Cu(II)-catalyzed enantioselective aldol condensation between malonic acid hemithioesters and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2003.12.089

A mild, decarboxylative, aldol-type addition of malonic acid hemithioesters to aldehydes has been shown to occur with up to 39% enantioselectivity when the reaction was carried out in the presence of catalytic amounts of a Cu(II) salt, an enantiopure, tartaric acid-derived bis-benzimidazole and an achiral base.

Full text of DOI:10.1016/j.tetlet.2003.12.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1747–1749
Cu(II)-catalyzed enantioselective aldol condensation between
malonic acid hemithioesters and aldehydes
Simonetta Orlandi, Maurizio Benaglia and Franco Cozzi*
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano and CNR-ISTM, Via Golgi 19,
I-20133 Milano, Italy
Received 5 November 2003; revised 10 December 2003; accepted 15 December 2003
Abstract—A mild, decarboxylative, aldol-type addition of malonic acid hemithioesters to aldehydes has been shown to occur with
up to 39% enantioselectivity when the reaction was carried out in the presence of catalytic amounts of a Cu(II) salt, an enantiopure,
tartaric acid-derived bis-benzimidazole and an achiral base.
Ó 2003 Elsevier Ltd. All rights reserved.
The development of mild, catalytic and enantioselective
O
O
O
O
OH
R1
versions of fundamental C–C bond forming processes is
a topic of paramount importance in modern organic
chemistry. In this context, the aldol reaction continues
to attract a great deal of interest.1 Very recently,2 the
decarboxylative3 condensation between S-benzyl-
malonic acid hemithioester and aldehydes catalyzed by a
combination of Cu(2-ethylhexanoate)2 (20 mol %) and
5-methoxybenzimidazole (22 mol %) has been described
as a new protocol to perform an aldol process under
exceptionally mild conditions (wet solvent, air, room
temperature), reminiscent of those typical of polyketide
biosynthesis. Here, we wish to report some preliminary
results obtained while developing an enantioselective
version of this reaction.
Cu(OTf)2, base, 9
+
R1
H
RS
1 R = Ph
OH
RS
THF, RT, 3 h
2 R1 = Ph(CH2)2
11 R1 = cC6H11
3, 13-15
10 R = PhCH2
12 R1 = 4NO2C6H4
Scheme 1. Synthesis of aldol adducts 3, 13–15 from thioesters 1, 10
and aldehydes 2, 11, 12.
4–9 collected in Figure 1 were screened to achieve an
enantioselective aldol process.
Among these compounds, the use of 9, derived from
inexpensive (2R,3R)-tartaric acid, led to the higher
enantiomeric excess (ee ¼ 21%; Table 1, entry 1), but this
was observed for a low yielding reaction (28%). Since it
seemed possible that the coordination of Cu(II) ions
with 9 could prevent the latterÕs action as a base, the
effect of the addition of different achiral bases to the
reaction mixture was investigated with the aim of
improving the chemical yield (Table 1, entries 2–8).à It
was found that in the presence of diisopropylethylamine
The condensation between the S-phenylthioester 1
(1 mol equiv) and 3-phenylpropanal 2 (1 mol equiv) car-
ried out in the presence of 20 mol % of various Cu(II)
salts and 22 mol % of chiral imidazoles to afford aldol
adduct 3 (THF, 3 h, room temperature) was used as a
model reaction (Scheme 1).
First, it was discovered that Cu(II) salts other than
Cu(2-ethylhexanoate)2 could be employed as promoters,
with Cu(OAc)2 and Cu(OTf)2 affording satisfactory
results (the latter was used in subsequent experiments).
Second, the enantiopure mono- and bisbenzimidazoles
Benzimidazoles 5, 6, 8 and 9 were prepared by reaction of the
appropriate aromatic diamines with (S)-lactic or (2R,3R)-tartaric
acid. The synthesis of compounds 4 and 7 involved nucleophilic
aromatic substitution of 2-fluoronitrobenzene with the enantiopure
amines, followed by reduction of the nitro group and reaction with
formic acid.4–6 All new compounds gave analytical and spectral data
in agreement with the proposed structures.
Keywords: Aldol process; Enantioselective catalysis; Malonic acid
hemithioesters; Enantiopure benzimidazoles.
à
A pale green solution was formed upon addition of Cu(OTf)2 to
bisbenzimidazole 9. The subsequent addition of the base did not lead
to any significant color change.
* Corresponding author. Tel.: +39-02-50314-170; fax: +39-02-50314-
159; e-mail: franco.cozzi@unimi.it
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.089

