Synthesis of the Core Framework of the Cornexistins by Intramolecular Nozaki-Hiyama-Kishi Coupling.

A new and direct approach to the construction of the core framework of the herbicidal natural products cornexistin and hydroxycornexistin has been developed. Formation of the nine-membered carbocycle found in the natural products has been accomplished by an intramolecular Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were produced. The cyclisation reaction was successful irrespective of the relative configuration of the stereogenic centres in the cyclisation precursor.

Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction.

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yields.

Cascade Metathesis Reactions for the Synthesis of Taxane and Isotaxane Derivatives.

Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring-closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem-dimethyl group), the RCEDYM reaction leads to 14,15-isotaxanes 16 a,b and 18 b with the gem-dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem-dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring-closing metathesis reaction, to give the tricyclic core of Taxol 44.

Electron density, disorder and polymorphism: high-resolution diffraction studies of the highly polymorphic neuralgic drug carbamazepine.

Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C-N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters. X-ray and neutron diffraction data on the dihydrate of carbemazepine strongly indicate a disordered orthorhombic crystal structure in the space group Cmca, rather than a monoclinic crystal structure in space group P2(1)/c. This disorder in the dihydrate structure has implications for both experimental and theoretical studies of polymorphism.

Synthesis of cyclopropyl-substituted furans by brønsted Acid promoted cascade reactions.

Chloroacetic acid promotes an efficient and diastereoselective intramolecular cascade reaction of electron-deficient ynenones to deliver products featuring a 2,3,5-trisubstituted furan bearing a fused cyclopropyl substituent at the 5-position. Synthetically relevant polycyclic building blocks featuring rings of various sizes and heteroatoms have been synthesized in high yield using this mild acid-catalyzed reaction.

Synthesis of four diastereomers of sclerophytin†F and structural reassignment of several sclerophytin natural products.

Synthesis of the triol that has been proposed to be the marine natural product sclerophytin F has been completed along with the syntheses of three diastereomers. Comparison of the NMR spectroscopic data for all four compounds to the data reported for the natural product reveals that sclerophytin F is not the 3S diastereomer of sclerophytin A as proposed by Friedrich and Paquette. Re-analysis of the NMR spectroscopic data for known sclerophytin natural products and synthetic analogues leads to the conclusion that sclerophytins E and F are the same compound. This finding has allowed structural reassignment of several other cladiellin natural products.

Accurate H-atom parameters from X-ray diffraction data.

The difficulties in defining the positions and thermal parameters for hydrogen atoms using X-ray diffraction data alone are discussed.

Total synthesis of the purported structure of sclerophytin F.

The synthesis of the compound that has been proposed to be the natural product sclerophytin F has been completed from a known vinylogous carbonate. The synthetic strategy relied upon rearrangement of a catalytically generated ylide-like intermediate to produce an oxabicyclo[6.2.1]-5-undecen-9-one and an intermolecular Diels-Alder reaction to construct the complete tricyclic core found in the natural product. Comparison of the spectroscopic data for synthetic material to that reported for sclerophytin F shows that the natural product does not have the revised structure possessing the 3S configuration (*) proposed previously.

Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole.

High resolution X-ray diffraction data on forms I-IV of sulfathiazole and neutron diffraction data on forms II-IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp's) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder. A minor disorder (∼1-2%) is evident for forms I and II, but a statistical analysis reveals no deleterious effect on the derived multipole populations. The topological analysis reveals an intramolecular S-O···S interaction, which is consistently present in all experimental topologies. Analysis of the gas-phase conformation of the molecule indicates two low-energy theoretical conformers, one of which possesses the same intramolecular S-O···S interaction observed in the experimental studies and the other an S-O···H-N intermolecular interaction. These two interactions appear responsible for "locking" the molecular conformation. The lattice energies of the various polymorphs computed from the experimental multipole populations are highly dependent on the exact refinement model. They are similar in magnitude to theoretically derived lattice energies, but the relatively high estimated errors mean that this method is insufficiently accurate to allow a definitive stability order for the sulfathiazole polymorphs at 0 K to be determined.

Synthesis of amino-substituted indanes and tetralins via consecutive multibond-forming tandem processes.

A rapid and general approach for the synthesis of amino-substituted indanes and tetralins from readily available alkyne-derived allylic alcohols via consecutive multibond-forming tandem processes has been developed. In the first one-pot tandem process, a series of cyclic dienes were prepared using an Overman rearrangement under thermal conditions, followed by a ruthenium(II)-catalyzed ring closing enyne metathesis reaction. The resulting exo-dienes were then subjected to a second one-pot tandem process involving a highly regioselective Diels-Alder reaction with alkynes, quinones or nitriles and a subsequent oxidation step to give a diverse library of C-1 amino-substituted indanes and tetralins in good overall yields.

Total syntheses of multiple cladiellin natural products by use of a completely general strategy.

The enantioselective total syntheses of 10 cladiellin natural products have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged tricyclic core of the cladiellins has been constructed via three ring-forming reactions: (i) an intramolecular reductive cyclization between an aldehyde and an unsaturated ester, mediated by samarium(II) iodide, to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated from a diazo ketone, with an ether to produce an ylide-like intermediate that rearranges to produce E- or Z-oxabicyclo[6.2.1]-5-undecen-9-one; and (iii) a Diels-Alder cycloaddition reaction to construct the third ring found in the core structure of the cladiellins. The key ring-forming reaction, in which a diazo ketone is converted into a bridged bicyclic ether, can be tuned to give either of the isomeric oxabicyclo[6.2.1]-5-undecen-9-ones as the major product by switching from a copper to a rhodium catalyst and selecting the appropriate reaction conditions. The tricyclic products obtained from the three-step sequence involving the Diels-Alder cycloaddition reaction can be employed as advanced intermediates to prepare a wide range of cladiellin natural products.

1,2,4,5-Tetrakis(phenylsulfonyl)benzene: a novel quadruped host with D2 symmetry having ordered sulfolane and cycloheptanone guests.

The title tetrasulfone 1, in common with higher members of the multi-armed aromatic hosts, forms host-guest complexes with polar guest molecules. In the sulfolane and cycloheptanone complexes the host molecule possesses an abab conformation with exact C(2,) and approximate D(2) symmetry with deviations owing to crystal packing forces. The conformation of the well-ordered cycloheptanone molecule, which normally undergoes facile pseudorotation, is unambiguously defined in the voids of the crystalline inclusion compound.

Discovery of a multi-bond forming, four-step tandem process: construction of drug-like polycyclic scaffolds.

A one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.

Stereoselective palladium-catalyzed functionalization of homoallylic alcohols: a convenient synthesis of di- and trisubstituted isoxazolidines and ß-amino-δ-hydroxy esters.

Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc-protected esters of ß-amino-δ-hydroxy acids and their γ-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19→21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity.

Stereoselective synthesis of functionalised carbocyclic amides: construction of the syn-(4aS,10bS)-phenanthridone skeleton.

A new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving a substrate-directed Overman rearrangement and ring closing metathesis reaction was developed for the stereoselective synthesis of a carbocyclic allylic trichloroacetamide. Conversion to a 6-bromopiperonyl amide, followed by a Heck reaction generated a homoallylic alcohol and completed the syn-(4aS,10bS)-phenanthridone carbon skeleton. Stereoselective epoxidation and dihydroxylation of the syn-(4aS,10bS)-phenanthridone framework was then investigated leading to the preparation of new analogues of 7-deoxypancratistatin.

On the unusual weak intramolecular C...C interactions in Ru3(CO)12: a case of bond path artifacts introduced by the multipole model?

In a recent publication in this journal, an experimental charge density analysis on the triruthenium cluster Ru(3)(CO)(12) showed unusual C...C bond paths linking the axial carbonyl ligands [Gervasio, G.; Marabello, D.; Bianchi, R.; Forni, A. J. Phys. Chem. A 2010, 114, 9368, hereafter GMBF]. These were also observed in one theoretical DFT calculation, and are associated with very low values of ρ(r(b)) and ∇(2)ρ(r(b)). Our independent experimental charge density analysis on Ru(3)(CO)(12) is entirely consistent with GMBF and confirms the presence of these apparent weak interactions in the multipole model density. However, we conclusively demonstrate that these unusual C...C bond paths between the axial carbonyl ligands are in fact artifacts arising from the Hansen-Coppens multipole model, which is used to analyze the experimental data. Numerous relativistic and nonrelativistic gas-phase DFT calculations, using very extensive basis sets and with corrections for dispersion effects, uniformly fail to reproduce these intramolecular features in the QTAIM topology of the electron density. Moreover, multipole fitting of theoretical static structure factors computed from these quantum electron densities results in the reappearance of the C...C bond paths between the axial carbonyl ligands in the derived molecular graphs. On the other hand, using the experimental structure factors to generate "experimental" X-ray constrained DFT wave functions once again yields molecular graphs which do not show these secondary C...C bond paths. The evidence therefore strongly implicates the multipole model as the source of these spurious features and in turn suggests that great caution should be applied in the interpretation of bond paths where the values of ρ(r(b)) and ∇(2)ρ(r(b)) are very low.

