Formation of quaternary stereogenic centers by copper-catalyzed asymmetric conjugate addition reactions of alkenylaluminums to trisubstituted enones

Article abstract of DOI:10.1002/chem.201302856

Alkenylaluminums undergo asymmetric copper-catalyzed conjugate addition (ACA) to β-substituted enones allowing the formation of stereogenic all-carbon quaternary centers. Phosphinamine-copper complexes proved to be particularly active and selective compared with phosphoramidite ligands. After extensive optimization, high enantioselectivities (up to 96 % ee) were obtained for the addition of alkenylalanes to β-substituted enones. Two strategies for the generation of the requisite alkenylaluminums were explored allowing for the introduction of aryl- and alkyl-substituted alkenyl nucleophiles. Moreover, alkyl-substituted phosphinamine (SimplePhos) ligands were identified for the first time as highly efficient ligands for the Cu-catalyzed ACA. Chiral synthesis made easy: The copper-catalyzed conjugate addition of alkenylaluminum reagents to 3-substituted cyclic enones allows for the formation of all-carbon chiral quaternary centers (see scheme; CuTC=copper(I) thiophene-2-carboxylate). Chiral phosphinamine (SimplePhos) ligands were found to be highly efficient for this transformation.

Full text of DOI:10.1002/chem.201302856

FULL PAPER
DOI: 10.1002/chem.201302856
Formation of Quaternary Stereogenic Centers by Copper-Catalyzed
Asymmetric Conjugate Addition Reactions of Alkenylaluminums to
Trisubstituted Enones
Daniel Mꢀller and Alexandre Alexakis*[a]
Abstract: Alkenylaluminums undergo
asymmetric copper-catalyzed conjugate
addition (ACA) to b-substituted
enones allowing the formation of
high
enantioselectivities
(up
to
tion of the requisite alkenylaluminums
were explored allowing for the intro-
duction of aryl- and alkyl-substituted
alkenyl nucleophiles. Moreover, alkyl-
substituted phosphinamine (Simple-
Phos) ligands were identified for the
first time as highly efficient ligands for
the Cu-catalyzed ACA.
96% ee) were obtained for the addition
of alkenylalanes to b-substituted
enones. Two strategies for the genera-
stereoACHTUNGTRENNUNGgenic all-carbon quaternary cen-
ters. Phosphinamine–copper complexes
proved to be particularly active and se-
lective compared with phosphoramidite
ligands. After extensive optimization,
Keywords: aluminum · asymmetric
synthesis
copper · phosphorous
· conjugate addition ·
Introduction
Asymmetric synthesis of all-carbon quaternary stereogenic
centers presents a significant challenge in organic synthesis
and has attracted much interest over the last decade.[1] One
of the many synthetic solutions disclosed in the literature
are rhodium and copper-catalyzed asymmetric conjugate ad-
dition (ACA) using organometallic reagents.[2] To overcome
the steric repulsion present in these addition reactions, sev-
eral strategies were envisaged, such as substrate activation
by electron-withdrawing substituents or Lewis acid activa-
tion and enhancement of the nucleophilicity of the nucleo-
phile by use of Grignard reagents or strongly electron-
Scheme 1. Reported protocols of the copper-catalyzed ACA of
alkenylalanes to 3-methylcyclohex-2-enone S1.
A
Furthermore, Hoveyda and co-workers very recently de-
scribed the NHC–Cu-catalyzed ACA of silyl-substituted
alkenylaluminums to various b-substituted cyclic enones af-
fording the addition products with high enantioselectivities
and good yields.[6] Finally, two recent contributions of our
group describe two methods for the introduction of a great
variety of alkenylaluminum reagents to b-substituted cyclic
enones with high enantioselectivities (Scheme 2).[7] This ac-
count will discuss in detail the two Cu-catalyzed ACA de-
picted in Scheme 2 with detailed information concerning the
optimization reactions, the nucleophile and substrate scope,
num reagents that combine nucleophilic and Lewis acidic
character were greatly explored and alkyl- as well as aryl
nucleophiles were introduced with high enantioselectivities
(up to 99% ee) to b-substituted cyclic enones.[3] Despite
their synthetic potential, only few metal-catalyzed ACA re-
actions were reported for alkenyl nucleophiles to generate
quaternary stereogenic centers. These involve additions of
alkenyl boronic acids to activated enones,[4] and single exam-
ples of ACA of alkenylaluminums generated from the corre-
sponding iodide (pathway 1, Scheme 1; 93% yield,
82% ee)[3c] and a tandem hydroalumination–Cu-catalyzed
ACA sequence (pathway 2, Scheme 1, 68% yield,
73% ee).[5]
[a] Dr. D. Mꢀller, Prof. A. Alexakis
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Genꢁve 4 (Switzerland)
E-mail: alexandre.alexakis@unige.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302856.
Scheme 2. Copper-catalyzed ACA of alkenylalanes to 3-methylcyclohex-
2-enone S1.
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as well as some insights into the mechanism of such transfor-
mations.
the aldehyde to the dibromide by the Ramirez protocol[10]
and bromine abstraction by dimethylphosphite, in the pres-
ence of triethylamine, afforded E/Z mixtures of desired al-
kenyl bromides (Table 1).[10] Heating the bromides in a solu-
tion of NaOH in isopropanol at reflux induces the elimina-
Copper-catalyzed ACA reactions employing alkenylalumi-
nums generated from the corresponding alkenyl bromides:
a,b-Unsaturated ketones used for the studies in this account
are depicted in Figure 1. Noncommercial enones S2, S3, S4,
S5, S6, S7, S9, S10, and S11 were prepared according to re-
ported procedures (see the Supporting Information).
Table 1. Multistep synthesis of various alkenyl bromides.
Entry
Bromide
t
E/Z
Yield
[%][c]
[h][a]
ratio[b]
1
2
B3
B4
1.5
1.5
85:15
92:8
70
22[d]
Figure 1. Trisubstituted a,b-unsaturated ketones studied.
3
4
B5
B6
1.5
1.5
92:8
50
29
67:33
Synthesis of alkenyl bromides: We started our investigations
concerning the Cu-catalyzed ACA employing alkenylalumi-
nums by generation of the latter from alkenyl iodides. The
previously developed protocol required a very precise tem-
perature protocol for the iodine–lithium exchange and the
transmetalation with Et2AlCl.[3c] This protocol and the fact
that only few alkenyl iodides are commercially available
made us focus our attention on alkenyl bromides, of which
many are commercially available or can be prepared in only
few steps.
5
6
B7
B8
0.75
9
67:33
57:43
33
12
[a] Time heating at reflux for the elimination step. [b] E/Z ratio after bro-
mide abstraction; determined by H NMR spectroscopy. [c] Total yield of
the pure isolated (E)-bromoolefin over three steps; not taking in to ac-
count the destruction of the (Z)-alkenyl bromide. [d] Yield not opti-
mized.
1
Simple alkyl-substituted alkenyl bromides are easily pre-
pared according to the Zweifel protocol by hydrolumination
of the alkyne followed by reaction of the alkenylalane with
a bromine electrophile such as N-bromosuccinimide (NBS)
tion of the Z isomer affording a separable mixture of the
terminal alkyne and the pure E isomer (Table 1).[11] The ab-
straction of the bromide and the elimination of the (Z)-bro-
mide were carried out on the crude mixtures. Hence, only
one purification step was required to prepare the desired
(E)-alkenyl bromides in good total yield over three steps
(see the Supporting Information). It is noteworthy that com-
pounds B4 and B5 were purified by trituration techniques,
whereas B3 and B6 were purified by distillation allowing for
a large-scale synthesis of these compounds. For compound
B3 the E/Z mixture is commercially available so that only
the elimination step had to be carried out. Compound B6 is
prone to polymerization even when stored at À408C under
argon and should be used within a few days. Unfortunately,
the reaction sequence was low yielding for the alkyl-substi-
tuted compound B8. This was due to a very low selectivity
in the abstraction step (E/Z=57:43) and the volatility of B8.
It is noteworthy that this very practical reaction sequence to
provide isomerically pure (E)-alkenyl bromides was not de-
scribed previously in the literature.
or Br2 (Eq. (1), Scheme 3).[8] Electron-rich conjugated al
ACTHNUTRGNEkUNG e-
ACHTUNGTRENNUNGnyl bromides can be prepared by a simple one-step proce-
dure described by Das and Roy.[9] Treatment of electron-
rich cinammic acid derivatives with NBS in the presence of
NEt3 afforded the corresponding b-bromostyrene B2 in an
excellent yield (Eq. (2), Scheme 3).
Conjugated, electron-neutral or -poor bromoalkenes, such
as B3–B8, have to be prepared differently. Conversion of
Optimimization of the experimental conditions: For the op-
timization of the experimental conditions for the conjugate
addition of alkenylaluminums to b-substituted enones we
Scheme 3. Synthesis of alkenyl bromides containing an alkyl group or an
electron-rich aromatic system.
