AraBOX and XyliBOX based catalysts for cyclopropanations, Diels Alder cycloadditions and allylic additions

Article abstract of DOI:10.1016/j.tetasy.2013.04.020

The syntheses of three novel chiral 4,4′BOX ligands are described. The three ligands each have a chiral backbone and chiral sidearms, two of which are diastereomeric. These new ligands have been applied as copper complexes to asymmetric cyclopropanation r

Full text of DOI:10.1016/j.tetasy.2013.04.020

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
AraBOX and XyliBOX based catalysts for cyclopropanations, Diels
Alder cycloadditions and allylic additions
David Kellehan a, Fiona Kirby a, David Frain a, Antonio M. Rodríguez-García b, José I. García c,
Patrick O’Leary a,
⇑
a
˙
National University of Ireland, Galway, School of Chemistry, SMACT (Synthetic Methods: Asymmetric Catalytic Transformations), Ireland
b Departamento de Química Inorganica, Organica y Bioquimica Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Avenida Camilo Jose Cela s/n, 13071 Ciudad
Real, Spain
c Instituto de Síntesis Química y Catálisis Homogénea, CSIC-Universidad de Zaragoza, Calle Pedro Cerbuna 12, E-50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
The syntheses of three novel chiral 4,40BOX ligands are described. The three ligands each have a chiral
backbone and chiral sidearms, two of which are diastereomeric. These new ligands have been applied
as copper complexes to asymmetric cyclopropanation reaction of styrene with ethyldiazoacetate. Enanti-
oselectivities of up to 70% were obtained, which is the highest ee reported from the use of this ligand class
in this reaction to date. The multiple stereogenic centres in the ligand resulted in a substantial additive
effect and this is discussed along with interpretation of the results for previously described 4,40BOX
ligands, and a major computational study of the multiple reaction channels involved with ligands of this
type. The use of complexes of 4,40BOX ligands, as catalysts, in an allylic alkylation is also reported for the
first time and ee’s of >70% have been achieved in this reaction. These ligands were also applied to a Diels–
Alder test reaction and again outperformed previous examples of this ligand type.
Article history:
Received 15 April 2013
Accepted 30 April 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral 2,20bis(oxazoline) (BOX) ligands were first reported
20 years ago1,2 and since this time a large number of such ligands
have been reported on.3 They have been applied, as their metal
complexes, to the asymmetric catalysis of a wide variety of key or-
ganic reactions, such as cyclopropanations,4,5 Diels Alder cycload-
ditions,6 ene reactions,7 Mukaiyama aldol reactions8 and so on.
The structure of the metal complexes has also been widely ex-
plored. Despite the success of these and other catalysts, there is
still a need to develop new catalysts, which increase the toolbox
available to those interested in developing asymmetric syntheses.
In general, the BOX ligands reported to date are predominantly
based around the same ligand backbone with variation in the pen-
dant groups at the two available positions in the oxazoline ring or
on the bridgehead carbon.
O
O
O
O
O
O
N
N
N
N
N
N
Ph
Ph
tBu
tBu
Ph
Ph
(S)-tBuAraBOX 2
(R)-PhAraBOX 1
PhXyliBOX 3
O
O
O
O
N
N
N
N
Me
Me
Ph
Ph
MePrXyliBOX 4
Figure 1. 4,40BOX ligands previously reported by this group.
PhPrXyliBOX 5
We have recently reported the first examples of 4,40BOX ligands
(Fig. 1).9–11 In these ligands, the backbone contains stereogenic
centres and upon complexation with a metal, these chiral centres
are internal to the metallocycle. These initial ligands have been
used in the catalysis of Diels–Alder and cyclopropanation reactions
with some success.
The ligands are derived from two different commercially avail-
able alcohols; arabitol leading to the AraBOX ligands and xylitol
leading to the XyliBOX ligands which are meso unless additional
chirality is incorporated into the pendant groups on the oxazoline
rings (3 vs 4 and 5).
⇑
Corresponding author. Tel.: +353 (0)91 492476; fax: +353 (0)91 525700.
E-mail address: patrick.oleary@nuigalway.ie (P. O’Leary).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.020
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2
D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
of our previous ligands and we again applied this methodology.
2. Results and discussion
Tosyl fluoride was used to deprotect the alcohols and activate them
as tosylates, thus facilitating the ring closure. The DBU plays a
catalytic role in the deprotection reaction but is required in excess
in the cyclization step. This method allows the ligands to be
prepared in excellent yields (up to 66%) considering that the
tandem DARC reactions involve 6 separate synthetic steps (three
on each side).
We wanted to evaluate the influence of the chirality in the
backbone of the ligand on the stereoselectivity achieved by the li-
gand’s copper complexes in the asymmetric cyclopropanation of
styrene. Furthermore, we wanted to see what influence chiral pen-
dant groups would have on the stereoselectivity. To that end we
synthesized three novel 4,40BOX ligands 9–11 (Scheme 1).
We now had available to us three new 4,40BOX ligands, and
eight in total, which we then applied to the asymmetric cycloprop-
anation reaction of styrene with ethyl diazoacetate (Table 1). We
were particularly interested in the two diastereomeric ligands 10
and 11, which would give us some insight into the relative influ-
ence of the chirality in the backbone and in the pendant groups
on the stereochemical outcome of the reaction.
