Asymmetric synthesis of aryl-substituted pyrrolidines by using CFAM ligand-AgOAc chiral system via 1,3-dipolar cycloaddition reaction.

We have prepared a ligand library based on a ferrocenyl aziridinyl methanol core unit (simply called FAM) having a phenyl group, a cyclohexyl group, and a naphthyl group to be used in 1,3-dipolar cycloaddition (1,3-DC) reactions for the synthesis of chiral pyrrolidines. These chiral ligands were used with AgOAc in 1,3-DC reactions taking place between the aryl-substituted azomethine ylides and N-methylmaleimide as the dipolarophile. In each case, the expected aryl-substituted pyrrolidines were obtained in good to excellent yields with acceptable enantioselectivities favoring only the endo product. The chiral catalyst system CFAM4-AgOAc was also used in 1,3-DC reaction with different dipolarophiles such as dimethyl maleate, tert-butyl acrylate, methyl acrylate, trans-chalcone, and vinyl sulfone. In each case, the cycloadducts were obtained in acceptable yields albeit with low ee. Fortunately, it was possible to increase the ee up to >99% upon crystallization.

FAM-Ag-catalyzed asymmetric synthesis of heteroaryl-substituted pyrrolidines.

New derivatives of FAM (ferrocenyl aziridinyl methanol) ligands NFAM1-4 (naphthyl ferrocenyl aziridinyl methanol) and CFAM1-4 (cyclohexyl ferrocenyl aziridinyl methanol) were synthesized to form a small ligand library and used as chiral catalysts with AgOAc for the asymmetric synthesis of heteroaryl-substituted pyrrolidines by the 1,3-dipolar cycloaddition (1,3-DC) reaction of azomethine ylides. 2-Thienyl, 2-furyl, 2-, 3-, and 4-pyridyl aldimines were prepared and used with N-methylmaleimide, dimethyl maleate, tert-butyl acrylate, methyl acrylate, and acrylonitrile to form the corresponding heteroaryl-substituted pyrrolidines. 1,3-DC reactions yielded the expected cycloadducts in up to 89% yield and up to 76% ee that could be increased up to 95% ee upon crystallization. New chiral ligands NFAM1-4 and CFAM1-4 were fully characterized, and their absolute stereochemistry was determined by single-crystal X-ray analysis.

Synthesis, Characterization and Evaluation of Cytotoxic Activities of Novel Aziridinyl Phosphonic Acid Derivatives.

New aziridine 2-phosphonic acids were prepared by monohydrolysis of the aziridine 2-phosphonates that were obtained by the modified Gabriel-Cromwell reaction of vinyl phosphonate or α-tosylvinyl phosphonate with a primary amine or a chiral amine. The cellular cytotoxicity of these compounds was tested against the HCT-116 colorectal cancer cell lines and the CCD-18Co normal colon fibroblast lines using the MTT assay. Three of the synthesized phosphonic acid derivatives 2e (ethyl hydrogen {(2S)-1-[(1S)-1-(naphthalen-2-yl)ethyl]aziridin-2-yl}phosphonate), 2h (ethyl hydrogen (1-benzylaziridin-2-yl)phosphonate), and 2i (ethyl hydrogen (1-cyclohexylaziridin-2-yl)phosphonate) showed higher cytotoxicity than the reference cancer treatment agent etoposide. Cell death was through a robust induction of apoptosis even more effectively than etoposide, a well-known apoptosis inducing agent.

Enantiomerically pure ß-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathways.

The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure ß-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC50. KUD983 induced G1 arrest of the cell cycle and subsequent apoptosis associated with down-regulation of several related proteins including cyclin D1, cyclin E and Cdk4, and the de-phosphorylation of RB. The levels of nuclear and total c-Myc protein, which could increase the expression of both cyclin D1 and cyclin E, were profoundly inhibited by KUD983. Furthermore, it inhibited PI3K/Akt and mTOR/p70S6K/4E-BP1 pathways, the key signaling in multiple cellular functions. The transient transfection of constitutively active myristylated Akt (myr-Akt) cDNA significantly rescued KUD983-induced caspase activation but did not blunt the inhibition of mTOR/p70S6K/4E-BP1 signaling cascade suggesting the presence of both Akt-dependent and -independent pathways. Moreover, KUD983-induced effect was enhanced with the down-regulation of anti-apoptotic Bcl-2 members (e.g., Bcl-2, and Mcl-1) and IAP family members (e.g., survivin). Notably, KUD983 induced autophagic cell death using confocal microscopic examination, tracking the level of conversion of LC3-I to LC3-II and flow cytometric detection of acidic vesicular organelles-positive cells. In conclusion, the data suggest that KUD983 is an anticancer ß-dipeptide against HRPCs through the inhibition of cell proliferation and induction of apoptotic and autophagic cell death. The suppression of signaling pathways regulated by c-Myc, PI3K/Akt and mTOR/p70S6K/4E-BP1 and the collaboration with down-regulation of Mcl-1 and survivin may explain KUD983-induced anti-HRPC mechanism.

