The development of new, efficient and economical methods for the preparation of functionalized, optically enriched piperidines is important in the field of drug discovery where this class of heterocycles is often deemed a privileged structure. We have optimized a Pd-catalyzed enantioselective borylative migration of an alkenyl nonaflate derivative of the simple precursor, N-Boc-4-piperidone. This anomalous borylation reaction lends access to a chiral optically enriched piperidinyl allylic boronate that can be employed in carbonyl allylboration and stereoselective cross-coupling to produce substituted dehydropiperidines related to numerous pharmaceutical agents. A systematic fine-tuning of reaction conditions revealed that diethyl ether and the green solvent cyclopentyl methyl ether are suitable reaction solvents providing the highest enantioselectivity (up to 92% ee) under a low catalyst loading of 3 mol%. Optimization of the aldehyde allylboration step led to higher yields with further solvent economy. The multigram-scalability of the entire process was demonstrated under the reaction conditions that provide optimal atom-economy and efficiency.
This study examines the levels of social interaction, depression, and homeboundness, and the effects of social interaction and depression on homeboundness in community-dwelling older adults living alone. Survey data were collected from 6444 older adults aged 65 and over, living alone, who registered for individualized home care services at 42 public health centers in Gyeonggi Province. A total of 5996 participants with complete questionnaire data were included in the analysis. The mean social interaction score was 2.90 out of 6, and the mean depression score was 6.21 out of 15. The mean homeboundness score was 0.42 out of 2. A hierarchical multiple regression analysis was performed with general characteristics, health factors, social interaction, and depression to identify their effects on homeboundness. In general characteristics and health factors, homeboundness is associated with decreasing social interaction (β = 0.17, p < 0.001) and increasing depression (β = 0.25, p < 0.001) in older adults living alone. Homeboundness was severe among participants aged 80 and over (β = 0.04, p = 0.015) and those with several chronic diseases (β = 0.04, p < 0.001), falling history (β = 0.14, p < 0.001), and lack of exercise (β = −0.20, p < 0.001). Thus, interventions that target social interaction, depression, and health functions are important for this demographic.
In 2009, one of our laboratories described a palladium-catalyzed enantioselective borylative migration reaction of heterocyclic enol perfluorosulfonates that provides ready access to optically enriched, synthetically useful dihydropyranyl and dehydropiperidinyl allylic boronates 3 and 4. However, several aspects of the catalytic cycle and the mechanism of enantiomeric induction of the anomalous borylation reaction that produces 3 and 4 remain unknown or ambiguous. Herein, a combination of experimental and computational studies suggests that the reaction is initiated by a Miyaura-type borylation, followed by an alkene isomerization pathway involving an electrophilic cationic palladium species. According to reaction kinetics analysis and computations, the first step of oxidative addition to afford the alkenylpalladium-(II) triflate complex Int-2 is the rate-determining step of the overall reaction. Following the complexation of pinacolborane to the cationic alkenylpalladium Int-4 to form the hydride complex Int-5, a face-selective enantio-determining transmetallation via σ-bond metathesis affords the η-2 alkenylboronate-bound palladium(II) hydride Int-6. While formation of this chiral intermediate is key, the calculations suggest that the stereoinduction process is further complicated by a possible reversibility in formation of the intermediate Int-5 preceding the σ-bond metathesis. Moreover, the enantioselectivity is inversely proportional to the pK aH of the amine base owing to protonation of the dimethylamine moiety on the Taniaphos ligand. From Int-6, alkene insertion, β-hydride elimination, and subsequent deprotonation and decomplexation lead to the allylboronate product with regeneration of the palladium(0) catalyst. The ratio of allylboronate to alkenylboronate products depends primarily on the presence of the heteroatom, which provides relative π-stabilization of the palladium hydride complex obtained after alkene isomerization.
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