Enantioselective copper-catalyzed conjugate addition to trisubstituted cyclohexenones: Construction of stereogenic quaternary centers

Article abstract of DOI:10.1002/anie.200462137

Trimethyl- and triethylaluminum undergo enantioselective conjugate addition to 3-and 2-substituted cyclohexenones in the presence of catalytic amounts of a Cu salt and a phosphoramidite ligand L* (see scheme). Thus, chiral quaternary centers can be built with up to 96.6% ee. Functionalized enones lead to bicyclic structures by a subsequent aldol reaction.

Full text of DOI:10.1002/anie.200462137

Communications
Asymmetric Synthesis
Enantioselective Copper-Catalyzed Conjugate
Addition to Trisubstituted Cyclohexenones:
Construction of Stereogenic Quaternary
Centers**
Magali dꢀAugustin, Laꢁticia Palais, and
Alexandre Alexakis*
Asymmetric conjugate addition has received increasing
interest during the last few years, and excellent results have
been obtained, particularly for Cu-[1] and Rh-catalyzed[2]
reactions. However, one of the main drawbacks of these two
systems is the lack of reactivity of b-trisubstituted enones,
thus preventing the formation of chiral quaternary centers.[3]
The Cu-catalyzed asymmetric conjugate addition of
dialkylzinc reagents has been successfully applied to many
substrates, including cyclic[4] and acyclic enones,[4a,b,5] lac-
tones[6] or lactams,[7] nitro olefins,[4b,8] amides,[9] and malo-
nates.[10] However, whatever the Michael acceptor, all reac-
tions with b-trisubstituted substrates failed, probably for
steric reasons. Some examples of enantioselective addition of
trialkylaluminum reagents have also been described for
cyclic[11] and acyclic enones,[12] and nitro olefins.[13] We
reasoned that the stronger Lewis acidity of Al would effect
a better activation of the substrate than Zn, thus overcoming
the inherent steric hindrance of trisubstituted substrates. We
report here the success of this approach.
Trialkylaluminum reagents are known to undergo Cu-
catalyzed conjugate addition, even with trisubstituted
enones.[14] With these reagents stronger coordinating solvents
are used than with dialkylzinc reagents (Et2O or THF instead
of toluene or CH2Cl2) as this allows the cleavage of the AlR3
dimeric species, thus increasing its reactivity. We first
extensively optimized experimental conditions for the con-
jugate addition of AlEt3 to 3-methylcyclohexenone, and
found that the reaction proceeds to completion after 18 h at
À308C, and more rapidly at higher temperatures. Two sets of
conditions were found, the choice of which depends on the
copper salt used: Et2O is best with copper thiophene
carboxylate (CuTC), whereas THF is better with
[Cu(CH3CN)4]BF4. Although the addition of Me3SiCl has
been reported to increase the chemical yield,[15] we found that
it was detrimental in the presence of phosphorus ligands.
In a second step, we screened several biphenol- and
binaphthol-based phosphoramidite ligands. The biphenol
ligands L4 (Table 1, entries 4 and 17) and, particularly, L7
(Table 1, entry 10) afforded the best results in terms of
enantioselectivity, whatever the solvent (up to 96.6% ee). In
Table 1: Addition of AlEt3 to 3-methyl-2-cyclohexenone in the presence of
various ligands.
Entry CuX
Ligand Solvent Conv. [%] ee [%] Config.[a]
1
2
3
4
5
6
7
8
CuTC
L1
L2
L3
L4
L4
L4
L4
L5
L6
L7
L8
L9
L10
L11
Et2O
Et2O
Et2O
Et2O
Et2O[b]
82
84
46
77
85
62
62
88
94
90
88
94
93
78
96.6
72
62
74
16
77
88
94
66
n.d.[d]
84
2
R
S
S
R
R
R
R
R
S
R
R
S
R
S
R
S
R
R
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
[Cu(CH3CN)4]BF4 L1
[Cu(CH3CN)4]BF4 L3
[Cu(CH3CN)4]BF4 L4
[Cu(CH3CN)4]BF4 L4
[Cu(CH3CN)4]BF4 L7
[Cu(CH3CN)4]BF4 L8
[Cu(CH3CN)4]BF4 L9
Et2O[c] >95
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
Et2O
THF
THF
THF
15
91
89
>95
82
51
>95
>95
76
46
64
9
10
11
12
13
14
15
16
17
18
19
20
21
7
<5
66
R
S
65
[a] Product configuration. [b] Reaction was carried out at À258C.
[c] Reaction was carried out at À158C. [d] n.d.=not determined.
general, the conversions are higher in Et2O than in THF,
although the enantioselectivity is unaffected. Raising the
reaction temperature increases the conversion at the cost of a
small drop in enantioselectivity (Table 1, entries 4, 5, and 6)
from 94% to 88% ee at À158C. The binaphthol ligands L8,
L9, L10, and L11 are less efficient. It should be noted that
[*] M. d’Augustin, L. Palais, Prof. Dr. A. Alexakis
Department de chimie organique, Universitꢀ de Genꢁve
30 quai E. Ansermet, 1211 Genꢁve 4 (Switzerland)
E-mail: alexandre.alexakis@chiorg.unige.ch
there is
a strong matched/mismatched effect (Table 1,
[**] The authors thank Stephane Rosset for help, the Swiss National
Research Foundation (no. 20-068095.02), and COST action D24/
0003/01 (OFES contract no. C02.0027) for financial support, and
BASF for a generous gift of chiral amines.
entries 13/14 and 20/21), and that the absolute configuration
of the product is dictated by the binaphthol part of the ligand.
In the next step we screened various 3-substituted cyclo-
hexenones (Table 2), which can be easily prepared by a simple
protocol from commercially available 3-ethoxycyclohex-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1376
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462137
Angew. Chem. Int. Ed. 2005, 44, 1376 –1378

Angewandte
Chemie
Table 2: Addition of AlMe3 to various 3-substituted cyclohexenones.
Scheme 2. Subsequent hydrolysis of adduct 12 yields the R-configured
bicyclic enone 13.
Entry Substrate Ligand Adduct Conv. [%][a] ee [%] Config.[b]
1
2
3
4
5
6
7
8
9
3
3
4
4
7
7
9
9
L4
L7
L4
L7
L4
L7
L4
L7
L4
2
2
5
5
8
>95 (78)
84
35
42
>95
94
96
93
93
91
95
93
95
S
S
R
R
R
R
S
S
R
trend. Scheme 2 also illustrates an aspect of the synthetic
potential of the above conjugate addition, as such an intra-
molecular aldol condensation might be applied to the
construction of other bicyclic structures.
8
>95 (80)
>95
10
10
12
>95 (76)
In addition to 3-substituted cyclohexenones, the 2-sub-
stituted analogues are known to be difficult substrates for
asymmetric conjugate addition.[1] The present method allows
such an extension, again with high yield and good enantio-
selectivity (84% ee for the trans isomer and 91% ee for the cis
isomer; Scheme 3). The mixture of cis and trans isomers of 15
could be equilibrated (DBU, MeOH, room temperature,
20 h) to trans/cis ratio of 80:20. The trans isomer could be
isolated in a pure form. The absolute configuration[17] (2S,3R)
shows that the face selectivity remains the same as usual.
11
>95 (81)[c] 95
[a] Yield of isolated product in parentheses. [b] Product configuration:
R/S notation may change according to the CIP priority rules. [c] 5 mol%
CuTC and 10 mol% L4.
enone (Scheme 1). The addition of AlMe3 to 3-ethylcyclo-
hexenone 3 afforded excellent yields and enantioselectivities,
which reached 96% ee with L7 (Table 2, entry 2). As
expected, the absolute configuration of the adduct 2 is
Scheme 3. Conjugate addition to 2-substituted cyclohexenones.
In summary, we have discovered a new way to build chiral
quaternary centers[18] that allows the straightforward con-
struction of chiral building blocks for more elaborate natural
products.
Scheme 1. Preparation of 3-substituted cyclohexenones.
Received: September 28, 2004
Revised: November 9, 2004
Published online: January 21, 2005
opposite to that given in Table 1 (entry 10), thus showing
that the face selectivity of the addition remains the same.
Although the enantioselectivity remained high (93% ee)
(Table 2, entries 3 and 4), the addition of AlMe3 to 3-
isobutylcyclohexenone 4 proceeded with lower conversion
owing to the increased steric demand. In this respect,
isophorone 6 did not give any adduct, whereas substrates 7
and 9, both of which contain a remote double bond, gave
excellent yields and enantioselectivities (91 and 93% ee,
respectively, with L4; Table 2, entries 5–8). Finally, an acetal
functionality on 11 is tolerated, again with high yield and
enantioselectivity (95% ee, Table 2, entry 9).
The absolute configuration of the conjugate adducts was
determined by chemical correlation with a known compound.
Thus, adduct 12, bearing an acetal functionality, was hydro-
lyzed and cyclized in situ to afford the bicyclic enone 13 in
68% yield (Scheme 2). The negative optical rotation (À74.6,
c = 1.53, CHCl3) corresponds to the R configuration of 13.[16]
It is assumed that all adducts listed in Table 2 follow the same
Keywords: aluminum · asymmetric catalysis · conjugate
.
addition · enones · phosphoramidite ligands
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[18] Typical procedure: A flame-dried Schlenk tube was charged with
CuTC (3.9 mg, 2.0 mol%) and L4 (19.8 mg, 4.0 mol%). Diethyl
ether (2.0 mL) was then added and the mixture was stirred at
room temperature for 30 min before being cooled to À308C.
Trimethylaluminum (1.0 mL of
a 2m solution in heptane,
2.0 equiv) was added dropwise at such a rate that the temper-
ature did not rise above À308C, and the reaction mixture was
stirred at À308C for a further 5 min before enone 3 (124.1 mg,
1.0 mmol) in diethyl ether (0.5 mL) was added dropwise. Once
the addition was complete the reaction mixture was held at
À308C overnight. The reaction was quenched at À308C by
addition of MeOH (0.5 mL) and then water. Workup followed
by flash chromatography afforded the product as a colorless oil
(109.4 mg, 78% yield). Chiral GC analysis (LipodexE) showed
an enantiomeric excess of 94% ee.
1378
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 1376 –1378