Investigation into the enantioselective protonation of enolate Schiff bases with (R)-pantolactone

Article abstract of DOI:10.1016/S0957-4166(00)00500-0

The effect of several factors on the enantioselective protonation of the enolates of α-amino acid derivatives with (R)-pantolactone were studied. The highest stereoselectivity (74-76% e.e.) was generally observed by associating lithium chloride with LHMDS

Full text of DOI:10.1016/S0957-4166(00)00500-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 49–52
Investigation into the enantioselective protonation of enolate
Schiff bases with (R)-pantolactone
Monique Calm e` s,* Christ e` le Glot and Jean Martinez
Laboratoire des Aminoacides, Peptides et Prot e´ ines, UMR-CNRS 5810-Universit e´ s Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier Cedex 5, France
Received 11 December 2000; accepted 19 December 2000
Abstract—The effect of several factors on the enantioselective protonation of the enolates of a-amino acid derivatives with
(
R)-pantolactone were studied. The highest stereoselectivity (74–76% e.e.) was generally observed by associating lithium chloride
with LHMDS and by using the optimum temperature for the formation of the enolate. © 2001 Published by Elsevier Science Ltd.
All rights reserved.
1
. Introduction
We have recently developed an efficient method for the
synthesis of enantiomerically pure a-amino acids by
4
In the last decade much effort has been devoted to the
enantioselective protonation of prochiral enolates as
reviewed by Fehr. However this reaction, which pro-
stereoselective addition of (R)-pantolactone to the cor-
responding prochiral ketenes. We then became inter-
ested in using this chiral alcohol for the enantioselective
protonation of a-amino acid enolates since hydroxy
esters have been reported to be efficient chiral proton
sources. To our knowledge, (R)-pantolactone has until
now been used only for the stereoselective protonation
1
vides direct access to chiral compounds, has only rarely
2
,3
2
been applied to a-amino acids. Duhamel et al. have
performed an extensive study into the enantioselective
protonation of a-amino acid derivatives, which
involved deprotonation of the corresponding benzalde-
hyde Schiff bases using lithium amides, followed by
addition of an acyl tartrate derivative as the homochiral
proton source. The Duhamel group concluded that the
nature of the proton source influenced the selectivity,
the use of aldimino groups with an electron-donating
substituent had a beneficial effect, and that the sec-
ondary amine liberated after metalation played a cru-
5
6
of prochiral ketones and lactones.
2. Results and discussion
2b
We first studied the effect of several factors (type of
base, reaction temperature and the presence of salts)
which could affect the stereocontrol in the protonation
of the benzophenone Schiff base phenylalanine ester
2c
2d
cial role in proton transfer.
Scheme 1. Enantioselective protonation of the benzophenone Schiff base enolates with (R)-pantolactone.
*
0
Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@univ-montp2.fr
957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00500-0

