Cyclic a-amino acids

Garbay reported the chemoselective reduction of a a-dehydrophenylala-nine substrate bearing a p-acrylate moiety [105]. Robinson et al. have also used a tandem, one-pot asymmetric hydrogenation-hydroformylation-cyclization approach to generate six- to eight-membered cyclic a-amino acids [136]. 

Cyclic a-amino acids with an enamine pattern can be obtained upon enantioselective hydrogenation followed by a hydroformylation/cyclization sequence in a single-pot version Rh(I)-DuPHOS acts as a catalyst for both steps, the enantioselective hydrogenation of prochiral dienamides and the hydroformylation of the resulting homoallylic amines (Scheme 13) [52,53]. 

Fig. 5.6 Oxidation of cyclic a-amino acid esters with RuO [42]...

The chiral ligand (44) was prepared starting from the cyclic a-amino acid (S)-proline80). Recently, similar chiral catalysts and related molybdenum complexes involving optically active N-alkyl-P-aminoalcohols as stable chiral ligands and acetylacetone as a replaceable bidentate ligand, were designed for the epoxidation of allylic alcohols with alkyl hydroperoxides which could be catalyzed by such metal complexes 8,). 

The [2,3]-sigmatropic rearrangement of (E)-(218a), a derivative of the chiral cyclic a-amino acid (S)-proline, produced the aminonitrile (219) in a stereoselective manner. Saponification of (219) yielded (+)-2-methyl-2-phenyl-3-butenal (220) with an enantiomeric excess of 90%219>. In replacing the benzyloxymethyl moiety in (218a) by a methyl group, the optical purity of the chiral aldehyde (220) obtained in the corresponding reaction sequence decreases considerably 219). 

Perindopril (A), an orally active pharmaceutical for the treatment of hypertension, is an important commercial target compound that has a cyclic a-amino acid as an intermediate in its synthetic route. The bicyclic a-amino acid building block is synthesized by reduction of the chiral indoline-2-carboxylic acid (B, R=R =H) shown in Figure 1.4. This chiral cyclic amino acid has so far proven very difficult to synthesize in a highly enantioselective manner using chiral hydrogenation. 

The asymmetric aziridination of a, P-unsaturated carboxylic acid derivatives is a direct route to optically active aza-cyclic a-amino acids, and this class of chiral aziridines can also be used as chiral building blocks for the preparation of other amino acids, P-lactams, and alkaloids. Prabhakar and coworkers carried out an asymmetric aziridination reaction of tert-butyl acrylate with O-pivaloyl-N-arylhydroxylamine 25 in the presence of cinchonine-derived chiral ammonium salt 2e under phase-transfer conditions, which furnished the corresponding chiral N-arylaziridine 26 with moderate enantioselectivity (Scheme 2.24) [46],... 

Cyclic a-amino acids J The unsaturated inline 1, prepared as shown, on treatment with TMS triflate (1 equiv.) cyclizes to a mixture of trans- and cis-2, with marked preference for the former cyclic amino acid. The selectivity is dependent on the solvent. It is highest (33 1) in toluene, but the highest yield (55%) and cleanest reaction is obtained in r-butyl methyl ether even though the diastereoselectivity is lower (18 l). Lewis acids do not initiate this cyclization. 

Our BNCT research has focused on radiolabeling BP A find on the creation of boron analogues of an unnatural cyclic a-amino acid, 1-aminocydobutanecarboxylic acid (ACBC), as a carrier molecule, Figure 3. This unnatural amino acid is known to be preferentially retained in intracerebral tumors. In fact, carbon-11 labeled ACBC, 3, is used for imaging brain tumors at the University of Tennessee Medical Center.6 Recently, we reported the syntheses of a m-carboranyl containing ACBC derivatives which were lipophilic in nature.7... 

Decarboxylative condensations of N-substituted or N-unsubstituted a-amino acids with carbonyl compounds offer the most convenient generation of a wide variety of azomethine ylides (Section II,E). The intermediacy of 5-oxazolidinones is ascertained by the fact that in several cases 5-oxazolidinones have been actually isolated and their thermolysis leads to the generation of azomethine ylides (76CSR377 77MI1 87BCJ4079). As the decarboxylation of the 5-oxazolidinone intermediates would take place stereospecifically in a concerted manner, 2,4-trans- and 2,4-cis-isomers of the 5-oxazolidinones give rise to anti- and syn-azomethine ylides, respectively. Condensations of cyclic a-amino acids with aldehydes produce 2,4-trans bicyclic oxazolidinones as thermodynamically more stable products. Accordingly, the exclusive formation of anti-ylides is expected in the decarboxylation route (Section II,E). 

This expectation has been realized in many cases involving the condensation of aldehydes with cyclic a-amino acids, such as proline, pipecoline, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydro- -carboline-2-carboxylic acid, and thiazoline-4-carboxylic acid (87CC47). The ylides generated by this route are trapped as the cycloadducts of anti-ylides, for example 111, 112,116, anti- 240, and 241, in cycloadditions using maleimides. 

Osipov, S. N., Artyushin, O. I., Kolomiets, A. F., et al. (2001) Synthesis of racemic cyclic amino acids Synthesis of fluorine-containing cyclic a-amino acid and a-amino phosphonate derivatives by alkene metathesis. Fur. J. Org. Chem., 3891-3897. 

Conformationally rigid cyclic a-amino acids in the design of peptidomimetics, peptide models, and bioactive compounds 04UK849. 

Glyoxylates as versatile building blocks for the synthesis of a-amino acid (including cyclic a-amino acids) and a-alkoxy acid derivatives via cationic intermedi-ates 03EJO2519. 

Alonso, E, Mico. L. Najera, C., Sansano, J.M.. Yus. M.. Ezquerra, J., Yruretagoyena, B.. and Gracia, L, Synthesis of 3- and 4-substituted cyclic a-amino acids stt-ucturally related to ACPD. Tetrahedron,... 

Zen (nitroacctic acid derivatives/ "" professor emeritus of Kitasato University), Seiichiro Ogawa (2-aminocyclohexyl D-glucosmninidcs/ " professor at Keio University), andEisuke Kaji (cyclic a-amino acids, professor at Kitasato University) also studied in Sumio s laboratory and took up senior positions in academia. For a rather recent project on fluorinated antibiotics, Takahiro Torii (3-fluoro-... 

CC180, 84CC182). Later it was discovered that the azomethine ylide generation by the decarboxylation route can be carried out between a wide variety of cyclic a-amino acids and aromatic aldehydes, aliphatic aldehydes, and formaldehyde (87BCJ4079, 87CC47, 87CC49). 

MpUer, B. and Undheim, K. (1998) Cyclic a-amino acids by Pd-mediated cycloisomerization and couphng reactions. Tetrahedron, 54, 5789-804. 

In 2010, Tanaka s group investigated whether a chiral cyclic a-amino acid included in an oligopeptide chain could catalyze the epoxidation of different enones with high enantiomeric excess. They demonstrated that the a-helical secondary structure of the peptide catalyst is directly related to the chosen a,a-disubstituted amino acid [134]. Thus, they found that 5 mol% of a-helical nonamer 92 with urea-H2O2 as oxidant can catalyze the reaction with ee > 95% (Scheme 12.18). 

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