Pronounced asymmetric amplification in the aldol condensation of Chan's diene promoted by a Ti(IV)/BINOL complex

Article abstract of DOI:10.1016/j.tetasy.2004.06.009

A strong enhancement of the enantiomeric excess can be obtained by performing the enantioselective aldol reaction of Chan's diene in the presence of enantiomerically enriched Ti(O-i-Pr)₄/BINOL catalysts derived from mixing pre-prepared solutions of enantiopure Ti(O-i-Pr)₄/(R)-BINOL and Ti(O-i-Pr)₄/(S)-BINOL at different concentrations.

Full text of DOI:10.1016/j.tetasy.2004.06.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2421–2424
Pronounced asymmetric amplification in the aldol condensation of
Chan’s diene promoted by a Ti(IV)/BINOLcomplex
Rosaria Villano, Maria Rosaria Acocella, Margherita De Rosa, Annunziata Soriente and
Arrigo Scettri*
Dipartimento di Chimica, Universit ꢀa di Salerno, 84081 Baronissi (Salerno), Italy
Received 25 May 2004; accepted 8June 2004
Available online 23 July 2004
Abstract—A strong enhancement of the enantiomeric excess can be obtained by performing the enantioselective aldol reaction of
Chan’s diene in the presence of enantiomerically enriched Ti(O-i-Pr)
of enantiopure Ti(O-i-Pr) /(R)-BINOL and Ti(O-i-Pr) /(S)-BINOL at different concentrations.
Ó 2004 Elsevier Ltd. All rights reserved.
4
/BINOL catalysts derived from mixing pre-prepared solutions
4
4
1. Introduction
the aldehyde function, to achieve high values of yields
and ees.
1
,3-Bis-trimethyl silyloxydienes of type 1 (Scheme 1)
represent preparatively useful masked forms of aceto-
acetate esters, as confirmed by their employment in
many important C–C bond forming reactions, such
However, the conversion of 1a into 3 has been shown to
occur with high levels of efficiency and enantioselectivity
(up to 99%) with a variety of aromatic, unsaturated,
1
1
as conjugate additions, oxidative dimerizations, cyclo-
2b;3
aliphatic aldehydes in the presence of reduced amounts
7
2
additions, reactions with 1,2-di-electrophiles, cyclo-
aromatizations with 1,3-dicarbonyl compounds and
4
of Ti(O-i-Pr) /BINOL catalytic system (2–8%).
4
2b
reactions with 1,4-dicarbonyl compounds.
The synthetic importance of the above procedure has
been further pointed out by its employment as a key-
8
step in two recent patents for the synthesis of chiral
OSiMe
3
OSiMe
3
OH
*
O
O
d-hydroxy-b-ketoesters of type 3, which are intermedi-
ates in the preparation of bioactive compounds used in
the treatment of hyperlipidemia and arteriosclerosis.
catalyst
+
RCHO
OR'
R
OR'
1
2
3
Scheme 1.
2. Results and discussion
0
Furthermore, Chan’s diene 1a (R ¼ Me) has been used
as the synthetic equivalent of acetoacetate dianion in
aldol condensations leading to racemic (catalyst:
9
Further experiments performed on benzaldehyde,
chosen as a representative substrate (Scheme 2, Table 1),
4
in the presence of enantioenriched 1/1 Ti(O-i-Pr) /
1a
TiCl or nonracemic polyfunctional aldols 3 (cata-
5
lysts: chiral B(III), Cu(II) and Ti(IV) complexes).
4
)
BINOL complexes pointed out the presence of positive
nonlinear effects, (þ)-NLE (Table 1, entry 2); never-
theless, the mode of preparation of the catalytic system
6
7
It is noteworthy that compounds 3 can only be obtained
in moderate ees by using a chiral borane as catalyst,
while the employment of a Cu(II)/pybox complex re-
quires the presence of a chelating group, a-situated to
10
proved to be a critical factor, so that linearity could be
OSiMe
3
OSiMe
3
OH
*
O
O
1
)Ti(IV)/BINOL
)H+
+
PhCHO
2
OMe
Ph
OMe
1a
2
3a
*
Corresponding author. Tel.: +39-089-965374; fax: +39-089-965296;
e-mail: scettri@unisa.it
Scheme 2.
0
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.009

