Synthesis and sequential diastereoselective incorporation of hydroxyl groups into hexahydrofuro[3,2-f]indolizin-7(2H)-one to give mono-, di- and tetra-hydroxyfuroindolizidines.

Dihydrofuro[2,3-f]indolizidinone obtained from biosourced reagents even at multigram-scale was used as an advanced building-block with up to five points of chemical diversification. This resulted in the sequential synthesis of a series of mono-, di- and tetra-hydroxyfuranoindolizidines belonging to a very scarce and elaborate tetrahydrofuran-fused indolizidine family with up to six controlled stereogenic centers. These sequences include, among others, diastereoselective olefin epoxidation, stereoselective epoxide ring opening into tetrahydrofuran trans-diols, their protection as an ester or acetonide, and lactam carbonyl reduction ultimately followed by acetate or acetonide deprotection.

Screening of Phenanthroquinolizidine Alkaloid Derivatives for Inducing Cell Death of L1210 Leukemia Cells with Negative and Positive P-glycoprotein Expression.

We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) negative for P-glycoprotein (P-gp) expression; ii) P-glycoprotein positive cells (R), obtained by selection with vincristine; iii) P-glycoprotein positive cells (T), obtained by stable transfection with a human gene encoding P-glycoprotein. We identified the most effective derivative 11 with a median lethal concentration of ≈13 µM in all three L1210 cell variants. The analysis of the apoptosis/necrosis induced by derivative 11 revealed that cell death was the result of apoptosis with late apoptosis characteristics. Derivative 11 did not induce a strong alteration in the proportion of cells in the G1, S or G2/M phase of the cell cycle, but a strong increase in the number of S, R and T cells in the subG1 phase was detected. These findings indicated that we identified the most effective inducer of cell death, derivative 11, and this derivative effectively induced cell death in S, R and T cells at similar inhibitory concentrations independent of P-gp expression.

Structure and Mechanism Revision of a Catalyzed Cyclization of Benzaldehyde Bearing Alkyne-Nitrile.

Pt(II)-catalyzed carbocyclization of benzaldehyde containing a keto-nitrile functionality resulted in the formation, respectively, of isochromenes and spiro-lactones instead of fused lactams and spiro-lactams as was previously reported. The reaction mechanism was proposed, and the products were identified by multidimensional NMR, IR, and X-ray analysis. The structure of these new products was also confirmed by their synthesis in an unambiguous manner using practical and short approaches.

Use of chiral-pool approach into epi-thieno analogues of the scarce bioactive phenanthroquinolizidine alkaloids.

The stereoselective synthesis of epi-thieno analogues of the phenanthroquinolizidine bioactive alkaloids (-)-Cryptopleurine and (-)-(15R)-Hydroxycryptopleurine was achieved in five steps starting from easily available enantiopure (S)-2-aminoadipic acid used as chiral pool and nitrogen atom source. During these investigations, both π-cationic cyclization of chiral N-thienylmethyl-6-oxopipecolinic acids into pure (S)-keto-lactams and theirs regioselective and diastereoselective reduction, considered as key steps of this sequence, were studied. Of particular interest, the Friedel-Crafts cyclization using (CF3CO)2O/BF3·Et2O show that near the expected keto-lactams, enamides and enamidones containing trifluoromethyl residue were isolated. A mechanism leading to the latter products with high synthetic potential was discussed.

Electronic structure, novel synthesis, and O-H...O and C-H...O interactions in two 6-oxopiperidine-2-carboxylic acid derivatives.

Molecules of (S)-6-oxo-1-(thiophen-2-ylmethyl)piperidine-2-carboxylic acid, C11H13NO3S, crystallize as single enantiomers in the space group P21 and the thiophene ring is disordered over two positions, while (S)-6-oxo-1-(thiophen-3-ylmethyl)piperidine-2-carboxylic acid, C11H13NO3S, crystallizes as a single enantiomer in the space group P212121. Their absolute configurations were confirmed by anomalous dispersion effects in diffraction measurements on the crystals. The molecules of each compound are linked by a combination of strong O-H...O hydrogen bonds and weak C-H...O interactions, resulting in two- and three-dimensional networks, respectively, in the crystal structures.

Antimicrobial activity of novel c2-substituted 1,4-dihydropyridine analogues.

The antimicrobial activity of 3-methyl-5-isopropyl (or ethyl) 6-methyl-4-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate derivatives was evaluated. Prokaryotes (bacteria) appeared to be more sensitive to their antimicrobial activity than were eukaryotes (filamentous fungi). The best antibacterial activity was shown by derivative 33, which was able to inhibit the growth of Mycobacterium smegmatis (MIC33 = 9 µg.ml(-1)), Staphylococcus aureus (MIC33 = 25 µg.ml(-1)), and Escherichia coli (MIC33 = 100 µg.ml(-1)). In addition, derivative 4 demonstrated its antibacterial power on the acid-fast bacterial species M. smegmatis and on Gram-positive S. aureus. Focusing on the structure-activity relationship, it appears that the increase in the substituent bulk at the C2 position improved the antibacterial activity of the set of compounds studied. Derivatives 33 and 4, carrying 2-cyano-3-oxo-3-phenylprop-1-en-1-yl and allyliminomethyl groups, respectively, showed significantly higher inhibition activities on all tested microorganisms in comparison with the rest of the derivatives. This enhancement was also in good correlation with different log P values (lipophilicity parameter).

