Cooperative activation of alkyne and thioamide functionalities; Direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides

Article abstract of DOI:10.1002/asia.201100050

A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst, comprising [Cu(CH₃CN)₄]PF₆,

Full text of DOI:10.1002/asia.201100050

FULL PAPERS
DOI: 10.1002/asia.201100050
Cooperative Activation of Alkyne and Thioamide Functionalities;
Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes
to a,b-Unsaturated Thioamides
Ryo Yazaki,[a, b] Naoya Kumagai,*[a] and Masakatsu Shibasaki*[a]
On the occasion of the 150th anniversary of Department of Chemistry, The University of Tokyo
Abstract: A detailed study of the direct
catalytic asymmetric conjugate addition
of terminal alkynes to a,b-unsaturated
thioamides is described. A soft Lewis
acid/hard Brønsted base cooperative
enolate functioned as a Brønsted base
to generate copper alkynylide from the
terminal alkyne, thus driving the cata-
lytic cycle through an efficient proton
transfer between substrates. These find-
ings led to the identification of a more
convenient catalyst using potassium
hexamethyldisilazane (KHMDS) as the
Brønsted base, which was particularly
effective for the reaction of silylacety-
lenes. Divergent transformation of the
thioamide functionality and a concise
enantioselective synthesis of a GPR40
receptor agonist AMG-837 highlighted
the synthetic utility of the present cat-
alysis.
catalyst, comprising [CuACHTUNGRTNE(UNG CH3CN)4]PF6,
bisphosphine ligand, and Li(OC6H4-p-
OMe) simultaneously activated both
substrates to compensate for the low
Keywords: alkynes
·
asymmetric
reactivity of copper alkynylide.
A
catalysis · copper · proton transfer ·
thioamide
series of control experiments revealed
that the intermediate copper-thioamide
Introduction
through the activation of both reaction partners. Recently,
in pursuit of direct-type catalytic asymmetric reactions, we
devoted much effort to exploiting the soft Lewis basic char-
acter of a thioamide functionality, which can be activated as
a nucleophile by a soft Lewis acid/hard Brønsted base coop-
erative catalyst. Although thioamides are widely utilized in
organic synthesis, especially for the construction of sulfur-
containing heterocyclic compounds,[3] their use in asymmet-
ric catalysis has been limited. Chemoselective activation
through soft–soft interaction allows for in situ catalytic gen-
eration of thioamide enolates, thereby leading to the devel-
opment of direct catalytic asymmetric Mannich-type and
aldol reactions of thioamides (Scheme 1a).[4] In our continu-
ing program on thioamide chemistry, we turned our atten-
tion to incorporating electrophilic activation of a thioamide
functionality in direct-type catalytic asymmetric reactions. In
the nucleophilic activation of thioamides, our primary focus
was on chemoselective activation in the presence of hard
Lewis basic substrates. In this study, we envisioned simulta-
neous activation of both reaction partners by using the soft
Lewis acid/hard Brønsted base cooperative catalyst, which
can be represented by a catalytic asymmetric conjugate ad-
dition of soft Lewis basic a,b-unsaturated thioamides as the
Cooperative catalysis has gained increasing attention in
asymmetric catalysis as an effective strategy to simultane-
ously activate multiple substrates with explicit control of the
stereochemical course of the reaction.[1] In particular, the
significance of this strategy is highlighted in so-called direct
catalytic asymmetric C C bond-forming reactions,[2] in
À
À
which the enantioselective intermolecular C C bond forma-
tion proceeds in a catalytic manner by proton transfer
[a] R. Yazaki, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax : (+81)3-3447-7779
E-mail: mshibasa@bikaken.or.jp
nkumagai@bikaken.or.jp
Homepage: http://www.bikaken.or.jp/research/group/shibasaki/
shibasaki-lab/index.html
[b] R. Yazaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100050.
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Chem. Asian J. 2011, 6, 1778 – 1790

In this context, our attention
was directed toward the devel-
opment of the direct catalytic
asymmetric addition of terminal
alkynes to a,b-unsaturated thio-
amides 1,[15] which addresses
the above-mentioned drawback
and proves the effectiveness of
a simultaneous activation strat-
egy. Despite the similar electro-
negativity of sulfur and carbon
atoms, the C=S bond of thioa-
mides shows a higher dipole
moment than that of the C=O
bond of the corresponding
amides.[16,17] In conjunction with
the soft Lewis basic nature of
sulfur atoms, the electrophilicity
at the b-position of a,b-unsatu-
rated thioamides 1 can be en-
hanced by activation with a soft
Scheme 1. Two modes of activation strategy with the soft Lewis acid/hard Brønsted base cooperative catalytic
system.
electrophile and soft Lewis basic terminal alkynes as the
pronucleophile (Scheme 1b).
Lewis acid. The combined use of a hard Brønsted base
would allow for the facile deprotonation of soft Lewis acid-
activated terminal alkynes 2 to generate a metal-alkynylide,
which would engage in an enantioselective coupling, with 1
activated in close proximity. On the basis of this hypothesis,
we identified that the soft Lewis acid/hard Brønsted base/
hard Lewis base cooperative catalyst comprising [Cu-
Catalytic asymmetric conjugate addition to an electron-
deficient olefin is one of the most efficient methodologies to
synthesize useful chiral building blocks for biologically
active compounds.[5] Terminal alkynes have established their
utility as carbon pronucleophiles in carbon–carbon bond-
forming reactions,[6] including catalytic asymmetric 1,2-addi-
AHCTNUGTER(GNNNU CH3CN)4]PF6, biaryl-type chiral bisphosphine ligands 3,
tions[7] and C
N
Li(OC6H4-p-OMe), and phosphine oxide 4 efficiently pro-
moted the desired conjugate addition of 2 to 1 under
proton-transfer conditions (Scheme 2).[18] Herein, we report
metal alkynylides are effective
nucleophiles in catalytic asym-
metric conjugate addition,[9] in
situ generation of active metal
alkynylides is more desirable in
terms of both atom and step
economy.[10] Pioneering work
on a direct catalytic asymmetric
conjugate addition of terminal
alkynes was reported by Car-
reira et al.; this involved em-
Scheme 2. Direct catalytic asymmetric conjugate addition of terminal alkynes 2 to a,b-unsaturated thioamides
1 under proton-transfer conditions.
ploying highly electron-defi-
cient olefins as electrophiles to
compensate for the inherent
low nucleophilicity of copper alkynylides.[11] Indeed, the
inert nature of copper alkynylides is exploited in organocup-
rate additions, in which alkynes function as dummy li-
gands.[12] Hayashi and co-workers[13] and Fillion and Zorzit-
to[14] subsequently showed that rhodium catalysis is effective
for enantioselective conjugate addition to enones, enals, and
nitro olefins. Conjugate addition to a,b-unsaturated carbox-
ylic acid derivatives, however, has remained elusive because
of their attenuated electrophilicity, despite the synthetic util-
ity of enantioenriched b-alkynylcarboxylic acid derivatives.
a comprehensive study on this synthetically versatile trans-
formation, which delivers enantiomerically enriched b-al-
kynyl thioamides 5. Control experiments and kinetic studies
revealed mechanistic insights of the efficient proton-transfer
process. The utility of the present protocol culminated in the
concise enantioselective synthesis of AMG-837, a potent ag-
onist of the G-protein coupled receptor GPR40.
