Synthesis of excitatory amino acid analogues

Article abstract of DOI:10.1055/s-2006-950399

A general route to excitatory amino acid analogues has been developed as exemplified by the synthesis of A-1 and A-2. The key reactions involved were a Negishi coupling of Jackson's organozinc reagent with vinyl bromide 8 and subsequent ring closure of 15

Full text of DOI:10.1055/s-2006-950399

LETTER
2407
Synthesis of Excitatory Amino Acid Analogues
Synthesis of
Excitatory
i
A
mino
l
A
cid A
l
nalogu
i
es am R. F. Goundry, Victor Lee,* Jack E. Baldwin*
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
Fax +44(1865)285002; E-mail: victor.lee@chem.ox.ac.uk; fax +44(1865)275632; E-mail: jack.baldwin@chem.ox.ac.uk
Received 26 June 2006
synthesis of A-1 and A-2 from a pyroglutamic acid deriv-
ative precursor, together with a biological evaluation of
the compounds.5
Abstract: A general route to excitatory amino acid analogues has
been developed as exemplified by the synthesis of A-1 and A-2. The
key reactions involved were a Negishi coupling of Jackson’s orga-
nozinc reagent with vinyl bromide 8 and subsequent ring closure of
15 and 16 using the Mitsunobu reaction.
Aiming to achieve maximum structural diversity, we
deliberately did not define the absolute stereochemistry of
the quaternary centre. Retrosynthetically, general struc-
ture A could be derived from precursor 9 (Figure 2), the
preparation of which is outlined in Scheme 1.
Key words: excitatory amino acids, Claisen rearrangement, Jack-
son’s organozinc reagent, Mitsunobu reaction
Excitatory amino acids (EAA) play an important role in
the physiology of higher organisms due to their abilities to
trigger synaptic excitation and hence influence neural
transmission. Naturally occurring EAA can be found in a
variety of organisms; kainic acid (1) was isolated from the
seaweed Digenea simplex,1 (–)-lycoperdic acid (2) was
extracted from the mushroom Lycoperdon perlatum2 and
(–)-dysiherbaine (3) was obtained from the marine sponge
Disidea herbacea.3 All of these natural products contain
the glutamic acid motif. Glutamic acid (4) is one of the
principal EAA in the mammalian central nervous system
(Figure 1).
OTBDMS
H
H
CO2H
NH2
CO2Bn
O
NHBoc
OH
O
A
9
Figure 2 Retrosynthetic analysis of analogue A.
Br
O
OH
OH
Br
a
b
6
5
7
H
CO2H
CO2H
c
CO2H
NH2
H
O
O
CO2Bn
N
CO2H
IZn
H
OTBDMS
OTBDMS
H
NHBoc
kainic acid (1)
CO2Bn
lycoperdic acid (2)
Br
H
O
NHBoc
H
HO2C
CO2H
9
CO2H
NH2
8
HO
Me
O
NH2
H
CO2H
N
Scheme 1 Reagents and conditions: (a) NaH, DMF then 1,2-dibro-
moprop-2-ene, 91%; (b) N,N-diethylaniline, sealed tube, 200 °C,
76%; (c) TBDMSCl, imidazole THF, 82%; (d) [(o-tol)3P]2PdCl2,
THF–N,N-dimethylacetamide (3:1), ultrasound, 90%.
H
(–)-dysiherbaine (3)
(S)-glutamic acid (4)
Figure 1 Some naturally occurring excitatory amino acids.
Phenol (5) was deprotonated with sodium hydride in N,N-
dimethylformamide which was followed by alkylation of
the resultant phenoxide with 1,2-dibromoprop-2-ene to
give ether 6 in 91% yield.6 Heating 6 in N,N-diethyl-
aniline effected a thermal Claisen rearrangement and de-
livered phenol 7 in 76% yield.7 Compound 7 was
protected as its TBDMS ether 8 in 82% yield by the action
of TBDMSCl and imidazole. Vinyl bromide 8 was cou-
pled with the L-serine derived Jackson’s organozinc
reagent8 under palladium catalysis to afford amino acid
derivative 9 in 90% yield. To the best of our knowledge,
the coupling of Jackson’s reagent with a vinyl bromide
has never been reported.
The EAA are considered to be valuable tools for the study
of neurophysiology. Hence, much effort is directed to-
wards their synthesis and the preparation of structural an-
alogues in order to understand and establish their
structural activities profiles.4 We report here the synthesis
of the general structure A, which can be considered as the
aromatic analogue of 2 and 3. Upon completion of our
synthetic investigations, Chamberlin et al. disclosed their
SYNLETT 2006, No. 15, pp 2407–2410
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950399; Art ID: D18606ST
© Georg Thieme Verlag Stuttgart · New York

