Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride.

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo- and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis.

Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein.

The H1047R mutation of is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3Kα over PI3Kα is crucial due to the role that PI3Kα plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3Kα-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage.

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program.

Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo- and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry.

Complex Problems and Dealing with them on a Research Methods Course in a Business School.

This study offers a conceptual explanation of a holistic methodology that has utility in how we engage with complex situations. This is the VIPLAN Methodology developed by Raul Espejo and first published in 1988. A case is presented that evaluates whether this methodology has impact when tacitly embedded in a postgraduate research methods course.

Conceptualising technology, its development and future: The six genres of technology.

One approach to developing futuristic views of technology is to draw upon experience and expertise. However, this becomes increasingly speculative as one moves to more distant timelines and visionary technological forms. This raises the question of whether it is possible to rationally predict how a technology development trajectory might unfold into the future, perhaps to some 'ultimate form', that is accessible, surfaces the necessary technological features for development as well as considers the implications for human-artefact relationships.

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes.

The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs but failed in delivering a crucial hydroxy group in the final step.

Radical Retrosynthesis.

In The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a "wise choice of appropriate simplifying transforms" ( Corey , E.

Total Syntheses of (-)-Majucin and (-)-Jiadifenoxolane A, Complex Majucin-Type Illicium Sesquiterpenes.

We report the first chemical syntheses of both (-)-majucin and (-)-jiadifenoxolane A via 10 net oxidations from the ubiquitous terpene (+)-cedrol. Additionally, this approach allows for access to other majucin-type sesquiterpenes, like (-)-jiadifenolide, (-)-jiadifenin, and (-)-(1R,10S)-2-oxo-3,4-dehydroxyneomajucin (ODNM) along the synthetic pathway. Site-selective aliphatic C(sp)-H bond oxidation reactions serve as the cornerstone of this work which offers access to highly oxidized natural products from an abundant and renewable terpene feedstock.

Technique for prolonged normothermic ex vivo lung perfusion.

Background: The inhibition of cellular metabolism induced by hypothermia obviates the possibility of substantial reparative processes occurring during organ preservation. The aim of this study was to develop a technique of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermia for assessment and protective maintenance of the donor lung.

Methods: Six double-lung blocks from 35-kg pigs and 5 single human lungs were subjected to 12 hours of normothermic EVLP using acellular Steen Solution.

Bivalirudin anticoagulation for cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia.

Purpose: To describe the perioperative management in a heparin-induced thrombocytopenia (HIT) positive patient who had prosthetic valve endocarditis and an aortic root abscess. The patient underwent high-risk cardiac re-operation with the use of the alternative anticoagulant, bivalirudin.

Clinical Features: A 62-yr-old patient who underwent stentless tissue aortic valve replacement with a Toronto-SPV valve in 1998, was admitted to hospital with symptoms of stroke.

The influence of cardiopulmonary bypass flow characteristics on the clinical outcome of 1820 coronary bypass patients.

Objective: To determine whether pulsatile perfusion is clinically beneficial for adult cardiac operations.

Methods: Data concerning consecutive patients undergoing isolated coronary bypass surgery (n=1820) from January 1, 1997 to July 31, 1999 were reviewed.

Results: Nine hundred fifteen patients received pulsatile perfusion (PP) while perfusion in the remaining 905 patients was nonpulsatile (NP).