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Formation of Quaternary Stereogenic Centers
FULL PAPER
chose 2-isopropenylalane A3 as nucleophile because it can
be easily prepared from commercial 2-isopropenyl bromide,
and commercially available 3-methylcyclohex-2-en-1-one S1
was chosen as the substrate. Bromine–lithium exchange of
B9 with 2 equiv of tBuLi at À788C in diethyl ether cleanly
afforded alkenyl lithium 3, which was then transmetalated
with Me2AlCl to give alane A3 (Scheme 4). Initially, the
servations with aluminum acetylides were previously made
by Corey and Kwak.[12]
It is noteworthy that nonfunctionalized alkenylalanes af-
forded comparable levels of enantioselectivity and conver-
sion when stored at room temperature over several weeks in
a tightly sealed Schlenk tube. With the optimized conditions
for the generation of the 2-isopropenylalane A3 in hand
(Scheme 4) we carried out a screening of a large number of
phosphormidite-, phosphinamine-, and ferrocene-based li-
gands for the Cu-catalyzed ACA of alane A3 to 3-methylcy-
clohex-2-enone S1 (Table 2). It has to be noted that at the
beginning of our investigations only a limited number of li-
gands displayed in Figure 2 were available. The ligands that
do not appear in Table 2 were discovered and synthesized
after the initial screening and hence only appear for the re-
action with alane A10 (Table 8) or with alane A19
(Table 14).[13]
Scheme 4. Preparation of isopropenylalane A3.
transmetalation time was carried out at À308C for 30 min as
indicated in the original protocol developed for alkenyl iodi-
des.[3c] However, nonreproducible conversions and almost
racemic products were observed when the thus-generated
alanes were subjected to the Cu-catalyzed ACA as depicted
in Table 2. After much experimentation we found that it
Table 2. Screening of various mono- and bidentate phosphorous li
ands.[a]
ACHTUNGERTNgNUNG -
ACHTUNGTRENNUNG
Entry
Ligand
Conv.
[%][b]
4/5[b]
ee
[%][c]
1
2
3
4
L28
L29
L30
L31
94
85
98
100
2
96:4
87:11
97:3
96:4
n.d.
12 (R)
5 (S)
18 (R)
32 (R)
n.d.
5
L32
6
7
8
9
10
11
12
13
(R)-BINAP
L10
L11
L12
L13
L14
L18
L22
57
98
100
70
97
98
100
100
n.d.
13 (R)
49 (R)
49 (R)
38 (R)
26 (R)
19 (R)
59 (R)
63 (R)
97:3
97:3
97:3
90:10
97:3
98:2
96:4
Figure 2. Ligands used in this study.
Several findings of the screening of ligands are notewor-
thy: 1) Phophoramidite ligands, which usually afford excel-
lent results for the addition of organozinc and organoalumi-
num reagents, resulted in relatively low enantioselectivities
(Table 2, entries 1–4); 2) Josiphos ligand L32 and (R)-
BINAP, two very powerful ligands for the copper-catalyzed
conjugate addition with trimethylaluminum, gave low con-
versions and enantioselectivities (Table 2, entries 5 and 6, re-
spectively);[14,15] 3) As previously observed by our group, the
choice of the amine moiety plays an important role for pro-
viding the products in high enantioselectivities; ligands with
[a] Reactions performed under argon on a 0.3 mmol scale; only the su-
pernatant solution of the aluminum reagent has been used; alane gener-
ated in Et2O. [b] Estimated by GC-MS. [c] Determined by chiral GC;
[d] 2.0 equiv of the alkenylaluminum reagent was used.
was important to stir 2-propenyl lithium 3 and Me2AlCl,
overnight, at room temperature to cleanly obtain alane A3
(Scheme 4). The reaction of lithium reagent 3 and MeAlCl
is probably very fast, yet we believe that the reaction instan-
taneously continues to afford alanate 4, which then slowly
equilibrates with Me2AlCl to furnish alane A3. Similar ob-
a 2-naphtyl substituted amine afford better enantiose
ACHTUNGTRENNUNGlec-
AHCTUNGTREGtNNNU ivites compared with ligands with a phenyl-substituted
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A. Alexakis and D. Mꢀller
Table 4. Screening of solvents.[a]
amine (L10 vs. L18, L12 vs. L22, and L30 vs. L31);[3c,5,16]
4) The catalyst screening studies demonstrates that phos-
phinamine ligands, in particular L22 (Table 2, entry 13) gave
the best results. Ligand L22 was recently found to be highly
efficient for the Cu-catalyzed ACA of alkyl-, alkenyl-, and
arylaluminums to trisubstituted and heterocyclic Michael ac-
ceptors.[3c,7,16,17]
Entry
Solvent
(alane)[b]
Solvent
(Cu)[c]
Conv.
[%][d]
4/5[e]
ee
U
[%][f]
1
2
3
5
Et2O
Et2O
Et2O
Et2O
Et2O
MTBE
Et2O
MTBE
Et2O
hexane
toluene
CH2Cl2
Et2O
Et2O
Et2O
MTBE
MTBE
THF
100
100
78
100
97
100
91
58
97:3
98:2
95:5
97:3
97:4
94:6
97:3
95:5
92:8
88
87
86
89
83
93
95
96
60
Evaluation of the amount of aluminum reagents used for the
Cu-catalyzed ACA: Biradar and Gau reported that the
amount of alane used had a significant impact on the enan-
tioselectivity for the addition of 2-thienylalane to 2’-aceto-
phenone.[18] These results made us consider if the number of
equivalents of alkenylaluminum A3 had an effect on the
enantioselectivity (Table 3). Surprisingly, changes in enantio-
selectivity of up to 30% ee were observed when changing
the number of equivalents of alane. Less than 2.0 equiv of
alane afforded the product in high enantioselectivity, albeit
accompanied with significant amounts of methyl-transfer
adduct 5 (Table 3, entries 5–7). In contrast, more than
6[f]
7
8
9
10
95
[a] Reactions performed under argon on a 0.3 mmol scale; only the su-
pernatant solution of the aluminum reagent was used. [b] Solvent used
for the preparation of alane. [c] Solvent used for the in situ-formation of
the chiral copper complex. [d] Estimated by GC-MS. [e] Determined by
chiral GC. [f] Alane including lithium salts added.
in situ-preparation of the copper complex; the enantioselec-
tivity significantly decreased only in the case of THF
(Table 4, entry 10). The precise reason for the lower enan-
tioselectivity is unclear but might partially be attributed to
the strongly coordinating properties of THF, which allows
for the generation of essentially monomeric aluminum spe-
cies.[19]
Table 3. Evaluation of the effect of the number of equivalents of alane
added.[a]
Entry
Alane
[equiv]
Conv.
[%][b]
4/5[b]
ee
Formation of the Cu complex in methyl tert-butyl ether
(MTBE) as the solvent gave rise to an increase in enantiose-
lectivity compared with diethyl ether, albeit with lower con-
version (Table 4; compare entries 5 and 8). Preparation of
alane A3 in MTBE gave high enantioselectivity (93% ee)
and full conversion when the Cu complex was prepared in
Et2O (Table 4, entry 7). The use of MTBE for both alane
and the Cu complex formation led to a strong drop in con-
version (Table 4; compare entries 7 and 9). The conditions
displayed in Table 4, entry 7 seemed to be ideal for the gen-
eration of alkenylaluminums but for some alkenyl bromides
we encountered solubility problems with MTBE as solvent
at À788C, and even isomerization of (Z)-alkenylaluminum
A18 (Table 7, entry 16); therefore, in many cases, Et2O was
used instead of MTBE. For all the initial studies we only
used the supernatant solutions of the alane because we were
aware that lithium salts might hamper the reaction.[3c] Addi-
tion of the alane solution including the lithium salts showed
a slightly perturbing influence on the conversion and enan-
tioselectivity of the reaction (Table 4, entry 6). To ensure
the best selectivity and conversion we continued to use only
the supernatant solution.
N
[%][c]
1
2
3
4
5
6
7
3.0
2.8
2.3
2.0
1.7
1.4
1.2
100
100
100
100
100
100
100
97:3
97:3
49
52
62
66
68
73
78
94:6
95:5
91:9
80:20
75:25
[a] Reactions performed under argon on a 0.3 mmol scale; only the su-
pernatant solution of the aluminum reagent was used; alane generated in
Et2O. [b] Estimated by GC-MS. [c] Determined by chiral GC.
2.0 equiv of the aluminum reagent led to a drop of enantio-
selectivity (Table 3, entries 1–3). This might be rationalized
by contamination of the alane with traces of lithium salts or
aluminum acetylides, which might perturb the structure of
the chiral copper complex. For all the reactions, only the su-
pernatant solutions of the alane have been used for catalysis.
Evidence of the perturbing influence of LiCl or LiBr (creat-
ed during the formation of the alane, Scheme 4) was ob-
tained when adding the alanes including lithium salts
(Table 4, entry 6).
Screening of solvents: Encouraged by the previous results,
we decided to screen several coordinating and non-coordi-
nating solvents for the copper-catalyzed ACA of propenyl-
Screening of copper salts: From previous work of copper-cat-
alyzed ACA with organoaluminums we knew that best con-
versions and enantioselectivities were usually obtained with
copper(I) thiophene-2-carboxylate (CuTC).[3c,5,16] Neverthe-
less, we tested several copper salts for their ability to pro-
mote copper-catalyzed ACA with alkenylaluminums
(Table 5).
