An Expedient Method for Resolution of 3-Amino-3-(3‘-pyridyl)propionic Acid and Related Compounds

Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, L. Keith; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani, and Frank J.; Walker, Donald G.

doi:10.1021/op990192m

Cited by 14 publications

(6 citation statements)

References 17 publications

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“…In the presence of HBF 4 ,11 the hydrogenation of methyl ( Z )‐β‐(3‐pyridyl)‐β‐(acetylamino)acrylate provided the chiral β‐(3‐pyridyl)‐β‐amino acid derivative 5 j with 96 % ee (Table 2, entry 10). 5 j is a key component for the synthesis of the GP IIb/IIIa antagonist RWJ‐53308 9b,c. To further test the catalytic efficiency of the Rh–binapine catalyst for the asymmetric hydrogenation of β‐aryl‐β‐(acetylamino)acrylates, substrate 4 g was subjected to hydrogenation in the presence of less [Rh( 1 )(nbd)]SbF 6 catalyst (0.1 mol %), and the chiral product 5 g was obtained in quantitative yield and with 99 % ee .…”

Section: Methodsmentioning

confidence: 99%

A Bisphosphepine Ligand with Stereogenic Phosphorus Centers for the Practical Synthesis of β‐Aryl‐β‐Amino Acids by Asymmetric Hydrogenation

et al. 2003

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Enantiomerically pure b-amino acids are important chiral building blocks for the synthesis of b-peptides, b-lactam antibiotics, and many other important chiral drugs. [1] Although chiral b-amino acids have been synthesized through several stoichiometric and catalytic methods, [2] an efficient and practical synthetic method is still needed. The Rh- [3] or Ru-catalyzed [4] asymmetric hydrogenation of b-(acylamino)-acrylic acid derivatives to make chiral b-amino acids has recently attracted much attention. Although many Rh [3] and Ru [4a,c] complexes with chiral phosphane ligands exhibited high enantioselectivities in the hydrogenation of b-alkyl-b-(acylamino)acrylic acid derivatives, the asymmetric hydrogenation of b-aryl-b-(acylamino)acrylic acid derivatives has met with much less success. Heller and co-workers recently reported that the use of a Rh-Et-ferrotane catalyst can give rise to ee values of over 99 % in the asymmetric hydrogenation of a set of (E)-b-aryl-b-(acylamino)acrylic acid derivatives.[3b] However, the preparation of (E)-b-aryl-b-(acylamino)acrylic acid derivatives requires their separation from the corresponding thermodynamically more stable Z isomers, and low yields are generally observed.[3b] On the other hand, (Z)-b-aryl-b-(acylamino)acrylic acid derivatives can be preferentially formed over their E isomers under suitable conditions, and high yields for the synthesis of Z substrates are attainable.[4b] A highly enantioselective asymmetric hydrogenation of (Z)-b-aryl-b-(acylamino)acrylic acid derivatives would allow the practical synthesis of chiral b-aryl-b-amino acids. In previous work we developed a set of Ru-o-binapo complexes, [4b] which gave rise to ee values of up to 99 % in the asymmetric hydrogenation of (Z)-b-aryl-b-(acylamino)acrylic acid derivatives.[5] However, the reactivities of the Ru complexes were moderate. A Rh-TangPhos catalyst promoted both high enantioselectivities (up to 98.5 % ee) and high reactivities in the hydrogenation of a series of Z substrates, with the exception of those with orthosubstituted b-aryl groups.[3e] Herein we present a new chiral catalyst for the hydrogenation of (Z)-b-aryl-b-(acylamino)-acrylic acid derivatives. The Rh complex of the chiral bisphosphepine ligand 1 (abbreviated as (S,S,S)-binapine),

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Section: Methodsmentioning

confidence: 99%

A Bisphosphepine Ligand with Stereogenic Phosphorus Centers for the Practical Synthesis of β‐Aryl‐β‐Amino Acids by Asymmetric Hydrogenation

et al. 2003

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“…Using initial rate data, it was estimated that ca. 50% inactive p-xylene complex was formed; this complex can be detected by 31 P NMR spectroscopy and was definitely identified with 103 Rh NMR spectroscopy. 24 Catalyst Preparation-Induction Period.…”

