Stereoselective Syntheses of Highly Functionalized Bicyclo[3.1.0]hexanes:  A General Methodology for the Synthesis of Potent and Selective mGluR2/3 Agonists

Tan, Lushi; Yasuda, Nobuyoshi; Yoshikawa, Naoki; Hartner, Frederick W.; Eng, Kan K.; Leonard, William R.; Tsay, Fuh‐Rong; Volante, R. P.; Tillyer, Richard D.

doi:10.1021/jo0511187

Cited by 20 publications

(13 citation statements)

References 32 publications

(32 reference statements)

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“…[65] The synthesis commenced with the reduction of 212 with AlH 3 , generated Researchers at Merck developed a Et 3 Al-mediated intramolecular epoxide opening/cyclopropane formation, which provided highly functionalized bicycle[3.1.0]hexane systems with high efficiency. [66] The m-GluR2/3 agonist 229 (Scheme 26) was prepared by this methodology on a large scale and in 43 % overall yield. The whole synthesis started from the chiral methyl ester 218, which was subjected to fluorination with NFSI to generate compound 219 in 84 % yield with 29:1 diastereoselectivity at the α carbon of the fluoroester.…”

Section: Monofluorinated Cyclic Amino Acidsmentioning

confidence: 99%

Recent Advances in the Synthesis of Fluorinated Amino Acids

2011

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Introduction of fluorine atoms or fluorine‐containing groups into amino acids has attracted much attention from bioorganic and medicinal chemists because the resulting fluorinated amino acids have found wide application as potential enzyme inhibitors and antitumor (antibacterial) agents. Additionally, it is well known that replacement of naturally occurring amino acid(s) in some peptide chains with their fluorinated counterparts can significantly increase specific protein–ligand or protein–protein interactions, leading to increases in the proteolytic and thermal stabilities of peptide compounds and, as a result, promote their therapeutic properties. This microreview summarizes important advances in the synthesis of fluorinated amino acids since 2005. The contents are simply divided into three groups on the basis of amino acid types: fluorinated α‐amino acids (F‐αAAs), fluorinated β‐amino acids (F‐βAAs), and fluorinated cyclic amino acids (F‐CAAs).

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Section: Monofluorinated Cyclic Amino Acidsmentioning

confidence: 99%

Recent Advances in the Synthesis of Fluorinated Amino Acids

2011

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“…8,[13][14][15][16][17][18][19][20] A less explored enantioselective method is the cyclisation of 4,5-epoxyenolates. The reaction affords 2-(hydroxymethyl)cyclopropyl esters [21][22][23][24][25] or ketones [26][27][28] when the appropriate 4,5-epoxycarbonyl derivative is treated with base. Hindered bases including lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LHMDS) have been reported in the case of ester cyclisations.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of enantiopure cyclopropyl esters from (−)-levoglucosenone

Stockton

Greatrex

2016

Org. Biomol. Chem.

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The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the GABAc receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the selective glutamate receptor antagonist PCCG-4.

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“…Modifications to this molecule resulted in the identification of the analogues MGS0008 ( 3 ) [11] and MGS0028 ( 4 ) [12–13]. In addition, the conformationally constrained analogues of L-Glu 6a,b , 7 , 8 and 9a,b were reported [14–18] as either ionotropic or metabotropic glutamate receptors ligands, obtained by “freezing” the glutamate skeleton in search for subtype selective bioactive conformations [19].…”

Section: Introductionmentioning

confidence: 99%

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

Bechi¹,

Amantini²,

Tintori³

et al. 2014

Beilstein J. Org. Chem.

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SummarySeveral strategies aimed to “freeze” natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson’s and Alzheimer’s and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3–C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction.

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Stereoselective Syntheses of Highly Functionalized Bicyclo[3.1.0]hexanes: A General Methodology for the Synthesis of Potent and Selective mGluR2/3 Agonists

Cited by 20 publications

References 32 publications

Recent Advances in the Synthesis of Fluorinated Amino Acids

Recent Advances in the Synthesis of Fluorinated Amino Acids

Synthesis of enantiopure cyclopropyl esters from (−)-levoglucosenone

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

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