ACHTUNGTRENNUNGalane A3 to substrate S1. The optimization was carried out
with ligand L22 instead of ligand L10 and 2.0 equiv of the
aluminum reagent (Table 4). Interestingly, the enantioselec-
tivity was only slightly affected by the solvent used for the
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Formation of Quaternary Stereogenic Centers
Table 5. Screening of the Cu salts.[a]
FULL PAPER
observation can be explained by the nature of the resulting
alkenylaluminums. For example, an excess of tBuLi gives
not only the “neutral” alane A3, but also significant
amounts of a very reactive alanate 4 (Scheme 4). Racemates
are typically afforded in the presence of chiral Cu-phosphin-
amine complexes and hence the presence of small amounts
of alanate 4 decreases the total enantioselectivity of the re-
action.[20] In the case of an excess of Me2AlCl, strong activa-
tion of the enone, or catalyst poisoning, might cause lower
enantioselectivity (Table 6, entry 2). Me2AlCl cannot be
easily titrated and the most practical way to assure the clean
generation of “neutral alane A3” is to vary the ratios be-
tween tBuLi and Me2AlCl for the alane generation, and
then to determine the best ratio for the copper-catalyzed
ACA.
Entry
CuX
Conv.
[%][b]
4/5
94:6
100:0
92:8
88:12
81:19
76:24
92:8
ee
[%][c]
1
2
3
4
5
6
7
8
CuTC
CuCN
100
54
100
92
96
80
93 (R)
32 (R)
83 (R)
78 (R)
84 (R)
64 (R)
75 (R)
85 (R)
[Cu
N
N
CuCl2
[Cu
[Cu
U
CuBr
Cu(II)naphthenate
84
100
86:14
[a] Reactions performed under argon on a 0.3 mmol scale; only the su-
pernatant solution of the aluminum reagent was used; alane generated in
MTBE. [b] Estimated by GC-MS. [c] Determined by chiral GC.
During our studies we found that the “nature” and
amount of the alane is at least as important as the right
choice of the chiral copper complex to afford full conversion
and high enantioselectivity for the Cu-catalyzed ACA with
alkenylaluminums.
Interestingly, many copper salts afforded the product with
good enantioselectivities. Only CuCN gave a relatively poor
result (Table 5, entry 2). [Cu
ACHUTGTNERN(NGU OAc)2]ACHTUTGNREN[NUGN H2O], Cu(II)naphthen-
ate, and [Cu(acac)2] (acac=acetylacetonato) afforded good
N
Scope and limitations
conversions and enantioselectivities, yet with higher levels
of methyl transfer. Hence, we continued to use CuTC as the
copper salt of choice affording high enantioselectivities and
conversion, while keeping the level of methyl transfer low.
Under the optimized conditions we found that the reac-
tion was complete within four hours. Shorter reaction times
might be expected for less-bulky nucleophiles but no further
investigations concerning the reaction times for other
Nucleophile scope: Before we started exploring the nucleo-
phile scope, several alkenylaluminums were prepared from
commercial and noncommercial alkenyl bromides
(Scheme 5).
nucleoACHTUNGTRENNUNGphiles were carried out.
Influence of the stoichiometry of the reagents on the enantio-
selectivity: In the course of our investigations we found that
the results of the Cu-catalyzed ACA greatly depended on
the stoichiometry of tBuLi and Me2AlCl used for the prepa-
ration of alane A3 (Table 6).
A slight excess of either tBuLi or Me2AlCl has deleterious
effects on the reaction leading to lower values of enantiose-
lectivity and even conversion (Table 6, entries 2 and 3). This
Table 6. Evaluating the different ratios of tBuLi and Me2AlCl in the
preparation of alane.[a]
Scheme 5. Preparation of alkenylaluminums used in this study.
Entry
Ratio of
BuLi/Me2AlCl
Conv.
[%][b]
4/5[b]
ee
[%][c]
Several general comments concerning the nucleophile
scope can be made: 1) The amount of methyl transfer corre-
lates to the steric bulk of the alkenylaluminums. In particu-
lar, for the conjugate addition with highly encumbered alke-
nylaluminums A6 and A7 significant amounts of methyl
transfer were observed (up to 94%, Table 7, entry 5); 2) In
1
2
3
2.0:1.0
1.8:1.0
2.0:0.9
100
91
100
94:6
70:30
96:4
93
83
77
[a] Reactions performed under argon on a 0.3 mmol scale; only superna-
tant solution of the aluminum reagent was used; alane generated in
MTBE. [b] Estimated by GC-MS. [c] Determined by chiral GC.
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A. Alexakis and D. Mꢀller
general, conjugated (E)-alkenylaluminums A11–A17 led to
superior enantioselectivities than alkyl-substituted alumi-
nums A3–A10; 3) Yields of the isolated product are typical-
ly higher when the reaction was carried out on a larger scale
(1.5 mmol) compared with reactions carried out on small
scale (0.6 mmol). Most of the reactions were carried out on
a 0.6 mmol scale, especially when employing noncommercial
alkenyl bromides.
Dimethylvinylaluminum A4 can be generated either by
bromine–lithium exchange of volatile vinyl bromide and
subsequent trapping with Me2AlCl or by transmetalation of
a vinyl Grignard reagent. Initial trials using vinyl bromide as
products with very low enantioselectivity compared with
their alkyl-substituted counterparts A3 and A8. Electronic
factors are probably the reason for this drop in enantioselec-
tivity. Styrenyl nucleophiles like A11–A13 generally afford
high enantioselectivities independent of the electronic prop-
erties of the aryl moiety (Table 7, entries 9–11). Enhanced
enantioselectivities of styrenyl aluminums were also ob-
served by Hoveyda and co-workers for the Cu-catalyzed
ACA with TMS-protected alkenylaluminums and seems to
be a general trend that is independent of the chiral catalyst
used.[6] Importantly, even heterocyclic alane A14 underwent
Cu-catalyzed ACA with high enantioslectivity and good
yield (Table 7, entry 12). Doubly conjugated aluminums A15
and A16 afforded the products with slightly lower enantiose-
lectivities and yields compared with the styrenyl products
A11–A14 (Table 7, entries 13 and 14). The conjugate addi-
tion with alane A16 was of particular interest because it
generates a quaternary stereogenic center, which is found in
the natural product riccardiphenol B.[21] However, the low
enantioselectivity for the formation of 18 (Table 7, entry 14)
and the poor total yield for the synthesis of the correspond-
ing alkenyl bromide B8 (Table 1, entry 6) discouraged fur-
ther attempts to access riccardiphenol B through this strat-
a
nucleophile precursor showed only low conversion
(Table 7, entry 1). Alternatively, we envisaged the transme-
Table 7. Screening of alkenylaluminums.
Entry
Alane/
Product
Conv.
[%][c]
Me
Yield
[%][e]
ee
Solvent[b]
[%][c,d]
[%][f]
1
2
2
3
4
5
6
7
A4/Et2O
6
6
4
7
8
9
63
>95
61
n.d.[g]
0
4
n.d.
n.d.
85
n.d.
n.d.
n.d.
50
25
62
64
71
84
66
32
38
27
n.d.
36
n.d.
23
91
20
79
82
76
0
46
91
96
93
95
89
76
94
n.d.
69
A4[h]/THF
A3/MTBE
A5/MTBE
A6/MTBE
A7/MTBE
A8/MTBE
A9/MTBE
A10/MTBE
A11/MTBE
A12/Et2O
A13/Et2O
A14/Et2O
A15/Et2O
A16/MTBE
A17/MTBE
A18/MTBE
A18/Et2O
egy. In addition, Hoveyda and co-workers were simul
ACHTUNGTRENNUNGta-
A
ACHTUNGTRENNUNG
they reported recently.[6] a-Substituted alane A17 gave com-
pound 19 in only low yield due to the formation of two side
products with very similar polarity (Table 7, entry 15). Com-
mercially available a-bromostyrene contains 4% of b-bro-
mostyrene. The corresponding b-aluminum reagent A11 un-
dergoes conjugate addition much faster than the a-alumi-
num reagent A17 and thus afforded 8% of b-styrenyl by-
product 13 (2 equiv of alane were used). Moreover, 11% of
methyl-transfer product 5 was observed, which is due to the
bulkiness of alane A17. (Z)-styrenalane A18 prepared in
MTBE suffered from partial isomerization of the double
bond and the corresponding addition product 20 contained
64% of the E isomer 13. Eisch and Hoveyda found that this
kind of isomerization can be suppressed by the addition of
Lewis basic additives or solvents such as tertiary amines or
THF.[22,23] Electron donation of the lone pair of the additive
into the empty p orbital of aluminum (B; Scheme 6) inhibits
isomerization to a thermodynamically favorable isomer (C;
Scheme 6).
0
79
57
94
2
4
0
0
1
11
0
0
9
>95
>95
84
10
11
12
13
14
15
16
17
18
19
20
20
8
9
>95
>95
>95
>95
>95
>95
>95
>95
79[i]
>95
10
11
12
13
14
15
16
17
0
11
0
0
[a] Reactions performed under argon on a 0.6–1.5 mmol scale; only the
supernatant solution of the aluminum reagent was used; preparation of
alane as indicated in Scheme 5. [b] Solvent used for alane preparation.
