Copper-catalyzed enantioselective intramolecular conjugate addition/trapping reactions: Synthesis of cyclic compounds with multichiral centers

Article abstract of DOI:10.1002/chem.200601327

The Cu-catalyzed enantioselective conjugate addition of dialkylzinc to bis-α,β-unsaturated carbonyl compounds followed by the intramolecular trapping of the zinc enolate in the presence of chiral phosphoramidite ligands was investigated. Cyclic and hetero

Full text of DOI:10.1002/chem.200601327

FULL PAPER
DOI: 10.1002/chem.200601327
Copper-Catalyzed Enantioselective Intramolecular Conjugate Addition/
Trapping Reactions: Synthesis of Cyclic Compounds with Multichiral Centers
Kangying Li and Alexandre Alexakis*[a]
Abstract: The Cu-catalyzed enantiose-
lective conjugate addition of dialkyl-
zinc to bis-a,b-unsaturated carbonyl
compounds followed by the intramo-
lecular trapping of the zinc enolate in
the presence of chiral phosphoramidite
ligands was investigated. Cyclic and
heterocyclic compounds with multichi-
ral centers were formed as a mixture of
two diastereomers with excellent dia-
stereoselectivities (up to 99:1) and
enantioselectivities (up to 94% ee, ee=
enantiomeric excess). The stereochem-
istry was determined to be trans,trans
for the major products and trans,cis for
the minor products. The absolute con-
figuration of the cyclic compounds was
assigned by comparison with the analo-
gous adduct derived from trans-3-
nonen-2-one and Et2Zn or the adduct
obtained through conjugate addition of
Me2Zn to trans-1-phenyl-non-2-en-1-
one. Further transformation of these
cyclic products into more complex
compounds is under investigation in
our laboratory.
Keywords: copper
·
cyclization
·
·
enolates
·
Michael addition
selectivity
Introduction
can be trapped as silyl enol ethers with trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf)[9] to build more func-
tionalized chiral compounds. Recently we found that the
halogenation, by using bromine, iodine, N-bromosuccini-
mide (NBS), or N-chlorosuccinimide (NCS), of the zinc eno-
late, derived through addition of diethyl zinc to a,b-unsatu-
rated ketones in the presence of copper/chiral phosphorami-
dite ligands, proceeded cleanly and efficiently to produce
the chiral a-bromo-b-alkylketones with excellent enantiose-
lectivity and good yields of isolated product.[10] Krische and
co-workers[11] disclosed that the conjugate addition of orga-
nozinc reagents to enones possessing appendant ketone,
ester, and nitrile moieties in the presence of catalytic Cu-
Asymmetric conjugate addition is recognized as one of the
most attractive strategies for carbon–carbon bond formation
and the construction of chiral building blocks.[1] During the
last decade, the copper-catalyzed conjugate addition of orga-
nozinc reagents to a,b-unsaturated carbonyl compounds has
been extensively studied.[2,7] More recently, organoaluminum
reagents[3] have also been successfully applied for the conju-
gate addition of a,b-unsaturated substrates, particularly for
the trisubstituted enones in which a new quaternary chiral
center was created with excellent enantioselectivity. Other
types of substrate, like cyclic or acyclic nitro olefins, a,b-un-
saturated N-acyloxazolidinones, dione monoacetals, lactones
or lactams, amides, and malonates, have also been devel-
oped for conjugate addition with the zinc reagent.[4,2e] More-
over, it is known that the in situ formed intermediate zinc
enolates can easily be trapped by electrophilic reagents,
such as aldehydes,[5] Pd–p-allyl,[5a,6] halides and tosylates,[7]
oxocarbenium ions,[2e] or activated electrophiles[8] or they
ACHRTE(UNG OTf)2/PACHTRE(UGN OEt)3 successfully provided the racemic cyclic
products in good to high yields and diastereoselectivities. In
a single example, they showed that the enantioselectivity
with L5 (L=ligand) was 80% but the diastereoselectivity
decreased to 2.3:1 (down from 10:1). To the best of our
knowledge, this is the only example reported so far for the
construction of chiral cyclic compounds through the zinc
enolate trapping process.
We herein present our results for the copper-catalyzed in-
tramolecular enolate trapping reactions,[12] which provide a
novel and promising pathway to construct cyclic compounds
with multiple chiral centers.
[a] Dr. K. Li, Prof. Dr. A. Alexakis
Department of Organic Chemistry
University of Geneva
30 quai E. Ansermet, 1211 Geneva 4 (Switzerland)
Fax : (+41)22-379-3215
E-mail: alexandre.alexakis@chiorg.unige.ch
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 3765 – 3771
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3765

Results and Discussion
The chiral phosphoramidite ligands L1–L8 used in our ex-
periments were easily prepared from biphenol or binaphthol
and the corresponding chiral amines were synthesized ac-
cording to the procedures we reported previously.[13]
Scheme 1. Conjugate addition/cyclization of substrates S1–S3.
As with S1, only the uncyclized 1,4-adducts were obtained
in both of these cases.
