Highly enantiomerically enriched chlorophosphine boranes: synthesis and applications as P-chirogenic electrophilic blocks

The stereoselective synthesis of P-chirogenic chlorophosphine boranes 4 was investigated by HCl acidolysis of the corresponding aminophosphine boranes 10. The reaction afforded the P-N bond cleavage with inversion of the configuration at the phosphorus center, leading to the chlorophosphine boranes 4 with high to excellent enantiomeric purities (80-99% ee), except in the case of the chloro-1-naphthylphenylphosphine borane 4d. Reaction conditions and workup significantly influence the enantiomeric purity of the product, with the exception of the o-anisyl- and o-tolylchlorophenylphosphine boranes, 4b and 4c, which were found to be particularly stable even after purification by chromatography on silica gel. Reaction of the chlorophosphine boranes 4 with various nucleophiles, such as carbanions, phenolates, thiophenolates, or amides, afforded the corresponding organophosphorus borane complexes via P-C, P-O, P-S, and P-N bond formation, respectively, in 34-93% yield and with up to 99% ee. This work demonstrates the importance of chlorophosphine boranes 4 as new and powerful electrophilic building blocks for the highly stereoselective synthesis of P-chirogenic organophosphorus compounds.     

1H and 13C NMR characterization of hemiamidal isoniazid-NAD(H) adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis

Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation of INH inside the bacteria Mycobacterium tuberculosis. Performed in the presence of NAD(+), this oxidation generates a family of isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors of InhA, an enzyme essential in mycolic acid biosynthesis. In this work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species of INH-NAD(H) adducts that coexist in solution. Two of them are open diastereoisomers consisting of the covalent attachment of the isonicotinoyl radical at position four of the nicotinamide coenzyme. The other two result from a cyclization involving the amide group from the nicotinamide and the carbonyl group from the isonicotinoyl radical to give diastereoisomeric hemiamidals. Although an INH-NAD(H) adduct with a 4S configuration has been characterized within the active site of InhA from Xray crystallography and this bound adduct interpreted as an open form (Rozwarski et al., Science 1998, 279, 98-102), it is legitimate to raise the question about the effective active form(s), open or cyclic, of INH-NAD(H) adduct(s). Is there a single active form or are several forms able to inhibit the InhA activity with different levels of inhibitory potency?     

Synthesis and Characterization of Various Benzyl Diethylenetriaminepentaacetic Acids (dtpa) and Their Paramagnetic Complexes,Potential Contrast Agents for Magnetic Resonance Imaging

Four derivatives of diethylenetriaminepentaacetic acid (=3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid (H₅dtpa)), potential contrast agents for magnetic resonance imaging (MRI), carrying benzyl groups at various positions of the parent structure were synthesized and characterized by a thorough multinuclear NMR study, i.e., the (S)‐ and (R)‐stereoisomers 1a and 1b of 4‐benzyl‐3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid (H₅[(S)‐(4‐Bz)dtpa] and H₅[(R)‐(4‐Bz)dtpa], the diamide derivative N,N″‐bis[(benzylcarbamoyl)methyl]diethylenetriamine‐N,N′,N″‐triacetic acid (=3,9‐bis[2‐(benzylamino)‐2‐oxoethyl]‐6‐(carboxymethyl)‐3,6,9‐triazaundecanedioic acid; H₃[dtpa(BzA)₂]; 2 ), and the diester derivative N,N″‐bis{[(benzyloxy)carbonyl]methyl}diethylenetriamine‐N,N′,N″‐triacetic acid (=3,9‐bis[2‐(benzyloxy)‐2‐oxoethyl]‐6‐(carboxymethyl)‐3,6,9‐triazaundecanedioic acid; H₃[dtpa(BzE)₂]; 3 ). From the ¹⁷O‐NMR chemical shift of H₂O induced by their dysprosium complexes with ligands 1 – 3 , it was concluded that only one H₂O molecule is contained in the first coordination sphere of these lanthanide complexes. The rotational correlation times (τ_R) of the complexes were estimated from the ²H‐NMR longitudinal relaxation rate of the deuterated diamagnetic lanthanum complexes. The exchange time of the coordinated H₂O molecule (τ_M) was studied through the temperature dependence of the ¹⁷O‐NMR transverse relaxation rate. As compared to [Gd(dtpa)]²⁻, the H₂O‐exchange rate is faster for [Gd{(S)‐(4‐Bz)dtpa}]²⁻ and [Gd{(R)‐(4‐Bz)dtpa}]²⁻‐, slower for [Gd{dtpa(BzA)₂}], and almost identical for [Gd{dtpa(BzE)₂}]. The analysis of the ¹H‐relaxivity of the gadolinium complexes recorded from 0.02 to 300 MHz established that i) the relaxivity of [Gd{dtpa(BzE)₂}] is similar to that of [Gd(dtpa)]²⁻, ii) the slightly slower molecular rotation of [Gd{dtpa(BzA)₂}] induces a mild enhancement of its relaxivity, and iii) the marked increase of relaxivity of [Gd{(S)‐(4‐Bz)dtpa}]²⁻ and [Gd{(R)‐(4‐Bz)dtpa}]²⁻ mainly results from an apparently shorter distance between the gadolinium ion and the H₂O protons of the coordinated H₂O molecule.     

