Synthesis of orthogonally protected azepane β-amino ester enantiomers

A simple and convenient route is presented for the preparation of regio- and stereoisomers of novel azepane β-amino esters, starting from bicyclic β-lactam isomers. The synthetic procedure consists of dihydroxylation of the olefinic bond of the alicyclic amino esters, followed by NaIO₄-mediated cleavage of the diol intermediate and reductive ring closure, which furnishes novel regioisomeric 5-aminoazepane-4-carboxylate and 3-aminoazepane-4-carboxylates. This method also allows the preparation of amino esters with an azepane skeleton in enantiomerically pure form.     

A new and convenient approach for the preparation of β-cyanoethyl protected trinucleotide phosphoramidites

Herein we report a convenient approach for the preparation of fully protected trinucleotide synthons to be used for the synthesis of gene libraries. The trinucleotide synthons bear β-cyanoethyl groups at the phosphate residues, and thus can be used in standard oligonucleotide synthesis without additional steps for deprotection and work-up.     

A new route to heterocyclic α-dehydro α-amino esters

Heterocyclic α-dehydro α -amino esters are obtained by the reaction of ethyl N-carbomethoxy oxamate with ω-halogened phosphorus ylids.     

A new strategy for the stereoselective synthesis of unnatural α-amino acids

A new method for the synthesis of racemic non-proteinogenic α-amino acids has been developed, which involves (i) hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to electron rich alkenes such as enol ethers, enamines and allylsilanes, (ii) NaCNBH₃ reduction of the CN bond in the oxazines thus generated, the stereochemistry of the products being controlled by epimerisation of the thermodynamically less stable isomer to the more stable one, (iii) protection of the N-H group as N-Boc and (iv) finally, N-O bond cleavage of both free and protected products to give proline or bis-homoserine derivatives, respectively. An example with concomitant reduction of the carboxylate group, resulting in the formation of the respective amino alcohol is reported. Applying this methodology to a homochiral enol ether, the protected parent d-proline was prepared in enantiomerically pure form, whereas the asymmetric synthesis of the respective bis-homoserine was unsuccessful.     

A new strategy for the synthesis of chiral β-alkynyl esters via sequential palladium and copper catalysis

A new strategy for the synthesis of chiral β-alkynyl esters which relies on sequential Pd and Cu catalysis is reported. Terminal alkynes bearing aryl, alkyl, and silyl groups can be employed without prior activation yielding a wide range of important chiral building blocks. The reaction sequence utilizes a robust Pd(II)-catalyzed hydroalkynylation of ynoates with terminal alkynes providing geometrically pure ynenoates which are readily reduced by CuH. In contrast to previous reports, where additions to ynenoates proceed with marginal preference for the 1,6-pathway, this conjugate reduction occurs with high 1,4-selectivity yielding β-alkynyl esters with excellent levels of enantioselectivity. Importantly, the method tolerates a wide range of functionality, including allylic carbonates and carbamates, and thus allows for rapid elaboration of the β-alkynyl esters into a variety of chiral, substituted heterocycles.     

Parallel kinetic resolution of racemic mixtures: a new strategy for the preparation of enantiopure compounds?

Kinetic resolution of racemic mixtures is a well-established methodology for the preparation of optically active compounds. However, excellent enantioselectivities are required to obtain them in enantiopure form, due to the decrease in ee when conversion values are close to 50%. To overcome this limitation, a parallel (asymmetric) reaction can remove the disfavored enantiomer. In this review, several examples of this strategy showing its wide range of applicability are described, as well as their mathematical treatment and some new applications in combinatorial chemistry.     

Asymmetric synthesis of allylic secondary alcohols: a new general approach for the preparation of α-amino acids

A new general approach for the synthesis of optically active α-amino acids has been developed. The key steps involve a ruthenium catalysed cross-coupling reaction to give a range of α,β-unsaturated ketones, which were then reduced to allylic secondary alcohols in the presence of a chiral CBS oxazaborolidine. A thermal Overman rearrangement was used to prepare a series of allylic trichloroacetimidates and these were converted under standard conditions to the target α-amino acids in good overall yields.     

Organocatalytic preparation of simple β-hydroxy and β-amino esters: low catalyst loadings and gram-scale synthesis

A combined amino- and N-heterocyclic carbene (NHC)-catalyzed one-pot reaction sequence for the synthesis of simple enantioenriched β-hydroxy and β-amino esters using commercially available catalysts at low catalyst loadings has been developed. The desired products were obtained in high yield and excellent enantiopurity. The generation of quaternary stereocenters and application in gram-scale synthesis were also realized, with no requirements of inert or anhydrous reaction conditions, thus making this transformation a highly practical protocol.     

A new strategy for the stereospecific syntheses of C-furanosides

This reaction provided an efficient method to synthesize C-furanoside derivatives in high yields and stereospecificity under mild conditions.The cyclization mechanism regarding benzyl group as a leaving group was discussed and their stereochemistry was deduced by 1H-1H NOESY data.     

A new enantioselective synthesis of β-amino acids

Enantioselective hydrogenation of some α,β-unsaturated nitriles and their corresponding methyl esters bearing a phthalimidomethyl substituent at the α-carbon using Rh-DuPHOS catalysts afforded β-amino acid precursors with modest e.e.s of up to 48%. Hydrogenation of the α,β-unsaturated methyl esters using a Ru-BINAP catalyst gave higher e.e.s of up to 84%. Method development for the determination of the enantiomeric excesses of these derivatives using chiral HPLC is also reported.     

