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.     

Synthesis of chiral 1-(imidazol-2-yl)alkanamines using neomenthanethiol as a chiral auxiliary

Diastereomeric N-(imidazol-2-ylmethylidene)neomenthane-3-sulfinamides were obtained from enantiomerically pure neomenthanethiol in three steps. The compounds obtained added Grignard reagents at the C=N bond. After separation of diastereomers, an acid resolution gave enantiomerically pure primary 1-(imidazol-2-yl)alkanamines. In this scheme, the neomenthane fragment played the role of a chiral auxiliary.     

Succinct synthesis of beta-amino acids via chiral isoxazolines

beta-Amino acids are important synthetic targets due to their presence in a wide variety of natural products, pharmaceutical agents, and mimics of protein structural motifs. While beta-amino acids containing geminal substitution patterns have enormous potential for application in these contexts, synthetic challenges to the stereoselective preparation of this class of compound have thus far limited more complete studies. We present here a straightforward method employing chiral isoxazolines as key intermediates to access five different beta-amino acid structural types with excellent selectivity. Of particular note is the use of this approach to prepare highly substituted cis-beta-proline analogues. The ready access to these diversely substituted compounds is expected to facilitate future studies of the structure and function of this important class of molecules.     

Synthesis of planar chiral ferrocene dicarboxylic acids using a sugar derivative as a resolution tool

The synthesis of planar chiral ferrocene dicarboxylic acids has been accomplished via diastereoselective esterification at the 2- and 3-positions with (+)-(4,6-O-benzylidene)methyl-α-d-glucopyranoside.     

Stereoselective synthesis of novel pyrazole derivatives using tert-butansulfonamide as a chiral auxiliary

A novel chiral pyrazole derivative was developed by our research program as a potent PDE4 inhibitor for the treatment of anti-inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. The asymmetric synthesis of the inhibitors carrying the pyrazole moiety, including nitrogen directly bonded to a chiral center, through a novel approach is disclosed. The key steps of the synthetic sequence begin with the preparation of chiral toluenesulfinyl imine by the condensation of (R)- and (S)-tert-butanesulfinamide with an aldehyde. Next, a corresponding chiral amine synthesis by a stereoselective addition reaction of 4-picolyl lithium to the chiral toluenesulfinyl imine is performed, followed by desulfination. The preparation of the cis-type enaminone from the addition of the enaminone to the corresponding chiral amine is then accomplished, with further transformation into the pyrazole derivatives through the amination of the enaminones and subsequent dehydro-cyclization. A total of 8 steps are completed to produce a 5.5% yield (100% ee).     

Role of pseudoephedrine as chiral auxiliary in the "acetate-type" aldol reaction with chiral aldehydes; asymmetric synthesis of highly functionalized chiral building blocks

We have studied in depth the aldol reaction between acetamide enolates and chiral α-heterosubstituted aldehydes using pseudoephedrine as chiral auxiliary under double stereodifferentiation conditions, showing that high diastereoselectivities can only be achieved under the matched combination of reagents and provided that the α-heteroatom-containing substituent of the chiral aldehyde is conveniently protected. Moreover, the obtained highly functionalized aldols have been employed as very useful starting materials for the stereocontrolled preparation of other interesting compounds and chiral building blocks such as pyrrolidines, indolizidines, and densely functionalized β-hydroxy and β-amino ketones using simple and high-yielding methodologies.     

Highly diastereoselective nucleophilic additions using a novel myrtenal-derived oxathiane as a chiral auxiliary

The synthesis of novel oxathiane 3 and its acetyl derivative 12, from commercially available (−)-myrtenal 4, is described. The addition of several nucleophilic reagents to 12 furnished the corresponding tertiary carbinols in highly diastereomeric excess. The hydrolysis of 11a, b yielded the expected α-hydroxycarbonyl compounds in excellent enantiomeric excess.     

Asymmetric strecker synthesis of alpha-amino acids via a crystallization-induced asymmetric transformation using (R)-phenylglycine amide as chiral auxiliary

[reaction: see text]. Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in 76-93% yield and dr > 99/1. The diastereomerically pure alpha-amino nitrile obtained from pivaldehyde (R1 = t-Bu, R2 = H) was converted in three steps to (S)-tert-leucine in 73% yield and >98% ee.     

