Photoinduced Formation of Cubyl Aryl Thioethers and Synthesis of Monocubyl Analogue of Dapsone.

1,4-Disubstituted cubyl aryl thioethers were generated from the corresponding iodocubanes and aryl thiolates upon UV irradiation in dimethyl sulfoxide at room temperature. This simple procedure was found to be compatible with a variety of substituted aryl thiolates. This finding paved the way to a synthesis of the monocubyl analogue of dapsone, a key molecule in the treatment of leprosy, also known as Hansen's disease, and of acne.

Intra- and Intermolecular Cation-π Interactions between Onium Salts and Alkynes/Acetylene: Experimental and Theoretical Insights.

Cation-π interactions between various onium salts, alkynes, and acetylene were studied, taking into account the substituents of the triple bond, the nature of the anions, and the polarity of the solvent, through a combination of MP2 calculations and experiments. In an intramolecular setting, these data (including single-crystal X-ray crystallography) concurred with the stability of folded conformers of alkynyl onium salts, even substituted with electron-withdrawing groups. To examine the contribution of these interactions on the alkyne electronic population, a thorough in silico study was carried out using natural bonding orbital analysis of the conformers. Intramolecular interactions from sulfonium salt tethered to phenylalkyne were highlighted, as illustrated above by the computed folded conformation (MP2) along with noncovalent interaction (NCI) analysis. Furthermore, investigations of intermolecular interactions, involving acetylene or phenylacetylene with various onium ions, revealed the high energy interactions of their complexes with phenyldimethylsulfonium chloride, as illustrated above with the complex PhC≡CH/PhMe2SCl (MP2 calculations and NCI analysis).

Organocatalyzed enantio- and diastereoselective isomerization of prochiral 1,3-cyclohexanediones into nonalactones bearing distant stereocenters.

The lactonization of 2-(2-nitrophenyl)-1,3-cyclohexanediones containing an alcohol side chain and up to three distant prochiral elements is reported by isomerization under the mediation of simple organocatalysts such as quinidine. Through a process of ring expansion, strained nonalactones and decalactone are produced with up to three stereocenters in high er and dr (up to 99 : 1). Distant groups, including alkyl, aryl, carboxylate and carboxamide moieties, were examined.

Synthetic study toward tridachiapyrone B.

A convergent approach to the skeleton of tridachiapyrone B is described taking advantage of the desymmetrization of α,α'-dimethoxy-γ-pyrone leading to α-crotyl-α'-methoxy-γ-pyrone in one step. To construct the quaternary carbon of the 2,5-cyclohexadienone of the target, a strategy based on the Robinson-type annulation of an aldehyde derived from α-crotyl-α'-methoxy-γ-pyrone was applied. The grafting of the simplified target's side chain was demonstrated through an oxidative anionic oxy-Cope rearrangement of the tertiary alcohol arising from the 1,2-addition of a 1,3-dimethylallyl reagent to 2,5-cyclohexadienone connected to the α'-methoxy-γ-pyrone motif.

Reactivity of 3-nitroindoles with electron-rich species.

The indol(in)e building block is one of the "privileged-structures" for the pharmaceutical industry since this fragment plays a central role in drug discovery. While the electron-rich character of the indole motif has been investigated for decades, exploiting the electrophilic reactivity of 3-nitroindole derivatives has recently been put at the heart of a wide range of new, albeit challenging, chemical reactions. In particular, dearomatization processes have considerably enriched the scope of C2[double bond, length as m-dash]C3 functionalizations of these scaffolds. This feature article showcases this remarkable electrophilic reactivity of 3-nitroindoles with electron-rich species and highlights their value in generating diversely substituted indol(in)es. This compilation underlines how these heteroaromatic templates have gradually become model substrates for electron-poor aromatic compounds in dearomatization strategies.

Convergent Synthesis of 2-Oxazolone-4-carboxylates Esters by Reaction of Aldehydes with Ambivalent N-Cbz-α-Tosylglycinate Ester.

N-Cbz-α-tosylglycinate ester was combined with aldehydes in a redox-neutral sequence leading to 2-oxazolone-4-carboxylates with high functional group tolerance. While the scope of the method was delineated to primary and secondary aliphatic aldehydes as well as aromatics, no racemization occurred with chiral aldehydes such as Garner's. Hitherto unknown, this process relies on the ambivalent role of N-Cbz-α-tosylglycinate ester acting as a pronucleophile.

H-bonding vs Protonation of Alkynes in Regioselective Hydroamination Reactions: A Glimpse into the Reactivity of Arylogous Ynolethers and Ynamines.

In this paper is described the competition and transition between hydrogen bonding and protonation of alkynes connected, on one side, to various aromatic rings and to chiral amino ester appendages on the other side. While the first mode of activation induced the cyclization into pyrrolidines, the protonation of the alkyne led preferentially to tetrahydropyridines due to the higher level of the highest occupied molecular orbital (HOMO) of the considered arylogous ynolethers and ynamines. The transition between H-bonding and protonation was observed with the alkyne substituted with 2-methoxyphenyl, for which the cyclization delivered either five- or six-membered rings depending on the temperature of the experiment. From there, the cyclization of dialkoxy- and trialkoxyphenyl-substituted alkynes into six-membered rings, i.e., tetrahydropyridines, was developed. When next applied to alkynylindoles, the same pattern of cyclization provided six-membered rings as an illustration of the reactivity of arylogous ynamines. Thanks to the high reactivity of the intermediate cationic species, weak nucleophiles such as NH-oxazolidinone participated efficiently in the hydroamination reaction of alkynylindoles. Pyrrolidines, tetrahydropyridines, and piperidines decorated with various aromatics and substituents were thus prepared in enantio- and stereoselective manner. Capitalizing on the enamine moiety of the azaheterocycles, the molecular diversity was extended through stereoselective oxidation and ring contraction processes.

