Organocatalytic enantioselective desymmetrisation.

Organocatalytic enantioselective desymmetrisation of achiral or meso compounds is a powerful strategy for the construction of enantiomerically enriched complex molecules, often with multiple stereocentres and in high selectivities. Recent years have seen increasing use of organocatalysts in desymmetrisation methodology, in contrast to traditional metal- or enzyme-catalysed reactions, with many impressive advances made in the current decade. This review will provide an overview of the field since 2010, with the aim of highlighting both the practical applications and elegance of enantioselective desymmetrisation to the wider synthetic community.

Highly diastereoselective Michael addition reactions of butane-2,3-diacetal desymmetrized glycolic acid. Preparation of alpha-hydroxy-gamma-amino acid derivatives.

[reaction--see text] The butane-2,3-diacetal (BDA) desymmetrized glycolic acid building block undergoes efficient and highly diastereoselective lithium enolate Michael additions to alpha,beta-unsaturated ketones, lactones, and nitro olefins. Subsequent deprotection of these Michael adducts gives alpha-hydroxy acids in very high yield. Hydrogenation of the nitro group in some of the adducts leads to gamma-lactams, which can be easily converted into alpha-hydroxy-gamma-amino acid derivatives.

Highly diastereoselective lithium enolate aldol reactions of butane-2,3-diacetal desymmetrized glycolic acid and deprotection to enantiopure anti-2,3-dihydroxy esters.

[reaction--see text] The butane-2,3-diacetal (BDA) desymmetrized glycolic acid building block 1 undergoes efficient and highly diastereoselective lithium enolate aldol reactions with both aromatic and aliphatic aldehydes to afford, after an acidic methanolysis deprotection step, the enantiopure anti-2,3-dihydroxy esters in good yield.

A short stereoselective total synthesis of the fusarium toxin equisetin.

A short stereoselective synthesis of the fusarium toxin equisetin, an N-methylserine-derived acyl tetramic acid and potent inhibitor of HIV-1 integrase enzyme, is described using as the key step a stereoselective lithium perchlorate mediated intramolecular Diels-Alder reaction of a fully conjugated E,E,E-triene with a trisubstituted gamma,delta-unsaturated beta-ketothioester.

Excrescent lesion: a diagnosis of lateral talar exostosis in chronically symptomatic sprained ankles.

The excrescent lesion is a symptomatic anterolateral exostosis at the insertion of the anterior talofibular ligament. It is found in patients with chronic ankle pain after inversion injuries. It is most reliably diagnosed by computed tomography scan, but physical examination and oblique radiographs are suggestive in most cases. A technique for surgical excision and, in some cases, repair of the anterior talofibular ligament is described. Five patients having a history of inversion sprains of the ankle, without significant symptomatic improvement for a mean of 21 months after the injury, were evaluated. None had significant instability in the ankle or subtalar joints, clinically or with stress radiographs. The diagnosis of excrescent lesion was confirmed with computed tomography scan in all five patients. Each underwent excision of the exostosis. Removal of the exostosis produced laxity of the anterior talofibular ligament in four of the patients and required an additional modified Broström procedure to tighten the anterior talofibular ligament. Clinical results were evaluated at a mean of 33 months postoperatively, using the Ankle-Hindfoot scale from the American Orthopaedic Foot and Ankle Society. The three patients without pending claims for Workers' Compensation or related litigation all had excellent results (mean score, 93 points). Two patients with active legal claims had fair and poor results (mean score, 53 points).

Plantarflexion torque following reconstruction of Achilles tendinosis or rupture with flexor hallucis longus augmentation.

Nine patients treated surgically for Achilles tendon rupture (7 patients) or tendinosis (2 patients) with primary repair or debridement and augmentation with the flexor hallucis longus muscle-tendon unit were evaluated at a mean of 19 months postoperative. Subjective evaluation revealed a high level of satisfaction. All patients returned to work and only two patients reported limitation in their recreational activities. The mean post-operative AOFAS Ankle-Hindfoot Score was 90 points. Four patients reported mild occasional pain and one patient complained of moderate daily pain. Motion assessment showed a 20% increase in the hallux MTP dorsiflexion compared to the non-operative side (p = 0.045). No difference in ankle motion was noted. Cybex II+ dynamic evaluation of plantarflexion peak torque was complete on both extremities. The torque deficit on the reconstructed extremity was 20% (p = 0.01) at 120 degrees per second and 26% (p = 0.003) at 30 degrees per second. There is no significant difference between the torque deficit recorded for patients with Achilles rupture and those with Achilles tendinosis. A trend toward improved torque production with longer follow up was observed.

Religious altruism and organ donation.

