Enantioselective synthesis of tertiary and quaternary stereogenic centers: Copper/phosphoramidite-catalyzed allylic alkylation with organolithium reagents

Article abstract of DOI:10.1002/anie.201107840

An efficient and highly enantioselective copper-catalyzed allylic alkylation of disubstituted allyl halides with primary and secondary organolithium reagents using phosphoramidite ligands is reported. The use of trisubstituted allyl bromides allows, for the first time, the enantioselective synthesis of all-carbon quaternary stereogenic centers with these reactive organometallic reagents.

Full text of DOI:10.1002/anie.201107840

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Angewandte
Communications
DOI: 10.1002/anie.201107840
Asymmetric Catalysis
Enantioselective Synthesis of Tertiary and Quaternary Stereogenic
Centers: Copper/Phosphoramidite-Catalyzed Allylic Alkylation with
Organolithium Reagents**
Martꢀn FaÇanꢁs-Mastral, Manuel Pꢂrez, Pieter H. Bos, Alena Rudolph,
Syuzanna R. Harutyunyan,* and Ben L. Feringa*
Copper-catalyzed asymmetric allylic alkylation (AAA) has
become a very powerful tool for the enantioselective con-
struction of optically active tertiary carbon stereocenters.[1]
À
Recently, this C C bond-forming reaction has also been
successfully applied to the challenging enantioselective syn-
thesis of all-carbon quaternary stereogenic centers in acyclic
systems.[2] Organozinc,[3] aluminium,[4] and Grignard[5]
reagents have been shown to be highly effective in the
AAA reaction. However, the cheap and readily available
organolithium reagents have not been successfully used in the
Scheme 1. Copper/TaniaPhos-catalyzed AAA of allyl bromides with
organolithium reagents
À
catalytic asymmetric C C bond formation of quaternary
centers until now.
Organolithium reagents are among the most versatile and
widely used reagents in organic synthesis.[6] However, the
nature of these extremely reactive reagents has hampered its
accessible phosphoramidites[12] might be suitable ligands for
this transformation.
Herein, we report that the use of phosphoramidites as
chiral ligands allows the use of both allyl chlorides or
bromides in highly enantioselective allylic alkylations in
combination with primary as well as secondary organolithium
reagents. We also found that a phosphoramidite-based copper
catalyst provides all-carbon quaternary stereogenic centers in
an enantioselective manner.
We started our study by screening different copper salts,
phosphoramidite ligands, and reaction conditions for the
addition of n-butyllithium to cinnamyl chloride (1a)
(Table 1). The use of copper(I) thiophene carboxylate
(CuTC)[13] as the copper salt and the phosphoramidite
ligand L1 (Figure 1) in a 1:2 ratio gave rise to modest
À
use in enantioselective catalytic C C bond-formation pro-
cesses, and successful applications pertain to the use of
stoichiometric amounts of chiral ligands[7] or to catalytic
asymmetric deprotonations[8] and additions to imines,[9] often
with high catalyst loadings and modest enantioselectivities.
Recently, we reported for the first time a general and
highly enantioselective catalytic method for the direct addi-
tion of organolithium reagents through a copper-catalyzed
asymmetric allylic alkylation.[10] By using a catalyst compris-
ing CuBr·SMe2 and TaniaPhos as a chiral ligand, and by
selecting a proper combination of dichloromethane and n-
hexane as solvent and co-solvent, we could tame the highly
reactive alkyllithium reagents and apply these in a catalytic,
highly regio- and enantioselective allylic alkylation of a large
variety of allyl bromides (Scheme 1). A limitation found for
the CuBr·SMe2/TaniaPhos system was that the use of simple
allyl chlorides or secondary organolithium reagents in combi-
nation with this catalyst led to disappointing selectivities.[11]
However, we showed in preliminary studies[10] that easily
Table 1: Screening of ligands and reaction conditions for the copper-
catalyzed allylic substitution with nBuLi.[a]
Entry Cu salt
L
[Cu]/L Addition 2a/3a[b] e.r.[c] (2a)
[*] Dr. M. FaÇanꢀs-Mastral, Dr. M. Pꢁrez, P. H. Bos, Dr. A. Rudolph,
Dr. S. R. Harutyunyan, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
time [h]
1
2
3
4
5
6
7
CuTC
CuTC
L1
L1
1:2
1:1
1:1
1:1
1:1
1:1
1:1
2
2
2
5
5
5
5
58:42
71:29
70:30
91:9
38:62
49:51
82:18
67:33
86:14
91:9
CuBr·SMe2 L1
CuBr·SMe2 L1
CuBr·SMe2 L2
CuBr·SMe2 L3
CuBr·SMe2 L4
98:2
b.l.feringa@rug.nl
Homepage: http://feringa.fmns.rug.nl/
66:34
86:14
20:80
[**] We thank the Netherlands Organization for Scientific Research
(NWO-CW) and the National Research School Catalysis (NRSC-C)
for financial support. M. P. thanks the Xunta de Galicia for an
Angeles AlvariÇo contract and Fondo Social Europeo.