1748
S. Orlandi et al. / Tetrahedron Letters 45 (2004) 1747–1749
N
N
OR
Me
OR
N
N
R
N
N
N
N
N
N
H
N
R
N
RO
Ph
O
O
5 R = H
6 R = SiMe2But
8 R = Me
9 R = CH2Ph
Me
Me
7
4
Figure 1. Structures of enantiopure mono- and bisbenzimidazoles 4–9.
Table 1. Stereoselective synthesis of adducts 3 and 13–15
Entry
Thioester
Aldehyde
Basea (mol %)
Product
Yield (%)b
Ee%c
1
1
1
2
2
None
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
13
28
33
53
39
45
58
34
53
51
36
25
41
21
31
24
23
22
20
28
28
24
18
35
39
2
NMBI (20)
NMBI (10)
NMBI (5)
DBU (20)
DIPEA (20)
Pyridine (20)
3
1
2
4
1
2
5
1
2
6
1
2
7
1
2
8
1
2
2,6-Lutidine (20)
9 (20)
9
1
2
10
11
12d
1
11
2
2,6-Lutidine (20)
2,6-Lutidine (20)
2,6-Lutidine (20)
10
10
14
15
12
a Abbreviations: NMBI ¼ N-methylbenzimidazole; DBU ¼ 1,8-diazabicyclo[5,4,0]undec-7-ene; DIPEA ¼ diisopropylethylamine.
b Isolated yields after flash chromatography.
c As determined by HPLC on a Chiracel OD column with hexane–isopropanol 90:10 as eluting mixture; flow rate: 1 mL/min; k: 254 nm.
d Reaction time 24 h.
(entry 6) the product could be obtained in up to 58%
yield while the ee remained almost unchanged (20%).
Other bases gave rise to a slightly increased ee, that
reached 31% when 20 mol % of N-methylbenzimidazole
was employed (entry 2). Lower amounts of this base
(entries 3 and 4) increased the yield but depressed the ee.
Perhaps the best combination was offered by the use of
2,6-lutidine (20 mol %). With this base, compound 3 was
isolated in 53% yield and 28% ee (entry 8). When 9 was
employed as the added base, the observed ee was 24%
(entry 9). The absolute configuration of compound 3
was established to be (S) by LiAlH4 reduction to ())-(S)-
5-phenylpentane-1,3-diol.7
Work is in progress to improve the chemical and ste-
reochemical efficiency of the reaction and to extend the
use of enantiopure benzimidazoles to other catalytic
enantioselective processes.8;9
Acknowledgements
Financial support by MIUR-COFIN ÔStereoselezione in
Sintesi Organica, Metodologie ed ApplicazioniÕ and
CNR is gratefully acknowledged.
The extension of the conditions of entry 8 to the addi-
tions of thioesters 1 and 10 to the branched aliphatic
aldehyde 11 and the aromatic aldehyde 12 to afford
adducts 13–15 was then attempted (Table 1, entries 10–
12). As can be seen from the reported data, the ee
remained moderate and reached a maximum of 39% in
the case of the condensation of S-benzylthioester 10
with 4-nitrobenzaldehyde 12, which led to product 15 in
41% yield.
References and notes
1. Review: Carreira, E. M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 29.1, pp 997–
1066.
2. Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc.
2003, 125, 2852–2853.
3. For other decarboxylative aldol reactions see: (a) Tanaka,
M.; Oota, O.; Hiramatsu, H.; Fujiwara, K. Bull. Chem. Soc.
Jpn. 1988, 61, 2473–2479; (b) Nokami, J.; Mandai, T.;
Watanabe, H.; Ohyama, H.; Tsuji, J. J. Am. Chem. Soc.
1989, 111, 4126–4127; (c) Kourouli, T.; Kefalas, P.;
Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67,
4615–4618.
In conclusion, a catalytic, enantioselective version of a
very mild aldol condensation process has been devel-
oped. The reaction relies on the unprecedented use of a
combination of 20 mol % each of a Cu(II) salt, an achiral
base, and a readily available and inexpensive tartaric
acid-derived enantiopure bisbenzimidazole.
4. Rosenfeld, D. A.; Pratt, J. W.; Richtmyer, N. K.; Hudson,
C. S. J. Am. Chem. Soc. 1951, 73, 5907–5908.

S. Orlandi et al. / Tetrahedron Letters 45 (2004) 1747–1749
5. Ralph, J. T. Synth. Commun. 1989, 19, 1381–1387. (5 mL), thioester
1749
(39.2 mg, 0.2 mmol), aldehyde
1
2
6. Katrizky, A. R.; Aslan, D. C.; Leeming, P.; Steel, P. J.
Tetrahedron: Asymmetry 1997, 8, 1491–1500.
(26.3 lL, 0.2 mmol), and 2,6-lutidine (4.6 lL, 0.04 mmol)
were added in this order. The mixture was stirred for 3 h at
RT and the reaction was quenched by the addition of 2 mL
of 0.5 M aqueous HCl. Ethyl acetate (5 mL) was then
added, the organic phase was separated, washed with a
saturated aqueous solution of NaHCO3 and with brine.
Evaporation of the solvent gave the crude product that was
purified by flash chromatography with an 80:20 hexanes–
ethyl acetate mixture as eluant to give 3 (30.5 mg) in 53%
yield.
~
ꢀ
7. Nunez, M. T.; Martın, V. S. J. Org. Chem. 1990, 55, 1828–
1932.
8. For an application of chiral benzimidazolium salts see:
Orlandi, S.; Caporale, M.; Benaglia, M.; Annunziata, R.
Tetrahedron: Asymmetry 2003, 14, 3827–3830.
9. Typical experimental procedure for the synthesis of com-
pound 3: To a stirred solution of bisimidazole 9 (29 mg,
0.04 mmol) and Cu(OTf)2 (14.5 mg, 0.04 mmol) in THF