Synthetic approach for novel bis(α‐aminophosphonic acid) derivatives of chromone containing 1,2,4,3‐triazaphosphole moieties

Terephthalic acid hydrazide ( 1 ) was reacted with phenylphosphonic dichloride to yield bis(1,3,4,2‐oxadiazaphosphole) derivative 3 , which was condensed with α‐aminophosphonic acid derivative 4 to afford bis[(1,2,4,3‐triazaphospholyl)(chromonyl)methylphosphonic acid] derivative 5 . The addition of diethyl phosphite to Schiff bases 9 and 10 derived from the condensation of bis(4‐amino‐1,2,4,3‐triazaphosphole) derivative 6 or bis(4‐phosphorylamino‐1,2,4,3‐triazaphosphole) derivative 7 with 3‐formyl‐6‐methylchromone ( 8 ) yielded bis[(1,2,4,3‐triazaphospholyl)(chromonyl)aminomethylphosphonate] derivative 11 and bis[(1,2,4,3‐triazaphospholyl)(chromonyl)phosphorylamino‐methylphosphonate] derivative 12 , respectively. The structures of all products were established by elemental analysis and spectral data. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:117–122, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20520     

Synthesis and bioactivities of novel organogermanium sesquioxides containingα‐aminophosphonate groups

In order to search for novel antitumor drugs with high activity and low toxicity, a series of novel organogermanium sesquioxides containing α‐aminophosphonate groups were synthesized by the hydrolysis of O,O‐diphenyl N‐trichlorogermylpropiono‐α‐aminophosphonates. Their structures were confirmed by ¹H NMR, ³¹P NMR, and IR spectroscopy and by elemental analysis. Data of ¹H NMR and IR spectroscopy indicated that the title compounds are polymeric organogermanium sesquioxides. The results of bioassay showed that the products possess potential anticancer activities. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 209–212, 1999     

Solid‐state conformations of linear depsipeptide amides with an alternating sequence of α,α‐disubstituted α‐amino acid and α‐hydroxy acid

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe₂ acetonitrile solvate, C₄₇H₅₈N₄O₉·C₂H₃N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe₂, C₂₈H₃₇N₃O₆, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂ (1:1), C₃₂H₄₁N₃O₆, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe₂, C₃₀H₃₇N₃O₆, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks.     

Synthesis of optically active N‐protected α‐aminoketones and α‐amino alcohols

A series of optically active N‐protected α‐aminoketones were synthesized via the Grignard reaction of the Weinreb amides of the N‐tert‐butoxycarbonyl amino acids. Reduction of the α‐aminoketones by sodium borohydride resulted in the corresponding 1,2‐amino alcohols. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:603–606, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10195     

Cyclopolymerization of α,ω‐heterodifunctional monomers containing styrene and maleimide moieties

A series of α,ω‐heterodifunctional monomers with styrene (St) and maleimide moieties bridged by a varied length of oligo‐ethylene glycol (OEG) linkers were synthesized. Cyclopolymerizations of these monomers through reversible addition–fragmentation chain transfer‐mediated alternating radical copolymerization between intramolecular St and maleimide moieties were investigated. For the monomers with three or more ethylene glycol (EG) units, their cyclopolymerizations can be realized properly in low monomer feeding concentrations, affording well‐defined cyclopolymers with crown ether encircled in their main chains. Importantly, the cyclopolymerizations of monomers with six or seven EG units in the presence of KPF₆ could be enhanced by the supramolecular effects between the OEG linkers and the potassium metal ion. Thus, the monomer feeding concentration could be largely improved, which may benefit preparation of the cyclopolymers with high degrees of copolymerization. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 330–338     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.     

Phosphonates containing sulfur and selenium. Synthesis of vinylphosphonates bearing α-sulfenyl, α-selenenyl, α-sulfinyl and α-seleninyl moieties and studies on nucleophilic addition

The selenenylation of racemic and optically active α-phosphoryl sulfoxides is a key step leading efficiently to α-phosphorylvinyl sulfoxides or α-phosphorylvinyl selenides depending on the reaction conditions. Oxidation of α-phosphorylvinyl selenides and subsequent thermolysis of selenoxides afford alkynylphosphonates. Studies of the stereochemical course of nucleophilic addition to α-phosphoryl sulfoxides show high facial stereoselectivity of the reaction, however, epimerisation at the α-carbon atom leads to mixtures of diastereomers.     