Induction of resistance in Mycobacterium smegmatis.

In this work, we assayed the ability of newly prepared indolizine derivates (epimers) 6C and 6A to inhibit the growth of Mycobacterium smegmatis and used them for resistance induction. 6A inhibited the growth of M. smegmatis at a concentration of 100 µg/mL. No inhibitory effect was observed in the presence of 6C. By incubating the bacteria with 6C and 6A, colonies resistant to 6A were observed. Finally, 37 stable resistant strains were isolated. These resistant strains were able to grow on a 5-fold higher concentration of 6A (500 µg/mL) than the minimal inhibitory concentration of the wild type (100 µg/mL), with no growth inhibition. Resistant strains were then tested for cross-resistance to other antibiotics: ampicillin, tetracycline, ciprofloxacin, chloramphenicol, gentamicin, and streptomycin. Determinations of resistance patterns to 6 antibiotics revealed 36 strains that were resistant to at least one drug.

(6S,7S,8S,8aS)-6-Ethyl-3-oxo-1,2,3,5,6,7,8,8a-octa-hydro-indolizine-7,8-diyl diacetate.

In the mol-ecular structure of the title compound, C(14)H(21)NO(5), the six-membered ring of the indolizine moiety adopts a chair conformation. There are two independent mol-ecules in the asymmetric unit. The oxopyrrolidine ring attached to the indolizine ring system is nearly planar, with mean deviations of 0.018 (3) and 0.010 (3) Šfor the two mol-ecules. The absolute configuration of the title compound was assigned from the synthesis.

(5S,11aS)-5-Hydro-per-oxy-1,5,11,11a-tetra-hydro-[1]benzothieno[3,2-f]indol-izin-3(2H)-one.

The absolute configuration of the title compound, C14H13NO3S, was assigned from the synthesis and confirmed by the structure determination. The central six-membered ring of the indolizine moiety adopts an envelope conformation, with the greatest deviation from the mean plane of the ring being 0.661 (2) Šfor the bridgehead C atom. The benzothiene ring attached to the indolizine ring system is planar to within 0.008 (2) Å. In the crystal, mol-ecules form chains parallel to the b axis via O-H⋯O hydrogen bonds.

(8aRS)-8,8a-Dihydro-furo[3,2-f]indolizine-6,9(4H,7H)-dione.

The title compound, C(10)H(9)NO(3), is a chiral mol-ecule with one stereogenic carbon atom, but which crystallizes as a racemate in the centrosymmetric space group P2(1)/n. The central six-membered ring of the indolizine moiety adopts a definite envelope conformation, while the conformation of the oxopyrrolidine ring is close to that of a flat-envelope with a maximum deviation of 0.352 (1) Šfor the flap atom.

(6S,7S,8R,8aS)-6-Ethyl-perhydro-indolizine-7,8-diol.

In the title compound, C(10)H(19)NO(2), the piperidine and pyrrolidine rings of the perhydro-indolizine ring system adopt chair and envelope conformations, respectively. In the crystal structure, inter-molecular O-H⋯N and O-H⋯O hydrogen bonds link the mol-ecules into a chain running along the a axis.

(3aR,8aS,9S,9aR)-9-Hydroxy-perhydro-furo[3,2-f]indolizin-6-one.

In the title compound, C(10)H(15)NO(3), the central six-membered ring of the indolizine system adopts a chair conformation, while the oxopyrrolidine and hydro-furan rings attached to the indolizine ring system have envelope conformations. In the crystal, the mol-ecules form chains parallel to the b axis via inter-molecular O-H⋯O hydrogen bonds. The absolute configuration was assigned from the synthesis.

(8aS)-7,8,8a,9-Tetra-hydro-thieno[3,2-f]indolizin-6(4H)-one.

In the mol-ecular structure of the title compound, C(10)H(11)NOS, the central six-membered ring of the indolizine unit adopts an envelope conformation, the maximum deviations from the mean plane of the ring being 0.533 (2) Å. The fused thieno ring is nearly coplanar [mean deviation = 0.007 (2) Å]. The conformation of the fused oxopyrrolidine ring is close to that of a flat-envelope, with a maximum deviation of 0.339 (3) Å. The crystal structure is stabilized by C-H⋯O hydrogen bonds.

(7R,8S,8aS)-8-Hydr-oxy-7-phenyl-perhydro-indolizin-3-one.

In the title compound, C(14)H(17)NO(2), the six-membered ring of the indolizine system adopts a chair conformation. In the crystal, mol-ecules form chains parallel to the b axis via inter-molecular O-H⋯O hydrogen bonds. The absolute mol-ecular configuration was assigned from the synthesis.

(11R,11aS)-11-Hydr-oxy-1,5,11,11a-tetra-hydro-1-benzothieno[2,3-f]indolizin-3(2H)-one.

