Literatura académica sobre el tema "Paolo Ketoff"

e19533 Background: Neurokinin-1 receptor antagonist (NK1 RA) is commonly administered in combination with a 5-HT3 RA such as palonosetron (PALO) to prevent the stimulus of nausea and vomiting caused by emetogenic chemotherapy. Netupitant (NETU), a new NK1 RA under evaluation for its antiemetic efficacy and tolerability, is both a substrate for and a competitive inhibitor of CYP3A4. Two studies were designed to determine the potential risk for drug-drug interaction in clinical practice. In the first study, the effects of NETU on the metabolism of two representative CYP3A4 substrates, erythromycin (ERY) and midazolam (MID) were determined. In the second study, a CYP3A4 inhibitor, ketoconazole (KETO), or an inducer, rifampicin (RIF) was coadministered with a fixed dose combination of NETU/PALO to observe the potential effects on NETU and PALO metabolism. Methods: Serial blood samples were collected from healthy volunteers and pharmacokinetic (PK) parameters were determined in both studies. The first trial was a 3-period crossover performed in 20 subjects receiving NETU (300 mg), ERY (500 mg) or MID (7.5 mg). The second trial was a 2-way crossover in 36 subjects receiving a single dose of NETU/PALO (300 mg/0.5mg, Day 1) administered as a fixed dose combination and KETO (400 mg QD, from Day-2 to Day 10) or RIF (600 mg QD from Day -7 to Day 10). Results: NETU, by inhibiting the CYP3A4, increased Cmax and AUC parameters by 40% and 130%, respectively, when administered with MID and by 30% when administered with ERY. KETO increased NETU AUC by 140% and Cmax by 25%, while RIF decreased NETU AUC by 83% and Cmax by 62%. A decrease of 19% was observed in PALO AUC when administered with RIF, while KETO had no relevant effect on PALO PK. Conclusions: The results of these studies suggest that the coadministration of NETU with drugs that are substrates, inhibitors, or inducers of the CYP3A4 enzymes, may require dose adjustments. These results are in line with pharmacokinetic data of aprepitant, the only commercially available NK1 RA. The effect of RIF on PALO is not considered clinically relevant. Treatments were well tolerated in all studies.

Abstract Resistance to androgen receptor-targeted therapy due to tumor heterogeneity and clonal evolution is a key challenge for improving prostate cancer outcomes. Despite this, the transcriptomic and chromatin accessibility changes contributing to the emergence of resistance remain incompletely understood at the level of individual cells. Using single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide, we previously identified pre-existing and persistent cell subpopulations that possess regenerative potential when subjected to treatment. Here we analyze the chromatin and transcriptomes of these single cells to characterize their gene regulation and gene expression trajectories. We present evidence of a model of enzalutamide resistance emergence in which the pre-existing and treatment-persistent cells regenerate the bulk of resistant cells. This process is underpinned by chromatin reprogramming that increases the overall relaxation of chromatin upon resistance. We show that the reprogramming of the chromatin further differentially contributes to transcription factor-mediated transcriptional reprogramming via DNA motif exposure in different cell subpopulations. For example, in the treatment-persistent cells, we identify chromatin configurations characterized by the exposure of DNA motifs for GATA2, RELA (a NFkB subunit), CREB1, and E2F1. Pre-existing and treatment-persistent cells consistently display transcriptional features of high developmental potential and RNA velocity analysis identifies them as precursors of cell populations that arise from enzalutamide treatment. We also analyze the pre-existing and treatment-persistent cells in spatial transcriptomics of prostate cancer patient specimens based on their characteristic gene expression profiles. We find these cells to be enriched in cancerous regions of the tissue but also detect them within apparent benign regions, which has potential implications for treatment choice. In summary, we show patterns of gene expression regulation in preclinical models and patient samples that uncover mechanisms of resistance to androgen receptor-targeted therapy in prostate cancer. Citation Format: Sinja Taavitsainen, Nikolai Engedal, Shaolong Cao, Florian Handle, Andrew Erickson, Stefan Prekovic, Daniel Wetterskog, Teemu Tolonen, Elisa M. Vuorinen, Antti Kiviaho, Reetta Nätkin, Tomi Häkkinen, Wout Devlies, Sallamari Henttinen, Roosa Kaarijärvi, Mari Lahnalampi, Heidi Kaljunen, Karolina Nowakowska, Heimo Syvälä, Merja Bläuer, Paolo Cremaschi, Frank Claessens, Tapio Visakorpi, Teuvo L. Tammela, Teemu Murtola, Kirsi J. Granberg, Alastair D. Lamb, Kirsi Ketola, Ian G. Mills, Gerhardt Attard, Wenyi Wang, Matti Nykter, Alfonso Urbanucci. Single-cell transcriptome and chromatin sequencing uncover gene expression and gene regulatory patterns associated with enzalutamide resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 401.

