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β-laktony pochodnych seryny jako prekursory aminokwasów wielofunkcyjnych

Olma A., Kudaj A.

Wiadomości Chemiczne

2010

[Z] 64, 9-10

831-857

Optically active unnatural amino acids play important roles in bioorganic and medicinal chemistry [1]. Thus, development of novel methods for the synthesis of these amino acids is of great interest for organic chemists. Incorporation of these building blocks often results in peptidomimetics with limited conformational flexibility, enhanced enzymatic stability, improved pharmacodynamics and bioavailability. This review summarizes the utilization of β-lactones of serine and of α-alkylserines in the enantioselective synthesis of β-substituted alanines. N-Protected β-hydroxy-α-amino acids can be cyclized under modified Mitsunobu conditions to β-lactones [2–19]. Serine and threonine β-lactones can be also obtained by carboxyl group activation using coupling reagents (DIC, TBTU, HBTU, BOP, PyBOP, HBTU) [16, 21–27]. Readily accessible β-lactone ring opening with various nucleophiles provides many unnatural amino acids and other chiral building blocks. In the first part, the synthesis of N-protected β-hydroxyamino acid β-lactones and the ring opening mechanism are discussed [30, 31]. The second part of this review describes the ring opening with various nucleophiles, including halogens, thiols, selenes and tellures, nitrogen, phosphorus and carbon nucleophiles. Reactions of N-protected β-hydroxyamino acid and α-alkylserines β-lactones with halogen nucleophiles (HCl, HBr, LiCl, and MgX_2) in all described cases yield α-halogenomethyl derivatives [2, 20, 25, 32, 33]. α-Halogenomethyl-α-amino acids are potential enzyme-activated irreversible inhibitors of parent amino acid decarboxylases. Only a few synthetic strategies directed towards the synthesis of the selected α-halogenomethylamino acids have been described. The difficulty associated with the synthesis of these molecules lies in the presence of a halogen atom on the carbon atom vicinal to quaternary center bearing amine and carboxylic acid functionalities (like the neopenthyl position). Sulphur, selenium and tellurium nucleophiles were used to obtain S-substituted cysteines, α-alkylcysteines and lanthionine derivatives and their seleno and telluro analogues [2, 28, 32, 33, 44, 45, 49–54]. The use of nitrogen nucleophiles leads to β-amino-, β-cyano- and β-azidoalanines [2, 11, 13–15, 32, 33, 55–71]. Properties of the nucleofile and of β-lactone determine regioselectivity of ring opening, giving β-aminoalanines or amides. The use of sodium azide as the nucleophile led to the formation of β-azidoalanine and β-azido-α-alkylalanines, useful building blocks in peptide synthesis and precursors of α, β-diamino acids. Among nitrogen nucleophiles the cyclic secondary amine (pyrolidine, morpholine), aromatic amines and heterobases were used to synthesize β-aminoalanine derivatives. The β-lactone ring openings were carried out with phosphorus [10, 18, 72, 73] and carbon nucleophiles [5, 74–76]. Serine, threonine and α-alkylserines β-lactones are widely used intermediates for the synthesis of new optically pure unnatural, multifunctional amino acids, which are difficult to obtain in other ways.