Synthesis of (+)-altholactone, (+)-7-epi-altholactone, (−)-etharvensin,and (+)-alumheptolide-A using Pd-catalyzed carbonylation

Syntheses of (+)-altholactone isolated from Goniothalamus giganteus and its C-7 epimer (+)-7-epi-altholactone, (?)-etharvensin and (+)-alumheptolide-A were achieved. The lactone ring of these compounds was constructed using Pd-catalyzed carbonylation.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

Protein recognition by bivalent, ‘turn-on’ fluorescent molecular probes

We show that the conversion of a known intercalating dye (i.e., thiazole orange) into a bivalent protein binder could lead to the realization of a novel class of ‘turn-on’ fluorescent molecular probes that detect proteins with high affinity, selectivity, and a high signal-to-noise (S/N) ratio. The feasibility of the approach is demonstrated with monomolecular probes that light-up in the presence of three different proteins: acetylcholinesterase (AChE), glutathione-s-transferase (GST), or avidin (Av) at low concentrations and with minimal background signal. The way by which such probes can be used to detect individual protein isoforms and be applied in inhibitor screening, cell imaging, and biomarker detection is described.     

Catalytic arylsulfonyl radical-triggered 1,5-enyne-bicyclizations and hydrosulfonylation of α,β-conjugates

A catalytic bicyclization reaction of 1,5-enynes anchored by α,β-conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using TBAI (20 mol%) and Cu(OAc)₂ (5 mol%) as co-catalysts under convenient conditions. In addition, the use of benzoyl peroxide (BPO) as the oxidant and pivalic acid (PivOH) as an additive was proven to be necessary for this reaction. The reactions occurred through 5-exo-dig/6-endo-trig bicyclizations and homolytic aromatic substitution (HAS) cascade mechanisms to give benzo[b]fluorens regioselectively. A similar catalytic process was developed for the synthesis of γ-ketosulfones. These reactions feature readily accessible starting materials and simple one-pot operation.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Unveiling the nature of supramolecular crown ether–C60 interactions

A series of exTTF-(crown ether)₂ receptors, designed to host C₆₀, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)₂·C₆₀ stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor–acceptor, π–π, n–π and CH···π interactions, which is the basis for the affinity of our novel receptors towards C₆₀.     

Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B

We report a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B based on the advanced intermediates of 3α-amino-hexahydropyrrolo[2,3-b]indole. To construct these structural motifs, a cascade reaction involving a BINOL-derived phosphoric anion-paired catalyst for enantioselective or diastereoselective azo-coupling/iminium-cyclizations was developed. The remaining key steps of the synthesis involve a sterically hindered amination via hypervalent iodine reagents and the Larock annulation. These transformations enable a general approach to the syntheses of indole alkaloids containing a 3α-amino-hexahydropyrrolo[2,3-b]indole motif and could be further applied to build a natural product-based library.     

A carbon–carbon hybrid – immobilizing carbon nanodots onto carbon nanotubes

The thrust of this work is to integrate small and uniformly sized carbon nanodots (CNDs) with single-walled carbon nanotubes (SWCNT) of different diameters as electron donors and electron acceptors, respectively, and to test their synergetic interactions in terms of optoelectronic devices. CNDs (denoted pCNDs, where p indicates pressure) were prepared by pressure-controlled microwave decomposition of citric acid and urea. pCNDs were immobilized on single-walled carbon nanotubes by wrapping the latter with poly(4-vinylbenzyl trimethylamine) (PVBTA), which features positively charged ammonium groups in the backbone. Negatively charged surface groups on the CNDs lead to attractive electrostatic interactions. Ground state interactions between the CNDs and SWCNTs were confirmed by a full-fledged photophysical investigation based on steady-state and time-resolved techniques. As a complement, charge injection into the SWCNTs upon photoexcitation was investigated by ultra-short time-resolved spectroscopy.     

Remote stereoselective deconjugation of α,β-unsaturated esters by simple amidation reactions

The thermodynamically disfavored isomerization of α,β-unsaturated esters to deconjugated β,γ-unsaturated analogues occurs readily when coupled to an amidation. Within the framework of macrocyclic derivatives, it is shown that 15, 16, and 18 membered macrocycles react with tBuOK and anilines to generate, in one-pot, β,γ-unsaturated amides (yields up to 88%). Importantly, single (chiral) diastereomers are isolated (d.r. > 49 : 1, ¹H NMR) irrespective of the size and nature of the rings, showing an effective transmission of remote stereochemistry during the isomerization process. CSP-chromatographic resolution and absolute configuration determination by VCD are achieved.     

