Modular amino acids-based chiral ligands for copper-catalyzed enantioselective conjugation addition of diethylzinc to cyclic enones

Article abstract of DOI:10.1002/chir.20881

New amino acid-based modular chiral ligands were readily synthesized and used to catalyze the asymmetric conjugate addition of Et₂Zn to various cyclic enones in the presence of a variety of copper sources. Moderately high ee of up to 72% were o

Full text of DOI:10.1002/chir.20881

CHIRALITY 23:105–112 (2011)
Modular Amino Acids-Based Chiral Ligands for Copper-Catalyzed
Enantioselective Conjugation Addition of Diethylzinc to
Cyclic Enones
*
SHAOHUA GOU AND ZAHER M. A. JUDEH
Division of Chemical and Biomolecular Engineering, School of Chemical and Biomedical Engineering,
Nanyang Technological University, Singapore
ABSTRACT
New amino acid-based modular chiral ligands were readily synthesized
and used to catalyze the asymmetric conjugate addition of Et2Zn to various cyclic
enones in the presence of a variety of copper sources. Moderately high ee of up to 72%
were obtained using ligand (S)-1e under mild conditions. Chirality 23:105–112,
C
VV
2011.
2010 Wiley-Liss, Inc.
KEY WORDS: alkylation; amino acids; conjugate addition; diethylzinc; enones
INTRODUCTION
ligands have the advantages of straightforward synthesis,
high resistance to oxidation (normally encountered in
phosphorus-containing ligands), and facile modular con-
struction that allows for easy variation of the amine substit-
uent and the amino acid backbone. This class of ligands
has been designed to mimic the most successful nonphos-
phorus chiral sulfonamides that are known to give up to
90% ee in the conjugate addition of Et2Zn to enones.32–34
The results of our investigation presented here demon-
strates the usefulness of these ligands in the copper-cata-
lyzed enantioselective conjugate addition of Et2Zn to sev-
eral cyclic enones.
The asymmetric conjugate addition of dialkylzinc
reagents to a,b-unsaturated substrates is a powerful car-
bon–carbon bond forming reaction.1–3 It has been success-
fully applied to many substrates such as cyclic and acyclic
enones, nitro olefins, amides, lactones, lactams, and malo-
nates to give desirable products useful for the synthesis of
biologically active compounds.4–9 Specifically, chiral cop-
per complexes have proved to be very effective in the con-
jugate addition of dialkylzinc derivatives to cyclic and acy-
clic enones. Key to this success is the design and develop-
ment of catalytic and highly efficient phosphorus-
containing chiral ligands such as phosphites,10–18 diphos-
phites,19,20 phosphoramidites,8,21–26 P,O-ligand,27 and P,N-
ligand.15,28–31 However, nonphosphorus chiral ligands
have been less explored and their success has remained
rather limited. For example, several chiral sulfona-
mides,32–36 diaminocarbenes,37–41 oxazolines,42 thioether-
hydroxyl ligand,43–47 N,N-ligand,48 and N,S-ligand48–50
have been reported to give moderate to excellent enantio-
selectivities depending upon the ligand, substrate, and
reaction conditions. Changes in the stereoelectronic prop-
erties of chiral ligands can often lead to dramatic variation
in the reactivity and enantioselectivity of reactions involv-
ing such ligands. Therefore, we are interested in new, sta-
ble, and modular chiral ligands with the aim of synthesiz-
ing a small library that can be used for efficient enantiose-
lective copper-catalyzed 1,4-conjugate addition of
dialkylzinc reagents to a,b-unsaturated compounds. To
achieve this aim, cheap and readily available components
that can undergo straightforward chemical modifications
to give the desired chiral catalysts in high yields are
needed. For this purpose, amino acids that are known to
catalyze a variety of enantioselective reactions have been
chosen.51–53 The general structure of the target ligands is
shown in Figure 1. These ligands are synthesized from L-
phenylalanine and incorporate a sulfonamide, an amide,
EXPERIMENTAL
General Remarks
All reactions were conducted in oven-dried glassware
under inert atmosphere of nitrogen using anhydrous sol-
vents unless otherwise stated. Analytical thin layer chro-
matography was performed on alumina- or glass-backed
silica plates (F254, 250-lm thickness) and visualized under
UV light. Flash column chromatography was carried out
on silica gel 60 (230–400 mesh) under air pressure. Enan-
tiomeric ratios of the products were determined using chi-
ral GC techniques. Specific rotations were determined as
[a]2D0 (c 5 0.02 g/ml in CH2Cl2). Melting points are uncor-
rected. Only the more representative frequencies (cm21
)
1
are reported for IR spectra. H NMR (300 MHz) and 13C
NMR (75 MHz) chemical shifts in CDCl3 are quoted as d
values relative to tetramethylsilane (d 5 0.00) and CDCl3
Contract
grant
sponsor:
Nanyang
Technological
University;
Contract grant number: RG27/07
*Correspondence to: Zaher Judeh, School of Chemical and Biomedical
Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2
B1-14, Singapore 637459. E-mail: zaher@ntu.edu.sg
Received for publication 21 July 2009; Accepted 22 April 2010
DOI: 10.1002/chir.20881
Published online 14 June 2010 in Wiley Online Library
and a hydroxyl or an alkoxy groups. These sulfonamide ( wileyonlinelibrary.com).
C
VV
2010 Wiley-Liss, Inc.

106
GOU AND JUDEH
Fig. 1. Structures of ligands synthesized from L-phenylalanine.
(d 5 77.0), respectively, in parts per million and coupling 129.2, 130.0, 136.9, 144.2, 168.2; HRMS (ESI) calculated
constants in hertz. The following abbreviations are used to for C22H23N2O3S 395.1429, found 395.1438.
indicate the multiplicity: s, singlet; d, doublet; t, triplet; q,
(S)-N-(p-Toluenesulfonyl)-phenylalanine
o-tolyla-
quartet; m, multiplet. High-resolution mass spectra
(HRMS) were obtained using positive electrospray ioniza-
tion (m/z values are given). All commercially available
chemicals were used as received, unless otherwise noted.
Chiral ligands 1d and 3a (Scheme 1) were synthesized
according to published literature procedures.54,55
mide (1b). White solid; 87% yield; m.p.183–1858C; [a]D20
291.50 (c 5 0.02 g/ml in CH2Cl2); IR mmax cm21 (KBr)
3237, 1531, 1442 (NHCO), 1665 (CO), 1334, 1163 (SO2);
1H NMR (CDCl3) d 2.13 (s, 3H), 2.42 (s, 3H), 2.98 (q, J 5
6.3 Hz, 1H), 3.09 (q, J 5 6.9 Hz, 1H), 4.03 (dd, J1 5 6.3 Hz,
J2 5 6.6 Hz, 1H), 5.04 (d, J 5 6.6 Hz, 1H), 6.96–6.99 (m,
2H), 7.05–7.24 (m, 8H), 7.56 (d, J 5 8.4 Hz, 2H), 7.71 (d, J
5 7.8 Hz, 1H), 8.03 (s,1H); 13C NMR (CDCl3) d 17.49,
21.59, 38.16, 58.44, 122.63, 125.50, 126.64, 127.22, 127.47,
129.14, 129.18, 129.44, 129.97, 130.50, 134.92, 135.00,
135.30, 144.21, 168.29; HRMS (ESI) calculated for
C23H25N2O3S 409.1586, found: 409.1598.
General Procedure for the Synthesis of Ligands
1, 2, and 3
3-Phenyl-2-(toluene-4-sulfonylamino)-propionyl
chlo-
ride54,55 (405 mg, 1.2 mmol) was added to a solution of ani-
line or phenylamine (1 mmol) and Et3N (0.21 ml, 1.5
mmol) in CH2Cl2 (10 ml) at 228C. After stirring for 2 h, the
reaction mixture was diluted with CH2Cl2 (50 ml), washed
with aqueous HCl (1.0 M, 2 3 20 ml), aqueous K2CO3 or
NaHCO3 (1.0 M, 2 3 20 ml), and then with brine (2 3 20
ml). The organic layer was dried over MgSO4, filtered,
and evaporated to dryness on a rotary evaporator. The
crude products were purified using column chromatogra-
phy on silica gel (EA-Hexane) and recrystallized from a
mixture of EA:hexane (10:1, v:v). The corresponding prod-
ucts were obtained as white solids in 80–95% yield.
(S)-N-(p-Toluenesulfonyl)-phenylalanine 2-isopro-
pylphenylamide (1c). White solid; 85% yield; m.p.160–
1628C; [a]D20 267.47 (c 5 0.02 g/ml in CH2Cl2); IR mmax
cm21 (KBr) 3312, 1522, 1436 (NHCO), 1665 (CO), 1332,
1
1156 (SO2); H NMR (CDCl3) d 1.19 (t, J 5 6.9, 6H), 2.43
(s, 3H), 2.95 (q, J 5 6.0 Hz, 1H), 3.15 (q, J 5 6.6 Hz, 1H),
3.15 (dd, J1 5 J2 5 6.3 Hz, 1H), 4.96 (d, J 5 6.6 Hz, 1H),
6.98 (t, J 5 5.4 Hz, 2H), 7.17–7.28 (m, 9H), 7.59 (d, J 5 7.8
Hz, 3H), 8.07 (s, 1H); 13C NMR (CDCl3) d 21.61, 22.94,
23.04, 27.67, 30.96, 38.02, 58.34, 124.02, 125.63, 126.25,
126.30, 127.22, 127.48, 129.15, 129.20, 130.00, 133.37,
134.95, 135.44, 140.55, 168.56; HRMS (ESI) calculated for
C25H29N2O3S 437.1899, found 437.1907.
(S)-N-(p-Toluenesulfonyl)-phenylalanine
phenyla-
mide (1a). White solid; 95% yield; m.p. 174–1768C; [a]D20
282.23 (c 5 0.02 g/ml in CH2Cl2); IR mmax cm21 (KBr)
3335, 1538, 1436 (NHCO), 1600 (CO), 1333, 1159 (SO2);
1H NMR (CDCl3) d 2.39 (s, 3H), 2.99 (q, J 5 6.3 Hz, 1H),
(S)-N-(p-Toluenesulfonyl)-phenylalanine 2-methoxy-
3.06 (q, J 5 6.9 Hz, 1H), 3.98 (dd, J 5 6.6 Hz, 1H), 5.04 (d, phenylamide (1e). White solid; 83% yield; m.p.166–
J 5 6.6 Hz, 1H), 6.96–6.99 (m, 2H), 7.12–7.37 (m, 10H), 1688C; [a]2D0 256.79 (c 5 0.02 g/ml in CH2Cl2); IR mmax
7.58 (q, J 5 6.6 Hz, 2H), 7.9 (s, 1H). 13C NMR (CDCl3) d cm21 (KBr) 3242, 1541, 1481 (NHCO), 1661 (CO), 1330,
1
21.6, 38.3, 58.4, 120.2, 124.9, 127.3, 127.5, 129.0, 129.1, 1159 (SO2); H NMR (CDCl3) d 2.36 (s, 3H), 2.98 (q, J 5
Scheme 1. Synthesis of amino acid-based ligands.
Chirality DOI 10.1002/chir

AMINO ACIDS-BASED CHIRAL LIGANDS
107
6.6 Hz, 1H), 3.09 (q, J 5 6.3 Hz, 1H), 3.80 (s, 3H), 4.04 (d,
(S)-N-(p-Toluenesulfonyl)-phenylalanine
benzyla-
J 5 6.6 Hz, 1H), 5.04 (d, J 5 6.6 Hz, 1H), 6.82–7.07 (m, mide (2a). White solid; 87% yield; m.p. 138–1408C; [a]D20
5H), 7.18–7.22 (m, 4H), 7.59 (d, J 5 8.4 Hz, 2H), 8.19–8.22 212.03 (c 5 0.02 g/ml in CH2Cl2); IR mmax cm21 (KBr)
(m, 1H), 8.39 (s, 1H); 13C NMR (CDCl3) d 21.50, 38.72, 3253, 1542, 1437 (NHCO), 1654 (CO), 1332, 1160 (SO2);
55.77, 58.67, 110.09, 119.74, 120.91, 122.45, 124.32, 127.20, 1H NMR (CDCl3) d 2.44 (s, 3H), 2.94 (q, J 5 6.0 Hz, 1H),
128.96, 129.28, 129.78, 135.15, 143.93, 167.86; HRMS (ESI) 3.02 (q, J 5 6.6 Hz, 1H), 4.32–4.37 (m, 1H), 4.99 (q, J 5
calculated for C23H25N2O4S 425.1535, found 425.1549.
7.2 Hz, 1H), 6.66 (d, J 5 4.8 Hz, 1H), 6.89 (d, J 5 6.3 Hz,
2H), 7.01–7.04 (m, 2H), 6.92–7.31 (m, 10H), 7.56 (m, 2H);
13C NMR (CDCl3) d 21.53,38.49, 43.50, 58.10, 127.04,
127.07, 127.38, 217.55, 128.55, 128.75, 129.24, 129.74,
135.40, 136.04, 137.51, 143.68, 170.36; HRMS (ESI) calcu-
lated for C23H25N2O3S 409.1586 found 409.1599.