We next turned our attention to the dienone S4, which
has been widely used for cyclization reactions.[18,16] The con-
jugate addition of diethyl zinc to S4 worked well and the ex-
pected cyclic product was formed as two diastereomers
(Scheme 2). In an attempt to evaluate the rate of the cycli-
In the literature, several groups have described the trap-
ping of zinc enolate species by olefins through a carbometal-
lation process. Normant and co-workers disclosed an effi-
cient access to substituted tetrahydrofurans and polysubsti-
tuted pyrrolidines and piperidine derivatives through the in-
tramolecular zinca ene-allene and zinc enolate cyclizations,
as well amino zinc enolate carbocyclization reactions.[14] In
2004, Nakamura and co-workers reported the a-alkylation
of ketones by addition of zinc enamides to unactivated ole-
fins.[15] On the other hand, Parsons and co-workers revealed
that the tributyltin hydride-mediated radical cyclization of
carbonyl compounds conveniently gave functionalized
oxygen and nitrogen heterocycles from the structurally simi-
lar substrates.[16] Houpis and Lee also reviewed the develop-
ment of the nickel-catalyzed reactions of nucleophiles with
unactivated and partially activated olefins.[17]
Our study began with the simple substrate S1 with a ter-
minal olefin. We hoped that the in situ formed zinc enolate,
derived from the conjugate addition of diethyl zinc to sub-
strate S1, could be intramolecularly trapped by the olefin to
form the corresponding cyclic compound. In our experi-
ment, however, only the normal 1,4-adduct was formed
(Scheme 1). The enolate trap-
Scheme 2. Conjugate addition/cyclization of substrate S4.
zation step, versus the rate of the Cu-catalyzed conjugate
addition, an excess (4.0 equiv) of diethyl zinc was added. No
second conjugate addition to the other enone moiety was
observed; this result indicated that the enolate trapping was
faster than the conjugate addition of diethyl zinc to the
enone. The results presented in Table 1 show that the ligand
structure has no significant influence on the diastereoselec-
tivity. With regard to the enantioselectivities, in most cases
moderate to good enantiomeric excesses were obtained. It
was found that the ligands with a bulky group in the amino
part, like L4 and L7 (Table 1, entries 4 and 7, respectively),
gave better enantiomeric excess values. Ligand screening re-
vealed that the best result was obtained with ligand L7,
which gave ee values of 79 and 88% for the two isomers, re-
spectively (entry 7). The use of CuTC as the copper salt
caused a slight decrease in the ee value and the diastereo-
ping by the terminal olefin did
Table 1. Conjugated addition/cyclization of substrate S4.
not happen at all, even with
changed reaction conditions,
such as the solvent, reaction
temperature, or different addi-
tives (LiBr, ZnBr2, Ni salts,
etc.). We reasoned that this is
probably because of the low ac-
tivity of the terminal olefin. As
modifications of the substrate,
S2 and S3, which were success-
fully applied in the nickel-cata-
lyzed cyclization,[17] were pre-
pared and subjected to the re-
Entry
Ligand
R2Zn
Conversion
[%][a]
dr[a]
ee
Configuration[c]
[%][b]
1
2
3
4
5
L1
ent-L2
L3
L4
ent-L5
L6
L7
ent-L7
L7
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
Me2Zn
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
80:20
82:18
84:16
80:20
79:21
80:20
80:20
72:28
70:30
60:40
53 (75)
60 (79)
27 (65)
62 (83)
67 (82)
58 (75)
79 (88)
65 (76)
88 (94)
33 (66)
ACHTREUNG
AHCTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
6
7
ACHTREUNG
ACHTREUNG
8[d]
9[e]
10[d]
ACHTREUNG
AHCTREUNG
ent-L7
ACHTREUNG
[a] Determined by GCMS. [b] Measured by chiral GC. [c] Absolute configuration assigned by comparison with
analogous adducts derived from trans-3-nonen-2-one and Et2Zn.[19, 3f] [d] With copper thiophene carboxylate
action under similar conditions. (CuTC) as the copper salt. [e] With toluene as the solvent.
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Chem. Eur. J. 2007, 13, 3765 – 3771

Conjugate Addition/Trapping Reactions
FULL PAPER
meric ratio (dr) (entry 8). The use of dimethyl zinc in tolu-
ene led to a slight decrease in the diastereoselectivity but
the enantioselectivity increased to 94% (entry 9). Both the
diastereoselectivity and enantioselectivity dropped a lot in
diethyl ether with CuTC as the copper source (entry 10).
To determine the stereochemistry of the cyclic products,
we ran the reaction in toluene with dimethyl zinc and sub-
excess values. For example, 86% ee (Table 2, entry 3) was
obtained with ligand L3, a value that is higher than those
obtained with ligands L1, L2, or L4 (entries 1, 2, and 4, re-
spectively). Among the binaphthol-type ligands, L6 afforded
a higher ee value (74% ee; entry 6) than ligands L5 and L7
(45 and 16% ee, respectively; entries 5 and 7). For ligand
L3, performance of the reaction in diethyl ether led to a
slightly improved enantiomeric excess (88% ee; entry 8) and
97% yield of isolated product, but a small decrease was
caused by using other copper salts, such as CuTC or Cu-
strate S5 in the presence of CuACHTRE(UNG OTf)2 and L3 (Scheme 3).
AHCTREUNG
like S6 with two different a,b-unsaturated carbonyl groups
(Scheme 5). It is known that the conjugate addition of dieth-
Scheme 3. Asymmetric conjugate addition/cyclization of substrate S5.
GCMS and NMR spectroscopic analysis suggested that only
one isomer was formed. The NMR spectrum (1H, 13C) is ab-
solutely identical to that of the structurally determined dia-
stereomer described by Krische and co-workers.[20] There-
fore, the stereochemistry obtained by this conjugate addi-
tion/cyclization process can be determined as trans,trans for
the major cyclic product and trans,cis for the minor diaste-
reomer.