2422
R. Villano et al. / Tetrahedron: Asymmetry 15 (2004) 2421–2424
Table 1. Correlation between the asymmetric amplification and the mode of the preparation of the catalyst
a
b
c
Entry
1
Catalyst solution (M)
BINOL ee (%)
3a Ee (%)
>99
3a Yield (%)
Ti(O-i-Pr)
4
/(R)-BINOL (0.0160)
100 (R)
94
9
2
3
Ti(O-i-Pr)
4
/(RþS)-BINOL (0.0160)
15 (R)
31 (R)
14 (S)
8
8
1
1
ꢀ
TiðO-i-PrÞ =ðRÞ-BINOL ð0:0160Þ
4
9
14 (S)
TiðO-i-PrÞ =ðSÞ-BINOL ð0:0160Þ
4
ꢀ
ꢀ
TiðO-i-PrÞ =ðRÞ-BINOL ð0:0077Þ
d
4
4
13 (S)
13 (R)
29 (S)
41 (R)
66
69
TiðO-i-PrÞ =ðSÞ-BINOL ð0:090Þ
4
TiðO-i-PrÞ =ðRÞ-BINOL ð0:090Þ
d
4
5
TiðO-i-PrÞ =ðSÞ-BINOL ð0:0077Þ
4
a
In entries 1–5 the catalytic species were prepared in order to have a final volume of THF of 5 mL. All reactions were performed in the presence of a
constant amount of molecular sieves (350 mg).
Ees have been determined by HPLC analysis.
b
c
Yield refers to chromatographically pure compounds.
d
4 4
The catalytic systems were obtained by mixing Ti(O-i-Pr) /(R)-BINOL and Ti(O-i-Pr) /(S)-BINOL solutions at different concentrations.
observed by using an enantioenriched complex derived
from mixing pre-prepared equimolar solutions of
involving the catalyst prepared in a more concentrated
solution.
Ti-(O-i-Pr)
entry 3).
4 4
/(R)-BINOL and Ti(O-i-Pr) /(S)-BINOL
(
In fact, in dilute solution, on the basis of previous re-
ports, the formation of homochiral monomeric species
was to be expected. H NMR analysis (400 MHz) in
15
11
1
As has been shown by Keck and Krishnamurthy, the
catalytic properties of Ti(IV)/BINOL complexes are
very often found to depend strongly on the experimental
conditions (source of Ti(IV), presence of suitable
amounts of water, stoichiometric ratios, tempera-
ture, solvent). High levels of efficiency and enantio-
selectivity can only be attained in a narrow window of
concentration values, for both the catalyst and the
reagents.
solution at rt of titanium complexes prepared in more
concentrated solutions showed a complex pattern of
NMR peaks, very similar to that reported by Mikami
12
13
16
and co-workers and attributed to highly enantioselec-
tive Ti/BINOL catalysts. Mikami et al. reported that the
active species corresponding to this spectrum was a high
16
nuclearity cluster.
The aggregates prepared according to the procedures of
entries 4 and 5 showed a negligible tendency to disso-
ciate by increasing, after their synthesis, the solvent
1
4
Over the course of a recent research we have shown
that a significant increase in size of the asymmetric
amplification could be observed by performing the
vinylogous aldol condensation of (2,2-dimethyl-6-
methylene-6H-[1,3]dioxin-4-yloxy)-trimethyl-silane in
the presence of enantioenriched Ti(O-i-Pr) /BINOL
complexes, previously prepared in more concentrated
solutions.
1
volume since no appreciable change in the H NMR
spectrum was observed after dilution up to 0.016 M
concentration value. Moreover, after mixing, the com-
1
4
bined solutions were again submitted to H NMR
analysis showing signal patterns corresponding to both
the cluster and the complex prepared in dilute solution.
Keeping in mind this unprecedented result, the experi-
ment of entry 3 (Table 1) was repeated (entries 4 and 5)
using catalytic systems obtained from mixing Ti-
This strong dependence of the enantioselectivity from
the initial concentrations was confirmed by performing a
set of experiments in the presence of Ti(O-i-Pr) /BINOL
4
(
tions at different concentrations.
O-i-Pr)
4
/(R)-BINOL and Ti(O-i-Pr)
4
/(S)-BINOL solu-
complexes at different ees, prepared according to the
procedure depicted in Scheme 3 and under conditions
It is notable that, although the experiments of entries
–5 were carried out under the same conditions as with
Ti(O-iPr) +(R)-BINOL
q mmol / x mlTHF
4
3
regards to the solvent volume, catalyst loading and final
Ti(IV), chiral ligand and reagent concentration, devia-
tions from linearity were detected in both entries 4
and 5.
Ti(IV)/BINOL (z% ee)
0
.08 mmol / 5 mlTHF
Ti(O-iPr) +(S)-BINOL
4
r mmol / y mlTHF
The presence of (þ)-NLE in entries 4 and 5 can be
tentatively explained by assuming that the formation of
structurally different Ti(IV)/BINOL systems takes place
in the separate solutions of enantiopure catalysts at
different concentrations and, after mixing, the aldol
reaction proceeds to a greater extent through a pathway
Enantiomerically enriched catalysts,
prepared by mixing enantiopure
Ti(IV)/(R)-BINOL and
Ti(IV)/(S)-BINOL solutions, each
prepared at a different concentration.
Conditions:
q + r = 0.08 mmol
x+ y= 5 ml
Scheme 3. Mode of catalyst preparation.

