Quinine-Derived Thiourea and Squaramide Catalyzed Conjugate Addition of α-Nitrophosphonates to Enones: Asymmetric Synthesis of Quaternary α-Aminophosphonates

Abstract

Conjugate addition of α-nitrophosphonates to enones was carried out in the presence of two sets of organocatalysts, viz. a quinine-thiourea and a quinine-squaramide. The quinine-thiourea provided the products possessing an α-quaternary chiral center in high enantioselectivities only in the case of electron rich enones. On the other hand, the quinine-squaramide was more efficient in that a wide variety of electron rich and electron poor enones underwent Michael addition of nitrophosphonates to afford the quaternary α-nitrophosphonates in excellent yields and enantioselectivities. The hydrogen bonding donor ability of the bifunctional catalyst, as shown in the proposed transition states, appears primarily responsible for the observed selectivity. However, a favorable π-stacking between the aryl groups of thiourea/squaramide and aryl vinyl ketone also appeared favorable. The reaction was amenable to scale up, and the enantioenriched quaternary α-nitrophosphonates could be easily transformed to synthetically and biologically useful quaternary α-aminophosphonates and other multifunctional molecules.

C3-Symmetric cinchonine-squaramide as a recyclable efficient organocatalyst for tandem Michael addition–cyclisation of malononitrile and nitrovinylphenols

“…While, when 2-(E)-2-nitrovinylphenol was used as substrate, product 4a was formed with 98% ee (entry 1). It is noteworthy that when the substitution occurred at the 5 position of the phenyl ring, the corresponding products were obtained with modest ee values (entries [8][9][10][11]. When (E)-3-(2-nitrovinyl)naphthalene-2-ol 2g was used in this reaction, 4g was obtained with modest enantioselectivity (72% ee) (entry 7).…”

“…A series of enantiomerically pure compounds, such as indoles, tetrahydroxanthones, chromenes, quinazoline, naphthoquinones and substituted amino acid derivatives, which are widely distributed in pharmaceutical compounds and complex natural products, have been synthesized in recent years. [8][9][10][11][12] We have developed a series of novel chiral squaramide organocatalysts; the C 3 -symmetric cinchonine-squaramide (CSCS) catalyst was one of the most useful organocatalysts, which showed remarkable behavior in asymmetric Michael additions, Friedel-Crafts reactions and asymmetric halolactonisations as well. [13][14][15] On the other hand, 2-amino-4H-chromene derivatives showed anticancer, antimitotic microtubule and anti-Alzheimer's disease activity.…”

Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds

“…[39] Then in 2015, Namboothiri and coworkers demonstrated the squaramide C2-catalyzed conjugate addition of a-nitrophosphonates to enones, providing a-aminophosphonates in high yield and enantioselectivity. [40] This methodology was also expanded to synthesize dehydrophos derivatives, which exhibited antibacterial, antifungal, antiviral, antitumor, and anti-HIV activities, etc. (Scheme 23).…”

“…In 2014, Wang developed the asymmetric synthesis of chiral β‐amino‐substituted α‐amino phosphonic acid derivatives by 1,2‐addition of α‐isothiocyanato phosphonates using squaramide C2 39. Then in 2015, Namboothiri and coworkers demonstrated the squaramide C2 ‐catalyzed conjugate addition of α‐nitrophosphonates to enones, providing α‐aminophosphonates in high yield and enantioselectivity 40. This methodology was also expanded to synthesize dehydrophos derivatives, which exhibited antibacterial, antifungal, antiviral, antitumor, and anti‐HIV activities, etc.…”

Enantioselective Synthesis of α-Quaternary Amino Acids by Alkylation of Deprotonated α-Aminonitriles

“…6,7 Consequently, a variety of synthetic methods has been developed for their synthesis, both in racemic or non-racemic form. [8][9][10][11][12][13][14][15][16][17][18] The pioneering chemical synthesis of α-amino acids reported by Adolph Strecker in 1850 made use of their close relationship with α-aminonitriles and even today, the Strecker synthesis is still used for the industrial scale synthesis of α-amino acids like methionine. 19 Due to the strong anion stabilizing capacity of the nitrile group and the latent iminium ion reactivity, [20][21][22][23] α-aminonitriles are not only useful precursors to amino acids but also versatile building blocks for the synthesis of a wide variety of nitrogen-containing compounds 24, 25 including diverse N-heteroarenes, [26][27][28] aliphatic amine derivatives 29,30 or alkaloids [31][32][33][34][35][36][37][38][39] .…”