Highly enantioselective catalytic conjugate additions to cyclohexadienones

Article abstract of DOI:10.1021/ol990707u

(Matrix presented) Enantioselective copper phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents (R₂Zn) to several 4,4-disubstituted cyclohexadienones was achieved with dr's up to 99/1 and ee's up to 99%.

Full text of DOI:10.1021/ol990707u

ORGANIC
LETTERS
1999
Vol. 1, No. 4
623-625
Highly Enantioselective Catalytic
Conjugate Additions to
Cyclohexadienones
Rosalinde Imbos, Mirjan H. G. Brilman, Mauro Pineschi, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
feringa@chem.rug.nl
Received June 3, 1999
ABSTRACT
Enantioselective copper phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents (R Zn) to several 4,4-disubstituted cyclohexa-
2
dienones was achieved with dr’s up to 99/1 and ee’s up to 99%.
Organocopper compounds are among the most widely used
reagents for C-C bond formation by virtue of their versatility
in conjugate addition reactions.1 Considerable progress has
been made in the enantioselective copper-catalyzed 1,4-
addition to prochiral enones, and this method offers an
attractive way to form enantiomerically enriched â-substi-
tuted carbonyl compounds.2 Recently, we reported a novel
chiral Cu(OTf)2-phosphoramidite catalyst based on ligand
L*-1 (for L*-1 see Figure 1) which allowed for the first time
highly enantioselective catalytic conjugate addition of several
(functionalized) dialkylzinc reagents to cyclic R,â-unsaturated
ketones.3,4
(1) For an excellent review on recent progress in organocopper chemistry,
see: Krause, N., Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186.
(2) (a) Krause, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 283. (b)
Kno¨bel, A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 1429. (c) Nakagawa,
Y.; Kanai, M.; Nagaoka, Y.; Tomioka, K. Tetrahedron 1998, 54, 10295.
(d) Yan, M.; Yang, L.-W., Wong, K.-Y.; Chan, A. S. C. Chem. Commun.
1999, 11. (e) Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney,
P. Tetrahedron Lett. 1998, 39, 7869. (f) Rossiter, B. E.; Swingle, N. M.
Chem. ReV. 1992, 92, 771. (g) Feringa, B. L.; De Vries, A. H. M. In
AdVances in Catalytic processes, Vol. 1; Doyle, M. D., Ed.; JAI Press:
Connecticut, 1995; p 151.
Figure 1. Phosphoramidite used as chiral ligand in the Cu-
catalyzed 1,4-addition of R2Zn.
(3) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.
(4) Highly enantioselective rhodium-catalyzed asymmetric 1,4-addition
of aryl- and alkenylboronic acids to enones has been reported by Hayashi
et al.: Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998,
120, 5579.
Enantioselective annulations via a 1,4-addition-aldol
cyclization protocol, employing functionalized organozinc
reagents, were also achieved with this catalyst.5
Cyclohexadienones are attractive substrates for conjugate
additions as the chiral products may be subject to further
(5) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J.
Am. Chem. Soc. 1999, 121, 1104.
10.1021/ol990707u CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/15/1999

