Stereoselective synthesis of α,γ-diamino-β-hydroxy amino acid esters: A new class of amino acids

Article abstract of DOI:10.1016/0957-4166(90)90036-A

Isocyano-acetic acid ethylester 3 undergoes a base catalyzed aldol-type addition to N,N-dibenzylamino aldehydes 6 to form oxazolines 7 stereoselectively; these can be ring-opened with NEt₃, affording α,γ-diamino-β-hydroxy amino acid esters 2.

Full text of DOI:10.1016/0957-4166(90)90036-A

Asymmetry Vol.
Printed in Great Britain
No.6 ,
1990
Press plc
SYNTHESIS OF
A
AMINO ACID ESTERS:
CLASS OF AMINO ACIDS
M.T.
T. Wiinsch and Harms
Fachbereich Chemie der Universitaet, Hans-Meerwein-Str., 3550
FRG
(Reccivcd 1 5 May
Abstract: Isocyano-acetic acid ethylester
undergoes a base catalyzed
aldol-type addition to N,N-dibenzylamino aldehydes
to form oxazolines
affording
these can be ring-opened with
stereoselectively;
amino acid esters
The synthesis of unnatural amino acids is of considerable current inte-
rest, primarily due to their observed or potential biological activity as
such or as components of larger molecules (e.g.,
In this
communication we report the stereoselective synthesis of
hydroxy amino acid derivatives of the type
starting from a-amino acids
R
OH
=
=
E t h y l )
Retrosynthetic analysis of
enolate or equivalent to N,N-dibenzylamino aldehydes
Indeed, previous studies have shown that simple ester enolates add to
points to an aldol-type addition of a glycine
derived from
with a high degree of non-chelation
relative stereochemistry at
which corresponds to the
Since
in the present target molecules
glycine enolates or equivalents are prochiral, simple diastereoselectivity
is also relevant. Such syn-selectivity was reported by
Schollkopf in the base-catalyzed addition of isocyano-acetic acid ester
at
in
the oxazolines
having the thermodynamically con-
These undergo stereospecific
to simple aldehydes,
trolled (racemic) trans
ring opening with
to form racemic amino acid derivatives
0
--
R
R
NHCHO
3
371

372
M.T.
et al.
we reacted the amino aldehydes
with
Indeed,
Using this methodology,
only two of the four possible diastereomers
stereoisomer
were observed, the desired
+
NHCHO
NHCHO
R
OH
OH
2
9
R
R
R
=
=
=
=
CH,
16 (62%)
16
b)
d)
19 (73%)
13 (51%)
R
67
The configurational assignments were made by NMR-spectroscopy
and x-ray
of the major product
structural analysis, for example,
Fig. 1. SHAKAL-drawing of
The results show that thermodynamically controlled simple
tivity (syn at is 98 % and that kinetically controlled
facial selectivity in favor of non-chelation amounts to 81-87 %. This is

373
an 'nte estin
at two different centers in one molecule. In order to show that
no racemization at Cl of the starting aldehydes occurs, the
were examined with an optically active HPLC column. Using a
no appreciable racemization was detected as shown by the ana-
and its racemic form.
lysis of
In order to increase diastereofacial selectivity, the lithium enolate of
the ester
enolate
was prepared followed by
was added in situ to the aldehyde
The resulting
affording a
(R =
mixture of four oxazolines and the corresponding two cis-forms).
The crude product was subjected to cis/trans-equilibration using weakly
basic NaCN/EtOH to form a 90 :
10 mixture of
Recrystallization from
This
ethanol resulted in an 81 % yield of pure
(R =
may be the method of choice, especially since separation of diastereomers
in the final stage, i.e., of
is not uniformly easy.
H
CN
90
:
10
In summary, we have devised a simple method for the stereoselective syn-
thesis of a new class of amino acid esters having differently protected
amino groups. Such regiospecific protection may be of utility in further
reactions.
enantiomers of the products
Since many amino acids
are also available in the D-form, the
are also accessible.
We thank the Deutsche Forschungsgemeinschaft (SFB 260 and
Leibniz Programm) and the Fonds der Chemischen Industrie for support.
References and Notes:
1) See for example: R.M. Williams, "Synthesis of Optically Active
Amino Acids",
Pergamon Press, Oxford 1989.
2) M.T. Reetz, M.W. Drewes, A.
Angew. Chem. Int. Ed. Engl. (1987) 1141.
chelation controlled reactions of alkoxv carbonyl compounds: M.T.
Angew. Chem.
(1987) 1186;
Review of chelation and
Angew. Chem.
(1984) 542; Angew. Chem. Int. Ed. Engl.
(1984) 556.
3) D. Hoppe, U.
Liebigs Ann. Chem. (1972) 1.

374
M.T.
et al.
4) Typical procedure: The mixture of the ester
0.3 in 30 ml of ethanol is stirred at room temp. for
and treated with 2.0 of an aldehyde in 5 ml
ethanol. After 0.5 h the temp. is raised to the mixture stirred for
another 0.5 h and then worked up by addition of sat. Following
several extractions with ether the combined org. phases are washed with
and dried over The solvent is removed and the brown oil
is dissolved in 20 ml of ethanol. Several drops of and 2 ml are
added and the mixture is heated under reflux for 6 h. The mixture is
extracted with ethyl acetate and dried over
Removal of solvents followed by flash chromatography (pet ether/ethyl
acetate 1 1) on affords
(0.22 ml, 2.0
and
(12.5 mg,
I5 min, cooled to
diluted with
5) Details of the crystal structure are available from the Cambridge
Crystallographic Date Centre, University Chemical Lab., Lensfield Road,
Cambridge CB2
U.K. Request should be accompanied by a full literature
citation for this communication.
6)
is commercially available from Merck (Darmstadt, FRG) and
is based on a Blaschke column: G. Blaschke, W. Broker, W. Fraenkel, Angew.
Chem.
(1986) 808; Angew. Chem. Int. Ed. Engl.
(1986) 830.
7) Zn-enolate of N,N-diethyl glycine ester: J.T.B.H. Iastrzebski, F.H. van
G. van Koten,
Chim. Pays-Bas
(1987) 516.
der Steen,
8) The solution of the ester (0.22 ml, 2.0
treated with 2.0
in 30 ml of dry THF is
of n-butyllithium in hexane at
A solution of
2.1
in 10 ml THF is added
and the mixture is
(473 mg,
stirred for 0.5 h. The aldehyde
is stirred for 17 h at sat.
in 10 ml THF is added and the mixture
is added, the mixture is extrac-
phases are washed with
and
The crude product is dis-
are added and the
is stirred at room temp. for 2 h. Water is added, the mixture is
extracted with ether, the combined org. phases are washed with
the combined org.
and the solvents are removed.
ted with ether,
dried over
solved in 50 ml of abs. ethanol, two crystals of
soln.
and the solvents are removed. The crude product is
having a
= 14.2, 32.1, 54.1, 61.8, 62.2, 71.7,
and dried over
recrystallized from ethanol to afford 717 mg (81%) of pure
m.p. of
126.2, 127.0, 128.2, 128.3, 128.8, 129.5, 139.0, 139.6, 156.2, 170.7
80.9,
ppm. The product can be transformed into
by treatment with
of
14.0, 32.4, 53.8, 54.5, 60.6, 61.7, 72.7, 126.1,
127.0, 128.3, 129.1, 129.5, 139.1, 141.1, 162.0, 171.4