Catalytic enantioselective conjugate addition of Grignard reagents to cyclic enones using C1-1,1′-bisisoquinoline-based chiral ligands

Article abstract of DOI:10.1080/00397911.2010.541969

New highly constrained chiral C₁-1,1′-bisisoquinoline ligands were examined in the enantioselective conjugate addition of Grignard reagents to cyclohexenone and cyclopentenone. The desired 1,4-adducts were obtained in excellent yield and moderate enantiomeric excess (up to 35%). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.541969

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Catalytic Enantioselective Conjugate
Addition of Grignard Reagents to Cyclic
Enones Using C 1-1,1′-Bisisoquinoline-
Based Chiral Ligands
Gao Qi a & Zaher M. A. Judeh a
a School of Chemical and Biomedical Engineering, Nanyang
Technological University, Singapore, Singapore
Accepted author version posted online: 17 Nov 2011.Version of
record first published: 03 Feb 2012.
To cite this article: Gao Qi & Zaher M. A. Judeh (2012): Catalytic Enantioselective Conjugate Addition
of Grignard Reagents to Cyclic Enones Using C 1-1,1′-Bisisoquinoline-Based Chiral Ligands, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:11, 1585-1592
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Synthetic Communications1, 42: 1585–1592, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.541969
CATALYTIC ENANTIOSELECTIVE CONJUGATE
ADDITION OF GRIGNARD REAGENTS TO CYCLIC
ENONES USING C1-1,1’-BISISOQUINOLINE-BASED
CHIRAL LIGANDS
Gao Qi and Zaher M. A. Judeh
School of Chemical and Biomedical Engineering, Nanyang Technological
University, Singapore, Singapore
GRAPHICAL ABSTRACT
Abstract New highly constrained chiral C1-1,10-bisisoquinoline ligands were examined in the
enantioselective conjugate addition of Grignard reagents to cyclohexenone and cyclopente-
none. The desired 1,4-adducts were obtained in excellent yield and moderate enantiomeric
excess (up to 35%).
Keywords Asymmetric catalysis; C1-1,10-bisisoquinoline; cyclic enones; enantioselective
conjugate addition
INTRODUCTION
The conjugate addition (1,4-addition) of carbon nucleophiles to a,b-unsaturated
carbonyl compounds is a key C-C bond-forming reaction. Tremendous efforts have
been devoted over the past three decades to perfect and develop robust, widely
applicable, and highly efficient chiral catalysts for the construction of numerous chiral
compounds using this reaction. Various nucleophiles sources including Grignard
reagents have been explored.[1] Because of the very high reactivity of Grignard
reagents, their conjugate addition to a,b-unsaturated carbonyl systems normally leads
to uncatalyzed 1,2- and=or 1,4-additions. However, because of their obvious advan-
tages, such as ready availability and cheap price, considerable effort has been made
to utilize Grignard reagents in copper-catalyzed asymmetric conjugated additions with
variable success.[2]
Received August 31, 2010.
Address correspondence to Zaher M. A. Judeh, School of Chemical and Biomedical Engineering,
Nanyang Technological University, 62 Nanyang Drive, N12 B1-14, Singapore 637459, Singapore. E-mail:
zaher@ntu.edu.sg
1585

1586
G. QI AND Z. M. A. JUDEH
Figure 1. C1-1,10-Bisisoquinoline ligands 1a–d.
Villacorta and coworkers reported the first successful case of conjugate addition
of Grignard reagents to enones using a catalytic amount of Cu-amide complexes.[3]
Subsequently, a variety of catalytic systems, mainly based on Cu-thiolates[4] and
phosphine-oxazolines,[5] were introduced. At this stage, the scope of the ligands
remained limited and the enantiomeric excesses (ees) infrequently reached the 90%
level. In 2004, Feringa and coworkers introduced chiral diphosphines, Taniaphos
and Josiphos, that provided excellent ees using cyclic (up to 96% ee)[6] and acyclic
(up to 98% ee)[7] enones. Recently, martin and coworkers reported extremely success-
ful Cu-diaminocarbene ligands for asymmetric conjugate addition of Grignard
reagents to b,b0-disubstituted enones (ees up to 96%).[8] Such catalytic results inspired
many researchers to use Grignard reagents for selective conjugate addition to a wide
range of substrates.
