Highly enantioselective Cu-catalysed allylic substitutions with Grignard reagents

Article abstract of DOI:10.1039/b513887f

A catalyst system able to perform highly enantioselective Cu-catalysed allylic alkylations with Grignard reagents is described. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b513887f

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Highly enantioselective Cu-catalysed allylic substitutions with Grignard
reagents{
Fernando Lo´pez, Anthoni W. van Zijl, Adriaan J. Minnaard and Ben L. Feringa*
Received (in Cambridge, UK) 30th September 2005, Accepted 2nd November 2005
First published as an Advance Article on the web 5th December 2005
DOI: 10.1039/b513887f
A catalyst system able to perform highly enantioselective Cu-
catalysed allylic alkylations with Grignard reagents is described.
Transition metal-catalysed allylic substitution with carbon nucleo-
philes is a powerful tool for the controlled formation of carbon–
carbon bonds.1 Most enantioselective versions of this reaction have
been reported with soft nucleophiles (i.e. malonates and related
stabilised anions) using Pd as the metal source,2 although Mo, W,
Ru, Rh and Ir catalysts have also been found effective for these
Scheme 1 Cu-catalysed enantioselective allylic alkylation with Grignard
nucleophiles.3 In contrast, the enantioselective allylic alkylation
reagents.
with hard carbon nucleophiles (i.e., organometallic reagents),
which allows the introduction of simple alkyl groups in an allylic
Furthermore, we describe for the first time a highly enantioselec-
position, has received far less attention, Cu being the current metal
tive allylic substitution of linear aliphatic allylic halides with
of choice.4 In 1995, Ba¨ckvall and van Koten reported the first
Grignard reagents, and the application of these methodologies to
asymmetric Cu-catalysed allylic alkylation with moderate enan-
the synthesis of syn and anti 1,2-dialkyl motifs.
tioselectivity using Grignard reagents.5 A few years later, Du¨bner
The present study started with the exploration of the ligands
and Knochel reported a highly enantioselective version using
dialkylzinc reagents.6 Since then, most efforts have been directed
(1a–1b) found effective in the 1,4-addition to acyclic a,b-unsatu-
rated compounds,10b,c using MeMgBr as the Grignard reagent.11
towards the development of new efficient Cu catalysts for these
The results are summarized in Table 1. The allylic alkylation of
organozinc reagents.7 A notable exception is the highly enantio-
selective Cu-phosphoramidite8 catalysed allylic substitution of
cinnamyl bromide (3a), catalysed by Josiphos (1a, 6 mol%) and
t
CuBr?SMe2 (5 mol%) in BuOMe proceeds with good regioselec-
cinnamyl chlorides with Grignard reagents reported by Alexakis
and coworkers in 2004.9
tivity (4a : 5a = 85 : 15), providing the chiral product 4a with high
enantioselectivity (85% ee, entry 1). The choice of solvent, type of
Josiphos ligand,12 and leaving group (LG) proved to be critical to
obtain high selectivities (i.e. entries 2–5).13 However, the nature of
Recently, we demonstrated that Cu-catalysed enantioselective
1,4-additions of Grignard reagents to a variety of a,b-unsaturated
carbonyl compounds can be achieved with enantioselectivities up
to 99% (Fig. 1).10 Herein, we report that the same catalyst systems
Table 1 Cu-catalysed enantioselective allylic alkylation with Josiphos
ligands and Grignard reagents (Scheme 1, L* = 1a or 1b)a,b
can perform regio- and enantioselective allylic alkylations with
Grignard reagents. Enantioselectivities up to 98% and excellent
regioselectivities can be achieved just by judicious selection of the
appropriate ligand and reaction parameters (Scheme 1).