One‐pot synthesis of novel 2′‐deoxyuridine derivatives containing α‐aminophosphonate moieties

A series of α‐aminophosphonate derivatives of 2′‐deoxyuridine ( 8a–k ) have been prepared from 5′‐O‐tert‐butyldimethylsilyl‐3′‐amino‐2′, 3′‐dideoxyuridine in good yields. The structures of all the products were confirmed by ¹H NMR, ³¹P NMR, ³¹C NMR, and IR spectroscopy, and mass spectrometry and elemental analyses. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:230–235, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20288     

The Generation of Difluoroketenimine and Its Application in the Synthesis of α,α‐Difluoro‐β‐amino Amides

Fluorine‐containing β‐amino acids and their derivatives have attracted significant attention due to their importance in life sciences. Herein the previously unknown difluoroketenimine, the analogue of the elusive difluoroketene, has been generated by the reaction of difluorocarbene and isocyanide, which further undergoes [2+2] cycloaddition with imine. The three‐component reaction affords α,α‐difluoro‐β‐amino amides in good yields. Mechanistic studies reveal the unique properties of the difluoroketenimine in the [2+2] cycloaddition with imine.     

Two N‐ortho‐nitro­benzene­sulfonyl α,α‐disubstituted amino acid adducts

The carboxy group of 2‐methyl‐N‐[(2‐nitrophenyl)sulfonyl]­alanine, C₁₀H₁₂N₂O₆S, forms centrosymmetric hydrogen‐bonded dimers with an O?O distance of 2.629 (2) Å and an intramolecular N—H?O(nitro) hydrogen bond N?O distance of 2.823 (2) Å. 1‐[(2‐Nitro­phenyl)­sulfonyl­amino]­cyclo­hexane­carboxyl­ic acid, C₁₃H₁₆N₂O₆S, has Z′ = 2 and forms similar interactions.     

Syntheses and antitumor activities of polymers containing amino acid and 5‐fluorouracil moieties

The new monomer, 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐5‐fluorouracil (ETEFU), was synthesized from 5‐fluorouracil (5‐FU) and 3,6‐endo‐methylene‐1,2,3,6‐tetrahydophthalimidoethanoyl chloride (ETEC). Its homopolymer and copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared by photopolymerization reactions using 2,2‐dimethoxy‐2‐phenylacetophenone (DMP) as the photoinitiator. The synthesized ETEFU and polymers were identified by FT‐IR, ¹H‐NMR, and ¹³C‐NMR spectra. The contents of ETEFU units in poly(ETEFU‐co‐AA) and poly(ETEFU‐co‐VAc) were 20 and 17 mol%, respectively. The number‐average molecular weights of the synthesized polymers determined by gel permeation chromatography (GPC) were 4,600 to 10,700 g mol⁻¹. In vitro cytotoxicities of samples were evaluated with cancer cell lines [mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937)] and a normal cell line [mouse liver cells (AC2F)]. Cytotoxicities of 5‐FU and synthesized samples against the cancer cell lines were ranked as follows: ETEFU > poly(ETEFU) > 5‐FU > poly(ETEFU‐co‐AA) > poly(ETEFU‐co‐VAc). The in vivo antitumor activities of poly(ETEFU) and poly(ETEFU‐co‐AA) against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all doses except for the activity of poly(ETEFU) at 0.8 mg/kg. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1589–1595, 1999     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

The homo‐PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α‐Oxo‐ or α‐Hydroxy‐γ‐acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α‐oxo‐γ‐acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection–acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo‐Passerini–amine deprotection–acyl migration (PADAM) strategy. Highly stereoselective reduction of the α‐oxo‐γ‐acylaminoamides afforded α‐hydroxy‐γ‐acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.