Bronsted base/Lewis acid cooperative catalysis in the enantioselective Conia-ene reaction

Article abstract of DOI:10.1021/ja9004859

(Chemical Equation Presented) A mutually compatible and cooperative combination of copper(I) triflate and bifunctional 9-amino-9-deoxyepicinchona- derived urea compounds for the enantioselective Conia-ene cyclization of alkyne-tethered β-ketoester substrates is reported. The reaction is efficient, broad in scope, and easy to perform and allows access to chiral methylenecyclopentane products with high enantiocontrol. The transformation illustrates the concept of combining inactive precatalysts with inactive transition-metal-ion complexes in situ to reversibly create a catalytically active combination of the two.

Full text of DOI:10.1021/ja9004859

Published on Web 06/15/2009
Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective
Conia-Ene Reaction
Ting Yang,† Alessandro Ferrali,† Filippo Sladojevich,‡ Leonie Campbell,§ and Darren J. Dixon*,‡
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K., Department of
Chemistry, Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road, Oxford OX1 3TA, U.K., and
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
Received January 27, 2009; E-mail: Darren.Dixon@chem.ox.ac.uk
Table 1. Catalyst Identification Studies
Cooperative catalysis is a powerful tool in asymmetric synthesis,
allowing access to new chemical reactivity and high stereocontrol in
a wide range of reactions.1 By mutual activation and organization of
reagents, this concept has been applied widely2 via combinations of
Lewis and Brønsted acids and bases distributed around a chiral scaffold.
The idea we wanted to investigate was that of using ligand/metal-
ion dynamic equilibria obtained by combining different metal-ion
sources with precatalyst structures bearing basic sites and hydrogen-
bond donors. We envisioned that such an approach could allow the
discovery of new reaction pathways by joining acid/base activation
of substrates with transition-metal-ion-catalyzed processes. This would
differ strategically from other cooperative systems in which full ligation
of the metal ion is normally imposed prior to the addition of the starting
materials. Although this approach is conceptually simple, for it to be
effective in asymmetric catalysis, a nonligated background reaction
must not compete in the enantiodetermining step. We reasoned that
cinchona-derived bifunctional catalysts such as 1, introduced by our
group3 and others,1a,b could act as the desired precatalysts (Figure 1).
entry
precat
[M]
time (h)
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
-
Au(PPh3)Cl/AgOTf
AgOTf
Zn(OTf)2
NiCl2(dppe)
CuOTf·1/2C6H6
Au(PPh3)Cl/AgOTf
AgOTf
18
18
18
18
18
18
18
18
18
18
16
16
0
0
0
0
0
0
0
31
68
79
0
-
-
-
-
-
-
-
Zn(OTf)2
+6
-30
+92
-
9
NiCl2(dppe)
CuOTf·1/2C6H6
-
10
11
12
CuOTf·1/2C6H6
0
-
triflate, good reactivity (79% conversion) with excellent enantiocontrol
(92% ee) was observed.
Control experiments (entries 11 and 12) confirmed that both the
precatalyst and the CuOTf were required for catalytic activity; no
background reaction was obserVed with either independently.
A series of experiments (Table 2) measuring conversion against
relative loadings of precatalyst and Cu(I) revealed that the optimal
1b/CuOTf molar ratio was between 20:5 and 20:2.5. Interestingly,
at both low (entry 2) and high (entries 1, 6, and 7) copper loadings,
the reaction rates were noticeably lower while the enantiocontrol
remained essentially constant.8
With optimal reactivity and enantiocontrol established, the scope
of the reaction was surveyed using 20 mol % 1b or 1d as the precatalyst
and 5 mol % copper(I)triflate in dichloromethane at room temperature.
A range of pentynyl ꢀ-ketoesters incorporating significant structural
and electronic changes to both the ester and ketone groups were
investigated, and the results are presented in Table 3. The reaction
was general for aliphatic and electron-rich or -poor aromatic ꢀ-ketoester
substrates. The steric demand of the ester group had little effect on
the reaction enantioselectivity (entries 1-3).
Figure 1. Pseudoenantiomeric cinchona-derived potential precatalysts to
Brønsted base/Lewis acid cooperative catalysts.
These compounds are effective in generating enolates of
ꢀ-ketoesters,1a and we postulated that these intermediates, in the
presence of metal ions, could be reactive toward alkyne functionalities.
We chose to examine the asymmetric Conia-ene reaction of ꢀ-ke-
toesters 2,4 recently developed by Toste,5 as a platform for this
cooperative catalysis concept.
Preliminary studies to assess reactivity and stereoinduction were
performed using readily prepared ꢀ-ketoester 2a. Initially, thiourea 1a
and urea 1b derived from a 9-amino-9-deoxyepicinchonidine scaffold
were screened in combination with a range of “soft” transition-metal
ions6 (Table 1). When thiourea 1a was employed as the precatalyst,
no conversion to the desired cycloisomerized product 3a was observed
in any experiment.7 Use of urea 1b in the presence of Au(PPh3)Cl or
