The immobilisation of chiral organocatalysts on magnetic nanoparticles: The support particle cannot always be considered inert

Article abstract of DOI:10.1039/c1ob06110k

A systematic study concerning the immobilisation onto magnetic nanoparticles of three useful classes of chiral organocatalyst which rely on a confluence of weak, easily perturbed van der Waals and hydrogen bonding interactions to promote enantioselective

Full text of DOI:10.1039/c1ob06110k

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PAPER
The immobilisation of chiral organocatalysts on magnetic nanoparticles:
the support particle cannot always be considered inert†
Oliver Gleeson,a Gemma-Louise Davies,b Aldo Peschiulli,a Renata Tekoriute,b Yurii K. Gun’ko*b and
Stephen J. Connon*a
Received 7th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1ob06110k
A systematic study concerning the immobilisation onto magnetic nanoparticles of three useful classes
of chiral organocatalyst which rely on a confluence of weak, easily perturbed van der Waals and
hydrogen bonding interactions to promote enantioselective reactions has been undertaken for the first
time. The catalysts were evaluated in three different synthetically useful reaction classes: the kinetic
resolution of sec-alcohols, the conjugate addition of dimethyl malonate to a nitroolefin and the
desymmetrisation of meso anhydrides. A chiral bifunctional 4-N,N-dialkylaminopyridine derivative
could be readily immobilised; the resulting heterogeneous catalyst is highly active and is capable of
promoting the kinetic resolution of sec-alcohols with synthetically useful selectivity under process-scale
friendly conditions and has been demonstrated to be reusable in a minimum of 32 consecutive cycles.
The immobilisation of a cinchona alkaloid-derived urea-substituted catalyst proved considerably less
successful in terms of both catalyst stability and product levels of enantiomeric excess. An immobilised
cinchona alkaloid-derived sulfonamide catalyst was also prepared, with mixed results: the catalyst
exhibits outstanding recyclability on a par with that associated with the successful
N,N-dialkylaminopyridine analogue, however product enantiomeric excess is consistently lower than
that obtained using the corresponding homogeneous catalyst. While no physical deterioration of the
heterogeneous catalysts was detected on analysis after multiple recycles, in the cases of both the
conjugate addition to nitroolefins and the desymmetrisation of meso anhydrides, significant levels of
background catalysis by the nanoparticles in the absence of the organocatalyst was detected, which
explains in part the poor performance of the immobilised organocatalysts in these reactions from a
stereoselectivity standpoint. It seems clear that the immobilisation of sensitive chiral organocatalysts
onto magnetite nanoparticles does not always result in heterogeneous catalysts with acceptable activity
and selectivity profiles, and that consequently the applicability of the strategy must be ascertained (until
more data is available) on a case-by-case basis.
these stable materials can be separated from solution after reaction
Introduction
by filtration and subsequently reused.1
In theory, a catalyst should emerge unaltered from a reaction it
The main disadvantages associated with the immobilisation of
promotes, and therefore its perpetual use should be theoretically
organocatalysts on polymer supports include reduced reaction
possible. In practice this is difficult, largely due to (partial)
rates associated with mass transfer and (particularly in the case
of polystyrene-based supports2) the requirement for a filtration
step (inconvenient on process scale) and physical degradation
of the support (particularly in the case of polystyrene-based
supports- often with concomitant mechanical loss on filtration)
upon continual reuse.
decomposition, product inhibition or mechanical loss on recovery.
Therefore there has been considerable recent interest in the immo-
bilisation of stable, largely moisture insensitive small molecule
organocatalysts on heterogeneous supports, with the idea that
In an attempt to circumvent some of these difficulties, attention
has recently begun to focus on the use of magnetic nanoparticles
as heterogeneous organocatalyst supports.3,4 The key premise
underpinning the design of these catalysts is that a combination of
a robust, high surface area support with moisture insensitive small
molecule catalysts potentially allows the practitioner to aspire
towards the design of catalysts of genuinely high recyclability.5
aCentre for Synthesis and Chemical Biology, School of Chemistry,
Trinity College Dublin, Dublin, 2, Ireland. E-mail: connons@tcd.ie;
Fax: +35316712826
bSchool of Chemistry and CRANN, Trinity College Dublin, Dublin, 2,
Ireland. E-mail: igounko@tcd.ie; Fax: +35316712826
† Electronic supplementary information (ESI) available: Synthesis of all
catalysts, general procedures, FTIR spectra, TGA curves, XRD patterns,
NMR spectra and HPLC chromatograms. See DOI: 10.1039/c1ob06110k
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Another key advantage associated with such systems is that a
filtration step is not required (which is particularly useful in
process-scale applications)- the catalyst can be separated from the
crude reaction mixture upon exposure to an external magnet and
subsequent decantation.
This class of catalyst has been shown to promote highly efficient
desymmetrisations of meso-anhydrides by alcoholysis21 and has
also been utilised in a tandem desymmetrisation/thiol kinetic res-
olution reaction.22 The three catalyst systems are readily prepared,
they are air/moisture insensitive and they represent a reasonably
broad (in an organocatalytic context) range of characteristics
(pKa, basicity/nucleophilicity, reaction mechanism and substrate
scope etc.), the interaction (if any) of which with magnetite
nanoparticle supports would be interesting to determine.
In 2007, we developed the first ‘hypernucleophilic’ 4-N,N-
dimethylaminopyridine (DMAP)6 catalyst immobilised on mag-
netite nanoparticles. The resultant heterogeneous catalyst was
highly active and recyclable in acyl transfer processes, Stieglitz
rearrangements and hydroalkoxylation7 reactions at loadings
between 1 and 10% and could be recovered and recycled over
30 times without any discernible loss of activity.8 Given the
unprecedented recyclability exhibited by this catalyst, we were
naturally eager to apply this immobilisation technology to more
valuable, chiral catalyst systems. The literature is replete with
examples of systems where highly active and selective chiral
homogeneous organocatalyst systems have, on immobilisation,
resulted in heterogeneous catalysts of moderate recyclability
(i.e. <10 cycles) and diminished capability to promote highly
enantioselective reactions.1 Thus the identification of a high-
surface area solid (magnetically recoverable) support which does
not interfere in catalysis to any appreciable extent would represent
a significant development in the field.
In a preliminary communication,23 we detailed the design
and evaluation of catalyst 5- an immobilised variant of 1-
as a recyclable promoter of the acylative KR of sec-alcohols.
This strategy was gratifyingly simple to implement- the catalyst
could be readily prepared (the magnetite nanoparticles of 7.9
1.5 nm were prepared via the coprecipitation technique),24,25
1
the loading could be monitored by H NMR spectroscopy, and
the activity/selectivity profiles were excellent: for example, the
racemic alcohol 6 could be asymmetrically acylated at ambient
temperature in the presence of a relatively low loading of catalyst
(5 mol%) for 20 consecutive recycles (Scheme 1). The protocol was
set up to be as practical and operationally simple as possible- we
utilised the cheap, unhindered acetic anhydride as the acylating agent
at ambient temperature (often artificial acylating agents require the
use of low reaction temperatures and more hindered and expensive
anhydrides such as (iBuCO)2O to obtain high selectivity).10,11,26
After each reaction, the catalyst was easily separated from the
products by exposure of the reaction vessel to an external magnet,
followed by decantation of the reaction solution. The catalyst
(which remains in the flask) was washed with THF to remove
residual product and dried under high vacuum, whereupon it
was ready for reuse. We have found that no special handling
precautions regarding exposure to air/moisture need be taken in
the use of catalyst 5.
