Synthesis of chiral bis-(2-chloroethyl)amino-substituted 1,3,2σ3λ3 (or σ4λ5)benzodiazaphosphorinones;: Resolution, oxidation reactions and X-ray structure determinations of individual enantiomers

The chiral N-methyl-N'-(1-phenylethyl)-substituted anthranilamides R-(+)-3 (R-C-enantiomer) and 3-(-)-3 (S-C-enantiomer) were formed by reaction of N-methylisatoic anhydride, 1, with R-(+)- and S-(-)-1-phenylethylamine, R-(+)-2 and S-(-)-2. Reaction of R-(+)-3 and S-(-)-3 with phosphorus trichloride led to mixtures of diastereomers of 5,6-benzo-2-chloro-1-methyl-3-(1-phenylethyl)-1,3,2 sigma(3)lambda(3)-diazapbosphorin-4-ones, (R-C, S-P)-4/(R-C, R-P)-4 and (S-C,R-P)-4/(S-C, S-P)-4. Attempted separation of the diastereomers of 4 by several methods failed. Reaction of the mixtures of (R-C, S-P)-4/(R-C,R-P)-4 and (S-C, R-P)-4/(S-C, S-P)-4 with bis-(2-chloroethyl)amine hydrochloride in the presence of triethylamine again led to mixtures of diastereomers of 5,6-benzo-2-[bis-(2-chloroethyl)amino]-1- methyl-3-(1-phenylethyl)-1,3,2 sigma(3)lambda(3)-diazaphosphorin-4-one, (R-C, S-P)-5/(R-C, R-P)-5 and (S-C,R-P)-5/(S-C, S-P)-5. By recrystallization it was possible to isolate the pure diastereomers (R-C, S-P)-5 and (S-C, R-P)-5. Oxidation reactions on (R-C, S-P)-5 and (S-C, R-P)-5 by the hydrogen peroxide-urea 1:1-adduct ((NH2)(2)C(:O). H2O2) or elemental sulfur led to the formation of the corresponding 2-oxo- and 2-thio-substituted 5,6-benzo-1,3,2 sigma(4)lambda(5)-diazaphosphorin-4-ones, (R-C, R-P)-6, (S-C, S-P)-6, (R-C, R-P)-7 and (S-C, S-P)-7 as pure diastereomers in each case. All compounds were characterized unambiguously by n.m.r.-spectroscopy, mass spectrometry and elemental analysis. Optical rotations were determined for most of the reaction products described. For compounds (R-C, S-P)-5, (R-C, R-P)-6, (S-C, S-P)-6 and (R-C, R-P)-7, X-ray crystal structure analyses were conducted. In all cases the absolute configuration at phosphorus was determined. The enantiomers of 6 crystallize in different space groups because only the (R-C, R-P) form contains solvent of crystallization.