(S)-N-(p-Toluenesulfonyl)-phenylalanine 3-methoxy-
phenylamide (1f). White solid; 88% yield; m.p. 145–
1478C; [a]D20 276.95 (c 5 0.02 g/ml in CH2Cl2); IR mmax cm21
(KBr) 3242, 1541, 1487 (NHCO), 1661 (CO), 1330, 1159
1
(SO2); H NMR (CDCl3) d 2.41 (s, 3H), 2.96 (q, J 5 6.6 Hz,
1H), 3.09 (q, J 5 6.9 Hz, 1H), 3.79 (s, 3H), 3.97 (q, J 5 6.9 Hz,
(S)-N-(p-Toluenesulfonyl)-phenylalanine 2-methoxy-
1H), 5.03 (d, J 5 6.9 Hz, 1H), 6.66–6.83 (m, 1H), 6.84–6.87 benzylamide (2b). White solid; 83% yield; m.p. 106–
(m, 1H), 6.88–6.99 (m, 2H), 7.08–7.23 (m, 7H), 7.57 (d, J 5 1088C; [a]2D0 212.15 (c 5 0.02 g/ml in CH2Cl2); IR mmax
8.4 Hz, 2H), 7.95 (s, 1H);13C NMR (CDCl3) d 21.54, 38.29, cm21 (KBr) 3244, 1542, 1439 (NHCO), 1641 (CO), 1258,
1
55.32, 58.45, 105.84, 110.75, 112.36, 127.24, 127.46, 129.13, 1161 (SO2); H NMR (CDCl3) d 2.42 (s, 3H), 2.80 (q, J 5
129.19, 129.63, 129.95, 138.04, 144.23, 160.08, 168.14; HRMS 6.9 Hz, 1H), 3.02 (q, J 5 6.6 Hz, 1H), 3.55 (s, 3H), 3.74 (s,
(ESI) calculated for C23H25N2O4S, 425.1535, found 425.1546.
1H), 4.32 (d, J 5 6.0 Hz, 2H), 4.91 (s, 1H), 6.65 (s, 1H),
6.83–6.92 (m, 4H), 7.07–7.33 (m, 7H), 7.56 (d, J 5 8.1 Hz,
2H); 13C NMR (CDCl3) d 21.60, 38.46, 39.60, 55.24, 57.78,
110.23, 120.54, 127.12, 128.82, 128.92, 129.21, 129.55,
129.80, 135.18, 143.84, 157.49, 169.45; HRMS (ESI) calcu-
lated for C24H27N2O4S 439.1692 found 439.1703.
(S)-N-(p-Toluenesulfonyl)-phenylalanine 4-methoxy-
phenylamide (1g). White solid; 90% yield; m.p. 144–
1468C; [a]D20 278.66 (c 5 0.02 g/ml in CH2Cl2); IR mmax
cm21 (KBr) 3330, 1533, 1411 (NHCO), 1660 (CO), 1334,
1
1250 (SO2); H NMR (CDCl3) d 2.17 (s, 3H), 2.93 (q, J 5
6.3 Hz, 1H), 3.10 (q, J 5 6.9 Hz, 1H), 3.79 (s, 3H), 3.96 (q,
(S)-N-(p-Toluenesulfonyl)-phenylalanine 3-methoxy-
J1 5 13.5 Hz, J1 5 6.6 Hz, 1H), 4.96 (d, J 5 6.6 Hz, 1H), benzylamide (2c). White solid; 86% yield; m.p. 107–
6.81–6.85 (m, 2H), 6.86–6.99 (m, 2H), 7.17–7.25 (m, 9H), 1098C; [a]2D0 25.28 (c 5 0.02 g/ml in CH2Cl2); IR mmax
7.58 (d, J 5 8.1 Hz, 2H), 7.79 (s, 1H); 13C NMR (CDCl3) d cm21 (KBr) 3248, 1541, 1490 (NHCO), 1654 (CO), 1339,
21.55, 38.41, 55.48, 58.43, 114.10, 122.10, 127.25, 127.43, 1157 (SO2); 1H NMR (CDCl3) d 2.43 (s, 3H), 2.89–3.02 (m,
129.08, 129.21, 129.92, 144.15, 156.84, 167.98; HRMS (ESI) 2H), 3.79 (s, 3H), 3.90 (d, J 5 6.3 Hz, 1H), 4.33 (d, J 5 6.0
calculated for C23H25N2O4S, 425.1535, found 425.1547.
Hz, 2H), 4.95 (s, 1H), 6.62–6.92 (m, 6H), 7.12–7.24 (m,
6H), 7.53 (d, J 5 8.4 Hz, 2H); 13C NMR (CDCl3) d 21.60,
38.27, 43.63, 55.29, 57.92, 64.40, 113.03, 113.23, 119.84,
127.14, 127.39, 128.96, 129.17, 129.67, 129.86, 135.10,
143.97, 159.86; HRMS (ESI) calculated for C24H27N2O4S
439.1692 found 439.1705.
(S)-N-(p-Toluenesulfonyl)-phenylalanine 2-methoxy-
5-methyl-phenylamide (1h). White solid; 92% yield;
m.p. 186–1898C; [a]D20 254.45 (c 5 0.02 g/ml in CH2Cl2);
IR mmax cm21 (KBr) 3367, 1541, 1491 (NHCO), 1664 (CO),
1330, 1162 (SO2); 1H NMR (CDCl3) d 2.29 (s, 3H), 2.36 (s,
3H), 2.97 (q, J 5 6.6 Hz, 1H), 3.10 (q, J 5 6.6 Hz, 1H), 3.76
(S)-N-(p-Toluenesulfonyl)-phenylalanine 4-methoxy-
(s, 3H), 4.04 (d, J 5 6.0 Hz, 1H), 5.11 (d, J 5 6.0 Hz, 1H), benzylamide (2d). White solid; 91% yield; m.p. 129–
6.72 (d, J 5 8.4 Hz, 1H), 6.84 (d, J 5 8.1 Hz, 1H), 6.92 (d, J 1318C; [a]2D0 26.09 (c 5 0.02 g/ml in CH2Cl2); IR mmax
5 9.6 Hz, 2H), 6.99–7.20 (m, 5H), 7.60 (d, J 5 8.1 Hz, 2H), cm21 (KBr) 3251, 1541, 1513 (NHCO), 1652 (CO), 1328,
1
8.04 (s, 1H), 8.36 (s, 1H); 13C NMR (CDCl3) d 20.95, 1161 (SO2); H NMR (CDCl3) d 2.43 (s, 3H), 2.88 (q, J 5
21.52, 55.90, 58.65, 109.96, 120.35, 124.54, 127.20, 128.98, 6.3 Hz, 1H), 2.99 (q, J 5 6.9 Hz, 1H), 3.79 (s, 3H), 3.90 (d,
129.09, 129.80, 130.39, 135.13, 143.92, 167.81; HRMS (ESI) J 5 6.6 Hz, 1H), 4.25 (d, J 5 5.4 Hz, 2H), 4.98 (d, J 5 6.3
calculated for C24H27N2O4S 439.1692, found 139.1702.