Effect of Oxygen Tension and Medium Components on Monomer Distribution of Alginate.

Alginate is a natural biopolymer composed of mannuronic and guluronic acid monomers. It is produced by algae and some species of Azotobacter and Pseudomonas. This study aims to investigate the effect of dissolved oxygen tension (DOT) and growth medium substrate and calcium concentrations on the monomeric composition of alginate produced by Azotobacter vinelandii ATCC® 9046 in a fermenter. Results showed that alginate production increased with increasing DOT from 1 to 5 %. The highest alginate production was obtained as 4.51 g/L under 20 g/L of sucrose and 50 mg/L of calcium at 5 % DOT. At these conditions, alginate was rich in mannuronic acid (up to 61 %) and it was particularly high at low calcium concentration. On the other hand, at extreme conditions such as high DOT level (10 % DOT) and low sucrose concentration (10 g/L), guluronic acid was dominant (ranging between 65 and 100 %).

2-[(1RS,3RS,3aRS,6aSR)-5-Benzyl-4,6-dioxo-3-phenyl-octa-hydro-pyrrolo-[3,4-c]pyrrol-1-yl]acetamide.

In the title compound, C(21)H(21)N(3)O(3), the relative stereochemistry of the four stereogenic C atoms has been determined. The dihedral angle between the phenyl rings is 77.63 (7)°. In the crystal, ribbons spread along the a axis are formed by N-H⋯O hydrogen bonds. C-H⋯π inter-actions also occur.

Synthesis of 2-aziridinyl phosphonates by modified Gabriel-Cromwell reaction and their antibacterial activities.

A set of new aziridinyl phosphonates (4a-g) were synthesized by using the Gabriel-Cromwell reaction and its modified version developed in this study and their structures confirmed by HRMS, IR, and NMR spectra. All the compounds were screened for their antibacterial activity. They all showed comparable moderate to good growth inhibitory activity in reference to ampicillin and streptomycin.

Bis[5-(4-bromo-phen-yl)-4-(tert-but-oxy-carbon-yl)pyrrolidine-2-carboxyl-ato]copper(II) dihydrate.

In the title compound, [Cu(C(16)H(19)BrNO(4))(2)]·2H(2)O, the Cu(II) ion resides on an inversion centre and is coordinated by two O and two N atoms from two enanti-omeric 5-(4-bromo-phen-yl)-4-(tert-but-oxy-carbon-yl)pyrrolidine-2-carboxyl-ate ligands in a distorted square-planar geometry. The relative stereochemistry of the three stereogenic C atoms in each ligand has been determined. In the crystal, inter-molecular N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. The crystal studied was twinned by pseudo-merohedry with twin fractions of 0.719 (3) and 0.281 (3).

Catalytic asymmetric nitroaldol (Henry) reaction with a zinc-Fam catalyst.

Ferrocenyl-substituted aziridinylmethanol (Fam-1) was used as a catalyst with zinc for the asymmetric nitroaldol (Henry) reaction. This catalyst worked with a variety of aldehydes (aromatic, aliphatic, alpha,beta-unsaturated, and heteroaromatic) and alpha-ketoesters to give the nitroaldol product in up to 97% yield and 91% ee. The chiral ligand can be recovered and recycled without losing its activity.

Fam-Ti catalyzed enantioselective alkynylation of aldehydes.

Ferrocenyl-substituted aziridinylmethanol (Fam-1) has been used as a chiral catalyst with titanium for enantioselective alkynylation of aromatic, heteroaromatic, aliphatic, and alpha,beta-unsaturated aldehydes to give the corresponding propargylic alcohols in up to 96% yield and 96% ee. The ligand can be prepared easily and recycled.

New zinc(II)-based catalyst for asymmetric azomethine ylide cycloaddition reactions.

[reaction: see text] A new chiral aziridino alcohol ligand for zinc(II)-catalyzed azomethine ylide cycloadditions is described. In the presence of this catalyst, N-arylidene glycine methyl esters react with a variety of dipolarophiles to give substituted pyrrolidines in very good to excellent chemical yields and up to 95% ee. The absolute sense of asymmetric induction appears to be dipolarophile-dependent.