The reactions were conducted using 10 mol % of the copper(I)
triflate ligand complex relative to ethyl diazoacetate and a three
fold excess of styrene. The results for ligands 1–5 have previously
been reported on but are included here for the sake of comparison
We have previously reported on the synthesis of 12 starting
from
thesis of ligand 11.9 The enantiomeric TBDMS protected bis-ami-
noalcohol 6 was prepared from
-(ꢀ)-arabitol and this was used
D-(+)-arabitol; this was used as the starting point for the syn-
L
as the starting point for the synthesis of ligands 9 and 10. In all
cases, the amines were reacted with chiral acid chlorides to form
amides. The acid chlorides were prepared from chiral acids and
thionyl chloride and were used without purification beyond sol-
vent removal. Amides 8 and 13 were isolated in good yield while
7 was isolated in modest 35% yield. We have developed a tandem
deprotection, activation and ring closure reaction for the synthesis
O
Cl
TBDMSO
Me
OTBDMS
Me
Me
TBDMSO
OTBDMS
NH HN
CH2Cl2,Et3N
0oC-rt, 16h,
NH2 NH2
O O
6
7
O
CH2Cl2,Et3N
0oC-rt, 16h,
TsF, DBU
Cl
MeCN, Δ, 16h
Ph
TBDMSO
Ph
OTBDMS
Ph
NH HN
O
N
O
N
O O
Me
Me
8
MePrAraBOX 9
TsF, DBU
MeCN, Δ, 16h
O
O
N
O
O
N
N
N
Ph
Ph
Ph
Ph
PhPrAraBOX 10
PhPrAraBOX 11
TsF, DBU
MeCN, Δ, 16h
TBDMSO
Ph
OTBDMS
Ph
NH HN
TBDMSO
OTBDMS
CH2Cl2,Et3N
0oC-rt, 16h,
NH2 NH2
O O
O
12
13
Cl
Ph
Scheme 1. Synthetic steps involved in the synthesis of ligands 9–10.
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D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
Table 1
At first, we calculated the structure of the cationic 1–Cu(I)-car-
bene intermediate, whose optimized geometry was similar to that
of the 1–CuCl2 complex, determined by X-ray diffraction.11Once
the adequacy of the theoretical level used to reproduce molecular
geometries was tested, we started modelling the cyclopropanation
reaction using ethylene as the alkene. Although the resulting cyclo-
propane was not chiral, the corresponding TS of the approaches of
ethylene through the Re and Si faces of the carbene carbon atom of
the chiral bisoxazoline–copper complexes were diastereomeric,
and hence different in energy. In previous studies5,17,18 we have
shown that the main steric interactions responsible for the enan-
tioselection are retained in this simplified model, leading to good
estimations of the enantioselectivity of real systems, and, conse-
quently, we adopted the same approach herein. As already men-
tioned, ethylene can approach the carbene carbon atom through
its Re or Si faces. Furthermore, there are two conformations of
the ester group for each approach. This leads to at least four possi-
ble reaction channels. Whereas the Re TS displays a chelate struc-
ture almost identical to that of the carbene intermediate, the Si TS
is much more deformed, and the six-membered copper chelate
ring changes its conformation from an initial half-chair to a boat-
like disposition. Figure 2 highlights these structural differences
by superimposing the 1–Cu(I)-carbene intermediate with the min-
imum energy Re and Si TS, respectively. However, by inspecting the
relative energies of the four possible TS, one realizes that the geo-
metric deformation observed has a rather low energy cost, since
three of the four TS have almost the same energy. The modest
enantioselectivity observed seems to have its origin with a slight
preference of one of the reaction channels over the other three
(Fig. 2). The calculated enantioselectivity [39% ee in the (1R)-enan-
tiomer] is in excellent agreement with the experimental values ob-
tained (Table 1, ligand 1).
Next we considered the case of XyliBOX ligands, namely that
of MePrXyliBOX 4. This situation turned out to be much more
complex. First, due to the different absolute configurations at
the oxazoline carbon atoms, the ligand is not C2-symmetric, so
the number of possible alkene approaches to the corresponding
carbene intermediate doubles, since we must consider the ap-
proach of the alkene through the S and R sides, both when the
ester group is up and down, which are now sterically non-equiv-
alent. Secondly, we must take into account the possible confor-
mations not only of the six-membered chelate ring, but also of
the 1-methylpropyl substituent. To this end, we carried out an
exploratory conformational analysis, and we concluded that,
with regard to the methylpropyl substituent, there are three
main conformational dispositions gathering most of the confor-
mational population, as shown in Figure 3. This means that if
we consider again ethylene as the alkene, we have at least
(2 ꢂ 2 ꢂ 2 ꢂ 3 =) 24 possible reaction channels for the reaction
(Re/Si approaches with the ester up/down by two possible rota-
mers for the ester by three possible conformations for the meth-
ylpropyl substituents).
Ligand performance in the copper(I) catalysed asymmetric cyclopropanation reaction
CO2Et
CO2Et
O
Cu(I)OTf
+
OEt
+
ligand,
CH2Cl2,
rt.
N2
Ligand
Conversiona
%
trans:cisa
%ee cisb (major)
%ee transb (major)
1
2
3
4
5
9
10
11
99
99
91
80
99
63
66
67
60:40
62:38
48:52
53:47
59:41
40:60
59:41
37:63
32 (1R,2S)
14 (1R,2S)
-
24 (1S,2R)
6 (1S,2R)
70 (1S,2R)
20 (1R,2S)
64 (1S,2R)
16 (1R,2R)
7 (1R,2R)
-
24 (1S,2S)
4 (1S,2S)
69 (1S,2S)
8 (1R,2R)
61 (1S,2S)
a
The conversion and trans/cis ratio were determined by 1H NMR.