Hz, 1H), 6.49 (s, 1H), 6.80 (d, J 5 6.9 Hz, 2H), 6.91 (d, J 5
7.5 Hz, 2H), 7.03–7.27 (m, 7H), 7.54 (d, J 5 6.6 Hz, 2H);
13C NMR (CDCl3) d 21.56, 34.60, 38.34, 40.99, 55.28,
57.88, 114.08, 127.16, 127.30, 128.94, 129.18, 129.66,
129.82, 130.49, 135.24, 143.92, 169.82; HRMS (ESI) calcu-
lated for C24H27N2O4S 439.1692 found 439.1702.
(S)-N-(p-Toluenesulfonyl)-phenylalanine 2-phenox-
ylphenylamide (1i). White solid; 87% yield; m.p. 103–
1058C; [a]D20 256.13 (c 5 0.02 g/ml in CH2Cl2); IR mmax
cm21 (KBr) 3256, 1535, 1451 (NHCO), 1663 (CO), 1329,
1
1218 (SO2); H NMR (CDCl3) d 2.35 (s, 3H), 2.98 (d, J 5
6.6 Hz, 2H), 3.98 (d, J 5 6.6 Hz, 1H), 4.00 (d, J1 5 J2 5 6.6
N-(p-Toluenesulfonyl)-L-phenylalanine
(R)-1-(4-
Hz, 1H), 4.89 (d, J 5 6.3 Hz, 1H), 6.83–7.37 (m, 14H), 7.55 methoxyphenyl)-ethylamide (3b). White solid; 91%
(d, J 5 8.4 Hz, 2H), 8.28 (d, J2 5 6.3 Hz, 1H), 8.42 (s, 1H); yield; m.p. 125–2178C; [a]2D0 116.02 (c 5 0.02 g/ml in
13C NMR (CDCl3) d 21.53, 38.43, 58.54, 101.80, 117.90, CH2Cl2); IR mmax cm21 (KBr) 3264, 1541, 1514 (NHCO),
118.63, 120.98, 123.87, 123.91, 124.69, 127.00, 127.37, 1652 (CO), 1330, 1240 (SO2); 1H NMR (CDCl3) d 1.32 (d, J
128.74, 128.99, 129.15, 129.81, 129.91, 134.85, 143.98, 5 6.9 Hz, 3H), 2.42 (s, 3H), 2.83 (q, J 5 6.9 Hz, 1H), 3.03
146.01, 156.24, 168.19; HRMS (ESI) calculated for (q, J 5 6.6 Hz, 1H), 3.79 (s, 3H), 3.84 (d, J 5 8.1 Hz, 1H),
C28H27N2O4S 487.1692, found 487.1706.
4.87–4.96 (m, 2H), 6.29 (d, J 5 7.2 Hz, 1H), 6.81–6.91 (m,
Chirality DOI 10.1002/chir

108
GOU AND JUDEH
TABLE 1. Asymmetric conjugate addition of Et2Zn to
2-cyclohexen-1-one 4a catalyzed by CuI complexes of
ligands 1-3
4H), 7.06 (d, J 5 8.7 Hz, 2H), 7.13–7.22 (m, 5H), 7.55 (d, J
5 8.1 Hz, 2H); 13C NMR (CDCl3) d 21.41, 21.60, 38.51,
48.53, 55.32, 57.75, 113.93, 127.13, 127.32, 128.98, 129.26,
129.86, 134.71, 135.21, 125.82, 143.92, 158.83, 168.88;
HRMS (ESI) calculated for C25H29N2O4S 453.1848 found
453.1856.
General Procedure for Catalytic Asymmetric Conjugate
Addition
Entrya
Ligand
Yield (%)b
ee (%)c
A mixture of copper source (0.03 mmol) and ligand
(0.03 mmol) in an appropriate solvent (1.0 ml) was stirred
under nitrogen atmosphere at 228C for 10 min and then
cooled to 08C. Et2Zn (0.44 mmol, solution in toluene) was
added dropwise and the mixture was stirred for 1 h. Enone
(0.20 mmol) was then added and the resulting mixture
was stirred for 24 h before being quenched by aqueous
HCl (1.0 M). The mixture was extracted with Et2O (3 3
20 ml), the organic phases were combined, dried over
Na2SO4, filtered, and evaporated to dryness using rotary
evaporator. The crude product was purified by column
chromatography on silica gel (EA-hexane). The ee values
of the products were determined by chiral GC G-TA as
follows.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
3a
3b
3c
88
84
61
54
77
70
80
83
53
73
62
90
83
87
73
43
40
39
37
35
72
31
17
48
55
19
63
31
20
35
38
10
9
10
11
12
13
14
15
16
3-(S)-Ethyl-cyclohexanone (5a). A 72% ee by GC
analysis (Chiracel G-TA column, 1108C, and flow: 2.0 ml/
min). Retention times, t1 5 5.4 (minor), t2 5 5.6 min
(major).56
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
bThe yield of the 1,2-product was not determined.
cDetermined by chiral GC (G-TA column). Absolute configuration was
assigned by comparison with the literature values.56
3-(R)-Ethyl-4,4-dimethyl-cyclohexanone
(5b). A
56% ee by GC analysis (Chiracel G-TA column, 1008C, and
flow: 1.0 ml/min). Retention times, t1 5 33.3 (minor), t2 5
34.2 min (major).8
and 3) gave similar ees to 1a indicating the insignificant
steric effects exerted by the alkyl substituents. This
expected outcome can be explained by free rotation of the
aniline aromatic ring of ligands 1a–1c. We then thought
of introducing a substituent at the aromatic ring to elimi-
nate the free rotation and form a ‘‘handle’’ where copper
and zinc can coordinate. Unfortunately, introduction of a 2-
OH group as in 1d did not improve the ee (35%) but
instead led to a decrease in the yield of 5a to 54% (Table
1, entry 4). Gratifyingly, significant improvements in the ee
to 72% and in the yield to 77% were achieved when ligand
1e with a 2-OMe was used (Table 1, entry 5). The use of
ligands 1f (having a 3-OMe substituent) and 1g (having a
4-OMe substituent) led to the formation of 5a in lower ees
of 31% and 17%, respectively (Table 1, entries 6 and 7).
The higher ee obtained using 1e indicated a better coordi-
nation between the metal center and the 2-OMe substitu-
ent. Interestingly, when ligand 1h with a 2-OMe and a 5-
methyl substituents was used, a decrease in the ee to 48%
was observed (Table 1, entry 8 vs. entry 5). To investigate
the effect of bulkier and coordinating ortho-substituents,
ligand 1i with a 2-OPh substituent was synthesized and
when used gave moderate 55% ee and 53% yield (Table 1,
entry 9). We then investigated the effect of increasing the
coordination sphere by using benzylamines (ligands 2 and
3; Table 1, entries 10–16) instead of aniline. Similar trends
to ligand 1 were observed in this case. Ligand 2a, with no
substituents on the aromatic ring, gave the lowest ee of
3-(S)-Ethyl-cycloheptanone (5c). A 52% ee by GC
analysis (Chiracel G-TA column, 1008C, and flow: 1.0 ml/min).
