Catalytic batch and continuous flow production of highly enantioenriched cyclohexane derivatives with polymer-supported diarylprolinol silyl ethers

Article abstract of DOI:10.1055/s-0030-1259528

Diarylprolinol silyl ethers immobilized onto polystyrene have been employed as catalysts in the enantioselective domino Michael-Knoevenagel reaction of dimethyl 3-oxoglutarate and 3-substituted acrolein derivatives, including aliphatic ones. The best catalyst allows the preparation of highly functionalized cyclohexane derivatives in a straightforward and efficient manner, both under batch and continuous flow conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259528

464
CLUSTER
Catalytic Batch and Continuous Flow Production of Highly Enantioenriched
Cyclohexane Derivatives with Polymer-Supported Diarylprolinol Silyl Ethers
P
olymer-Suppo
s
y
t
lprolin
h
ol
S
ilyl Ether
e
s
as Cataly
r
sts Alza,a Sonia Sayalero,a Xacobe C. Cambeiro,a Rafael Martín-Rapún,a Pedro O. Miranda,a Miquel A. Pericàs*a,b
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
Fax +34(977)920222; E-mail: mapericas@iciq.es
b
Received 15 December 2010
those of their homogeneous counterparts, and has allowed
the implementation of single-pass, continuous flow pro-
cesses for enantioselective Mannich reactions.11e
Abstract: Diarylprolinol silyl ethers immobilized onto polystyrene
have been employed as catalysts in the enantioselective domino
Michael–Knoevenagel reaction of dimethyl 3-oxoglutarate and 3-
substituted acrolein derivatives, including aliphatic ones. The best
catalyst allows the preparation of highly functionalized cyclohex-
ane derivatives in a straightforward and efficient manner, both un-
der batch and continuous flow conditions.
As a part of this project, we have recently reported the
preparation and use in Michael reactions of polystyrene-
supported diphenylprolinol trimethylsilyl ether (5a)11f and
we thought that this class of catalysts (Scheme 1) could be
suitable for the direct synthesis of highly functionalized
cyclohexane derivatives in enantiopure form through a
domino process.
Key words: asymmetric organocatalysis, domino process, Michael
addition, Knoevenagel condensation, flow reactors
Domino processes1 are gaining progressive interest for
their enormous potential in the synthesis of complex mol-
ecules. More specifically, catalytic enantioselective dom-
ino reactions2 not involving the use of metals have
potential for importantly modifying the scenario of the
synthesis of active pharmaceutical ingredients.
R
CO2Me
CHO
+
5a or 5b (cat.)
O
R
O
MeO2C
CO2Me
CO2Me
6
R
R
NaBH4
From a practical perspective, the optimal catalytic enanti-
oselective domino process should be performed in such a
manner that catalyst separation would not introduce any
complexity3 and, desirably, should be amenable to contin-
uous flow operation.4,5
R
CO2Me
R
N
O
OTMS
NH
R
OH
CO2Me
N
N
5a R = H
Domino processes involving the combination of Michael
and aldol-type reactions (Michael initiated ring closure re-
actions, MIRC)6 represent one of the most efficient, con-
vergent approaches to cyclic compounds. Of particular
interest are processes where a single catalytic species, like
an enantiomerically pure amine, is able to catalyze the
enantiodifferentiating step and to mediate the final cy-
clization thus allowing the formation of enantiomerically
pure products.7 In this context, Hayashi and co-workers8
and Jørgensen and co-workers9 have recently reported the
use of diarylprolinol silyl ethers as catalysts for enantiose-
lective domino processes involving amine-catalyzed
Michael and aldol reactions.10
5b R = CF3
7
Scheme 1 Enantioselective synthesis of highly functionalized
cyclohexane derivatives with polystyrene-immobilized catalysts 5
We wish to report in this communication the preparation
of a new polystyrene-supported diarylprolinol trimethyls-
ilyl ether catalyst [aryl: 3,5-bis(trifluoromethyl)phenyl,
5b], the evaluation of 5a and 5b for the domino Michael–
Knoevenagel process, the recycling and reuse of the opti-
mal resin (5a), and the implementation of a flow process
allowing the continuous production of highly enantioen-
riched cyclohexane derivatives from substituted acrolein
derivatives and dimethyl 3-oxoglutarate with the same
catalyst.
In the context of a research project devoted to the devel-
opment of chemical processes with improved sustainabil-
ity characteristics, we have studied the immobilization of
organocatalytic species onto polymers11 using the copper-
catalyzed alkyne-azide cycloaddition (CuAAC).12,13 This
strategy has led to supported species with catalytic activi-
ties and enantioselectivities similar to or even better than
Supporting diarylprolinol trimethylsilyl ethers onto a
Merrifield resin using copper-catalyzed alkyne–azide cy-
