Direct versatile route to conformationally constrained glutamate analogues

Article abstract of DOI:10.1039/a708429c

Novel conformationally constrained glutamate analogues are readily available from (S)-pyroglutamic acid; using a bicyclic lactam template, diastereocontrolled and sequential modification of the pyrrolidine ring is possible, allowing a versatile access to several glutamate and kainoid analogues; variations in the C(2)H-C(3)H coupling constants were observed depending upon the nature of remote substituents on the heterocyclic ring, consistent with modification of the ring conformation.

Full text of DOI:10.1039/a708429c

View Article Online / Journal Homepage / Table of Contents for this issue
Direct versatile route to conformationally constrained glutamate analogues
James Dyer,a Steve Keelingb and Mark G. Moloney*a
a The Department of Chemistry, Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, UK OX1 3QY
b GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY
Novel conformationally constrained glutamate analogues
are readily available from (S)-pyroglutamic acid; using a
bicyclic lactam template, diastereocontrolled and sequential
modification of the pyrrolidine ring is possible, allowing a
versatile access to several glutamate and kainoid analogues;
variations in the C(2)H–C(3)H coupling constants were
observed depending upon the nature of remote substituents
on the heterocyclic ring, consistent with modification of the
ring conformation.
diastereomers in very good yield. In all arylations, a diastereo-
meric mixture was obtained, in which preferential addition of
the aryl substituent to the exo face of 2 was predominant,
although for the alkylation with benzyl bromide, a slight
preference for endo addition was observed.
EtO2C
O
EtO2C
O
CO2But
7
5
N
N
Nitrogen heterocycles occur widely in nature, in isolation and as
structural subunits in many families of alkaloids, and possess
wide ranging biological and pharmacological activities.1–3 Of
particular current interest are conformationally constrained
glutamines,4 which have been shown to possess potent activity
at both the ionotropic and metabotropic receptors.5,6 These
receptors are selectively activated by excitatory amino acids,
and are known to play an important role in various physiological
processes, such as memory and learning, neuroendocrine
regulation, and acute and chronic neuronal disfunction.7
Excessive activation of these receptors can in some cases lead to
cell death.8 The search for selective agonists and antagonists
offers the potential for both the structural and physiological
characterisation of the receptors, and treatment of a range of
physiological disorders, in particular Alzheimer’s and Parkin-
son’s diseases. Highly functionalised pyrrolidines have been
found to have activity at these receptors,9 and there has
therefore been considerable recent interest in the development
of practical and versatile methodology for the preparation of
this important class of compound;10,11 particularly elegant
protocols have been developed by Shirahama12,13 and by
Baldwin14–16 which use 4-hydroxyproline as a chiral starting
material, and which offer considerable simplicity and generality
for the introduction of the ring substituents. We report here an
alternative but equally versatile and simple approach to
functionalised pyroglutamates which uses a sequential con-
2
O
O
Ph
Ph
1
2
R1
4
R
7
R2
EtO2C
O
CO2But
CO2But
2
5
O
N
H
N
2
OH
O
4a R1 = CO2Et, R2 = Ph
b R1 = Ph, R2 = CO2Et
c R1 = Ph, R2 = H
Ph
3a R = Ph
b R = p-BrC6H4
c R = p-MeOC6H4
d R = o-MeOC6H4
e R = Bn
d R1 = H, R2 = Ph
e R1 = Ph, R2 = CO2H
f
R1 = Bn, R2 = CO2Et
g R1 = CO2Et, R2 = Bn
h R1 = Bn, R2 = CO2H
i
R1 = R2 = H
R1
R1
R2
O
Ph
R2
O
CO2Me
CO2Me
CO2H
CO2H
CO2H
4
4
7
2
2
5
O
N
H
N
H
N
2
O
Ph
3,4
jugate addition/alkylation or arylation strategy to a D
5
7a R1 = Ph, R2 = H
7b R1 = H, R2 = Ph
6a R1 = Ph, R2 = H
b R1 = H, R2 = Ph
c R1 = Bn, R2 = H
d R1 = H, R2 = Bn
e R1 = CO2Et, R2 = Bn
f R1 = CO2Me, R2 = Bn
h R1 = R2 = H
pyrrolidinone derivative. This method has been applied to the
synthesis of a novel class of conformationally restricted
glutamates, which possess a similar ring substitution pattern to
the kainoid group of amino acids.
We used the recently described and readily available lactam
1 as a template for manipulation to a variety of functionalised
pyrrolidinones.17,18 Thus, conjugate addition of the Refor-
matsky reagent derived from tert-butyl bromoacetate generated
in THF and DMPU with ultrasonic irradiation gave the diester
2, in 77% yield as a mixture of diastereomers at the C(7)
position, using our previously reported method;19 conjugate
additions to a related enone have been reported previously,
although not with Reformatsky reagents.19,20 This compound
was readily functionalised at C(7) by direct arylation using
several aryllead triacetates [ArPb(OAc)3, CHCl3, Py, reflux, 72
h]21,22 to give the aryl derivatives 3a–d in good yield as
mixtures of diastereomers at C(7) (Table 1) which could be
separated only with some difficulty.23 In the case of 3a,b, the
stereochemistry of the C(7)–Ar exo- diasteromer was assigned
by a series of NOE experiments. Alternatively, alkylation with
benzyl bromide under previously reported conditions (NaH,
THF, reflux)24 gave the derivative 3e as a separable mixture of
Table 1 Yields of C(7) functionalised products of 3
Diastereomer
ratioa
Isolated
Compound
R
yield (%)
exo:endo
3a
3b
3c
3d
3e
Ph
86
76
38b
72
75
2.4:1
2.25:1
2.3:1
1.7:1
1:1.2
p-BrC6H4
p-MeOC6H4
o-MeOC6H4
Bn
a Determined by 1H NMR analysis of the crude reaction mixture. b Contains
starting material, in the ratio 2:3c = 1:1.3.
Chem. Commun., 1998
461

