Cyclotrimerization Approach to Symmetric [9]Helical Indenofluorenes: Diverting Cyclization Pathways.

Catalytic cyclotrimerization routes to symmetrical [9]helical indenofluorene were explored by using different transition-metal complexes and thermal conditions. Depending on the reaction conditions, the cyclotrimerizations were accompanied by dehydro-Diels-Alder reaction giving rise to another type of aromatic compounds. Structures of both symmetrical [9]helical cyclotrimerization product as well as the dehydro-Diels-Alder product were confirmed by single-crystal X-ray diffraction analyses. Limits of enantioselective cyclotrimerization were assessed as well. DFT calculations shed light on the reaction course and the origin of diminished enantioselectivity.

Catalytic vs. uncatalyzed [2 + 2] photocycloadditions of quinones with alkynes.

Photoreactions of quinones with alkynes under catalytic and non-catalytic conditions were studied. In contrast to recent reports, simple irradiation with blue light is sufficient to trigger [2 + 2] photocycloadditions, which afford either fused cyclobutenes or reactive para-quinone methides (p-QMs) depending on the quinone structure. Revision of the chemo- and regioselectivity of the uncatalyzed photoreactions provided useful insight into their overlooked relatedness to the recently developed catalytic protocols. Experimental evidence indicates that the reactivity of the photochemically generated p-QMs is sufficient to perform uncatalyzed reactions with nucleophiles, which can help to explain the existing transformations and develop new cascade transformations involving quinones and alkynes.

Ir-Catalyzed Cycloaddition of Tribenzocyclyne with Biphenylenes.

We demonstrate that Ir-catalyzed C-C bond activation in biphenylenes followed by a reaction with tribenzocyclyne is a suitable method for synthesizing strained and unknown monoadducts with the tetradehydrotetrabenzo[a,c,e,i]cyclododecene scaffold ([12]annulenes). Modification of reaction conditions also furnished [12]annulene products with cis and/or trans double bonds formed by hydrogen transfer. The [9]annulene side product was formed upon the reaction of the benzyl radical with tribenzocyclyne during the Bergman cyclization. All isolated compounds were fully characterized by HRMS, NMR, and X-ray diffraction analysis.

Unusual Scaffold Rearrangement in Polyaromatic Hydrocarbons Driven by Concerted Action of Single Gold Atoms on a Gold Surface.

Chemical transformation of polyaromatic hydrocarbon (PAH) molecules following different reaction strategies has always been the focus of organic synthesis. In this work, we report the synthesis of a PAH molecule, formation of which consists of an unusual C-C bond cleavage accompanied by a complex π-conjugated molecular scaffold rearrangement. We demonstrate that the complex chemical transformation is steered by concerted motion of individual Au0 gold atoms on a supporting Au(111) surface. This observation underpins the importance of single-atom catalysis mediated by adatoms in on-surface synthesis as well as catalytic activity of single Au0 atoms facilitating cleavage of covalent carbon bonds.

On-Surface Strain-Driven Synthesis of Nonalternant Non-Benzenoid Aromatic Compounds Containing Four- to Eight-Membered Rings.

The synthesis of polycyclic aromatic hydrocarbons containing various non-benzenoid rings remains a big challenge facing contemporary organic chemistry despite a considerable effort made over the last decades. Herein, we present a novel route, employing on-surface chemistry, to synthesize nonalternant polycyclic aromatic hydrocarbons containing up to four distinct kinds of non-benzenoid rings. We show that the surface-induced mechanical constraints imposed on strained helical reactants play a decisive role leading to the formation of products, energetically unfavorable in solution, with a peculiar ring current stabilizing the aromatic character of the π-conjugated system. Determination of the chemical and electronic structures of the most frequent product reveals its closed-shell character and low band gap. The present study renders a new route for the synthesis of novel nonalternant polycyclic aromatic hydrocarbons or other hydrocarbons driven by internal stress imposed by the surface not available by traditional approaches of organic chemistry in solution.

Rhodium-Catalyzed Enantioselective Synthesis of Highly Fluorescent and CPL-Active Dispiroindeno[2,1-c]fluorenes.

The enantioselective synthesis of chiral [7]-helical dispirodihydro[2,1-c]indenofluorenes (DSF-IFs) was achieved for the first time in good yields with high er values (er up to 99 : 1). The crucial step of the whole reaction sequence was the enantioselective intramolecular [2+2+2] cycloaddition of tethered triynediols to indenofluorenediols, which was catalyzed by a Rh/SEGPHOS® complex. Further transformations led to the corresponding DSF-IFs. The prepared helically chiral DSF-IFs combine circularly polarized luminescence (CPL) activity (glum =∼10-3 ) with exceptionally high fluorescence quantum yields (up to Φlum =0.97).

Special Issue: Recent Advances in Transition-Metal Catalysis.

This special issue "Recent Advances in Transition-Metal Catalysis" containing forty-two personal accounts and seven record reviews, discusses the ascendancy of transition metals in modern organic synthesis. The included articles portray the manifold application of transition metals in various processes such as addition/cyclization reactions, asymmetric synthesis, olefin metathesis reactions, coupling reactions, C-H bond activation/functionalization reactions. Additionally, reports describing novel organic transformations based on the employment of transition-metal catalysis in the fields of radical chemistry and materials science are also presented in this collection.

Applications of Bolm's Ligand in Enantioselective Synthesis.

One pathway for the preparation of enantiomerically pure compounds from prochiral substrates is the use of metal complex catalysis with chiral ligands. Compared to the other frequently used chiral ligands, chiral 2,2'-bipyridines have been underexploited, despite the data indicating that such ligands have considerable potential in synthetic chemistry. One of those is the so-called Bolm's ligand, a compound possessing chiral alcohol moieties in the side chains attached to the 2,2'-bipyridine scaffold. Various metal salts have been used in combination with Bolm's ligand as potent catalysts able to bring about enantioselective alkylations, allylations, conjugate additions, desymmetrization of meso-epoxides, aldol reactions, etc. This review aims to summarize Bolm's ligand applications in the area of enantioselective synthesis over the last three decades since its preparation.

Straightforward Synthesis and Properties of Highly Fluorescent [5]- and [7]-Helical Dispiroindeno[2,1-c]fluorenes.

This work presents a general approach for synthesis of substituted [5]-helical dispiroindeno[2,1-c]fluorenes based on Rh-catalyzed intramolecular cyclotrimerization of triynes. This approach was further extended for the first synthesis of configurationally stable [7]-helical dispiroindeno[2,1-c]fluorenes. A series of variously substituted derivatives was prepared and their photophysical and electrochemical properties were evaluated. Their fluorescence emission maxima were in the region of 351-428 nm and quantum yields up to 88 % are the highest measured among the full-carbon helical compounds.

Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery.

PURPOSE: To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. METHODS: Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. RESULTS: Initial evaluation identified 1-(α-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 µM. CONCLUSIONS: Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.

Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids.

PURPOSE: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. METHODS: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. RESULTS: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. CONCLUSIONS: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

Synthesis of selectively 4-substituted 9,9'-spirobifluorenes and modulation of their photophysical properties.

Synthesis of selectively 4-substituted 9,9'-spirobifluorenes was accomplished by using catalytic [2 + 2 + 2]-cyclotrimerization of specifically substituted diynols with alkynes to the corresponding fluorenols. Further synthetic transformations provided the target molecules. The measurement of the photophysical properties of the prepared 4-substituted 9,9'-spirobifluorenes revealed that their emission maxima depended on the electronic properties of the substituents present in the para position: the presence of an electron accepting group strongly favored the maxima red shift toward the blue VIS region (CF3λmax = 361 nm vs. MeO λmax = 330 nm). Adding further substituents (aryl or arylethynyl moieties) on the phenyl ring in position 4 did not lead to a dramatic improvement in the emission maxima (CF3C6H4, λmax = 369 nm, CF3C6H4C[triple bond, length as m-dash]C, λmax = 370 nm), but increased their quantum yields considerably. In addition, a series of 9,9'-spirobifluorenes possessing various extended π-systems (pyrene, anthracene, etc.) were synthesized. In general, the emission maxima pattern reflected that of the parent π-systems, but they were red shifted by 10-30 nm. Finally, also a 1-[4-(9,9'-spirobifluorene-4-yl)phenyl]-2-aryl-ortho-carborane was prepared. These data thus may provide guidelines for further design of 9,9'-spirobifluorenes with tailored properties.

Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-ß-Lactams.

Ru-catalyzed cross-metathesis (CM) reaction between ß-arylated α-methylidene-ß-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding α-alkylidene-ß-aryl-ß-lactams in good isolated yields (41-83%) with exclusive Z-selectivity. The developed protocol was successfully applied for stereoselective preparation of Ezetimibe, the commercial cholesterol absorption inhibitor.

Enantioselective Allylation of (2E,4E)-2,4-Dimethylhexadienal: Synthesis of (5R,6S)-(+)-Pteroenone.

