Enantioselective synthesis of α-deuterium labelled chiral α-amino acids via dynamic kinetic resolution of racemic azlactones

Catalytic dynamic kinetic resolution (DKR) of racemic azlactones with EtOD using squaramide-based dimeric cinchona alkaloid organocatalysts is shown to be a highly effective strategy for the preparation of enantiomerically pure α-deuterated chiral α-amino acids.     

Naphthyl-l-α-amino acids via chemo-enzymatic dynamic kinetic resolution

A double catalyst system (protease + base) was applied to the dynamic kinetic resolution (DKR) of isomeric 1- and 2-α-naphthyl-glycines and -alanines exploiting the in situ racemization of their thioesters. Due to the different C-acidity of the two sets of compounds, different experimental conditions have been devised to perform the simultaneous resolution/racemization process.In all cases, the racemic N-Boc-thioesters were converted into the aminoacids with an l-configuration almost quantitatively and with complete enantioselectivity.     

Dynamic kinetic resolution of azlactones catalyzed by chiral Brønsted acids

Chiral Br?nsted acids have been shown for the first time to catalyze the dynamic kinetic resolution of azlactones. 3,3'-Bis-(9-anthryl)-BINOL phosphoric acid 3c is particularly effective in the case of 4-aryl-substituted substrates, producing 85-92% ee's.     

Dynamic kinetic resolution of racemic α-sulfonylaldehydes via asymmetric transfer hydrogenation

Hydrogen transfer reduction of α-sulfonylaldehydes using HCOOH-Et₃N system as hydrogen source and (S,S)-TsDPEN-based Ru(II) as catalyst proceeds with dynamic kinetic resolution, providing optically active β-sulfonyl primary alcohols in moderate-to-good yields and up to 90% ee.     

Enantioselective synthesis of α-amino acids in chiral reverse micelles

Through alkylation of ethyl 2-phthalimidoacetate in chiral reverse micelles formed from chiral surfactants, followed by hydrazinolysis and hydrolysis of the resulting products, optically active α-amino acids were synthesized. The highest enantioselectivity was 59.5%. Meanwhile, we have found that the asymmetric induction depends on the reaction temperature, the alkyl chain length of surfactant and the strucure of the surfactants.     

Enantioselective synthesis of functionalized α-amino acids via a chiral guanidine catalyzed Michael addition reaction

Several chiral guanidines were evaluated as catalysts for the Michael reaction of glycine derivatives 7 with acrylic esters 8. The best result (30.4% ee) was obtained when 7b was reacted with 8b under the catalysis of guanidine 1 in THF.     

Asymmetric synthesis of quaternary α-amino acids using d-ribonolactone acetonide as chiral auxiliary

We describe a new simple methodology to prepare enantiopure α,α-dialkylglycines based on the use of commercially available d-ribonolactone as a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of d-ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4-disubstituted 3-methyl-2-pyrazolin-5-ones.     

Asymmetric synthesis of α-alkyl α-selenocarbonyl compounds catalyzed by bifunctional organocatalysts

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%.     

Nonenzymatic kinetic resolution of racemic β-hydroxyalkanephosphonates with a chiral copper catalyst

Kinetic resolution of β-hydroxyalkanephosphonates was efficiently performed by 2-fluorobenzoylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst with good s value of up to 21.     

Synthesis and resolution of new paramagnetic α-amino acids

New, paramagnetic unnatural α-amino acids were synthesized by the O'Donnell method. In the new amino acids nitroxide is condensed with thiophene, benzene, and tetrahydroisoquinoline ring, or linked through a methylene, benzyl or propargyl spacer. Some of the racemic paramagnetic α-amino acid esters described earlier or in this work were resolved by fractional crystallization of diastereomeric salts. Another approach for optically active paramagnetic amino acids is the modification of S-tyrosine derivatives with Pd-catalyzed cross-coupling reactions with paramagnetic acetylene and with a paramagnetic boronic acid.     

Absolute asymmetric synthesis of tertiary α-amino acids

Frozen: the spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the deprotonation/alkylation. α-Amino acid derivatives are synthesized in up to 96 % ee.     

Direct asymmetric synthesis of α-deuterated α-amino acid derivatives from the parent α-amino acids via memory of chirality

A method for asymmeyric α-deuteration of α-amino acid derivatives has been developed by a memory of chirality (MOC) strategy. The α-deuterated α-amino acid derivatives with 88–93% D were obtained in 60–98% ee in retention of the configuration (7 examples). The characterisrtic feature of the present procedure is that asymmeric induction was achieved by employing the parent amino acid derivatives as a sole source of chirality without the use of any external chiral souces.     

Highly enantioselective synthesis of α-trichloromethyldihydropyrans catalyzed by bifunctional organocatalysts

The enantioselective Michael addition of α-cyanoketones to α,β-unsaturated trichloromethyl ketones was firstly reported. With a phenylalanine-derived bifunctional piperazine/thiourea catalyst, a series of α-trichloromethyldihydropyrans were obtained with up to 95% ee and 99% yield.     

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.     

Asymmetric synthesis of β-amino acids through application of chiral sulfoxide

This paper describes asymmetric synthesis of β-aminophenylpropionic acid through application of a homochiral sulfoxide auxiliary. High kinetically controlled (3R,2S,R_S)-diastereoselectivity (−60°C) is achieved during addition of the lithium enolate of tert-butyl (+)-(R)-p-toluenesulfinylacetate to substituted N-(benzylidene)toluene-4-sulfonamides 2a–2d. The reductive cleavage of adduct 3a with sodium amalgam yielded tert-butyl 3-(toluene-4-sulfonamido)-3-phenylpropionate 5a, which was subjected to ester hydrolysis and subsequent detosylation with sodium in liquid ammonia to yield (S)-β-aminophenylpropionic acid in good yield and high 91% e.e.     

Baeyer–Villiger monooxygenase-catalyzed kinetic resolution of racemic α-alkyl benzyl ketones: enzymatic synthesis of α-alkyl benzylketones and α-alkyl benzylesters

The application of three BVMOs for the enantioselective oxidation of 3-phenylbutan-2-ones with different substituents in the aromatic moiety is described. By choosing the appropriate biocatalyst and substrate combination, chiral ketones and esters can be obtained with excellent enantiopurities. This methodology could also be applied to the resolution of racemic α-alkyl benzylketones with longer alkyl chains as well as with two substituted α-substituted benzylacetones. A kinetic analysis revealed that the BVMOs studied effectively convert all tested compounds showing that the enzymes are tolerant towards the substrate structure while being highly enantioselective. These properties render BVMOs as valuable biocatalysts for the preparation of compounds with high interest in organic synthesis.     

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids

An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane–water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.     

Enantioselective Michael addition of diethyl cyanomethylphosphonate to chalcones using bifunctional cinchona-derived organocatalysts: synthesis of chiral precursors of α-substituted β-aminophosphonates

An enantioselective Michael addition of diethyl cyanomethyl phosphonate to chalcones catalysed by bifunctional catalysts based on cinchona alkaloids has been developed, producing enantiomerically enriched cyanophosphonate precursors of α-substituted β-aminophosphonates.