[a] Reactions performed on a 0.2 mmol scale. nBuLi was diluted with n-
hexane and added dropwise. Full conversion was reached in all cases.
[b] SN2’/SN2 ratio determined by GC and 1H NMR analysis. [c] Deter-
mined by GC analysis using a chiral stationary phase.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107840.
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Chemie
The phosphoramidite/copper-catalyzed AAA proved to
be also very efficient with allyl bromides, thus providing a
complementary catalytic procedure for the earlier TaniaPhos-
based method.[10] The addition of nBuLi to cinnamyl bromide
(4a) afforded the product 2a with comparable regio- and
enantioselectivity as observed for 1a (Table 2, entry 2).
Different primary alkyl lithium reagents gave also very
good enantioselectivities both with the chloride 1a and
bromide 4a (entries 3–6). When the allyl chloride 1b bearing
the more sterically demanding 1-naphthyl substituent was
used, the reaction still gave a good level of enantioselectivity
but the SN2’/SN2 products were obtained in a 1:1 ratio
(entry 7). However, when the analogous allyl bromide 4b
was used the corresponding product 2d was obtained with
high enantioselectivity and good regioselectivity (entry 8).
Remarkably, the catalytic system also tolerates the presence
of aromatic halides. Both p-chloro-substituted cinnamyl
chloride (1c) and bromide (4c) could be used without any
lithium–halogen exchange and with excellent enantioselec-
tivity (97:3 to > 99:1 e.r.; entries 9–12). Alkyl-substituted allyl
halides could also be used for this transformation. Both
substrates bearing cyclic (R = Cy; entry 13) and acyclic (R =
Me; entry 14) aliphatic substituents afforded the correspond-
ing products 2h and 2i with good selectivity but with slightly
lower e.r. values.
Figure 1. Phosphoramidite ligands.
selectivity (entry 1). A drastic improvement in the regio- and
enantioselectivity was observed when a 1:1 copper/ligand
ratio was used (entry 2). By changing the copper salt to
CuBr·SMe2 we observed an enhancement of the enantiose-
lectivity, thus obtaining 2a with a 91:9 e.r. (entry 3). A longer
addition time of 5 hours, using CuBr·SMe2 as the preferred
copper salt, afforded the desired product 2a with an excellent
SN2’/SN2 ratio of 91:9 and 98:2 e.r. (entry 4). The use of
different phosphoramidite ligands (Figure 1) did not improve
these results (entries 5–7).
Once having established the optimized reaction condi-
tions (Table 1, entry 4), we examined the scope of the copper/
phosphoramidite-catalyzed addition of primary organo-
lithium reagents to both allyl chlorides and bromides
(Table 2). Excellent yields and enantiomeric ratios were
obtained in nearly all cases.
The use of the optimal ligand L1 for the addition of
primary organolithium reagents in the reaction of a secondary
organolithium reagent, such as sec-BuLi, to 1a afforded the
desired compound 5a as a mixture of diastereoisomers with
good regioselectivity (SN2’/SN2 91:9) but with disappointing
enantioselectivity (Table 3, entry 1). The phosphoramidite L3
Table 3: Optimization for the allylic substitution with sec-BuLi.[a]
Table 2: Copper/phosphoramidite-catalyzed allylic substitution of allyl
chlorides and bromides with primary organolithium reagents.[a]
Entry
X
L
5/6[b,c]
e.r.[b]
5a
5a’
Entry
X
1/4 (R)
R’
2/3[b] Yield [%][c]
e.r.[d] (2)
1[d]
2[e]
3[f]
4[g]
Cl
Cl
Cl
Br
L1
L2
L3
L3
91:9
90:10
97:3
60:40
28:72
91:9
66:34
26:74
91:9
1
2
3
4
5
6
7
8
Cl 1a (Ph)
Br 4a (Ph)
Cl 1a (Ph)
Br 4a (Ph)
Cl 1a (Ph)
Br 4a (Ph)
nBu 91:9
nBu 87:13
nHex 80:20
nHex 89:11
90
92
90
91
98:2 (2a)
96:4 (2a)
98:2 (2b)
99:1 (2b)
96:4 (2c)
95:5 (2c)
96:4 (2d)
95:5 (2d)
98:2 (2e)
97:3 (2e)
98:2 (2 f)
>99:1 (2g)
88:12 (2h)
91:9 (2i)
79:21
69:31
71:29
[a] Reaction conditions: see Table 2. Full conversion was reached in all
cases. [b] Determined by GC analysis using a chiral stationary phase.
