Cross-coupling reactions of unactivated alkyl halides

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.Vita.Includes bibliographical references.My graduate research at MIT has been focused on the development of palladium- or nickel-catalyzed cross-coupling reactions using unactivated alkyl electrophiles (e.g., halides and sulfonates). Although aryl and alkenyl electrophiles have been commonly used in such processes, the utility of alkyl substrates has been underdeveloped, and merits further exploration. We have developed the first palladium-based catalyst that is effective for Negishi couplings of primary alkyl electrophiles. A single protocol (2%Pd₂(dba)₃/8%P(Cyp)₃/NMI in THF/NMP at 80⁰C) can be applied to a broad spectrum of electrophiles, including chlorides, bromides, iodides, and tosylates. Concerning the scope of the nucleophilic components, an array of alkyl-, alkenyl-, and arylzinc halides can be coupled. The process is tolerant of a variety of functional groups, including esters, amides, imides, nitriles, and heterocycles. Furthermore, geometrically- defined alkenylzinc species, generated from titanium-mediated hydrozincation of internal alkynes, can be directly used in the process. Despite the progress in nickel- and palladium-catalyzed C(sp³)-C(sp³) bond formation, the methods had been limited to primary alkyl electrophiles.(cont.) No doubt, the ability to use more challenging, secondary ones will further augment the usefulness of these metal- catalyzed processes. To this end, we have determined that Ni(cod)₂/s-Bu-Pybox can catalyze room-temperature Negishi couplings of an array of functionalized alkyl bromides and iodides. To the best of our knowledge, this is the first nickel- or palladium- catalyzed cross-coupling procedure for unactivated, [beta]-hydrogen-containing secondary alkyl halides. In addition, preliminary studies using substrate-based probes suggest that the oxidative addition proceeds through a radical pathway. This may explain the unparalleled reactivity of the nickel catalyst. As an extension of the nickel catalysis, we have established that the combination of Ni(cod)₂ and bathophenanthroline can effect Suzuki reactions of secondary halides and organoboronic acids. These organoboron reagents are particularly widely used in the cross-coupling chemistry, owing to their chemical stability, biological non-toxicity, and commercial availability. Again, mechanistic evidence has been collected to support the involvement of organic radicals during the oxidative addition step.by Jianrong (Steve) Zhou.Ph.D

Reinforced Lin-Kernighan-Helsgaun Algorithms for the Traveling Salesman Problems

TSP is a classical NP-hard combinatorial optimization problem with many practical variants. LKH is one of the state-of-the-art local search algorithms for the TSP. LKH-3 is a powerful extension of LKH that can solve many TSP variants. Both LKH and LKH-3 associate a candidate set to each city to improve the efficiency, and have two different methods, $\alpha$-measure and POPMUSIC, to decide the candidate sets. In this work, we first propose a Variable Strategy Reinforced LKH (VSR-LKH) algorithm, which incorporates three reinforcement learning methods (Q-learning, Sarsa, Monte Carlo) with LKH, for the TSP. We further propose a new algorithm called VSR-LKH-3 that combines the variable strategy reinforcement learning method with LKH-3 for typical TSP variants, including the TSP with time windows (TSPTW) and Colored TSP (CTSP). The proposed algorithms replace the inflexible traversal operations in LKH and LKH-3 and let the algorithms learn to make a choice at each search step by reinforcement learning. Both LKH and LKH-3, with either $\alpha$-measure or POPMUSIC, can be significantly improved by our methods. Extensive experiments on 236 widely-used TSP benchmarks with up to 85,900 cities demonstrate the excellent performance of VSR-LKH. VSR-LKH-3 also significantly outperforms the state-of-the-art heuristics for TSPTW and CTSP.Comment: arXiv admin note: text overlap with arXiv:2107.0687

Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase

Abstract Background Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo. Methods The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases. Results The red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge. Conclusion This is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes