Browsing by Subject "Total synthesis"
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Item Application of the Moore rearrangement to the synthesis of 1,4-dioxygenated xanthones and efforts toward the total synthesis of lundurine B(2012-12) Nichols, Alexander Lindsey; Martin, Stephen F.; Iverson, Brent; Willson, C. G.; Kerwin, Sean; Keatinge-Clay, AdrianA novel application of the Moore rearrangement was successfully developed and applied to the synthesis of 1,4-dioxygenated xanthones that would have been difficult to obtain otherwise. The 1,4-dioxygenated xanthone moiety is found in several naturally occurring, biologically active compounds. Several methods by which to obtain the 1,4-dioxygenated xanthone core have been reported; however, high step counts, low yields, and harsh reaction conditions preclude the use of these methods to complex xanthone natural products. Using the Moore rearrangement as a key step in the synthetic sequence has allowed us to prepare several xanthone natural products quickly and more efficiently than what is possible with the prior art. Using the Martin group’s prior experience with the application of ring closing metathesis (RCM) to the field of alkaloid natural product synthesis, the preparation of lundurine B was undertaken. Key features of the proposed synthesis to lundurine B include the formation of a cyclopropane ring by the formation pyrazoline intermediate via [3+2] dipolar cycloaddition followed by dinitrogen extrusion. A second key step in the proposed sequence to lundurine B is a double RCM to form a five- and eight-membered ring in a single operation. While double RCM strategies have been applied to several elegant natural product syntheses, the formation of a five- and eight-membered ring in a single sequence has not been reported. Should the double RCM strategy prove successful for lundurine B, the conditions could in principle be applied to other structurally related natural products.Item An approach towards the synthesis of Nakadomarin A and Manzamine A Using Pauson-Khand technology(2004-05) Wells, Charles Eugene; Magnus, Philip D.This dissertation is devoted to our synthetic studies towards the total synthesis of the natural product Nakadomarin A, and Manzamine A using the Pauson-Khand reaction as the key step. Chapter 1 reviews past work using Pauson-Khand technology. Chapter 2 reviews the N-alkyl piperidine family of natural products. Chapter 3 reviews published total syntheses of Manzamine A and Nakadomarin A. Chapter 4 explores our work using the Pauson-Khand reaction to form the ABC rings of Nakadomarin A and subsequent B ring expansion to form the ABC ring core of Manzamine A. Chapter 5 explores our approaches to the furan portion, as well as, our approaches to the macrocyclic F ring. Finally Chapter 6 contains the description of the experiments performed along with relevant analytical data.Item Carbon-carbon bond formation via catalytic hydrogenation and transfer hydrogenation : application in the total synthesis of bryostatin 7(2012-08) Lu, Yu, active 2012; Krische, Michael J.Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, two protocols of iterative chain elongation of 1,3-diols to furnish 1,3-polyols were developed. First, one-directional chain elongation employing mono-protected 1,3-diols as starting materials was achieved. In all cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Then, double asymmetric allylation of 1,n-glycols to deliver C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Iterative two-directional elongation of 1,3-diols to furnish 1,3-polyols with high level of catalyst-directed diastereoselectivity was then achieved. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of a known bryostatin A-ring fragment and the total synthesis of bryostatin 7.Item Development and application of metal catalyzed transfer hydrogenative C-C bond forming reactions(2016-05) Waldeck, Andrew Robert; Krische, Michael J.; Martin, Stephen F; Dong, Guangbin; Brodbelt, Jennifer S; Kerwin, Sean MWhile polyketides display a diverse range of biological properties and are used extensively in human medicine, a lack of methods for the concise preparation of these complex structures still poses a significant challenge in the field of synthetic organic chemistry. To address this issue, metal catalyzed methods for transfer hydrogenative C-C bond formation have been developed. These methods construct products of carbonyl addition through direct C-H bond functionalization, which provides a more atom economic and efficient approach to carbonyl addition products and circumvents the need for stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-carbonyl redox reactions. Efforts have been focused on the development of ruthenium-catalyzed coupling reactions of secondary alcohols to basic chemical feedstocks as well as the application of iridum-catalyzed couplings of primary alcohols with π-unsaturates in the context of the total syntheses of (−)-cyanolide A and (+)-cryptocaryol A. These total syntheses represent the most concise route reported to date for each natural product and illustrate the synthetic utility of transfer hydrogenative C-C bond forming methodology.Item Development of multicomponent assembly processes and their application to the synthesis of novel heterocyclic scaffolds and the total synthesis of actinophyllic acid : application of an iminium ion mediated cascade(2013-08) Granger, Brett Adam; Martin, Stephen F.Several novel multicomponent assembly processes have been developed for the preparation of a diverse array of complex heterocyclic systems from relatively simple starting materials. These studies resulted in the discovery of a new quinazolone forming reaction, which was applied to the one-step synthesis of the quinazolinocarboline alkaloid rutaecarpine. Biological screening of these complex heterocycles culminated in the identification of a potent sigma-2 receptor ligand. A novel N-acyliminium ion mediated cascade reaction was employed for the concise synthesis of (±)-actinophyllic acid. The completion of the synthesis relied on the development of a reaction sequence that avoided a potentially detrimental fragmentation process. Furthermore, several anti-cancer compounds were identified through a diverted total synthesis approach.Item Development of new transition metal catalyzed C-C bond forming reactions and their application toward natural product synthesis(2011-12) Hassan, Abbas; Krische, Michael J.; Anslyn, Eric V.; Siegel, Dionicio R.; Brodbelt, Jennifer S.; Liu, Hung-WenIn Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes.Item Formation of C-C bonds via transfer hydrogenation : from methodology development to natural product synthesis(2013-08) Gao, Xin, active 2013; Krische, Michael J.Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, selective silylallylation and CF₃-allylation were developed. In both cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Column chromatography was then tested as a new protocol to purify the iridium precatalyst; this single component precatalyst was proved to be more efficient to promote carbonyl crotylation reactions, both diastereo- and enantioselectivity were increased. Then, double asymmetric crotylation of 1,3-diols to deliver (pseudo-)C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of two known polypropionate natural product fragments of C19-C25 of scytophycin C, C19-C27 of rifamycin S and the total synthesis of 6-deoxyerythronolide B.Item MECHANISTIC STUDIES AND SYNTHETIC APPLICATIONOF MONOHYDROLYSIS OF SYMMETRIC DIESTERS(2010-12) Wang, Hezhen; Niwayama, Satomi; Bartsch, Richard A.; Li, GuigenThe hydrolysis of esters is among the most common and useful reactions in organic chemistry. The monohydrolysis of symmetric diesters can produce half esters, which form intermediates for total syntheses of various important compounds. However, the efficiency for the monohydrolysis of symmetric diesters is low by classical saponification. In order to obtain high yields of products of monohydrolysis from symmetric diesters, enzymes are used in total syntheses. However, because mechanisms of enzyme reactions are not well understood, they often require extensive screening with no clue for the mononhydrolysis of symmetric diesters. Due to these reasons, a new method has been proposed and developed, which can produce a very high yield up to 99% for the mononhydrolysis of symmetric diesters. In this research, we studied co-solvent effects for the reaction rate in the monohydrolysis reaction. Moreover, we expanded the research result of the co-solvent system from organic-aqueous systems to polar-less polar systems, which are used for the drug conjugation, pegylation and coupling reaction. The product of the mononhydrolysis of symmetric dimethyl bicyclo[2.2.1] hept-2,5-diene-2,3-dicarboxylate was used as the starting material for the total synthesis of CMP-New5AC mimics and an important intermediate for the syntheses of natural products with the methylene-bicylo[2.2.1] heptane framework. Asymmetric monohydrolysis of dimethyl bicyclo[2.2.1] Texas Tech University, Hezhen Wang, December 2010 viii hept-2,5-diene-2,3-dicarboxylate was studied without enzymes. In addition, chiral phase transfer catalysts, chiral bases, chiral ionic liquids and chiral catalysts were examined for the asymmetric reaction.Item Selective monohydrolysis of symmetric diesters and total synthesis of a series of pyrenyl maleimide fluorescent chemosensors(2011-08) Zhao, Tian; Niwayama, Satomi; Birney, David M.As an important desymmetriztion reaction, monohydrolysis facilitates modern synthetic organic chemistry by significantly shortening synthetic routes. Half esters produced by monohydrolysis play an important role in organic synthesis. In chapter 2, we studied the monohydrolysis of symmetric dialkyl benzendicarboxylates, including ortho-phthalate, meta-phthalate, para-phthalate. In addition to the stereochemical effect, the solubility was found to be a possible factor that would affect the selectivity of monohydrolysis. The ultrasound-assisted monohydrolysis of bulky symmetric diesters was also discussed in this chapter. Several bulky diesters were monohydrolyzed with ultrasound. We found out that it was possible to increase the reaction rate