cloaddition (CuAAC)12 was easily achieved from com-
mercially available N-Boc-(2S,4R)-4-hydroxyproline
methyl ester via its propargyloxy derivative 1.11f As
shown in Scheme 2, Grignard alkylation followed by sily-
lation with concomitant carbamate deprotection of 2 pro-
vided the key intermediate 3, which was subjected to
copper(I)-catalyzed azide-alkyne cycloaddition with azi-
SYNLETT 2011, No. 4, pp 0464–0468
x
x.
x
x.
2
0
1
1
Advanced online publication: 02.02.2011
DOI: 10.1055/s-0030-1259528; Art ID: Y02710ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Polymer-Supported Diarylprolinol Silyl Ethers as Catalysts
465
OH
F3C
F3C
CF3
F3C
N
N
N
N
N
Ph
MgCl
N
CF3
Ph
N
Cu
N
O
O
N
Cl
COOMe
THF, 0 °C
4
Ph
OH
NBoc
NBoc
N3
CF3
1
2
CF3
CF3
CF3
F3C
F3C
CF3
N
TMSOTf, Et3N
N
O
O
CH2Cl2
4
N
THF–DMF
MW 80 °C
–20 °C to r.t.
NH
CF3
OTMS
NH
5b
OTMS
200 W, 60 min
CF3
3
Scheme 2 Synthesis of the polystyrene-supported catalyst 5b
domethylpolystyrene. The tris(triazolyl)methanol copper markably shorter reaction time (2 h) and with excellent
complex 414 was an effective catalyst for the ‘click’ cy- enantioselectivity (entries 1 and 2). Interestingly, the use
cloaddition due to its compatibility with free amino of 5 mol% of 5a and 10 mol% of benzoic acid was enough
groups in the substrate. In this manner, the polymer- to induce the complete conversion of cinnamaldehyde in
supported organocatalyst 5b can be prepared with high re- four hours without compromising the enantioselectivity
producibility in four simple steps.15
of the process (entry 3). The catalyst loading could be re-
duced even further to 1 mol%, although the reaction
turned somewhat sluggish (entry 4). In the presence of
resin 5b the reaction also proceeded efficiently allowing
isolation of 7a in similar yield and with only a slight ero-
sion in enantioselectivity (entry 5). However, the consid-
erable increase recorded in the reaction time makes
apparent the better performance of catalyst 5a.
According to previously reported results8 and to the swell-
ing properties of resin 5a,11f dichloromethane was select-
ed as the solvent for this study. Moreover, it has been also
reported that a small excess of dimethyl 3-oxoglutarate
(1.1 equiv) increases the yield of the reaction and prevents
the formation of side products.8
Taking these considerations into account, organocatalysts
5 were examined in a first series of experiments in the
reaction of dimethyl 3-oxoglutarate and trans-cinnamal-
dehyde, with the results summarized in Table 1. It was
found that the use of benzoic acid as an additive increased
the yield of the domino process, providing alcohol 7a as a
Under the optimized reaction conditions [resin 5a (10
mol%), benzoic acid (20 mol%) in dichloromethane at
room temperature]16 the generality of the process was in-
vestigated with a representative set of a,b-unsaturated al-
dehydes (Table 2).
single isomer with good yield over the two steps, in a re- As shown in the Table 2, the process is compatible with
the presence of different functional groups on the aryl ring
Table 1 Optimization of the Reaction Conditions
in substituted cinnamaldehyde substrates (entries 1–6).
For these substrates, reactions with catalyst 5a proceeded
1) 5, PhCO2H
CH2Cl2, r.t.
2) NaBH4, 0 °C
CH2Cl2–MeOH
CO2Me
Ph
smoothly to completion in short reaction times (less than
2 h) to afford the products in good yield and excellent
enantioselectivity (97% to >99% ee), regardless of the
electronic nature of the substituent in the aryl ring. A sim-
ilar behavior was observed with other aromatic and het-
eroaromatic substrates (entries 7–9), although with a
moderate decrease in the enantioselectivity for 3-furylac-
rolein (entry 9). With catalyst 5b the reaction was in all
the cases slower than that with 5a and slightly less enanti-
oselective (entries 2, 4 and 8).
CHO
+
Ph
OH
O
CO2Me
7a
MeO2C
CO2Me
Entry
Catalyst/PhCO2H
(mol%)
Time
(h)a
Yield
ee
(%)b
(%)c
1
2
3
4
5
5a (10)
12
2
60
96
98
98
98
93
5a (10)/(20)
5a (5)/(10)
5a (1)/(2)
5b (10)/(20)
73
Noteworthy, the reaction also worked well with an ali-
phatic substrate such as trans-2-heptenal (entry 10), in
contrast with previous reports.8
4
72
50d
48
49
71
Gratifyingly enough, resin 5a compares favorably with
the most efficient homogeneous organocatalyst described
so far for the same reaction and substrates, from the per-
spectives of both catalytic activity and enantioselectivi-
ty.8,9 Moreover, the relative configuration of the four
a Total conversion to cyclohexenone intermediate 6a was obtained in
all cases, as determined by 1H NMR of the crude mixture.
b Isolated yield of 7a after reductive workup.
c Determined by HPLC (see Supporting Information).
d An 84% conversion was obtained in this case.
Synlett 2011, No. 4, 464–468 © Thieme Stuttgart · New York