Chem. Asian J. 2011, 6, 1778 – 1790
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M. Shibasaki and N. Kumagai et al.
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Results and Discussion
Mechanistic Elucidation
Recently our group reported a soft Lewis acid/hard Brønst-
ed base cooperative catalytic system comprising cationic
copper(I), chiral bisphosphine ligand, and lithium aryloxide
À
to promote several direct-type C C bond-forming reactions
with high enantioselectivity under proton-transfer condi-
tions.[19] The application of 5 mol% of a cooperative catalyst
Figure 1. Equilibrium of the catalyst components.
prepared from [CuACHTUNGTRENNUNG(CH3CN)4]PF6, 2,2’-bis(diphenylphosphi-
no)-1,1’-biphenyl (BIPHEP)-type ligand (R)-3a, and
Li(OC6H4-p-OMe) to the attempted reaction of phenylace-
tylene (2a) and a,b-unsaturated thioamide 1a delivered the
desired b-alkynylthioamide 5aa in 81% yield and 94% ee
(Scheme 3a, entry 1).[18,20] In the absence of either the hard
thoxyphenol, and (R)-3a, in which Cu(OC6H4-p-OMe)/(R)-
3a was produced, exhibited almost identical catalytic activi-
ty to promote the desired alkynylation reaction
(Scheme 3b). In the absence of lithium salt, Li(OC6H4-p-
OMe) was never formed, there-
by
Li(OC6H4-p-OMe)
Cu(OC6H4-p-OMe)/(R)-3a
indicating
that
both
and
would function as a Brønsted
base in this catalytic system to
generate copper alkynylide.
This is in marked contrast to
the catalytic asymmetric addi-
tion of allyl cyanide to ketones
promoted by a similar catalytic
system, in which Li(OC6H4-p-
OMe) is the actual Brønsted
base
and
lithium-free
Cu(OC6H4-p-OMe) failed to
promote the reaction.[19j] To
gain more insight in this crucial
deprotonation step, in which
the active nucleophile copper
alkynylide was formed, the ki-
netic profile of the reaction was
traced by using deuterated phe-
nylacetylene [D1]2a. By com-
paring the initial rate of the re-
action with that of 2a revealed
a kinetic isotope effect of kH/
kD =1.9, thus suggesting that
copper alkynylide formation,
rather than the nucleophilic ad-
dition step of copper alkynylide
is likely the rate-determining
Scheme 3. Control experiments of direct catalytic asymmetric conjugate addition of phenylacetylene (2a) to
a,b-unsaturated thioamides (1a).
Brønsted base Li(OC6H4-p-OMe) or the soft Lewis acid
[Cu(CH3CN)4]PF6, the reaction did not proceed at all, there-
step (Figure 2).[25] Higher catalytic efficiency was observed
owing to the presence of hard Lewis basic bisphosphine
oxide 4, which coordinated to the lithium cation to enhance
the basicity of Li(OC6H4-p-OMe).[26] With a catalyst loading
of 2 mol%, the combined use of 4 mol% of 4 was effective
for accelerating the deprotonation step to complete the re-
action without a detrimental effect on enantioselectivity
(Scheme 4).[19j,27,28] The smooth conjugate addition to thioa-
mides would be explained by assuming that the copper-acti-
vated thioamide was located in close proximity to copper al-
ACHTUNGTRENNUNG
by verifying that both the soft Lewis acid and hard Brønsted
base were essential for catalysis (Scheme 3a, entries 2 and
1
3). In H NMR analysis of the tetrahydrofuran solution of
[CuACHTUNGTRENNUNG(CH3CN)4]PF6 and Li(OC6H4-p-OMe), coalescing peaks
were observed derived from para-methoxyphenoxide at var-
ious temperatures;[21] this suggests that ([Cu/(R)-
3a]PF6+Li(OC6H4-p-OMe)) and ([Cu(OC6H4-p-OMe)]/(R)-
3a+LiPF6) were in equilibrium (Figure 1).[19j,22,23] The lithi-
um-free catalyst prepared from mesitylcopper,[24] para-me-
À
kynylide, with a favorable topology for carbon carbon bond
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Chem. Asian J. 2011, 6, 1778 – 1790

Asymmetric Conjugate Addition
Figure 3. Proposed six-membered transition state.
Scheme 5. The reaction with a,b-unsaturated thiolactams.
tween the enantiopurity of (R)-3a and the enantioselectivity
of 5aa implied that the monomeric Cu/(R)-3a complex was
involved in the enantiodiscrimination step (Figure 4).[31]
After the addition of copper alkynylide to thioamide, the
possible proton source for protonation of the intermediary
copper-thioamide enolate is HOC6H4-p-OMe or the termi-
nal alkyne. If the protonation with HOC6H4-p-OMe is oper-
ative, the first catalyst set is regenerated with liberation of
the product. If the proton exchange between the intermedi-
ary copper-thioamide enolate and the terminal alkyne
occurs, the copper-alkynylide nucleophile for the next cata-
lytic cycle is directly formed and the reaction system can be
simplified by omitting the alkali
Figure 2. Kinetic isotope effect.
metal aryloxide base. The at-
tempted reaction of 1a and
phenylacetylene (2a) using a
catalyst prepared from copper
alkynylide of phenylacetylene
(2a) and (R)-3a proceeded
smoothly to afford 5aa, thus in-
dicating the efficient proton
transfer from 2a to the copper-
thioamide enolate to generate
the copper alkynylide of 2a
(Scheme 6a). The catalyst pre-
Scheme 4. Effect of phosphine oxide 4 as hard Lewis basic additive.
pared from mesitylcopper[24]
and (R)-3a was also effective,
formation at the b-position through the six-membered tran-
sition state, thereby highlighting the benefit of simultaneous
activation (Figure 3). This assumption was consistent with
the observation that the attempted reaction using a,b-unsa-
turated thiolactam 1b and 1c, the locked s-trans conforma-
tion of which disrupted the formation of the six-membered
transition state, resulted in no reaction at all, even in the
presence of 4 (Scheme 5).[29,30] The linear relationship be-
and is applicable to the reaction with any terminal alkynes
(Scheme 6b). These experimental results together clearly re-
vealed that the catalytic cycle efficiently drives the proton
transfer between terminal alkyne and copper-thioamide eno-
late after the initial formation of copper alkynylide. We
sought a more operationally simple catalyst set and identi-
fied a catalyst comprising [Cu
ACHTNUGTRENN(UGN CH3CN)4]PF6, (R)-3a, and
KHMDS that was effective, and all of the necessary materi-
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M. Shibasaki and N. Kumagai et al.
FULL PAPERS
entially with HOC6H4-p-OMe with poor enantioselection; in
the absence of HOC6H4-p-OMe, partial enantioselective
proton transfer with copper-coordinated phenylacetylene
(2a) occurred under the influence of the asymmetric envi-
ronment provided by ligand (R)-3b. This result is consistent
with the observed similar enantioselectivity (59% ee) of 5da
with the [CuACTHNUTRGNE(UNG CH3CN)4]PF6/(R)-3b/KHMDS catalytic
system, in which the proton transfer proceeded between
copper-thioamide enolate and phenylacetylene (2a;
Scheme 7c).
On the basis of the experimental results mentioned
above, the proposed catalytic cycle is illustrated in Figure 5.
When
Li(OC6H4-p-OMe) (referred to as catalyst 1) is used, both
[CuPF6/(R)-3a+Li(OC6H4-p-OMe)] and [Cu(OC6H4-p-
a catalyst comprising [CuCATHUNTGNRUE(GN CH3CN)4]PF6, (R)-3a,
Figure 4. Linear relationship between the enantioselectivity of 5aa and
enantiopurity of (R)-3a.
OMe)/(R)-3a+LiPF6] states under equilibrium are catalyti-
cally active to deprotonate phenylacetylene (2a) to give
copper alkynylide A. Bisphosphine oxide 4 enhances the ba-
sicity of Li(OC6H4-p-OMe) and facilitates the deprotona-
tion. Thioamide 1a then coordinates to copper through a
soft–soft interaction, and this leads to a six-membered tran-
als are commercially available and storable (Scheme 6c).[32]
Potassium alkynylide generated at the first cycle was con-
verted to copper alkynylide by transmetallation and the
copper alkynylide drove the following catalytic cycle. The
proton-transfer process was further investigated by using
N,N-dimethylthiomethacrylamide (1d) as a probe. The a-
methyl group of 1d is expected to provide information on
the stereoselection at the protonation step. Under the stan-
dard conditions using (R)-DTBM-Segphos (R)-3b and
Li(OC6H4-p-OMe) as the Brønsted base, the alkynylation
product 5da was obtained with only 9% ee (Scheme 7a;
DTBM=3,5-di-tert-butyl-4-methoxy). On the other hand,
the copper alkynylide/(R)-3b catalyst delivered 5da in 60%
ee; this suggests that a different protonation pathway was
operative (Scheme 7b); in the presence of HOC6H4-p-OMe,
copper-thioamide enolate underwent proton transfer prefer-
À
sition state B for enantioselective carbon carbon bond for-
mation, in which both of the substrates are activated in
close proximity and overcome the intrinsic low reactivity of
copper alkynylide A. Indeed, the reaction with more elec-
trophilic a,b-unsaturated ketone (chalcone) 6 does not pro-
ceed at all with this catalytic system, thus highlighting the
significance of the simultaneous activation of 1a and 2a
(Scheme 8). The thus-obtained copper-thioamide enolate C
is protonated preferentially with HOC6H4-p-OMe, which is
formed in the initial deprotonation step, liberating the de-
sired product 5aa with regeneration of the catalyst. In the
case of catalyst 2, comprising the copper alkynylide of 2a
and (R)-3a, coordination of 1a
affords the key transition state
structure B. Subsequent proton
transfer directly proceeds with
the copper-activated phenylace-
tylene (2a) as shown in D, and
the coordination of 1a leads to
the transition state B, thereby
completing the catalytic cycle.
Therefore, once the copper al-
kynylide is formed, these two
substrates engage in the
À
carbon carbon bond formation
catalytically through efficient
proton transfer. Other catalyst
sets, such as mesitylcopper and
(R)-3a (catalyst 3), [Cu-
AHCTNUGTREN(GNNU CH3CN)4]PF6, (R)-3a, and
KHMDS (catalyst 4), also gen-
erate copper alkynylide at the
first stage of the reaction, and
the following catalytic cycle is
the same as that of catalyst 2.
Scheme 6. Control experiments using different types of copper catalyst. KHMDS= potassium hexamethyldisi-
lazane.
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Asymmetric Conjugate Addition
of
catalyst
was
required
(entry 4). Substituents at the
ortho- or para-position did not
interfere with enantioselection
(entries 5 and 6). The present
catalysis is sensitive to the elec-
tronic nature of the b-substitu-
ent of thioamide; thioamides
1h and 1i bearing methoxy sub-
stituents required 808C to pro-
mote the reaction efficiently
and thioamide 1j with a 3,4-
methylenedioxy group afforded
the desired product in 56%
yield and high enantioselectivi-
ty with 5 mol% of catalyst (en-
tries 7–9). Thioamides 1a and
1k bearing para-bromine sub-
stituents exhibited high reactivi-
ty in the present catalytic
system and trials to reduce cat-
alyst loading conducted with
these substrates led to the reac-
tion with a catalyst loading of
0.5 and 0.25 mol%, respective-
ly, without any loss of enantio-
selectivity (entries 2, 3, 10, and
11). The conjugate alkynylation
of a,b,g,d-unsaturated thioa-
mide 1l derived from sorbic
Scheme 7. Catalytic asymmetric conjugate alkynylation of thiomethacrylamide 1d.
acid proved that the alkynyla-
tion proceeded exclusively at
Scope of Catalytic Asymmetric Conjugate Addition of
Terminal Alkynes to a,b-Unsaturated Thioamides
the b-position with high enantioselectivity (entry 12). Thioa-
mides 1m and 1n having b-alkyl substituents were applica-
ble with 5 mol% of the catalyst (entries 13 and 14), and the
1,3-enyne 2b afforded the product in 96% ee, albeit in mod-
erate yield.
The substrate scope of the direct catalytic asymmetric conju-
gate alkynylation of a,b-unsaturated thioamide with catalyst
1
([CuACHTUNGTRENNUNG(CH3CN)4]PF6+(R)-3a+Li(OC6H4-p-OMe)) rein-
forced with a hard Lewis base 4 is summarized in Table 1.
Further reduction in the catalyst loading to 1 mol% was
achieved by changing the solvent from tetrahydrofuran to n-
hexane, presumably because the formation of an intimate
copper alkynylide/thioamide association was enhanced in
the nonpolar reaction medium (entry 1 vs 2). A morpholine
thioamide other than N,N-dimethylthioamide was a suitable
substrate to achieve high enantioselectivity, albeit 5 mol%
Conjugate addition using saturated aliphatic terminal al-
kynes proved elusive even after ligand screening. Using 1-
heptyne (1c) as a model substrate, catalyst 1 using (R)-3a
with phosphine oxide 4 exhibited poor catalytic activity in
tetrahydrofuran, and this produced the product 5ac in less
than 10% yield with 60% ee (Scheme 9, entry 1).[33] The
other biaryl-type ligand (R)-DTBM-Segphos (R)-3b in-
creased the yield but the stereoselectivity remained unsatis-
factory (entry 2). None of the reactions using other phos-
pholane-type ligands 7 and 8 and ferrocene-conjugated li-
gands 9 and 10 improved enantioselectivity (entries 3–6).
These results prompted us to focus on other strategies to
solve this problem. We turned our attention to the counter
anion, located near the copper cation, which we expected
could be used to influence the asymmetric environment. We
planned to endow the counter anion with chirality as an ad-
ditional stereocontrolling element to reinforce stereodiscri-
mination at the transition state.[34,35] Various chiral phospho-
ric acids were used with mesitylcopper and ligand (R)-3b,[36]
generating the copper/(R)-3b phosphate as a new soft Lewis
Scheme 8. Direct catalytic asymmetric conjugate alkynylation in the pres-
ence of chalcone (6).
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M. Shibasaki and N. Kumagai et al.
