Stereochemical consequences of threefold symmetry in asymmetric catalysis: Distorting C3 chiral 1,1,1-tris(oxazolinyl)ethanes ("trisox") in CuII lewis acid catalysts

Article abstract of DOI:10.1002/chem.200701085

The underlying conceptual differences in exploiting two- and threefold rotational symmetry in the design of chiral ligands for asymmetric catalysis have been addressed in a comparative study of the catalytic performance of bisoxazoline (BOX) and tris(oxaz

Full text of DOI:10.1002/chem.200701085

DOI: 10.1002/chem.200701085
Stereochemical Consequences of Threefold Symmetry in Asymmetric
Catalysis: Distorting C3 Chiral 1,1,1-Tris(oxazolinyl)ethanes (“Trisox”) in
CuII Lewis Acid Catalysts
Carole Foltz,[a] Bjçrn Stecker,[a] Guido Marconi,[a] StØphane Bellemin-Laponnaz,*[b]
Hubert Wadepohl,[a] and Lutz H. Gade*[a]
Dedicated to Professor Christina Moberg on the occasion of her 60th birthday
Abstract: The underlying conceptual
differences in exploiting two- and
threefold rotational symmetry in the
design of chiral ligands for asymmetric
catalysis have been addressed in a com-
parative study of the catalytic perfor-
mance of bisoxazoline (BOX) and tris-
the trisox–copper complex [CuII(iPr3-
trisox)(k2-O,O’-MeCOCHCOOEt)]+
identical selectivity of the Ph3-trisox-
(R,R,R)- and Ph2-BOX(R,R)-derived
catalysts is as expected from the pro-
posed model of the active catalyst
A
ACHTREUNG
A
X-ray diffraction, two of the oxazoline
groups are coordinated to the central
copper atom, whilst the third oxazoline
unit is dangling with the N-donor
pointing away from the metal centre.A
similar arrangement is found for the
stereochemically “mixed” C1-trisox
based on
a partially decoordinated
podand.The behaviour of the “desym-
metrised” trisox–Cu catalysts may be
rationalised in terms of a general
A
copper(II) Lewis acid catalysts.The
differences become apparent in con-
structing new catalysts by systematical-
ly “deforming” the stereodirecting
ligand by inverting chiral centres or re-
placing chiral by achiral oxazolines.
The catalytic a-amination of ethyl 2-
methylacetoacetate with dibenzyl azo-
dicaboxylate, which occurs with high
enantioselectivity for both Ph2-BOX
and Ph3-trisox copper catalysts, has
been employed as the test reaction.In
steady-state kinetic model for the three
possible active bisoxazoline–copper
species, which are expected to be in
rapid exchange with each other in solu-
tion.This applies to both the trisox de-
rivatives with stereochemically inverted
and achiral oxazoline rings.The study
underscores previous observations of
superior performance of the catalysts
bearing C3-chiral stereodirecting li-
gands as compared to systems of lower
symmetry.
complex
O,O’-MeCOCHCOOEt)
[ClO4]ꢀ (2), in which the phenyl sub-
stituents adopt first coordination
sphere meso arrangement.The almost
[CuII{(Ph3-trisox
(R,S,S)}(k2-
ACHTREUNG
AHCTREUNG
AHCTREUNG
a
Keywords: asymmetric catalysis
chirality copper threefold
symmetry · trisoxazolines
·
·
·
Introduction
Bisoxazoline (BOX) ligands have been extensively applied
[a] C.Foltz, Dr.B.Stecker, Dr.G.Marconi, Prof.Dr.H.Wadepohl,
Prof.Dr.L.H.Gade
in asymmetric CuII Lewis acid catalysis for a wide variety of
[1–3]
Anorganisch-Chemisches Institut
Universität Heidelberg
ꢀ
ꢀ
C C and C heteroatom coupling reactions.
The key fea-
tures that render oxazoline units “privileged” structural ele-
ments in ligand design for enantioselective catalysis are
their rigidity and quasi-planarity as well as facile accessibili-
ty by condensation of amino alcohols with carboxylic acid
derivatives.[4] Upon coordination of the oxazoline ring
through the N atom, the stereodirecting substituents are sit-
uated in close proximity to the metal centre and thus direct-
ly control the active space available for the substrate(s).
The reduction of the generally high catalyst loadings with
BOX–Cu and related systems, which are due to the kinetic
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax.: (+49)6221-545609
E-mail: lutz.gade@uni-hd.de
[b] Dr.S.Bellemin-Laponnaz
Institut de Chimie, UMR 7177
Institut Le Bel, UniversitØ Louis Pasteur
4 rue Blaise Pascal, 67000 Strasbourg (France)
Fax : (+33)
E-mail: bellemin@chimie.u-strasbg.fr
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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FULL PAPER
lability of copper(II), has been attempted through the po-
tential facial coordination of the metal centre by a chiral tri-
dentate oxazoline ligand.[5] Using the C3-chiral 1,1,1-tris(ox-
attack of a prochiral face of a substrate molecule) is expect-
ed to be based on the same principles.
However, from the point of view of ligand design there is
a remarkable difference between C2- and C3-chiral podands
that becomes apparent when one chiral element (e.g., a
chiral centre) out of n (n=2, 3 respectively) is inverted,
while leaving all other structural features unchanged.The
rotational symmetry is thus destroyed.Whereas the inver-
sion of a chiral centre in a C2-symmetrical chelate ligand
will generate a meso-structure, that is, an achiral ligand pos-
sessing mirror symmetry (Cs), the same process carried out
for one of the three “ligand arms” of a C3-chiral tripod will
leave the system chiral and C1 symmetrical (Scheme 2).
ACHTREUNG
azolinyl)ethane (“trisox”) ligand system,[6–8] the resting state
of the copper complexes was expected to be stabilised due
to this additional (presumably weak) ligation.This third po-
tential oxazoline coordination reduces the Lewis acidity and
thus deactivates the copper complexes as was shown in a
theoretical study on BOX–Cu catalysts.[9] The transforma-
tion of the stabilised but inactive resting state into the active
(17 electron CuII) species occurs by decoordination of an ox-
azoline unit induced by the strong dynamic Jahn–Teller
effect of the d9 metal centre.As a consequence of the three-
fold rotational symmetry of the system, all of the possible
dicoordinated catalytically active species (A–C; Scheme 1)
Scheme 1.Equilibrium between the three symmetry-equivalent trisox iso-
mers with the dicoordinate stereodirecting ligand.
are equivalent.
In a first test of this concept, we applied [CuII
ACHTREUNG
ACHTREUNG
ACHTREUNG
oxazoline catalysts.[11] Upon stepwise reduction of the cata-
Scheme 2.Transformation of a C2-chiral chelate (left) and a C3-chiral
podand upon inversion of the configuration at a chiral ligand “arm”.
Note the mapping of the C2-symmetric system onto an isomorphic Cs-
symmetric derivative.
lyst loading by a factor of 103, from 10 to 0.01 mol% of cata-
lyst, the enantioselectivity remained unchanged and the se-
lectivity was found to be higher that for the corresponding
BOX derivative.[7]
The comparison of the catalytic performance of BOX and
trisox containing catalysts aside, there are underlying con-
ceptual differences in exploiting two- and threefold rotation-
al symmetry in the design of chiral ligands for asymmetric
catalysis that have not been addressed previously.They
become apparent in constructing new catalysts by systemati-
cally “deforming” the stereodirecting ligand and are de-
lineated in this work.The observed effects are also pertinent
to the design of “side-arm”-functionalised bisoxazolines in
general.[12,13]
Regarding symmetry considerations alone, for the former,
this particular situation is related to the isomorphism be-
tween the point groups C2 and Cs (as well as Ci for non-
podand structures), whilst no such isomorphism exists for
C3.It should be noted that the higher rotational symmetry
in the C3-symmetric system will lead to a greater degree of
structural degeneracy than achieved for twofold symmetry,
whereas deviations from it will necessarily give structures of
greater complexity.
