Short malonyl dehydro peptides as potential scaffolds for peptidomimetics by an efficient Knoevenagel reaction

Abstract

Non-symmetric disubstituted malonamides rAA-mGly-AA', obtained from Meldrum's acid, were considered as methylene active compounds and a Knoevenagel condensation methodology was developed involving piperidine and activated 4 A molecular sieves as catalysts. The reaction is efficient, broad in scope, and easy to perform and allows access to E/Z mixtures of short malonyl dehydro peptides (MDHPs) rAA-m Delta(2)AA''-AA', partially modified retro peptides characterized by an interesting combination of retro and dehydro modifications in the same structure.

One‐Pot Two‐Step Microwave‐Assisted Synthesis of Alkylidene Acetoacetamido Esters, Useful Intermediates for β‐Dehydropeptides

“…a first challenge, the preparation of amino-acid-derived -keto amides 1 (Figure 1). Similar compounds containing malonate have been reported by Fioravanti et al [5] as potential scaffolds for the preparation of peptidomimetics and malonyl dehydropeptides (MDHP). This method for the synthesis of alkylidene acetoacetamides represents a versatile procedure to obtain key precursors of biologically relevant molecules.…”

“…In particular, we decided to synthesize amino‐acid‐derived unsaturated acetoacetamides 2 by a two‐step protocol involving, as a first challenge, the preparation of amino‐acid‐derived β‐keto amides 1 (Figure ). Similar compounds containing malonate have been reported by Fioravanti et al as potential scaffolds for the preparation of peptidomimetics and malonyl dehydropeptides (MDHP).…”

2.14 Other Condensation Reactions (Knoevenagel, Perkin, Darzens)

“…Asymmetrically disubstituted malonamide (rAA-mGly-AA 0 , 127), obtained from Meldrum 0 s acid, was considered as methylene-active compound. 80 Short malonyl dehydro peptide (rAA-mD 2 AA 00 -AA 0 , 128) can be obtained efficiently. One example is shown in Scheme 38.…”

“…aryl-2-(perfluoroalkanesulfonyl)propenoates 81 were prepared by the Knoevenagel condensation of various aldehydes with ethyl (trifluoromethanesulfonyl)acetate(80) or ethyl (nonafluorobutanesulfonyl)acetate in the presence of piperidine (Scheme 24) 67. The compound 80 was prepared by the reaction of sodium triflate (82) with ethyl bromoacetate (83) (Scheme 25).…”

Synthesis of New (E)-2-(1H-Indole-3-ylcarbonyl)-3-heteroaryl-acrylonitriles via Microwave-Assisted Knoevenagel Condensation

“…Knoevenagel condensation reaction has been widely used for the formation of new olefinic scaffolds [1]. Since the first report of Knoevenagel [2], methylene active compound has been one of the most useful synthetic methods to prepare , -unsaturated systems [3][4][5][6] like alkenes with structural diversity and 3-aryl-2-heteroaryl-acrylonitriles [7][8][9][10][11][12].…”