Background and Aims: Dukan diet, a popular diet with high content of protein and carbohydrate and fat restriction has been widely used for weight loss. We aimed to compare the effects of the Dukan diet with traditional low-calorie diet in nutritional, laboratory and vascular parameters in obese subjects. Methods and Results: Obese subjects classes I or II of both genders, aging 19 to 65 years were allocated into two groups: Traditional low-calorie diet (n=17) and Dukan Diet (n=17). Anthropometric, laboratory and vascular evaluations were performed at baseline, 3, 6 and 12 months. Body composition was evaluated by bioelectric impedance and endothelial function by flow-mediated dilation of the brachial artery, at same times. After 12 months, it was verified that Dukan diet was more effective (p<0.05) than traditional diet for: weight loss (-10.6 vs -2.9 kg), body mass index (-3.7 vs -1.1 kg/m2), waist circumference (-11.2 vs -2.1 cm), fat (-5.7 vs -2.0 kg) and lean mass (-4.8 vs 0.8 kg) and basal metabolic rate (-152 vs -28 cal). In Dukan diet group, improvement (p<0.05 vs baseline) was observed in triglyceride levels (172.40 to 111.90 mg/dL) and insulin resistance, based on HOMA-IR index (4.98 to 3.26). The glomerular filtration rate decreased in this group after 3 months (132.50 to 113.80 mL/min) and no changes in flow-mediated dilation were observed throughout the study with both diets. Conclusion: Dukan diet was more effective than traditional diet for weight loss and laboratory parameters and without changes in endothelial function, in the 12-months follow-up of obese subjects. Introduction Low-carbohydrate diets have been one of the most recently used dietary therapies in patients with diabetes and obesity in clinical studies(1). Among them, in addition to carbohydrate restriction, fat restriction and high protein concentration, as in the Diet Dukan, has been widely used by the general population, aiming at weight loss. The Dukan diet is designed to reduce carbohydrate and fat intake in the first phase of the diet, with exclusive intake of protein, followed by another Three phases, with progressive and slow reintroduction of other nutrients such as fiber, carbohydrates and fats. In recent years, there has been increasing interest in the effectiveness of very low carbohydrate diets, called ketogenic diets, in the effectiveness of weight loss in order to combat obesity and cardiovascular disease risk(2). In this diet, ketone bodies are formed and they are used as an alternative energy source in the absence of glucose. Ketogenic diet promotes weight loss reducing appetite, increasing satiety and thermogenesis, due to the high protein consumption(3) affect hormones that control appetite, such as ghrelin and leptin(4) reduces lipogenesis and increases lipolysis(5,6) and gluconeogenesis(7). Replacing carbohydrates by proteins in the diet have been the aim of several studies but with inconsistent results. High protein intake has positive effects on weight loss, acting on satiety, body composition, lipid profile and glucose homeostasis. Furthermore, it increases thermogenesis, energy expenditure(8) and the elevation in the amino acid level in the plasma acts on the satiety center, decreasing appetite, since amino acids also stimulate insulin secretion resulting in decreased or maintained blood glucose levels(9). Few studies have been published with Dukan diet. Freeman et al. were the first to publish an article with the Dukan Diet in 2014, describing adverse effects in one patient undergoing this diet(10). Nouvenne et al. reviewed studies about the influence of popular diets on kidney stone formation risk. In this article, the authors suggest that in the Dukan diet, due to the high consumption of animal protein, urinary calcium can increase and the citrate urinary excretion can decrease, increasing the risk of kidney stone formation(11). In 2015, Wyka et al. evaluated dietary consumption in women adopting the Dukan-diet, based on the menu consumed in each of 4 phases of diet. They observed weight loss of around 15 kg after 8 to 10 weeks of diet and higher intake of proteins, mainly of animal origin, high consumption of potassium, iron and vitamins A, D and B2 and reduced consumption of carbohydrates, vitamin C and folates. They suggest that this diet may be harmful to health if adopted for a long time, developing of kidney and liver disease, osteoporosis and cardiovascular disease(12). Considering that the Dukan Diet is widely disseminated and it is used by the population in general for weight loss and few scientific studies are found in the literature, we propose to evaluate the nutritional, laboratory parameters related to cardiovascular disease, comparing this diet with traditional hypocaloric diet in obese individuals. Methods Study design This study was a clinical trial with nutritional intervention, for one year. Patients were recruited from the Lipids, Atherosclerosis and Vascular Biology Division of the Universidade Federal de São Paulo (UNIFESP). The study conforms to the ethical