Highly Enantioselective Cross-Aldol Reactions of Acetaldehyde Mediated by a Dual Catalytic System Operating under Site Isolation

Article abstract of DOI:10.1002/chem.201404215

Polystyrene-supported (PS) diarylprolinol catalysts 1 a (Ar=phenyl) and 1 b (Ar=3,5-bis(trifluoromethyl)phenyl) have been developed. Operating under site-isolation conditions, PS-1 a/1 b worked compatibly with PS-bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5 equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two-step synthesis of a phenoperidine analogue (68 % overall yield; 98 % ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.

Full text of DOI:10.1002/chem.201404215

DOI: 10.1002/chem.201404215
Communication
&
Site Isolation
Highly Enantioselective Cross-Aldol Reactions of Acetaldehyde
Mediated by a Dual Catalytic System Operating under Site
Isolation
Xinyuan Fan,[a] Carles Rodrꢀguez-Escrich,[a] Shoulei Wang,[a] Sonia Sayalero,[a] and
Miquel A. Pericꢁs*[a, b]
challenge due to its high reactivity and its inherent tendency
to oligomerize.[4] In 2008, Hayashi and co-workers reported the
Abstract: Polystyrene-supported (PS) diarylprolinol cata-
first asymmetric aldol reaction of acetaldehyde with good
yields and excellent enantioselectivities by using diaryprolinol
as the catalyst.[5] Shortly after, the same reaction was tested
with a diamine catalyst to afford aldol products with varying
yields (34–99%) and enantioselectivities (69–92%).[6] Recently,
a water compatible diarylprolinol derivative has been reported
to promote this reaction in brine, affording aldol products in
good yields and ee’s.[7]
lysts 1a (Ar=phenyl) and 1b (Ar=3,5-bis(trifluoromethyl)-
phenyl) have been developed. Operating under site-isola-
tion conditions, PS-1a/1b worked compatibly with PS-
bound sulfonic acid catalyst 2 to promote deoligomeriza-
tion of paraldehyde and subsequent cross-aldol reactions
of the resulting acetaldehyde in one pot, affording aldol
products in high yields with excellent enantioselectivities.
The effect of water on the performance of the catalytic
system has been studied and its optimal amount
(0.5 equiv) has been determined. The dual catalytic system
(1/2) allows repeated recycling and reuse (10 cycles). The
potential of this methodology is demonstrated by a two-
step synthesis of a phenoperidine analogue (68% overall
yield; 98% ee) and by the preparation of highly enantioen-
riched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5,
key intermediates in the synthesis of a variety of druglike
structures.
Despite the excellent results in these reports, some prob-
lems remain unsolved in this reaction, especially from the prac-
tical point of view. For instance, the low boiling point of acetal-
dehyde (218C) seriously hampers its transportation, storage,
and handling, therefore increasing cost and energy consump-
tion. From the reaction perspective, the tendency to oligomeri-
zation and high reactivity of acetaldehyde is detrimental, since
side reactions are common. To overcome these drawbacks, an
interesting example was reported recently using vinyl acetate
as acetaldehyde precursor in cross-aldol reactions. The record-
ed enantioselectivities, however, were very low (10–20% ee).[8]
On the other hand, the high catalyst loading required for the
reaction to take place in a reasonable time makes desirable
the development of a recyclable catalytic system.[9]
The aldol reaction has attracted plenty of interest due to its
pivotal role in organic synthesis.[1] Among the various methods
available to carry out this reaction enantioselectively, the orga-
nocatalytic methods stand out for several reasons: 1) under ex-
tremely mild reaction conditions excellent stereocontrol can be
achieved in up to two newly formed stereocenters, 2) no pre-
functionalization of any of the reactants is required, and 3) the
reactions take place in a metal-free environment, which avoids
product contamination with toxic metal derivatives.[2] There-
fore, important developments have been achieved since the
first report on the direct asymmetric intermolecular aldol reac-
tion catalyzed by proline in 2000.[3] The use of acetaldehyde
(the simplest enolizable aldehyde), however, has been a great
We have recently introduced a “wolf-and-lamb” reaction
system[10] for the asymmetric Michael reaction of acetaldehyde.
In our approach,[11] cheap and easy-to-handle paraldehyde
(3.7 E per mol; b.p. 1238C) is employed as a convenient
source of acetaldehyde, which is slowly generated by acid-cat-
alyzed deoligomerization (polystyrene-bound sulfonic acid). In
this way, the concentration of the reactive species in the reac-
tion media remains low and the problems mentioned above
are avoided. Acetaldehyde generated in this way is able to un-
dergo a Michael reaction mediated by a polystyrene-supported
(PS)-supported diphenylprolinol TIPS (triisopropylsilyl) ether,
furnishing the addition products in good yield with excellent
enantioselectivity. The implementation of this approach re-
quired the operation of the two catalysts under strict site isola-
tion[12] conditions (tea bag) to avoid their mutual deactivation.