Ligand screening has been performed for diethyl zinc ad-
dition to S5 (Scheme 4). The results were summarized in
Table 2. In all cases, the reactions proceeded with full con-
version and excellent diastereoselectivities (dr=up to 99:1).
In terms of enantioselectivities, the ligands with an ethyl
group in the amino moiety gave the better enantiomeric
Scheme 5. Conjugate addition/cyclization of substrate S6.
yl zinc selectively occurs on the enone instead of the a,b-un-
saturated ester moiety. So we hoped that the newly formed
zinc enolate could be trapped by the terminal a,b-unsaturat-
ed ester through the intramolecular pathway. In fact, the re-
action worked well under the catalytic conditions and went
to completion after several hours. Ligand screening showed
that ligand L7 exhibited the best diastereoselectivity (81:18)
and 81% enantiomeric excess for the major diastereomer.
The other ligands gave low to moderate diastereoselectivi-
ties and enantioselectivities. When L1 was used, moderate
diastereoselectivity (74:26) was obtained which remained
almost unchanged (76:24) after an attempted isomerization
with 1,8-diazabicycloACHTRE[UGN 5,4,0]undec-7-ene (DBU) in MeOH.
To examine the effect of substrate structure on the diaste-
reoselectivity and enantioselectivity, we synthesized com-
pound S7 containing an aromatic group on the enone
moiety. In comparison with sub-
Scheme 4. Ligand screening for the conjugate addition/cyclization of sub-
strate S5.
strate S6, the replacement of
Table 2. Ligand screening for the conjugate addition/cyclization of substrate S5.
the methyl group with a phenyl
Entry
Ligand
CuX
Conversion [%][a]
(yield [%][b]
/
dr[a]
ee
Configuration[d]
moiety remarkably improved
both the diastereomeric ratios
and the enantioselectivities
(Scheme 6, Table 3). This trend
is also observed in the work of
Krische and co-workers.[11] Sim-
ilarly to the results described in
Table 2, ligands L3 and L6
(Table 3, entries 3 and 6, respec-
tively) with an ethyl group in
the amino part proved to be
more efficient for the improve-
ment of diastereoselectivity and
enantioselectivity under the
A
)
[%][c]
1
2
3
4
5
L1
L2
L3
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
>99
>99
>99 (83)
>99
>99 (84)
>99
>99
>99(97)
>99
>99
>99 (68)
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
62
66
86
66
45
74
16
88
79
79
72
ACHTREUNG
ACHTREUNG
ACHTREUNG
L4
ACHTREUNG
ent-L5
L6
ACHTREUNG
6
7
ACHTREUNG
L7
L3
L3
L3
ACHTREUNG
8[e]
9
ACHTREUNG
CuTC
Cu
Cu
ACHTREUNG
10
ACHTREUNG
11[f]
L3
ACHTREUNG
[a] Determined by GCMS. [b] Yield of isolated product. [c] Determined by SFC. [d] Absolute configuration as-
signed by comparison with analogous adducts derived from (E)-1-phenylnon-2-en-1-one and Me2Zn.[21]
[e] Et2O as the solvent. [f] Me2Zn was used.
Chem. Eur. J. 2007, 13, 3765 – 3771
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www.chemeurj.org
3767

A. Alexakis and K. Li
tween the amino group in substrate S8 and the Lewis acid
Et2Zn. The highest enantiomeric excess was only 60% and
resulted with ligand L3.
We then tested substrate S9, which was easily synthesized
from readily available starting materials in several steps. In
this molecule, there are two possible reactive positions. It
could be anticipated that the
Scheme 6. Conjugate addition/cyclization of substrate S7.
Table 3. Conjugate addition/cyclization of substrate S7.
expected product will be
formed without enantioselectiv-
Entry
Ligand
CuX
Conversion [%][a]
(yield [%])
/
dr[a]
ee [%][b]
Configuration[e]
ity if the conjugate addition
first takes place at the a,b-satu-
rated triple-bond moiety. In
fact, 86% ee was achieved
when the conjugate addition
was performed in toluene with
the optimized ligand L3 and
CuACHTRE(UNG OTf)2 (Scheme 8), a result
indicating that the reaction
preferentially occurred at the
AHCTREUNG
1
2
3
4
5
6
7
8
L1
L2
ent-L3
L4
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99(43)
91:9
47 (62)
54 (48)
88 (90)
45 (43)
7 (49)
72 (51)
45 (2)
91 (90)
92 (87)
92(86)
ACHTREUNG
78:22
81:19
65:35
76:24
80:20
69:31[d]
92:8
ACHTREUNG
ACHTREUNG
ACHTREUNG
L5
L6
L7
ACHTREUNG
ACHTREUNG
ACHTREUNG
ent-L3
ent-L3
L3
CuTC
Cu(OAc)2·H2O
CuTC
ACHTREUNG
9
90:10
93:7
ACHTREUNG
10[c]
ACHTREUNG
[a] Determined by GCMS. [b] Measured by SFC. [c] Toluene used as the solvent. [d] 70:30 ratio after isomeri- a,b-unsaturated ketone part.
zation with DBU in MeOH. [e] Absolute configuration assigned by comparison with analogous adduct derived
The other ligands exhibited
lower enantioselectivities. NMR
from (E)-1-phenylnon-2-en-1-one and Me2Zn.[21]
spectroscopic analysis showed
same conditions. An ee value of 90%, for instance, was ob-
tained by using L3 (Table 3, entry 3) whereas the levels of
enantiomeric excess obtained from L1, L2, and L4 (en-
tries 1, 2, and 4, respectively) were below 60%. Ligand L6
produced the corresponding product with 72% ee and with
a dr of 80:20 (entry 6), which was better than the results
with ligands L5 and L7 (entries 5 and 7, respectively). In the
case of ligand L3, further investigation into the copper salt
the formation of the bicyclic lactone which was probably ob-
tained by the pathway shown in Scheme 8.
effect was performed. CuTC (entry 8) and CuACHTREU(GN OAc)2·H2O
(entry 9) seemed to be beneficial to get slightly higher dia-
stereomic ratios and enantiomeric excesses. Toluene was
also found to be a good choice for this reaction; with this
solvent, the ratio increased to 93:7 and the ee value re-
mained high (entry 10). As expected, isomerization of the
product by using DBU (entry 7) did not change the ratio.
