Mechanochemical enzymatic synthesis of 1,4‐dihydropyridine calcium antagonists and derivatives

Abstract

BACKGROUND: Enzyme promiscuity has attracted significant attention from chemists and biochemists in recent years. However, long reaction time and use of toxic organic solvents limit its applications for industrial processes. 1,4-Dihydropyridine (1,4-DHP) calcium antagonists are recommended for the first line treatment of hypertension. Although some chemical protocols for the preparation of 1,4-DHP calcium antagonists have been developed, enzymatic synthesis of these compounds still remains uncovered. RESULTS: Solvent-free quick synthesis of 1,4-DHP calcium antagonists felodipine, nitrendipine, nifedipine and nemadipine B and their derivatives was achieved by Lipozyme ® RM IM (triacylglycerol acylhydrolase, EC3.1.1.3)-catalyzed multicomponent reactions of aromatic aldehyde, alkyl acetoacetate and alkyl 3-aminocrotonate under ball-milling conditions. The products were obtained in moderate yields (up to 86.8%) and the influence of reaction conditions including catalyst loading, grinding auxiliary and grinding frequency was investigated. CONCLUSION: The protocol successfully overcame some longstanding problems in the field of enzymatic promiscuity research, such as long reaction time and use of harmful organic solvents, and demonstrated the potential application value of promiscuous enzyme-catalyzed reactions under ball-milling conditions for pharmaceutical synthesis.

Mechano-Biocatalytic Rapid Synthesis of 2-Amino-3-cyano-4H-pyran Derivatives

“…After optimization of the reaction conditions (see Electronic Supplementary Information S3-5), it was found that all reactions proceeded smoothly to furnish the target compounds in good yields (Table 4, entries 1-18). The results demonstrated that substituted benzaldehydes carrying either electron-withdrawing or electron-donating substituents reacted successfully to give the corresponding 2-amino-3-cyano-4H-pyrans (Table 4, entries [2][3][4][5][6][7][8][9][10][11][12][13][14]. The results also indicated that the substituent in the para-position led to a higher yield than the same substituent in the ortho-or meta-position (Table 4, entry 6 vs entries 4-5; entry 9 vs entries 7-8; entry 12 vs entries 10-11).…”

“…12 In 2020, the Liao group described a mechano-biocatalytic one-pot approach to release sugars from lignocellulosic materials. 13 In continuation of our work on the mechano-biocatalytic reactions, 14 herein, we report a novel mechano-biocatalytic one-pot method for the rapid synthesis of 2-amino-3-cyano-4H-pyran derivatives using bovine serum albumin (BSA) as the catalyst under ball-milling conditions (Scheme 1).…”

Lipase-Mediated Mechanoenzymatic Synthesis of Sugar Esters in Dissolved Unconventional and Neat Reaction Systems

“…Higher enzyme loading resulted in a significant decrease in glycolipid concentration, which is also reported for other transesterification reactions. 43 , 68 − 70 On the one hand, this observation might be due to product hydrolysis by the excess enzyme and the water formed as a by-product. 43 , 44 On the other hand, a high enzyme excess could affect mass transfer, as a higher enzyme concentration correlates to a higher observed viscosity of the reaction mixture.…”

L-Cysteine Catalyzed One-Pot Synthesis of Bicyclic δ-Lactones under Ball-Milling Conditions

“…20 In 2019, Jiang et al developed a mechanochemical enzymatic method for the synthesis of 1,4-dihydropyridine calcium antagonists. 21 Very recently, we reported a novel mechano-biocatalytic method for the rapid synthesis of 2-amino-3-cyano-4H-pyrans. 22 Herein, as part of our ongoing study on the mechanochemical reactions, we report a novel and eco-friendly protocol for the rapid synthesis of bicyclic -lactones using L-cysteine as the catalyst under ball-milling conditions (Scheme 1).…”