Creation of quaternary stereogenic centers via copper-catalyzed asymmetric conjugate addition of alkenyl alanes to α,β-unsaturated cyclic ketones

Article abstract of DOI:10.1055/s-0029-1219958

SimplePhos ligands proved to be very powerful ligands in the generation of quaternary stereogenic centers by Michael addition of alkenyl-aluminum reagents to cyclic enones. Using commercially available and easily accessible alkenylbromides as alane precursors the present procedure offers a facile access to β-alkenyl-substituted cyclohexanones with high enantioselectivities up to 96%. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219958

1694
CLUSTER
Creation of Quaternary Stereogenic Centers via Copper-Catalyzed Asymme-
tric Conjugate Addition of Alkenyl Alanes to a,b-Unsaturated Cyclic Ketones
C
reationof Quarte
a
rnaryStere
n
ogenic Cente
i
r
s
el Müller, Christine Hawner, Matthieu Tissot, Laëtitia Palais, Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneve 4, Switzerland
Fax +41(22)3793215; E-mail: alexandre.alexakis@unige.ch
Received 16 March 2010
other nucleophile precursors, namely bromoolefins, of
Abstract: SimplePhos ligands proved to be very powerful ligands
in the generation of quaternary stereogenic centers by Michael ad-
dition of alkenyl-aluminum reagents to cyclic enones. Using com-
mercially available and easily accessible alkenylbromides as alane
which many are commercially available or easily accessi-
ble synthetically.8 Using a variant of the procedure pub-
lished by Seebach,9 we employed two equivalents of
precursors the present procedure offers a facile access to b-alkenyl- t-BuLi to perform the bromo–lithium exchange and then
substituted cyclohexanones with high enantioselectivities up to
96%.
quenched the corresponding alkenyllithium with Me2AlCl
to generate the mixed alane species (Scheme 1). On the
Key words: aluminum, alkenes, copper, Michael addition, asym-
metric catalysis
contrary the use of n-BuLi for the Br–Li exchange lead in
the case of 2-bromopropene to acetylenic byproducts.9
R2
R2
R2
Me
Al
Me2AlCl
The landmark discovery about the rhodium-catalyzed
conjugate addition of organoboron reagents to electron-
deficient olefins by Miyaura and co-workers1 in 1997
gave rise to tremendous research efforts towards its asym-
metric version.2 Already in 1998 Hayashi showed that the
use of a rhodium–BINAP complex achieved high enantio-
selectivities for the ACA of boronic acids to acyclic and
cyclic enones.3 In his report he also employed alkenyl bo-
ronic acids which afforded the corresponding products
with high enantioselectivity. In contrast to the advances in
this fast-growing field of rhodium-catalyzed ACA, the
copper-catalyzed ACA employing alkenyl nucleophiles
has been rather neglected and only few examples have
been reported so far.4
t-BuLi
Br
Li
R3
R3
R3
Me
(2 equiv)
(1 equiv)
R1
R1
R1
Scheme 1 Generation of mixed alane species
It is well known, that in the case of mixed alane species
the substituents with sp- and sp2-carbon centers attached
to the aluminum are faster transferred than substituents
bearing sp3-carbon centers.10,13 Therefore the two alkyl
substituents act usually as ‘dummy substituents’ meaning
in most cases they transfer in small quantities or not at
all.4d To investigate the 1,4 addition to b-substituted cy-
clic enones we chose 3-methylcyclohex-2-enone as a
Michael acceptor and dimethyl(prop-1-en-2-yl)aluminum
as nucleophile. From our experiences with the conjugate
addition employing trialkylalanes and mixed aryl-
alanes,4c,d,f we knew that CuTC as copper source, diethyl
ether as solvent, and temperatures about –30 °C were
good parameters to start with and screened under these
conditions various ligands (Table 1, Figure 1, Scheme 2).