[c] Compound 6a was obtained as a racemic mixture in all cases.
[d] d.r.=1.5:1. [e] d.r.=1.2:1. [f] d.r.=1:1. [g] d.r.=1.3:1.
Et[e]
85:15
88:12
90[f]
95[f]
93
Et[e]
Cl 1b (1-naphthyl) nBu 50:50
Br 4b (1-naphthyl) nBu 85:15
91
89
88
9
Cl 1c (4-ClC6H4)
Br 4c, 4-Cl-C6H4
Cl 1c (4-ClC6H4)
Cl 1c (4-ClC6H4)
Cl 1d (Cy)
nBu 90:10
nBu 85:15
10
11
12
13
14
was found to be the most effective ligand for the addition of
sec-BuLi, thus affording the compound 5a with a high SN2’/
SN2 ratio (97:3) and 91:9 e.r. for both diastereoisomers
(entry 3).[14] In this case, the use of the more reactive cinnamyl
bromide (4a) led to a decrease in both regio- and enantio-
selectivity of the reaction (entry 4).
By using the optimized ligand L3, the addition of sec-BuLi
to different allyl chlorides 1 provided the corresponding
products 5 in high yields and with high regioselectivities and
Et[e]
89:11
72
nHex 80:20
nBu 90:10
nHex 90:10
87
91
Br 4d (Me)
99[f]
[a] Reactions performed on a 0.2 mmol scale. The corresponding
organolithium reagent was diluted with n-hexane and added over 5 h.
[b] SN2’/SN2 ratios determined by GC and 1H NMR analysis. [c] Yield of
isolated product. [d] Determined by GC analysis using a chiral stationary
phase. [e] EtLi was diluted with toluene. [f] Conversion.
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Communications
Table 4: Copper/phosphoramidite-catalyzed allylic substitution with
Table 5: Enantioselective copper/phosphoramidite-catalyzed synthesis
secondary organolithium reagents.[a]
of quaternary carbon atoms with organolithium reagents.[a]
Entry 9 (R)
R’
10/11[b] Yield [%][c] e.r.[d] (10)
Entry
1 (R)
R’
5/6 or
7/8[b]
Yield
[%][c]
e.r.[e]
(5[d] or 7)
1
9a (Ph)
nBu
nHex
nBu
nHex
nBu
nHex
nBu
98:2
92:8
97:3
92
92
72
90
91
74
77
92
90
89
90
93
93
92:8 (10a)
86:14 (10b)
90:10 (10c)
91:9 (10d)
88:12 (10e)
89:11 (10 f)
88:12 (10g)
53:47 (10h)
53:47 (10i)
95:5 (10j)
2
9a (Ph)
1[d]
2[d]
3[d]
1a (Ph)
Me
Me
Me
97:3
92:8
93:7
80
85
96
91:9 (5a)
91:9 (5a’)
88:12 (5b)
88:12 (5b’)
90:10 (5c)
88:12 (5c’)
96:4 (7a)
94:6 (7b)
96:4 (7c)
91:9 (7d)
3
4
5
6
9b (4-ClC6H4)
9b (4-ClC6H4)
9c (4-MeC6H4)
9c (4-MeC6H4)
9d (Cy)
94:6
94:6
91:9
1b (1-naphthyl)
1c (4-ClC6H4)
7
98:2
92:8
91:9
8
9
9e (2-MeC6H4)
9e (2-MeC6H4)
nBu
nHex
4
5
6
7
1a (Ph)
H
H
H
H
90:10
96:4
92:8
77
98
95
83
1b (1-naphthyl)
1c (4-ClC6H4)
1d (Cy)
10
11
12
13
9 f (2-MeOC6H4) nBu
9 f (2-MeOC6H4) nHex
9g (2-BrC6H4)
9g (2-BrC6H4)
98:2
95:5
>98:2
95:5 (10k)
92:8 (10l)
89:11
nBu
nHex >98:2
91:9 (10m)
[a]–[c] See Table 2. Full conversion was reached in all cases. [d] d.r. =1:1.
