Asymmetric synthesis of structurally diverse aminophosphonic acids by using enantiopure N-(p-Tolylsulfinyl)cinnamaldimines as reagents

Article abstract of DOI:10.1002/ejoc.201201589

We have developed new approaches to diverse enantiopure aminophosphonic acids by using enantiomeric (S)-N-(p-tolylsulfinyl)cinnamaldimine (1) as a single starting material. The synthetic strategy is based on a highly diastereoselective addition reaction of phosphite anion or α-phosphonate carbanion to a sulfinimine followed by isolation of the major diastereoisomeric α-amino- or β-amino adducts and their further conversion to the desired targets through proper transformation of the cinnamylidene moiety. Both diastereoisomerically pure (S_S,R_C)- and (S _S,S_C)-α-amino adducts 2 and 4 obtained were converted under acidic conditions into the unknown enantiomerically pure (R)- and (S)-α-amino-β,γ-propenylphosphonic acids 3. In the same way, the enantiopure (R)- and (S)-β-amino-γ,δ-butenylphosphonic acids were synthesized from the corresponding (S_S,R_C)- and (S_S,S_C)-β-amino adducts. Starting from the (S_S,R_C)-β-amino adduct a new stereoselective synthesis of (R)-2-amino-3-phosphonopropanoic acid (9) has been accomplished in three simple steps (tandem ozonolysis/reduction reaction, oxidation reaction and acidic hydrolysis) in an overall 40 % yield. The 3-amino regioisomer of 9 has been prepared from the (S_S,R_C)-α-amino adduct 2 through a two-reaction sequence involving a tandem ozonolysis/reduction reaction and a Mitsunobu cyanation/acidic hydrolysis. The overall yield of this conversion to 11 was 52.5 %. According to our strategy, we have been able to complete the first synthesis of the enantiopure (R)-phosphoemeriamine 15, which is an unknown phosphonic analogue of emeriamine (aminocarnitine). The conversion of the (S_S,R_C)-β-amino adduct 5 into (R)-phosphoemeriamine has been accomplished in five simple synthetic steps (ozonolysis/reduction reaction, mesylation reaction, amination reaction, methylation reaction and acidic hydrolysis) in 24 % overall yield. The stereochemistry of the addition of P^III-nucleophiles and α-phosphonate carbanion to a chiral sulfinimine is also discussed. Starting from sulfinimine (+)-(S)-1, as a single reagent, the synthesis of diverse enantiopure aminophosphonic acids was accomplished. In addition to the synthesis of unsaturated α- and β-aminophosphonic acids, the first synthesis of (-)-(R)-phosphoemeriamine and new approaches to (+)-(R)-2-amino-3-phosphonopropanoicacid (8) and its 3-amino regioisomer 11 are reported. Copyright