Catalytic, enantioselective, conjugate alkyne addition

Article abstract of DOI:10.1021/ja052411r

We document a copper-catalyzed, enantioselective, conjugate addition involving the direct use of a terminal acetylene, which undergoes in situ metalation. The addition reactions of phenylacetylene to Meldrum's acid derived acceptors take place in aqueous

Full text of DOI:10.1021/ja052411r

Published on Web 06/16/2005
Catalytic, Enantioselective, Conjugate Alkyne Addition
Thomas F. Kno¨pfel, Pablo Zarotti, Takashi Ichikawa, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg, CH-8093 Zu¨rich, Switzerland
Received April 14, 2005; E-mail: carreira@org.chem.ethz.ch
Scheme 1
The conjugate addition reaction of carbon nucleophiles to
acceptors provides important avenues to access optically active
building blocks.1 Transmetalation of organometallic compounds to
the corresponding organocopper reagents is widely employed to
ensure regioselective 1,4-addition to R,â-unsaturated carbonyl
compounds.2 Absent from these reagents, however, are the corre-
sponding copper alkynylides, which are, in general, insufficiently
reactive for this purpose.3 Known methods for the conjugate
addition of alkynes include the use of boron4-6 and aluminum5,7
alkynylides.8 Recently, catalytic asymmetric variants of these unique
reactions have been reported for a limited set of substrates.9,10 These
represent the only examples for this enantioselective reaction, albeit
both methods require the stoichiometric formation of a moisture-
sensitive metal alkynylide prior to the addition. We have recently
reported a novel Cu-catalyzed conjugate addition reaction of
aromatic alkynes to Meldrum’s acid derived acceptors under very
mild reaction conditions.3,11 In this communication, we document
the first example of a catalytic, enantioselective, conjugate addition
involving the direct use of terminal acetylenes (eq 1). The addition
reactions of 1 to afford 2 take place in aqueous media, without
recourse to inert atmosphere. The success of the enantioselective
process was enabled by the use of a new class of conveniently
accessed P,N-ligands, which we have termed PINAP (Scheme 1).12
Table 1. PINAP Ligands 3-8 in the Screening of the Reaction of
PhCtCH and 1a to Give 2a (R ) i-Pr), as Shown in Eq 1
entry
ligand
T (°
C)
t (h)
eea (%)
conversion (%)
1
2
3
4
5
6
7
8
(R)-QUINAP
23
23
0
5
6
42 (R)
69 (S)
80 (S)
37 (R)
94 (R)
48 (S)
95 (R)
8 (S)
100
43b
58
3
3
4
5
6
7
8
18
20
11
11
14
14
0
33
0
40
49
0
0
100
0
44b
a The enantioselectivity was determined by chiral HPLC after conversion
to the corresponding anilide by heating in aniline/DMF. The absolute
configuration of the major enantiomer of 2a is given in parentheses.
b Isolated yield.
was unanticipated. One would have expected minimal influence
by the remote stereocenter, as we have observed for PINAP in other
metal-catalyzed reactions studied to date.12 This strongly suggested
a critical role for the chiral amine controlling group, giving rise to
matched/mismatched effects. Therefore, we reasoned that its
variation would allow fine-tuning of the enantioselectivity.
A set of amines that can be conveniently appended to the PINAP
scaffold are the amino alcohols derived from amino acids. In a
screening of several simple derivatives (i.e., 2-phenylglycinol, the
tertiary alcohols isolated from the addition of MeMgBr, EtMgBr,
n-PrMgBr, and BnMgBr to phenylglycine methyl ester), the diethyl
derivative 5 was singled out by its ability to afford product in high
enantioselectivity (94% ee, entry 5), albeit sluggishly (40% conver-
sion after 11 h). Surprisingly, the use of the methoxy-substituted
ligand 7 (Table 1, entry 7)15 resulted in product formation at a
significantly faster rate (full conversion after 14 h), while maintain-
ing high enantioselectivity in the process (95% ee).16 Once again,
the atropdiastereomeric ligands 6 and 8 gave, as in the case of 4,
products with dramatically diminished enantioselectivity (entries
6 and 8).
In initial investigations of the catalytic, enantioselective addition
of acetylenes to Meldrum’s acid derived acceptors, we screened a
variety of ligand classes, that is, phosphines, such as BINAP,
JOSIPHOS, MONOPHOS, MOP, as well as nitrogen donors, as
exemplified by PYBOX and BOX.13 For all but one ligand
examined with 1a (R ) i-Pr) as a test substrate, the extent of
asymmetric induction observed was low, at best 25% ee for tol-
BINAP. QUINAP14 was the singular exception, giving full conver-
sion to product in 42% ee (Table 1, entry 1). Building upon this
result proved difficult, as QUINAP analogues bearing structural
as well as electronic modifications are not readily prepared.
Consequently, we developed PINAP ligands12 (Scheme 1) which
can be accessed in an easy four-step sequence from commercially
available starting materials. This project permitted us to examine
structural and electronic effects of this new modular class of ligands.
In exploratory studies, we examined the Cu-catalyzed addition
of phenylacetylene to 1a (R ) i-Pr) employing the simplest member
of the PINAP class of ligands derived from optically active
R-phenethylamine, namely, 3 and 4 (Table 1). The adduct 2a was
obtained in enhanced optical purity using 3 at 23 °C (69% ee, entry
2). At 0 °C, the enantioselectivity was further improved to 80% ee
(entry 3). We found that 3 gave much better results than its
diastereomer 4, which furnished adduct in 37% ee. This behavior
In the optimized procedure, a 1:1 mixture of ligand 7 and
Cu(OAc)2‚H2O17 is employed at 5-20 mol % loading. In general,
because of the heterogeneous nature of the reaction, on 0.25 mmol-