In light of these results, we speculated that application of this
concept could provide a convenient solution for the asymmet-
ric cross-aldol reactions of acetaldehyde (Scheme 1).
[a] X. Fan, Dr. C. Rodrꢀguez-Escrich, S. Wang, Dr. S. Sayalero,
Prof. Dr. M. A. Pericꢁs
Institute of Chemical Research of Catalonia (ICIQ)
Avinguda Pa¨ısos Catalans 16, 43007, Tarragona (Spain)
Fax: (+34)977-920-243
E-mail: mapericas@iciq.es
[b] Prof. Dr. M. A. Pericꢁs
Departament de Quꢀmica Orgꢁnica,
Universitat de Barcelona, 08080 Barcelona (Spain)
In view of precedents with homogeneous catalysts,[5] we se-
lected and prepared the new PS-diarylprolinols 1a–b (Figure 1)
to mediate the cross-aldol reaction in combination with the
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404215.
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sion, several solvents were screened. Surprisingly, no conver-
sion was observed in DMF, which was the optimal solvent in
the analogous homogeneous catalytic reaction (entry 3).[5a]
However, increased conversion and ee were recorded in THF,
MeCN, and THF/MeCN or even under neat conditions (en-
tries 4–8). Particularly in MeCN, 64% conversion and 98% ee
were achieved. In full agreement with our working hypothesis,
no conversion was observed when the reaction was carried
out with a soluble acid, in this case pTsOH, instead of catalyst
2, due to salt formation with 1b (entry 6). Higher conversions
could be achieved when increasing the temperature in MeCN,
but at the cost of lowering the enantioselectivity of the reac-
tion (entry 9). Water (entry 10) and brine (entry 11) were also
tested, but almost no conversion was observed in both cases.
To evaluate the impact of moisture on the performance of
the dual catalytic system, the reaction was carried out in strict-
ly anhydrous media (glovebox, dry MeCN), but only 8% con-
version was observed (compare entries 12 and 7). These results
encouraged us to quantify the influence of added water to the
reaction media on the performance of the reaction.[13] While its
presence in small amounts entailed an increase in conversion
(entries 13, 14), larger quantities were found to slow down the
process (entry 15), albeit enantioselectivity remained un-
changed. It was eventually found (entry 16) that excellent con-
version (91%) and enantioselectivity (98%) could be achieved
with 20 mol% of 1b and 0.5 equivalents of water as an addi-
tive. Most likely, water is required to reactivate catalyst 1b,
which might be deactivated by slow oxazolidine formation
with any of the aldehydes present in the reaction mixture
(vide infra). Noteworthy, the combined use of 1b/2 under
these conditions does not require the physical separation of
the two resins, as was the case for the combined use of the
silyl ether of 1a and 2 in Michael additions of acetaldehyde.[11]
The scope of the cross-aldol reaction was studied next
under the optimized reaction conditions, and the results are
listed in Table 2. It was established that benzaldehydes with
either ortho, meta, or para electron-withdrawing substituents
afforded the desired cross-aldol products with generally good
yields and excellent enantioselectivities (Table 2, entries 1–9). In
addition, disubstituted aromatic aldehydes, such as 2,4-dichlor-
obenzaldehyde and 2-methoxy-4-nitro-benzaldehyde, were
also tolerated (entries 10 and 11). Benzaldehyde and aromatic
aldehydes bearing electron-donating substituents, in turn, are
not reactive when using this method.
Scheme 1. Cascade deoligomerization plus cross-aldol reaction mediated by
two incompatible catalysts operating under site isolation.
Figure 1. Catalysts used in this study.
same PS-bound sulfonic acid 2, already used to deoligomerize
paraldehyde for Michael additions.[11] For the optimization of
reaction conditions, the cascade deoligomerization plus cross-
aldol reaction between 4-nitrobenzaldehyde and paraldehyde
leading after reduction to 4e was selected (Table 1). The dual
catalytic system 1a/2 was rather inefficient in CH2Cl2, with low
conversion and moderate ee recorded after 26 h (Table 1,
entry 1). In contrast, 1b provided much higher enantioselectivi-
ties in this solvent, although conversion remained low
(entry 2). The use of 1b was adopted and, to improve conver-
Table 1. Cascade paraldehyde deoligomerization and asymmetric cross-
aldol reaction of 4-nitrobenzaldehyde with paraldehyde mediated by 1b/
2.[a]
Entry
Solvent
Water content
Conv. [%][b]
ee [%][c]
1[d]
2
CH2Cl2
CH2Cl2
DMF
–
–
–
19
15
0
73
94
–
3
4
5
6[e]
7
Neat
THF
THF
MeCN
THF/MeCN
MeCN
H2O
–
–
–
–
–
–
–
–
47
59
0
64
59
88
4
0
8
74
71
65
91
94
98
n.d.
