606 research outputs found
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Synthetic studies of the Thio-Nazarov Cyclization, Biomimetic Total Syntheses of Shimalactones and Exiguamines, and Synthesis of Photoswitchable Dopamine Analogs
No full textSynthetic studies of the Thio-Nazarov CyclizationBiomimetic Total Syntheses of Shimalactones and ExiguaminesSynthesis of Photoswitchable Dopamine AnalogsVladimir SofiyevDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor Dirk Trauner, Co-ChairPart 1 of this thesis describes progress towards thio-Nazarov electrocyclization utilizing substrates with a removable docking group, such as alkyl sulfides, for Lewis acid coordination. This work builds on the successful asymmetric catalysis of Nazarov electrocyclization using non-removable docking groups for coordination of Lewis acids.Parts 2 and 3 of this thesis describe the biomimetic syntheses of the natural products shimalactones and exiguamines respectively. While the synthesis of alkaloids exiguamines A and B is an improvement of our previous work, the synthesis of polyketides shimalactones A and B is their first synthesis and describes a novel intramolecular addition of a b-ketolactone across a diene. Both syntheses feature pericyclic reactions in their key step biomimetic cascade reactions.Part 4 of this thesis describes the synthesis of photoswitchable derivatives of dopamine, containing azobenzenes
Pro-apoptotic activity of lipidic α-amino acids isolated from Protopalythoa variabilis
No full textLipidic alpha-amino acids (LAAs) have been described as non-natural amino acids with long saturated or unsaturated aliphatic chains. In the continuing prospect to discover anticancer agents from marine sources, we have obtained a mixture of two cytotoxic LAAs (1a and 1b) from the zoanthid Protopalythoa variabilis. The anti-proliferative potential of 14 synthetic LAAs and 1a/1b were evaluated on four tumor cell lines (HCT-8, SF-295, MDA-MB-435, and HL-60). Five of the synthetic LAAs showed high percentage of tumor cell inhibition, while 1a/1b completely inhibited tumor cell growth. Additionally, apoptotic effects of 1a/1b were studied on HL-60 cell line. 1a/1b-treated cells showed apoptosis morphology, loss of mitochondrial potential, and DNA fragmentation. (C) 2010 Elsevier Ltd. All rights reserved
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I. Total Synthesis of Smenochromene B and Halenaquinone and II. Studies on the Chemical and Biological Properties of Azobenzene Photoswitches
No full textPart one of this dissertation describes synthetic efforts toward two separate but structurally related groups of marine sesquiterpene quinone natural products, the smenochromene/likonide family and halenaquinone, and culminates in the total synthesis of smenochromene B and halenaquinone. The total synthesis of smenochromene B and efforts towards likonide A centered around the use of smenochromene D as a synthetic intermediate. A macrocyclic ring contraction and double bond isomerization was the key transformation necessary to produce smenochromene B. During the optimization of the synthesis of smenochromene D, two different and remarkable oxidative dimers were isolated, and the mechanism by which they are formed is discussed. Additionally, density functional theory calculations were used to investigate the oxa-6π electrocyclization used to synthesize smenochromene D and are believed to be biologically relevant to the markedly different levels of enantiomeric excess observed within members of the structural family. Halenaquinone, a biologically active pentacyclic quinone isolated from the marine sponge Xestospongia exigua, is biosynthetically related to the smenochromene/likonide family. The total synthesis of halenaquinone reported here features two key steps: a diastereoselective intramolecular Heck reaction, which sets the all-carbon quaternary stereocenter, and an intramolecular inverse-electron-demand Diels-Alder cycloaddition using a vinyl-orthoquinone methide as a diene. This is the first application of such a Diels-Alder cycloaddition to total synthesis. In order to better understand the Diels-Alder reaction, density functional theory calculations were performed to analyze two relevant transition states. Part two describes several projects focused around the synthesis of photoswitchable azobenzene ligands. In order to build on previous work that demonstrated photoregulation of wild-type voltage-gated potassium channels by membrane permeable blockers, a new series of compounds was synthesized with red-shifted absorption maxima. Two new azobenzene containing blockers were identified as being able to regulate voltage-gated potassium channels by toggling between darkness and irradiation with 472 nm light; one compound blocked voltage-gated potassium channels in the trans form, the other in the cis form. Additionally, azobenzene compounds based on the drugs lidocaine and retigabine were synthesized, and preliminary biological data are reported. Finally, the syntheses of azobenzene analogs of the anti-cancer and life-extending (in lower organisms) compound resveratrol and a related protein-tyrosine kinase inhibitor piceatannol are reported
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Total Synthesis of (+)-Spectinabilin, Taiwaniaquinoids, Synthetic Progress toward Aspergillin PZ, and Synthesis of a Photoswitchable Agonist of Glutamate Receptor-dMAG
No full textA new and highly enantioselective synthetic route to γ-methoxypyranone addressed the long unsolved racemization problem in literature. A concise total synthesis of (+)-Spectinabilin was achieved with this method in 10 linear steps. Concept of kinetic resolution with temporary stereocenter was used to improve the enantiomeric excess.A new variant of Nazarov reaction, aromatic Nazarov triflation was discovered which allowed rapid access of polycyclic ring skeleton. The triflation product, indene triflate, was further elaborated with modern palladium cross coupling methods in the total syntheses of many taiwaniaquinoid natural products. Also, the triflation method worked well with electron rich and neutral substrates and was not compatible with electron deficient substrates.Effort toward total synthesis of Aspergillin PZ was described. The biomimetic synthetic hypothesis was pursued. Synthesis of all components was achieved. Future work would be focused on mild reaction condition to bring all components together to for the key intermediate for Aspergillin PZ.Finally, based on the similar principle of previous work in our group, a photoswitchable agonist for metabotropic glutamate receptors was designed and synthesized. Preliminary results confirmed the agonist activity and reversible isomerization with radiation of light of different wavelengths. Further studies are under investigation under collaboration
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Synthesis of Coralloidolide B, Coralloidolide C, a Photochemical Synthesis of Intricarene, and Progress Towards the Synthesis of Bielschowskysin
No full textThe total synthesis and synthetic efforts towards several diterpene natural products are described. The syntheses of the furanocembranoids coralloidolide B and coralloidolide C were both achieved in a single step from coralloidolide E. The furanocembranoid bipinnatin J was used in a model system to explore the conditions necessary to effect a transannular [2+2] cycloaddition in assembling the pentacyclic core of bielschowskysin. Two distinct strategies were evaluated as part of this model system for their effectiveness in synthesizing the cyclobutane ring of bielschowskysin. Progress was also made towards synthesizing a macrocyclic precursor of bielschowskysin. Numerous selective oxidations of the furanocembranoid carbon framework were discovered which should find utility in the synthesis of other members of this family of diterpenes. Several novel transformations of furanocembranoid derivatives are described, along with a synthesis of the furanocembranoid intricarene through photochemical means
Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder
No full textBoth Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD
Patterns of Sensitivity to Emotion in Children with Williams Syndrome and Autism: Relations Between Autonomic Nervous System Reactivity and Social Functioning
No full textWilliams syndrome (WS) and autism spectrum disorder (ASD) are associated with atypical social-emotional functioning. Affective visual stimuli were used to assess autonomic reactivity and emotion identification, and the social responsiveness scale was used to determine the level social functioning in children with WS and ASD contrasted with typical development (TD), to examine syndrome-specific and syndrome-general features. Children with ASD exhibited the highest arousal in response to faces, with a lack of difference in autonomic sensitivity across different emotional expressions, unlike in WS and TD. The WS group demonstrated unique deficits in identifying neutral stimuli. While autonomic responsivity to neutral faces was associated with social functioning in all children, converging profiles characterized children with WS contrasted with TD and ASD
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Total Synthesis of Amphilectolide, Sandresolide B, Archazolid B and towards Archazolid A and Caribenol A
No full textThe total synthesis and synthetic efforts toward norditerpene natural products isolated from Pseudopterogorgia elisabethae and macrocyclic polyketides from Archangium gephyra is described. A highly convergent synthesis of archazolid B, uniting three linear subunits, is accomplished using various modern transition-metal catalyzed reactions. A relay ring-closing metathesis is featured for closure of the 24-membered macrocyclic ring. Construction of the carbon skeleton of archazolid A is also described, featuring two robust, scaleable building blocks and their unification. New strategies for the construction and elaboration of a 1,4 skipped diene moiety are established in this synthesis.The total synthesis of norditerpenes amphilectolide and sandresolide B are also described. A palladium mediated carbonylative coupling is featured en route to the preparation of a key furan building block that can be used to access several norditerpene natural products produced from Pseudoterogorgia elisabethae. This key building block was then elaborated to amphilectolide utilizing a lanthanide catalyzed ring closure and furan oxidation with singlet oxygen. The ring-closure product may also be used to access caribenol B. The furan building block was also used to construct sandresolide B, where a Myers alkylation overcame steric constraints in this system. An intramolecular Friedel Crafts acylation is used to close a 7-membered ring. These strategies also provide insight to a next generation route toward caribenol A, and the progress toward the initial strategy via Stork-Danheiser ring closure is described
Possibilities, Limitations and Problems in Retiming - a View from a Logical Perspective
No full textThis paper gives a formal description of retiming and analyzes its possibilities. The paper is based on a theory for automata in HOL, which is dedicated towards formal hardware representation and transformations
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