The ion tag strategy as a route to highly efficient organocatalysts for the direct asymmetric aldol reaction

Article abstract of DOI:10.1002/adsc.200800608

The installation of an imidazolium tag via acetate connection to the C-4 of cis-4-hydroxy-l-proline provides a highly efficient catalyst for the direct asymmetric aldol reaction, that works in a remarkably low catalyst loading (0.1 mol%) affording TONs up

Full text of DOI:10.1002/adsc.200800608

UPDATES
DOI: 10.1002/adsc.200800608
The Ion Tag Strategy as a Route to Highly Efficient
Organocatalysts for the Direct Asymmetric Aldol Reaction
Marco Lombardo,a,* Srinivasan Easwar,a Filippo Pasi,a and Claudio Trombinia,*
a
Dipartimento di Chimica “G. Ciamician”, Universitꢀ degli Studi di Bologna, via Selmi 2, 40126, Bologna, Italy
Fax : (+39)-051-209-9456; phone: (+39)-051-209-9513; e-mail: marco.lombardo@unibo.it or claudio.trombini@unibo.it
Received: October 7, 2008; Revised: December 12, 2008; Published online: January 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800608.
Abstract: The installation of an imidazolium tag via
acetate connection to the C-4 of cis-4-hydroxy-l-
proline provides a highly efficient catalyst for the
direct asymmetric aldol reaction, that works in a re-
markably low catalyst loading (0.1 mol%) affording
TONs up to 930 in the case of electron-poor aro-
matic aldehydes with ee up to >99%.
ported in the literature.[4] Catalytic efficiency was the
major limit of the former protocols, since TONs of 10
were hardly achieved in the literature up to 2004.
The presence of water, the solvent where class I al-
dolases catalyze the direct aldol reaction with excel-
lent stereocontrol,[5] had in the original organocatalyt-
ic protocols a deleterious effect on enantioselectivi-
ty,[6] while proline in water does not work at all.[7]
In 2006 the field of enantioselective organocatalytic
aldol and related reactions in water recorded an ex-
ceptional breakthrough, with the contributions report-
ed by Barbas and co-workers,[7,8] Hayashi and co-
workers,[9] and other groups.[10]
Keywords: asymmetric aldol reactions; catalyst re-
cycling; ionic-tagged catalysts; organic catalysis;
solvent-free conditions
The key to success was to develop heterogeneous
aqueous biphasic conditions which simulated the hy-
drophobic pocket where class I aldolases are sup-
posed to promote their aldol reactions through the so
Introduction
One of the most pressing challenges facing synthetic called “asymmetric aminocatalysis”. Process design
chemists is to join efficiency, traditionally determined focus on the preparation of water-insoluble catalysts
as yield and selectivity parameters, to sustainability which, together with an excess of donor ketone (2–5
issues. Paraphrasing Noyori, chemists must pursue equivalents with respect to the limiting aldehyde) and
“practical elegance” in developing new synthetic pro- the acceptor aldehyde, form a concentrated hydro-
tocols, where “practical” has to be read as efficient phobic medium which is in contact with the aqueous
and sustainable at once.[1] A biomimetic approach to phase.