466
E. Alza et al.
CLUSTER
Table 2 Scope of the Domino Michael–Knoevenagel Process of
a,b-Unsaturated Aldehydes and Dimethyl 3-Oxoglutarate
Table 3 Recycling Experiments in the Reaction between trans-Cin-
namaldehyde and Dimethyl 3-Oxoglutarate Leading to 7a, Catalyzed
by 5a
1) 5, PhCO2H
CO2Me
CH2Cl2, r.t.
2) NaBH4, 0 °C
CH2Cl2–MeOH
R
Run
1
Time (h)
Conv. (%)a
>99
Yield (%)b ee (%)c
CHO
+
R
OH
CO2Me
7a–g
2
2
73
71
68
70
65
54
98
98
98
98
98
98
O
MeO2C
CO2Me
2
>99
3
2
>99
Entry Product
R
Catalyst Time Yield
ee
(h)
(%)a
(%)b
4
4
>99
1
2
7a
7a
7b
7b
7c
7d
7e
7e
7f
Ph
5a
5b
5a
5b
5a
5a
5a
5b
5a
5a
2
73
98
93
5
8
>99
Ph
48
71
6
12
82
3
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
2-naphthyl
2-naphthyl
2-furyl
1.5
86
97
a Conversion into cyclohexenone 6a was determined by 1H NMR
analysis of the crude mixture.
4
96
2
ndc
69
nd
b Isolated yield of 7a after reductive workup.
c Determined by HPLC (see Supporting Information).
5
99
6
2
73
>99
>99
nd
In view of the high catalytic activity exhibited by 5a, we
considered that the process could be adapted to continu-
ous flow operation. For this purpose, a system was built
up as depicted in Scheme 3, sharing the design principle
with previously described systems for similar process-
es.11e Namely, the setup for continuous flow experiments
consisted of a glass column filled with the supported cat-
alyst 5a as the central element. Upstream from the col-
umn, a pump and a flask containing a solution with all the
reagents were placed and, finally, downstream from the
column, a receiving flask. The column was filled with 900
mg of the supported catalyst, and a 0.12 mL/min flow rate
(equivalent to ca. 10 min residence time) and 0.1 M con-
centration for the aldehyde (limiting reagent) were used.
7
1
59
8
96
ndd
63
9
1.5
80
10
7g
n-butyl
3
68
87
a Isolated yield of 7 after reductive workup.
b Determined by HPLC (see Supporting Information).
c A 25% conversion into 6b was obtained as determined by 1H NMR
of the crude mixture.
d A 5% conversion into 6e was obtained as determined by 1H NMR of
the crude mixture.
stereocenters in the final cyclohexanes could be con-
firmed in the present instance by X-ray diffraction analy-
sis of 7b (Figure 1),17 which was consistent with the
diastereoselective, substrate-controlled reduction by
borohydride.
Direct translation of the reaction conditions used in batch
to the continuous flow system (1.1 equiv dimethyl 3-oxo-
glutarate, 0.2 equiv benzoic acid) resulted in low conver-
sion (ca. 10%). However, this initial drawback could be
overcome by simply increasing the amount of benzoic
acid in the feed mixture, with 64% conversion being
achieved with one equivalent of benzoic acid.
Gratifyingly enough, 5a showed an excellent stability un-
der these conditions, as illustrated by the results recorded
in continuous flow operation for 72 hours (Table 4).
In this experiment, in order to avoid deterioration of the
reaction product, the receiving flask was flushed with ar-
gon and kept at –40 °C during operation. Workup involv-
ing borohydride reduction of the cyclohexenone product
allowed isolation of cyclohexanol 7b. After continuous
flow operation for 72 hours, 8.7 g of pure 7b were isolated
without any deterioration of the enantioselectivity during
the process (97% ee). The use of continuous flow condi-
tions, thus, allowed achieving a TON of 66 (referred to the
product formed), meaning an approximately tenfold in-
crease with respect to batch conditions, in an easy and
practical manner. Noteworthy, this experiment was car-
ried out with a sample of repeatedly used resin 5a, which
was resilylated (see above) for this purpose.
Figure 1 ORTEP plot of substituted cyclohexanol 7b
As a further step towards our ultimate goal of developing
a continuous flow process, we next explored the possibil-
ity of a repeated use of samples of 5a. Very interestingly,
in six consecutive runs with trans-cinnamaldehyde, the
excellent stereochemical performance of the resin re-
mained intact, while the catalytic activity started decreas-
ing after the third run (Table 3).18 In any case, samples of
partially deactivated 5a could be fully reactivated by treat-
ment with trimethylsilyl N,N-dimethylcarbamate.11f
Synlett 2011, No. 4, 464–468 © Thieme Stuttgart · New York

