Derivatives of α‐ and β‐S‐thiophosphates of 2‐bromo‐2‐deoxy‐D‐hexopyranose

The first examples of S‐thiophosphate derivatives of 2‐bromo‐2‐deoxy sugars 7–12 were synthesized by reacting alkyl ammonium salts 1–4 of thiophosphoric acids with α‐1,2‐cis (5) or α‐1,2‐trans dibromo sugars (6) and addition of free thiophosphoric acids 1a or 2a to 2‐bromo‐D‐glucal (13). It was observed that the solvent determines formation of either the O‐ or S‐glycosyl compound. β‐Thiophosphates can be transformed to the α‐configuration in the presence of acid in quantitative yield. The structures of the synthesized derivatives of 7–12 were confirmed by spectroscopic methods. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 465–470, 1999     

Brominations of Cyclic Acetals from α-Amino Acids and α- or β-Hydroxy Acids with N-Bromosucinimide

The preparation of novel electrophilic building blocks for the synthesis of enantiomerically pure compounds (EPC) is described. Thus, the 2-(tert-butyl)dioxolanones, -oxazolidinones, -imidazolidinones, and -dioxanones obtained by acetalization of pivalaldehyde with 2-hydroxy-, 3-hydroxy-, or 2-amino-carboxylic acids are treated with N-bromosuccinimide under typical radical-chain reaction conditions (azoisobuytyronitril/CCl₄/reflux). Products of bromination in the α-position of the carbonyl group of the five-membered-ring acetals are isolated or identified ( 2, 5 , and 8 ; Scheme 1). The dioxanones are converted to 2H, 4H-dioxinones under these conditions ( 12 , 14 , 15 , 21 , and 22 ; Schemes 2 and 3). The products can be converted to chiral derivatives of pyruvic acid (methylidene derivatives 3 and 6 ) or of 3-oxo-butanoic and -pentanoic acid ( 16 and 23 ). The mechanism of the brominations is interpreted. The conversion of serine to enactiomcrically pure dioxanones 26–28 (Scheme 4) is also discussed.     

Carbon-13 chemical shifts of α,β-unsaturated acids

Carbon-13 spectra of 59 α,β-unsaturated carboxylic acids have been measured. Large differential shieldings of ethylenic carbons in the cis and trans isomers of acrylic acid derivatives were found (altogether 15 isomeric Z- and E-pairs of acids were investigated). The origin of differential shieldings is complex and both molecular ground states as well as changes in excited states appear to be involved. All measured ¹³C chemical shifts can be described by additive parameters that provide a straightforward new technique by which structural assignments can be made for a wide variety of isomeric mono-, di- and tri- substituted α,β-unsaturated acids.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Reaction of α,β‐unsaturated ketones with cerium(IV) salts in alcohol

Reaction of α,β‐unsaturated ketones with cerium(IV) salts or lanthanide triflates in alcohols gave good yields of the corresponding β‐alkoxy compounds. In the case of 2‐cyclopentenone and 2‐cyclohexenone, the 1,1,3‐trialkoxy acetal derivatives were obtained preferentially accompanied by β‐alkoxyketone, except 2‐cycloheptenone. However, in the reaction of 2‐cycloheptenone with alcohol using cerium(IV) sulfate (CS)‐molecular sieve, 1,1,3‐trialkoxy derivatives were obtained. Also, in the cases of 1‐penten‐3‐one, 4‐hexen‐3‐one and 3‐hepten‐2‐one, 1,1,3‐trialkoxy derivatives were obtained preferentially. Copyright © 2006 John Wiley & Sons, Ltd.     

New Synthetic Routes to β-Olefinic Triphenylphosphonium Salts via (Diolefin)tricarbonyliron Complexes

The regio- and stereospecific preparation of β-olefinic triphenylphosphonium salts, starting from (diolefin)tricarbonyliron compounds is described. The latter are converted by various routes into either [(allyl)Fe(CO)₄]⁺ - or [(dienyl)Fe(CO)₃]⁺ - derivatives. The allylic cations, when reacted with P (C₆H₅)₃, yield uncomplexed (2-en-l-yl)triphenylphosphonium salts in good yields, while treatment of the dienyl cations with P(C₆H₅)₃ leads to the quantitative formation of (2,4-diene-l-yl)triphenylphosphonium ions still coordinated to the Fe (CO)₃-moiety. A method of oxidative decomplexation is described, by which the free phosphonium salts can be obtained. All new compounds were characterized by ¹³C-NMR spectra and also, where necessary, by ¹H-NMR decoupling experiments to confirm the stereochemical assignments. Many of the new phosphonium salts, potentially useful as Wittig reagents for natural product syntheses, are difficult to obtain by conventional unequivocal routes.     

Reactions of α,β‐Enones with Diazo Compounds,Part 3

Carbonyl ylides arising from ethyl acetodiazoacetate/dimethyl diazomalonate and α,β‐enones with mainly s‐cis conformations underwent disrotatory cyclization to produce dihydrofuran derivatives. This process proved to be sensitive to steric effects. The corresponding ylides arising from rather s‐trans α,β‐enals yielded dioxole derivatives. The mechanisms of the reactions are discussed.     

α-Alkyl-α-aminosilanes: Synthesis via Alkylation and Hydrosilylation

The readily available aminomethylsilanes can be utilized to prepare the less available α-alkyl-α-aminosilanes. Versatile t-butoxy-carbonal (Boc) derivatives can be metalated between nitrogen and silicon, and then alkylated by an electrophile at this position. Two alternative procedures were also developed, including an aza-reverse-Brook rearrangement of metalated N-silylcarbamates and hydrosilylation of N-alkenylcarbamates. © 1997 by John Wiley & Sons, Ltd.     

Unusual Acid-Catalyzed Rearrangement of Two α,α′-Diimino-oximes

2-[2-(Alkylimino)-2-phenylethylidene]pyrrolidines (vinamidines, 3 – 6 ) were obtained either via activation of the corresponding vinologous amide 1 with Meerwein salt and subsequent treatment of the intermediate 2 with an amine, or more directly by acid-catalyzed condensation of the Schiff bases derived from acetophenone with 2-ethoxy-1-pyrroline. Nitrosation of these vinamidines led to α,α′-diimino-oximes. In two cases ( 10 , 11 ), these oximes underwent acid-catalyzed rearrangement with formation of a 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine ring system ( 12 , 13 ). X-Ray analysis of one of these products ( 13 ) and also of one of the vinamidine salts ( 6 ) are presented.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

Stereocontrolled Synthesis of syn‐β‐Hydroxy‐α‐Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

β‐Hydroxy‐α‐amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β‐hydroxy‐α‐amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one‐flask protocol. Enolization of (R,R)‐ or (S,S)‐pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L ‐ or D ‐threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55–98 %, and are readily transformed into β‐hydroxy‐α‐amino acids by mild hydrolysis or into 2‐amino‐1,3‐diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.     

Preparation and Structure of β-Peptides Consisting of Geminally Disubstituted β2,2- and β3,3-Amino Acids: A Turn Motif for β-Peptides

We report on the synthesis of new and previously described β-peptides ( 1 – 6 ), consisting of up to twelve β^2,2- or β^3,3-geminally disubstituted β-amino acids which do not fit into any of the secondary structural patterns of β-peptides, hitherto disclosed. The required 2,2- and 3,3-dimethyl derivatives of 3-aminopropanoic acid are readily obtained from 3-methylbut-2-enoic acid and ammonia (Scheme 1) and from Boc-protected methyl 3-aminopropanoate by enolate methylation (Scheme 2). Protected (Boc for solution-, Fmoc for solid-phase syntheses) 1-(aminomethyl)cycloalkanecarboxylic-acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1-cyanocycloalkanecarboxylates and the corresponding dihaloalkanes (Scheme 3). Fully ¹³C- and ¹⁵N-labeled 3-amino-2,2-dimethylpropanoic-acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4). Coupling of these amino acids was achieved by methods which we had previously employed for other β-peptide syntheses (intermediates 18 – 23 ). Crystal structures of Boc-protected geminally disubstituted amino acids ( 16a – d ) and of the corresponding tripeptide ( 23a ), as well as NMR and IR spectra of an isotopically labeled β-hexapeptide ( 2a* ) are presented (Figs. 1 – 4) and discussed. The tripeptide structure contains a ten-membered H-bonded ring which is proposed to be a turn-forming motif for β-peptides (Fig. 2).     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

