A reusable, insoluble polymer-bound bis(oxazoline) (IPB-box) for highly enantioselective heterogeneous cyclopropanation reactions

Article abstract of DOI:10.1039/b306483b

A reusable, insoluble polystyrene-supported bis(oxazoline) was developed, affording e.e.s > 90% in the heterogeneous enantioselective cyclopropanation of styrene and 1,1-disubstituted alkenes with ethyl diazoacetate.

Full text of DOI:10.1039/b306483b

A reusable, insoluble polymer-bound bis(oxazoline) (IPB-box) for highly
enantioselective heterogeneous cyclopropanation reactions†
Alessandro Mandoli, Simonetta Orlandi, Dario Pini and Piero Salvadori*
Dipartimento di Chimica e Chimica Industriale, Via Risorgimento 35, Pisa, Italy.
E-mail: psalva@dcci.unipi.it; Fax: +39-050-2219409; Tel: +39-050-2219273
Received (in Cambridge, UK) 9th June 2003, Accepted 4th August 2003
First published as an Advance Article on the web 4th September 2003
A reusable, insoluble polystyrene-supported bis(oxazoline)
was developed, affording e.e.s > 90% in the heterogeneous
enantioselective cyclopropanation of styrene and 1,1-dis-
ubstituted alkenes with ethyl diazoacetate.
linking or to the occurrence of unfavourable site–site inter-
actions,5 from the practical point of view of e.e. maximization
it seemed however possible that the relatively unsuccessful
attempts reported to date would result from the failure to
replicate the optimal structure of 1 in the materials described so
far. For this reason we decided to evaluate the asymmetric
cyclopropanation reaction of the supported ligand 2, whose box
units were likely to experience a minimal increase of steric
hindrance at the bridging methylene carbon compared to 1 (Rox
= t-Bu, Rbr = Me).
The stereoselective synthesis of cyclopropane derivatives is a
topic of major current interest,1 in view of the strong
configuration–bioactivity relationship displayed by several
pharmaceutical and agrochemical compounds containing this
structural unit. Given the ready availability of the starting
materials and the high activity/low cost of copper salts, as far as
the preparation of enantioenriched chiral cyclopropanecar-
The highly ( ~ 54%) cross-linked material 2 (ligand loading:
0.31 mmol g21, from nitrogen elemental analysis) was obtained
by AIBN-initiated radical copolymerisation of the correspond-
ing monomers, as described before.10 In spite of the remarkably
compact texture by SEM analysis (Fig. 1) and low surface area
in the dry state ( < 5 m2 g21), 2 appeared to swell in a solution
of Cu(OTf)2 in THF. Accordingly, the rapid uptake of
0.18–0.20 mmol g21 of the metal salt took place, demonstrating
that about 60% of the supported box units could be readily
engaged in the metal complexation.
boxylic acids is concerned, the Cu( )-catalysed enantioselective
I
cyclopropanation of olefins with diazoesters is one of the most
convenient options. Besides the use of chiral Schiff base–Cu
complexes (Sumitomo process for Cilastatin intermediate),2