Inverting chiral centres in C2- and C3-symmetric stereo-
ACHTREUNGdirecting tripod ligands: When it comes to the “mecha-
The modular nature of BOX and trisox ligands allows for
a systematic investigation of the implications which the con-
siderations put forward in this section have on a given cata-
lytic reaction.The former may be assembled in two subse-
quent cyclisation steps from a malonic acid derivative, whilst
the latter are synthesised by way of 2+1 coupling of a lithi-
ated bisoxazoline with a 2-bromooxazoline derivative.The
ligands employed in this work are depicted here.
nisms” of stereoselection with reagents or catalysts possess-
ing rotational symmetry there is no specific difference be-
tween C2- and C3-symmetric systems.[14,15] For both systems
the rotational symmetry may reduce the number of diaste-
reomers involved in the sequence of transformation steps,
but the mechanism of chiral induction (e.g., the preferential
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L.H.Gade, S.Bellemin-Laponnaz et al.
Scheme 3.Direct Cu-catalysed a-amination of an a-substituted b-ketoest-
er using dibenzyl-azodicaboxylate.
thought to facilitate the analysis of the stereochemical study,
which is the objective of this work.We chose ethyl 2-methyl-
acetoacetate as the substrate of the Cu-catalysed transfor-
mation.
Results and Discussion
Catalytic a-amination of ethyl 2-methylacetoacetate—the
effect of the inversion of one of the chiral centres in BOX
and trisox ligands: The test reaction introduced above was
carried out using Ph3-trisox
stereodirecting podands as well as the bisoxazolines Ph2-
BOX(R,R) and Ph2-BOX(R,S).The results of the catalytic
ACHRTU(NEG R,R,R) and Ph3-trisoxACHTREU(GN R,S,S) as
A
ACHTREUNG
runs performed with 1 mol% of catalyst are summarised in
Table 1.
Table 1. a-Amination of ethyl 2-methylacetoacetate with dibenzyl azodi-
carboxylate with 1 mol% catalyst.
Ph3-trisox
(R,R,R)
Ph2-BOX
(R,R)
Ph3-trisox
(R,S,S)
Ph2-BOX
(R,S)
G
G
G
ACHTREUNG
ee [%]
yield [%]
99
91
98
93
-41
94
0
88
The selectivity of the transformation catalysed by CuII
complexes of Ph3-trisox(R,R,R) and the chelating Ph2-BOX-
(R,R) is almost identical.This is as expected from the pro-
The effect of the inversion of a chiral centre, schematical-
ly shown in Scheme 2, is investigated by comparison of C3-
ACHTREUNG
ACHTREUNG
chiral Ph3-trisox
the pair of bisoxazoline ligands Ph2-BOX
BOX(R,S).In addition, the combination of chiral and achi-
ral podand “arms” has been investigated in a comparative
study of Ph2-dm-trisox and Ph-dm2-trisox with the bidentate
Ph-dm-BOX, the latter representing a minimal structure in
asymmetric oxazoline–copper(II) catalysis.
N
G
posed model of the active catalyst based on a partially de-
coordinated podand.In this model, the dangling oxazoline
ring adopts a remote orientation (vide infra), and the trisox
system therefore effectively coordinates like the correspond-
ing bisoxazoline.Whereas the use of the meso-BOX ligand
AHCTREUNG
ACHTREUNG
Ph2-BOX
formed with the stereochemically mixed C1-chiral podand
Ph3-trisox
ACHTRE(UNG R,S) leads to a racemic product, the catalyst
(R,S,S) gives the reaction product with ꢀ41% en-
A test reaction in copper(II) Lewis acid catalysis: An enan-
tioselective catalytic a-amination of carbonyl compounds
using azodicaboxylates was first reported by Evans and
Nelson who used a chiral bis(sulphonamide)magnesium
complex as a catalyst.[16] This reaction is of interest for the
synthesis of b-hydroxy-a-amino acids.An efficient copper-
antiomeric excess (ee).In this case the interplay of three iso-
meric forms of dicoordinated trisox has to be considered, all
three being catalytically active.These three diastereomeric
catalysts, which are thought to be involved, are depicted in
Scheme 4.
It is instructive to regard the local environment (i.e., the
arrangement of the coordinated oxazoline rings) at the
metal centre more closely in the discussion of the effect,
which the formal inversion of one of the chiral centres in
ACHTREUNG(II)–bisoxazoline catalysed version, involving the direct a-
amination of a-substituted b-ketoesters (Scheme 3), has
been subsequently reported by Jørgensen and co-workers.[17]
High yields and excellent enantioselectivities have been
Ph-trisoxACHTER(UNG R,S,S) has on the catalyst system.As is readily ap-
observed by using 2,2-bis
(“Ph-BOX”) as ancillary ligand.These characteristics were
A
parent, only one of the three isomers expected to be in equi-
librium with each other contains the metal centre in an es-
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Asymmetric Catalysis
FULL PAPER
1.973(3) and 1.985(3) Š), whilst
the third oxazoline unit is dan-
gling with the N-donor pointing
away from the metal centre.
From the view depicted in
Figure 1 it is clear that the third
oxazoline ring will have little
influence upon the attack of an
electrophile on the acylenolate
(expected to approach from the
left) and that the complex may
therefore be effectively treated
as a (substituted) bisoxazoline–
Cu derivative.The notion will
be of importance in the discus-
sion of the catalytic perfor-
mance of stereochemically dif-
ferent trisox–Cu derivatives in
the subsequent sections of this
work.The complex geometry of
1 is square pyramidal with a flu-
orine atom of the (weakly coor-
Scheme 4.Effect of the inversion of a chiral centre in Ph 3-trisox (top) leading to an equilibrium between three
inequivalent dicoordinate species in solution (bottom).In two of these the arrangement of the oxazoline sub-
stituents at the rings coordinated to the metal centre correspond to a local meso-environment.
sentially C2-chiral BOX-like environment to be found for
the three symmetry-equivalent species of the catalyst de-
rived from the C3-chiral derivative Ph-trisoxACHTER(UNG R,R,R).This
local molecular shape and, specifically, the effective local
symmetry of a coordinated ligand at a metal centre will be
designated as first-coordination-sphere symmetry (fcs-sym-
metry) and will play a key role in the following discus-
sions.[18] The other two isomeric forms have a fcs meso-ar-
rangement of the oxazoline substituents.Given the orienta-
tion and distance of the dangling ligand arm (vide infra), the
catalytic behaviour of the latter two forms should be similar
to that of the complex bearing the achiral ligand Ph-BOX-
ACHTREUNG(R,S).It is evident that this line of argument requires sup-
port by detailed structural data obtained for suitable models
for intermediates of the catalytic cycle with both the C3- and
the C1-chiral tripods.
Figure 1.Molecular structure of the copper complex [Cu II(iPr3-trisox)(k2-
+A[BF4]ꢀ (1).The principal bond lengths and
O,O’-MeCOCHCOOEt)] CHTREUNG
Crystal structure analyses of copper(II) acylenolate com-
plexes bearing C3- and C1-chiral trisox ligands: The Lewis
acid catalytic activity of the CuII centre is thought to play
the key role in the activation of the b-ketoester and the for-
mation of the reactive enolate intermediate.Such metal
bonded acylenolates proved to be directly accessible by re-
action of trisox–Cu complexes with ethyl 2-acetoacetate.
Crystallisation from the reaction mixture using the isopro-
pyl-substituted derivative iPr3-trisox, gave X-ray quality
crystals of [CuII(iPr3-trisox)(k2-O,O’-MeCOCHCOOEt)]+
angles are given in Table 2.Hydrogen atoms omitted for clarity.
Table 2.Comparison of selected bond lengths [Š] and angles [ 8] in com-
plexes 1 and 2.
Complex 1
Complex 2
ꢀ
Cu(1) N(1)
1.973(3)
1.985(3)
1.939(3)
1.891(3)
2.376(2)
1.973(4)
1.990(4)
1.921(4)
1.886(3)
2.293(4)
ꢀ
Cu(1) N(2)
ꢀ
Cu(1) O(1)
ꢀ
Cu(1) O(2)
[a]
ꢀ
Cu(1) X
[BF4]ꢀ (1).[7]
A side-on view of the molecular structure of complex 1 is
N(1)-Cu(1)-N(2)
N(1)-Cu(1)-O(1)
N(1)-Cu(1)-O(2)
N(2)-Cu(1)-O(1)
N(2)-Cu(1)-O(2)
O(1)-Cu(1)-O(2)
89.40(12)
91.05(12)
177.36(13)
171.12(12)
88.51(12)
90.77(12)
87.42(16)
90.92(16)
177.36(16)
169.48(17)
90.12(16)
91.33(16)
depicted in Figure 1, and selected bond lengths and angles
are listed in Table 2.In the trisox–copper complex, contain-
ing the C3-chiral ligand, two of the oxazoline groups are co-
ꢀ
ordinated to the central copper atom (Cu N bonds lengths:
[a] Atom in apical position.
