Highly enantioselective copper(I)-phosphoramidite-catalysed additions of organoaluminium reagents to enones

Article abstract of DOI:10.1039/b503074a

Simple phosphoramidite ligands afford good to excellent levels of enantioselectivity in 1,4-additions of AIR₃ species to enones; sequential carboalumination-ACA cascades are possible. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503074a

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COMMUNICATION
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Highly enantioselective copper(I)-phosphoramidite-catalysed additions
of organoaluminium reagents to enones{
a
Alexandre Alexakis,* Victoria Albrow, Kallolmay Biswas, Magali d’Augustin, Oscar Prieto and
b
b
a
b
b
Simon Woodward*
Received (in Cambridge, UK) 3rd March 2005, Accepted 7th April 2005
First published as an Advance Article on the web 21st April 2005
DOI: 10.1039/b503074a
Simple phosphoramidite ligands afford good to excellent levels
of enantioselectivity in 1,4-additions of AlR species to enones;
from our own reports Chan attained 96% ee in the addition of
AlMe to 2-cyclohexenone using (S ,R ,S )-L1 (2 mol%) and
Cu(MeCN) ]BF (1 mol%); together with related additions to
3
3
a
a
a
[
sequential carboalumination–ACA cascades are possible.
4
4
5
2
-cyclopentenone. Van Leeuwen and Claver reached 62% ee in
6
Ligand-driven catalytic asymmetric processes that attain wide-
spread popularity typically display two features: technical
simplicity and widespread (preferably commercial) availability of
both enantiomers of the chiral ligand. In the last five years this
position has been reached for the addition of organozinc reagents
related additions of AlEt using the complex ligand (R ,R )-L2.
3
P
C
1
,2
(
especially ZnEt ) to many Michael acceptors. In studies parallel
2
to these we have developed an interest in the utilisation of
3
organoaluminium reagents, especially AlR (R 5 Me, Et, etc.)
species, in related Asymmetric Conjugate Addition (ACA)
3
,4
reactions. As a significant range of organoaluminium reagents
are either commercially available, or attained by technically simple
hydro- and carboalumination reactions, they offer high potential
for use in synthesis. Despite this reports in this area have been
rather limited due to an apparent need for specialist ligands. Aside
{
Electronic supplementary information (ESI) available: supporting
experimental data. See http://www.rsc.org/suppdata/cc/b5/b503074a/
alexandre.alexakis@chiorg.unige.ch (Alexandre Alexakis)
simon.woodward@nottingham.ac.uk (Simon Woodward)
*
a
3
Table 1 Optimisation of AlR (R 5 Et, Me) ACA to 2-cyclohexenone
Run
Solvent
Cu-source (mol%)
L (mol%)
Conv./%
Yield/%
Ee/% (Config.)
AlEt
3
1
2
3
4
5
6
7
8
9
CH
Et
Bu OMe
2
Cl
O
2
[Cu(MeCN)
[Cu(MeCN)
Cu(TC) (1)
Cu(TC) (1)
Cu(TC) (2)
Cu(TC) (2)
Cu(TC) (2)
Cu(TC) (1)
Cu(TC) (1)
4
] BF
] BF
4
(1)
(1)
L3 (4)
L3 (4)
L3 (4)
L3 (4)
L3 (4)
L5 (4)
L3 (4)
L3 (4)
L3 (4)
. 98
40
47
22
77
80
54
40
28
, 20
, 5
76 (R)
45 (R)
90 (R)
90 (R)
86 (R)
89 (R)
89 (R)
88 (R)
2
t
4
4
. 98
. 98
. 98
. 98
. 98
. 98
20
Et
2
Et
2
Et
2
O
O
O
b
b
b
THF
Toluene
MeCN
, 5
AlMe
3
1
1
1
1
a
0
1
2
3
Et
Et
Et
Et
2
2
2
2
O
O
O
O
Cu(OTf)
Cu(TC) (2)
Cu(OTf) (2)
Cu(TC) (2)
2
(2)
L3 (4)
L5 (4)
L4 (4)
L6 (4)
. 98
. 98
. 98
. 98
30
85
77
64
95 (R)
92 (R)
95 (R)
97 (R)
2
Addition of 1.4 equiv. of AlR
3
(2 M hexane or heptane solution) to 2-cyclohexenone and Cu-salt/L at 230 uC followed by 20 min reaction at
b
this temperature. Yield by GC against internal standard, ee by chiral GC. Standard conditions followed by 16 h at 230 uC.
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We wondered if optimal conditions could be identified whereby
7
the simplest of monodentate phosphoramidite ligands could
Table 2 ACA Reactions of AlR
enones catalysed by Cu(TC)/L3
3
reagents (R 5 Me, Et) to various
a
afford very highly enantioselective reactions across a range of
cyclic and acyclic enones under easily utilised reaction conditions.
Run Starting material
Time/h Yield/% Ee/% (Config.)
