Total Synthesis of Cyclotripeptidic Natural Products Anacine, Aurantiomide C, Polonimides A and C, and Verrucine F.

The total synthesis of cyclotripeptidic natural products possessing a central piperazino[2,1-b]quinazolin-3,6-dione core is described through an original strategy involving the pivotal cyclocondensation of an electrophilic homoserine lactone intermediate. The alkylidene group was spontaneously installed by autoxidation during the cyclocondensation process, while the propionamide side chain was introduced through the nickel-catalyzed aminocarbonylation of a bromoethyl intermediate. This last reaction is unprecedented on such highly functionalized intermediates. Finally, we explored structural modifications and interconversions of the natural products. Overall, this work led to anacine, aurantiomide C, polonimides A and C, and verrucine F.

Tandem Hock and Friedel-Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold.

The Hock cleavage, which is compatible with tandem processes, was applied to the synthesis of 1-aryltetralines through a one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a benzyl moiety on the substrate resulted in tandem Friedel-Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel-Crafts reactions, rather than an oxocarbenium.

Electronic Effects in Phosphino-Iminophosphorane PdII Complexes upon Varying the N Substituent.

Three series of palladium(II) complexes supported by a phosphine-iminophosphorane ligand built upon an ortho-phenylene core were investigated to study the influence of the iminophosphorane N substituent. Cis-dichloride palladium(II) complexes 1 in which the N atom bears an isopropyl (iPr, 1 a), a phenyl (Ph, 1 b), a trimethylsilyl (TMS, 1 c) group or an H atom (1 d) were synthesized in high yield. They were characterized by NMR, IR spectroscopy, HR-mass spectrometry, elemental analysis, and X-ray diffraction. A substantial bond length difference between the Pd-Cl bonds was observed in 1. Complexes 1 a-d were converted into [Pd(LR )Cl(CNt Bu)](OTf)] 2 a-d whose isocyanide is located trans to the iminophosphorane. The corresponding dicationic complexes [Pd(LR )(CNt Bu)2 ](OTf)2 3 a-d were also synthesized, however they exhibited lower stability in solution than 2, the isopropyl derivative 3 a being the most stable of the series. Molecular modeling was performed to rationalize the regioselectivity of the substitution of the single chloride by isocyanide (from 1 to 2) and to study the electronic distribution in the complexes. In particular differences between the TMS and H containing complexes vs. the iPr and Ph ones were found. This suggests that the nature of the N substituent is far from innocent and can help tune the reactivity of iminophosphorane complexes.

Phosphinoquinoline supported CoII, NiII, and FeII complexes: divergent behaviour upon reduction.

The reduction of [CoLBr2], a CoII complex supported by a diisopropylphosphinoquinoline (L) ligand, induced a ligand coupling giving access to a (PNNP) supported CoII complex which was isolated in 70% yield. This complex was formed using a minimum of 2 equivalents of a reductant (either Mn or KC8). The fate of [CoLBr2] in the presence of 1 equivalent of a reductant was more difficult to study; nevertheless, a CoI complex was characterised in the solid state. In order to determine whether this ligand coupling could occur with other 3d metals, L supported FeII and NiII complexes were synthesised. While no compound could be identified upon reduction of [FeLBr2], both [NiLBr2] and [NiL2Br](Br) led to the reduction at the metal center allowing the isolation of an original Ni0 trimer in a satisfactory yield. This study shows the different behaviours of these 3d metal complexes in the presence of a reductant.

FeII complexes supported by an iminophosphorane ligand: synthesis and reactivity.

The synthesis of iron complexes supported by a mixed phosphine-lutidine-iminophosphorane (PPyNP) ligand was carried out. While bidentate κ2-N,N coordination was observed for FeCl2, pincer coordination modes were adopted at cationic iron centers, either through dechlorination of [LFe(PPyNP)Cl2] (1) or direct coordination of PPyNP to Fe(OTf)2. Reaction with tert-butylisocyanide gave access to the diamagnetic octahedral complex [Fe(PPyNP)(CNtBu)3]X2 (X = OTf (4), Cl (4')). Both 1 and 4 were shown to undergo deprotonation of the phosphinomethyl group, but the resulting complexes were not active for the dehydrogenative coupling of hexan-1-ol. The hydrosilylation of acetophenones was catalyzed at room temperature with 1 mol% of a catalyst generated in situ from cationic PPyNP-supported iron triflate complexes and KHBEt3.

Diastereo- and Enantioselective Palladium-Catalyzed Cycloadditions of 5-Vinyloxazolidine-2,4-diones with Electrophilic Imines.

Despite the importance of the 4-imidazolidinone scaffold in bioactive compounds or organocatalysts, methodologies to access these nitrogenated heterocycles remain scarce. This manuscript describes a novel preparation of 4-imidazolidinones via a diastereo- and enantioselective (3 + 2) cycloaddition between 5-vinyloxazolidine-2,4-diones (VOxD) and electrophilic imines under palladium catalysis. This work supports the synthetic potential of VOxD as a promising equivalent of the C-C(═O)-N synthon.

Diastereo- and Enantioselective (3 + 2) Cycloaddition of a New Aza-π-Allylpalladium Zwitterionic Intermediate.

Cycloaddition of azaoxyallyl cations or other C─(C═O)─N synthon precursors is a well-established route toward lactams and other N-heterocycles, but despite the wide synthetic scope of this approach, enantioselective versions remain scarce. We herein report 5-vinyloxazolidine-2,4-diones (VOxD) as a suitable precursor of a new palladium-π-allylpalladium intermediate. In the presence of electrophilic alkenes, (3 + 2) γ-lactam cycloadducts could be formed with a high level of diastereo- and enantioselectivity.

Bicyclic N-dihalocyclopropylamide derivatives as precursors of nitrogen-containing fused polycyclic systems.

Examples of carbon-carbon bond-forming cyclisation reactions, involving allyl cations generated by the thermal ring-opening of halocyclopropanes, have been scarcely reported. In this contribution, we are describing the results of a study conducted with N-dihalocyclopropylamide substrates, designed as precursors of cyclic iminium intermediates that were aimed at participating in intramolecular reactions with electron-rich aromatic groups. Competitive side-reactions were identified, and access to the desired polycyclic products was carefully evaluated. The results were found to be strongly dependent on the substitution pattern of the nucleophilic aromatic moieties, as well as on the sizes of the rings of the target products. In spite of the rather moderate yields generally obtained, this approach represents a particularly short and inexpensive route to various interesting nitrogen-containing polycyclic systems, namely benzoindolizidine, benzoquinolizidine, piperidinobenzoazepane and azepanoisoquinoline compounds.

Asymmetric synthesis of a stereopentade fragment toward latrunculins.

Latrunculins are marine toxins used in cell biology to block actin polymerization. The development of new synthetic strategies and methods for their synthesis is thus important in order to improve, modulate or control this biological value. The total syntheses found in the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and analogue synthesis, starting from (+)-ß-citronellene. Key stereoselective transformations involve an asymmetric Krische allylation, an aldol reaction under 1,5-anti stereocontrol, and a Tishchenko-Evans reduction accompanied by a peculiar ester transposition, allowing to install key stereogenic centers of the natural products.

Phosphonium Ylides vs Iminophosphoranes: The Role of the Coordinating Ylidic Atom in cis-[Phosphine-Ylide Rh(CO)2] Complexes.

The coordinating properties of two families of ylides, namely, phosphonium ylides and iminophosphoranes, differently substituted at the ylidic center (CH2- vs NiPr-), have been investigated in structurally related cationic phosphine-ylide Rh(CO)2 complexes obtained from readily available phosphine-phosphonium salt precursors derived from an ortho-phenylene bridge. However, while the Rh(CO)2 complex bearing the P+-CH2- donor moiety proved to be stable, the P═NiPr donor end appeared to induce lability to one of the CO groups. All of the RhI carbonyl complexes in both ylide series were fully characterized, including through X-ray diffraction analysis. Based on the experimental and calculated infrared (IR) CO stretching frequencies in Rh(CO)2 complexes, we evidenced that the phosphonium ylide ligand is a stronger donor than the iminophosphorane ligand. However, we also found that the difference in the intrinsic electronic properties can be largely compensated by the introduction of an iPr substituent on the N atom of the iminophosphorane, hence pointing to the noninnocent role of the peripheral substituent and opening novel possibilities to tune the properties of metal complexes containing ylide ligands.

Total Synthesis of (+)-Cinereain and (-)-Janoxepin through a Fragment Coupling/Retro-Claisen Rearrangement Cascade.

Total syntheses of (+)-cinereain and (-)-janoxepin, two fungal cyclotripeptides featuring a complex heterocyclic core and interesting phytotoxic and antimalarial activities, have been achieved in a convergent manner. A key step in this synthesis is a one-pot cascade initiated by the cyclocondensation of two fragments-a hindered 2-vinylcyclopropane-1-acyl fluoride and an electron-deficient cyclic amidine-to release a reactive spiro[2-vinylcyclopropane-1,5'-pyrimidine-4',6'-dione]. This intermediate underwent a spontaneous retro-Claisen rearrangement that was rationalized by DFT calculations. The cascade directly afforded a 2,5-dihydrooxepin-fused heterotricyclic product, and the challenging oxepin ring was finally forged by the palladium-catalyzed ß-hydride elimination of an allylic fluoride intermediate.

Cobalt Complexes Supported by Phosphinoquinoline Ligands for the Catalyzed Hydrosilylation of Carbonyl Compounds.

P,N phosphinoquinoline based ligands differing by the nature of the phosphorus substituent (i Pr, Ph) were employed to synthesize a series of cobalt(II) complexes ([LCoBr2 ], [L2 CoBr](PF6 ) and [L'2 CoBr](PF6 )). The latter were obtained in high yield and characterized among others by X-ray analysis and elemental analysis. Complex [L2 CoBr](PF6 ) showed a very good catalytic activity for the hydrosilylation of various ketones. The catalysis proceeds at a low catalytic loading (1 mol %) with only 1 equivalent of Ph2 SiH2 in mild conditions and was efficient with aliphatic or aromatic ketones giving moderate to excellent yields of the corresponding silylated ether.