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L.H.Gade, S.Bellemin-Laponnaz et al.
ꢀ
ꢀ
dinating) BF4 counterion occupying the apical position
molecule occupying the apical position (Cu(1) O(7)
2.293(4) Š).
ꢀ
(Cu(1) F(1) 2.376(2) Š).
It has also been possible to crystallise the stereochemical-
ly “mixed” C1-trisox complex [CuII{(Ph3-trisox
A
Catalytic a-amination of ethyl 2-methylacetoacetate. A
steady-state kinetic model for the behaviour of the stereo-
O,O’-MeCOCHCOOEt)
action of [Ph3-trisox(R,S,S)–Cu] with the deprotonated b-
ketoester.In complex 2, as in complex 1, the trisox ligand
A
G
G
chemicallymixed Ph -trisoxACHTREUNG
3
ACHTREUNG
ꢀ
adopts bidentate coordination (Cu N bonds lengths:
1.976(3) and 1.989(3) Š), the third oxazoline unit pointing
away from the coordinated oxazoline rings and thus also
generating an effective bisoxazoline copper system
(Figure 2).
ACHTREUNG
with each other, contains the metal centre in the fcs C2-
chiral BOX-like environment, whilst the other two isomeric
forms have an fcs meso-arrangement of the oxazoline sub-
stituents.To understand the observed enantiomeric excess
for the catalytic a-amination of ethyl 2-methylacetoacetate
of 41%, the ratio of these isomeric species as well as their
relative catalytic activity needs to be established.The con-
ꢀ
version curves of the Cu-catalysed C N coupling reaction
(under the standard catalytic conditions of 1.0 mol% cata-
lyst loading) for the four catalysts bearing Ph3-trisox
Ph3-trisox(R,S,S) as well as Ph2-BOX(R,R) and Ph2-BOX-
(R,S) as stereodirecting ligands, are depicted in Figure 3.
Whereas the Ph2-BOX(R,R) derivative displays the high-
est activity (first-order rate constant derived from an expo-
nential fitting analysis of the conversion curve: kRR
2.484 hꢀ1), the corresponding meso-system (Ph2-BOX
(R,S))
ACHTREUNG(R,R,R),
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
=
ACHTREUNG
proved to be the least active catalyst (kRS =0.756 hꢀ1).Since
it is thought that the stereodirecting ligand in the active
trisox–copper catalyst is actually dicoordinate and thus ef-
fectively corresponds to the BOX analogues, the behaviour
of both the homo and heterochiral systems should be expli-
cable in reasonable approximation in terms of these data.
The copper(II) catalyst bearing the C3-chiral trisox ligand
Figure 2.Molecular structure of the copper complex [Cu II(Ph3-trisox-
(R,R,R) possesses an activity (kRRR =1.638 hꢀ1)
Ph3-trisoxACHTREUNG
ACHTREUNG ACHRET(UNG H2O)] CHTREUNG
(R,S,S))(k2-O,O’-MeCOCHCOOEt) +A[ClO4]ꢀ (2).The counterion
is omitted for clarity.The principal bond lengths and angles are given in
Table 2.Hydrogen atoms omitted for clarity.
that is close to that of the C2-chiral bisoxazoline, whilst the
As delineated above, three
stereochemically distinct ways
of coordination of the trisox
ligand are to be expected: one
leading to an fcs C2-symmetric
species and two representing fcs
achiral
meso
species
(Scheme 4).One of the two dia-
stereomeric species with an fcs
meso arrangement of the coor-
dinated bisoxazoline unit crys-
tallised with the phenyl sub-
stituents of the coordinated ox-
azoline units located on the
same side (with respect to the
CuN2O2 plane) as the dangling
free oxazoline ring.Similar to
complex 1, the coordination
Figure 3.Conversion curves of the Cu-catalysed C-N coupling reaction (10. mol% catalyst loading) for the
four catalysts bearing Ph3-trisoxACHTRE(UNG R,R,R), Ph3-trisoxACTHREU(NG R,S,S) as well as Ph2-BOXACHTEURG(N R,R) and Ph2-BOXAHCTRE(UGN R,S) as ste-
geoACHTREUNGmetry is square pyramidal
with an oxygen atom of a water reodirecting ligands.
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Asymmetric Catalysis
FULL PAPER
d½PRŠ xRkAA½ðA,Aފ þ 2 xR0kAB½ðA,Bފ
activity of the catalytic system based on the heterochiral
tripod lies between this value and the conversion rate of the
meso-BOX catalyst (kRSS =1.074 hꢀ1).This last observation
may indeed be an indication that both the fcs C2-symmetric
chiral isomer as well as the two meso forms may play a role
ð3Þ
¼
d½PSŠ xSkAA½ðA,Aފ þ 2 xS0 kAB½ðA,Bފ
Assuming steady state conditions gives the following ex-
pression [Eq.(4)] for the observed ee values in which Ccat
=
[(A,A)]+2ACHTER[UNG (A,B)] represents the total amount of catalyst
in the transformation catalysed by Ph3-trisoxACHTREU(NG R,S,S)–Cu.
present.
The behaviour of the “desymmetrised” trisox–Cu catalysts
may be rationalised in terms of a general steady-state kinet-
ic model for the three possible active bisoxazoline–copper
species that are expected to be in rapid exchange with each
other in solution.This assumption is based on the well-es-
tablished substitutional lability of divalent copper com-
plexes.
ðkAAfCcatꢀ2½ðA,BފgeeAA þ 2 kABeeAB½ðA,BފÞ
ðkAAfCcatꢀ2½ðA,Bފg þ 2 kAB½ðA,BފÞ
ð4Þ
ee ¼
This general equation, [Eq.(4)], may be directly applied
to the case of the Ph3-trisox(R,S,S)–Cu system presented
AHCTREUNG
above.In this case the “hetero-substituent” B is a stereo-
chemically inverted A, that is, B=ꢀA and the two species
(A,B) and (B,A) possess the two meso-configurations.Con-
sequently eeA,ꢀA ꢁeeꢀA,A ꢁ0, which gives the simplified ex-
pression in Equation (5).
Given is a trisoxazoline (trisox-derivative) in which two of
the heterocycles bear a substituent A, whilst the third sub-
stituent B is assumed to be different.This leads to three di-
coordinate species in solution, in which the Cu atom is
either coordinated by two equally substituted oxazoline
rings (A,A) or by a non-equal combination, (A,B) or (B,A).
The two last possibilities are diastereomers; however, since
they differ only in terms of the orientation of the third, dan-
gling oxazoline ring which, moreover, is pointing away from
the active centre, they may be assumed in reasonable ap-
proximation to be equivalent (both in terms of activity and
stability).All three catalyst isomers will transform the sub-
ðkAAfCcatꢀ2½ðA,ꢀAފgeeAA
Þ
ð5Þ
ee ¼
ðkAAfCcatꢀ2½ðA,ꢀAފg þ 2 kAꢀA½ðA,ꢀAފÞ
To apply this equation, the pseudo-first-order rate con-
stants derived from the conversion curves discussed above
for the different BOX and trisox copper systems may be
employed.It is assumed that the (A, ꢀA) and (ꢀA,A) active
species from the trisox-based catalyst have approximately
strate to a given product P with enantioselectivities of eeAA
,
eeAB and eeBA (eeAB ꢁ eeBA) as shown in Scheme 5.
the same activity as the meso-
A
that the (A,A) active (trisox-derived) species has the same
activity as the (A,A)-BOX/Cu catalyst.Assuming further-
more, that the meso and C2-symmetric active species give
the same enantioselectivities as their corresponding BOX/
Cu catalysts, as implied by the data reported in the previous
section, the relative concentrations and activities of the com-
ponents of the Ph3-trisoxACHTER(UNG R,S,S)-Cu may be estimated.
