Ketoreductases in the synthesis of valuable chiral intermediates: application in the synthesis of α-hydroxy β-amino and β-hydroxy γ-amino acids

A general method for the synthesis of β-alkyl α-hydroxy β-amino and α- and γ-alkyl substituted β-hydroxy-γ-amino acids is described. The synthesis of all three classes of amino acids proceeds through a common chiral alcohol intermediate that is generated from a pro-chiral ketone diester via the action of a nicotinamide-dependent ketoreductase. Regioselective chemical or enzymatic hydrolysis followed by rearrangement under Hofmann or Curtius conditions gives the final amino acid products. High yields of single diastereomers of the final amino acids are obtained. Amino acids with both natural and unnatural alkyl substituents can be accessed using this methodology.     

The Synthesis of β,γ- and α,β-Unsaturated Aldehydes via Polyene Epoxides

A substitute for the Darzens glycidic ester synthesis for converting unsaturated ketones or aldehydes into the homologated β,γ- or α,β-unsaturated aldehydes employing sulfur ylides is described. The carbonyl group is converted into the unsaturated oxirane which is then rearranged to the new aldehyde. High yields of isomerically pure aldehydes are available by this method and the process is of practical importance in the conversion of β-ionone into the β-C₁₄-aldehyde, a key intermediate in the Isler synthesis of vitamin A. The efficient preparation of α- and β-cyclocitral by the novel process is also described.     

Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

Simple, facile and one-pot conversion of the Baylis-Hillman acetates into 3,5,6-trisubstituted-2-pyridones

A facile route for the synthesis of novel 3,5,6-trisubstituted-2-pyridones from the acetylated Baylis-Hillman esters with β-enamino esters or β-enamino nitriles in one pot with good yields is described.     

Synthèse de β-imidazolylcétones

The synthesis of β-imidazolylketones 1 and 2 is described. The compounds 1 are prepared by reaction of Mannich bases with the imidazole. Treatment of the imidazole with haloketones or α-ethylenic ketones or the reaction β-kétol with N,N'-thinoyldiimidazole lead to β-imidazolylketones 2 .     

Chemoselective mono halogenation of β-keto-sulfones using potassium halide and hydrogen peroxide; synthesis of halomethyl sulfones and dihalomethyl sulfones

The synthesis of α-halo β-keto-sulfones using potassium halide and hydrogen peroxide as a chemoselective mono halogenation reagent and the synthesis of α,α-symmetrical and asymmetrical dihalo β-keto-sulfones and α-halo, α-alkyl and β-keto-sulfones is described. Base induced cleavage of α-halo β-keto-sulfones, α,α-dihalo β-keto-sulfones, and α-halo, α-alkyl β-keto-sulfones afforded the corresponding halomethyl sulfones, dihalomethyl sulfones and haloalkyl sulfones.     

Synthesis and reactivity of 2-(porphyrin-2-yl)-1,3-dicarbonyl compounds

A simple and efficient procedure for the synthesis of porphyrins bearing 1,3-dicarbonyl moieties at the β-position is described. The new compounds were further functionalized and new derivatives containing an heterocyclic ring, an ethyl acetate residue or a 2-oxopropyl group at the β-position have been obtained.     

Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction

Highly stereoselective synthesis of 3-pyrrole substituted β-lactams is accomplished. The first step involves the synthesis of 3-phthalimido substituted β-lactams following Staudinger cycloaddition reaction of acid chloride equivalent with imines. Synthesis of 3-amino β-lactams is achieved via the deprotection of phthalimido group with ethylenediamine. These 3-amino β-lactams are converted to a new series of N-substituted pyrroles at room temperature as well as using microwave-induced bismuth nitrate-catalyzed reaction with an excellent yield. Exclusive formation of trans pyrrole-substituted β-lactams is observed with N-chrysenyl system. The method is equally efficient for the synthesis of racemic as well as optically pure 3-pyrrole substituted β-lactams.     

Synthesis of β-hydroxy selenides using benzeneselenol and oxiranes under supramolecular catalysis in the presence of β-cyclodextrin in water

A simple and efficient method for the synthesis of β-hydroxy selenides is reported at room temperature in impressive yields for the first time by the highly the regioselective ring-opening of oxiranes with benzeneselenol in water under supramolecular catalysis in the presence of β-cyclodextrin. This is a direct one-pot synthesis of β-hydroxy selenides under mild conditions using water as solvent and has many advantages over the existing methodologies. β-Cyclodextrin can also be recovered and reused.     

The first ionic liquid-promoted three-component coupling strategy for an expeditious synthesis of β-nitrocarbonitriles/thiocyanates

A novel and convenient three-component coupling reaction of nitromethane, aromatic aldehydes and trimethylsilyl cyanide (TMSCN) or ammonium thiocyanate has been developed for an expeditious synthesis of β-nitrocarbonitriles or β-nitrothiocyanates, respectively, via C-C and C-S bond-forming reactions. The synthetic protocol strategically involves a one-pot sequential Henry reaction and a Michael addition efficiently promoted by the same ionic liquid [bmim]OH. The main advantages of the present approach include the use of inexpensive simple substrates and an ionic liquid as an efficient reaction promoter for the mild synthesis in a one-pot procedure.     