this challenge is proposed by organocatalysis,[2] which
These heterogeneous systems are claimed to benefit
aims to mimic the action of enzymes with small or- from a catalytic effect by the water molecules at the
ganic molecules, and, possibly, perform reactions in oil-water interface, as rationalized by Jung and
water with comparable efficiency and stereoselectiv- Marcus.[11] The best results are obtained with catalysts
ity. At its outset, organocatalysis provided enantiose- resulting from the installation of hydrophobic sub-
lective reaction protocols that that took place in or- stituents on the scaffold of a reference catalyst such
ganic solvents, only. For example, the proline-cata- as proline. Following this guideline, Barbas developed
lyzed asymmetric cross-aldol reaction afforded good (S)-N-decyl-N-(2-pyrrolidinylmethyl)decan-1-amine,
enantioselectivity and yield when excess acetone and trifluoroacetic salt (TONmax =10),[8a] Hayashi pre-
aromatic aldehydes were treated with a catalytic pared 4-tert-butyldimethylsiloxy-l-proline and 4-dec-
amount of (S)-proline (typically 20–30 mol%) in anoyloxy-l-proline (TONmax =8), the latter working
DMSO or DMF.[3] Several other amino acid deriva- with aliphatic aldehydes as donors.[9]
tives, including primary, cyclic and acyclic secondary
A slightly different approach combined partially
amino acids, were screened as catalysts, while an in- water-soluble catalysts with salts that facilitate hydro-
tense catalyst design and development started result- phobic aggregation by “salting out”.[12] The result was
ing in an ever increasing number of new solutions re- on outstanding increase of the reaction efficiency ex-
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The Ion Tag Strategy as a Route to Highly Efficient Organocatalysts
UPDATES
pressed as TONs. Indeed, TON=58 was observed reported by Cꢂrdova and co-workers using DMSO as
using 2.5–5 mol% of a l-prolinethioamide, dichloro- the solvent under homogeneous conditions.[22]
acetic acid salt[12a], a value that increased to 170 using
The counter-intuitive benign presence of water in
0.5 mol% of amides deriving from proline and chiral the generally accepted enamine mechanism of the
1,2-amino alcohols.[12b]
proline-catalyzed aldol raction was due to the inhibi-
In all the foregoing cases, process design and cata- tion of the formation of iminium ion 1 and other
lyst optimization aimed at magnifying the catalyst sol- downstream products 2 and 3, deriving from proline
ubility in the organic phase, where the aldol reaction and the acceptor aldehyde (Scheme 1), as elegantly
must take place to ensure the best yields and stereo- demonstrated by Blackmond and co-workers.[23] The
chemical results. Recent contributions by Arm- occurrence of these off-cycle processes with respect to
strong[13] and Pericꢀs[14] further implemented the the generally accepted enamine-driven catalytic cycle,
value of the organocatalytic aldol reaction.
reduces the concentration of catalytically active spe-
Solvent-free reactions[15] provide the most straight- cies causing the reaction rate and the yield to be
forward answer to the solvent problem, the most im- lower than that expected for the given initial donor
portant contributor to the sheer magnitude of the and acceptor concentrations.
waste problem in chemical manufacture.[16] Bolm and
co-workers reported that the reaction time of proline-
catalyzed intermolecular aldol reactions was signifi-
cantly shortened when magnetic stirring was replaced
by ball-milling under solvent-free conditions, afford-
ing anti-aldols in high ees.[17] The best results were ob-
tained using stoichiometric amounts of donor ketone
and acceptor aldehyde. A few other examples of
asymmetric aldol reactions were reported from Lu
Scheme 1. Off-cycle side-products responsible for the low ef-
ficiency of proline in the catalytic asymmetric aldol reaction.
and Hayashi labs to occur in the absence of organic
solvents, but, at a deeper insight, the excess of donor
ketone used plays the role of the reaction “diluent”.
In this context, we approached the design of a new
The excess of donor partner affects the green creden- cross-aldolization catalyst working under solvent-free
tials of the process in terms of waste production, conditions in the presence of water, adopting the ion-
unless the recovery of the excess ketone is easily per- tag strategy to modify the proline scaffold.[24] Miao
formed, as in the case of sufficiently volatile com- and Chan first reported the use of imidazolium ion-
pounds that can be collected in a cold trap after evap- tagged catalysts of the general structure 4 (Figure 1),
oration under vacuum. The first example refers to the where the tag is connected to the 4-OH group of
use of l-tryptophan, in the presence of 5 equivalents trans-4-hydroxy-l-proline. The authors reported the
of water with respect to the aldehyde, which acted as use of 4a (X=BF4) as catalyst in DMSO or acetone
an efficient catalyst (the highest TON was 17) for the as the solvent but the catalyst loading (30 mol%) was
aldol reaction under solvent-free conditions.[18]
very high resulting in poor TONs.[25]
Lu and Teo, independently, observed that incorpo-
ration of hydrophobic siloxy groups into threonine[19]
and serine[20] resulted in effective organocatalysts ca-
pable of catalyzing the asymmetric aldol reaction
under solvent-free conditions in the presence of 1
equivalent of water with TONs up to 29.[19]
Proline[21] and trans-siloxy-l-proline[21] were report-
ed by Hayashi to work under solvent-free conditions,
and the latter resulted in one of the most effective
catalysts ever developed for the aldol reaction, afford-
ing products with excellent diastereo- and enantiose-
lectivities under neat conditions in the presence of 3
equivalents of water. The critical effects of the
Figure 1. Ion-tagged trans-4-hydroxy-l-prolines. 4a: X=BF4;
4b: X=Tf2N.
