Promiscuous Lipase-Catalyzed Markovnikov Addition of H-Phosphites to Vinyl Esters for the Synthesis of Cytotoxic α-Acyloxy Phosphonate Derivatives

Abstract

An enzymatic route for phosphorous-carbon- bond formation is developed by discovering new promiscuous activity of lipase. This biocatalytic transformation of phosphorous-carbon- bond addition leads to biologically and pharmacologically relevant α-acyloxy phosphonates with methyl group in α-position. A series of target compounds were synthesized with yields ranging from 54% to 83% by enzymatic reaction with Candida cylindracea (CcL) lipase via Markovnikov addition of H-phosphites to vinyl esters. We carefully analyzed the best conditions for the given reaction such as the type of enzyme, temperature, and type of solvent. The developed protocol is applicable to a range of H-phosphites and vinyl esters significantly simplifying the preparation of synthetically challenging α-pivaloyloxy phosphonates. Further, the obtained compounds were validated as new potential antimicrobial drugs with characteristic E. coli bacterial strains and DNA modification recognized by the Fpg protein, N-methyl purine glycosylases as new substrates. The impact of the methyl group located in the α-position of the studied α-acyloxy phosphonates on the antimicrobial activity was demonstrated. The pivotal role of this group on inhibitory activity against selected pathogenic E. coli strains was revealed. The observed results are especially important in the case of the increasing resistance of bacteria to various drugs and antibiotics.

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik−Fields Reaction

“…The Kabachnik–Fields reaction is the most efficient method for the formation of carbon−phosphorus bonds using an aldehyde, amine, and H -phosphite. A number of other synthetic approaches have also been reported for the preparation of α-aminophosphonates [ 7 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. These methods are generally conducted in the presence of various organic and inorganic bases [ 56 , 57 , ...…”

“…As a continuation of our research on seeking new catalytic activities of hydrolases [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 94 , 95 ], we focused our efforts on elaborating a sustainable metal-free method towards desired α-aminophosphonates 1 – 16 ( Figure 2 ).…”

“…All microorganisms and media were accurately described in detail in the previous work [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] and analyzed by a Tukey test.…”

“…All the chemicals were described in detail in the previous work [ 74 ]. All specific strains, such as Pseudomonas cepacia (PcL) and wheat germ, were provided by Sigma-Aldrich (Merck).…”

Promiscuous Lipase-Catalyzed Knoevenagel–Phospha–Michael Reaction for the Synthesis of Antimicrobial β-Phosphono Malonates

“…An increasing number of reports on lipase-catalyzed, unconventional reactions have directed attention towards lipase promiscuity [ 34 , 35 , 36 , 37 , 38 ]. As a continuation of our research on seeking new catalytic activities for hydrolases [ 39 , 40 , 41 , 42 , 43 ], we focused our efforts to elaborate sustainable metal-free methods towards desired β-phosphonomalononitriles and β-phosphononitriles ( Figure 2 and Figure 3 ). Therefore, the possibility of using the biocatalytic approach in the synthesis of target β-phosphonates should be considered.…”