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Table 1. Direct catalytic asymmetric conjugate alkynylation.[a]
acid entity bearing
a chiral
phosphate anion.[37] In this cata-
lyst design, a hard Lewis basic
phosphate would function as a
hard Lewis base in the same
manner as phosphine oxide 4.
The screening of the chiral
phosphoric acid is summarized
in Table 2. In the absence of
chiral counter anion, the ([Cu-
Entry Thioamide 1
Alkyne 2
x
T [8C] Product Yield[b] [%] ee [%]
R1
R2
1[c]
2
Ph
Ph
1a
1a
1a
1e
1 f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2a
1
1
50
50
50
50
50
50
80
80
50
50
5aa
5aa
5aa
5ea
5 fa
5ga
5ha
5ia
51
98
72
84
97
74
77
81
56
98
83
51
97
63
58
94
98
98
94
98
97
95
94
99
97
97
94
80
92
96
3
Ph
Ph
2a 0.5
AHCTUNGTRENNUNG
4[d]
5
2a
2a
2a
2a
2a
2a
2a
5
1
1
1
1
5
1
catalyst
o-Me-C6H4
p-Me-C6H4
m-MeO-C6H4
p-MeO-C6H4
performed better in n-hexane
and gave 5ac in 90% yield with
82% ee. The use of the parent
nonsubstituted binaphthyl-type
phosphoric acid 11a hardly af-
6
7[e]
8[e]
9
3,4-methylenedioxy 1j
5ja
10
11
12
13
14
15
p-Br-C6H4
p-Br-C6H4
(E)-CH3CH=CH
Me
iPr
Ph
1k
1k
1l
5ka
5ka
5la
2a 0.25 50
fected
the
stereochemical
2a
2a
2a
5
5
5
1
50
50
50
50
1m Ph
5ma
5na
5ab
course of the reaction irrespec-
tive of its chirality (entries 2
and 3). In contrast, bulkier
phosphoric acid (S)-11b, in
which the 2,4,6-triisopropyl-
phenyl groups were installed at
the 3,3’-positions, improved
enantioselectivity to 89% ee
(entry 5). Intriguingly, its anti-
pode (R)-11b completely shut
down the reaction, thus suggest-
ing that the chiral phosphate
anion is involved in the enan-
1n
1a
Ph
1-cyclohexenyl 2b
[a] 1: 0.2 mmol; 2: 0.4 mmol. [b] Isolated yield. [c] THF was used as the solvent instead of n-hexane. [d] Mor-
pholine thioamide was used instead of N,N-dimethylthioamide. [e] n-Heptane was used instead of n-hexane.
tioselective
carbon–carbon
bond formation. Other even
bulkier phosphoric acids 11c–e
with (S)-axial chirality were ex-
amined, and (S)-11b proved op-
timal for this purpose (en-
tries 6–8). The thus-identified
optimal reaction conditions for
aliphatic terminal alkynes were
evaluated in the reaction of var-
ious alkynes (Table 3). Al-
though 5 mol% of catalyst was
required, branched and non-
branched aliphatic terminal al-
kynes 2c–g provided the de-
sired alkynylation product in
moderate to high yield with up
to 91% ee (entries 1–5). The
combination of aliphatic termi-
nal alkyne and
a thioamide
bearing b-alkyl substituent re-
mained difficult to achieve high
enantioselectivity,
thereby
giving the alkynylation product
5mc with 69% ee (entry 6). The
use of silylacetylenes in alkyny-
Figure 5. Proposed catalytic cycle.
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Asymmetric Conjugate Addition
lation is of particular signifi-
cance because they are general-
ly regarded as acetylene equiva-
lents.[38] The direct application
of catalyst 1 in the reaction of
trimethylsilylacetylene
(2h)
produced only trace amounts of
the desired product (entry 1).
On the basis of the mechanistic
studies, the key to the present
catalysis is the generation of
copper alkynylides. We envi-
sioned applying catalyst 4 with
a strong HMDS-type base to
the reaction of silylacetylenes,
thereby generating alkali metal
alkynylides to trigger the alky-
nylation reaction. In entries 2–
4, the HMDS-type base proved
effective and the HMDS-type
base of the more electropositive
alkali metal performed even
better. The bulkier triethylsily-
lacetylene (2i) displayed dimin-
ished reactivity to afford the
product in 63% yield, even
Scheme 9. Direct catalytic asymmetric conjugate alkynylation of 1-heptyne (2c). DTBM=3,5-di-tert-butyl-4-
methoxy, Ph-BPE=1,2-bis(2,5-diphenylphospholano)ethane.
with
the
KHMDS
base
(entry 5), and no products were
Table 2. Direct catalytic asymmetric conjugate alkynylation of 1-heptyne
obtained with tert-butyldimethylsilyl (TBS) or triisopropyl-
silyl (TIPS) substituted acetylenes 2j and 2k (entries 6 and
7). Increasing the amount of 2h led to a higher chemical
yield (entry 8). Under these optimal conditions, (trimethylsi-
lyl)methylacetylene (2l) and TMS-protected propargyl alco-
hol (2m) furnished the desired alkynylation product with
86% ee and 87% ee, respectively (entries 9 and 10). The in-
volvement of copper alkynylide was confirmed by the reac-
tion using catalyst 3 comprising mesitylcopper and (R)-3b,
and this exhibited a similar reaction outcome. The ineffec-
tiveness of catalyst 1, in which Li(OC6H4-p-OMe) was used
as the base and HOC6H4-p-OMe existed in the reaction mix-
ture, can be explained by assuming that the copper silylace-
tylide has higher aptitude for reprotonation with HOC6H4-
p-OMe, thereby reducing the concentration of active copper
silylacetylide. In the absence of Li(OC6H4-p-OMe) with cat-
alyst 3 or catalyst 4, reprotonation of copper acetylide with
HMDS or silylacetylenes would be slower (Table 4).
(2c) using a chiral counter anion.[a]
Entry Chiral phosphoric acid 11
Yield[b] [%] ee [%]
1[c]
2
3
–
–
90
88
90
0
90
89
83
74
82
81
81
–
89
81
87
84
(R), R=H
(S), R=H
(R), R=2,4,6-(iPr)3C6H2
(S), R=2,4,6-(iPr)3C6H2
(S), R=SiPh3
(R)-11a
(S)-11a
(R)-11b
(S)-11b
(S)-11c
(S)-11d
4
5[d]
6
7
8
(S), R=9-anthracenyl
(S)-VAPOL phosphoric acid (S)-11e
1
[a] 1: 0.2 mmol, 2: 0.4 mmol. [b] Determined by H NMR analysis with 2-
methoxynaphthalene as an internal standard. [c] The reaction conditions
were identical to those described in Table 1 except for phosphine ligand
((R)-3b instead of (R)-3a). ([CuACHTNUGTRNE(UNG CH3CN)4]PF6/(R)-3b/Li(OC6H4-p-
OMe)): 5 mol%, 4: 10 mol%. [d] Isolated yield. VAPOL=2,2’-diphenyl-
3,3’-(4-biphenanthrol).