In our continuing interest in the copper-catalyzed ACA
we are focusing our attention towards the creation of qua-
ternary centers via Michael addition.4d,5 To this date no
example has been published of the creation of quaternary
stereogenic centers via the rhodium-catalyzed ACA with
alkenyl nucleophiles and enones as substrates.6 For
copper-catalyzed ACA only some examples have been
published so far; which include the drawback of using
high catalyst loadings up to 30 mol%.4c,d,f
Mixed alanes as previously shown,4d,7 combine strong nu-
cleophilicity as well as electrophilic activation via com-
plexation of the carbonyl moiety and thus allow the
addition of various nucleophiles to tertiary substituted
a,b-unsaturated ketones. From our previous investiga-
tions we knew that iodoolefins as precursors underwent
this transformation with good enantioselectivity.4d How-
ever, this protocol was quite sensitive to the presence of in
situ generated LiI, and so we decided to experiment with
The results of the ligand screening confirmed previous ob-
servations: An increase of the steric bulk on the BIPOL or
aryl part and on the amine part promotes the enantioselec-
tivity.4f This trend holds true for BIPOL (entries 3 vs. 4,
Table 1), as well as for the SimplePhos ligands (entries 5
vs. 10, Table 1). To our delight SimplePhos ligands, a new
class of ligands recently developed in our group,4f,11
showed to be superior over all other classes of ligands we
employed for the screening (Figure 1). SimplePhos ligand
L11 which was already successfully used for the copper-
catalyzed ACA using trialkyl- and mixed aryl-alanes
proved to be the most selective of its class.4d,f Interesting-
ly, the electronic properties seem to play a major role in
this transformation, the electron-poor ligand L9 gave al-
most racemic mixtures whereas the phenyl-substituted
ligand L10 gave similar results as L11. For the majority
of the optimization reactions we continued using the sim-
SYNLETT 2010, No. 11, pp 1694–1698
x
x
.x
x
.2
0
1
0
Advanced online publication: 04.06.2010
DOI: 10.1055/s-0029-1219958; Art ID: Y00110ST
© Georg Thieme Verlag Stuttgart · New York

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Creation of Quaternary Stereogenic Centers
1695
Table 1 Screening of the Ligandsa
Table 2 Study of the Effect of the Amount of Alane Added in the
ACA as Described in Scheme 2a,b
Entry
Ligand
Conv.
(%)b
Methyl/alkenyl ee
transferb
4:96
11:87
3/97
4:96
2:98
3:97
10:90
3:97
2:98
2:98
4:96
n.d.
(%)c
Entry
Alane
(equiv)
Conv.
(%)c
Methyl/alkenyl ee
transferc
(%)d
1
2
L1
94
85
12 (R)
5 (S)
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
3:97
49 (R)
52 (R)
62 (R)
66 (R)
68 (R)
73 (R)
78 (R)
L2
3:97
3
L3
98
18 (R)
32 (R)
43 (R)
49 (R)
26 (R)
19 (R)
rac.
6:94
4
L4
100
98
5:95
5
L5
9:91
6
L6
100
97
20:80
25:75
7
L7
8
L8
98
a Reaction conditions as described in Scheme 2.
b Ligand L5 was used for the optimization.
c Determined by GC-MS.
9
L9
88
d Determined by chiral GC.
10
11
12
13
L10
L11
L12
(R)-BINAP
100
100
2
59 (R)
63 (R)
n.d.
tivity in the addition of 2-thienylalane to 2¢-acetophen-
one,12 therefore we considered investigating the
dependency of the enantioselectivity on the amount of
alane used for the reaction (Table 2). To our surprise the
amount of alane added had a huge influence on the enan-
tioselectivity and caused significant changes up to 30% in
difference.
57
n.d.
13 (R)
a Reaction conditions as described in Scheme 2.
b Determined by GC-MS.
c Determined by chiral GC.
Even though less equivalents of alane afforded higher
enantioselectivity it also led to an increase of undesired
methyl transfer. We considered therefore the use of 2.0
plest SimplePhos ligand L5 due to its simple one-step
synthesis.4f Gau and co-workers showed that the amount
of alane used had a significant impact on the enantioselec-
R1
(S)
R1
(S)
R2
(S)
O
O
O
O
P
N
(S)
P
N
(S)
P
N
(S)
P
P
Fe
R2
R1
R1
H
. EtOH
R1 = Ph, R2 = H
L5:
L6:
L7:
L8:
L9:
R
R
R
R
1 = Ph, R2 = 4-Me
1 = Ph, R2 = 2-OMe
1 = Ph, R2 = 2-Naph
1 = 2-Naph, R2 = 3-CF3
L3: R1 = Ph
L1 (R,S,S)
L2 (S,S,S)
L12
L4: R1= 2-Naph
R1 = 2-Naph, R2 = H
L10:
L11:
R
1 = 2-Naph, R2 = 3, -Me2
Figure 1 Screened ligands
Me
Me
Br
Li
Al
Me2AlCl (1.0 equiv)
t-BuLi (2.0 equiv)
Et2O, −78°C, 1 h
Et2O, −78 °C, 1 h,
then 20 °C, 18 h
1
2
3
O
O
(3.0 equiv)
supernatant solution
(R)
CuTC (10 mol%), ligand (11mol%)