In a first step the concentration of the meso-species,
[(A,ꢀA)] is calculated [Eq.(6)] by re-arranging Equa-
tion (5).
Scheme 5.
Designating two enantiomers of the product as PR and PS,
it is possible to express the rate of formation of these two
products as a function of the different rate constants, selec-
tivities and the proportions xR and xS of (A,A) that give PR
or PS, respectively, as well as the proportions xR’ and xS’ of
(A,B) and (B,A) that give PR or PS, respectively, with PR
being assumed to be the major product [Eqs.(1) and (2)]:
fkAAðeeAAꢀeeÞ
½ðA,ꢀAފ ¼ 1=
Ccat
ð6Þ
2
2fee kAꢀA þ kAAðeeAAꢀeeÞg
Using the experimental value of ee=41ꢂ2% and the cat-
alyst concentration Ccat of 1.5 mmol in Equation (6) (as well
as kAꢀA =kRS =0.756, kAA =kRR =2.484 hꢀ1 and eeAA =eeRR
=
0.98 derived from the two BOX-systems) gives a concentra-
tion of 0.615ꢂ0.005 mmol for each meso diastereomer of the
d½PRŠ
ð1Þ
ð2Þ
¼ xRkAA½ðA,Aފ þ 2 xR0 kAB½A,BŠ
¼ xSkAA½ðA,Aފ þ 2 xS0 kAB½A,BŠ
Ph3-trisox
(R,S,S)–Cu catalyst and of 0.270ꢂ0.005 mmol for
dt
the C2-symmetric active species.This shows that the amount
of each meso species is significantly greater than the propor-
tion of the C2-symmetric species and that the former there-
fore possesses slightly greater stability (DG<1 kcalmolꢀ1).
The greater amount of the meso isomers in the equilibrium
of exchanging species could explain the observed preferred
crystallisation of a catalyst–substrate intermediate with the
(R,S,S)-trisox in which the two oxazoline units adopt a heter-
ochiral relationship as demonstrated above.The domination
d½PSŠ
dt
In this simplified form, the properties of (A,B) and (B,A)
are treated as equal (for details, see Supporting Informa-
tion).In that case, the ratio of the two rates of formation is
given by Equation (3).
Chem. Eur. J. 2007, 13, 9912 – 9923
ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
9917

L.H.Gade, S.Bellemin-Laponnaz et al.
of the fcs meso active species also explains the magnitude of
the pseudo-first order rate constant for the stereoselective
a-amination found for the C1-symmetric tripod.This is
Scheme 6 also shows the expected equilibria between the
three diastereomeric dicoordinate Cu complexes that have
different sets of fcs symmetries[18] for the two nonsymmetri-
closer to that observed for the Ph2-BOX
A
cal tripodal ligands.Whilst the Ph -dm-trisox–Cu system is
2
the one of the C2-symmetric bisoxazoline (kRSS =1.074, kRS
0.756 and kRR =2.484 hꢀ1).
=
composed of one isomer with fcs C2 symmetry and two
which are fcs chiral but unsymmetrical, the proposed equi-
librium of the catalytic species derived from Ph-dm2-trisox
comprises one fcs achiral and two unsymmetrical chiral spe-
cies.
Combination of chiral and achiral oxazolines—synthesis and
catalysis with trisox-ligands containing achiral ligating
“arms”: The inversion of one chiral centre in a C3-chiral
tripod is one way of systematically distorting such a three-
fold symmetric species with the consequences for CuII Lewis
acid catalysis discussed above.Another such operation is
the successive replacement of chirally substituted oxazoline
rings in a trisox system by achiral oxazolines.This transfor-
mation of the threefold symmetric chiral ligand Ph3-trisox is
represented in Scheme 6.Exchanging one 4-phenyloxazolin-
2-yl unit for a 4,4’-dimethyloxazolin-2-yl unit gives the non-
symmetrical tripod Ph2-dm-trisox and upon a similar re-
placement of a second oxazolinyl ring one arrives at Ph-
dm2-trisox.
The results of the a-amination of ethyl 2-methylacetoace-
tate with dibenzyl azodicarboxylate with 1 mol% catalyst
using the CuII complexes of Ph2-BOX
ACHTREUNG
AHCTREUNG
Table 3. a-Amination of ethyl 2-methylacetoacetate with dibenzyl azodi-
carboxylate with 1.0 mol% catalyst.
Ph2-BOX Ph2-dm- trisox
(R,R) (S,S)
Ph-dm2- trisox
(R)
Ph-dm-BOX
(R)
N
A
ee [%]
yield [%]
98
93
-97
90
82
73
83
85
It is notable that the replace-
ment of one 4-phenyloxazolin-
2-yl by a 4,4’-dimethyloxazolin-
2-yl unit barely affects the cata-
lyst performance (97% ee, 90%
yield) and even the introduc-
tion of the second 4,4’-dimethy-
loxazolin-2-yl ring within the
trisox system only leads to a re-
duction of the selectivity of this
particular transformation to
82% ee (1 mol% of catalyst)
and a reduced yield due to a
decreased catalyst activity.Re-
markably, the bisoxazoline–
copper catalyst that bears Ph-
dm-BOX as the stereodirecting
ꢀ
ligand generates the C N coup-
ling product with an enantio-
meric excess of 83% (88% ee
for 10 mol% of catalyst!).This
catalyst with the bidentate
ligand, which only contains one
chiral centre, may therefore be
viewed as possessing the mini-
mal catalyst structure for effi-
cient stereoselective catalysis of
this transformation.
The relative activities of the
CuII Lewis acid catalysts bear-
ing the bisoxazolines Ph2-BOX,
Ph-dm-BOX and dm2-BOX as
well as the trisoxazolines Ph2-
Scheme 6.Successive replacement of chirally substituted oxazoline rings in a trisox system by achiral oxazo-
lines: Exchanging one 4-phenyloxazolin-2-yl unit by a 4,4’-dimethyloxazolin-2-yl unit gives the non-symmetri-
cal tripod Ph2-dm-trisox and upon a similar replacement of a second oxazolinyl ring one arrives at Ph-dm2-
trisox.Both non-symmetrical trisox–Cu systems give rise to three isomeric dicoordinate isomers (not account-
ing for different orientations of ligands in the “active” coordination sites).
9918
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Chem. Eur. J. 2007, 13, 9912 – 9923

Asymmetric Catalysis
FULL PAPER
Figure 4.The conversion curves of the asymmetric C-N coupling under pseudo-first order conditions for the stereochemically “mixed” catalysts invo lving
the bisoxazolines Ph2-BOX, Ph-dm-BOX and dm2-BOX as well as the trisoxazolines Ph2-dm-trisox, Ph-dm2-trisox and dm3-trisox.
dm-trisox, Ph-dm2-trisox and dm3-trisox were established in
for eeAA and eeAB for both systems are derived from the
data listed in Table 3.
ꢀ
a kinetic study of the asymmetric C N coupling under
pseudo-first-order conditions for the respective catalyst.The
conversion curves are depicted in Figure 4 and display the
general trend that the replacement of a 4-phenyloxazolin-2-
yl by a 4,4’-dimethyloxazolin-2-yl unit leads to reduced ac-
tivity.
Calculation of the quantity of respective non-symmetrical
(A,B) isomer from Equation (4) in the following rearranged
form [Eqs.(7) and (8)] shows that all three isomers relevant
in the exchange equilibrium are present in about equal
amount (Table 5):
In general, the ligands with two 4-phenyloxazolin-2-yl
rings are more active than the ones with one 4-phenyloxazo-
CcatkAAðeeAAꢀeeÞ
lin-2-yl unit.The catalysts with the achiral ligands dm -BOX
2
ð7Þ
½ðA,Bފ ¼
ð2 kABðeeꢀeeABÞ þ 2 kAAðeeAAꢀeeÞ
and dm3-trisox possess very low activity and only incomplete
conversion of the substrates is observed even after more
than 40 h reaction time.An exponential analysis of the con-
version curves gives the pseudo-first-order rate constants
kAA and kAB in Equation (4) (Table 4) and the relevant data
For Ph-dm2-trisox–Cu, in which A is achiral and thus
eeAA ꢁ0:
Table 5.Estimated composition of the non-symmetrical A 2B-trisox-cop-
per(II) catalysts based on the steady state model of exchange between
the diastereomers.The relative amounts of fcs C2-symmetric species are
given in bold and those for fcs achiral (including meso) species in italics.
