Agnieszka Październiok-Holewa

Synthesis of β- and γ-Hydroxy α-Amino Acids via Enzymatic Kinetic Resolution and Cyanate-to-Isocyanate Rearrangement

A new strategy for stereoselective preparation of all four isomers of β- and γ-hydroxy α-amino acids is presented. The developed procedure is based on enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement as key steps. Stereocontrol is achieved by proper choice of the starting hydroxyacid, the course of kinetic resolution, and the stereospecific sigmatropic rearrangement step, which proceeds with full chirality transfer.

α-Amidoalkylating Agents: Structure, Synthesis, Reactivity and Application

Abstract This review provides a summary of a wide range of α-amidoalkylating reagents and their precursors, especially novel developments in their synthesis and applications in a wide variety of inter- and intramolecular α-amidoalkylation reactions with O , N , S , P , C and other nucleophiles. A special attention is paid to (1) the introduction of new α-amidoalkylation reagents that join easy access from simple starting materials, structural diversity, high stability, easy handling and storage and high reactivity toward nucleophilic reagents under mild conditions; (2) the development of intramolecular α-amidoalkylation reactions to cyclic products via N -acyliminium ion or N -acylimine cyclizations; (3) the recent development of stereoselective α-amidoalkylation reactions using asymmetric catalysis, and (4) the application of α-amidoalkylation reactions for the synthesis of natural and/or bioactive compounds.This review provides a summary of a wide range of α-amidoalkylating reagents and their precursors, especially novel developments in their synthesis and applications in a wide variety of inter- and intramolecular α-amidoalkylation reactions with O, N, S, P, C and other nucleophiles. A special attention is paid to (1) the introduction of new α-amidoalkylation reagents that join easy access from simple starting materials, structural diversity, high stability, easy handling and storage and high reactivity toward nucleophilic reagents under mild conditions; (2) the development of intramolecular α-amidoalkylation reactions to cyclic products via N-acyliminium ion or N-acylimine cyclizations; (3) the recent development of stereoselective α-amidoalkylation reactions using asymmetric catalysis, and (4) the application of α-amidoalkylation reactions for the synthesis of natural and/or bioactive compounds.

α-Amidoalkylating Agents from N-Acyl-α-amino Acids: 1-(N-Acylamino)alkyltriphenylphosphonium Salts

N-Acyl-α-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium salts, new powerful α-amidoalkylating agents. The effect of the α-amino acid structure, the base used [MeONa or a silica gel-supported piperidine (SiO(2)-Pip)], and the main electrolysis parameters (current density, charge consumption) on the yield and selectivity of the electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids (Hofer-Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic α-amino acids, very good results were obtained using a substoichiometric amount of SiO(2)-Pip as the base. Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer-Moest reaction in the applied conditions failed, probably because of the susceptibility of these α-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)amides was effectively displaced with the triphenylphosphonium group by dissolving an equimolar amount of N-(1-methoxyalkyl)amide and triphenylphosphonium tetrafluoroborate in CH(2)Cl(2) at room temperature for 30 min, followed by the precipitation of 1-N-(acylamino)alkyltriphenylphosphonium salt with Et(2)O.

N-Acyl-α -triphenylphosphonio-α -amino Acids: Synthesis and Decarboxylation to α -(N-Acylamino)alkyltriphenylphosphonium Salts

4-Phosphoranylidene-5(4H)-oxazolones 1 undergo hydrolysis in THF in the presence of HBF 4 at room temperature to give N-acyl-α -triphenyphosphonioglycines 3 (R 2 = H) in very good yields. 4-Alkyl-4-triphenylphosphonio-5(4H)-oxazolones 2 react with water in CH 2 Cl 2 /THF solution without any acidic catalyst at 0–5°C in a few days yielding N-acyl-α -triphenylphosphonio-α -amino acids 3 (R 2 = Me) or α -(N-acylamino)alkyltriphenylphosphonium salts 4 (R 2 = alkyl, other then Me). α -Triphenylphosphonio-α -amino acids 3 upon heating to 105–115°C under reduced pressure (5 mm Hg) or upon treatment with a Hünig base in CH 2 Cl 2 at 20°C undergo decarboxylation to give the corresponding α -(N-acylamino)-alkyltriphenylphosphonium salts 4 , usually in very good yields.

Amidoalkylating Properties of 1-(N-Acylamino)Alkyltriphenylphosphonium Salts

Abstract Easily accessible 1-(N-acylamino)alkyltriphenylphosphonium salts react smoothly with nitrogen, sulfur, phosphorus and oxygen nucleophiles in the presence of (i-Pr)2EtN to give the expected α-amidoalkylation products, usually in good or very good yields. α-Amidoalkylation of dialkyl malonates or acetylacetates requires the application of a much stronger base (DBU) and gives the best results under the influence of microwave irradiation. α-Amidoalkylation of enamines was carried out successfully in the presence of (i-Pr)2EtN in a microwave reactor. 1-(N-Acylamino)alkyltriphenylphosphonium salts can be considered as new, convenient and effective α-amidoalkylation agents. GRAPHICAL ABSTRACT

Comparative Studies on the Amidoalkylating Properties of N-(1-Methoxyalkyl)Amides and 1-(N-Acylamino)Alkyltriphenylphosphonium Salts in the Michaelis–Arbuzov-Like Reaction: A New One-Pot Transformation of N-(1-Methoxyalkyl)Amides into Phosphonic or Phosphinic Analogs of N-Acyl-α-Amino Acids

Abstract It was demonstrated that N-(1-methoxyalkyl)amides do not react with trimethyl phosphite under neutral or basic conditions. The treatment of N-(1-methoxyalkyl)amides with trialkyl phosphites or dialkyl phosphonites, triphenylphosphonium tetrafluoroborate, and Hünigs base caused immediate formation of the corresponding 1-(N-acylamino)-alkyltriphenylphosphonium tetrafluoroborates, followed by the slow Michaelis–Arbuzov-like reaction of phosphonium salt with phosphites or phosphonites to α-(N-acylamino)-alkanephosphonic or α-(N-acylamino)alkanephosphinic acid esters, respectively. A plausible mechanism of the considered transformations, assuming an equilibrium between N-(1-alkoxyalkyl)amide, triphenylphosphonium tetrafluoroborate, 1-(N-acylamino)alkyltriphenyl-phosphonium salt, N-acylimine, and N-acyliminium salts, is discussed. GRAPHICAL ABSTRACT

A Novel Synthesis of 1-Aminoalkanephosphonic Acid Derivatives from 1-(N-Acylamino)- alkyltriphenylphosphonium Salts

Efficient and convenient procedures for the α-amidoalkylation of trialkylphosphites with 1-(N-acylamino)alkyltriphenylphosphonium salts followed by a Michaelis–Arbuzov-type reaction to afford 1-(N-acylamino)alkanephosphonic acid esters have been developed. High yields and simple isolation and purification protocols are the main advantages of this method.