Highly efficient synthesis of chiral beta-amino acid derivatives via asymmetric hydrogenation

The Rh-TangPhos complex is an efficient hydrogenation catalyst for making chiral beta-amino acid derivatives. With the Rh-TangPhos system, high enantioselectivities (up to 99.6%) and turnover numbers have been obtained in the hydrogenation of E/Z isomeric mixtures of both beta-alkyl and beta-aryl beta-(acylamino)acrylates. [reaction: see text]     

Stereoselective formation of N-acyliminium ion via chiral N,O-acetal TMS ether and its application to the synthesis of beta-amino acids

[reaction: see text] The highly stereoselective synthesis of beta-amino acids via the chiral 4-phenyloxazolidinone-controlled linear N-acyliminium ion reaction has been achieved by employing chiral N,O-acetal TMS ethers. In addition, the mechanism of the excellent stereochemical outcome has been elucidated. The oxazolidinone auxiliary plays a dual role in stereocontrol: the E/Z geometry control of the N-acyliminium ion induced by an initial stereoselective amide reduction, leading to the chiral N,O-acetal TMS ether, and face control of the nucleophile attack in the N-acyliminium ion reaction.     

Synthesis of alpha-substituted beta-amino acids using pseudoephedrine as a chiral auxiliary

[reaction: see text] beta-Amino acids are becoming increasingly attractive as intermediates in the synthesis of a variety of molecular structures. However, few methods are available for the synthesis of alpha-substituted beta-amino acids that are both readily scalable and highly stereoselective. Herein we report a new method for synthesizing alpha-substituted beta-amino acids that satisfies both of these requirements using enantiomerically pure pseudoephedrine as a chiral auxiliary.     

The first aminoacylase-catalyzed enantioselective synthesis of aromatic beta-amino acids

The first aminoacylase-catalyzed enantioselective synthesis of aromatic beta-amino acids is reported. The presence of an N-chloroacetyl group as acyl group in the substrate as well as the use of porcine kidney acylase I as a suitable enzyme component are prerequisites for this resolution process whereby optically active beta-amino acids are formed with high enantioselectivities of >98% ee.     

Stereoselective synthesis of beta-substituted beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines

[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.     

Solid-phase synthesis of isoxazolines

The polymer-supported synthesis of isoxazolines is described via nitrile oxide intermediates, starting from primary nitroalkanes in a one-pot process.     

Liquid chromatographic separation of enantiomers of beta-amino acids using a chiral stationary phase

The enantiomers of both alpha-substituted beta-alanines and beta-substituted beta-alanines may be chromatographically separated using silica-bonded chiral stationary phases derived from N-acetylated alpha-arylalkylamines. The amino acids are chromatographed as alkyl esters of N-3,5-dinitrobenzoyl derivatives; separability factors range from 1.11 to 1.65 for nine alpha-substituted beta-alanines and from 1.08 to 1.20 for nine beta-substituted beta-alanines. The enantiomers of beta-aminoisobutyrate and beta-leucine, chiral beta-amino acids occurring in animal tissues and physiological fluids, are among those resolved. The enantiomers of R,S-beta-aminoisobutyrate and several related alpha-alkyl-beta-alanines were prepared by chromatographic resolution of diastereomeric dipeptides.     

Traceless solid-phase synthesis of chiral 3-aryl beta-amino acid containing peptides using a side-chain-tethered beta-amino acid building block

[reaction: see text] A general method for the attachment of a chiral aromatic side-chain-containing beta-amino acid to a polymer support using a traceless silyl linkage strategy has been developed. Using this building block, solid-phase synthesis was carried out to obtain tripeptide analogues with the aromatic ring either unsubstituted or halogenated (Br, I) at the position of the silyl group. The building blocks could generate libraries of peptidomimetics or cyclic peptides containing beta-amino acids with nonpolar side chains.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

