Cobalt versus Osmium: Control of Both trans and cis Selectivity in Construction of the EFG Rings of Pectenotoxin 4

Catalytic oxidative cyclisation reactions have been employed for the synthesis of the E and F rings of the complex natural product target pectenotoxin 4. The choice of metal catalyst (cobalt‐ or osmium‐based) allowed for the formation of THF rings with either trans or cis stereoselectivity. Fragment union using a modified Julia reaction then enabled the synthesis of an advanced synthetic intermediate containing the EF and G rings of the target.     

Intramolecular reactions of 2-indolylacyl radicals: cyclisation upon aromatic rings

The generation of 2-indolylacyl radicals from the corresponding selenoesters under reductive (tributyltin hydride-AIBN) and nonreductive (hexabutylditin, 300 W) conditions and their behaviour in cyclisation reactions upon benzene rings attached either to the indole nitrogen or the C-3 ring position have been studied.     

Five- and six-membered ring formation from the intramolecular reaction of a protonated oxirane and alkene

Computational studies of competing five- and six-membered cyclisation of alkenyloxiranes 1a-d show that intramolecular reaction of a protonated oxirane and alkene is a concerted, single-step, exothermic process. The reactions proceed via reactant-like transition states, but where the oxirane C-O bond is considerably stretched. Two factors are seen to affect the regiochemistry: (1) stabilisation of the transitory positive charge in the transition state favours cyclisation to the more highly substituted oxirane carbon; and (2) there is an inherent stereoelectronic preference for six-membered cyclisation over five-membered cyclisation. The inherent preference for six-membered cyclisation has a parallel in Baldwin's rules for six-membered ring closure of a carbocation with an alkene, rather than Baldwin's rule for intramolecular nucleophilic reaction of three-membered rings, suggesting that the protonated oxirane mimics a carbocation. The electronic and stereoelectronic effects for cyclisation are modified by steric interactions of axial methyl groups. These systems provide a model for the A-ring cyclisation of oxidosqualene.     

Synthetic applications of aryl radical building blocks for cyclisation onto azoles

2-(2-Bromophenyl)ethyl groups have been used as building blocks in radical cyclisation reactions onto azoles to synthesise tri- and tetra-cyclic heterocycles. 2-(2-Bromophenyl)ethyl methanesulfonate was used to alkylate azoles (imidazoles, pyrroles, indoles and pyrazoles) for the synthesis of the radical precursors. Cyclisations of the intermediate aryl radicals yield new 6-membered rings attached to the azoles. The aryl radicals undergo intramolecular homolytic aromatic substitution onto the azole rings. Tributylgermanium hydride has been used with success to replace the toxic and troublesome tributyltin hydride. Initial studies show that the protocol can be used on solid phase resins. The molecular and crystal structures of methyl 5,6-dihydroimidazo[5,1-a]iso-quinoline-1-carboxylate and methyl 5,6-dihydroimidazo[2,1-a]isoquinoline-3-carboxylate were determined by X-ray crystallography.     

Combining the Power of TiIII‐Mediated Processes for Easy Access to Hydroxylated Polycyclic Terpenoids: Synthesis of Sesterstatin 1 and C–D Rings of Aspergilloxide

A straightforward access to polyhydroxylated terpenoids based on two key titanocene(III)‐mediated reactions is presented: the “head‐to‐tail” Barbier‐type addition of prenyl chlorides to α,β‐unsaturated aldehydes, which allows the introduction of hydroxy groups at desirable positions of the acyclic precursor, and the subsequent bioinspired radical cyclisation. This methodology has been also used in the first total synthesis of pentacyclic sesterstatin 1 and a model compound of the C–D rings of aspergilloxide.     

The Baylis-Hillman approach to quinoline derivatives

Baylis-Hillman reactions of 2-nitrobenzaldehydes with various activated alkenes afford adducts that undergo reductive cyclisation to quinoline derivatives. The chemo- and regioselectivity of cyclisation appears to be influenced by the choice of both the substrate and the reagent system, and competing reactions have been observed.     

Stable gold(III) complexes with thiosemicarbazone derivatives

Novel thiosemicarbazonato complexes of gold(III) have been prepared from reactions of [Au(damp-C1,N)Cl2(damp- = 2-(N,N-dimethylaminomethyl)phenyl) or [NBu4][AuCl4] with 2-pyridineformamide thiosemicarbazones (HL). The thiosemicarbazones deprotonate and coordinate as mononegative, tridentate NNS ligands to gold to give [Au(Hdamp-C1)(L)]Cl2 or [AuCl(L)]Cl complexes. The organometallic damp- ligand is protonated during the reactions and the Au-N bond is cleaved. The [AuCl(L)]+ cations represent the first gold(III) complexes with thiourea derivatives which are not stabilised by an additional organometallic ligand. Reactions of [NBu4][AuX4](X = Cl, Br) with diphenylthiocarbazone (dithizone) result in reduction of the metal and the formation of gold(I) complexes of the composition [AuX(SCN4-3,4-Ph2)] where SCN4-3,4-Ph2 is 3,4-diphenyltetrazole thione which is formed from cyclisation of dithizone.     

