Recent advances in aryl C-glycoside synthesis.

Aryl C-glycosides are stable analogs of the corresponding O-glycosides. Because of their favorable pharmacological profiles attributed primarily to the C-glycosyl moiety, aryl C-glycosides have gained increasing popularity as drug candidates. In this review we focus on the synthesis of aryl C-glycosides including puerarin and kendomycin. This review is organized based on the type of chemistry used in the assembly of the C-glycosides with the following sub-sections: electrophilic reaction, cross-coupling reaction, free radical reaction, cyclization, intramolecular O-C rearrangement, umpolung, and miscellaneous reactions.

Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents.

A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified, and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo.

Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents.

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.

Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy.

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

8-Azatetracyclines: synthesis and evaluation of a novel class of tetracycline antibacterial agents.

A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.

Rh-catalyzed highly enantioselective formation of functionalized cyclopentanes and cyclopentanones.

A catalyst system, [Rh(COD)Cl](2)-BINAP-AgSbF(6), has been developed as a second-generation catalyst for the cycloisomerization of 1,6-enynes tethered by carbon chains. Cyclopentanes and cyclopentanones, which can contain functional groups, such as the 1,4-dienes, vinyl ether, aldehyde etc., were obtained from readily available starting materials in high yields and selectivities. Both regioselectivities and enantioselectivities are excellent: only 1,4-dienes were observed and in over 99% ee.

Synthesis and in vitro pharmacological studies of new C(4)-modified salvinorin A analogues.

Salvinorin A, a compound isolated from the plant Salvia divinorum, is a potent and highly selective agonist for the kappa opioid receptor. For exploration of its structure and activity relationships, further modifications, such as reduction at the C(4) position, have been studied and a series of salvinorin A derivatives were prepared. These C(4)-modified salvinorin A analogues were screened for binding and functional activities at the human kappa-opioid receptor and several new full agonists have been identified.

Synthesis and in vitro pharmacological studies of C(4) modified salvinorin A analogues.

Salvinorin A is the most potent naturally occurring opioid agonist with a high selectivity and affinity for kappa-opioid receptor. To explore its structure-activity relationships, modifications at the C(4) position have been studied and a series of salvinorin A derivatives were prepared. These C(4)-modified salvinorin A analogues were screened for binding and functional activities at the human kappa-opioid receptor and several potent new agonists have been identified.

Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues.

Salvinorin A is the most potent naturally occurring opioid agonist yet discovered with high selectivity and affinity for kappa-opioid receptor. To explore its structure and activity relationships, a series of salvinorin A derivatives modified at the C2 position were prepared and studied. These salvinorin A derivatives were screened for binding and functional activities at the human kappa-opioid receptor. Compound 4, containing a methoxymethyl group at the 2-position, was a full kappa-agonist with an EC50 value at 0.6 nM, which is about 7 times more potent than salvinorin A.

Rh-catalyzed kinetic resolution of enynes and highly enantioselective formation of 4-alkenyl-2,3-disubstituted tetrahydrofurans.

Rh-catalyzed cycloisomerization of enynes ether with a substituent at the allylic position was examined using (rac)-BINAP, and excellent selectivity was observed. When enantiomerically pure BINAP was used as the ligand, a process that combines kinetic resolution and diastereoselectivity together was developed, in which an enantiomeric product with multiple stereogenic centers was obtained in >99% ee from a racemic starting material via single step, and half of the remaining starting material was recovered in >99% ee, also.

Highly enantioselective syntheses of functionalized alpha-methylene-gamma-butyrolactones via Rh(I)-catalyzed intramolecular Alder ene reaction: application to formal synthesis of (+)-pilocarpine.

A highly enantioselective Rh(I)-catalyzed intramolecular Alder ene reaction has been developed. The desired products, 3-vinyl, vinyl acetate, and vinyl ether-substitued alpha-methylene-gamma-butyrolactones were formed in high yields. Aldehydes were produced with the formation of gamma-lactones when alcohols were substituted at allylic position in the substrates. All reactions with listed substrates proceeded in over 99% ee. A formal synthesis of (+)-pilocarpine is an excellent example to demonstrate the synthetic utility of this methodology.

Highly enantioselective asymmetric hydrogenation of alpha-phthalimide ketone: an efficient entry to enantiomerically pure amino alcohols.

A new type of alpha-phthalimide ketones was hydrogenated in excellent enantioselectivity by using a Ru-(C3-TunePhos) complex as the catalyst. Up to 10 000 turnovers have been achieved in more than 99% ee in the hydrogenation reaction. A dynamic kinetic resolution study for the synthesis of threonine was performed, and high anti selectivity (>97:3) was observed for the first time. An efficient method to synthesize enantiomerically pure amino alcohols has been developed.