A higher efficiency was achieved by working with
amount of water in solvent-free aldol reactions had 4b, where the counterion was the lipophilic bis(tri-
been previously demonstrated by Hayashi, who got fluoromethylsulfonyl)imide ion (X=Tf2N). In particu-
his highest TON (96) using 1 mol% of O-TBDPS-4- lar, TONs up to 17 were achieved in ionic liquids.[26]
hydroxy-l-proline, 2 equivalents of cyclohexanone, b- At last, even more efficient from a synthetic (chemi-
naphthaldehyde and 3 equivalents of water at room cal yields) and stereochemical point of view (diaste-
temperature in 42 h.[21] Analogous observations on reomeric ratios and ees) was found in the use of 4b
the role of water on enantioselectivity had been also under aqueous biphasic conditions.[27]
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Marco Lombardo et al.
UPDATES
Scheme 3. Direct asymmetric aldol reaction.
less satisfactory with respect to the use of 4b; that is,
using 5 mol% of 5, 4-nitrobenzaldehyde (6a) afforded
the corresponding aldol 7a in only 67% yield after
24 h at 258C [anti/syn=96:4, ee (anti)=97%]. In the
same conditions, 4b afforded a 97% yield [anti/syn=
96:4, ee (anti)=99%].
Scheme 2. Synthesis of the ionic-tagged cis-4-hydroxy-l-pro-
line 5.
Results and Discussion
On the basis of our previous experience using 4b we
After a screening of different reaction conditions,
planned a systematic investigation on the use of 4b we were delighted to observe that using 8 equivalents
and its epimer 5 (Scheme 2) in a number of reaction of cyclohexanone with respect to the limiting 4-nitro-
protocols, with the aim to give a contribution to the benzaldehyde (6a) and 5 mol% of 5 under solvent-
TON optimization challenge without affecting the free conditions, in the presence of 1.2 equivalents of
high standards achieved in the literature in terms of water, a quantitative amount of aldol 7a could be iso-
stereocontrol. A complete overview of all the study lated after stirring for 6 h at 258C, with remarkably
still in course on 4b, 5 and analogues will be present- high stereoselectivity: anti/syn=93:7, ee (anti)> 99%.
ed in an independent report; here we wish to antici- Under the same conditions, the less reactive 4-chloro-
pate the best results obtained with 5 under neat con- benzaldehyde (6b) was converted after 17 h to the
ditions in the presence of water. In the rational design anti aldol 7b in >99% yield, anti/syn=90:10, ee
of 5 we pursued the following considerations: rotation (anti)=98% (Scheme 3).
À
around the C-4 O bond can produce two effects, i)
Once having selected the 6a/cyclohexanone aldol
orienting the ionic tag towards the concave face of system as the benchmark reaction, we started the op-
the octahydropentalene-like structure of side-products timization study shown in Table 1. The work-up
2 and 3, thus destabilizing them and ensuring a higher simply consisted of pouring the crude reaction mix-
amount of available catalytically active species; ii) ture on the top of a silica gel column and eluting with
bringing the ionic tag and its Tf2NÀ counterion in spa- cyclohexane/ethyl acetate mixtures.
tial proximity to the reactive centers during the rate-
Our focus was on reducing the catalyst loading
determining enamine addition step. If an internal without compromising the reaction times. Entry 1
electrostatic stabilization of the transition state was in demonstrated that using 5 mol% catalyst loading and
action, a reaction rate enhancement should be ob- 5 equivalents of donor ketone the reaction did pro-
served. Henceforth, we refer to this hypothesis as a ceed almost to completion in 20 min, corresponding
“cis effect”.
to a TON of 19 and a TOF of 64 hÀ1. The catalyst
The synthesis of
5
provided no difficulties loading was then lowered to 2 mol% and after 2 h the
(Scheme 2, see Supporting Information) as it was reaction was virtually complete (entry 2, TON=49).
smoothly met in just four operations from Cbz-pro- Under these last conditions we checked the possible
tected trans-4-hydroxy-l-proline, benzyl ester. A stan- reuse of 5 (entries 3–6).
dard Mitsunobu protocol applied to protected trans-4-
The recovery of excess cyclohexanone was a facile
hydroxy-l-proline and chloroacetic acid was followed step, just requiring to trap it in a cold-finger trap
by the installation of N-methylimidazole on the under vacuum at 258C (10À2 mmHg).[28] The aldol
chloro ester moiety and anion exchange with lithium product was extracted from the crude residue with
triflamide. Hydrogenolytic cleavage of the protective ether, leaving the catalyst that was reloaded with the
groups completed the synthesis of 5 in 53% overall reactants and water. Only in the fourth cycle (entry 6)
yield from Cbz-protected trans-4-hydroxy-l-proline, did the yield decrease (20% less than in the first run),
benzyl ester.
but with a remarkably constant stereoselectivity.