Determined by chiral GC (Cyclodex-B 30 m ꢂ 0.252 mm ꢂ 0.25
b
lm)
as they allow us to build a picture of the stereochemical influence
of each portion of the ligand.
In all cases, the ligands proved to be ineffective in influencing
the diastereoselectivity of the reaction to any major degree. How-
ever, the enantioselectivities were much more encouraging.
Ligands 1 and 2 both gave low enantioselectivities, which indi-
cated that the chiral backbone did influence the enantioselectivity
of the reaction. Although these two ligands are derived from the
opposite enantiomers of arabitol, they favour the same enantiomer
of the product. This behaviour has previously been seen in copper
2,20bis(oxazoline) catalysis of Diels–Alder and ene reactions.12–16
In these cases the alteration was attributed to the change in co-
ordination geometry around the metal when the pendant groups
on the oxazoline rings were altered or when extra coordinating li-
gands/anions were present in the metal co-ordination sphere. This
change in co-ordination geometry is often simplified as a switch
between tetrahedral and square planar geometry around the me-
tal, although the reality is thought to be someway short of these
extremes.
The reaction was, as expected, not stereoselective with the
meso XyliBOX ligand 3. When the chiral sidearms were added to
the same backbone to give ligands 4 and 5, then modest enantiose-
lectivities were obtained. It was apparent that the chirality in
either the backbone of the ligand or in the sidearms influenced
the stereoselectivity of the reaction. Ligands 9–11 were designed
to combine both of these facts. The MePrAraBOX ligand 9 gave
the highest enantioselectivities at ꢁ70% for both the cis- and
trans-isomers. The PhPrAraBOX ligand 10 gave much lower enanti-
oselectivity, even though it had been the more effective sidearm
with the XyliBOX backbone. However upon closer examination
we realized that the enantiomer of the cyclopropane produced in
both the cis and trans case is the opposite of that seen with 9. Given
that both ligands share a common backbone and the only differ-
ence is the chirality and groups on the sidearms, this gave a strong
indication that we were getting a negative effect when the back-
bone chirality and that on the sidearm were mismatched. The
PhPrAraBOX ligand 11, which is diastereomeric with 10, gave
much better results with enantioselectivities of up to 64% ee. This
again gives very clear evidence of an additive effect between the
stereogenic centres present in ligands 10 and 11.
Table 2 shows the results of the calculated energies. As can be
seen, the lowest energy TS corresponds to a Si approach and, over-
all, the (1S)-cyclopropane product is favoured. Furthermore, only
the reaction channels through conformation I of the methylpropyl
substituent contribute significantly in determining the enantiose-
lectivity. Again, there is a reasonably good agreement between
the calculated [29% ee in (1S)-cyclopropane] and experimental re-
sults [24% ee in both (1S,2R)-cis- and (1S,2S)-trans-cyclopropanes).
The minimum energy TS, contributing the most to the final enanti-
oselectivity is shown in Figure 4.
In order to gain some insight on the origin of the enantiodiffer-
entiation leading to the enantioselectivities and absolute configu-
rations of the major enantiomers found, we undertook
Finally, we considered the analogous MePrAraBOX ligand 9. It
should be noted that the only difference with ligand 4 lies in the
absolute configuration of one of the carbon atoms at C-4, but this
difference results in a significant asymmetric induction. Ligand 9
a
computational study, based on the previous successful results ob-
tained with 2,20-bisoxazolines.5,17–20
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4
D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Figure 2. Superimposition of the calculated 1–Cu-carbene geometry (green) with those of the Re (blue) and Si (red) transition structures. Left, zenithal view, right, front view.
Figure 3. Most populated conformations of the methylpropyl substituents in MePrXyliBOX 4.
Table 2
Calculated enantioselectivity in the reaction of ethylene with methyl diazoacetate
catalysed by the 4–Cu complex
TS
DDGà,a
Re/Si
Ester up/down
MePr rotam.
Ester rotam.
Re
Re
Re
Re
Re
Re
Re
Re
Re
Re
Re
Re
Si
Si
Si
SI
Si
Si
Si
Si
Si
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
Down
Up
I
I
1
1
1
1
1
1
2
2
2
2
2
2
1
1
1
1
1
1
2
2
2
2
2
2
0.7
0.3
5.2
3.0
2.3
5.9
1.3
1.1
3.3
4.0
2.9
5.8
0.4
0.0
2.6
3.5
2.6
2.8
1.5
0.3
2.9
2.9
3.9
3.8
II
II
III
III
I
Figure 4. Minimum energy TS for the Re (left) and Si (right) alkene approaches to
the 4–Cu-carbene intermediate
I
II
II
III
III
I
Table 3
Calculated enantioselectivity in the reaction of ethylene with methyl diazoacetate
catalysed by the 9–Cu complex
I
II
II
III
III
I
TS
DDGà,a
Re/Si
MePr rotam.
Ester rotam.
Re
Re
Re
Re
Re
Re
Si
Si
Si
Si
Si
I
I
1
2
1
2
1
2
1
2
1
2
1
2
1.2
1.8
2.3
4.3
4.6
4.0
0.0
0.5
4.6
5.0
2.1
5.7
II
II
III
III
I
I
II
II
III
III
Si
Si
Si
Down
I
Measured in kcal molꢀ1
.
a
II
II
III
III
Si
is again C2-symmetric, which reduces the number of possible reac-
tion channels to 12.
a
Measured in kcal molꢀ1
.
Table 3 shows the calculated relative energies of the corre-
sponding TS, while the minimum energy TS contributing the most
to the final enantioselectivity are shown in Figure 5. As in the case
of XyliBOX, only the reaction channels through conformation I of
the methylpropyl substituent contribute significantly to the reac-
tion. However, unlike XyliBOX, the AraBOX ligand displays a clear
preference for the Si reaction channels, leading to a calculated
enantioselectivity of 75% ee in (1S)-cyclopropane, which is again
in excellent agreement with the experimental observations [ca.
70% ee in both (1S,2R)-cis- and (1S,2S)-trans-cyclopropanes]. If
we compare the minimum energy TS for the Re- and Si-approaches
(Fig. 5b), we can see that there are only very minor changes in the
global geometry of the ligand, associated to the spatial disposition
of the carbonyl group. These minor changes in the position of one
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D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
Table 5
Cu(II)AraBOX complex catalysed Diels–Alder reaction
Cu(OTf)2 10 mol%
ligand 10 mol%
O
O
O
N
O
CH2Cl2, N2, RT
N
O
O
Ligand
Conversion (%)
endo/exo
ee endo
1
9
10
11
60
100
97
70:30
82:18
70:30
64:36
44 (S)
1 (R)
45 (R)
57 (S)
85
moderate conversion but showed diastereoselectivity (de 40%
endo) and enantioselectivity (ee 44% in the endo) diastereomer.
The MePrAraBOX 9 showed good diastereoselectivity but no
enantioselectivity. However, the performance of ligands 10 and
11 again showed different selectivities. The complex based on li-
gand 10 gave good conversion and an enantioselectivity of 45%
ee. The diastereomeric ligand 11 in the same reaction gave better
enantioselectivity (57%). The major enantiomer produced by the
two diastereomeric ligands is different. This seems to indicate that
the major control of the enantioselectivity of the reaction comes
from the chirality in the backbone of the ligand. We did see a co-
operative effect between the chirality on the backbone of the li-
gands and that on the sidearms; the ee of 57% represents the high-
est ee we have recorded in this reaction using the 4,40BOX ligands.
We are currently applying these and related ligands to catalytic
reactions to test their reactivity and we are also seeking to maxi-
mize the co-operative effect between various stereogenic centres.
Figure 5. (a) Minimum energy TS for the Re (left) and Si (right) alkene approaches
to the 9-Cu-carbene intermediate. (b) Superimposition of both TS (red, Re TS, blue,
Si TS).
Table 4
Results of the allylic alkylation reaction using AraBOX ligands
MeO2C
CO2Me
Ph
OAc
Ph
ligand/Pd2(dba)3
NaH/DMM
toluene,
80oC
Ph
Ph
Ligand Time (h), Temperature Metal salt Conversion (%) %ee (R)/(S)
3. Conclusions
10
9
11
60, 80
60, 80
60, 80
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
16
99
90
6 (R)
72 (R)
68 (S)
We have completed the synthesis of three novel chiral 4,40BOX
ligands 9–10. We have applied these ligands to the asymmetric cop-
per catalysed cyclopropanation of styrene and achieved enantiose-
lectivities of up to 70% ee. We have conducted a preliminary
investigation into the factors which affect the enantioselectivity ob-
tained when using copper complexes of these ligands. The multiple
stereogenic centres in the new ligands resulted in a substantial
additive effect. We are currently working on a computer based
model in order to fully explore these effects and assist us in future
ligand design. An additive effect was also observed in the catalysis
of a Diels–Alder reaction giving the highest ee we have yet recorded
with 4,40BOX ligands in this reaction. We have also applied these li-
gands for the first time to the palladium catalysed allylic alkylation
reaction, achieving ee’s of up to 72%. Our synthetic work in this area
is currently ongoing particularly in the application of metal com-
plexes of these ligands to the catalysis of different reactions.
of the methylpropyl substituents seem to be in the origin of the
small energy differences leading to the enantiodiscrimination.
We also applied the new ligands 9–11 to the allylic alkylation of
( )-(E)-1,3-diphenyl-3-acetoxyprop-1-ene with the anion of di-
methyl malonate (Table 4). We hoped that we would again see a
co-operative effect between the chirality on the backbone of the li-
gands and that on the sidearms. The first ligand we tested was li-
gand 10, which had performed well in the cyclopropanation
reaction. However, the reactivity was poor as was the stereoselec-
tivity. When we applied ligands 9 and 11 to the reaction however,
the reactivity was much higher and the selectivity was also im-
proved. When ligand 9 was used, the conversion was 99% and the
product was produced in 72% ee, with the (R)-enantiomer being
predominant. Ligand 11 also gave good conversion and the product
in 68% ee, with the (S)-enantiomer being predominant in this case.
It would seem from the structures of the ligands that the backbone
chirality has a substantial influence on the stereochemical outcome
of the reaction, since the opposite stereochemistry on the backbone
in 9 and 11 gave the opposite enantiomer of product diastereomet-
ric with the same chirality on the sidearms but opposite ligands 10
and 11 are chirality in the backbone. The interaction between the
chirality in the backbone and that on the sidearms is evident from
the stereoselectivity achieved with catalysts derived from these
ligands from 11 leading to 68% ee (S) to 10 giving 6% ee (S).
