The resolution of acyclic P‐stereogenic phosphine oxides via the formation of diastereomeric complexes: A case study on ethyl‐(2‐methylphenyl)‐phenylphosphine oxide

Abstract

As an example of acyclic P-chiral phosphine oxides, the resolution of ethyl-(2-methylphenyl)-phenylphosphine oxide was elaborated with TADDOL derivatives, or with calcium salts of the tartaric acid derivatives. Besides the study on the resolving agents, several purification methods were developed in order to prepare enantiopure ethyl-(2-methylphenyl)-phenylphosphine oxide. It was found that the title phosphine oxide is a racemic crystal-forming compound, and the recrystallization of the enantiomeric mixtures could be used for the preparation of pure enantiomers. According to our best method, the (R)-ethyl-(2-methylphenyl)-phenylphosphine oxide could be obtained with an enantiomeric excess of 99% and in a yield of 47%. Complete racemization of the enantiomerically enriched phosphine oxide could be accomplished via the formation of a chlorophosphonium salt. Characterization of the crystal structures of the enantiopure phosphine oxide was complemented with that of the diastereomeric intermediate. X-ray analysis revealed the main nonbonding interactions responsible for enantiomeric recognition.

Asymmetric Synthesis of Chiral‐at‐P Alkenylphosphonamidates through Nickel‐Catalyzed C−P Coupling of Phosphoramidites and Alkenyl Halides

“…Unlike C-stereocenters, the chiral pool does not represent a viable source of P-stereogenic building blocks and, consequently, their preparation has been traditionally restricted to the resolution of racemates, [6] the use of chiral auxiliaries, [7] asymmetric catalysis, [18,9] or the formation of diastereomeric complexes. [10,11] Alkenyl phosphonates, and their derivatives, proved to be versatile scaffolds in phosphorus chemistry due to their ability to act as Michael acceptors, offering two electrophilic sites susceptible of being selectively functionalized (Scheme 1A). [12] This feature renders them useful in bioconjugation, [13] material science, [14] and as precursors of important pharmaceuticals such as fosfomycin [15] (sold as Monurol ® ), agrochemicals such as (�)-phosphinothricin [16] (sold as PESTANAL ® ) or ligands for organometallic catalysis.…”

Preparation of Enantiomerically Enriched P-Stereogenic Dialkyl-Arylphosphine Oxides via Coordination Mediated Optical Resolution

“…Methods developed for the preparation of P-chiral compounds include stereoselective syntheses from racemic or prochiral starting materials using chiral catalysts [14,15] or auxiliaries [16][17][18][19][20][21][22][23][24], stereospecific transformations of secondary phosphine oxides or phosphinates [16,[25][26][27][28], as well as kinetic [29][30][31][32][33], dynamic kinetic [34][35][36][37][38], chromatographic [39,40] or classical resolutions [41][42][43][44][45][46]. Classical resolutions are generally robust, bench-stable processes that can be scaled up.…”

“…Other resolution strategies rely on interactions between the P = O group of a phosphine oxide and the H-bond donor functional groups of the resolving agent. BINOL [41], TADDOL- [44,45], camphorsulfonic acid- [50], mandelic acid- [42] or tartaric acid derivatives [37,43] were used for the optical resolution of P-stereogenic phosphine oxides. BINOL and TADDOL-derivatives are relatively expensive, whereas optical resolutions with chiral acids had a rather limited scope.…”

“…This coordination mediated resolution technique was used to separate the enantiomers of chiral alcohols, hydroxy-or halo carboxylic acids [51][52][53][54][55]. Moreover, Ca 2+ -and Mg 2+ -salts of tartaric acid derivatives were suitable resolving agents for the preparation of several five-and six-membered P-heterocycles in optically active form [44], and our research group published one example for the enantiomeric separation, an acyclic diaryl-alkylphoshophine oxide [45]. Antipodes Tenofovir Alafenamide could also be separated using a coordination mediated resolution.…”

Optical Resolution of Dimethyl α-Hydroxy-Arylmethylphosphonates via Diastereomer Complex Formation Using Calcium Hydrogen O,O′-Dibenzoyl-(2R,3R)-Tartrate; X-Ray Analysis of the Complexes and Products

“…Earlier, we were successful in the optical resolution of a series of cyclic phosphine oxides and phosphinates using the acidic calcium salt of O,O -dibenzoyl-(2R,3R)-tartaric acid as the resolving agent [32]. It was successfully used for the resolution of tertiary phosphine oxides [33,34], α-alkoxyalcohols [35], α-alkoxycarboxylic acids [36], as well as αand β-hydroxycarboxylic esters [37] and the biologically active Tenofovir Alafenamide [38].…”