Desymmetrisation of: Meso -diones promoted by a highly recyclable polymer-supported chiral phosphoric acid catalyst

Article abstract of DOI:10.1039/c7ra13471a

A polystyrene-supported BINOL-derived chiral phosphoric acid has been applied to the desymmetrisation of meso-diones to produce enantioenriched cyclohexenones. The catalytic resin has proven highly active and robust, giving rise to Hajos-Parrish or Wieland-Miescher type products in good yields and enantioselectivities, while allowing for extended recycling.

Full text of DOI:10.1039/c7ra13471a

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Desymmetrisation of meso-diones promoted by
a highly recyclable polymer-supported chiral
phosphoric acid catalyst†
Cite this: RSC Adv., 2018, 8, 6910
a
a
ab
*
and Miquel A. Pericas
`
*
Lidia Clot-Almenara,
Carles Rodrıguez-Escrich
´
Received 19th December 2017
Accepted 4th February 2018
A polystyrene-supported BINOL-derived chiral phosphoric acid has been applied to the desymmetrisation
of meso-diones to produce enantioenriched cyclohexenones. The catalytic resin has proven highly active
and robust, giving rise to Hajos–Parrish or Wieland–Miescher type products in good yields and
enantioselectivities, while allowing for extended recycling.
DOI: 10.1039/c7ra13471a
rsc.li/rsc-advances
and high temperatures, which is why several protocols involve
addition of an acid aer the starting material is consumed.
Introduction
Actually, even Brønsted acids alone are known to promote the
Robinson annulation in an efficient manner.1b
The Robinson annulation represents one of the most powerful
synthetic strategies for the synthesis of cyclohexenone deriva-
tives,1 which are extremely versatile building blocks for the
preparation of natural products. In 1971, two industrial research
groups, Hajos and Parrish2 (working at Hoffmann-La Roche) and
Eder, Sauer and Weichert3 (from Schering AG), independently
discovered a catalytic asymmetric variant of the Robinson
annulation that was mediated by proline, in what is nowadays
considered one of the most important breakthroughs in orga-
nocatalysis.4 This transformation, also known as the Hajos–Par-
rish–Eder–Sauer–Wiechert reaction (Scheme 1, top), has emerged
as a powerful tool for the total synthesis of natural products5 and
bioactive compounds,6 predominantly sesquiterpenoids,7 terpe-
noids8 and steroids,9 which stand out for their antimicrobial,
antiviral and anticancer effect (Scheme 1, bottom).
On the basis of these precedents, Akiyama and co-workers
hypothesised that chiral phosphoric acids (CPA) should be
able to mediate the desymmetrisation of meso-1,3-diones in the
absence of an acidic additive; indeed, the proof of concept was
reported in 2009.18 In this case, in contrast to what happens in
the aminocatalytic processes, the stereoselectivity was
controlled via non-covalent interactions and the same catalyst
promoted the desymmetrisation and the nal dehydration.
Efforts to identify an alternative organocatalyst able to
promote the asymmetric Robinson annulation include proline
derivatives,10 amines,11 amino acids,12 peptides,13 antibodies,14
prolinamide15 or chiral vicinal diamines.16 It is thus evident that
the common motif in most of the catalytic entities employed so
far is the presence of a chiral amine, which is assumed to
promote the reaction through the enamine activation mode.17
However, according to the commonly accepted mechanistic
rationalisations, the presence of a base slows down the second
half of the process, namely, the dehydration of the b-hydrox-
yketone intermediate. This step is accelerated in acidic media
aInstitute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science
¨
and Technology, Av. Paısos Catalans 16, 43007 Tarragona, Spain. E-mail: mapericas@
iciq.es
b
´
`
`
Departament de Quımica Inorganica i Organica, Universitat de Barcelona, 08080
Barcelona, Spain
† Electronic supplementary information (ESI) available: Experimental procedures,
characterisation data, NMR spectra and HPLC traces. See DOI:
10.1039/c7ra13471a
Scheme
1 Wieland–Miescher and Hajos–Parrish ketones; natural
products prepared via Robinson annulation.
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Chiral phosphoric acids were independently developed in
RSC Advances
2004 by Akiyama and Terada19 in an attempt to harness the
reactivity of imines. However, these Brønsted acid catalysts have
proven to be much more versatile than initially expected, giving
high levels of enantioinduction in very disparate reactions.20
Perhaps the main drawback of these CPAs is the long and
tedious reaction sequences required for their preparation. In
this scenario, catalyst immobilisation21 can provide a solution
by rendering materials that ideally retain the properties of the
monomer while being insoluble in the reaction media. With
this idea in mind, several research groups, including our own,
have studied the immobilisation of CPAs to assess the impact of
this approach on the activity and recyclability of the resulting
catalytic materials.22 Indeed, solid-supported CPAs23 turned out
to be very active and robust; remarkably, in the event of loss of
catalytic activity, simply washing the catalytic resin with acid
restored its initial behaviour. More recently, we turned our
attention to the CPA that has been more successful to date,
namely, the TRIP catalyst developed by List et al.24 Thus, we
prepared PS-TRIP (Fig. 1) based on a co-polymerisation strategy
and applied it to the asymmetric allylboration of aldehydes.25
The catalytic resin admitted recycling in batch and the imple-
mentation of a ow process spanning 28 h. It is worth noting
that, about the same time, Kobayashi et al. reported on a very
similar immobilisation strategy to obtain a hybrid material that
combined supported TRIP and Au/Pd nanoparticles.26 This
heterogeneous catalyst exploited the benets of both catalysts,
allowing to carry out a sequence of oxidation and enantiose-
lective aza-Friedel–Cras reaction.
Fig. 2 Selection of previously reported immobilised catalysts for the
desymmetrisation of meso-diones.
catalyst16 has been supported onto polystyrene, proving to be
recyclable and allowing operation in continuous ow.30
Results and discussion
On the basis of the homogeneous precedent,18 we decided to
initiate our investigation using 1a as a model substrate with our
PS-TRIP catalyst in different solvents (Table 1, entries 1–5). As
expected, almost no reactivity was observed at room tempera-
ture with the exception of toluene and hexane (35% yield).
These previous results encouraged us to tackle the applica-
bility of the PS-TRIP catalyst to the desymmetrisation of meso-
1,3-diones to produce chiral cyclohexenones, with particular
interest in the easy separation of nal product and catalyst and
the recovery of the latter. As previously mentioned, the acidic
nature of the catalyst enables the application of the same
reaction conditions to carry out both the desymmetrisation and
the dehydration, without having to use any additive or modify
the temperature. In contrast, previous attempts to apply solid-
supported catalysts to promote this reaction have relied in
aminocatalytic approaches involving proline or prolinamide
derivatives supported on polystyrene,27 silica15,28 or poly-
ethyleneglycol (Fig. 2).29 More recently, the Luo diamine
Table 1 Screening of reaction conditions for the desymmetrisation of
meso-dione 1aa
Temp
[ꢀC]
Cat. loading
[%]
Time
[h]
Yieldb
[%]
eec
[%]
Entry
Solvent
1
2
3
4
5
6
7
8
Hexane
EtOAc
CH2Cl2
THF
Toluene
Hexane
Hexane
DCE
Hexane
Hexane
Hexane
Hexane
rt
rt
rt
rt
5
5
5
5
5
5
10
10
10
15
20
20
32
32
32
32
32
48
24
24
24
24
24
48
35
—
—
—
Traces
50
80
64
75
90
—
—
—
—
91
89
90
88
88
88
89
rt
70
70
70
70
70
70
70
9
10
11
12
64
69
98
a
Reactions were carried out with 0.2 mmol of 1a in 2 mL of solvent.
b
c
Yield of isolated product. Determined by HPLC on
stationary phase.
a chiral
Fig. 1 Polystyrene-supported TRIP phosphoric acid catalyst.