4. Experimental
4.1. General
All other chemicals were purchased from Aldrich Chemical
Company and generally used without further purification. Any nec-
essary reagent purification, along with the drying and distillation
of solvents, was carried out according to literature procedures.21
Melting points were measured on a Stuart Scientific SMP3 appara-
tus. IR spectra were measured on a Perkin Elmer Spectrum 1000
FT-IR, or a Perkin Elmer Spectrum One FT-IR. Optical rotations were
measured on a Schmidt+Haensch L1000 polarimeter at 589 nm (Na)
We next applied our new ligands as their copper(II) complexes
to the catalysis of Diels–Alder test reactions (Table 5). The phenyl–
AraBOX ligand 1, which we previously reported gave the product in
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6
D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
in a 10 cm cell. Thin layer chromatography (TLC) was carried out
on precoated silica gel plates (Merck 60 F254); column chromatog-
raphy was conducted using Merck silica gel 60 or Apollo Scientific
25.9 (6 ꢂ CCH3), 18.2 (2 ꢂ CCH3), 12.4 (2 ꢂ CH3CH2), ꢀ5.6 ppm
(2 ꢂ Si(CH3)2); IR (neat): m0 = 3314, 2957, 2930, 2857, 1649 cmꢀ1
(C@O); HRMS (ESI): m/z calcd for C37H62N2O4Si2- H+: 653.4170
[MꢀH+]; found: 653.4168. Both 1H and 13C NMR showed the pres-
ence of ethyl acetate which was extremely difficult to remove
completely.
silica gel 40–63 lm. Elemental analysis was performed on a Perkin
Elmer 2400 analyser. 1H NMR (400 MHz), 13C NMR (100 MHz)
were recorded on a JEOL ECX-400 NMR spectrometer. All spectra
were recorded at probe temperatures (ꢁ20 °C) using tetramethyl-
silane as the internal standard. All chiral liquid–liquid chromatog-
raphy (HPLC) was carried out on a Varian instrument, with an UV/
Vis detector at the specified wavelength, with a Daicel CHIRALCEL
OD 0.46 cm ꢂ 25 cm column, using isopropanol/hexane as the sol-
vent, under conditions described for each experiment.
4.4. Preparation of amide 13
Thionyl chloride (0.83 g, 7.0 mmol) was added to a flask con-
taining (S)-(+)-2-phenylbutyric acid (0.77 g, 4.67 mmol). The solu-
tion was heated at reflux for 3 h and then concentrated in vacuo.
The residue was taken up in CH2Cl2 and concentrated once more
to remove any remaining thionyl chloride. The product was then
dissolved in CH2Cl2 and added dropwise to a solution of 12
(678 mg, 1.87 mmol) and triethylamine (0.57 ml, 4.11 mmol) at
0 °C. This solution was left to stir for 14 h, and then warmed to
room temperature. The solution was then concentrated in vacuo.
Purification by column chromatography (petrol/ethyl acetate
80:20) yielded 13 (910 mg, 74%) as a colourless oil. Rf = 0.60 (pet-
4.2. Preparation of amide 7
Thionyl chloride (0.27 ml, 3.7 mmol) was added to a flask con-
taining (S)-(+)-2-methylbutyric acid (0.27 ml, 2.5 mmol). The solu-
tion was heated at reflux for 3 h and then concentrated in vacuo.
The residue was taken up in CH2Cl2 and concentrated once more
to remove any remaining thionyl chloride. The product was then
dissolved in CH2Cl2 and added dropwise to a solution of 6 (0.4 g,
1.1 mmol) and triethylamine (0.34 ml, 2.5 mmol) at 0 °C. This solu-
tion was left to stir for 14 h, then warmed to room temperature.
The solution was then concentrated in vacuo. Purification by col-
rol/ethyl acetate 80:20); ½a D20
ꢃ
¼ þ18:3 (c 0.003, CH3CN); 1H NMR
(400 MHz, CDCl3, 22 °C, TMS): d = 7.31–7.21 (m, 10H; Ar-H), 6.19
(d, 1J(H,H) = 7.9 Hz, 2H; 2 ꢂ NH), 3.74–3.64 (m, 2H; 2 ꢂ CHN),
3.55 (d, 1J(H,H) = 4.6 Hz, 2H; one of CH2OSi), 3.53–3.47 (m, 2H;
one of CH2OSi), 3.26–3.12 (m, 2H; 2 ꢂ CHAr), 2.20–2.08 (m, 2H;
one of CH2CH3), 1.83–1.69 (m, 2H; one of CH2CH3), 1.61 (t,
3J(H,H) = 6.0 Hz, 2H; CHCH2CH), 0.85–0.75 (m, 24H; 2 ꢂ t-Bu,
2 ꢂ CH3CH2), 0.08–0.06 ppm (m, 12H; Si(CH3)2); 13C NMR
(100 MHz, CDCl3, 22 °C, TMS): d = 173.6 (2 ꢂ C@O), 140.0
(2 ꢂ ArCCH), 128.8 (4 ꢂ meta/ortho ArC), 128.1 (4 ꢂ meta/ortho
ArC), 127.1 (2 ꢂ para ArC), 64.4 (2 ꢂ CH2O), 55.3 (2 ꢂ CHAr), 48.6
(2 ꢂ CHN), 33.4 (CHCH2CH), 26.5 (2 ꢂ CH2CH3), 25.8 (6 ꢂ CCH3),
18.2 (2 ꢂ CCH3), 12.5 (2 ꢂ CH3CH2), ꢀ5.5 ppm (2 ꢂ Si(CH3)2); IR
umn chromatography (petrol/ethyl acetate 80:20) yielded
7
(203 mg, 35%) as a colourless oil. Rf = 0.3 (petrol/ethyl acetate
80:20); ½a 2D0
ꢃ
¼ ꢀ15:2 (c 0.003, CH3CN); 1H NMR (400 MHz, CDCl3,
22 °C, TMS): d = 6.23–6.13 (m, 2H; 2 ꢂ NH), 3.89–3.78 (m, 2H;
2 ꢂ CHN), 3.69–3.64 (m, 4H; 2 ꢂ CH2OSi), 2.13–2.05 (m, 2H;
2 ꢂ CHCH3), 1.81 (t, 3J(H,H) = 6.4 Hz, 2H; CHCH2CH), 1.69–1.56
(m, 2H; one of CH2CH3), 1.46–1.35 (m, 2H; one of CH2CH3), 1.13–
1.09 (dd, J = 6.9 Hz, 3.2 Hz, 6H; CH3CH), 0.88 (m, 24H; 2 ꢂ t-Bu,
2 ꢂ CH3CH2), 0.05–0.04 ppm (series of singlets due to rotamers,
12H; Si(CH3)2); 13C NMR (100 MHz, CDCl3, 22 °C, TMS): d = 176.5
(2 ꢂ C@O), 65.0 (2 ꢂ CH2O), 48.3 (2 ꢂ CHN), 43.4 (2 ꢂ CHCH3),
36.7 (CHCH2CH), 27.5 (2 ꢂ CH3CH2), 25.9 (6 ꢂ CCH3), 18.3 (2 ꢂ C),
17.5 (2 ꢂ CH3CH), 12.0 (2 ꢂ CH3CH2), ꢀ5.3 ppm (2 ꢂ Si(CH3)2); IR
(neat):
m
= 3312, 2956, 2929, 2857, 1647 cmꢀ1 (C@O); HRMS
(ESI): m/z calcd for C37H62N2O4Si2-H+: 653.4170 [MꢀH+]; found:
653.4175.
(neat):
m
= 3294, 2957, 2932, 2862, 1642 cmꢀ1 (C@O); HRMS
4.5. Preparation of ligand 9
(ESI): m/z calcd for C27H58N2O4Si2-H+: 529.3857 [MꢀH+]; found:
529.3880.
To a solution of 7 (190 mg, 0.36 mmol) and p-toluenesulfonyl
fluoride (138 mg, 0.79 mmol) in dry acetonitrile (10 ml) was added
4.3. Preparation of amide 8
DBU (118 lL, 0.79 mmol). The mixture was stirred at reflux over-
night, cooled and concentrated in vacuo. Purification by column
chromatography (petrol/ethyl acetate 30:70) yielded 9 (52.6 mg,
55%) as a colourless oil. Rf = 0.06 (petrol/ethyl acetate 80:20);
Thionyl chloride (0.66 ml, 9.12 mmol) was added to a flask con-
taining (S)-(+)-2-phenylbutyric acid (1.1 ml, 6.1 mmol). The solu-
tion was heated at reflux for 3 h and then concentrated in vacuo.
The residue was taken up in CH2Cl2 and concentrated once more
to remove any remaining thionyl chloride. The product was then
dissolved in CH2Cl2 and added dropwise to a solution of 6 (1.6 g,
2.76 mmol) and triethylamine (1.45 ml, 6.1 mmol) at 0 °C. This
solution was left to stir for 14 h, and then warmed to room temper-
ature. The solution was then concentrated in vacuo. Purification by
column chromatography (petrol/ethyl acetate 80:20) yielded 8
(1.08 g, 60%) as a colourless oil. Rf = 0.64 (petrol/ethyl acetate
½
a 2D0
ꢃ
¼ þ17:6 (c 0.003, CH3CN); 1H NMR (400 MHz, CDCl3, 22 °C,
TMS): d = 4.38–4.30 (m, 2H; one of CH2O), 4.25–4.14 (m, 2H;
2 ꢂ CHN), 3.85 (t, 3J(H,H) = 8.1 Hz, 2H; one of CH2O), 2.42–2.33
(m, 2H; 2 ꢂ CHCH3), 1.76–1.71 (m, 2H; CHCH2CH), 1.68–1.58 (m,
2H; one of CH2CH3), 1.52–1.41 (m, 2H; one of CH2CH3), 1.14 (d,
1J(H,H) = 6.9 Hz, 6H; 2 ꢂ CHCH3), 0.90 ppm (t, 3J(H,H) = 7.3 Hz,
6H; 2 ꢂ CH3CH2); 13C NMR (100 MHz, CDCl3, 22 °C, TMS):
d = 171.2 (2 ꢂ C@N), 73.1 (2 ꢂ CH2O), 64.8 (2 ꢂ CHN), 47.3
(CHCH2CH), 35.1 (2 ꢂ CHCH3), 27.2 (2 ꢂ CH2CH3), 17.4
80:20); ½a 2D0
ꢃ
¼ ꢀ13:6 (c 0.003, CH3CN); 1H NMR (400 MHz, CDCl3,
(2 ꢂ CHCH3), 11.7 ppm (CH3CH2); IR (neat):
m
= 2971, 1669 cmꢀ1
22 °C, TMS): d = 7.30–7.25 (m, 10H; Ar-H), 6.05 (d, 1J(H,H) = 8.3 Hz,
2H; 2 ꢂ NH), 3.74–3.64 (m, 2H; 2 ꢂ CHN), 3.53–3.44 (m, 4H;
2 ꢂ CH2OSi), 3.21 (t, 3J(H,H) = 7.4 Hz, 2H; 2 ꢂ CHAr), 2.21–2.09
(m, 2H; one of CH2CH3), 1.84–1.73 (m, 2H; one of CH2CH3), 1.64
(t, 3J(H,H) = 6.4 Hz, 2H; CHCH2CH), 0.87 (t, 3J(H,H) = 7.4 Hz, 6H;
2 ꢂ CH3CH2), 0.78–0.77 (series of singlets due to rotamers, 18H;
2 ꢂ t-Bu), ꢀ0.01 to ꢀ0.12 ppm (series of singlets due to rotamers,
12H; Si(CH3)2); 13C NMR (100 MHz, CDCl3, 22 °C, TMS): d = 173.6
(2 ꢂ C@O), 140.2 (2 ꢂ ArCCH), 128.8 (4 ꢂ meta/ortho ArC), 128.1
(4 ꢂ meta/ortho ArC), 127.2 (2 ꢂ para ArC), 64.7 (2 ꢂ CH2O), 55.3
(2 ꢂ CHAr), 48.5 (2 ꢂ CHN), 33.4 (CHCH2CH), 26.2 (2 ꢂ CH2CH3),
(C@N); HRMS (ESI): m/z calcd for C15H26N2O2+H+: 267.2072
[M+H+]; found: 262.2078.