New synthesis of optically active 5-isoxazolidinones and beta-amino acids

A new simple and stereoselective synthesis of 5-isoxazolidinones based on the reaction of lithiated 2-isopropyl-2-oxazolines with nitrones is described. A chiral version of such a methodology allows the preparation of highly enantioenriched 5-isoxazolidinones which are useful precursors for the synthesis of beta-amino acids     

New strategy for the stereoselective synthesis of fluorinated beta-amino acids

Racemic and chiral nonracemic alpha-substituted and alpha-unsubstituted beta-fluoroalkyl beta-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained gamma-fluorinated beta-enamino esters 4 by using ZnI(2)/NaBH(4) in a nonchelated aprotic medium (dry CH(2)Cl(2)) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral beta-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.     

Asymmetric synthesis of quaternary alpha- and beta-amino acids and beta-lactams via proline-catalyzed mannich reactions with branched aldehyde donors

[reaction: see text] L-Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected alpha-imino ethyl glyoxylate with various alpha,alpha-disubstituted aldehydes affords quaternary beta-formyl alpha-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted to the corresponding quaternary alpha- and beta-amino acids and beta-lactams.     

Asymmetric synthesis of beta-amino alcohols by reductive cross-coupling of benzylideneamine with planar chiral benzaldehydes

[reaction: see text] Samarium iodide mediated reductive cross-coupling of N-tosyl benzylideneamine with benzaldehydes or the corresponding chromium complexes gave syn-beta-amino alcohol derivatives. A dynamic kinetic resolution of a configurationally equilibrated reactive species occurred in the cross-coupling with planar chiral benzaldehyde chromium complexes.     

Asymmetric synthesis of beta-hydroxy amino acids via aldol reactions catalyzed by chiral ammonium salts

The Cinchona alkaloid derived chiral ammonium salt developed by Park and Jew functions as an effective catalyst for the synthesis of beta-hydroxy alpha-amino acids via asymmetric aldol reactions under homogeneous conditions. The syn diastereomers are obtained in good ee, and aryl-substituted aliphatic aldehydes are the best substrates for the reaction. These results represent the highest ee's obtained to date in direct aldol reactions of glycine equivalents catalyzed by inexpensive, readily prepared chiral ammonium salts.     

Synthesis of cyclic and acyclic beta-amino acids via chelation-controlled 1,3-dipolar cycloaddition

Isoxazolidines have been synthesized in diastereomeric excess up to 94% via a MgBr2-induced chelation-controlled 1,3-dipolar cycloaddition reaction with N-hydroxyphenylglycinol as a chiral auxiliary. The diastereomerically pure isoxazolidines were further transformed into cyclic and acyclic beta-amino acid derivatives.     

Liquid chromatographic separation of the enantiomers of beta-amino acids on a ligand exchange chiral stationary phase

A liquid chromatographic ligand exchange chiral stationary phase (CSP) derived from (S)-leucinol was applied in the separation of the enantiomers of 12 beta-amino acids. The resolution was quite successful especially for the enantiomers of beta-amino acids containing aromatic functional group in the side chain. The chromatographic resolution behaviors were dependent on the organic modifier and Cu(II) concentration in aqueous mobile phase and the column temperature.     

Recent developments in the catalytic asymmetric synthesis of alpha- and beta-amino acids

The stereoselective synthesis of amino acids is of great importance for the construction of optically active natural products and pharmaceuticals. Apart from enzymes, a broad repertoire of chiral reagents, auxiliaries, and catalysts can be used for the formation of amino acids. Asymmetric reactions using catalytic amounts of chiral molecules provide efficient methods for the generation of optically active proteinogenic and nonproteinogenic amino acids. This minireview collects recent work on catalytic asymmetric synthesis of alpha- and beta-amino acids.     

手性蒎烯酮亚胺用于立体选择性合成

研究了一系列新蒎烯酮亚胺用于不对称烷基化, 羰基加成和双手性诱导反应。具有π结构的烯酮亚胺具有90%~~99%的立体选择性, 它们可用我们提出的过渡模型来解释。