Diastereoselective Synthesis of γ-Amino-δ-hydroxy-α,α-difluorophosphonates: A Vehicle for Structure−activity Relationship Studies on SMA-7, a Potent Sphingomyelinase Inhibitor

Abstract

A highly diastereoselective synthesis of 2-amino alcohol derivatives bearing a difluoromethylphosphonothioate group at the 3-position was achieved through LiAlH(O-t-Bu)(3)-mediated reduction of the corresponding alpha-amino ketones. The phosphonothioate moiety of the product was readily converted into the corresponding phosphonate by oxidation with m-CPBA, followed by aqueous workup. The developed methods should be useful for SAR studies of SMA-7, a potent inhibitor of SMases.

Chemistry of difluoromethylene phosphonates: history, state of the art, and prospects

“…Phosphonodifluoromethyl phenylalanine (F2Pmp) derivatives are potent inhibitors of protein tyrosine phosphatases (PTPs) [37,38], an enzyme central to type 2 diabetes, obesity, and cancer (Figure 1) [39]. Other identified targets for CF2-phosphonates are SH2 domains of signal transducer and activator of transcription proteins STAT6 and STAT3 [40], purine nucleoside phosphorylase (PNP) [41], sphingomyelinase [42], phosphoribosyltransferase [43], lysophosphatidic acid receptors [44], and polo-like kinase 1 (Plk1) [45]. The enzymes responsible for synthesizing or utilizing biogenic phosphonates are novel and exciting targets.…”

Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids

“…During studies directed toward the synthesis of novel inhibitors for sphingomyelinases, modification of sphingomyelin by replacement of the phosphocoline moiety with a metabolically stable difluoromethylenephosphonate group has been described on the basis of highly diastereoselective reduction of a-amino ketones 113 (Scheme 28). 56 The required a-amino keto-derivatives 113 were prepared by the method of Otaka and Berkowitz starting from (S)-Garner aldehyde 107. 57 Treatment of (S)-Garner aldehyde 107 with the lithium anion of diethyl difluoromethylphosphonate 90 gave adduct 108, which was subjected to deoxygenation furnishing 109 in a good overall yield.…”

Asymmetric synthesis of $\boldsymbol{\gamma}$ -aminophosphonates: The bio-isosteric analogs of $\boldsymbol{\gamma}$ -aminobutyric acid

“…42 The successful application of this synthesis to obtain a phosphonothioate analogue by treating derivative of intermediate 94 with Lawesson's reagent was reported in the diastereoselective synthesis of γ -aminoδ-hydroxy-α,α-difluorophosphonates (scheme 20). 43 β-oxo-γ -aminophosphonic acid derivatives may be regarded as a subclass of γ -aminophosphonic acid and are known to be the precursors or target molecules among medicinally relevant compounds. They can be synthesized by slightly modifying the reagents and conditions.…”