CLUSTER
Polymer-Supported Diarylprolinol Silyl Ethers as Catalysts
467
Table 4 Continuous Flow Production of 7b from 3-(4-Methoxyphe- Acknowledgment
nyl)acrolein and Dimethyl 3-Oxoglutarate Catalyzed by 5a
This work was funded by the MICINN (Grant CTQ2008-00947/
BQU), the DIUE (Grant 2009SGR623), the Consolider Ingenio
2010 (Grant CSD2006-0003) and the ICIQ Foundation. E.A. thanks
the ICIQ Foundation for a predoctoral fellowship. The authors gra-
tefully acknowledge M. Martínez Belmonte and J. Benet-Buchholz,
as well as G. Gómez Castresana for their invaluable help with X-ray
diffraction and NMR techniques, respectively.
Entry
Time (h)
Conv. (%)a
ee (%)b
1
2
3
4
5
6
7
8
1
2
64
64
63
65
65
64
62
62
–
–
3
–
4
–
References and Notes
5
–
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24
48
72
97
97
97
a Instant conversion into cyclohexenone, determined by 1H NMR of
the crude mixture.
b The ee value of isolated 7b was determined by HPLC (see Support-
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In conclusion, we have shown the suitability of the immo-
bilized catalyst 5a for the Michael–Knoevenagel domino
reaction of 3-substituted acrolein derivatives and dimeth-
yl 3-oxoglutarate. Catalyst 5a allows repeated recycling
under batch conditions, and offers the possibility of easy
re-conditioning. Under flow conditions, 5a exhibits a re-
markable robustness, which allows its use for three con-
secutive days without any appreciable deterioration of its
performance (activity and enantioselectivity) for the con-
tinuous production of highly substituted cyclohexane de-
rivatives.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Scheme 3 Schematic representation of the build up for continuous flow operation
Synlett 2011, No. 4, 464–468 © Thieme Stuttgart · New York

468
E. Alza et al.
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(15) See Supporting Information for details.
(16) General Procedure for the Domino Michael–
Knoevenagel Process of a,b-Unsaturated Aldehydes and
Dimethyl 3-Oxopentanedioate: Benzoic acid (0.05 mmol),
the corresponding aldehyde (0.25 mmol) and dimethyl 3-
oxopentanedioate (0.275 mmol) were added to catalyst 5
(0.025 mmol) previously swollen in CH2Cl2 (1 mL). The
suspension was shaken at r.t. for the time indicated in
Table 2 and then directly filtered. The resin was rinsed with
CH2Cl2 (3 × 1 mL) and the organic filtrate was concentrated
under reduced pressure. MeOH (1 mL) and NaBH4 (0.25
mmol) were added to a solution of the resulting crude in
CH2Cl2 (0.5 mL) at 0 °C, which was stirred at that temper-
ature for 20 min. After addition of the pH 7 phosphate buffer,
the organic materials were extracted with CH2Cl2 and the
combined organic phase was dried over Na2SO4, and then
concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (CH2Cl2–
EtO2) to afford 7.
(17) The deposition number at the Cambridge Crystallographyc
Data Centre is CCDC 804763.
(18) These recycling experiments show the results obtained in six
consecutive runs. After each run, the reaction mixture was
filtered and the solid-supported catalyst was washed with
CH2Cl2 and directly reused.
Synlett 2011, No. 4, 464–468 © Thieme Stuttgart · New York

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