Algorithms for exact multi-object muscle wrapping and application to the deltoid muscle wrapping around the humerus.

Lines of action of muscle forces imply the function and performance of muscles acting around joints. It is not always possible to determine muscle force lines of action in vivo, and so computational techniques are often used to predict them. It is common to model a muscle as a taut elastic string that follows the shortest geodesic path between attachments over the wrapping geometry.

Blinded comparison of faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation.

Aim: To compare faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation.

Methods: The study group was a convenience sample of patients attending the Durham Constipation Clinic. All patients underwent transit studies according to an established protocol, and severity of constipation was assessed contemporaneously using a validated questionnaire (PAC-SYM).

Chiral N-heterocyclic carbene ligands for asymmetric catalytic oxindole synthesis.

The Pd-catalysed asymmetric intramolecular alpha-arylation of amide enolates containing heteroatom substituents gives chiral 3-alkoxy or 3-aminooxindoles in high yield and with enantioselectivities up to 97% ee when a new chiral N-heterocyclic carbene ligand is used.

Total synthesis of the immunosuppressants myriocin and 2-epi-myriocin.

Total syntheses of the natural immunosuppressant myriocin (1) and the equipotent unnatural analogue 2-epi-myriocin (in protected form) have been achieved through a common strategy. The key transformations are the efficient synthesis of a quaternary (E)-vinylglycine by asymmetric deconjugative alkylation of a dehydroamino acid and an unusually highly diastereoselective dihydroxylation of the vinylglycine alkene.

Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates.

A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

Convenient synthesis of 3-alkoxy-3-aryloxindoles by intramolecular arylation of mandelic amides.

Medicinally important 3-alkoxy-3-aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.

Facile and general synthesis of quaternary 3-aminooxindoles.

A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines.

Catalytic aza-Wittig cyclizations for heteroaromatic synthesis.

The first examples of heterocycle synthesis by iminophosphorane formation/intramolecular aza-Wittig cyclizations that are catalytic in the organophosphorus component are reported. The reaction has been demonstrated in the synthesis of both azine (phenanthridine) and azole (benzoxazole) heterocycles. Catalyst loadings down to 1 mol % have been used with little or no loss in reaction efficiency.

A novel approach to the prediction of musculotendon paths.

One of the most important aspects of the modelling of musculoskeletal systems is the determination of muscle moment arms which are dependent upon the paths of the muscles. These paths are often required to wrap around passive structures that can be modelled as simple geometric shapes. A novel technique for the prediction of the paths of muscles modelled as strings when wrapping around smooth analytical surfaces is presented.

Total synthesis of the indolizidine alkaloid tashiromine.

Background: Tashiromine 1 is a naturally occurring indolizidine alkaloid. It has been the subject of thirteen successful total syntheses to date. Our own approach centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane.

Isotopic labeling for determination of enantiomeric purity by 2H NMR spectroscopy.

The use of 2H NMR spectroscopy as a tool for the analysis of enantiomeric purity is reported. Enantiopure isotopically chiral substrates bearing a monodeuterated methylene unit were prepared; introduction of an additional asymmetric center leads to diastereomers which can be distinguished by 2H NMR on a standard spectrometer. The assays allow for simple semiquantitative analysis of asymmetric transformations.

Biophysical studies of the translation initiation pathway with immobilized mRNA analogs.

A growing number of biophysical techniques use immobilized reactants for the quantitative study of macromolecular reactions. Examples of such approaches include surface plasmon resonance, atomic force microscopy, total reflection fluorescence microscopy, and others. Some of these methods have already been adapted for work with immobilized RNAs, thus making them available for the study of many reactions relevant to translation.

Synthesis and application of P-stereogenic phosphines as superior reagents in the asymmetric aza-Wittig reaction.

A wide variety of P-stereogenic aryldialkylphosphines were prepared in enantioenriched form by a systematic diversification of the (-)-sparteine-mediated dynamic kinetic resolution of racemic lithiophosphine-boranes reported by Livinghouse. Excellent asymmetric induction was observed provided that the intermediate lithiophosphine/sparteine complex precipitated from solution; more soluble derivatives returned poor ee's or racemic material. The resulting phosphine-boranes were deprotected and used as reagents in the desymmetrizing asymmetric aza-Wittig reaction of 2-alkyl-2-(3-azidopropyl)cyclohexane-1,3-diones, delivering the highest ee's yet observed in this process (up to 84% ee).

A concise, convergent total synthesis of monocerin.

A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core 2,3,5-trisubstituted tetrahydrofuran. End-game approaches based around intramolecular Heck chemistry revealed an interesting example of formal 6-endo cyclisation, the origin of which was probed using model substrates.

Contemporary organosilicon chemistry.

Editorial for the Thematic Series on Contemporary Organosilicon Chemistry.

Efficient asymmetric synthesis of quaternary (E)-vinylglycines by deconjugative alkylation of dehydroamino acids.

A two-step protocol for the asymmetric synthesis of protected quaternary (E)-vinylglycines from simple aldehydes is reported. The key step is a regiocontrolled deconjugative asymmetric alkylation of dehydroamino acids, giving the targets as single geometric isomers with high diastereoselectivity (92-96% de). The products can be converted to valuable quaternary beta-amino alcohols by chemoselective reduction.

Concise access to indolizidine and pyrroloazepine skeleta via intramolecular Schmidt reactions of azido 1,3-diketones.

Readily prepared 2-alkyl-2-azidopropylcycloalkyl-1,3-diones undergo intramolecular Schmidt rearrangement with a range of hard Lewis acids, leading to indolizidinediones and pyrroloazepinediones. Chiral aluminium-based Lewis acids could also be used to mediate this symmetry-breaking transformation, but no significant asymmetric induction was observed.

Unwinding single RNA molecules using helicases involved in eukaryotic translation initiation.

The small (40 S) subunit of the eukaryotic ribosome may have to scan more than 2000 nucleotides (>600 nm) from its 5'cap recruiting point on an mRNA molecule before initiating on a translation start codon. As with many other processes in living cells, including transcription, editing, mRNA splicing, pre-rRNA processing, RNA transport and RNA decay, scanning is facilitated by helicase activity. However, precise quantitative data on the molecular mechanism of scanning, including the roles of helicases, are lacking.

Outsourcing to exploit a key asset.

Much has been written and debated about the economic and organizational advantages of outsourcing a growing list of operations in drug discovery. In what has been described as a modular approach to drug discovery, whole sections of the process are now handled very effectively by a wide variety of specialist suppliers to the pharmaceutical industry. Here we report on a novel outsourced solution to the challenge of consolidating and managing some of the key assets residing within a major research organization - its chemical intermediates.

Synthesis of highly substituted allenylsilanes by alkylidenation of silylketenes.

Background: Allenylsilanes are useful intermediates in organic synthesis. An attractive, convergent but little used approach for their synthesis is the alkylidenation of stable silylketenes. Reactions thus far have been limited to the use of unsubstituted silylketenes (or equivalents) with stabilised or semi-stabilised ylides only.

Reagent-controlled asymmetric homologation of boronic esters by enantioenriched main-group chiral carbenoids.

[reaction: see text] Putative enantioenriched carbenoid species, (R)-1-chloro-2-phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generated in situ by sulfoxide ligand exchange from (-)-(R(S),R)-1-chloro-2-phenylethyl p-tolyl sulfoxide (8), effected the stereocontrolled homologation of boronic esters. sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approaching that of sulfoxide 8 in examples employing Li-carbenoid 26.

Deconjugation of dehydroamino acids: stereoselective synthesis of racemic (E)-vinylglycines.

[reaction: see text] A practical and general two-step synthesis of carbamate-protected (E)-vinylglycines from aliphatic aldehydes is reported. The key step involves the kinetic alpha-protonation of dianionic dienolates derived from dehydroamino acids.

Stereocontrolled assembly of tetrasubstituted tetrahydrofurans: a concise synthesis of virgatusin.

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1).