An Efficient Asymmetric Synthesis of L-α,ω-Diaminoalkanoic acids

Article abstract of DOI:10.1016/0040-4039(93)88028-H

Efficient asymmetric syntheses of L-2,7-diaminoheptanoic acid and L-2,8-diaminooctanoic acid are described.

Full text of DOI:10.1016/0040-4039(93)88028-H

Vol. 33. No.
Britain
in
An Efficient Asymmetric Synthesis
Acids
of
Zhengxin Dong
The Unit for
Drug Design.
East
University Hospital.
University Medical
Boston. MA 02118. U.S.A.
asymmetric syntheses of
acid and
acid are described.
acid (homolysine) is a nonproteinogenic amino acid and has been widely used in
and drug design.
It has served as a precursor for the syntheses of various lysine derivatives in
human
and as a lysine replacement in cyclic enkephalin2 and in vasopressin analogues.3
As part of an ongoing project in this laboratory to develop highly potent and selective substrate analogue
inhibitors of human tissue
acid. In contrast to the lysine analogues
inaccessible, especially in enantiomerically pure
we
optically
L-homolysine and
shorter
chains, the higher homologues am relatively
all the synthetic methods developed in the last
5
The
In this communication efficient enantioselecdve syntheses of L-homolysine and
providing a general approach to various optically pure
yielding D-homolyslne
is
several decades produce
lengthy and
form of homolysine.
acid are
The protocol is based on the principle advanced by Wiiams, in which the configuration at the a position
of an a-amino acid is unambiguously built up by employing a proper diphenyloxazinone as a template.7 As
shown scheme I, the
enolate alkylation of the
‘ally available diphenyloxaxinone
1
with diiodides afforded the alkylated oxaxinone 2
yield.7 Iodide 2 was then converted into axide 38
by treatment with an excess of sodium axide in
in 71-74 %
in 87-89%
m.p.=lOl-102
at
for 15 h. The removal of the
and the reduction of the axide functional group in axide 3 were accomplished by hydrogenation (50 psi of H2.
1: 1, RT. 24h). producing the
yield.11
L-homolysine
and L-
diaminooctanoic acid
in
7725

7726
I
RT
-78
then
87-89
71-74
I
2
1
a)
RT
NY
(
.
a:
b:
COOH
71-78
4
Acknowledgment: I would like to thank Dr. Cathy Sultany at Ohio University for performing high
temperame NMR experiments. This research is supported by
grant
38212.
References and Notes:
1.
Doherty, A.M.;
J.S.; Hudspeth, J.P.; Pepine, J.T.;
W.H.;
I.; Tinney, F.J.;
Connolly, C.J.; Hodges, J.C.; Taylor, M.D.;
B.L.; Ryan, M.J.; Essenburg, A.D.; Rapundalo,
E.A. Med. 1991.34, 1258.
L.A.; Lemieux, C. and Wilkes, B.C.
Symposium); D. Ed.; W. de
S.T.;
RE.; Humblet, C. and
P.W.; Nguyen, TM-D.;
2.
1986
of the 19th European
Berlin, 1987;
389-392.
3.
4.
5.
6.
7.
8.
M. and
M.S. and Burton, J. J. Med. Chem. 1 9 9 2 . in press.
Payne, L.S. and J. 1277 (and references cited therein).
G. J. Med. Chem. 1971.14, 1197.
Beaulieu.
and
P.W. Tetrahedron
M-N. J. Am.
Williams, RM. and
NMR (400
385
4.81
1.40-1.60
Hz).
2.10-2.16
dt,
3.31
6.22
5.28
d,
6.58
m).
9.
(silica,
with ninhydrin);
3.89
+ 1) m/z 161.1290. found 161.1285.
NMR (400
1.31-1.33
Exact mass calculated for
1.55
1.82
1.78
m). 2.86
10.
11.
(decomposed);
1.19-1.26
Exact mass calculated for
(silica,
with ninhydrin);
2.85
+ 1) m/z 175.1446, found 175.1447.
of 4: a) ion-exchange chromatography on Bio-Rad AG
b) treatment with 2N c) recrystallization from
NMR (400
m). 1.51
3.87
(M
The
then
with water and
ether.
(Received in USA 4 September 1992)