Mutual stabilisation between MII 4L6 tetrahedra and MIIX4 2– metallate guests

A complex host–guest equilibrium employing metal ions incorporated into both the host and guest is discussed. M^IIX₄ ^2– metallate guests are shown to provide a good size and shape match for encapsulation within the M₄L₆ tetrahedral capsules, facilitating the generation of previously unreported Zn₄L₆ complexes. Displacement of the initial, primary template anion (ZnBr₄ ^2–) by a secondary template anion (ClO₄ ^–) is shown to result in the formation of a pentagonal-prismatic Zn₁₀L₁₅ structure that incorporates both Br^– and ClO₄ ^–. Furthermore, the formation of heterometallic complexes provides direct evidence for metal exchange between the guest and host complex.     

Mechanism,reactivity, and selectivity of the iridium-catalyzed C(sp3)–H borylation of chlorosilanes

The iridium-catalyzed C(sp³)–H borylation of methylchlorosilanes is investigated by means of density functional theory, using the B3LYP and M06 functionals. The calculations establish that the resting state of the catalyst is a seven-coordinate Ir(v) species that has to be converted into an Ir(iii)tris(boryl) complex in order to effect the oxidative addition of the C–H bond. This is then followed by a C–B reductive elimination to yield the borylated product, and the catalytic cycle is finally completed by the regeneration of the active catalyst over two facile steps. The two employed functionals give somewhat different conclusions concerning the nature of the rate-determining step, and whether reductive elimination occurs directly or after a prior isomerization of the Ir(v) hydride intermediate complex. The calculations reproduce quite well the experimentally-observed trends in the reactivities of substrates with different substituents. It is demonstrated that the reactivity can be correlated to the Ir–C bond dissociation energies of the corresponding Ir(v) hydride intermediates. The effect of the chlorosilyl group is identified to originate from the α-carbanion-stabilizing effect of the silicon, which is further reinforced by the presence of an electron-withdrawing chlorine substituent. Furthermore, the source of selectivity for the borylation of primary over secondary C(sp³)–H can be explained on a steric basis, by repulsion between the alkyl group and the Ir/ligand moiety. Finally, the difference in the reactivity between C(sp³)–H and C(sp²)–H borylation is investigated and rationalized in terms of distortion/interaction analysis.     

In vitro reconstitution of α-pyrone ring formation in myxopyronin biosynthesis

Myxopyronins are α-pyrone antibiotics produced by the terrestrial bacterium Myxococcus fulvus Mx f50 and possess antibacterial activity against Gram-positive and Gram-negative pathogens. They target the bacterial RNA polymerase (RNAP) “switch region” as non-competitive inhibitors and display no cross-resistance to the established RNAP inhibitor rifampicin. Recent analysis of the myxopyronin biosynthetic pathway led to the hypothesis that this secondary metabolite is produced from two separate polyketide parts, which are condensed by the stand-alone ketosynthase MxnB. Using in vitro assays we show that MxnB catalyzes a unique condensation reaction forming the α-pyrone ring of myxopyronins from two activated acyl chains in form of their β-keto intermediates. MxnB is able to accept thioester substrates coupled to either N-acetylcysteamine (NAC) or a specific carrier protein (CP). The turnover rate of MxnB for substrates bound to CP was 12-fold higher than for NAC substrates, demonstrating the importance of protein–protein interactions in polyketide synthase (PKS) systems. The crystal structure of MxnB reveals the enzyme to be an unusual member of the ketosynthase group capable of binding and condensing two long alkyl chains bound to carrier proteins. The geometry of the two binding tunnels supports the biochemical data and allows us to propose an order of reaction, which is supported by the identification of novel myxopyronin congeners in the extract of the producer strain. Insights into the mechanism of this unique condensation reaction do not only expand our knowledge regarding the thiolase enzyme family but also opens up opportunities for PKS bioengineering to achieve directed structural modifications.     