We therefore set out to answer two questions: firstly, can
magnetite nanoparticles be used to generate chiral heterogeneous
catalysts with activity and selectivity profiles not significantly
different from that of their parent homogeneous analogues?
Secondly, how broad is the potential scope of this strategy—
can it be extended with advantage beyond DMAP-based systems
to other proven organocatalysts which rely on weak interactions
(particularly hydrogen bonding and general acids/base catalysis)?
We selected three classes of homogeneous organocatalyst sys-
tems for immobilisation: the chiral DMAP9,10 derivative 1, the
bifunctional (thio)urea-substituted cinchona alkaloid catalysts 2–
3 and the analogous sulfonamide system 4. Catalyst 1- which is
readily accessible from L-proline- has been demonstrated to be
capable of promoting highly enantioselective acylation reactions.11
It has also found application in the development of a chemically
driven information ratchet.12 The second (thio)urea system (i.e.
2–3, Fig. 1) has been the focus of intensive investigation over the
past six years13 -for example our group (among others) have shown
that these catalysts promote enantioselective Michael addition-
14
16
,
Dynamic Kinetic Resolution- (DKR),15 desymmetrisation-,
Henry reaction-17 and transthioesterification18 processes, while
others have demonstrated their utility in a range of applications-
mostly in either addition or cycloadditions reactions.19 The third
sulfonamide-based catalyst system (i.e. 4) has emerged recently.20
Scheme 1 Heterogeneous catalyst 5 as a promoter of acylative KR.
The same batch of catalyst 5 was then employed in the KR of
other sec-alcohols and after having been used in 31 consecutive
cycles, we returned the KR of 6 at ambient temperature. We were
delighted to find that the by now heavily recycled catalyst performed
Fig. 1 Homogeneous bifunctional catalyst targets for immobilisation on
magnetite nanoparticles.
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exceptionally well, promoting the acylation with a selectivity factor
of 9.9 (recovered alcohol -93% ee at 64% conversion). In addition,
TEM analysis of the nanoparticles after the 32nd cycle indicated
a complete absence of particle degradation.
The immobilisation of the chiral DMAP-derivative exceeded
our expectations: it has been shown that a chiral organocat-
alyst which relies on a confluence of weak, easily perturbed
van der Waals and hydrogen bonding interactions to promote
enantioselective reactions can be readily immobilised on magnetite
nanoparticles and that the resulting heterogeneous catalyst is
highly active and is capable of promoting the kinetic resolution
of sec-alcohols with synthetically useful selectivity under process-
scale friendly conditions (ambient temperature, low catalyst
loading and acetic anhydride as the acylating agent)- which allows
the isolation of resolved alcohols with good-excellent enantiomeric
excess. Perhaps most importantly, the somewhat surprising lack of
interaction between the nanoparticle core and the organocatalyst
unit results in a chiral heterogeneous catalyst which is recyclable to
an unprecedented extent- in this study it has been demonstrated to
be reusable in a minimum of 32 consecutive cycles while retaining
high activity and selectivity profiles. It is worthwhile to note that
the previous literature benchmark for this class of supported chiral
acylation catalyst was a Merrifield resin-supported system which
could promote the KR of selected mono-protected cis-diols with
good selectivity (S up to 13 but inconsistent between runs) and
could be recycled four times.26
Scheme 2 Synthesis of the immobilised bifunctional urea 8.
Attempted clean synthesis of the corresponding thiourea ana-
logue repeatedly produced complex mixtures involving catalyst
decomposition and incomplete loading, in addition the resulting
heterogeneous catalyst failed to perform reproducibly in a range
of processes known to be susceptible to the influence of the
homogeneous catalyst 3.
Results and discussion
Catalyst 8 however, exhibited no such instability initially. This
catalyst was evaluated as a promoter of the asymmetric addition
of dimethyl malonate (13) to (E)-b-nitrostyrene (12). We had
previously reported14a that this reaction could be catalysed by
2 (at 5 mol% loading) to furnish adduct 14 in 74% ee in 5 h
reaction time.31 Under identical conditions use of the immobilised
material 8 allowed the formation of 14 in a comparable 71%
ee (Table 1, entry 1), however the catalyst’s activity proved
disappointing: only 70% conversion of 12 was recorded after
24 h. While the catalyst initially appeared to be as robust as the
heterogeneous DMAP-derivative 5 (product enantiomeric excess
actually increased during cycles 2 and 3, entries 2–3: we note that
this ‘ageing’ effect was previously observed by Takemoto in the use
of a homogeneous PEG-immobilised thiourea-based catalyst),29
Immobilisation of chiral bifunctional (thio)urea derivatives
We were next interested in an investigation of the effect of immo-
bilisation on (thio)urea-based catalyst systems. These catalysts are
of considerably broader scope (vide supra) than DMAP derivatives
and would thus represent an attractive target for immobilisation.
The interplay between the Brønsted-acidic and Brønsted-basic
catalyst components of the homogeneous promoters 2 and 3
represents a more delicate balance than that associated with
the corresponding DMAP-based catalyst 1, and as such any
interaction between the catalyst and the solid support would
be likely to disrupt the activity/selectivity profile considerably.
The sparse literature concerning the immobilisation of bifunc-
tional (thio)urea catalysts is not yet extensive enough to allow
conclusions to be drawn on the suitability of these catalysts for
immobilisation: for instance one report concerning their immo-
bilisation on mesoporous silica surfaces indicates that improved
activity/selectivity can be achieved relative to the homogeneous
system,27 while another clearly indicates that considerably reduced
activity results on loading a bifunctional28 thiourea catalyst
onto either polystyrene or polyethylene glycol.29 In both cases
continuous recyclability was poor (<6 cycles).
Table 1 Immobilised urea 8: Asymmetric catalysis of a Michael addition
reaction
To determine if magnetite could serve as a useful support for
these catalysts we synthesised the immobilised bifunctional urea 8
as follows: addition of the thiol 10 to the known quinine-derived
urea 9 in the presence of AIBN afforded the sulfide 11,30 which
could be isolated and then loaded onto magnetite nanoparticles
as before (using 4-iodoanisole as an internal standard to facilitate
quantitative 1H NMR spectroscopic analysis) with 100% efficiency
to afford 8 with a catalyst loading of 0.1 mmol g-1 (Scheme 2).
Entry
Cycle
Conversion (%)a
ee (%)b
1
2
3
4
1
2
3
4
70
70
71
46
71
72
77
n.d.
a Conversion determined by 1H NMR spectroscopy. b Determined by CSP-
HPLC.
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Table 2 Investigation of the potential influence of the nanoparticles on
product enantiomeric excess
Fig. 2 TEM images of (a) magnetite nanoparticles, (b) urea cata-
lyst-loaded nanoparticles (8) and (c) urea catalyst-loaded nanoparticles
(8) after recycling several times. Scale bar 100 nm.
