Enantioselective copper-catalyzed conjugate addition of trimethylaluminium to β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1002/anie.201107324

Not a cop out: The copper-catalyzed asymmetric conjugate addition of organometallic reagents to Michael acceptors is an important methodology for forming a C-C bond in an enantioselective manner. Such an addition of Me ₃Al to β,γ-unsaturated α-

Full text of DOI:10.1002/anie.201107324

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DOI: 10.1002/anie.201107324
Asymmetric Catalysis
Enantioselective Copper-Catalyzed Conjugate Addition of Trimethyl-
aluminium to b,g-Unsaturated a-Ketoesters**
Ludovic Gremaud and Alexandre Alexakis*
Dedicated to Professor Alfredo Ricci on the occasion of his retirement
Since the end of the last century, transition metal catalyzed
asymmetric conjugate addition (ACA) of organometallic
reagents to Michael acceptors has been one of the most
powerful methods for obtaining enantioenriched b-substi-
tuted natural or unnatural building blocks as intermediates
through C C bond formation.[1] The advantages of the ACA
in the presence of copper as the transition-metal catalyst are
À
Scheme 1. Copper-catalyzed ACA of b,g-unsaturated a-ketoesters.
the low cost of the copper salts, the high regio- and
enantioselectivity, and the compatibility with many functional
groups.[2] In this field, a large variety of a,b-unsaturated
compounds such as carbonyl derivatives, sulfones, and nitro-
alkenes have been used successfully. All of the corresponding
products obtained during this transformation were used as
chiral building blocks, but methyl-substituted derivatives are
the most important if we consider natural compounds
described in the literature. To access new families of chiral
and complex synthons at the same time, we aimed at
developing an efficient methodology that would allow
access to natural and unnatural products using the same
starting material. To achieve this purpose, we investigated a
new copper-catalyzed asymmetric conjugate addition of
various organometallic reagents to functionalized b,g-unsatu-
rated a-ketoesters (Scheme 1).
by an asymmetric conjugate addition of cyclic diketones to
b,g-unsaturated a-ketoesters with the same kinds of chiral
organocatalysts. During our investigations, Gravel and co-
workers developed an interesting enantioselective intermo-
lecular Stetter reaction on b,g-unsaturated a-ketoesters in the
presence of triazolium catalysts to obtain useful synthetic
building blocks with promising selectivities. After a small
derivatization, they obtained disubstituted lactones, trisubsti-
tuted tetrahydrofuranes, or a-amino esters.[15] b,g-unsaturated
a-ketoesters are therefore considered versatile synthons
because of their dense functionalization. Four pathways give
access to a wide range of aryl and alkyl derivatives in good
yield: 1) nucleophilic substitution,[16] 2) aldol condensation,[17]
3) Mukaiyama aldol addition,[18] or 4) Horner–Wadsworth–
Emmons[3]
.
So far, these compounds have never been used for the
asymmetric conjugate addition of organometallic reagents in
the presence of a transition-metal catalyst. However, during
the last decade a wide range of asymmetric organocatalytic
conjugate additions to various b,g-unsaturated a-ketoesters
were described in the literature.[3–9] One of the most studied
reactions with b,g-unsaturated a-ketoesters was the Michael
addition of hydroxycoumarines catalyzed by chiral squara-
mides,[10] thioureas,[11] or bisoxazoline-copper complexes[12] to
obtain coumarine derivatives, which are reported to have
anti-HIVand antimalaria activities. More recently, the groups
of Calter[13] and Feng[14] were able to obtain new derivatives
During our previous work with a,b-unsaturated alde-
hydes, we were faced with much more challenging substrates
than the corresponding ketones, due to the high reactivity of
the carbonyl group, which easily leads to the formation of an
undesired mixture of 1,4-, 1,2-addition products as well as
aldol by-product.[19] b,g-Unsaturated a-ketoesters pose the
same problems, the keto functionality being as reactive as an
aldehyde. From a synthetic point of view, the resulting chiral
g-substituted building blocks can be easily transformed into
the corresponding b-substituted aldehydes, coumarines, qui-
nolinones, tolterodines, chiral b-turn or a-amino acid pre-
cursors.
We initially investigated the ACA with the simplest
derivative, 1, containing an ethyl ester and a phenyl group
appended to the alkene. This first attempt was done using the
reaction conditions developed for the asymmetric conjugate
addition to a,b-unsaturated aldehydes: 1.2 equivalents of an
organometallic reagent, 5 mol% of copper(I) thiophene-2-
carboxylate (CuTC), 5.25 mol% of (R)-binap in diethyl ether
(Et2O) at À788C (Table 1).
[*] L. Gremaud, Prof. A. Alexakis
Department of Organic Chemistry, University of Geneva
30 quai Ernest-Ansermet, 1211 Genꢀve 4 (Switzerland)
E-mail: alexandre.alexakis@unige.ch
Homepage: http://www.unige.ch/sciences/chiorg/alexakis/group/
Welcome.html
[**] The authors thank the Swiss National Research Foundation (grant
No. 200020-126663) and COST action D40 (SER contract No.
C07.0097) for financial support, as well as Stꢁphane Grass (Lacour’s
group, University of Geneva) for some chiral separation on HPLC.
BINAP was generously provided by Takasago company, Japan.
With the Grignard reagent, the substrate was totally
consumed after 13 hours, but unfortunately we obtained
exclusively the 1,2-addition product (Table 1, entry 1). By
adding TMSCl as an additive[20] the regioselectivity was not
improved (Table 1, entry 2). Use of Me2Zn under the same
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107324.
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Table 1: Screening of organometallic reagents.
ester, no improvement in the selectivity was obtained
(Table 2, entry 7).
Although various copper salts were tested in Et2O
(Table 3, entries 1 and 2), CuTC was found to be the most
efficient in terms of conversion, as well as regio- and
Entry
RM
T [8C]
Conv. [%][a]
1,4/1,2[a]
ee [%][b,c]
Table 3: Screening of copper salts and solvents.
1[d]
2
MeMgBr
MeMgBr
Me2Zn
Me2Zn
Me3Al
À78
À78
0
0
À20
>99
>99
0
1:99
1:99
n.d.
99:1
43:57
n.d.
n.d.
n.d.
93
3
4[e]
5
>99(14)[f]
>99(40)[f]
55
[a] Determined by 1H NMR spectroscopy. [b] Determined by GC analysis
using a chiral stationary phase[c] Enantiomeric excess for 1,4-addition
product. [d] Reaction performed with 1.3 equiv TMSCl. [e] Reaction
performed with 2 equiv Me2Zn, 5 mol% CuTC, and (R)-binap in THF.
[f] Yield of isolated product. binap=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl, TMS=trimethylsilyl.
Entry
CuX
Sol.
Conv. [%][a]
1,4/1,2[a]
ee [%][b]
1
2
3
4
5
6
7
Cu(OAc)2
Cu(OTf)2
CuTC
CuTC
CuTC
Cu(OAc)2
Cu(OTf)2
CuTC
Et2O
Et2O
MTBE
EtOAc
THF
THF
THF
THF
THF
>99
>99
>99
>99
70
50:50
20:80
8:92
77:23
>99:1
97:3
85:15
>99:1
80:20
95
27
n.d.
48
98
42
87
>99
>99
31
0
reaction conditions, with the exception of temperature,
resulted in no conversion. However, with the best reaction
conditions developed, 14% of 1,4-addition product could be
isolated with 93% ee (Table 1, entry 3). The use of trimethyl-
aluminium was envisaged to introduce the methyl group
because it is a mild organometallic reagent. At À208C we
obtained full conversion with approximately a 1:1 ratio for the
1,4-adduct to 1,2-adduct selectivity, thus reaching a promising
55% ee for the 1,4-adduct (Table 1, entry 4).
8[c]
9[d]
>99.5
65
CuTC
[a] Determined by 1H NMR spectroscopy. [b] Reported values are for the
1,4-adduct. Determined by GC analysis using a chiral stationary phase.
[c] Used 2 equiv of organometallic reagents. [d] Reaction performed with
1 mol% CuTC, and (R)-binap. MTBE=methyl tert-butyl ether, Tf=tri-
fluoromethanesulfonyl.
By changing the reaction temperature from À208C to
À788C, and increasing the reaction time from 3 hours to
17 hours, the 1,4-addition adduct was obtained as the major
product (Table 2, entries 1–5). Upon changing the order of
addition no improvement was observed for the regio- and
enantioselectivity (Table 2, entry 6). It was reasoned that in
presence of a more hindered ester moiety the undesired
conformational flexibility of the molecule could be avoided
and thus lead exclusively to the 1,4 addition product.
However, by substituting the ethyl ester by an isopropyl
enantioselectivity. Keeping CuTC as copper source, different
solvents were screened, and tetrahydrofuran (THF) was
identified as the solvent of choice (Table 3, entry 3–5).[21] The
formation of the product 2 was observed with full regiose-
lectivity and very high enantiomeric excess. Various other
solvents and copper salts were screened but did not manage to
improve this result (Table 3, entry 6–7).[22] When using excess
trimethylaluminium (2 equiv), full conversion and complete
regioselectivity in favor of the 1,4-adduct were reached with a
very high ee value (Table 3, entry 8). If the catalyst loading
was decreased from 5 mol% to 1 mol% the reactivity and
selectivity fell (Table 3, entry 9). Finally, it should be men-
tioned that other chiral ligands were tested but were less
efficient than the simple commercially available binap.
As mentioned previously, the ester can play a very
important role for some organocatalyzed ACAs. However,
in our case, the use of more hindered ester moieties did not
affect the reactivity or selectivity, even when using the tert-
butyl ester (Scheme 2).
Table 2: Screening of reaction temperature and reaction time.
Entry
t [h]
T [8C]
Conv. [%][a]
1,4/1,2[a]
ee [%][b]
1
2
3
4
13
3
3
À20
À40
À60
À78
À78
À78
À78
>99
>99
>99
52
>99
85
43:57
60:40
63:37
72:28
70:30
67:33
64:36
55
60
94
95
94
96
n.d.
3
5
17
17
17
6[c]
7[d]
>99
[a] Determined by 1H NMR spectroscopy. [b] Reported values are for the
1,4-adduct. Determined by GC analysis using a chiral stationary phase.
[c] Addition of substrate before the organometallic reagents. [d] Reaction
performed with 5 where OiPr is used in place of OEt.
Scheme 2. Scope of ester reagents.
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Table 4: Scope of substrate.
Entry
Sub.
R
Prod.
Yield [%]
ee [%][a]
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
p-FC6H4
p-ClC6H4
p-BrC6H4
m-BrC6H4
o-BrC6H4
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-NO2C6H4
m-NO2C6H4
o-NO2C6H4
m-iPrC6H4
C7H15
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
68
87
91
85
89
55
35
29
88
91
90
93
93
90
92
97
97
98
>99.5
99
97
94
27
96
88
Scheme 3. Synthesis of (S)-florhydral (40).
florhydral.[29] The synthesis of this compound was already
described in the literature but with poor yield or enantiose-
lectivity.[30] With our strategy, we were able to obtain the (S)-
florhydral (40) with very good yield, and high regio- and
enantioselectivity (Scheme 3).
