Fluorine on fluorenes.

A practical synthesis of 1,8-difluorofluorenone and of its (2,7)-dibromo and (2,4,5,7)-tetrabromo derivatives has been developed. Fluorinated fluorenones are the starting materials for polyhalogenated dibenzochrysenes as well as for geodesic hydrocarbons. 2,7-Dibromo-1,8-difluoro-9-fluoren-9-one was converted to 3,14-dibromo-4,13-difluorodibenzo[,]chrysene through a novel strategy.

Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo.

Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC 0.

Synthesis of Fluorenes and Dibenzo[]chrysenes through an Oxidative Cascade.

We have developed robust, operationally simple syntheses of fluorenes and of dibenzo[]chrysenes through oxidative cascade processes. These structures that are commonly encountered in optoelectronic materials, dyes, and pharmaceutical products are accessible from 1,4-dioxaspiro[4.5]decan-8-one.

Oxa-adamantyl cannabinoids.

As a continuation of earlier work on classical cannabinoids bearing bulky side chains we report here the design, synthesis, and biological evaluation of 3'-functionalized oxa-adamantyl cannabinoids as a novel class of cannabinergic ligands. Key synthetic steps involve nucleophilic addition/transannular cyclization of aryllithium to epoxyketone in the presence of cerium chloride and stereoselective construction of the tricyclic cannabinoid nucleus. The synthesis of the oxa-adamantyl cannabinoids is convenient, and amenable to scale up allowing the preparation of these analogs in sufficient quantities for detailed in vitro evaluation.

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of ()-azetidine-2-carboxamide analogues that have sub-micromolar potencies. , and have STAT3-inhibitory potencies (IC) of 0.55, 0.

()Trifluoromethyl-Trisubstituted Alkenes or Isoxazolines: Divergent Pathways from the Same Allene.

Because of a charge-dipole interaction involving nonbonding electron pairs on fluorine, protonation of trifluoromethyl allenes leads to tri- or tetrasubstituted alkenes with high ()-selectivity. Treatment of the same allenes with catalytic Au(I) initiates a reaction cascade that produces isoxazolines in high yield.

Linker Variation and Structure-Activity Relationship Analyses of Carboxylic Acid-based Small Molecule STAT3 Inhibitors.

The molecular determinants for the activities of the reported benzoic acid (SH4-54), salicylic acid (BP-1-102), and benzohydroxamic acid (SH5-07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an -methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH group of the glycinamide scaffold were separately modified.

C1'-Azacycloalkyl Hexahydrocannabinols.

We report the design, synthesis, and biological evaluation of a novel class of cannabinergic ligands, namely C1'-azacycloalkyl hexahydrocannabinols. Our synthetic approaches utilize an advanced common chiral intermediate triflate from which all analogues could be derived. Key synthetic steps involve microwave-assisted Liebeskind-Srogl C-C cross-coupling and palladium-catalyzed decarboxylative coupling reactions.

The Evolution of the Total Synthesis of Rocaglamide.

The complex flavagline, (-)-rocaglamide, possesses a synthetically intriguing tricyclic scaffold with five contiguous stereocenters and also exhibits potent anticancer, anti-inflammatory and insecticidal activity. This full account details distinct approaches to (±)- and (-)-rocaglamide utilizing Brønsted acid catalyzed and asymmetric Pd -catalyzed Nazarov chemistry developed in our laboratory, respectively. The successful asymmetric synthesis revealed unforeseen mechanistic complexity that required adjusting our strategy to overcome an unanticipated racemization process, an unusual reversible ring-cleavage step and a very facile trialkylsilyl group migration.

Origins of the Stereoselectivity in a Thiourea-Primary Amine-Catalyzed Nazarov Cyclization.

The origins of stereoselectivity of the Nazarov reactions of α-hydroxydivinylketones catalyzed by a vicinal thiourea-primary amine first reported by Tius have been explored with density functional theory. The electrocyclization transition structures in which the thiourea group of the catalyst donates two hydrogen bonds to the keto carbonyl group of the Nazarov reactant and the primary amine accepts a hydrogen bond from the hydroxyl group of the reactant have been modeled. The enantiomeric Nazarov transition structures, which are conventionally described by the absolute sense of conrotation of the dienone termini ("clockwise" or "counterclockwise") in the literature, are nonplanar and adopt helically chiral conformations.

Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo.

STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts.

Isotetronic acids from an oxidative cyclization.

Oxidation of α,β-unsaturated methyl ketones with selenium dioxide leads to a cascade of reactions culminating in the formation of isotetronic acids.

Enantioselective palladium(0)-catalyzed Nazarov-type cyclization.

A Pd(0)-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity.

Synthesis of each enantiomer of rocaglamide by means of a palladium(0)-catalyzed Nazarov-type cyclization.

A recently reported Pd(0)-catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (-)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.

3'-functionalized adamantyl cannabinoid receptor probes.

The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids, and we have previously shown that this chain could be substituted successfully by adamantyl or other polycyclic groups. In an effort to explore the pharmacophoric features of these conformationally fixed groups, we have synthesized a series of analogues in which the C3 position is substituted directly with an adamantyl group bearing functionality at one of the tertiary carbon atoms. These substituents included the electrophilic isothiocyanate and photoactivatable azido groups, both of which are capable of covalent attachment with the target protein.

First total synthesis of the marine natural products clavulolactones II and III.

The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the β-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine steps, in overall yields of 21 and 7% respectively.

Mixed aggregates of 1-methoxyallenyllithium with lithium chloride.

A combined computational and (13)C NMR study was used to investigate the formation of mixed aggregates of 1-methoxyallenyllithium and lithium chloride in tetrahydrofuran (THF) solution. The observed and calculated chemical shifts, as well as the calculated free energies of mixed aggregate formation (MP2/6-31+G(d)), are consistent with the formation of a mixed dimer as the major species in solution. Free energies of mixed dimer, trimer, and tetramer formation were calculated by using the B3LYP and MP2 methods and the 6-31+G(d) basis set.

Catalytic enantioselective Nazarov cyclization: construction of vicinal all-carbon-atom quaternary stereocenters.

The diastereoselective asymmetric synthesis of vicinal all-carbon-atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported.

Allene ether Nazarov cyclization.

The ease of synthesis and the exceptional reactivity of alkoxyallenes has led to their use in a large number of highly diverse applications. This Report describes their use in various versions of the allene ether Nazarov cyclization. Following a brief introduction to the Nazarov cyclization (Section 1), the oxidative cyclization of vinyl alkoxyallenes is discussed first (Section 2).