Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics

Ever since the world‐shaping discovery of penicillin, nature's molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug‐development stories, the overwhelming majority of which have their origin in natural products. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on total synthesis, analogue design, and biological evaluation of molecules with novel mechanisms of action.     

η3‐Diphosphavinylcarbene: A P2 Analogue of the Dötz Intermediate

Do the twist : The reaction of in situ generated phosphinidenes with phosphaalkynes is a facile route to the new metal‐coordinated η³‐diphosphavinylcarbene 1 , which shows facile ligand‐exchange reactions and undergoes an unprecedented rearrangement that involves phosphinidene complex 2 and η³‐phosphaalkenylphosphinidene complex 3 , the 1,3 isomer of 1 .

     

Cover Picture: A Phosphorus Analogue of Bis(η4‐cyclobutadiene)iron(0) (Angew. Chem. Int. Ed. 17/2009)

A rare phosphorus analogue of the elusive complex bis(η⁴‐cyclobutadiene)iron(0) is reported by K. Lammertsma et al. in their Communication on page 3104 ff. The background of the cover picture shows John Montagu (1718–1792), 4th Earl of Sandwich and 1st Lord of the Admiralty, who certainly would not have dreamt that an important class of organometallic compounds, sandwich complexes, would bear his name one day. The synthesis of [Fe(P₂C₂tBu₂)₂] shows that sandwich complexes are still topical objects of research.

     

On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions

Intramolecular Diels–Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6‐31+G(d) and CBS‐QB3 levels of theory for a series of 1,3,8‐nonatrienes, H₂C?CH? CH?CH? CH₂? X? Z? CH?CH₂ [? X? Z? =? CH₂? CH₂? ( 1 ); ? O? C(?O)? ( 2 ); ? CH₂? C(?O)? ( 3 ); ? O? CH₂? ( 4 ); ? NH? C(?O)? ( 5 ); ? S? C(?O)? ( 6 ); ? O? C(?S)? ( 7 ); ? NH? C(?S)? ( 8 ); ? S? C(?S)? ( 9 )]. For each system studied ( 1 – 9 ), cis‐ and trans‐TS isomers, corresponding, respectively, to endo‐ and exo‐positioning of the ? C? X? Z? tether with respect to the diene, have been located and their relative energies (E_rel^TS) employed to predict the cis/trans IMDA product ratio. Although the E_rel^TS values are modest (typically <3 kJ mol^?1), they follow a clear and systematic trend. Specifically, as the electronegativity of the tether group X is reduced (X?O→NH or S), the IMDA cis stereoselectivity diminishes. The predicted stereochemical reaction preferences are explained in terms of two opposing effects operating in the cis‐TS, namely (1) unfavorable torsional (eclipsing) strain about the C4? C5 bond, that is caused by the ? C? X? C(?Y)? group’s strong tendency to maintain local planarity; and (2) attractive electrostatic and secondary orbital interactions between the endo‐(thio)carbonyl group, C?Y, and the diene. The former interaction predominates when X is weakly electronegative (X?N, S), while the latter is dominant when X is more strongly electronegative (X?O), or a methylene group (X?CH₂) which increases tether flexibility. These predictions hold up to experimental scrutiny, with synthetic IMDA reactions of 1 , 2 , 3 , and 4 (published work) and 5 , 6 , and 8 (this work) delivering ratios close to those calculated. The reactions of thiolacrylate 5 and thioamide 8 represent the first examples of IMDA reactions with tethers of these types. Our results point to strategies for designing tethers, which lead to improved cis/trans‐selectivities in IMDAs that are normally only weakly selective. Experimental verification of the validity of this claim comes in the form of fumaramide 14 , which undergoes a more trans‐selective IMDA reaction than the corresponding ester tethered precursor 13 .     