guidelines and approval was obtained from the ethics committee and it was registered in the Brazilian Registry of Clinical Trials. All participants provided written informed consent and received no monetary incentive. A total of 40 subjects were initially recruited and the participants were followed up clinically by a cardiologist and nutritionist during the 12-month period with monthly visits. Of the 40 participants who started the study, 34 completed the 12-month follow-up, whose data are presented in this study. The inclusion criteria were: both genders, aging 19-65 years old, obesity grade I or II (body mass index between 30 kg/m² and 39.9 kg/m²), stable body weight in the previous 3 months and desire to lose weight. The main exclusion criteria were: patients in primary or secondary prevention of coronary heart disease with low-density lipoprotein cholesterol (LDL-C) levels greater than 190 mg/dL and triglycerides greater than 400 mg/dL; diabetes mellitus; untreated hypothyroidism; psychiatric and hepatic disease; chronic renal failure; cardiac and respiratory insufficiency; systemic infections; use of antidepressants, corticoids, diuretics and diabetes medications; bariatric surgery, cancer and failure to accept the conditions necessary to conduct the research. Two groups were constituted: Traditional low-calorie diet (TD): n=17, 14 females and 3 males, 45±11 years old, 90±11 Kg body weight and body mass index (BMI) 34±2Kg/m2; High protein/Low carbohydrate diet-Dukan Diet (DD): n=17, 10 females and 7 males, 38±11 years old, 95±9 Kg of body weight and BMI 34±2 Kg/m2. The TD group received orientations according to the Food Guideline for the Brazilian Population, with 1 500–1 800 calories/day. They were stimulated to improve healthy eating habits increasing the consumption of natural foods without preservatives, such as vegetables and fruits rich in fiber and antioxidants. Daily consumption of fruits and vegetables at meals was recommended; carry out the fractionation of the meals throughout the day, avoiding prolonged fasting. Hydration and regular physical activity were recommended, according to healthier life habits(13). The DD group followed the high-protein/low-carbohydrate diet as proposed by Dukan Diet, available at https://www.dietadukan.com.br and received an illustrated book about this diet(14). This diet is structured in four phases: two for weight loss (1st and 2nd phases) and two for weight maintenance (3rd and 4th phases): 1st stage - Attack: For 5 consecutive days, it is allowed to consume only proteins with lean meats, eggs, light cheese and milk, 1.5 tablespoons of oat bran per day and light physical activity for 20 minutes. 2nd stage - Cruise: This phase is maintained until the desired weight loss. The vegetables are introduced alternating with the pure protein day (first stage). It is recommended 2 tablespoons of oat bran per day and light physical activity for 30 minutes. 3rd phase - Consolidation: The time of this phase is equivalent to 10 days per kg of lost weight. In this stage carbohydrates and lipids are introduced by a controlled and moderate way, being divided in two parts: in the first part, corresponding to half of the period to be followed, is allowed: 1 fruit, 2 slices of bread (50 g) or 1 spoon of farinaceous per day and 1 gala dinner per week. In the second part, it is allowed 2 fruits, 4 slices of bread (100 g) or 2 spoons of farinaceous per day and 2 gala dinners per week. This phase has one rule: make one day of the week with pure protein (first stage) and it is recommended 2.5 tablespoons of oat bran per day and light physical activity for 35 minutes. 4th phase - Stabilization: In this phase, three rules must to be followed: one day a week it should follow up the pure protein diet, the daily consumption of 3 tablespoons of oat bran and at least 40 minutes of daily walking. From this phase, the participants followed up the low calorie diet. The adherence of the participants was monitored by the interview with the nutritionist and qualitative evaluation of ketone bodies in the urine, using Labtest UriAction 10 reagent strips. At baseline, 3, 6 and 12 months, the following evaluations were performed: nutritional assessment determining anthropometry, blood samples were collected for laboratory tests. Endothelial function was evaluated in fasting and 2-hours post prandial situations. In the periods between the predetermined visits, the participants were followed up by the nutritionist monthly and by telephone contact whenever requested and with medical attention whenever necessary. Nutritional evaluation Nutritional assessment was performed by anthropometric determinations of weight, height, BMI, abdominal circumference and bioelectric impedance (BIA). BIA was carried out using the Biodynamics Model 450 TBW® apparatus, with portable plethysmograph and patients were instructed according to the manufacturer's instruction(15). Laboratory parameters Peripheral blood samples were collected for dosages of total cholesterol and