Free radical cyclisation of enamides leading to biologically important γ-lactams

This review describes the free radical cyclisation of enamides using tributyltin hydride, manganese(III) acetate, copper(I) complexes or dichlorotris(triphenylphosphine)ruthenium(II). These cyclisations can proceed via either 4-exo or 5-endo pathways, to produce β- or γ-lactam products, respectively. In general, the reactions produce γ-lactams derived from an unusual (disfavoured) 5-endo-trig radical cyclisation. These results can be explained on the basis of a reversible cyclisation mechanism; the 4-exo cyclisation produces the kinetically favoured β-lactam while the 5-endo cyclisation produces the thermodynamically more stable γ-lactam.     

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

A strategy for the synthesis of medium‐sized lactones and lactams from linear precursors is described in which an amine acts as an internal nucleophilic catalyst to facilitate a novel cyclisation/ring expansion cascade sequence. This method obviates the need for the high‐dilution conditions usually associated with medium‐ring cyclisation protocols, as the reactions operate exclusively via kinetically favourable “normal”‐sized cyclic transition states. This same feature also enables biaryl‐containing medium‐sized rings to be prepared with complete atroposelectivity by point‐to‐axial chirality transfer.     

Synthesis of new steroid analogues by samarium diiodide induced cyclisations of γ-naphthyl 1,3-diones

We present the synthesis of new steroid analogues via samarium diiodide mediated intramolecular ketyl–aryl coupling reactions of γ-naphthyl-substituted 1,3-diones. From previous experiments with γ-naphthyl monoketones high stereoselectivities with the ‘unnatural’ cis/cis annulation of rings B/C/D were expected. Surprisingly, we observed the formation of two diastereomers with cis- and trans-fused rings B and C of the tetracyclic skeleton. The diastereoselectivity proved to be strongly dependent on the amount of the proton source employed in the reaction. A rationale for this unexpected behaviour is discussed. In addition, we observed a smooth aluminium chloride induced cyclisation of one of the γ-naphthyl-substituted 1,3-diones to furnish an equilenine precursor. Another cyclisation product was converted by Grob-fragmentation into a naphthannulated cyclononane derivative.     

An efficient and recyclable water-soluble cyclopalladated complex for aqueous Suzuki reactions under aerial conditions

Several water-soluble cyclopalladated complexes with five- or six-membered rings have been prepared as air-stable solids from Schiff base ligands bearing an N-phenyl sulfonate groups. Cyclopalladated complexes with six-membered rings show high catalytic efficiency for the Suzuki reactions of aryl bromides with phenylboronic acid in aqueous solvents under mild conditions. Palladium complex 1 can be used for five reaction cycles in high conversions for the Suzuki reactions in neat water without additives. The catalytic process for the Suzuki couplings is proved by TEM analysis to proceed on Pd(0) nanoparticles. Surfactant-protected palladium nanoparticles present lower activities and poorer recyclability for the coupling reactions than those generated in situ without additives.     

Macrocyclisation en series lactone,thiolactone et lactame à motif ethylenedioxy: Effets de matrice du siliceum et de l'etain

The orientation of the macrocyclizacion reaction leading to the di or tetrafunctional titled compounds has been studied for 12 and 24 membered rings containing ethylene dioxy moieties. The reactions were carried out from not activated diol, dithiol or diamine and from their silyl and stannyl derivatives. They were not performed at high dilution. The intracyclic oxygen atoms had a strong influence on the orientation of the cyclisation towards the monomer. However, it was also possible to obtain the dimeric forms with yields ranging from 10 to 40%.     

Amides as precursors of imidoyl radicals in cyclisation reactions

Amides have been successfully used as precursors of imidoyl radicals for radical cyclisation. The amides have been converted to imidoyl selanides via reaction with phosgene to yield imidoyl chlorides followed by reaction with potassium phenylselanide. Imidoyl selanides were reacted with tributyltin hydride (Bu₃SnH) as the radical mediator with triethylborane or AIBN as initiators to yield imidoyl radicals for cyclisation reactions. Imidoyl radicals have been cyclised onto alkenes to yield 2,3-substituted-indoles and -quinolines and also onto pyrroles and indoles to give bi- and tricyclic heteroarenes.     

Radical cyclisation reactions with indoles

Several radical cyclisation reactions involving indoles are described. Most notably, we have shown that radical additions to C3 of an indole are frequently facile. A dichotomy in the course of radical cyclisation reactions to C2 of the indole has also been exposed wherein 6-endo-trig cyclisations are propagated by the loss of a hydrogen atom from C2 while 5-exo-trig cyclisations are propagated by hydrogen atom abstraction at C3 from tributyltin hydride. Cyclisations involving the addition of indolyl radical intermediates to arenes have also been demonstrated.     

Synthesis of fused multicyclic compounds containing macrocycles by dienyne ring-closing metathesis and Diels-Alder reactions

Fused bicyclic compounds comprising small and large rings were synthesised by dienyne ring-closing metathesis (RCM) using Grubbs' catalyst. By taking advantage of faster small ring cyclisation compared with macrocyclisation, single isomers were obtained rather than mixtures of two isomers with different ring sizes. Using this process, various fused bicyclic compounds comprising small rings (5-7- membered) and large rings (14-17- membered) were obtained. By increasing reaction temperature and catalyst loading, the product conversion was improved in a predicted manner. This method produced E-olefins on the macrocycles with high selectivity. Also, the selectivity issues of tandem RCM for the synthesis of fused bicyclic compounds comprising small and medium rings were investigated. Lastly, the prepared bicyclic compounds with small and large rings contained 1, 3-dienes that underwent a further modification reaction, such as Diels-Alder, to produce more complex compounds. These Diels-Alder reactions produced tri- and tetracyclic compounds containing a macrocycle with single diastereomers, suggesting that the methodology demonstrated here could be a powerful tool for rapid preparation of highly complex molecules.     

Quantum-chemical calculation of molecular structures of (5656)macrotetracyclic 3d-metal complexes “self-assembled” in quaternary systems M(II) ion-ethanedithioamide-formaldehyde-ammonia by the density functional theory method

The geometric parameters of (5656)macrotetracyclic complexes of Mn(II), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II) with the NNNN-coordination of donor sites of the chelant formed by the template reactions in the M(II)-ethanedithioamide-formaldehyde-ammonia systems have been calculated by the OPBE/TZVP hybrid density functional theory (DFT) method with the use of the Gaussian09 program package. In all complexes, five-membered chelate rings (almost identical to each other in each complex) are nonplanar. For all M(II) ions under consideration, two additional six-membered nonplanar chelate rings formed as a result of template “cross-link” are turned at considerable angles with respect to the five-membered rings. The six-membered rings are located on different sides of the NNNN plane of the nitrogen donor atoms.     

Sulfur-mediated radical cyclisation reactions on solid support

Two methods for effecting radical cyclisation reactions of solid-supported 1,6-dienes are described. Additions of thiophenol and p-tolyl benzeneselenosulfonate have each been achieved with a concomitant 5-exo-trig radical cyclisation leading to the formation of highly functionalised cyclopentanes.     

Substrate dependent intramolecular palladium-catalysed cyclisation and subsequent β-H elimination or C-H activation: a general method for the synthesis of fused pyran rings

An efficient and convenient method for the synthesis of fused pyran rings via intramolecular palladium-catalysed cyclisation followed by β-H elimination or C-H activation has been developed. It is possible to utilise this method for the synthesis of benzopyran systems.     

Alpha-oximono-esters as precursors to heterocycles--generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles

Preparation of a series of terminally and internally substituted delta-alkenyl and delta-alkynyl esters 6, 7 and 9, potential precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other cases--most especially during reactions with alpha-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime isomers whilst benzoylformic acid derivatives afforded mixed geometrical isomers. The E-oxime of 4a1 carrying an internal Me group undergoes facile thermal cyclisation affording nitrones 1c and 1d in good yield. Oximes E-5a,b with a terminal methyl substituent on the alkene moiety furnish nitrone only under the influence of an external electrophile [PhSeBr/AgBF4]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective of reaction conditions, and whilst 5d reacts to afford a bicyclic isoxazolofuranone 13 by an IOOC reaction (intramolecular oxime olefin cyclisation) 5c remains thermally inert. Finally delta-alkynyl oximes 9c,d also failed to cyclise. The regio- and stereochemical characteristics of the cycloadditions between the new dipoles and electron poor olefinic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospecifically to give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any dipolarophiles bar dimethyl acetylenedicarboxylate.     

Synthetic applications in radical/radical cationic cascade reactions

Oxidative photoinduced electron transfer (PET) reactions have been performed with various cyclic cyclopropyl(vinyl) silyl ethers bearing an olefinic or acetylenic side chain. The reactions result in bi- to tetracyclic ring systems via a fragmentation-radical/radical cationic addition reaction pathway with well defined ring juncture. The mode of cyclisation (endo/exo) can be partially controlled by addition of nucleophiles due to the suppression of radical cationic reaction pathways. Quantum chemical calculation of the cyclisation transition states underline the experimentally found selectivities. Additional mechanistic studies concerning the saturation step reveal that the final radical is saturated mostly by the solvent and traces of water in the solvent.