NON-RACEMIZING SYNTHESIS AND STEREOSELECTIVE REDUCTION OF CHIRAL α-AMINO KETONES

Article abstract of DOI:10.1016/0957-4166(90)90037-B

α-Amino acids can be doubly benzylated at nitrogen, forming N,N-dibenzyl amino acids which can be converted into α-amino ketones 4 without appreciable racemization.The latter undergo stereoselective reduction with NaBH4 under non-chelation control to form

Full text of DOI:10.1016/0957-4166(90)90037-B

Tetrahedron:
Printed Great Britain
Vol. 1.
1990
1990
plc
NON-RACEMIPING
AND STEREOSELECTIVE REDUCTION
OF CHIRAL a-AMINO KETONES
K. A.
Hans-Meerwein-Str., 3550
and X. Holdgrun
M.W. Drewes,
Fachbereich Chemie
FRG
der Universitaet,
15
Abstract: a-Amino acids can be doubly benzylated at nitrogen, forming
dibenzyl amino acids which can be converted into a-amino ketones without
appreciable racemization. The latter undergo stereoselective reduction
with under non-chelation control to form amino alkohols
1990)
We have previously shown that
aldehydes, prepared in
undergo
optically active form from the corresponding amino acids
Grignard reactions and other nucleophilic additions with a high degree of
non-chelation control to form
of the type which can be
using
The source of this surprising
vity was traced to the presence of
protective groups at nitrogen (pro-
tective group
tivity, Lewis acidic
were
In order to reverse the sense of
such as
but the
reagent systems
and
degree of chelation con-
trol was not consistently 90%. An alternative strategy for the synthesis
of diastereomers would be the stereoselective reduction of the corres-
ponding ketones
provided hydride delivery occurs with non-chelation
control and no racemization sets in along the sequence
cation we report that this is indeed possible.
In this communi-
1
a )
b)
R
R
=
=
2
a) 72%
69%
O H
+
-
-
yield by treatment of amino
to form the benzyl esters of
The protected acids
acids with benzyl bromide and
were prepared in
375

et al.
followed by hydrolysis of the crude products with KOH in
or
The amides were then
by chemoselective 0-debenzylation using
prepared according to the Weinreb
or Grignard reagents to form ketones
and reacted with alkyllithium
(Table 1). In the case of
was tested using the
with 2.2 equivalents of methyllithium
Alternatively, the
from acids was also successful
=
benzyl) a
ketone
at
conversion to the ketone
Treatment of
in THF afforded ketone
in 75% yield.
Mukaiyama one-vot ketone synthesis
76%: 77%; 79%;
cc1
4
=
b) R =
R =
= Me
R' = Et
=
R =
R' = Et
The crucial reduction was performed with
Indeed, the
desired diastereomers
control') (Table 1).
along the sequence,
were obtained with a high degree of non-chelation
In order to check whether any racemization occurs
several of the products
were 0-acylated using the
Mosher-Chloride"): As in the case of the Grignard additions to the
the ee-values turned out to be
showing that essentially no racemization occurs, provided the conversion
corresponding
of the amides
-3ooc to
to the ketones
is performed in the temperature range of
10% racemization may occur). Reduc-
(at -1ooc to ooc 5%
is generally more diastereoselective
:
tion using
at
but racemization may occur
is therefore not general-
= 98 :
ly recommended.
In the case of ketone
obtained directly from the acid
(R = benzyl) by
the Gilman-Reaction, the reduction product
is also essentially
The same applies to the reduction of
pre-
the
pure (ee = 99%).
The
can be
pared by the Mukaiyama one-pot ketone synthesis.
at nitrogen using
or
depending upon the substrate and catalyst used.
yields range from

a-Aminoketones
377
Table 1. Weinreb-Synthesis and stereoselective
reduction of ketones
Ratio
Amide
Ketone
yield)
Yield of
(%)
Me-Li
88
88
93
94
86
90
87
90
92
98
95
84
81
93
90
86
92
a)
a)
b)
c)
d)
e)
f)
94
94
95
95
95
95
95
90
92
94
95
95
94
92
91
95
95
6
6
5
Me-MgI
n-Bu-Li
Ph-Li
5
(72)
(89)
(74)
(52)
5
5
5
2-Thienyl-Li
Undecyl-MgBr
Me-Li
g)
h)
i)
(96)
(89)
(57)
Et-Li
8
6
5
5
6
8
9
5
5
n-Bu-Li
Ph-Li
j)
k)
1)
m)
n)
0)
p)
(87)
(75)
(83)
(66)
(67)
(96)
(78)
2-Thienyl-Li
Me-Li
Et-Li
n-Bu-Li
Ph-Li
:
:
2-Thienyl-Li
a) Me = methyl: Et = ethyl: Ph = phenyl; n-Bu = n-butyl
Additional functionality in the R-substituent of ketones
does not inter-
fere with non-chelation control, e.g., in the case of the
derived ketone
99%):
prepared from commercially available
(ee of
is
KOH
(71%)
7
OH
+
(78%)
12
3
11
In
this is the first
of a non-racemizina
nd their non-c
sis of chi 1
0
eton s
tion
controlled reduction to amino alcohols.

378
M.T.
et al.
We thank the Deutsche Forschungsgemeinschaft (SFB and
Leibniz-Programm) and the Fonds der Chemischen Industrie for support.
References and Notes
1) M.T. Reetz, M.W. Drewes, A.
Angew. Chem.
(1987) 1186;
Angew. Chem. Int. Ed. Engl.
(1987) 1141. Review of chelation and
chelation controlled reactions of alkoxv carbonyl compounds: M.T. Reetz,
Angew. Chem.
(1984) 542; Angew. Chem. Int. Ed. Engl.
(1984) 556.
2) M.T. Reetz, J. Binder, Tetrahedron
(1989) 5425.
3) BOC-type-protected a-amino aldehydes: J.V.N. Vara Prasad, D.H. Rich,
Tetrahedron Lett. (1990) 1803; Y. Takemoto, T. Matsumoto, Y.
Terashima, Tetrahedron (1990) 217).
S.
4) The reduction of a-amino ketones has been described many times pre-
viously with varying degrees of success, depending upon the protective
group. Most often racemic materials were used, so that little information
is available regarding possible racemization during their synthesis and
reactions (review: M. Tramontini, Synthesis
605).
Bulky
kylamino ketones are generally reduced with non-chelation control.
protected a-amino ketones can be reduced under chelation-control with
Et
Le
S. Kano, T. Yokomatsu, H. Iwasawa, S. Shibuya, Tetrahedron
(1987) 6331.
5) S. Nahm, S.M. Weinreb, Tetrahedron Lett.
6) M.J. Jorgenson, Org. React. (1970) 1.
7) M. Araki, T. Mukaiyama, Chem.Lett. 1974 663.
(1981) 3815.
8) General procedures: At
the stirred soln of 3
of a protected
in 20 ml of dry THF is treated with 0.42 ml (3
of
amino acid
and 0.47 ml (3 mmol) of
min the soln is cooled to
propionic acid chloride01)After 20
and slowly (10 min) treated with 3.2
of a Grignard reagent. After an additional 20 min at
10 ml of sat.
soln is added. The org. phase is separated, the aqueous phase is
extracted several times with ether, the combined org. phases are washed
with
soln and dried over
Following chromatography, the ketones
(0.54 mmol) are dissolved in 10 ml of dry CH OH (some THF is added if
the ketone is not soluble enough), cooled to
and treated with
1.1 mmol). After 3-4 h the mixture is quenched with
and ex-
soln and drying
(42
tracted several times with ether. After washing with
over
over
the solvents are removed and the residue is chromatographed
pet ether/ether
or pet ether/ethyl acetate
9) In a
synthesis we have previously used
to reduce
N,N-dibenzylamino ketoesters: M.T. Reetz, M.W. Drewes,
Matthews, K.
J. Chem.
Chem. Commun.
D.L. Dull, H.S. Mosher, J. Org. Chem.
11) K. Yoshida, S. Nakajima, T. Wakamatsu, Y. Ban, M. Shibasaki,
1474.
10) J.A. Dale,
(1969) 2543.
cycles (1988) 1167.
12) Ketones derived from N-sulfonyl serine react with L-selectride or
to form or mixtures of non-chelation/chelation controlled
respectively, but this has not been generalized to include other
amino acids:
R.C. Roemmele, H. Rapoport, J. Org. Chem.
(1989) 1866.