Preparation of α-Aminobenzylphosphonic Acids with a Stereogenic Quaternary Carbon Atom via Microscopically Configurationally Stable α-Aminobenzyllithiums

The enantiomers of 1-phenylethylamine were phosphorylated with diethyl chlorophosphate/Et(3)N and then Boc-protected (Boc=tert-butoxycarbonyl) at the nitrogen atom. These phosphoramidates were metalated by using sBuLi/N,N,N',N'-tetramethylethylenediamine (TMEDA) to give alpha-aminobenzyllithiums that isomerised to alpha-aminophosphonates in yields of up to 80 % with retention of the configuration at the carbon atom. The intermediate tertiary organolithiums were found to be microscopically configurationally stable from -78 to 0 degrees C in Et(2)O. The protected alpha-aminophosphonates were deblocked by using boiling 6 M HCl or preferably Me(3)SiBr/(allyl)SiMe(3). When the Boc group was replaced by the diethoxyphosphinyl group, the alpha-aminobenzyllithium intermediate partially enantiomerised even at -78 degrees C and rearranged to yield an alpha-aminophosphonate with 50 % ee (ee=enantiomeric excess). Similarly, N-Boc-protected phosphoramidates derived from racemates and/or enantiomers of 1-(1-naphthyl)ethyl-, 1-indanyl- and 1,2,3,4-tetrahydro-1-naphthylamine or 1-azidoindan- and 1-azido-1,2,3,4-tetrahydronaphthalene were converted to aminophosphonates in good yields. Deblocking gave alpha-aminophosphonic acids of excellent enantiomeric excess (97-99 %), as determined by means of HPLC on a chiral ion-exchange stationary phase based on quinine carbamate. When racemic Boc-protected diethyl phosphoramidate derived from 1,2,3,4-tetrahydro-1-naphthylamine was metalated with LiTMP/TMEDA (TMP=2,2,6,6-tetramethylpiperidine), 1-hydroxyethylphosphonamidates resulted. The configuration of the main isomer was determined by means of a single-crystal X-ray structure analysis.