Preparation of α-Bromo- and α-Chlorocarboxylic Acids from α-Amino Acids

Diazotization of α-amino acids in 48:52 (w/w) hydrogen fluoride/pyridine along with excess of potassium halide results in the corresponding α-halocarboxylic acids in good to excellent yields (Table 1 and 2).     

Asymmetric Synthesis of α-Amino Acids from Glycine

Enantioselective synthesis of optically active α-amino acids from glycine via Schiff base employing (+)-N,N-diisopropyl-10-camphorsulfonamide as a chiral template is described.     

Bioorganometallic Chemistry - Transition Metal Complexes with α-Amino Acids and Peptides

A new, interdisciplinary research area has emerged known as bioorganometallic chemistry. It focuses on the introduction of organometallic fragments into biomolecules (see, for example, structure on the right). “Classical” α-amino acid and peptide ligands have proven particularly versatile, and provide access to compounds that display interesting stereochemistry. α-Amino acids and peptides can be synthesized, labeled, stabilized, or activated by organometallic fragments.     

A New General Approach to Enantiomerically Pure Cyclic and Open-Chain (R)- and (S)-α,α-Disubstituted α-Amino Acids

A wide range of cyclic and open-chain α,α-disubstituted α-amino acids 1a-p were prepared. The racemic N-acylated α,α-disubstituted amino acids were resolved by coupling to chiral amines 15-18 derived from (S)-phenylalanine to form diastereoisomers 19/20 or 21/22 that could be separated by crystallization and/or flash chromatography on silica gel (Scheme 3). Selective cleavage via the 1,3-oxazol-5(4H)-ones 10a-p gave the corresponding optically pure α,α-disubstituted amino-acid derivatives 11 or 12 in high yield (Scheme 3). The absolute configurations of the α,α-disubstituted amino acids were determined from X-ray structures of the diastereoisomers 20, 21g′, 22d .     

Versatile Stereoselective Synthesis of Completely Protected Trifunctional α-Methylated α-Amino Acids Starting from Alanine

A new route to completely protected α-methylated α-amino acids starting from alanine is described (see Scheme). These derivatives, which are obtained via base-catalyzed opening of the oxazolidinones (2S,4R)- and (2R,4S)- 2 , can be directly employed in peptide synthesis. The synthesis of both enantiomers of Z-protected α-methylaspartic acid β-(tert-butyl)ester (O⁴-(tert-butyl) hydrogen 2-methylaspartates (R) or (S)- 4a ), α-methyl-glutamic acid γ-(tert-butyl) ester (O⁵-(tert-butyl) hydrogen 2-methylglutamate (R)- or (S)- 4b ), and of N^ε-bis-Boc-protected α-methyllysine (N⁶,N⁶-bis[(tert-butyloxy)carbonyl]-2-methyllysine (R)- or (S)- 4c ) is described in full detail.     

Novel Heterospirocyclic 3-Amino-2H-azirines as Synthons for Heterocyclic α-Amino Acids

The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N-methyl-N-phenylamino)-2H-azirines) 1a - d with a tetrahydro-2H-thiopyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring, respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCI), and sodium azide (Scheme 4). The reaction of these aminoazirines with thiobenzoic acid in CH₂Cl₂ at room temperature gave the thiocarbamoyl-substituted benzamides 13a - d in high yield. The azirines 1a-d were used as synthons for heterocyclic α-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me ( 18 ) by following the protocol of the ‘azirine/oxazolone method’: treatment of Z-Aib with 1 to give the dipeptide amide 15 , followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3-amine 17 gave 18 , again in high yield (Scheme 5). With some selected examples of 18 , the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a - d , as well as that of the corresponding carbocyclic analogue 18e , were determined by X-ray crystallography (Figs. 1-3 and Tables 1-3). All five tripeptides adopt a β-turn conformation of type III or III′. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid β-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.     

Preparation and Structure of β-Peptides Consisting of Geminally Disubstituted β2,2- and β3,3-Amino Acids: A Turn Motif for β-Peptides

We report on the synthesis of new and previously described β-peptides ( 1 – 6 ), consisting of up to twelve β^2,2- or β^3,3-geminally disubstituted β-amino acids which do not fit into any of the secondary structural patterns of β-peptides, hitherto disclosed. The required 2,2- and 3,3-dimethyl derivatives of 3-aminopropanoic acid are readily obtained from 3-methylbut-2-enoic acid and ammonia (Scheme 1) and from Boc-protected methyl 3-aminopropanoate by enolate methylation (Scheme 2). Protected (Boc for solution-, Fmoc for solid-phase syntheses) 1-(aminomethyl)cycloalkanecarboxylic-acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1-cyanocycloalkanecarboxylates and the corresponding dihaloalkanes (Scheme 3). Fully ¹³C- and ¹⁵N-labeled 3-amino-2,2-dimethylpropanoic-acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4). Coupling of these amino acids was achieved by methods which we had previously employed for other β-peptide syntheses (intermediates 18 – 23 ). Crystal structures of Boc-protected geminally disubstituted amino acids ( 16a – d ) and of the corresponding tripeptide ( 23a ), as well as NMR and IR spectra of an isotopically labeled β-hexapeptide ( 2a* ) are presented (Figs. 1 – 4) and discussed. The tripeptide structure contains a ten-membered H-bonded ring which is proposed to be a turn-forming motif for β-peptides (Fig. 2).     

Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and their use as building blocks for the solid-phase synthesis of β-peptides

N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β³-amino acids β³: side chain and NH₂ at C(3)(= C(β)) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β²- Amino acids (β² side chain at C(2), NH₂ at C(3)(= C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β³-heptapeptides 5–8 , a β³- pentadecapeptide 9 and a β²-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β³-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12 ). The CD spectra of the β²- and β³-peptides 5 , 9 , and 10 show the typical pattern previously assigned to an (M) 3₁ helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5 , this corresponds to a 2.5 fold increase in the molar ellipticity per residue!