2408
W. R. F. Goundry et al.
LETTER
After many exploratory studies the following synthetic Acid 13 was treated with benzyl bromide and triethyl-
route was found to be successful for converting 9 into the amine in N,N-dimethylformamide to give benzyl ester 14
desired target molecules A-1 and A-2.
together with phenols 15 and 16, which resulted from
deprotection of the silicon protecting group under the
basic conditions. This is inconsequential as both 15 and 16
would be produced in the next step (Scheme 3). These
compounds were separated and the tert-butyldimethyl-
silyl group in diastereoisomeric mixture 14 was removed
by TBAF buffered with acetic acid12 to provide more 15
and 16. The overall yields of 15 and 16 were 42% and
31%, respectively, over two steps from 13. Compounds
15 and 16 could be separated after repeated flash chroma-
tography. At this stage the absolute configurations of the
quaternary centres in 15 and 16 were unknown and the
absolute stereochemistries of all the compounds depicted
in Schemes 3-5 were later established by chemical corre-
lations (see below).
OTBDMS
OTBDMS
H
H
CO2Bn
a
CO2Bn
NHBoc
N(Boc)2
9
10
b
OTBDMS
OTBDMS
H
H
CO2Bn
CO2Bn
c
HO
HO
HO
O
N(Boc)2
N(Boc)2
X
11
12 X = H
13 X = OH
d
Having obtained pure samples of 15 and 16 we proceeded
to convert them individually into their corresponding
target molecule.
Scheme 2 Reagents and conditions: (a) (Boc)2O, DMAP,
MeCN, 82%; (b) OsO4 (cat.), NMO, t-BuOH, H2O, 96%; (c) DMSO,
py·SO3, Et3N, CH2Cl2, 82%; (d) NaClO2, KH2PO4, 2-methylbut-2-
ene, t-BuOH, H2O, 100%.
OH
H
H
CO2Bn
CO2Bn
a
First, 9 was converted to its bis-tert-butoxycarbonyl de-
rivative 10 in 56% yield using di-tert-butyl dicarbonate
and DMAP9 (Scheme 2). Recovered starting material 9
(34%) was recycled in an iterative fashion, giving a com-
plete conversion of 82% (three cycles). Compound 10 was
subjected to catalytic osmium tetroxide dihydroxylation
in the presence of N-methylmorpholine N-oxide10 to fur-
nish diol 11 as an inseparable mixture of two diastereoiso-
mers in 96% yield. Diol mixture 11 was oxidised to
aldehyde 12 in 82% yield by using the Parikh–Doering
conditions.11 Further oxidation of aldehyde 12 by sodium
chlorite under buffered conditions delivered acid 13 in
quantitative yield.11
HO
O
N(Boc)2
N(Boc)2
O
O
OBn
O
Bn
15
17
b
H
H
CO2H
NH2
CO2H
c
N(Boc)2
O
O
OH
OH
O
O
18
A-1
Scheme 4 Reagents and conditions: (a) PBu3, DIAD, toluene, 0 °C,
85%; (b) Pd/C, H2, MeOH, 100%; (c) HCO2H, then ion-exchange
chromatography, 100%.
OTBDMS
H
CO2Bn
The Mitsunobu ring closure of 15 to 17 required some
experimentation (Scheme 4). The optimum conditions for
the reaction were to treat 15 with tributylphosphine and
diisopropyl azodicarboxylate in toluene at 0 °C. This ef-
fected an intramolecular Mitsunobu etherification to af-
ford 17 in 85% yield.13 This was very gratifying because
there are only a small number of literature accounts of
such a reaction and all those reactions were performed on
simple, uncrowded substrates. Compound 17 was subject-
ed to catalytic hydrogenolysis with palladium on charcoal
to deliver dicarboxylic acid 18 in quantitative yield. Ami-
no acid A-114 was obtained in quantitative yield by remov-
al of the tert-butoxycarbonyl groups with formic acid15
and purification by ion-exchange chromatography.
HO
N(Boc)2
O
O
Bn
14
b
OTBDMS
+
OH
H
H
CO2Bn
CO2Bn
a
HO
O
HO
N(Boc)2
N(Boc)2
O
H
O
O
Bn
13
15
OH
+
H
CO2Bn
Similarly, compound 16 was subjected to the Mitsunobu
reaction to afford 19 in 88% yield. Removal of the benzyl
ester in 19 was effected by hydrogenolysis to deliver di-
carboxylic acid 20 in quantitative yield. Finally, treatment
of 20 with formic acid followed by purification by ion-ex-
change chromatography gave A-216 in quantitative yield
(Scheme 5).
HO
O
N(Boc)2
O
Bn
16
Scheme 3 Reagents and conditions: (a) BnBr, Et3N, DMF; (b)
TBAF, AcOH, THF, 42% for 15 and 31% for 16.
Synlett 2006, No. 15, 2407–2410 © Thieme Stuttgart · New York

