Biomedical Engineering Reference
In-Depth Information
O
O
(
S
,
S
)-
5
(1 mol%)
Ph
2
C
=
N
+
Ph
2
C
=
N
RBr
O
t-
Bu
O
t-
Bu
50% KOH aq
Toluene, 0°C
H
R
2a
3
Ar
5a
5b
5c
5d
5e
: 73% (ee = 79%)
: 81% (ee = 89%)
: 95% (ee = 96%)
: 91% (ee = 98%)
: 90% (ee = 99%)
Br
-
(R : PhCH
2
)
+
N
(R : 1-NpCH
2
)
5e
: 90% (ee = 99%)
(R : CH
2
=
CHCH
2
)
5e
: 80% (ee = 99%)
Ar
(
S
,
S
)-
5
Ph
F
F
Ar = H
Ph
F
5a
5b
5c
5d
5e
SCHEME 7.3
Compared to cinchona alkaloid-derived phase-transfer catalysts, 1 mol% of (
S
,
S
)-
5e
is sufficient for a smooth alkylation. Since both enantiomers of the catalyst of type
5
can be readily assembled starting from (
S
)- or (
R
)-1,1
0
-bi-2-naphthol, awide variety of
natural and unnatural
-amino acids can be synthesized in enantiomerically pure form
by the phase-transfer catalytic alkylation of
2a
.
These reports have accelerated the research focused on improving the asym-
metric alkylation of
2a
and have resulted in the emergence of a series of cinchona
alkaloid-derived catalysts, as well as the elaboration of purely synthetic chiral
quaternary ammonium salts. The performances of the representative catalysts in the
benzylation of
2a
are summarized in Table 7.1.
To fully induce the potential catalytic activity of
N
-spiro chiral ammonium salts
such as
5d
, we have developed binary phase-transfer catalysts using an appropriate
achiral cocatalyst. For instance, while the phase-transfer-catalyzed alkylation of
2a
with benzyl bromide in the presence of (
R
,
R
)-
5d
(0.05mol%) turned out to be sluggish
and afforded
3a
in only 4%yield (ee
a
92%), similar benzylation of
2a
in the presence
of 18-crown-6 (0.05 mol%) proceeded smoothly and furnished
3a
in 90% yield and
98% ee. The origin of this dramatic rate enhancement would be the ability of the
crown ether to extract KOH into the toluene phase and thus accelerate the slow
deprotonation process (Scheme 7.4) [22].
We discovered that the very powerful chiral quaternary ammonium bromide
17a
possessing flexible straight chain alkyl groups instead of a rigid binaphthyl moiety
functioned as an unusually active chiral phase-transfer catalyst. Most notably, the
reaction of
2a
with various alkyl halides proceeded smoothly undermild phase-transfer
conditions in the presence of only 0.01-0.05 mol% of (
S
)-
17a
to afford the corre-
sponding alkylation products with excellent enantioselectivities (Scheme 7.5) [23].
The enantioselective synthesis of
¼
-amino acids employing easily available and
reusable chiral catalysts or reagents presents clear advantages for large-scale appli-
cation. Najera and coworkers prepared the resin-supported ammonium salt
18a
by
reaction with cross-linked chloromethylated polystyrene (Merrifield resin) and
employed it as a chiral phase-transfer catalyst for the alkylation of glycine isopropyl
ester-derived Schiff base
2b
[24]. Optimization of the reaction parameters for the
benzylation led to the formation of
3b
in 90% yield and 90% ee (Scheme 7.6). Cahard
a
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