Clinicians performing psychiatric assessments of potential organ donors must consider the motivations behind an act that is--strictly in terms of its physiological implications--entirely altruistic. The authors present two case reports in which proposed kidney donors conceptualized their offers exclusively in terms of their religious beliefs and not in terms of kinship or emotional intimacy with the intended recipients. The negative reactions of some clinicians to the offers reveal the readiness with which religious beliefs can be pathologized and the way in which biological relationships can unduly restrict the clinical understanding of healthy altruism.

Evolution of a complex coevolved trait: active pollination in a genus of fig wasps.

Only three insect lineages have evolved complex active pollination behaviour and only fig wasps (Agaonidae) have also reverted from active to passive pollination. Previously, it was assumed that there was a single origin of active pollination in fig wasps, followed by one independent loss in each of five genera. We show here that there have been three to six changes in pollination behaviour within just one genus (Pleistodontes). The results suggest multiple gains of active pollination in fig wasps, but are sensitive to assumptions about the relative costs of gaining and losing this complex behaviour. In addition, previous comparative studies at higher taxonomic levels have reported correlated evolution between active pollination in wasps and low anther/ovule ratios in figs. We report that changes in pollination behaviour between congeneric species correlate perfectly with changes in anther/ovule ratios in the host figs, showing no phylogenetic inertia in coadaptation at the species level.

Polymeric microspheres prepared by spraying into compressed carbon dioxide.

PURPOSE: The objective was to prepare polymeric microparticles by atomizing organic polymer solutions into a spray chamber containing compressed CO2 (PCA-process) and to study the influence of various process parameters on their morphological characteristics. METHOD: The swelling of various pharmaceutically acceptable polymers [ethyl cellulose, poly(methyl methacrylate), poly(epsilon-caprolactone), poly(dl-lactide), poly(l-lactide) and poly(dl-lactide-glycolide) copolymers] in CO2 was investigated in order to find polymers which did not agglomerate during the spraying process. Poly(l-lactide) (L-PLA) microparticles were prepared by spraying the organic polymer solution into CO2 in a specially designed spraying apparatus. The effect of various process (pressure and temperature of the CO2 phase, flow rate) and formulation (polymer concentration) variables on the morphology and particle size of L-PLA-microparticles was investigated. RESULTS: Polymers with low glass transition temperatures agglomerated even at low temperatures. The formation of microparticles was favored at moderate temperatures, low polymer concentrations, high pressures and high flow rates of CO2. High polymer concentrations and low flow rates resulted in the formation of polymeric fibers. Colloidal L-PLA particles could also be prepared with this technique in a surfactant-free environment. Initial studies on the microencapsulation of drugs resulted in low encapsulation efficiencies. CONCLUSIONS: The PCA method is a promising technique for the preparation of drug-containing microparticles. Potential advantages of this method include the flexibility of preparing microparticles of different size and morphology, the elimination of surfactants, the minimization of residual organic solvents, low to moderate processing temperatures and the potential for scale-up.

Iron chelation by deferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: a randomized, double-blind study of the dose-response relationship.

Transfusion-induced hemosiderosis is a serious and potentially life-threatening complication for some patients with sickle cell anemia. The use of high-dose intravenous deferoxamine (DFO) has become widespread in spite of a paucity of published data on safety and efficacy. We report a randomized double-blind study of the dose-response relationship of intravenous DFO in six subjects with sickle cell anemia and severe transfusion-induced hemosiderosis (serum ferritin 4100 to 14,176 ng/ml). Each subject received three different doses of intravenous DFO for 3 days each while consuming a constant diet. Total iron excretion (urine and fecal) was 91% greater at 180 mg/kg/day DFO than at 60 mg/kg/day DFO, and fecal iron excretion became a relatively larger proportion of total excretion at higher doses. Subsequent treatment for 3 months with 150 mg/kg/day DFO caused a 33% to 60% reduction in serum ferritin and demonstrable improvement in hepatic function in all patients. No toxicity was encountered, but DFO at 180 mg/kg/day was associated with a significant increase in fecal zinc excretion when compared with that observed at lower doses.

Experience with donors matched for minor blood group antigens in patients with sickle cell anemia who are receiving chronic transfusion therapy.

Clinically significant alloimmunization to red cell antigens occurred in 28 percent of transfused patients in a sickle cell clinic. Therefore, a prospective study was undertaken to determine whether matching donors carefully for 17 blood group antigens would diminish the risk of further alloimmunization in patients on a chronic transfusion program. Alloantibodies had developed previously in 8 of the 12 patients. After chronic transfusion with selected donors, four new antibodies developed in three patients. Three antibodies were due to errors in phenotyping or matching, and one was due to an antigen that was not tested for in the protocol. The incidence of developing antibodies per unit transfused was diminished tenfold when selected donors were used. Autoantibodies developed in five patients (42%), but these did not seriously interfere with the transfusion therapy. It was concluded that matching for red cell antigens may diminish the incidence of alloimmunization in patients with sickle cell anemia requiring transfusion.