scale, excess phenylacetylene (10 equiv) is used. However, the
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J. AM. CHEM. SOC. 2005, 127, 9682-9683
10.1021/ja052411r CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Conjugate Addition of Phenylacetylene
to the Acceptors 1a-ga
We have reported a novel method for the catalytic, enantiose-
lective, conjugate alkyne addition to Meldrum’s acid derived
acceptors to give adducts in 82-97% ee and useful yields.
Importantly, the study has resulted in a unique process for conjugate
addition wherein the terminal alkyne undergoes in situ metalation
under mild conditions that are catalytic in metal. Moreover, in the
context of this reaction-driven study, we have examined PINAP as
a ligand. The observations with this new ligand for copper
underscore the salient features of PINAP as a modular monophos-
phine scaffold, whose steric and electronic properties can be tuned
in a variety of ways with the aim of optimizing both reaction rate
and product enantioselectivity. The ability of Cu-acetylides20 to
participate in enantioselective conjugate additions opens up new
possibilities for these carbon-nucleophiles in organic synthesis and
sets the stage for additional investigations of these in related
processes to provide wide access to useful building blocks.
entry
R
t (h)
7 (mol %)
yield (%)
ee(%)b
1
2
3
4
5
6
7
8
i-Pr (1a)
C6H11 (1b)
c-Pr (1c)
i-Bu (1d)
Et (1e)
14
14
51
24
24
66
66
14
10
10
10
20
20
20
20
5
94
95
81
94
79
97
85
90
83
82
Ph (1f)
64
83
m-tol (1g)
i-Pr (1a)
87 (60)c
93
90 (98)c
94
a Reactions were run using 10 equiv of phenylacetylene, except entry 8,
which was run using 1 equiv. Reactions were run at 0.25 mmol scale, except
for entries 6 and 7, which were run at 0.5 mmol scale, and entry 8, which
was run at 1.25 mmol scale. b The enantioselectivity was determined by
chiral HPLC analysis after conversion to the corresponding anilide by
heating in aniline/DMF (see Supporting Information). c After one recrys-
tallization from EtOAc.
Acknowledgment. We are grateful for the support of Sumitomo
Chemical Co., Ltd., Fine Chemicals Research Laboratory. We thank
Dr. B. Schweizer for the determination of the X-ray structures.
Supporting Information Available: Experimental procedures as
well as full characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
amount of phenylacetylene used can be reduced to 1 equiv already
at 1.25 mmol-scale (see below). The scope of the reaction was then
examined (Table 2). In the case of γ-branched acceptors (entries
1-3), the reactions can be conducted with 10 mol % of catalyst.
The products 2a-c were obtained in 94-97% ee and 79-94%
yield. In the absence of γ-branching, the acceptors required
20 mol % of catalyst and gave slightly lower selectivities (entries
4 and 5). Acceptors bearing aromatic groups required prolonged
reaction times (entries 6 and 7). All the products obtained are
crystalline solids (see Supporting Information). As exemplified by
2g (entry 7), the optical purity could be upgraded by a simple
recrystallization (mp 136-137 °C (EtOAc), 90 f 98% ee). The
absolute configuration of the adducts was established for 2a and
2f by conversion into known compounds; for 2b, an X-ray structure
was obtained of the corresponding 4-bromoanilide derivative (in
situ generation of the putative ketene and trapping by the amine:
2b + 4-bromoaniline, DMF, 100 °C, 1 h).18
It should be noted that the reactions we have described are
heterogeneous, thus, efficient stirring of the reaction mixture is
essential for high conversion. In our current working hypothesis,
water does not serve per se as the reaction solvent, but rather as
the medium in which the reactive copper species is generated. The
conjugate addition reaction itself is believed to take place in the
organic phase, namely, phenylacetylene. Importantly, when the
reaction is conducted on larger scale, more efficient mixing allows
for diminution of the amount of phenylacetylene used. Thus, in
the reaction with 1a, the use of 1 equiv of phenylacetylene furnished
2a in 93% yield and 94% ee when the reaction was run on 1.25
mmol-scale (250 mg of 1a) using 5 mol % of 7 (Table 2, entry 8).
Aliphatic alkynes also react under these conditions; for example,
the addition of 4-phenyl-1-butyne to 1a furnishes the corresponding
adduct in 29% yield and 68% ee after 24 h at 23 °C using 20% of
7. Nonetheless, the phenylacetylene adducts we document have
immediate value. Similar compounds generated in racemic form
by addition of lithium phenylacetylide to a Meldrum’s acid acceptor
have been shown to be precursors to substances that display broad
pharmacological activity as tumor necrosis factor (TNF) inhibitors
and gastrin-releasing peptide (GRP) receptor antagonists.19 The
inability to access γ,δ-alkynyl acids in optically active form has
led to their resolution by preparative chiral HPLC.
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(15) The relative configuration of the ligand 7 was unambiguously established
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(16) The absolute configuration of the ascorbate has no effect on the asymmetric
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(17) We found that a 2:1 ligand/copper ratio led to complete inhibition of the
reaction.
(18) CCDC 268029 (4-bromoanilide of 2b) and CCDC 268030 (7) contain
the supplementary crystallographic data for this communication. These
data can be obtained online free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html (or from Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21 EZ, U.K.; Fax (+44) 1223-336-033; or
deposit@cccd.cam.ac.uk).
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