1,4-additions or may be employed in asymmetric cyclo-
additions. Furthermore, this class of compounds has hardly
been explored in enantioselective catalysis and the highly
symmetric nature offers a critical test for any chiral catalyst.
Here we wish to report the use of the Cu(OTf)2-phosphor-
amidite (L*-1) system in the catalytic conjugate addition of
dialkylzinc reagents to several symmetric 4,4-disubstituted
cyclohexadienones resulting in a short route to optically
active cyclohexenones.
The 4,4-disubstituted cyclohexadienones are highly ver-
satile benzoquinone equivalents6 due to their multifunctional
nature. Several elegant methods have been reported to obtain
chiral synthons based on 4,4-disubstituted cyclohexadi-
enones; most of these approaches involve the temporary
conversion to tricyclic adducts which are obtained in optically
active form, either by diastereoselective [4 + 2]-cycloaddi-
tion using a chiral cyclopentadiene,7a via desymmetrization
of meso-tricycloadducts with the aid of lipase7b or by using
Rh(I)(BINAP) catalysis.7c
Conjugate additions reactions of for example alkyllithium
reagents,8a dimethylmalonate,8b and acyl-nickel complexes8c
to 4,4-disubstituted cyclohexadienones have been reported,
but none of these are catalytic or enantioselective. To our
knowledge the only catalytic enantioselective conjugate
addition to 4,4-disubstituted cyclohexa-2,5-dienones was
reported by Iwata et al.9 which involved Cu-catalyzed
addition of trimethylaluminum to afford 3,4,4,5-tetrameth-
ylcyclohex-2-enone with ee’s up to 68%.10
Scheme 1b). Will the chiral catalyst based on L*-1 be able
to distinguish Re/Si faces and pro-R/pro-S positions in these
highly symmetric dienones? Since the 4,4-disubstituted
cyclohexadienones can be easily prepared in one step from
the corresponding phenols10,11 Scheme 1 represents an
attractive route for the preparation of chiral multifunctional
synthons in just two steps from phenols.
To investigate the behavior of the novel catalytic system
in the conjugate addition of R2Zn to these cyclohexadienones
and the influence of the substituents on product ratio and
ee, cyclohexadienones 2-6 and 13-16 with different C-4
substituents were examined.
All reactions were performed under Ar on a 1 mmol scale
at -30 °C. The catalyst was prepared in situ by stirring 2.0
mol % of Cu(OTf)2 and 4 mol % of L*-1 in 5 mL of dry
toluene for 30 min and at -30 °C substrate (1.0 equiv) and
1.2 equiv of R2Zn were added sequentially. After 24 h, the
reaction mixture was quenched with water or diluted NH4-
Cl solution and the product was immediately extracted with
diethyl ether. Workup had to be performed fast to avoid
aromatization of the 1,4-adduct to the corresponding 3-alkyl-
4-alkoxy- or 3,4-dialkylphenols. After column chromatog-
raphy (SiO2, hexane/EtOAc, 5/1) the pure cyclohexenones
(7-12 and 17-20) were obtained. The results are sum-
marized in Tables 1 and 2.
Table 1. Conjugate Addition of R2Zn to Symmetrical
Cyclohexadienones, Catalyzed by Cu(OTf)2-L*-1
Conjugate addition to symmetric dienones results in
desymmetrization of the prochiral dienone moiety (Scheme
1). Side selective addition affords a single stereocenter in
Scheme 1
yielda eeb
entry dienone
R1
Me
Et
-CH2CH2-
-CH2CH2CH2-
R1
Me
R
1,4-adduct
(%) (%)
1
2
3
4
5
6
2
3
4
5
6
2
Et
Et
Et
Et
7
8
9
10
11
12
65
59
68
62
75
76
97
92
92
89
85
99
Et
-CH2C(Me)2CH2- Et
Me Me Me
a Isolated yield. b Ee values of 7-12 were determined by GC (see
Supporting Information); no 1,2-adducts were observed.
The conjugate addition of Et2Zn to cyclohexadienone
monoacetals with R1 ) R2 (2 and 3) proceeded with high
case the 4,4-substituents are equal, i.e., Re versus Si face
attack of the organometallic reagent (side selectivity; Scheme
1a). When the substituents at the 4-position are different, Si
or Re face selective attack gives rise to the formation of two
stereocenters in a single step (side and face selectivity;
(8) (a) Stern, A. J.; Rhode, J. J.; Swenton, J. S. J. Org. Chem. 1989, 54,
4413. (b) Torii, S.; Hayashi, N.; Kuroboshi, M. Synlett 1998, 599. (c)
Semmelhack, M. F.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W. J. Org.
Chem. 1985, 5567.
(9) Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Iwata, C. Tetrahedron:
Asymmetry 1996, 7, 993.
(6) Swenton, J. S. The chemistry of quinoid compounds; Rappoport, Z.,
Patai, S., Eds.; John Wiley: New York, 1988; Vol. 2, Part 2, p 899.
(7) (a) Jones, P. G.; Weinmann, H.; Winterfeldt, E. Angew. Chem., Int.
Ed. Engl. 1995, 34, 448. (b) Takano, S.; Moriya, M.; Higashi, Y.;
Ogasawara, K. Chem. Commun. 1993, 177. (c) Kamikubo, T.; Hiroya, K.;
Ogasawara, K. Tetrahedron Lett. 1996, 37, 499.
(10) Diastereoselective conjugate additions of trimethylaluminum to [(p-
tolylsulfinyl)methyl]quinols have been reported: Pirrung M. C., Nunn D.
S. Tetrahedron Lett. 1992, 33, 1992.
(11) (a) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc., Perkin Trans. 1
1993, 1891. (b) Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem.
1987, 52, 3927.
624
Org. Lett., Vol. 1, No. 4, 1999