Utility of Direct Catalytic Asymmetric Conjugate Addition
of Terminal Alkynes to a,b-Unsaturated Thioamides
The utility of the present catalysis is due to the highly che-
moselective nature of the reaction and divergent transfor-
mation of thioamide functionality.[3] The reaction using sub-
strate 1p bearing both a,b-unsaturated thioamide and a,b-
unsaturated ester moieties showcased the stringent chemo-
selectivity (Scheme 10). By using catalyst 2 comprising
copper alkynylide of phenylacetylene (2a) and (R)-3a, the
Chem. Asian J. 2011, 6, 1778 – 1790
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1785

M. Shibasaki and N. Kumagai et al.
FULL PAPERS
yield.[42] An Eschenmoser reac-
tion using methyl bromoacetate
promoted by PPh3 and 2,6-luti-
dine furnished b-ketoester 16 in
66% yield.[43]
Table 3. Direct catalytic asymmetric conjugate alkynylation of aliphatic terminal alkynes using a chiral counter
anion.[a]
We envisioned applying the
present catalysis to the concise
ee [%] enantioselective synthesis of the
Entry
Thioamide 1
Aliphatic alkyne 2
Product
Yield[b] [%]
R1
R2
G-protein coupled receptor
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Me
1a
1a
1a
1a
1a
1m
nC5H11
cC3H5
cC6H11
AHCTNURTGEG(NNNU CH3)2CHCH2
PhCH2CH2
2c
2d
2e
2 f
2g
2c
5ac
5ad
5ae
5af
5ag
5mc
90
88
63
63
72
43
89
83
91
87
90
69
GPR40
agonist
AMG-837.
GPR40 has received growing
attention as a potential thera-
peutic target for insulin-derived
disorders, such as type-2 diabe-
tes.[44] Recently, the b-alkynyl
acid derivative AMG-837 was
nC5H11
[a] 1: 0.2 mmol, 2: 0.4 mmol. [b] Isolated yield.
documented to be
a potent
Table 4. Direct catalytic asymmetric conjugate alkynylation of silylacetylenes using [Cu
and HMDS-type bases.[a]
ACHTNUGTRNEN(NUG CH3CN)4]PF6, (R)-3b,
GPR40 agonist at Amgen (Ap-
plied Molecular Genetics).[45] In
their report, the introduction of
chirality to
a b-alkynyl acid
entity was achieved using a stoi-
chiometric amount of Me2Zn
and cinchonidine.[46] Consider-
ing the clinical potency of
AMG-837, it would be a viable
synthetic target to demonstrate
the utility of the present cataly-
sis. We began our study by ex-
amining the direct catalytic
asymmetric conjugate alkynyla-
tion of trimethylsilylacetylene
(2h) of thioamides bearing a
para-oxygen functionalized b-
Entry Thioamide 1
Aliphatic alkyne 2
Equiv Base
Product Yield[b] [%] ee [%]
R1
R2
1[c]
2
Ph
Ph
1a TMS
1a TMS
1a TMS
1a TMS
1a TES
1a TBS
1a TIPS
1a TMS
1o TMSCH2
1a TMSOCH2
2h
2h
2h
2h
2i
2
2
2
2
2
2
2
5
5
5
Li(OC6H4-p-OMe) 5ah
trace
32
59
74
63
0
–
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
5ah
5ah
5ah
5ai
89
88
92
92
–
3
Ph
Ph
Ph
4[d]
5
6
Ph
2j
5aj
7
Ph
Ph
p-I-C6H4
Ph
2k
2h
2l
5ak
5ah
5ol
0
–
8[d]
9[d]
10[d]
85
72
79
91
86
87
2m
5am
[a] 1: 0.2 mmol. [b] Determined by 1H NMR analysis with 2-methoxynaphthalene as an internal standard.
[c] 10 mol% of phosphine oxide 4 was used. [d] Isolated yield.
enantioselective conjugate addition of 2a proceeded exclu-
sively at the b-position of a,b-unsaturated thioamide and
the intermediate copper-thioamide enolate underwent dia-
stereoselective intramolecular conjugate addition to the a,b-
unsaturated ester to give rise to cyclopentane 5pa with
three continuous stereogenic centers as a single diastereo-
mer with 97% ee. The present catalysis can be performed
with a catalyst loading of 1 mol% on the gram scale without
any problem and facile recrystallization provided an opera-
tionally simple procedure to produce the enantioenriched b-
alkynyl thioamide entity (Scheme 11). Transformation of the
thioamide functionality of the alkynylation product is out-
lined in Scheme 12. Conversion into other carboxylic acid
derivatives is useful from a synthetic point of view; activa-
Scheme 10. Direct catalytic asymmetric conjugate alkynylation followed
by intramolecular diastereoselective conjugate addition.
tion of thioamide with MeI/H2O[39] or trifluoroacetic anhy-
[40]
dride (TFAA)
provided the corresponding thioester 12
and amide 13, respectively. S-Methylation with MeOTf[41]
followed by alkylation with MeLi gave methyl ketone 14 in
88% yield. Treatment with MeI and subsequent hydride re-
duction with NaBH4 afforded tertiary amine 15 in 86%
Scheme 11. Direct catalytic asymmetric conjugate alkynylation performed
on the gram scale.
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Chem. Asian J. 2011, 6, 1778 – 1790

Asymmetric Conjugate Addition
para-methoxy group, even with
catalyst 4 using KHMDS
(entry 1). Thioamides 1q and
1r with a para-acyloxy group
improved the chemical yield
(entries 2 and 3), while thioa-
mide 1s with a more electron-
withdrawing
para-mesylate
group resulted in no reaction
(entry 4). The reaction of thioa-
mide 1q was further improved
by extending the reaction time
to afford the product 5qh in
80% yield and 90% ee
(entry 5). The catalyst loading
could be reduced to 5 mol%
(entry 6). Although the alkyny-
lation using propyne (2n) sig-
nificantly simplified the enan-
tioselective synthesis of AMG-
837, the desired alkynylation
product 5qn was obtained in
24% yield with 81% ee under
Scheme 12. Divergent transformation of the alkynylation product.
the same reaction conditions.
The absolute configuration of
5qh was unequivocally deter-
mined by single crystal X-ray crystallographic analysis
(Figure 6).[48]
The highly crystalline character of 5qh allowed for a
facile recrystallization in a dichloromethane/n-hexane binary
solvent system to give 5qh in enantiomerically pure form
(Scheme 13). The synthesis was initiated with 5qh, which
has the requisite stereogenic center for the synthesis of
AMG-837. The protocol for thioester formation was used
with MeI in the presence of H2O under an acidic medium,[39]
followed by methanolysis of the acetyl group and thioester
moiety with Cs2CO3/MeOH as well as removal of TMS
group, affording methy lester 18. Without purification, an
ether side chain was installed using aryl bromide 19, and
this afforded 20 in 48% yield over 3 steps from 5qh. Intro-
duction of a methyl group at the terminal alkyne was ach-
ieved by Sonogashira coupling with MeI, using a bulky car-
bene ligand generated from precursor 21, to give 22 in 63%
yield.[49] Finally, conventional basic hydrolysis of methyl
ester delivered AMG-837, a potent GPR40 agonist.
