Dean J. Tantillo

Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species.

Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated with the small molecules NO, CO, H₂S (and the nonendogenously generated O₂), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.

Charge ordering in the TMTTF family of molecular conductors

Using one- and two-dimensional NMR spectroscopy applied to 13C spin-labeled (TMTTF)2AsF6 and (TMTTF)2PF6, we demonstrate the existence of an intermediate charge-ordered phase in the TMTTF family of charge-transfer salts. At ambient temperature, the spectra are characteristic of nuclei in equivalent molecules. Below a continuous charge-ordering transition temperature T(co), there is evidence for two inequivalent molecules with unequal electron densities. The absence of an associated magnetic anomaly indicates only the charge degrees of freedom are involved and the lack of evidence for a structural anomaly suggests that charge-lattice coupling is too weak to drive the transition.

Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: implications of their possible biological activity and utility.

Hydrogen sulfide (H2S) is an endogenously generated and putative signaling/effector molecule. Despite its numerous reported functions, the chemistry by which it elicits its functions is not understood. Moreover, recent studies allude to the existence of other sulfur species besides H2S that may play critical physiological roles. Herein, the basic chemical biology of H2S as well as other related or derived species is discussed and reviewed. This review particularly focuses on the per- and polysulfides which are likely in equilibrium with free H2S and which may be important biological effectors themselves.

Theozymes and compuzymes: theoretical models for biological catalysis

A theozyme is a theoretical enzyme constructed by computing the optimal geometry for transition-state stabilization by functional groups. It is created in order to permit quantitative assessment of catalytic function. Theozymes have been used to elucidate the role of transition-state stabilization in the mechanisms underlying enzyme- and antibody-catalyzed hydroxyepoxide cyclizations, eliminations and decarboxylations, peptide and ester hydrolyses, and pericyclic and radical reactions. The enzymes studied include orotodine monophosphate decarboxylase, HIV protease and ribonucleotide reductase.

Total Synthesis of Oxidized Welwitindolinones and ()-N- Methylwelwitindolinone C Isonitrile

We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.

The Correct Structure of Aquatolide—Experimental Validation of a Theoretically-Predicted Structural Revision

Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography.

Consequences of conformational preorganization in sesquiterpene biosynthesis: theoretical studies on the formation of the bisabolene, curcumene, acoradiene, zizaene, cedrene, duprezianene, and sesquithuriferol sesquiterpenes.

Quantum chemical calculations on cyclization mechanisms for several sesquiterpene families proposed to be closely related to each other in a biogenic sense (the bisabolene, curcumene, acoradiene, zizaene (zizaene, isozizaene, epi-zizaene, and epi-isozizaene), cedrene (alpha/beta-cedrenes and 7-epi-alpha/beta-cedrenes), duprezianene, and sesquithuriferol families) are described. On the basis of the results of these calculations, we suggest that the conformation of the bisabolyl cation attainable in an enzyme active site is a primary determinant of the structure and relative stereochemistry of the sesquiterpenes formed. We also suggest that substantial conformational changes of initially formed conformers of the bisabolyl cation are necessary in order to form zizaene and epi-cedrene. Given that the productive conformation of the bisabolyl cation does not necessarily reflect the original orientation of farnesyl diphosphate bound in the corresponding enzyme active site, we conclude that folding of farnesyl diphosphate alone does not always dictate the structure and relative stereochemistry of cyclization products. In addition, the potential roles of dynamic matching in determining product distributions and enzyme-promoted formation of secondary carbocations are discussed.

A gold-catalysed enantioselective Cope rearrangement of achiral 1,5-dienes

Since the discovery of the Cope rearrangement in the 1940s, no asymmetric variant of the rearrangement of achiral 1,5-dienes has emerged, despite the successes that have been achieved with its heteroatom variants (Claisen, aza-Cope, and so on). This article reports the first example of an enantioselective Cope reaction that starts from an achiral diene. The new gold(I) catalyst derived from double Cl−-abstraction of ((S)-3,5-xylyl-PHANEPHOS(AuCl)2), has been developed for the sigmatropic rearrangement of alkenyl-methylenecyclopropanes. The reaction proceeds at low temperature and the synthetically useful vinylcyclopropane products are obtained in high yield and enantioselectivity. Density functional theory calculations predict that: (1) the reaction proceeds via a cyclic carbenium ion intermediate, (2) the relief of strain in the methylenecyclopropane moiety provides the thermodynamic driving force for the rearrangement and (3) metal complexation of the transition-state structure lowers the rearrangement barriers. The Cope rearrangement has been known since the 1940s but, until now, no catalytic asymmetric variant has been reported. Here, a gold(I) catalyst is shown to induce an asymmetric Cope rearrangement of achiral 1,5-dienes containing a cyclopropylidene moiety to produce vinyl cyclopropanes in high yield and good to excellent enantioselectivities.

Biosynthetic consequences of multiple sequential post-transition-state bifurcations

Selectivity in chemical reactions that form complex molecular architectures from simpler precursors is usually rationalized by comparing competing transition-state structures that lead to different possible products. Herein we describe a system for which a single transition-state structure leads to the formation of many isomeric products via pathways that feature multiple sequential bifurcations. The reaction network described connects the pimar-15-en-8-yl cation to miltiradiene, a tricyclic diterpene natural product, and isomers via cyclizations and/or rearrangements. The results suggest that the selectivity of the reaction is controlled by (post-transition-state) dynamic effects, that is, how the carbocation structure changes in response to the distribution of energy in its vibrational modes. The inherent dynamical effects revealed herein (characterized through quasiclassical direct dynamics calculations using density functional theory) have implications not only for the general principles of selectivity prediction in systems with complex potential energy surfaces, but also for the mechanisms of terpene synthase enzymes and their evolution. These findings redefine the challenges faced by nature in controlling the biosynthesis of complex natural products.

Total synthesis and isolation of citrinalin and cyclopiamine congeners

Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.