R. Villano et al. / Tetrahedron: Asymmetry 15 (2004) 2421–2424
Table 2. Influence of the initial concentration of the catalyst on NLEs
2423
BINOL-catalyzed reactions is deeply influenced by the
experimental parameters and, in particular, as regards
the aldol condensation of Chan’s diene, by the mode of
preparation of the catalyst. More interestingly, the dis-
closure of the unprecedented dependence of NLE on the
starting concentration in the separate catalyst solutions
has been conveniently exploited for the achievement of a
process characterized by pronounced amplification of ees.
a
Entry
Concentration of
solutions (M)
BINOL
ee (%)
3a
Ee (%)
3a
Yield
b
c
(
%)
Ti(IV)/(R)- Ti(IV)/(S)-
BINOL
BINOL
1
2
3
4
5
6
7
0.016
0.013
0.010
0.090
0.100
0.106
0.100
––
0.040
0.070
100 (R)
50 (R)
12 (R)
R)
>99 (R)
41 (R)
3 (S)
94
74
8
9
2
0.007813 (
0.0067
0.0060
0.016
41 (R)
8
69
4
. Typical experimental procedure for asymmetric aldol
reaction in the presence of Ti(O-i-Pr) /(R)-BINOL+
25 (R)
32 (R)
25 (R)
R) 2 (8
77 (R)
53 (R)
61
98
4
Ti(O-i-Pr)
4
/(S)-BINOL(Table 2, entry 5)
a
All the reactions were performed in the presence of a constant
amount of molecular sieves (350 mg).
Ees have been determined by HPLC analysis.
0
Two mixtures of (S)-1,1 -bi-2-naphthol (0.030 mmol),
Ti(O-i-Pr)
ꢁ
(0.030 mmol) and 3 A molecular sieves
b
c
4
0
(
(
131 mg) in THF (4.5 mL) and (R)-1,1 -bi-2-naphthol
Yield refers to chromatographically pure compounds.
ꢁ
0.050 mmol), Ti(O-i-Pr) (0.050 mmol) and 3 A mole-
4
cular sieves (219 mg) in THF (0.5 mL) were separately
stirred at rt for 1 h under an argon atmosphere. The
ensuring the usual catalyst loading (0.08equiv) and
constant final concentration of Ti(IV), chiral ligand and
reagents. The experimental results are reported in Table
(
R)- and (S)-catalyst were then mixed and the mixture
cooled to ꢀ78 °C. Benzaldehyde 2 (1 mmol) was then
added followed, after 30 min, by a solution of silyl-
oxydiene 1a (2 mmol) in THF (1 mL). This mixture was
stirred at ꢀ78 °C for 2 h and then at rt overnight. Then,
after cooling the mixture at ꢀ78 °C, TFA (0.4 mL) was
added and the solution warmed to rt. After stirring at rt
for 1 h, desilylation was complete and the reaction
mixture diluted with ether and a saturated aqueous
2
.
In entries 2 and 3 slightly negative deviations from lin-
earity, (ꢀ)-NLE, were observed. These results can be
reasonably attributed to the greater enantioselectivity of
the Ti(IV)/(S)-BINOL complex, generated in the more
concentrated solution.
NaHCO
3
solution (3 mL) was added dropwise. The pure
This hypothesis was confirmed by carrying out the aldol
reaction in the presence of catalytic species obtained by
mixing enantiopure Ti(IV)/(R)-BINOL solutions at ever
increasing concentrations and enantiopure Ti(IV)/
product (R)-3a was obtained by the usual work-up and
purification procedures. (82% yield, 82% ee).
7b
(5R)-5-Hydroxy-3-oxo-5-phenyl-pentanoic acid methyl
ester. The physical and spectroscopic data of compound
(
S)-BINOL solutions at ever decreasing concentrations.
7b
A pronounced amplification of the ee was observed in
entries 4–6 confirming the more enhanced level of
enantioselectivity of the catalyst prepared at higher
concentrations. The observed amplification of ees could
be considered the overall result of two opposite effects,
that is, the initial concentration of one Ti(IV)/BINOL
complex and the initial dilution of the other one. In fact,
when the experiment of entry 7 was carried out under the
same conditions as entry 5, with the exception of the use
of a Ti(IV)/(S)-BINOL catalyst prepared at higher con-
centration, the reaction was shown to take place with a
noticeable drop of enantioselectivity. Furthermore, the
replacement in entry 5 of Ti(IV)/(S)-BINOL (0.030/4.5)
solution with Ti(IV)/(rac)-BINOL (0.030/4.5) did not
cause any significant variation in terms of both efficiency
and enantioselectivity since aldol 3a was isolated in 84%
yield and 77% ee. Finally, the stereochemical outcome of
entry 6, where a slightly lower value of ee (77%) was
obtained in comparison with entry 5 (82% ee) in spite of
the use of a more enantiomerically enriched catalyst,
seemed to indicate that the most favourable combination
of concentration and dilution of the separate catalyst
solutions was obtained in entry 5.
3a match those described.
Acknowledgement
We are grateful to MIUR for financial support.
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