Enantioselective Organocatalytic Michael Addition of Aldehydes to Nitroethylene: Efficient Access to γ²-Amino Acids

Abstract

The development of asymmetric conjugate addition reactions for C-C bond formation remains an important challenge in organic synthesis. 1,2 Much recent work has focused on organocatalytic Michael addition of carbonyl compounds to nitroalkenes. [3][4][5] Among these reactions, Michael addition of aldehydes to nitroalkenes is of particular interest because of the valuable synthetic intermediates that are generated. 4 β-Aryl nitroalkenes have been the most common Michael acceptors for reactions developed by other research groups. [3][4][5] These Michael reactions provide α,β-disubstituted-γ-nitrobutanals. Our attention was drawn to nitroethylene as a Michael acceptor because the adducts would bear a single substituent adjacent to the carbonyl and could be readily converted to γ 2 -amino acids. γ 2 -Amino acids represent potential building blocks for γ-peptide 6 and heterogeneous backbone foldamers. 7 In addition, derivatives of the neurotransmitter γ-amino butyric acid (GABA) 8 are of potential biomedical utility, as illustrated by the use of Pregabalin and Baclofen to treat neurological disorders. 9 The preparation of enantiomerically pure γ-amino acids is challenging, and this synthetic burden has limited the study of γ-peptide foldamers to date. A variety of routes to enantioenriched γ 2 -amino acids have been described, 10 but these approaches often involve specialized chiral auxiliaries and may not be ideal for preparing multigram quantities of protected γ 2 -amino acids bearing diverse side chain functionality, which is necessary for foldamer research. 6,7 Here we report an asymmetric organocatalytic method for aminoethylation of aldehydes, which leads to a new and efficient synthesis of γ 2 -amino acids (Scheme 1). Our approach pairs a chiral pyrrolidine catalyst with a carefully chosen acidic co-catalyst to promote Michael addition of aldehydes to nitroethylene with high enantioselectivity.We initially evaluated two widely used chiral pyrrolidines, L-proline and (S)-diphenylprolinol silyl ether (A), 11 for the ability to promote the Michael reaction between npentanal and nitroethylene (2:1 molar ratio). We assumed that such reactions would proceed via enamine intermediates. L-Proline (20 mol %) provided very little of the Michael adduct; instead the major product in a variety of solvents resulted from aldol condensation of npentanal, a process that is known to be catalyzed by proline. 12 In contrast, when 20 mol % of A was employed in toluene, the desired Michael adduct was generated in 95% yield with >95% ee, and little or no aldol product was formed. Previous work has shown that carefully chosen acidic co-catalysts can enhance pyrrolidineor imidazolidinone-catalyzed Michael addition of aldehydes to enones, 13 and we therefore examined co-catalyst effects 14 on the Michael addition of n-pentanal to nitroethylene. When 5 mol % of A was employed as catalyst, without any co-catalyst, <10% Michael adduct was generated after 1 h, and little further adduct was generated after 24 h (Table 1). However, use of 5 ...

Highly Enantioselective Conjugate Additions of Aldehydes to Vinyl Sulfones

“…[4,5] The behaviour of these catalysts is significant, but the method holds important limitations with regards to substrate scope and enantioselectivity: a large excess (10 equivalents) of the aldehyde is usually required and modest selectivities (typically 70 % ee) are obtained. On the other hand, while the direct catalytic and asymmetric 1,4-addition of aldehydes to certain electron-deficient olefins, [6,7] most particularly nitroolefins, [7,8] have met success recently, one accompanying problem to the reaction with vinyl sulfone acceptors is the retroaddition, which causes formation of undesired dimeric side products. [3] Herein we report the use of less basic chiral amine catalysts (see Figure 1) to provide a solution to these problems thus considerably expanding the utility of vinyl sulfones in organic synthesis.…”

Enantioselective addition of aryl ketones and acetone to nitroalkenes organocatalyzed by carbamate-monoprotected cyclohexa-1,2-diamines

“…8g; 19 Thus, the addition of benzoic acid (20 mol%) resulted in a slight improvement of yield and enantioselectivity compared to when no additive was used (Table 1, compare entries 5 and 12). This positive result prompted us to explore if a modulation of the pKa of the additive by changing the substituent in the aromatic ring could be beneficial.…”

Conformational choices for the stereochemically constrained γ‐amino acid residue gabapentin: Theoretical studies and correlation with experimental results

“…Synthetic routes to multiply substituted chiral b and c amino acids have been developed. 12 For purposes of exploring conformational space it is advantageous to employ readily available achiral, substituted b and c residues. The use of symmetrical, geminal disubstitution is a device that has proved extremely successful in the generation of well defined, folded peptides in a amino acid sequences.…”