3,5-Diethyl-4,4-dimethoxycyclohexanone (5b).
1
Isolated yield 72%. H NMR d 0.82 (t, Jˆ7.5 Hz, 6H),
Toluene was distilled from sodium and dichloromethane,
Et2O and hexane were distilled from P2O5. All solvents
were stored under nitrogen. Cu(OTf)2 and Et2Zn (1.1 M in
toluene) were purchased from Aldrich. Phosphoramidites
and cyclohexenones 2 and 4 were synthesised analogously
to a procedure previously reported.11 All reactions were
carried out under an argon atmosphere using dried glass-
ware. Column chromatography was performed using: silica
gel Merck Type 9385, 230±400 mesh, TLC was performed
on silica gel 60, Merck, 0.25 mm. Mass spectra (HRMS)
1.05 (m, 2H), 1.62 (m, 2H), 2.08 (m, 2H), 2.11 (d, Jˆ
10 Hz, 2H), 2.61 (dd, Jˆ12, 4.5 Hz, 2H), 3.15 (s, 3H),
3.21 (s, 3H). 13C NMR d 13.32 (q), 22.07 (t), 41.38 (d),
43.92 (t), 47.66 (q), 49.78 (q), 101.77 (s), 211.87 (s).
HRMS calcd for C12H22O3 214.157, found 214.154.
4.2.3. trans-3,5-Diethyl-4-methyl-4-methoxycyclohexa-
1
none (6a). Isolated yield 81%. H NMR d 0.80 (t, Jˆ
7.7 Hz, 3H), 0.86 (t, Jˆ7.2 Hz, 3H), 0.91 (m, 2H), 1.21 (s,
3H), 1.38±1.55 (m, 3H), 1.95 (m, 1H), 2.07 (dd, Jˆ15.1,
4.2 Hz, 1H), 2.54 (m, 2H), 2.55 (dd, Jˆ15.1, 4.3 Hz, 1H),
3.16 (s, 3H). 13C NMR d 10.32 (q), 10.99 (q), 18.02 (t),
19.94 (t), 21.09 (q), 39.25 (d), 40.18 (d), 42.74 (t), 42.97
were obtained on an AEI MS-902. H NMR and 13C NMR
1
(CDCl3) (300 MHz): d in ppm (dˆ7.2 ppm) for protons and
(dˆ77 ppm) for carbon atoms.

R. Imbos et al. / Tetrahedron 57 (2001) 2485±2489
2489
(c) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis, Vol. 9; Pergamon: Oxford, 1992.
(t), 46.82 (q), 74.87 (s), 210.95 (s). HRMS calcd for
C12H22O2 198.162, found 198.162.
6. Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 1269±
1272.
4.2.4. cis-3,5-Diethyl-4-methyl-4-methoxycyclohexanone
(6b). Isolated yield 76%. 1H NMR d 0.80 (t, Jˆ7.3 Hz, 6H),
1.11 (m, 2H), 1.27 (s, 3H), 1.40 (m, 2H), 1.77 (m, 2H), 2.34
(m, 4H), 3.28 (s, 3H). 13C NMR d 10.92 (q), 16.33 (q), 21.66
(t), 40.42 (t), 48.96 (d), 51.51 (q), 74.52 (s), 211.82 (s).
HRMS calcd for C12H22O2 198.162, found 198.163.
7. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
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Acknowledgements
Financial support from The Netherlands Organisation
for Scienti®c Research (NWO-CW) is gratefully acknowl-
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