Synthesis of 9,10-Phenanthrenes via Palladium-Catalyzed Aryne Annulation by <i>o</i>‑Halostyrenes and Formal Synthesis of (±)-Tylophorine

A novel palladium-catalyzed annulation reaction of in situ generated arynes and <i>o</i>-halostyrenes has been developed. This methodology affords moderate to excellent yields of substituted phenanthrenes and is tolerant of a variety of functional groups such as nitrile, ester, amide, and ketone. This annulation chemistry has been successfully applied to the formal total synthesis of a biologically active alkaloid (±)-tylophorine

Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted acyclic enol carbonates providing linear α-quaternary ketones is reported. Investigation into the reaction revealed that the use of an electron-deficient phosphinooxazoline ligand renders the enolate geometry of the starting material inconsequential, with the same enantiomer of product obtained in the same level of selectivity regardless of the starting ratio of enolates. As a result, a general method toward acyclic all-carbon quaternary stereocenters has been developed

Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted acyclic enol carbonates providing linear α-quaternary ketones is reported. Investigation into the reaction revealed that the use of an electron-deficient phosphinooxazoline ligand renders the enolate geometry of the starting material inconsequential, with the same enantiomer of product obtained in the same level of selectivity regardless of the starting ratio of enolates. As a result, a general method toward acyclic all-carbon quaternary stereocenters has been developed

Single-Step Synthesis of 5,6,7,8-Tetrahydroindolizines via Annulation of 2‑Formylpiperidine and 1,3-Dicarbonyl Compounds

An expedient single-step synthesis of 5,6,7,8-tetrahydroindolizines has been achieved via the annulation of commercially available 2-formylpiperidine hydrochloride and 1,3-dicarbonyl compounds in THF in the presence of pyrrolidine and 4 Å molecular sieves. A variety of β-ketoesters, ketones, and amides participated in this annulation chemistry, affording the desired 5,6,7,8-tetrahydroindolizines in moderate to good yields

Negishi Approach to 1,5-Disubstituted 3‑Amino‑1<i>H</i>‑1,2,4-triazoles

An efficient synthesis of 1,5-disubstituted 3-amino-1<i>H</i>-1,2,4-triazoles has been achieved via a Negishi coupling of aryl or vinyl bromides and 1-substituted 3-amino-1<i>H</i>-1,2,4-triazoles in the presence of Knochel’s base tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl·LiCl) and catalytic bis­(di-<i>tert</i>-butylphenylphosphine)palladium chloride. This chemistry tolerates a variety of electronically diverse aryl or vinyl bromides and 1-substituted 3-amino-1<i>H</i>-1,2,4-triazoles

Systemic Concentrations Can Limit the Oral Absorption of Poorly Soluble Drugs: An Investigation of Non-Sink Permeation Using Physiologically Based Pharmacokinetic Modeling

In the early drug discovery environment, poorly soluble compounds with suboptimal potency are often used in efficacy studies to demonstrate in vivo preclinical proof-of-concept for new drug discovery targets and in preclinical toxicity studies to assess chemical scaffold safety. These compounds present a challenge to formulation scientists who are tasked with improving their oral bioavailability because high systemic concentrations are required. Despite the use of enabling formulations, increases in systemic exposure following oral delivery are often not achieved. We hypothesize that in some cases non-sink intestinal permeation can occur for poorly soluble compounds where their high systemic concentrations can act to inhibit their own oral absorption. Rats were given a 30 mg/kg oral dose of 1,3-dicyclohexyl urea (DCU) alone or concurrently with deuterated DCU (D8-DCU) intravenous infusions at rates of 13, 17, and 22 mg/kg/h. D8-DCU infusions dose dependently inhibited DCU oral absorption up to a maximum of 92%. Physiologically based pharmacokinetic modeling was utilized to understand the complex interaction between high DCU systemic concentrations and its effect on its own oral absorption. We show that high systemic concentrations of DCU act to suppress its own absorption by creating a condition where intestinal permeation occurs under non-sink conditions. More importantly, we identify relevant DCU concentrations that create the concentration gradient driving the intestinal permeation process. A new parameter, the maximum permeation extraction ratio, is proposed and provides a simple means to assess the extent of non-sink permeation

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the <i>E</i>/<i>Z</i> Selectivities

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately <i>Z</i>-selective in neat tetrahydrofuran (THF) and <i>E</i>-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of <i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, and <i>Z</i>,<i>Z</i>-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for <i>E</i> and <i>Z</i> isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in <i>N</i>,<i>N</i>-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing <i>E</i> and <i>Z</i> isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures

One-Pot Synthesis of 4‑Substituted 3‑Amino-2-cyanothiophenes Involving <i>O</i>‑Ethyl Thioformate

An efficient one-pot synthesis of 4-substituted 3-amino-2-cyanothiophenes is described. Treatment of 2-alkyl or aryl substituted acetonitrile sequentially with 2.1 equiv of LDA, 1.1 equiv of <i>O</i>-ethyl thioformate, and 1.2 equiv of 2-chloroacetonitrile afforded the thiophenes in moderate to good yields. The thiophene core can be readily incorporated into more elaborate pharmaceutically relevant structures as demonstrated by converting 3-amino-2-cyano-4-phenyl­thiophene (<b>1g</b>) to various functionalized thieno­[3,2-<i>d</i>]­pyrimi­dines in only two steps

Highly Diastereoselective α‑Arylation of Cyclic Nitriles

A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles

Isocanthine Synthesis via Rh(III)-Catalyzed Intramolecular C–H Functionalization

An efficient synthesis of substituted isocanthines has been achieved using an intramolecular Rh­(III)-catalyzed C–H functionalization of alkyne-tethered indoles in the presence of catalytic tris­(acetonitrile)­pentamethylcyclopentadienylrhodium­(III) hexafluoroantimonate and stoichiometric copper­(II) acetate. This isocanthine synthesis tolerates a variety of electronically diverse 5- or 6-substituted indoles with <i>N</i>-tethered alkyne coupling partners and can also be extended to pyrrole derivatives for the synthesis of annulated 5-azaindoles