LETTER
Synthesis of Excitatory Amino Acid Analogues
2409
OH
H
CO2Bn
H
H
a, b
CO2Bn
H
a
CO2Bn
CO2Bn
N(Boc)2
HO
O
O
O
N(Boc)2
NH
OBn
N(Boc)2
O
O
O
O
OBn
Bn
O
O
19
22
19
16
He
O
NH
Hc
CO2Bn
Hd
Hb
Ha
b
H
H
CO2H
NH2
CO2H
c
N(Boc)2
NOE studies of 22
O
O
O
OH
A-2
OH
O
Scheme 7 Reagents and conditions: (a) HCO2H, then pH 7 buffer;
20
(b) xylenes, 100 °C, 89% for two steps.
Scheme 5 Reagents and conditions: (a) PBu3, DIAD, toluene, 0 °C,
88%; (b) Pd/C, H2, MeOH, 100%, (c) HCO2H, then ion-exchange
chromatography, 100%.
Analysis of the 1H NMR spectrum of A-1 revealed a dia-
stereomeric ratio of 10:1 at the g-chiral centre. This was
consistent upon repetition of the route. We surmised that
the slight erosion of the stereochemical integrity of A-1
probably occurred during the Mitsunobu ring closure of
15 to form 17. It is possible that the incomplete inversion
of the quaternary centre during the Mitsunobu cyclisation
is due to some form of anchimeric assistance from various
oxygen-containing functional groups near the activated
Our next task was to determine the absolute configura-
tions of 15, 17, 18 and A-1. We decided to make use of the
existing a-chiral centre of the amino acid side chain as our
reference point. Thus, compound 17 was treated with for-
mic acid, which resulted in removal of the two tert-but-
oxycarbonyl groups. The crude product obtained after
neutralisation was heated in xylenes to give lactam 21 in
an overall yield of 89% over two steps (Scheme 6).
1
tertiary alcohol. Unexpectedly, the H NMR analysis of
A-2 showed a greater diastereomeric ratio of 19:1. How-
ever, this was also consistent upon repetition.
H
CO2Bn
In summary, we have achieved the synthesis of amino
acid analogues A-1 and A-2 and demonstrated the first ex-
ample of a coupling reaction between the Jackson orga-
nozinc reagent and a vinyl bromide. In addition we have
performed the challenging intramolecular etherification
of sterically cumbersome substrates using the Mitsunobu
reaction.
a, b
H
CO2Bn
N(Boc)2
O
O
NH
OBn
O
O
O
He
Hd
21
17
O
NH
Hc
CO2Bn
Hb
Ha
References and Notes
NOE studies of 21
(1) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc.
Jpn. 1953, 73, 1026.
(2) (a) Lamotte, J.; Oleksyn, B.; Dupont, L.; Dideberg, O.;
Campsteyn, H.; Vermeire, M.; Rmugenda-Banga, N. Acta.
Crystallogr., Sect B 1978, 34, 3635. (b) Rmugenda-Banga,
N.; Welter, A.; Jadot, J.; Casimir, J. Phytochemistry 1978,
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(3) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am.
Chem. Soc. 1997, 119, 4112.
(4) For leading reviews in this area, see: (a) Moloney, M. G.
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Prod. Rep. 1999, 16, 485. (c) Moloney, M. G. Nat. Prod.
Rep. 2002, 19, 597.
Scheme 6 Reagents and conditions: (a) HCO2H, then pH 7 buffer;
(b) xylenes, 100 °C, 89% for two steps.
The NOE studies of 21 proved to be informative. Irradia-
tion of Ha caused signal enhancement for only Hb but not
Hc and Hd. The NOE interaction between Hc and Hd sug-
gested that they are in close proximity. Hence Hc and Hd
must be on the opposite face of the lactam ring with re-
spect to Ha and Hb. Therefore this established the absolute
configurations of 15, 17, 18 and A-1. Similarly, com-
pound 19 was deprotected and cyclised to give 22
(Scheme 7).
(5) Cohen, J. L.; Limon, A.; Miledi, R.; Chamberlin, A. R.
Bioorg. Med. Chem. Lett. 2006, 16, 2189.
(6) Organ, M. G.; Arvanitis, E. A.; Dixon, C. E.; Cooper, J. T. J.
Am. Chem. Soc. 2002, 124, 1288.
Lactam 22 was subjected to NOE studies, using Ha as the
reference point. NOE interactions were observed between
Ha-Hb, Hb-Hd and Ha-Hd. Thus the benzyl methylene
group must reside on the same face of the lactam ring with
respect to Ha. Hence this established the absolute config-
urations of compounds 16, 19, 20 and A-2.
(7) Benbow, J. W.; Katoch-Rouse, R. J. Org. Chem. 2001, 66,
4965.
(8) (a) Jackson, R. F. W.; James, K.; Wythes, M. J.; Wood, A. J.
Chem. Soc., Chem. Commun. 1989, 10, 644. (b) Jackson, R.
F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J.
Org. Chem. 1992, 57, 3397.
Synlett 2006, No. 15, 2407–2410 © Thieme Stuttgart · New York