Entry
3
R2 [Cu]
Solvent
4
4 : 5c
ee (%)c
1
2
a
a
a
b
c
a
a
a
a
a
g
c
Me CuBr?SMe2
Me CuBr?SMe2
Me CuBr?SMe2
Me CuBr?SMe2
Me CuBr?SMe2
Me CuTC
tBuOMe
CH2Cl2
a
a
a
a
a
a
a
a
a
b
c
85 : 15
49 : 51
66 : 34
81 : 19
0 : 100
60 : 40
85 : 15
85 : 15
84 : 16
38 : 62
82 : 18
75 : 25
88 : 12
94 : 6
85
73
79
58
—
84
86
84
84
56
46
44h
72i
69i
3d
4e
5f
6
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
7
8
9
Me CuCN
Me CuCl
Me Cu(MeCN)4PF6 tBuOMe
10
11g
12
13
14
a
Et CuBr?SMe2
Me CuBr?SMe2
tBuOMe
tBuOMe
Et Cu(MeCN)4PF6 CH2Cl2
b
c
d
Fig. 1 Successful ligands for the enantioselective conjugate addition of
Grignard reagents to a,b-unsaturated carbonyl compounds.
g
g
Me CuBr?SMe2
Et CuBr?SMe2
CH2Cl2
CH2Cl2
Reagents and conditions: RMgBr (2.50 equiv.), 1a (6 mol%),
CuBr?SMe2 (5 mol%), 275 uC, 12 unless otherwise noted.
All conv . 98% (GC) unless otherwise noted. Regio- and
Department of Organic Chemistry and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen, Nijenborgh 4, 9747AG,
Groningen, The Netherlands. E-mail: B.L.Feringa@rug.nl;
Fax: +31 50 363 4296; Tel: +31 50363 4235
{ Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data of previously unknown reaction
products. See DOI: 10.1039/b513887f
h
b
c
enantioselectivity determined by chiral GC; see ESI for details.
Reaction carried out with Josiphos 1b. Conv , 10% (GC). 29%
d
e
f
g
Conv (GC). 50% Conv (GC). EtMgCl (1.15 equiv.) used instead
h
i
of EtMgBr. 1.15 Equiv. RMgBr. TC = 2-thiophenecarboxylate.
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Chem. Commun., 2006, 409–411 | 409

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the copper source, which is usually a crucial factor for the
selectivity in related Cu-catalysed allylic substitutions,7,9 did not
influence the outcome of the process significantly (entries 6–9).
Unfortunately, when other Grignard reagents such as EtMgBr,
or aliphatic allylic bromides such as 3g were applied, the regio- and
enantioselectivity of the reactions were affected dramatically
(entries 10 and 11). A detailed optimization of the leaving group,
and the reaction conditions was, therefore, undertaken. Only a
moderate increase in the regio- and enantioselectivity of these
reactions could be obtained (entries 12–14). In attempts to further
improve the level of stereocontrol, we turned our attention to
another ferrocenyl ligand, recently reported to be successful in the
conjugate addition of Grignard reagents to cyclic enones:
Taniaphos (2),14 (Fig. 1).10a
Table 2 Cu-catalysed enantioselective allylic alkylation with Cu/
Taniaphos (2) and Grignard reagents (Scheme 1, L* = 2)a,b
Entry
1e,f
3
a
R2
4 : 5c
4
Yieldd ee (%)c
Et
31 : 69
4b 99g
32 (S)
2f
3
a
a
d
Et
Et
Et
82 : 18
81 : 19
87 : 13
4b 99g
4b 92
4e 86
96 (S)
95 (S)
90 (S)
4
5
6
7
e
a
a
Et
82 : 18
87 : 13
91 : 9
4f 80
4g 92
4h 93
96 (S)
94 (S)
95 (S)
nBu
The allylic alkylation of cinnamyl bromide 3a with EtMgBr
catalysed by Taniaphos (2, 6 mol%) and CuBr?SMe2 (5 mol%) in
tBuOMe, provided a modest regioselectivity and only 32% ee
(Table 2, entry 1). However, a dramatic improvement in the
selectivity was observed using CH2Cl2 instead of tBuOMe,
providing the desired product 4b with a regioselectivity of 82 :
18 and an excellent ee (96%, entry 2).15 In addition, the catalyst
loading could be reduced to only 1 mol% without significant
deterioration in the selectivity obtained (entry 3). Comparable
selectivities were achieved in the alkylation of other aryl-
substituted allylic bromides (3d–3e, Scheme 1) with EtMgBr
(entries 4 and 5).