by ultrasound without decreasing selectivity. In chapter 3, a mechanism of monohydrolysis was proposed, and the possibility to prove the mechanism by measuring critical micelle concentrations of intermediates is discussed. In additional to the research on monohydrolysis, a synthetic study of a series of new and effective pyrenyl maleimide fluorescent probes for sampling of longer inter-thiol distances was also conducted. In chapter 4, the syntheses of pyrenylbutyl maleimide, pyrenyloctyl maleimide and pyrenyldecyl maleimide were discussed. Further spectroscopic characterization of pyrenylbutyl maleimide showed it was an excellent probe to assess proximities between cysteine in proteins or thiols in macromolecules, and to follow conformational changes.Item Studies directed toward the total synthesis of cortistatin A(2010-08) Littich, Ryan Andrew; Magnus, Philip D.; Anslyn, Eric V.; Siegel, Dionicio R.; Fast, Walter L.; Jones, Richard A.Studies directed toward the total synthesis of the cytotoxic steroidal alkaloid cortistatin A were carried out. In a model system, it was determined that a sequence of reactions involving a lithiocyclopropene addition-intramolecular [4 + 2] cycloaddition cascade and subsequent cyclopropylcarbinyl rearrangement allowed for ready access to the BCD rings of the core steroid. Implementation of this methodology en route to the fully functionalized natural product proved an effective means for the elaboration of the A ring carbocyclic framework.Item Studies on the total synthesis of (±)-rocaglamide(2009-08) Freund, Wesley Allen; Magnus, Philip D.; Bielawski, Christopher W.; Siegel, Dionicio R.; Jones, Richard A.; Fast, Walter L.The use of a Nazarov cyclization for the diastereoselective synthesis of rocaglamide was studied. Chapter 1 discusses the biological activity of the rocaglamide family of natural products and details the previous synthetic work on these compounds. Chapter 2 discusses the approaches taken in the Magnus group for the total synthesis of rocaglamide. Several approaches to the natural product were undertaken. Using a novel acid bromide induced Nazarov cyclization, construction of the C-ring of the natural product was achieved. Attempts to construct the remainder of rocaglamide were ultimately unsuccessful.Item Studies toward the total synthesis of (–)-stolonidiol : a small molecule inducer of choline acetyltransferase(2012-05) Barton, Thomas John; Siegel, Dionicio R.; Magnus, Philip D.; Kerwin, Sean M.; Cowley, Alan H.; Willson, GrantThe marine diterpene (–)-stolonidiol (1) has been shown to upregulate neuronal levels of acetylcholine. The mechanism through which a small molecule can impart this allosteric-like effect is currently unknown. A laboratory preparation of the natural product was undertaken in order to produce matieral for biological testing and elucidation of the unknown mechanism of action. During the course of this study, a tandem enyne-Suzuki reaction was investigated to form both rings of the fused bi-cyclic structure 26 in a single operation, but was met with undesired diastereoselectivity in the first cyclization step. The directing effect was found to be general on 1,6-homopropargyl enynes. Further efforts toward the molecule focused on an enantioselective formation of the cyclopentane core through an extension of a copper-mediated silylcyclization of epoxyalkyne 71. Using this intermediate two routes involving acrylate as a lynchpin to close the large ring were investigated. Additionally, a route designed to employ an intramolecular Knoevenagel condensation was explored to generate this ring system.Item Synthetic studies on the pluramycin family of antitumor antibiotics : the total synthesis of isokidamycin(2010-12) O'Keefe, Brian Michael; Martin, Stephen F.; Krische, Michael J.; Bielawski, Christopher W.; Laude, David A.; Whitman, Christian P.A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling.Item Synthetic studies towards the total synthesis of cortistatin A synthesis of the pentacyclic core of citreamicin µ and GA-ring model studies(2016-08) Blumberg, Shawn Thomas; Martin, Stephen F.; Krische, Michael J; Anslyn, Eric V; Kerwin, Sean M; Willson, Carlton GThe route to the key bicyclic intermediate was streamlined to eight steps in 16% yield, using a TMSI promoted coupling of a furan and an enone. Additionally, methodology for the selective ozonolysis of the bicyclic intermediate was developed via ozone titration. Work on the dihydroxylation step led to the discovery and development of a new pH-neutral Sharpless-style asymmetric dihydroxylation. The synthesis of pentacyclic core of citreamicin µ was accomplished in 12 steps. New methodologies were developed, including: an ortho- selective bromination of a vanillin derivative and the use of 4-(Phenylazo)diphenylamine (PDA) as an internal indicator for the acetylide coupling. The usefulness of PDA led to its development as a general all-purpose indicator for the titration of strong bases, Lewis acids and reducing agents. The discovery of (n-Bu)4NOAc as a privileged additive led to the development of new methods for the synthesis of isocoumarins