Synthesis of C-protected alpha-amino aldehydes of high enantiomeric excess from highly epimerizable N-protected alpha-amino aldehydes

A new procedure for the preparation of C-protected alpha-amino aldehydes of high enantiomeric excess is illustrated using five differently substituted alpha-(N-Fmoc)amino aldehydes as starting materials. Highly epimerization-prone substrates were converted to the corresponding morpholino nitrile-protected alpha-amino aldehydes with minimal racemization (products >/= 89% ee). Morpholino nitrile derivatives of phenylglycinal were crystallized and subjected to X-ray structural analysis, allowing for definitive determination of the stereochemistry of amino nitrile formation. A rationale for the stereoselectivity of amino nitrile formation is presented.     

Copper nanoparticles catalyzed N-H functionalization: An efficient solvent-free N-tert-butyloxycarbonylation strategy

A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives (NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate, mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino acid esters and amino alcohols were performed without racemization.     

Dynamic Kinetic Asymmetric Transformations of β‐Stereogenic α‐Ketoesters by Direct Aldolization

Dynamic kinetic asymmetric transformations (DyKAT) of racemic β‐bromo‐α‐keto esters by direct aldolization of nitromethane and acetone provide access to fully substituted α‐glycolic acid derivatives bearing a β‐stereocenter. The aldol adducts are obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions. Mechanistic studies determined that the reactions proceed through a facile catalyst‐mediated racemization of the β‐bromo‐α‐keto esters under a DyKAT Type I manifold.     

Efficient and mild microwave-assisted stepwise functionalization of naphthalenediimide with alpha-amino acids

Microwave dielectric heating proved to be an efficient method for the one-pot and stepwise syntheses of symmetrical and unsymmetrical naphthalenediimide derivatives of alpha-amino acids. Acid-labile side chain protecting groups are stable under the reaction conditions; protection of the alpha-carboxylic group is not required. The stepwise condensation of different amino acids resulted in high yields of unsymmetrical naphthalenediimides. The reaction proceeds without racemization and is essentially quantitative.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

An easy stereoselective access to beta,gamma-aziridino alpha-amino ester derivatives via mannich reaction of benzophenone imines of glycine esters with N-sulfonyl alpha-chloroaldimines

Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl) alpha-chloroaldimines afforded gamma-chloro-alpha,beta-diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The gamma-chloro-alpha,beta-diamino esters were efficiently cyclized under basic conditions to the corresponding beta,gamma-aziridino alpha-amino ester derivatives, representing a new class of conformationally constrained heterocyclic alpha,beta-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the beta,gamma-aziridino alpha-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to alpha,beta-diamino esters and a gamma-amino alpha,beta-unsaturated amino ester.     

Selective synthesis of N-substituted pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives via alkyne cyclization

A novel and efficient synthesis of N-substituted pyrrolo-pyrazinone derivatives has been developed. A trichloroacetyl group connected to the pyrrole ring was converted into the desired carboxamide derivatives. Promoted by NaH, the pyrrole carboxamide derivatives underwent a tandem reaction with propargyl bromide to afford pyrrolo-pyrazinones with high efficiency under very mild conditions. The mechanism for the formation of the products is discussed and supported by DFT calculations.     

Improved Cs2CO3 Promoted O-Alkylation of Acids

Cesium carbonate mediated O-alkylation of carboxylic acids was efficiently carried out under mild in situ conditions to give the corresponding esters exclusively. Chiral templates including α-hydroxy and α-alkoxy acids were also converted to their corresponding esters with no observed racemization.     

Optisch aktive phosphine durch asymmetrische substitution prochiraler,homochiral substituierter phosphonite

Phenylphosphonous acid dimenthylester and its dibornylester react with bulky nucleophiles to give diastereomeric phosphinous acid esters. The asymmetric induction is as high as 95% d.e. If reaction conditions favouring inversion at phosphorus are used then the (R)-menthoxy group of the prochiral starting material is substituted. The phosphinous acid esters can be converted, with partial racemization, into optically active Horner-phosphines.     

Enantioselective benzoylation of alpha-amino esters using (S)-1-benzoyl-2- (alpha-acetoxyethyl)benzimidazole, a chiral benzimidazolide

A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic alpha-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for alpha-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.     

Hypervalent Iodine(III)‐Mediated Benzannulation of Enamines with Alkynes: an Efficient Synthesis of Substituted Aminonaphthoic Acid Derivatives

An intermolecular two C? C bond formation procedure for the synthesis of carbocycles mediated by hypervalent iodine(III) reagents was developed. This metal free protocol provided a new approach for the synthesis of useful substituted 1‐amino‐2‐naphthoic acid derivatives via benzannulation reactions. Various N‐unsubstituted and N‐alkyl substituted aromatic enamines with terminal alkynes and non‐terminal alkynes can be converted into corresponding 1‐amino‐2‐naphthoic acid derivatives under mild reaction conditions. When meta‐substituted phenyl enamines were employed in the reaction, two cyclization paths were detected in the reaction and ortho‐cyclization products were the only or major products. Good functional group tolerance, readily available material and high atom utilization efficiency make this method a potential procedure which may find broad application in organic synthesis.     

