A short synthesis of both enantiomers of 2-aminobicyclo[3.2.0]heptane-2,7-dicarboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2021.152912

A concise method is reported for the synthesis of 2-aminobicyclo[3.2.0]heptane-2,7-dicarboxylic acid, a close analogue of the glutamate receptor ligand LY354740, in both enantiomeric forms. The strategy features the creation of the core structure at the start of the synthesis via a photochemical [2 + 2] cycloaddition reaction, an efficient resolution procedure using a chiral oxazolidinone, and requires only minimal purification of the synthetic intermediates. The title compounds showed little or no affinity for the mGlu2 and mGlu3 receptors.

Full text of DOI:10.1016/j.tetlet.2021.152912

Tetrahedron Letters 68 (2021) 152912
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Tetrahedron Letters
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A short synthesis of both enantiomers of 2-aminobicyclo[3.2.0]heptane-
2,7-dicarboxylic acid
Florence Charnay-Pouget a,1, Matthieu Le Liepvre a, Hendrik Eijsberg a,b, Régis Guillot a, Jean Ollivier a,
Francesco Secci b, Angelo Frongia b, David J. Aitken a,
⇑
a Université Paris Saclay, CNRS, ICMMO, CP3A Organic Synthesis Group & Services Communs, 420 rue du Doyen Georges Poitou, 91405 Orsay, France
b Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-09042 Monserrato, Cagliari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise method is reported for the synthesis of 2-aminobicyclo[3.2.0]heptane-2,7-dicarboxylic acid, a
close analogue of the glutamate receptor ligand LY354740, in both enantiomeric forms. The strategy fea-
tures the creation of the core structure at the start of the synthesis via a photochemical [2 + 2] cycload-
dition reaction, an efficient resolution procedure using a chiral oxazolidinone, and requires only minimal
purification of the synthetic intermediates. The title compounds showed little or no affinity for the mGlu2
and mGlu3 receptors.
Received 13 December 2020
Revised 25 January 2021
Accepted 4 February 2021
Available online 10 February 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Glutamic acid analog
Synthetic photochemistry
Bicyclo[3.2.0]heptane derivatives
Resolution procedure
Introduction
the smaller of the two rings (Fig. 1). Pharmacological evaluation
of 1 revealed a weak agonist activity for mGlu1, mGlu2, mGlu4
Glutamic acid is the most abundant mammalian excitatory
amino acid and is involved in many aspects of brain function and
in the regulation of numerous neuropathological conditions [1].
It interacts with both fast-acting ionotropic (iGlu) receptors and
slow-acting G protein-coupled metabotropic (mGlu) receptors.
Eight mGlu receptor subtypes have been identified and classified
into three groups, and have been targeted over several decades
in the search for treatment of anxiety and stress disorders, includ-
ing schizophrenia, Alzheimer’s disease and Parkinson’s disease [2].
The search for analogues of glutamic acid that behave as selective
ligands for the group II receptors, mGlu2 and mGlu3, led to the dis-
covery of the potent agonist LY354740 (Eglumegad)[3] (Fig. 1),
which entered clinical trials as a potential anti-psychotic agent
[4] and has recently been shown to alleviate dyskinesia [5] and
to counter retinal cell apoptosis in glaucoma [6].
and mGlu6 receptor subtypes, although the activity towards the
mGlu3 receptor subtype was not reported [9]. There is still a need
for glutamate analogs that differentiate between mGlu2 and
mGlu3 receptors [10], so we felt that the mGlu3 activity should
also be assessed. Furthermore, in a more general context there is
considerable current interest in polyfunctional compounds with a
bicyclo[3.2.0]heptane core for drug discovery [11] and as rigid
molecular scaffolds for multiple functional group displays [12].
The published synthesis [9] of 1 adopted a ‘‘chiral pool” strat-
egy, starting from L-serine. It involved a lengthy sequence (10
steps; undisclosed yield) featuring a late-stage intramolecular pho-
tochemical [2 + 2]-cycloaddition reaction to construct the bicyclic
core, which took place with low diastereoselectivity. We report
here our own investigation focusing on an alternative synthesis
of 1, which we reasoned should be more expedient. The pivot of
this simplified strategy is to conduct an early-stage intermolecular
photochemical [2 + 2]-cycloaddition reaction, which is followed by
a resolution protocol. As we will show, it has the advantage of pro-
viding both (1S,2S,5S,7S)-2-aminobicyclo[3.2.0]heptane-2,7-dicar-
boxylic acid (1) and its enantiomer (ent-1).
While the bicyclo[3.1.0]hexane core of LY354740 has featured
in other group II mGlu receptor ligands [7], numerous cyclic glu-
tamic acid derivatives have been investigated over the years [8].
One such compound is (1S,2S,5S,7S)-2-aminobicyclo[3.2.0]hep-
tane-2,7-dicarboxylic acid (1) whose molecular structure is very
similar to that of LY354740, having just one extra carbon atom in
The photochemical [2 + 2]-cycloaddition reaction between
cyclopent-2-enone and methyl acrylate was previously reported
to give a roughly 1:1 mixture of head-to-head and head-to-tail
regioisomers, in which the former was a 86:14 mixture of exo:endo
⇑
Corresponding author.
E-mail address: david.aitken@universite-paris-saclay.fr (D.J. Aitken).
Present address: ICCF (UMR 6296), 63178 Aubière, France.
1
stereoisomers,
respectively
[13].
We
reexamined
this
https://doi.org/10.1016/j.tetlet.2021.152912
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