fractions, triglycerides, glucoses, insulin, iron, ferritin, ALT, AST, urea, creatinine, hemoglobin and hematocrit. Biochemical parameters were determined through the automated colorimetric enzymatic method in Cobas Mira® (Roche, Switzerland) and LDL-c was estimated by the Friedewald equation. Serum insulin concentration was determined by immunofluorometry and the insulin resistance calculated by the HOMA-IR – Homeostasis Model Assessment Insulin Resistance, and values ≥ 2.5 values were considered as presence of insulin resistance(16). Glomerular Filtration Rate (GFR) was estimated by the Cockroft-Gault equation adapted to obese patients(17). Endothelial function Endothelial function was assessed by Endothelial-dependent flow-mediated dilation (FMD) of the brachial artery(18), using an ultrasound system (Sonos5500; Hewlett-Packard-Phillips, Palo Alto, CA), equipped with vascular software for two-dimensional imaging, color and spectral Doppler ultrasound modes, internal electrocardiogram monitor and linear-array transducer with a frequency range from 7.5 to 12.0 MHz. FMD evaluation was performed in two stages: fasted at least 6 hours and 2 hours after the consumption of a small meal, according to each diet. These meals were consisted of 374.04 calories, 36g proteins, 16g carbohydrates and 18g lipids in the DD and in TD, it was composed by 361.20 calories, 24g of protein, 41g of carbohydrates and 11g of lipids. Statistical Analysis The variables were expressed as mean and standard deviation. The distribution of the date normality was analyzed by the Kolmogorov-Smirmov (KS) test. When they did not present normal distribution, a logarithm [log(Y)] transformation was performed prior to analysis. The comparison between the variables of two groups was performed using Student's t-test for independent numerical variables and Fisher's exact test for categorical variables. Comparisons between more than two groups were performed by analysis of variance (ANOVA) for repeated measures, followed by the Tukey test, if differences were found. For the sample power calculation, the Statistical Software, Statistica Ultimate Academic, version 12.7, Concurrent Network was used. Values of p ≤ 0.05 were considered for statistical significance and analysis was performed using the software [GraphPadPrism 4.0 (GraphPad Software, San Diego, CA, USA)]. Results Participants’ characteristics At the beginning of the study, the groups were matched for age, gender, weight and BMI. At 3 months, all participants of DD group (100%) were in phase 2; at 6 months, 13 participants (76.4%) were in phase 3 and 4 (23.5%) in phase 2; and at 12 months, all (100%) were already in phase 4. The TD group followed the same recommendation during the 12 months. The qualitative evaluation of the presence of ketone bodies in the urine of the DD group participants, which were still in phase 2, was positive in 94% at 3rd month and 80% at the 6th month. The following adverse effects have been reported during the course of the study: weakness, fatigue, dizziness, lack of concentration, irritability, constipation, ketone breath and social life impairment. These symptoms were of low intensity and transient, especially in the early stages of the DD diet. These adverse effects were not causes for withdrawal from the study. Anthropometry The changes in body weight, BMI, waist abdominal circumference and BMR were more effective in DD than TD group during all follow-up evaluations. The changes after 12 months in relation to baseline of the anthropometric parameters in the DD and DT groups respectively were: Weight loss (-10.6 Kg, p<0.0001 and – 2.9 Kg, p<0.0001), BMI (-3.7 Kg/m2, p<0.0001 and -1.1 Kg/m2, p<0.0001), waist abdominal circumference (-11.2 cm, p<0.0001 and -2.1 cm, p=0.0008) and BMR (-152 cal, p<0.0001 and -28 cal, p=0.0198). After 12 months, the participants of DD group reached the overweight level but the TD group was still within the obesity range. Reductions were observed in both groups, in fat mass (-5.7 Kg, p<0.0001 and -2.0 Kg, p<0.0001), and in lean mass (-4.8 Kg, p<0.0001 and -0.8 Kg, p=0.0196, in DD and DT group, respectively). Laboratory parameters and endothelial function In TD group, there was only hematocrit reduction after 6 months (p=0.0103) and glucose level after 3 months (p=0.0021) compared to baseline. In DD group, laboratory alterations occurred in relation to hemoglobin, hematocrit, triglycerides, insulin, HOMA-IR and GFR. It was observed an improvement in the triglycerides levels (172.40 ± 62.36 mg/dL and 111.90 ± 43.22 mg/dL, p=0.0001) and insulin resistance determined by HOMA-IR at all times of study (4.98 ± 3.03 and 3.26 ± 2.03, p=0.0008) at baseline and 12 months, respectively. GFR was reduced only after 3 months (132.50 ± 31.13 and 113.80 ± 24.25 mL/min, p=0.0063) in the DD group. No differences were observed in endothelial function in the two study groups, in both fasting and postprandial. Discussion This study demonstrated higher weight loss in the Dukan diet group, compared to the traditional low calorie diet. The effect of weight loss in the DD group