FeCp]+-induced hexafunctionalization of hexamethylbenzene with dendrons for the direct synthesis of redox-active iron-centered metallodendrimers

Phenol tri- and nonaallyl dendrons (3 and 7, respectively) were functionalized at the focal position to give the new triallyl dendrons 4 and 6 and the nonaallyl dendrons 11 and 13 that contain a iodoalkyl or a bromobenzyl termini. All these dendrons were used for the [FeCp]+-induced hexafunctionalization of hexamethylbenzene in [FeCp(eta6-C6Me6)][PF6] (1) under mild conditions in the presence of KOH. These reactions directly yielded the 18-allyl and 54-allyl dendrimers 9, 10, and 14 with a [FeCp(eta6-arene)]+ unit located at the dendrimer core. Cyclic voltammetry studies were recorded in THF and DMF with these metallodendrimers and compared with those of analogous dendrimers or complexes of smaller size that contain a [FeCp(eta6-arene)]+ unit at the core. The decreased rate of heterogeneous electron transfer when the dendritic size increases first disclosed by Diederich and Gross is confirmed. The variation of the redox potential of the Fe(II/I) redox system with increasing dendritic size is negligible even in a solvent of high dielectric constant such as DMF. This trend is attributed to fact that the involved "redox" orbital is buried on the metal center, well protected by the shell of alkyl chains (electron-reservoir nature), unlike in ferrocene. The chemical irreversibility increases in THF as the dendrimer size increases, due to more facile ligand substitution with THF at the 19-electron level when the chain bulk increases.     

Diastereoselective carbonyl phosphonylation using chiral N,N′-bis-[(S)-α-phenylethyl]-bicyclic phosphorous acid diamides

Addition of aldehydes to the P-anion derivatives of chiral phosphorous acid diamides (1S,2S,1′S,1″S)-2 and (1R, 2R,1′S,1″S)-2 in THF gave α-hydroxyphosphonamides in good yield (64-100%) and moderate diastereoselectivities.     

First synthesis of arylpyrrolo- and pyrazolopyrrolizinones as useful agents with potential biological interest

Novel arylpyrrolo- and pyrazolopyrrolizinones were prepared in three or four steps starting from aminoarylpyrrole and pyrazole carboxylates through the cyclisation of a Vilsmeier-Haack intermediate. This synthesis was enhanced by diverse N-protections of the aza-heterocycle and furnish new series with potential biological interest.     

Efficient and simple synthesis of 3-aryl-1H-pyrazoles

Efficient preparation of 3-aryl-1H-pyrazoles by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles with (het)aryl halides is described. The choice of THP protecting group is discussed.     

Synthesis of fluorinated trithioether compounds: X-ray structures of 1,3,5-(CH2SRf)3-2,4,6-(CH3)3C6, Rf = C6F5, 4-HC6F4, or 2-FC6H4

A series of three new trithioether compounds containing fluorinated phenyl moieties, 1,3,5-(CH₂SR_f)₃-2,4,6-(CH₃)₃C₆, R_f = C₆F₅ (1), 4-HC₆F₄ (2), or 2-FC₆H₄ (3), were prepared by treatment of 1,3,5-(CH₂Br)₃-2,4,6-(CH₃)₃C₆ with the corresponding Pb(SC₆F₅)₂ or NaSR_f. The new structures were verified by elemental analyses, IR, ¹H NMR, ¹⁹F NMR spectroscopies, and mass spectra. The single crystal X-ray diffraction studies of 1-3 show a similar cis,trans,trans-conformation for the three fluorophenylthiomethyl groups attached to the central benzene ring with all dihedral angles between planes of central ring and external rings close to 0°, giving flat molecules. Comparing, 1-3 with closely related tripodal molecules built-up on 2,4,6-trimethylbenzene, arrangement of one SR group respect to others seems to be defined by the nature of the R substituent. Then in the case of 1-3, a parallel arrangement of rings is favored over an orthogonal one, which would bring the ortho-F atoms close to H atoms of the methylene groups.     

Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza‐Heterocycles

A two‐step synthesis of structurally diverse pyrrole‐containing bicyclic systems is reported. ortho‐Nitro‐haloarenes coupled with vinylic N‐methyliminodiacetic acid (MIDA) boronates generate ortho‐vinyl‐nitroarenes, which undergo a “metal‐free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug‐like” molecules. Interestingly, an ortho‐nitro‐allylarene derivative furnished a cyclic β‐aminophosphonate motif.