Et2O, −30 °C, 18 h
4
5
Scheme 2 Standard reaction used for optimization
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1696
D. Müller et al.
CLUSTER
equivalents of alane as the best compromise between Diethyl ether as a solvent for complex formation seems to
enantioselectivity and methyl transfer (entry 4, Table 2). be necessary for good conversions (entries 1 and 5,
Screening of various copper sources led in a couple of cas- Table 4), whereas MTBE favored high enantioselectivites
es to a significant increase in enantioselectivity but also to (entries 5 and 6, Table 4). To ensure complete conversion
an increase in methyl transfer (entries 3 and 4, Table 3). and at the same time to increase the enantioselectivity we
Therefore we decided to continue using CuTC as a copper prepared the complex in diethyl ether and the alane in
source which afforded acceptable levels of enantioselec- MTBE which afforded the same levels of enantioselectiv-
tivities while reducing the amount of methyl transfer.
ity as observed when employing 15 mol% of the ligand
(entry 2). For all the above results the reactions were per-
formed on a typical scale of 10.8 mmol, in order to ensure
the consistency of the alane we prepared. To exclude a de-
pendency of the reaction outcome on the amount of alane
prepared we synthesized several propenyl-alane solutions
in diethyl ether in a 1.8–4.5 mmol scale and observed no
major difference in enantioselectivity by using these solu-
tions. We also investigated the stability of the propenyl-
alane stock solutions and observed that storing the solu-
tion at room temperature over one month afforded compa-
rable levels of enantioselectivity and conversion. This
finding shows that alkenylalanes possess the same levels
of stability as previously observed for arylalanes.7 Before
testing the optimized conditions for different substrates
we wanted to check if the addition of lithium salts and
variations in the t-BuLi/Me2AlCl ratio would have an in-
fluence on the reaction (Table 5).
Table 3 Screening of Different Copper Sourcesa,b
Entry
CuX
Conv.
(%)c
Methyl/alkenyl ee
transferc
(%)d
1
2
3
4
5
6
7
CuTC
100
63
5:95
66 (R)
32 (R)
73 (R)
70 (R)
66 (R)
63 (R)
59 (R)
CuCN
4:96
Cu(OAC)2·H2O
CuCl2
100
73
12:88
11:89
21:79
19:81
5:95
Cu(acac)2
Cu(OTf)2
CuBr
100
93
97
a Reaction conditions as described in Scheme 2, except the use of
2.0 equiv of alane.
b Ligand L5 was used for the optimization.
c Determined by GC-MS.
Table 5 Influence of Lithium Salts and Variation of the t-BuLi/
Me2AlCl Ratio on the Reaction Outcomea,b
d Determined by chiral GC.
Entry
Ratio t-BuLi/ Conv. (%)c Methyl/alkenyl ee (%)d
Me2AlCl
2.0:1.0
2.0:1.0
1.8:1.0
2.0:0.9
transferb
We also investigated the influence of the solvent on the re-
action and found that THF led to almost racemic mixtures,
CH2Cl2 to high methyl transfer and hexane to low conver-
sion. Good results were only observed with methyl tert-
butyl ether (MTBE) and diethyl ether (Table 4).
1
100
100
91
6:94
93 (R)
83 (R)
83 (R)
77 (R)
2e
3
4:96
30:70
4:96
Table 4 Investigation of Various Ratios of MTBE and Et2O on the
4
100
Enantioselectivitya,b
a Reaction conditions as described in Scheme 2, except the use of
2.0 equiv of alane and complex formation in MTBE.
b Ligand L11 was employed.
Entry Solventc
Solventd
Conv.
(%)e
Methyl/alke- ee
nyl transfere (%)f
c Determined by GC-MS.
d Determined by chiral GC.
1
2
3
4
5
6
Et2O
Et2O
100
96
3:97
6:94
23:67
3:97
6:94
5:95
89 (R)
e Addition of salts.