Evidence for side-chain π-delocalization in a planar substituted benzene: an experimental and theoretical charge density study on 2,5-dimethoxybenzaldehyde thiosemicarbazone.

The charge density in 2,5-dimethoxybenzaldehyde thiosemicarbazone (1) has been studied experimentally using Mo-K(α) X-ray diffraction at 100 K, and by theory using DFT calculations at the B3LYP/6-311++G(2d,2p) level. The quantum theory of atoms in molecules (QTAIM) was used to investigate the extent of π-delocalization in the thioamide side-chain, which is virtually coplanar with the benzene ring. The experimental and theoretical ellipticity profiles along the bond paths were in excellent agreement, and showed that some of the formal single bonds in the side-chain have significant π-bond character. This view was supported by the magnitudes of the topological bond orders and by the delocalization indices δ(Ω(A), Ω(B)). An orbital decomposition of δ(Ω(A), Ω(B)) demonstrated that there was significant π-character in all the interchain non-H chemical bonds. On the other hand, the source function referenced at the interchain bond critical points could not provide any evidence for π-delocalization, showing instead only limited σ-delocalization between nearest neighbors. Overall, the topological evidence and the atomic graphs of the oxygen atoms did not provide convincing evidence for π-delocalization involving the methoxy substituents.

Metal-metal and metal-ligand bonding at a QTAIM catastrophe: a combined experimental and theoretical charge density study on the alkylidyne cluster Fe3(µ-H)(µ-COMe)(CO)10.

The charge density in the tri-iron methoxymethylidyne cluster Fe(3)(µ-H)(µ-COMe)(CO)(10) (1) has been studied experimentally at 100 K and by DFT calculations on the isolated molecule using the Quantum Theory of Atoms in Molecules (QTAIM). The COMe ligand acts as a nearly symmetric bridge toward two of the Fe atoms (Fe-C = 1.8554(4), 1.8608(4) Å) but with a much longer interaction to the third Fe atom, Fe-C = 2.6762(4) Å. Complex 1 provides a classic example where topological QTAIM catastrophes render an exact structure description ambiguous. While all experimental and theoretical studies agree in finding no direct metal-metal interaction for the doubly bridged Fe-Fe vector, the chemical bonding between the Fe(CO)(4) unit and the Fe(2)(µ-H)(µ-COMe)(CO)(6) moiety in terms of conventional QTAIM descriptors is much less clear. Bond paths implying direct Fe-Fe interactions and a weak interaction between the COMe ligand and the Fe(CO)(4) center are observed, depending on the experimental or theoretical density model examined. Theoretical studies using the Electron Localizability Indicator (ELI-D) suggest the metal-metal bonding is more significant, while the delocalization indices imply that both Fe-Fe bonding and Fe···C(alkylidyne) bonding are equally important. The source functions at various interfragment reference points are similar and highly delocalized. The potential-energy surface (PES) for the migration of the alkylidyne group from a µ(2) to a semi-µ(3) coordination mode has been explored by DFT calculations on 1 and the model complexes M(3)(µ-H)(µ-CH)(CO)(10) (M = Fe, 2; Ru, 3; and Os, 4). These calculations confirm a semi-µ(3) bridging mode for the alkylidyne ligand as the minimum-energy geometry for compounds 2-4 and demonstrate that, for 1, both Fe-Fe and Fe···C(alkylidyne) interactions are important in the cluster bonding. The PES between µ(2) and semi-µ(3) alkylidyne coordination for 1 is extremely soft, and the interconversion between several topological isomers is predicted to occur with almost no energy cost. Analysis of the density ρ(r) and the Laplacian of the density ▽(2)ρ(r(b)) in the methoxymethylidyne ligand is consistent with a partial π-bond character of the C-O bond, associated with an sp(2) hybridization for these atoms.

The first members of the octasubstituted naphthalene spider-host series with type I (abababab) conformation: gateway to new nano-host gas storage materials.

Octakis(m-tolyloxymethyl)naphthalene, the first Type I spider host produced, crystallises from tetraglyme forming a novel channel structure with the host molecule attaining exact D(2) symmetry. The (flexible) channel structure is retained for guest CS(2), the host now only having exact C(2) symmetry. The octa-sulfone octakis(m-tolylsulfonylmethyl)naphthalene is also of Type I in its triclinic DMSO clathrate. DNMR establishes a substantial difference in molecular flexibilities in solution.