Total Syntheses of (-)-Minovincine and (-)-Aspidofractinine through a Sequence of Cascade Reactions.

We report 8-step syntheses of (-)-minovincine and (-)-aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta- and hexacyclic frameworks. These cascade transformations included organocatalytic Michael-aldol condensation, a multistep anionic Michael-SN 2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo- and regioselective transformations.

Size-Exclusion Borane-Catalyzed Domino 1,3-Allylic/Reductive Ireland-Claisen Rearrangements: Impact of the Electronic and Structural Parameters on the 1,3-Allylic Shift Aptitude.

The reductive Ireland-Claisen rearrangement through borane-mediated hydrosilylation is reported. The method employs a borane catalyst with a special structural design and affords access to synthetically relevant products with high diastereoselectivity. Depending on electronic and structural parameters, the reaction can be coupled with a 1,3-allylic shift, thus the valence isomer of the Ireland-Claisen product is formed.

Transformation of Zwitterionic Pyridine Derivatives to a Spiro-Fused Ring System: Azoniabenzo[de]fluorine. Synthesis and Mechanistic Rationalization.

Reaction of aryl- and benzylsulfanopyridinium amidates bearing a methyl group in position 6 with 2 equiv of diphenylketene afforded a spiro-fused ring system: azoniabenzo[de]fluorine. By use of an excess amount of ketene, a distinct reaction was observed via which a 1H-pyrrolo[3,2-b]pyridin-2(3H)-one derivative was furnished. The structure of the tetracyclic spiro-fused ring system was unambiguously confirmed by X-ray diffraction, and its formation was rationalized by DFT calculations.

Temperature dependence of backbone dynamics in human ileal bile acid-binding protein: implications for the mechanism of ligand binding.

Human ileal bile acid-binding protein (I-BABP), a member of the family of intracellular lipid binding proteins plays a key role in the cellular trafficking and metabolic regulation of bile salts. The protein has two internal and, according to a recent study, an additional superficial binding site and binds di- and trihydroxy bile salts with positive cooperativity and a high degree of site-selectivity. Previously, in the apo form, we have identified an extensive network of conformational fluctuations on the millisecond time scale, which cease upon ligation. Additionally, ligand binding at room temperature was found to be accompanied by a slight rigidification of picosecond-nanosecond (ps-ns) backbone flexibility. In the current study, temperature-dependent (15)N NMR spin relaxation measurements were used to gain more insight into the role of dynamics in human I-BABP-bile salt recognition. According to our analysis, residues sensing a conformational exchange in the apo state can be grouped into two clusters with slightly different exchange rates. The entropy-enthalpy compensation observed for both clusters suggests a disorder-order transition between a ground and a sparsely populated higher energy state in the absence of ligands. Analysis of the faster, ps-ns motion of (15)N-(1)H bond vectors indicates an unusual nonlinear temperature-dependence for both ligation states. Intriguingly, while bile salt binding results in a more uniform response to temperature change throughout the protein, the temperature derivative of the generalized order parameter shows different responses to temperature increase for the two forms of the protein in the investigated temperature range. Analysis of both slow and fast motions in human I-BABP indicates largely different energy landscapes for the apo and holo states suggesting that optimization of binding interactions might be achieved by altering the dynamic behavior of specific segments in the protein.

Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect.

Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.

Selective hydroboration of dieneamines. Formation of hydroxyalkylphenothiazines as MDR modulators.

N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH(3) × Me(2)S) resulted in selective hydroboration of one double bond and full reduction of the other double bond to give 2-hydroxybutylphenothiazines. Position of the hydroxyl group was supported by NMR spectroscopy and verified by X-ray analysis. Comparison of MDR modulatory activity of the new derivatives revealed that the hydroxybutyl compounds are promising candidates for development of novel MDR inhibitors.

Rearrangement of aryl- and benzylthiopyridinium imides with participation of a methyl substituent.

6-Methyl substituted 2-aryl- and 2-benzylthiopyridinium N-imides reacted with an excess of isocyanates to give N,N-disubstituted exocyclic1H-imidazo[4,5-b]pyridin-2(3H)-ones. The products easily underwent spontaneous [1,5] hydrogen shift to provide the heteroaromatic imidazopyridinone isomers. The transformation implied the initial formation of [1,2,4]triazolo[2,3-a]pyridinium salt, followed by deprotonation and carbamoylation of the methylene moiety, and, finally, a rearrangement following a [1,3] sigmatropic pattern. Mechanistic considerations suggest and some experimental findings reveal the nonconcerted two-step mechanism of the ring transformation step.

The ortho effect in directed C-H activation.

The success of transition metal-catalysed ortho-directed C-H activation is often plagued by the effects of undesirable interactions between the directing group (DG) and other groups introduced into the aromatic core of the substrate. In particular, when these groups are in neighbouring positions, their interactions can affect profoundly the efficacy of the C-H activation by transition metals. In this work we introduce a simple substrate-only-based model to interpret the influence of steric hindrance of a group in ortho position to the DG in directed ortho-C-H bond activation reactions, and coined the term Ortho Effect (OE) for such situations. We consider simple descriptors such as torsion angle and torsional energy to predict and explain the reactivity of a given substrate in directed C-H activation reactions. More than 250 examples have been invoked for the model, and the nature of the ortho effect was demonstrated on a wide variety of structures. In order to guide organic chemists, we set structural and energetic criteria to evaluate a priori the efficiency of the metalation step which is usually the rate-determining event in C-H activations, i.e. we provide a simple and general protocol to estimate the reactivity of a potential substrate in C-H activation. For borderline cases these criteria help set the minimum reaction temperature to obtain reasonable reaction rates. As an example for the practical applicability of the model, we performed synthetic validations via palladium-catalysed 2,2,2-trifluoroethylation reactions in our lab. Furthermore, we give predictions for the necessary reaction conditions for several selected DGs.

Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification.

We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff-Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (-)-aspidospermidine, (-)-limaspermidine, and (+)-17-demethoxy-N-acetylcylindrocarine and the formal total synthesis of (-)-1-acetylaspidoalbidine.

Synthesis and structural study of variously oxidized diastereomeric 5'-dimethoxytrityl-thymidine-3'-O-[O-(2-cyanoethyl)-N,N-diisopropyl]-phosphoramidite derivatives. Comparison of the effects of the P=O, P=S, and P=Se functions on the NMR spectral and chromatographic properties.

R(P)- and S(P)-diastereomers of 5'-dimethoxytrityl-thymidine-3'-O-[O-(2-cyanoethyl)-N,N-diisopropyl]-phosphoramidite (T-CED) were separated by silica gel chromatography. Oxidation of both isomers with H(2)O(2), elemental sulfur and selenium, respectively, resulted in the corresponding oxidized analogues in nearly quantitative yields. All reactions were found to proceed with retention of P-configuration. This was confirmed by thorough NMR analysis which, in addition, aimed to study the spectral properties of the diastereomers with special respect to differences in the heteroatom effect of the O, S and Se atoms, double-bonded to the phosphorus, on the vicinal carbon-phosphorus couplings. It was found that the changes in the DeltaJ (=(3)J(P,C4') - (3)J(P,C2')) values were basically induced by the electronegativity of the heteroatoms, rather than differences in the rotational preferences about the C3'-O3' bond. The impact of the benzene solvent on the above couplings is also discussed. The effect of these heteroatoms on the chromatographic (normal and reverse phase HPLC) behavior of the compounds was also investigated and the reverse phase HPLC profiles showed an unambiguous correlation between the electronegativity of the heteroatoms and the chromatographic mobility of the analogues.

Synthesis of Multifunctional Aryl(trifloxyalkenyl)iodonium Triflate Salts.

A convenient procedure for the synthesis of aryl(trifloxyalkenyl)iodonium triflate salts from commercially available (diacetoxyiodo)benzene, trimethylsilyl trifluoromethanesulfonate, and acetylenes under mild conditions was developed. The obtained multifunctional hypervalent vinyliodonium salts equipped with electrophilic and nucleophilic functions could serve as novel C2 synthons for organic transformations. The structure of the iodonium salts was identified by multidimensional NMR spectroscopy and X-ray crystallography.

Ligand entry in human ileal bile acid-binding protein is mediated by histidine protonation.

Human ileal bile acid-binding protein (hI-BABP) has a key role in the intracellular transport of bile salts. To explore the role of histidine protonation in the binding process, the pH-dependence of bile salt binding and internal dynamics in hI-BABP was investigated using NMR spectroscopy and biophysical tools. Thermodynamic and kinetic measurements show an increase in the overall binding affinity and the association rate constant of the first binding step below the pKa of the histidines, suggesting that ligand binding is favoured by the protonated state. The overlap between residues exhibiting a high sensitivity to pH in their backbone amide chemical shifts and protein regions undergoing a global ms conformational exchange indicate a connection between the two processes. According to 15N NMR relaxation dispersion analysis, the slow motion is most pronounced at and above the pKa of the histidines. In agreement with the NMR measurements, MD simulations show a stabilization of the protein by histidine protonation. Hydrogen-bonding and van der Waals interactions mediating the flow of information between the C/D- and G/H-turn regions hosting the three histidines, suggest a complex way of pH-governed allosteric regulation of ligand entry involving a transition between a closed and a more open protein state.

Preparation of 2-amino-2-C-glycosyl-acetonitriles from C-glycosyl aldehydes by Strecker reaction.

Synthesis of new 2-amino-2-C-D-glycosyl-acetonitriles in a Strecker reaction from various C-glycosyl aldehydes, chiral amines, and HCN was carried out. While aminonitriles from glycal and 2-deoxy-ß-D-glycosyl aldehydes were prepared in satisfactory yields, lower yields were obtained with C-glycosyl aldehydes. Strecker reaction with the benzyl-protected 1-C-formyl-D-galactal and S- or R-1-phenylethylamine (S-PEA or R-PEA) yielded predominantly the R-configured C-glycosyl aminoacetonitrile. The direction of the nucleophilic addition appears to be governed by the configuration of the anomeric carbon with ß-linked sugars. Since the stereochemistry of the transition state is unknown according to the configuration of the major product a Felkin-Ahn selectivity can be mainly presumed.

A new cyclization to fused pyrazoles tunable for pericyclic or pseudopericyclic route: an experimental and theoretical study.

2-Pyrazinyl (2) and 3-pyridazinylketone arylhydrazones (6) and their benzologues undergo a ring closure reaction to yield pyrazolo[3,4- b]pyrazines (4) and pyrazolo[4,3- c]pyridazines (7), respectively, in acceptable to good yields. The reaction was found to be accelerated by using acidic or basic conditions. Quantum chemical calculations suggest the key step of the mechanism to be a direct cyclization; analysis of aromaticity based on computed magnetic properties revealed its medium-dependent pericyclic or pseudopericyclic character. The cyclization reaction has also been extended for the synthesis of related ring systems ( 9, 12, 14).

New facile tandem route to oxo- and thioxo[1,2,4]triazolo[1,5-a]pyridinium salts.

2-Arylsulfanyl- and benzylsulfanylpyridinium N-arylimides (2), easily available from tetrazolo[1,5-b]pyridinium salts (1), participate in 1,3-dipolar cycloaddition with aryl isothiocyanates and aryl isocyanates to result in formation of fused thioxo- and oxo[1,2,4]triazolium salts (5 and 12), respectively. This transformation is interpreted as a regular 1,3-cycloaddition followed by spontaneous elimination of the aryl- or benzylsulfanyl group. Formation of these triazolium salts can be followed--under appropriate reaction conditions--by ring-opening reactions to afford some new triazolyldienes (6). Recognition of the intermediate participation of the thiolate anion along the pathway 1 --> 5 allowed elaboration of a simple procedure to 5 implying a tandem reaction sequence.

Fluorous click chemistry as a practical tagging method.

Highly efficient fluorous tagging methodology was developed based on catalytic 1,3-dipolar cycloaddition as the key step.

Procedure for the parallel preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acid derivatives involving Meldrum's acid.

We describe here an efficient and versatile method for the preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acids involving, as a key step, a three-component Michael-type reaction. The extended and validated procedure allowed us to prepare various acids with three diversity points. The method was easily adaptable for parallel synthesis and an approximately 2000-membered 3-imidazo[1,2-a]pyridin-3-yl-propionic acid amide library was prepared in a semiautomated manner.

Unexpected ring transformation to pyrrolo[3.2-b]pyridine derivatives. Fused azolium salts. 22.

2-Arylsulfanyl and 2-benzylsulfanylpyridinium N-arylimides (2) easily prepared from 3-aryltetrazolopyridinium salts (1) with aryl and benzylthiolates, respectively, reacted with various dipolarophiles yielding cycloadducts that underwent transformation to give tetrahydropyrrolo[3,2-b]pyridines (5, 6, and 8) in good yields. A similar rearrangement (formation of 15) was also observed in the case of parent derivatives being unsubstituted in position 2 (12). The abscence of any significant solvent effect, comparison of the sulfur and non-sulfur analogues, as well as the stereoselective nature of the observed ring transformation seem to support a sigmatropic mechanism. Structure elucidation of the products has been carried out by single-crystal X-ray diffraction and (1)H NMR experiments.