work by several groups1 demonstrated that bis(oxazolines) 1
(box) often represent the ligand of choice in terms of
enantiodiscrimination ability. However, the high cost of 1
(especially for Rox = t-Bu) severely limits the practical
application of this class of auxiliaries in asymmetric synthesis,
prompting the search for easily recoverable analogues, either by
preparation of modified soluble box3 and aza-box ligands,4 or
by immobilization onto insoluble supports.5
1
In order to avoid the use of toxic and unstable CuOTf·2C6H6,6
the resulting supported complex was directly used as the
catalyst precursor. To obtain the catalytically active Cu( )
I
species, reduction of the metal centre was effected in situ before
the catalysis runs, by warming 2·Cu(OTf)2 with a slight excess
of the diazoester 4.6
The cyclopropanation experiments (Scheme 1) were carried
out in CH2Cl2 at 0 °C, normally with 2 equiv. of the alkene
substrate and adding the diazoester dropwise, to improve the
chemoselectivity by minimization of maleate and fumarate
byproducts. In view of the modifications introduced to the
standard procedure by Evans,6 homogeneous control runs with
the soluble ligand 1 (Rox = t-Bu, Rbr = Me) were initially
repeated under the conditions of heterogeneous experiments
(Table 1, entries 1, 3 and 5). Because only minor reductions of
stereoselectivity were observed with respect to the best
literature results,6 and considering that e.e. values in the
Focusing on the latter IPB approach, it is worth noting that
while satisfactory activity and stereoselectivity values have
been achieved for a few miscellaneous transformations,5 the
results in the case of heterogeneous catalytic cyclopropanation
appear to lag behind those provided by the best soluble parent
ligands 1 (Rox = t-Bu, Rbr = H or Me), that are known to afford
93–99% e.e. in the benchmark reaction of styrene with ethyl
diazoacetate.6 In spite of considerable efforts, most notably by
Mayoral’s group,7,8 only recently the use of composite organic/
inorganic ion exchange supports led in fact to e.e. values higher
than 90%, albeit with low yields and some ligand leaching
problems.9 Regarding the covalent anchoring to insoluble
organic materials, best results (e.e. 5 79%) were obtained with
resins prepared from box monomers bearing two 4-vinylbenzyl
groups at the bridging carbon, although these materials suffer
from inefficient use of the chiral ligand, with only 4–38% of the
chiral units available for Cu complexation.8 While the reduction
of stereoselectivity with respect to the soluble counterparts has
been correlated to the loss of C2 symmetry, excessive cross-
Fig. 1 SEM image of the material 2.
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b3/b306483b/
Scheme 1 Cyclopropanation of alkenes with ethyl diazoacetate 4.
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CHEM. COMMUN., 2003, 2466–2467
This journal is © The Royal Society of Chemistry 2003

