Sterol profiling of Leishmania parasites using a new HPLC-tandem mass spectrometry-based method and antifungal azoles as chemical probes reveals a key intermediate sterol that supports a branched ergosterol biosynthetic pathway.

Human leishmaniasis is an infectious disease caused by Leishmania protozoan parasites. Current chemotherapeutic options against the deadly disease have significant limitations. The ergosterol biosynthetic pathway has been identified as a drug target in Leishmania.

Exploiting Iminoquinones as Electrophilic at Nitrogen "N+" Synthons for C-N Bond Construction.

New methods for C-N bond construction exploiting the N-centered electrophilic character of iminoquinones are reported. Iminoquinones, generated via the condensation of -vinylanilines with benzoquinones, undergo acid-catalyzed cyclization to afford -arylindoles in excellent yields. Under similar reaction conditions, homoallylic amines react analogously to afford -arylpyrroles.

Silylcyclopropanes by Selective [1,4]-Wittig Rearrangement of 4-Silyl-5,6-dihydropyrans.

4-Silyl-5,6-dihydropyrans undergo remarkably selective [1,4]-Wittig rearrangements to give silylcyclopropanes in good yields. The selectivity is independent of the silyl group, but it is influenced by the electronic character of the migrating center. Electron-rich and electron-neutral (hetero)aryl groups and aliphatic substituents at the migrating center lead to exclusive [1,4]-migration, whereas electron-deficient aryl groups predominantly afford [1,2]-Wittig products.

Formal α-Allylation of Primary Amines by a Dearomative, Palladium-Catalyzed Umpolung Allylation of -(Aryloxy)imines.

-(Aryloxy)imines, readily accessible by condensation/tautomerization of (pseudo)benzylic primary amines and 2,6-di--butyl-1,4-benzoquinone, undergo efficient allylation to afford a wide range of homoallylic primary amines following hydrolytic workup. Deprotonation of -(aryloxy)imines generates a delocalized 2-azaallyl anion-type nucleophile that engages in dearomative C-C bond-forming reactions with allylpalladium(II) electrophiles generated from allylic -butyl carbonates. This reactivity umpolung enables the formal α-allylation of (pseudo)benzylic primary amines.

A Unified Strategy for the Syntheses of the Isoquinolinium Alkaloids Berberine, Coptisine, and Jatrorrhizine.

Total syntheses of the antibacterial alkaloids berberine, coptisine, and jatrorrhizine have been achieved in four steps through a unified route. The key step of this strategy is an efficient intramolecular Friedel-Crafts alkoxyalkylation which, following oxidation, establishes the isoquinolinium core of these natural products. Herein, the design and development of this synthetic strategy, which has enabled the shortest and most efficient syntheses of these alkaloids reported to date, is described.

Exploiting Alkylquinone Tautomerization for the Total Synthesis of Calothrixin A and B.

The pentacyclic alkaloid calothrixin B (1) has been synthesized in 5 steps from murrayaquinone A (9). The key step involved the union of boryl aniline 31 with brominated murrayaquinone A (26). In this transformation, alkylquinone 26 undergoes tautomerization to a quinone methide, which is intercepted by boryl aniline 31 to forge a new C-N bond.

Copper-Catalyzed Amidation of Primary and Secondary Alkyl Boronic Esters.

The oxidative copper-catalyzed cross-coupling of functionalized alkyl boronic esters with primary amides is reported. Through the identification of appropriate diketimine ligands, conditions for efficient coupling of both primary and secondary alkyl boronic esters with diverse primary amides, including acetamide, have been developed.

Exploiting Alkylquinone Tautomerization: Amine Benzylation.

A general protocol for the synthesis of benzylic amines via side-chain amination of alkylquinones is reported. The reactions are initiated by the tautomerization of an alkylquinone to the corresponding quinone methide, which is subsequently trapped in situ by an amine nucleophile. This process is promoted by tertiary amines in protic solvents under mild conditions and is compatible with many functional groups.

Stereoconvergent [1,2]- and [1,4]-Wittig rearrangements of 2-silyl-6-aryl-5,6-dihydropyrans: a tale of steric vs electronic regiocontrol of divergent pathways.

The regiodivergent ring contraction of diastereomeric 2-silyl-5,6-dihydro-6-aryl-(2H)-pyrans via [1,2]- and [1,4]-Wittig rearrangements to the corresponding α-silylcyclopentenols or (α-cyclopropyl)acylsilanes favor the [1,4]-pathway by ortho and para directing groups in the aromatic appendage and/or by sterically demanding silyl groups. The [1,2]-pathway is dominant with meta directing or electron-poor aromatic moieties. Exclusive [1,2]-Wittig rearrangements are observed when olefin substituents proximal to the silyl are present.

Selective formation of secondary amides via the copper-catalyzed cross-coupling of alkylboronic acids with primary amides.

For the first time, a general catalytic procedure for the cross-coupling of primary amides and alkylboronic acids is demonstrated. The key to the success of this reaction was the identification of a mild base (NaOSiMe3) and oxidant (di-tert-butyl peroxide) to promote the copper-catalyzed reaction in high yield. This transformation provides a facile, high-yielding method for the monoalkylation of amides.

[1,2]- and [1,4]-Wittig Rearrangements of α-Alkoxysilanes: Effect of Substitutions at both the Migrating Benzylic Carbon and the Terminal sp Carbon of the Allyl Moiety.

Substituted α-alkoxysilanes can be deprotonated by alkyllithium bases and made to undergo Wittig rearrangements to afford the #x0005B;1,4]- and [1,2]-rearranged products in varying ratios. Substitution at the benzylic migrating carbon and/or at the allylic carbon of the allyl moiety impacts the rearrangement reaction, influencing the reactivity as well as the [1,4]-/[1,2]-selectivity. Diastereomeric α-alkoxysilanes show different reactivities with the diastereomer being the more reactive isomer.