Manganese(II) and cobalt(II) complexes of 1,4‐bis(diphenylphosphinoyl)butane

The title complexes, catena‐poly[[[diaquadiethanolmanganese(II)]‐μ‐1,4‐bis(diphenylphosphinoyl)butane‐κ²O:O′] dinitrate 1,4‐bis(diphenylphosphinoyl)butane solvate], {[Mn(C₂H₆O)₂(C₂₈H₂₈O₂P₂)(H₂O)₂](NO₃)₂·C₂₈H₂₈O₂P₂}_n, (I), and catena‐poly[[[diaquadiethanolcobalt(II)]‐μ‐1,4‐bis(diphenylphosphinoyl)butane‐κ²O:O′] dinitrate 1,4‐bis(diphenylphosphinoyl)butane solvate], {[Co(C₂H₆O)₂(C₂₈H₂₈O₂P₂)(H₂O)₂](NO₃)₂·C₂₈H₂₈O₂P₂}_n, (II), are isostructural and centrosymmetric, with the M^II ions at centres of inversion. The coordination geometry is octahedral, with each metal ion coordinated by two trans ethanol molecules, two trans water molecules and two bridging 1,4‐bis(diphenylphosphinoyl)butane ligands which link the coordination centres to form one‐dimensional polymeric chains. Parallel chains are linked by hydrogen bonds to uncoordinated 1,4‐bis(diphenylphosphinoyl)butane molecules, which are bisected by a centre of inversion. Further hydrogen bonds, weak C—H...O interactions to nitrate anions, and weak C—H...π interactions serve to stabilize the structure. This study reports a development of the coordination chemistry of bis(diphenylphosphinoyl)alkanes, with the first reported structures of complexes of the first‐row transition metals with 1,4‐bis(diphenylphosphinoyl)butane.     

Alternative formulations of a combined trip generation,trip distribution,modal split,and trip assignment model

The traditional four-step model has been widely used in travel demand forecasting by considering trip generation, trip distribution, modal split and traffic assignment sequentially in a fixed order. However, this sequential approach suffers from the inconsistency among the level-of-service and flow values in each step of the procedure. In the last two decades, this problem has been addressed by many researchers who have sought to develop combined (or integrated) models that can consider travelers’ choice on different stages simultaneously and give consistent results. In this paper, alternative formulations, including mathematical programming (MP) formulation and variational inequality (VI) formulations, are provided for a combined travel demand model that integrates trip generation, trip distribution, modal split, and traffic assignment using the random utility theory framework. Thus, the proposed alternative formulations not only allow a systematic and consistent treatment of travel choice over different dimensions but also have behavioral richness. Qualitative properties of the formulations are also given to ensure the existence and uniqueness of the solution. Particularly, the model is analyzed for a special but useful case where the probabilistic travel choices are assumed to be a hierarchical logit model. Furthermore, a self-adaptive Goldstein–Levitin–Polyak (GLP) projection algorithm is adopted for solving this special case.     

An argument-based approach to reasoning with clinical knowledge

Better use of biomedical knowledge is an increasingly pressing concern for tackling challenging diseases and for generally improving the quality of healthcare. The quantity of biomedical knowledge is enormous and it is rapidly increasing. Furthermore, in many areas it is incomplete and inconsistent. The development of techniques for representing and reasoning with biomedical knowledge is therefore a timely and potentially valuable goal. In this paper, we focus on an important and common type of biomedical knowledge that has been obtained from clinical trials and studies. We aim for (1) a simple language for representing the results of clinical trials and studies; (2) transparent reasoning with that knowledge that is intuitive and understandable to users; and (3) simple computation mechanisms with this knowledge in order to facilitate the development of viable implementations. Our approach is to propose a logical language that is tailored to the needs of representing and reasoning with the results of clinical trials and studies. Using this logical language, we generate arguments and counterarguments for the relative merits of treatments. In this way, the incompleteness and inconsistency in the knowledge is analysed via argumentation. In addition to motivating and formalising the logical and argumentation aspects of the framework, we provide algorithms and computational complexity results.     

Primitive divisors of some Lehmer-Pierce sequences

We study primitive prime divisors of the terms of Δ(u)=(Δn(u))_n?1, where Δn(u)=NK/Q(un−1) for K a real quadratic field, and u a unit element of its ring of integers. The methods used allow us to find the terms of the sequence that do not have a primitive prime divisor.     

The admissibility of sporadic simple groups

In 1955 Hall and Paige conjectured that a finite group is admissible, i.e., admits complete mappings, if its Sylow 2-subgroup is trivial or noncyclic. In a recent paper, Wilcox proved that any minimal counterexample to this conjecture must be simple, and further, must be either the Tits group or a sporadic simple group. In this paper we improve on this result by proving that the fourth Janko group is the only possible minimal counterexample to this conjecture: John Bray reports having proved that this group is also not a counterexample, thus completing a proof of the Hall–Paige conjecture.