A simple method for the oxidation of α-amino acid esters to α-oximino esters

Magnesium bis(monoperoxyphthalate) hexahydrate (MMPP) was found to be an effective reagent for the oxidation of various α-amino acid esters to the corresponding α-oximino acid esters. This transformation could be completed under mild conditions within 2.5 h using 1.1 equiv of MMPP in THF. Clean oximino esters were obtained after quenching and extracting the reaction from sodium thiosulfate solution. The O-phosphorylated derivative of 2-oximinoglutarate exhibited slow binding inhibitory potency for the metallopeptidase prostate-specific membrane antigen (PSMA) with an IC₅₀ value of 58 nM.     

A new method for the preparation of fluoro-λ-sulfanenitriles: reaction of sulfimides with Selectfluor™

Several diaryl(fluoro)-λ⁶-sulfanenitriles 3 were synthesized by the reaction of S,S-diarylsulfimides 1 with Selectfluor™. This reaction also allows the first preparation of heterocyclic fluoro-λ⁶-sulfanenitrile, 5-fluoro-10,10-dioxo-5,10-dihydro-5λ⁶,10λ⁶-thianthren-5-nitrile (5) and its molecular structure was determined by X-ray crystallographic analysis.     

A new concise stereoselective method for the preparation of a β-hydroxyfurfurylamine derivative and synthesis of 1-deoxyazasugar isomers

A new method to prepare a chiral building block, a β-hydroxyfurfurylamine derivative, is achieved and 1-deoxyazasugar isomers are synthesized.     

A novel oxidative ring-opening reaction of isoxazolidines: syntheses of β-amino ketones and β-amino acid esters from secondary amines

A novel oxidative ring-opening reaction of isoxazolidines upon treatment with an electrophile and subsequently with a basegives β-amino ketones and β-amino acid esters highly efficiently.     

A new synthetic route for the preparation of β-acyloxy mercaptans via the addition of thioacids to epoxides

A new synthetic route for the preparation of S-benzylated β-acyloxy mercaptans starting from the one-pot reaction of thioacids and epoxides using a silica gel/Et₃N combined catalyst is described. The thiol functionality in the crude product is then protected via benzylation and the corresponding thioethers are isolated after chromatography.     

A new method for the synthesis of β-halonitroalkanes

Summary A new method is elaborated for the synthesis of -chloronitroalkanes; it consists in the reaction of phosphorus pentachloride with acetals obtained by the addition of primary -nitro alcohols to vinyl alkyl ethers.     

Polyfunctionalized pyrrolidinones via the coupling of N,N-disubstituted β-amino esters with ethyl glyoxalate

N,N-Disubstituted amino esters were prepared by stereoselective conjugate addition of (S)- or (R)-lithium N-benzyl-N-α-methylbenzylamide to α,β-unsaturated esters. The couplings of the formed esters with ethyl glyoxalate followed by hydrogenation afforded 5-alkyl-4-carboethoxy-3-hydroxy-pyrrolidinones stereoselectively.     

Uncommon expansion of piperidine ring into hydroazocine ring in reactions of some piperidine β-acyl derivatives with acetylenecarboxylic acids esters

Cyclohexanone condensation with formaldehyde and methylamine led to the formation of 4ahydroxy-2-methyloctahydrospiro[isoquinoline-4,1'-cyclohexan]-2'-one whose structure was established by means of X-ray diffraction (XRD) analysis. This spiro compound reacted with acetylenecarboxylic acids esters with unexpected conversion of its piperidine ring into a hexahydroazocine cycle. The uncommon expansion reaction of the β-acyl-substituted piperidine ring into a hexahydroazocine cycle is confirmed by the analogous conversion of 4-hydroxy-1-methyl-4-phenylpiperidin-3-yl(phenyl)methanone into azocine derivative at treating with methyl propiolate.     

Preparation of highly enantiopure β-amino esters by Candida antarctica lipase A

The enantioselectivities for the reactions of aliphatic β-substituted β-amino esters [RCH(NH₂)CH₂CO₂Et with R=Me, Et, n-Pr, i-Pr, CHEt₂, cyclohexyl and Ph] with butyl butanoate in neat butyl butanoate and with 2,2,2-trifluoroethyl butanoate in diisopropyl ether were studied in the presence of Candida antarctica lipase A. Enantioselectivities ranging from good (E=70–100) to excellent (E>100) were commonly observed, allowing gram-scale resolution of the substrates.     

Enantioselective synthesis of α-fluoro-β(3)-amino esters: synthesis of enantiopure, orthogonally protected α-fluoro-β(3)-lysine

The scope of a tandem conjugate addition-fluorination sequence performed on α,β-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(α-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide has been investigated. Using this method, α-fluoro-β(3)-amino esters can be obtained in up to quantitative yield and 80:20 to >99:1 dr. This simple methodology does not rely on the use of α-amino acids from the chiral pool and thus provides the potential for the preparation of enantiopure α-fluoro-β(3)-amino acids with a wide variety of side chains. Its utility was demonstrated through the synthesis of orthogonally protected (2S,3S)-α-fluoro-β(3)-lysine.