View Article Online
H10.1%
tamates 6 (Table 2); molecular modelling studies of each of
these compounds27 indicated that the dihedral angle of the
energy minimised structures also varied with the nature of the
C(4) substituent, particularly for the more sterically congested
C(4)–aryl series of compounds 6a,b. Thus, it would appear that
analogues of well-defined glutamate conformers could be
available by variation in the C(4) substituent of compounds of
type 6.
5.0%
H
H
H
H
H
1.5%
2.8%
H
H
2.3%
H
CO2Me
CO2Me
H
H
CO2Me
H
O
N
H
H
2.4%
O
N
H
CO2Me
3.9%
6a
6b
This route represents a novel and simple, but potentially
generalisable, approach to highly functionalised pyrrolidinones,
and is complementary to existing literature protocols. It in
particular provides access to novel pyroglutamate analogues of
the kainoid group of amino acids possessing substituents with
p-electron density at C(4).
Fig. 1 NOE enhancements for 6a and 6b
In the case of the arylated derivative 3a, acidic deprotection
of the hemiaminal ether function gave the separable dia-
stereomeric alcohols 4a,b in 28 and 52% yield, respectively.
Treatment of 4b with 1 m NaOH in EtOH gave the hydrolysed
and decarboxylated products 4c,d on extraction of the basic
mixture with EtOAc, and a mixture of the acid 4e and product
4c,d on extraction of the aqueous mixture after acidification
with 2 m HCl. Heating of this mixture at 135 °C at 0.8 mBar for
30 min gave the product 4c,d as a 1:1 mixture of diastereomers,
in a combined yield of 82%. Acidic deprotection (TFA–
CH2Cl2) of the tert-butyl ester function of 4c,d and then
oxidation (RuO2, NaIO4, MeCN, CCl4, H2O) afforded the acid
5 [as a mixture of diastereomers at C(4)] which was partially
purified using base wash and then treated with MeOH–H2SO4
(catalytic) giving the diesters 6a and 6b each in 33% yield (from
4c,d), whose relative stereochemistry was determined by NOE
experiments (Fig. 1). An alternative route to 6a,b, which
involved treatment of 3a with 2 m NaOH–EtOH at 50 °C for 5
h to give concomitant ethyl ester hydrolysis, decarboxylation
and tert-butyl ester hydrolysis, was limited by incomplete and
variable hydrolysis of the ester functions, leading to impure
7a,b.
We thank the EPSRC and GlaxoWellcome for funding of a
studentship to J. D., and we gratefully acknowledge the use of
the EPSRC Chemical Database Service at Daresbury28 and the
EPSRC National Mass Spectrometric Service Centre at Swan-
sea.
Note and References
† E-mail: mark.moloney@chem.ox.ac.uk
1 A. O. Plunkett, Nat. Prod. Rep., 1994, 11, 581.
2 M. S. Chorghade and C. Csehe, Pure Appl. Chem., 1994, 2211.
3 G. Massiot and C. Delaude, The Alkaloids, 1986, 27, 300.
4 J. S. Sabol, G. A. Flynn, D. Friedrich and E. W. Huber, Tetrahedron
Lett., 1997, 38, 3687.
5 D. T. Monaghan and R. J. Wenthold, Ionotropic Glutamate Receptors,
Humana, Totowa (New Jersey), 1997.
6 B. S. Meldrum, Excitatory Amino Acid Antagonists, Blackwell
Scientific, Oxford, 1991.
The benzyl derivative 3e was also amenable to similar
manipulation. Thus, hemiaminal ether cleavage of each of the
benzyl diastereomers of 3e (TFA in CH2Cl2) afforded the
products 4f,g. Hydrolysis (NaOH–EtOH) of 4f gave 4h in 99%
crude yield, which after heating to effect decarboxylation, and
then tert-butyl ester removal, oxidation (RuO2, NaIO4, MeCN,
