Radical reaction of Williams' glycinate auxiliaries with α-amidoacrylates: Synthesis of orthogonally functionalized (2R,4R)- and (2R,4S)-diaminoglutamic acids

Article abstract of DOI:10.1016/S0040-4039(01)01600-8

Orthogonally functionalized (2R,4S)- and (2R,4R)-diaminoglutamic acids 10, 11, and 12, 13 were obtained in three steps starting from (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate 5, employing a radical reaction of selenide 6 with methyl 2-acetami

Full text of DOI:10.1016/S0040-4039(01)01600-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7521–7524
Radical reaction of Williams’ glycinate auxiliaries with
a-amidoacrylates: synthesis of orthogonally functionalized
(2R,4R)- and (2R,4S)-diaminoglutamic acids
Marek M. Kabat*
Hafslund Pharma SA, N-0371 Oslo, Norway
Received 20 June 2001; accepted 24 August 2001
Abstract—Orthogonally functionalized (2R,4S)- and (2R,4R)-diaminoglutamic acids 10, 11, and 12, 13 were obtained in three
steps starting from (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate 5, employing a radical reaction of selenide 6 with
methyl 2-acetamidoacrylate 7 as a key step. © 2001 Elsevier Science Ltd. All rights reserved.
Glutamic acid is an important chemical messenger
which is released in most of the excitatory synapses of
mammalian central nervous systems.1 However, exces-
sive or disregulated release has been linked to neuronal
degeneration in such devastating brain disorders as
Huntington’s chorea, Alzheimer’s disease, schizophre-
nia and others.2 The interest in identifying and mapping
the role of different glutamic acid receptors has stimu-
lated the synthesis of a number of 4-substituted
analogs.3
metic research for peptides having hemoregulatory
activity.4
It has been demonstrated by R. M. Williams5 and
others6 that enantiomerically pure morpholinecarboxy-
lates 3 are useful templates for the stereoselective prepa-
ration of a number of proteino- and non-proteinogenic
amino acids. Although these auxiliaries have been
applied for amino acid synthesis under various nucleo-
philic and electrophilic conditions, to the best to our
knowledge, a homolytic process has not been explored.
It was anticipated that the title aminoglutamic acid
derivatives should be accessible via a radical reaction of
morpholinecarboxylates 3 and a-amidoacrylates. Based
on precedents in ionic reactions5a we expected the
Disclosed herein is the synthesis of differentially func-
tionalized (2R,4S)- and (2R,4R)-diaminoglutamic
acids 1 and 2 (Scheme 1) by adaptation of an approach
which has previously found utility in peptidomi-
R
R
COOR2
R4OOC
S COOR2
R
R4OOC
R3HN
NHR1
R3HN
NHR1
2
1
O
COOR2
?
O
R4OOC
R3HN
COOR2
COOR2
NHR1
X
O
NHR1
O
NR3
NHR1
NR3
Ph
Ph
?
Ph
Ph
3 X=H
4 X=SePh
Scheme 1.
Keywords: amino acids and derivatives; selenium and compounds; radicals and radical reactions; diastereoselection.
* Present address: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Tel.: 973-235-4320; fax: 973-235-2663;
e-mail: marek m.kabat@roche.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01600-8