To examine the application of this strategy for the synthe-
sis of chiral heterocyclic compounds, we synthesized sub-
strate S8 from readily available materials. The conjugate ad-
dition/cyclization of diethyl zinc to S8 proceeded smoothly
and went to completion within several hours (Scheme 7).
The products were formed with good to excellent diastereo-
mic ratios (up to 96:4) which were completely dependent
upon the ligand used. As compared to the results obtained
with substrate S7, a great drop in enantioselectivity was ob-
served; this is presumably because of the coordination be-
Scheme 8. Conjugate addition/cyclization of substrate S9.
Compound S10 with a terminal ketone moiety was recent-
ly used as substrate in the Cu-catalyzed nonasymmetric
tandem conjugate addition/electrophilic trapping by Krische
and co-workers.[11] Up to 95:5 diastereoselectivity and a
good yield of isolated product were achieved. In our asym-
metric version of the reaction, we got 98:2 diastereoselectiv-
ity and 80% chemical yield (Scheme 9). With regard to the
enantiomeric excesses, poor to moderate ee values were at-
tained in all cases. Generally, the biphenol-type ligands L1–
Scheme 7. Conjugate addition/cyclization of substrate S8.
Scheme 9. Conjugate addition/cyclization of substrate S10.
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Conjugate Addition/Trapping Reactions
FULL PAPER
2H), 2.29–2.36 (m, 9H), 5.92–5.95 (d, 2H), 6.74–6.85 ppm (m, 2H);
L4 were better (27–51% ee) than the ligands with a binaph-
thol framework (4–32% ee).
13C NMR: d=26.24, 26.73, 31.40, 131.55, 147.01, 198.17 ppm.
Substrate S5: A mixture of glutaric dialdehyde (10 mmol, 1.8 mL) and
(benzoylmethylene)triphenylphosphorane (25 mmol, 9.51 g) in CH2Cl2
(20 mL) was stirred at room temperature for 48 h. Removal of the sol-
vent gave the crude product which was purified by flash chromatography
to afford the pure product (2.4 g, 79% yield) as a yellow oil. 1H NMR:
d=1.75–1.79 (m, 2H; CH2), 2.36–2.40 (m, 4H; 2CH2), 6.90–6.94 (d, 2H;
2CH), 7.44–7.94 ppm (m, 10H; 2PhH); 13C NMR: d=26.88, 32.40,
126.66, 128.51, 128.67, 128.77, 128.81, 130.35, 133.01, 138.01, 148.91,
190.93 ppm. The NMR spectrum is identical to those reported before.[26]
Substrate S6:[18a] A mixture of 7-oxo-5-octenal (10 mmol, 1.45 g) and
methyl (triphenylphosphoranylidene)acetate (20 mmol, 6.69 g) in CHCl3
(20 mL) was stirred at room temperature for 60 h under argon. The sol-
vent was evaporated and the residue was purified by flash chromatogra-
phy to give the pure product (1.07 g, 55% yield) as a light yellow oil.
1H NMR: d=1.63–1.70 (m, 2H), 2.25–2.35 (m, 7H), 3.74 (s, 3H), 5.83–
5.87 (d, 1H), 6.07–6.11 (d, 1H), 6.75–6.81 (m, 1H), 6.91–6.99 ppm (m,
1H); 13C NMR: d=26.38, 26.94, 31.54, 51.46, 121.63, 131.74, 147.06,
148.27, 166.90, 198.44 ppm.
Conclusion
We have developed an efficient asymmetric conjugate addi-
tion/trapping reaction for the synthesis of cyclic and hetero-
cyclic compounds with multiple chiral centers. In all cases,
only two diastereomers were formed with full conversion
and moderate to high enantiomeric excesses. The stereo-
chemistry of this process and the absolute configurations of
the products were determined. The application of this strat-
egy for the synthesis of more elaborate natural compounds
is still in progress in our laboratory.
Substrate S7:[18c]
A
solution of (E)-7-phenyl-7-oxohept-5-enal[27]
Experimental Section
(22 mmol, 4.46 g) in CH2Cl2 (20 mL) was added to a mixture of methyl
(triphenylphosphoranylidene)acetate (44 mmol, 14.75 g) and CH2Cl2
(110 mL). The resulting solution was stirred at room temperature for
40 h. The solvent was evaporated and the residue was purified by chro-
matography to give the pure product (2.86 g, 50% yield) as a light yellow
oil. 1H NMR: d=1.68–1.79 (m, 2H), 2.27–2.42 (m, 4H), 3.77 (s, 3H),
5.85–5.92 (d, 1H), 6.92–7.07 (m, 3H), 7.49–7.62 (m, 3H), 7.96–7.98 ppm
(d, 2H); 13C NMR: d=26.52, 31.59, 32.09, 51.51, 121.65, 126.44, 128.54,
132.77, 137.86, 148.41, 148.54, 166.98, 190.64 ppm.
