Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides – a key step in the synthesis of pregabalin

Abstract

Asymmetric organocatalytic 1,4-additions provide access to a large number of biologically relevant compounds. Chiral squaramides efficiently catalyse enantioselective Michael addition of 1,3-dicarbonyl compounds to aliphatic nitroalkenes. The resulting γ-nitro carboxylic derivatives were obtained in high yields and in high enantiomeric purities. Quantum chemical calculations helped us to devise a transition state model, which explains the observed stereochemical course of the addition. The best results were obtained with Meldrum's acid as a donor, with which enantiomeric purity of the Michael adduct was 97 : 3 e.r. Using this methodology pregabalin was synthesized in three steps in overall 52% yield.

N-Alkylated Sulfamic Acid Derivatives as Organocatalyst in Multicomponent Synthesis of Fatty Dihydropyrimidinones

“…The loading of 10 or 20 mol% of NSA 01-06 were investigated under the same experimental conditions (Scheme 2). The dihydropyrimidinone 1 was formed in good yields in all examined cases ( Table 1, entries [3][4][5][6][7][8][9][10][11][12][13][14]. The best catalytic behavior was observed when 20 mol% of organocatalyst NSA 04 was employed (Table 1, entry 10).…”

“…2 The main advantage is due to avoiding contamination risk by metals. 3 In addition, the organocatalysts are generally cheap, stable in atmospheric conditions, allow reproducible results and require simple reaction conditions. 4 Sulfamic acid (SA, H 2 NSO 3 H) has emerged as a substitute for conventional Bronsted and Lewis acid catalysts in organic synthesis.…”

Meldrum's Acid: A Useful Platform in Asymmetric Organocatalysis

“…The group of Šebesta developed the catalyst 12 with a cyclohexanediamine backbone and bearing a squaramide function instead of a thiourea (Scheme ) . With 10 mol % of this Brønsted base 12 , they accessed the desired product 8 a in good yield and excellent ee (94 %).…”

ChemInform Abstract: Meldrum′s Acid: A Useful Platform in Asymmetric Organocatalysis

“…The group of Šebesta developedthe catalyst 12 with acyclohexanediamine backbone and bearing as quaramide function insteado fathiourea (Scheme 7). [11] With 10 mol %o ft his Brønsted base 12,t hey accessed the desired product 8a in good yield and excellent ee (94 %). Other 1,3-dicarbonylc ompounds were evaluated in the place of Meldrum's acid 1a and these were revealed to be poor substrates in this transformation.…”