98
98
78
–
From the mechanistic point of view, the whole procedure in-
volves two separate reactions that take place in a cascade
manner. First, paraldehyde is deoligomerized into acetalde-
hyde, a process catalyzed by the supported Brønsted acid 2.
Then acetaldehyde condenses with catalyst 1b to generate
the enamine intermediate, which reacts with the correspond-
ing aldehyde to afford the product. A catalyst off-cycle, regu-
lated by the addition of water to the reaction media also
needs to be considered. In Scheme 2, oxazolidine formation is
shown for the aldol product 3e, but similar parasitic species
can also be proposed with acetaldehyde or the aromatic alde-
hyde involved in the cross-aldol reaction.
8
9[f]
10
11
12[g]
13
14
15
16[h]
brine
–
MeCN
MeCN
MeCN
MeCN
MeCN
0
n.d.
98
98
98
98
0.5
1.0
5.0
0.5
[a] The reaction was carried out with 4-nitrobenzaldehyde (0.1 mmol), pa-
raldehyde (0.2 mmol), 1b (10 mol%), and 2 (10 mol%) in 0.1 mL solvent.
[b] By 1H NMR spectroscopy. [c] By HPLC analysis. [d] Compound 1a was
used instead of 1b. [e] pTsOH was used instead of 2. [f] At 508C. [g] In
the glovebox. [h] 20 mol% of 1b was used.
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Table 2. Asymmetric cross-aldol reaction of acetaldehyde.[a]
Entry
1
Product
t [h]
4
Yield [%][b]
62
ee [%][c]
52
4a
97
2
3
4
52
28
72
4b
4c
4d
40
77
78
99
99
99
5
26
52
72
72
28
52
4e
4 f
4g
4h
4i
80
28
47
68
61
63
98
97
97
97
98
98
Scheme 2. Schematic mechanistic picture of the paraldehyde deoligomeriza-
tion plus cross-aldol cascade process mediated by 1b/2.
6
7
(see Scheme 2 and the Supporting Information). To circumvent
this problem, after each cycle, the combined resins were
washed with AcOH in moist MeCN with the goal of hydrolyz-
ing this parasitic species, thus setting the aminocatalyst free
again (see the Supporting Information for details). To our de-
light, this strategy proved to have a tremendous impact on
the reusability of the 1b/2 combination. Keeping the reaction
time constant (26 h) we could achieve roughly the same re-
sults for the first 5 runs. After that, the isolated yield decreased,
albeit in a very mild manner. For instance, in the tenth run, the
aldol product was still isolated in 56% yield. Even more re-
markably, the enantioselectivity remained constant at 97%
throughout the ten runs (Scheme 3).
8
9
10
4j
11
28
4k
89
96
Enantioenriched diols with the general structure 4 are key
intermediates in the synthesis of a variety of marketed drugs
(Tolterodine,[14] Dapoxetine[15]) and natural products (Diospon-
gins A and B[16]). Amino alcohols 5, in turn, are intermediates in
the synthesis of important drugs (Atomoxetine,[17] Fluoxe-
tine,[18] Nisoxetine,[18d] and Duloxetine.[18a,d,e]) Traditional meth-
ods for the preparation of enantioenriched 4 normally involve
Sharpless epoxidation of allylic alcohols,[19] and a cross-aldol,
organocatalytic approach would represent important advan-
tages.[20] Enantiopure amino alcohols 5 have been synthesized
from 4 in two steps,[19] but could also be acceded by simple re-
ductive amination from cross-aldol products 3. Taking the
cross-aldol reaction of p-nitrobenzaldehyde as an example, we
show in Scheme 4 how crude 3e can be directly converted to
amino alcohol 5e by reductive amination with MeNH2 in good
overall yield (71%) and excellent ee (99%). In a further applica-
tion, the phenoperidine[21] analogue 6 has been prepared
(68% overall yield, 98% ee) by reductive amination of crude
3e with ethyl 4-phenylpiperidine-4-carboxylate and NaBH-
[a] Reactions were carried out with aldehyde (0.2 mmol), paraldehyde
(0.4 mmol), H2O (0.1 mmol), 1b (20 mol%), and 2 (10 mol%) in 0.2 mL
MeCN. [b] Isolated yield. [c] ee was measured by HPLC analysis.
