Difluorinated thromboxane A reveals crosstalk between platelet activatory and inhibitory pathways by targeting both the TP and IP receptors.

Background And Purpose: Thromboxane A (TXA) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function.

Iridium-Catalyzed Enantioselective Alkene Hydroalkylation via a Heteroaryl-Directed Enolization-Decarboxylation Sequence.

Upon exposure to a cationic Ir(I)-complex modified with the chiral diphosphine DuanPhos, hydroalkylations of styrenes and α-olefins with diverse heteroaryl -butyl acetates occur with complete branched selectivity and very high enantioselectivity. The initial adducts undergo acid promoted decarboxylation in situ to provide alkylated heteroarenes possessing defined β-stereocenters. The processes are postulated to proceed via a stereodefined chiral Ir-enolate, which arises upon heteroarene directed enolization of the heteroaryl acetate precursor.

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost.

Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created through an inverse-electron demand Diels-Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination-aromatization reaction.

Cyclopropane-Fused -Heterocycles via Aza-Heck-Triggered C(sp)-H Functionalization Cascades.

Unique examples of aza-Heck-based C(sp)-H functionalization cascades are described. Under Pd(0)-catalyzed conditions, the aza-Heck-type cyclization of -(pentafluorobenzoyloxy)carbamates generates alkyl-Pd(II) intermediates that effect C(sp)-H palladation en route to cyclopropanes. Key factors that control the site selectivity of the cyclopropanation process have been elucidated such that selective access to a wide range of ring- or spiro-fused systems can be achieved.

Total Synthesis of Thromboxane B via a Key Bicyclic Enal Intermediate.

A 12-step asymmetric synthesis of thromboxane B (TxB) from 2,5-dimethoxytetrahydrofuran is described. The synthesis employs our organocatalytic aldol reaction of succinaldehyde to give a key bicyclic enal intermediate. From here, the synthetic strategy involves a conjugate addition of an alkenyl side chain to the bicyclic enal, Baeyer-Villiger oxidation, and a highly -selective Wittig olefination of a hemiacetal.

Iridium-Catalyzed Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes by 1,3-Difunctionalization of [1.1.1]Propellane.

Bicyclo[1.1.1]pentanes (BCPs) have found application as bioisosteres of aromatic rings in drug development.

Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A.

Platelet activation results in the generation of thromboxane A (TxA), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its production is the target of antiplatelet drugs such as aspirin. However, the study of TxA-stimulated cellular function has been limited by its instability ( = 32 s, pH = 7.

Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles.

The stereospecific 1,2-migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2-migration of boronate complexes is driven by displacement of an α-leaving group, oxidation of an α-boryl radical, or electrophilic activation of an alkenyl boronate complex.

1,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate Rearrangements of Boronate Complexes.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings.

A sustainable catalytic enantioselective synthesis of norstatine derivatives.

Norstatine derivatives are of important value in pharmaceutical science. However, their catalytic asymmetric synthesis is rare. We developed a sustainable method via chiral phosphoric acid (CPA)-[Rh(OAc)] co-catalyzed multi-component reactions (MCR) of diazoacetates with alcohol/water and imines.

Discovery of Bisindole as a Novel Scaffold for Protein Tyrosine Phosphatase 1B Inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity.

Enantioselective oxidative functionalization of the C-H bond adjacent to a nitrogen atom for rapid access to β-hydroxyl-α-amino acid derivatives.

Highly chemoselective and enantioselective one-pot reactions involved in the oxidative functionalization of C-H bonds adjacent to nitrogen atoms in N-aryl glycine esters were developed. The method provided rapid access to a variety of highly functionalized β-hydroxyl-α-amino acid derivatives from simple starting materials under mild conditions.

Highly Regio- and Enantioselective Formal [3 + 2]-Annulation of Indoles with Electrophilic Enol Carbene Intermediates.

Chiral cyclopentane-fused indolines are synthesized with high regio- and enantiocontrol by formal [3 + 2]-annulation reactions of indoles and electrophilic enol carbenes. High enantioselectivity and exclusive regiocontrol occurred with enoldiazoacetamides using a less sterically encumbered prolinate-ligated dirhodium(II) catalyst in reactions with N-substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation, donor-acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene intermediates.

