Synthesis of (−)-Epi-Indolactam V by an Intramolecular Buchwald–Hartwig C–N Coupling Cyclization Reaction

The synthetic efforts toward the concise synthesis of (−)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular <i>N</i>-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C–N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (−)-epi-indolactam V and its enantiomer have been accomplished

Iron-Catalyzed Direct C3-Benzylation of Indoles with Benzyl Alcohols through Borrowing Hydrogen

We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated indoles and H₂O that is catalyzed, for the first time, by a complex of earth-abundant iron. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, sustainability, high functional-group tolerance, and amenability to gram-scale synthesis. On the basis of the preliminary experimental observations, we propose that the reaction proceeds through a borrowing hydrogen process

Synthesis of (±)-<i>cis</i>-Clavicipitic Acid by a Rh(I)-Catalyzed Intramolecular Imine Reaction

A new and short synthesis of racemic <i>cis</i>-clavicipitic acid was achieved by taking advantage of the double nucleophilic character of indole-4-pinacolboronic ester. Key to the success of the synthesis were an efficient and selective C-3 indole Friedel–Crafts alkylation and the development of an unprecedented intramolecular rhodium-catalyzed 1,2-addition of an aryl pinacolboronic ester to an unactivated imine

Palladium(II)-Catalyzed Cross-Dehydrogenative Coupling (CDC) of <i>N</i>‑Phthaloyl Dehydroalanine Esters with Simple Arenes: Stereoselective Synthesis of <i>Z</i>‑Dehydro­phenyl­alanine Derivatives

Pd­(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl <i>N</i>-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp² C–H bonds followed by C–C bond formation, stereoselectively generates highly valuable <i>Z</i>-dehydro­phenyl­alanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties

Synthesis of Tryptamine Derivatives via a Direct, One-Pot Reductive Alkylation of Indoles

An efficient, one-pot reductive alkylation of indoles with <i>N</i>-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin

Synthesis and Biological Evaluation of Metabolites of 2‑<i>n</i>‑Butyl-9-methyl-8-[1,2,3]triazol-2-yl‑9<i>H</i>‑purin-6-ylamine (ST1535), A Potent Antagonist of the A_2A Adenosine Receptor for the Treatment of Parkinson’s Disease

The synthesis and preliminary in vitro evaluation of five metabolites of the A_2A antagonist ST1535 (<b>1</b>) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9<i>H</i>-purine (<b>2</b>) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A_2A receptor with affinities (<i>K</i>_i 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i>_i 10.7 nM), thus showing that the long duration of action of <b>1</b> could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed

Synthesis of (<i>E</i>)‑8-(3-Chlorostyryl)caffeine Analogues Leading to 9‑Deazaxanthine Derivatives as Dual A_2A Antagonists/MAO‑B Inhibitors

A systematic modification of the caffeinyl core and substituents of the reference compound (<i>E</i>)-8-(3-chlorostyryl)­caffeine led to the 9-deazaxanthine derivative (<i>E</i>)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1<i>H</i>-pyrrolo­[3,2-<i>d</i>]­pyrimidine-2,4-(3<i>H</i>,5<i>H</i>)-dione (<b>17f</b>), which acts as a dual human A_2a antagonist/MAO-B inhibitor (<i>K</i>_i(A_2A) = 260 nM; IC₅₀(MAO-B) = 200 nM; IC₅₀(MAO-A) = 10 μM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A_2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson’s agents. A number of analogues of <b>17f</b> were synthesized and qualitative SARs are discussed. Two analogues of <b>17f</b>, namely <b>18b</b> and <b>19a</b>, inhibit MAO-B with IC₅₀ of 68 and 48 nM, respectively, being 5–7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC₅₀ = 334 nM)