Tuning the enantioselective N-acetylation of racemic amines: A spectacular salt effect

Article abstract of DOI:10.1021/ja051302+

We have described a spectacular salt effect in the kinetic resolution of (±)-1-phenylethylamine, which leads to an increase in reactivity, high levels of selectivity, and a complete reversal of the stereoselectivity. By tuning the reaction conditions, we

Full text of DOI:10.1021/ja051302+

Published on Web 04/08/2005
Tuning the Enantioselective N-Acetylation of Racemic Amines: A Spectacular
Salt Effect
Stellios Arseniyadis,# Pithani V. Subhash,# Alain Valleix,‡ Suju P. Mathew,† Donna G. Blackmond,†
Alain Wagner,*,# and Charles Mioskowski*,#,‡
Laboratoire de Synthe`se Bio-Organique associe´ au CNRS, UniVersite´ Louis Pasteur de Strasbourg, Faculte´ de
Pharmacie, 74 route du Rhin, 67401 Illkirch-Graffenstaden, France, CEA-Saclay, SerVice des Mole´cules Marque´es,
Baˆt. 547, De´partement de Biologie Cellulaire et Mole´culaire, F-91191, Gif-sur-YVette, France, and Department of
Chemistry, Imperial College, London SW7 2AZ, United Kingdom
Received March 2, 2005; E-mail: mioskow@aspirine.u-strasbg.fr
Since the pioneering work of Pasteur,1 kinetic resolution (KR)2
Scheme 1. Kinetic Resolution of Racemic Amines using (1S,2S)-1
has become one of the most powerful tools for the preparation of
optically active compounds. Hence, during the past decade, a
plethora of reagents and catalysts have been designed for the KR
of alcohols through enantioselective acylation.3 In contrast, there
have been very few nonenzymatic methods developed for amines,4,5
and significant progress has only recently been made.6 Indeed, the
design of an enantioselective acyl transfer reagent/catalyst for the
resolution of amines is rendered difficult because of the easy
nonselective acylation occurring through direct reaction of the amine
Table 1. Salt Effect on the Enantioselectivity using (1S,2S)-1
with the achiral acyl source. Thus, the strong nucleophilicity of
the amine compared to that of its corresponding alcohol requires
tuning the leaving group ability of the chiral selector in order to
enable chiral induction. Whereas prior to 1998, no such reagents
entry
timea (min)
salt (1 M)
solvent
eeb (%)
had even been described in the literature; since that time, several
quite different reagents and one catalyst have been reported that
provide useful levels of enantioselection (selectivity factor s g 10).6
In an earlier study, we established that (1S,2S)-N-acetyl-1,2-
bistrifluoromethanesulfonamidocyclohexane 1 could serve as a
highly enantioselective acetylating agent for the KR of primary
amines with a unique solvent-induced reversal of stereoselectivity
(Scheme 1).7,8 Building on these results, we developed the first
example of a fully recyclable polymer-supported reagent for the
KR of amines.9 Herein, we wish to report a spectacular salt effect
observed while using (1S,2S)-1 in the KR of (()-1-phenylethy-
lamine, which leads to an increase in both reactivity and selectivity,
along with a complete reversal of the stereoselectivity.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
60
20
10
10
10
20
10
20
20
20
10
20
20
10
-
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
42 (R)c
42 (S)
68 (S)
54 (S)
68 (S)
22 (S)
74 (S)
82 (S)
88 (S)
54 (S)
76 (S)
44 (S)
70 (S)
90 (S)
LiBr
LiClO4
TFSI-Li
n-BuPyBr
n-Et4NBr
n-Et4NCl
n-Bu4NCl
n-Bu4NBr
n-Bu4NI
n-Bu4NBF4
n-Bu4PCl
n-Bu4PBr
n-Oct3NMeCl
As salts are well-known to modify certain intrinsic parameters
of solvents, such as their viscosity, their permittivity, and, more
interestingly, their empirical constant of polarity, we decided to
carry out a first series of experiments using the standard acetylation
conditions10 while only varying the nature of the salts (1 M solution
in THF). As revealed in Table 1, an increase of the reaction rate
by 3-6 times was observed with every salt examined, along with
a complete reversal of stereoselectivity. LiBr (entry 2), LiClO4
(entry 3), lithium trifluoromethane sulfonimide (TFSI-Li; entry
4), pyridinium salts (entry 5), ammonium salts (entries 6-11 and
14), and phosphonium salts (entries 12 and 13) all lead to
preferential acetylation of the S enantiomer, while the R enantiomer
was favored in neat THF (entry 1). Finally, we observed a
tremendous increase in the selectivity from 42% ee (s ) 3.6 at
50% conversion;11 entry 1) up to 90% ee (s ) 58 at 50% conversion;
entry 14) using n-Oct3NMeCl (1 M solution in THF).
a The reaction was run until 1 disappeared, unless otherwise stated.
b Enantiomeric excess of the acetamide determined by HPLC analysis using
a chiral phase column. c Absolute configuration of the major enantiomer.
the best of our knowledge, the highest level of selectivity ever
observed in this field.
Interestingly, variations in the selectivity were observed depend-
ing on the nature of both the cation and the anion species. As a
general trend, phosphonium and lithium salts induced selectivities
lower than those of ammonium salts, whereas for a given anion
(e.g., Cl-), the selectivity appeared to increase with the lipophilicity
of the cation species (entries 7, 8, and 14).
These results are in agreement with those observed previously
while screening the effect of the solvents on the selectivity. In
dipolar solvents, it is suggested that the attack of the amine is guided