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M. M. Kabat / Tetrahedron Letters 42 (2001) 7521–7524
respective Williams’ radicals to react stereoselectively
with the amidoacrylate acceptors. The stereochemical
outcome of such designed radical reactions at newly
created centers which could result in formation of four
possible diastereomers was of interest.
The reaction of selenide 6 with n-Bu3SnH/AIBN and
methyl 2-acetamidoacrylate 7, carried out in toluene
solution at 80°C for 2 h, produced a 2:3 mixture of only
two, out of the four possible, diastereomers. The
diastereomers were separated by chromatography and
1
analyzed by H NMR. The stereochemical assignment
Treatment of commercially available (2S,3R)-(+)-6-
was based on the chemical shifts and coupling con-
stants of the methine benzylic proton signals. In less
polar diastereomer 8, these methine protons appeared
at l 5.11 ppm (1H, d, J 3Hz) and 6.18 ppm (1H, d, J
3 Hz) and in the more polar diastereomer 9, at l 5.13
ppm (1H, d, J 3Hz) and 6.20 ppm (1H, d, J 3 Hz).
Correlation with reported data showed that the sub-
stituent was introduced anti to the phenyl groups and
therefore, the absolute configuration at this center is R
in both diastereomers.7 However, at this stage the
configuration could not be established at the second
oxo-2,3-diphenyl-4-morpholinecarboxylate
5
with
lithium bis(trimethylsilyl)amide (THF, −78°C) followed
by PhSeBr produced selenide 6 in 84% yield (Scheme
2). 1H NMR analysis of the crude product revealed that
alkylation with PhSeBr occurred exclusively anti to the
phenyl groups with 98% ds [1H NMR, l: benzyl
methine protons at 5.16 (d, J 3Hz) and 6.17 (d, J 3 Hz),
PhSeCH6
at 6.26 (s)].7 A single recrystallization of crude
6 from MeOH afforded diastereomerically pure selenide
6.
O
H
X
O
NR
Ph
R=Boc
1. Li(TMS)2
2. PhSeBr (84%)
Ph
5 X=H
6 X=SePh
COOMe
7
1.
NHAc
74%
n-Bu3SnH, AIBN
2. Chromatography
O
H
O
H
COOMe
COOMe
+
O
O
NR NHAc
H2, Pd-C
NR NHAc
Ph
H2, Pd-C
THF, rt
Ph
Ph
Ph
THF, rt
(2:3)
9
8
O
O
H
H
COOMe
COOMe
O
O
NHR NHAc
NHR NHAc
H2, Pd-C
THF, reflux
Ph
Ph
96%
89%
Ph
Ph
13
12
HOOC
BocHN
COOMe
NHAc
HOOC
BocHN
COOMe
NHAc
11
10
6N HCl
92%
94%
COOH
HOOC
H2N
HOOC
(meso)
COOH
.
.
NH2
2HCl
H2N
NH2 2HCl
15
14
Scheme 2.

M. M. Kabat / Tetrahedron Letters 42 (2001) 7521–7524
7523
COOt-Bu
18
1.
NHBoc
O
O
O
H
n-Bu3SnH, AIBN
H
H
X
COOt-Bu
COOt-Bu
O
O
2. Chromatography
O
+
NR
NR NHBoc
NR NHBoc
Ph
Ph
75%
Ph
R=Cbz
Ph
Ph
Ph
(2:3)
1. Li(TMS)2
2. PhSeBr
19
16 X=H
17 X=SePh
20
80%
Scheme 3.
Acknowledgements
newly created asymmetric center and therefore correla-
tion to known substances was necessary.
The author would like to thank Professor Kjell
Undheim (University of Oslo, Norway) for many help-
ful discussions and addressing the problem of synthesis
of orthogonally protected aminoglutamic acids.
Compounds 8 and 9 were subjected separately to
hydrogenolysis in a refluxing mixture of THF/EtOH
(10% Pd/C, 3 h) producing the desired orthogonally
functionalized amino acids 10 and 11, respectively.
Interestingly, we observed that when the hydrogenolysis
reaction of compounds 8 and 9 was carried out at room
temperature a selective cleavage of the carbonꢀnitrogen
bond occurred, thus providing compounds 12 and 13.
Assignment of the second stereogenic center was solved
by the removal of all protecting groups from 10 and 11
and correlation to the known meso-2,4-diaminoglu-
tamic acid8 and (2R,4R)-2,4-diaminoglutamic acids.9
Thus, hydrolysis of 10 in boiling 6N HCl afforded
diaminoglutamic acid hydrochloride with optical rota-
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1
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M. M. Kabat / Tetrahedron Letters 42 (2001) 7521–7524
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