This hypothesis could be confirmed by simple trial of AlR
3
(R 5 Et,
Me) additions to 2-cyclohexenone (Table 1{) using the readily
commercially available Feringa ligand (R ,S,S)-L3 and ligands
AlEt
1
3
2
87
89 (R)
a
8
L4–L7 (all attainable in a single step from commercial materials).
b
2
16
80
90 (R)
c
c
3
4
5
16
3
90
86(R)
88
84 (R)
98 (R)
3
85
This initial screening revealed that reactions in diethyl ether
9
using the versatile Cu(TC) source were extremely fast, completing
in 20 min at 230 uC. Use of alternative copper(I) pre-catalysts,
1
0
such as [Cu(MeCN)
some cases Cu(OTf)
2). Solvents less or more polar than Et O or Bu OMe were also
4
]BF
4
,
was not effective (Runs 1–2) but in
d
6
8
88
. 98 (S)
2
was the preferred copper source (Runs 10,
t
1
2
not effective (Runs 7–9). In cases where the yields were appreciably
lower than the conversion (e.g. Run 10) the mass balance was
accounted for by undesired trapping of the aluminium enolate on
AlMe
7
3
4
2
4
2
55
65
60
88
72 (R)
70 (R)
70 (R)
96 (R)
to additional unreacted 2-cyclohexenone. In Et O, running the
2
reaction overnight also led to reduction in the yields and
enantioselectivities realised (Runs 5–6). Subsequent adverse kinetic
resolution in by-product forming reactions of the initial chiral
enolate may be the explanation for this. Good stereoselectivities
8
9
(82% ee) were also attained using our recently introduced air-stable
equivalent of trimethylaluminium DABAL-Me3 [(Me Al) -
3
2
1
1
(
DABCO)] with ligand L5, but here also enolate trapping by-
product formation limited the yield of 1,4-addition product (27%).
As the test ACA-AlR reaction conditions had proved completely
3
robust against changes in the reaction protocols (e.g. different
1
0
3 2
sources of AlR reagents, quality of Et O, different batches of
Cu(TC), presence of traces of oxygen and water) we looked to
extend the range of substrates. Ligand L3 was chosen due to its
ready commercial availability in both enantiomeric forms.
Against a range of aliphatic enones the simple Cu(TC)/L3
system gave synthetically useful enantioselectivities and chemical
yields (Table 2{), although longer reaction times than with
11
3
3
89
84
96 (R)
92 (R)
1
2
2-cyclohexenone were necessary in all cases. The only exception
was the addition of AlMe to linear aliphatic enones which could
3
only be realised in 70–72% ee with simple L3 (Runs 7–9).
However, a branching in such substrates increased the selectivity
to . 20 : 1 (Runs 10–11). Again all the reactions proved tolerant to
any organoaluminium sources used and to variations in technique
of multiple researchers in two different sites.
a
3
Addition of 1.4 equiv. of AlR (2 M hexane or heptane solution)
to enone and Cu(TC) (1 mol%) (R ,S,S)-L3 (4 mol%) at 230 uC
a
followed by 20 min reaction at this temperature. Yields by isolation,
ee by chiral GC unless noted otherwise. Using 2 mol% Cu(TC)
b
One final attraction of organoaluminium reagents is the ease
with which novel reagents can be attained by hydro- and
c
lowering this to 1 mol% led to 82% ee. Using Cu(TC) (2 mol% and
d
R,R)-L7 (4 mol%); yield by GC. Ee value determined by
13
(
C
NMR spectroscopy on (R,R)-PhCH(NH )CH(NH )Ph derived
1
3
carboalumination reactions. Carboalumination of phenylacety-
2
2
1
4
aminal (see ref. 12); change of stereo-descriptor caused only by CIP
priority rules.
lene, under modified Negishi conditions (using 0.2 to 1.0 equiv.
of Cp ZrCl ) in dichloromethane led to an . 85% yield of
2
2
2
844 | Chem. Commun., 2005, 2843–2845
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Notes and references
{ For details of the catalytic conditions and spectral and chiral
chromatographic data on the products see the electronic supplementary
information.
§
Carboalumination reactions are usually performed in the presence of
excess AlMe . To minimise competitive methylation in the subsequent
ACA reaction 2 equivalents AlMe were used necessitating a slightly longer
reaction time (see supplementary data for experimental details).
3
3
1
2
Leading overviews: (a) A. Alexakis and C. Benhaim, Eur. J. Org. Chem.,
002, 3221; (b) N. Krause and A. Hoffmann-Roder, Synthesis, 2001,
71; (c) A. H. Hoveyda, Chem. Commun., 2004, 1779.
Recent developments: (a) A. P. Duncan and J. L. Leighton, Org. Lett.,
2004, 6, 4117; (b) M. Shi, C.-J. Wang and W. Wang, Chem. Eur. J.,
2004, 10, 5507; (c) I. J. Krauss and J. L. Leighton, Org. Lett., 2003, 5,
2
1
Scheme 1 Enantioselective addition of in situ formed vinylalanes.
vinylalane after 32 h in our hands.§ Removal of the CH
solvent and direct addition of Et O to the orange residue, followed
by Cu(TC) and (R ,S,S)-L3 at 230 uC, led to a useful sequential
2 2
Cl
2
3
201.