Retention times, t1 5 26.7 (major), t2 5 27.2 min (minor).56
RESULTS AND DISCUSSION
The ligands were synthesized by reacting L-phenylala-
nine with tosyl chloride to give the tosyl-L-phenylalanine,
which upon reaction with PCl5 gave the tosyl-L-phenylala-
nine acid chloride (Scheme 1).54,55 Condensation of this
acid chloride with an appropriate amine nucleophile gave
the respective ligands 1–3 in 80–98% yield (Fig. 1). Substi-
tuted and unsubstituted aniline 1a–i, benzylamine 2a–d,
and (R)- and (S)-a-methyl benzylamine 3a–c nucleophiles
were used. The ligands 1–3 were designed in such a way
to probe the effects of (i) different substituents at the am-
ide nitrogen, (ii) various substituents at the aromatic ring
(iii), the substitution pattern at the aromatic ring, and (iv)
match/mismatch characteristics due to additional chirality.
Preliminary screening involved the addition of 2-cyclo-
hexen-1-one 4a to a complex of ligands 1, 2, or 3 (15 mol
%) and CuI (15 mol %) with Et2Zn (2.2 equiv) in dry tolu-
ene at 08C (Table 1). The results in Table 1 show a strong
influence of the ligand structure on the enantioselectivity
of 5a. Ligand 1a (R 5 H) gave 5a in 88% yield and 40% ee
(Table 1, entry 1). More sterically demanding ligands 1b
(R 5 2-methyl) and 1c (R 5 2-isopropyl; Table 1, entries 2
Chirality DOI 10.1002/chir

AMINO ACIDS-BASED CHIRAL LIGANDS
109
TABLE 2. Effects of different copper sources on the
addition of Et2Zn to 2-cyclohexen-1-one
Cu(acac)2, Cu(OAc)2ꢀH2O, and PhCuS gave ees between 5
and 33% (Table 2, entries 2, 5, 7–10, 20, and 21).
The effects of catalyst loading and optimum mole ratio
of ligand-to-CuI were investigated using 1e (Table 3). The
best catalyst loading was found to be 15 mol %; higher or
lower catalyst loadings afforded inferior ee (Table 3,
entries 2–6 vs. entry 1). The highest ee of 72% was
obtained when the mole ratio ligand-to-CuI was 1:1 (Table
3, entry 1). Higher (Table 3, entry 2) or lower (Table 3,
entries 3 and 5) mole ratio of CuI versus 1e led to the for-
mation of 5a in lower ee and yield.
Next, we investigated the effect of various coordinating
and noncoordinating solvents (PhCH3, CH2Cl2, THF, Et2O,
and hexane) using complexes of ligands 1e and 2b with
CuI and CuSO4ꢀ5H2O (Table 4 entries 1–15). Complexes of
ligands 1e and 2b with CuI gave cloudy solutions. These
complexes showed similar ee trends in various solvents
(Table 4, entries 1–9) except with hexane where 1e gave ee
of 43% while 2b afforded only 8% (Table 4, entry 10). Gener-
ally, PhCH3 and Et2O gave the highest ees (Table 4, entries
1, 4, 6, and 9), CH2Cl2 gave moderate ees (Table 4, entries 2
and 7), whereas THF gave very low ees (Table 4, entries 3
and 8). No clear distinction between the effects of coordinat-
ing and noncoordinating solvents could be obtained. In com-
parison, complexes of 2b with CuI (Table 4, entries 6 and
10) and CuSO4ꢀ5H2O (Table 4, entries 11 and 15) showed a
significant increase in the yield of 5a but no clear trends in
the ees. The highest ee of 55% was obtained in PhCH3,
whereas the lowest ee of 18% was obtained in CH2Cl2.
Entrya
Ligand
Copper source
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1i
1i
1i
1i
2b
2b
2b
2b
2b
2b
2b
CuI
CuBr
CuCl
CuCN
77
49
54
92
41
62
59
38
71
62
53
64
56
69
62
88
88
75
38
82
80
72
29
51
47
5
41
12
12
7
15
55
55
38
40
63
27
33
55
31
14
19
CuCl2
CuSO4ꢀ5H2O
CuNO3ꢀ5H2O
Cu(acac)2
Cu(OAc)2ꢀH2O
PhSCu
CuI
CuCl
CuCN
9
10
11
12
13
14
15
16
17
18
19
20
21
CuSO4ꢀ5H2O
CuI
CuCl
CuBr
CuSO4ꢀ5H2O
Cu(acac)2
PhCuS
Cu(OAc)2
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
bDetermined by chiral GC (G-TA column). Absolute configuration was
assigned by comparison with the literature values.8
19% (Table 1, entry 10), whereas 2b with a 2-OMe gave
the best ee of 63% (Table 1, entry 11). Ligands 2c with a 3-
OMe substituent and 2d with a 4-OMe substituent gave lower
ees of 31% and 20%, respectively (Table 1, entries 12 and 13).
Ligand 3 with (R)- and (S)-a-methyl benzylamine side chains
was also examined to probe the effect of additional chirality
(Table 1, entries 14–16). Again, similar trends to ligands 1
and 2 were observed. Ligand (S,S)-3a (R 5 H) gave 35% ee
while ligand 3c (R 5 4-OMe) gave 10% ee (Table 1, entries 14
and 16). To determine whether there is a cooperative effect
between the stereocenters of the ligand backbone, (S,R)-3b
was examined. Unfortunately, no significant effect was
observed and the ee obtained was 38% (Table 1, entry 15).
Having realized the potential of ligands 1–3 in the
asymmetric copper-catalyzed 1,4-conjugate addition of
Et2Zn to 2-cyclohexen-1-one 4a, the effect of several reac-
tion parameters such as copper source, catalyst loading,
ligand-to-copper ratio, and reaction solvent were studied
with the aim of optimizing the reaction conditions and
developing more efficient ligands.
Initially, the effects of various copper sources such as
CuBr, CuCl, CuCN, CuCl2, CuSO4ꢀ5H2O, CuNO3ꢀ5H2O,
Cu(acac)2, Cu(OAc)2ꢀH2O, and PhSCu57 were investigated
using the most promising ligands 1e, 1i, and 2b under the
same reaction conditions mentioned in Table 1 (Table 2).
In all cases, except in entries 16 and 17, a combination
between 1e, 1i, or 2b and CuI, CuCl, CuCN, or
CuSO4ꢀ5H2O gave the best ees (Table 2, entries 1, 3, 4, 6,
11–15, and 18). Ligands 1e, 1i, and 2b with CuI showed
the highest ees of up to 72% (Table 2, entries 1, 11, and 13).