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ꢀ
Heating up the reaction mixture to 70 C effectively increased
the yield while maintaining high enantioselectivities (entry 6).
Increasing the catalyst loading to 10 mol%, higher yields were
achieved (entry 7). Aer these preliminary results, we decided to
expand the solvent screening (entries 8–9), but toluene and DCE
did not improve the results observed with hexane. Finally, we
increased the catalyst loading and the reaction time (entries
10–12), establishing the optimised reaction conditions to
obtain the cyclohexenone product as follows: 20 mol% catalyst,
ꢀ
70 C and 48 h (98% yield, 89% ee).
With the optimised conditions in hand, we moved to explore
the reaction scope, starting with the benzo-fused meso-diones
(Scheme 2). The methyl-substituted analogue 2b was obtained
in excellent yield and enantioselectivity (94%, 88% ee).
The compound bearing a phenyl group gave moderate yields,
which can be attributed to the low solubility of the starting
material. Indeed, when the reaction was carried out in toluene
at 90 ꢀC, 2c was obtained in good yields. In comparison, the
benzyl-substituted compound gave rise to the cyclohexenone 2d
in considerably higher yields. As for the propargylic substrate, it
displayed an excellent behaviour, furnishing 2e (an interme-
diate used in the synthesis of a gibbane framework2d) in excel-
lent yield and ee. In general, we can say that this type of
substrates give rise to the desired cyclohexenones in very good
yields and enantioselectivities, despite the somewhat elevated
reaction temperatures employed.
Scheme 3 Scope of the desymmetrisation reaction with cyclic meso-
diones 3.a a Reactions were carried out with 0.12 mmol of 3, 20 mol%
of PS-TRIP in 1.2 mL of hexane.
The results obtained with meso-diones 3, lacking the fused
benzene ring, are summarised in Scheme 3; in this case the
results were not as good as those recorded for the tricyclic
compounds. For instance, the Hajos–Parrish 4a and
Wieland–Miescher 4b ketones were synthesised in decent yields
but moderate ee's. Our PS-TRIP catalyst was also able to give rise
to 4c, bearing a tetrasubstituted alkene moiety, in 68% yield,
but unfortunately in low enantioselectivity. Higher yield was
observed in the case of the synthesis of Wieland–Miescher
ketone derivative 4d, bearing the classical dimethylallyl group
present in many terpene derivatives.
The PS-TRIP resin has shown not only to be active in a wide
variety of substrates, but also to be highly recyclable. Remark-
ably, all substrates have been run with two samples of polymer,
which were already employed in the screening table. Accord-
ingly, each sample of catalyst has been used 9 times in total
without appreciable decay in activity. Aer each run, the catalyst
was rinsed, dried in the vacuum line overnight and reused again
without further reconditioning. Considering the multi-step,
tedious preparation of the TRIP catalyst, this feature allows
saving huge amounts of solvent and chemical waste, thus
contributing to the greenness of the overall process.
Conclusions
In summary, we have established an efficient strategy for the
desymmetrisation of meso-1,3-diones catalysed by an immobi-
lised version of the TRIP phosphoric acid catalyst. This
approach can be applied to a broad range of starting meso-
diones, giving rise to the corresponding cyclised products in up
to 98% yield and 92% enantiomeric excess. In this work, we also
demonstrate the efficiency of the PS-TRIP catalyst, which is
easily recovered by simple ltration and reused at least nine
times, thus facilitating the isolation of the nal product.
Scheme 2 Scope of the desymmetrisation reaction with benzene-
fused meso-diones 1.a a Unless otherwise stated, the reactions were
carried out with 0.12 mmol of 1, 20 mol% of PS-TRIP in 1.2 mL of
hexane. b In toluene at 90 ꢀC.
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There are no conicts to declare.
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