was persistent and remained until 6th month, but in 12 months it was observed a gain around 3.41 ± 0.21 Kg. The DD is performed in phases, with severe restriction until the 3rd phase and at about the 6th month; carbohydrates and a gala meal are reintroduced, promoting a weight gain. Sacks et al. observed that regardless of the nutritional composition of the diet, obese participants that had a weight loss, after 12 months of treatment, they can gain weight, but with a reduction of approximately 11.4% of the initial weight(19). We observed that participants of TD group also presented significant weight reduction, suggesting the effectiveness of the close follow up with nutritionist and physician. Abdominal circumference is an indirect parameter of fat mass corresponding to visceral fat that is associated with a higher risk for cardiovascular diseases. In our data, we observed a reduction in waist circumference in both groups after 12 months. Moreno et al. comparing ketogenic diet with standard diet in a group of obese patients found an important reduction in abdominal circumference with partial recovery after 24 months(20). Although DEXA Scan is considered the gold standard for body composition determination, BIA is a non-invasive and relatively inexpensive method and widely used(21). A significant reduction in the relative values of body fat was observed at 3 and 6 months in the DD group and only after 3 months in the TD. Increase in percent of lean mass was observed in the DD group at 3 and 6 months, but this increase does not represent a gain of lean mass, since the relative increase is a result of the reduction of body weight, promoting a relative increase in the values of lean mass. The loss of lean mass in the DD group may be due to the low caloric intake of the diet, as Chaston et al. (2007) pointed out that diet with low-calorie diet promote marked weight loss, but there is a decline in lean mass resulting from this process(22) . In our study, in spite of consuming a large amount of protein, this nutrient alone is not enough to promote the maintenance of lean mass and exercise stimulation is still necessary, which did not happen in this study, since the participants were all sedentary. In obese individuals, weight gain after marked loss is common, with reduction in basal metabolic rate(23). Several studies have observed this phenomenon during rapid weight loss(24) and diets with low carbohydrate intake are among the factors that influence metabolic adaptation. Some studies suggest that low amounts of carbohydrate (<45%) decrease the basal metabolic rate during and after weight loss. This type of diet can promote fat mass loss and preservation of lean mass during weight loss, reducing the basal metabolic rate. Reduction in BMR was observed in both groups, but in the DD group, the reduction occurred at all times in relation to baseline whereas in TD group the reduction was greater only after 6 months of intervention. Improvement in insulin resistance and triglycerides were observed only in the DD group. Individuals with insulin resistance have greater difficulty to metabolize carbohydrates, diverting a greater amount of dietary carbohydrates to the liver, where much of it is converted to fat (lipogenesis), rather than being oxidized in energy in the skeletal muscle. For this reason, very low carbohydrate diets applied in obese individuals, in addition to leading to weight loss also improves glycemic and lipid control. The effects of the very prolonged ketogenic diet are still poorly investigated and for this reason this diet should only be used for a limited period (from 3 weeks to a few months) to stimulate fat loss, improve metabolism, and then adjusting a transition to a normal diet(25). No changes in levels of total cholesterol, HDL-c and LDL-c were observed in any group. However, only in the DD group there was a significant reduction in TG level. In general, diets with reduced carbohydrates and high levels of proteins and fats increase LDL-c and TG levels showing beneficial effects of the ketogenic diet on cardiovascular risk factors. Most studies show that reducing carbohydrates can bring significant benefits in reducing total cholesterol, increases in HDL-c and reduction of triglycerides in the blood. HMG-CoA reductase, a key enzyme in the synthesis of endogenous cholesterol is activated by insulin, so that a reduction in blood glucose and hence insulin levels, leads to lower cholesterol synthesis. Thus, a reduction in dietary carbohydrate associated with adequate cholesterol consumption leads to inhibition of cholesterol biosynthesis(26). When insulin is elevated, lipolysis is reduced and lipogenesis is increased, resulting in overproduction of VLDL containing TG, formation of small and dense LDL particles and reduction of HDL. Low concentrations of glucose and insulin also reduce the expression of the carbohydrate-sensitive response element binding protein (ChREBP) transcription factor, and expression of the binding protein of the sterol regulatory element (SREBP-1c), responsible