Chemoselective Reduction of the P=O Bond in the Presence of P–O and P–N Bonds in Phosphonate and Phosphinate Derivatives

Abstract

Chemoselective reduction of the strong P=O bond in the presence of weaker P–O (ester) and P–N (amide) bonds in phosphonic acid derivatives has constituted an unresolved problem in organophosphorus chemistry for years. This long‐standing problem is now solved for biologically relevant α‐hydroxy and α‐amino phosphonic as well as phosphinic acids esters and amides. The reduction of the P=O bond without concomitant scission of the ester and amide bonds is affected by use of BH3, a mild reducing agent, which affords the corresponding borane protected PIII phosphonite and phosphinite derivatives in one step. A mechanistic rationale is proposed for the role played by neighboring OH and NHR groups in facilitating the reduction, and for the observed chemo‐ and stereoselectivity. The reduction methodology described opens previously unavailable synthetic options in chemistry of α‐functionalized phosphonic and phosphinic acids by offering a unique possibility for direct modifications of oxidation level of the P‐center in these compounds.

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity

“…In this work, a series of organophosphorus compounds ( 1 – 7 ), i.e., derivatives of phosphonous acid-boranes: benzylphosphonous acid-borane diisopropyl ester ( 1 ); α-hydroxyphosphonite-boranes: 1-hydroxy-1-methylethylphosphonous acid-borane diisopropyl ester ( 2 ) and 1-hydroxy-1-methylethylphosphonous acid-borane N , N -diethylamide isopropyl ester ( 3 ); α-aminophosphonite-boranes: [1-( N - p -bromophenylamino)]-1-( p -nitrophenyl)methylphosphonous acid-borane ( 4 ), [1- N - p -hydroxyphenylamino)]-1-phenylmethylphosphonous acid-borane ( 5 ), [1-( N - p -tolylamino)]-1-phenylmethylphosphonous acid-borane ( 6 ), and [1-( N - p -bromophenylamino)]-1-( p -anisyl)methylphosphonous acid-borane ( 7 ) were synthesized with the methods described previously ( Table 1 ) [ 23 , 24 ].…”

“…OPs have been proved to be potent anti-tumor agents. This prompted us to evaluate whether the recently described new OP analogs, i.e., borane-protected phosphonousacid esters 1 – 7 [ 23 , 24 ], exert both physicochemical/pharmacokinetic properties attributed to small-molecule drugs and anti-osteosarcoma activities. The phosphonous acid-borane derivatives 1 – 7 were prepared as diisopropyl ( 1 , 2 , 4 , 5 , 6 , 7 ) or isopropyl ( 3 ) esters.…”

“…All of the tested compounds ( 1 – 7 ) were synthesized with the methods described previously [ 23 , 24 ]. The stock solutions of these compounds were prepared in DMSO, whereas their working solutions at the required concentrations were made by dilution in the appropriate culture medium.…”

“…To assess the anti-proliferative activity of compounds 1 – 7 against the HOS and Saos-2 osteosarcoma cells, 3.0 × 10 4 cells/mLseeded (low density culture) into 96-well plates (Nunc, Roskilde, Denmark) were incubated with each compound at concentrations of 3.125, 6.25, 12.5, 25, 50, 100 and 200 µM prepared in medium with 10% FBS (growth medium) for 96 h. Additionally, cisplatin (Sigma Aldrich), i.e., a common cytostatic used in osteosarcoma treatment, was included as a positive control in this study [ 23 ]. It was tested in the same conditions as compounds 1 – 7 .…”

“…Additionally, to the best of our knowledge, there are no studies on the use of NEP inhibitors, including those derived from OPs, as potential anti-osteosarcoma agents. Recently, the synthesis of new OPs compounds, which are a series of esters of borane-protected phosphonous acid, has been described [ 23 , 24 ]. To the best of our knowledge, their α-hydroxy and α-amino derivatives (α-hydroxy and α-aminophosphonite-boranes) have not been examined in terms of biological activities and medical applications.…”