Enantiopure cyclic amino acid

Several enantiomerically-enriched templates have also been employed in the preparation of chiral, non-racemic piperidines. The RCM of N, O- and O, O-acetals have been developed by Rutjes and co-workers into a powerful method for the preparation of a wide-variety of heterocycles <02MI736> (Scheme 17). Here the reaction of an enantiopure Ts-protected allyl glycine is employed to prepare a chiral, non-racemic, cyclic amino acid derivative. These N,0-acetals can be readily transformed into synthetically useful iV-sulfonyliminium ions by treatment with BF3 OEt2 <00CC699>. 

Pandey, G., Laha, J.K., and Lakshmaiah, G. 2002. Stereoselective construction of X-azabicyclo[ i.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine. Tetrahedron 58, 3525-3534. 

Anodic decarboxylative methoxylation has also been used to generate an efficient electrophilic chiral glycine equivalent. This is produced from the cyclic dipeptide of L-proline and aminomalonic acid diester. Anodic decarboxylation of the remaining carboxylic function leads to the chiral iV,<9-acetal, which can undergo nucleophilic substitution followed by hydrolysis to give back L-proline and the nonproteinogenic new enantiopure i)-amino acid [Eq. (49)] [201]. 

K. C. M. F. Tjen, S. S. Kinderman, H. E. Schoemaker, H. Hiemstra, and E. P. J. T. Rutjes, A ring closing metathesis-mediated route to novel enantiopure conformationally restricted cyclic amino acids, Chem. Commun., (2000) 699-700. 

Enantiopure unsaturated amino acids are ideally suited for further selective transformations. In this section some selected examples are given. Radical additions will lead to enantiopure sulfur-containing amino acids. Ring-closing olefin metathesis will give cyclic amino acids, whereas Pd-catalyzed oxy palladation, amido palladation, and cross-coupling will lead to a vast array of enantiopure heterocyclic compounds. 

Finally, the synthesis of a variety of unsaturated (alkenyl and alkynyl) amino acids is described. Those trifunctional amino acids are ideal starting materials for a series of highly functionalized, conformationally restricted cyclic amino acids using either Pd catalysis or Ru-catalyzed ring-closing metathesis. The resulting enantiopure functionalized cyclic amino acids appear to be versatile scaffolds in combinatorial approaches. 

Direct and indirect enzymatic methods for the preparation of enantiopure cyclic fi-amino acids and derivatives from /1-lactams 04MI36. 

Following the same strategy, further improvements in similar catalytic asymmetric [4 + 2] cycloaddition reaction have been made by Lectka group. The cyclic 1,4-benzoxazinones 3 (Scheme 10.4) that rely on the highly enantioselective [4 + 2] cycloaddition of o-benzoquinone imides with chiral ketene enolates were efficiently constructed, which can be derivatized in situ to provide a-amino acid derivatives in good to excellent yields and with virtual enantiopurity [9]. 

R. erythropolis A4, Rhodococcus sp. R312, and R. erythropolis NCIMB 11540 were used in the hydrolysis of five- and six-membered ahcyclic trans-aminonitriles (Figure 11.6), which are the precursors of cyclic p-amino acids. The enzymes discriminated between the trans- and cis-isomers, the transformation of the former proceeding slowly or stopping at the amide stage. Moreover, hydrolysis of the latter resulted in excellent enantiopurity of the trans-amino acids or amides [38]. 

Gallagher et al. reported on various IV-heterocycle construction via cyclic sulfamides. Using this strategy, they synthesized enantiopure 1,4-benzoxazine 311, which was the precursor of the blockbuster antibiotic levolloxacin 312 (Scheme 40.67). Starting from Boc-protected amino alcohol 305, sulfamidate 306 was prepared using RuCU and NaI04. 306 was treated with halo phenol 308 followed by acidic hydrolysis to afford amino ether 310. The compound 310 underwent Pd-catalyzed C—N alkylative cyclization to produce benzoxazine 311, which was the potential precursor from which Levolloxacin 312 can be synthesized. 

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