1
General procedures: H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were recorded in CDCl3 and chemical shifts (d) are given in ppm rela-
tive to residual CHCl3. The evolution of each reaction was followed with
by GCMS with a Hewlett–Packard (EI mode) HP6890-5973 instrument.
Enantiomeric excesses were determined by chiral GC (capillary column,
10 psi H2) or chiral SFC with the stated column. Temperature programs
are described as follows: initial temperature (8C)–initial time (min)–tem-
perature gradient (8CminÀ1)–final temperature (8C); retention times (tR)
are given in min.
Substrate S8:
A mixture of methyl (E)-5-aza-5-benzyl-7-oxohept-2-
enoate[28] (15 mmol, 3.71 g) and (benzoylmethylene)triphenylphosphor-
ane (7.6 g, 20 mmol) in CH2Cl2 (20 mL) was allowed to stir at room tem-
perature for 16 h. The solvent was removed to give the crude product
which was purified by flash chromatography. The pure product was iso-
lated in 65% yield (4.54 g). 1H NMR: d=3.339–3.346 (d, 2H, CH2),
3.403–3.41 (d, 2H, CH2), 3.72 (s, 2H, CH2), 3.80 (s, 3H, MeO), 6.12–6.16
(d, 1H, =CH), 7.08–7.15 (m, 3H, 3=CH), 7.30–7.51 (m, 5H, PhH), 7.53–
7.95 ppm (m, 5H, PhH); 13C NMR: d=51.64, 54.73, 55.13, 58.61, 122.77,
127.24, 127.40, 137.71, 146.01, 166.66, 190.43 ppm; MS (ESI): m/z (%):
349 (13), 245 (16), 244 (73), 204 (20), 158 (16), 144 (12), 105 (51), 91
(100); HRMS: calcd for C22H23NO3: 350.1756 [M+1]; found: 350.1759.
Flash chromatography were performed by using silica gel 32–63 mm with
cyclohexane/ethyl acetate as the eluent. All reactions were conducted
under an argon atmosphere. Diethyl ether and dichloromethane were dis-
tilled from sodium benzophenone ketyl under nitrogen. Substrates S1[22]
and S10[23] were synthesized according to the procedures reported previ-
ously.
Substrate S2: The Swern oxidation of 6-phenylhex-5-yn-1-ol[24] (15 mmol,
2.61 g) under standard conditions with oxalyl chloride (23.6 mmol, 2 mL),
dimethylsulfoxide (DMSO; 59.6 mmol, 4.2 mL), and triethyl amine
(74.6 mmol, 10.4 mL) in CH2Cl2 gave quantitatively the corresponding al-
dehyde 6-phenylhex-5-ynal, which is used directly without further purifi-
cation. A mixture of the 6-phenylhex-5-ynal and 1-triphenylphosphorany-
lidene-2-propanone (19.5 mmol, 6.20 g) in CH2Cl2 (40 mL) was stirred at
room temperature for 60 h under argon. After removal of the solvent,
the residue was purified by flash chromatography to give the pure prod-
uct S2 (2.58 g, 81% yield) as a light yellow oil. 1H NMR: d=1.81–1.88
(m, 2H; CH2), 2.30 (s, 3H; Me), 2.44–2.53 (m, 4H; 2CH2), 6.16–6.21 (d,
1H; CH), 6.85–6.92 (m, 1H; CH), 7.31–7.34 (m, 3H; PhH), 7.43–
7.45 ppm (m, 2H; PhH); 13C NMR: d=18.97, 26.96, 27.11, 31.51, 81.51,
89.08, 123.74, 127.75, 128.28, 131.56, 131.86, 147.24, 198.58 ppm.
Substrate S3: A mixture of 4,6-heptadienal[25] (17 mmol, 1.87 g) and (ben-
zoylmethylene)triphenylphosphorane (20 mmol, 7.6 g) in CH2Cl2 (20 mL)
was stirred at room temperature for 48 h. The solvent was evaporated
and the residue was purified by flash chromatography to give the product
S3 (2.28 g, 63% yield) as a light yellow oil. 1H NMR: d=2.27–2.45 (m,
4H; 2CH2), 4.98–5.15 (dd, 2H; =CH2), 5.65–5.75 (m, 1H; =CH), 6.06–
6.14 (m, 1H; =CH), 6.24–6.37 (m, 1H; =CH), 6.85–6.91 (d, 1H; =CH),
6.99–7.08 (m, 1H; =CH), 7.42–7.51 (m, 3H; PhH), 7.90–7.92 ppm (m,
2H; PhH); 13C NMR: d=10.85, 26.39, 29.84, 33.09, 35.33, 42.91, 113.89,
128.13, 128.61, 131.08, 132.92, 135.12, 137.27, 200.55 ppm.
Substrate S4:[24] Glutaric dialdehyde (2 mmol, 0.35 mL) was added to a
solution of 1-triphenylphosphoranylidene-2-propanone (5 mmol, 1.59 g)
in CH2Cl2 (10 mL). The resulting solution was stirred at room tempera-
ture for 70 h and was then washed with water and dried over MgSO4.
The crude product was purified by chromatography. The pure product
was obtained as a yellow oil in 65% yield. 1H NMR: d=1.64–1.73 (m,
Substrate S9: This compound was obtained from 6-hydroxy-hex-2-ynoic
acid methyl ester[29] (2.843 g, 20 mmol) and (benzoylmethylene)triphenyl-
phosphorane (9.50 g, 25 mmol) through typical Swern oxidation proce-
dures and with classical Wittig reaction conditions in CH2Cl2. Pure prod-
uct was isolated through flash chromatography in 68% yield (3.28 g).
1H NMR: d=2.56–2.58 (t, 4H; 2CH2), 3.73 (s, 3H; MeO), 6.96 (m, 2H;
CH=CH), 7.43–7.52 (m, 3H; PhH), 7.54 ppm (m, 2H; PhH); 13C NMR:
d=17.78, 30.52, 52.69, 73.85, 87.58, 127.44, 129.00, 132.93, 137.62, 145.28,
153.90, 190.40 ppm; MS (ESI): m/z (%): 242 (8), 227 (22), 183 (22), 155
(22), 117 (47), 105 (100), 91 (30), 77 (92), 51 (66); HRMS: calcd for
C15H14O3: 243.1021 [M+1]+; found: 243.1014.
Typical procedure for the asymmetric conjugate addition/trapping (for
0.5 mmol of substrate): Dry diethyl ether (2 mL) was added to a mixture
of CuACTHRE(UNG OTf)2 (0.02 equiv) and ligand (0.04 equiv) under nitrogen. The so-
lution was allowed to stir at room temperature for 30 min and was then
cooled to À308C. Diethyl zinc (1.5 equiv, 0.75 mL, 1m in hexane) was
added dropwise while the temperature was maintained below À308C.
The solution was stirred for 5 min, and a solution of the substrate
(0.5 mmol) in diethyl ether (0.5 mL) was added dropwise. The reaction
mixture was stirred at À308C for 2 h and was then warmed to room tem-
perature until all of the starting material was consumed. The solution
was diluted with diethyl ether (20 mL) and washed successively with 2n
HCl and brine. The organic layer was dried over sodium sulfate. Removal
of the solvent gave the crude product which underwent to GC and ee
analysis or NMR spectroscopy measurements after flash chromatography.
Chem. Eur. J. 2007, 13, 3765 – 3771
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3769

A. Alexakis and K. Li
1
Compound 1a: dr=72:28; H NMR: d=0.82–1.06 (m, 5H), 1.21–1.46 (m,
CH), 7.46–7.51 (m, 3H; PhH), 7.78–7.79 ppm (m, 2H; PhH); 13C NMR:
d=12.04, 25.93, 29.90, 30.42, 42.60, 107.56, 124.27, 127.55, 128.65, 129.97,
132.52, 154.19, 163.11, 166.48 ppm; MS (ESI): m/z (%): 240 (45), 212
(38), 211 (100), 184 (9), 156 (14), 105 (71), 77 (73), 51 (24); HRMS: calcd
for C16H16O2: 241.1228 [M+1]+; found: 241.1225; SFC (Chiral OD-H, 5–
2–1–15%, 200 bar, 2 mLminÀ1, 308C): tR1 =8.19, tR2 =8.87 min.
3H), 1.49–1.62 (m, 2H), 1.70–1.91 (m, 3H), 2.06–2.11 (m, 6H), 2.19–
2.67 ppm (m, 2H); 13C NMR: d=10.79, 11.08, 20.58, 25.28, 26.34, 26.81,
27.21, 29.42, 29.62, 29.88, 30.56, 31.22, 31.36, 32.14, 33.76, 34.57, 35.21,
35.38, 41.09, 43.19, 48.35, 48.71, 57.70, 63.52, 207.75, 207.86, 212.66,
213.96 ppm; MS (ESI): m/z (%): 210 (11), 181 (27), 153 (56), 109 (100),
81 (60), 67 (52), 55 (24); HRMS: calcd for C13H22O2: 210.1619 [M]+;
found: 210.1619; chiral GC (hydrodex-B-3P, 60–0–1–17–10, 30 cmsÀ1):
Compound 8:[11] 1H NMR: d=0.82–0.86 (t, 3H; CH3), 1.32 (s, 3H; CH3),
1.33–1.48 (m, 3H; CH2, CH), 1.80–1.86 (m, 1H; CHH), 1.93–2.00 (m,
1H; CHH), 2.18–2.27 (m, 1H; CHH), 2.59–2.65 (m, 1H; CHH), 3.45–
3.48 (d, 1H; CH), 3.84 (s, 1H; OH), 7.52–7.65 (m, 3H; PhH), 8.00–
8.02 ppm (m, 2H; PhH); 13C NMR: d=12.71, 27.40, 28.61, 29.04, 40.99,
46.62, 60.22, 81.99, 128.47, 128.80, 133.66, 138.49, 206.36 ppm; SFC
t
R1 =78.33, tR2 =79.48, tR3 =85.48, tR4 =86.27 min.
Compound 1b: 1H NMR: d=0.82–0.83 (d, 3H; CH3), 1.30–1.44 (m, 2H;
CH2), 1.63–1.84 (m, 6H; 2CH, 2CH2), 2.084 (m, 3H; CH3), 2.087 (m,
3H; CH3), 2.11–2.28 ppm (m, 3H; CH2, CH); 13C NMR: d=20.55, 25.38,
28.92, 30.54, 31.91, 34.33, 34.96, 35.26, 48.68, 65.07, 207.76, 213.76 ppm;
MS (ESI): m/z (%): 196 (3), 178 (37), 163 (19), 139 (27), 122 (32), 109
(100), 95 (72), 82 (70), 67 (21), 55 (20); HRMS: calcd for C12H20O2:
196.1463 [M]+; found: 196.1469; chiral GC (hydrodex-B-3P, 60–0–1–17–
10, 50 cmsÀ1): tR1 =66.07, tR2 =69.22, tR3 =72.13, tR4 =73.50 min.