[e] Determined by GC or HPLC analysis using a chiral stationary phase.
[a]–[c] See Table 2. Addition time: 10 h. Full conversion was reached in all
cases. [d] Determined by GC or HPLC analysis using a chiral stationary
phase.
enantioselectivities (Table 4, entries 1–3). Although the
e.r. values are only up to 91:9, it is important to note that
these examples represent, to the best of our knowledge, the
first catalytic asymmetric transfer of the sec-butyl moiety.
Furthermore, the isopropyl moiety has been a challenging
secondary alkyl group to transfer by the copper-catalyzed
AAA, and generally only modest enantioselectivities are
obtained with cinnamyl substrates and other organometallic
reagents.[3b,15] Remarkably, by using iPrLi in combination with
CuBr·SMe2 and L3, we could achieve 96:4 e.r. in the allylic
alkylation of 1a (entry 4). Similar to the addition of primary
organolithium reagents, the addition of iPrLi to the more
sterically demanding 1b and the p-chloro-substituted 1c gave
rise to high enantioselectivities (entries 5 and 6). The
cyclohexyl-substituted allyl chloride 1d could also be used,
but with slightly lower regio- and enantioselectivity were
obtained (entry 7).
This new protocol was found to be very efficient with
primary alkyl organolithium reagents, such as nBuLi and n-
HexLi, which gave excellent regioselectivity and good
enantioselectivities ranging from 86:14 to 92:8 e.r. when the
phenyl derivative 9a (entries 1 and 2) and p-chloro- and p-
methyl-substituted allyl bromides 9b,c were used (entries 3–
6). An alkyl-substituted allyl bromide, such as the cyclohexyl
derivative 9d, could also be used in this transformation to
afford the desired product 10g with excellent regioselectivity
and good enantioselectivity (entry 7). An intriguing and
synthetically highly significant observation was made when
ortho-substituted cinnamyl bromides were used. Reactions
with the o-methyl-substituted bromide 9e still showed very
good regioselectivity but the corresponding products 10h,i
were obtained as a nearly racemic mixture (entries 8 and 9).
In sharp contrast, when the o-methoxy-substituted bromide
9 f was used the desired products 10j,k were obtained with
excellent stereoselectivity (95:5 e.r.) and with almost total
SN2’ selectivity (entries 10 and 11). A similar trend in the
regio- and enantioselectivity was observed when another
substrate bearing a coordinating functionality in the ortho
position, such as o-bromo-substituted cinnamyl bromide (9g),
was used (entries 12 and 13). These results suggest that a
possible coordination between the methoxy or bromide
substituent atom and the copper complex can be a key
factor to afford high enantioselectivity when ortho-substi-
tuted cinnamyl bromides are used. It is also important to note,
as described above for other aromatic halides, that there was
no evidence of the common lithium–halogen exchange even
in the case of o-bromo-substituted cinnamyl bromide 9g.
In summary, we have developed efficient catalytic and
highly enantioselective methodology for the asymmetric
alkylation of both allyl chlorides and bromides with organo-
lithium reagents using monodentate phosphoramidites as
chiral ligands. These protocols include efficient asymmetric
Notably, by using the same catalytic system (CuBr·SMe2/
L3) phenyllithium could be used in the allylic substitution of
p-chloro cinnamylbromide 4c, thus providing the correspond-
ing diaryl-substituted product with > 99:1 e.r. but with low
regioselectivity (SN2’/SN2 40:60).[10]
This protocol could also be extended to the first enantio-
selective synthesis of all-carbon quaternary stereogenic
centers employing organolithium reagents. After extensive
screening of different phosphoramidite ligands (see the
Supporting Information for details), ligand L4 (Figure 1)
turned out to be the best ligand for the addition of nBuLi to
E-trisubstituted allyl bromide 9a (Table 5). When nBuLi was
added over a 10 hour period to a solution of 9a and the
catalyst at À808C, the reaction gave rise to the product 10a
with 92:8 e.r. and with nearly perfect SN2’ selectivity (entry 1).
The use of the trisubstituted allyl chloride analogue of 9a did
not result in any conversion. By using these optimized
reaction conditions we examined the scope of this new
method for the enantioselective synthesis of all-carbon
quaternary centers (Table 5).