9
10
11
12
13
14
15[b]
92
98
91
82
The b-substituted aldehyde was obtained with complete
retention of the chiral information. By a simple one-pot
procedure, the same result was obtained. This application also
allowed us to determined the absolute configuration by
comparison of the results with our previous work.[19]
We can also easily prepare chiral a-amino acid precursors
from the corresponding g-substituted-a-ketoesters by a one-
step procedure. By simple reductive amination on chiral g-
substituted-a-ketoesters we obtained, under nonoptimized
reaction conditions, the corresponding unnatural chiral a-
amino acid precursors with complete retention of the chiral
information and with a promising diastereoselectivity of up to
3:1 (Scheme 4).
cyclohexyl
C6H4CH CH
=
98
[a] Determined by either GC, SFC, or HPLC using a chiral stationary
phase. [b] No 1,6-addition product was observed.
Finally, the substrate scope was investigated. Table 4
shows that a wide range of substituted aromatic b,g-unsatu-
rated a-ketoesters with electron-donating and electron-with-
drawing groups are compatible under the reaction conditions.
As can be seen in Table 4, halogenated, nitro, or methoxy aryl
derivatives tolerate the reaction conditions. Linear and cyclic
b,g-unsaturated a-ketoesters also gave very good selectivities
considering the conformational flexibility of the alkyl chain
and comparing theses results with previous ACA to enones or
enals. Only strongly donating groups (o,m,p-OMePh)
afforded lower conversions and yields, although no by-
products were observed. For R = o-OMePh we also observe
a dramatic drop of enantioselectivity to 27%. It is interesting
to notice that dienic substrate 24 (Table 4, entry 15) provides
exclusively the 1,4-adduct, without trace of the 1,6-regioiso-
mer.
The generality of the reaction was finally explored using
other organoaluminium and organozinc reagents, but
unfortunately a mixture of the 1,4- and 1,2-addition products
or low enantioselectivities were obtained under our reaction
conditions. Such divergent results with higher aluminium
homologues are not unprecedented, although no clear
explanation could be given.[23]
As mentioned in the introduction, the functionalities on
b,g-unsaturated a-ketoesters give access to a wide range of
chiral building blocks for further derivatization. To comple-
ment our previous work with a,b-unsaturated aldehydes,[19]
we decided to apply a simple derivatization procedure to
obtain the corresponding chiral b-substituted aldehyde. The
groups of Feringa,[24] Hoveyda,[25] Palomo,[26] and Mazet[27]
have already developed alternative methodologies to obtain
this type of product but the yield, regio- and/or enantiose-
lectivity left room for improvement. A two-step, reduction/
oxidation[28] procedure was applied to the synthesis of (S)-
Scheme 4. Synthesis of unnatural a-amino acid precursors.
In conclusion, b,g-unsaturated a-ketoesters are shown to
be very efficient substrates for the copper-catalyzed asym-
metric conjugate addition.[31] Whilst a lower reaction temper-
ature and THF are required for the case where trimethylalu-
minium is used as the organometallic reagent, just 5 mol% of
CuTC and (R)-binap afforded the desired reaction product.
The simple commercially available binap ligand can catalyze
the reaction with very high efficiency. A wide range of
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were tolerated under our reaction conditions to give full
conversion and regioselectivities up to 99.5% ee. However, a
strong electronic, steric, and chelating effect with aryl
methoxy derivatives was observed, and resulted in a decrease
of reactivity and enantioselectivity. Some alkyl derivatives
were also screened and are compatible under our reaction
conditions even if a small drop in the enantioselectivity was
observed. Progressively increasing the steric bulk of the ester
moiety from methyl to tert-butyl did not affect the enantio-
selectivity of the reaction. Furthermore, g-substituted-a-
ketoesters were used as chiral building blocks for further
derivatization. We obtained the corresponding b-substituted
aldehydes by a simple one-pot methodology with complete
retention of the chiral information. Finally, a convenient
reductive amination was used to access unnatural chiral a-
amino acid precursors also with complete retention of the
chiral information and with promising diastereoselectivity.
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Received: October 17, 2011
Published online: December 1, 2011
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Keywords: amino acids · asymmetric catalysis · copper ·
enantioselectivity · synthetic methods
.
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