Design and Synthesis of DR Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a DR-selective compound. The effect of the flexible linker (,-), SBFs (,-), and the chirality of orthosteric binding fragments (OBFs) (,, , ,, ,, and ,) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP110 of the DR, thereby reducing the DR affinity to a suboptimal level.

Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine D and D receptors.

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (DR) and dopamine 3 receptor (DR) has been used in the design of compounds displaying selectivity for the DR versus DR. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for DR versus DR. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in DR versus DR selectivity.

Identification of a Putative α-synuclein Radioligand Using an in silico Similarity Search.

Purpose: Previous studies from our lab utilized an ultra-high throughput screening method to identify compound 1 as a small molecule that binds to alpha-synuclein (α-synuclein) fibrils. The goal of the current study was to conduct a similarity search of 1 to identify structural analogs having improved in vitro binding properties for this target that could be labeled with radionuclides for both in vitro and in vivo studies for measuring α-synuclein aggregates.

Methods: Using 1 as a lead compound in a similarity search, isoxazole derivative 15 was identified to bind to α-synuclein fibrils with high affinity in competition binding assays.

Lignin-First Monomers to Catechol: Rational Cleavage of C-O and C-C Bonds over Zeolites.

A catalytic route is developed to synthesize bio-renewable catechol from softwood-derived lignin-first monomers. This process concept consists of two steps: 1) O-demethylation of 4-n-propylguaiacol (4-PG) over acidic beta zeolites in hot pressurized liquid water delivering 4-n-propylcatechol (4-PC); 2) gas-phase C-dealkylation of 4-PC providing catechol and propylene over acidic ZSM-5 zeolites in the presence of water. With large pore sized beta-19 zeolite as catalyst, 4-PC is formed with more than 93 % selectivity at nearly full conversion of 4-PG.

Palladium-catalyzed post-Ugi arylative dearomatization/Michael addition cascade towards plicamine analogues.

A palladium-catalyzed intramolecular cyclization of Ugi-adducts a cascade dearomatization/aza-Michael addition process has been developed. Diverse plicamine analogues are constructed in a rapid, highly efficient and step-economical manner, through the combination of an Ugi-4CR and a palladium-catalyzed dearomatization. The synthetic utility of this approach is illustrated by further functional group transformations.

A Gold(I)-Catalyzed Hydroamination/Cycloisomerization Cascade: Concise Synthesis of (±)-seco-Antofine and (±)-Septicine.

A concise and flexible procedure for the synthesis of highly functionalized N-heterocyclic 1,6-annulated 2-pyridones and 2,3-annulated 4-pyrimidinones has been elaborated through a gold-catalyzed tandem hydroamination/cycloisomerization cascade. This novel and highly efficient method allows the rapid construction of these diverse N-heterocyclic scaffolds starting from readily available building blocks, and shows a wide scope and good functional group tolerance. The total synthesis of (±)-seco-antofine and (±)-septicine were realized employing this strategy.

Synthesis of Pyrrolo[1,2-]isoquinolines via Gold(I)-Catalyzed Cyclization/Enyne Cycloisomerization/1,2-Migration Cascade.

A gold(I)-catalyzed cascade transformation of -alkynic 2-ynamides for the rapid and efficient synthesis of the indolizidine scaffold is developed. Through a sequential nucleophilic cyclization/enyne cycloisomerization/1,2-migration process, diverse pyrrolo[1,2-]isoquinolines are obtained under mild conditions in a regiospecific and convergent manner. Various alkyl and aryl migrating groups are tolerated in this process.

Chemo- and Regioselective Catalyst-Controlled Carbocyclization of Alkynyl Ketones: Rapid Synthesis of 1-Indanones and 1-Naphthols.

A catalyst-controlled intramolecular carbocyclization of 2-alkynyl aryl ketones is presented. Under rhodium(III) catalysis, 1-indanones are formed through 5-exo-dig carbocyclizations with exclusive chemo-, regio- and stereoselectivity. When catalyzed by copper(I), 1-naphthols are obtained through 6-endo-dig carbocyclizations with exclusive chemo- and regioselectivity.

Intramolecular cascade annulation triggered by rhodium(III)-catalyzed sequential C(sp)-H activation and C(sp)-H amination.

A rhodium(III)-catalyzed intramolecular oxidative annulation of -substituted -hydroxyacrylamides for the construction of indolizinones via sequential C(sp)-H activation and C(sp)-H amination has been developed. This approach shows excellent functional-group tolerance. The synthesized scaffold forms the core of many natural products with pharmacological relevance.

Gold-catalyzed post-MCR transformations towards complex (poly)heterocycles.

Post multicomponent reaction (MCR) transformations are one of the most successful methods leading to high structural diversity and molecular complexity. A well-known MCR, the Ugi reaction typically affords a linear peptide backbone, enabling post-Ugi transformations as an elegant solution to rigidify the Ugi adduct into more drug-like species. Not surprisingly, the development of such transformations leading to new structural frameworks has expanded rapidly over the last few years.

Rhodium(iii)-catalyzed intramolecular annulation through C-H activation: concise synthesis of rosettacin and oxypalmatime.

A flexible and efficient rhodium(iii)-catalyzed intramolecular annulation of benzamides bearing tethered alkynes for the synthesis of indolizinones and quinolizinones is reported. This reaction shows a broad substrate scope and excellent functional-group tolerance, including different kinds of heterocyclic substrates, such as furan, thiophene, pyrrole, benzofuran, benzothiophene, indole and isonicotinamide substrates. This method also provides a practical and efficient approach for the synthesis of rosettacin and oxypalmatime.

Gold-catalyzed diastereoselective domino dearomatization/ipso-cyclization/aza-Michael sequence: a facile access to diverse fused azaspiro tetracyclic scaffolds.

A facile and diversity-oriented access to complex tetracyclic benzo[e]pyrrolo[2,3-c]indole-2,4,7(5H)-triones through a post-Ugi gold(i)-catalyzed domino dearomatization/ipso-cyclization/aza-Michael sequence is elaborated. This process furnishes tetracyclic scaffolds in good yields from readily available precursors with unique diastereoselectivity.

Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C.

An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization.