Stereoselective Synthesis of Mechanically Planar Chiral Rotaxanes.

Chiral interlocked molecules in which the mechanical bond provides the sole stereogenic unit are typically produced with no control over the mechanical stereochemistry. Here we report a stereoselective approach to mechanically planar chiral rotaxanes in up to 98:2 d.r. using a readily available α-amino acid-derived azide. Symmetrization of the covalent stereocenter yields a rotaxane in which the mechanical bond provides the only stereogenic element.

Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins.

To improve access to a key synthetic intermediate we targeted a direct hydrobromination-Negishi route. Unsurprisingly, the anti-Markovnikov addition of HBr to estragole in the presence of AIBN proved successful. However, even in the absence of an added initiator, anti-Markovnikov addition was observed. Re-examination of early reports revealed that selective Markovnikov addition, often simply termed "normal" addition, is not always observed with HBr unless air is excluded, leading to the rediscovery of a reproducible and scalable initiator-free protocol.

Stereocontrolled synthesis of adjacent acyclic quaternary-tertiary motifs: application to a concise total synthesis of (-)-filiformin.

Lithiation/borylation methodology has been developed for the synthesis of acyclic quaternary-tertiary motifs with full control of relative and absolute stereochemistry, thus leading to all four possible isomers of a stereodiad. A novel intramolecular Zweifel-type olefination enabled acyclic stereocontrol to be transformed into cyclic stereocontrol. These key steps have been applied to the shortest enantioselective synthesis of (-)-filiformin to date (9 steps) with full stereocontrol.

Stereoselective total synthesis of (+)-giganin and its C10 epimer by using late-stage lithiation-borylation methodology.

The first total synthesis of (+)-giganin and its unnatural diastereoisomer (+)-C10-epi-giganin has been completed in a total of 13 linear steps, and 7 % and 8 % overall yield, respectively (see scheme; (-)-sp= (-)-sparteine, (+)-sps=(+)-sparteine surrogate). Lithiation-borylation methodology has been successfully applied in the key step, to couple together advanced intermediates with very high diastereoselectivity, thus demonstrating its power as a tool for total synthesis.

Health professionals' attitudes towards acupuncture/acupressure for post-operative nausea and vomiting: a survey and implications for implementation.

PURPOSE: Level 1 evidence supports the use of acupuncture/acupressure (A/A) to manage post-operative nausea and vomiting (PONV). This study aimed to survey healthcare professionals' attitudes towards A/A, influencing factors and barriers to implementing this effective non-drug intervention into peri-operative care. METHODS: A validated, anonymous survey with 43 questions was emailed or distributed as a hard copy at meetings to anaesthetists, midwives, nurses, obstetricians, gynaecologists and surgeons at a public hospital in Australia. Descriptive data were presented. Influencing factors were explored using chi-square analysis. Multinomial logistical regression was used to identify the influences of confounding factors. RESULTS: A total of 155 completed surveys were returned, reflecting a response rate of 32%. The majority of participants were female (69%), nurses/midwives (61%) and aged between 20 and 50 years old (76%). Eighty-three percent of respondents considered A/A 'clearly alternative' medicine or 'neither mainstream nor alternative'. Eighty-one percent would encourage patients to use acupressure for PONV if it was offered at the hospital. Previous personal use of A/A was the key factor influencing attitudes and openness to clinical use. The key barriers to implementation were perceived lack of evidence and lack of qualified providers and time. CONCLUSION: Hospital-based healthcare professionals strongly supported the evidence-based use of A/A for PONV despite considering the therapy to be non-mainstream and having limited A/A education or history of personal use, providing a positive context for an acupressure implementation study. Significant gaps in training and a desire to learn were identified.

Electrostatically-guided inhibition of Curli amyloid nucleation by the CsgC-like family of chaperones.

Polypeptide aggregation into amyloid is linked with several debilitating human diseases. Despite the inherent risk of aggregation-induced cytotoxicity, bacteria control the export of amyloid-prone subunits and assemble adhesive amyloid fibres during biofilm formation. An Escherichia protein, CsgC potently inhibits amyloid formation of curli amyloid proteins. Here we unlock its mechanism of action, and show that CsgC strongly inhibits primary nucleation via electrostatically-guided molecular encounters, which expands the conformational distribution of disordered curli subunits. This delays the formation of higher order intermediates and maintains amyloidogenic subunits in a secretion-competent form. New structural insight also reveal that CsgC is part of diverse family of bacterial amyloid inhibitors. Curli assembly is therefore not only arrested in the periplasm, but the preservation of conformational flexibility also enables efficient secretion to the cell surface. Understanding how bacteria safely handle amyloidogenic polypeptides contribute towards efforts to control aggregation in disease-causing amyloids and amyloid-based biotechnological applications.

Nucleus accumbens dopamine and discriminated approach learning: interactive effects of 6-hydroxydopamine lesions and systemic apomorphine administration.

RATIONALE: Although dopaminergic mechanisms have been implicated in incentive motivational processes, their role in appetitive conditioning remains poorly understood. OBJECTIVES: To investigate the effects of dopamine (DA) depleting lesions of the nucleus accumbens and the direct acting dopamine receptor agonist apomorphine on the learning of discriminated appetitive approach behavior in a Pavlovian autoshaping paradigm. METHODS: Rats received bilateral infusions of either phosphate-buffered saline (shams) or 6-hydroxydopamine (lesions) directly into the nucleus accumbens. Ten days later, rats were trained on an autoshaping task whereby a previously neutral light stimulus was paired with food reward. Presentation of another stimulus (CS-) was never followed by reward. Over 100 pairings subjects developed a conditioned response of approaching the reward-predictive stimulus (CS+). Prior to each autoshaping session subjects were administered either saline (1 ml/kg SC) or apomorphine (30 microg/kg; 100 microg/kg), in a between-subjects design. RESULTS: Lesioned subjects showed a delay in the acquisition of discriminated approach and were insensitive to a subsequent change in the contingency of the task whereby approaches to the CS+ now prevented food delivery. Low dose apomorphine profoundly impaired learning in both sham and lesioned subjects. Despite increasing the overall number of CS+ and CS- approaches, the higher dose of apomorphine allowed discriminated approach in sham-operated animals only. CONCLUSIONS: These data are compatible with the hypothesis that nucleus accumbens dopamine serves to energize rather than guide conditioned approach to appetitive cues. They also support the notion that DA inputs in this region confer flexibility of approach to cues predictive of reward.

Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation of challenging boronic esters.

(-)-Sparteine induced lithiation of primary 2,4,6-triisopropylbenzoates and subsequent homologation of boronic esters is reported. A comparative study with lithiated N,N-diisopropylcarbamates has demonstrated the superiority of the hindered benzoate.