8
a
d
e
Me
Me
Me
97 : 3
100 : 0
99 : 1
4a 91
4i 87
4j 95
98 (S)
96
9
10
97
11
f
Me
Me
Et
98 : 2
100 : 0
100 : 0
4k 94
4c 99g
4d 99g
97 (S)
92
Furthermore, the allylic substitution of 3a could also be
performed with other Grignard reagents, providing the corre-
sponding products 4g–h,a (Table 2) with excellent enantioselec-
tivities (94–98% ee) and good regioselectivities (entries 6–8). The
alkylation with MeMgBr is particularly noteworthy.11 The product
4a, as well as the compounds 4i–k were obtained with almost
complete control of the regioselectivity and enantioselectivities
¢ 96% (entries 8–11).16 Gratifyingly, aliphatic allylic bromides
such as 3g–h were also excellent substrates, affording under these
conditions, almost exclusively, the branched products 4 with
enantioselectivities ¢ 92% (entries 12–15). The presence of a
benzyloxy group in the substrate (3h) was tolerated providing
excellent building blocks (4l–m) for natural product synthesis
(entries 14 and 15).17
12f
13f
g
g
93
14
15
a
h
h
Me
Et
100 : 0
98 : 2
4l 93
92 (S)
4m 97
94
Reagents and conditions: RMgBr (1.15 equiv.),
2
(1.1 mol%),
CuBr?SMe2 (1.0 mol%), CH2Cl2, 278 uC, 12 h unless otherwise
b
c
noted.
enantioselectivities determined by chiral GC or HPLC (see ESI for
All conversions
.
98% (GC).
Regio- and
d
details). Isolated yield of combined 4 and 5 unless otherwise noted.
In summary, we have demonstrated that the catalyst systems
developed recently for the enantioselective conjugate addition of
Grignard reagents to a,b-unsaturated carbonyl compounds are
Reaction in tBuOMe. Taniaphos (2, 6.0 mol%), CuBr?SMe2
(5.0 mol%). Conversion (GC).
e
f
g
also able to perform highly enantioselective allylic alkylations with
Grignard reagents. The combination of Taniaphos (2) and
CuBr?SMe2 in CH2Cl2 provides excellent regio- and enantioselec-
tivities in the substitution of aliphatic and aromatic allylic
bromides. The potential of these two new methodologies for the
catalytic and enantioselective preparation of 1,2-dialkyl motifs is
shown in Scheme 2.
The allylic alkylation of 3a with MeMgBr afforded 4a with
98% ee. The crude reaction was submitted to cross metathesis with
methyl acrylate to afford (S)-6 in 66% overall yield.18 Gratifyingly,
enoate 6 proved to be an excellent substrate for the recently
developed enantioselective conjugate addition of Grignard
reagents.10c Thus, the conjugate addition of EtMgBr to 6,
catalyzed by (R,S)-1b or its enantiomer (S,R)-1b, provided,
Scheme 2 Reagents and conditions: a) i) MeMgBr (1.15 eq.),
2
(1.1 mol%), CuBr?SMe2 (1.0 mol%), CH2Cl2, 278 uC; ii) Hoveyda–
Grubbs 2nd generation, methyl acrylate (5.0 eq.), CH2Cl2, rt; b) EtMgBr
(5.0 eq.), (R,S)-1b (6.0 mol%), CuBr?SMe2 (5.0 mol%), CH2Cl2, 278 uC; c)
EtMgBr (5.0 eq.), (S,R)-1b (6.0 mol%), CuBr?SMe2 (5.0 mol%), CH2Cl2,
278 uC.