Table 4.Enantiomeric excesses and pseudo-first-order rate constants of
the asymmetric amination of ethyl 2-methylacetoacetate with dibenzyl
azodicarboxylate with the CuII Lewis acid catalysts.[a]
Ph2-BOX
(R,R)
Ph2-dm-
trisox
Ph-dm-
BOX
Ph-dm2-
trisox
dm2-
BOX
dm3-
trisox
[(AA)]
[%]
[(AB)]+[(BA)]
[%]
G
ee [%]
k [hꢀ1
98
2.484
-97
0.594
83
0.222
82
0.096
0
0
Ph3-trisox
Ph2-dm-trisox
Ph-dm2-trisox
A
A=Ph(S) B=Ph(R)
A=Ph B=dm
A=dm B=Ph
18ꢂ0.5
56ꢂ10
18.4ꢂ8
2”41ꢂ0.5
2”22ꢂ10
2”40.8ꢂ8
]
0.012
0.060
[a] Experimental conditions: The catalytic runs were carried out at 08C
using 1 mol% catalyst (Ccat =1.5 mmol) and a ratio of ligand/Cu=1.2.
Chem. Eur. J. 2007, 13, 9912 – 9923
ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
9919

L.H.Gade, S.Bellemin-Laponnaz et al.
CcatkAAee
2 kABeeAB þ 2 eeðkAAꢀkAB
obtained on a Perkin–Elmer 1600 FT-IR spectrometer.Mass spectra and
elemental analysis were recorded by the analytical services of Heidelberg
University.
½ðA,Bފ ¼
ð8Þ
Þ
Preparation of the trisox ligands and their precursors
2,2-Dimethyl malonic acid ethyl monoester N-(2-hydroxy-1,1-dimethyl-
AHCTREUNG
Therefore, the relatively high enantioselectivity of the cat-
alysts bearing the Ph2-dm-trisox and Ph-dm2-trisox ligands is
a consequence of the significantly greater activity of the spe-
cies in which 4-phenyloxazolin-2-yl rings are coordinated to
the metal centre as compared to for example, the fcs achiral
catalytic species in which the Cu atom is coordinated
through both dm-oxazolines in Ph-dm2-trisox.
a
36.5 mmol) in CH2Cl2 (250 mL).After 2 h of stirring, 2-amino-2-methyl-
propan-1-ol (3.6 g, 40.1 mmol) was added and the solution was stirred at
room temperature (RT) for 3 days.The reaction mixture was filtered
through Celite to remove the dicyclohexylurea (DCU) formed and
washed with CH2Cl2 (4”80 mL).The organic solution was washed with
an aqueous solution of KHCO3 10% (100 mL), with H2O (100 mL) and
with brine (100 mL) and was then dried over Na2SO4.After evaporation
of the solvent the crude product was purified by flash chromatography
(hexane/EtOAc, 50:50) to give the product as a colourless oil (3.8 g, 45%
Conclusion and Outlook
yield). 1H NMR (CDCl3, 400 MHz): d=1.26 (m, 9H; CH3(ethyl)
,
The aim of this study was to shed some light onto the impli-
cations which the use of chiral tridentate podands may have
in stereoselective catalysis as compared to the more estab-
lished bidentate chelates.The different order of the rota-
tional axis in symmetrical systems, whilst not affecting the
principles of stereoselection by intermolecular interaction
between substrate and catalyst, becomes apparent when the
symmetry of the stereodirecting ligand is systematically re-
duced or modified.Here, the twofold rotational symmetry
may in principle be mapped onto mirror-/centrosymmetry
(as may play a role when chiral molecules adopt a confor-
mation which renders their shape close to achiral), whilst
such a scenario is not possible for chiral threefold symmetric
systems.
Regarding only the systems bearing ligated tripods, it
should be noted, that this study underscores previous obser-
vations of superior performance of the catalysts bearing C3-
chiral stereodirecting ligands as compared to systems of
lower symmetry.[8] The simplified behaviour with regard to
potential catalyst equilibria in solution along with the ste-
reochemical non-ambiguity of the active catalytic species
appear to play the principal underlying role in this trend.
This may be considered in targeted catalyst screening pro-
cesses.
CH3(future oxa)), 1.41 (s, 6H; CH3(bridge)), 3.56 (s, 2H; CH2(future oxa)), 4.18 (q,
J=7.1 Hz, 2H; CH2(ethyl)), 4.33 (brs, 1H; OH), 6.48 ppm (brs, 1H; NH);
13C {1H} NMR (CDCl3, 100 MHz): d=14.0 (CH3(ethyl)), 23.7 (CH3(bridge)),
24.5 (CH3), 50.0 (Cquat(bridge)), 56.0 (Cquat), 61.7 (CH2(ethyl)), 70.3 (CH2),
172.7 (NCO), 175.1 ppm (OCO); MS (FAB): m/z (%): 200.1 (12) [M+
ꢀCH2OH], 214.1 (6) [M+ꢀOH], 232.1 (100) [M++H]; HRMS (FAB):
m/z: calcd for C11H22NO4 ([M++H]): 232.1549; found: 232.1559.
N-((R)-2-Hydroxy-1-phenylethyl)-N’-(2-hydroxy-1,1-dimethylethyl)di-
AHCTREUNG
AHCTREUNG
ence of catalytic amount of NaH.After evaporation of the ethanol
formed the crude product was purified by flash chromatography (CH2Cl2/
MeOH, 95/5) to give the product as a colourless oil (943 mg, 55% yield).
1H NMR (CDCl3, 400 MHz): d=1.22 (s, 3H; CH3(future oxa)), 1.23 (s, 3H;
CH3), 1.44 (s, 3H; CH3(bridge)), 1.46 (s, 3H; CH3(bridge)), 3.48 (d, J=11.5 Hz,
1H; CH2(methylside)), 3.63 (d, J=11.5 Hz, 1H; CH2(methylside)), 3.79 (ddd, J=
1.0 Hz, J=4.0 Hz, J=11.5 Hz, 1H; CH2(phenylside)), 3.88 (dd, J=6.1 Hz, J=
11.5 Hz, 1H; CH2(phenylside)), 5.03 (ddd, J=4.1 Hz, J=6.5 Hz, J=7.0 Hz,
1H; CH(phenylside)), 6.51 (brs, 1H; NH(methylside)), 7.11 (s, J=7.3 Hz, 1H;
NH(phenylside)) 7.23–7.35 ppm (m, 5H; CH(arom)); 13C {1H} NMR (CDCl3,
100 MHz): d=23.7, 23.8 (CH3(bridge)) 24.0, 24.5 (CH3), 50.0 (Cquat(bridge)),
55.7 (Cquat(methylside)), 55.9 (CH), 66.2 (CH2(phenylside)), 69.6 (CH2(methylside)),
126.4, 128.0, 128.9 (CH(arom)), 138.7 (Cquat(arom)), 173.9, 174.0 ppm (CO);
MS (FAB): m/z (%): 305.1 (36) [M+ꢀOH], 323.2 (100) [M++H]; HRMS
(FAB): m/z: calcd for C17H27N2O4 ([M++H]) 323.1971; found: 323.2009
1-{(4R)-4-Phenyloxazolin-2-yl}-1-(4,4-dimethyloxazolin-2-yl)-1-methyl-
ethane[22] (Ph-dm-BOX): SOCl2 (0.80 mL, 10.9 mmol) was added drop-
wise to a cooled solution (08C) of N-{(R)-2-hydroxy-1-phenylethyl}-N’-
(2-hydroxy-1,1-dimethylethyl)-dimethylmalonamide (737 mg, 2.29 mmol)
in CH2Cl2 (150 mL).The reaction mixture was stirred overnight at ambi-
ent temperature, cooled to 08C and quenched by addition of aqueous
NaHCO3 (65 mL).After an additional 5 min of stirring, the aqueous
phase was separated and extracted with CH2Cl2 (3”70 mL).The com-
bined organic phases were dried over Na2SO4 and the solvent was evapo-
rated to give 800 mg of the chlorinated compound.The colourless oil was
used directly without further purification.A solution of the chlorinated
product (800 mg, 2.23 mmol) and NaOH (223 mg, 5.58 mmol) in ethanol
(125 mL) was heated to reflux for 3 h and then cooled to room tempera-
ture followed by evaporation of the solvent under reduced pressure.
CH2Cl2 (50 mL) and a saturated aqueous solution of NH4Cl (40 mL) was
added to the resulting crude product, the phases were separated and the
aqueous layer was extracted with CH2Cl2 (3”50 mL).The combined or-
ganic phases were dried over Na2SO4 and the solvent was evaporated to
give the oily yellowish crude product.Purification by flash chromatogra-
phy (hexane/EtOAc, 50:50) gave the product as a colourless oil (391 mg,
60% yield). 1H NMR (CDCl3, 600 MHz): d=1.30 (s, 6H; CH3(oxa)), 1.58
(s, 3H; CH3(bridge)), 1.60 (s, 3H; CH3(bridge)), 3.97 (s, 2H; CH2(methyloxa)), 4.11
(pseudo-t, J=8.0 Hz, 1H; CH2(phenyloxa)), 4.62 (dd, J=8.4 Hz, J=10.1 Hz,
1H; CH2(phenyloxa)), 5.19 (dd, J=7.6 Hz, J=10.1 Hz, 1H; CH(oxa)), 7.23–
Experimental Section
All manipulations, except those indicated, were carried out under an
inert atmosphere of dry argon by using standard Schlenk techniques.Sol-
vents were purified and dried by standard methods.Starting compounds
monoethyl malonate,[19] (4R)-2-bromo-4-phenyloxazoline,[20] 1,1-bis[(4S)-
4-phenyloxazolin-2-yl]ethane,[21] 2-bromo-4,4-dimethyloxazoline,[6a] 1,1-
bis[(4,4-dimethyloxazolin-2-yl]ethane[6a] (dm2-BOX), 1,1,1-tris[(4R)-4-
phenyloxazolin-2-yl]ethane[8] (Ph3-trisox
ACHTREUNG
methyloxazolin-2-yl]ethane[6a] (dm3-trisox) were synthesised according to
ACHTRE(UGN R,R,R)) and 1,1,1-tris[4,4-di-
literature procedures.Ethyl 2-methylacetoacetate and dodecane were
commercially available and were purified by bulb to bulb distillation.All
other reagents were commercially available and were used without fur-
ther purification. 1H and 13C NMR spectra were recorded on a Bruker
DRX 200 spectrometer at 200 and 50 MHz, respectively, on a Bruker
Avance 300 spectrometer at 300 and 75 MHz, respectively, on a Bruker
Avance II400 spectrometer at 400 and 100 MHz, respectively, and on a
Bruker Avance III600 spectrometer at 600 and 150 MHz, respectively,
and were referenced to the residual proton solvent peak.IR spectra were
9920
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9912 – 9923

Asymmetric Catalysis
FULL PAPER
7.35 ppm (m, 5H; CH(arom)); 13C {1H} NMR (CDCl3, 150 MHz): d=24.4,
24.5 (CH3(bridge)) 28.0, 28.1 (CH3(oxa)), 38.5 (Cquat(bridge)), 67.1 (Cquat(methyloxa)),
69.4 (CH), 75.5 (CH2(phenyloxa)), 79.4 (CH2(methyloxa)), 126.6, 127.5, 128.6
(CH(arom)), 142.5 (Cquat(arom)), 167.4 (NCO(methyloxa)), 170.5 ppm
(NCO(phenyloxa)); HRMS (FAB): m/z: calcd for C17H23N2O2 ([M++H])
287.1760; found: 287.1757.
tion was evaporated to dryness.The residue was redissolved in dichloro-
methane (100 mL) and washed with water (10 mL).The organic extract
was dried over Na2SO4 and concentrated in vacuo to give an orange oil.
Purification by flash chromatography (hexane/EtOAc, 95:5 to 50:50)
gave the desired product as a white solid (906 mg, 39% yield). 1H NMR
(CDCl3, 400 MHz): d=2.13 (s, 3H; CH3), 4.27–4.34 (m, 3H; CH2), 4.79–
4.85 (m, 3H; CH2), 5.33–5.41 (m, 3H; CH), 7.25–7.42 ppm (m, 15H;
CH(arom)); 13C {1H} NMR (CDCl3, 100 MHz): d=21.7 (CH3), 45.1
2,2-Dimethyl malonic acid ethyl monoester N-((S)-2-hydroxy-1-phenyl-
ACHTREUNGethyl) monoamide: DCC (9.3 g, 45 mmol) and HOBt (61 g, 45 mmol)
((CH3)CACHTREU(GN oxa)3), 69.6, 69.6, 69.6 (CH), 75.9, 75.9, 76.0 (CH2), 126.8, 126.8,
were added under argon flow to a solution of monoethyl malonate
(6.54 g, 41 mmol) in CH2Cl2 (250 mL).After 2 h of stirring, ( S)-phenyl-
glycinol (6.1 g, 45 mmol) was added and the solution was stirred at room
temperature for 3 days.The reaction mixture was filtered through Celite
to remove the DCU formed and washed with CH2Cl2 (4”100 mL).The
organic solution was washed with an aqueous solution of KHCO3 10%
(350 mL), H2O (300 mL) and brine (300 mL) and was then dried over
Na2SO4.Evaporation of the solvent gave the product as a white solid
(9.8 g, 86% yield). The compound was used in the next step without fur-
126.9, 127.6, 127.6, 127.6, 128.6, 128.7, 128.7 (CH(arom)), 142.0, 142.1
(Cquat(arom)), 165.9, 166.0, 166.1 ppm (NCO); elemental analysis calcd (%)
C25H27N3O3: C 71.92, H 6.52, N 10.06; found: C 71.85, H 6.50, N 10.10;
HRMS (FAB): m/z: calcd for C25H28N3O3 ([M++H]) 418.2131; found:
418.2118.
1-[(4R)-4-phenyloxazolin-2-yl]-1,1-di[(4S)-4-phenyloxazolin-2-yl]ethane
[Ph3-trisox (R,S,S)]: tBuLi (2 mL, 1.5m in pentane, 3 mmol) was added
dropwise to
a solution of 1,1-bis[(4S)-4-phenyloxazolin-2-yl]ethane
1
ther purification. H NMR (CDCl3, 400 MHz): d=1.31 (t, J=7.1 Hz, 3H;
(794 mg, 2.5 mmol) in THF (80 mL) at ꢀ788C.The resulting orange solu-
tion was stirred for an additional 30 min prior to the addition of 1.2 equiv
of (4R)-2-bromo-4-phenyloxazoline (673 mg, 3 mmol).The solution was
allowed to warm slowly to room temperature for 12 h and then concen-
trated to remove the pentane and finally the Schlenk tube was sealed.
The stirred solution was heated at 708C for 5 days.The resulting orange
solution was evaporated to dryness.The residue was redissolved in di-
chloromethane (100 mL) and washed with water (10 mL).The organic
extract was dried over Na2SO4 and concentrated in vacuo to give an
orange oil.Purification by flash chromatography (hexane/EtOAc, 50:50)
gave the desired product as a pale orange solid (350 mg, 30% yield).
