A Facile Cu(I)/TF-BiphamPhos-Catalyzed Asymmetric Approach to Unnatural α-Amino Acid Derivatives Containinggem-Bisphosphonates

Abstract

A novel catalytic asymmetric Michael addition of azomethine ylide with β-substituted alkylidene bisphosphates was realized in the presence of a chiral copper(I)/TF-BiphamPhos complex. The present system provides a unique and facile access to enantioenriched unnatural α-amino acid derivatives containing gem-bisphosphonates (gem-BPs) in high yields with excellent diastereoselectivities and enantioselectivities. Subsequent transformations lead to the expedient preparation of biologically active unnatural α-amino acid derivatives containing BPs and bisphosphonic acids without loss of diastereo- and enantiomeric excess.

Synergistic Cu/Pd Catalysis for Enantioselective Allylic Alkylation of Aldimine Esters: Access to α,α‐Disubstituted α‐Amino Acids

“…Despite considerable progress, the construction of α,α‐disubstituted α‐AAs through AAA reactions with high enantioselectivity is still underdeveloped. Inspired by the fact that metallated azomethine ylides were not only the dipoles in cycloadditions, but also viable nucleophiles in Michael additions, as reported by our group, we envisioned that a synergistic Cu/Pd catalyst system would be an ideal solution to overcome these problems. As shown in Scheme c, we reasoned that intercepting the reactive achiral allylpalladium intermediate B with the in‐situ‐formed α‐substituted metallated azomethine ylide A , activated by a chiral copper(I) complex, could result in a linearly selective allylic alkylation process which permits control of the configuration of the generated α‐quaternary stereogenic center.…”

Asymmetric synthesis of $\boldsymbol{\gamma}$ -aminophosphonates: The bio-isosteric analogs of $\boldsymbol{\gamma}$ -aminobutyric acid

“…Recently, Wang group reported a highly diastereoand enantioselective synthesis of γ -amino-gembisphosphonates 215 (scheme 50). 91 The reaction was efficiently catalysed by (S)-TF-BiphamPhos C8-CuBF 4 complex affording Michael adduct 215 in good yields, diastero-and enantioselectivities. These reaction conditions are tolerant to several functional groups and they provided a broad spectrum of substrate scope.…”

Silver-catalyzed asymmetric Michael addition of azomethine ylide to arylidene diphosphonates using ThioClickFerrophos ligand

“…2 Wang and coworkers recently reported the highly enantioselective Michael addition of glycine imino esters to a,b-unsaturated diphosphonates (arylidene diphosphonates) using a chiral copper/TFBiphamPhos catalyst, which is an efficient route to optically active a-amino acid derivatives containing geminal bisphosphonates. 3 Optically active phosphonic acids and phosphonates are interesting compounds because they have potential biological activities as antibacterial agents, as enzyme inhibitors, or as intermediates in biosynthetic processes. 4 Geminal bisphosphonates are a particularly important class of bioactive compounds used for the prevention and treatment of several bone diseases.…”

“…The absolute and relative configuration of 3a was determined as (2S,3R) by conversion to the corresponding amine 4a by acid hydrolysis, and comparing its optical rotation and HPLC retention time with those of reported compounds (see Supporting information). 3 temperature, and the results are summarized in Table 1. When Cs 2 CO 3 was added to the reaction mixture, the combined product yield (86%) and selectivity for the syn isomer (87/13, syn/anti) of 3a increased while retaining a high enantioselectivity (99%, syn) (entry 2).…”

“…The syn-to-anti ratio was determined by 1 H NMR integration of the CHN proton by reference to the literature. 3 The enantiomeric excess of the syn isomer was 98%, as determined by chiral HPLC (Table 1, entry 1). The absolute and relative configuration of 3a was determined as (2S,3R) by conversion to the corresponding amine 4a by acid hydrolysis, and comparing its optical rotation and HPLC retention time with those of reported compounds (see Supporting information).…”