Convenient synthesis of fluoroalkyl α- and β-aminophosphonates

Addition of both alkyl phosphites and phosphonate α-carbanions to N-substituted aldimines derived from fluoroalkyl aldehydes presents a convenient method for synthesis of fluoroalkyl α- and β-aminophosphonates in good yield (55-86%) under mild conditions.     

Modular synthesis of 1-α- and 1-β-(indol-2-yl)-2'-deoxyribose C-nucleosides

A simple two-step method for the selective preparation of anomerically pure 1α- and 1β-(indol-2-yl)deoxyribose derivatives was developed. The synthesis was based on the Sonogashira reaction of 1α- and 1β-ethynyldeoxyribose and 2-haloanilines followed by a Pd-complex catalyzed cyclization to the corresponding indolyldeoxyribosides.     

Triazolyl C-nucleosides via the intermediacy of β-1′-ethynyl-2′-deoxyribose derived from a Nicholas reaction: Synthesis,photophysical properties and interaction with BSA

We report the design and synthesis of triazolyl donor/acceptor unnatural C-nucleosides via alkyne (sugar)—azide (aromatic) 1, 3-dipolar cyclo-addition reaction as a key step and studies on their photophysical properties. We have chosen β-1′-ethynyl-2′-deoxyribose as a precursor to synthesize triazolyl-C-nucleosides. Overcoming the difficulties, we obtain β-1′-ethynyl-2′-deoxyribose as a major product following a Co₂(CO)₈ catalyzed intramolecular Nicholas reaction. The 1,3-diaxial interaction is the driving force for the α to β-anomeric conversion while performing cobalt complexation followed by oxidation to afford β-1′- ethynyl-2′-deoxyribose as the major product. A Cu(I)-catalyzed click reaction between different aromatic donor/acceptor azides and β-1′- ethynyl-2′-deoxyribose generates the desired unnatural triazolyl donor-acceptor aromatic C-nucleosides (^cTB_Do/Ac) within 30 min. Single crystal X-ray structure shows the puckered conformation of sugar as C3′-exo. Studies on the photophysical properties suggests good fluorophoric as well as solvatochromic characteristics of these nucleosides. Two of the synthesised nucleosides, ^cTAnthB_Do and ^cTPyB_Do, are found to interact with BSA as the only tested protein with quenching of fluorescence signal. The designed bases, thus, might find applications in stabilizing a DNA and in the biophysical study thereof, if a pair of such donor acceptor C-nucleosides could be incorporated into a DNA sequence.     

Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes 3: Total synthesis of (+)-1-epi-castanospermine

Stereoselective allylation reactions of acyclic, chiral α-amino-β-hydroxy aldehydes containing four contiguous stereocenters were conducted. Allylation mediated by MgBr₂?OEt₂ afforded the anti-product. A plausible mechanism of the allylation reaction is also described. The resulting allylation product was used for the total synthesis of (+)-1-epi-castanospermine.     

The synthesis and stereoselective conjugate addition reactions of α-alkoxyorganocuprate reagents

α-Alkoxyorganocuprate reagents have been prepared from α-alkoxyorganostannanes. The cuprates undergo diastereoselective conjugate addition reactions with cyclohexenone with up to 8:92 selectivity. The effects of trimethylsilyl chloride on the chemical yields and the diastereoselectivity of the reaction are described.     

One-pot highly enantioselective catalytic Mannich-type reactions between aldehydes and stable α-amido sulfones: asymmetric synthesis of β-amino aldehydes and β-amino acids

A highly enantioselective catalytic route to carbamate- and benzoate-protected β-amino aldehydes and β-amino acids is presented. The amino acid-catalyzed one-pot asymmetric reaction between unmodified aldehydes and α-amido sulfones gives the corresponding β-amino compounds with up to 95:5 dr and 97->99% ee.     

Stereoselective synthesis of α- and β-glycofuranosyl amides by traceless ligation of glycofuranosyl azides

A highly stereoselective synthesis of α- or β-glycofuranosyl amides based on the traceless Staudinger ligation of glycofuranosyl azides of the galacto, ribo, and arabino series with 2-diphenylphosphanyl-phenyl esters has been developed. Both α- and β-isomers can be obtained with excellent selectivity from a common, easily available precursor. The process does not depend on the anomeric configuration of the starting azide but appears to be controlled by the C2 configuration and by the protection/deprotection state of the substrates. A mechanistic interpretation of the results, supported by (31)P NMR experiments, is offered and merged with our previous mechanistic analysis of pyranosyl azide ligation reactions.     

C-H functionalization of tertiary amines by cross dehydrogenative coupling reactions: solvent-free synthesis of α-aminonitriles and β-nitroamines under aerobic condition

A solvent-free synthesis of α-aminonitriles and β-nitroamines by oxidative cross-dehydrogenative coupling under aerobic condition is reported. A catalytic amount of molybdenum(vi) acetylacetonoate was found to catalyze cyanation of tertiary amines to form α-aminonitriles, whereas vanadium pentoxide was found to promote aza-Henry reaction to furnish β-nitroamines. Both of these environmentally benign reactions are performed in the absence of solvents using molecular oxygen as an oxidant.     