The absolute configuration of the title compound, C(14)H(13)NO(2)S, was assigned from the synthesis and confirmed by the structure determination. The central six-membered ring of the indolizine system adopts an envelope conformation, the greatest deviation from the mean plane of the ring being 0.459 (2) Šfor the N atom. The benzothieno system is planar [mean deviation = 0.009 (2) Å]. In the crystal structure, mol-ecules form chains parallel to the b axis via inter-molecular O-H⋯O hydrogen bonds.

Intermolecular and intramolecular alpha-amidoalkylation reactions using bismuth triflate as the catalyst.

Bismuth(III) triflate was found to promote the formation of stable cyclic N-acyliminium species in remarkable catalytic amounts (1 mol %). The alpha-amidoalkylation process seems to be effective in intermolecular and intramolecular manners leading to alpha-substituted lactams and heterocyclic systems containing azacycles, respectively. By comparing our results with those obtained with the classical Lewis acids as catalysts, it was evidenced clearly that the use of bismuth(III) triflate had been efficient for nearly all alpha-acetoxy lactams we used, except for N-acyliminium precursors bearing a sulfur atom. Also, the process seems to be easy, general, and clean, having diastereoselectivity comparable to protocols using classical Lewis acids and resulting in the formation of polyheterocyclic systems in good to excellent yields (64-99% in acetonitrile as solvent).

Tandem Michael addition/amino-nitrile cyclization from 2-formyl-1,4-DHP in the synthesis of novel dihydroindolizine-based compounds.

A simple and efficient methodology for the synthesis of a small library of substituted indolizines with different degrees of saturation starting from the racemic 2-formyl-1,4-DHP reagent was described. The large synthetic possibilities of this reagent as well as of its Knoevenagel corresponding 2-dicyanovinyl-1,4-DHP reagent were investigated using four kinds of activated methylenes as nucleophiles. The key step of the sequential reaction was based on the highly diastereoselective tandem Michael addition/intramolecular amino-nitrile cyclization catalyzed by an organic base, which resulted in the formation of 1,7-dihydroindolizines in a diastereoselective manner. The process seems to be a straightforward one and can be extended to numerous active methylenes such as malononitrile, 1,3-diketones, and alkyl acetoacetates. The 1,3-hydrogen shift of partially hydrogenated indolizines was accomplished easily with a base at room temperature, giving rise to the corresponding 7,8-dihydroindolizines in very good yields. Interestingly, when the active methylene bears a leaving group, the latter process could not be accomplished because a rare cis-elimination of phenylsulfinic acid and nitrous acid preceded the hydrogen shift. The resulting 1,7-dihydroindolizines bearing an exo-methylene group at C1 were not isolated in all cases, as they turned rapidly to indolizines as the thermodynamically more stable products. During these investigations, oxidization of 1,7-dihydroindolizines with CuCl(2) resulted in the formation of polysubstituted pyridines. Also, the epimerization of certain 1,7-dihydroindolizines was evidenced in the solution studied by NMR spectroscopy, whereas in the solid state, they existed only in a unique form as shown by X-ray diffraction analysis of a representative structure. Finally, all products reported herein bear a primary amine and a nitrile function crucial for further transformations. These include the introduction of various pharmacophore groups at either NH(2) or CN groups as well as at both groups at the same time to access the more elaborated indolizines fused to N- or N,N-heterocycles.

New resolution of 2-formyl-1,4-dhp derivatives using CIDR methodology. Facile access to new chiral tricyclic thiolactam.

(R)- and (S)-alpha-phenylethylamine (alpha-PEA: 7) have been used separately to resolve successfully a racemate 2-formyl-1,4-DHP derivative 4. The process was based on the difference of the solubility of both Schiff bases (6) since one of them crystallized out from the solution. These imines obtained by condensation of (R)-alpha-PEA (7) or (S)-alpha-PEA (7) with aldehyde (rac-4) were separated and analyzed by X-ray diffraction, and their exposition to an hydrochloric hydrolysis conditions led to the enantiopure (4R)-4 or (4S)-4 in excellent yields. Separate condensation of other chiral (8 and 13) and racemic (18) amino thiols as auxiliary with rac-4, (4S)-4, or (4R)-4 is accompanied by an in situ crystallization-induced dynamic resolution, whereby one distereomer of thiazole template selectively precipitates and can be isolated by simple filtration in 76-82% yield with dr > 99. The thiazole species isolated from this process resulted from an amino aldehyde condensation followed by a spontaneous thiol-imine cycloaddition. Finally, the racemate (+/-)-(4R,2'R)-19 and the diastereomerically pure homologous (4S,2'R)-23 and (4R,2'S)-20 (obtained in good yields (79-82%) from 2-aminoethanethiol (18) and 2-formyl-1,4-DHP derivative rac-4, (4S)-4, or (4R)-4, respectively) were converted conveniently in a one-pot procedure into newly tricyclic thiolactams in the DHP series in racemic ((+/-)-(6R,9bR)-21, 72% yield)) and enantiopure ((6S,9bR)-24, 71% yield); (6R,9bS)-24, 70% yield) forms.