4.6. Preparation of ligand 10
To a solution of 8 (1.00 g, 2.2 mmol) and p-toluenesulfonyl fluo-
ride (843 mg, 4.84 mmol) in dry acetonitrile (30 ml) was added
DBU (724 lL, 4.84 mmol). The mixture was stirred at reflux over-
night, cooled and concentrated in vacuo. Purification by column
chromatography (petrol/ethyl acetate 30:70) yielded 10
(316.8 mg, 37%) as a colourless oil. Rf = 0.56 (Petrol:ethyl acetate
Please cite this article in press as: Kellehan, D.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.04.020

D. Kellehan et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
7
30:70); ½a 2D0
ꢃ
¼ ꢀ18:7 (c 0.003, CH3CN); 1H NMR (400 MHz, CDCl3,
was stirred for a further 15 min. The catalyst was transferred to
the substrate–nucleophile mixture via a gas-tight syringe, along
with a toluene rinse (1 mL). The reaction mixture was then stirred
at 80 °C for 60 h. At this point, a saturated NH4Cl solution (10 mL)
was added, the organic layer was separated and the aqueous layer
was extracted with diethyl ether (3 ꢂ 10 mL). The combined or-
ganic layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4, filtered and concentrated in vacuo to yield the
crude product. A 1H NMR spectrum was recorded to determine
the conversion [unreacted ( )-(E)-1,3-diphenyl-3-acetoxyprop-1-
ene signal at 2.14 (3H) compared to the product signal at 4.27
(1H)]. The crude product was then purified by column chromatog-
raphy (pet. ether/ethyl acetate, 25:1). The enantiomeric excess (ee)
of the product was then measured using chiral HPLC (CHIRACEL
OD, 254 nm, hexane (0.1% diethylamine):iso-propyl alcohol, 98:2,
0.5 mL/min), t(R) 25.2, t(S) 26.9.
22 °C, TMS): d = 7.29 (m, 10H; Ar-H), 4.30–4.38 (m, 2H; one of
CH2O), 4.19–4.27 (m, 2H; 2 ꢂ CHN), 3.82–3.88 (m, 2H; one of
CH2O), 3.40–3.46 (m, 2H; 2 ꢂ CHAr), 2.01–2.10 (m, 2H; one of
CH3CH2), 1.75–1.87 (m, 2H; one of CH3CH2), 1.70–1.74 (m, 2H;
CHCH2CH), 0.89 ppm (t, 3J(H,H) = 7.3 Hz, 6H; 2 ꢂ CH3CH2); 13C
NMR (100 MHz, CDCl3, 22 °C, TMS): d = 168.8 (2 ꢂ C@N), 140.2
(2 ꢂ ArCCH), 128.6 (4 ꢂ meta/ortho ArC), 128.0 (4 ꢂ meta/ortho
ArC), 127.1 (2 ꢂ para ArC), 73.3 (2 ꢂ CH2O), 64.8 (2 ꢂ CHN), 47.3
(2 ꢂ CHAr), 43.4 (CHCH2CH), 27.2 (2 ꢂ CH2CH3), 12.3 ppm
(2 ꢂ CH3); IR (neat) IR (neat):
m
= 2964, 2932, 1656 cmꢀ1 (C@N);
HRMS (ESI): m/z calcd for C25H30N2O2ꢀH+: 389.2229 [MꢀH+];
found: 389.2240.
4.7. Preparation of ligand 11
To a solution of 13 (800 mg, 1.22 mmol) and p-toluenesulfonyl
fluoride (469 mg, 2.68 mmol) in dry acetonitrile (30 ml) was added
4.10. General procedure for the Diels–Alder reaction
DBU (400 lL, 2.68 mmol). The mixture was stirred at reflux over-
night, cooled and concentrated in vacuo. Purification by column
To
a flame-dried N2 filled Schlenk were added Cu(OTf)2
(0.033 mmol, 10 mol %), ligand (0.033 mmol, 10 mol %), 4 Å pow-
dered molecular sieves (20 mg) and CH2Cl2 (2 mL). This mixture
was stirred under N2 for 90 min at room temperature. To this stir-
ring catalyst was added trans-(crotonoyl)-2-oxazolidinone (51 mg,
0.33 mmol) and freshly distilled cyclopentadiene (0.10 ml,
1.21 mmol). The reaction proceeded at room temperature for
16 h. A mixture of endo and exo products was isolated as an oil.