(a) M. d’Augustin, L. Palais and A. Alexakis, Angew. Chem., Int. Ed.,
005, 44, 2; (b) D. Polet and A. Alexakis, Tetrahedron Lett., 2005, 46,
1529.
a
3
reaction on addition of 2-cyclohexenone or 2-cycloheptenone
fashioning 1a–b (Scheme 1). In both cases the (+) stereoisomer is
isolated which is assigned to the same facial selectivity as the other
additions herein. Remarkably, the presence of the Cp ZrCl is
2
4 (a) P. K. Fraser and S. Woodward, Chem. Eur. J., 2003, 9, 776; (b)
S. M. W. Bennett, S. M. Brown, J. P. Muxworthy and S. Woodward,
Tetrahedron Lett., 1999, 40, 1769.
5
6
7
2
2
largely tolerated in the subsequent asymmetric conjugate addition
chemistry. To the best of our knowledge only racemic additions of
(a) L. Liang and A. S. C. Chan, Tetrahedron: Asymmetry, 2002, 13,
1393; (b) L. Su, X. Li, W. L. Chan, X. Jia and A. S. C. Chan,
Tetrahedron: Asymmetry, 2003, 14, 1865.
M. Di e´ guez, S. Deerenberg, O. P a` mies, C. Claver, P. W. N. M. van
Leeuwen and P. Kramer, Tetrahedron: Asymmetry, 2000, 11,
1
5
such vinylalanes to enones have been reported before. Attempts
to further increase the utility of these cascade reactions through
trapping of the kinetically formed aluminium enolates are being
actively pursued in our laboratories.
3161.
B. L. Feringa, Acc. Chem. Res., 2000, 33, 346.
We thank the COST-D24 programme of the European Science
Foundation and EU for promoting scientific exchange between
our laboratories. The Woodward group thank the EU
8 (a) For L4: L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. De Vries,
R. Naasz and B. L. Feringa, Tetrahedron, 2000, 56, 2865; (b) For L5
and L7: A. Alexakis, S. Rosset, J. Allamand, S. March, F. Guillen and
C. Benhaim, Synlett, 2001, 1375; (c) For L6: A. Alexakis, D. Polet,
C. Benhaim and S. Rosset, Tetrahedron: Asymmetry, 2004, 15,
2199.
(LIGBANK, FP6-NMP3-CT-2003-505267) and the EPSRC
(grants GR/R69051/01 and GR/S56054/01 and a DTA contribu-
9
Cu(TC) 5 copper(I) thiophene-2-carboxylate. G. D. Allred and
L. S. Liebeskind, J. Am. Chem. Soc., 1996, 118, 2748.
tion to VA) for financial support. The Alexakis group thank
St e´ phane Rosset for help, the BASF company for a generous gift
of chiral primary amines, the Swiss National Research Foundation
No 200020-105368 and COST action D24/0003/01 (OFES contract
Nu C02.0027) for financial support.
1
1
0 G. J. Kubas, Inorg. Synth., 1990, 28, 68.
1 K. Biswas, O. Prieto and S. Woodward, Angew. Chem., Int. Ed., 2005,
44, 2232–2234.
2 A. Alexakis, J. C. Frutos and P. Mangeney, Tetrahedron: Asymmetry,
993, 12, 2431.
3 (a) Titanium and Zirconium in Organic Synthesis, Ed. I. Marek, 2002,
1
1
a
Alexandre Alexakis,* Victoria Albrow, Kallolmay Biswas,
b
b
1
a
Magali d’Augustin, Oscar Prieto and Simon Woodward*
b
b
Wiley-VCH Verlag GmbH, Weinheim, Germany; (b) E. Negishi and
T. Takahashi, Synthesis, 1988, 1; (c) E. Negishi, Acc. Chem. Res., 1987,
20, 65; (d) G. Zweifel and J. A. Miller, Org. React., 1984, 32, 375.
14 E. Negishi, D. E. van Horn and T. Yoshida, J. Am. Chem. Soc., 1985,
107, 6639.
a
Department of Organic Chemistry, University of Geneva, Geneva,
Switzerland. E-mail: alexandre.alexakis@chiorg.unige.ch;
Fax: +41-22-379-3215; Tel: +41-22-379-6522
b
School of Chemistry, The University of Nottingham, Nottingham, UK.
E-mail: simon.woodward@nottingham.ac.uk; Fax: +44-115-951-3564;
Tel: +44-115-951-3541
15 P. Wipf, J. H. Smitrovich and C.-W. Moon, J. Org. Chem., 1992, 57,
3178.
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Chem. Commun., 2005, 2843–2845 | 2845