aryl substituent (Table 5).[47] As described in Table 1, the
present catalysis is sensitive to the electronic nature of the
b-aryl substituent, and only trace amounts of product 1ih
were obtained in the reaction with thioamide 1i bearing a
Table 5. Direct catalytic asymmetric conjugate alkynylation of trimethyl-
silylacetylene (2h).[a]
Conclusions
Entry
R
x
Product
t [h]
Yield[b] [%]
ee [%]
In summary, we have developed a catalytic asymmetric con-
jugate addition of terminal alkynes to thioamides based on a
simultaneous activation strategy. A prototype soft Lewis
acid/hard Brønsted base cooperative catalyst comprising
1
2
3
4
5
6
OMe
OAc
OPiv
OMs
OAc
OAc
1i
10
10
10
10
10
5
5ih
18
18
18
18
40
40
trace
58
31
–
92
–
–
90
91
1q
1r
1s
1q
1q
5qh
5rh
5sh
5qh
5qh
ND
80
[CuACTHNUTRGENUGN(CH3CN)4]PF6, bisphosphine ligand, and Li(OC6H4-p-
83[c]
OMe) was effective. A series of control experiments re-
vealed that the copper-thioamide enolate intermediate func-
tioned as a Brønsted base to generate copper alkynylides
[a] 1: 0.2 mmol, 2h: 1.0 mmol. [b] Determined by 1H NMR analysis with
2-methoxynaphthalene as an internal standard. [c] Isolated yield.
Chem. Asian J. 2011, 6, 1778 – 1790
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1787

M. Shibasaki and N. Kumagai et al.
FULL PAPERS
enantioselective synthesis of AMG-837, a potent GPR40 re-
ceptor agonist.
Experimental Section
See the Supporting Information for characterization data,
experimental procedures, and NMR spectra.
Figure 6. Ortep drawing of a single crystal of 5qh.
Acknowledgements
This work was financially supported by a Grant-in-Aid for Scientific Re-
search (S). N. K. thanks the Sumitomo Foundation for finantial support.
R. Y. thanks the JSPS predoctral fellowship. Dr. Motoo Shiro at the
Rigaku Corporation is gratefully acknowledged for X-ray crystallograph-
ic analysis of 5aa and 5qh.
[1] Recent reviews on cooperative catalysis, see: Lewis acid/Brønsted
base a) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187;
b) S. Matsunaga, M. Shibasaki, Bull. Chem. Soc. Jpn. 2008, 81, 60.
Lewis acid/Lewis base: c) M. Kanai, N. Kato, E. Ichikawa, M. Shiba-
saki, Synlett 2005, 1491; d) D. H. Paull, C. J. Abraham, M. T. Scerba,
E. Alden-Danforth, T. Lectka, Acc. Chem. Res. 2008, 41, 655. Lewis
acid/Brønsted acid and Lewis acid/Lewis acid: e) H. Yamamoto, K.
Futatsugi, Angew. Chem. 2005, 117, 1958; Angew. Chem. Int. Ed.
2005, 44, 1924; f) H. Yamamoto, K. Futatsugi in Acid Catalysis in
Modern Organic Synthesis (Eds.: H. Yamamoto, K. Ishihara), Wiley-
VCH, Weinheim, 2008.
[2] For reviews of direct aldol reactions, see: a) B. Alcaide, P. Almen-
dros, Eur. J. Org. Chem. 2002, 1595; b) W. Notz, F. Tanaka, C. F.
Barbas, III, Acc. Chem. Res. 2004, 37, 580; c) S. Mukherjee, W. J.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471. Also see
ref. 1a. For reviews of direct MannichACTHNUTRGNEUNG(-type) reactions, see:
d) M. M. B. Marques, Angew. Chem. 2006, 118, 356; Angew. Chem.
Int. Ed. 2006, 45, 348; e) A. Ting, S. E. Schaus, Eur. J. Org. Chem.
2007, 5797; f) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M.
Quaedflieg, F. P. J. T. Rutjes, Chem. Soc. Rev. 2008, 37, 29.
´
[3] Utility of thioamide functionality, see: S. T. Jagodzinski, Chem. Rev.
2003, 103, 197.
[4] a) Y. Suzuki, R. Yazaki, N. Kumagai, M. Shibasaki, Angew. Chem.
2009, 121, 5126; Angew. Chem. Int. Ed. 2009, 48, 5026; b) M. Iwata,
R. Yazaki, Y. Suzuki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc.
2009, 131, 18244; c) M. Iwata, R. Yazaki, N. Kumagai, M. Shibasaki,
Tetrahedron: Asymmetry 2010, 21, 1688.
[5] For general reviews of catalytic asymmetric conjugate addition: a) P.
Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Per-
gamon, Oxford, 1992; b) N. Krause, A. Hoffmann-Rçder, Synthesis
2001, 0171; c) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033;
d) M. Kanai, M. Shibasaki in Catalytic Asymmetric Synthesis,
2nd ed., (Ed.: I. Ojima), Wiley, New York, 2000, pp. 569; e) M. Ya-
maguchi, in Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacob-
sen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, Germany, 2003,
Suppl. 1, pp. 151; f) A. Alexakis, C. Benhaim, Eur. J. Org. Chem.
2002, 3221; g) J. Christoffers, A. Baro, Angew. Chem. 2003, 115,
1726; Angew. Chem. Int. Ed. 2003, 42, 1688; h) S. B. Tsogoeva, Eur.
J. Org. Chem. 2007, 1701.
[6] For reviews, see: a) S. Fujimori, T. F. Knçpfel, P. Zarotti, T, Ichika-
wa, D. Boyall, E. M. Carreira, Bull. Chem. Soc. Jpn. 2007, 80, 1635;
b) B. M. Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351, 963; c) For
a review of metal alkynyl s complexes, see: N. J. Long, C. K. Wil-
liams, Angew. Chem. 2003, 115, 2690; Angew. Chem. Int. Ed. 2003,
42, 2586.
Scheme 13. Enantioselective synthesis of AMG-837.
for the subsequent catalytic cycle, thus achieving highly effi-
cient proton transfer between substrates to promote enan-
tioselective carbon–carbon bond formation. Examination of
the catalytic cycle indicated that the copper alkynylide was
an entry point into the catalytic cycle, allowing for the iden-
tification of a more operationally simple catalyst comprising
[CuACHTUNGTRENNUNG(CH3CN)4]PF6, bisphosphine ligand, and KHMDS, all of
which are commercially available. Divergent transformation
of the thioamide functionality of the alkynylation product is
of particular importance for the synthetic utility of the pres-
ent catalysis. The production of an enantioenriched b-alkyn-
yl carboxylic acid derivative through the present alkynyla-
tion methodology was successfully applied to a concise
[7] For reviews, see: a) L. Pu, Tetrahedron 2003, 59, 9873; b) P. G.
Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2004, 4095;
c) C. Wei, Z. Li, C.-J. Li, Synlett 2004, 9, 1472; d) L. Zani, C. Bolm,
1788
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Chem. Asian J. 2011, 6, 1778 – 1790

Asymmetric Conjugate Addition
Chem. Commun. 2006, 4263; e) C.-J. Li, Acc. Chem. Res. 2010, 43,
581.
[23] Li(OC6H4-p-OMe) itself is known to exist as a tetramer in [D8]THF
and is characterized in the literature: a) D. J. MacDougall, B. C.
Noll, A. R. Kennedy, K. W. Henderson, Dalton Trans. 2006, 1875;
b) T. J. Boyle, D. M. Pedrotty, T. M. Alam, S. C. Vick, M. A. Rodri-
guez, Inorg. Chem. 2000, 39, 5133.