by the strong hydrogen bonding with the acidic free sulfonamide,
as no reversal of stereoselectivity is observed when using the
N-methylated analogue of (1S,2S)-1.
This remarkable result obtained at room temperature with only
2 equiv of amine relative to the amount of chiral (1S,2S)-1 is, to
A survey of various solvents having a low relative permittivity,
such as dioxane, CH2Cl2, and toluene in the presence of n-Oct3-
NMeCl (1 M solution in THF), revealed the same phenomenon of
# Universite´ Louis Pasteur de Strasbourg.
‡ CEA-Saclay.
† Imperial College.
9
6138
J. AM. CHEM. SOC. 2005, 127, 6138-6139
10.1021/ja051302+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Effect of the Solvent on the Enantioselectivity
entry
temperature (
°
C)
salt (1 M)
solvent
eea/eeb (%)
1
2
3
4
5
6
25
n-Oct3NMeCl THF
90 (S)c/42(R)
25
25
25
n-Oct3NMeCl dioxane 72 (S)/50 (R)
n-Oct3NMeCl CH2Cl2 76 (S)/40 (R)
n-Oct2NMeCl Toluene 78 (S)/58 (R)
-20(0.5 equiv of 1)
-20(0.33 equiv of 1) n-Oct3NMeCl THF
n-Oct3NMeCl THF
94 (S)
95 (S)
Figure 1. Fraction conversion of acetylating agent versus time for reactions
carried out at room temperature using 0.04 M racemic amine, 0.015 M
(1S,2S)-1, and n-Oct3NMeCl at 0, 0.001, and 0.005 M.
a Enantiomeric excess of the acetamide determined by HPLC analysis
using a chiral phase column. b Enantiomeric excess observed without using
a salt. c Absolute configuration of the major enantiomer.
selectivity may be attributed to a significant promotion of the
reactivity of (1S,2S)-1 toward the S enantiomer, concomitant with
only moderate change in its reactivity toward the R enantiomer of
the amine.
Table 3. Effect of the Concentration of the Salt on the
Enantioselectivity
In summary, we have described a spectacular salt effect observed
when using (1S,2S)-1 in the KR of (()-1-phenylethylamine, which
leads to an increase in reactivity, high levels of selectivity, and a
complete reversal of the stereoselectivity. Thus, by modifying the
reaction conditions, we were able to isolate the acetamide with an
unprecedented 94% ee at -20 °C and 50% conversion (s ) 115).
entry
salt
concentration
salt:1 ratio
eea (%)
1
2
3
4
5
6
n-Oct3NMeCl
n-Oct3NMeCl
n-Oct3NMeCl
n-Oct3NMeCl
n-Oct3NMeCl
n-Oct3NMeCl
1 M
25:1
2.5:1
1:4
1:40
1:400
0
90 (S)b
80 (S)
30 (S)
0
26 (R)
42 (R)
0.1 M
0.01 M
0.001 M
0.0001 M
-
Acknowledgment. The authors would like to thank Rhodia for
financial support to S.A., and Dr. David H. Wells, Jr. for carrying
out calculations from the kinetic profiles.
a Enantiomeric excess of the acetamide determined by HPLC analysis
using a chiral phase column. b Absolute configuration of the major
enantiomer.
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
inversion of the stereoselectivity followed by an increase of the
selectivity (entries 2-4, Table 2). Optimizing the reaction conditions
produced an additional increase in the enantiomeric excesses,
primarily by decreasing the temperature and by increasing the
amine/acetylating reagent ratio. Consistent with this expectation,
by conducting the reaction at -20 °C under otherwise identical
conditions, we were able to isolate the acetamide with 94% ee (s
) 115 at 50% conversion; entry 5, Table 2) and up to 95% ee (s
) 62 at 33% conversion; entry 6, Table 2) when using 3 instead of
2 equiv of amines versus chiral (1S,2S)-1.
Under these reaction conditions, we could achieve the stereo-
selective acylation of a family of racemic amines with good to
excellent enantioselection. Thus, the KR values of (()-1-phenyl-
propylamine, (()-1-naphthylethylamine, (()-1,2,3,4-tetrahydro-1-
naphthylamine, and (()-phenylalanine methyl ester were obtained
with 90, 84, 70, and 68% ee, respectively.
Table 3 shows the effect of salt concentration on selectivity.
Remarkably, concentrations as low as 0.1 M (salt:1 ratio ) 2.5:1)
lead to enantiomeric excesses as high as 80% (s ) 22 at 50%
conversion; entry 2). Comparison with the results of the kinetic
study discussed below, which was carried out under overall more
dilute conditions, shows that the role of the salt is complex. The
same relative salt:1 ratio gave significantly higher selectivity under
overall more dilute conditions.
Figure 1 shows kinetic profiles obtained by reaction calorimetry
and relative rate constants calculated from these profiles. The overall
concentrations employed in these reactions were much lower in
order to keep reaction rates in the range observable by reaction
calorimetry. These studies reveal that the influence of the salt on
References
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(8) With chiral 1 in hand, KR of (()-1-phenylethylamine was achieved with
unprecedented levels of enantioselectivity. Up to 84% ee (s ) 30) was
obtained at room temperature using 0.5 equiv of reagent and up to 90%
ee using 0.33 equiv of reagent at -20 °C.
(9) Arseniyadis, S.; Subhash, P. V.; Valleix, A.; Wagner, A.; Mioskowski,
C. Submitted.
(10) Standard conditions: the enantioselective N-acetylation reactions were
performed on (()-1-phenylethylamine using 0.5 molar equiv of chiral
(1S,2S)-1 in THF and at room temperature.
(11) Conversion percent determined by GC analysis using an internal standard
and by quantifying the isolated acetylated product after flash
chromatography.
JA051302+
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J. AM. CHEM. SOC. VOL. 127, NO. 17, 2005 6139