New synthesis of 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), a potent metabotropic receptor agonist

Article abstract of DOI:10.1016/S0040-4039(00)00588-8

A new versatile synthesis of racemic ABHxD-I, a potent mGluR agonist, is presented. The synthesis was achieved by means of a Wolff rearrangement, which converted a 3-diazobicyclo[2.2.1]heptan-2-one into a bicyclo[2.1.1]hexane derivative. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00588-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4053–4056
New synthesis of 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic
acid-I (ABHxD-I), a potent metabotropic receptor agonist
Paola Conti and Alan P. Kozikowski ∗
Drug Discovery Program, Institute for Cognitive & Computational Sciences, Georgetown University Medical Center,
3900 Reservoir Road NW, Washington DC 20007-2197, USA
Received 14 February 2000; revised 4 April 2000; accepted 5 April 2000
Abstract
A new versatile synthesis of racemic ABHxD-I, a potent mGluR agonist, is presented. The synthesis was
achieved by means of a Wolff rearrangement, which converted a 3-diazobicyclo[2.2.1]heptan-2-one into a bicy-
clo[2.1.1]hexane derivative. © 2000 Elsevier Science Ltd. All rights reserved.
The excitatory amino acid, glutamate (Glu), plays a pivotal role in many biological processes such as
neuronal plasticity, memory and learning as well as in neuronal degeneration.1 Glutamate interacts with
two families of receptors, the ionotropic glutamate receptors and the metabotropic glutamate receptors,
each of which is composed of several subtypes.2,3 In recent years, research has been focusing on the
design and synthesis of new ligands that selectively interact with different receptor subtypes, in order to
better characterize the physiological and pathophysiological role of the different GluRs and to identify
molecules of potential use in therapy.
As a step towards this goal, we previously reported the synthesis of ABHxD-I,4,5 a potent mGluR ago-
nist which selectively activates metabotropic receptors without any activity at the ionotropic receptors.
In this paper we report a new versatile synthesis of racemic ABHxD-I by means of a Wolff rearran-
gement, which converts a 3-diazobicyclo[2.2.1]heptan-2-one into a bicyclo[2.1.1]hexane derivative.6–10
This new synthesis was designed to take advantage of the key intermediate 8a (Scheme 1) in which
the carbon in α position to the carbonyl group can be suitably functionalized in order to develop the
structure–activity relationships of this series of compounds. Based upon results from modeling studies,
we hypothesized that functionalization at this site might lead to improved metabotropic receptor subtype
selectivity.
The synthesis of 8a together with its diastereoisomer 8b starting from bicyclo[2.2.1]heptadiene has
been described by Meinwald and Crandall.9 We developed an alternative approach (Scheme 1) using
5-norbornen-2-ol (1) as starting material, which was converted into the required α-diazoketone in six
steps. Thus, commercially available 5-norbornen-2-ol was oxidized under Swern conditions, and the
∗
Corresponding author. E-mail: kozikowa@giccs.georgetown.edu (A. P. Kozikowski)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00588-8
tetl 16867

