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.

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.

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 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.

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 QTAIM approach to chemical bonding between transition metals and carbocyclic rings: a combined experimental and theoretical study of (eta(5)-C5H5)Mn(CO)3, (eta(6)-C6H6)Cr(CO)3, and (E)-{(eta(5)-C5H4)CF=CF(eta(5)-C5H4)}(eta(5)-C5H5)2Fe2.

Experimental charge densities for (C(5)H(5))Mn(CO)(3) (2), (eta(6)-C(6)H(6))Cr(CO)(3) (3), and (E)-{(eta(5)-C(5)H(4))CF=CF(eta(5)-C(5)H(4))}(eta(5)-C(5)H(5))(2)Fe(2) (4) have been obtained by multipole refinement of high-resolution X-ray diffraction data at 100 K. The resultant densities were analyzed using the quantum theory of atoms in molecules (QTAIM). The electronic structures of these and related pi-hydrocarbyl complexes have also been studied by ab initio density functional theory calculations, and a generally good agreement between theory and experiment with respect to the topological parameters was observed. The topological parameters indicate significant metal-ring covalency. A consistent area of disagreement concerns the topology of the metal-ring interactions. It is shown that because of the shared-shell bonding between the metal and the ring carbons, an annulus of very flat density rho and very small wedge rho is formed, which leads to topologically unstable structures close to catastrophe points. This in turn leads to unpredictable numbers of metal-C bond paths for ring sizes greater than four and fewer M-C bond paths than expected on the basis of the formal hapticity. This topological instability is a general feature of metal-pi-hydrocarbyl interactions and means that a localized approach based on individual M-C(ring) bond paths does not provide a definitive picture of the chemical bonding in these systems. However, other QTAIM indicators, such as the virial paths, the delocalization indices, and the source function, clearly demonstrate that for the n-hapto (eta(n)-C(n)H(n))M unit, there is generally a very similar level of chemical bonding for all M-C(ring) interactions, as expected on the basis of chemical experience.

Model systems for flavoenzyme activity: an investigation of the role functionality attached to the C(7) position of the flavin unit has on redox and molecular recognition properties.

We describe the role functionality attached to the C(7) position of a family of flavin derivatives has in tuning their redox and recognition properties and the subsequent exploitation of two of these derivatives as a three-component electrochemically controllable molecular switch.

On the interpretation of the source function.

The chemical information present in the source function (SF) is analyzed in several case studies by decomposition into the relative contributions from the core and valence densities. Both experimental and quantum derived densities are examined, and for the latter case, the decomposition of the SF into contributions from the individual Kohn-Sham molecular orbitals is also investigated. For pairs of atoms A and B, the orbital decomposition of the SF at the A-B bond critical point SF(A-B)bcp is compared with that for the delocalization index delta(OmegaA,OmegaB). For second and third period atoms, the valence density generally provides the determining contribution to the total SF, but for heavier elements such as transition metals, the core density plays an increasingly important role. Moreover, when the reference point is close to the nodal plane of an orbital, this orbital makes a low to negligible contribution to the SF, which has clear implications for the interpretation of pi-interactions. This leads us to recommend caution in associating some chemical concepts with features of the SF, especially for heavier elements.

Experimental and theoretical charge density study of polymorphic isonicotinamide-oxalic acid molecular complexes with strong O...H...N hydrogen bonds.

Two polymorphs of the 2:1 molecular complex of isonicotinamide and oxalic acid have been characterized by combined X-ray charge density and single-crystal neutron diffraction studies at 100 K. Both polymorphs show strong O-H...N intermolecular hydrogen bonding between the acid and the pyridine base. As is typical of short, strong hydrogen bonds (SSHBs), the covalent O-H bonds are considerably elongated to 1.161(3) and 1.235(5) A, and the H...N interactions are correspondingly short at 1.398(3) and 1.313(6) A in Forms I and II, respectively. The neutron diffraction data indicate no pronounced H dynamics in the SSHBs, and in the case of Form II the SSHB can be described as quasicentered. In addition to the experimental charge densities, theoretical charge densities have been determined from ab initio calculations within the full periodic environment of the crystalline state. The SSHBs are found to be covalent in nature according to the topological analysis of the experimental and theoretical charge densities and application of the source function. Aside from the SSHBs, moderate N-H...O and weak C-H...O interactions are also present in the molecular complexes, for which hydrogen bond energies are estimated from energy densities and independent ab initio calculations. Finally, an attempt is made to evaluate the intermolecular interactions governing the manifestation of polymorphism in this compound.

Weak intra- and intermolecular interactions in a binaphthol imine: an experimental charge-density study on (+/-)-8'-benzhydrylideneamino-1,1'-binaphthyl-2-ol.