Catalyst Loading Nanoparticle Loading
Entry
(mol%)
(mg mg-1 of 12)
Conv. (%)a ee (%)b
According to TEM analysis, the average particle diameter was
10 2 nm (Fig. 2). After loading the nanoparticles with catalyst to
prepare 8 and after recycling several times, the TEM images show
no changes in either nanoparticle size or morphology, however
they do appear slightly more aggregated.
FTIR analysis showed that the catalyst had been successfully
functionalised onto the magnetite nanoparticles (ESI†).24 It also
demonstrated that no degradation or damage appeared to occur
as a result of recycled use. Interestingly, TGA analysis indicated
that the amount of organic material on the catalyst-loaded
nanoparticles appeared to increase after recycling, indicating a
minute alteration in the compound due to multiple uses (ESI†).
This change could be responsible for the decrease in the catalytic
activity over time. The nature of the change however is not obvious,
as FTIR and XRD analysis (ESI†) displayed no changes in the
composition of the core nanoparticles or the nature of the organic
functionalities.
1
2
3
4
0
5
0
5
0
0
3.36
3.36
0
90
6
—
94
0
100
84
a Conversion determined by 1H NMR spectroscopy. b Determined by CSP-
HPLC.
it ultimately proved incapable of promoting the reaction with
appreciable efficacy after 4 cycles (entry 4). This instability was
unfortunately a characteristic of each catalyst batch prepared and
points to an inherent design limitation rather than any kind of
mishandling during experimentation. It is also interesting to note
that we found that the decline in catalyst performance was more a
function of time elapsed since loading rather than the number of
iterative recycles the catalyst had been used in.
We next carried out three experiments aimed at investigating the
potential role (if any) of the nanoparticle in reducing the catalyst
efficacy from a stereoselectivity perspective (Table 2). As expected,
we observed no background uncatalysed reaction between 12 and
13 in the absence of either catalyst or nanoparticle (entry 1).
The homogeneous catalyst 3— in the absence of nanoparticles,
promoted the reaction with excellent enantioselectivity (entry 2).
It is important to note that these reactions were carried out using
a mechanical shaker, to ensure that the experimental conditions
are as close as possible to those associated with the use of the
heterogeneous catalyst 8. We were surprised to find that the
nanoparticles themselves (when utilised in identical mass loadings
to that used in the application of the heterogeneous catalyst 8)
catalysed the formation of (rac)-14 in the absence of 3 (entry
3). This is disappointing— as in the acylation study (vide supra)
the nanoparticles themselves were completely inert— however it
explains (at least in part) the origin of the relatively poor levels of
product ee observed in reactions catalysed by 8. To confirm this
hypothesis, we repeated the conjugate addition in the presence of
both 3 and the nanoparticles: as expected 14 was isolated with only
84% ee (entry 4), which indicates that the nanoparticles (despite
attempts to protect the surface through siloxane functionalisation)
compete with 3 for the substrate to an appreciable extent under
these conditions.
Immobilisation of chiral bifunctional sulfonamide derivatives
Given the somewhat surprising lack of recyclability of the urea-
based catalyst 8 (vide supra), our attention turned to the immobil-
isation of the sulfonamide derivatives of general type 4. Song has
shown that a polystyrene-supported sulfonamide-based catalyst 15
(Fig. 3) could promote the methanolytic desymmetrisation of meso
succinic-anhydrides with >90% ee and 3-phenyl glutaric anhydride
with 89% ee. Remarkably for a polystyrene-based material, the
catalyst proved extremely recyclable and could be used 10 times
without loss of either activity or selectivity.32 This undoubtedly
represents the literature benchmark in heterogeneous catalysis of
this asymmetric process.33
Fig. 3 A polystyrene-supported organocatalyst reported by Song et al.
In an attempt to better understand the fate of catalyst 8 after
multiple cycles, we characterised three batches of nanoparticles:
one batch which had not been loaded with catalyst, one which had
been loaded but then simply stored under argon and not used in
any catalytic processes, and finally the batch associated with the
data outlined in Table 1.
The asymmetric addition of alcohols to meso anhydrides is a
reaction we have had considerable interest in from a homoge-
neous catalysis perspective,16,22 and we were thus intrigued as to
the potential of a nanoparticle-immobilised sulfonamide-based
catalyst, where we envisaged that the lower Lewis-basicity and
considerably augmented hydrolytic stability characteristics of the
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Table 3 Selection of the optimal aryl sulfonamide group in a homoge-
neous model system
Table 4 Evaluation of the homogeneous catalyst 4b in the desymmetri-
sation of meso succinic anhydrides
Entry Substrate
Product
Time (h) Conv. (%)a
ee (%)b
1
6
6
87
85
95
Entry
Catalyst
Time (h)
ee (%)a
2
94.5
96.5
1
2
3
4
4b
4c
4d
4e
20
20
20
52
87
85
82
75
3b
18
99c
a Determined by CSP-HPLC.
sulfonamide functional group relative to the urea would prove a
distinct advantage in terms of catalyst recyclability.
a Conversion determined by 1H NMR spectroscopy. b Reaction at 0.05 M
concentration. c Isolated yield.
The design process began with the selection of the sulphonamide
aryl group. To facilitate the rapid evaluation of catalysts incor-
porating several different aryl moieties in this particular reac-
tion the homogeneous model sulfonamides 4b–4e were prepared
and compared in the desymmetrisation of meso anhydrides by
methanolysis (Table 3).34 Before discussing the data, two points
are noteworthy: firstly, since we intended to eventually investigate
the use of nanoparticle-supported catalysts, we decided to only
evaluate the homogeneous model systems under conditions likely
to be both operationally convenient and conducive to smooth
heterogeneous catalysts later on, thus reactions were carried out
using the traditionally challenging 3-methyl glutaric anhydride
(16) substrate (so that the potential limits of the catalyst could
be identified early), and both low temperature and high dilution
conditions (known to be beneficial to enantioselectivity in these
reactions but likely to be a problem when used in conjunction
with heterogeneous catalysis) were avoided. Secondly, we had
experience of the use of these materials in a related process
involving simultaneous kinetic resolution and meso anhydride
desymmetrisation,22 and from these studies had divined that 4b
was a more efficacious promoter of the desymmetrisation of
glutaric anhydrides in that process than the literature catalyst 4a,21
therefore the latter catalyst was excluded from this study.
The results of these initial experiments are outlined in Table
3. The pentafluoro-substituted catalyst 4b (entry 1) represented a
useful combination of superior activity and ability to promote
the reaction (at low loading, ambient temperature and 0.1 M
concentration) with higher levels of product ee than either the
less acidic 4c (entry 2) or the more hindered (and also less acidic)
4d and 4e (entries 3 and 4) and was therefore selected for further
investigation.
The catalyst performance here was most satisfactory. An-
hydrides 18–20 could be converted to either acyclic or cyclic
hemiesters 21 (entry 1) and 22–23 (entries 2–3) respectively in
excellent enantiomeric excess at ambient temperature using a
catalyst loading of 2 mol%.
