Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester.

A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno-Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z-selective cross-metathesis to introduce the (Z)-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z-selective cross-metathesis protocol to construct (Z)-ß,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18 O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction.

A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.

Catalytic Deoxygenative Coupling of Aromatic Esters with Organophosphorus Compounds.

We have developed a deoxygenative coupling of aromatic esters with diarylphosphine oxides/dialkyl phosphonates under palladium catalysis. In this reaction, aromatic esters can work as novel benzylation reagents to give the corresponding benzylic phosphorus compounds. The key of this reaction is the use of phenyl esters, an electron-rich diphosphine as a ligand, and sodium formate as a hydrogen source. Arylcarboxylic acids were also applicable in this reaction using (Boc)2O as an additive. Palladium/dcype worked to activate the acyl C-O bond of the ester and to support the reduction with sodium formate.

Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis.

Because diaryl ethers are present as an important motif in pharmaceuticals and natural products, extensive studies for the development of novel methods have been conducted. A conventional method for the construction of the diaryl ether moiety is the intermolecular cross-coupling reaction of aryl halides and phenols with a copper or palladium catalyst. We developed a catalytic decarbonylative etherification of aromatic esters using a palladium or nickel catalyst with our enabling diphosphine ligand to give the corresponding diaryl ethers. The present reaction can be conducted on gram scale in excellent yield. This reaction not only functions in an intramolecular setting but also allows for a cross-etherification using other phenols.

Decarbonylative C-P Bond Formation Using Aromatic Esters and Organophosphorus Compounds.

Ni-catalyzed C-P bond formation was achieved using aromatic esters as unconventional aryl sources. The key to success was the use of a thiophene-based diphosphine ligand (dcypt). Several aromatic esters including heteroaromatics can be coupled with phosphine oxides and phosphates, providing aryl phosphorus compounds. The synthetic utility of the method was demonstrated by application of the present protocol to the sequential coupling reactions.

Pd-Catalyzed Decarbonylative C-H Coupling of Azoles and Aromatic Esters.

A decarbonylative C-H coupling of azoles and aromatic esters by palladium catalysis is described. Our previously reported Ni-catalyzed C-H coupling of azoles and aromatic esters has a significant drawback regarding the substrate scope. Herein, we employ palladium catalysis instead of nickel, resulting in a broader substrate scope in terms of azoles and aromatic esters.