Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

Abstract

For almost 40 years, difluoromethylene phosphonates have proven to be versatile molecular tools in biochemical studies owing to their close resemblance to naturally occurring phosphates and phosphonates. As bioisosteric, non‐hydrolyzable analogs of these essential molecules, difluoromethylene phosphonates can target the critical parts of the cellular machinery and therefore exhibit a diverse spectrum of biological activity. In the past ten years, there have appeared many new methods for the synthesis of difluoromethylene phosphonates. Most notably, photoredox catalysis has firmly entered the field, while cross‐coupling and nucleophilic strategies have met considerable elaboration and refinement, entirely in accord with the current trends in synthetic organic chemistry. Herein, we introduce difluoromethylene phosphonates as a distinct, high‐tech subclass of synthetic phosphonates resulting from the research efforts on the cross‐section of organophosphorus, organofluorine, and bioorganic chemistry. We then proceed to the discussion of general methods for the preparation of difluoromethylene phosphonates, comprehensively reviewing reactions developed in the past 15 years while providing the context of earlier works where appropriate. Finally, we present selected examples of molecules with high biological activity, their biological targets, and the synthetic steps employed for their preparation.

Cooperative Palladium/Isothiourea Catalyzed Enantioselective Formal (3+2) Cycloaddition of Vinylcyclopropanes and α,β‐Unsaturated Esters

“…Using a CF 2 H substituent gave 10 in similar yield and dr, but with slightly reduced enantioselectivity (90 : 10 er). The medicinally relevant difluorophosphonate group CF 2 P(O)(OEt) 2 [31] was also tolerated, although derivatization with MeOH and purification proved difficult, giving 11 in moderate yield, >95 : 5 dr but reduced enantioselectivity (81 : 19 er). The incorporation of other electron‐withdrawing β‐substituents was also tolerated, with ethyl and tert ‐butyl ester derivatives 12 and 13 isolated with excellent diastereo‐ and enantioselectivity (≥91 : 9 dr, up to 95 : 5 er).…”

Multigram Synthesis of Difluoromethylene Phosphonic and Phosphinic Amides and Phosphine Oxides via Formal [2,3]-Sigmatropic Allyl Phosphite–Allylphosphonate Rearrangement

“…A more detailed discussion can be found in our group’s recent review on the synthesis of DFMPs for biological applications. 14…”

Synthesis, characterized, QSAR studies and molecular docking of some phosphonates as COVID-19 inhibitors

“…Research based on chemistry and biology greatly contributes to the production of bio-inhibitors. According to the electronic and structural properties of phosphonates such as the phosphorus-carbon stable covalent bond and their high potential in biology, Phosphonate chemistry can be introduced as a suitable candidate for the production of biomaterials [ [1] , [2] , [3] ]. Phosphonates have a wide range of application in radiopharmaceuticals [ 4 ], enzyme inactivators [ 5 ], HIV protease inhibitor [ 6 ], cardiovascular drugs [ 7 ], anti-parasitic drugs [ 8 ], and antiviral drug [ 9 ].…”