Synthesis of Functionalized Novel α‐Amino‐β‐alkoxyphosphonates through Regioselective Ring Opening of Aziridine‐2‐phosphonates

Abstract

Aziridines are highly useful compounds as building blocks for the synthesis of important organic compounds. Amino acid synthesis by aziridine ring opening reaction is a good example to the use of aziridines. Although this reaction is studied by many groups, the synthesis of amino phosphonic acids is less explored. In this study, we have carried out the ring opening reaction of aziridinyl phosphonates with a variety of alcohols including the more functional propargylic and allylic alcohols. These reactions provided functionalized α‐amino‐β‐alkoxyphosphonates in 40–91 % yield.

Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral β-Amino Alcohols with 2-Pyridyl and 6-(2,2′-Bipyridyl) Moieties

“…The observed regioselectivity seems to be due to the protonation, thus activation of the phenyl-substituted carbon in the aziridine ring ( Figure 2). The observed difference in the position of nucleophilic opening for analogous aziridines has already been reported [9,10,14,38].…”

Synthesis of Aminomethylene-gem-bisphosphonates Containing an Aziridine Motif: Studies of the Reaction Scope and Insight into the Mechanism

“…In a second step, the N-carbamoyl phosphonate intermediate may be subject to a second nucleophilic attack of the diethylphosphite anion affording an α-hydroxybisphosphonate derivative as a second intermediate (Scheme 3B). This scaffold is known to undergo [1,2]-phospha-Brook rearrangement (phosphonate-phosphate rearrangement) in the presence of a base, leading to the formation of a phosphate moiety (Scheme 3C). 38 To go further in the study of the impact of the lithium ion in the proposed mechanism and rearrangement as well as the nature of the base, we envisaged additional experiments (Table 3).…”

“…The proposed model (Scheme 3B) is hypothesized from the mechanism of the reverse reaction, the phosphate-phosphonate rearrangement, in the presence of strong lithiated base 46,47 and on the basis of the work of Ranga et al 45 This point further reinforces the crucial role of lithium in the stabilization of the transition states. The [1,2]-phospha-Brook rearrangement likely ends by the lithium-proton exchange between DEP and the transition state III.…”

“…As example, the synthesis of aziridine-2-phosphonates and aziridine-1-ylmethylphosphonates have been well described in the literature. [2][3][4][5] However, the association of a chiral aziridine with several phosphonate groups is rather limited and may lead to promising scaffolds for obtaining biomolecules of interest. Indeed, bisphosphonates (or BPs, Figure 1) have been developed…”

“…When combined with a phosphonate moiety (widely used in medicinal chemistry as a bioisoster of organic phosphate and insensitive to enzymatic cleavage), they are useful building blocks for the synthesis of aminophosphonates that can be considered as analogues of α-amino acids. For example, the synthesis of aziridine-2-phosphonates and aziridin-1-yl methylphosphonates have been well described in the literature. − However, the association of a chiral aziridine with several phosphonate groups is rather limited and may lead to promising scaffolds for obtaining biomolecules of interest. Indeed, bisphosphonates (or BPs, Figure ) have been developed for their coordination abilities and their structural analogy with inorganic pyrophosphate (the P–C–P bridge replacing the P–O–P bonds is not sensitive to enzymatic cleavage), making them suitable for the treatment of bone diseases or drug delivery. − N-BPs are nitrogen-containing bisphosphonates, targeting enzymes of the mevalonate pathway and exhibiting antiosteoporosis and antiproliferative activities. , For example, the incadronate (Figure ) is an antiosteoporosis drug with a 1-aminobisphosphonate motif.…”