Et2O
Et2Og
Et2Oh
MTBE
Et2O
93 (R)
93 (R)
95 (R)
93 (R)
96 (R)
Et2O
100
91
The addition of salts proved to be detrimental for the
enantioselectivity (Table 5, entry 2). The investigation of
the t-BuLi/Me2AlCl showed that ensuring a precise ratio
of t-BuLi and Me2AlCl was critical to achieve good con-
versions and enantioselectivities.13 Any excess of either
t-BuLi or Me2AlCl led to a loss of enantioselectivity (en-
tries 3 and 4) and in the case of an excess of Me2AlCl also
to low conversion and high methyl transfer (entry 3).
Therefore we used only fresh solutions of t-BuLi and
Me2AlCl to ensure that the used concentration was as
close to the indicated concentrations as possible. With the
optimized conditions in hand we applied this methodolo-
gy to various nucleophiles and substrates and carried out
the reactions on a 1.5 mmol scale instead of a 0.3 mmol
scale, as used for the optimization reactions, in order to
Et2O
MTBE
MTBE
100
58
MTBE
a Reaction conditions as described in Scheme 2, except the use of
2.0 equiv of alane.
b Ligand L11 was employed.
c Solvent used for the generation of the alane.
d Solvent used for the complex formation (CuTC and ligand).
e Determined by GC-MS.
f The ee was determined by chiral GC.
g 15mol% of ligand used.
h Cu(OAc)2·H2O was used as copper source.
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Creation of Quaternary Stereogenic Centers
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Table 6 Screening of Alkenylalanes15
H
AlMe2
R2
R1
O
O
5: R1 = Me, R2 = H
H
(2.0 equiv)
supernatant solution
6: R1 = H, R2 = n-Bu
7: R1 = H, R2 = Ph
R2
(R)
CuTC (10 mol%), L11 (11 mol%)
Et2O, MTBE, pentane, heptane
8: R1 = Ph, R2 = H
R1
9: R1 = H, R2 = 4-ClC6H4
4
−30 °C, 18 h
Conv. (%)a
Methyl/alkenyl transfera Yield (%)b
[a]D
ee (%)c
91 (R)
76 (R)
91 (R)
94 (R)
96 (R)
20
Entry
Product
1
2
3
4
5
5
6
7
8
9
100
94
97
94
97
4:96
2:98
85
50
64
27
71
–62.5
–39.2
–70.8
–35.6
–92.1
0:100
11:89
1:99
a Determined by GC-MS.
b Isolated yield.
c The ee was determined by chiral GC and chiral SFC.
prove its synthetic use (Table 6). For methcyclohexenone drop of conversion and enantioselectivity was observed.
4 all the tested nucleophiles gave good to excellent levels The difficulties encountered when using cyclopentenones
of enantioselectivity. The difference in enantioselectivity as substrates for the copper-catalyzed ACA have been re-
for product 5 (entry 1, Table 5 vs. entry 1, Table 6) is ported several times in the literature.4d,e,5 We believe that
probably due to a slightly different ratio in the t-BuLi/ the reason for the drop in reactivity is the diminished or-
Me2AlCl ratio. Due to the sensitivity of the reaction to- bital overlap between the p-orbitals of the C=O bond and
wards the purity of the alkenyl alane slight variations on
enantioselectivity are inevitable. In the case of product 6,
n-hexenylbromide as nucleophile precursor contained 9%
of an impurity which we could not remove by common
purification methods. Whether this impurity is responsi-
ble for the drop in enantioselectivity is not clear yet. Prod-
uct 8 has been isolated in poor yield due to the fact that
commercially available a-bromostyrene contains approx-
imately 4% of the trans-b-bromostyrene which was much
faster transferred and thus led to a 8:92 ratio of 7/8.14 Nev-
ertheless we succeeded in separating compound 8 from 7
and the methyl adduct by column chromatography. This
shows that, especially in the case of secondary bromoalk-
enes as nuclophile precursors, it is absolutely vital to
avoid b-bromoalkene impurities which might lead to a
large amount of undesired and difficult to separate side
product.
Table 7 Screening of Substrates
Me
Me
Al
O
3
O
(2.0 equiv)
supernatant solution
CuTC (10 mol%), L11 (11 mol%)
Et2O, MTBE, pentane, heptane
−30 °C, 18 h
R
n
R
n
Entry
1
Substrate
Conv.
(%)a
Methyl/alkenyl ee
transfera
(%)b
49
n.d.
48
O
It should also be noted that encumbered nucleophiles led
to higher levels of methyl transfer whereas in the case of
unhindered nucleophiles, such as the nucleophiles leading
to products 6, 7, and 9 almost no methyl transfer was ob-
served. The absolute configuration of compound 6 has
been determined by comparison of its optical rotation with
previously reported data,4d whereas for compounds 5, 7–9
we suppose that the ligand directs the attack towards the
same facial side, as demonstrated for SimplePhos ligands
before.4f
10
O
2
3
19
17
0:100
n.d.
43
83
Ph
11
12
O
Having explored different kinds nucleophiles, we wanted
to explore the reaction scope by choosing more challeng-
ing substrates such as 10–12. Unfortunately, in all cases a
a Determined by GC-MS.
b The ee was determined by chiral GC.
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D. Müller et al.
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Simpson, M. J.; Nyman, S. Tetrahedron 1996, 52, 12509.
(b) Abbas, S.; Hayes, C. J.; Worden, S. Tetrahedron Lett.
2000, 41, 3215. (c) Wolfe, J. P.; Yang, Q.; Hay, M. B.; Ney,
J. E. Adv. Synth. Catal. 2005, 347, 1614.
the C=C bond due to a smaller interior angle of the cyclo-
pentenone scaffold. This would lead to a higher LUMO at
the b-position and thus lower the reactivity. A conjugating
group such as phenyl will probably also lead to a deacti-
vation of the b-position of the conjugated system by de-
creasing the positive partial charge via p-donation. This
would explain the drop in conversion for substrate 11.
Substrate 12 shows that the reaction is much more sensi-
tive to bulky substrates than to sterically demanding nu-
cleophiles such as 8. The level of enantioselectivity,
however, did only drop slightly (entry 3, Table 7).
(9) (a) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847.
(b) Seebach, D.; Neumann, H. Tetrahedron Lett. 1976, 52,
4839.
(10) (a) Zezschwitz, P. Synthesis 2008, 1809. (b) Wipf, P.;
Smitrovich, J. H.; Moon, C. J. Org. Chem. 1992, 57, 3178.
(c) Zweifel, G.; Miller, J. A. Org. React. (N.Y.) 1984, 32,
375.
(11) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.; Falciola,
C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.; Bernardinelli,
G.; Alexakis, A. Angew. Chem. Int. Ed. 2007, 46, 7462.
(12) Biradar, D.; Zhou, S.; Gau, H. Org. Lett. 2009, 11, 3386.
(13) The same observation was made previously for the addition
of trimethylsilylacetylene to 2-cyclohexen-1-one: Corey,
E. J.; Kwak, Y. Org. Lett. 2004, 6, 3385.
(14) The same observation has been reported previously:
Otomaru, Y.; Hayashi, T. Tetrahedron: Asymmetry 2004,
15, 2647.
In summary, we have described an efficient copper-cata-
lyzed 1,4-addition of vinyl alanes to cyclic enones. Reac-
tions are promoted by SimplePhos ligands which afford
the desired b-alkenylcycloalkanones in up to 96% enanti-
oselectivity. The present methodology allows ACA reac-
tions to create quaternary stereogenic centers employing
commercially available or easily accessible alkenylbro-
mides.
(15) General Procedure for the Cu-Catalyzed ACA
Employing Alkenylalanes Exemplified for Product 5
To a solution of 2-propenylbromide (480 mL, 653 mg, 5.4
mmol, 1.0 equiv) in MTBE (6.0 mL) was added under inert
atmosphere a fresh solution of t-BuLi (6.75 mL, 10.8 mmol,
1.6 M in pentane, 2.0 equiv) at –78 °C. The reaction was
stirred for 30 min at this temperature. Then a fresh solution
of Me2AlCl (6.0 mL, 5.4 mmol, 0.9 M in heptane, 1.0 equiv)
was added, and the reaction mixture was stirred for another
2 h maintaining the temperature at –78 °C. Now the cooling
bath was removed, and the reaction vessel was immediately
submerged in a water bath. The alane was stirred over night
at r.t., and 1 h before use of the solution for catalysis stirring
was stopped to ensure precipitation of the salts. Then, 10.5
mL corresponding to 2.0 equiv of the supernatant solution of
alane was taken out with a syringe and slowly added to the
metal complex. In a separate flask, CuTc (28.5 mg, 0.15
mmol, 10 mol%), ligand L11 (93.5 mg, 0.17 mmol, 11
mol%), and Et2O (5.0 mL) were thoroughly stirred at r.t.
