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Organocopper for the Craftsman Cunning at His Trade.

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DOI: 10.1002/anie.200501204
Organometallic Chemistry
Organocopper for the Craftsman Cunning at His Trade**
Simon Woodward*
aluminum · copper · Grignard reactions ·
nucleophilic substitution · zinc
chemistry emerged from the use of CuCl
as a catalyst to promote 1,4-additions of
Grignard reagents to enones by Kharasch and Tawney in 1941,[1] such reactivity has until recently remained the
poorer cousin of stoichiometric cuprate
reactivity, as exemplified by the use of
Gilman"s cuprate, LiCuMe2, which recently celebrated its 50th birthday.[2]
However, in the last twelve months an
influx of papers that describe coppercatalyzed asymmetric reactions of organozinc, aluminum, and especially
Grignard reagents has provided new,
highly enabling methodologies. The exceptional utility of these reactions promises to displace stoichiometric cuprates
from their preferred position as the
reagents of choice for conjugate addition and SN2’ displacement reactions of
allylic electrophiles.
The synthetic potential of general
asymmetric 1,4-additions of RMgX species to enones has been recognized since
the earliest days of organometallic
chemistry. However, a near-enantiospecific catalyst for such reactions was
considered viable “only in dreams”,
even as recently as 1997.[3e] Despite the
screening of a wide range of ligands,
including thiolates, phosphanes, and
imines, the R/S selectivity in even the
simple test reaction of 2-cyclohexenone
[*] Dr. S. Woodward
School of Chemistry
The University of Nottingham
Nottingham NG7 2RD (UK)
Fax: (+ 44) 115-951-3564
[**] Title taken from the opening line of the
poem “Cold Iron” by Rudyard Kipling
(1865–1936): “Gold is for the mistress—
silver for the maid—copper for the craftsman
cunning at his trade”.
and nBuMgX remained moderate for
over a decade (Figure 1), and ee values
remained persistently in the range 60–
80 %.[3] The benchmark result of
Figure 1. Selected maximum ee values for catalytic additions of BuMgX to 2-cyclohexenone,
except (d), which involves addition of MeMgI
to benzylideneacetone (< 10 mol % CuI ;
< 12 mol % chiral ligand, L*). Data points a–i
correspond to References [3a–i], respectively.
Cy = cyclohexyl.
van Koten and co-workers in this area
on benzylideneacetone (76 % ee) in
1994[3d] has also been included in Figure 1 for comparison. However, a huge
improvement in R/S selectivity has very
recently (2004–2005) been reported in a
series of three publications by the group
of Feringa.[4–6] Use of the key ferrocenyl
ligands TaniaPhos (L1) and JosiPhos
(L2) allows a wide range of Grignard
1,4-additions to cyclic and acyclic
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
enones as well as a,b-unsaturated esters,
with R/S selectivities that are 5–10 times
higher than those seen with all previous
catalysts. These ligands typically afford
85–95 % ee for a wide range of substrates. The very high rate efficiency of
the catalyst minimizes, or eliminates, the
direct 1,2-addition of the Grignard reagent to the carbonyl group. Of additional note is the forgiving nature of
these reactions with respect to their
tolerance of traces of water and oxygen
and that they can operate at very low
catalyst loadings (down to 0.2 mol % in
one case). Further synthetic simplicity in
the form of an air-stable precatalyst
prepared from L2 and CuBr·SMe2 lead
to near-optimal reaction conditions. The
currently tolerated combinations of preferred ligands per substrate type are
summarized in Table 1.
The current limitations of this system are few but are worth summarizing
for those who are interested in using the
reaction in target synthesis. 1) The presence of a branching in the Grignard
component often leads to a catastrophic
loss in enantioselectivity; 2) highly hindered enones, such as RCH=CHC(O)tBu (R = alkyl), lead to a poor selectivity ( 40 % ee); 3) for the less-reactive
a,b-unsaturated esters, the rate of addition of MeMgBr is slow (high ee values
were still observed, but at low chemical
yields); and 4) the presence of a double
bond in the Grignard reagent leads to
approximately 10 % lower enantioselectivity than that observed for the parent
hydrocarbon. These minor limitations
represent goals for the future design of
catalysts. However, the new methodology of Feringa and co-workers offers
one last important advantage: as a result
of the inherently high reactivity of the
magnesium enolate formed in these
reactions, great opportunities exist for
Angew. Chem. Int. Ed. 2005, 44, 5560 – 5562
Table 1: Typical ee values (%) for Grignard reagents and substrates in 1,4-additions promoted by
ligands L1 and L2.