5
0
M. Calm e` s et al. / Tetrahedron: Asymmetry 12 (2001) 49–52
enolates 2 with (R)-pantolactone (Scheme 1). The
(entries 7–10), whereas use of LDA under otherwise
12
results are shown in Table 1.
identical conditions gave rise to the (R)-enantiomer
entries 2, 5 and 6). It is known that the reactivity of
the enolate is further complicated by the existence in
(
Deprotonation of the methyl ester 1a at low tempera-
ture (−78°C over 30–90 minutes) with lithium diiso-
propylamide (LDA) or lithium hexamethyldisilazide
8e,10c,13
solution of higher aggregated species.
The sec-
ondary amine produced by deprotonation of the start-
ing material with metal amide may become part of an
aggregate and therefore influence the stereoselectivity in
7
a,8
(
LHMDS)
and
under
either
kinetic
or
7
b,8
thermodynamic
control, followed by reprotonation
10c,14
at −85°C with (R)-pantolactone afforded low to moder-
ate enantiomeric excesses of 2–40% (entries 1–4). How-
ever, when the enolate was generated at higher
temperatures (−40 to 0°C over 2 hours), a noticeable
increase in the enantiomeric excess of the product was
often observed (entries 5–9) and the best results were
obtained using LHMDS (entries 8 and 9).
the protonation reaction.
Among possible explana-
tions it can be considered that hexamethyldisilazane,
generated after deprotonation, ligates poorly to lithium
in comparison to diisopropylamine because of its low
10,14
basicity
and could promote direct chelation to the
carbonyl group of the proton donor, thus giving rise to
different stereoselectivity.
In order to control formation of the lithium enolate we
first used TMSCl which, because it reacts even at
This inversion of selectivity associated only with a
structural modification of the achiral base used has not
been previously described in enantioselective protona-
tion studies.
−
78°C, can be considered a good enolate trapping
agent. Proton NMR analysis after quenching the eno-
9
late form at −78°C with TMSCl indicated that only
1
0–15% of the corresponding silyl ketene actetal was
The addition of lithium salts (LiCl, LiBr), which must
13,15a
obtained at this temperature instead of 80–85% when
using higher temperatures. These experiments did not
allow us to determine the (E)/(Z)-enolate composition.
In addition, only a poor percentage of a-deuterated
already be present during enolate generation,
had
no effect when LDA was used as the base (entry 11)
whereas a remarkable enhancement of the stereoselec-
tivity was obtained when using LHMDS (entries 12–
14). It is known that added salts can change the
10
product was obtained using the Seebach method (suc-
cessive addition of one equivalent of n-BuLi and excess
CH CO D deuterating agent) when the enolate was
15
stereoselectivity of the protonation reaction, mainly
by altering the aggregation states of the ion pairs
and/or by forming mixed aggregates.
3
2
quenched at −78°C. Therefore, it can be assumed that
incomplete deprotonation occurs at low temperature
1
1
16
probably owing to high steric hindrance and was thus
responsible for the observed poor enantiomeric
excesses.
The presence of DMPU as co-solvent had a deleteri-
ous effect on the stereoselectivity (entry 15). Further-
more, the enantiomeric excess decreased when the
protonation step was conducted at −100°C (entry 16)
whereas only a minor effect was observed at 0°C (entry
17). This may be related to the reduced rate of proton
Moreover, when using LHMDS or KHMDS as the
base and with the same chiral proton source, the amino
ester with (S)-configuration was predominantly formed
17
transfer occurring at lower temperature. The enan-
Table 1. Enantioselective protonation of phenylalanine derivatives with (R)-pantolactone
Entry
Ester
Base
Additive
T enolate (°C)
T protonation (°C)
Config.
% e.e.
7
7
a
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
LDA
LDA
-
-
-
-
-
-
-
-
−78
−78
−78
−78
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−85
−100
0
(R)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
10
40
8
b
7
7
a
LHMDS
LHMDS
b
2
7
a
LDA
LDA
−78“−40
−40“0
−78“−40
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−40“0
−78
40
40
30
60
58
58
40
68
76
66
24
48
66
14
2
7
a
7
7
7
a
a
b
LHMDS
LHMDS
LHMDS
-
-
7
a
10
11
12
13
14
15
16
17
18
19
20
21
KHMDS
7
a
LDA
LiCl (3 equiv.)
LiCl (1 equiv.)
LiCl (3 equiv.)
LiBr
DMPU
LiCl (3 equiv.)
LiCl (3 equiv.)
-
-
-
-
7
7
7
7
7
7
a
a
a
a
a
a
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
7
a
LDA
0
0
0
0
7
7
7
a
a
a
LHMDS
LHMDS
LHMDS
−40“0
−40“0
42
72

M. Calm e` s et al. / Tetrahedron: Asymmetry 12 (2001) 49–52
51
Scheme 2. Enantioselective protonation of a-amino acid derivatives with (R)-pantolactone.
Table 2. Enantioselective protonation of amino acid derivatives with (R)-pantolactone
Entry
R1
R2
Base7a,
*
Additive
Config.
% e.e.
1
2
3
4
5
6
7
8
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
LDA
*
*
(R)
(S)
(S)
(R)
(R)
(R)
(S)
(S)
18
34
76
12
20
74
38
54
LHMDS
LHMDS
LDA
LHMDS
LHMDS
LDA
LiCl (3 equiv.)
*
*
LiCl (3 equiv.)
*
LiCl (3 equiv.)
CH Ph
CH Ph
2
H
LHMDS
2
*
Enolate formation at −40 to 0°C; 2 h.
tioselective protonation at −85°C gave the highest enan-
tiomeric excess. No improvement in stereoselectivity
resulted from the use of the more sterically hindered
tert-butyl ester 1b (entries 18–21).
Soc. Chim. Fr. II 1982, 75–83; (d) Duhamel, L.; Fouquay,
S.; Plaquevent, J. C. Tetrahedron Lett. 1986, 27, 4975–
4978.
3. Vedejs, E.; Kruger, A. W.; Suna, E. J. Org. Chem. 1999,
6
4, 7863–7870.
The same reaction with two other racemic amino acids
was then studied (Scheme 2 and Table 2). In all cases as
above, the best results were observed by associating
LiCl with LHMDS and using the optimal temperature
to form the enolate (Table 1, entry 12 and Table 2,
entries 3 and 6).
4
. (a) Calm e` s, M.; Daunis, J.; Jacquier, R.; Mai, N.; Natt,
F. Tetrahedron Lett. 1996, 37, 379–380; (b) Calm e` s, M.;
Daunis, J.; Mai, N. Tetrahedron: Asymmetry 1997, 8,
1
641–1648; (c) Calm e` s, M.; Escale, F. Tetrahedron:
Asymmetry 1998, 9, 2845–2850.
. Matsumoto, K.; Ohta, H. Tetrahedron Lett. 1991, 32,
5
4
729–4732.
. (a) Gerlach, U.; H u¨ nig, S. Angew. Chem., Int. Ed. Engl.
987, 26, 1283–1285; (b) Gerlach, U.; Haubenreich, T.;
However, it can be noted that in the case of phenylglycine
6
(
Table 2, entry 6), the configuration of the newly gener-
1
ated stereogenic center was opposite to that obtained
with alkyl amino acids (Table 1, entry 12 and Table 2,
entry 3). The importance of phenyl groups in the amino
acid derivatives was also demonstrated by using a ben-
zaldehyde Schiff base (Table 2, entries 7 and 8) instead
of benzophenone (Table 1, entries 6, 8, 12 and 13) since
in the benzaldehyde case neither of the bases used (LDA
or LHMDS) caused any inversion of configuration.
H u¨ nig, S. Chem. Ber. 1994, 127, 1981–1988; (c) Cavelier,
F.; Gomez, S.; Jacquier, R.; Verducci, J. Tetrahedron:
Asymmetry 1993, 4, 2501–2505.
. (a) Thermodynamic conditions: Enolization by addition
of the ester 1 to a pre-cooled solution of the base (no
self-condensation is observed); (b) Kinetic conditions:
enolization by addition of the base to a pre-cooled solu-
tion of the ester 1, see Ref. 7.
7
8
. (a) House, H. O.; Trost, B. M. J. Org. Chem. 1965, 30,
In conclusion, we have shown that (R)-pantolactone
can act as a proton source for the enantioselective
protonation of enolate Schiff bases. By a suitable
choice of the various parameters, either (R)- or (S)-a-
amino acids can be selectively obtained with modest to
high enantiomeric excess.
1341–1348; (b) Ireland, R. E.; Mueller, R. H.; Willard, A.
K. J. Am. Chem. Soc. 1976, 98, 2868; (c) Moreland, D.
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9
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6
6
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3
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18
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