1H NMR (CDCl3, 400 MHz): d=1.38 (s, 3H; CH3(oxa)), 1.39 (s, 3H;
CH3(oxa)), 2.04 (s, 3H; CH3(apical)), 4.11 (d, J=8.0 Hz, 1H; CH2(methyloxa)),
4.13 (d, J=8.0 Hz, 1H; CH2(methyloxa)), 4.26 (dd, J=2.5 Hz, J=8.0 Hz, 1H;
CH2(phenyloxa)), 4.28 (dd, J=2.4 Hz, J=7.9 Hz, 1H; CH2(phenyloxa)), 4.78 (m,
2H; CH2(phenyloxa)), 5.32 (dd, J=7.7 Hz, J=9.8 Hz, 1H; CH(oxa)), 5.35 (dd,
J=7.6 Hz, J=10.0 Hz, 1H; CH(oxa)), 7.25–7.38 ppm (m, 5H; CH(arom));
13C {1H} NMR (CDCl3, 100 MHz): d=21.6 (CH3(apical)) 27.9 (CH3(oxa)),
CH3(ethyl)), 1.52 (s, 3H; CH3(bridge)), 1.53 (s, 3H; CH3(bridge)), 2.56 (brs, 1H;
OH), 3.91 (pseudo-t, J=3.9 Hz, 2H; CH2), 4.25 (q, J=7.1 Hz, 2H;
CH2(ethyl)), 5.10 (m, 1H; CH), 7.25 (d, J=6.3 Hz, 1H; NH), 7.31–7.35 (m,
3H; CH(arom)), 7.39–7.42 ppm (m, 2H; CH(arom)); 13C {1H} NMR (CDCl3,
100 MHz): d=13.9 (CH3(ethyl)), 23.6, 23.8 (CH3(bridge)), 49.9 (Cquat(bridge)),
55.9 (CH), 61.7 (CH2(ethyl)), 66.5 (CH2), 126.5, 127.8, 128.8 (C(arom)), 138.9
(Cquat(arom)), 172.3 (OCO), 174.9 ppm (NCO); MS (FAB): m/z (%): 262.1
(11) [M+ꢀOH], 280.1 (100) [M++H]; HRMS (FAB): m/z: calcd for
C15H22NO4 ([M++H]): 280.1549; found: 280.1521.
N-((S)-2-Hydroxy-1-phenylethyl)-N’-((R)-2-hydroxy-1-phenylethyl)di-
ACHTREUNG
ACHTREUNG
heated at 1108C for 2 days in the presence of a catalytic amount of NaH.
The white precipitate obtained was filtered and washed with Et2O (3”
40 mL).Evaporation of the solvents gave the product as a white solid
(5 g, 42% yield). 1H NMR ([D6]DMSO, 200 MHz)
d 1.37 (s, 3H;
CH3(bridge)), 1.39 (s, 3H; CH3(bridge)), 3.37 (brs, 1H; OH), 3.59 (pseudo-t,
J=5.0 Hz, 4H; CH2), 4.89 (m, 2H; CH), 7.17–7.31 (m, 10H; CH(arom)),
7.25 ppm (d, J=7.8 Hz, 2H; NH); 13C {1H} NMR ([D6]DMSO, 50 MHz):
d=23.1, 24.1 (CH3(bridge)), 49.4 (Cquat(bridge)), 55.4 (CH), 64.4 (CH2), 126.6,
126.8, 128.0 (C(arom)), 141.2 (Cquat(arom)), 172.7 (OCN); HRMS (FAB): m/z:
calcd for C21H27N2O4 ([M++H]): 371.1971; found: 371.1969.
44.8 ((CH3)CACHTRE(NUG oxa)3), 67.5 (Cquat(methyloxa)), 69.5 (CH), 75.8, 75.9
(CH2(phenyloxa)), 79.8 (CH2(methyloxa)), 126.8, 126.9, 127.4, 127.5, 128.5, 128.6
(CH(arom)), 142.2 (Cquat(arom)), 163.0 (NCO(methyloxa)), 166.2, 166.3 ppm
(NCO(phenyloxa)); HRMS (FAB): m/z (%): 466.2137 (100) [M++H]; ele-
mental analysis calcd (%) C29H27N3O3: C 74.82, H 5.85, N 9.03; found: C
74.80, H 5.81, N 9.10; HRMS (FAB): m/z: calcd for C29H28N3O3 ([M+
+H)]): 466.2131; found: 466.2137.
1-[(4R)-4-Phenyloxazolin-2-yl]-1-((4S)-4-phenyloxazolin-2-yl)-1-methyl-
ethane[21] (Ph2-BOX
ACHTREUNG(R,S)): A solution of TsCl (5.4 g, 28.5 mmol) in
1-[(4R)-4-phenyloxazolin-2-yl]-1,1-di(4,4-dimethyloxazolin-2-yl)ethane
CH2Cl2 (30 mL) was slowly added to an ice-cooled solution of N-[(S)-2-
hydroxy-1-phenylethyl]-N’-((R)-2-hydroxy-1-phenylethyl)dimethylmalo-
namide (4.8 g, 13 mmol), triethylamine (14.5 mL, 104 mmol) and DMAP
(160 mg, 1.3 mmol) in CH2Cl2 (200 mL).The mixture was warmed to
room temperature, stirred for 10days and washed with a saturated aque-
ous solution of NH4Cl and brine.The organic phase was dried over
Na2SO4 and concentrated in vacuo to give a dark brown oil.Purification
by flash chromatography (hexane/EtOAc, 80:20) gave the desired prod-
uct as a pale yellow oil (3.7 g, 86% yield). 1H NMR (CDCl3, 400 MHz):
d=1.73 (s, 3H; CH3), 1.76 (s, 3H; CH3), 4.22 (pseudo-t, J=8.1 Hz, 2H;
CH2), 4.72 (dd, J=8.4 Hz, J=10.1 Hz, 2H; CH2), 5.28 (dd, J=7.7 Hz, J=
10.1 Hz, 2H; CH), 7.25–7.35 ppm (m, 10H; CH(arom)); 13C {1H} NMR
(CDCl3, 100 MHz): d=24.4, 24.7 (CH3) 38.9 (Cquat(bridge)), 69.5 (CH), 75.5
(CH2), 126.6, 127.6, 128.7 (CH(arom)), 142.4 (Cquat(arom)), 170.3
(NCO(phenyloxa)); HRMS (FAB): m/z: calcd for C21H23N2O2 ([M+ +H]):
335.1760; found: 335.1771.
(Ph-dm2-trisox): tBuLi (1.7 mL, 1.5m in pentane, 2.6 mmol) was added
dropwise to
a solution of 1,1-bis[(4,4-dimethyloxazolin-2-yl]ethane
(485 mg, 2.2 mmol) in THF (80 mL) at ꢀ788C.The resulting bright
yellow solution was stirred for an additional 30 min prior to the addition
of 1.2 equiv of (4R)-2-bromo-4-phenyloxazoline (588 mg, 2.6 mmol). The
solution was allowed to warm slowly to room temperature for 12 h and
then concentrated to remove the pentane and finally the Schlenk tube
was sealed.The stirred solution was heated at 75 8C for 5 days.The re-
sulting orange solution was evaporated to dryness.The residue was redis-
solved in dichloromethane (100 mL) and washed with water (10 mL).
The organic extract was dried over Na2SO4 and concentrated in vacuo to
give an orange oil.Purification by flash chromatography (hexane/EtOAc,
50:50) gave the desired product as an orange oil (360 mg, 45% yield).
1H NMR (CDCl3, 400 MHz): d=1.30 (s, 3H; CH3(oxa)), 1.31 (s, 9H;
CH3(oxa)), 1.91 (s, 3H; CH3(apical)), 4.00 (d, J=8.0 Hz, 1H; CH2(methyloxa)),
4.01 (d, J=8.0 Hz, 1H; CH2(methyloxa)), 4.04 (d, J=8.0 Hz, 1H;
CH2(methyloxa)), 4.05 (d, J=8.0 Hz, 1H; CH2(methyloxa)), 4.17 (pseudo-t, J=
8.1 Hz, 1H; CH2(phenyloxa)), 4.69 (dd, J=8.4 Hz, J=10.1 Hz, 1H;
CH2(phenyloxa)), 5.24 (dd, J=8.4 Hz, J=10.1 Hz, 1H; CH(oxa)), 7.23–
7.34 ppm (m, 5H; CH(arom)); 13C {1H} NMR (CDCl3, 100 MHz): d=21.8
1,1-Di[(4S)-4-phenyloxazolin-2-yl]-1-(4,4-dimethyloxazolin-2-yl)ethane
(Ph2-dm-trisox): tBuLi (4.4 mL, 1.5m in pentane, 6.6 mmol) was added
dropwise to a solution of 1,1-bis[(4S)-4-phenyloxazolin-2-yl]ethane (1.8 g,
5.5 mmol) in THF (100 mL) at ꢀ788C.The resulting red solution was
stirred for an additional 30 min prior to the addition of 1.2 equiv of 2-
bromo-4,4-dimethyloxazoline (1.17 mg, 6.6 mmol). The solution was al-
lowed to warm slowly to room temperature for 12 h and then concentrat-
ed to remove the pentane and finally the Schlenk tube was sealed.The
stirred solution was heated at 708C for 4 days.The resulting orange solu-
(CH3(apical)) 27.8 (CH3(oxa)), 44.4 ((CH3)CCATHERU(GN oxa)3), 67.3, 67.4 (Cquat(methyloxa)),
69.4 (CH), 75.8 (CH2(phenyloxa)), 79.6, 79.7 (CH2(methyloxa)), 126.8, 127.5,
128.5 (CH(arom)), 142.4 (Cquat(arom)), 163.1, 163.2 (NCO(methyloxa)), 166.4
(NCO(phenyloxa)); HRMS (FAB): m/z: calcd for C21H28N3O3 ([M++H]):
370.2131; found: 370.2135.