Allylation, trans- and cis-crotylation of (2E,4E)-2,4-dimethylhexadienal, a representative α,ß,γ,δ-unsaturated aldehyde, was carried out under different catalytic and stoichiometric conditions. The reactions catalyzed by organocatalysts TRIP-PA and N,N'-dioxides gave the best results with respect to yields, asymmetric induction, and catalyst load in comparison to other procedures. The developed methodology was applied in the enantioselective synthesis of (5R,6S)-(+)-pteroenone, a defensive metabolite (ichthyodeterrent) of the Antarctic pteropod Clione antarctica.

A [2+2+2]-Cyclotrimerization Approach to Selectively Substituted Fluorenes and Fluorenols, and Their Conversion to 9,9'-Spirobifluorenes.

Synthesis of selectively substituted fluorenes and fluorenols was achieved by using catalytic [2+2+2]cyclotrimerization. Various starting diynes were reacted with different alkynes in the presence of a catalytic amount of Wilkinson's catalyst (RhCl(PPh3)3) providing the compounds possessing the fluorene scaffold in good isolated yields. A set of four regioselectively substituted fluorenols was converted to the corresponding 9,9'-spirobifluorenes and their spectral characteristics were measured.

Cross-metathesis reaction of α- and ß-vinyl C-glycosides with alkenes.

Cross-metathesis of α- and ß-vinyl C-deoxyribosides and α-vinyl C-galactoside with various terminal alkenes under different conditions was studied. The cross-metathesis of the former proceeded with good yields of the corresponding products in ClCH2CH2Cl the latter required the presence of CuI in CH2Cl2 to achieve good yields of the products. A simple method for the preparation of α- and ß-vinyl C-deoxyribosides was also developed. In addition, feasibility of deprotection and further transformations were briefly explored.

Cross-coupling reaction of saccharide-based alkenyl boronic acids with aryl halides: the synthesis of bergenin.

A convenient synthetic pathway enabling D-glucal and D-galactal pinacol boronates to be prepared in good isolated yields was achieved. Both pinacol boronates were tested in a series of cross-coupling reactions under Suzuki-Miyaura cross-coupling conditions to obtain the corresponding aryl, heteroaryl, and alkenyl derivatives in high isolated yields. This methodology was applied to the formal synthesis of the glucopyranoside moiety of papulacandin D and the first total synthesis of bergenin.

Synthesis of aromatic compounds by catalytic C-C bond activation of biphenylene or angular [3]phenylene.

Substituted phenanthrenes and picenes were easily prepared by reaction of biphenylene or angular [3]phenylene with various alkynes in the presence of a catalytic amount of [IrCl(cod)](2) /dppe (cod=1,5-cyclooctadiene, dppe=1,2-bis(diphenylphosphino)ethane). The reaction is based on C-C bond activation of the cyclobutane ring. The reaction tolerates the presence of bulky groups on the alkyne, such as the ferrocene moiety. In addition, a catalytic system based on [RhCl(cod)](2)/dppe enabled the, hitherto unreported, reaction of biphenylene with nitriles to provide phenanthridines.

Synthesis of ferrocenestrone: the first metallocene based steroid analogue.

Ferrocenestrone, the first steroid derivative containing a metallocene moiety, was stereoselectively prepared. The key steps included the enantioselective functionalization of ferrocene, elongation of the side chain, intramolecular enyne metathesis, Diels-Alder reaction, heterogeneous hydrogenation of the sterically hindered double bond, and finally inversion of the configuration at C13.

Computational, Mechanistic, and Experimental Insights into Regioselective Catalytic C-C Bond Activation in Linear 1-Aza-[3]triphenylene.

C-C bond activation by transition metal complexes in ring-strained compounds followed by annulation with unsaturated compounds is an efficient approach to generate structurally more complex compounds. However, the site of catalytic C-C bond activation is difficult to predict in unsymmetrically substituted polycyclic systems. Here, we report a study on the (regio)selective catalytic cleavage of selected C-C bonds in 1-aza-[3]triphenylene, followed by annulation with alkynes, forming products with extended π-conjugated frameworks. Based on density functional theory (DFT) calculations, we established the stability of possible transition metal intermediates formed by oxidative addition to the C-C bond and thus identified the likely site of C-C bond activation. The computationally predicted selectivity was confirmed by the following experimental tests for the corresponding Ir-catalyzed C-C cleavage reaction followed by an alkyne insertion that yielded mixtures of two mono-insertion products isolated with yields of 34-36%, due to the close reactivity of two bonds during the first C-C bond activation. Similar results were obtained for twofold Ir- or Rh-catalyzed insertion reactions, with higher yields of 72-77%. In a broader context, by combining DFT calculations, which provided insights into the relative reactivity of individual C-C bonds, with experimental results, our approach allows us to synthesize previously unknown pentacyclic azaaromatic compounds.