F. Charnay-Pouget, M. Le Liepvre, H. Eijsberg et al.
Tetrahedron Letters 68 (2021) 152912
Fig. 1. Structures of glutamic acid and two restricted analogs.
photochemical reaction using ethyl acrylate as the alkene compo-
nent (Scheme 1). When the gram scale reaction was carried out in
acetone (25 °C, 4 h, 10 equiv. ethyl acrylate, 400 W Hg vapor lamp)
we obtained a 2:1 mixture of regioisomers which were separated
by simple column chromatography in good overall yield. The major
compound was the head-to-head regioisomer ( )-2, isolated in 49%
yield as a single diastereomer. By analogy with the literature [13],
the exo configuration was expected and was subsequently con-
firmed by transformation into compound 5 (vide infra). The minor
head-to-tail regioisomer 3 was isolated in 24% yield as a 2:1 mix-
ture of exo and endo diastereomeric forms. To confirm the identity
of 3 we took advantage of compound 4 [14], available from previ-
ous studies.[12b] A four-step procedure involving hydrogenation,
ester hydrolysis, oxidation then esterification gave an authentic
sample of endo-3 in 65% overall yield (Scheme 2). Comparison of
the spectroscopic data indicated that this was the minor diastere-
omer present in the endo/exo-3 mixture obtained in Scheme 1.
To validate the photochemical strategy for accessing the target
amino acid, ( )-2 was transformed into a hydantoin using a
Bucherer-Bergs reaction to provide derivative ( )-5 as a single
diastereomer, albeit in modest yield, after crystallization from
water [15]. The molecular structure and the relative stereochem-
istry of ( )-5 were confirmed by X-ray diffraction analysis (Fig. 2)
[16]; the requisite endo orientation of the ring-bound nitrogen is
in agreement with the attack of cyanide on the least hindered face
of the bicyclic core during the Bucherer-Bergs reaction. Rapid
transformation of ( )-5 into the target compound now seemed
clearly feasible. Treatment with moderately strong aqueous base
resulted in the efficient selective hydrolysis of the ester to provide
( )-6, while slightly stronger basic conditions achieved the desired
complete hydrolysis to give ( )-1 in 46% isolated yield. In this way,
a very short and simple synthesis (3 steps) of (1S*,2S*,5S*,7S*)-2-
aminobicyclo[3.2.0]heptane-2,7-dicarboxylic acid ( )-1 was vali-
dated (Scheme 1).
Scheme 1. Synthesis of ( )-1.
Scheme 2. Independent preparation of endo-3.
In order to adapt this strategy to allow access to enantiomeri-
cally pure samples, our initial plan was to incorporate a resolution
step implicating fractional crystallization of a diastereomeric salt
mixture obtained by treatment of ( )-6 with readily available (S)-
Fig. 2. X-ray structure of compound ( )-5.
a-methylbenzylamine. Indeed, this approach had proven success-
ful for the resolution of the corresponding hydantoin-acid precur-
sor of LY354740 [3]. Despite considerable efforts, however, we
were unable to crystallize salt samples with any significant
diastereoselectivity.
We then turned our attention to a resolution strategy based on
diastereomeric derivatization by covalent attachment of a chiral
resolving agent. Previously, our group has employed non-racemic
oxazolidinones in this way to resolve a number of cyclic amino
acids [17]. Derivatization of ( )-6 seemed likely to be problematic
due to the reactivity of the hydantoin so we focused on the simpler
keto derivative. Saponification of ( )-2 in aqueous base gave the
corresponding carboxylic acid which was activated as a mixed
anhydride by reaction with pivaloyl chloride, then treated with
the lithium salt of (R)-4-phenyloxazolidine-2-one (Scheme 3).
The two diastereomers 7a and 7b obtained from this three-step
procedure were separated easily by column chromatography and
were isolated as single compounds in gratifying overall yields of
33% and 24% respectively from ( )-2. Single crystal X-ray
diffraction analysis of 7b provided the absolute configuration
assignment (Fig. 3) [16].
Scheme 3. Resolution procedure and synthesis of 1 and ent-1.
2

F. Charnay-Pouget, M. Le Liepvre, H. Eijsberg et al.
Tetrahedron Letters 68 (2021) 152912
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23
which had not been previously reported, were [
a
]
D
= –26.3
23
(c = 0.99, H2O) for 1 and [
a
]
D
= +26.4 (c = 1.00, H2O) for ent-1.
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FRET) immuno-assay with LY354740 as the control ligand.
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Declaration of Competing Interest
[13] D. Andrew, D.J. Hastings, A.C. Weedon, J. Am. Chem. Soc. 116 (1994) 10870–
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[14] The sample of compound 4 used here was obtained from the work described in
ref. 12b and was non racemic, with the 1S,5R,6R configuration shown in
Scheme 2.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[15] NMR analysis of the crude reaction mixture (before crystallization) showed
only one set of signals (see ESI document), suggesting the reaction to be highly
stereoselective.
Acknowledgments
[16] Crystallographic data for compounds 5 and 7b have been deposited at the
CCDC with file numbers 2021891 and 2021892 respectively (see ESI file for
details).
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istère de l’Enseignement Supérieur et de la Recherche.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152912.
(d) V. Declerck, D.J. Aitken, Amino Acids 41 (2011) 587–595.
3