[c] Estimated by GC-MS. [d] Amount of methyl transfer in the crude
mixture; estimated by GC-MS. [e] Yield of the isolated product. [f] De-
termined by chiral-GC or supercritical fluid chromatography (SFC).
[g] Not determined. [h] Vinylaluminum reagent prepared from vinylmag-
nesium bromide and Me2AlCl. [i] In the absence of Et2O, the (Z)-alane
partially isomerized to the (E)-alane (64% of the E isomer was detected
by GC-MS).
Even though Eisch states that diethyl ether is not Lewis
basic enough to inhibit the isomerization for iBu2Al-alkeny-
laluminums, we found that in the case of Me2Al-alkenyl-
AHCTUNGTREaGNNUN luminums Et2O completely suppressed the isomerization
talation from the corresponding commercially available
Grignard reagent (Table 7, entry 2). Upon addition of the vi-
nylaluminum A4 generated from the Grignard reagent we
observed the formation of a brownish precipitate, which
might explain the disappointing result obtained (Table 7,
entry 2). Due to the importance of the vinyl group we con-
sidered other vinyl synthons, such as silyl-protected vinyl
aluminums A9 and A10 (Table 7, entries 7 and 8, respective-
ly). Surprisingly, vinyl aluminums A9 and A10 furnished
Scheme 6. Isomerization of (Z)-alkenylaluminums to thermodynamically
more stable (E)-alkenylaluminums in non-coordination solvents.
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Formation of Quaternary Stereogenic Centers
FULL PAPER
Table 9. Screening of substrates with alane A3.[a]
process affording the pure
Z
product 20 (Table 7,
entry 17).[24] Importantly, this phenomenon was only ob-
served for alane A18, as alane A5 did not suffer from iso-
merization. This shows that isomerization can only occur
when the carbocation (B; Scheme 6) can be stabilized by
a neighboring group such as phenyl.
Entry
Substrate
Product
Me transfer
[%][b]
Conv.
[%][b]
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
S1
S2
S4
S5
S6
S8
S9
S10
S11
4
4
3
0
1
7
0
n.d.
2
n.d.
>95
>95
19
17
>95
30
49
>95
>95
85
44
91
15
43
83
19
88
48
rac
rac
Attempts to optimize the Cu-catalyzed ACA with TMS-pro-
tected vinylaluminum reagent: The vinyl group is certainly
the synthetically most interesting alkenyl group because it
can easily undergo many chemical transformations such as
hydroboration or metathesis reactions. Therefore, we tried
to improve the obtained enantioselectivity of the addition
product 12 (Table 7, entry 8) by testing the ability of the
newly synthesized aryl- and alkyl-substituted phosphinamine
ligands to promote the Cu-catalyzed ACA of alane A10 to
enone S1 (Table 8).
21
22
23
24
25
26
27
28
n.d.
n.d.
66
n.d.
n.d.
52
7[e]
8
9
54
[a] Reactions performed under argon on a 0.6–1.5 mmol scale; only the
supernatant solution of the aluminum reagent was used. [b] Estimated by
GC-MS. [c] Yield of the isolated product. [d] Determined by chiral GC.
[e] Result difficult to reproduce due to the sensitivity of the substrate to-
wards the “nature” of the alane (see the main text for more details).
Table 8. Screening of selected ligands for the ACA with alane A10.[a]
Substrate scope: Next, we explored the substrate scope by
the addition of 2-isopropenylalane A3 to various cyclic and
acyclic enones depicted in Figure 1 (Table 9).
Entry
Ligand
Conv.
[%][b]
Yield
[%][c]
ee
[%][d]
As displayed in Table 9, the scope of the addition of 2-iso-
propenylalane A3 to numerous substrates was very limited
and only 3-methyl-cyclohexenone S1 afforded the corre-
sponding product with good yield and enantioselectivity
(Table 9, entry 1). Changing the substituent on the b-posi-
tion on cyclohexenone from methyl to ethyl- or butenyl led
to a significant drop in enantioselectivity demonstrating the
great substrate dependence for the ACA with isopropenyl-
1
2
3
4
5
6
7
9
L17
L18
L19
L20
L21
L22
L23
L24
L25
L26
L27
100
99
98
100
98
100
100
100
100
95
64
44
14
rac
34
8
46
30
48
31
rac
rac
n.i
n.i
66
n.i.
62
n.i.
40
n.i.
n.i.
n.i.
10
11
12
AHCTUNGTREGaNNUN lane A3 (Table 9, entries 2 and 5). Low conversion and
enantioselectivities were observed for phenyl-substituted
substrate S4, which is known to be significantly less-reactive
than alkyl-substituted substrates (Table 9, entry 3).[5,6] The
lack of reactivity is probably due to the donation of electron
density of the phenyl ring into the p system of the enone.
Sterically congested iBu-substituted substrate S5 afforded
the product in high optical purity albeit in low conversion
(Table 9, entry 4). Isophorone S8, another challenging sub-
strate, afforded similar results as S5 (Table 9, entry 6). De-
spite substantial effort to optimize the conditions for Cu-cat-
alyzed ACA to cyclopentenone S9 we were unable to con-
trol this reaction. A slight excess of Me2AlCl for the
88
[a] Reactions performed under argon on a 0.3 mmol scale; only superna-
tant solution of the aluminum reagent was used; alane prepared in
MTBE; n.i.=not isolated. [b] Estimated by GC-MS. [c] Yield of the iso-
lated product. [d] Determined by chiral GC.
Unfortunately, only ligand L24 (Table 8, entry 9) slightly
improved the enantioselectivity compared with L22. In gen-
eral, electron-poor ligands such as L21 and L27 afford race-
mic mixtures, whereas electron-rich and lipophilic ligands
L17, L22, and L24 afford the highest enantioselectivities.
The result obtained with L17 is particularly interesting be-
cause it represents the first application of an alkyl-substitut-
ed phosphinamine for the Cu-catalyzed ACA. Surprisingly,
ligand L17 afforded comparable levels of enantioselectivity
as L22. Ligand L26 formed a white precipitate with CuTC,
which might explain the formation of a racemic mixture.
Ligand L25 is electron-rich but only poorly soluble in pen-
tane and hence lacking lipophilicity, which we believe to be
important for obtaining high enantioselectivites. Although
ligand L24 gave a slightly higher enantioselectivity than
L22, we continued to use L22 due to the significantly lower
costs of the aryl bromide used for its synthesis.[13]
alkenylACHTNUTRGNEaUNG luminum preparation led to great amounts of aldol
byproducts, whereas a slight excess of tBuLi afforded the
product as a racemate (Table 9, entry 7). Conjugate addition
to the seven-membered substrate S10, as well as acyclic
enone S11, furnished the product as racemic mixtures
(Table 9, entries 8 and 9). Interestingly, Corey and Lalic re-
ported that Rh-catalyzed ACA reactions with potassium iso-
propenyl trifluoroborate to acyclic substrates also afforded
racemic mixtures. This demonstrates the difficulty for the
conjugate addition of this nucleophile to acyclic substrates.
The disappointing results obtained for most of the tested
cyclic and acyclic enones made us wonder if the limited sub-
Chem. Eur. J. 2013, 00, 0 – 0
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A. Alexakis and D. Mꢀller
strate scope was unique for the branched isopropenylalane
A3 or was also true for unhindered alkenylaluminums.
Therefore, we subjected styrenylalane A11 to several b-sub-
stituted cyclic enones in the presence of CuTC and phos-
phinamine L22 (Table 10).
Table 10. Screening of substrates with styrenylalane A11.
Scheme 7. Preparation of alane A8 through intermediate A19.
tion and bis-hydroalumination products.[26a] In particular, the
generated acetylide is known to strongly bind to copper and
thus can greatly influence Cu-catalyzed reactions in which
copper is used in catalytic amounts.[12] Several strategies
were devised to deal with the aforementioned concerns:
First, we envisaged to decrease the amount of nucleophile
to lower the amount of deleterious aluminum acetylides
present in the alane solution. Second, we intended to screen
several strongly donating phosphinamine ligands, which bind
tightly to copper and thus hamper the complexation of
copper by acetylides. Third, we were aware of a recently re-
ported protocol for the Nickel-catalyzed hydroalumination,
which greatly suppresses the Al-acetylide formation and
even allows, by the choice of ligand, a selective a- or b-hy-
droalumination.[27] Table 11 displays the various hydroalumi-
Entry Substrate, n R1, R2
Product Yield[b] ee
[%]
[%][c]
1
S1, 1
S2, 1
S3, 1
S7, 1
S8, 1
S10, 2
H, Me
H, Et
H, n-Bu
H, (CH2)3CH=CH2 31
Me, Me
H, Me
13
29
30
64
83
81
91
91
94
2[d]
3[d]
4[d]
5[d]
6
79
92
n.d.
77
32
33
n.d.[e]
51
[a] Reactions performed under argon on a 0.6–1.5 mmol scale; 100%
conversion if not indicated otherwise; no Me-transfer was observed; A11
was prepared in Et2O. [b] Yields of the isolated products. [c] Determined
by chiral SFC. [d] Reaction performed at À108C; [e] 45% conversion; es-
timated by GC-MS.
