Teresa A. Palazzo

Heterocycle-heterocycle strategies: (2-nitrophenyl)isoxazole precursors to 4-aminoquinolines, 1H-indoles, and quinolin-4(1H)-ones.

Reductive heterocycle-heterocycle (heterocycle → heterocycle; H-H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.

Facile One-Pot Assembly of Imidazotriazolobenzodiazepines via Indium(III)-Catalyzed Multicomponent Reactions

An operationally simple, one-pot multicomponent reaction has been developed for the assembly of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepines adorned with three diversification points via an atom-economical transformation incorporating α-diketones, o-azidobenzaldehydes, propargylic amines, and ammonium acetate. This process involves tandem InCl3-catalyzed cyclocondensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions; optimization data, substrate scope, and mechanistic insights are discussed.

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase.

Significance Diterpenes play important roles in plant biology and serve as industrial bioproducts and therapeutics, including the anticancer drug Taxol. Enzymes of the diterpene synthase family produce the many core structural scaffolds that form the foundation of the large diversity of biologically active diterpenes. This paper describes the identification and the mechanism of a distinct diterpene synthase, pseudolaratriene synthase, from the golden larch tree, Pseudolarix amabilis. The enzyme catalyzes the first committed reaction in the biosynthesis of pseudolaric acids, complex diterpenes with potential anticancer activity. The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined “pseudolaratriene.” Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P. amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene.

One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies.

Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-b]quinoxalines. Optimization data and substrate scope for these atom-economical transformations, which engage commercially available o-phenylenediamines and o-cyanobenzaldehydes, are discussed.

Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies.

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λ(max) of excitation for DBNs with varying electronic character.

Cyclic Azacyanines: Experimental and Computational Studies on Spectroscopic Properties and Unique Reactivity

AbstractThe absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined in several solvents. The presence of electron donating or withdrawing groups on the CAC impacts spectroscopic properties. The general solvent relaxation displayed by azacyanine derivatives is in accordance with Lippert-Mataga’s prediction but exception is noted in the case of protic solvent due to specific hydrogen bonding interactions. Fluorescence lifetime decay studies indicate a relaxation time in the nanosecond timescale with mono exponential decay. Donating substituents markedly increase the excited state lifetime, whereas withdrawing groups marginally decrease the excited state lifetime. Quantum chemical computations were used to explore the origins of the reactivity and spectroscopic properties of CACs; results are consistent with a model in which regioselectivity results from differences in mechanistic steps occurring after initial attack by hydroxide on the CAC.

Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach.

An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.

CCDC 1586657: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

CCDC 1586659: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141