Aldol reactions of racemic enolizable dioxolan-protected a-substituted-b-ketoaldehydes with representative achiral ketones catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet DMSO proceed with dynamic kinetic resolution (or via DYKAT with an a-substituted-b-alkoxyaldehyde) to give adducts with high dr and ee.The first examples of proline-catalyzed enantioselective direct intermolecular aldol reactions were reported in a landmark paper by List, Lerner, and Barbas in 2000. 1 In the ensuing decade, this reaction has been extensively studied by numerous research groups, and remarkable progress has been achieved. 2 Despite the impressive stereoselectivity that has been obtained in many examples and with diverse organocatalysts, a continuing limitation to synthetic applications of this process has been the rather narrow substrate scope; that is, few competent ketone donors and mainly simple achiral or aromatic aldehyde acceptors. Our interest in this process stemmed from its possible application to our thiopyran-based synthetic route to polypropionates via stereoselective sequential two-directional aldol reactions of 1 and 2a (Scheme 1). 3 Scheme 1 Proline-catalyzed reaction of 1 with (±)-2a via DKR 8aIn a preliminary study, we established that proline-catalyzed aldol reactions of 1 with simple achiral aldehydes in DMF or DMSO (with controlled amounts of water) are highly diastereo-and enantioselective. 4 This was significant because 3-pentanone is a poor substrate in prolinecatalyzed aldol reactions. 2 Among the scattered examples of proline-catalyzed aldol reactions of chiral aldehydes, 5 generally moderate levels of enantiotopic group selectivity 6 (or double stereodifferentiation) 7 were observed. Nonetheless, we reasoned that because of its near exclusive Felkin diastereoface selectivity, racemic aldehyde (±)-2a would be a good candidate to undergo proline-catalyzed direct aldol with 1 with high enantiotopic group selectivity (i.e., kinetic resolution 6 ). 8 Under optimized conditions, (-)-5a was obtained essentially as a single stereoisomer in a process that proceeded via dynamic kinetic resolution (DKR, 9 Scheme 1). 8 In this paper, we report the extension of this concept to other ketones and aldehydes and simple procedures for the preparation of 5a on >30 gram scale.We next investigated the efficacy of the more soluble catalyst 6. 10 Aldol reactions of 1 with (±)-2a, benzaldehyde (2c), and isobutyraldehyde (2d) catalyzed by 6 (0.2 equiv) were conducted under the conditions previously optimized using 4 (0.5 equiv) revealing that 6 was the superior catalyst for the reactions with (±)-2a and 2c, (Table 1; cf. entries 1, 2, 4, 5, and 7, 8). The individual reactions were optimized by examining the effects of various reaction parameters including the amount of added water, 4 stoichiometry, catalyst loading, and reaction time. A solvent screen revealed that DMF was superior for 2c and DMSO for 2d and (±)-2c. 11 The addition of controlled amounts of water improved all reactions and the adducts 5a, 5c...
The putative contiguous polypropionate precursor of dolabriferol was synthesized using as the key step a rationally designed enantiomer-selective aldol coupling (i.e., with kinetic resolution) of a racemic C1-C8 ketone fragment with an enantiopure C9-C15 aldehyde fragment. When exposed to alumina, the precursor was cleanly transformed into dolabriferol via a regioselective retro-Claisen fragmentation, providing the first experimental evidence for the proposed origin of dolabriferol and demonstrating that it is a plausible isolation artifact.
BackgroundTargeting angiogenesis is nowadays one of the most promising approaches for breast cancer. Bevacizumab (BEV), a VEGF-trap monoclonal antibody, was recently approved in combination with paclitaxel (PAC) for the first line treatment of advanced breast cancer (ABC). The activity of this combination in pretreated patients is not known.MethodsPatients with pretreated ABC and progressive disease received BEV 10 mg/kg with PAC 135 mg/m2 every two weeks for six months and then maintenance with BEV 15 mg/kg every three weeks until progression. This regimen was chosen for better patient convenience, while maintaining the same dose intensity for both drugs.Results42 patients were reviewed retrospectively (41 f, 1 m, mean age 57 years). Overall response rate was 35.7%. Stable disease was observed in 45.2% of patients, whereas 14.3% of patients progressed. The median overall survival was greater than 20 months, with a one year rate of 83.4%. The median progression free survival was 12.1 months, with a one year rate of 51.8%. Toxicity was in general acceptable.ConclusionThis biweekly BEV/PAC combination seems to be active with acceptable toxicity in pretreated ABC with an advantage over the weekly regimen regarding quality of life and preservation of resources.
BackgroundSince its introduction in the early 1980s, percutaneous endoscopic gastrostomy has become the most popular method for performing a gastrostomy for long-term enteral feeding. It has been associated, however, with a lot of minor and major complications.Case presentationA case of mediastinitis with concominant sepsis caused by a masked esophageal perforation after percutaneous endoscopic gastrostomy in a multi-traumatized, brain-injured patient is presented. Ten – fourteen days after the procedure, the patient became febrile and gradually septic with tenderness of the sternum and upper abdomen. Computerized tomography of the thorax revealed mediastinitis. An urgent left thoracotomy and laparotomy were performed for drainage of the mediastinum, removal of the gastrostomy and insertion of a jejunostomy tube. The patient improved soon after the surgery. He was successfully weaned off the ventilator and was discharged from the Intensive Care Unit.ConclusionPerforating mediastinitis is a rare but potentially lethal complication of percutaneous endoscopic gastrostomy. When diagnosed and properly treated it may have a favourable outcome.
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