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Chemie
[3] a) N. Harrington-Frost, H. Leuser, M. I. Calaza, F. F. Kneisel, P.
addition of both primary and secondary organolithium
reagents. Furthermore, for the first time, the enantioselective
synthesis of quaternary carbon stereogenic centers using
these extremely reactive organometallic reagents is pre-
sented.
Knochel, Org. Lett. 2003, 5, 2111 – 2114; b) H. Leuser, S.
Perrone, F. Liron, F. F. Kneisel, P. Knochel, Angew. Chem.
2005, 117, 4703 – 4707; Angew. Chem. Int. Ed. 2005, 44, 4627 –
4631; c) M. A. Kacprzynski, A. H. Hoveyda, J. Am. Chem. Soc.
2004, 126, 10676 – 10681; d) J. J. Van Veldhuizen, J. E. Campbell,
R. E. Giudici, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127,
6877 – 6882; e) M. A. Kacprzynski, T. L. May, S. A. Kazane,
A. H. Hoveyda, Angew. Chem. 2007, 119, 4638 – 4642; Angew.
Chem. Int. Ed. 2007, 46, 4554 – 4558.
Experimental Section
Typical procedure: A Schlenk tube equipped with septum and stirring
bar was charged with CuBr·SMe2 (0.01 mmol, 2.06 mg, 5 mol%) and
the appropriate ligand (0.012 mmol, 6 mol%). Dry dichloromethane
(2 mL) was added and the solution was stirred under nitrogen at room
temperature for 15 min. Then, the allyl halide (0.2 mmol) was added
and the resulting solution was cooled to À808C. In a separate Schlenk
tube, the corresponding organolithium reagent (0.24 mmol, 1.2 equiv)
was diluted with n-hexane (combined volume of 1 mL) under
nitrogen and added dropwise to the reaction mixture over 5 h (over
10 h for quaternary centers) using a syringe pump. Once the addition
was complete, the mixture was stirred for another 2 h at À808C. The
reaction was quenched with a saturated aqueous NH4Cl solution
(2 mL) and the mixture was warmed up to room temperature, diluted
with dichloromethane and the layers were separated. The aqueous
layer was extracted with dichloromethane (3 ꢀ 5 mL) and the
combined organic layers were dried with anhydrous Na2SO4, filtered,
and the solvent was evaporated in vacuo. The crude reaction mixture
was purified by flash chromatography on silica gel using different
mixtures of n-pentane/Et2O as the eluent.
[4] a) F. Gao, K. P. McGrath, Y. Lee, A. H. Hoveyda, J. Am. Chem.
Soc. 2010, 132, 14315 – 14320; b) F. Gao, Y. Lee, K. Mandai,
A. H. Hoveyda, Angew. Chem. 2010, 122, 8548 – 8552; Angew.
Chem. Int. Ed. 2010, 49, 8370 – 8374.
[5] a) B. Breit, P. Demel, C. Studte, Angew. Chem. 2004, 116, 3874;
Angew. Chem. Int. Ed. 2004, 43, 3785 – 3789; b) Y. Lee, A. H.
Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604 – 15605; c) O.
Jackowski, A. Alexakis, Angew. Chem. 2010, 122, 3418 – 3422;
Angew. Chem. Int. Ed. 2010, 49, 3346 – 3350.
[6] The Chemistry of Organolithium Compounds (Eds.: Z. Rappo-
port, I. Marek), Wiley-VCH, Weinheim, 2004.
[7] a) E. J. Corey, R. Naef, F. J. Hannon, J. Am. Chem. Soc. 1986,
108, 7114 – 7116; b) S. E. Denmark, C. M. Stiff, J. Org. Chem.
2000, 65, 5875 – 5878; c) M. R. Luderer, W. F. Bailey, M. R.
Luderer, J. D. Fair, R. J. Dancer, M. B. Sommer, Tetrahedron:
Asymmetry 2009, 20, 981 – 998.
[8] a) J. L. Bilke, S. P. Moore, P. OꢅBrien, J. Gilday, Org. Lett. 2009,
11, 1935 – 1938; b) T. K. Beng, R. E. Gawley, J. Am. Chem. Soc.
2010, 132, 12216 – 12217.
[9] a) K. Tomioka, I. Inoue, I. Mitsuru, S. Kenji, K. Koga,
Tetrahedron Lett. 1991, 24, 3095 – 3098; b) S. E. Denmark, N.
