Lanny S. Liebeskind

A Simple, Modular Synthesis of Substituted Pyridines

A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N-O bond of alpha,beta-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43-91%). Starting materials are readily available, and functional group tolerance is very good.

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine A NOVEL CATEGORY OF BIOACTIVE 1-DEOXYSPHINGOID BASES AND 1-DEOXYDIHYDROCERAMIDES BIOSYNTHESIZED BY MAMMALIAN CELL LINES AND ANIMALS

Fumonisin B1 (FB1) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. Inhibition of CerS by FB1 increases sphinganine (Sa), Sa 1-phosphate, and a previously unidentified metabolite. Analysis of the latter by quadrupole-time-of-flight mass spectrometry assigned an m/z = 286.3123 in positive ionization mode, consistent with the molecular formula for deoxysphinganine (C18H40NO). Comparison with a synthetic standard using liquid chromatography, electrospray tandem mass spectrometry identified the metabolite as 1-deoxysphinganine (1-deoxySa) based on LC mobility and production of a distinctive fragment ion (m/z 44, CH3CH=NH +2) upon collision-induced dissociation. This novel sphingoid base arises from condensation of alanine with palmitoyl-CoA via serine palmitoyltransferase (SPT), as indicated by incorporation of l-[U-13C]alanine into 1-deoxySa by Vero cells; inhibition of its production in LLC-PK1 cells by myriocin, an SPT inhibitor; and the absence of incorporation of [U-13C]palmitate into 1-[13C]deoxySa in LY-B cells, which lack SPT activity. LY-B-LCB1 cells, in which SPT has been restored by stable transfection, however, produce large amounts of 1-[13C]deoxySa. 1-DeoxySa was elevated in FB1-treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK1 and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB1, substantial amounts of 1-deoxySa are made and acylated to N-acyl-1-deoxySa (i.e. 1-deoxydihydroceramides). Thus, these compounds are an underappreciated category of bioactive sphingoid bases and “ceramides” that might play important roles in cell regulation.

N-Amidation by Copper-Mediated Cross-coupling of Organostannanes or Boronic Acids with O-Acetyl Hydroxamic Acids

A general nonoxidative N-amidation of organostannanes and boronic acids has been developed. Under nonbasic conditions a wide variety of aryl, alkenyl, and heteroaryl organostannanes and boronic acids couple efficiently with O-acetyl hydroxamic acids in the presence of Cu(I) sources.

Cyclobutenediones as precursors to quinones and cyclopentenones

For many years, cyclobutenediones and benzocyclobutenediones were studied as theoretically interesting molecules without any obvious potential for use in the intentional design of complex organic molecules. Within the last 10 years this situation has begun to change. A variety of simple, yet powerful, methods have been developed that allow the conversion of cyclobutenediones and benzocyclobutenediones into highly functionalized quinones and cyclopentenone derivatives. This article will highlight the synthetic potential of some of these recent reactions, and demonstrate that substituted cyclobutenediones are readily available starting materials

Silver Mediated Cyclizations of 4-Allenyl-and 4-(2-Propynyl)azetidinones. A Stereoselective Synthesis of 3-Substituted Δ1-Carbapenems Via N-C3 Closure.

Abstract A silver catalyzed cyclization of 4-allenylazetidinones to Δ 1 -carbapenems and of 4-(2-propynyl)-azetidinones to Δ 2 -carbapenems is described. The silver mediated cyclization is stereospecific: starting withstereodefined 4-allenylazetidinones, specific stereoisomers of C-3 substituted Δ2-carbapenems can be prepared.

Optimized Stille coupling reactions catalyzed by palladium on carbon with CuI as cocatalyst

Abstract The coupling reaction of aryl and vinyl iodides, bromides, and triflates with organostannanes can be effectively conducted using palladium on carbon as a source of Pd0. The yield and rate of reaction are significantly affected by the addition of copper iodide as co-catalyst and triphenylarsine as ligand.

Palladium-mediated 2,6-dialkylation of N-benzilidine imines: Preparation of 2,6-dialkylbenzaldehydes

Abstract Treatment of di-μ-trifluoroacetatobis[o-(N-phenylbenzimidoyl)]dipalladium with two equivalents of primary alkyl iodides and subsequent hydrolysis provides an efficient route to 2,6-disubstituted benzaldehydes.

A Copper‐Catalyzed, pH‐Neutral Construction of High‐Enantiopurity Peptidyl Ketones from Peptidic S‐Acylthiosalicylamides in Air at Room Temperature

A copper-catalyzed transformation of peptidic thiol esters and boronic acids gives peptidyl ketones and takes place in DMF or DMF/H(2)O at room temperature in air (see scheme). This aerobic reaction only occurs at a thiol ester group capable of coordinating to Cu through its appendage on the sulfur center and is not hampered by racemization of the reactants or products.

Palladium Mediated Formation of Δ1- and Δ2-Carbapenems by Cyclofunctionalization of 4-Allenylazetidinones and 4-(2-Propynyl)azetidinones.

A palladium catalyzed cyclofunctionalization of a 4-allenylazetidinone to Δ1-carbapenems and of 4-(2-propynyl)-azetidinones to Δ2-carbapenems is described. A palladium(+2) catalyst induces nucleophilic closure of the azetidinone nitrogen on a pendant allene or alkyne, and the resulting vinyl palladium intermediate reacts in a subsequent step with allyl halides or activated alkenes (CH2CHE, E = COOEt, COMe, CHO, CN) to provide 2-functionalized carbapenems. The allylation is catalytic in palladium, while the reaction with CH2CHE, as currently performed, is stoichimetric in palladium.

Unprecedented asymmetric induction from a chiral acetate enolate equivalent. The condensation of acetyl(triphenylphosphine)carbonyl-.eta.-cyclopentadienyliron [(.eta.-C5H5)Fe(CO)(PPh3)(Ac)] with imines

Diverses imines se condensent avec le diethyl-Al-enolate du racemique (η-C 5 H 5 )Fe(CO)(PPh 3 )COCH 3 en donnant des produits de condensation avec un bon rendement