2410
W. R. F. Goundry et al.
LETTER
(9) Englund, E. A.; Gopi, H. N.; Appella, D. H. Org. Lett. 2004,
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(10) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron
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H, Ar), 7.19 (d, J = 7.5 Hz, 1 H, Ar). 13C NMR (125.7 MHz,
D2O): d = 38.3, 39.5, 51.9, 90.2, 110.2, 121.9, 125.7, 126.4,
128.8, 158.3, 174.4, 180.0. MS (ES, –ve): m/z (%) = 250.3
(100) [M – H]–. HRMS: m/z [M – H]– calcd for C12H13NO5:
250.0715; found: 250.0713.
(15) Roos, E. C.; Mooiweer, H. H.; Hiemstra, H.; Speckamp, W.
N.; Kaptein, B.; Boesten, W. H. J.; Kamphuis, J. J. Org.
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(11) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Masaki, H.; Goto, T.
Tetrahedron 1987, 43, 4767.
(12) Zhu, T.; Boons, G.-J. J. Am. Chem. Soc. 2000, 122, 10222.
(13) (a) Aristoff, P. A.; Harrison, A. W.; Huber, A. M.
Tetrahedron Lett. 1984, 25, 3955. (b) Reisch, J.; Voerste, A.
A. W. J. Chem. Soc., Perkin Trans. 1 1994, 3251. (c) Shi,
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(16) A-2: white solid; [a]D21 –16.3 (c = 0.32, H2O). 1H NMR (400
MHz, D2O): d = 2.17 (dd, J1 = 11.5 Hz, J2 = 15.5 Hz, 1 H,
NCHCHAHB), 2.67 (dd, J1 = 2.0 Hz, J2 = 15.5 Hz, 1 H,
NCHCHAHB), 3.16 (d, J = 16.5 Hz, 1 H, ArCHAHB), 3.44 (d,
J = 16.5 Hz, 1 H, ArCHAHB), 3.70 (dd, J1 = 2.0 Hz, J2 = 11.5
Hz, 1 H, NCH), 6.80 (d, J = 8.0 Hz, 1 H, Ar), 6.86 (t, J = 7.5
Hz, 1 H, Ar), 7.11 (t, J = 7.5 Hz, 1 H, Ar), 7.16 (d, J = 7.5
Hz, 1 H, Ar). 13C NMR (125.7 MHz, D2O): d = 39.0, 40.9,
53.8, 91.7, 110.2, 121.8, 125.7, 126.0, 128.7, 157.9, 174.0,
179.1. MS (ES, –ve): m/z (%) = 250.3 (100) [M – H].
HRMS: m/z [M – H]– calcd for C12H13NO5: 250.0715;
found: 250.0721.
(14) A-1: white solid; [a]D21 –103.2 (c = 0.12, H2O). 1H NMR
(400 MHz, D2O): d = 2.40 (dd, J1 = 9.0 Hz, J2 = 15.5 Hz,
1 H, NCHCHAHB), 2.56 (dd, J1 = 3.0 Hz, J2 = 15.5 Hz, 1 H,
NCHCHAHB), 3.29 (d, J = 16.5 Hz, 1 H, ArCHAHB), 3.45 (d,
J = 16.5 Hz, 1 H, ArCHAHB), 3.84 (dd, J1 = 3.0 Hz, J2 = 9.0
Hz, 1 H, NCH), 6.83 (d, J = 8.0 Hz, 1 H, Ar), 6.88 (dt, J1 =
1.0 Hz, J2 = 7.5 Hz, 1 H, Ar), 7.13 (apparent t, J = 7.5 Hz, 1
Synlett 2006, No. 15, 2407–2410 © Thieme Stuttgart · New York