Encouraged by the excellent catalytic abilities exhibited by
sulfonamide 4b under homogeneous conditions, we decided to
synthesise a nanoparticle-supported heterogeneous analogue and
concentrated our attention on the identification of a suitable
immobilisation strategy. Again we chose the quinuclidine vinyl
group, which is not located in close proximity to the catalytically
relevant functionality (i.e. the acidic sulfonamide proton and the
quinuclidine nitrogen), as the location at which to anchor the
nanoparticle via a sulfide tether. After some experimentation,
reproducible conditions for the synthesis of the supported catalyst
37 were identified (Scheme 3): treatment of sulfonamide 4b with
excess 10 in toluene at 60 ◦C and in the presence of AIBN (50
mol%), led to the isolation of 25 in 65% yield after purification by
flash-chromatography. The subsequent loading step involving this
new species could then be conveniently accomplished by allowing
25 to react with magnetite nanoparticles (average particle size 9.7
◦
3.5 nm), in CDCl3 at 50 C under mechanical agitation, in the
presence of 2,5-diphenylfuran as an internal standard (Scheme 3).
The catalyst loading (1.00 mmol g-1) was determined as before
1
by H NMR spectroscopic analysis of a sample of the reaction
mixture after 20 h. No traces of the resonances corresponding
to either 25 or derived decomposition products were detected.
Capping of the particles with n-propyl triethoxysilane was not
carried out as no advantage in terms of catalyst performance
was observed in catalyst batches which had been treated with this
reagent.
To ensure that 4b was compatible with other synthetically
relevant substrates, it was then utilised in the desymmetrisation of
a selection of succinic meso anhydrides under identical conditions
(Table 4).
As before, both the nanoparticle batch utilised in the load-
ing process and the loaded catalyst itself were characterised.
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Table 5 Evaluation of 24 as a recyclable catalyst in the desymmetrisation
of 20
Entry
Cycle
Conversion (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
100
99
99
98
98
98
99
97
98
97
97
97
96
97
96
96
96
97
96
97
80
80
80
78
78
78
77
77
77
78
77
77
77
77
78
77
77
77
77
77
Scheme 3 Synthesis of the immobilised bifunctional sulfonamide 24.
a Determined by 1H NMR spectroscopy. b Determined with excellent
agreement by either CSP-HPLC or 1H NMR spectroscopic analysis after
derivatisation, see Experimental Section.
According to TEM analysis, the average nanoparticle size was
9.7 3.5 nm. After loading the nanoparticles with catalyst, the
TEM images show no changes in either the size or behaviour of
the nanoparticle (Fig. 4).
very small diminution of product ee was observed between the first
and 20th iteration, with all reactions being carried out at ambient
temperature. However the magnitude of asymmetric induction—
which lay in the range of 80% (cycles 1–3, entries 1–3) to 77% (e.g.
cycle 20, entry 20)— was disappointing relative to that associated
with the use of the homogeneous analogue 4b (Table 3).
The same catalyst batch utilised in the experiments outlined
in Table 5 was then tested in the desymmetrisation of a set of
monocyclic, bicyclic and tricyclic prochiral anhydrides (Table 6).
Thus, when bicyclic-succinic anhydride 19 was treated with MeOH
(10 equiv.) in the presence of 5 mol% of 24, the corresponding
hemiester could be isolated in 97% yield and 78% ee after 24 h
(cycle 21, entry 1). The consistency of such findings was confirmed
by repeating the desymmetrisation of 19 under identical conditions
in two subsequent consecutive cycles (78–79% ee, cycles 22–
23, entries 2–3). Reproducible results were also observed in the
methanolysis reaction of 18 (cycles 24–26, entries 4–6) that yielded
hemiester 22 in 78% ee (average value from three consecutive runs).
The desymmetrisation protocol was found to be compatible with
more challenging, sterically demanding substrates, such as tricyclic
anhydrides 26 and 27: the endo-hemiester 28 was isolated in 92%
yield and 82% ee (cycle 27, entry 7) after 4 d at room temperature,
while in the case of the formation of the corresponding exo-adduct
(i.e. 29) we observed a slightly lower level of product enantiopurity
(79% ee, cycle 28, entry 8).
Fig. 4 TEM images of (a) magnetite nanoparticles and (b) catalyst loaded
nanoparticles (24). Scale bar 100 nm.
FTIR spectroscopy and TGA analysis of the samples confirmed
that the sulfonamide catalyst had been successfully loaded onto
the surface of the nanoparticles (ESI†).24 XRD also confirms no
changes or degradation of the magnetite core occur (ESI†).24
Catalyst 24 was then evaluated as a recyclable promoter of
the asymmetric ring-opening of 20 (Table 5). We found 24 to
be highly recyclable— it could be reused in twenty consecutive
cycles without any significant decrease in catalytic activity and
enantioselectivity. We observed near quantitative conversion of 20
to product 23 after 18 h in the first three cycles of our recyclability
study (entries 1–3) and only a slight decrease in catalyst activity
between cycles 3 and 20: for instance conversion in cycle 20 was
determined to be 97% (entry 20)— which is strongly indicative that
24 is not decomposing significantly between runs. From a chiral
information transfer standpoint the catalyst is also robust: only a
We had previously found that methanol could be advan-
tageously replaced with allyl alcohol in the desymmetrisation
reaction of succinic anhydrides.15 This is useful as we previously
demonstrated that the adduct in these cases could be readily
converted to the enantiomer of that which one obtains from
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Table 6 Evaluation of 24 in the desymmetrisation of meso succinic
anhydrides
Entry
1
Cycle
21
Substrate
Product
Yield (%)a
97
Ee (%)b
Scheme 5 Cycle 30: A repeat of the first iterative cycle to examine catalyst
loss/decomposition.
in the first cycle (shown in Scheme 5), the outstanding durability
of sulfonamide 24 is readily apparent: after 30 cycles the catalyst
retains almost all of its activity and ability to discriminate the two
prochiral carbonyl substrate moieties: the reduction in catalyst
performance through either mechanical loss or decomposition
over 30 iterative recycles is perceptible, but minimal.
78
2
3
22
23
96
96
78
79
Finally, we carried out a pair of control experiments as before
to investigate the potential of the nanoparticle support to act as a
catalyst in this process (at the same mass loadings as used in Tables
5 and 6). We found that both batches of nanoparticles which had
been capped with n-PrSi(OEt)3 and those which had not been
treated were capable of serving as catalysts in the alcoholysis of
19 (Scheme 6). In the case of the uncapped particles, catalysis was
extraordinarily effective, while even the capped material proved
efficient enough a promoter of the formation of (rac)-22 for it to
be considered a credible cause of the reduced levels of enantiomeric
excess observed using 24 relative to its homogeneous analogue 4b.
4
24
94
78
5
6
25
26
92
94
77
78
7c
27
92
82
8c
28
97
79
a Isolated Yield. b Determined by 1H NMR spectroscopic analysis after
derivatisation, see Experimental Section. c 10 mol% of catalyst used, 96 h
reaction time.