Surprisingly, several substrates bearing linear alkyl-sub-
stituents, such as S1, S2, and S3, gave much better enantio-
selectivities with styrenylalane A11 compared with isoprope-
nylalane A3 (Table 10, entries 1–4). Even for the conjugate
addition to cycloheptenone S10, a good enantioselectivity
was observed with A11, whereas 2-isopropenylalane A3 af-
forded the product as a racemic mixture (Table 10, entry 6).
The low reactivity obtained with A3 for the addition to iso-
phorone S8 could not be improved with the less-encum-
bered styrenylalane A11 (Table 10, entry 5). Conjugate addi-
tions to cyclopentenone S9 were unsuccessful, providing
many side products such as aldol products, which were also
observed with alane A3.
Table 11. Representative protocols for the generation of various alkenyl-
AHCTUNGTRENGNaUN lanes.
Protocol
1[a]
Reaction
Alane
A19
2[b]
3[c]
4[d]
A20
A21
A22
[a] Contains 6% of metalation and 4% of bis-hydroalumination product.
[b] Directing groups such as OtBu afford purely the syn-hydroalumina-
tion product. [c] The b-hydroalumination product and the metalation
product are formed in <2%; dppp=1,3-bis(diphenylphosphino)propane;
[d] 7% of the a-hydroalumination product is formed; the metalation
product is formed in <2%.
Taken together, these results show that alane A11 is sig-
nificantly less-susceptible to changes in the substrate struc-
ture than A3, providing good yields and high enantioselec-
tivity, especially for cyclohexenones bearing linear b-sub-
stituents (Table 10, entries 1–4).
Copper-catalyzed ACA reactions employing alkenylalumi-
nums generated by the hydroalumination of alkynes: In the
course of our investigations we noticed that the use of non-
commercial alkyl-substituted alkenyl bromides was not very
efficient (Scheme 7). Alane A8 had to be prepared in a two-
step procedure from 1-hexyne 1 with alane A19 as an inter-
mediate in the synthesis. Therefore, we revisited the tandem
hydroalumination–ACA reaction employing A19 directly
for the asymmetric conjugate addition (pathway 2,
Scheme 1).[5]
nation reactions utilized in this account. Hydroaluminations
of unfunctionalized terminal alkynes usually proceed to
cleanly afford the (E)-alkenylaluminums in high yields with
small amounts of Al-acetylide (Table 11, protocol 1). Direct-
ing groups such as tert-butoxy in close proximity to the
À
triple bond changes the mode of Al H addition and the
(Z)-alkenylalane is typically obtained (Table 11, proto-
col 2).[26b] Ni-catalyzed hydroalumination in the presence of
a bidentate ligand cleanly affords the a-hydroalumination
product, whereas in the presence of monodentate ligand the
b-hydroalumination product is observed (Table 11, proto-
cols 3 and 4).[27]
We were aware of the difficulties involved in this type of
reaction because the generation of alkenylalanes often in-
volves the generation of side products such as the metala-
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Formation of Quaternary Stereogenic Centers
FULL PAPER
Optimization of the experimental conditions: We began our
investigations by varying the amounts of alane used for the
tandem hydroalumination–ACA reaction. Previously opti-
mized conditions with phosphoramidite ligand L30 in combi-
The easy and high yielding preparation of L17 stimulated
our interest in further optimizations for this ligand.[13] There-
fore, we wanted to examine the best reaction conditions for
this type of alkyl-substituted ligand.
nation with [CuACHTUNGTRENNUNG(CH3CN)4]ACHTUNTGREN[NUNG BF4] in THF led to moderate
conversion and enantioselectivity (Table 12, entry 1).[5] Inter-
Solvent screening: Several coordinating and non-coordinat-
ing solvents were evaluated for the ACA with ligand L17
(Table 13). It is important to note that the reactions per-
formed with alkyl-substituted phosphinamine ligands have
to be carried out under strict inert conditions because the
Cu complexes are highly air-sensitive.
Table 12. Screening of ligands for the tandem hydroalumination-ACA re-
action.[a]
Table 13. Screening of solvents for the tandem hydroalumination–ACA
reaction.[a]
Entry
L*
Solvent
Conv.[b]
10/35[b,c]
ee
[%][d]
1[e,f]
2[f]
3
4
5
L30
L30
L31
L10
L22
L17
L17
–
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
56
92
98
100
98
100
100
75
100:0
100:0
53:47
65:35
51:49
85:15
87:13
25:75
62
67
77
51
83
75
76
–
Entry
L*
Solvent
Conv.[b]
1,4/1,2[b,c]
ee
[%][d]
6
7[g]
8
1
2
3
4
5
6
L17
L17
L17
L17
L17
L22
L17
L17
Et2O
THF
100
80
98
88
97
96
100
96
85:15
92:8
94:6
42:58
84:16
24:77
82:18
32:68
76
66
75
74
84
83
83
79
EtOAc
CH2Cl2
toluene
toluene
toluene
toluene
[a] Reactions performed under argon on a 0.3 mmol scale. [b] Estimated
by GC-MS. [c] Ratio estimated by GC-MS: Integration of the 1,4-addi-
tion product versus 1,2-addition-dehydration products. [d] Determined by
chiral GC; [e] 2.0 equiv of alkenylaluminum used. [f] Copper catalyst:
[CuACHTUNGTRENNUNG(CH3CN)4]ACHTUNGTRENNUNG[BF4]=Kubaꢃs salt (30 mol%) and L30 (30 mol%);
[g] 1.2 equiv of aluminum reagent was added.
7[e]
8[f]
[a] Reactions performed under argon on a 0.3 mmol scale. [b] Estimated
by GC-MS. [c] Ratio estimated by GC-MS: Integration of the 1,4-addi-
tion product versus 1,2-addition–dehydration products. [d] Determined
by chiral GC. [e] Addition of 20 mol% of hex-1-yne. [f] Addition of
20 mol% of hex-1-ynyldiisobutylaluminum.
estingly, we found that diminishing the amount of alane A19
to 1.5 equiv of hexenylalane achieved almost full conversion
with
a slight increase in enantioselectivity (Table 12,
entry 2). The clean reaction obtained with this salt in THF is
noteworthy; not even traces of 1,2-addition products were
observed. Hence, we decided to use 1.5 equiv of alane for
all the following studies.
Several points concerning the results displayed in Table 13
are noteworthy: 1) Non-coordinating solvents, such as
hexane and CH2Cl2, favor the formation of the 1,2-addition
product, whereas coordinating solvents, such as THF and
EtOAc, favor the formation of the desired 1,4-product
(Table 13, entries 1–4); 2) Surprisingly, toluene, as a non-co-
ordinating solvent, furnished the 1,4-addition product in
high regio- and enantioselectivity in combination with L17
(Table 13, entry 5). In toluene, the less s-donating ligand
L22 led to a strong preference for the undesired 1,2-addition
product (Table 13, entry 6); 3) Alkenylaluminum reagents
are very mild organometallic reagents with a good function-
al group compatibility; even ethyl acetate as the solvent
does not hamper the catalysis (Table 13, entry 3). The find-
ing that ester groups are tolerated by organoaluminums was
previously reported for the nickel-catalyzed conjugate addi-
tion with AlMe3;[28] 4) Addition of terminal alkynes did not
have a substantial effect on the outcome of the reaction
(Table 13, entry 7). In contrast, addition of 20 mol% of the
corresponding aluminum acetylide caused the opposite re-
gioselection and a slight decrease in the enantioselectivity
(Table 13, entry 8). This observation clearly shows that alu-
minum acetylides interfere with copper-catalyzed reactions.
Screening of monodentate phosphorous ligands: Previous re-
sults obtained with ligand L30 clearly showed that reactions
in diethyl ether afforded better enantioselectivity, albeit
with a lower selectivity for the 1,4-addition.[5] Hence, we
screened highly efficient phosphoramidite and phosphin-
ACHTUNGTRENNUNGamine ligands for the copper-catalyzed ACA with diethyl
ether as the solvent as depicted in Table 12. Ligands L31
and L22 furnished the highest enantioselectivities, albeit
with low regioselectivities (Table 12, entries 3 and 5, respec-
tively). L17 gave the highest selectivity for the desired 1,4-
addition product with acceptable enantioselectivities
(Table 12, entry 6). A further decrease to 1.2 equiv of alane
was slightly beneficial for alane A19 (Table 12, entry 7).
Nevertheless, we continued to use 1.5 equiv of alane because
with other alanes a low conversion was observed with
1.2 equiv. Interestingly, the phosphorous ligand plays an im-
portant role for the regioselectivity; in the absence of
ligand, the 1,2-addition product is predominantly formed
(Table 12, entry 8).
Chem. Eur. J. 2013, 00, 0 – 0
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A. Alexakis and D. Mꢀller
Table 15. Screening of various alkyl-substituted phosphinamine ligands.[a]
Screening of copper salts: Next, we examined several copper
salts for their ability to promote the ACA of alkenylalanes
to substrate S1. The screening was limited to copper salts
bearing a carboxylate-containing anion because the mecha-
nistic proposals suggest the involvement of a carboxylate
group in the catalytic cycle of Cu-catalyzed ACA
(Table 14).[29] Moreover, such copper salts generally show
higher solubility in toluene than common inorganic Cu salts.
Entry
L*
Conv.[b]
1,4/1,2[b,c]
ee
[%][d]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
100
100
100
71
85
83
100
100
100
100
100
97
74:26
76:24
88:12
66:32
28:72
15:85
4:96
57:43
47:53
59:41
68:32
93:7
49
65
70
38
4
Table 14. Screening of copper salts for the tandem hydroalumination–
ACA reaction.[a]
3
0
66
64
58
74
82
9
L9
10
11
12
L15
L16
L17
Entry
L*
CuX
Conv.
[%][b]
1,4/1,2[b,c]
ee
[%][d]
[a] Reactions performed under argon on a 0.3 mmol scale. [b] Estimated
by GC-MS. [c] Ratio estimated by GC-MS: Integration of the 1,4-addi-
tion product versus 1,2-addition-dehydration products. [d] Determined by
chiral GC.
1
2
3
4
L17
L17
L17
L17
L17
L22
L22
L22
CuTC
100
90
66
99
97
20
64
98
84:16
88:12
66:34
91:9
93:7
n.d.
84 (R)
68 (R)
51 (S)
80 (R)
82 (R)
75 (R)
75 (R)
83 (R)
[Cu
[Cu
U
ACHTUNGRTEN[NUNG H2O]
Cu(II)naphthenate
Cu(II)naphthenate
Cu(II)naphthenate
Cu(II)naphthenate
CuTC
5[e]
6
viously optimized reactions conditions were applied
(Table 14, entry 5).
7[f]
8[f]
76:24
51:49
The results of the ligand screening displayed in Table 15
showed several general trends: 1) The best results in terms
of enantioselectivity and regioselectivity were obtained with
ligands that contain linear alkyl substituents on phosphorous
(Table 15, entries 1–3 and 10–12). Enantioselectivity and re-
gioselectivity increased with the chain length of the alkyl
substituent (Table 15, entries 1–3 and 10–12); 2) Remotely
branched alkyl substituents on phosphorous also afforded
good levels of enantioselectivity but with low regioselectivi-
ty (Table 15, entries 8 and 9); 3) Bulky ligands such as phos-
phinamines L6 and L7 bearing a-branched alkyl substituents
on phosphorous are inefficient (Table 15, entries 6 and 7).
This might be due to insufficient coordination of the bulky
phosphorous ligands to copper or weak interaction between
the bulky copper complex and the substrate; 4) Ligand L5
bearing alkyne substituents on phosphorous afforded the
product as a racemate with high levels of 1,2-addition
(Table 15, entry 5). In terms of alkyl substitution, the best
result was obtained with L3 bearing the n-hexyl motif
(Table 15, entry 3). This confirms our previous finding for
aryl-substituted ligands; the more electron-donating and lip-
ophilic the ligand, the better its efficiency (compare with
Table 8). Unsurprisingly, enantioselectivities increased by
almost 20% when introducing the 2-naphtyl substituent on
the amine moiety (Table 15, compare entries 2 and 12). Al-
though the n-hexyl motif afforded better enantioselectivities
than the n-butyl motif, we preferred to continue our work
with ligand L17 due to the simpler and higher-yielding
ligand synthesis with the n-butyl substituent.[13]
[a] Reactions performed under argon on a 0.3 mmol scale. [b] Estimated
by GC-MS. [c] Ratio estimated by GC-MS: Integration of the 1,4-addi-
tion product versus 1,2-addition-dehydration products. [d] Determined by
chiral GC. [e] Use of 13 mol% Cu(II)naphthenate. [f] Et2O as solvent for
complex formation.
Cu(II)naphthenate, a wood preservative and the most in-
expensive organic copper salt, gave slightly improved regio-
selectivities compared with CuTC (Table 14, entries 1 and
4).[30] Moreover, Cu(II)naphthenate can be used as a stock
solution in pentane, making it particularly easy to handle.
Interestingly, [CuACHTUNGTRENNUNG(OTf)2] (OTf=trifluoromethanesulfonate)
afforded the (S)-enantiomer in combination with L17
(Table 14, entry 3). This inversion of configuration was not
observed for conjugate additions with 2-propenylalane A3
(Table 5, entry 6). Finally an excess of ligand L17 in combi-
nation with 13 mol% of Cu(II)naphthenate gave rise to
a
slight increase in the regio- and enantioselectivity
(Table 14, entry 5). In the presence of diethyl ether, Cu(II)-
naphthenate also improved the regioselectivity for L22,
albeit with a lower conversion and enantioselectivity com-
pared with CuTC (Table 14, entries 7 and 8). In view of the
many practical advances and good results obtained with
Cu(II)naphthenate, we used the conditions described in
entry 5 (Table 14) for the following reactions.
Evaluation of several alkyl-substituted phosphinamine li-
gands: To better understand the influence of the substitution
pattern of the alkyl substituents on phosphorous on the
regio- and enantioselectivity, we tested several newly synthe-
sized alkyl-phosphinamine ligands[13] for the Cu-catalyzed
ACA depicted in Table 15. For all of the reactions, the pre-
Nucleophile scope: With the optimized conditions in hand,
we tested the improved protocol for the ACA with various
nucleophiles (Table 16). To our great surprise, we found that
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Formation of Quaternary Stereogenic Centers
FULL PAPER
Table 16. Cu-catalyzed ACA of various alkenylalanes to S1.[a]
L17 the reaction was highly regioselective, but product 40
was afforded in poor enantioselectivity (Table 16, entry 15).
In contrast, ligand L22 furnished the product in good optical
purity but with low levels of regioselectivity (Table 16,
entry 16). After many optimization reactions we found that
co-activation with AlMe3 in the presence of Et2O as the sol-
vent for complexation totally suppressed the 1,2-addition
and afforded the product cleanly in good enantioselectivity
(Table 16, entry 17). Further optimization identified the
Entry Method[b] Reagent; R
1,4/1,2[c,d] Yield [%][e] ee
A
[%][f]
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
B
B
B
A
B
n-Bu (A19)
n-Bu (A19)
92:8
51:49
72 (10)
n.i.[g] (10)
49 (35)
n.i. (35)
n.i. (36)
61 (36)
91 (37)
n.i. (37)
n.i. (38)
75 (38)
n.d. (39)
62 (39)
n.i. (13)
59 (13)
n.i. (40)
n.i. (40)
90 (40)
78 (40)
n.i. (10)
n.i. (19)
64 (19)
83
83
75
73
71
82
79
79
75
85
69
76
74
80
38
75
77
90
75
65
88
A
2A
combination of Kubaꢃs salt ([CuACTHNUTRGENN(GU CH3CN)4]ACHTUNGTERN[NUGN BF4]), THF, and
A
CHTUNGTRENNUNG
L22 as an even more efficient catalyst, affording the desired
product in good yield and with high enantioselectivity
(Table 16, entry 18). These reaction conditions were particu-
larly suitable for the Z-configured alane A18 as, for the
linear alane A17, only low conversion was observed
(Table 16, entry 19). Co-activation with AlMe3 was also cru-
cial for the conjugate addition of sterically encumbered
alane A19 and for the reactions with substrates other than
S1 (compare with Table 17). In conclusion, methods A and
B afford similar results for the conjugate addition of unhin-
dered alkenylaluminums to S1. In the case of hindered nu-
cleophiles, such as A20 or A22, method B gave better enan-
tioselectivities than method A. Full conversion was achieved
by means of co-activation with AlMe3.
Bn (A26)
Bn (A26)
Cy (A23)
96:4
95:5
94:6
95:5
96:4
95:5
100:0
94:6
100:0
100:0
100:0
82:18
100:0
100:0
76:24
81:19
91:9
Cy
tBu (A24)
tBu(A24)
(CH2)2Cl (A27)
(CH2)2Cl (A27)
A
9
10
11
12
13
14
15[h]
16[i]
17[j]
18[j,k]
19[j,k,l]
20[j]
21[j]
G
T
ACHTUNGTRENNUNG
b-Ph (A22)
b-Ph (A22)
CH2OtBu (A20)
CH2OtBu (A20)
CH2OtBu (A20)
CH2OtBu (A20)
n-Bu (A10)
a-Ph (A21)
a-Ph (A21)
[a] Reactions performed under argon on a 0.6 mmol scale, >95% conv. if
not stated otherwise; alkenylaluminum prepared by hydrolalumination of
alkyne according to Table 11. [b] Method A: L17, toluene; Method B:
L22, Et2O. [c] Estimated by GC-MS. [d] Ratio of 1,4- and 1,2-addition.
[e] Yield of the isolated product. [f] Determined by chiral GC or SFC;
[g] n.i.=not isolated; [h] 80% conv; [i] 48% conv. [j] Activation with
1.0 equiv of AlMe3. [k] Complex formation in THF with Kubaꢃs salt [Cu-
Substrate scope: The results for the substrate scope shown in
Table 17 resemble the results previously observed for the
addition of 2-propenylalane A3 (compare with Table 9).
Table 17. Substrate scope for the tandem hydroalumination–ACA reac-
tion.[a]
ACHTUNGTRENNUNG(CH3CN)4]ACHTUNGTRENNUNG[BF4] instead of Cu(II)naphthenate; [l] 64% conv.