[24] Synthesis, characterization, and application of mesitylcopper, see:
a) T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, T. Saegusa, J. Org.
Chem. 1981, 46, 192; b) T. Tsuda, Encyclopedia of Reagents for Or-
ganic Synthesis (L. Paquette), Wiley, New York, 1995, p. 3271; c) H.
Eriksson, M. Hꢃkansson, Organometallics 1997, 16, 4243.
[8] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
16, 4467; b) R. Chinchilla, C. Nꢁjera, Chem. Rev. 2007, 107, 874.
[9] Catalytic asymmetric conjugate addition of preactivated terminal al-
kynes, see: a) Y.-S. Kwak, E. J. Corey, Org. Lett. 2004, 6, 3385;
b) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2005, 127, 3244;
c) O. V. Larionov, E. J. Corey, Org. Lett. 2010, 12, 300.
[10] a) B. M. Trost, Science 1991, 254, 1471; b) P. A. Wender, V. A.
Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40.
[11] a) T. F. Knçpfel, E. M. Carreira, J. Am. Chem. Soc. 2003, 125, 6054;
b) T. F. Knçpfel, P. Zarotti, T. Ichikawa, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 9682; c) S. Fujimori, E. M. Carreira, Angew.
Chem. 2007, 119, 5052; Angew. Chem. Int. Ed. 2007, 46, 4964.
[12] E. J. Corey, D. J. Beams, J. Am. Chem. Soc. 1972, 94, 7210.
[13] a) T. Nishimura, X.-X. Guo, N. Uchiyama, T. Katoh, T. Hayashi, J.
Am. Chem. Soc. 2008, 130, 1576; b) T. Nishimura, S. Tokuji, T.
Sawano, T. Hayashi, Org. Lett. 2009, 11, 3222; c) T. Nishimura, T.
Sawano, T. Hayashi, Angew. Chem. 2009, 121, 8201; Angew. Chem.
Int. Ed. 2009, 48, 8057; d) T. Nishimura, T. Sawano, S. Tokuji, T.
Hayashi, Chem. Commun. 2010, 46, 6837.
[25] A recent comprehensive review of the kinetic isotope effect, see: T.
Giagou, M. P. Meyer, Chem. Eur. J. 2010, 16, 10616.
[26] Phosphine oxide 4 preferentially coordinated to the lithium cation
in the presence of CuI cation, see Ref. [19j].
[27] A comprehensive review of Lewis base catalysis: a) S. E. Denmark,
G. L. Beutner, Angew. Chem. 2008, 120, 1584; Angew. Chem. Int.
Ed. 2008, 47, 1560 and references therein. Selected examples for
Lewis base activation of Brønsted base, see: b) M. J. McGrath, P.
OꢄBrien, J. Am. Chem. Soc. 2005, 127, 16378; c) S. Saito, T. Tsubogo,
S. Kobayashi, J. Am. Chem. Soc. 2007, 129, 5364; d) H. Morimoto,
T. Yoshino, T. Yukawa, G. Lu, S. Matsunaga, M. Shibasaki, Angew.
Chem. 2008, 120, 9265; Angew. Chem. Int. Ed. 2008, 47, 9125.
[28] Enhanced Lewis basicity of LiOPh was observed by using bidentate
phosphine oxide 4 in Mukaiyama aldol reactions. X-ray crystallo-
graphic analysis revealed that 4 coordinates to the lithium cation in
a bidentate fashion. M. Hatano, E. Takagi, K. Ishihara, Org. Lett.
2007, 9, 4527.
[14] E. Fillion, A. K. Zorzitto, J. Am. Chem. Soc. 2009, 131, 14608.
[15] a,b-Unsaturated thioamides as electrophiles, see: alkyllithium or
magnesium: a) Y. Tamaru, T. Harada, H. Iwamoto, Z. Yoshida, J.
Am. Chem. Soc. 1978, 100, 5221; b) Y. Tamaru, M. Kagotani, Z.
Yoshida, Tetrahedron Lett. 1981, 22, 3409; c) Y. Tamaru, T. Harada,
S. Nishi, Z. Yoshida, Tetrahedron Lett. 1982, 23, 2383. Lithium eno-
lates: d) Y. Tamaru, T. Harada, Z. Yoshida, J. Am. Chem. Soc. 1979,
[29] For conjugate addition of alkynylaluminium to 2-cyclohexenone,
see: J. Hooz, R. B. Rayton, J. Am. Chem. Soc. 1971, 93, 7320.
[30] The possibility that the low reactivity of 1b and 1c is due to the Z-
geometry of the olefin cannot be ruled out.
´
101, 1316. Nitroalkanes: e) J. G. Sosnicki, Tetrahedron 2009, 65,
1336.
[16] Sulfur has an electronegativity close to that for carbon: a) L. Pauling
in The Nature of Chemical Bond, 3rd ed., Cornel University, Ithaca,
NY, 1960, pp. 88; b) K. B. Wiberg, Acc. Chem. Res. 1999, 32, 922; for
the dipole moment of thioamides, see: c) C. H. Lee, W. D. Kumler,
J. Org. Chem. 1962, 27, 2052. Considerable charge transfer from ni-
trogen to sulfur is suggested for thioamides, see: d) K. B. Wiberg,
P. R. Rablen, J. Am. Chem. Soc. 1995, 117, 2201; e) D. Lauvergnat,
P. C. Hiberty, J. Am. Chem. Soc. 1997, 119, 9478; f) B. Galabov, S.
Ilieva, B. Hadjieva, E. Dinchova, J. Phys. Chem. A 2003, 107, 5854.
[17] These observations are consistent with the rotational barrier of the
[31] For recent comprehensive reviews on nonlinear effects in asymmet-
ric catalysis: a) C. Girard, H. B. Kagan, Angew. Chem. 1998, 110,
3088; Angew. Chem. Int. Ed. 1998, 37, 2922; b) D. G. Blackmond,
Acc. Chem. Res. 2000, 33, 402; c) T. Satyanarayana, S. Abraham,
H. B. Kagan, Angew. Chem. 2009, 121, 464; Angew. Chem. Int. Ed.
2009, 48, 456 and references therein.
[32] Li(OC6H4-p-OMe) was prepared from HOC6H4-p-OMe and nBuLi
under strictly anhydrous conditions and used immediately.
[33] The reaction of 1a and 2c using 5 mol% of catalyst 4 ([Cu-
AHCTNUGTER(GNNNU CH3CN)4]PF6 5 mol%, (R)-3b 5 mol%, KHMDS 5 mol%) afford-
ed 5ac in 67% yield with 83% ee.
[34] For reviews on chiral counteranions, see: a) J. Lacour, V. Hebbe-
Viton, Chem. Soc. Rev. 2003, 32, 373; b) A. Macchioni, Chem. Rev.
2005, 105, 2039; c) J. Lacour, D. Moraleda, Chem. Commun. 2009,
7073.
