Angewandte
Chemie
fied the structurally advantageous, proline-derived ligands 3,
which can be readily prepared in both the S- and R-
enantiomeric forms on any scale.[19] In this work, we report
that with the fully recyclable ligands 3, the DKR of
unprotected TM-a-AAs proceeds with virtually complete
stereoselectivity under operationally simple and convenient
reaction conditions. Furthermore, the present method has
broad synthetic generality, and can be applied to most
challenging, sterically constrained substrates with tertiary
side chains. These features, in combination with the very low
cost of the recyclable ligands 3, bode well for their wide
application for the practical preparation of enantiomerically
pure TM-a-AAs of academic and pharmaceutical impor-
tance.
The optimization of the reaction conditions for the DKR
of racemic a-AAs with ligand (S)-3 was methodically studied,
considering the strengths of bases, polarities of solvents,
various NiII ion sources, the effects of the reaction temper-
ature and time, as well as varying the stoichiometric ratios of
all starting materials. Some key experimental data leading to
the optimized conditions are presented in Table 1. For the
optimization study, we selected racemic alanine (rac-4a),
which bears a sterically and electronically unimposing methyl
group. The best conditions that we were able to attain are
given in entry 1: Under these conditions, the DKR of rac-4a
led to the formation of a single diastereomer (> 98% d.e.) of
(S,2S)-5a in an excellent chemical yield (97%). The strength
of the base that catalyzes the intermediate formation of the
corresponding Schiff bases as well as the thermodynamic
equilibration of the diastereomers (S,2S)-5a and (S,2R)-5a
was found to be particularly important. For example, the use
of organic bases, such as triethylamine (TEA; entry 2) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; entry 3), for the
DKR of rac-4a resulted in an unimpressive stereochemical
outcome, most likely owing to rather slow reaction rates. An
improved chemical yield, but still incomplete diastereoselec-
tivity, was also observed with Na2CO3 (entry 4). A near-
perfect stereochemical outcome could be obtained at ambient
temperature for reactions mediated by K2CO3. However, in
this case, full thermodynamic control took about 48 hours
(entry 5). To achieve better reaction rates, we used a 10%
excess of rac-4a, considering the fact that racemic amino acids
are usually relatively inexpensive starting materials. How-
ever, in view of a possible situation where the racemate may
be rather expensive, the chiral ligand (S)-3 can be used in
excess without virtually any effect on the DKR outcome
(entry 6). Finally, the major and minor diastereomeric prod-
ucts, (S,2S)-5a and (S,2R)-5a, were isolated in diastereomeri-
1
cally pure form. Their structures were confirmed by H and
13C NMR spectroscopy and mass spectrometry, and their
absolute stereochemistry was undoubtedly determined by
single-crystal X-ray diffraction (see the Supporting Informa-
tion for details).
With optimized reaction conditions in hand, we were in
a position to carry out a systematic substrate generality study
using various types of TM-a-AAs with different steric,
functional, and electronic characteristics (for the full sub-
strate scope, which contains 78 examples, see the Supporting
Information). Here, we will discuss only the most represen-
tative examples (Table 2).
First, we investigated a series of TM-a-AAs containing
straight alkyl chains, such as methyl, ethyl, n-propyl, and n-
butyl (Table 1, entries 1 and 2; for all examples, see the
Supporting Information). Excellent stereoselectivities were
observed in all cases, suggesting that the stereocontrol
provided by ligand (S)-3 might handle any TM-a-AA bearing
an unbranched alkyl chain. An unusual example in this series
is a-AA 4c, possessing a chloro-substituted phenethyl phar-
macophore; its racemate was readily converted into the
S enantiomer in a practically useful yield (entry 3). Next, we
studied a relatively large series (8 examples) of AAs featuring
benzyl-type side chains (4d–4 f; entries 4–6). Essentially
perfect stereoselectivities were generally observed regardless
of the electronic nature or the position of substituents on the
aryl ring. The same, nearly complete diastereoselectivities and
excellent chemical yields were observed for other types of
TM-a-AAs bearing heterocyclic (4g, 4h) or alkene (4i)
moieties (entries 7–9). With these very inspiring results in
hand, we were excited to test more challenging TM-a-AAs
with bulky and multifunctional side chains. First, we con-
ducted the DKR of a-branched, valine-type AAs; these
reactions produced the desired products 5j and 5k with
excellent yields and stereoselectivities (entries 10 and 11).
Even more gratifying outcomes were obtained for the tert-
butyl and adamantyl-substituted derivatives 4l and 4m, as the
diastereomerically pure products 5l and 5m were isolated in
good yields. It is noteworthy that the results presented in
entries 12 and 13 are the first successful DKR reactions of
AAs bearing tertiary alkyl groups, underscoring the remark-
able performance and potential of ligands 3.
Table 1: Optimization of the reaction conditions for the DKR of racemic
alanine 4a using ligand (S)-3.[a]
Entry
Base
T [8C]
t [h]
Yield [%][b]
d.r.[c]
1
2
3
4
K2CO3
TEA
DBU
Na2CO3
K2CO3
K2CO3
60
60
60
60
RT
60
3
36
36
36
48
8
97
13
61
94
94
85
99:1
91:9
96:4
96:4
99:1
99:1
5
6[d]
[a] Reaction conditions: (S)-3 (0.20 mmol), rac-4a (0.22 mmol),
Ni(OAc)2·4H2O (0.22 mmol), and base (1 mmol) in methanol (4 mL).
[b] Combined yield of isolated (S,2S)-5a and (S,2R)-5a. [c] Determined
by HPLC and 1H NMR analysis of the crude products (S,2S)-5a/(S,2R)-
5a. [d] (S)-3 (0.22 mmol), rac-4a (0.20 mmol), Ni(OAc)2·4H2O
(0.22 mmol), K2CO3 (1 mmol) in methanol (4 mL).
Phenylglycines represent yet another type of structurally
difficult TM-a-AAs owing to both steric and direct electronic
Angew. Chem. Int. Ed. 2015, 54, 12918 –12922
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