Table 2. Conjugate Addition of Et2Zn to 4,4-Disubstituted Cyclohexadienones with R1 * R2, Catalyzed by a Cu(OTf)2-L*-1
Complex
entry
dienone
R1
R2
1,4-adduct
yield (%)a
drb
ee major (%)b
ee minor (%)b
1
2
3
4
13
14
15
16
OMe
OMe
CH2CH2CH2O
OMe
Me
CH2Ph
17
18
19
20
60
53
66
58
90/10
97/3
99/1
1/1
97
93
65
98
85
ndc
ndc
98
OCH2Ph
a Isolated yield; no 1,2 adducts were detected. b Dr and ee determination for 17 and 18 could not be directly performed by either GC or HPLC. Hydrogenation
of the double bonds afforded products which could be separated by HPLC, Daicel AS column. Dr and ee determination of 19 and 20 was performed by
HPLC, Daicel AS column. (see Supporting Information for details). c Not determined.
enantioselectivity (Table 1, entries 1 and 2): for instance,
3-ethyl-4,4-dimethoxycyclohexenone (7) with an ee of 97%
was isolated. When the methoxy substituents are replaced
by the larger ethoxy groups, the ee of the enone 8 dropped
to 92%; probably this is due to some steric interference.
When cyclic acetals are used, it is interesting to notice
that the ee drops from 92% to 85% with an increase of ring
size and the bulk of substituents (Table 1, entries 3-5).
Cyclohexadienone-ethylene glycol monoacetal (4) gave a
slightly lower enantioselectivity in the 1,4-addition compared
to dimethoxy dienone 2 (92 vs 97% ee). Probably this is
due to the rigidity of the ethylene glycol acetal and not the
result of a difference in size. Conjugate addition of Me2Zn
to dimethoxycyclohexadienone 2 affords the 1,4-adduct 12
with a rewarding 99% enantiomeric excess.
Since the acetal moiety might have a coordinating effect
to the chiral Cu catalyst, it is interesting to know what the
stereochemical result of the conjugate addition of Et2Zn
would be in the case of 4,4-disubstituted cyclohexadienones
with only one alkoxy moiety attached to the cyclohexadi-
enone. The introduction of two different substituents at C-4
will give rise to the formation of two stereogenic centers as
depicted in Scheme 1. It is interesting to elucidate if this
substitution pattern leads to a high diastereoselectivity and
a considerable enantioselectivity for both diastereoisomers
and if the stereoselectivity only depends on the size of the
C-4 substituents.
one diastereoisomer of adduct 18 is observed (dr 97/3) with
an ee of 93% for the major diastereoisomer. When the alkoxy
and alkyl substituent are linked as in spiro dienone 15, a
high diastereoselectivity (dr 99/1) in the formation of adduct
19 is observed. The ee of the major diastereoisomer was,
however, only 65%. NOESY experiments indicated that in
the cyclohexenones 17-19 the ethyl substituent was intro-
duced cis to the alkoxy group in the major isomer.12
The origin of the observed diastereoselectivity could be a
steric effect or coordination of the oxygen of the alkoxy
moiety to the catalytic species. The conjugate addition of
diethylzinc was therefore performed with cyclohexadienone
16, which contains two alkoxy substituents of different sizes.
Adduct 20 was obtained as a 1:1 mixture of the two possible
diastereoisomers, but much to our delight both isomers were
nearly enantiomerically pure (ee 98%). It is therefore likely
that the oxygen of the acetal or alkoxy substituent interacts
with the metal complex and therefore exerts a directing effect
on the activated organometallic species in the copper-
catalyzed enantioselective conjugate addition of dialkylzinc
reagents to 4,4-disubstituted cyclohexadienones.
In conclusion the copper-phosphoramidite chiral catalyst
shows remarkably high levels of stereoselectivity in the 1,4-
addition to symmetric dienones. On the basis of this finding,
a new catalytic method was developed to prepare several
multifunctional cyclohexenones with high dr and high ee.
The 1,4-additions to substrates 13-16 reveal that for
cyclohexadienone 13 with one MeO and one Me substituent
the formation of a mixture of two diastereoisomers of 17
occurs. The diastereomeric ratio was 9/1, and the ee’s of
the major and minor product are 97% and 85%, respectively
(see Table 2).
Acknowledgment. Financial support from The Nether-
lands Foundation of Scientific Research is gratefully ac-
knowledged.
Supporting Information Available: Standard procedure
for conjugate addition of R2Zn reagents to cyclohexadi-
enones, spectroscopic data for 1,4-adducts 7-12 and 17-
20, and NOESY interactions for 17-19. This material is
available free of charge via the Internet at http://pubs.acs.org.
In the case of cyclohexadienone 14, with the methoxy
substituent and a substantially larger benzyl group, nearly
(12) A cis-directing effect of the methoxy substituent in the organoalu-
minum mediated conjugate addition of RLi and RMgBr to quinol ethers
has been observed, see ref 8a.
OL990707U
Org. Lett., Vol. 1, No. 4, 1999
625