410 | Chem. Commun., 2006, 409–411
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K. E. Murphy and A. H. Hoveyda, J. Am. Chem. Soc., 2003, 125,
4690; (c) U. Piarulli, P. Daubos, C. Claverie, M. Roux and C. Gennari,
Angew. Chem., Int. Ed., 2003, 42, 234; (d) A. W. van Zijl, L. A. Arnold,
A. J. Minnaard and B. L. Feringa, Adv. Synth. Catal., 2004, 346, 413; (e)
M. A. Kacprzynski and A. H. Hoveyda, J. Am. Chem. Soc., 2004, 126,
10676; (f) A. O. Larsen, W. Leu, C. N. Oberhuber, J. E. Campbell and
A. H. Hoveyda, J. Am. Chem. Soc., 2004, 126, 11130; (g) K. E. Murphy
and A. H. Hoveyda, Org. Lett., 2005, 7, 1255; (h) P. J. Goldsmith,
S. J. Teat and S. Woodward, Angew. Chem., Int. Ed., 2005, 44, 2235; (i)
J. J. Van Veldhuizen, J. E. Campbell, R. E. Giudici and A. H. Hoveyda,
J. Am. Chem. Soc., 2005, 127, 6877.
respectively, the anti and syn--1,2-dialkyl substituted esters 7 and 8
with excellent yields and diastereoselectivities.19 These results
demonstrate the efficiency of this chiral catalyst in the control of
the configuration at the new stereocenter, independent of the
absolute configuration of the chain.17
Financial support from the Dutch Ministry of Economic Affairs
under the EET scheme (EETK-97107 and 99104) and the
European Community’s 6th Framework Programme (Marie
Curie Intraeuropean Fellowship to F. L.) is acknowledged. We
are grateful to Dr H.-U. Blaser (Solvias, Basel) for a gift of
Josiphos ligands.
8 B. L. Feringa, Acc. Chem. Res., 2000, 33, 346.
9 (a) K. Tissot-Croset, D. Polet and A. Alexakis, Angew. Chem., Int. Ed.,
2004, 43, 2426 and references therein; (b) K. Tissot-Croset and
A. Alexakis, Tetrahedron Lett., 2004, 45, 7375.
10 (a) B. L. Feringa, R. Badorrey, D. Pen˜a, S. R. Harutyunyan and
A. J. Minnaard, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5834; (b)
F. Lo´pez, S. R. Harutyunyan, A. J. Minnaard and B. L. Feringa, J. Am.
Chem. Soc., 2004, 126, 12784; (c) F. Lo´pez, S. R. Harutyunyan,
A. Meetsma, A. J. Minnaard and B. L. Feringa, Angew. Chem., Int. Ed.,
2005, 44, 2752; (d) R. Des Mazery, M. Pullez, F. Lo´pez,
S. R. Harutyunyan, A. J. Minnaard and B. L. Feringa, J. Am. Chem.
Soc., 2005, 127, 9966; (e) For a recent highlight, see: S. Woodward,
Angew. Chem., Int. Ed., 2005, 44, 5560.
11 The introduction of a methyl group is the most valuable from a
synthetic point of view. However, very few successful examples have
been reported with either Me2Zn or MeMgX reagents. See ref. 9b and
references cited therein.
12 H.-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer and
A. Togni, Top. Catal., 2002, 19, 3–16 and references therein.
i
13 Other solvents (Et2O, Pr2O, THF) or leaving groups (LG = OAc,
OCO2Me) tested under these conditions provided lower conversions
and/or selectivities.
14 T. Ireland, G. Grossheimann, C. Wieser-Jeunesse and P. Knochel,
Angew. Chem., Int. Ed., 1999, 38, 3212.