Section: Resultsmentioning

confidence: 83%

“…An alternative method for the preparation of chiral -amino acid derivatives is (dynamic) kinetic resolution. 31 The necessary racemicamino acids seem partly efficiently available very recently. 32 …”

Section: Discussionmentioning

confidence: 99%

“…For the β-amino acid derivatives the central problem is rather the substrate synthesis than the catalytic step because of the impressive results reported in the past few years, particularly for the Rh complexes. An alternative method for the preparation of chiral β-amino acid derivatives is (dynamic) kinetic resolution . The necessary racemic β-amino acids seem partly efficiently available very recently …”

Section: Discussionmentioning

confidence: 99%

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Chiral β-Amino Acid Derivatives via Asymmetric Hydrogenation

Drexler

You

Zhang

et al. 2003

Org. Process Res. Dev.

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This contribution gives an overview of the synthesis of chiral -amino acids via asymmetric hydrogenation of the corresponding dehydroamino derivatives. Literature results are discussed regarding substrate synthesis and catalyst performance and how it is affected by substrate and catalyst structure as well as experimental parameters. A tentative mechanistic concept for the hydrogenation step is also presented. IntroductionEnantiomerically pure -amino acids and their derivatives not only exhibit broad biological activity but are also the building blocks for the synthesis of -peptides. The latter are characterized by a high enzymatic stability and show interesting three-dimensional structures. 1 The cyclization of -amino acids leads to the important family of the -lactams. Scheme 1 shows examples of pharmaceutically interesting structures containing a -aryl-substituted -amino acid as a common structural component. 2 Methods for the preparation of optically enriched -amino acids are predominantly based on stoichiometric reactions with chiral auxiliary agents and to a clearly smaller extent on stereoselective catalytic reactions. 2d,e,3 One of the most promising methodologies, also regarding industrial application, is the asymmetric hydrogenation of the appropriate -dehydroamino acid precursors catalyzed by homogeneous Rh or Ru complexes containing chiral phosphane ligands. In contrast to the synthesis of R-amino acid precursors where it is a standard method with many industrial applications, 4

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“…The resulting ester 10 was saponified with LiOH to afford the corresponding crystalline acid 11 . Coupling of acid 11 with methyl ( S )-3-amino-3-(3‘-pyridyl)propionate dihydrochloride ( 3 ) (prepared via classical resolution of the corresponding 3-( tert -butoxycarbonyl)amino-3-(3‘-pyridyl)propionic acid) afforded intermediate 12 . The ester was saponified using LiOH, and finally the Cbz group was removed via catalytic hydrogenation to afford crude elarofiban which was purified via recrystallization from n -BuOH.…”

Section: Resultsmentioning

confidence: 99%

A Practical Synthesis of the Platelet Fibrinogen Antagonist, Elarofiban

Cohen

Bos

Cesco-Cancian

et al. 2003

Org. Process Res. Dev.

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Elarofiban is a novel, nonpeptide, orally active fibrinogen receptor antagonist useful for the treatment of platelet mediated thrombotic disorders (Costanzo, M. J.; Hoekstra, W. J.; Maryanoff, B. E. WO, 97/41102, 1997). Herein we describe the process research that was carried out for the synthesis of elarofiban that eventually led to the development of a safe and cost-effective commercial scale process.

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An Expedient Method for Resolution of 3-Amino-3-(3‘-pyridyl)propionic Acid and Related Compounds

Cited by 14 publications

References 17 publications

A Bisphosphepine Ligand with Stereogenic Phosphorus Centers for the Practical Synthesis of β‐Aryl‐β‐Amino Acids by Asymmetric Hydrogenation

A Bisphosphepine Ligand with Stereogenic Phosphorus Centers for the Practical Synthesis of β‐Aryl‐β‐Amino Acids by Asymmetric Hydrogenation

Chiral β-Amino Acid Derivatives via Asymmetric Hydrogenation

A Practical Synthesis of the Platelet Fibrinogen Antagonist, Elarofiban

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