Scheme 6 Background catalysis of anhydride alcoholysis by magnetic
nanoparticles.
direct methanolysis of the substrate with the other antipode
of the catalyst (i.e. enantiodivergent synthesis) after a simple
esterification/deprotection sequence.15 In cycle 29 we therefore
investigated the desymmetrisation reaction of anhydride 20 with
allyl alcohol in the presence of catalyst 24. We were pleased to find
that hemiester 30 was obtained with enhanced enantiopurity (82%
ee) and in 83% yield after 48 h (Scheme 4).
Conclusions
A systematic study concerning the immobilisation onto magnetic
nanoparticles of three useful classes of chiral organocatalyst which
rely on a confluence of weak, easily perturbed van der Waals
and hydrogen bonding interactions to promote enantioselective
reactions has been undertaken for the first time. The catalysts were
evaluated in three different synthetically useful reaction classes:
the kinetic resolution of sec-alcohols, the conjugate addition of
dimethyl malonate to a nitroolefin and the desymmetrisation of
meso anhydrides. Somewhat surprisingly, it is clear that, despite
early indications to the contrary, the success of this strategy
hinges on the structure of the catalyst being immobilised. In
the case of chiral DMAP derivatives such as 1 (i.e. catalyst
5) the resulting heterogeneous catalyst is highly active and
is capable of promoting the kinetic resolution of sec-alcohols
with synthetically useful selectivity under process-scale friendly
conditions (ambient temperature, low catalyst loading and acetic
anhydride as the acylating agent)- which allows the isolation of
resolved alcohols with good-excellent enantiomeric excess. The
magnetic catalyst is simple to prepare, insensitive to air/moisture
and easily recoverable by exposure of the reaction vessel to an
Scheme 4 Cycle 29: Desymmetrisation using allyl alcohol as the
nucleophile.
Finally, to further investigate the robust nature of 24, we
returned to the desymmetrisation reaction of anhydride 20 under
identical conditions to those used in the first iterative cycle
involving this catalyst (i.e. Table 5, entry 1). Gratifyingly, we found
that, after being used for 29 consecutive runs, 24 could still perform
exceptionally well, promoting the formation of hemiester 23 to a
satisfying level of conversion (95%, 92% isolated yield) and in
78% ee (Scheme 5). If one compares this to the data obtained
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external magnetic field. Perhaps most importantly, the lack of
interaction between the nanoparticle core and the organocatalyst
unit results in a chiral heterogeneous catalyst which is recyclable to
an unprecedented extent— in this study it has been demonstrated to
be reusable in a minimum of 32 consecutive cycles while retaining
high activity and selectivity profiles.35
In stark contrast, urea catalyst 2 was demonstrated to be wholly
incompatible with immobilisation onto magnetite nanoparticles.
A marked drop in catalyst efficacy (from both activity and
selectivity standpoints) is observed on immobilisation and the
catalyst proved unstable over only a handful of iterative recycles.
Most significantly, a short study aimed at uncovering the origin
of this poor performance from a stereoselectivity perspective
determined categorically that background catalysis by the particles
themselves is problematic in the conjugate addition reaction under
study. This is a somewhat startling observation which should serve
as a warning that these particles cannot be automatically considered
to be inert in catalytic processes.
The heterogeneous sulfonamide catalyst 24 represents an inter-
mediate scenario: the catalyst exhibits outstanding recyclability
on a par with that associated with the nucleophilic catalyst
5, however product enantiomeric excess using the immobilised
catalyst is consistently lower (ca. 80% ee) than that obtained using
the corresponding homogeneous catalyst 4b. Again, unhelpful
background catalysis by the nanoparticle support was shown to
be a likely cause of this phenomenon.
The compatibility of this magnetite nanoparticle immobilisa-
tion methodology with a dialkylaminopyridine organocatalyst
known to be highly sensitive to its environment11 is extremely
promising. In particular, this emerging nanotechnology possesses
strong potential for further general applicability at the frontiers
of (asymmetric) catalysis. This study aims to highlight that
carrier nanoparticles can and do interact with both the loaded
catalyst, and (on occasion) the substrate- compromising either
activity/stability or selectivity (or both). Therefore, it cannot be
regarded as a general, all-encompassing solution to the problem
of the design of genuinely recyclable, highly active and selective
immobilised chiral organocatalysts. As such, studies are currently
underway in our laboratory aimed at further charting the limits of
this strategy on a case by case basis.
Autopol IV instrument and are quoted in units of 10-1 deg
cm2 g-1. Toluene, ether and THF were distilled from sodium.
Methylene chloride and triethylamine were distilled from calcium
hydride. Ammonium hydroxide (NH4OH, 0.88 M) was obtained
from BDH Chemicals. Ferric chloride hexahydrate (FeCl3·6H2O)
and ferrous chloride tetrahydrate (FeCl2·4H2O), were obtained as
powders from Sigma-Aldrich. Acetic anhydride was freshly dis-
tilled before use. Analytical CSP-HPLC was performed on Daicel
CHIRALCEL OD-H (4.6 mm ¥ 25 cm), CHIRALPAK AD-H
(4.6 mm ¥ 25 cm) and AS (4.6 mm ¥ 25 cm) columns. TEM images
were obtained on a Jeol JEM-2100, 200 kV LaB6 instrument,
operated at 120 kV with a beam current of about 65 mA. Samples
for TEM were prepared by deposition and drying of a drop of
the powder dispersed in water onto a formvar-coated 300-mesh
copper grid. Diameters were measured using the ImageJ version
1.40 software program; average values were calculated by counting
a minimum of 100 particles. Samples for TEM were prepared
by deposition and drying of a drop of the powder dispersed in
Millipore water onto a formvar coated 400 mesh copper grid. The
thermogravimetric analysis (TGA) was carried out on a Pyris 1
TGA from Perkin Elmer and the samples (1.5–2 mg) were burned
in air at a constant heating rate of 10 ◦C min-1 from 30 to 900 ◦C.
X-Ray powder diffraction was performed using a Siemens-500
X-Ray diffractometer. Powder samples were deposited on silica
glass using silica gel to adhere the sample to the glass surface.
Overnight spectra were run for all samples. Diffractograms were
then compared to the JCPDS database. Unless otherwise stated, all
other chemicals were obtained from commercial sources and used
as received. Unless otherwise specified, all reactions were carried
out in oven-dried glassware under an atmosphere of argon.
Synthesis of magnetite nanoparticles
Magnetite nanoparticles were prepared by the co-precipitation
of FeCl2·4H2O and FeCl3·6H2O in a molar ratio of 1 : 2 with
0.5 M NaOH. This alkaline solution was stirred at 80 ◦C for 1 h,
yielding a black colloidal suspension of magnetite nanoparticles
which were washed several times with water until pH neutral. The
nanoparticles were then dried under vacuum for 24 h.
