Homologation of α-aryl amino acids through quinone-catalyzed decarboxylation/Mukaiyama–Mannich addition

Abstract

A new method for amino acid homologation by way of formal C–C bond functionalization is reported. This method utilizes a 2-step/1-pot protocol to convert α-amino acids to their corresponding N-protected β-amino esters through quinone-catalyzed oxidative decarboxylation/in situ Mukaiyama–Mannich addition. The scope and limitations of this chemistry are presented. This methodology provides an alternative to the classical Arndt–Eistert homologation for accessing β-amino acid derivatives. The resulting N-protected amine products can be easily deprotected to afford the corresponding free amines.

Quinone-catalyzed oxidative deformylation: synthesis of imines from amino alcohols

“…With this plan in mind, we first explored the ability of several quinone catalysts to promote the deformylation of 2-phenylglycinol ( 1a ) to deliver N -PMP imine 7a ( Table 1 ). We selected quinone catalysts ( 2a − c ) that have previously been utilized in amine oxidation reactions [ 21 , 32 , 40 – 41 ], and began with reaction conditions similar to those developed for our quinone-catalyzed oxidative decarboxylation chemistry [ 32 ]. To our delight, the desired deformylation product 7a was formed in 63% yield when catalyst 2a was employed ( Table 1 , entry 1).…”

“…To demonstrate the synthetic utility of this methodology, we performed a sequential oxidative deformylation/Mukaiyama−Mannich addition under our previously reported conditions for decarboxylative amino acid homologation ( Scheme 4 ) [ 32 ]. In this reaction sequence, (thio)silyl ketene acetal 10 was united with 2-phenylglycinol and para -anisidine in a two-step, one-pot process to provide β-amino acid derivative 11 in a 60% yield.…”

“…The majority of these methods involve cleavage of a C−H bond at the α-position of an amine substrate [ 7 – 28 ]. Methods that deliver imines through amine α-C−C bond cleavage are far less common [ 29 – 32 ] despite the fact that these methods employ renewable resources, such as amino acids and their derivatives, as starting materials. In fact, only a few reports describing the oxidative deformylation of amino alcohols have been published [ 33 – 35 ], and in all of these reports stoichiometric oxidants, such as NaIO 4 and Pb(OAc) 4 , must be employed to enable the desired transformations.…”

“…Our group has recently reported the quinone-catalyzed decarboxylative homologation of α-amino acids [ 32 ], which demonstrated for the first time that quinone organocatalysts can be utilized to enable oxidative C–C bond cleavage to provide versatile imine intermediates. To further exploit the utility of this chemistry, we sought to develop a new method for the preparation of a wide range of imine products through the quinone-catalyzed deformylation of 1,2-amino alcohols.…”

Self-Assembly of Partially Alkylated Dextran-graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties

“…The stabilized nanoparticles were found to be effective for incorporation of drug molecules . Most of the reported amphiphilic hydrogels or amphiphilic conetworks (APCN) for hydrophobic drug delivery systems have been prepared in organic solvent and were not directly injectable. − Entrapment of drug-loaded micelles in an injectable hydrogel matrix was reported for controlled delivery . Thus, a novel strategy is required to incorporate hydrophobic drug, and to control the release behavior, degradation behavior, mechanical property, and degree of water swelling of a hydrogel without affecting the injectability criteria and without incorporation of any drug-loaded micelles.…”