Other copper sources such as CuBr, CuCl2, CuNO3ꢀ5H2O,
To examine the scope and limitation of ligands 1e and
2b, the enantioselective 1,4-conjugate addition of Et2Zn to
other cyclic enones was examined under the optimized
reaction conditions mentioned in Table 1. Conjugate addi-
tion of Et2Zn to 4,4-dimethyl-cyclohex-2-enone 4b using
CuI, CuCN, and CuSO4ꢀ5H2O complexes of 1e or 2b
resulted in the formation of 5b in very moderate ees of 12–
42% (Table 5, entries 1–7). The highest ee of 42% was
obtained with a 1e-CuCN complex (Table 5, entry 3).
Interestingly, when this reaction was performed at 2208C,
an increase in the ee of 5b to 56% was observed indicating
the scope for further optimization (Table 5, entry 4).
Likewise, moderate ees (29–50%) of 5d using CuI,
CuCN, and CuSO4ꢀ5H2O complexes of ligands 1e and 2b
were used for addition to cyclohept-2-enone 4c (Table 6,
TABLE 3. The effect of catalyst loading and ratio of
ligand-to-CuI on the conjugate addition of Et2Zn to
2-cyclohexen-1-one 4a
Entrya
1e (mol %)
CuI (mol %)
Yield (%)
ee (%)b
1
2
3
4
5
6
15
10
20
30
15
7.5
15
15
5
30
10
7.5
77
65
40
45
54
57
72
49
18
35
40
62
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
bDetermined by chiral GC (G-TA column). Absolute configuration was
assigned by comparison with the literature values.56
Chirality DOI 10.1002/chir

110
GOU AND JUDEH
TABLE 4. Effect of different solvents on the addition of
TABLE 6. Asymmetric conjugate addition of Et2Zn to
cyclohept-2-enone catalyzed by copper complexes of
ligands 1e and 2b
Et2Zn to 2-cyclohexen-1-one 4a
Entrya Ligand Copper source Solvent Yield (%) ee (%)b
1
2
3
4
5
6
7
8
1e
1e
1e
1e
1e
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
PhCH3
CH2Cl2
THF
Et2O
Hex
PhCH3
CH2Cl2
THF
Et2O
Hex
PhCH3
CH2Cl2
THF
Et2O
Hex
77
57
86
73
76
62
67
67
74
80
75
60
97
98
90
72
54
6
65
43
63
43
7
Entrya
Ligand
Copper source
Yield (%)
ee (%)b
1
2
3
4
5
6
1e
1e
1e
2b
2b
2b
CuI
CuCN
58
78
53
51
79
66
40
50
24
29
36
41
9
CuI
CuI
60
8
10
11
12
13
14
15
CuSO4ꢀ5H2O
CuSO4ꢀ5H2O
CuSO4ꢀ5H2O
CuSO4ꢀ5H2O
CuSO4ꢀ5H2O
CuSO4ꢀ5H2O
55
18
35
38
49
CuI
CuCN
CuSO4ꢀ5H2O
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
bDetermined by chiral GC (G-TA column).
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
bDetermined by chiral GC (G-TA column). Absolute configuration was
assigned by comparison with the literature values.56
selective copper-catalyzed 1,4-conjugate addition of Et2Zn to
various cyclic enones. These chiral ligands are inexpensive,
very stable, and readily synthesized in excellent yields by
reacting tosyl-L-phenylalanine acid chloride with various chi-
ral and achiral amines. Ligand 1e, with 2-OMe substituent,
catalyzed the addition of Et2Zn to enones to give up to 72%
ee. This work paves the way for synthesis and evaluation of
larger libraries based on the same general structure.
entries 1–6). The highest ee of 50% was obtained when
1e–CuCN complex was used (Table 6, entry 2).
It is well established that sulfur can strongly coordinate
to late transition metals58 and that olefins and sulfur atom
have greater affinity for Cu(I) atom.59 Noyori and co-
workers60,61 reported that N-benzylbenzenesulfonamide
catalyzed the 1,4-addition of dialkylzincs to enones
smoothly. In catalytic cycle proposed by them, oxygen
atom on sulfonamide coordinated to Cu(I) center. In this
case, although the real active species is not fully under-
stood, we believe that coordination using the present
bidentate ligands can happen in a similar fashion.59–61
In summary, we have synthesized a new class of amino
acid-based modular ligands and used them for the enantio-
LITERATURE CITED
1. Tomioka K. Conjugate addition of organometallic reagents. In: Jacobsen
EN, Pfaltz A, Yamamoto H, editor. Comprehensive asymmetric cataly-
sis. Verlag, Berlin, Heidelberg, NY: Springer; 2004. Volume Supplement
to Chapter 31.1.
2. Tomioka K, Nagaoka Y. Conjugate addition of organometallic reagents.
In: Jacobsen EN, Pfaltz A, Yamamoto H, editors.Comprehensive asym-
metric catalysis, Vol.3. New York: Springer-Verlag; 1999. p1105–1120.
3. Feringa BL, de Vries AHM. Carbon–carbon bond formation by catalytic
enantioselective conjugate addition. In: Doyle M, editor. Advances in
catalytic processes, Vol.1. Greenwich, CT: JAI Press; 1995. p151–192.
TABLE 5. Asymmetric conjugate addition of Et2Zn to
4,4-dimethyl-cyclohex-2-enone catalyzed by copper
complexes of ligands 1e and 2b
4. Alexakis A, Ba¨ckvall JE, Krause N, Pa`mies O, Die´guez M. Enantiose-
lective copper-catalyzed conjugate addition and allylic substitution
reactions. Chem Rev 2008;108:2796–2823.
5. Harutyunyan SR, den Hartog T, Geurts K, Minnaard AJ, Feringa BL.
Catalytic asymmetric conjugate addition and allylic alkylation with Gri-
gnard reagents. Chem Rev 2008;108:2824–2852.
6. Krause N, Hoffmann-Ro¨der A. Recent advances in catalytic enantiose-
lective Michael additions. Synthesis 2001;2:171–196.
7. Alexakis A, Benhaim C. Enantioselective copper-catalysed conjugate
addition. Eur J Org Chem 2002;2002:3221–3236.
Entrya
Ligand
Copper source
Yield (%)
ee (%)b
8. Feringa BL. Phosphoramidites: marvellous ligands in catalytic asym-
metric conjugate addition. Acc Chem Res 2000;33:346–353.
1
2
3
4
5
6
7
1e
1e
1e
1e
2b
2b
2b
CuI
54
26
98
48
48
45
70
12
21
42
56c
23
32
15
9. Sibi MP, Manyem S. Enantioselective conjugate additions. Tetrahe-
dron 2000;56:8033–8061.
CuSO4ꢀ5H2O
CuCN
10. Alexakis A, Vastra J, Burton J, Mangeney P. Asymmetric conjugate
addition of diethyl zinc to enones with tartrate chiral phosphite
ligands. Tetrahedron: Asymmetry 1997;8:3193–3196.