C–H arylation of triphenylene,naphthalene and related arenes using Pd/C

A highly selective arylation of a number of polyaromatic hydrocarbons (PAHs) with aryliodonium salts and Pd/C as the only reagent is reported. The first C–H functionalization of triphenylene is explored, and proceeds at the most sterically hindered position. This non-chelate assisted C–H functionalization extends the reactivity profile of Pd/C and provides controlled access to π-extended PAHs, an important aspect of work towards the preparation of nanographenes. Mechanistic studies suggest in situ formation of catalytically active insoluble nanoparticles, and that the reaction likely proceeds via a Pd(0)/Pd(ii) type reaction manifold.     

Nature of anion-templated π(+)-π(+) interactions

Interaction between positively charged aromatic groups (π(+)-π(+)) is characterized by anti-parallel, displaced-stacked structures in the presence of counteranions. Binding energies of pyridinium, N-methylpyridinium and N-methylimidazolium dimers are much larger than that of benzene-pyridine (π-π) and pyridinium-benzene (π(+)-π). Stabilization is attributed to attractive electrostatic interaction with significant dispersion contribution.     

Copper-catalyzed intermolecular C(sp3)–H bond functionalization towards the synthesis of tertiary carbamates

We describe the development of an intermolecular unactivated C(sp³)–H bond functionalization towards the direct synthesis of tertiary carbamates. The transformation proceeded using a readily available, abundant first-row transition metal catalyst (copper), and isocyanates as the source of the amide moiety. This is a novel strategy for direct transformation of a variety of unactivated hydrocarbon feedstocks to N-alkyl-N-aryl and N,N-dialkyl carbamates without pre-functionalization or installation of a directing group. The reaction had a broad substrate scope with 3° > 2° > 1° site selectivity. The reaction proceeded even on a gram scale, and a corresponding free amine was directly obtained when the reaction was performed at high temperature. Kinetic studies suggested that radical-mediated C(sp³)–H bond cleavage was the rate-determining step.     

Diastereoselective Syntheses of (+)-α-Cyperone and Its C-10 Epimer

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A convergent approach to batzelladine alkaloids. Total syntheses of (+)-batzelladine E, (−)-dehydrobatzelladine C,and (+)-batzelladine K

We recently reported a convergent strategy to access the polycyclic guanidinium alkaloid (+)-batzelladine B via an aldol addition–retro-aldol–aza-Michael addition cascade. Here we describe the application of this approach toward the total syntheses of (+)-batzelladine E, (?)-dehydrobatzelladine C, and (+)-batzelladine K. The identification of suitable methods to functionalize a common tropane core by electrophilic alkynylation and nucleophilic 1,2-addition were essential to generalizing this approach. We provide evidence for the intermediacy of an acylallene species in the cascade reaction.     

Rh-catalyzed desymmetrization of α-quaternary centers by isomerization-hydroacylation

We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from α,α-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C–H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of α-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation.     

Synthesis and structures of Cu<Superscript>I,II</Superscript> complexes with a 2,2´-bipyridine derivative bearing a (+)-3-carene moiety

The complex salt {[CuL₂][Cu₄I₆]?MeCN}_n (1) and the compound [Cu₄L₃I₄]?3 MeCN (2) (L is a chiral ligand bearing a natural monoterpene (+)-3-carene moiety) were synthesized. The crystal structures of compounds 1 and 2 were determined by X-ray diffraction. The structure of compound 1 consists of complex cations [CuL₂]²⁺ (N₃O₂ polyhedron is a trigonal bipyramid) and Cu^I coordination polymers (CuI₄ polyhedron is a tetrahedron) as anions. The experimental magnetic moment μ_eff at 300 K is 1.90 μ_B, which is consistent with the X-ray diffraction data and the assumption that compound 1 is mixed-valence. The structure of compound 2 comprises a tetranuclear Cu^I complex, in which three Cu atoms are coordinated by two N atoms of the ligand L and two I atoms, and the fourth Cu atom is coordinated by four I atoms (coordination polyhedra are distorted tetrahedra). Compounds L and 2 were found to influence the viability of human laryngeal carcinoma cells (Hep2). The IC₅₀ value for complex 2 (13.0±1.7 μM) is substantially smaller than IC₅₀ for compound L (30.5±0.5 μM).