Bicyclic Α-amino Acids Research Articles

Direct Synthesis of Free α-Amino Acids by Telescoping Three-Step Process from 1,2-Diols.

A practical telescoping three-step process for the syntheses of α-amino acids from the corresponding 1,2-diols has been developed. This process enables the direct synthesis of free α-amino acids without any protection/deprotection step. This method was also effective for the preparation of a 15N-labeled α-amino acid. 1,2-Diols bearing α,β-unsaturated ester moieties afforded bicyclic α-amino acids through intramolecular [3 + 2] cycloadditions. A preliminary study suggests that the resultant α-amino acids are resolvable by aminoacylases with almost complete selectivity.

Synthesis of Angularly Fused (Homo)triquinane-Type Hydantoins as Precursors of Bicyclic Prolines

An efficient strategy for a four-step synthesis of angularly fused tricyclic hydantoins as suitable precursors of cis-fused bicyclic α-amino acids is developed by combining a highly diastereoselective Bucherer–Bergs reaction of 2-alkenylcycloalkanones and a regiospecific selenium-induced closure of pyrrolidine ring. This methodology was applied in a five-step synthesis of bicycloproline derivatives in high overall yield. The method could be used for the multigram preparation of free conformationally constrained bicyclic α-amino acids with two points of diversity (size of cycloalkyl ring and substituent at the pyrrolidine ring).

Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

ChemInform Abstract: Chiral (Z)-α,β-Didehydroamino Acid Derivatives from a New Chiral Glycine Equivalent with a 1,2,3,6-Tetrahydropyrazin-2-one Structure: Applications to the Synthesis of 1-Aminocyclopropanecarboxylic Acids and Bicyclic α-Amino Acids.

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Synthesis of Bicyclic Tertiary α-Amino Acids

Novel bicyclic alpha-amino acids, exo and endo-1-azabicyclo[2.2.1]heptane-2-carboxylic acid, 1-azabicyclo[2.2.1]heptane-7-carboxylic acid, and 1-azabicyclo[3.2.2]nonane-2-carboxylic acid have been readily synthesized for the generation of neuronal nicotinic receptor ligands. Alkylation of glycine-derived Schiff bases or nitroacetates with cyclic ether electrophiles, followed by acid-induced ring opening and cyclization in NH4OH, allowed for the preparation of substantial quantities of the three tertiary bicyclic alpha-amino acids.

Synthesis of a Bicyclic Proline Analogue from l-Ascorbic Acid

The efficient synthesis of a bicyclic α-amino acid from L-ascorbic acid is presented. The synthetic procedure is a three-step process involving an S N 2 reaction of an amino acetal with an L-ascorbic acid derivative, followed by protection of the amine as a Fmoc urethane, and acid-promoted trans-acetalization to give the title compound. Inversion of the configuration at the stereocenter of the precursor derived from L-ascorbic acid allowed the formation of the corresponding bicyclic α-amino acid bearing the carboxylic group in the 2-exo configuration. Such Fmoc-protected α-amino acids can be considered as bicyclic mimetics of proline, and are particularly suited for solid-phase peptidomimetic chemistry.

A new bicyclic proline-mimetic amino acid

A new constrained bicyclic α-amino acid proline-mimetic was developed. The synthesis was achieved starting from derivatives of the chiral pool, thus allowing to prepare analogues of either l- or d-proline by choosing appropriate stereoisomers of serine and α,β-isopropylidene-glycerol derivatives. The scaffolds were prepared as N-Fmoc-amino acid suitable for solid-phase peptide synthesis.

Functionalized cis- and trans-fused bicyclic alpha-amino acids via stereoselective double annulation and dequaternization reactions.

Fused bicyclic alpha-amino acids can be prepared by a double Michael reaction of p-anisyl ethynyl ketone and a tethered diacid, cyclization via hydrogenation or hydration of a CN group, and oxidation of the p-anisyl group. The substitution level of the alpha-amino acids can be adjusted by decyanation or decarboethoxylation of the intermediates. Bicyclic alpha-amino acids prepared in this way include cis- and trans-perhydroisoquinoline-3-carboxylic acids and cis-perhydro-2-pyrindine-3-carboxylic acids of various substitutions and oxidation levels. The bicyclic alpha-amino acids may be regarded as functionalized and conformationally restricted analogues of proline, pipecolic acid, 2-aminoadipic acid, or glutamic acid.

Syntheses of both the putative and revised structures of aeruginosin EI461 bearing a new bicyclic alpha-amino acid.