[35] Recent examples of catalytic asymmetric reactions using chiral
counteranions, see: a) D. B. Llewellyn, D. Adamson, B. A. Arndtsen,
Org. Lett. 2000, 2, 4165; b) C. Carter, S. Fletcher, A. Nelson, Tetra-
hedron: Asymmetry 2003, 14, 1995; c) D. B. Llewellyn, B. A. Arndt-
sen, Tetrahedron: Asymmetry 2005, 16, 1789; d) S. Mayer, B. List,
Angew. Chem. 2006, 118, 4299; Angew. Chem. Int. Ed. 2006, 45,
4193; e) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science
2007, 317, 496; f) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007,
129, 11336; g) I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2007, 129, 13404; h) S. E. Reisman, A. G.
Doyle, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 7198; i) X.
Wang, B. List, Angew. Chem. 2008, 120, 1135; Angew. Chem. Int.
Ed. 2008, 47, 1119; j) G. L. Hamilton, T, Kanai, F. D. Toste, J. Am.
Chem. Soc. 2008, 130, 14984; k) P. Garcꢅa-Garcꢅa, F. Lay, P. Garcꢅa-
Garcꢅa, C. Rabalakos, B. List, Angew. Chem. 2009, 121, 4427;
Angew. Chem. Int. Ed. 2009, 48, 4363; l) K. Aikawa, M. Kojima, K.
Mikami, Angew. Chem. 2009, 121, 6189; Angew. Chem. Int. Ed.
2009, 48, 6073; m) S. J. Zuend, M. P. Coughlin, M. P. Lalonde, E. N.
Jacobsen, Nature 2009, 461, 968; n) S. J. Zuend, M. P. Coughlin,
M. P. Lalonde, E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358;
o) R. L. LaLonde, Z. J. Wang, M. Mba, A. D. Lackner, F. D. Toste,
Angew. Chem. 2010, 122, 608; Angew. Chem. Int. Ed. 2010, 49, 598;
p) S. Liao, B. List, Angew. Chem. 2010, 122, 638; Angew. Chem. Int.
À
C N bond of thioamides is larger than that of the corresponding
amides. For the rotational barriers of thioamides, see: a) K. A.
Jensen, Acta. Chem. Scand. 1963, 17, 551; b) A. Loewenstein, A.
Melera, P. Rigny, W. Walter, J. Phys. Chem. 1964, 68, 1597; c) W. E.
Stewart, T. H. Siddall, Chem. Rev. 1970, 70, 517.
[18] R. Yazaki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132,
10275.
À
[19] For selected examples of catalytic asymmetric C C bond formation
using copper alkoxides, see: a) J. Krꢂger, E. M. Carreira, J. Am.
Chem. Soc. 1998, 120, 837; b) B. L. Pagenkopf, J. Krꢂger, A. Stoja-
novic, E. M. Carreira, Angew. Chem. 1998, 110, 3312; Angew. Chem.
Int. Ed. 1998, 37, 3124; c) Y. Suto, N. Kumagai, S. Matsunaga, M.
Kanai, M. Shibasaki, Org. Lett. 2003, 5, 3147; d) Y. Suto, R. Tsuji,
M. Kanai, M. Shibasaki, Org. Lett. 2005, 7, 3757; e) R. Wada, T. Shi-
buguchi, S. Makino, K. Oisaki, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2006, 128, 7687; f) R. Motoki, M. Kanai, M. Shibasaki,
Org. Lett. 2007, 9, 2997; g) Y. Asano, K. Hara, H. Ito, M. Sawamura,
Org. Lett. 2007, 9, 3901; h) R. Yazaki, T. Nitabaru, N. Kumagai, M.
Shibasaki, J. Am. Chem. Soc. 2008, 130, 14477; i) R. Yazaki, N. Ku-
magai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 3195; j) R.
Yazaki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132,
5522.
[20] For CuOtBu catalyzed asymmetric 1,2-addition reaction of terminal
alkynes, see: Refs. [19 f] and [19g].
[21] See the Supporting Information.
[22] Formation of CuOAr upon addition of alkali metal aryloxide to CuI
salt, see: a) W. T. Reichie, Inorg. Chim. Acta 1971, 5, 325; b) P. G.
Eller, G. J. Kubas, J. Am. Chem. Soc. 1977, 99, 4346.
Chem. Asian J. 2011, 6, 1778 – 1790
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1789

M. Shibasaki and N. Kumagai et al.
FULL PAPERS
Ed. 2010, 49, 628; q) H. Xu, S. J. Zuend, M. P. Woll, Y. Tao, E. N. Ja-
cobsen, Science 2010, 327, 986.
[44] For a comprehensive review, see: S. B. Bharate, K. V. S. Nemmani,
R. A. Vishwakarma, Expert Opin. Ther. Pat. 2009, 19, 237 and refer-
ences therein.
[45] a) M. Akerman, J. Houze, D. C. H. Lin, J. Liu, J. Luo, J. C. Medina,
W. Qiu, J. D. Reagan, R. Sharma, S. J. Shuttleworth, Y. Sun, J.
Zhang, L. Zhu, Int. Appl. PCT, WO 2005086661, 2005; b) Y. Xie, W.
Tao, H. Morrison, R. Chiu, J. Jona, J. Fang, N. Couchon, J. Pharm.
Sci. 2008, 362, 29.
[46] a) S. Cui, S. D. Walker, J. C. S. Woo, C. J. Borths, H. Mukherjee,
M. J. Chen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 436; b) J. C. S.
Woo, S. Cui, S. D. Walker, M. M. Faul, Tetrahedron 2010, 66, 4730;
c) H. Morrison, J. Jona, S. D. Walker, J. C. S. Woo, L. Li, J. Fang,
Org. Process Res. Dev. 2011, 15, 104 and references therein.
[47] R. Yazaki, N. Kumagai, M. Shibasaki, Org. Lett. 2011, 13, 952.
[48] The crystallographic data of 5qh is reported in Ref. [46].
[49] M. Eckhardt, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 13642.
[36] For reviews of chiral phosphoric acids, see: a) T. Akiyama, Chem.
Rev. 2007, 107, 5744; b) M. Terada, Chem. Commun. 2008, 4097.
[37] Chiral copper(I) phosphate was reported in the diamination of con-
jugated olefins, see: B. Zhao, H. Du, Y. Shi, J. Org. Chem. 2009, 74,
8392.
[38] a) D. Boyall, F. Lꢆpez, H. Sasaki, D. Frantz, E. M. Carreira, Org.
Lett. 2000, 2, 4233; b) S. Harada, R. Takita, T. Ohshima, S. Matsuna-
ga, M. Shibasaki, Chem. Commun. 2007, 948.
[39] D. C. Harrowven, M. C. Lucas, P. D. Howes, Tetrahedron 1999, 55,
1187.
[40] R. Masuda, M. Hojo, T. Ichi, S. Sasano, T. Kobayashi, C. Kuroda,
Tetrahedron Lett. 1991, 32, 1195.
[41] Y. Mutoh, T. Murai, Org. Lett. 2003, 5, 1361.
[42] R. J. Sundberg, C. P. Walters, J. D. Bloom, J. Org. Chem. 1981, 46,
3730.
[43] a) M. Roth, P. Dubs, E. Gçtschi, A. Eschenmoser, Helv. Chim. Acta
1971, 54, 710; b) P. Marchand, M.-C. Fargeau-Bellassoued, C. Bellec,
G. Lhommet, Synthesis 1994, 1118.
Received: January 22, 2011
Published online: May 2, 2011
1790
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Chem. Asian J. 2011, 6, 1778 – 1790