90 L1
94–96 L1
54–92 L1
95 L1
40 L2
97–98 L2
90–95 L2
48–86 L2
92 L2
76 L2
93 L2 (slow)
84–99 L2
[a] Not reported.
only in special cases. However, the use
of a combination of a Grignard reagent
and a key chiral ligand has again led to a
general strategy for this reaction. For a
range of allylic chlorides and Grignard
reagents, the a-chiral alkenes 1 are
isolated in good yield and with outstanding enantioselectivity. The presence of the methoxy group in L3 is
crucial, but whether this unit can act as a
bridging ligand to magnesium can only
be speculated on at present. Direct
exposure of the reaction mixture to
ethyl acrylate and 5 mol % of the
Grubbs II catalyst allows direct formation of the unsaturated esters 2 in
moderate to good yield. Esters 2 would
be excellent substrates for Josiphos
(L2)-promoted addition of a further
Grignard reagent using Feringa"s system. The potential for creating one-pot
multiple cascades that lead to
two or three contiguous stereocenters is indeed very high.
Unfortunately, the zinc analogues of Grignard reagents,
RZnX, often lack sufficient
reactivity to be useful in catalytic asymmetric 1,4- or
SN2’ additions. Recently, we
demonstrated a method to
overcome this difficulty: By
promoting the reverse Schlenk
equilibrium, RZnCl can be
transformed back into R2Zn
and ZnCl2.[9] As the resultant
diorganozinc reagent is of
higher reactivity it could be
utilized in copper-catalyzed
SN2’ reactions of (Z)-ArCH=
C(CH2Cl)CO2Me to afford
Scheme 1. Preparation of chiral esters. R = Ph, 4-Me=
C6H4, Cy; R2 = Et, 3-butenyl, 4-pentenyl; CuTC = copper(i) ArCHRC( CH2)CO2Me with
good enantioselectivity (80–
thiophene-2-carboxylate; Mes = 2,4,6-trimethylphenyl.
90 % ee) in the presence of
one-pot consecutive trapping reactions
and these will undoubtedly be realized
in the near future.
The use of Grignard nucleophiles
has also allowed remarkable recent
progress in SN2’ displacement reactions
of allylic halides, as demonstrated by the
group of Alexakis (Scheme 1).[7] Such
reactions are mechanistically akin to
1,4-enone additions except that, in this
case, the two-electron shift is accommodated by loss of “X ” rather than its
storage at the carbonyl oxygen atom.[8]
The asymmetric transition state for
ligand-promoted additions of organometallic
CHCH2X species is presently not well
understood and appears rather fragile.
Despite intensive efforts in the last five
years, catalytic systems have been able
to afford stereoselectivities of over 90 %
Angew. Chem. Int. Ed. 2005, 44, 5560 – 5562
simple chiral amines. (Normally Z-allylic halides give far lower ee values in
SN2’ chemistry, and to improve this remains a significant challenge in this
area). The key trick in this chemistry
of RZnCl is to add methylaluminoxane
[MeAlO]n to the reaction mixture to
scavenge ZnCl2 and give ZnR2 rather
than the usual, highly thermodynamically favored RZnCl species. The formation of strong Al Cl bonds probably
accounts for the thermodynamic driving
force. Thus, although this reaction does
not use zinc Grignard reagents as such,
the success of the approach is clearly
As a last example from this influx of
Alexakis and co-workers have also exploited the strong Lewis acidity and
oxophilicity of organoaluminum reagents to conquer another demanding
class of substrates in classical organocuparate chemistry: b-disubstituted
enones (Scheme 2).[10] Traditionally, the
Scheme 2. Preparation of stereogenic quaternary centers with high enantiopurity by conjugate addition of AlMe3. R = Et, iBu,
(CH2)nCH=CH2 (n = 2,3), (CH2)2CH(OR)2 ;
Np = naphthyl.
additional steric hindrance afforded by
enones of type 3 leads to very poor
reactivity. However, by using AlMe3 and
as little as 4 mol % of chiral ligands
L4 a–b, highly efficient catalytic syntheses of species 4 (91–95 % ee), which
contains a quaternary center, were reported. Interestingly, in this chemistry
the presence of acetal groups is tolerated and allows rapid access to bicyclic
structures such as 5.