Table 1 boxCu-catalysed homogeneous and heterogeneous enantioselective cyclopropanation of alkenes with ethyl diazoacetate 4
5
Chemosel.
(%)a,b
Run
3 (R1,R2)
Ligand
4/box
4/Cu
Time/h
Yield (%)c D.r.b,d
E.e. (%)e
1
2
3
4
5
6
7
8
9
Ph,H
Ph,H
1 (Rox = t-Bu, Rbr = Me)
45
28
45
50
50
50
3
3
3
63
61
n.d.m
n.d.m
97
85
88
88
89
61
60
97
75
92
53
84o
84o
84o
71 : 29
67 : 33
—
—
—
—
—
—
—
94f,g (99) 92g,h (97)
2
93
90
Ph,Ph
Ph,Ph
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
1 (Rox = t-Bu, Rbr = Me)
98i ( > 99)
2
28
50
3
91
1 (Rox = t-Bu, Rbr = Me)
455
566
283n
283n
283n
500
1000
500
500
500
16
44
22
22
22
97l ( > 99)
2
2
2
2
92
92
91
91
a Chemoselectivity in the formation of cyclopropane products. b By GLC. c Isolated yields. d Trans : cis ratio. e Absolute configuration of the prevailing
1
enantiomer: 1R. In parentheses, e.e. values with CuOTf·2C6H6 as the catalyst precursor (from ref. 6). f E.e. of trans product. g By HPLC (Chiralcel OJ, hexane
: 2-propanol = 99.5 : 0.5). h E.e. of cis product. i By HPLC (Chiralcel OD–H, hexane : 2-propanol = 99.4 : 0.6). l By GLC (Astec G-TA). m Not determined.
n Recycled ligand from the previous run. o Overall yield, by distillation of the pooled crude products from runs 7–9.
92–98% range could be nonetheless attained for all the
substrates examined, the modified procedure was judged
suitable for this exploratory study.
would eventually result in catalyst deactivation, further runs
with recovered material were carried out at a 4/Cu ratio of 500
and adding 4 over 16 h with a syringe pump. Indeed, although
direct reuse of the 2·Cu complex was precluded at these low
catalyst loadings, probably because of extensive metal leaching,
after recharging the recovered ligand with the copper salt and
repeating the reduction step, conversion values of 95–99% and
e.e.s of 91–92% could be attained in 22 h under these conditions
(entries 7–9). Actually, by making use of the concept of ligand
economy introduced by Mayoral and co-workers,7 the data from
runs 6–9 correspond to a total TON of 1010 with respect to the
supported box, demonstrating that 2·Cu is significantly more
effective than any recoverable box–Cu cyclopropanation cata-
lytic system reported to date,11 either soluble4 or insoluble.5,8
In conclusion, this preliminary work demonstrates that
proper design of the copolymer architecture, with a single,
flexible spacer linking the ligand moiety to the inert polystyrene
backbone, appears effective in providing the box units in 2 with
solution-like behaviour, leading to satisfactory ligand availabil-
ity and catalytic activity. Even more importantly, in spite of the
formal loss of C2 symmetry of the supported ligand, e.e. values
higher than 90% could be obtained for the first time in the
heterogeneous cyclopropanation of different alkenes, using a
bis(oxazoline) covalently anchored to an insoluble support.
Work is currently underway to optimise the stereoselectivity
and to address in greater detail the issue of catalyst recycling.
Work supported by the University of Pisa, MIUR (Project
“Stereoselezione in Sintesi Organica”) and ICCOM-C.N.R. Mr.
P. Narducci is gratefully acknowledged for the SEM analysis.
With this information, the heterogeneous catalysis in the
benchmark cyclopropanation of styrene was examined first.
Using 3.6 mol% of the supported box 2 (2 mol% of catalyst
precursor, estimated from Cu uptake), total conversion of the
diazoester was observed within 5 min of the addition comple-
tion, with formation of the cyclopropane product 5, as a mixture
of trans and cis diastereomers, in satisfactory overall yield
(entry 2). Control experiments demonstrated that no activity
was present in the filtrate from 2·Cu, confirming the truly
heterogeneous nature of the catalytic system. Concerning the
stereoselectivity, a slight reduction in the diastereomeric ratio
was observed with the supported complex, possibly as a result
of increased steric hindrance at the box methylene, but this did
not translate into a substantial decrease of enantioselectivity, as
e.e. values within 1–2% of the homogeneous reference run were
obtained in both the trans and cis manifold.
To assess the possibility of reusing the supported catalyst, at
the end of the reaction the polymer material was filtered,
washed with CH2Cl2, dried and directly used in a further run.
Following this procedure 5 recycles could be easily carried out
(Fig. 2), achieving in each case complete conversion and almost
unchanged chemo- and stereoselectivity values.
The scope of the heterogeneous asymmetric cyclopropana-
tion with 2·Cu could also be extended to the 1,1-disubstituted
olefins 1,1-diphenylethylene (entry 4) and isobutene (entry 6),
obtaining for both alkenes e.e. values > 90%. In fact, for the
latter substrate the reaction was initially run at a diazoester/Cu
ratio of 1000, to have a comparison with the results published
for the soluble ligand 1 (Rox = t-Bu, Rbr = Me),6 but under
these conditions (7.5 equiv. isobutene vs. 4, 6 h addition time)
the reaction proved relatively slow, with largely incomplete
conversion (66%) even after 44 h. Speculating that the
diazoester accumulation, due to the reduced catalytic activity,
Notes and references
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Sánchez-Verdú and J. Tolosa, Tetrahedron: Asymmetry, 2003, 14, 773
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11 For a recent example of a highly recyclable Rh catalyst: T. Nagashima
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Fig. 2 Recycling of 2·Cu in the cyclopropanation of styrene.
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