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The structures of iminium salts formed from diarylprolinol or imidazolidinone derivatives and α,β-unsaturated aldehydes have been studied by X-ray powder diffraction (Fig. 1), single-crystal X-ray analyses (Table 1), NMR spectroscopy (Tables 2 and 3, Figs. 2–7), and DFT calculations (Helv. Chim. Acta2009, 92, 1, 1225, 2010, 93, 1; Angew. Chem., Int. Ed.2009, 48, 3065). Almost all iminium salts of this type exist in solution as diastereoisomeric mixtures with (E)- and (Z)-configured +NC bond geometries. In this study, (E)/(Z) ratios ranging from 88 : 12 up to 98 : 2 (Tables 2 and 3) and (E)/(Z) interconversions (Figs. 2–7) were observed. Furthermore, the relative rates, at which the (E)- and (Z)-isomers are formed from ammonium salts and α,β-unsaturated aldehydes, were found to differ from the (E)/(Z) equilibrium ratio in at least two cases (Figs. 4 and 5, a, and Fig. 6, a); more (Z)-isomer is formed kinetically than corresponding to its equilibrium fraction. Given that the enantiomeric product ratios observed in reactions mediated by organocatalysts of this type are often ≥99 : 1, the (E)-iminium-ion intermediates are proposed to react with nucleophiles faster than the (Z)-isomers (Scheme 5 and Fig. 8). Possible reasons for the higher reactivity of (E)-iminium ions (Figs. 8 and 9) and for the kinetic preference of (Z)-iminium-ion formation are discussed (Scheme 4). The results of related density functional theory (DFT) calculations are also reported (Figs. 10–13 and Table 4).

We have previously shown that the beta-aminopeptidases BapA from Sphingosinicella xenopeptidilytica and DmpA from Ochrobactrum anthropi can catalyze reactions with non-natural beta(3)-peptides and beta(3)-amino acid amides. Here we report that these exceptional enzymes are also able to utilize synthetic dipeptides with N-terminal beta(2)-amino acid residues as substrates under aqueous conditions. The suitability of a beta(2)-peptide as a substrate for BapA or DmpA was strongly dependent on the size of the C(alpha) substituent of the N-terminal beta(2)-amino acid. BapA was shown to convert a diastereomeric mixture of the beta(2)-peptide H-beta(2)hPhe-beta(2)hAla-OH, but did not act on diastereomerically pure beta(2),beta(3)-dipeptides containing an N-terminal beta(2)-homoalanine. In contrast, DmpA was only active with the latter dipeptides as substrates. BapA-catalyzed transformation of the diastereomeric mixture of H-beta(2)hPhe-beta(2)hAla-OH proceeded along two highly S-enantioselective reaction routes, one leading to substrate hydrolysis and the other to the synthesis of coupling products. The synthetic route predominated even at neutral pH. A rise in pH of three log units shifted the synthesis-to-hydrolysis ratio (v(S)/v(H)) further towards peptide formation. Because the equilibrium of the reaction lies on the side of hydrolysis, prolonged incubation resulted in the cleavage of all peptides that carried an N-terminal beta-amino acid of S configuration. After completion of the enzymatic reaction, only the S enantiomer of beta(2)-homophenylalanine was detected (ee>99 % for H-(S)-beta(2)-hPhe-OH, E>500); this confirmed the high enantioselectivity of the reaction. Our findings suggest interesting new applications of the enzymes BapA and DmpA for the production of enantiopure beta(2)-amino acids and the enantioselective coupling of N-terminal beta(2)-amino acids to peptides.

The title compound 1 was prepared from L-leucine. The key steps include a Grignard addition to Bn2-leucinal, a CO/CF2 replacement with Et2NSF3 (DAST) and use of a Ph group as synthetic equivalent of a COOH group. The difluoro-δ-amino acid 1 was incorporated into a peptide 8; tests with various proteases showed no inhibition by this particular peptide.

β-Amino acids with a single side chain in the α-position (β 2 -aminoacids or H-β 2 -aminoacids or H-β 2 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 -homo-aminoacids, the β 2 -homo-aminoacids, the β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -AminoAcid Building Blocks for Peptide Synthesis

The synthesis of the dihydrochloride salts of ( R )- 1 and ( S )- 1 2-(aminomethyl)piperidine is reported starting from either ( S ) or ( R ) lysine, respectively. A key step in the synthetic protocol involves the in situ formation of aziridinium 8 , which then undergoes an intramolecular ring opening with concomitant piperidinium ring formation, in a stereoselective manner. The route offers a practical synthesis of ( R )- 1 and ( S )- 1 , and it should make them more accessible for exploration in asymmetric catalysis or as building blocks in pharmaceutical research.

Gamma-aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calculations were carried out in a continuum solvent model (PCM-B3LYP) to estimate the preferred conformations of 3F-GABA in aqueous solution. NMR coupling constants were calculated for each conformer and were then used to simulate the NMR spectra to evaluate the solution conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABA(A) receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).

Gamma-aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of alpha-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biological behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily determined by other biophysical approaches.

The α-ketoacid–hydroxylamine (KAHA) ligation enables the direct cyclization of unprotected peptides upon cleavage, without coupling reagents or purification of precursors. We report the synthesis of a library of 24 cyclic peptides and a detailed mechanistic study., The α-ketoacid–hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including 2H and 18O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported.

The steroid 17-PA is a GABA A receptor antagonist which is finding use as a tool in evaluating agonistic/antagonistic activity at GABA A receptors. Compounds with improved efficacy over 17-PA would be are advantageous for such studies. Accordingly a series of novel analogues of the neurosteroid 17-PA have been prepared and a convenient two-step route is presented which is amenable to the synthesis of analogues with electron-donating para -aromatic substituents including fluorine. However, for the meta -fluoro analogue then the original four-step route to 17-PA remains more efficient overall. The paper describes these syntheses and discusses the electronic factors which influence this synthetic chemistry.

The enantiomers of 3F-GABA were evaluated on GABA(C) receptors. Both enantiomers were agonists, with the (R)-enantiomer being an order of magnitude more potent. This result is consistent with a folded binding mode for GABA, a conclusion which suggests a different binding mode to that found in the related but pharmacologically distinct GABA(A) receptors.