Conversion of nitriles to 1-aminophosphonic acids and preparation of phosphahomocysteines of high enantiomeric excess

<p></p> <p>A variety of nitriles was reduced to diisobutylaluminum salts of aldimines, to which diisopropyl phosphite was added. The corresponding 1-aminophosphonates were either deprotected to give racemic 1-aminophosphonic acids or reacted with Boc₂O to yield <i>N</i>-Boc-protected 1-aminophosphonates. The enantiomers of 2-benzylthio-1-(<i>t</i>-butoxycarbonylamino)propylphosphonate were obtained from the racemate by chiral HPLC and converted to phosphonic acid analogs of (<i>R</i>)- and (<i>S</i>)-homocysteine, (<i>R</i>)- and (<i>S</i>)-2-aminobutyric acid and (<i>S</i>)-methionine, all of ee >97% as determined by chiral HPLC.</p

Phosphonate–Phosphinate Rearrangement

LiTMP metalated dimethyl <i>N</i>-Boc-phosphoramidates derived from 1-phenyl­ethylamine and 1,2,3,4-tetrahydro­naphthalen-1-ylamine highly selectively at the CH₃O group to generate short-lived oxymethyllithiums. These isomerized to diastereomeric hydroxy­methyl­phosphonamidates (phosphate–phosphonate rearrangement). However, <i>s</i>-BuLi converted the dimethyl <i>N</i>-Boc-phosphoramidate derived from 1-phenylethylamine to the <i>N</i>-Boc α-aminophosphonate preferentially. Only <i>s</i>-BuLi deprotonated dimethyl hydroxymethyl­phosphonamidates at the benzylic position and dimethyl <i>N</i>-Boc α-aminophosphonates at the CH₃O group to induce phosphonate–phosphinate rearrangements. In the former case, the migration of the phosphorus substituent from the nitrogen to the carbon atom followed a retentive course with some racemization because of the involvement of a benzyllithium as an intermediate

Phosphonate–Phosphinate Rearrangement

LiTMP metalated dimethyl <i>N</i>-Boc-phosphoramidates derived from 1-phenyl­ethylamine and 1,2,3,4-tetrahydro­naphthalen-1-ylamine highly selectively at the CH₃O group to generate short-lived oxymethyllithiums. These isomerized to diastereomeric hydroxy­methyl­phosphonamidates (phosphate–phosphonate rearrangement). However, <i>s</i>-BuLi converted the dimethyl <i>N</i>-Boc-phosphoramidate derived from 1-phenylethylamine to the <i>N</i>-Boc α-aminophosphonate preferentially. Only <i>s</i>-BuLi deprotonated dimethyl hydroxymethyl­phosphonamidates at the benzylic position and dimethyl <i>N</i>-Boc α-aminophosphonates at the CH₃O group to induce phosphonate–phosphinate rearrangements. In the former case, the migration of the phosphorus substituent from the nitrogen to the carbon atom followed a retentive course with some racemization because of the involvement of a benzyllithium as an intermediate

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ¹‑Pyrroline-5-carboxylate Reductase Inhibitors

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding (<i>S</i>)-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and <i>N</i>-hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and (<i>R</i>)-enantiomers (ee 92–99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ¹-pyrroline-5-carboxylate synthetase, and δ¹-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM