Amino acids methylene activation

For both the preliminary and fined test peptides, it was necessary to prepare all possible isomers as standards for analysis. These reference peptides were synthesized using a PE-ABD 430A peptide synthesizer configured for FastMoc synthesis protocols. Piperidine (20%) in N-methylpyrrolidone (NMP) was used to deprotect the N-terminal amino acid. To activate each amino acid in the reaction vessel, the following was used 1.0 mM amino acid, 1.0 mM 2-(lH-benzotriazol-l-yl)-l-l-2,3, tetramethyluronium hexafluorophosphate (HBTU) in 1 M 1-hydroxybenzotriazole (HOBT) in NMP, 2.0 mM diisopropylethylamine (DIEA). Each His residue was double-coupled. HBTU, DIEA, piperidine, DMF and NMP were purchased from ABI. Methylene chloride was purchased from Burdick and Jackson. 

Lactim ethers and thioethers are reported to react with imides <93H(35)1055>, amino ketones and acetals <82jhci93>, amino acids <90JHC1973>, active methylene compounds <82JHC193, 82JHC43I, 88T3309), and diethyl ethoxymethylenemalonate <84H(22)2285>. 7,8,9,10-Tetrahydro-6//-l,3,5-tri-azino[l,2-fl]azepine-2,4(3/f)-dione has been prepared from 7-amino-3,4,5,6-tetrahydro-2(//)-azepine and diphenyl imidodicarboxylate <93JHC55l>, and caprolactam acetals are reported to react with amino heterocycles <938521 > and ureas and urethanes <82KGS1553>. Most of these reactions lead to fused azepines either directly or after subsequent treatment of the isolated intermediate. 

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

Coupling constants are routinely used to determine the side-chain conformation of amino acids in peptides and proteins. Whereas proteins nowadays are almost exclusively studied as C- and N-labeled isotopomers, peptides usually have these isotopes in natural abundance, i.e. the magnetically active heteronuclei are highly diluted. Most amino acids contain a methylene group at the ji-position for which the X angle is determined by the conformation of the Ca—Cp bond. Two vicinal Jhh coupling constants can be measured Ha to and H to Usually... 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

The protoberberine alkaloid, xylopinine, has been synthesized in an optically active form by Kametani et al.22 ). A key reaction in this synthesis was the photochemical cyclization of the optically active amino acid derivative 1,2,3,4-tetrahydro-6,7-dimethoxy-3-methoxycarbonyl-1 -methylene-2-veratroylisoquinoline with 1,3... 

The methylene group of a-amino acid metal complexes such as the copper(II) glycinato complex is activated to some extent by the polarizing influence of the metal.46,47 Consequently, carban-ion-type reactions can be carried out at this position, while the amino and carboxyl groups are protected by coordination. These reactions cannot be performed on either the free ligand or the conjugate base. 

The kinetic acidity of the methylene protons on coordinated amino acid fragments is enhanced in imine complexes such as those derived from the ligands (116)307 and (117).308 This enhanced acidity is responsible for both racemization309 310 and transamination311-313 processes, which have been studied in detail because of the biologically important pyridoxal-activated enzyme... 

Other chiral PTC alkylations of active methylene compounds leading to amino acid derivatives have been reported [24] as have other alkylations [25]. Several reported asymmetric PTC alkylations have been disputed [26-29]. 

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