(S)-2H-2-oxo-5,5-dimethyl-4(R)-phenyl-1,3,2-dioxaphosphorinane, a new reagent for the enantiomeric excess determination of unprotected amino acids using 31P NMR

Abstract

Abstract:Diastereomeric amide derivatives of title phosphorinane 2 and unprotected amino acids are easily prepared in aqueous solutions, showing well separated signals in the 31 P NMR spectra allowing accurate e.e. determination.The tremendous effort in asymmetric synthesis and the rapidly increasing use of enantiomerically pure compounds as chiral building blocks, auxiliaries, ligands or catalysts requires the development of fast and accurate methodologies for the determination of the enantiomeric composition 1 . Especially the rapid assessment of the stereochemical results of the enzymatic resolution of synthetic amino acids and the increasing use of natural and unnatural amino acids and their derivatives in protein modifications and the applications as chiral ligands in numerous asymmetric syntheses is a strong incentive for the development of new methods for the enantiomeric excess determination of this type of compound 2 .The enantiomeric purity of amino acids can routinely be analyzed by means of several gas or liquid chromatographic techniques 3 . Moreover, a number of NMR methods for the analysis of amino acid derivatives exist 4,5,6 . Methods for the analysis of free amino acids, however, are scarce, mainly due to their low solubility in organic solvents. Besides the use of aqueous chiral shift reagents 7 , new methodologies developed in our laboratory include the derivatization using α-chloropropionyl chloride (for 1 H NMR) 8 and chiral phosphorinane 1 (for 31 P NMR) 9 . Although phosphorinane 1 is readily coupled with amino acids in aqueous solutions using the Atherton, Openshaw and Todd reaction conditions 10 , the diastereomeric shift differences obtained are relatively small and sometimes resolution is not sufficient for quantification purposes 9 .We now wish to report a simple and efficient new chiral derivatizing agent, (S)-2H-2-oxo-5,5-dimethyl-4(R)-1,3,2-dioxaphosphorinane 2, for the derivatization of amino acids in aqueous solutions using the 1701 1702 R. HULST et al.conditions mentioned before (Scheme 1). Scheme 1Phosphorinane 2 strongly resembles phosphoric acid chloride 3, that we recently reported as a chiral derivatizing agent for the enantiomeric excess determination of alcohols, amines and esters of amino acids,showing excellent diastereomeric shift differences using 31 P NMR 11 . It appeared, however, not to be possible to use reagent 2 for enantiomeric excess determination of substrates in aqueous solutions, due to substantial hydrolysis and pyrophosphate formation (vide infra).Enantiomerically pure 2 is easily obtained in 65% yield from (R)-phencyphos 4 12 by reduction to the free diol 5 using LiAlH 4 in THF (or ether). Subsequent reaction with PCl 3 , followed by an Arbuzov rearrangement 13 using ethanol (or water 14 ), yields (S)-2H-2-oxo-5,5-dimethyl-4(R)-phenyl-1,3,2-dioxaphosphorinane 2 as a single diastereomer in 83% overall yield (Scheme 2). Scheme 2Phosphorinane 2 reacts with a variety of nucleophiles including alcohols, amines, amino acid esters and unprotected amino acids u...

Iridium-Catalysed Allylic Substitution: Stereochemical Aspects and Isolation of IrIII Complexes Related to the Catalytic Cycle

“…1 H NMR chemical shifts are relative to residual non-deuterated solvent in CDCl 3 (δ ϭ 7.26 ppm) or CD 2 Cl 2 (δ ϭ 5.32 ppm). 13 C NMR shifts are given relative to the solvents CDCl 3 (δ ϭ 77.0 ppm) and CD 2 Cl 2 (δ ϭ 53.8 ppm) and 31 [37] L5 [38] and [IrCl(COD)] 2 , [39] were prepared according to published procedures. The allylic esters were prepared by reaction of the corresponding alcohols with acetic anhydride [1a, [40] 1b, [41] 1c, [42] 1d, [43] (E)-2a, [40] (E)-2b, [44] (E)-2c, [42] ], methyl chloroformate (25b) [45] or diethyl chlorophosphate (26b).…”

“…Crystal data and details of the structure refinement for compounds 12, 29, 30, and 31 COD), 33.6 (CH 2 -COD),37.9 (CH 2 -COD), 42.6 (allyl CH 2 ), 80.8 (CH-COD), 81.7(CH-COD) 89.4 (CH-COD), 92.6 (CH-COD), 102.2 (allyl CH), 123.0 (allyl CHPh), 128.5, 128.9, 130.8 (C 6 H 5 ), 147.6 (C ipso -C 6 H 5 ) ppm. C17 H 21 Cl 2 Ir (488.52): calcd.…”

6-Membered P-Heterocycles: Ring-Condensed 1,3,2-Diheterophosphorinane 2-Chalcogenides

“…A number of 1,3,2-dioxaphosphorinanes have been reported to exhibit diverse bioactivities and have different synthetic applications, e.g. a potent calcium antagonist [39], microsomal triglyceride-transfer protein inhibitors [40], cytochrome P 450 3A-activated prodrugs [41], efficient resolving agents for the resolution of amines and amino acids [42] and chiral auxiliaries for diastereoselective condensation reactions [43]. The most exhaustive studies, however, have been focused on the conformational analyses of diastereomeric 1,3,2-diheterophosphorinanes.…”

Diversity Oriented Synthesis of Chiral Hexacoordinated Phosphate Anions

“…Otherwise, starting from hydrobenzoin and tartrate diols, only low yields of pure phosphoramidites were obtained. [33,34] In the case of BINOL, clean preparation of the derived phosphoramidite was achieved, [39] but its very slow oxidation by 6 made the overall process inefficient. [40] It is only when using 7 as ligand aa that both the phosphoramidite (8) synthesis and the subsequent oxidation can be achieved in high yield and purity.…”