Nakajima, O. J.-C. Nicaise, J. Am. Chem. Soc. 1994, 116, 8797 –
8798; c) A. Alexakis, F. Amiot, Tetrahedron: Asymmetry 2002,
13, 2117 – 2122.
[10] M. Pꢃrez, M. FaÇanꢄs-Mastral, P. H. Bos, A. Rudolph, S. R.
Harutyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 377 – 381.
[11] The CuBr·SMe2/TaniaPhos-catalyzed addition of nBuLi to
cinnamyl chloride gave rise to an SN2’/SN2 ratio of 10:90 with
55:45 e.r. for the SN2’ product. The addition of sec-BuLi to
cinnamyl bromide in combination with this catalyst gave a
13:42:43 mixture of SN2’/SN2/homocoupling products, with the
SN2’ product being racemic.
Received: November 7, 2011
Revised: December 9, 2011
Published online: January 19, 2012
Keywords: allylic compounds · copper · ligand effects ·
.
organolithium reagents · synthetic methods
[1] For reviews, see: a) A. S. E. Karlstrçm, J. E. Bꢁckvall in Modern
Organocopper Chemistry (Ed.: N. Krause), Wiley-VCH, Wein-
heim, 2002; b) H. Yorimitsu, K. Oshima, Angew. Chem. 2005,
117, 4509 – 4513; Angew. Chem. Int. Ed. 2005, 44, 4435 – 4439;
c) S. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard,
B. L. Feringa, Chem. Rev. 2008, 108, 2824 – 2852; d) A. Alexakis,
J. E. Bꢁckvall, N. Krause, O. Pꢂmies, M. Diꢃguez, Chem. Rev.
2008, 108, 2796 – 2823; For recent examples, see: e) K. B. Selim,
Y. Matsumoto, K. Yamada, K. Tomioka, Angew. Chem. 2009,
121, 8889 – 8891; Angew. Chem. Int. Ed. 2009, 48, 8733 – 8735;
f) K. Akiyama, F. Gao, A. H. Hoveyda, Angew. Chem. 2010, 122,
429 – 433; Angew. Chem. Int. Ed. 2010, 49, 419 – 423; g) J. F.
Teichert, S. Zhang, A. W. van Zijl, J. W. Slaa, A. J. Minnaard,
B. L. Feringa, Org. Lett. 2010, 12, 4658 – 4660; h) J.-B. Langlois,
A. Alexakis, Angew. Chem. 2011, 123, 1917 – 1921; Angew.
Chem. Int. Ed. 2011, 50, 1877 – 1881; i) M. FaÇanꢄs-Mastral, B.
ter Horst, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2011,
47, 5843 – 5845; j) P. Tosatti, A. J. Campbell, D. House, A.
Nelson, S. P. Marsden, J. Org. Chem. 2011, 76, 5495 – 5501.
[2] For a review, see: a) J. Prakash, I. Marek, Chem. Commun. 2011,
47, 4593 – 4623; For a review on the formation of quaternary
centers through metal-catalyzed asymmetric conjugate addition,
see: b) C. Hawner, A. Alexakis, Chem. Commun. 2010, 46,
7295 – 7306.
[12] J. F. Teichert, B. L. Feringa, Angew. Chem. 2010, 122, 2538 –
2582; Angew. Chem. Int. Ed. 2010, 49, 2486 – 2528.
[13] CuTC has been shown to be an effective copper salt in
combination with phosphoramidite ligands in the copper-cata-
lyzed AAA with Grignard reagents. For some examples, see:
a) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. 2004,
116, 2480 – 2482; Angew. Chem. Int. Ed. 2004, 43, 2426 – 2428;
b) M. FaÇanꢄs-Mastral, B. L. Feringa, J. Am. Chem. Soc. 2010,
132, 13152 – 13153; c) J.-B. Langlois, A. Alexakis, Adv. Synth.
Catal. 2010, 352, 447 – 457.
[14] It is important to note that the configuration of the newly formed
stereocenter is controlled by the catalyst while the presence of
two diastereoisomers is the result of using a racemic alkyllithium
reagent.
[15] a) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147 – 4149;
b) A. W. van Zijl, L. A. Arnold, A. J. Minnaard, B. L. Feringa,
Adv. Synth. Catal. 2004, 346, 413 – 420; c) W. Lçlsberg, S. Ye, H.-
G. Schmalz, Adv. Synth. Catal. 2010, 352, 2023 – 2031.
Angew. Chem. Int. Ed. 2012, 51, 1922 –1925
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