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.     

Synthesis and crystal structure of a novel chiral compound prepared from (-)-borneol as a natural chiral auxiliary

Ｒｅｃｅｎｔｌｙ,ｍｕｃｈｅｆｆｏｒｔｈａｓｂｅｅｎｍａｄｅｉｎｔｈｅｄｅｖｅｌｏｐｍｅｎｔｏｆｇｅｎｅｒａｌｌｙａｐｐｌｉｃａｂｌｅｏｒｇａｎｉｃｓｙｎｔｈｅｓｉｓｏｆ5ｈｙｄｒｏｘｙ2(5Ｈ)ｆｕｒａｎｏｎｅ1ｄｕｅｔｏｉｔｓｅｓｓｅｎｔｉａｌｓｔｒｕｃｔｕｒｅｅｎｔｉｔｙｉｎｔｈｅｓｙｎｔｈｅｓｉｓｏｆｓｏｍｅｂｉｏｌｏｇｉｃａｌｌｙａｃｔｉｖｅｎａｔｕｒａｌｐｒｏｄｕｃｔｓａｎｄｉｔｓａｐｐｌｉｃａｔｉｏｎａｓａｕｓｅｆｕｌｉｎｔｅｒｍｅｄｉａｔｅｉｎｏｒｇａｎｉｃｓｙｎｔｈｅｓｉｓ[1—3].Ｃｏ…     

Synthesis of a new fluorinated oxazolidinone and its reactivity as a chiral auxiliary in Aldol reactions

A new enantiomerically pure fluorinated oxazolidinone has been prepared from a fluorinated imidoyl chloride and an optically pure sulfoxide. The diastereoselective reduction of the β-iminosulfoxide thus formed followed by elimination of the sulfoxide and cyclization of the created aminoalcohol furnishes the desired product. The fluorinated oxazolidinone was subsequently used as a chiral auxiliary in Aldol reactions. We also found that the selective formation of the syn-Evans and syn-non-Evans diastereoisomer can be controlled by adjusting the Lewis acid/base ratio.     

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids using (S,S)-cyclohexane-1,2-diol as a chiral auxiliary

Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a-f and 5a-f) of 92->95% de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF(3)-OEt(2) afforded beta-keto esters (3 and 6) bearing a chiral quaternary carbon. The beta-keto esters could be easily converted into optically active alpha-methylated and/or alpha-ethylated alpha,alpha-disubstituted amino acids (12 and 13) in 21-99% yields using Schmidt rearrangement.     

Asymmetric synthesis of beta-amino esters by aza-Michael reaction of alpha,beta-unsaturated amides using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Chiral nonracemic beta-amino esters were prepared in good yields and enantioselectivities using the diastereoselective conjugate addition of nitrogen nucleophiles to alpha,beta-unsaturated amides derived from (S,S)-(+)-pseudoephedrine as the key step. In this way, several beta-amino amide adducts were prepared using different conjugate acceptors and two different lithium benzylamides as nucleophiles. These adducts were easily converted in only one step, into the final, highly enantioenriched beta-amino esters     

Synthesis of substituted cyclohexenyl-based beta-amino acids by ring-closing metathesis

[structure: see text] A versatile ring-closing metathesis (RCM) approach has been developed for the preparation of cis and trans cyclohexenyl-based beta-amino acids that are either unsubstituted (3) or substituted (10 and 12) at the alpha-position.     

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.     

Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.     

Synthesis and evaluation of a new polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase

A polymer-supported pseudoephedrine auxiliary linked to the support through nitrogen, has been developed for use in asymmetric alkylations on solid phase.     

Practical optical resolution of dl-muscone using tartaric acid derivatives as a chiral auxiliary

A simple and practical synthesis of (R)-(−)-muscone was achieved by optical resolution of dl-muscone using tartaric acid derivatives. The acetalization of dl-muscone with N,N′-dibenzyl-l-tartaramide in the presence of Sc(OTf)₃ and methyl orthoformate furnished a diastereomeric mixture of acetals, which were readily separated by simple recrystallization. Diastereomerically pure acetal was hydrolyzed to give optically pure muscone and recovered N,N′-dibenzyl-l-tartaramide.