Divergent Synthesis of Multisubstituted Tetrahydrofurans and Pyrrolidines via Intramolecular Aldol-type Trapping of Onium Ylide Intermediates.

This paper reports a divergent strategy for the synthesis of multisubstituted tetrahydrofurans and pyrrolidines, starting from easily accessible β-hydroxyketones or β-aminoketones to react with diazo compounds. Under Rh(II) catalysis, this transformation is proposed to proceed through a metal-carbene-induced oxonium ylide or ammonium ylide formation followed by an intramolecular aldol-type trapping of these active intermediates. A series of highly substituted tetrahydrofurans and pyrrolidines are synthesized in high yields with good to excellent diastereoselectivities.

Catalytic Asymmetric Four-Component Reaction for the Rapid Construction of 3,3-Disubstituted 3-Indol-3'-yloxindoles.

A Rh(II)/chiral phosphoric acid cocatalyzed four-component reaction of indoles, 3-diazooxindoles, arylamines, and ethyl glyoxylate is developed, offering an extremely efficient strategy for the construction of 3,3-disubstituted 3-indol-3'-yloxindoles with excellent diastereoselectivities and high to excellent enantioselectivities. This transformation is proposed to proceed through a Mannich-type trapping of the zwitterionic intermediate generated from a metal carbene and an indole with an iminoester derived from an arylamine and a glyoxylate.

Hg(OTf)2 Catalyzed Intramolecular 1,4-Addition of Donor-Acceptor Cyclopropenes to Arenes.

A Hg(OTf)2 catalyzed intramolecular arene 1,4-addition reaction of N-benzyl donor-acceptor cyclopropenecarboxamides was developed to synthesize a series of [3.2.2]nonatriene derivatives.

Dinitrogen extrusion from enoldiazo compounds under thermal conditions: synthesis of donor-acceptor cyclopropenes.

Donor-acceptor cyclopropenes are formed quantitatively or in high yield from enoldiazoacetates and enoldiazoacetamides under moderate thermal conditions. They are more versatile than their corresponding enoldiazocarbonyl compounds as carbene precursors.

Facile synthesis of 3-aryloxindoles via brønsted acid catalyzed Friedel-Crafts alkylation of electron-rich arenes with 3-diazooxindoles.

A simple metal-free method for the synthesis of 3-aryloxindoles via Brønsted acid catalyzed aromatic C-H functionalization of electron-rich arenes with 3-diazooxindoles is developed. In the presence of a catalytic amount of TfOH, a series of 3-aryloxindoles are synthesized as single regioisomers in good to excellent yields. This transformation is proposed to proceed through acid-catalyzed protonation of 3-diazooxindoles into diazonium ions followed by Friedel-Crafts-type alkylation of arenes.

Highly diastereoselective synthesis of 3-hydroxy-2,2,3-trisubstituted indolines via intramolecular trapping of ammonium ylides with ketones.

A Rh2(OAc)4-catalyzed diazo decomposition reaction of diazo esters with 2-aminophenyl ketones is reported. A series of 3-hydroxy-2,2,3-trisubstituted indolines are produced in good yields with excellent diastereoselectivities via an intramolecular aldol-type trapping of ammonium ylides with ketone units.

Highly efficient synthesis of mixed 3,3'-bisindoles via Rh(II)-catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate.

A series of mixed 3,3'-bisindoles were efficiently synthesized via a Rh2(OAc)4-catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate in high yields with excellent diastereoselectivities. The product easily underwent further synthetic transformations and could be potentially applied to the total synthesis of (±)-gliocladin C and related natural alkaloids.

A highly enantioselective four-component reaction for the efficient construction of chiral β-hydroxy-α-amino acid derivatives.

An enantioselective four-component reaction of a diazoketone, water, an aniline and ethyl glyoxylate in the presence of catalytic Rh2(OAc)4 and a chiral Brønsted acid was developed to efficiently produce β-hydroxy-α-amino acid derivatives in good yields with high diastereoselectivity and enantioselectivity.

A highly diastereoselective three-component tandem 1,4-conjugated addition-cyclization reaction to multisubstituted pyrrolidines.

A highly diastereoselective three-component tandem 1,4-conjugate addition-cyclization reaction of diazoacetophenones with anilines and unsaturated ketoesters was developed. The reaction provides general, easy, and highly efficient access to multisubstituted pyrrolidines in good yield with high diastereoselectivity.