CuCN
CuI
CuSO4ꢀ5H2O
11. Alexakis A, Vastra J, Mangeney P. Acceleration of the conjugate addi-
tion of diethyl zinc to enones by either Cu(OTf)2 or trivalent phospho-
rus ligands. Tetrahedron Lett 1997;38:7745–7748.
CuCN
aConditions: 2.2 equiv Et2Zn (PhCH3 solution), 2-cyclohexen-1-one con-
centration 0.2 M in PhCH3.
12. Alexakis A, Vastra J, Burton J, Benhaim C, Mangeney P. Asymmetric
conjugate addition of diethyl zinc to enones with chiral phosphorus
ligands derived from TADDOL. Tetrahedron Lett 1998;39:7869–7872.
bDetermined by chiral GC (G-TA column).
cReaction performed at 2208C for 7 days.
Chirality DOI 10.1002/chir

AMINO ACIDS-BASED CHIRAL LIGANDS
111
13. Pa`mies O, Net G, Ruiz A, Claver C. Enantioselective copper-catalysed
1,4-addition of diethylzinc to cyclohexenone using chiral diphosphite
ligands. Tetrahedron: Asymmetry 1999;10:2007–2014.
33. Ongeri S, Piarulli U, Jackson RFW, Gennari C. Optimization of new
chiral ligands for the copper-catalysed enantioselective conjugate addi-
tion of Et2Zn to nitroolefins by high-throughput screening of a parallel
library. Eur J Org Chem 2001;4:803–807.
14. Alexakis A, Burton J, Vastra J, Benhaim C, Fournioux X, van den Heu-
vel A, Leveque JM, Maze F. Synthesis and application of chiral phos-
phorus ligands derived from TADDOL for the asymmetric conjugate
addition of diethyl zinc to enones. Eur J Org Chem 2000;2000:4011–
4027.
34. Chataigner I, Gennari C, Piarulli U, Ceccarelli S. Discovery of a new
efficient chiral ligand for copper-catalyzed enantioselective Michael
additions by high-throughput screening of a parallel library13. Angew
Chem Int Ed Engl 2000;39:916–918.
35. Wendisch V, Sewald N. Enantioselective copper(I) catalyzed 1,4-addi-
tion of diethylzinc to cyclohexenone: asymmetric induction as an
unexpected source of structural information. Tetrahedron: Asymmetry
1997;8:1253–1257.
15. Escher IH, Pfaltz A. New chiral oxazoline-phosphite ligands for the
enantioselective copper-catalyzed 1,4-addition of organozinc reagents
to enones. Tetrahedron 2000;56:2879–2888.
16. Liang , Au-Yeung TTL, Chan ASC. Highly enantioselective 1,4-addi-
tion of diorganozinc reagents to cyclic enones using chiral diphos-
phite ligands derived from H8-binaphthol. Org Lett 2002;4:3799–3801.
36. Nakagawa Y, Matsumoto K, Tomioka K. Approach to enantioselective
conjugate addition of organocopper reagents to cycloalkenones by the
aid of chiral lactam bearing phosphine group. Tetrahedron
2000;56:2857–2863.
17. Cramer N, Laschat S, Baro A. Chiral phosphites and phosphorami-
dites based on the tropane skeleton and their application in catalysis.
Organometallics 2006;25:2284–2291.
37. Guillen F, Winn CL, Alexakis A. Enantioselective copper-catalyzed
conjugate addition using chiral diaminocarbene ligands. Tetrahedron:
Asymmetry 2001;12:2083–2086.
18. Kawamura K, Fukuzawa H, Hayashi M. Novel N,N,P-tridentate
ligands for the highly enantioselective copper-catalyzed 1,4-addition of
dialkylzincs to enones. Org Lett 2008;10:3509–3512.
38. Pytkowicz J, Roland S, Mangeney P. Enantioselective conjugate addi-
tion of diethylzinc using catalytic silver(I) diaminocarbenes and
Cu(OTf)2. Tetrahedron: Asymmetry 2001;12:2087–2089.
19. Yan M, Yang LW, Wong KY, Chan ASC. Enantioselective conjugate
addition of diethylzinc to enones catalyzed by a copper complex of chi-
ral aryl diphosphite. Chem Commun 1999:11–12.
39. Clavier H, Coutable L, Toupet L, Guillemin J-C, Mauduit M. Design
and synthesis of new bidentate alkoxy-NHC ligands for enantioselec-
20. Yan M, Chan ASC. Enantioselective conjugate addition of diethylzinc
to cyclic enones with chiral aryl diphosphite-copper catalysts. Tetrahe-
dron Lett 1999;40:6645–6648.
tive copper-catalyzed conjugate addition.
2005;690:5237–5254.
J Organomet Chem
40. Clavier H, Coutable L, Guillemin J-C, Mauduit M. New bidentate
alkoxy-NHC ligands for enantioselective copper-catalysed conjugate
addition. Tetrahedron: Asymmetry 2005;16:921–924.
21. Feringa B, Pineschi M, Arnold LA, Imbos R, de Vries AHM. Highly
enantioselective catalytic conjugate addition and tandem conjugate
addition-aldol reactions of organozinc reagents. Angew Chem Int Ed
Engl 1997;36:2620–2623.
41. Winn CL, Guillen F, Pytkowicz J, Roland S, Mangeney P, Alexakis A.
Enantioselective copper catalysed 1,4-conjugate addition reactions
22. Naasz R, Arnold LA, Pineschi M, Keller E, Feringa BL. Catalytic enan-
tioselective annulations via 1,4-addition-aldol cyclization of functional-
ized organozinc reagents. J Am Chem Soc 1999;121:1104–1105.
using chiral N-heterocyclic carbenes.
2005;690:5672–5695.
J
Organomet Chem
42. Schinnerl M, Seitz M, Kaiser A, Reiser O. New applications of bis(oxa-
zoline) ligands in catalysis: asymmetric 1,2- and 1,4-addition of ZnR2
to carbonyl compounds. Org Lett 2001;3:4259–4262.
23. Arnold LA, Imbos R, Mandoli A, de Vries AHM, Naasz R, Feringa BL.
Enantioselective catalytic conjugate addition of dialkylzinc reagents
using copper-phosphoramidite complexes; ligand variation and non-
linear effects. Tetrahedron 2000;56:2865–2878.
43. Borner C, Dennis MR, Sinn E, Woodward S. Copper-catalysed asym-
metric 1,4-addition of organozinc compounds to linear aliphatic
enones using 2,20-dihydroxy 3,30-dithioether derivatives of 1,10-binaph-
thalene. Eur J Org Chem 2001;13:2435–2446.
24. Zhou H, Wang W-H, Fu Y, Xie J-H, Shi W-J, Wang L-X, Zhou Q-L.
Highly enantioselective copper-catalyzed conjugate addition of diethyl-
zinc to enones using chiral spiro phosphoramidites as ligands. J Org
Chem 2003;68:1582–1584.