[structure: see text] The putative structure of the naturally occurring aquatic peptide aeruginosin EI461 has been prepared from d-tyrosine. A corrected structure for aeruginosin EI461 is proposed, and the structure is proven by synthesis, which was accomplished using the new alpha-amino acid (2S,3aR,6R,7aR)-6-hydroxy-2-carboxyoctahydroindole, prepared from l-tyrosine. Succesive couplings of the dipeptide d-Leu-3a,7a-diepi-l-Choi with l-Hpla and NH(4)OH and a deprotection step gave aeruginosin EI461.

Asymmetric synthesis of α-amino acids from α,β-( Z)-didehydroamino acid derivatives with 1,2,3,6-tetrahydropyrazin-2-one structure

Chiral ( Z)-α,β-didehydroamino acid (DDAA) derivatives 14, 15 and 16 are obtained from a new chiral iminic cyclic glycine template with 1,2,3,6-tetrahydropyrazin-2-one structure 10 by condensation with carbonyl compounds, Eschenmoser's salt and Bredereck's reagent, respectively. The didehydroalanine derivative 15 and the enaminone 16 can give DDAA derivatives 14 using Heck olefination and vinylic nucleophilic substitution. These DDAA derivatives 14 and 15 undergo diastereoselective cyclopropanation, 1,3-dipolar and Diels–Alder cycloaddition reactions giving, after hydrolysis, the corresponding cyclic and bicyclic α-amino acids.

THE PAUSON-KHAND REACTION IN SYNTHESIS OF BICYCLIC RIGID α-AMINO ACIDS

The combination of intramolecular Pauson-Khand methodology for Co2(CO)8 mediated cyclization, and the Schöllkopf chiral auxiliary for stereoselective preparation of appropriate 1,6-heptenynes constitutes a powerful method for the preparation of rigidified bicyclic α-amino acids.

Chiral ( Z)-α,β-didehydroamino acid derivatives from a new chiral glycine equivalent with a 1,2,3,6-tetrahydropyrazin-2-one structure: applications to the synthesis of 1-aminocyclopropanecarboxylic acids and bicyclic α-amino acids

The new chiral glycine equivalent 9, easily obtained from (+)-α-aminoisovalerophenone and glycine, afforded chiral ( Z)-α,β-didehydroamino acid (DDAA) derivatives 13 and 14 with a 1,2,3,6-tetrahydropyrazin-2-one structure. Compounds 13 and 14 were synthesised by reaction of 9 with Eschenmoser’s salt and by condensation reactions with aldehydes or acetone under PTC conditions, respectively. The diastereoselective cyclopropanation of 14, followed by hydrolysis, furnished (−)- allo-norcoronamic acid with high ee, whilst diastereoselective Diels–Alder reaction of dienophile 13 and cyclopentadiene afforded, after double bond hydrogenation and hydrolysis, (−)-2-aminonorbornane-2-carboxylic acid.

Novel Bridged Bicyclic α-Amino Acid Esters and Key Derivatives from Quincorine and Quincoridine

Oxidation of Quincorine (QCI) and Quincoridine (QCD) has been investigated, giving bicyclic α-amino acids and dicarboxylic acid derivatives, which are epimerically and also enantiomerically pure. Acidic Cr(VI)-mediated oxidation (Jones oxidation) has been optimized with respect to reaction conduct and work up (addition of ethylenediamine).

Asymmetric synthesis of bicyclic α-amino acids by a Diels–Alder reaction to a new chiral α,β-didehydroalanine derivative

A new chiral cyclic α,β-didehydroalanine derivative, (6 S)-6-isopropyl-3-methylene-5-phenyl-3,6-dihydro-2 H-1,4-oxazin-2-one, has been prepared by in situ aminomethylation–elimination of a chiral glycine-derived precursor. This oxazin-2-one acts as a reactive dienophile in highly diastereoselective Diels–Alder reactions with cyclopenta- and cyclohexadiene. The major cycloadducts have been isolated and hydrolyzed to afford enantiomerically pure (−)- endo-2-aminobicyclo[2.2.1]heptane-2-carboxylic and exo-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.

Chiral, bicyclic proline derivatives and their application as ligands for copper in the catalytic asymmetric allylic oxidation of olefins

The preparation of the unnatural, bicyclic α-amino acids 7 and 8 is described, along with their utility as chiral ligands in the copper-catalyzed enantioselective allylic oxidation of cyclohexene with tert-butyl perbenzoate. These bicyclic amino acids were found to be superior to ( l)-proline and gave optically active 2-cyclohexenyl benzoate in 48–67% yield and up to 65% e.e.

Synthesis of Bridged Bicyclic β-Trifluoroacetoxy β-Trifluoromethyl α-Amino Acid Derivatives by an Original Dakin-West/Diels-Alder Tandem Sequence

The reaction of hippuric acid with trifluoroacetic anhydride in the presence of cyclopentadiene affords useful bicyclic α-amino acid derivatives bearing β-trifluoroacetoxy and β-trifluoromethyl groups.