Furthermore, we reduced the catalyst loading to
With this new catalyst in our hands, we first
checked the aqueous biphasic conditions previously 0.5 mol%, a level that has been reached only by
applied to 4b.[27] While stereoselectivities were compa- Maya et al., as previously discussed.[12a] We carried
rable, yields obtained using catalyst 5 were in general out a reaction over 24 h, which furnished, too, the
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The Ion Tag Strategy as a Route to Highly Efficient Organocatalysts
UPDATES
Table 1. Optimization studies for the reaction of cyclohexanone and 4-nitrobenzaldehyde.[a]
Entry
Catalyst, [mol%]
H2O [equiv]
Time [h]
Yield [%][b]
anti/syn[c]
anti ee [%][d]
TON
1
2
5, 5
5, 2
5, 2
5, 2
5, 2
5, 2
5, 0.5
5, 0.5
4b, 0.5
5, 0.5
5, 0.1
5, 0.1
5, 0.1
5, 0.1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.25
3.2
32
0.3
2
2
2
2
2
24
5
96
98
97
98
98
75
98
87
37
99
32
6
92:8
93:7
92:8
94:6
92:8
92:8
93:7
92:8
94:6
95:5
80:20
73:27
93:7
55:45
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
19
49
49
49
49
38
196
174
74
198
320
60
3[e]
4[f]
5[g]
6[h]
7
8
9
5
10[i]
11
12
13
14
18
24
24
24
24
97
>99
35
38
7
380
70
[a]
Reactions are conducted at 258C using 5 equiv, of ketone with respect to the limiting aldehyde (1 mmol).
[b]
[c]
[d]
[e]
[f]
Refers to isolated yields.
1
Determined by H NMR of the crude mixture.
Determined by chiral HPLC (see Supporting Information).
1st run.
2nd run.
3rd run.
[g]
[h]
[i]
4th run.
Reaction on 10 mmol of 4-nitrobenzaldehyde.
aldol in quantitative yield and remarkable stereose- organocatalysis to date. Using 1.2 equivalents of
lectivity (entry 7, TON=196). A drop in the yield water, after 24 h we obtained a yield of 32% of the
was observed only when we carried out a reaction aldol but, surprisingly, there was a drop in the diaste-
over only 5 h using 0.5 mol% of the catalyst, where- reoselectivity (entry 11). This prompted us to study
upon we obtained an 87% yield of the aldol (entry 8, the reaction with different amounts of water and the
TON=174, TOF=35 hÀ1).
best yield of 38% was obtained using a slightly larger
For a direct comparison, when 4b had been subject- amount of water (entry 13, 3.2 equivalents), with the
ed to these identical reaction conditions (entry 9) sim- diastereoselectivity restored to its original ratio. This
ilar results were again obtained in terms of stereose- reaction marked a hitherto unrealized TON of 380 in
lectivities, but the corresponding aldols were isolated asymmetric organocatalytic aldol reactions. Both ac-
in only 37% yield, anti/syn=94:6, ee (anti) >99%.
tivity and stereoselectivity are destroyed by higher
The better performance of 5 seems to be consistent amounts of water (entry 14). The last entries demon-
with the favorable previously quoted “cis effect” be- strate that, in an optimization study of these catalytic
tween the ion tag-containing substituent and the car- processes, catalyst loading, amount of water, reaction
boxyl group that drives the reaction stereoselectivity. time, plus excess of donor which was arbitrarily set at
From a general synthetic point of view, to validate 5 equivalents in this work, have to be carefully inves-
the results obtained in entries 7 and 8, we scaled up tigated.
the reaction to 10 mmol of limiting 4-nitrobenzalde-
The next task was to explore the scope of the cata-
hyde (entry 10). After 18 h at 258C removal of excess lyst. A careful optimization will be presented in due
cyclohexanone under vacuum and silica gel chroma- time, while we present here a simple extension of the
tography provided us 2.47 g (9.9 mmol) of product, conditions reported in Table 1 to a number of accept-
corresponding to a 99% yield, with a slightly higher or aldehydes in the reaction with cyclohexanone first
anti/syn ratio (95:5) and a virtually complete enantio- (Table 2), then to a few different donors in the reac-
selectivity (ee (anti) >99%).