44. Bennett SMW, Brown SM, Cunningham A, Dennis MR, Muxworthy
JP, Oakley MA, Woodward S. Copper-catalysed asymmetric conjugate
addition of organometallic reagents to linear enones. Tetrahedron
2000;56:2847–2855.
25. Alexakis A, Polet D, Rosset S, March S. Biphenol-based phosphorami-
dite ligands for the enantioselective copper-catalyzed conjugate addi-
tion of diethylzinc. J Org Chem 2004;69:5660–5667.
45. Pa`mies O, Net G, Ruiz A, Claver C, Woodward S. Copper-catalysed
asymmetric conjugate addition of organometallic reagents to enones
using S,O-ligands with a xylofuranose backbone. Tetrahedron: Asym-
metry 2000;11:871–877.
26. Boeda F, Rix D, Clavier H, Cre´visy C, Mauduit M. Design and synthe-
sis of new bidentate phosphoramidite ligands for enantioselective cop-
per-catalyzed conjugate addition of diethylzinc to enones. Tetrahe-
dron: Asymmetry 2006;17:2726–2729.
46. Bennett S, Brown SM, Conole G, Dennis MR, Fraser PK, Radojevic S,
McPartlin M, Topping CM, Woodward S. Catalytic conjugate addition
promoted by the copper(I)-monothiobinaphthol system, Part 3: Com-
parison of three thiolate-based catalytic systems. J Chem Soc Perkin
Trans 1 1999;21:3127–3132.
27. Fuchs N, d’Augustin M, Humam M, Alexakis A, Taras R, Gladiali S.
Asymmetric conjugate addition of metal alkyl reagents catalyzed by
copper complexes with BINPO: a hemilabile P,O-heterobidentate axi-
ally chiral ligand. Tetrahedron: Asymmetry 2005;16:3143–3146.
28. Kno¨bel AKH, Escher IH, Pfaltz A. Enantioselective copper-catalyzed
1,4-addition of organozinc reagents to enones using chiral oxazoline-
phosphite ligands. Synlett 1997;12:1429–1431.
47. Kang J, Lee JH, Lim DS. Stereoselective conjugate addition of diethyl-
zinc to enones and nitroalkenes. Tetrahedron: Asymmetry
2003;14:305–315.
29. Hu X, Chen HL, Zhang XM. Development of new chiral P,N ligands and
their application in the Cu-catalyzed enantioselective conjugate addition
of diethylzinc to enones. Angew Chem Int Ed 1999;38:3518–3521.
48. Arink AM, Braam TW, Keeris R, Jastrzebski JTBH, Benhaim C, Ros-
set S, Alexakis A, van Koten G. Copper(I) thiolate catalysts in asym-
metric conjugate addition reactions. Org Lett 2004;6:1959–1962.
30. Helmchen G, Pfaltz A. Phosphinooxazolines: a new class of versatile,
modular P,N-ligands for asymmetric catalysis. Acc Chem Res
2000;33:336–345.
49. Shi M, Wang CJ, Zhang W. Enantioselective conjugate addition of dia-
lkylzinc and diphenylzinc to enones catalyzed by a chiral copper(I)
binaphthylthiophosphoramide or binaphthylselenophosphoramide
ligand system. Chem—Eur J 2004;10:5507–5516.
31. Mizutani H, Degrado SJ, Hoveyda AH. Cu-catalyzed asymmetric con-
jugate additions of alkylzinc reagents to acyclic aliphatic enones. J Am
Chem Soc 2002;124:779–781.
50. Shi M, Zhang W. Asymmetric 1,4-addition of diethylzinc to cyclic
enones catalyzed by Cu(I)-chiral sulfonamide-thiophosphoramide
ligands and lithium salts. Adv Synth Catal 2005;347:535–540.
32. Chataigner I, Gennari C, Ongeri S, Piarulli U, Ceccarelli S. Discovery
of a new efficient chiral ligand for copper-catalyzed enantioselective
51. Richmond ML, Seto CT. Modular ligands derived from amino acids
for the enantioselective addition of organozinc reagents to aldehydes.
J Org Chem 2003;68:7505–7508.
Michael additions by high-throughput screening of
library13. Chem—Eur J 2001;7:2628–2634.
a parallel
Chirality DOI 10.1002/chir

112
GOU AND JUDEH
52. Wu J, Mampreian DM, Hoveyda AH. Enantioselective synthesis of
nitroalkanes bearing all-carbon quaternary stereogenic centers
through Cu-catalyzed asymmetric conjugate additions. J Am Chem
Soc 2005;127:4584–4585.
57. Alexakis A, Benhaim C, Rosset S, Humam M. Dramatic improvement
of the enantiomeric excess in the asymmetric conjugate addition
reaction using new experimental conditions.
2002;124:5262–5263.
J Am Chem Soc
53. Luchaco-Cullis CA, Hoveyda AH. Cu-catalyzed enantioselective conju-
gate addition of alkylzincs to cyclic nitroalkenes: catalytic asymmetric
58. Brubaker GR, Brown JN, Yoo MK, Kutchan TM, Mottel EA. Crystal
and molecular structures of (1,8-bis(2-pyridyl)-3,6-dithiaoctane)cop-
per(I) hexafluorophosphate and perchlorato(1,8-bis(2-pyridyl)-3,6-
dithiaoctane)copper(II) perchlorate: stereodynamics of the copper(II)-
copper(I) couple. Inorg Chem 1979;18:299–302.
synthesis of cyclic (6)-substituted ketones.
J Am Chem Soc
2002;124:8192–8193.
54. Castro L, Tlahuext M, Antonio R, Benavides T, Tlahuext H. Synthesis
and structural studies of new N-(p-toluenesulfonyl)amino acid o-phe-
nolamides. Heteroatom Chem 2003;14:247–253.
59. Yamamoto H, editor. Lewis acid in organic synthesis. Weinheim:
Wiley-VCH, 2000.
55. Grotjahn DB, Groy TL. Formation of coordinatively unsaturated
Cp*Ir-amino acid complexes and their highly diastereoselective com-
plexation reactions. J Am Chem Soc 2002;116:6969–6970.
60. Kitamura M, Miki T, Nakano K, Noyori R. 1,4-Addition of diorgano-
zincs to a,b-unsaturated ketones catalyzed by a copper(I)-sulfonamide
combined system. Bull Chem Soc Jpn 2000:73:999–1014.
56. Degrado SJ, Mizutani H, Hoveyda AH. Modular peptide-based phos-
phine ligands in asymmetric catalysis: efficient and enantioselective
Cu-catalyzed conjugate additions to five-, six-, and seven-membered
cyclic enones. J Am Chem Soc 2001;123:755–756.
61. Nakano K, Bessho Y, Kitamura M. 1,4-Addition of diethylzinc to cyclo-
hexenone catalyzed by CuOTf-sulfonamide combined system. Evi-
dence supporting a concerted mechanism. Chem Lett 2003;32:224–
225.
Chirality DOI 10.1002/chir