Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls.

A novel non-C2-symmetric bis-benzimidazolium salt derived from (±)-valinol has been prepared by a simple and straightforward process in good yield. The structure of bis-benzimidazolium salt provided a bulky steric group on the ethylene bridge; which facilitates the catalytic efficacy in the C(sp2)-C(sp2) formation. Its catalytic activity in Suzuki-Miyaura cross-coupling reaction of unactivated aryl chlorides has been found to have high efficacy in 1 mol% Pd loading. This protocol demonstrated the potential on the synthesis of sterically hindered biaryls.

An efficient class of bis-NHC salts: applications in Pd-catalyzed reactions under mild reaction conditions.

This study describes an efficient class of bis-N-heterocyclic carbene (bis-NHC) salts that can be easily made from commercially available and inexpensive starting materials. The application of these salts to Pd-catalyzed reactions is described. The palladium (Pd) catalyst generated in situ was highly effective under mild reaction conditions.

Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O-tridentate Phenol Ligands Derived From Camphor.

Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80-95% ee) at room temperature.

Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells.

Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 µM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.

Asymmetric synthesis of α-methyl-α-amino acids via diastereoselective alkylation of (1S)-(+)-3-carene derived tricyclic iminolactone.

A novel carene-based alanine-equivalent tricyclic iminolactone 16 has been synthesized via stereoselective dihydroxylation of the double bond, IBX oxidation of the secondary alcohol, esterification of the tertiary alcohol, deprotection of the resulting ester, and subsequent cyclization from commercially available (1S)-(+)-3-carene in 79% overall yield. The iminolactone 16 demonstrated high reactivity toward alkylation with a wide range of electrophiles at room temperature under phase-transfer catalysis conditions. The alkylated products were produced with excellent diastereoselectivities (>98% de) in good isolated yields (86-94%). High yields (83-91%) of optically pure (S)-α-methyl-α-substituted-α-amino acids were obtained by basic hydrolysis of the dialkylated iminolactones with the recovery of the chiral auxiliary 15 (78-87%).

Asymmetric synthesis of alpha-amino acids: preparation and alkylation of monocyclic iminolactones derived from alpha-methyl trans-cinnamaldehyde.

Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12 was obtained from alpha-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones, each in 82% overall yield. Alkylation of the iminolactone 14a afforded the alpha-methyl-alpha,alpha-disubstituted products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations of the iminolactone 14b furnished the alpha-benzyl-alpha,alpha-disubstituted products 15a, 16b, 17, and 18 in good yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%) and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the alpha,alpha-disubstituted alpha-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with good recovery of compound 12 (83-92%).

Is association of labile enediyne chromophore a mutually assured protection for carrier protein?

Most conjugate proteins undergo both conformational and stability changes on ligand removal. When architecture remains unchanged in the protein holo and apo forms, it is uncertain whether the protein stability also remains unaltered in both of the forms. Neocarzinostatin (NCS), a chromoprotein possessing a potent enediyne chromophore stands for such an instance. Protein-chromophore interaction has not been thoroughly explored previously due to a lack of strategies to independently and simultaneously monitor changes in the NCS conjugates. Here we report a method by which one can detect the signal exclusively from only one of the NCS conjugates without the spectral interference from the other. Stability of the NCS protein is significantly correlated to the protein-bound chromophore, irrespective of denaturation by heat, pH, urea, or ethanol. Despite the similarity in protein backbone conformation, protein stability of the NCS holo form diminishes and equalizes to that of the apo form when the chromophore is released and degraded. Although the enediyne chromophore is highly unstable, it intriguingly protects the protein by which it is protected. Significant mutual reliance between the carrier protein and its naturally associated ligand unveils important information on the NCS drug stability.

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids by diastereoselective alkylation of camphor-based tricyclic iminolactone.

A novel and convenient route for the preparation of chiral tricyclic iminolactones 9 and 10 from camphorquinone has been developed. Alkylation of iminolactones 9 and 10 provided iminolactones 16 and 17 in high yields which were, in turn, alkylated again to afford the alpha,alpha-disubstituted products in good yields (70-90%) and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired alpha,alpha-disubstituted alpha-amino acids in good yields and high enantiomeric excesses with good recovery yields of the chiral auxiliary 12 and 13. The extremely high endo-face selectivity for alkylation is discussed using semiempirical (MOPAC 93) calculations.

Cold instability of aponeocarzinostatin and its stabilization by labile chromophore.

The conformational stability of aponeocarzinostatin, an all-beta-sheet protein with 113 amino-acid residues, is investigated by thermal-induced equilibrium unfolding between pH 2.0 and 10.0 with and without urea. At room temperature, the protein is stable in a pH range of 4.0-10.0, whereas the stability of the protein drastically decreases below pH 4.0. The thermal unfolding of aponeocarzinostatin is reversible and follows a two-state mechanism. By two-dimensional unfolding studies, the enthalpy change, heat capacity change, and free energy change for unfolding of the protein are estimated. Circular dichroism profiles suggest that this protein undergoes both heat- and cold-induced unfolding. The ellipticity changes at far- and near-UV circular dichroism suggest that the tertiary structure is disrupted but the secondary structure remains folded at low temperatures. Interestingly, the labile enediyne chromophore, which is highly stabilized by the protein, is able to protect the protein against cold-induced unfolding, but not the heat-induced unfolding.

Selective synthesis of either enantiomer of alpha-amino acids by switching the regiochemistry of the tricyclic iminolactones prepared from a single chiral source.

Preparation of l-alpha-amino acids was easily accomplished simply by exchanging the position of the lactone group of our recently reported chiral template 1 from C2 to C3. The new chiral template 7 was prepared in 54% overall yield over five steps from (1R)-(+)-camphor. Alkylation of iminolactone 7 afforded the alpha-monosubstituted products in good yields and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired l-alpha-amino acids in good yields and ee with nearly quantitative recovery of chiral auxiliary 4.

Chiral tricyclic iminolactone derived from (1R)-(+)-camphor as a glycine equivalent for the asymmetric synthesis of alpha-amino acids.

The development of a highly efficient and stereoselective methodology for the preparation of alpha-amino acids is described. The chiral template, tricyclic iminolactone 7, was synthesized from (1R)-(+)-camphor in five steps in 50% overall yield. Alkylation of iminolactone 7 afforded the alpha-monosubstituted products in good yields (74-96%) and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired alpha-amino acids in good yields and enantioselectivities with nearly quantitative recovery of the chiral auxiliary 4.

Pinane-Type Tridentate Reagents for Enantioselective Reactions: Reduction of Ketones and Addition of Diethylzinc to Aldehydes.

The reduction of aryl and alkenyl methyl ketones using lithium aluminum hydride modified with (1R,2S,3S,5R)-(+)-10-anilino-3-ethoxy-2-hydroxypinane (10b) afforded chiral secondary alcohols in 83-96% chemical yields and 50-91% ee with dominance of R enantiomers. The reduction of acetophenone in the presence of lithium iodide gave the alcohol product with higher ee. On the other hand, the addition reaction of diethylzinc to benzaldehyde using the pinane-based diols 5-9 as promoters gave 1-phenylpropanol in favor of the S enantiomer up to 88% ee. Using the pinane-based alcohols 10a-e as promoters, the R enantiomer was obtained as the major product. The addition reactions of diethylzinc to various substituted benzaldehydes, employing the diol ligands 5c and 8e, afforded predominantly the corresponding (S)-alcohols. The chiral modifiers 5-10 were prepared from (1R)-(-)-myrtenol and were readily recovered (>90%) after the asymmetric reactions. In this study, LAH reduction and Et(2)Zn addition are complementary methods for the preparation of optically active secondary alcohols. The ligand 10-butylanilino-2,3-dihydroxypinane 5c promoted the Et(2)Zn additions effectively, whereas the modifier 10-anilino-3-ethoxy-2-hydroxypinane 10binduced the LAH reductions in a highly enantioselective manner.