(Chiral AD, 5–2–1–15%–3, 200 bar, 2 mLminÀ1, 308C): tR1 =5.13, tR2
=
6.85 min.
Compound 2:[20] 1H NMR: d=0.77–0.79 (d, 3H; CH3), 1.02–1.23 (m, 2H;
CH2), 1.32–1.42 (m, 1H; CH), 1.63–1.88 (m, 4H; 2CH2), 2.38–2.51 (m,
2H; CH2), 2.82–2.92 (q, 1H; CH), 3.06–3.15 (t, 1H; CH), 7.39–7.58 (m,
6H; PhH), 7.77–7.79 (d, 2H; PhH), 7.99–8.30 ppm (d, 2H; PhH);
13C NMR: d=21.10, 25.38, 31.46, 34.99, 37.03, 38.38, 44.14, 56.59, 128.26,
128.29, 128.83, 132.99, 133.28, 136.77, 139.34, 199.44, 206.33 ppm; SFC
Acknowledgements
The authors thank Stephane Rosset for help and the Swiss National Re-
search Foundation (grant no. 200020-105368) and COST action D24/0003/
01 (OFES contract no. C02.0027) for financial support.
(Chiral AD, 2–2–1–15%, 2 mLminÀ1, 200 bar, 308C): tR1 =8.48, tR2
=
9.07 min.
[1] For recent reviews on asymmetric conjugate addition: a) N. Krause,
A. Hoffmann-Roder, Synthesis 2001, 171–196; b) M. P. Sibi, S.
Manyem, Tetrahedron 2000, 56, 8033–8061; c) M. Kanai, M. Shiba-
saki, Catalytic Asymmetric Synthesis (Ed.: I. Ojima), 2nd ed., Wiley,
New York, 2000, p. 569.
Compound 3: 1H NMR: d=0.75–0.77 (t, 3H; Me), 0.94–1.07 (m, 2H;
CH2), 1.15–1.39 (m, 4H; 2CH2), 1.73–1.82 (m, 2H; CH2), 1.94–1.98 (m,
1H; CH), 2.43–2.52 (m, 2H; CH2), 2.83–2.91 (q, 1H; CH), 3.18–3.23 (t,
1H; CH), 7.38–7.77 (m, 6H; PhH), 7.78–7.80 (d, 2H; PhH), 8.02–
8.04 ppm (d, 2H; PhH); 13C NMR: d=11.27, 25.27, 27.72, 30.54, 31.69,
38.84, 43.35, 44.22, 55.16, 128.24, 128.27, 128.58, 128.84, 132.98, 133.29,
136.75, 139.38, 199.42, 206.66 ppm; MS (ESI): m/z (%): 334 (6), 224 (20),
215 (69), 109 (38), 105 (100), 77 (73); HRMS: calcd for C23H26O2:
335.2011 [M+1]+; found: 335.2001; SFC (Chiral AD, 2–2–1–15%,
2 mLminÀ1, 200 bar, 308C): tR1 =4.90, tR2 =6.49 min.
Compound 4: dr=95:5; 1H NMR: d=0.83–0.87 (m, 3H; CH3), 0.97–1.11
(m, 2H; CH2), 1.25–1.37 (m, 2H; CH2), 1.46–1.57 (m, 1H; CH), 1.74–
1.90 (m; 4H), 2.06 (s, 3H; CH3), 1.95–2.36 (m, 4H; CH2, 2CH), 3.63–
3.64 ppm (d, 2.85H, 0.15H; CH3); 13C NMR: d=10.80, 25.22, 26.94,
27.12, 29.88, 31.73, 36.82, 39.31, 41.37, 51.56, 62.73, 172.73, 213.69 ppm;
MS (ESI): m/z (%): 226 (7), 194 (16), 165 (32), 151 (16), 136 (36), 109
(100), 81 (45), 74 (59); HRMS: calcd for C13H22O3: 249.1466 [M+Na]+;
found: 249.1476; chiral GC (hydrodex-B-3P, 60–0–1–170–10, 40 cmsÀ1):
[2] For examples of the copper-catalyzed asymmetric conjugate addition
of organozinc reagents: a) A. Alexakis, D. Polet, S. Rosset, S.
March, J. Org. Chem. 2004, 69, 5660–5667; b) A. Alexakis, C. Ben-
haim, Eur. J. Org. Chem. 2002, 3221–3236; c) A. Alexakis, C. Ben-
haim, S. Rosset, M. Human, J. Am. Chem. Soc. 2002, 124, 5262–
5263; d) L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J.
Am. Chem. Soc. 2001, 123, 5841–5842; e) A. Alexakis, G. P. Trevitt,
G. Bernardinelli, J. Am. Chem. Soc. 2001, 123, 4358–4359; f) A.
Alexakis, J. Burton, J. Vastra, C. Benhaim, X. Fournioux, A. Van
den Heuvel, J. M. Leveque, F. Maze, S. Rosset, Eur. J. Org. Chem.
2000, 4011–4027; g) A. Alexakis, C. Benhaim, Org. Lett. 2000, 2,
2579–2581; h) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346–353;
i) I. H. Escher, A. Pfaltz, Tetrahedron 2000, 56, 2879–2888; j) M.
Yan, A. S. C. Chan, Tetrahedron Lett. 1999, 40, 6645–6648; k) S. J.