We have studied the structures and properties of bisisoquinolines for a long time[9]
and recently reported the synthesis of novel chiral C1-1,10-bisisoquinoline ligands and
their successful application in the enantioselective addition of diethylzinc to various
aldehydes.[10] Herein, application of chiral C1-1,10-bisisoquinolines 1a–d (Fig. 1) is exam-
ined in the copper-prompted asymmetric conjugate addition of Grignard reagents to
cyclic enones with the aim of expanding the utility of these ligands and finding the
factors that affect the enantioinduction using these ligands.
RESULTS AND DISCUSSION
At first, the reaction conditions were optimized using EtMgCl as Grignard
reagent, 2-cyclohexenone 2a as the enone, and (ꢀ)-1a as a model ligand. During
the experimental process, we found that almost all the reactions gave quantitative
yield of products. Therefore, only the ratio between 1,4-=1,2-adduct and ee of
1,4-adduct were studied. The optimization was examined using metal ions ZnCl2
and Cu(OTf)2. The reaction with either ZnCl2=(ꢀ)-1a or Cu(OTf)2=(ꢀ)-1a was com-
pleted within 15 min at ꢀ90 ꢁC to give a mixture of 1,4-adduct 3a and 1,2-adduct 4a
(Table 1, entries 1 and 2). Reaction with Cu(OTf)2=(ꢀ)-1a provided better regioselec-
tivity (3a=4a: 87=13) and enantioselectivity (22% ee) of the desired product 3a com-
pared to the regioselectivity (3a=4a: 84=16) and enantioselectivity (2% ee) obtained
with ZnCl2=(ꢀ)-1a. Having confirmed that the copper ion was superior for this
reaction, the effects of various copper sources [CuI, CuCl2, and Cu(AcAc)2] were
investigated (Table 1, entries 3–5). The reactions using CuI and Cu(AcAc)2 gave
products with similar and moderate regioselectivity (3a=4a as 81=19 and 82=18,
respectively) and poor enantioselectivity (4% and 7% ee of 3a, respectively) (Table 1,
entries 3 and 5). In comparison, the reaction performed with CuCl2 (Table 1, entry 4)

ENANTIOSELECTIVE CONJUGATE ADDITION OF ENONES
1587
Table 1. EtMgCl conjugate addition to enone 2a in the presence of salt=ligand
ee of 3ab
%
Entry
Ligand (mol%)
Metal salt
Solvent
Temp. (ꢁC)
3a=4aa
(configuration)c
1
2
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (5)
ZnCl2
Cu(OTf)2
CuI
THF
THF
THF
THF
THF
Et2O
toluene
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ30
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
84=16
87=13
81=19
89=11
82=18
95=5
2 (S)
22 (S)
4 (S)
35 (S)
7 (S)
0
3
4
CuCl2
Cu(AcAc)2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
5
6
7
91=9
0
8
68=32
100=0
89=11
97=3
28 (S)
3 (S)
24 (S)
13 (S)
13 (S)
8 (S)
0
9
10
11
12
13
14
15
(ꢀ)-1a (20)
(ꢀ)-1a (100)
(þ)-1b (10)
(þ)-1c (10)
(þ)-1d (10)
100=0
94=6
68=32
85=15
0
aThe ratio of 3a=4a was determined by GC-mass using an HP-5 column.
bThe ee was determined by GC using a Chiraldex G-TA column.
cThe configuration was determined by comparing the sign of optical rotation value with the literature
value.[11a]
gave enhanced regioselectivity (3a=4a as 89=11) and enantioselectivity of 3a (35% ee).
Thus, CuCl2 was chosen for further investigations.
