Structures of four types of novel high-valent manganese complexes obtained by the reactions of KMnO4 with tridentate Schiff base ligands

X-ray structure analysis revealed that four types of novel manganese complexes, Mn^IV(N-EtO-sal)₂, Mn^III(N-PhO-sal)(L), [Mn^IV(5,6-Benzo-L)₂(μ-O)]₂ and Mn^III(L-4-Me)₃ have been found to be obtained by the reactions of KMnO₄ with various tridentate Schiff base ligands (N-EtOH-salH, N-PhOH-salH and its derivatives) in dry MeCN, where N-EtOH-salH, N-PhOH-salH, LH, 5,6-Benzo-LH and L-4-MeH denote N-2-hydroxyethyl-salicylideneamine, N-2-hydroxyphenyl-salicylideneamine, 2-(2-hydroxyphenyl)-benzoxazole 2-(2-hydroxynaphthyl)-benzoxazole and 2-(2-hydroxyphenyl)-5-methylbenzoxazole, respectively. The reactions of KMnO₄ and N-PhOH-salH and its derivatives have especially been found to afford benzoxazole derivatives which may be formed by intramolecular oxidative coupling between the phenolic oxygen atom of aminophenol moiety and the carbon atom of imine moiety.     

Efficient synthesis of N-Me, N-Boc-protected α-hydrazinoacids: access to 1:1:1 [N-Me α-hydrazino/α/N-Me α-hydrazino]trimers

The preparation of optically pure N^α-Me, N^β-Boc-protected α-hydrazinoacids in large scale is described via a S_N2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N^α-Me α-hydrazino/α/N^α-Me α-hydrazino]trimers.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Low-cost and multi-gram scale synthesis of chiral Nβ-Boc protected α-Nα-hydrazino diesters

An efficient and general low-cost method is described to obtain chiral N^β-Boc protected α-N^α-hydrazino diester building-blocks (orthogonally and non-orthogonally protected diesters) on multi-gram scale (30 mmol) using two successive S_N2 reactions. This method is also convenient for the introduction of both polar and nonpolar side chains on the N^α-atom and represents an inexpensive and attractive alternative compared to the more expensive method using commercial oxaziridine reagents for N-amination of α-amino acids.     

Thebaine Adducts with Maleimides. Synthesis and Transformations

Diels-Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3′,4′ ]-succinimido-endo-ethenotetrahydrothebaines containing N′-alkyl, cycloalkyl, aralkyl or aryl substituents. N′-[1(S)-hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo-ethenotetrahydrothebaine formed in reaction of S-valinol with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH₄ afforded N′-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH₄ resulted in the corresponding 2′α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine pyrrolidine derivatives effected by BBr₃ afforded compounds of the tetrahydrooripavine series. The O-demethylation of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-ethenotetrahydrooripavines. Alkylation conditions were found for N′-(4-hydroxyphenethyl)-substituted tetrahydrothebaine succinimide derivatives.     

Blocking-Deblocking of the NH-Functionality of Uracil and its Derivatives

We have been interested in various 5,6-dihydrouracils and 5,6-dihydroorotic acid derivatives as possible inhibitors of dihydrouracil dehydrogenase, dihydroorotase, and dihydroorotate dehydrogenase.² The known methods for the synthesis of 5,6-dihydrouracils and 5,6-dihydroorotic acid derivatives are either a low yield cyclization process³ or a catalytic hydrogenation⁴ procedure which frequently led to the elimination of desired functionality⁵. In order to obviate these difficulties, we have recently developed⁶ a mild non-catalytic method for the reduction of 5,6-double bond of uracil and orotic acid derivatives. By using lithium tri-sec-butyl borohydride^7–8 we have been able to reduce N₁, N₃-dialkyl uracil and orotic acid derivatives to the corresponding 5,6-dihydrouracil and orotic acid derivatives as shown in scheme (1).     

Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl₄ have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivities. When (αR)- and (αS)-N-(α-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereoisomer products. Examination of the enolates formed in each case by ¹⁹F NMR, after treatment with TiCl₄, indicated that both preparations gave the same predominant enolate. This was assumed to be the E-enolate. The α-fluoro-β-hydroxy-aldol products were removed from the auxiliary either by alcoholysis or reduction and converted to the corresponding α,β-difluoro products by treatment with Deoxofluor™.     

Proximal heteroalkylation of monoalkoxycalix[4]arenes in synthesis of inherently chiral molecules

Proximal heteroalkylation of monoalkyl ethers of calix[4]arenes or p-tert-butylcalix[4]arenes in NaH/CH₃CN or NaOH/DMSO, respectively, was applied for synthesis of inherently chiral calixarenes with ABHH substitution pattern. The introduction by the method of (R)- or (S)-N-(α-phenylethyl)acetamide chiral auxiliary group gives mixtures of diastereomeric derivatives of inherently chiral calixarenes, which were separated by column chromatography. The chiral calixarenes were thoroughly characterized by ¹H, ¹³C NMR, and X-ray diffraction methods.     

Synthesis of N-Z, N-Fmoc or Boc protected α-hydrazinoacids and study of the coupling reaction in solution of N-Z-α-hydrazinoesters

The preparation of chiral orthogonally protected N^α-Z, N^β-Fmoc- or Boc-α-hydrazinoacids derivatives, directly suitable for SPPS, is described in six steps with good yields starting from the corresponding α-aminoacids. The coupling reaction assays performed in liquid phase between N^α-Z-hydrazinoesters and N-Fmoc-α-aminoacids demonstrated the low reactivity of the hydrazinoester derivatives. However, we found that the acid fluoride method allowed the formation of hydrazinodipeptides almost quantitatively.     

Diels-Alder adducts of 3-N-substituted derivatives of (−)-Cytisine as influenza A/H1N1 virus inhibitors; stereodifferentiation of antiviral properties and preliminary assessment of action mechanism

The synthesis and anti-influenza activity study of Diels-Alder adducts of 3-N-substituted derivatives of (−)-cytisine with N-substituted maleimides are described. Synthesized compounds were studied for antiviral activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK. The values of CC₅₀, IC₅₀ and selectivity indexes (SI) of obtained derivatives were determined. It was shown that anti-influenza activity of ‘α-endo’ adducts is higher (SI of three samples is 79 and higher) than activity of ‘β-endo’ adducts. By means of ‘time-of-addition’ experiment it was established that the leading compound (3aS,4R,8S,12R,12aR,12bS)-10-benzyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3′,4':3,4]pyrido[1,2-a][1,5]diazocine-1,3,5(4H)-trione (16a) demonstrates anti-influenza activity at the middle and late stages of the virus life cycle. The possibility of interaction of synthesized derivatives with the active sites of the PA_N and PB2 was estimated via in silico approach. The difference in the locations of ‘α-endo’ and ‘β-endo’ adducts in PB2 active site (5JUN) is offered as an explanation of the dependence of their virus-inhibiting properties on stereochemistry.     

New organic activators for the enantioselective reduction of aromatic imines with trichlorosilane

N-Picolinoyl-(2S)-(diphenylhydroxymethyl)pyrrolidine was found to work as an organic activator in the reduction of aromatic imines to the corresponding amines by Cl₃SiH. The highest selectivity was 80% ee. These are the first data showing that N-formyl group is not always essential as N-protecting group of pyrrolidine derivatives for the reduction of imines by Cl₃SiH.     

α-乙酰氧基-N-亚硝基吡咯烷的解离及其致癌代谢机理的理论研究

用ab initio方法, 在MP2/6-31G**水平下讨论了α-乙酰氧基-亚硝基吡咯烷(α-Acetoxy-NPYR)在各种条件下的解离反应机理, 并对形成终致癌物B, C, D的代谢机理进行研究. 发现在OH^－和H₂O作用下的解离都遵循羟基进攻羰基机理, OH^－作用下是一个经四面体中间体阴离子的无位垒过程, H₂O作用下有相对高的活化能(165.36 kJ/mol). H₃O^＋作用下是先形成阳离子产物的S_N1过程, 并没有发现遵循两种综合的解离情形. 同时, 羟基化产物异构化为终致癌物B, C, D是一个相对容易进行的过程.     

Coordination properties of the multifunctional S,N,S zwitterionic ligand EtNHC(S)Ph2PNPPh2C(S)NEt

The reaction of trialkylphoshanes and amino-phosphanes with isothiocyanates yields adducts containing the zwitterionic thioamidyl-phosphonium P⁺C(S)N^? functional group. Ligands containing this group were not previously studied, probably due to their instability towards dissociation, in the presence of metal species able to coordinate the P atom. The ligand EtNHC(S)Ph₂PNPPh₂C(S)NEt (HEtSNS) was obtained by reaction of Ph₂PNHPPh₂ with ethylisothiocyanate and proved to be very versatile: it can be protonated giving cation H₂EtSNS⁺ and deprotonated forming the dianion–cation EtSNS^?. HEtSNS and its derivatives behave as ligands showing five possible coordination fashions, S,N,S tridentate and S,S-bidentate (with a bite-angle varying from 180° to 90°), S-monodentate, S,S bridging and N,N,N interaction. Here we describe the coordination chemistry of HEtSNS, in particular towards Rh, Cu, Ag and Au, and some properties of its complexes which are still the only examples containing the P⁺C(S)N^? zwitterionic group.     

Crystal structure of bis(α,α′-dithio-bis(formamidinium)) bis(μ2-chloro)hexachlorodimercurate(II)

The crystal and molecular structure of bis(α,α′-dithio-bis(formamidinium)) bis(μ₂-chloro)hexachlorodimercurate(II) C₄H₁₆Hg₂Cl₈N₈S₄ (I), where α,α′-dithio-bis(formamidine) is C₂H₆N₄S₂, was solved. Crystals are monoclinic, a = 8.6417(6) Å, b = 14.648(1) Å, c = 10.2111(8) Å, β = 104.949(1)°, V = 1248.8(2) ų, space group P2₁/n, Z = 4. The crystal structure is built of HgCl ₄ ^2? ions linked via inversion centers into [Hg₂Cl₈]^4? pairs and C₂H₈N₄S ₂ ²⁺ cations. [Hg₂Cl₈]^4? anions and C₂H₈N₄S ₂ ²⁺ cations form alternating layers linked by N-H…Cl hydrogen bonds into a framework structure.     

An expedient and short synthesis of chiral α-hydrazinoesters: synthesis and conformational analysis of 1:1 [α/α-Nα-hydrazino]mers

Different α-hydrazinoesters with high optical purity have been obtained in large scale via an S_N2 protocol. A coupling reaction with a natural amino acid leads to the corresponding dimers, which have been oligomerized in order to obtain the 1:1 [α/α-N^α-hydrazino]mer series. Conformational studies show that these mixed oligomers are self-organized in solution via a succession of γ-turn and hydrazinoturn whatever the absolute configuration of the chiral carbons.     

Synthesis of enantiopure (αMe)Dip and other α-methylated β-branched amino acid derivatives

This report describes the synthesis of the two enantiomerically pure α-methylated β-branched phenylalanine derivatives, (S)- and (R)-α-methyl-β,β-diphenylalanine—(αMe)Dip—starting from the chiral building blocks (R)- and (S)-N-Boc-N,O-isopropylidene-α-methylserine methyl esters, respectively. The key step involves a double alkylation with a Grignard reagent on an ester group. The use of the same protocol for the preparation of other α-methylated β-branched serine derivatives is also described.     

Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety

With respect to the strong antiviral activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine various types of its side chain fluorinated analogues were prepared. The title compound, (S)-1-[3-fluoro-2-(phosphonomethoxy)propyl]-5-azacytosine (FPMP-5-azaC) was synthesised by the condensation reaction of (S)-2-[(diisopropoxyphosphoryl)methoxy)-3-fluoropropyl p-toluenesulfonate with a sodium salt of 5-azacytosine followed by separation of appropriate N¹ and O² regioisomers and ester hydrolysis. Transformations of FPMP-5-azaC to its 5,6-dihydro-5-azacytosine counterpart, amino acid phosphoramidate prodrugs and systems with an annelated five-membered imidazole ring, i.e. imidazo [1,2-a][1,3,5]triazine derivatives were also carried out. 1-(2-Phosphonomethoxy-3,3,3-trifluoropropyl)-5-azacytosine was prepared from 5-azacytosine and trifluoromethyloxirane to form 1-(3,3,3-trifluoro-2-hydroxypropyl)-5-azacytosine which was treated with diisopropyl bromomethanephosphonate followed by deprotection of esters. Antiviral activity of all newly prepared compounds was studied. FPMP-5-azaC diisopropyl ester inhibited the replication of herpes viruses with EC₅₀ values that were about three times higher than that of the reference anti-HCMV drug ganciclovir without displaying cytotoxicity.     

Synthesis and resolution of an α-phenyl substituted ortho-palladated matrix

A novel ortho-palladated benzylaminate matrix bearing phenyl substituent at the α-carbon stereocenter was prepared in the racemic state by direct intramolecular palladation of tertiary diphenylmethylamine with palladium(II) acetate; its structure and palladacycle conformation were determined by ¹H NMR studies of the mononuclear triphenylphosphine adduct. The resolution of the dimeric complex was performed via recrystallization of its diastereomeric (S)-prolinate derivatives. The absolute configuration (R_C,R_C) of the enantiopure dimer thus obtained was determined by an X-ray diffraction investigation of the less soluble (R_C,S_CS_N)-diastereomer of its (S)-prolinate adduct.     

α-Chloroacetone as a donor in the BINAM-l-prolinamide organocatalyzed aldol reaction: application to the enantioselective synthesis of α,β-epoxy ketones

Recoverable (S_a)-BINAM-l-prolinamide in combination with benzoic acid catalyzed the direct aldol reaction between α-chloroacetone and several aldehydes in different solvents, including water. It is possible to obtain mainly one of the isomers with good regio-, diastero-, and enantioselectivity by choosing the appropriate solvent and reaction conditions. Thus, α-chloroacetone mainly gives the anti-aldol isomer in DMF/H₂O with up to 97% ee. The crude α-chloro-β-hydroxy ketones obtained are transformed stereospecifically into the corresponding enantioenriched trans-α,β-epoxy ketones derivatives with up to 97% ee through an S_N2 displacement reaction by treatment with Et₃N.     

Synthesis and characterization of cyclopentadienyl/alkoxo titanium dichlorides: structural analysis of monocyclopentadienyl titanium dichlorides with ligands derived from menthol and borneol

A variety of monocyclopentadienyl alkoxo titanium dichloride and bisalkoxo titanium dichloride complexes have been prepared and characterized by spectroscopic techniques. The titanium derivatives containing both cyclopentadienyl and various alkoxo ligands [Ti(η⁵-C₅H₅)(OR)Cl₂] (1-5) have been synthesized from the reaction of [Ti(η⁵-C₅H₅)Cl₃] with 1 equivalent of the corresponding alcohol in THF in the presence of triethylamine (ROH = Adamantanol, 1R,2S,5R-(−)-menthol, 1S-endo-(−)-borneol, cis-1,3-(−)-benzylideneglycerol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose). The bisalkoxo titanium dichloride derivatives [TiCl₂(OR)₂] (6-10) have been prepared by a redistribution reaction between Ti(OR)₄ and TiCl₄ compounds 6-8 (OR = Adamantanoxy, (1R,2S,5R)-(−)menthoxy, (1S-endo)-(−)-borneoxy) and by reaction of [Ti(OR)₂(OPrⁱ)₂]₂ with CH₃COCl compounds 9 and 10 (OR = 1,2:3,4-di-O-isopropylidene-α-d-galactopyranoxy, and 1,2:5,6-di-O-isopropylidene-α-d-glucofuranoxy). The molecular structures of 2 and 3 have been determined by single crystal X-ray diffraction studies.