for 1 h. Then the flask was cooled to –30 °C, and the
corresponding alane (10.5 mL, 3.0 mmol, 2.0 equiv) was
added. After 15 min of stirring 3-methyl-2-cyclohexenone
4 (170 mL, 165 mg, 1.50 mmol, 1 equiv) was added, and the
reaction mixture was stirred for 18 h at this temperature.
Then the reaction mixture was quenched at –30 °C with
MeOH (1.0 mL) and let warm to r.t. An aqueous solution of
HCl (10%, 15 mL) was added, followed by Et2O (50 mL).
Extraction of the aqueous phase with Et2O (2 × 50 mL) and
addition of NaOCl solution (10%, 4 mL) to the combined
organic solvents afforded a pale yellow suspension which
after extensive shaking turned into a blue suspension.16 After
removal of the aqueous phase the organic phase was dried
over Na2SO4, and the solvent was removed in vacuo. The
remaining crude oil was purified by flash chromatography
(SiO2; pentane–Et2O = 7:1), and the pure compound 5 was
afforded as a colorless oil with a pleasant eucalyptus like
fragrance (194 mg, 1.27 mmol, 85%, Rf = 0.23 in pentane–
Et2O = 9:1). The analytical data were in accord with the ones
reported in the literature.17 Chiral separation: Chirasil
DEX-CB, 60-0-1-115-0-20-170, 50 cm/s, tR1 = 44.80 min,
tR2 = 47.35 min.
Challenging substrates, such as 10–12 evidently need
more powerful ligands for better enantioselectivity and
conversion. The development of such ligands and applica-
tion of the methodology towards the synthesis of natural
products are among the objectives being pursued in our
laboratories.
Acknowledgment
We thank the Swiss National Research Foundation (grant
N° 200020-126663) and COST action D40 (SER contract N°
C07.0097) for financial support, as well as BASF for the generous
gift of chiral amines.
References and Notes
(1) Sakai, M.; Hayashi, H.; Miyaura, N. J. Organomet. Chem.
1997, 16, 4229.
(2) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(3) Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc.
1998, 120, 5579.
(4) (a) Ahn, K. H.; Klassen, R. B.; Lippard, S. J.
Organometallics 1990, 9, 3178. (b) Alexakis, A.; Albrow,
V.; Biswas, K.; d’Augustin, M.; Prietob, O.; Woodward, S.
Chem. Commun. 2005, 2843. (c) Vuagnoux-d’Augustin,
M.; Alexakis, A. Chem. Eur. J. 2007, 13, 9647.
(d) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew.
Chem. Int. Ed. 2008, 47, 8211. (e) Lee, K.; Hoveyda, A. H.
J. Org. Chem. 2009, 74, 4455. (f) Palais, L.; Alexakis, A.
Chem. Eur. J. 2009, 15, 10473. (g) Robert, T.; Velder, J.;
Schmalz, H.-G. Angew. Chem. Int. Ed. 2008, 47, 7718.
(5) (a) d’Augustin, M.; Palais, L.; Alexakis, A. Angew Chem.
Int. Ed. 2005, 44, 1376. (b) Vuagnoux-d’Augustin, M.;
Kehrli, S.; Alexakis, A. Synlett 2007, 2057.
(6) Creation of quaternary stereogenic centers to a highly
activated substrate via Rh-catalyzed ACA with
alkenylboronic acids: Mauleón, P.; Carretero, J. C. Chem.
Commun. 2005, 4961.
(16) NaOCl solution was added to oxidize remaining SimplePhos
ligand L11 and thus facilitate the purification.
(17) Xiong, H.; Rieke, D. R. J. Org. Chem. 1991, 56, 3109.
(7) May, L. T.; Brown, M. K.; Hoveyda, A. H. Angew. Chem.
Int. Ed. 2008, 47, 7358.
(8) For some examples for the synthesis of various
bromoolefins, see: (a) Al Dulayymi, J. R.; Baird, M. S.;
Synlett 2010, No. 11, 1694–1698 © Thieme Stuttgart · New York