15 The use of other Cu(I) sources (CuTC, Cu(MeCN)4PF6, CuCl),
solvents, or EtMgCl instead of EtMgBr provided the same selectivities.
See ESI for more details.
16 To the best of our knowledge, these are the highest selectivities reported
so far for the substitution with a methyl group in this kind of allylic
bromides.
17 The application of this methodology for the synthesis of relevant natural
products is currently underway.
18 J. Cossy, S. BouzBouz and A. H. Hoveyda, J. Organomet. Chem., 2001,
634, 216 and references therein.
Notes and references
1 S. A. Godleski, in Nucleophiles with Alkyl-Metal Complexes, ed. B. M.
Trost and I. Fleming, Pergamon Press, New York, 1991, Vol. 4,
pp. 585–661.
2 A. Pfaltz and M. Lautens, in Allylic Substitution Reactions, ed. E. N.
Jacobsen, A. Pflatz and H. Yamamoto, Comprehensive Asymmetric
Catalysis I-III; Springer-Verlag, Berlin, Germany, 1999, Vol. II,
pp. 833–884.
3 Mo: (a) O. Belda and C. Moberg, Acc. Chem. Res., 2004, 37, 159; (b)
B. M. Trost, S. Hildbrand and K. Dogra, J. Am. Chem. Soc., 1999, 121,
10416; W: (c) G. C. Lloyd-Jones and A. Pfaltz, Angew. Chem., Int. Ed.
Engl., 1995, 34, 462; Ru: (d) Y. Matsushima, K. Onitsuka, T. Kondo,
T. Mitsudo and S. Takahashi, J. Am. Chem. Soc., 2001, 123, 10405; Rh:
(e) T. Hayashi, A. Okada, T. Suzuka and M. Kawatsura, Org. Lett.,
2003, 5, 1713 and references therein; Ir: (f) G. Lipowsky, N. Miller and
G. Helmchen, Angew. Chem., Int. Ed., 2004, 43, 4595 and references
therein; (g) C. A. Kiener, C. Shu, C. Incarvito and J. F. Hartwig, J. Am.
Chem. Soc., 2003, 125, 14272.
4 (a) For a recent review on Cu-catalysed allylic substitutions, see:
H. Yorimitsu and K. Oshima, Angew. Chem., Int. Ed., 2005, 44, 4435;
(b) For a Ni-catalysed example, see: N. Nomura and T. V. RajanBabu,
Tetrahedron Lett., 1997, 38, 1713; (c) For a Pd-catalysed example, see:
F. Fotiadu, P. Cros, B. Faure and G. Buono, Tetrahedron Lett., 1990,
31, 77.
5 (a) M. van Klaveren, E. S. M. Persson, A. del Villar, D. M. Grove,
J.-E. Ba¨ckvall and G. van Koten, Tetrahedron Lett., 1995, 36, 3059. See
also: (b) G. J. Meuzelaar, A. S. E. Karlsto¨m, M. van Klaveren, E. S.
M. Persson, A. del Villar, G. van Koten and J.-E. Ba¨ckvall,
Tetrahedron, 2000, 56, 2895; (c) A. S. E. Karlsto¨m, F. F. Huerta,
G. J. Meuzelaar and J.-E. Ba¨ckvall, Synlett, 2001, 923.
19 The conjugate addition of EtMgBr to (S)-6 using racemic-1b led to an
84 : 16 mixture of 7 and 8, indicating a strong preference for the
formation of the 1,2-anti product.
6 F. Du¨bner and P. Knochel, Angew. Chem., Int. Ed., 1999, 38, 379.
7 (a) H. Malda, A. W. van Zijl, L. A. Arnold and B. L. Feringa, Org.
Lett., 2001, 3, 1169; (b) C. A. Luchaco-Cullis, H. Mizutani,
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Chem. Commun., 2006, 409–411 | 411