Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Abstract

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…The authors eventually provided an enantioselective version of their work by using pseudoephedrine as a chiral auxiliary. 445 A similar asymmetric α-arylation of urea derivatives of amino acids was besides brought by Tomohara et al, who obtained the chiral hydantoins via a memory of chirality strategy in 55−98% ee, by generation of axially chiral enolates of the urea derivatives. 446 The development by Gore et al of a low-melting mixture of (+)-tartaric acid and N,N′-dimethylurea (DMU) as a solvent, a catalyst, and a reactant offered environmentally friendly conditions to the diastereoselective formation of 1,3,5trisubstituted hydantoins from β,γ-unsaturated ketocarboxylic acids (Scheme 84).…”

“…Usually, the hydantoins are prepared from the corresponding ketone following the Bucherer−Bergs conditions and are then hydrolyzed chemically or enzymatically. This approach is generally used to prepare quaternary 444,445 and constrained amino acids, 197,330,333,472−476 such as spiro structures, 477−480 which can then find applications as potent bioactive compounds, 481−486 as peptidomimetics for peptide modification, 29,332,487−490 or as intermediates in the synthesis of natural products. 491 In this section, we will present the different methods to prepare amino acids from hydantoins (Scheme 94).…”

Enantioselective Intramolecular α‐Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

“…Alternative substituents ( 8 g , h , i) were tolerated on the nitrogen atom remote from the reactive centre. A trisubstituted urea 8 j carrying an “unprotected” nitrogen atom was also remarkably successful, provided the substrate was silylated in situ [20] . Deprotonating an unsubstituted benzyl group led to slightly less enantioselective arylation with a range of migrating groups, giving 8 k – 8 o .…”

Axially chiral hemiaminals from nonracemic α‐amino acid derivatives (thiohydantoins): Synthesis and isomer identification

“…Based on our experience on this topic, we presumed that thiohydantoins (2‐thioxo‐imidazolidin‐4‐ones) whose asymmetric synthesis has been shown recently 12 could be reduced to reach to stable nonracemic, axially chiral hemiaminals. Other hydantoin derivatives were recently exploited as scaffolds to obtain various α‐amino acid derivatives 13 . The present paper reports the stereoselective syntheses of structurally interesting axially chiral hemiaminals from the corresponding thiohydantoins whose isomer ratios are summarized in Table 1.…”