J. Carlos Menéndez

Total synthesis of the ionophore antibiotic CP-61,405 (routiennocin)

Abstract The total synthesis of the spiroketal ionophore antibiotic routiennocin 1 (CP-61,405) employing π-allyltricarbonyl iron lactone complexes is described. These complexes were used as precursors for the preparation of substituted 2-phenylsulphonyl pyrans which, in turn, were coupled with iodoacetonides to afford spiroketals. Elaboration of the spiroketals by tetra- n -propylammonium perruthenate (TPAP) oxidation and coupling with 2-lithio-1-[β-(trimethylsilyl)ethoxymethyl] pyrrole followed by further oxidation, deprotection, oxidation and benzoxazole formation afforded the natural product. The preparation of the amino phenol fragment necessary for benzoxazole formation involved a novel amination procedure using benzeneselenenic anhydride and hexamethyldisilazane followed by samarium diiodide reduction.

L-Proline-catalysed sequential four-component “on water” protocol for the synthesis of structurally complex heterocyclic ortho-quinones

The L-proline-catalyzed synthesis of 7-(aryl)-8-methyl-10-phenyl-5H-benzo[h]pyrazolo-[3,4-b]quinoline-5,6(10H)-diones via the four-component sequential reaction of phenylhydrazine, 3-aminocrotononitrile, substituted benzaldehydes and 2-hydroxynaphthalene-1,4-dione is described. This “on water” protocol proceeds in high atom economy and leads to the generation of two rings, together with two C–C, one C–N and two CN bonds in a single operation. The environmental advantages of the method include short reaction time, excellent yield, easy work-up, and the absence of extraction and chromatographic purification steps.

Cerium(IV) ammonium nitrate is an excellent, general catalyst for the Friedländer and Friedländer-Borsche quinoline syntheses: very efficient access to the antitumor alkaloid luotonin A.

The use of cerium(IV) ammonium nitrate as a catalyst of the Friedländer reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedländer reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

Chemodivergent, multicomponent domino reactions in aqueous media: L-proline-catalyzed assembly of densely functionalized 4H-pyrano[2,3-c]pyrazoles and bispyrazolyl propanoates from simple, acyclic starting materials

A library of 4H-pyrano[2,3-c]pyrazol-6-amines was synthesized in excellent yield employing an L-proline-catalyzed, on-water four-component domino reaction from hydrazines, β-dicarbonyl compounds, nitriles and dialkyl acetylenedicarboxylates that generates two rings by the creation of C–C (two), C–N, CN and C–O bonds and presumably involves a sequence of hydrazone formation, cyclocondensation, Michael, [1,3]-hydrogen shift, Michael addition and 6-exo-dig annulation steps. When alkyl propiolates were employed, a three-component reaction took place furnishing alkyl 3,3-bis(5-hydroxy-1H-pyrazol-4-yl)propanoates via a double Michael domino process.

Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition

Spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrid compounds were obtained in excellent yields from the regio- and stereoselective reaction between β-nitrostyrenes and non-stabilized azomethine ylides, generated in situ from isatin and phenylglycine/proline/thiaproline. These compounds were evaluated for their in vitro activity against Mycobacterium tuberculosisH37Rv (MTB). Eleven compounds were more active than pyrazinamide and one of them, namely 6′-(3-nitrophenyl)-7′-nitro-3′,6′,7′,7a′-tetrahydro-1′H-spiro-[indoline-3,5′-pyrrolo-[1,2-c]thiazol]-2-one, displayed a 7.6 μM MIC value, which represents a potency similar to that of the first-line anti-TB drug ethambutol and 6.7 times higher than that of pyrazinamide.

L-proline-catalyzed three-component domino [3+2+1] annulation for the regio- and diastereoselective synthesis of highly substituted thienothiopyrans containing three or four stereocenters.

L-proline-catalyzed three-component reactions of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy-2-oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5-aryltetrahydro-3-thiophenone furnished a variety of highly substituted thieno[3,2-c]thiopyran derivatives. This facile transformation presumably occurs via a one-pot domino sequence of enamine formation/aldol condensation/Michael addition/6-exo-trig cyclization/elimination and involves the creation in a single operation of three C-C bonds and the generation of three new stereocenters with complete diastereoselectivity in all cases and a fourth one in ca. 7:3 diastereomeric ratio when starting from a 5-substituted tetrahydro-3-thiophenone derivative.

Two-Step Stereocontrolled Synthesis of Densely Functionalized Cyclic β-Aminoesters Containing Four Stereocenters, Based on a New Cerium(IV) Ammonium Nitrate Catalyzed Sequential Three-Component Reaction

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential, one-pot reaction between alkylamines, beta-ketoesters, and chalcones afforded cis-4,6-disubstituted 2-alkylaminocyclohexene-1-carboxylic esters with complete diastereoselectivity. The carbon-carbon double bond of these compounds was reduced with sodium triacetoxyborohydride, again with complete diastereoselectivity. This novel two-step route allows the transformation of very simple acyclic starting materials into tetrasubstituted cyclohexane derivatives bearing four functional groups, including a cis-beta-aminoester moiety, and generates four stereocenters, three of which are adjacent and one of which is quaternary.

Ultrasound assisted Diels-Alder reactions of 1-azadienes with normal electronic demand

Abstract Ultrasound irradiation accelerates hetero Diels-Alder reactions between 1-dimethylamino-1-azadienes and electron-defficient dienophiles. Besides the lower reaction times and increased yields, other advantages of the sonicated reactions are the possibility of isolating previously unknown adducts due to the milder reaction conditions and, in some cases, the decrease in side reactions.

A facile, three-component domino protocol for the microwave-assisted synthesis of functionalized naphtho[2,3-b]furan-4,9-diones in water

A three-component domino reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and a pyridinium salt in the presence of ammonium acetate, under microwave irradiation and using water as solvent, furnished a library of novel 2-arylcarbonyl-3-aryl-4,9-dihydronaphtho[2,3-b]furan-4,9-diones in good yields, in a transformation that presumably proceeds via an α,β-unsaturated triketone generation/Michael addition/intramolecular cyclisation/air oxidation one-pot sequence.

Domino reactions in water: diastereoselective synthesis of densely functionalized indolyldihydrofuran derivatives†

A library of trans-5-aroyl-2-(indol-3-yl)-4-aryl-4,5-dihydrofuran-3-carbonitriles was diastereoselectively synthesized in excellent yields from the reaction of 2-(3-indolylcarbonyl)-3-aryl-2-propenenitriles with (2-aryl-2-oxoethyl)pyridinium bromides in the presence of triethylamine via a simple, user-friendly domino process carried out in water. Extraction and chromatographic steps were avoided, since the final products could be simply filtered from the aqueous reaction medium and recrystallized. This one-pot transformation generates one C–C and one C–O bond and presumably proceeds by a domino sequence involving the generation of a pyridinium ylide, a Michael addition and a final annulation via intramolecular nucleophilic substitution.