CCl4, H2O) and esterification (CH2N2) provided the separable
diastereomeric benzyl derivatives 6c,d in a ratio of 1:4.4 and
38% overall yield. An alternative path, involving hydrolysis of
4g, followed by direct tert-butyl ester removal, oxidation, and
esterification using the above conditions gave a 1:1 mixture of
products 6e,f, indicating that the initial hydrolyis was in-
complete.
Pyrrolidinones which were unfunctionalised at C(4) were
also available by this route. Thus, direct decarboxylation of the
starting lactam 2, by treatment with ethanolic NaOH followed
by thermolysis and deprotection with TFA, afforded 4i in 33%
yield, a compound which has been previously reported in the
literature.25 Conversion to lactam 6h was achieved by tert-butyl
ester removal, oxidation as before and esterification (CH2N2) in
53% yield over the three steps.
7 D. Lodge, Excitatory Amino Acids in Health and Disease, Wiley-
Interscience, Chichester, 1988.
8 A. Guidotti, Neurotoxicity of Excitatory Amino Acids, Raven Press, New
York, 1990.
9 M. G. Moloney, Nat. Prod. Rep., 1998, in the press.
10 A. F. Parsons, Tetrahedron, 1996, 52, 4149.
11 T. Harrison, Contemp. Org. Synth., 1996, 259.
12 M. Horikawa, Y. Shima, K. Hashimoto and H. Shirahama, Hetero-
cycles, 1995, 40, 1009.
13 M. Horikawa and H. Shirahama, Synlett., 1996, 95.
14 J. E. Baldwin, A. M. Fryer, M. R. Spyvee, R. C. Whitehead and
M. E. Wood, Tetrahedron Lett., 1996, 6923.
15 J. E. Baldwin, S. J. Bamford, A. M. Fryer and M. E. Wood, Tetrahedron
Lett., 1995, 36, 4869.
16 J. E. Baldwin and M. Rudolph, Tetrahedron Lett., 1994, 35, 6163.
17 M. Bamford, M. Beard, D. T. Cherry and M. G. Moloney, Tetrahedron:
Asymmetry, 1995, 6, 337.
18 J. H. Bailey, D. T. Cherry, K. M. Crapnell, M. G. Moloney, S. B. Shim,
M. Bamford and R. B. Lamont, Tetrahedron, 1997, 11731.
19 J. Dyer, S. Keeling and M. G. Moloney, Tetrahedron Lett., 1996, 37,
4573.
20 A. Diaz, J. G. Siro, J. L. Garcia-Navio, J. J. Vaquero and J. Alvarez-
Builla, Synthesis, 1997, 559.
21 J. T. Pinhey, in Comprehensive Organometallic Chemistry II, ed. A.
McKillop, Pergamon, Oxford, 1995, vol. 11.
Noteworthy was variation of the C(2)–H/C(3)–H vicinal
proton coupling constants for each of the substituted pyroglu-
22 J. T. Pinhey, Aust. J. Chem., 1991, 44, 1353.
23 All new compounds gave satisfactory spectroscopic and/or high
resolution mass spectrometric or analytical data.
24 M. J. Beard, J. H. Bailey, D. T. Cherry, M. G. Moloney, S. B. Shim,
K. Statham, M. Bamford and R. B. Lamont, Tetrahedron, 1996, 52,
3719.
Table
2 Proton–proton C(2)–H/C(3)–H coupling constant data and
corresponding dihedral angles
J/Hza
25 T. Sato, K. Matsubayashi, K. Yamamoto, H. Ishikawa, H. Ishibashi and
M. Ikeda, Heterocycles, 1995, 40, 261.
26 Structures optimised with CACHE Scientific Worksystem Version 3.9,
available from Oxford Molecular Group (Medawar Centre, Oxford
Science Centre, Oxford, UK) (Augmented MM2 Parameters using
Conjugate Gradient Optimisation Method).
Dihedral
Compound
angle (°)b
6h
6a
6b
6c
6d
5.5 (5.5)
6.5 (6.5)
8.0 (8.0)
2.5 (2.5)
6.0 (6.5)
117
121
153
125
118
27 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746.
a In CDCl3 (in C6D6). b Ref. 27.
Received in Liverpool, UK, 21st November 1997; 7/08429C
462
Chem. Commun., 1998