A highly enantioselective route to either enantiomer of both alpha- and beta-amino acid derivatives

This report describes the unprecedented use of unmodified aldehydes as donors in a catalytic asymmetric Mannich-type reaction. The proline-catalyzed reaction of N-PMP-protected alpha-imino ethyl glyoxylate with unmodified aliphatic aldehydes provided a general and very mild entry to either enantiomer of beta-amino and alpha-amino acids and derivatives in high yield and stereoselectivity. Six of the seven aldehydes studied yielded products with ee values of 99% or greater. The diastereoselectivity of the reaction increased with the bulkiness of the substituents of the aldehyde donor in the order R = Me < Et < i-Pr < n-Pent. In five of the cases studied, excellent syn stereoselectivities were achieved. In addition, the corresponding chiral beta-amino aldehyde adducts can be readily converted to the corresponding amino acid derivatives. Most significantly, this approach provides facile access to substituted beta-lactams.     

High-pressure transesterification of sterically hindered esters

A mild, rapid, and efficient method for the solvolysis of sterically hindered esters under high pressure is described. Transesterification is carried out in the presence of DBU at room temperature and at a pressure of 10 kbar to give quantitative conversions within short reaction times. The substrates examined included aromatic and aliphatic esters of sterically hindered alcohols and phenols. An optically pure benzyl ester of phenylalanine was chosen to study racemization of the amino acid esters under high-pressure reaction conditions.     

Stereoselective synthesis of trifluoromethylated vicinal ethylenediamines with alpha-amino N-tert-butanesulfinimines and TMSCF3

Isolable alpha-amino N-tert-butanesulfinimines were prepared through the condensation of Reetz's alpha-amino aldehydes (prepared from alpha-amino acids) with Ellman's (R)-N-tert-butanesufinamide without any racemization, and these were trifluoromethylated with TMSCF3 and TMAF (tetramethylammonium fluoride) to the corresponding vicinal ethylenediamines derivatives. Imines derived from l-amino acids gave exclusively one diastereomer with a very high yield.     

One-step synthesis of O-benzyl hydroxamates from unactivated aliphatic and aromatic esters

We have developed a simple and high yielding one-step method for the synthesis of hydroxamate derivatives directly from a broad range of unactivated esters and the anion of O-benzyl-hydroxylamine generated in situ. The reaction takes place in minutes at -78 degrees C. Very importantly, the method was successfully employed with enolizable esters, including chiral alpha-amino acid esters and peptides, with no trace of racemization/epimerization at the alpha carbon detected.     

An efficient synthesis of tert-butyl ethers/esters of alcohols/amino acids using methyl tert-butyl ether

A facile synthesis of a wide variety of tert-butyl ethers and tert-butyl ester derivatives under mild conditions is described. Alcohols etherified with tert-butyl methyl ether as tert-butyl source and solvent, in the presence of sulfuric acid. Many amino acid tert-butyl esters have been synthesized by this procedure. The reaction is simple, inexpensive, easily scaled up, and proceeds without observable racemization. A green method was developed for the deprotection of this group using Amberlite resin IR 120-H as catalyst.     

Synthesis of Optically Active 2‐Amino‐1,3,4‐oxadiazoles and their Hybrid Peptides

Synthesis of 2‐amino‐1,3,4‐oxadiazole derivatives of N^α‐Cbz(benzyloxycarbonyl)/Boc‐protected amino/peptide acids under sonication is described. The conditions involved in the present protocol are simple, mild, and racemization free. The utility of 2‐amino group in the substituted oxadiazoles for the incorporation of peptide and ureido bonds to obtain hybrid peptidomimetics is also delineated. The 2‐amino‐1,3,4‐oxadiazole 3b was obtained as a single crystal, and its molecular structure has been confirmed through X‐ray crystallographic study.     

A facile approach to the synthesis of chiral 2-substituted benzofurans

An effective route to chiral optically active 2-substituted benzofurans directly from carboxylic acids is reported. This procedure, which allows the preparation of alpha-alkyl-2-benzofuranmethanamines from N-protected alpha-amino acids without sensible racemization phenomena, proceeds in good yields under mild conditions with the help of microwave irradiation.     

Syntheses of amino alkyl sulphonic acids and their peptide analogues

New amino alkyl sulphonic acids have been synthesized, including some substituted derivatives and several peptide analogues containing the ---CO·NH--- group formed from amino acid and amino alkyl sulphonic acid components. Peptide-like compounds containing the ---SO₂·NH--- group were prepared from N-substituted taurine and esters of amino acids. Theoretical aspects underlying the reactions involved are discussed.     

Stereoselective synthesis of dipeptide beta-turn mimetics: 7-benzyl and 8-phenyl substituted azabicyclo[4.3.0]nonane amino acid esters

A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide beta-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3 or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent asymmetric hydrogenations with Burk's DuPHOS Rh(I)-based catalysts to furnish alpha-amino acid derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the beta-turn mimetics 6,5-bicyclic lactams 1a-d in high yields.