A convenient synthesis of α-amino-β-lactams

A safe and convenient method is described for the synthesis of α-amido-β-lactams starting with glycine and an azomethine. The amino group of glycine is protected by reaction with a β-dicarbonyl compound following the method of Dane etal. and the carboxyl group is activated through the formation of a mixed anhydride or an active ester. Condensation between these glycine derivatives and acyclic or cyclic imino compounds (including thioimidates) in presence of triethylamine leads to stereospecific synthesis of 3-(β-carbonyl-vinylamino)-2-azetidinones in 40–60% yield. The vinylamino side chain can be hydrolyzed under mild acid conditions to form 3-amino-2-azetidinones which can be acylated to α-amido-β-lactams. Alternatively, the vinylamino side chain can be converted to an amido side chain by ozonolysis. The molecular parameters of a 3-(β-carbonyl-vinylamino)-2-azetidinone were determined by X-ray crystallography. Usefulness of this α-amido-β-lactam synthesis is illustrated by the preparation of isotopelabeled β-lactams and intermediates for some β-lactam antibiotics.     

A method of synthesis of phosphinic acids on the basis of hypophosphites: VII. Synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid

A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxycarbonyl)ethyl, β-phenylethyl, or β-(diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.     

First asymmetric synthesis of β-amino-β-trifluoromethylated aldehyde

The first asymmetric synthesis of the β-trifluoromethylated β-amino aldehyde, which is one of the most promising precursors for the synthesis of trifluoromethylated bioactive compounds, is described.     

氨基磺酸做催化剂催化多组分反应合成β-Acetamido Ketones

氨基磺酸作为一种可回收、绿色催化剂在室温下能高效地催化合成β-乙酰氨基酮.反应产物通过红外、~1HNMR和~(13)CNMR表征,其结果证明为合成的目标分子. 特别值得强调的是二元官能团的β-乙酰氨基酮也可通过乙酰氯、苯乙酮、间苯二甲醛和腈类化合物交联得到. 而且二元官能团的β-乙酰氨基酮的催化合成很少见报导. 在氨基磺酸催化的酮、芳醛、乙酰氯和乙腈参与的多组分反应体系中,反应有条件温和、产率较高、催化剂用量少、催化剂可以回收再利用等优势.     

Switch in regioselectivity of epoxide ring-opening by changing the organometallic reagent

The regio- and stereoselective ring-opening of a 2-(2'-oxiranyl)-1,2,3,6-tetrahydropyridine using organometallic reagents is reported. The choice of the organometallic reagent determines the formation of either 2-[(R)-1-hydroxyalkyl]- or 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines. The formation of 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines is a rare example of epoxide ring-opening with retention of configuration. The process has been applied to the asymmetric synthesis of β-(+)-conhydrine and to the formal synthesis of (2S,2'R)-erythro-methylphenidate from a common precursor. Extension of the structural diversity of the process has allowed the synthesis of several β-(+)-conhydrine analogs.     

Synthesis of β-Amino Acid Derivatives

In recent years, β-amino acids and their derivatives have attracted considerable attention due to their occurrence in biologically active natural products, such as dolastatins,cyclohexylnorstatine and Taxol. β-Amino acids also find application in the synthesis of β-lactams,piperidines, indolizidines. Moreover, the peptides consisting of β-amino acids, the so-called β-peptides, have been extensively studied recently. Consequently, considerable efforts have been directed to the synthesis of β-amino acids and their derivatives1. In particular, stereoselective synthesis of β-amino acids has been a challenging project, and there are only limited methods available. In this presentation, we report our efforts in this area.     

Thermolyse des β-énaminodiesters cycliques: Accès à divers β-énaminoesters, β-énaminothioesters et β-enaminoamides.

A new synthesis of β-enaminoesters, β-enaminothioesters et β-enaminoamides by thermic decomposition of β-enaminodiesters is described.     

Substrate dependent intramolecular palladium-catalysed cyclisation and subsequent β-H elimination or C-H activation: a general method for the synthesis of fused pyran rings

An efficient and convenient method for the synthesis of fused pyran rings via intramolecular palladium-catalysed cyclisation followed by β-H elimination or C-H activation has been developed. It is possible to utilise this method for the synthesis of benzopyran systems.     

Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates

Mimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. β-Sheet mimics have a storied history in bioorganic chemistry and are typically designed with synthetic or natural turn segments. We hypothesized that replacement of terminal inter-β-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic β-sheets without the requirement for natural or synthetic β-turns, thereby providing a minimal mimic of a protein β-sheet. To access turn-less antiparallel β-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein β-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic–aromatic, cation-π and ionic interactions in β-sheets. In correspondence with natural β-sheets, we find that minimal HBS mimics show robust β-sheet formation when specific amino acid residue pairings are incorporated. In isolated β-sheets, aromatic interactions endow superior conformational stability over ionic or cation-π interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles.