The PPARs: from orphan receptors to drug discovery.

Stereochemical Control in Organic-Synthesis Using Silicon-Containing Compounds

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.

Enantioselective Construction of Quaternary Stereocenters

The SAMP-/RAMP-hydrazone methodology in asymmetric synthesis

Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives.

A series of substituted pyridyl- and quinolinyl-containing 2,4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARγ by 5a/5a maleate did not show any significant transactivation of PPARα or PPARγ.

Novel Euglycemic and Hypolipidemic Agents. 4. Pyridyl- and Quinolinyl-Containing Thiazolidinediones‡

α-Silylated ketones (S)−2 (ee ≥ 98%), easily available through silylation or silylation/alkylation from ketones 1 using the (−)-(S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)−/(+)-(R)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP)-hydrazone method, are oxidized to give α-hydroxy-ketones (R)−5 of high enantiomeric purity (ee ≥ 98%) and in good overall yields (51-70%). The key step of the procedure is the silicon-directed diastereoselective oxidation of the corresponding silyl enol ethers of (S)−2, with m-chloroperbenzoic acid or 3-phenyl-2-(phenylsulfonyl)oxaziridine, followed by flash chromatography and desilylation.

Silicon‐Directed Regio‐ and Enantioselective Synthesis of α‐Hydroxy‐ketones Preliminary Communication

Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2-ylmethoxy]phenylene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 ± 1 mM, and is the most potent and efficacious compound reported in this series.

B. B. Lohray

Papers

Novel Euglycemic and Hypolipidemic Agents. 4. Pyridyl- and Quinolinyl-Containing Thiazolidinediones‡

Silicon‐Directed Regio‐ and Enantioselective Synthesis of α‐Hydroxy‐ketones Preliminary Communication

Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones.

Enantioselective Synthesis of α‐Trialkylsilyl Ketones and Aldehydes

Diastereo‐ and Enantioselective Aldol Reactions via α‐Silyl Ketones, Asymmetric Synthesis of the Aggregation Pheromone Sitophilure