Siloxane 11
Experimental
A 5 mL round bottom flask, equipped with a stirring bar, was
charged with urea 9 (300 mg, 0.52 mmol) and azobisisobutyroni-
trile (AIBN, 51 mg, 0.31 mmol). The flask was fitted with a septum
and flushed with argon. Dry toluene (2.0 mL) was added via
syringe followed by 3-mercaptopropyltriethoxysilane (10, 313 mL,
1.30 mmol) and the resulting mixture was heated to 60 ◦C and
stirred for 16 h. The solvent was removed in vacuo and the residue
purified by column chromatography (EtOAc-NEt3 90 : 10) to give
11 ◦in 9.5% yield (40 mg) as an amorphous beige solid. Mp 77–
81 C; [a]2D0 = +9.2 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.72–0.76
(m, 2H), 0.97–1.02 (m, 1H), 1.21–1.25 (t, 9H), 1.47–1.76 (m, 9H),
2.10–2.19 (m, 1H), 2.33–2.39 (m, 2H), 2.49–2.53 (t, 2H), 2.70–2.77
(m, 1H), 3.06–3.17 (m, 2H), 1.09 (bs, 1H), 3.80–3.85 (q, 6H), 4.03
(s, 3H), 5.51 (bs, 1H), 6.19 (br s, 1H), 7.39–7.41 (m, 2H), 7.44–7.47
(dd, J 2.4, 6.8, 1H), 7.72–7.74 (m, 3H), 8.08–8.10 (d, J 9.2, 1H),
8.24 (br s, 1H), 8.85–8.86 (d, J 4.4, 1H); dC (100 MHz, CDCl3)
9.9, 18.3, 23.2, 25.1, 26.9, 27.9, 29.7, 33.7, 34.4, 35.3, 41.5, 50.7,
General
Proton Nuclear Magnetic Resonance spectra were recorded on
400 and 600 MHz spectrometers in CDCl3 referenced relative
to residual CHCl3 (d = 7.26 ppm) and DMSO-d6 referenced
relative to residual DMSO (H) (d = 2.51 ppm). Chemical shifts are
reported in ppm and coupling constants in Hertz. Carbon NMR
spectra were recorded on the same instruments (100 MHz and
150 MHz) with total proton decoupling. All melting points are
uncorrected. Infrared spectra were obtained using neat samples
on a diamond Perkin Elmer Spectrum 100 FT-IR spectrometer
using a universal ATR sampling accessory. Flash chromatography
was carried out using silica gel, particle size 0.04–0.063 mm. TLC
analysis was performed on precoated 60F254 slides, and visualised
by either UV irradiation or KMnO4 staining. Optical rotation
measurements were made on a Rudolph Research Analytical
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55.8, 57.0, 58.4, 59.7, 101.9, 115.4, 188.0, 118.2 (q, J19F–13C 4 Hz),
122.5, 123.0 (q, J19F–13C 273 Hz) 128.5, 132.0, 132.0 (q, J19F–13C 30
Hz), 140.5, 144.3, 145.1, 147.2, 154.6, 158.5; dF (376 MHz, CDCl3)
-63.67; nmax(neat)/cm-1 2974, 2928, 1703, 1622, 1566, 1509, 1387,
1276, 1241, 1226, 1169, 1101, 944, 780, 681; m/z (ES) 817.3267
(M + H+. C38H50N4O5F6SSi requires 816.3175).
data associated with this compound are consistent with those in
the literature.36
Siloxane 25
A 5 mL round bottom flask, equipped with a stirring bar, was
charged with sulfonamide 4b (250 mg, 0.45 mmol) and azobi-
sisobutyronitrile (AIBN, 38 mg, 0.23 mmol). The flask was fitted
with a septum and flushed with argon. Dry toluene (2.0 mL) was
added via syringe followed by 3-mercaptopropyltriethoxysilane
(10, 2◦70 mL, 1.13 mmol) and the resulting mixture was heated
to 60 C and stirred for 12 h. The solvent was removed in vacuo
and the residue purified by column chromatography (EtOAc–NEt3
95 : 5) to give 25 in 65% yield (230 mg) as an amorphous white
Magnetic nanoparticle-supported urea catalyst 8
A 50 mL reaction vessel was charged with siloxane 11 (0.020 mmol,
16.3 mg) and 4-iodoanisole (internal standard, 0.0203 mmol,
4.7 mg). The reaction vessel was placed under an argon atmosphere
and fitted with a septum and dry C6D5CD3 (4.0 mL) was added via
syringe. At this point 1H NMR spectroscopic analysis (t = 0 min)
was carried out. Magnetite nanoparticles (200.0 mg) were then
added in one portion and the resulting suspension was sonicated
for 5 min at room temperature. The resulting mixture was heated
to 50 ◦C for 24 h under mechanical agitation. The vessel was then
placed in proximity of an external magnet and the solution was
separated from the nanoparticles via a Pasteur pipette. Catalyst
loading (1.00 mmol g-1) was determined by 1H NMR spectroscopic
analysis of the resulting solution which showed no traces of
the peaks corresponding to the catalyst loading precursor. The
remaining particles were subjected to five consecutive washing
cycles with dry toluene (4.0 mL) which was decanted in the
presence of an external magnet. In order to cap the remaining oxide
surface of the nanoparticles, 5 mL of dry toluene was added to the
nanoparticles under an Ar atmosphere, n-propyltriethoxysilane
(1 mL) via syringe and the suspension shaken under mechanical
1
solid. Note: The H-NMR spectrum of this compound indicates
the presence of two rotameric species (rt, CDCl3) in a 6/4 ratio.
Mp 92–94 ◦C; [a]D20 = +6.2 (c 0.75, CHCl3); dH (600 MHz, CDCl3)
0.66–0.80 (m, 2H), 0.88 (br dd, J 7.0, 13.1, 0.4H), 1.04 (br dd, J 7.0,
13.1, 0.6H), 1.19–1.28 (m, 9H), 1.36–1.52 (m, 3H), 1.53–1.84 (m,
6H), 2.38–2.59 (m, 4.6H), 2.73 (br d, J 12.9, 0.4H), 2.77–2.91 (m,
1H), 3.02–3.13 (m, 0.6H), 3.24–3.43 (m, 1.4H), 3.51 (br dd, J 18.1,
9.3, 1H), 3.78–3.86 (m, 6H), 3.95 (s, 1.8H), 4.04 (s, 1.2H), 4.60 (d, J
10.9, 0.6H), 4.82 (br s), 5.28 (d, J 10.9, 0.4H), 7.32–7.38 (m, 1.2H,
0.6H), 7.41–7.54 (m, 1.8H), 7.96 (d, J 9.0, 0.6H), 8.00 (d, J 9.0,
0.4H), 8.65 (d, J 4.2, 0.4H), 8.68 (d, J 4.2, 0.6H); nmax(neat)/cm-1
2927, 1621, 1499, 1486, 1167, 1097, 1075, 985, 776, 715; m/z (ES)
792.2595 (M + H+. C35H47N3O6F5S2Si requires 792.2596).