All of the strategies described above
have been attained with loadings of
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
copper(i) salts of 5 mol % or less. It is
clear that the nature of asymmetric
copper-promoted reactivity is changing
rapidly from a situation in which chiral
stoichiometric reagents of low general
utility (often targeting just a single
substrate) were the norm to more-powerful, general catalytic asymmetric procedures. While some problematic combinations of organometallic reagents
and substrates still exist in both conjugate addition and SN2’ chemistry, we can
be confident that in the near future
ligand structures will be identified to
overcome these difficulties and an essentially complete set of synthetic methodologies in this area will be available.
Published online: July 29, 2005
[1] M. S. Kharasch, P. O. Tawney, J. Am.
Chem. Soc. 1941, 63, 2308 – 2315.
[2] a) J. J. Eisch, Organometallics 2002, 21,
5439 – 5463; b) Modern Organocopper
Chemistry (Ed.: N. Krause), WileyVCH, Weinheim, 2002.
[3] a) K.-H. Ahn, R. B. Klassen, S. J. Lippard, Organometallics 1990, 9, 3178 –
3181 (74 % ee, 3–5 mol % L*); b) M.
Specha, G. Rihs, Helv. Chim. Acta 1993,
76, 1219 – 1230 (60 % ee, 4–mol % L*);
c) Q. Zhou, A. Pfaltz, Tetrahedron 1994,
50, 4467 – 4478 (60 % ee, 5–10 mol %
L*); d) M. van Klaveren, F. Lambert,
D. J. F. M. Eijelkamp, D. M. Grove, G.
van Koten, Tetrahedron Lett. 1994, 35,
6135 – 6138 (76 % ee, 9 mol % L*); e) D.
Seebach, G. Jaeschke, A. Pichota, L.
Audergon, Helv. Chim. Acta 1997, 80,
2515 – 2519 (78 % ee, 5 mol % L*);
f) E. L. Strangeland, T. Sammakia, Tetrahedron 1997, 53, 16 503 – 16 510 (83 %
ee, 12 mol % L*); g) M. Kanai, Y. Nakagawa, K. Tomioka, Tetrahedron 1999,
55, 3831 – 3842 (81 % ee, 10 mol % L*;
improved to 92 % ee but at 32 mol %
L*); h) A. L. Braga, S. J. N. Silva, D. S.
LPdtke, R. L. Drekener, C. C. Silveira,
J. B. T. Rocha, L. A. Wessjohann, Tetrahedron Lett. 2002, 43, 7329 – 7331 (62 %
ee, 10 mol % L*); i) S. A. Modin, P.
Pinho, P. G. Andersson, Adv. Synth.
Catal. 2004, 346, 549 – 553 (71 % ee,
5 mol % L*).
[4] B. L. Feringa, R. Badorrey, D. PeQa,
S. R. Harutyunyan, A. J. Minnaard,
Proc. Natl. Acad. Sci. USA 2004, 101,
5834 – 5838: Prior to this report, only
hints existed that JosiPhos-type ligands
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
may be powerful additives in asymmetric 1,4-addition chemistry. For example,
see: H.-U Blaser, W. Brieden, B. Pugin,
F. Spindler, M. Studer, A. Togni, Top.
Catal. 2002, 19, 3 – 16.
F. LRpez, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc.
2004, 126, 12 784 – 12 785.
F. LRpez, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard, B. L. Feringa, Angew. Chem. 2005, 117, 2812 – 2816; Angew. Chem. Int. Ed. 2005, 44, 2752 –
K. Tissot-Croset, D. Polet, A. Alexakis,
Angew. Chem. 2004, 116, 2480 – 2482;
Angew. Chem. Int. Ed. 2004, 43, 2426 –
N. Krause, A. Gerold, Angew. Chem.
1997, 109, 194 – 213; Angew. Chem. Int.
Ed. Engl. 1997, 36, 186 – 204.
P. J. Goldsmith, S. J. Teat, S. Woodward,
Angew. Chem. 2005, 117, 2275 – 2277;
Angew. Chem. Int. Ed. 2005, 44, 2235 –
M. d"Augustin, L. Palais, A. Alexakis,
Angew. Chem. 2005, 117, 1400 – 1402;
Angew. Chem. Int. Ed. 2005, 44, 1376 –
Angew. Chem. Int. Ed. 2005, 44, 5560 – 5562
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