Sulfone as a Transient Activating Group in the Palladium-Catalyzed Asymmetric [4 + 3] Cycloaddition of Trimethylenemethane Enabling the Enantioselective Synthesis of Fused Azepines.

The palladium-catalyzed asymmetric [4 + 3] cycloaddition of a sulfonyl-trimethylenemethane (TMM) donor with azadienes furnished various sulfonyl-fused azepines with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 dr, >99% ee) in high yields (up to 93%). Moreover, sulfone, serving as a transient activating group of the TMM species, can be easily removed from the cycloadducts to provide the structurally simple fused azepines with excellent enantioselectivities. This strategy demonstrates sulfonyl-TMM as an effective surrogate of naked TMM with high reactivity, exclusive regioselectivity, and excellent stereoselectivity.

Palladium-Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio-, Diastereo-, and Enantioselective Construction of Benzofuro[3,2-b]azepine Skeletons.

The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.

Stereoselective Synthesis of Pyrrolidines Containing a 3-Fluoro Quaternary Stereocenter via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition.

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to ß,ß-disubstituted ß-fluoroacrylates catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system is reported, affording chiral densely substituted pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, in good to excellent yields (up to 99%), with excellent levels of diastereo- and enantioselectivities (dr >20:1; ee up to 99%).

Chiral N,O-Ligand/[Cu(OAc)2 ]-Catalyzed Asymmetric Construction of 4-Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with α-Phthalimidoacrylates.

A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both ß-substituted and ß-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.

The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides.

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides catalyzed by a novel chiral N,O-ligand/Cu(OAc)2 system is reported, affording dispiropyrrolidine derivatives with spiro quaternary stereogenic centers in good to excellent yields (up to 90%), excellent levels of diastereoselectivities (>20 : 1 dr) and enantioselectivities (up to 97% ee).

Catalytic asymmetric construction of quaternary α-amino acid containing pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides to α-aminoacrylates.

The first catalytic enantioselective 1,3-dipolar cycloaddition of azomethine ylides to α-aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo- and enantioselectivity (92-99 % ee). This process provides efficient access to useful 4-aminopyrrolidine-2,4-dicarboxylic acid (APDC)-like compounds containing a unique quaternary α-amino acid unit.

[Biotransformation by human intestinal flora and absorption-transportation characteristic in a model of Caco-2 cell monolayer of d-corydaline and tetrahydropalmatine].

OBJECTIVE: To study the biotransformation by human intestinal flora, and the absorption and transportation characteristic in a model of human colon adenocarcinoma cell lines (Caco-2 cell) monolayer of d-corydaline (CDL) and tetrahydropalmatine (THP). METHOD: CDL or THP was incubated with crude enzymes of human intestinal flora under the anaerobic environment and 37 degrees C conditions to transform CDL or THP. Caco-2 cell monolayer was used as an intestinal epithelial cell model for determination of the permeability of CDL or THP from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. Transportation parameters and permeability coefficients (P(app)) were then calculated, and P(app) values were compared with the reported values for model compounds, propranolol as a well absorbed drug and atenolol as a poor absorbed drug. The concentration of CDL or THP was measured by HPLC coupled with photodiode array detector. RESULT: CDL or THP in the human intestinal flora incubation system did not happen biotransformation. In the Caco-2 cell monolayer model, the P(app) magnitudes of both CDL and THP were 1 x 10(-5) cm x s(-1) in the bi-directional transport, which were identical with propranolol. And their transports were concentration dependent between 0-180 min. CONCLUSION: Both CDL and THP may be stable in the human intestinal flora incubation system, and their absorption and transportation in the human Caco-2 cell monolayer model are mainly via passive diffusion mechanism.