Trifluoromethylated amino alcohols as chiral ligands for highly enantioselective Reformatsky reaction

Article abstract of DOI:10.1016/S0040-4039(03)01392-3

The enantioselective Reformatsky reaction of PhCHO was achieved by the use of trifluoromethylated amino alcohols as chiral ligands to afford the corresponding optically active β-hydroxy ester with up to 90% ee.

Full text of DOI:10.1016/S0040-4039(03)01392-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6161–6163
Trifluoromethylated amino alcohols as chiral ligands for highly
enantioselective Reformatsky reactionꢀ
Yasuyuki Fujiwara, Toshimasa Katagiri and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Received 3 April 2003; revised 30 May 2003; accepted 30 May 2003
Abstract—The enantioselective Reformatsky reaction of PhCHO was achieved by the use of trifluoromethylated amino alcohols
as chiral ligands to afford the corresponding optically active b-hydroxy ester with up to 90% ee.
© 2003 Elsevier Ltd. All rights reserved.
The Reformatsky reaction is a fundamental reaction in
organic syntheses.1,2 Attainment of high stereoselectiv-
ity of the reaction would be a key issue for further
extension of its applicability. Until now, the selectivities
of stereoselective Reformatsky reactions using a chiral
ligand remained moderate.3–5 The best record of the
reaction of PhCHO with haloacetate is 75% ee, which
was attained by the use of (R)-DPMPM, an amino
alcohol derived from proline.3a
rized in Table 1. Among the examined amino alcohols,
tert-amino alcohols, 1c and 1d, were found effective
(entries 3 and 4); the fluorinated amino alcohol 1d was
superior to non-fluorinated analog 3, which result is
similar to that in the reaction of Et2Zn with PhCHO.7
Further modification of the amino moieties (entries 3,
4, and 6) gave a better result, 81% ee, with 1c. This
selectivity is as high as the best record which has been
attained.3 Contrary to the result of Andres’ reports,3f,h,j
double-headed amino alcohols, 2a and 2b, were not
effective.
Recently, we revealed that the origin of the stereochem-
ical interaction of a trifluoromethyl group arises from
its negatively charged nature.6 Therefore, trifluoro-
methylated ligands would be effective for stereoselective
alkylation with a carbanion species. Moreover, we have
found that a trifluoromethylated ligand (CF3-C*H-
(OH)-CH2-NR2) promoted association of an organo-
zinc species; in this instance, the association of the
organozinc species seemed to play a crucial role in
stereoselective Et2Zn alkylation of PhCHO.7 Further-
more, a structural study on the Reformatsky reagents
suggested a key role of such aggregation of the
reagent.8 These findings encouraged us to attempt the
enantioselctive Reformatsky reaction using chiral tri-
fluoromethylated amino alcohol ligands.
Among the solvents examined, THF was found to be
the best for this reaction. Other ethereal solvents, such
as Et2O and DME (entries 10 and 11) led to moderate
stereoselectivity of the reaction. The much polar DMF
resulted in no reaction (entry 12) and nonpolar toluene
(entry 13) gave the product in high yield with low
stereoselectivity.
A time course study of the reaction showed that the
reaction was completed within a minute under THF
reflux conditions. Thus, we considered that better selec-
tivity would be attained under milder conditions.
Instead of ethyl bromoacetate, utilization of ethyl
iodoacetate enabled us to carry out the reaction
smoothly even at 20°C; the reaction gave the product
with 89% ee (entry 3, Table 2). Further elaboration of
the conditions improved the stereoselectivity of the
reaction up to 90% ee (entry 6).
Trifluoromethylated amino alcohols 1a–f and 2a–b were
used as the chiral ligand for stereoselective Refor-
matsky reaction of PhCHO.9 The results are summa-
Keywords: trifluoromethylated amino alcohol; chiral ligand; enan-
tioselective Reformatsky reaction.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01392-3
Further application of these trifluoromethylated ligands
for enantioselective alkylation with carbanions is under
investigation and will be reported in due course.
* Corresponding author. E-mail: uneyamak@cc.okayama-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01392-3

6162
Y. Fujiwara et al. / Tetrahedron Letters 44 (2003) 6161–6163
Table 1. Stereoselective Reformatsky reaction of PhCHO conducted by trifluoromethylated chiral ligands, 1 and 2
Table 2. Elaboration of the reaction conditions in stereoselective Reformatsky reaction using 1c or 1d
Entrya
Ligand
Temp. (°C)
Time
THF1 (ml)/THF2 (ml)
Yield (%)
Ee (%)b
1
2
3
4
5
6
1c
1c
1c
1c
1c
1d
Reflux
50
20
10
0
30 min
Overnight
3 h
Overnight
Overnight
3 h
2.0/1.0
4.0/2.0
6.0/6.0
6.0/6.0
6.0/6.0
6.0/6.0
69
46
61
8
28
81
89
82
–
No reaction
68
30
90
a Reaction was carried out with PhCHO (1 mmol):Zn:ligand:ICH2CO2Et=1.0:5.0:1.5:2.6.
b Determined by HPLC analysis using a Daicel Chiralcel OD-H (hexane:iPrOH=7:1).

Y. Fujiwara et al. / Tetrahedron Letters 44 (2003) 6161–6163
6163
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