L22 in combination with Cu(II)naphthenate in Et2O often
furnished comparable or even better results for nucleophiles
other than hexenylalane A19. This observation might be
due to lower amounts of Al-acetylides present in alanes
other than A19 (Figure 3).[26]
Entry Sub., n
R
Method[b] 1,4/1,2[c] Product Yield ee
[%][d] [%][e]
1
2
S2
S2
S5
S5
S9
S9
S10
S10
Et
Et
A
B
A
B
A
B
A
B
92:8
91:9
91:9
63:37
82:18
80:20
93:7
41
41
42
42
43
43
44
44
65
55
60
70
89
34
11
79
61
n.i.
n.i.
41
44
n.i.
57
3[f]
4[f]
5
iBu
iBu
Me
Me
Me
Me
6
7
8
Figure 3. Aluminum-acetylide contamination present in the depicted al-
kenylalanes.
83:17
n.i.
[a] Reactions performed under argon on a 0.6 mmol scale; conversion
>95%. [b] Method A: L17, toluene; Method B: L22, Et2O. [c] Ratio es-
timated by GC-MS: Integration of the 1,4-addition product versus 1,2-ad-
dition–dehydration products. [d] Yield of the isolated product. [e] Deter-
mined by chiral GC. [f] Reaction carried out at À108C.
Hence, Tables 16 and 18 display the results obtained with
the two protocols, using L17 and L22, for a variety of
nucleoACHTUNGTRENNUNGphiles and substrates.
As illustrated in Table 16, a variety of alkenyl substitu-
ents, such as primary-, secondary-, and tertiary alkyl-substi-
tuted substrates, were introduced in good yields and enan-
tioselectivity (Table 16, entries 1–10). Even halide-contain-
ing alkenylaluminums (Table 16, entries 11 and 12) and con-
jugated alane A22 (entries 13 and 14) were introduced suc-
cessfully. The introduction of Z-configured alane A20
caused no particular problems. In the presence of ligand
Conjugate additions to b-ethyl-substituted substrate S2 pro-
ceeded with lower enantioselectivity (Table 17, entries 1 and
2). This selectivity change shows the sensitivity of the
copper complex to the substitution pattern of the substrate.
Interestingly, a further increase in steric bulk by changing
the b-substituent from ethyl to iBu gave rise to an increase
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A. Alexakis and D. Mꢀller
in enantioselectivity, albeit with moderate regioselectivity
(Table 17, entries 3 and 4). Cyclopentenones are notoriously
difficult substrates for the Cu-catalyzed ACA in terms of
isolated product yields and enantioslectivity.[29] Unsurpris-
ingly, compound 43 was obtained in low yield and enantiose-
lectivity (Table 17, entries 5 and 6). We were pleased to see
that the seven-membered substrate S10 reacted cleanly af-
fording the product in good yields and with good selectivity.
This was particularly interesting because Hoveyda and co-
workers reported that such substrates were inefficient for
ACA addition reactions with alkenylaluminums.[6]
tivity or conversion (Table 18, entries 8 and 9). In summary,
trialkylaluminum organyls, such as AlMe3 or AlEt3, in ether-
al solvents such as diethyl ether are ideal co-activating
agents for the copper-catalyzed ACA with sterically encum-
bered alkenylaluminums. A rate acceleration of the conju-
gate addition and improved regioselectivities were observed
without affecting the enantioselectivity (Table 18, entries 4
and 6). Moreover, trialkylaluminum reagents are commer-
cially available as solutions in hydrocarbon solvents, which
makes them particularly easy to handle.
Experimental details and mechanistic insights: The present-
ed chemistry relies on the fact that an alkenyl substituent on
the aluminum reagent is generally transferred faster than an
alkyl substituent (Scheme 8). The preference for the alkenyl
Evaluation of several Lewis acids as co-activating reagents:
To better understand the role of AlMe3 as co-activating
agent we tested some common Lewis acids for the co-activa-
tion of substrate S1 in the presence of ligand L22 (Table 18).
Table 18. Lewis acid activation in the tandem hydroalumination–ACA
reaction.[a]
Scheme 8. Transmetalation as the substituent-determining step.
Entry
L*
Lewis acid
Solvent
Conv.[b]
1,4/1,2[b,c]
ee
group can however change to the alkyl group when the al-
kenyl group exposes steric bulk; hence increased methyl
transfer was observed for bulky alkenylaluminums in weakly
coordinating solvents. The 1,4-addition of the copper-alkenyl
complex is however slower than the 1,4-addition with the
same copper-methyl complex. For example, the Cu-cata-
lyzed conjugate addition with 2-propenyl aluminum A3 to
S1 was complete within 4 h whereas AlMe3 underwent con-
jugate addition in less than 15 min under the same condi-
tions.[32] These observations suggest that the transmetalation
reaction from aluminum to copper is the substituent-deter-
mining step. Once the alkenyl or alkyl group is bound to
copper it will reside there until the relatively slow 1,4-addi-
tion takes place.
[%][d]
1
2
L28
L28
L28
L28
L28
L28
L28
L28
L28
–
–
toluene
Et2O
toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
20
64
100
100
0
89
64
94
23
n.d.
76:24
n.d.
95:5
n.d.
86:14
n.d.
68:32
n.d.
75
75
n.d.
76
n.d.
80
rac
66
82
3[e]
4
AlMe3
AlMe3
BF3·Et2O
AlEt3
Me2AlCl
TMS-Cl
5
6
7
8
9
[TiN
[a] Reactions performed under argon on a 0.3 mmol scale. [b] Estimated
by GC-MS. [c] Ratio estimated by GC-MS: Integration of the 1,4-addi-
tion product versus 1,2-addition–dehydration products. [d] Determined
by chiral GC. [e] Only Me transfer observed by GC-MS.
Several results depicted in Table 18 are noteworthy: 1) In
the absence of Lewis acids, the combination of L13 and
Cu(II)naphthenate afforded only a low conversion for the
addition of alane A19 to substrate S1 (Table 18, entry 2);
2) The presence of an ethereal solvent for AlMe3 co-activa-
tion is absolutely vital as its absence results in mere methyl-
instead of alkenyl transfer (Table 18, entry 3); 3) Surprising-
ly, addition of BF3·Et2O completely hampered the reaction
(Table 18, entry 5); 4) The use of AlEt3 activated the sub-
strate slightly less than AlMe3 but afforded the product with
better enantioselectivity (Table 18, entry 6); 5) From previ-
ous experiments (Table 6) we knew that even a small excess
of Me2AlCl led to a drop in enantioselectivity and we ex-
pected the reaction in the presence of one equivalent of
Conclusion
Mixed alkyl–alkenylaluminum reagents can be prepared
easily either through bromine–lithium exchange of an alken-
yl bromide followed by transmetalation with R2AlCl or hy-
droalumination of an alkyne with diisobutylaluminium hy-
dride (DIBAL-H). Both types of mixed alanes can success-
fully undergo asymmetric conjugate addition in the presence
of chiral copper-phosphine amine complexes. We demon-
strated in this account that an optimized synthesis and
number of equivalents of the aluminum reagent is crucial to
obtain high enantioselectivities. Therefore, the choice of
ligand, copper salt, and solvent, as well as the preparation of
the aluminum reagent, depends on the structure of the cor-
responding alkenylaluminum reagent. As a general guide-
line, the following Scheme summarizes the methodology
Me2AlCl to proceed in
entry 7); 6) Addition of other common Lewis acids such as
TMS-Cl or [Ti(OiPr)4] either resulted in lower enantioselec-
a racemic manner (Table 18,
ACHTUNGTRENNUNG
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Formation of Quaternary Stereogenic Centers
FULL PAPER
Acknowledgements
The authors thank the Swiss National
Research Foundation (grant No.:
200020–144344) and COST action D40
(SER contract No.: C07.0097) for fi-
nancial support, as well as BASF for
the chiral amines.
Scheme 9.
that should be applied for
(Scheme 9).[33]
a
specific alkenylalane
[1] J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593–4623.
With these conditions in hand, a large number of alkenyl
nucleophiles can undergo the Cu-catalyzed ACA with good
to very good levels of enantioselectivity (typically 70–
90% ee) when cyclohexenones and derivatives are used as
substrates. The reaction protocols are practical and the
ligand and copper salt used relatively inexpensive. We be-
lieve that these key benefits will stimulate further applica-
tions of the presented chemistry especially in the field of
natural product synthesis.
[2] C. Hawner, A. Alexakis, Chem. Commun. 2010, 46, 7295–7306.
[3] With AlMe3: a) L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin,
C. A. Falciola, M. Vuagnoux dꢃAugustin, S. Rosset, G. Bernardinelli,
A. Alexakis, Angew. Chem. 2007, 119, 7606–7609; Angew. Chem.
Int. Ed. 2007, 46, 7462–7465. With Me2ArAl or Et2ArAl: b) T. L.
May, M. K. Brown, A. H. Hoveyda, Angew. Chem. 2008, 120, 7468–
7472; Angew. Chem. Int. Ed. 2008, 47, 7358–7362; c) C. Hawner, K.