From a practical perspective, one of the main advantages of-
fered by heterogenized catalysts is their easy recovery by
simple filtration and the consequent possibility of reusing. In
this respect, the fact of recycling two different polystyrene-
supported catalysts without having to separate them is of par-
ticular interest. Therefore, the recyclability of the 1b/2 dual
catalyst system was tested in the cross-aldol reaction with 4-ni-
trobenzaldehyde using different protocols. It was found that
thoroughly drying the resin between cycles improved the per-
formance on the forthcoming runs. However, the system was
still suffering from a gradual deactivation. We then hypothe-
sized that an oxazolidine off-cycle species might be responsi-
ble for sequestering part of the catalytically active species 1b
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crude cross-aldol products for the straightforward
preparation of enantiopure drug analogues high-
lights the potential of the present methodology in
medicinal chemistry.
Experimental Section
General procedure for the aldol reaction
Catalyst 1b (0.04 mmol, 20 mol%), Catalyst
2
(0.02 mmol, 10 mol%) and the aldehyde (0.2 mmol) were
mixed in a vial with acetonitrile (0.2 mL). Then paralde-
hyde (0.4 mmol) and deionized water (0.1 mmol) were
added and the vial was capped and shaken at room
temperature. After reaction completion (see Table 2), the
mixture was filtered and the resin was washed with
methanol (3ꢃ0.5 mL). The filtrates were combined and
cooled to 08C. Then NaBH4 (0.6 mmol) was added and
the mixture was stirred for 20 min. The reaction was
quenched with aqueous NH4Cl (3 mL), and extracted
with ethyl acetate (3ꢃ5 mL). The organic phases were
combined, washed with brine (2 mL), and dried over
Na2SO4. After solvent removal, products were purified by
flash chromatography on silica gel, with hexanes/ethyl
acetate mixtures as the eluent.
Scheme 3. Recycling tests of the dual catalytic system.
Acknowledgements
Financial support from the Institute of Chemical Re-
search of Catalonia (ICIQ) Foundation, MINECO (grant
CTQ2012–38594-C02–01) and DEC Generalitat de Cat-
alunya (Grant 2014SGR827) is gratefully acknowl-
edged. We also thank MINECO for support through
Severo Ochoa Excellence Accreditation 2014–2018
(SEV-2013-0319). X.F. thanks the CSC (Chinese Schol-
arship Council) for the scholarship support. C.R.-E.
thanks the AGAUR (Generalitat de Catalunya) for
a Beatriu de Pinꢄs B fellowship.
Scheme 4. Synthesis of drug analogues and intermediates from crude cross-aldol ad-
ducts 3.
Keywords: acetaldehyde · cross-aldol · recycling ·
site-isolation · wolf and lamb
(OAc)3. Polymer-supported 1b, which could act as a competi-
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[21] For synthesis of racemic Phenoperidine and its physiological activity
studies, see: a) C. L. Duc, C. Charlon, C. A. Delord, J. Cros, B. Monsarrat,
J. Labelled Compd. Radiopharm. 1978, 15, 693–696; b) M. Fischler, J. C.
Levron, H. Trang, J. F. Vaxelaire, B. Flaisler, G. Vourch, Br. J. Anaesth.
1985, 57, 872–876; c) M. Fischler, J. C. Levron, H. Trang, D. Brodaty, C.
Dubois, D. Guilmet, G. Vourch, Br. J. Anaesth. 1985, 57, 877–882.
[22] An attempt to purify 3e by chromatography failed, probably due to de-
composition of this hydroxy aldehyde on silica gel.
[13] For water effect in aldol reaction, see ref. 2d and: a) N. Zotova, A.
Franzke, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2007, 129,
15100–15101; b) A. K. Sharma, R. B. Sunoj, Angew. Chem. 2010, 122,
Received: July 2, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Site Isolation
X. Fan, C. Rodrꢀguez-Escrich, S. Wang,
S. Sayalero, M. A. Pericꢁs*
&& – &&
Highly Enantioselective Cross-Aldol
Reactions of Acetaldehyde Mediated
by a Dual Catalytic System Operating
under Site Isolation
Together, yet apart: Unwanted acid–
base neutralization is not a problem
anymore! Under the site-isolation con-
cept, polystyrene-supported (PS)-acidic
and -basic catalysts worked compatibly
as a “wolf-and-lamb” system for the cas-
cade deoligomerization of paraldehyde
and subsequent highly enantioselective
cross-aldol reaction with benzaldehydes
(see scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!