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Scheme 1. (a) Swern oxidation; (b) HOCH2CH2OH, TsOH, toluene, reflux; (c) BH3–THF, THF; (d) PCC, CH2Cl2, reflux; (e)
(Me2N)2CHOt-Bu, 80°C; (f) TsN3, Et2O; (g) hν, MeOH; (h) 2N HCl, acetone
ketone function was protected as ethylene ketal to give 3. A second carbonyl group was introduced via
hydroboration of the double bond, followed by oxidation with PCC. A mixture of the ketones 4a,b was
obtained, which was then converted into a mixture of the corresponding α-diazoketones by alkylation
with Bredereck’s reagent followed by treatment with p-toluenesulfonyl azide.11 It was not necessary
to separate the two diazoketone regioisomers as they both underwent ring contraction by irradiation
with UV light in MeOH,12 leading to the bicyclo[2.1.1]hexane derivatives 7a,b in an exo:endo ratio
of 13:87. The exo:endo ratio reflects the preferred attack of MeOH from the less hindered face of the
ketene intermediate and is consistent with the literature.9,10 The two diastereoisomers, 7a and 7b, can
be separated by silica gel chromatography at this stage and then hydrolyzed in turn with 2N HCl and
acetone. However, we found it more convenient to hydrolyze 7a,b as a mixture. The obtained ketones 8a
and 8b were chromatographically separated and characterized.
1
The assignment of the stereochemistry of 8a and 8b was based on their H NMR spectra; highly
diagnostic is the W-coupling between 5-H and the bridgehead proton 6-H which is observed only in
the exo isomer 8a (typically J=7–8 Hz).13 Thus, the proton observed at highest field which, according
to the literature,9,13 is 6-H, appears as a doublet (J6–6 =7.5 Hz) in the endo isomer 8b, and as a triplet
0
0
(J6–6 =J6–5=7.8 Hz) in the exo isomer 8a.
In order to increase the percentage of the stereoisomer 8a, which is the direct precursor of the
target compound ABHxD-I, we first treated the undesired endo isomer 7b with base both under
thermodynamic (DBU, toluene, reflux) and kinetic (LDA, THF, −78°C) conditions. However, in both
cases, the unmodified endo isomer 7b was recovered. We then operated under radical conditions by
converting 7b into the corresponding phenylthio derivative 9, which was subsequently desulfurized with
Raney-nickel; in this case a mixture of 7a and 7b, in a 1:3 ratio, was obtained. After chromatographic
separation on silica gel, 7b could be recycled (Scheme 2).
The keto group of 8a was converted into a spirohydantoin under Bucherer–Bergs14 reaction conditions,
giving rise to a mixture of stereoisomers 10 and 11 with identical chromatographic mobility. Without
separation, the mixture of spirohydantoins was hydrolyzed by alkali, and the two carboxyl groups were
subsequently protected as methyl esters. The resulting free amines 12 and 13 were easily separated by

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Scheme 2. (a) LDA, PhSSPh, −78°C; (b) H2/Raney-nickel, EtOH
column chromatography, and the ester groups were hydrolyzed with 6N HCl to give the amino acid
ABHxD-I and its isomer ABHxD-II,15 respectively (Scheme 3).
Scheme 3. (a) KCN, (NH4)2CO3, MeOH:H2O 1:1, 55°C, 18 h; (b) 2N NaOH reflux; (c) MeOH, SOCl2; (d) 6N HCl, reflux
In conclusion, we have developed a new, shortened synthesis of ketone 8a and a method for the
partial conversion of the major endo isomer into the desired exo isomer. This ketone is not only the
key intermediate for the synthesis of ABHxD-I, but is also a useful starting material for the synthesis of
functionalized derivatives. Trapping of the ketene intermediate with an optically pure alcohol should also
permit access to non-racemic products.
Acknowledgements
We are indebted to the National Institute of Health (NS 35449) for support of this work. P.C. also
acknowledges the CNR for a NATO fellowship.
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Oxford, 1991; Vol. 3, pp. 887–912.
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12. A previously degassed methanol solution of the α-diazoketones was irradiated for 20 hours at 20°C with a Hanovia 450 W
medium pressure mercury lamp through a Pyrex filter.
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15. 100 mg of 8a, 86 mg of KCN (2 equiv.) and 312 mg of (NH4)2CO3 (5 equiv.) in 2 mL of MeOH:H2O 1:1 were heated
at 55–60°C for 18 h. The solution was evaporated, the residue was taken up in MeOH, and the solution was filtered and
concentrated. The crude material was dissolved in 4 mL 2N NaOH and heated at 120°C in a resealable Pyrex vial for 8
h. The solution was acidified to pH 2 and evaporated to dryness. To the crude material, in 6 mL of MeOH, was added
at 0°C 0.5 mL of SOCl2, and the mixture was stirred at rt overnight. After evaporation of the solvent, the residue was
dissolved in water, and the solution was basified with NaHCO3 and extracted with EtOAc. Flash chromatography on silica
gel (hexanes:AcOEt 1:4) gave 26 mg of 12 and 38 mg of 13 (overall yield: 46%). The aminoesters 12 and 13 were treated
with 6N HCl at reflux for 4 h to afford the final products ABHxD-I and ABHxD-II, respectively, as hydrochloric acid salts.
The spectroscopic data for the final compounds are identical to those previously reported (see Ref. 4).