The reactions of perfluorinated α- and β-alkoxyradicals with hydrogen chloride, chlorine and fluorine

The kinetics of the reactions of the macroradicals R_f′OCF₂ (I) and R_f′OCF₂CF₂ (II) with HCl, Cl₂ and F₂ have been studied in the liquid phase, being R_f′ a poly(oxydifluoromethylene-oxytetrafluoroethylene) chain with average molecular weight of about 10⁴ Da. Radical (I) showed a higher reactivity compared to radical (II) with all the three radical transfer agents.In case of HCl the activation energy for the reaction:

     

Surface electrochemistry of the oxidation reactions of α- and β-alanine at a platinum electrode

The electrochemical oxidation reactions of α- and β-alanine at a Pt electrode were investigated in aqueous solutions at pH 1, 7, and 13 using steady-state current-potential measurements, cyclic voltammetry, and open circuit potential decay. The capacitance behaviour and the high Tafel slopes suggest the production of free radicals at the surface of the electrode accompanied by a second reaction involving loss of CO₂ which is the rate determining step. In the surface electro-oxidation of α-alanine, it appears that the adsorbed intermediate species is either hydrolyzed anodically to acetaldehyde and ammonia, or is oxidized to a carbonium ion which is subsequently hydrolyzed to acetaldehyde and ammonia in solution, analogous to the behaviour observed for glycine [D.G. Marangoni, R.S. Smith and S.G. Roscoe, Can. J. Chem., 67 (1989) 921]. The mechanisms for β-alanine would be similar except carbonium ion formation would probably be accompanied by a hydride transfer to form acetaldehyde. No dimerized products were detected by gas chromatography. These mechanisms differ from the dimerization process typical of the radical reactions associated with the Kolbe mechanism.     

Solution-phase synthesis of novel seven-membered cyclic dipeptides containing α- and β-amino acids

A convenient synthetic procedure for the preparation of seven-membered cyclic α,β-dipeptides is described. Following coupling of N-protected α-amino acids with N-substituted β-amino acid tert-butyl esters, that affords linear α,β-dipeptides, the protecting groups at the terminal functionalities were removed and the open-chain dipeptides were cyclized with phenylphosphonic dichloride, PhP(O)Cl₂, to give the desired cyclic α,β-dipeptides in good yields. NMR studies, X-ray diffraction analysis, and DFT calculations provided evidence for the conformation adopted by these cyclic dipeptides in solution, in the solid-state, and in the gas phase.     

Efficient synthesis of fluorinated α- and β-amino nitriles from fluoroalkylated α,β-unsaturated imines

A simple and efficient synthesis of fluoroalkylated α-amino nitrile (4) derivatives by regioselective 1,2-addition of trimethylsilyl cyanide to fluoroalkylated α,β-unsaturated imines (1) is described. Fluoroalkylated β-amino nitriles (7) are also prepared by regioselective 1,2-addition of α-carbanions derived from acetonitrile to fluoroalkylated α,β-unsaturated imines (1). Fluoroalkylated α-(4) and β-amino nitriles (7) are also prepared through an ‘one pot’ procedure by reaction of enaminophosphonate 2 with BuLi, addition of aldehydes and subsequent addition of either trimethylsilyl cyanide or α-carbanion derived from acetonitrile. Basic hydrolysis of α-(4) and β-amino nitriles (7) gives fluoroalkylated α-(5) and β-amino acids (8).     

The synthesis,structure, and some reactions of sterically hindred α-silylisoxazoles

4-(4,5-Dihydro-4,4-dimethyl-2-isoxazolyl)-3-phenyl-5-silylmethylisozazole and 3-phenyl-5-silylmethyl-4-isoxazole-t-carboxamide derivatives were synthesized in synthetically useful yields from the corresponding oxazolyl-isoxazole or t-carboxamide by metalation of the isoxazole systems at the C(5) alkyl group followed by electrophilic quenching with either t-butylchlorodiphenylsilane or t-butylchlorodimethylsilane. The silylisoxazole systems were metalated at the C(5) position, producing the corresponding α-silyl carbanion, which upon quenching with MeOD produced C(5) deuterium incorporation. The reaction of silyloxazolylisoxazoles with titanium tetrachloride caused the oxazoline ring to open forming chloro-substituted carboxamide. The X-ray structure of a silyloxazolylisoxazole was obtained and indicates an “s-trans” ring juncture with respect to the heterocyclic rings.     

Asymmetric synthesis of β,β-difluoroamino acids via cross-coupling and Strecker reactions

β,β-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reactions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling products, which were transformed to 2-difluoromethyl-1,3-oxazolidines in two steps. Boron trifluoride etherate promoted Strecker reaction of 2-difluoromethyl-1,3-oxazolidines gave α-amino nitriles in good yields and diastereoselectivities. After removal of chiral auxiliary and hydrolysis of the nitrile group, β,β-difluorophenylalanine was obtained with 73% ee. Partial racemization occurred during the hydrolysis of nitrile group.     

Multicomponent reactions in a one-pot synthesis of α-aminophosphonates and α-aminophosphonic diamides with anti-inflammatory properties

Abstract  

Schiff-base Kabachnik–Fields intermediates generated in situ from substituted pyrazole-4-carbaldehyde and 2-aminothiophene derivatives were trapped by dialkyl phosphites to produce the corresponding α-aminophosphonates in moderate yields. The latter products could be also obtained in excellent yields (≥75%) by directly applying the phosphorus reagents to the Schiff bases. Next, dialkyl phosphites were applied to one of the parent aldehydes to give the expected α-hydroxyphosphonate derivatives. Applying hexaalkyl triamidophosphites to the Schiff base in ethanol afforded methylphosphonic diamide derivatives, whereas ring attack on the pyrazole ring occurred when the same amidophosphites were applied to the parent aldehyde to give the corresponding alkylidenephosphorane ylides in an open structure form in good yields. Some of the new compounds exhibited considerable anti-inflammatory properties.     

Organocatalytic synthesis of α-hydroxy and α-aminophosphonates

A new and highly flexible procedure is described for the synthesis of α-amino- and α-hydroxy phosphonates. In the presence of a catalytic amount of oxalic acid (10 mol %), trimethyl phosphite reacts with aldehydes or imines (generated in situ from an aldehyde and an amine) to yield the corresponding coupled products in good yield.