The Direct Catalytic Enantioselective Synthesis of Protected Aryl β‐Hydroxy‐α‐Amino Acids

Abstract

The combination of three reagents—a tridentate pybox ligand (pybox=pyridine bis(oxazoline)), magnesium perchlorate, and Hünig base (iPr2EtN)—allows the catalytic generation of a chiral glycine enolate from 1 that undergoes highly enantioselective addition to a range of aryl aldehydes 2. The protected aryl β‐hydroxy‐α‐amino acid products obtained include a protected version of one of the aryl serine units present in the glycopeptide antibiotic vancomycin.

Addition of Azomethine Ylides to Aldehydes: Mechanistic Dichotomy of Differentially Substituted α‐Imino Esters

“…It was quickly discovered that both epimerization (Table 4, dr 18 vs. 21 ) and decomposition of substrates 18a – h occurred. Interestingly, in other reports of access to β‐aryl‐β‐hydroxy‐α‐amino esters, the deprotection of the benzophenone‐derived oxazolidine results in 50 % yield, or is not disclosed 38,39,44. In our case, we believe that protonation of the oxygen atom in 18 can lead to a retro‐aldol reaction, resulting in either epimerization to the thermodynamic product45,38 or to further breakdown to the original starting materials 9,12,46.…”

Taking Up the Cudgels for Perchlorates: Uses and Applications in Organic Reactions under Mild Conditions

“…This is the case in the direct synthesis of protected β-hydroxy α-amino acids starting from the oxazolidinone 51 as a glycine equivalent, proposed by Willis (Scheme 24). [60] The bipyridine employed in the achiral version [42] was exchanged with an appropriate enantiopure bidentate ligand, and the best results were obtained with the pyridine bis(oxazoline) (pybox) 52 and Mg(ClO 4 ) 2 . The presence of iPr 2 EtN as the base efficiently generates a chiral glycine enolate of 51, which undergoes enantioselective addition to a range of aryl aldehydes to provide protected aryl β-hydroxy-α-amino acids 53 in good yields and with high enantioselectivities.…”

Preparation of Enantiomerically Pure β,β‐Diaryl β‐Hydroxy‐α‐Amino Acids and Evaluation of Their Potential as Organocatalysts

“…[12][13][14][15][16][17] For these reasons, many synthetic methods have been developed for enantiomerically pure β-hydroxy-α-amino acids over the years. There are many reported enantio-and diastereoselective syntheses of β-monosubstituted β-hydroxyα-amino acids (Type i, Figure 1); the aldol reaction of α-amino carbonyls and aldehydes utilizing chiral auxiliaries [18][19][20] or chiral catalysts [21][22][23][24] and the Sharpless asymmetric aminohydroxylation of α,β-unsaturated esters [25,26] are reliable because these methods can control all the possible stereochemical patterns of these β-hydroxy-α-amino acids. Aldol reaction with a chiral auxiliary, such as pseudoephenamine glycinamide developed by Myers, can be further extended for β,β-dialkyl-substituted βhydroxy-α-amino acids (Type ii, Table 1).…”