Passerini-Smiles Reaction of α-Ketophosphonates: Platform for Phospha-Brook/Smiles Embedded Cascades.

The Passerini-Smiles reactions of α-ketophosphonates with nitrophenols has been used as a platform to observe complex cascades involving multiple Smiles transfers coupled with phospha-Brook rearrangement. When using 4-nitrophenols a rare 1,3-Truce-Smiles rearrangement is observed leading to diarylacetamide derivatives. 2-Nitro-derivatives lead to a completely different reactivity pattern that may be explained by a nitro to nitroso conversion followed by a σ-π metathesis. All mechanistic assumptions are confirmed by DFT calculations performed on both families of adducts. The potential of this work has been further demonstrated by the use of N-aryl α-ketoamides as alternative starting materials for these cascades as well as the disclosure of new aza-Nazarov access to hydroxy-indolones.

A Modular Access to 1,2- and 1,3-Disubstituted Cyclobutylboronic Esters by Consecutive Radical Additions.

A modular approach to substituted cyclobutylboronic esters is described. It proceeds by successive intermolecular radical additions of xanthates to pinacolato 1-cyclobutenylboronate and to pinacolato bicyclo[1.1.0]but-1-ylboronate. Success hinges on tuning the stability of the α-boryl radical by exploiting the stabilizing influence of the trivalent boronic ester and the slightly destabilizing cyclobutane, which increases the σ-character of the radical. Reductive removal of the xanthate group finally provides a range of 1,2- and 1,3-disubstituted cyclobutylboronic esters. The contrast with cyclopropylboronic esters is striking, since the strong destabilization by the highly strained cyclopropane ring allows the first radical addition to take place but not the second. Furthermore, the first adducts are geminal xanthyl boronic esters that can be converted into cyclobutanones. This chemistry furnishes cyclobutylboronic esters that would be quite difficult to obtain otherwise and thus complements existing methods.

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A.

Aspochalasins are leucine-derived cytochalasins. Their complexity is associated with a high degree of biosynthetic oxidation, herein inspiring a two-phase strategy in total synthesis. We thus describe the synthesis of a putative biomimetic tetracyclic intermediate. The constructive steps are an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, whose branched precursor was obtained from a stereoselective Ireland-Claisen rearrangement performed from a highly unsaturated substrate. This also constitutes a formal synthesis of trichoderone A.

Deciphering Electron Interplay at the Fullerene/Sputtered TiOx Interface: A Barrier-Free Electron Extraction for Organic Solar Cells.

Organic photovoltaics (OPVs) technology now offers power conversion efficiency (PCE) of over 18% and is one of the main emerging photovoltaic technologies. In such devices, titanium dioxide (TiOx) has been vastly used as an electron extraction layer, typically showing unwanted charge-extraction barriers and the need for light-soaking. In the present work, using advanced photoemission spectroscopies, we investigate the electronic interplay at the interface between low-temperature-sputtered TiOx and C70 acceptor fullerene molecules. We show that defect states in the band gap of TiOx are quenched by C70 while an interfacial state appears. This new interfacial state is expected to support the favorable energy band alignment observed, showing a perfect match of transport levels, and thus barrier-free extraction of charges, making low-temperature-sputtered TiOx a good candidate for the next generation of organic solar cells.

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.

Vinylcyclopropanes as All-Carbon 1,5-Dipoles: A Reactivity Switch for Palladium-Catalyzed (5 + 4) Cycloadditions.

Azonanes were prepared by a palladium-catalyzed (5 + 4) cycloaddition between activated vinylcyclopropanes and 1-azadienes. During this process, the vinylcyclopropane partner displayed an unusual reactivity and behaved as an all-carbon 1,5-dipole. A N,N-bidentate ligand was required to inhibit the formation of thermodynamic (3 + 2) cycloadducts.

Reaction of Phosphines with 1-Azido-(2-halogenomethyl)benzene Giving Aminophosphonium-Substituted Indazoles.

The reaction between a 1-azido-(2-halogenomethyl)benzene and a phosphine gives different products depending on the nature of the halogen, the phosphine itself, and the solvent employed. While PPh3 (2 equiv) reacts with the chloro reagent in toluene to give the expected iminophosphorane-phosphonium adduct, trialkylphosphines (PCy3 and PEt3) surprisingly furnish an aminophosphonium substituted by a zwitterionic indazole. The bicyclic product can also form from PPh3 using the bromo reagent in acetonitrile. A mechanism is proposed for this cyclization based on DFT calculations.

Atom economical coupling of benzophenone and N-heterocyclic aromatics with SmI2.

The use of stoechiometric SmI2 in combination with benzophenone and N-heterocyclic aromatics such as bipyridine, phenanthroline and pyridine allows the direct ortho-coupling of both partners in an atom economical reaction free of any other coupling additives. The transformation was investigated by 1H NMR, X-ray studies and theoretical calculations providing reaction intermediates and the reaction mechanism.