Organocatalytic Enantioselective Direct Vinylogous Michael Addition of α,β-Unsaturated γ‑Butyrolactam to β‑Acyl Acrylates and 1,2-Diacylethylenes

A highly efficient Michael addition of α,β-unsaturated γ-butyrolactam to various β-acyl acrylates and ene-diones to provide synthetically useful compounds was developed. The products were obtained with high diastereo- and enantioselectivities (up to >25:1 dr and 99% ee) containing adjacent tertiary stereocenters

Preparation of Functional Phosphorus Zwitterions from Activated Alkanes, Aldehydes, and Tributylphosphine: Synthesis of Polysubstituted Furo[3,2-<i>c</i>]coumarins

A general preparation of new types of highly functional phosphorus zwitterions is realized via tandem three-component reactions using the corresponding functional alkanes, aldehydes, and Bu₃P. Starting from our novel zwitterions as synthetic reagents with commercially available acid chlorides in a one-step procedure provides an attractive approach toward furo[3,2-<i>c</i>]coumarins

Preparation of Functional Phosphorus Zwitterions from Activated Alkanes, Aldehydes, and Tributylphosphine: Synthesis of Polysubstituted Furo[3,2-<i>c</i>]coumarins

A general preparation of new types of highly functional phosphorus zwitterions is realized via tandem three-component reactions using the corresponding functional alkanes, aldehydes, and Bu₃P. Starting from our novel zwitterions as synthetic reagents with commercially available acid chlorides in a one-step procedure provides an attractive approach toward furo[3,2-<i>c</i>]coumarins

Design and Optimization of 1<i>H</i>‑1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR

The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, we report the structural optimization of a series of 1H-1,2,3-triazole-4-carboxamides compounds that led to the discovery of compound 85 as a selective and the most potent inverse agonist and antagonist of PXR, with low nanomolar IC50 values for binding and cellular activity. Importantly, compound 89, a close analog of 85, is a selective and pure antagonist with low nanomolar IC50 values for binding and cellular activity. This study has provided novel, selective, and most potent PXR inhibitors (a dual inverse agonist/antagonist and a pure antagonist) for use in basic research and future clinical studies and also shed light on how to reduce the binding affinity of a compound to PXR

Chemoselective Intramolecular Wittig Reactions for the Synthesis of Oxazoles and Benzofurans

A chemoselective approach was developed for the synthesis of highly functionalized oxazoles and benzofurans using an intramolecular Wittig reaction as the key step. By choosing proper trapping reagent or method of addition of reagents, chemoselectivity can be controlled toward either oxazole or benzofuran derivatives

Organocatalytic Enantioselective Synthesis of Tetrahydrofluoren-9-ones via Vinylogous Michael Addition/Henry Reaction Cascade of 1,3-Indandione-Derived Pronucleophiles

An unprecedented organocatalytic enantioselective vinylogous Michael addition/Henry cyclization cascade is presented for the synthesis of highly substituted tetrahydrofluoren-9-ones <b>3</b> employing novel 1,3-indandione-derived pronucleophiles <b>1a</b>–<b>g</b> and nitroalkenes <b>2</b>. Following a very simple protocol, a wide range of products were obtained in good to excellent yields and with excellent enantioinduction (43–98% yield, up to 98% ee). The reaction proceeded with excellent diastereocontrol despite the simultaneous generation of four stereogenic centers. Surprisingly, when 2-(1-phenylethylidene)-1<i>H</i>-indandione (<b>1h</b>) was used as a pronucleophile, no cyclization was observed, and only Michael addition adducts <b>4a</b>–<b>x</b> were furnished in very good yields and excellent enantioselectivities

Design and Optimization of 1<i>H</i>‑1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR

The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, we report the structural optimization of a series of 1H-1,2,3-triazole-4-carboxamides compounds that led to the discovery of compound 85 as a selective and the most potent inverse agonist and antagonist of PXR, with low nanomolar IC50 values for binding and cellular activity. Importantly, compound 89, a close analog of 85, is a selective and pure antagonist with low nanomolar IC50 values for binding and cellular activity. This study has provided novel, selective, and most potent PXR inhibitors (a dual inverse agonist/antagonist and a pure antagonist) for use in basic research and future clinical studies and also shed light on how to reduce the binding affinity of a compound to PXR

Chemo- and Diastereoselective Michael–Michael-Acetalization Cascade for the Synthesis of 1,3-Indandione-Fused Spiro[4.5]decan Scaffolds

A novel, organobase-catalyzed and highly chemoselective Michael–Michael-acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons. Following this very simple protocol, a broad range of products was obtained in good yields with excellent diastereocontrol. The role of steric factors in the acetalization step was evaluated

Chemo- and Diastereoselective Michael–Michael-Acetalization Cascade for the Synthesis of 1,3-Indandione-Fused Spiro[4.5]decan Scaffolds

A novel, organobase-catalyzed and highly chemoselective Michael–Michael-acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons. Following this very simple protocol, a broad range of products was obtained in good yields with excellent diastereocontrol. The role of steric factors in the acetalization step was evaluated

Chemoselective Intramolecular Wittig Reactions for the Synthesis of Oxazoles and Benzofurans

A chemoselective approach was developed for the synthesis of highly functionalized oxazoles and benzofurans using an intramolecular Wittig reaction as the key step. By choosing proper trapping reagent or method of addition of reagents, chemoselectivity can be controlled toward either oxazole or benzofuran derivatives