Dearomatization of 3-Nitroindoles with Highly γ-Functionalized Allenoates in Formal (3+2) Cycloadditions.

3-Nitroindoles are easily reacted with highly substituted γ-allenoates in the presence of a commercially available phosphine catalyst. For instance, allenoates derived from biomolecules such as amino and deoxycholic acids are combined for the first time with 3-nitroindole. The corresponding dearomatized (3+2) tricyclic cycloadducts are obtained as α-regioisomers exclusively. DFT computations shed light on this multi-step reaction mechanism and on the selectivities observed in the sequence.

Nucleophilic-Addition-Initiated Ring Expansion and Selectivity in Anionic Fragmentation.

The expansion of rings into larger ones by a mechanism of anionic fragmentation is a potent tool for exploring new structural space in a concise manner. As the concept has been known and applied for decades now, going a step further calls for selectivity in the production of new scaffolds. In this regard, recent results demonstrated promising levels of regio-, dia- and enantioselectivity which give impulses to the concept of ring expansion involving the fragmentation of anionic species generated from unstrained cycles. Initiated by addition of a nucleophile, the energy received in the form of electrons triggered skeletal rearrangements of simple starting materials while revealing new stereocenters and/or regioisomers. Disrupting the symmetry of smaller rings in some cases, the strategy gives access to complex larger rings.

Domino Ring Expansion: Regioselective Access to 9-Membered Lactones with a Fused Indole Unit from 2-Nitrophenyl-1,3-cyclohexanediones.

The domino anionic fragmentation of 2-nitrophenyl-1,3-cyclohexanediones containing an electrophilic appendage such as aldehyde and epoxide is disclosed. This reaction, initiated by a series of nucleophiles, involves the generation of an intermediate hydroxylate followed by the regioselective formation and fragmentation of an intermediate lactolate into enolate. This strategy, devoid of any protecting group, enlarges the initial ring and provides an original access to decorated 9-membered lactones with a fused indole unit.

Borinic Acid Catalysed Reduction of Tertiary Amides with Hydrosilanes: A Mild and Chemoselective Synthesis of Amines.

A reduction of various aryl, alkyl, and α,ß-unsaturated amides with phenylsilane, catalysed by a borinic acid, is reported. The unprecedented reaction was carried out under very mild conditions and led to useful amines. Furthermore, the reaction tolerates a variety of functional groups. Initial investigations implicated that an intermediate diarylhydroborane is involved in the reaction mechanism.

Flexible Total Synthesis of (±)-Aureothin, a Potent Antiproliferative Agent.

Amenable to late-stage preparation of analogues, a flexible and convergent total synthesis of (±)-aureothin is presented. The strategy was based on a desymmetrization of α,α'-dimethoxy-γ-pyrone by a process combining 1,4-addition and alkylation of vinylogous enolate to stereoselectively reach the backbone of the target. Palladium-catalyzed cyanation of an elaborated and isomerizable E,Z dienyl motif followed by Pinner cyclization enabled the construction of the tetrahydrofuran motif while a first approach based on a late-stage oxidation was unsuccessful.

An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles.

A concise and regioselective preparation of 2-heteroarylmethylene decorated N-arylpyrroles is described through a metal-free Mannich/Wittig/hydroamination sequence followed by isomerization of the N-arylpyrrolidine adducts. Furthermore, the C-H regioselective oxidation of these substrates is demonstrated, extending the molecular diversity and versatility of these scaffolds.

Stereoselective access to heteroarylmethylene-substituted pyrrolidines: fully organocatalytic Mannich-hydroamination reactions.

A one-pot sequence of organocatalytic transformations delivers heteroarylmethylene-substituted pyrrolidines with high stereo- and enantioselectivity. A Mannich coupling of N-heteroarylalkyne aldehydes with aldimine and an original metal-free hydroamination of the resulting adducts are the key transformations of the process delivering highly functionalized molecules with high potential for synthetic applications.

Recent advances in stereoselective synthesis of 1,3-dienes.

The aim of this review is to present the latest developments in the stereoselective synthesis of conjugated dienes, covering the period 2005-2010. Since the use of this class of compounds is linked to the nature of their appendages (aryls, alkyls, electron-withdrawing, and heterosubstituted groups), the review has been categorized accordingly and illustrates the most representative strategies and mechanisms to access these targets.

One-pot regio- and stereoselective synthesis of α'-methoxy-γ-pyrones: biological evaluation as mitochondrial respiratory complex inhibitors.

The one-pot construction of functionalized α'-methoxy-γ-pyrones is detailed. Starting from α,α'-dimethoxy-γ-pyrone, molecular diversity is attained by a regio- and stereoselective desymmetrization using allyllithium followed by vinylogous aldol reaction. Mechanistic considerations including density functional theory calculations and insightful experiments have been gathered to shed light on this complex multistep process. To illustrate the versatility of this methodology, some of the molecules prepared were evaluated for their ability to inhibit NADH-oxidase and NADH-ubiquinone oxidoreductase. In the process, a potent new inihibitor of NADH-oxidase activity (IC(50) 44 nM) was identified.

Domino alkylation/oxa-Michael of 1,3-cyclohexanediones: steering the C/O-chemoselectivity to reach tetrahydrobenzofuranones.

An unprecedented domino synthesis of tetrahydrobenzofuran-4-ones is described implicating chemoselective alkylation of various 1,3-cyclohexanediones with bromocrotonate or crotonitrile followed by oxa-Michael cyclization. Further transformations of this core to reach molecular diversity are also presented.