Degrado, H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124,
13362–13363.
[3] For cyclic enones: a) M. dꢁAugustin, L. Palais, A. Alexakis, Angew.
Chem. 2005, 117, 1400–1402; Angew. Chem. Int. Ed. 2005, 44, 1376–
1378; b) L. Su, X. Li, W. L. Chan, X. Jia, A. S. C. Chan, Tetrahedron:
Asymmetry 2003, 14, 1865–1869; c) L. Liang, A. S. C. Chan, Tetrahe-
dron: Asymmetry 2002, 13, 1393–1396; d) M. Diegez, S. Deerem-
berg, O. Pamies, C. Claver, P. W. N. M. van Leeuwen, P. Kamer, Tet-
rahedron: Asymmetry 2000, 11, 3161–3166; e) Y. Takemoto, S. Kur-
aoka, N. Hamaue, C. Iwata, Tetrahedron: Asymmetry 1996, 7, 993–
996; for acyclic enones: f) A. Alexakis, V. Albrow, K. Biswas, M.
dꢁAugustin, O. Pireto, S. Woodward, Chem. Commun. 2005, 2843–
2845; g) P. K. Fraser, S. Woodward, Chem. Eur. J. 2003, 9, 776–783;
h) S. M. W. Bennett, S. M. Brown, J. P. Muxworthy, S. Woodward,
Tetrahedron Lett. 1999, 40, 1767–1770; for nitro olefins: i) D. Polet,
A. Alexakis, Tetrahedron Lett. 2005, 46, 1529–1532; j) U. Eilitz, F.
Lessmann, O. Seidelmann, V. Wendisch, Tetrahedron: Asymmetry
2003, 14, 3095–3097.
tR1 =72.39, tR2 =72.84, tR3 =76.86, tR4 =77.32 min.
Compound 5: 1H NMR: d=0.85–0.89 (t, 3H; CH3), 1.07–1.21 (m, 2H;
CH2), 1.46–1.66 (m, 4H; 2CH2), 1.80–1.91 (m, 3H; CH2, CH), 2.39–2.41
(m, 2H; CH2), 2.55 (m, 1H; CH), 3.44–3.48 (dd, 1H; CH), 3.56 (s, 3H;
CH3O), 7.44–7.48 (m, 3H; PhH), 7.94–7.99 ppm (m, 2H; PhH);
13C NMR: d=11.27, 20.09, 26.84, 29.15, 29.99, 32.42, 33.99, 35.03, 51.41,
128.11, 128.69, 132.91, 137.46, 173.58, 202.90 ppm; MS (ESI): m/z (%):
288 (31), 256 (23), 214 (12), 161 (39), 136 (32), 109 (55), 105 (100), 77
(71); HRMS: calcd for C18H24O3: 289.1803 [M+1]+; found: 289.1813;
SFC (Chiral OD-H, 5–6–1–15%, 2 mLminÀ1, 130 bar, 108C): tR1 =3.91,
tR2 =4.11, tR3 =4.48, tR4 =4.80 min.
Compound 6: 1H NMR: d=0.82–0.85 (t, 3H; CH3), 1.07 (m, 1H; CH2),
1.38–1.43 (m, 1H; CH2), 1.80–1.86 (t, 1H), 2.20–2.29 (m, 2H), 2.29–2.34
(dd, 1H), 2.52–2.53 (m, 1H), 2.77–2.83 (m, 2H), 3.05–3.07 (d, 1H), 3.36–
3.39 (m, 2H), 3.46 (s, 3H; OCH3), 3.62–3.65 (d, 1H), 7.23–7.31 (m, 5H;
PhH), 7.44–7.48 (t, 2H; PhH), 7.54–7.57 (t, 1H; Ph-H), 7.92–7.94 ppm (d,
2H; PhH); 13C NMR: d=11.35, 25.33, 32.55, 33.64, 34.48, 51.36, 57.08,
58.35, 62.92, 126.95, 128.78, 133.14, 137.12, 138.69, 173.62, 202.00 ppm;
MS (ESI): m/z (%): 379 (15), 219 (21), 218 (90), 174 (82), 105 (26), 91
(100); HRMS: calcd for C24H29NO3: 380.2225 [M+1]+; found: 380.2227;
[4] For nitro olefins: a) A. Alexakis, D. Polet, C. Benhaim, S. Rosset,
Tetrahedron: Asymmetry 2004, 15, 2199–2203; b) A. Duursma, A.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2003, 125, 3700–3701;
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amides: d) A. W. Hird, A. H. Hoveyda, Angew. Chem. 2003, 115,
1314–1317; Angew. Chem. Int. Ed. 2003, 42, 1276–1279; for lac-
tones: e) L. Liang, L. Su, X. Li, A. S. C. Chan, Tetrahedron Lett.
SFC (Chiral OJ, 2–2–1–15%, 200 bar, 2 mLminÀ1, 308C): tR1 =4.41, tR2
5.61 min.
Compound 7: 1H NMR: d=0.88–0.92 (t, 3H; CH3), 1.30–1.36 (m, 2H;
CH2), 1.53–1.59 (m, 1H; CH2), 1.90–2.00 (m, 1H; CH2), 2.17–2.25 (m,
1H; CH2), 2.79–2.88 (m, 2H; CH2), 3.38–3.42 (m, 1H; CH), 6.18 (s, 1H;
=
3770
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3765 – 3771

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Received: September 15, 2006
Published online: January 24, 2007
Chem. Eur. J. 2007, 13, 3765 – 3771
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3771