The endo:exo product ratio was measured by 1H NMR. The crude
mixture was then purified by column chromatography (petrol/
ethyl acetate, 3:2) affording a mixture of endo and exo products
as a colourless oil, from which the enantiomeric excess (ee) of
the endo diastereomer was measured on the purified product using
chiral HPLC (CHIRACEL OD, 254 nm, hexane/iso-propyl alcohol,
98:2, 1.0 ml/min), t(S) 22.5, t(R) 28.5.
chromatography (petrol/ethyl acetate 20:80) yielded 11 (315 mg,
66%) as
a yellow oil. Rf = 0.50 (petrol/ethyl acetate 20:80);
½
a 2D0
ꢃ
¼ þ59:8 (c 0.003, CH3CN); 1H NMR (400 MHz, CDCl3, 22 °C,
TMS): d = 7.29 (m, 10H; Ar-H), 4.40–4.35 (m, 2H; one of CH2O),
4.28–4.17 (m, 2H; 2 ꢂ CHN), 3.88–3.81 (m, 2H; one of CH2O),
3.47–3.40 (m, 2H; 2 ꢂ CHAr), 2.12–2.00 (m, 2H; one of CH3CH2),
1.88–1.79 (m, 2H; one of CH3CH2), 1.79–1.67 (m, 2H; CHCH2CH),
0.88 ppm (t, 3J(H,H) = 7.5 Hz, 6H; 2 ꢂ CH3CH2); 13C NMR
(100 MHz, CDCl3, 22 °C, TMS): d = 168.7 (2 ꢂ C@N), 140.1
(2 ꢂ ArCCH), 128.5 (4 ꢂ meta/ortho ArC), 127.8 (4 ꢂ meta/ortho
ArC), 127.0 (2 ꢂ para ArC), 73.3 (2 ꢂ CH2O), 64.6 (2 ꢂ CHN), 47.2
(2 ꢂ CHAr), 43.4 (CHCH2CH), 27.0 (2 ꢂ CH2CH3), 12.2 ppm
(2 ꢂ CH3); IR (neat):
m
= 2964, 2932, 1657 cmꢀ1 (C@N); HRMS
(ESI): m/z calcd for C25H30N2O2ꢀH+: 389.2229 [MꢀH+]; found:
389.2238.
4.11. Computational studies
4.8. General procedure for asymmetric cyclopropanation
catalysed by ligand–Cu(I) complexes
The geometries of the reaction intermediates and transition
states were optimized using density functional theory (DFT) calcula-
tions with the 6-31G(d) basis set, employing Becke’s three parame-
terized Lee–Yang–Parr exchange functional (B3LYP),22,23 and using a
GAUSSIAN 09 Programs suite.24Frequency analyses were carried out at
the same level to test the nature of the intermediates and transition
structures found, according to the correct number of negative eigen-
values of the corresponding Hessian matrices, and the vibrational
frequencies associated to the negative eigenvalues. In some cases,
single point energy calculations were carried out using different
functionals and basis sets, to check the consistency of the results.
Enantioselectivities were estimated based on the calculated relative
Gibbs free energies of the TS, unless otherwise stated.
A solution of ligand (0.013 mmol) and [Cu(OTf)]2ꢄC6H6 (3 mg,
0.006 mmol) in CH2Cl2 (1 mL) was stirred under a nitrogen atmo-
sphere at room temperature for 90 min and then transferred
through a cotton plug to a flame-dried N2-filled Schlenk. Styrene
(690
(137
l
l
L, 5 mmol) was then added. A solution of ethyldiazoacetate
L, 1.2 mmol) in dry CH2Cl2 was added over approximately
6 h via a syringe pump. After the addition was complete, the reac-
tion was stirred for an additional 12 h. The reaction was then con-
centrated in vacuo to afford the crude product. The conversion and
trans/cis ratio were determined by 1H NMR. Flash chromatography
of the residue (petrol/EtOAc; 25:1) provided a mixture of trans/cis
isomers. The enantiomeric excess of each isomer was determined
Acknowledgments
by chiral GC (Cyclodex-B 30 m ꢂ 0.252 mm ꢂ 0.25
lm).
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland (RFP/06/
CHO039).
4.9. General procedure for the asymmetric allylic alkylation
reactions
Tri(benzylideneacetone)dipalladium (10 mol %) was added to a
flame dried N2 filled Schlenk. Next, the BOX ligand (15 mol %)
was weighed into a second flame dried N2 filled Schlenk and dis-
solved in toluene (1 mL). The ligand solution was then transferred
under N2, into the Schlenk containing the metal. The resulting mix-
ture was then stirred for 2 h at 80 °C. Next, NaH (2.2 equiv), di-
methyl malonate (2.0 equiv) and toluene (8 mL), were weighed
into a third flame dried N2 filled Schlenk. The resulting solution
was stirred at 80 °C for 15 min, before the addition of ( )-(E)-1,3-
diphenyl-3-acetoxyprop-1-ene (1 equiv) in toluene (1 mL), and
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