Asymmetric synthesis of cyclopropane phosphonates as a route to 2-substituted cyclopropylglycine, antagonist of metabotropic receptors

Article abstract of DOI:10.1080/10426507.2012.738740

We describe two attempts to the synthesis of novel constrained L-AP4 analogs of potential antagonist activity. Although the first approach to introduce alkyl substituent on the amino acid carbon using cyclopropyl keton failed, conversion of cyclopropanecarboxylate into corresponding β-ketophosphonate is promising and more general.

Full text of DOI:10.1080/10426507.2012.738740

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Phosphorus, Sulfur, and Silicon and the
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Asymmetric Synthesis of Cyclopropane
Phosphonates as A Route To 2-
Substituted Cyclopropylglycine,
Antagonist of Metabotropic Receptors
Jerzy A. Krysiak a , Aneta Rzewnicka a & Wanda H. Midura a
a Department of Heteroorganic Chemistry , Polish Academy of
Sciences, Centre of Molecular and Macromolecular Studies , 90-363
Łódź, Sienkiewicza 112 , Poland
Accepted author version posted online: 01 Nov 2012.
To cite this article: Jerzy A. Krysiak , Aneta Rzewnicka & Wanda H. Midura (2013) Asymmetric
Synthesis of Cyclopropane Phosphonates as A Route To 2-Substituted Cyclopropylglycine, Antagonist
of Metabotropic Receptors, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:4, 483-486,
DOI: 10.1080/10426507.2012.738740
To link to this article: http://dx.doi.org/10.1080/10426507.2012.738740
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Phosphorus, Sulfur, and Silicon, 188:483–486, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.738740
ASYMMETRIC SYNTHESIS OF CYCLOPROPANE
PHOSPHONATES AS A ROUTE TO 2-SUBSTITUTED
CYCLOPROPYLGLYCINE, ANTAGONIST
OF METABOTROPIC RECEPTORS
Jerzy A. Krysiak, Aneta Rzewnicka, and Wanda H. Midura
Department of Heteroorganic Chemistry, Polish Academy of Sciences, Centre of
Molecular and Macromolecular Studies, 90-363 Ło´dz´, Sienkiewicza 112, Poland
GRAPHICAL ABSTRACT
Abstract We describe two attempts to the synthesis of novel constrained L-AP4 analogs of
potential antagonist activity. Although the first approach to introduce alkyl substituent on the
amino acid carbon using cyclopropyl keton failed, conversion of cyclopropanecarboxylate into
corresponding β-ketophosphonate is promising and more general.
Keywords Cyclopropylglycine; antagonist; phosphonate; sulfonium ylide
INTRODUCTION
(S)-Glutamic acid is the major excitatory neurotransmitter in the central nervous sys-
tem (CNS) and is involved in most brain functions. Glutamate activates several types of
receptors and is the substrate of transporters and enzymes that all play an important role in
synaptic transmission. A large number of its analogs have been assayed at glutamatergic
transmission systems in order to identify selective ligands, some of which have proved to be
successful1 and even reached the advanced clinical phase. Among the several classes of Glu
analogues, carboxycyclopropylglycines (CCG) represent a valuable source of both potent
and selective agonist and antagonist ligands for the various members of the Glu receptor
family. (2S,1ꢁS,2ꢁS)-2-(2ꢁ-Carboxycyclopropyl) glycine (LCCG-1) is a selective and potent
agonist for group II mGluRs. It has been reported that the stereoselective introduction of a
bulky, hydrophobic group in the 3ꢁ-position confers antagonism to the corresponding CCG
analog, (2S,1ꢁS,2ꢁS,3ꢁR)-2-(2ꢁ-carboxy-3ꢁ-phenylcyclopropyl) glycine.2 Ornstein et al. have
Received 5 October 2012; accepted 5 October 2012.
Address correspondence to Wanda H. Midura, Department of Heteroorganic Chemistry, Polish Academy
of Sciences, Centre of Molecular and Macromolecular Studies, 90-363 Ło´dz´, Sienkiewicza 112, Poland. E-mail:
whmidura@cbmm.lodz.pl
483

484
JERZY A. KRYSIAK ET AL.
demonstrated that incorporation of an alkyl substituent also on the amino acid carbon (2
position) converts the agonist into analog of antagonistic activity for the same group re-
ceptors (LY341495).3,4 Since bioisosteric replacement of planar carboxylic acid (CO2H)
by a tetrahedral phosphonic acid functionality (PO3H2) is another way to improve phar-
macological properties of amino acids, we decided to perform the synthesis of phosphoryl
analog of 2-substituted cyclopropylglycine based on our earlier achievements.5–7 In this
paper, we present our preliminary investigations in this field.
RESULTS AND DISCUSSION
Asymmetric cyclopropanation of (1-diethoxyphosphoryl)vinyl p-tolyl sulfoxide was
a key step in our approach8 to the synthesis of 2-(2-phosphonocyclopropyl)glycines (PCG-1
and PCG-2) and their phenyl analogs (PPCG-1 and PPCG-2), conformationally constrained
L-AP4 analogs of confirmed potency as mGluR agonists.9,10 Our general approach to the
desired cyclopropane amino acids of potential antagonist activity envisioned the analogous
scheme of the reactions, but with cyclopropyl ketone 1 as a basic substrate. In this way,
one of ketone substituent after conversion to amino acid becomes desired substituent on
the amino acid carbon.
We initially investigated asymmetric cyclopropanation using sulfonium ylide 3 con-
taining ketone moiety bonded to ylidic carbon atom. The source of chirality was an enan-
tiomerically pure sulfinyl group in the vinylphosphonate 2. Cyclopropane cis-4, formed as
a major diastereomer under conditions applied, was easily isolated in a high yield, but we
were not able to remove sulfinyl group from this structure in order to obtain ketone 1a,
neither by classical methods (Raney nickel, sodium amalgam), nor with Grignard reagents
(Scheme 1).
Unfortunately, our effort of further functionalization of cis-4 without removing sulfur
substituent also failed. Classical amino acid synthesis techniques were not able to convert
the cyclopropane cis-4 to the desired products. Even after reduction to less sterically
demanding sulfide 5, using Bucherer–Bergs methodology under standard conditions, only
corresponding cyanohydrin 6 was formed (Scheme 2).
Failure in our attempts using cyclopropanation mediated by sulfonium ylide stabilized
by ketone moiety forced us to apply our former methodology,6 leading to enantiopure cyclo-
propylcarboxylate 7. The latter was then converted into corresponding β-ketophosphonate
8 and subsequently condensed with a benzaldehyde to give 9 in a good yield (Scheme 3).

ASYMMETRIC SYNTHESIS OF CYCLOPROPANE PHOSPHONATES
485
Scheme 1
Scheme 2
Scheme 3

486
JERZY A. KRYSIAK ET AL.
This way seems to be promising and more general, because when using variety of
aldehydes in Wittig–Horner reaction, different substituent can be incorporated to desired
structure.
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