Ag(OTf) also gave no conversion. Pleasingly, however, the analogous
experiment with Zn(OTf) gave 31% conversion to (R)-3a with 6%
ee. In the presence of NiCl2(dppe) complex, 68% conversion with 30%
ee in favor of the S enantiomer was obtained. However, with copper(I)
Similarly, aryl amide 2r was also a good substrate in the process.
Reaction times reflected in part the acidity of the substrates, with the
Table 2. Studies of Copper Loading versus Conversion
1b and CuOTf·1/2C6H6
2a.
8 (R)-3a
CH2Cl2, rt, 16 h
entry
1b (mol %)
CuOTf· 1/2C6H6 (mol %)
conv. (%)
ee (%)
1
2
3
4
5
6
7
20
20
20
20
20
20
20
0
1
2.5
5
10
20
40
0
56
67
68
56
16
6
-
92
92
92
92
92
90
† The University of Manchester.
‡ University of Oxford.
§ AstraZeneca.
9
9140 J. AM. CHEM. SOC. 2009, 131, 9140–9141
10.1021/ja9004859 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope of the Catalytic Asymmetric Conia-Ene Reaction
Scheme 2. Proposed Mechanistic Pathway via a Copper Enolate
entry product
R1
R2
catalyst time (days) yield (%) ee (%)
1
2
3
4
5
6
7
8
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(R)-3g
(R)-3h
(R)-3i
(R)-3j
(R)-3k
Ph
Ph
Ph
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4 OMe
3-MeOC6H4 OMe
4-FC6H4
2-FC6H4
4-BrC6H4
OMe
OEt
OBn
OMe
OMe
OMe
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1d
1d
1.5
1.5
1.5
3
2
1
10
1.5
4
1
1
1
1
2
1.5
1.5
3.5
5
2
2
98
82
95
97
99
67
91
96
74
77
87
83
89
84
85
67
77
85
92
90
92
91
89
92
92
87
91
93
92
89
93
92
89
91
83
80
79
83
89
74
9
OMe
OMe
OMe
These data are suggestive of a cooperative mechanism where the
copper ion, the amine, and the N-H urea are all essential for the
observed reactivity. Although further mechanistic studies are required,
we postulate that the precatalyst has two distinct roles: (1) as a Brønsted
base in the deprotonation of the ꢀ-ketoester, and (2) as an effective
ligand for the copper enolate, which imparts high levels of enantio-
control. This hypothesis is also consistent with data in Table 2, which
illustrates that an excess of precatalyst compared to CuOTf is required
for optimal reactivity.
10
11
12
13
14
15
16
17
18
19
20
a
(R)-3 L 3,4-Cl2C6H3 OMe
(R)-3m 4-PhC6H4
OMe
OMe
OEt
OBn
OMe
NHPh
Ph
(R)-3n
(R)-3o
(R)-3p
(R)-3q
(R)-3r
(S)-3a
(S)-3o
2-naphthyl
Me
Me
Et
Ph
a
a
OMe
OEt
Me
In summary, a combination of copper(I) triflate and bifunctional
9-amino-9-deoxyepicinchona-derived urea compounds has proven to
be an effective catalytic system in the enantioselective Conia-ene
reaction. Further investigations in this field of catalysis are ongoing
and will be reported in due course.
Acknowledgment. We thank the EPSRC (a grant to F.S. and a
Leadership Fellowship to D.J.D.), the European Commission [IEF to
A.F. (MEIF-CT-2006-039981)], Universities UK, the University of
Manchester, and AstraZeneca (a studentship to T.Y.) for support and
Dr. M. Helliwell for single-crystal X-ray diffraction analysis.
a For proof of the absolute stereochemical configuration, see the
Supporting Information.
fastest finishing after 1 day and the slowest after 10 days. Enantiomeric
excesses ranged from 79 to 93%, with the highest arising from aryl
ketone substrates. The substitution of 1b for pseudoenantiomeric
precatalyst 1d in the cyclization reaction of 2a afforded (S)-3a in good
yield and enantiocontrol (entry 19, 92% yield, 89% ee); 2o yielded
(S)-3o in an improved yield but with a slightly diminished ee of 74%
(entry 20 vs entry 15).
To ascertain the possible contributions of the functional groups of
the precatalysts to the observed reactivity, 1b and 1d were replaced
by combinations of Brønsted bases and ureas 4a/4b. Conversion versus
loading experiments were performed. Two experimental series, one
employing 20 mol % quinuclidine and the other 20 mol % 2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphospho-
rine (BEMP) were performed on 2a with 5 mol % copper(I) triflate,
and conversion was measured against a variable quantity of urea 4a
(Scheme 1). In both series, a significant rate acceleration effect due to
the urea was observed. When both experiments were repeated using
cyclic urea 4b, no rate acceleration was observed. These results indicate
the importance of the urea N-H bonds in the rate-determining step
and point to a potential ligand acceleration effect arising from the urea
group. Further mechanistic insight was gained by repeating the reaction
with the deuterated substrate 5. At low conversion,9 the predominant
monodeuterated product was (E)-8. This is consistent with the
intermediacy of a ligated copper enolate that undergoes an enantiose-
lective syn carbocupration6a (Scheme 2).
Supporting Information Available: Experimental procedures, spec-
tral data for compounds 3 and 4, assignments of absolute stereochemistry,
and crystallographic data (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 1. Studies of Conversion versus Urea Loading
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JA9004859
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J. AM. CHEM. SOC. VOL. 131, NO. 26, 2009 9141