The charge density in (+/-)-8'-benzhydrylideneamino-1,1'-binaphthyl-2-ol (1) has been studied experimentally using Mo Kalpha X-ray diffraction at 100 K, and by theory using density-functional thoery (DFT) calculations at the B3LYP/6-311++G** level. The nature of the weak intramolecular peri-C...N, CH...pi, H...H and C(pi)...C(pi) interactions has been examined by topological analysis using the Quantum Theory of Atoms in Molecules (QTAIM) approach. An analysis of the density rho(r), the Laplacian of the density inverted Delta(2)rho(r(b)) and other topological properties at the bond-critical points were used to classify these interactions. The study confirms the presence of the intramolecular CH...pi interaction in (1), which was previously suspected on geometrical grounds. An analysis of the ellipticity profiles along the bond paths unambiguously shows the pi-delocalization between the imine unit and one N-phenyl group. The weak intermolecular interactions in the crystal of (1) were examined experimentally and theoretically through the pairwise interactions of the seven independent dimeric pairs of (1) responsible for the set of unique intermolecular interactions, and also through examination of the Hirshfeld surface d(norm) property. The theoretical dimeric-pair calculations used the BLYP-D functional which supplements the exchange-correlational functional with an empirical dispersion term to provide a more accurate determination of the energies for the weak intermolecular interactions.

A combined experimental and theoretical charge density study of the chemical bonding and magnetism in 3-amino-propanolato Cu(II) complexes containing weakly coordinated anions.

The experimental (100 K) and theoretical charge densities in the binuclear complexes [Cu2(ap)2(L)2] (ap = 3-aminopropanolate) 1 (L = nitrite), 2 (L = nitrate), and 3 (L = formate) have been examined. These complexes contain the same centrosymmetric alkoxy-bridged motif, where each strongly Jahn-Teller distorted Cu(II) ion is ligated to three O atoms and one N atom in a square-planar arrangement. This primary coordination sphere is augmented by a long contact with the O atom of a pendant L anion from an adjacent molecule in the crystal lattice. Topological analyses of the experimental and theoretical densities according to the quantum theory of atoms in molecules (QTAIM) are in excellent agreement. Consideration of a number of topological indicators including rho(r), vector differential(2)rho(r), the delocalization indices delta(A,B), and the contour integral(A intersection B) rho(r) of the density over the zero flux surface shared by the two atoms confirms that the Cu-O and Cu-N bonding in the primary coordination sphere has a strong covalent component, but the weak Cu...O interactions are primarily electrostatic in nature. In this first investigation of the source function in a coordination complex, it is shown to provide an insight into the differing electrostatic and covalent contributions to the chemical bonds. The two Cu(II) centers are strongly antiferromagnetically coupled, but the topological analyses indicates the lack of any direct Cu...Cu interaction. The molecular graph suggests an exchange pathway via the bridging O-atoms, thus providing experimental support of the classical superexchange mechanism. Periodic DFT calculations on 2 and 3 show that the intradimer coupling proceeds via spin-delocalization and provide values of the magnetic coupling constants -2 J of 324.5 and 244.8 cm(-1), respectively, which compare well with the previously determined experimental values.

On the calculation of the electrostatic potential, electric field and electric field gradient from the aspherical pseudoatom model.

Accurate, yet simple and efficient, formulae are presented for calculation of the electrostatic potential (ESP), electric field (EF) and electric field gradient (EFG) from the aspherical Hansen-Coppens pseudoatom model of electron density [Hansen & Coppens (1978). Acta Cryst. A34, 909-921]. They are based on the expansion of |r' - r|(-1) in spherical harmonics and the incomplete gamma function for a Slater-type function of the form R(l)(r) = r(n) exp(-alpha ). The formulae are valid for 0 < or = r < or = infinity and are easily extended to higher values of l. Special treatment of integrals is needed only for functions with n = l and n = l + 1 at r = 0. The method is tested using theoretical pseudoatom parameters of the formamide molecule obtained via reciprocal-space fitting of PBE/6-31G** densities and experimental X-ray data of Fe(CO)(5). The ESP, EF and EFG values at the nuclear positions in formamide are in very good agreement with those directly evaluated from density-functional PBE calculations with 6-31G**, aug-cc-pVDZ and aug-cc-pVTZ basis sets. The small observed discrepancies are attributed to the different behavior of Gaussian- and Slater-type functions near the nuclei and to imperfections of the reciprocal-space fit. An EF map is displayed which allows useful visualization of the lattice EF effects in the crystal structure of formamide. Analysis of experimental 100 K X-ray data of Fe(CO)(5) yields the value of the nuclear quadrupole moment Q((57)Fe(m)) = 0.12 x 10(-28) m(2) after taking into account Sternheimer shielding/antishielding effects of the core. This value is in excellent agreement with that reported by Su & Coppens [Acta Cryst. (1996), A52, 748-756] but slightly smaller than the generally accepted value of 0.16 +/- 5% x 10(-28) m(2) obtained from combined theoretical/spectroscopic studies [Dufek, Blaha & Schwarz (1995). Phys. Rev. Lett. 25, 3545-3548].

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.