The effect of typical coordinating [tetrahydrofuran (THF) and Et2O] and
noncoordinating solvents (toluene and CH2Cl2) were examined in the addition of
EtMgCl to enone 2a. Surprisingly, reactions using Et2O or toluene gave racemic 3a
(Table 1, entries 6 and 7), while reactions in THF and CH2Cl2 gave 3a in moderate
ees (35% and 28% respectively, Table 1, entries 4 and 8). Furthermore, the reaction
in THF showed much better regioselectivity than the reaction in CH2Cl2 (3a=4a as
89=11 vs 68=32). Thus, THF was inferred to be the best solvent. Temperature was
found to greatly affect the reactions; increasing the temperature from ꢀ90 ꢁC to
ꢀ30 ꢁC resulted in dramatic reduction of the enantioselectivity, where product 3a
showed only 3% ee (Table 1, entry 9). Catalyst loading was another factor examined.
Reactions in the presence of 5, 10, 20, and 100 mol% loading of CuCl2=(ꢀ)-1a (with
respect to enone 2a) were carried out in THF at ꢀ90 ꢁC (Table 1, entries 4 and 10–12).
An increase of CuCl2=(ꢀ)-1a from 5 mol% to 100 mol% resulted in an increase in the
ratio of 3a=4a from 89=11 to 100=0. This observation indicated that ligand (ꢀ)-1a had
positive influence on the regioselectivity of the reaction. However, the highest ee of
3a was observed when 10 mol% of CuCl2=(ꢀ)-1a was used; higher or lower catalyst

1588
G. QI AND Z. M. A. JUDEH
loading afforded inferior ees. Thus, 10 mol% loading was chosen as the best loading
amount of CuCl2=(ꢀ)-1a for this reaction.
Other chiral ligands were examined in conjugate addition of EtMgCl to enone
2a under the condition established in Table 1, entry 4. The reaction using ligand (þ)-
1b gave product 3a in 8% ee with the major enantiomer having the (S) configuration
(Table 1, entry 13). When using urea (þ)-1c or thiourea (þ)-1d as ligand, only
racemic products were obtained (Table 1, entries 14 and 15). Those results might
have arisen because of the crowdedness brought by the substituents on the amino
nitrogen, which prevented inefficient coordination of CuCl2 and Grignard reagent
to the ligands.
Several Grignard reagents besides EtMgCl were added to enone 2a under opti-
mum conditions to study the scope and limitation of ligand (ꢀ)-1a. In general, good
regioselectivities of the desired 1,4-adducts (compounds 3b–3e) were obtained in all
cases. Of the Grignard reagents examined, only BuMgCl gave the 1,4-adduct 3c in
significant ee (35%, Table 2, entry 2), while i-PrMgCl gave the 1,4-adduct 3b in a
low 8% ee (Table 2, entry 1), and the rest of the Grignard reagents such as PhMgCl
Table 2. Grignard reagent conjugate addition to enone 2a or 2b in the presence of copper salt=ligand
Ligand
(mol%)
1,4-Adduct=
1,2-adductc
ee of 1,4-adductd (%)
(configuration)e
Entry
N
R
1a
2a
1
1
1
1
0
0
0
0
0
0
i-Pr
Bu
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (10)
(ꢀ)-1a (15)
(þ)-1a (15)
(þ)-1b (15)
(þ)-1c (15)
(þ)-1d (15)
(ꢀ)-1a (15)
90=10
100=0
91=9
8 (S)
35 (S)
0
3a
Ph
Bn
4a
100=0
89=11
97=3
0
5b
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Cy
27 (S)
30 (R)
25 (S)
0
6b
7b
96=4
8b
89=11
83=17
100=0
9b
0
18 (S)
10b
aReaction conditions: 10 mol% (ꢀ)-1a, 10 mol% CuCl2, THF, ꢀ90 ꢁC, 15 min.
bReaction conditions: 15 mol% ligand, 15 mol% Cu(OTf)2, THF, ꢀ90 ꢁC, 15 min.
cThe ratio of 1,2-adduct=1,4-adduct was determined by GC-mass using HP-5 column.
dThe ee was determined by GC using Chiraldex G-TA column or TBDAc column.
eThe configuration was determined by comparing the sign of optical rotation value with literature.[4b,11]

ENANTIOSELECTIVE CONJUGATE ADDITION OF ENONES
1589
and BnMgCl provided only racemic products (Table 2, entries 3 and 4). Those results
indicated that the bulkiness of the alkyl substituents in the Grignard reagents affected
the ees of products significantly. The Grignard reagents with small groups such as Et
and Bu gave the products in greatest ee, while bulkier groups (i-Pr, Ph, and Bn) gave
negligible ee or racemic products.
Next, the substrate scope was examined where 2-cyclopentenone 2b was used.
The optimization of the reaction conditions was performed using i-PrMgCl as the
standard Grignard reagent and (ꢀ)-1a as the standard ligand. After careful screening
of the factors such as copper salts, solvents, reaction temperature, and loading of
catalyst, the optimum condition was established as shown in Table 2. Addition of
i-PrMgCl to enone 2b under this condition afforded 1,4-adduct 3f in moderate ee
(27%, Table 2, entry 5). The efficiencies of other chiral ligands on addition of i-
PrMgCl to enone 2b were also investigated under the optimum reaction conditions.
The reaction catalyzed by Cu(OTf)2=(þ)-1a gave the complementary (R)-3f in a simi-
lar ee of 30% (Table 2, entry 6). It was interesting that ligand (þ)-1b gave product 3f
in similar ee as that of (þ)-1a but with inverse configuration [25% ee of (S)-3f,
Table 2, entry 7]. Not surprisingly, ligands (þ)-1c and (þ)-1d gave product 3f in
racemic form (Table 2, entries 8 and 9). Only CyMgCl was attempted besides
i-PrMgCl in the addition to enone 2b, and the reaction proceeded to give exclusively
the 1,4-adduct 3 g in 18% ee (Table 2, entry 10).
CONCLUSION
Chiral C1-1,10-bisisoquinoline ligand 1a showed moderate efficiency in the
enantioselective conjugate addition of EtMgCl and BuMgCl to cyclohexenone and
i-PrMgCl to cyclopentenone. The desired 1,4-adducts were obtained in excellent yield
and moderate ee (up to 35%). However, other chiral bisisoquinoline ligands 1c and 1d
were found inefficient for this reaction because of the ineffective coordination of
CuCl2 and Grignard reagent to the ligands.
EXPERIMENTAL
All commercial materials were used as received. Anhydrous THF, diethyl ether,
and toluene were obtained from the Pure Solv PS-400-5-MD system. Anhydrous
CH2Cl2 was distilled from calcium hydride. Gas chromatography (GC) was
performed on an Agilent 6890 using Agilent HP-5, Astec Chiraldex G-TA, or MN
Hydrodex-b-TBDAc column. GC–mass spectra were recorded on an Agilent 6890
GC system with an Agilent 5973 mass selective detector. Optical rotations were
measured using a Jasco P-1020 polarimeter.
General Procedure for Conjugate Addition of Grignard
Reagents to Enones
Ligand and copper salt were dissolved in THF to form a solution. The mixture
was stirred at room temperature for 1 h, and the enone was injected via a syringe
needle. The mixture was stirred for another 1 h at room temperature and then cooled
to ꢀ90 ꢁC (MeOH mixed with liquid nitrogen). The Grignard reagent was injected in

1590
G. QI AND Z. M. A. JUDEH
a dropwise fashion over a period of 5 min, and the mixture was stirred for another
15 min. The reaction was then quenched with saturated NH4Cl solution, and the
resulting mixture was allowed to warm up to rt. The organic phase was separated,
washed with HCl solution and saturated Na2CO3 solution, dried over MgSO4,
and filtered. The resulting organic solution was diluted with THF and subjected to
GC-mass and GC directly for analysis. The ratio of 1,4-=1,2 adduct was determined
by GC-mass using HP-5 column. The ee value was determined by GC using a
Chiraldex G-TA column or Hydrodex-b-TBDAc column. The absolute configur-
ation of the major enantiomer of product was assigned by comparing the sign of
optical rotation value with literature data.
Selected Data
(S)-3-Ethylcyclohexanone (S)-3a (Table 1, Entry 4). The ee of 35% was
determined by GC. GC (Chiraldex G-TA column): helium flowrate ¼ 2.0 mL=min,
25
oven ¼ 110 ꢁC, t1 ¼ 5.48 min for (R) and t2 ¼ 5.64 min for (S). ½aꢂD ¼ ꢀ13:3
(c ¼ 0.66, CHCl3) (lit.[11a] ½aꢂD ¼ þ119:7 (c ¼ 1.0, CHCl3) for 76% ee (R)).
(S)-3-Isopropylcyclohexanone (S)-3b (Table 2, Entry 1). The ee of 8% was
determined by GC. GC (Hydrodex-b-TBDAc column): helium flowrate¼ 2.0 mL=min,
25
oven ¼ 130 ꢁC, t1 ¼ 8.73min for (R) and t2 ¼ 9.22min for (S). ½aꢂD ¼ ꢀ5:3 (c ¼ 0.70,
CHCl3) (lit.[4b] [a]D ¼ þ 13.6 (c ¼ 1.92, CHCl3) for 72% ee (R)).
(S)-3-Butylcyclohexanone (S)-3c (Table 2, Entry 2). The ee of 35% was
determined by GC. GC (Hydrodex-b-TBDAc column): helium flowrate ¼ 2.0 mL=
25
min, oven ¼ 130 ꢁC, t1 ¼ 14.78 min for (R) and t2 ¼ 15.31 min for (S). ½aꢂD ¼ ꢀ10:5
22
(c ¼ 1.24, CHCl3) (lit.[11b] ½aꢂD ¼ þ12:2 (c ¼ 1.0, CHCl3) for 90% ee (R)).
(S)-3-Isopropylcyclopentanone (S)-3f (Table 2, Entry 5). The ee of 27%
was determined by GC. GC (Chiraldex G-TA column): helium flowrate¼ 0.8 mL=
25
min, oven ¼ 77 ꢁC, t1 ¼ 40.70 min for (S) and t2 ¼ 41.93 min for (R). ½aꢂD ¼ ꢀ13:8 (c ¼
23
0.30, CHCl3) (lit.[11c] ½aꢂD ¼ ꢀ87:5 (c ¼ 0.28, CHCl3) for (S)).
(S)-3-Cyclohexylcyclopentanone (S)-3g (Table 2, Entry 10). The ee of
18% was determined by GC. GC (Hydrodex-b-TBDAc column): helium flowrate ¼
2.0 mL=min, oven ¼ 160 ꢁC, t1 ¼ 11.83 min for (S) and t2 ¼ 12.10 min for (R).
25
22
½aꢂD ¼ ꢀ6:3 (c ¼ 0.75, CHCl3) (lit.[11b]½aꢂD ¼ þ8:6 (c ¼ 1.0, CHCl3) for 93% ee (R)).
ACKNOWLEDGMENT
We gratefully acknowledge Nanyang Technological University for financial
support (Grant No. RG27=07).
