An improved synthesis of enantiopure 2-azabicyclo[2.2.1]heptane-3-carboxylic acid

Tararov, Vitali I.; Kadyrov, Renat; Kadyrova, Zenfira; Dubrovina, Natalia V.; Börner, Armin

doi:10.1016/s0957-4166(02)00048-4

Cited by 24 publications

(16 citation statements)

References 12 publications

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“…For the synthesis of pure 3 S - and 3 R - exo -2-azabicyclo[2.2.1]heptane-carbonitriles 9a and 9b , we used the intermediates 6a and 6b , correspondingly. The 3 S -acid 6a was prepared from the precursor 14a as described in the literature [ 38 , 41 , 42 , 43 , 44 , 45 , 46 ] and shown in Figure 8 . The use of ( R )-1-phenylethylamine 13a followed by two-step hydrogenation and saponification afforded the only isomer 14a with the desired S -configuration of carbon in 3-position.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

et al. 2022

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Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

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Section: Resultsmentioning

confidence: 99%

“…The synthesis was made according to the procedure described in [ 42 , 46 ]. To EtOH (15 mL) solution of compound 14a (0.9 g, 6.4 mmol) BOC2O (1.6 g, 7.4 mmol) was added.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

et al. 2022

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“…97 The latter was prepared from enantiomerically pure (1 S ,3 S ,4 R )- 56 , obtained by a Diels–Alder reaction between ethyl 2-(( R )-(1-phenylethyl)imino)acetate and cyclopentadiene, under conditions similar to those reported for the racemic material. 98…”

Section: Nitrogen Containing Saturated Heterocycles In Peptidomimeticsmentioning

confidence: 99%

Recent developments in the utility of saturated azaheterocycles in peptidomimetics

Singh

Lakshman

2022

Org. Biomol. Chem.

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“…9 It is available in a multi-gram scale now. 10 Since a related aminophosphine phosphinite ligand ProloPHOS 2 derived from prolinol is known from the work of Cesarotti and Chiesa, 11 a comparison of the hydrogenation properties seemed to be simultaneously of considerable interest. Thus the role of the rigid backbone in the ligand for the enantioselection would become clear.…”

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Versatile Synthesis of Chiral Aminophosphine Phosphinites (AMPPs) as Ligands for Enantioselective Hydrogenation

Dubrovina¹,

Tararov²,

Kadyrova³

et al. 2004

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New chiral aminophosphine phosphinite (AMPP) ligands with different P-aryl substituents were prepared from (1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-ylmethanol by a new and chemoselective synthetic approach. The ligands showed good enantioselectivity (up to 91%) in the Rh-catalyzed enantioselective hydrogenation of benchmark substrates.Among enantioselective catalytic reactions in an industrial scale, the hydrogenation with rhodium complexes bearing chiral P-ligands is of pivotal importance. 1 Since the design of more efficient and selective catalysts is far from being understood, the synthesis and test of new ligands is still one of the most promising method for the optimization of enantioselective hydrogenations. This situation is forced by the increasing level of modern high-throughput methods, which allow the fast testing of series of catalysts and reaction conditions. For this approach the availability of broad arrays of related ligands is indispensable.For the establishment of comprehensive ligand libraries, aminophosphine phosphinites (AMPPs) 2 are of particular value. 3 They can be synthesized from chiral amino alcohols in one step. An overwhelming part of the latter can be easily derived from chiral amino acids, which are available in a large variety, sufficient quantity and high optical purity from nature or industrial processes. In the past several research groups have shown the versatility of this approach. 4 In due course several aminophosphine phosphinites as efficient ligands for enantioselective hydrogenations were disclosed.Generally, the synthesis of aminophosphine phosphinites is carried out by condensation reaction of the amino alcohol with dialkyl-or diarylchlorophosphines in the presence of a tertiary amine as a base. Hydroxyl and amino group can be esterified simultaneously. However, on the other hand under these conditions the selective synthesis of 'mixed' ligands with different substituents on both phosphorous atoms, which opens up another level of variation, frequently fails due to the similar reactivity of amino and hydroxyl group. As an alternative the 'borane methodology' was suggested, which allows even the preparation of P-stereogenic AMPPs. 5 However, this method requires several additional steps. A protocol for a convenient one-pot procedure could be the transphosphinylation reaction of phosphinous amides (aminophosphines). 6 To the best of our knowledge this methodology has never been used for the synthesis of 'mixed' P-ligands.In order to show the high potential of this methodology, herein we report our results in the preparation of AMPPligands of type 1 (Figure 1) starting from the amino alcohol (1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-ylmethanol (3) (Scheme 1). 7 The amino alcohol 3 represents a prolinol analogue bearing a rigid backbone. 8 In particular the group of Andersson investigated the potential of this unnatural enantiopure material as a chiral auxiliary and ligand. 9 It is available in a multi-gram scale now. 10 Since a related aminophosphine phosphinite ligand ProloPHOS 2 d...

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An improved synthesis of enantiopure 2-azabicyclo[2.2.1]heptane-3-carboxylic acid

Cited by 24 publications

References 12 publications

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

Recent developments in the utility of saturated azaheterocycles in peptidomimetics

Versatile Synthesis of Chiral Aminophosphine Phosphinites (AMPPs) as Ligands for Enantioselective Hydrogenation

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