Chemoenzymatic Synthesis of Phosphonic Acid Analogues of L‐Lysine, L‐Proline, L‐Ornithine, and L‐Pipecolic Acid of 99 % ee – Assignment of Absolute Configuration to (–)‐Proline

Abstract

(Ϯ)-ω-Halo-α-(chloroacetoxy)phosphonates were kinetically resolved by use of a protease (Chirazyme ® P-2). The esters recovered at levels of conversion between 56 and 72 % furnished (S)-alcohols of 99 % ee. These were converted via azides into the phosphonic acid analogues of L-lysine, L-pro-

Triazole‐Based Anion‐Binding Catalysis for the Enantioselective Dearomatization of N‐Heteroarenes with Phosphorus Nucleophiles

“…Although a lower asymmetric induction was observed with this acylating agent, it permitted the straightforward synthesis of pipecolic phosphonic acid 9 by hydrogenation and phosphonate hydrolysis. Consequently, the absolute configuration ( S ) was determined by comparison of the optical rotation with the reported literature …”

Chemoenzymatic Synthesis of Racemic and Enantiomerically Pure Phosphaaspartic Acid and Phosphaarginine

“…For the synthesis of the enantiomers of phosphaaspartic acid and phosphaarginine, the enantiomers of diisopropyl 1‐hydroxy‐3‐butenylphosphonate were needed. In order to obtain them with a high ee , the racemate was resolved by enzyme‐catalyzed hydrolysis of the respective chloroacetate . Therefore, the α‐hydroxyphosphonate (±)‐ 6 was chloroacetylated with chloroacetic anhydride and pyridine (see Scheme ).…”

“…We tested a series of lipases (SAM I and II, AP 6, FAP 15, SP 523, Chirazyme L9, and from Candida antarctica, Candida cylindracea , and Thermomyces lanuginosus ) and found that the lipase from Thermomyces lanuginosus was best (Scheme ). Briefly, chloroacetate (±)‐ 7 was hydrolyzed in a vigorously stirred biphasic system of phosphate buffer pH 7.0 and organic solvent (hexanes/ t BuOMe, 1:1) by the lipase from Thermomyces lanuginosus by using an autotitrator to add 0.5 m NaOH to maintain the pH constant at 7.0 . When 40 % of the substrate, based on the consumption of 0.5 m NaOH, had been hydrolyzed, the mixture was extracted with EtOAc.…”

“…These phosphonic acids are analogs of the racemic and the proteinogenic ( S ) form (the different descriptors are caused by the fact that CO 2 H has lower and PO 3 H 2 higher priority compared to NH 2 according to the CIP rules) of aspartic acid (Scheme ). The hydroxyl group of (±)‐ and ( S )‐ 6 was replaced by the azide group with inversion of configuration by using the Mitsunobu reaction [Ph 3 P/diisopropyl azodicarboxylate (DIAD)/HN 3 ] , . The conversion of the azides to the phosphaaspartic acids was performed without characterization of the intermediate products.…”

“…The aminophosphonic acids were deblocked at the phosphorus atom with refluxing 6 m HCl and purified by cation‐exchange chromatography. A final crystallization afforded the phosphaaspartic acids (±)‐ and ( R )‐ 10 as colorless crystals in 61 % and 59 % overall yield for the three steps, respectively . The ee of ( R )‐ 10 was determined by HPLC on a chiral stationary anion exchange phase (unmodified OH‐QN‐AX column) based on quinine .…”