Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts

Abstract

The large-scale applications of the kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asymmetric reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids 6 and chiral half-esters 2 on an industrial scale, because the organocatalyst recovery and product purification can be carried out by a simple extractive procedure obviating a chromatographic purification step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng and co-workers, are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivatives were prepared and screened as catalysts for the kinetic resolution of phenylalanine UNCA with alcohol. The readily prepared O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of chiral propargylglycine 24 and the key intermediate of BAY10-8888/PLD-118, 26, on an industrial scale, by the kinetic resolution of UNCA 22 and the desymmetrization of cyclic meso-anhydride 25, respectively.

Mono‐ and bis‐quinidine organocatalysts in the asymmetric methanolysis of cis‐1,2,3,6‐tetrahydrophthalic anhydride: A conformational and mechanistic NMR study

“…Therefore, it may be estimated that if any complex is formed between the reaction partners and alkaloid derivatives (e.g., of the kind depicted in the Deng's study) 22 the corresponding equilibrium constant should be lower than about 1-10 mM 21 . 57 Nonetheless, the observation of large shifts of the resonances of 4, 13, and 14 only in the presence of an excess of MeOH-d 4 (100 equiv.…”

“…18 In particular, by using the phenanthrene and anthraquinone 9-O ether derivatives 3 and 4, an effective protocol could be disclosed whose landmarks are wide substrate scope, mild reaction conditions, relatively short reaction times and, especially, the possibility of using just a limited amount (10 mol %) of the expensive alkaloid derivative in the absence of any added achiral base. Since then several improvements followed, including the use of different alcohol nucleophiles, [19][20][21] modified alkaloid organocatalysts (either monofunctional [20][21][22] or bifunctional), 23,24 recoverable variants, [25][26][27][28] and additives. 29 Nonetheless, most of these efforts appear largely empirically-driven because the lack of a detailed mechanistic understanding of the reaction prevents a rational approach to the design of improved catalytic systems.…”

Mimicking Nature to Make Unnatural Amino Acids and Chiral Diamines

“…This kinetic resolution method has been scaled up to 100 kg levels by DAISO for the production of l-propargyl glycine in 39 % yield out of a possible maximum of 50 % yield. [30] It would be difficult to synthesize this amino acid by hydrogenation. Our own interest in stereoselective ring opening of meso anhydrides led to the development of bifunctional catalysts (8) based on cinchona alkaloids.…”

“…In addition, kinetic resolution may be coupled with recycling of the unwanted enantiomer by multiple rounds of racemization and kinetic resolution. [30] Desymmetrization of meso anhydrides [36] and kinetic resolution of azalactones [37] were first reported by Seebach using a chiral Ti IV complex as a catalyst. Phase transfer catalysts have been developed by O'Donnell, [38] Corey, [39] Maruoka (12) [40] and others [41] for stereoselective alkylation of imino esters (Scheme 6d).…”

Effecient Kinetic Resolution of Racemic Amino Aldehydes by Oxidation with N‐Iodosuccinimide

“…[3] Among the asymmetric catalytic methods for the synthesis of natural and non-natural amino acids, [4][5][6] the kinetic resolution of amino acid derivatives is frequently used. [7] However, there are few examples applicable to the synthesis of various optically active amino acids, including cyclic amino acids, and to the best of our knowledge, there is no chemical oxidation method for their preparation. We report herein the first efficient kinetic resolution of racemic amino aldehydes by oxidation.…”