2-Siloxy-2-alkenyl-1,1-dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening/Nazarov cyclization. The resulting 2-siloxycyclopentenyl cations are ...intercepted by the pendant arenes to furnish tricyclic adducts in moderate to good yields. In cases where the arene trap was tethered through the cyclopropane unit, a new mode of trapping occurred to generate unique bridged carbon frameworks.
Trimethylaluminum and molecular oxygen are used in tandem to interrupt the Nazarov cyclization. α-Hydroxycyclopentanones are produced in moderate to good yield as a mixture of epimers. This sequence ...is the first example of combined nucleophilic/electrophilic trapping of the Nazarov oxyallyl intermediate.
A two-step modular synthesis of an α-hydroxycyclopentenone and α-amido-indanones has been developed based on the Nazarov cyclization of 2-amido-1,4-pentadien-3-ones, readily accessed via formal ...hydroacylation of allenamides.
Simple N-substituted azetidines were heated with diazocarbonyl compounds in the presence of catalytic Cu(acac)2 to furnish substituted pyrrolidines via Stevens 1,2-shift. In all but two examples, ...complete selectivity was seen for ring expansion rather than migration of the other exocyclic group on the azetidinium nitrogen. The two exceptions, observed with ylides substituted with two carbonyl groups and lacking a stabilizing group at the 2-position of the azetidine, underwent exocyclic benzyl migration in preference to ring expansion.
Between 10% and 40% of hospital-acquired infections have been attributed to cross-contamination of healthcare personnel hands. This study described frequency of hand hygiene within a fixed US ...military facility, in participants wearing a military uniform and hospital-provided scrubs. The median frequency of hand hygiene reported in both uniforms was 10 per hour. However, two-thirds of staff indicated that the military uniform decreased their ability to perform hand hygiene. Stakeholders should re-evaluate policies requiring wear of long-sleeved military uniforms by nursing staff to facilitate hand hygiene. Non-military facilities may also consider the impact of long-sleeved garments on hand hygiene.
Azetidinecarboxylate esters react readily with metallocarbenes in an inter- or intramolecular fashion to generate azetidinium ylides. Efficient 1,2-shift by the ester-substituted carbon furnishes ...ring-expanded pyrrolidine products. In the case of substrate 1, this provides access to the pyrrolizidine alkaloids turneforcidine and platynecine via a high-yield, five-step sequence starting with readily available methyl 1-benzylazetidine-2-carboxylate.
The study of the N-quaternization of substituted piperidines has been mostly dormant for the last 40 years, despite the demand for ammonium salts as drugs, ionic liquids, chiral catalysts or ligands, ...phase transfer reagents, and reagents for the Stevens and Sommelet–Hauser rearrangements. In this perspective article, the complexity of this seemingly simple reaction is studied by a summary and analysis of literature experimental results. Computational methods are applied to various literature reactions as case studies.
This paper reports on the results of chemical synthesis and biological assays performed on several new analogues of noscapine. We have successfully synthesized four noscapine analogues called
1a–4a
, ...as well as their four corresponding enantiomers called
1b–4b
. The chemical pathway consisted of three steps with yields in excess of 60% in each step. Subsequently, we have performed biological activity assays intended to reveal the mode of action of these compounds on microtubules in buffer and in cancer cell lines. We have assayed fluorescence quenching effects in microtubule polymerization experiments, cytotoxicity evaluation in breast cancer cell lines, as well as microtubule dynamicity assessments, for each of the synthesized compounds. Finally, we performed computational docking simulations to two binding sites on β-tubulin: (a) the colchicine binding site and (b) the noscapine binding site. Our results indicate that these compounds have relatively low cytotoxicity profile and less pronounced effects on microtubule dynamics compared with noscapine. Our computational results indicate that these compounds bind to both putative binding sites but have higher affinity for the colchicine site.
It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a ...genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD.
Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years.
Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events.
Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.
As a result of difficulties in scaling up silicon-directed Nazarov cyclization for use in the synthesis of taxane natural products, the effect of additives was examined. Hydroxylic additives were ...found to convey a consistent beneficial effect on the rate, overall yield, and scalability of these reactions. Optimal conditions (1.5equiv methanol or water with substoichiometric FeCl3), were successfully applied to a range of β-silyl dienone substrates, including several complex polycyclic examples, as well as simpler dienones previously shown to be low-yielding or completely unreactive under the conventional conditions.
