Enantioselective Addition of Bromonitromethane to Aliphatic N-Boc Aldimines Using a Homogeneous Bifunctional Chiral Organocatalyst

Abstract

This report details the enantioselective synthesis of β-amino-α-bromo nitroalkanes with β-alkyl substituents, using homogeneous catalysis to prepare either antipode. Use of a bifunctional Brønsted base/acid catalyst allows equal access to either enantiomer of the products, enabling the use of Umpolung Amide Synthesis (UmAS) to prepare the corresponding L- or D-α-amino amide bearing alkyl side chains – overall, in only 4 steps from aldehyde. The approach also addresses an underlying incompatibility between bromonitromethane and solid hydroxide bases.

Rational Design of an Organocatalyst for Peptide Bond Formation

“…Exciting approaches to obtain a native peptide bond from nonstandard reaction partners and reaction pathways offer intriguing alternatives to carboxylic acids and esters. For example, the Staudinger ligation utilizes an amino acid phosphine and azido amino acid derivative to afford a native amide bond. , Tangible success has also been obtained with nonclassical approaches, which include the activation of reducible aldehydes with nucleophilic carbenes, , umpolung amide synthesis that employs the oxidative coupling of bromonitroalkanes with amines, − and α-ketoacidhydroxylamine condensation. , …”

1,3,4-Oxadiazole and Heteroaromatic-Fused 1,2,4-Triazole Synthesis­ Using Diverted Umpolung Amide Synthesis

“…The value of this approach was further highlighted by the use of chiral nonracemic α-bromo nitroalkane donors 20,21 to prepare triazole derivatives (Table 3). The first case was met with minimal success, as pyridyltriazole 12 was formed in approximately 24% yield.…”

Enantioselective Synthesis of β-Fluoro Amines via β-Amino α-Fluoro Nitroalkanes and a Traceless Activating Group Strategy

“…Under the standard conditions, α-fluoro phenyl nitromethane engaged the imine to produce the product in moderate yield (53%, two steps from the α-amido sulfone) at 0 °C and serviceable stereoselection (6.1:1 dr, 84% ee) (Table , entry 8). Gratifyingly, improved stereocontrol and yield were obtained at −20 °C (9:1 dr, 93% ee, 70% yield over 2 steps: Table , entry 9) as a result of decreased imine tautomerization . Alkyl fluoronitroalkanes can be easily prepared (2 steps from various alkyl bromides) and are also suitable here for the first time in enantioselective catalysis, in direct contrast to previously reported attempts (Table , entries 10–12).…”

“…Gratifyingly, improved stereocontrol and yield were obtained at −20 °C (9:1 dr, 93% ee, 70% yield over 2 steps: Table 2, entry 9) as a result of decreased imine tautomerization. 24 Alkyl fluoronitroalkanes can be easily prepared (2 steps from various alkyl bromides) 19 and are also suitable here for the first time in enantioselective catalysis, in direct contrast to previously reported attempts 15 (Table 2, entries 10–12). Notably, the alkyl fluoronitroalkanes react only at warmer temperatures (24 °C), allowing for an even more simplified reaction setup.…”