REFERENCES
1. For comprehensive reviews, see (a) Feringa, B. L. Phosphoramidites: Marvelous ligands in
catalytic asymmetric conjugate addition. Acc. Chem. Res. 2000, 33, 346–353; (b) Alexakis,
`
´
A.; Ba¨ckvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Enantioselective copper-catalyzed
conjugate addition and allylic substitution reactions. Chem. Rev. 2008, 108, 2796–2823;

ENANTIOSELECTIVE CONJUGATE ADDITION OF ENONES
1591
Also see (c) Alexakis, A.; Frutos, J. C.; Mangeney, P. Chiral phosphorus ligands for the
asymmetric conjugate addition of organocopper reagents. Tetrahedron: Asymmetry 1993,
4, 2427–2430; (d) Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P. Asymmetric conjugate
addition of diethyl zinc to enones with chiral phosphine ligands. Tetrahedron: Asymmetry
1997, 8, 3987–3990; (e) Yamanoi, Y.; Imamoto, T. Methylene-bridged P-chiral dipho-
sphines in highly enantioselective reactions. J. Org. Chem. 1999, 64, 2988–2989; (f) Reetz,
M. T.; Gosberg, A.; Moulin, D. Copper-catalyzed enantioselective conjugate addition of
diethylzinc to a,b-unsaturated carbonyl compounds using diphosphonites as chiral
ligands. Tetrahedron Lett. 2002, 43, 1189–1191; (g) Li, K.; Alexakis, A. Copper catalyzed
asymmetric conjugate addition-bromination of a,b-unsaturated ketones: A highly efficient
one-pot reaction for the synthesis of chiral a-bromo-b-alkylketones. Tetrahedron Lett.
2005, 46, 5823–5826; (h) d’Augustin, M. V.; Alexakis, A. Tandem asymmetric conjugate
addition-enolacetates formation of enantiomerically enriched zinc and aluminium eno-
´
lates. Tetrahedron Lett. 2007, 48, 7408–7412; (i) Esquivias, J.; Arrayas, R. G.; Carretero,
J. C. Copper-catalyzed enantioselective conjugate addition of dialkylzinc reagents to (2-
pyridyl)sulfonyl imines of chalcones. J. Org. Chem. 2005, 70, 7451–7454; (j) Zhao, Q.
L.; Wang, L. L.; Kwong, F. Y.; Chan, A. S. C. Cu-catalyzed enantioselective conjugate
addition of diethylzinc to cyclic enones with chiral phosphite ligands derived from
1,2:5,6-di-O-cyclohexylidene-d-mannitol. Tetrahedron: Asymmetry 2007, 18, 1899–1905;
(k) Alexakis, A.; Polet, D.; Rosset, S.; March, S. Biphenol-based phosphoramidite ligands
for the enantioselective copper-catalyzed conjugate addition of diethylzinc. J. Org. Chem.
2004, 69, 5660–5667.
´
2. For comprehensive reviews, see Lopez, F.; Minnaard, A. J.; Feringa, B. L. Catalytic
enantioselective conjugate addition with Grignard reagents. Acc. Chem. Res. 2007, 40, 179–188.
3. Villacorta, G.M.; Rao, C. P.; Lippard, S. J. Synthesis and reactivity of binuclear tropocor-
onand and related organocopper(I) complexes: Catalytic enantioselective conjugate
addition of Grignard reagents to 2-cyclohexen-1-one. J. Am. Chem. Soc. 1988, 110,
3175–3182
4. (a) Spescha, M.; Rihs, G. Enantioselective copper-catalyzed 1,4-addition of Grignard
reagents to b-unsaturated carbonyl compounds. Helv. Chim. Acta 1993, 76, 1219–1230;
(b) Zhou, Q. L.; Pfaltz, A. Chiral mercaptoaryl-oxazolines as ligands in enantioselective
copper-catalyzed 1,4-additions of Grignard reagents to enones. Tetrahedron 1994, 50,
4467–4478; (c) Klaveren, M.; Lambert, F.; Eijkelkamp, D. J. F. M.; Grove, D. M.; van
Koten, G. Arenethiolatocopper(I) complexes as homogeneous catalysts for Michael
addition reactions. Tetrahedron Lett. 1994, 35, 6135–6138; (d) Seebach, D.; Jaeschke, G.;
Pichota, A.; Audergon, L. Enantioselective 1,4-addition of aliphatic Grignard reagents
to enones catalyzed by readily available copper(I) thiolates derived from TADDOL:
Preliminary communication. Helv. Chim. Acta 1997, 80, 2515–2519.
5. (a) Stangeland, E. L.; Sammakia, T. New chiral ligands for the asymmetric copper cata-
lyzed conjugate addition of Grignard reagents to enones. Tetrahedron 1997, 53, 16503–
16510; (b) Kanai, M.; Tomioka, K. Catalytic asymmetric conjugate addition of Grignard
reagents mediated by copper(I)-chiral bidentate phosphine complex. Tetrahedron Lett.
1995, 36, 4275–4278.
6. Feringa, B. L.; Badorrey, R.; Pena, D.; Harutyunyan, S. R.; Minnaard, A. J. Copper-cat-
alyzed asymmetric conjugate addition of Grignard reagents to cyclic enones. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5834–5838.
´
7. Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. Copper-catalyzed enan-
tioselective conjugate addition of Grignard reagents to acyclic enones. J. Am. Chem.
Soc. 2004, 126, 12784–12785.
8. Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. Copper-
catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones:

1592
G. QI AND Z. M. A. JUDEH
Construction of all-carbon quaternary chiral centers. J. Am. Chem. Soc. 2006, 128,
8416–8417.
9. (a) Shen, H. Y.; Ying, L. Y.; Jiang, H. L.; Judeh, Z. M. A. Efficient copper-bisisoquinoline-
based catalysts for selective aerobic oxidation of alcohols to aldehydes and ketones. Int. J.
Mol. Sci. 2007, 8, 505–512; (b) Craig, D. C.; Judeh, Z. M. A.; Read, R. W. Structural stu-
dies of N-acyl 1,10-bis(1,2,3,4-tetrahydroisoquinoline) derivatives. Aust. J. Chem. 2002, 55,
733–736; (c) Busato, S.; Craig, D. C.; Judeh, Z. M. A.; Read, R. W. New N-acyl, N-alkyl,
and N-bridged derivatives of rac-6,60,7,70-tetramethoxy-1,10,2,20,3,30,4,40-octahydro-1,10-
bisisoquinoline. Tetrahedron 2003, 59, 461–472; (d) Judeh, Z. M. A.; Ching, C. B.; Bu,
J.; McCluskey, A. The first Bischler–Napieralski cyclization in a room temperature ionic
liquid. Tetrahedron Lett. 2002, 43, 5089–5091; (e) Xi, H. W.; Judeh, Z. M. A.; Lim, K.
H. Theoretical studies of the conformers of rac-6,60,7,70-tetramethoxy-1,10,2,20,3,30,4,40-
octahydro-1,10-bisisoquinoline and its N-acyl and N-alkyl derivatives. J. Mol. Struc.: Theo-
chem. 2009, 897, 22–32; (f) Pephonen, S. O.; Judeh, Z. M. A. Mechanism of interactions
between Hg(II) and demeton S: An NMR study. Environ. Sci. Technol. 2005, 39, 2586–
2591.
10. (a) Gao, Q.; Yao, Q. J.; Judeh, Z. M. A. Novel chiral C1-10,20,30,40-tetrahydro-1,10-bisiso-
quinolines: Synthesis, resolution, and applications in catalytic enantioselective reactions.
Tetrahedron 2010, 66, 4195–4205; (b) Gao, Q.; Judeh, Z. M. A. Structurally constrained
C1-1,10-bisisoquinoline-based chiral ligands: Geometrical implications on enantioinduc-
tion in the addition of diethylzinc to aldehydes. Tetrahedron: Asymmetry 2010, 21, 429–
436.
11. (a) Malhotra Sanjay, V.; Wang, Y. Application of chiral ionic liquids in the copper cata-
lyzed enantioselective 1,4-addition of diethylzinc to enones. Tetrahedron: Asymmetry
2006, 17, 1032–1035; (b) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. Organocatalytic
transfer hydrogenation of cyclic enones. J. Am. Chem. Soc. 2006, 128, 12662–12663; (c)
Paquette, L. A.; Maynard, G. D.; Choon, S. R.; Hoppe, M. Cleavage of carbon-carbon
bonds with high stereochemical control. 7. Chiral a-silyl benzoylcycloalkanes undergo
base-catalyzed cleavage with retention of configuration when not sterically congested.
J. Org. Chem. 1989, 54, 1408–1418.