Chem. Eur. J. 2007, 13, 9912 – 9923
ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
9921

L.H.Gade, S.Bellemin-Laponnaz et al.
Preparation of the copper complexes
[CuII(iPr3-trisox)(k2-O,O’-MeCOCHCOOEt)]
Cu[BF4]2·6H2O (44 mg; 0.116 mmol) and trisoxazoline (46 mg;
Table 6.Details of the X-ray structure determinations of complexes
and 2.
1
G
+A[BF4]ꢀ (1): A mixture of
CHTREUNG
1[7]
2
ACHTREUNG
0.128 mmol) in THF (2 mL) was stirred for 3 h. A 5.76·10ꢀ2 m solution of
diethylmethylmalonate/tBuOK (2.2 mL, 0.128 mmol) was subsequently
added and the resulting green mixture was stirred overnight.After re-
moval of the volatiles in vacuo, the crude product was washed with cold
hexane until it solidified.The solid was extracted with toluene and the re-
sulting suspension was filtered through a Teflon microfilter (0.2 mm).Re-
moval of the solvent gave 1 as a dark green solid (69 mg; 91%).Slow
vapour diffusion of hexane into a solution of 1 in THF gave crystals suit-
able for X-ray analysis.Elemental analysis calcd (%) C 27H44BCuF4N3O6:
C 49.36, H 6.75, N 6.40; found: C 48.52, H 6.66, N 6.76; MS (FAB+):
426.3 [M+ꢀBF4ꢀC7H11O3].
formula
Mr
crystal size [mm]
crystal system
space group
a [Š]
C27H44BCuF4N3O6
657.00
0.2·0.1·0.05
orthorhombic
P212121
9.5673(5)
11.3995(7)
28.6673(16)
3126.5(3)
4
C50H56ClCuN3O11
973.97
0.2·0.2·0.1
tetragonal
P41212
15.9231(8)
b [Š]
c [Š]
36.637(3)
9289.2(9)
8
1.393
0.593
0.926/0.890
ꢀ13ꢃhꢃ13
0ꢃkꢃ19
0ꢃlꢃ44
1.4–25.7
4088
117733 [0.0729]
8663
8663/94/615
V [Š3]
Z
1calcd [Mgmꢀ3
]
1.396
0.766
[Cu(Ph3-trisox
of Cu[ClO4]2·6H2O (54 mg; 0.143 mmol) and Ph3-trisox
ACHTREUNG ACHTRENUG
(R,S,S))(k2-O,O’-MeCOCHCOOEt)]
m [mmꢀ1
]
A
ACHTREUNG
max/min transmission
index ranges
0.963/0.862
ꢀ11ꢃhꢃ11
0ꢃkꢃ13
0ꢃlꢃ34
1.4–25.0
1380
18621
5535 [0.0633]
5535/0/389
0.150 mmol) in THF (2 mL) was stirred for 1.5 h. A 5.8·10ꢀ2 m solution of
diethylmethylmalonate/tBuOK (2.7 mL, 0.157 mmol) was subsequently
added and the resulting green mixture was stirred overnight.After re-
moval of the volatiles in vacuo, the crude product was washed with
hexane (3”5 mL) and the green solid was dried under vacuum.This solid
material was extracted with toluene and the resulting suspension was fil-
tered through a Teflon microfilter (0.2 mm).Slow vapour diffusion of
hexane into the solution at ꢀ48C gave green crystals of compound 2
(57 mg; 52%).Elemental analysis calcd (%) C 36H40ClCuN3O11: C 54.75,
H 5.11, N 5.32; found: C 54.39, H 5.09, N 5.36.
q range [8]
F000
reflns collected
independent reflns [Rint
data/restraints/parame-
ters
]
goodness-of-fit on F2
R indices [I>2s(I)]
1.058
1.064
R1=0.0415,
wR2=0.0847
R1=0.0593,
wR2=0.0918
-0.002(14)
R1=0.0529,
wR2=0.1395
R1=0.0657,
wR2=0.1485
0.002(17)
Procedure for the asymmetric a-amination reaction of ethyl 2-methyl-
ACHTREUNGacetoACHTREUNGacetate: A stock solution of CuAHCTRE[UGN OTf]2 (8.1 mg, 22.5 mmol) and the
ligand (27 mmol) in distilled CH2Cl2 (1.5 mL) was prepared under air.
The homogeneous solution was stirred for 30 min and successive aliquots
were taken to obtain the desired catalyst loading for each run.The b-
R indices (all data)
absolute structure
AHCTREpGNU arameter
ketoACHTREUNGester (21.4 mL, 0.15 mmol) was added to each catalyst solution and
largest residual peaks
0.396/ꢀ0.396
0.522/ꢀ0.754
the resulting mixture was cooled down to 08C.Pre-cooled dibenzylazodi-
carboxylate (54.8 mg, 0.18 mmol) in solution in CH2Cl2 (0.5 mL) was
then added.After 16 h at 0 8C, the product was isolated by flash chroma-
tography (hexane/EtOAc 75:25).The ee of the product was determined
by HPLC using a Daicel Chiralpak AD-H column.Yields and ee values
are the average of at least two corroborating runs.
ꢀ3]
[eŠ
CCDC 277609 (1) and 653021 (2) contain the supplementary crystallo-
graphic data for this paper.These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
The comparative studies of the catalytic activities were conducted for
each experiment using copper catalysts prepared in situ by reacting the
respective ligand with the CuACHTRE[UGN OTf]2 salt at room temperature for 0.5 h in
CH2Cl2.The catalytic a-amination reactions were carried out at 08C with
1.0 mol% catalyst loading. The progress of the reaction was monitored
by measuring the disappearance of the ethyl 2-methylacetoacetate by
GC, with dodecane as internal standard.
Acknowledgements
Crystal structure determinations: Crystal data and details of the structure
determinations are listed in Table 6.Intensity data were collected at
100(2) K with a Bruker AXS Smart 1000 CCD diffractometer (MoKa ra-
diation, graphite monochromator, l=0.71073 Š). Data were corrected
for Lorentz, polarisation and absorption effects (semiempirical,
SADABS).[23] The structures were solved by the heavy-atom method
combined with structure expansion by direct methods applied to differ-
ence structure factors and refined by full-matrix least squares methods
based on F2 with all measured unique reflections.All non-hydrogen
atoms were given anisotropic displacement parameters.Hydrogen atoms
were input at calculated positions and refined with a riding model.The
calculations were performed using the programs DIRDIF[24] and
SHELXL-97.[25]
We thank the Deutsche Forschungsgemeinschaft (SFB 623, Project B6),
the European Union (RTN Network AC3S), the Deutsch-Franzçsische
Hochschule (DFH) and the CNRS (France) for funding.We thank Dr.
Vincent CØsar for helpful comments and critical suggestions.Support by
BASF (Ludwigshafen) and Degussa (Hanau) is gratefully acknowledged.
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9922
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9912 – 9923

Asymmetric Catalysis
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Received: July 16, 2007
Published online: October 23, 2007
Chem. Eur. J. 2007, 13, 9912 – 9923
ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
9923