Aqueous reactions amino acids/derivatives

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Liquid/liquid partition chromatography was explored by Willstatter from 1913. The process was extensively developed by Martin and Synge (ca. 1941-1948) who partitioned amino acid derivatives between chloroform and water using precipitated silica as support for the aqueous phase. The preparations of silica were again very variable and it was difficult to prevent adsorption which interfered with the expected behavior of the aminoacids. At first methyl orange was added to the water phase to visualize the amino acids the separation of the acids then caused a red band to move down the columns. The quantitative reaction with ninhydrin was introduced by Moore and Stein in 1948 for both the detection and estimation of the amino acids. Consid-... 

Scheme 17 illustrates enantioselective synthesis of a-amino acids by phase-transfer-catalyzed alkylation (46). Reaction of a protected glycine derivative and between 1.2 and 5 equiv of a reactive organic halide in a 50% aqueous sodium hydroxide-dichloromethane mixture containing 1-benzylcinchoninium chloride (BCNC) as catalyst gives the optically active alkylation product. Only monoalkylated products are obtained. Allylic, benzylic, methyl, and primary halides can be used as alkylating agents. Similarly, optically active a-methyl amino acid derivatives can be prepared by this method in up to 50% ee. 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

It was mentioned in the beginning that azlactones and oxazinones are activated amino acid derivatives. In the KR discussed here, the remaining oxazinone enantiomer can be reacted further, in the crude reaction mixture, with nucleophiles. For example, treatment with resin-bound and N-terminally nonprotected peptides results in coupling with a P-amino acid. Heating of the homogeneous crude reaction mixture (typically toluene as solvent) with dilute aqueous hydrochloric acid results in hydrolysis of the unreacted oxazinone enantiomer and precipitation of the corresponding N-acyl P-amino acid. The latter can be isolated in excellent enantiomeric purity by simple filtration. The filtrate contains the P-amino acid ester of opposite configuration (Berkessel et al. 2005). 

Silyl esters are stable to nonaqueous reaction conditions, but are often too labile to mild acid or base or even neutral aqueous media to survive many simple manipulations. Thus, they have not found wide application in peptide synthesis. Due to easy formation and cleavage they may play an important role as intermediates in the synthesis of amino acid derivatives and for temporary carboxy protection in the preparation of small peptide fragments. The TMS group has been used for the solubilization of H-Arg-OH for the synthesis of Z-Arg(Z2)-OHP l and in the synthesis of Al -Nps- and Al -Tfa-protected amino acids.P Amino acid trimethylsilyl esters as well as the related A1 -TMS derivatives react rapidly with acylating agents and are used for the preparation of peptides with amino acid active esters, e.g. A-hydroxysuccinimide-, 4-nitrophenyl-, or 2,4,5-trichlorophenyl esters, or mixed anhydrides. 

Tilak et described the use of excess mixed carbonic anhydrides to force condensation reactions to completion followed by the destruction of the excess mixed anhydride via the addition of aqueous potassium hydrogencarbonate. Hydrolysis of the nnixed anhydride was rapid and the resulting protected dipeptide could be extracted into ethyl acetate in a high state of purity, leaving the excess amino acid derivative and the salts in the aqueous phase. Without further purification the protected dipeptide was N -deprotected and reacted with the next mixed anhydride, and the process repeated until the desired peptide was obtained. Beyerman et al. substantially expanded the scope of this procedure and named it the REMA method for peptide synthesis (Repetitive Excess Mixed Anhydride).P°1 These reaction conditions provide an excellent method to ensure complete reaction of the amine component as well as rapid reaction rates and minimal side products. However, care must be taken to ensure that the excess carboxylic acid component is soluble in sodium hydrogencarbonate solution, e.g. when Z-Asp(OBzl)-OH is the acid component, it is extracted into the ethyl acetate as the sodium salt along with the product. With the due precautions the yields of small peptides are so high that the method could be applied without purification of the intermediate products, that is, in a repetitive way. 

Lopez-Deber, M. P., Castedo, L., Granja, J. R. Synthesis of N-(3-Arylpropyl)amino Acid Derivatives by Sonogashira Types of Reaction in Aqueous Media. Org. Lett. 2001, 3, 2823-2826. 

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

PEG-supported cinchona ammonium salts 54 were applied to the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives 52 [34]. The use of a water-soluble polymer support allowed the reaction to be conducted in a 1M KOH aqueous solution to give the a-amino acid derivatives 53 in high chemical yields (up to 98%). Ten different types of electrophile have been tested for the reaction, with the best enantioselectivity being obtained with o-chlorobenzylchloride (97% ee) (Scheme 3.15). 

The reaction is carried out at pH 7.7 (in 0.02 M borate buffer) in order to prevent extensive reaction with phenolic or alcoholic hydroxyls. In this way tyrosine can be measured as a monosubstituted derivative. To 0.5 ml of sample solution is added 0.5 ml of reagent (15 mM FMOC-Cl in acetone). After about 40 s the mixture is extracted with three 2 ml portions of n-pentane. The aqueous solution with the amino acid derivatives is ready for chromatographic separation. If the reaction volumes are reduced to 10—50 1 and the amount of the reagent is minimized, it is not necessary to extract the surplus reagent, even though it is fluorescent. The chromatographic procedure must be suitable to separate the derivatives from the reagent and its hydrolysis product. 

The dehydroamino acid derivative 146 (0.117 g, 0.27 mmol) was dissolved in MeOH (10 mL) and nitrogen was bubbled through this solution. (/ ,/ )-[Rh(DIPAMP)(cod)]BF4 (13.0 mg, 0.018 mmol, 0.065 equiv) was added under a nitrogen atmosphere and the mixture was degassed under vacuum. The mixture was then hydrogenated (65 psi) at 48 C for 16 h. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator, and then the residue was purified by column chromatography on silica gel (25% EtOAc in hexanes) to afford 0.105 g of the desired a-amino acid derivative 147 in 89% yield as viscous oil. Analytical RP HPLC MeCN 0.05% aqueous acetic acid/60 40, 2.0 mL/min at 225 nm, tR 5.44 min, 99% ee. 

Li and coworkers reported the conjugate addition of alkyl groups to enamides mediated by zinc in aq. NH4CI to generate a -amino acid derivatives (Eq. 4.73). No reaction was observed in the absence of water. Both secondary and tertiary alkyl groups such as linear (2-butyl, 2-propyl, 2-pentyl), cyclic (cyclohexyl, cyclopentyl, cycloheptyl), and bulky ones (tert-butyl) were all transferred to the substrate successfully. Even simple primary iodides and methyl iodide provided the desired products in good yields. Miyabe et al. as well as Jang and Cho reported the addition of alkyl radicals from alkyl iodide to a,p unsaturated ketones, esters, and nitriles mediated by indium in aqueous media. Indium-mediated Michael addition of allyl bromide to l,l-dicyano-2-arylethenes also proceeded well in aqueous medium. ... 

---