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b-phenyl-b-alanine, (S),(3R)-8aa and (S),(3S)-9aa, were
obtained in 60% yield and in a ratio of 89:11 (entry 3).
These results were quite encouraging, as they established
that direct chemical resolution of unprotected b-AAs by
a simple reaction with (S)-7a is possible. However, for this
method to be of practical significance further improvement of
the stereochemical outcome was clearly necessary. After
numerous attempts to modify both the reaction conditions
and the structural features of (S)-7, we found that the
presence of the chlorine atom in the position para to the
amino group on the benzophenone moiety [(S)-7b; for
preparation of all ligands (S)-7a–d, see the Supporting
Information[13]] allowed a noticeable improvement of both
the chemical yield of (S),(3R)-8ab and (S),(3S)-9ab, and the
enantioselectivity of the nickel(II) complexes formed
(entry 4). Another important result was observed with
modification of the phenyl ring of the N-benzyl group. We
discovered that introduction of chlorine atoms at the p- and
m-positions (7c) had a beneficial effect on the enantioselec-
tivity. As shown in entry 5 of Table 1, the products (S),(3R)-
8ac and (S),(3S)-9ac were obtained in a ratio of 94:6. In
contrast, the yields of (S),(3R)-8ac and (S),(3S)-9ac were
quite low, and similar to those obtained using (S)-7a (entry 5
versus 3). Eventually, we designed a new ligand, (S)-7d, thus
combining the substitutions on both the benzophenone as
well as N-benzyl moieties. Hence, the reaction of (rac)-6a
with the trichlorosubstituted ligand (S)-7d gave the long
sought after result, that is, preparation of the major product
(S)(3R)-8a in 98% yield with a d.r. value of 96:4 (entry 6).
Additional experiments were conducted to further optimize
the reaction conditions and revealed that NaH, as a base, can
be substituted with KOtBu (entry 7). In this case, the reaction
yield was a bit lower, whereas the stereoselectivity was
slightly improved. The complexes (S),(3R)-8a and (S),(3S)-9a
were isolated in diastereomerically pure form and their
structure as well as the absolute configuration of the major
product (S),(3R)-8a was determined by X-ray analysis[14] (see
the Supporting Information). Accordingly, the minor diaste-
reomer 9a was assigned a (S)(3S) configuration.
Having established the optimized reaction conditions and
structure of the chiral ligand, our next goal was to explore the
generality of (S)-7d for reactivity and enantioselectivity in
reactions with various b-AAs. All reactions presented in
Table 2 were conducted under the standard reaction condi-
tions (see the footnote) to evaluate the effect of the b-AA
structure on the stereochemical outcome.[15] First we studied
the effect of electronic properties of the substituents. As
shown in entries 1–6, the b-aryl-substituted b-amino prop-
anoic acids (rac)-6a–f, bearing electron-withdrawing as well
as electron-donating groups, all gave the products with
excellent yields and diastereoselectivity. The chemical yields
were in the 87–97% range and the diastereomeric ratios were
greater than 97:3. Furthermore, the reaction could be
extended to the sterically bulky 2-naphthyl 6g and hetero-
cyclic b-amino acids 6h,i. Also, in these cases the stereo-
chemical outcome was exceptionally good (entries 7–9). Of
greater importance were the reactions of the b-alkyl-contain-
ing b-AAs 6j–o (entries 10–16). Gratifyingly, the reactions
proceeded quite smoothly and with excellent stereoselectiv-
Figure 1. Tridentate ligand successfully used for chemical resolution of
a-AAs.
of b-AAs. Interestingly, the reactions of racemic b-phenyl-b-
alanine [(rac)-6a; Table 1] with either 4 or 5 did not give even
a trace of the desired nickel(II) complex products. Then,
taking into account that the corresponding nickel(II) complex
Table 1: Optimization of chiral ligand.[a]
Entry
(S)-7
R1, R2
8/9
Base
Yield [%][b]
d.r.[c]
1[d]
2
3
4
5
(S)-7a
(S)-7a
(S)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-7d
H, H
H, H
H, H
Cl, H
H, Cl
Cl, Cl
Cl, Cl
8aa/9aa
8aa/9aa
8aa/9aa
8ab/9ab
8ac/9ac
8a/9a
NaOH
NaOH
NaH
NaH
NaH
trace
15
60
98
60
–
–
89:11
92:8
94:6
96:4
97:3
6
7
NaH
KOtBu
98
95
8a/9a
[a] Reaction conditions: (S)-7 (0.2 mmol), rac-3-amino-3-phenylpropa-
noic acid 6a (0.4 mmol), anhydrous Ni(OAc)2 (0.4 mmol), and base
(2 mmol) were refluxed in methanol (4 mL) for 8–10 h. [b] Combined
yield of the isolated crude reaction mixture of 8/9. Yield is based on
ligands 7a–d. [c] Determined by 1H NMR and LC/MS analyses of the
crude reaction mixture of 8/9. [d] Ni(NO3)2·6H2O as the source of NiII
ions.
can be prepared from achiral unsubstituted b-alanine and
ligands of type (S)-7,[12] we conducted the reaction of the
compound (S)-7a with (rac)-6a under the standard reaction
conditions: heating a methanol solution of the ligand (S)-7a,
(rac)-6a, Ni(NO3)2·6H2O, and NaOH.[13] In this case, we
observed the formation of colored nickel(II) complex prod-
ucts, however, in only trace amounts (Table 1, entry 1). After
extensive experimentation, we found that the presence of
H2O in the reaction mixture had a detrimental effect on the
reaction progress. Thus, the first significant breakthrough in
this study was made with application of anhydrous Ni(OAc)2
as the source of nickel(II) ions (entry 2). Further optimization
of the reaction conditions was made by using NaH as a base.
In this case, the target diastereomeric nickel(II) complexes of
2
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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