J. Chen et al. / Tetrahedron Letters 57 (2016) 4612–4615
4613
NH2
CO2
cat
O
NH2
O
(10-20 mol %)
*
+
+
Ph
N
CO2H
R
CO2H
R
N
CO2H
Ph
Ph
Ph
solvent-H2O, rt
1
2
3
4
O
Ar
Ar
N
O
OSiEt3
H2N
HO
O
HN
R
HO
Ar'
5 (Ar = 3,5-Ph2C6H3
)
6
previous work
this work
Scheme 1.
O
S
O
S
O
S
MOMO
MOMO
MOMO
MOMO
N
HN
HN
MOMO
Br
MOMO
Ar
8
Ar
Ar
+
n-BuLi, -78 oC
N
N
N
-9
(R,S)
(S,S)-9
7
(1) HCl, Dioxane/CH3OH
(2) RCOCl, Et3N, THF
Figure 1. X-ray structure of compound R-10g.
O
O
HN
O
BocHN
BocO
HO
HO
MOMO
HN
R
(1) DPPA
R
HN
R
keto acids (Table 1). Using 20 mol% of 6a as the catalyst, the reac-
tion of 4-(naphthalen-1-yl)-2-oxobutanoic acid (1a) with 2,2-
diphenylglycine (2)12–14 occurred smoothly under mild conditions
to give the corresponding amino acid 3a in 61% yield and 15% ee
(Table 1, entry 1). Under similar conditions, catalysts 6b–i were
also examined (Table 1, entries 2–9). The pyridoxamine 6g dis-
played the highest enantioselectivity in the transamination
(Table 1, entry 7). Further studies showed that a mixed system of
MeOH and H2O (8:2) was the optimal solvent for the reaction as
judged by enantioselectivity (Table 1, entry 15 vs 10–14 and 16).
Under the established optimal conditions, substrate scope was
investigated using 10 mol% of 6g as the catalyst (Table 2). A variety
TMSCl
MeOH
(2) Pd/C, H2
MOMO
Ar
Ar
Ar
(3) Boc2O
N
N
11
N
10
12
TMSCl
MeOH, rt
O
H2N
HO
6a
: Ar = 2-Naph, R = n-C3H7
HN
R
6b: Ar = 2-Naph, R = CHEt2
6c
6f: Ar = Ph, R = CPh3
6g
: Ar = 2-Naph, R = CHPh2
: Ar =2-PhC6H4, R = CPh3
Ar
6d: Ar = 2-Naph, R = cyclohexyl 6h: Ar = 3-PhC6H4, R = CPh3
6e
: Ar = 2-Naph, R = CPh3
6i
: Ar = 3,5-Ph2C6H3, R = CPh3
N
6
Scheme 2. Synthesis of chiral pyridoxamines 6a–i.
of
a
-keto acids were smoothly transaminated with 2,2-diphenyl-
-amino acids in low to good
remove the tert-butylsulfinyl group, followed by reaction with acyl
chloride to give compound 10. According to single-crystal X-ray
glycine (2) to give the corresponding
a
yields with promising ee’s. The ee can be further improved via
recrystallization if desired. For example, recrystallization of 3j in
methanol/ethanol gave the amino acid in 40% yield with 88% ee.
(CuK ) analysis (Fig. 1), the structure of 10g (Ar = 2-PhC6H3,
a
R = CPh3) was further confirmed and its absolute configuration
was assigned as R. The two MOM groups of 10 were cleanly
removed with acid. Compounds 11 were treated with
diphenylphosphoryl azide (DPPA) and then hydrogenated to form
the corresponding pyridoxamines 6. For 6a, 6e–f, and 6h–i, the
pure pyridoxamines were directly obtained by precipitation of
the corresponding pyridoxamine-HCl salts from HCl solution in
ethyl ether after the hydrogenative reduction. However, pyridox-
amines 6b–d and 6g were difficult to be purified by the precipita-
tion method, thus they were further converted into Boc-protected
pyridoxamines 12 for chromatographic purification. Compounds
12 were then submitted to deprotection with TMSCl/MeOH to give
pure pyridoxamines 6b–d and 6g as HCl salts.
c-Substituted a-keto acids such as 4-methyl-2-oxopentanoic acid
and 4,4-dimethyl-2-oxopentanoic acid exhibited relatively higher
enantioselectivity in the reaction (Table 2, for 3h and 3k). How-
ever, as the recently-reported chiral pyridoxal 5, pyridoxamine cat-
alyst 6g also is less effective for sterically bulky substrates such as
2-oxoisovaleric acid and 2-oxo-2-phenylacetic acid in the asym-
metric transamination.
In summary, we have developed a class of new chiral pyridox-
amines 6a–i containing an adjacent stereocenter via a multi-step
synthesis from bromopyridine 7 and N-(tert-butylsulfinyl)imines
8 (Scheme 2). With 10 mol% of pyridoxamine 6g as catalyst, vari-
ous
a-keto acids were transaminated in MeOH–H2O at room tem-
In the preparation of pyridoxamines 6, the major diastereomer
of intermediates 9 was used for the following synthesis merely
because of the more amount of the compound. The catalyst only
has one stereogenic center after removal of the tert-butylsulfinyl
group, therefore, the chiral pyridoxamine derived from the minor
diastereomer theoretically could inverse the enantioselectivity in
asymmetric transamination, but the catalyst should display the
same performance in terms of catalytic activity and capability of
chiral induction. The absolute configuration of pyridoxamine 6g
was assigned as R based on the single-crystal X-ray structure of
10g (Fig. 1), but the absolute configurations of 6a–f and 6h–i were
not determined.
perature, giving the corresponding chiral
a
-amino acids 3a–k in
27–78% yields with 34–62% ee’s. This work provides a synthetic
strategy to construct new chiral pyridoxamine catalysts using bro-
mopyridine 7 as a key synthon and also demonstrates an applica-
tion of chiral pyridoxamines in asymmetric catalysis.16 Further
studies on development of more efficient catalysts for asymmetric
transamination, mechanistic studies of the reaction, and exploring
new catalytic applications of chiral pyridoxals/pyridoxamines are
currently underway.
Acknowledgments
With the chiral pyridoxamines 6a–i in hand, we then investi-
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21272158,
gated their catalytic activity in asymmetric transamination of
a-