for the synthesis of fatty acids, as well as their incorporation into triglycerides and phospholipids, activating the main lipogenic enzymes, reducing hepatic lipogenesis and VLDL production(27). When we evaluated the GFR, a reduction only in DD group was observed at 3 months of intervention, but still in normal reference levels. Our results did not show significant changes in serum creatinine levels, but GFR decrease in DD group. Carbohydrate-restricted diets have higher amounts of protein may affect glomerular filtration leading to progressive loss of renal function(28). In the study conducted by Brinkworfh et al. (2010), renal function was evaluated in 68 obese individuals without renal dysfunction who consumed two similar hypocaloric diets for one year, one with carbohydrate reduction and another with high carbohydrate content, and observed that creatinine serum levels and the GFR did not change in any of the dietary groups(29). In general, endothelial function improves after weight loss in obese individuals(30). However, associations between changes in endothelial function with anthropometric and biochemical parameters are still controversial(31). We observed that the endothelial function did not present a significant difference in the two study groups, both in fasting and in the 2 hours postprandial. Volek et al. (2009) observed that low-carbohydrate diet improves postprandial vascular function compared to a low-fat diet in overweight individuals with moderate hypertriglyceridemia(32). Low-carbohydrate diets, may improve vascular function in individuals with metabolic adaptations(32) and carbohydrate-restricted diets may induce benefits in endothelial function in the presence of insulin resistance, since impaired insulin action may be related to endothelial dysfunction. In our study, the meal offered for postprandial evaluation was not high in fat, but correspond to the diet proposed in each group. According to Nicholls et al. (2006), a single carbohydrate-restricted meal does not alter endothelial function(33) and this may be the reason we did not observe a change in endothelial function in the DD group in this study. Conclusion Comparing the nutritional and laboratory effects of traditional and hyper-protein diets with carbohydrate reduction, we can conclude that Dukan diet was more effective than traditional diet for weight loss, as well as for laboratory parameters and without changes in endothelial function, in the 12-months follow-up of obese subjects. Conflict of interest No conflict of interest. Acknowledgement Patricia Naomi Sakae had a scholarship from CAPES – Brazil. References Gogebakan O.; Kohl A.; Osterhoff MA.; van Baak MA.; Jebb SA.; Papadaki A.; et al. Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial. Circulation. 2011, 124(25), 2829-2838. Merino J.; Kones R.; Ferre R.; Plana N.; Girona J.; Aragones G.; et al. 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The catalytic reduction of the alkene 1 gave the cis-fused product (not illustrated), by kinetic H₂ addition to the less congested face of the alkene. Ryan A. Shenvi of Scripps La Jolla found (J. Am. Chem. Soc. 2014, 136, 1300) conditions for stepwise HAT, con­verting 1 to the thermodynamically-favored trans-fused ketone 2. Seth B. Herzon of Yale University devised (J. Am. Chem. Soc. 2014, 136, 6884) a protocol for the reduc­tion, mediated by 4, of the double bond of a haloalkene 3 to give the saturated halide 5. The Shenvi conditions also reduced a haloalkene to the saturated halide. Daniel J. Weix of the University of Rochester and Patrick L. Holland, also of Yale University, established (J. Am. Chem. Soc. 2014, 136, 945) conditions for the kinetic isomerization of a terminal alkene 6 to the Z internal alkene 7. Christoforos G. Kokotos of the University of Athens showed (J. Org. Chem. 2014, 79, 4270) that the ketone 9, used catalytically, markedly accelerated the Payne epoxidation of 8 to 10. Note that Helena M. C. Ferraz of the Universidade of São Paulo reported (Tetrahedron Lett. 2000, 41, 5021) several years ago that alkene epoxidation was also easily carried out with DMDO generated in situ from acetone and oxone. Theodore A. Betley of Harvard University prepared (Chem. Sci. 2014, 5, 1526) the allylic amine 12 by reacting the alkene 11 with 1-azidoadamantane in the presence of an iron catalyst. Rodney A. Fernandes of the Indian Institute of Technology Bombay developed (J. Org. Chem. 2014, 79, 5787) efficient conditions for the Wacker oxida­tion of a terminal alkene 6 to the methyl ketone 13. Yong-Qiang Wang of Northwest University oxidized (Org. Lett. 2014, 16, 1610) the alkene 6 to the enone 14. Peili Teo of the National University of Singapore devised (Chem. Commun. 2014, 50, 2608) conditions for the Markovnikov hydration of the alkene 6 to the alcohol 15. Internal alkenes were inert under these conditions, but Yoshikazo Kitano of the Tokyo University of Agriculture and Technology effected (Synthesis 2014, 46, 1455) the Markovnikov amination (not illustrated) of more highly substituted alkenes.

In a continuation of his studies (OHL20141229, OHL20140811) of organocatalyzed 2+2 photocycloaddition, Thorsten Bach of the Technische Universität München assembled (Angew. Chem. Int. Ed. 2014, 53, 7661) 3 by adding 2 to 1. Li-Xin Wang of the Chengdu Institute of Organic Chemistry also used (Org. Lett. 2014, 16, 6436) an organocatalyst to effect the addition of 5 to 4 to give 6. Shuichi Nakamura of the Nagoya Institute of Technology devised (Org. Lett. 2014, 16, 4452) an organocatalyst that mediated the enantioselective opening of the aziridine 7 to 8. Zhi Li of the National University of Singapore cloned (Chem. Commun. 2014, 50, 9729) an enzyme from Acinetobacter sp. RS1 that reduced 9 to 10. Gregory C. Fu of Caltech developed (Angew. Chem. Int. Ed. 2014, 53, 13183) a phosphine catalyst that directed the addition of 12 to 11 to give 13. Armido Studer of the Westfälische Wilhelms-Universität Münster showed (Angew. Chem. Int. Ed. 2014, 53, 9622) that 15 could be added to 14 to give 16 in high ee. Akkattu T. Biju of CSIR-National Chemical Laboratory described (Chem. Commun. 2014, 50, 14539) related results. The photostimulated enantioselective ketone alkylation developed (Chem. Sci. 2014, 5, 2438) by Paolo Melchiorre of ICIQ was powerful enough to enable the alkyl­ation of 17 with 18 to give 19, overcoming the stereoelectronic preference for axial bond formation. David W. Lupton of Monash University established (J. Am. Chem. Soc. 2014, 136, 14397) the organocatalyzed transformation of the dienyl ester 20 to 21. James McNulty of McMaster University added (Angew. Chem. Int. Ed. 2014, 53, 8450) azido acetone 23 to 22 to give 24 in high ee. There are sixteen enantiomerically-pure diastereomers of the product 27. John C.-G. Zhao of the University of Texas at San Antonio showed (Angew. Chem. Int. Ed. 2014, 53, 7619) that with the proper choice of organocatalyst, with or without subsequent epimerization, it was possible to selectively prepare any one of eight of those diastereomers by the addition of 26 to 25. William P. Malachowski of Bryn Mawr College showed (Tetrahedron Lett. 2014, 55, 4616) that 28, readily prepared by a Birch reduction protocol, was converted by heating followed by exposure to catalytic Me3P to the angularly-substituted octalone 29.

Benjamin List at the Max-Planck-Institute in Mülheim reported (Angew. Chem. Int. Ed. 2013, 52, 3490) that the chiral phosphoric acid TRIP catalyzed the asymmet­ric SN2-type intramolecular etherification of 1 to produce tetrahydrofuran 2 with a selectivity factor of 82. The coupling of alkenol 3 with 4 to give the α-arylated tetra­hydropyran 5 via a method that combined gold catalysis and photoredox catalysis was disclosed (J. Am. Chem. Soc. 2013, 135, 5505) by Frank Glorius at Westfälische Wilhelms-Universität Münster. Mark Lautens at the University of Toronto reported (Org. Lett. 2013, 15, 1148) the conversion of cyclohexanedione 6 and phenylboronic acid to bicyclic ether 8 using rhodium catalysis in the presence of dienyl ligand 7. Propargylic ether 9 was found (Org. Lett. 2013, 15, 2926) by John P. Wolfe at the University of Michigan to undergo conversion to furanone 10 upon treatment with dibutylboron triflate and Hünig’s base followed by oxidation with hydrogen peroxide. Tomislav Rovis at Colorado State University demonstrated (Chem. Sci. 2013, 4, 1668) that the spirocyclic compound 13 could be prepared in enantioenriched form from 11 by a photoisomerization- coupled Stetter reaction using carbene catalyst 12. Antonio C. B. Burtoloso at the University of São Paulo reported (Org. Lett. 2013, 15, 2434) the conversion of ketone 14 to lactone 15 using samarium(II) iodide and methyl acrylate. The merger of diketone 16 and pyrone 17 in the presence of Amberlyst-15 to pro­duce (−)- tenuipyrone 18 was disclosed (Org. Lett. 2013, 15, 6) by Rongbiao Tong at the Hong Kong University of Science and Technology. Joanne E. Harvey at Victoria University of Wellington in New Zealand found (Org. Lett. 2013, 15, 2430) that tricy­clic ether 20 could be generated efficiently from dihydropyran 19 and pyrone 17 via a palladium-catalyzed double allylic alkylation cascade. Two rings and four stereocenters were generated in the construction of bicyclic ether 23 from dienol 21 and acetal 22 via a Lewis acid-mediated cascade, as reported (Org. Lett. 2013, 15, 2046) by Christine L. Willis at the University of Bristol.

Haifeng Du at the Chinese Academy of Sciences reported (J. Am. Chem. Soc. 2013, 135, 6810) the borane-catalyzed asymmetric hydrogenation of imine 1 to 2 using the diene 3 as a chiral ligand for boron. A single-enzyme cascade for the reductive transam­ination of acetophenone 4 with amine 5 to produce enantiopure sec-phenethylamine 6 was developed (Chem. Commun. 2013, 49, 161) by Per Berglund at the KTH Royal Institute of Technology in Sweden. A group at Boehringer Ingelheim in Ridgefield, Connecticut, led by Jonathan T. Reeves, disclosed (J. Am. Chem. Soc. 2013, 135, 5565) a procedure for the addition of DMF anion to N-sulfinyl imine 7 to furnish tert-leucine amide 8 with high diastereoselectivity. The tertiary carbinamine 10 was synthesized (Org. Lett. 2013, 15, 34) via the carbolithiation/rearrangement of vinyl­urea 9 as reported by Jonathan Clayden at the University of Manchester. Gregory C. Fu at Caltech reported (Angew. Chem. Int. Ed. 2013, 52, 2525) that the chiral phosphine 12 catalyzed the enantioselective addition of trifluoroacetamide to allene 11 to produce γ-amino ester 13 in enantioenriched form. Adeline Vallribera at the Autonomous University of Barcelona found (Org. Lett. 2013, 15, 1448) that a euro­pium pybox complex effected the highly enantioselective α-amination of β-ketoester 14 to generate 15 on the way to the Parkinson’s disease co-drug L-carbidopa. Hisashi Yamamoto at the University of Chicago and Chubu University reported (J. Am. Chem. Soc. 2013, 135, 3411) that a halfnium(IV) complex of the bishydroxamic acid 17 catalyzed the enantioselective epoxidation of the tertiary homoallylic alcohol 16 to 18. The rearrangement of the allylic carbonate 19 to produce allyl ether 21 with high ee under iridium catalysis in the presence of ligand 20 was disclosed (Org. Lett. 2013, 15, 512) by Hyunsoo Han at the University of Texas, San Antonio. The asymmetric vinylogous aldol reaction of 3-methyl-2-cyclohexen-1-one 22 and α-keto ester 23 to furnish tertiary carbinol 25 using the bifunctional catalyst 24 was developed (Org. Lett. 2013, 15, 220) by Paolo Melchiorre at ICREA and ICIQ in Spain.

Kazuaki Kudo of the University of Tokyo showed (Angew. Chem. Int. Ed. 2013, 52, 11585) that the dienyl aldehyde 1 could be reduced to the saturated aldehyde 2 with high ee. Alexandre Alexakis of the University of Geneva effected (Angew. Chem. Int. Ed. 2013, 52, 12701) conjugate addition to the unsaturated amide 3 to give 4 in high ee. Professor Alexakis also carried out (Chem. Eur. J. 2013, 19, 11352) enantioselective conjugate addition to the alkynyl nitro alkene 5, leading to 6. Gerrit J. Poelarends of the University of Groningen found (Chem. Eur. J. 2013, 19, 14407) that the enzyme 4-oxalocrotonate tautomerase mediated the conjugate addition of acetaldehyde to a nitroalkene 7 to deliver the aldehyde 8 in high ee. Tohru Yamada of Keio University developed (Chem. Commun. 2013, 49, 8371) an enantioselective Cu catalyst for the Claisen rearrangement of 9 to 10. Shi-Kai Tian of USTC Hefei made (Chem. Commun. 2013, 49, 8190) the primary amine of 11 a leaving group, coupling 11 with 12 to make 13. David W. C. MacMillan of Princeton University alkylated (J. Am. Chem. Soc. 2013, 135, 11756) the aldehyde 14 with the boronic acid 15, to give 16 in high ee. Paolo Melchiorre of ICIQ Tarragona effected (Nature Chem. 2013, 5, 750) the enantioselective construction of the quaternary cen­ter of 19 by alkylation of the aldehyde 17 with 18. Other methods for the enantioselective construction of quaternary alkylated cen­ters have also been put forward. Varinder K. Aggarwal of the University of Bristol elaborated (J. Am. Chem. Soc. 2013, 135, 16054) the inexpensive secondary ester 20 into the alkylated product 21. Jianwei Sun of the Hong Kong University of Science and Technology cyclized (Angew. Chem. Int. Ed. 2013, 52, 13593) the prochiral diol 22 to 23 in high ee. Amir H. Hoveyda of Boston College effected (Angew. Chem. Int. Ed. 2013, 52, 8156) enantioselective conjugate addition to the enone 24 to give 25. Xiaoming Feng of Sichuan University devised (Angew. Chem. Int. Ed. 2013, 52, 10883) a catalyst for the addition of the bulky α-diazo ester 26 into the α-keto ester 27, leading to 28.