A method for the synthesis of unsymmetric bisphosphoric analogs of α-amino acids

Abstract

Herein, we describe the first universal strategy for the synthesis of unsymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogs of N-protected 1-aminobisphosphonates. The proposed user-friendly procedure, based on a one-pot reaction of the α-ethoxy derivatives of phosphorus analogs of protein and non-protein α-amino acids with triphenylphosphonium tetrafluoroborate and an appropriate phosphorus nucleophile (diethyl phenylphosphonite or methyl diphenylphosphinite), provides good to very good yields of 53-91% under mild catalyst-free conditions (temperature: rt to 40 °C, time: 1 to 6 hours). The progress of the transformation, running through the corresponding phosphonium salt as a reactive intermediate, was monitored by ³¹P NMR spectroscopy, which is a convenient tool for the identification of the transient species formed here. In this paper, we present the full characteristics of the spectroscopic properties of all 13 synthesized models of structurally diverse N-protected unsymmetric bisphosphoric analogs of α-amino acids. Therefore, these results contribute to increasing the practical applicability of our recently reported synthesis protocol of symmetric models of α-aminobisphosphonates derivatives and thus justify its universality.

Fig. 1. Comparison of the structures of 1-amino-1,1-bisphosphonate and its unsymmetric phosphonyl–phosphinyl and phosphonyl–phosphinoyl analogs.

Scheme 1. Known routes for the synthesis of 1-amino-1-phosphinoylalkylphosphonate derivatives: reaction of diethyl 2,3-dihydro-4H-1,3-benzoxazin-4-one-2-phosphonate with diphenylphosphine oxide or diphenyl(trimethylsilyl)phosphine oxide (route A); reaction of diphenylphosphine oxide with activated iminophosphonates (route B); reaction of dialkyl phosphite with N,N-dialkylamine derivatives of phosphine oxide functionalized at the α-position by chlorine atom or ethoxy group (route C).

Scheme 2. Known routes for the synthesis of 1-amino-1-phosphinylalkylphosphonate derivatives: reaction of 1-bromo-1-aminoethoxymethylphosphinic acid derivative with diethyl phosphonate (route A); reaction of diethyl diethoxymethylphosphonate with 2-amino-3-methylpyridine and ethyl methylphosphinate (route B); synthesis of 1-aminophosphinylmethylphosphonic acids through reduction of azide derivatives (route C).

Scheme 3. Synthetic pathways for the preparation of phosphonyl–phosphinyl and phosphonyl–phosphinoyl analogs of 1-aminobisphosphonates from α-functionalized derivatives of phosphorus analogs of α-amino acids, such as diethyl 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates 2 obtained from α-methoxyphosphonates (pathway A) or α-ethoxyphosphonates (pathway B).

Scheme 4. Scope of the Michaelis–Arbuzov-type reaction in the synthesis of phosphonyl–phosphinoyl and phosphonyl–phosphinyl analogs of 1-aminobisphosphonates. Conditions: substrate 1 (1.0 mmol), Ph₃P·HBF₄ (1.1 mmol, 1.1 equiv.), Ph₂POMe or PhP(OEt)₂ (1.5 mmol, 1.5 equiv.), DCM (5.0 mL). Isolated yield.

Fig. 2. (a) ³¹P NMR spectrum of α-ethoxyphosphonate 1c. (b) ³¹P NMR spectrum of the reaction mixture obtained in the synthesis of 3i carried out at 40 °C for 1 h. (c) ³¹P NMR spectrum of isolated product 3i.