tion with 4-nitrobenzaldehyde (Table 3). As Table 2
As refers to the stereochemical outcome of en- (entries 1–20) depicts, reactions were carried out with
tries 1–8, anti-aldols were invariably obtained in a vir- 2, 0.5, and 0.1 mol% catalyst loading, depending on
tually pure configuration, while diastereomeric ratios the reactivity of the acceptor aldehyde. Outstanding
fluctuated in the 13(Æ2):1 range.
yields were obtained in the case of all the reactive al-
We were curious to attempt a reaction with just dehydes, and, regardless of the electronic nature of
0.1 mol% catalyst loading, a level very rarely met in the aromatic aldehydes, excellent enantioselectivities
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Marco Lombardo et al.
UPDATES
Table 2. Asymmetric aldol reactions of cyclohexanone with aldehydes, catalyzed by the cis-ionic-tagged proline 5 under sol-
vent-free conditions in the presence of water.[a]
Entry
R in RCHO
5 [mol%]
Time [h]
Yield [%][b]
anti/syn[c]
anti ee [%][d]
TON
1
2
3
4
5
6
7
8
4-CN-C6H4
4-CN-C6H4
2-NO2-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Br-C6H4
4-MeO-C6H4
4-MeO-C6H4
Ph
2
0.5
2
2
2
0.5
2
5
2
2
0.5
0.5
0.1
0.5
0.1
0.5
0.1
0.1
10
10
6
6
6
>99
86
95
97
95
88
50
60
86
90
44
>99
93
96
46
94
62
68
72
68
92:8
92:8
92:8
92:8
95:5
95:5
80:20
75:25
92:8
88:12
85:15
99:1
>99
>99
>99
> 99
>99
>99
97
97
>99
98
>50
172
48
49
48
176
25
12
43
45
18
15
30
60
60
19
24
42
4
24
24
24
24
24
24
72
72
9
10
11
12
13
14
15[e]
16
17[e]
18[f]
19
20
2-naphthyl
2-naphthyl
C6F5
98
88
>99
>99
99
98
98
36
70
99
99
>198
930
192
460
188
620
680
7
C6F5
99:1
3-pyridyl
3-pyridyl
4-pyridyl
4-pyridyl
4-pyridyl
i-Pr
85:15
84:16
85:15
80:20
86:14
>99:1
>99:1
c-C6H11
7
[a]
Reactions are conducted at 258C using 5 equiv, of donor, 0.5 mmol of acceptor aldehyde and 1.2 equiv, of water.
[b]
[c]
[d]
[e]
[f]
Refers to isolated yields.
1
Determined by H NMR of the crude reaction mixture.
Determined by HPLC using chiral columns (see Supporting Information).
2.2 equiv. of water were used.
6.6 equiv. of water were used.
Table 3. Asymmetric aldol reactions of different donors with p-nitro-benzaldehyde, catalyzed by the cis-ionic-tagged proline
5 under solvent-free conditions in the presence of water.[a]
Entry
Ketone
5 [mol%]
Time [h]
Yield [%][b]
anti/syn[c]
anti ee [%][d]
TON
1
2
3
cyclopentanone
cycloheptanone
acetone
1
5
2
3.5
60
24
97
45
87
70:30
71:29
–
98
>99
70
97
9
44
[a]
Reactions are conducted at 258C using 5 equiv. of ketone with respect to the limiting aldehyde.
[b]
[c]
[d]
Refers to isolated yields.
1
Determined by H NMR of the crude mixture.
Determined by chiral HPLC (see Supporting Information).
were obtained. In particular, stereoselectivity was not almost 99% enantiomerically pure anti-aldol was ob-
affected by changing the reaction conditions, unless tained in these reactions as the single product (en-
the catalyst loading limit of 0.1 mol% was used. In tries 19 and 20).
the last case a careful optimization of the water con-
Results collected in Table 3 point out the great dif-
tent is necessary. Astonishing are the TONs recorded ference in terms of reactivity between cyclopentanone
with 4- and 3-pyridinecarboxaldehyde (entries 14–18) and cycloheptanone (entries 1 and 2), the latter often
with a top TON value of 930 reached by pentafluoro- displaying disappointing results in the organocata-
benzaldehyde (entry 13).
lysed aldol reaction.[8a,17a] Acetone displayed a reactiv-
Unfortunately, aliphatic aldehydes were the poorest ity intermediate between cyclopentanone and cyclo-
substrates for this solvent-less reaction protocol. To heptanone, and a lower enantioselectivity with respect
force them to provide acceptable yields of aldols, to cycloalkanones.