Li, V. Cirriez, A. Alexakis, Angew. Chem. 2008, 120, 8334–8337;
Angew. Chem. Int. Ed. 2008, 47, 8211–8214; for a recent review on
the conjugate addition of organoaluminum species, see: d) O.
Pꢅmies, M. Diꢆguez, Conjugate Addition of Organoaluminum Spe-
cies to Michael Acceptors and Related Processes: Topics in Organo-
metallic Chemistry, Springer, Heidelberg, 2013.
[4] a) P. Mauleꢇn, J. C. Carretero, Chem. Commun. 2005, 4961–4963.
For a recent review on Rh- and Cu-catalyzed ACA employing al-
kenyl nucleophiles, see: b) D. Mꢀller, A. Alexakis, Chem. Commun.
2012, 48, 12037–12049.
[5] M. Vuagnoux-d’Augustin, A. Alexakis, Chem. Eur. J. 2007, 13,
9647–9662.
[6] T. L. May, J. A. Dabrowski, A. H. Hoveyda, J. Am. Chem. Soc. 2011,
133, 736–739.
[7] a) D. Mꢀller, C. Hawner, M. Tissot, L. Palais, A. Alexakis, Synlett
2010, 1694–1698; b) D. Mꢀller, M. Tissot, A. Alexakis, Org. Lett.
2011, 13, 3040–3043.
[8] G. Zweifel, C. C. Whitney, J. Am. Chem. Soc. 1967, 89, 2753–2754.
[9] J. P. Das, S. Roy, J. Org. Chem. 2002, 67, 7861–7864.
[10] a) F. Ramirez, N. B. Desai, N. McKelvie, J. Am. Chem. Soc. 1962, 84,
1745–1747; b) S. Abbas, C. J. Hayes, S. Worden, Tetrahedron Lett.
2000, 41, 3215–3219.
[11] L. J. Dolby, D. C. Wilkins, T. G. Frey, J. Org. Chem. 1966, 31, 1110–
1116.
[12] E. J. Corey, Y. Kwak, Org. Lett. 2004, 6, 3385–3388.
[13] The synthesis of new SimplePhos ligands was reported very recent-
ly: D. Mꢀller, L. Guꢆnꢆe, A. Alexakis, Eur. J. Org. Chem. 2013;
DOI: 10.1002/ejoc.201300729.
Experimental Section
Typical procedure for Cu-catalyzed ACA employing alkenylaluminums
generated from the alkenyl bromides: Exemplified for the synthesis of 4:
CuTC (28.5 mg, 0.15 mmol, 10 mol%), ligand L22 (93.5 mg, 0.17 mmol,
11 mol%), and Et2O (5.0 mL) were thoroughly stirred at room tempera-
ture for 1 h. Then, the flask was cooled to À308C and alane A3 (10.0 mL,
3.0 mmol, 2.0 equiv) was added. After 15 min of stirring, 3-methyl-2-cy-
clohexenone S1 (170 mL, 165 mg, 1.50 mmol, 1.0 equiv) was added at
once and the reaction mixture was stirred for 14 h at this temperature.
Then, the reaction was quenched at À308C with MeOH (1.0 mL) and the
solution was allowed to warm to room temperature. An aqueous solution
of HCl (10%, 15 mL) was then added, followed by Et2O (50 mL). Ex-
traction of the aqueous phase with Et2O (2ꢄ50 mL) and addition of a so-
lution of NaOCl (10%, 4 mL) to the combined organic solvents afforded
a pale-yellow suspension, which, after extensive shaking, turned into
a blue suspension. After separation of the aqueous phase, the organic
phase was dried over Na2SO4 and the solvent was removed under re-
duced pressure. The remaining crude oil was purified by flash chromatog-
raphy on silica gel (pentane/Et2O=7:1; Rf =0.23 in pentane/Et2O=9:1)
and the pure compound 4 was afforded as a colorless oil (194 mg,
1.27 mmol, 85%) with a pleasant eucalyptus-like fragrance.
[14] M. Tissot, D. Mꢀller, S. Belot, A. Alexakis, Org. Lett. 2010, 12,
2770–2773.
Cu-catalyzed ACA employing alkenylaluminums generated from the al-
kenyl bromides: Exemplified for the synthesis of 10: A flame-dried
Schlenk tube was charged with a solution of Copper(II)naphthenate in
[15] L. Gremaud, A. Alexakis, Angew. Chem. 2012, 124, 818–821;
Angew Chem. Int. Ed. 2012, 51, 794–797.
[16] L. Palais, A. Alexakis, Chem. Eur. J. 2009, 15, 10473–10485.
[17] a) P. Cottet, D. Mꢀller, A. Alexakis, Org. Lett. 2013, 15, 828–831;
b) D. Mꢀller, A. Alexakis, Org. Lett. 2012, 14, 1842–1845.
[18] D. B. Biradar, H. Gau, Org. Lett. 2009, 11, 499–502.
[19] For previous discussions concerning the impact of the aggregation
state of alanes on the enantioselectivity, see: M. G. Pizzuti, A. J.
Minnaard, B. L. Feringa, Org. Biomol. Chem. 2008, 6, 3464–3466.
[20] D. Mꢀller, A. Alexakis, Org. Lett. 2013, 15, 1594–1597.
[21] M. Tori, T. Hamaguchi, K. Sagawa, M. Sono, Y. Asakawa, J. Org.
Chem. 1996, 61, 5362–5370.
[22] J. J. Eisch, S. Rhee, J. Am. Chem. Soc. 1975, 97, 4673–4682.
[23] K. Akiyama, F. Gao, A. H. Hoveyda, Angew. Chem. 2010, 122, 429–
433; Angew. Chem. Int. Ed. 2010, 49, 419–423.
[24] J. J. Eisch, M. W. Foxton, J. Org. Chem. 1971, 36, 3520–3526.
[25] E. J. Corey, G. Lalic, Tetrahedron Lett. 2008, 49, 4894–4896.
[26] a) G. Zweifel, J. A. Miller, Org. React. 1984, 32, 375–517; b) A.
Alexakis, J.-M. Duffault, Tetrahedron Lett. 1988, 29, 6243–6246.
[27] F. Gao, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 10961–10963.
pentane (1.0 mL, 0.08 mmol CuII, 13 mol%) and
a solution of L17
(64 mg, 0.13 mmol, 22 mol%) in toluene (2.0 mL). This mixture was
stirred under an atmosphere of argon for 1 h at 228C. Then, the in
situ-formed complex was cooled to À308C and alane A19 (1.0 mL,
1.5 equiv, 0.9m solution in heptane) and 3-methylcyclohex-2-enone S1
(68 mL, 66 mg, 0.60 mmol, 1.0 equiv) were sequentially added through
a syringe. The solution was allowed to stir at À308C for 14 h, after which
the reaction was quenched with methanol (0.2 mL) at À308C. Then, an
aqueous solution of HCl (10%, 4 mL) was added followed by Et2O
(10 mL). The phases were separated, and the aqueous phase was extract-
ed with Et2O (2ꢄ15 mL). The combined organic phases were vigorously
shaken with an aqueous solution of H2O2 (0.2 mL, 0.6m solution), passed
through a short plug of Na2SO4 and silica gel and eluted with Et2O. Then,
the filtrate was concentrated under reduced pressure to provide a green
oil, which was purified by silica gel chromatography (pentane/Et2O=9:1)
to afford ((E)-3-(hex-1-enyl)-3-methylcyclohexanone 10 (84 mg,
0.43 mmol, 72% yield) as a colorless viscous oil.
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A. Alexakis and D. Mꢀller
[28] J. Kabbara, S. Flemming, K. Nickisch, H. Neh, J. Westermann, Tetra-
hedron 1995, 51, 743–754.
[32] Table 18, entry 3 shows that the preference for fast transmetalation
of the alkenyl group is solvent dependent.
[29] A. Alexakis, J. E. Bꢈckvall, N. Krause, O. Pꢅmies, M. Diꢆguez,
Chem. Rev. 2008, 108, 2796–2823.
[33] A comparison of the methodologies was recently carried out; see
ref. [17b].
[30] F. Green, C. A. Clausen, Int. Biodeterior. Biodegrad. 2005, 56, 75–
79.
[31] Q. Naeemi, T. Robert, D. Kranz, J. Velder, H.-G. Schmalz, Tetrahe-
dron: Asymmetry 2011, 22, 887–892.
Received: July 21, 2013
Published online: && &&, 2013
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Formation of Quaternary Stereogenic Centers
FULL PAPER
Asymmetric Synthesis
D. Mꢀller, A. Alexakis* ..... &&&& — &&&&
Formation of Quaternary Stereogenic
Centers by Copper-Catalyzed Asym-
metric Conjugate Addition Reactions
of Alkenylaluminums to Trisubstituted
Enones
Chiral synthesis made easy: The
centers (see scheme; CuTC=copper(I)
thiophene-2-carboxylate). Chiral phos-
phinamines (SimplePhos) ligands were
found to be highly efficient for this
transformation.
copper-catalyzed conjugate addition of
alkenylaluminum reagents to 3-substi-
tuted cyclic enones allows for the for-
mation of all-carbon chiral quaternary
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15
&
ÞÞ
These are not the final page numbers!