Magnetic nanoparticle-supported sulfonamide catalyst 24
◦
A
5
mL round bottom flask was charged with 25
agitation at 50 C for 16 h. The reaction solution was decanted
(0.020 mmol, 15.8 mg) and 2,5-diphenylfuran (internal standard,
0.020 mmol, 4.4 mg). The flask was placed under an argon
atmosphere and fitted with a septum and dry CDCl3 (0.5 mL) was
added via syringe. The resulting solution was injected into a 20 mL
reaction vessel previously charged with magnetite nanoparticles
(200 mg) which had been suspended in dry CDCl3 (0.5 mL) and
sonicated for 5 min at room temperature and under argon. The
resulting mixture was heated to 50 ◦C for 24 h under mechanical
agitation. The vessel was then placed in proximity of an external
magnet and the solution was separated from the nanoparticles via
a Pasteur pipette. Catalyst loading (1.00 mmol g-1) was determined
by 1H NMR spectroscopic analysis of the resulting solution which
showed no traces of the peaks corresponding to the catalyst
loading precursor. The remaining particles were subjected to
five consecutive washing cycles with dry MTBE (methyl tert-
butylether, 1.0 mL) before being evaluated as a recyclable catalyst.
in the presence of an external magnet and the nanoparticles were
washed five times with dry toluene (5 mL) before being evaluated
as a recyclable catalyst.
General procedure for the addition of dimethyl malonate to
(E)-b-nitrostyrene catalysed by 8
A 50 mL reaction vessel containing 8 (200 mg, 0.020 mmol) was
charged with (E)-b-nitrostyrene 12 (59.6 mg, 0.400 mmol) and
placed under an atmosphere of Ar (balloon). Dry toluene (6 mL)
was added via syringe and the resulting suspension shaken under
mechanical agitation for ca. 30 min. Dimethyl malonate 13 (91 mL,
0.800 mmol) was then added via syringe and the suspension
shaken for a further 20 h at room temperature. The reaction was
stopped by placing the reaction vessel over an external magnet. The
reaction vessel was kept over the external magnet until the reaction
suspension became transparent (approximately 1 h) and the liquid
was then decanted and the nanoparticles washed with dry toluene.
The combined toluene washings were concentrated in vacuo and
the conversion determined by 1H NMR spectroscopy. The residue
was purified by column chromatogra◦phy (hexane–CH2Cl2, 1 : 1) to
give 14 as a white solid. Mp 62–64 C; Enantiomeric excess was
determined by CSP-HPLC: Chiralcel AD-H (4.6 mm ¥ 25 cm),
hexanes/i-PrOH, 90/10, 1 mL min-1, RT, UV detection at 220 nm,
retention times: 17 min (minor) and 29 min (major). [a]2D0 +4.6 (c
0.87, CHCl3, 70% ee); dH (400 MHz, CDCl3) 3.59 (s, 3H), 3.79 (s,
3H), 3.88 (d, J 9.0, 1H), 4.26 (app dt, 2H), 4.87–4.98 (m, 2H), 7.24–
7.26 (m, 2H), 7.31–7.37 (m, 3H). The physical and spectroscopic
General procedure for the evaluation of 24 in the desymmetrisation
of meso anhydrides by methanolysis
A 10 mL reaction vessel was charged with the appropriate
anhydride (0.2–0.4 mmol), fitted with a stirring bar and a septum
and placed under an argon atmosphere. Dry MTBE (2.0–4.0 mL)
and dry methanol (2.0–4.0 mmol) were injected via syringe and
the mixture was stirred until all the anhydride had dissolved.
The resulting solution was then transferred via syringe into the
20 mL vessel containing the supported catalyst 24 which had been
previously suspended in dry MTBE (2.0–4.0 mL) and the final
mixture was shaken (mechanical agitation) for the time indicated
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in Tables 5–6, under an argon atmosphere. The vessel was then
placed in proximity of an external magnet and the solution was
separated from the nanoparticles via a Pasteur pipette. After
5 consecutive washing cycles with dry MTBE (1.0 mL), the
combined organic washings were concentrated in vacuo and the
crude product purified by column chromatography.
(2S,3R)-3-endo-Methoxycarbonylbicyclo[2.2.1]hept-5-ene-2-endo-
carboxylic acid (28)
The described general methanolysis procedure was followed using
cis-5-norbornene-endo-2,3-dicarboxylic anhydride (26, 32.8 mg,
0.20 mmol) and dry methanol (81.0 mL, 2.00 mmol) in MTBE
(4.0 mL). After purification by flash chromatography, the desired
monomethyl ester 28 was obtained in 92% yield (36.1 mg) as a
white solid. The enantiomeric excess (82% ee) was determined
General procedure for the determination of the enantiomeric excess
of hemiester products by derivatisation
1
by H NMR spectroscopic analysis of the corresponding amide
derived from (R)-1-(1-naphthyl)ethylamine, prepared as outlined
above. This could be confirmed by CSP-analysis of the amide
derivative: Chiralpak AD-H (4.6 mm ¥ 25 cm), hexane–IPA:
90/10, 0.75 mL min-1, RT, UV detection at 220 nm, retention
times: 11.0 min (major diastereomer) and 16.5 (minor diastere-
A solution of thionyl chloride (9.0 mL, 0.12 mmol) in dry toluene
(1 mL) was added to a solution of the appropriate monoester
(0.10 mmol) in dry toluene (2 mL) at 0 ◦C and under an argon
atmosphere. The mixture was stirred at 0 ◦C for 10 min. Dry NEt3
(46.0 mL, 0.33 mmol) and (R)-1-(1-naphthyl)ethylamine, 18.0 mL
0.11 mmol) were added successively via syringe. The mixture was
stirred at 0 ◦C for 1 h and at room temperature for an additional
1 h. The residue was then dissolved in ethyl acetate (15 mL). The
organic solution was washed with HCl (1 N, 10 mL), saturated
aq. NaHCO3 (10 mL) and brine (10 mL). The organic layer
was then dried over magnesium sulphate and concentrated in
vacuo to give the diastereoisomeric mixture in quantitative yield.
The enantiomeric excess of the appropriate hemiester could be
determined by comparison of the product methyl ester resonances
in the 1H NMR spectrum and confirmed by CSP-HPLC analysis
for some representative cases.
◦
◦
omer). Mp 75–76 C; (lit.,39 75–78 C). [a]D20 -7.4 (c 1.53, CCl4);
lit.39 [a]D = -7.8 (c 4.76, CCl4, 99% ee); dH (600 MHz, CDCl3)
rt
1.36 (app. br d, 1H), 1.52 (app. dt, 1H), 3.15–3.28 (m, 2H), 3.31
(dd, J 10.0, 3.0, 1H), 3.37 (dd, J 10.0, 3.0, 1H), 3.62 (s, 3H), 6.24
(dd, J 5.5, 3.0, 1H), 6.36 (dd, J 5.5, 3.0, 1H); dC (150 MHz, CDCl3)
46.1, 46.6, 48.0, 48.2, 48.8, 51.5, 134.3, 135.6, 172.9, 178.2.
(2S,3R)-3-exo-Methoxycarbonylbicyclo[2.2.1]hept-5-ene-2-exo-
carboxylic acid (29)
The described general methanolysis procedure was followed using
cis-5-norbornene exo-2,3-dicarboxylic anhydride (27, 32.8 mg,
0.20 mmol) and dry methanol (81.0 mL, 2.00 mmol) in MTBE
(4.0 mL). After purification by flash chromatography, the desired
monomethyl ester 29 was obtained in 97% yield (38.0 mg) and as a
as a white solid. The enantiomeric excess (79% ee) was determined
(1S,2R)-cis-2-Methoxycarbonylcyclohexane-1-carboxylic acid
(22)
The described general methanolysis procedure (vide supra) was
followed using cis-1,2-cyclohexanedicarboxylic anhydride (19,
61.7 mg, 0.40 mmol) and dry methanol (162 mL, 4.00 mmol)
in MTBE (8.0 mL). After purification by flash chromatography,
the desired monomethyl ester 22 was obtained in 97% yield
(72.0 mg) as a colourless oil. The enantiomeric excess (78%
1
by H NMR spectroscopic analysis of the corresponding amide
derived from (R)-1-(1-naphthyl)ethylamine, prepared as outlined
◦
above. Mp 61–62 C; (lit.,39 61 ◦C); dH (600 MHz, CDCl3) 1.53
(app. dt, 1H), 2.12 (app. br d, 1H), 2.67–2.69 (m, 2H), 3.13–3.17
(m, 2H), 3.68 (s, 3H), 6.23–6.27 (m, 2H); dC (100 MHz, CDCl3)
44.9, 45.0, 45.3, 46.8, 47.0, 51.4, 137.4, 137.6, 173.4, 178.8.
1
ee) was determined by H NMR spectroscopic analysis of the
corresponding amide derived from (R)-1-(1-naphthyl)ethylamine,
prepared as outlined above. [a]2D0 = +2.4 (c 0.74 in CHCl3), lit.37
[a]2D5 -1.6 (c 4.4 in CHCl3, 97% ee, (1R,2S)-enantiomer); dH (600
MHz, CDCl3) 1.38–1.62 (m, 4H), 1.74–1.84 (m, 2H), 1.97–2.10
(m, 2H), 2.80–2.92 (m, 2H), 3.69 (s, 3H); dC (100 MHz, CDCl3)
23.2, 23.3, 25.5, 25.8, 41.9, 42.1, 51.3, 173.7, 179.5. The NMR
spectra data associated with this compound were consistent with
those in the literature.37
(1S,2R)-6-(Allyloxycarbonyl)cyclohex-3-enecarboxylic acid (30,
cycle 29)
A
10 mL reaction vessel was charged with cis-1,2,3,6-
tetrahydrophthalic anhydride (20, 30.4 mg, 0.20 mmol), fitted with
a septum and placed under an argon atmosphere. Anhydrous
MTBE (2.0 mL) and dry allyl alcohol (137 mL, 2.00 mmol)
were injected via syringe and the mixture was stirred until all
the anhydride had dissolved. The resulting solution was then
transferred via syringe into the 20 mL vessel containing the MNP-
supported catalyst which had been previously suspended in dry
MTBE (2.0 mL) and the final mixture was shaken (mechanical
agitation) for 48 h at room temperature and under an argon
atmosphere. The vessel was then placed in proximity of an external
magnet and the solution was separated from the nanoparticles
via a Pasteur pipette. After 5 consecutive washing cycles with
dry MTBE (1.0 mL), the combined organic washings were
concentrated in vacuo and the crude product purified by column
chromatography to obtain the desired monoallyl ester 30 in 83%
yield (35.0 mg) as a colourless oil. The enantiomeric excess (82%
(2S,3R)-cis-4-Methoxy-2,3-dimethyl-4-oxobutanoic acid (21)
The described general methanolysis procedure was followed using
meso-2,3-dimethylsuccinic anhydride (18, 51.3 mg, 0.40 mmol)
and dry methanol (162 mL, 4.00 mmol) in MTBE (8.0 mL). After
purification by flash chromatography, the desired monomethyl
ester 21 was obtained in 94% yield (60.2 mg) as a white solid.
1
The enantiomeric excess (78% ee) was determined by H NMR
spectroscopic analysis of the corresponding amide derived from
(R)◦-1-(1-naphthyl)ethylamine, prepared as outlined above. Mp 50–
51 C; (lit.,38 49 ◦C, rac); [a]D20 -5.3 (c 1.16 in EtOH), lit.37 [a]D25
=
+8.4 (c 1.40, EtOH, 98% ee, (2R,3S)-enantiomer); dH (400 MHz,
CDCl3) 1.20–1.30 (m, 6H), 2.76–2.90 (m, 2H), 3.73 (s, 3H); dC (100
MHz, CDCl3) 14.6, 14.8, 42.1, 42.3, 51.9, 175.0, 180.2.
1
ee) was determined by H NMR spectroscopic analysis of the
corresponding amide derived from (R)-1-(1-naphthyl)ethylamine,
7938 | Org. Biomol. Chem., 2011, 9, 7929–7940
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prepared as outlined above. This could be confirmed by CSP-
analysis of the amide derivative: Chiralcel OD-H (4.6 mm ¥ 25 cm),
hexane–IPA: 95 : 5, 1.0 mL min-1, RT, UV detection at 220 nm,
retention times: 17.0 min (minor diastereomer) and 20.0 (major
diastereomer). dH (400 MHz, CDCl3) 2.34–2.48 (m, 2H, H-3b and
H-6b), 3.55–2.69 (m, 2H), 3.06–3.16 (m, 2H), 4.57–4.68 (m, 2H),
5.24 (dd, 1H, J 10.5, 1.5), 5.33 (dd, 1H, J 17.1, 1.5), 5.66–5.77 (m,
2H), 5.86–5.97 (m, 1H); dC (125 MHz, CDCl3) 25.1, 25.3, 39.0,
39.1, 65.0, 117.7, 124.6, 124.7, 131.5, 172.4, 178.4; nmax(neat)/cm-1
3029, 2924, 1730, 1701, 1183, 1158, 933, 659; m/z (ES) 209.0809
(M - H+. C11H13O4 requires 209.0814).
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(1S,2R)-cis-2-Methoxycarbonylcyclohex-4-ene-1-carboxylic acid
(23, cycle 30)
The described general methanolysis procedure was followed using
cis-1,2,3,6-tetrahydrophthalic anhydride (20, 60.9 mg. 0.40 mmol)
and dry methanol (162 mL, 4.00 mmol) in MTBE (8.0 mL). After
purification by flash chromatography, the desired monomethyl
ester 23 was obtained in 92% yield (67.8 mg) as a colourless
oil. The enantiomeric excess (78% ee) was determined by 1H
NMR spectroscopic analysis of the corresponding amide derived
from (R)-1-(1-naphthyl)ethylamine, prepared as outlined above.
This could be confirmed by CSP-analysis of the amide derivative:
Chiralcel OD-H (4.6 mm ¥ 25 cm), hexane–IPA: 93 : 7, 0.50 mL
min-1, RT, UV detection at 220 nm, retention times: 34.4 min
(minor diastereomer) and 40.4 (major diastereomer). [a]2D0 -1.6 (c
1.22 in CHCl3), lit.40 [a]D25 -3.44 (c 1.68, CHCl3, 99% ee); dH (400
MHz, CDCl3) 2.34–2.45 (m, 2H), 2.55–2.65 (m, 2H), 3.05–3.13
(m, 2H), 3.72 (s, 3H), 5.70 (m, 2H); dC (100 MHz, CDCl3) 25.1,
25.3, 39.0, 39.1, 51.5, 124.6, 124.7, 173.2, 179.0.
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