3‐(3,5‐Dimethyl‐1H‐Pyrazol‐1‐yl)‐3‐Oxopropanenitrile as Precursor for Some New Mono‐Heterocyclic and Bis‐Heterocyclic Compounds

3‐(3,5‐Dimethyl‐1 H ‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 1 was used as a cyanoacetylating agent for synthesis of the acetanilide derivative 3 . Compound 3 was utilized as a key intermediate for the synthesis of some new mono‐chromene and di‐chromene derivatives 9 and 13 , the dihydrazo derivatives 15 , and the dithiazole derivatives 18 via the condensation with o‐hydroxybenzaldehyde derivatives, the coupling with aryl diazonium salts, or the reaction with phenyl isothiocyanate in presence of KOH followed by phenacyl bromide derivatives respectively.     

Reaction of β‐Bromo‐β,γ‐unsaturated Pyrroline Nitroxide Aldehydes and Nitriles with Aromatic N,S‐Binucleophiles

Reactions of β‐bromo‐β,γ‐unsaturated pyrroline nitroxide aldehyde ( 1 ) or nitrile ( 4 ) or their diamagnetic forms ( 5, 6 ) with 2‐aminothiophenol or 2‐mercaptobenzimidazole were evaluated. The reaction could be reproduced more easily with the application of O‐acetyl derivatives of nitroxides to generate 2‐substituted‐benzothiazole, pyrrolo[3,4‐b ]benzo[1,5]tiazepine scaffolds with 2‐aminothiophenol and benzimidazo[2,1‐b ]pyrrolo[3,4‐e ]‐[1,3]thiazine scaffold with 2‐mercaptobenzimidazole.     

Preparation and antibacterial activity of aromatic derivatives of β-aminopropionic and γ-aminobutyric acid

Ten aromatic derivatives of β-aminopropionic acid and γ-aminobutyric acid were prepared.Their compositions and structures were identified by elemental analysis,IR,and 1H NMR.They have been examined for their antibacterial action against Staphylococcua aurens and Escherichia coli.These compounds showed higher activity than the aromatic derivatives of ct-amino acid which were reported previously.The general conclusion to be drawn is that the distance between amino and carboxylic group in these molecules could affect their antibacterial activity.Furthermore,those compounds with p-methyl substituent in phenyl ring exhibit higher activity than the others,and all the compounds exhibit higher activity against Escherichia coli and against Staphylococcua aureus.     

Copper‐Catalyzed Bis(methoxycarbonyl)carbene Reactions of α,β‐Unsaturated Carboxamides

The [Cu(acac)₂]‐catalyzed reactions of α,β‐unsaturated carboxamides with dimethyl diazomalonate yielded dihydrofuran derivatives by a 1,5‐electrocyclic reaction at C(β), and butadiene derivatives by carbene addition reaction at C(α) (Schemes 4 and 5; Table). Phenyl substituents at the N‐atom of the amides seem to be effective on the reaction pathways (Table).     

Synthesis of Phenanthrene Derivatives through the Reaction of an α,α‐Dicyanoolefin with α,β‐Unsaturated Carbonyl Compounds

Phenanthrene derivatives were prepared by reacting an α,α‐dicyanoolefin with different α,β‐unsaturated carbonyl compounds resulting from Wittig reaction of ninhydrin and phosphanylidene or condensation of barbituric acid and an aldehyde. The easy procedure, mild and metal‐catalyst free, reaction conditions, good yields, and no need for chromatographic purifications are important features of this protocol. The structures of the product of type 3 and 5 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 1).