Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity.

A broadly improved second generation catalytic two-phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C-, N-, O- and S- substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP-catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second-generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late-stage enantiospecific SN2@P reactions with Grignard reagents.

Electronic Effects in Phosphino-Iminophosphorane PdII Complexes upon Varying the N Substituent.

Three series of palladium(II) complexes supported by a phosphine-iminophosphorane ligand built upon an ortho-phenylene core were investigated to study the influence of the iminophosphorane N substituent. Cis-dichloride palladium(II) complexes 1 in which the N atom bears an isopropyl (iPr, 1 a), a phenyl (Ph, 1 b), a trimethylsilyl (TMS, 1 c) group or an H atom (1 d) were synthesized in high yield. They were characterized by NMR, IR spectroscopy, HR-mass spectrometry, elemental analysis, and X-ray diffraction. A substantial bond length difference between the Pd-Cl bonds was observed in 1. Complexes 1 a-d were converted into [Pd(LR )Cl(CNt Bu)](OTf)] 2 a-d whose isocyanide is located trans to the iminophosphorane. The corresponding dicationic complexes [Pd(LR )(CNt Bu)2 ](OTf)2 3 a-d were also synthesized, however they exhibited lower stability in solution than 2, the isopropyl derivative 3 a being the most stable of the series. Molecular modeling was performed to rationalize the regioselectivity of the substitution of the single chloride by isocyanide (from 1 to 2) and to study the electronic distribution in the complexes. In particular differences between the TMS and H containing complexes vs. the iPr and Ph ones were found. This suggests that the nature of the N substituent is far from innocent and can help tune the reactivity of iminophosphorane complexes.

Base-Stabilized Phosphinidene Oxide, Imide and Sulfide.

Oxidation of a base-stabilized phosphinidene (κ2 -NNP)P (12, NNP=phosphinoamidinate) with N2 O afforded a labile phosphinidene oxide (κ2 -NNP)P=O (16) which was characterized by NMR spectroscopy. Further oxidation of 16 by N2 O or reaction of 12 with two equivalents of pyridine oxide afforded the isolable dioxide (κ2 -NNP)PO2 which was characterized by NMR and SC XRD. Trapping of 16 with tolyl isocyanate resulted in P=O/N=C metathesis, eventually affording a urea-ligated phosphine (κ1 -NNP)P(NTol)2 C=O (17) The mechanism of this reaction was elucidated by DFT calculations. Reactions of phosphinidene 12 with azides generated transient imines (NNP)P=NR, which in the case of R=Tol underwent cycloaddition with tolyl Isocyanate to afford the urea product 17, and in the case of R=SiMe3 reacts with N3 SiMe3 via the addition of N-Si across the P=N bond affording, after the extrusion of dinitrogen, a P,N-heterocyclic compound. Both products of the reactions with azides have been fully characterized, both in solution and the solid-state. Finally, reaction of phosphinidene 12 with one equivalent of sulfur resulted in the isolation of the base-stabilized phosphinidene sulfide (κ2 -NNP)P=S that has also been fully characterized.

Synthesis of a New Chelating Iminophosphorane Derivative (Phosphazene) for U(VI) Recovery.

A new synthetic chelating N-hydroxy-N-trioctyl iminophosphorane (HTIP) was prepared through the reaction of trioctylphosphine oxide (TOPO) with N-hydroxylamine hydrochloride in the presence of a Lewis acid (AlCl3). Specifications for the HTIP chelating ligand were successfully determined using many analytical techniques, 13C-NMR, 1H-NMR, FTIR, EDX, and GC-MS analyses, which assured a reasonable synthesis of the HTIP ligand. The ability of HTIP to retain U(VI) ions was investigated. The optimum experimental factors, pH value, experimental time, initial U(VI) ion concentration, HTIP dosage, ambient temperature, and eluents, were attained with solvent extraction techniques. The utmost retention capacity of HTIP/CHCl3 was 247.5 mg/g; it was achieved at pH = 3.0, 25 °C, with 30 min of shaking and 0.99 × 10-3 mol/L. From the stoichiometric calculations, approximately 1.5 hydrogen atoms are released during the extraction at pH 3.0, and 4.0 moles of HTIP ligand were responsible for chelation of one mole of uranyl ions. According to kinetic studies, the pseudo-first order model accurately predicted the kinetics of U(VI) extraction by HTIP ligand with a retention power of 245.47 mg/g. The thermodynamic parameters ΔS°, ΔH°, and ΔG° were also calculated; the extraction process was predicted as an exothermic, spontaneous, and advantageous extraction at low temperatures. As the temperature increased, the value of ∆G° increased. The elution of uranium ions from the loaded HTIP/CHCl3 was achieved using 2.0 mol of H2SO4 with a 99.0% efficiency rate. Finally, the extended variables were used to obtain a uranium concentrate (Na2U2O7, Y.C) with a uranium grade of 69.93% and purity of 93.24%.

Chemistry of Tetradentate [C,N : C,N] Iminophosphorane Palladacycles: Preparation, Reactivity and Theoretical Calculations.

A theoretical and experimental study of tetradentate [C,N : C,N] iminophosphorane palladacycles was carried out for the purpose of elucidating their behavior as compared to the parent Schiff base analogues to determine the prospect of encountering new A-frame structures for the iminophosphorane derivatives. The DFT calculations were in agreement with the experimental results regarding the performance of these ligands. New insights into the chemistry of the related dinuclear species have been obtained.

Novel 3,3-disubstituted oxindole derivatives. Synthesis and evaluation of the anti-proliferative activity.

3,3-Disubstituted oxindole derivatives bearing a nitrogen atom at the C-3 position have been synthesized starting from 3-alkyl oxindole through a metal free pathway. These derivatives have been tested in five human tumor cell lines (PC3, MCF7, SW620, MiaPaca2 and A375) and on primary cells (PBMCs) from healthy donors providing compound 6d showing a strong anticancer effect in all cancer lines on the low micromolar range.

Sulfonylimino Group Transfer Reaction Using Imino-λ³-iodanes with I2 as Catalyst Under Metal-free Conditions.

A new practical procedure of imination for sulfide has been developed. The treatment of (N-tosylimino)-phenyl-λ³-iodane, PhINTs, with various sulfides in the presence of a catalytic amount of I2 under metal-free conditions affords the corresponding N-tosylsulfilimine compounds with moderate to good yields. This facile transfer procedure of the sulfonylimino group can also be applied to triphenylphosphine to produce the respective iminotriphenylphosphoranes in high yields. According to the reaction mechanism studies, the process of imination from (N-tosylimino)-phenyl-λ³-iodane to sulfide under the conditions may involve radical steps within the reaction mechanism.

Origin of problems related to Staudinger reduction in carbopeptoid syntheses.

We report the solid phase synthesis of -GG-X-GG- type α/ß-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc derivative (e.g., Fmoc-RibAFU(ip)-OH) and the azido derivative (e.g., N3-RibAFU(ip)-OH) via Staudinger reaction with nBu3P can be successfully applied. Both X-ray diffraction, 1H- and 31P-NMR, and theoretical (QM) data support and explain why the application of Ph3P as Staudinger reagent is "ineffective" in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (-CONH-) bond. The failure of the polypeptide chain elongation with N3-cX originates from the "coincidence" of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack during the hydrolysis of a quasi penta-coordinated triphenylphosphinimine. Nevertheless, the synthesis of the above α/ß-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo- and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid.

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin-Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

Powerful Bispyridinylidene Organic Reducing Agents with Iminophosphorano π-Donor Substituents.

Four members of a new family of powerful bispyridinylidene organic reducing agents have been prepared, which exploit iminophosphorano (-N=PR3; R = Ph, Cy) π-donor substituents. Electrochemical studies show exceptionally high oxidation potentials, ranging from 1.30 to 1.51 V versus SCE. These new reductants were shown to effectively convert 1-bromonaphthalene to naphthalene under mild reaction conditions. From the redox potentials, substituent constants (σp(+)) for the iminophosphorano groups Ph3P=N- (-1.82) and Cy3P=N- (-2.21) were determined, demonstrating their superior π-donating properties compared to traditional amino substituents.