10 mol% of catalyst was necessary, even though an
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The Ion Tag Strategy as a Route to Highly Efficient Organocatalysts
UPDATES
Conclusions
Recycling Procedure (Table 1, entries 3–6)
Cyclohexanone (0.26 mL, 2.5 mmol) and water (0.011 mL,
In conclusion, stereochemical considerations applied
to the ion-tagging strategy led us to develop a new
highly active and selective proline-based organocata-
lyst for the asymmetric aldol reaction. As mentioned
earlier, the best performances were exhibited in a re-
action protocol which did not use organic solvents in
the reaction stage but 1.2 equivalents of water and a 5
molar excess of a liquid ketone as aldol donor which
ensured the reaction to occur under homogeneous
conditions with no mass transfer problems. Exception-
ally high values of TON for the organocatalytic aldol
condensation were achieved with the most reactive ar-
omatic aldehydes.
Being a salt, the catalyst was not soluble in slightly
aprotic polar solvents, and this allowed us to develop
an easy separation procedure of the product from the
catalyst, which could eventually be recycled. Indeed,
once having eliminated the excess ketone under
vacuum, the aldol is easily extracted with ether and
the catalyst can be directly reused for another cycle.
Stereocontrol was maintained at an identical level for
four cycles, while the limited drop in recovered aldol
in the 4th cycle should be reduced by a technical im-
plementation of the separation step.
0.6 mmol) were added to the catalyst
5
(1.3 mg,
0.0025 mmol) and the mixture was allowed to stir for 20 min
at room temperature, whereupon complete catalyst dissolu-
tion was observed. 4-Nitrobenzaldehyde (75 mg, 0.5 mmol)
was then added to the reaction mixture and allowed to stir
for 2 h at room temperature. The excess of cyclohexanone
was removed under reduced pressure (~1 mmHg) and the
reaction mixture was further dried under vacuum for
45 min. The aldol product was then extracted with Et2O
(2 mLꢃ5) following which, the reaction flask was again
dried under vacuum for 1 h. It was then charged with the re-
actants and water in identical amounts and fashion as above.
The aldol product was purified by evaporation of the com-
bined organic extracts and subjecting the residue to silica
gel column chromatography.
Acknowledgements
The University of Bologna is aknowledged for financial sup-
port.
References
The process presented here was optimized for the
benchmark reaction of cyclohexanone and 4-nitroben-
zaldehyde and under these conditions many substrates
afforded “enzymatic-like” levels of ees. Work is in
course to widen the scope and optimize the efficiency
of 5 and other closely related catalysts.
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Experimental Section
Typical Procedure (Table 1, entry 8)
Cyclohexanone (0.52 mL, 5 mmol) and water (0.022 mL,
1.2 mmol) were added to the catalyst 5 (2.7 mg, 0.005 mmol)
and the mixture was allowed to stir for 20 min at room tem-
perature, whereupon complete catalyst dissolution was ob-
served. 4-Nitrobenzaldehyde (0.151 g, 1 mmol) was then
added to the reaction mixture and allowed to stir. At the be-
ginning 4-nitrobenzaldehyde, cyclohexanone and water do
not form a homogenous mixture, but as soon as the conver-
sion proceeds, the solution turns clear and homogeneous.
The faster the reaction mixture turns homogeneous, the
faster is the reaction. After 5 h stirring at room temperature,
the reaction mixture was charged directly onto a silica gel
column and the pure aldol was obtained upon eluting with
cyclohexane/ethyl acetate (7:3) in 87% yield. The ee was de-
termined by chiral HPLC using a CHIRALPAK AD
column (hexane/2-propanol=85:15, flow rate: 1.0 mLminÀ1,
l=254 nm); tR syn=11.1 min, tR syn=13.6 min, tR anti
(minor)=14.6 min, tR anti (major)=18.8 min.
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282
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Adv. Synth. Catal. 2009, 351, 276 – 282