and new methodology for the condensation of amino acids using LiMe4 was developed.Item Total syntheses of the neuroregenerative natural products vinaxanthone and xanthofulvin and biosynthetic studies(2012-12) Axelrod, Abram Joseph; Siegel, Dionicio R.; Philip, Magnus D; Michael, Krische J; Keatinge-Clay, Adrian T; Pierce-Shimomura, JonathanTotal syntheses of the neuroregenerative natural products vinaxanthone and xanthofulvin have been accomplished. The synthetic routes to both molecules utilize a highly regioselective furan Diels-Alder cycloaddition - aromatization sequence to furnish the catechol fragment present in both natural products. The pentasubstituted catechol was elaborated to a vinylogous amide which was used twice in both syntheses, exploiting the pseudosymmetry found in vinaxanthone and xanthofulvin. This approach enabled the dimerization of 5,6-dehydropolivione forming vinaxanthone, lending significant evidence to a non-enzymatically driven formation of vinaxanthone in Nature. The total synthesis of vinaxanthone was accomplished in nine steps, the shortest synthesis to date, and an additional route was devised to access a set of analogs for biological study. The first total synthesis of xanthofulvin was accomplished in 18 steps and the convergent nature of the synthetic plan allows for analog synthesis. The sets of vinaxanthone and xanthofulvin analogs will be used to examine their inhibition of Semaphorin3A, a protein which inhibits neuronal regeneration, and is the biological target for both molecules.Item Total synthesis and chemical modification of small molecules: a study of axonal regeneration and aryl oxidation(2015-05) Eliasen, Anders Mikal; Willson, C. Grant, 1939-; Siegel, Dionicio R.; Anslyn, Eric; Keatinge-Clay, Adrian; Liu, Hung-Wen; Sessler, JonathanInjuries to the central nervous system are irreversible and debilitating due to the limited regrowth of damaged or severed neurons. Two small molecules, xanthofulvin and vinaxanthone, isolated from P. vinaceum and P. glabrum promote spinal cord regeneration in animal models. It is speculated that these natural products inhibit semaphorin 3A, a chemorepellent that mitigates axonal growth-cone formation. In addition to promoting axonal growth, rats treated with vinaxanthone and xanthofulvin following complete spinal cord transection experienced greater remyelination, increased angiogenesis, attenuated apoptosis, and depressed scaring of the lesion site. The only prior synthesis of vinaxanthone speculated that the xanthone core is constructed via enzyme-catalyzed intermolecular Diels-Alder reaction. We have demonstrated, however, that warming a functionalized acetoacetyl chromone in water, furnishes vinaxanthone in good yield, providing an alternative biosynthetic pathway. With a robust syntheses of both natural products, we determined the protein target of the observed regeneration: succinate receptor 1, providing a new therapeutic target to promote neuronal regeneration. Among the various methods of incorporating oxygen into aryl rings, the direct conversion of a C-H bond into a C-OH bond is ideal. The metal-free hydroxylation of arenes developed in our laboratory, utilizing phthaloyl peroxide, marks the first disclosure of this transformation using mild conditions. Computational and experimental evidence obtained thus far has supported a mechanism involving a diradical intermediate. The reactivity of phthaloyl peroxide was increased by the incorporation of two chlorine atoms onto the ring. To minimize the accumulation of large quantities of peroxide, the optimization of the preparation of the peroxide in flow has been developed. This protocol immediately consumes the peroxide as it is generated. Finally, a new dearomatization reaction has been optimized. This reaction forms two carbon-oxygen bonds and dearomatizes the ring system.Item The total synthesis of (±)-Cepharatine A(2013-12) Seipp, Charles Aaron; Magnus, Philip D.The hasubanan alkaloid cepharatine A, was efficiently synthesized in 8 steps from commercially available starting materials in overall 16% yield. Highlighted in this synthesis, is a tandem phenolic alkylation – annulation which formed both a quaternary center as well as an unsaturated ring. This key step allowed for rapid construction of the core of the molecule. Subsequent reductive amination and acid catalyzed cyclization afforded the title compound.Item The total synthesis of (±)-morphine and (-)-galanthamine(2009-12) Sane, Neeraj Prakash; Magnus, Philip D.; Martin, Stephen F.; Siegel, Dionicio R.; Jones, Richard A.; Kerwin, Sean M.The opiate alkaloid (-)-morphine and the Amaryllidaceae alkaloid (-)-galanthamine are well known for their analgesic and anticholinergic properties, respectively. The chemical feature that connects these two molecules is that they are both biosynthesized from an ortho-para phenolic oxidative coupling. Attempts to mimic this aesthetic chemistry in the laboratory for the practical production of these alkaloids have not resulted in good yields of these compounds and there is a lot of scope for improvement. Despite the enormous amount of work devoted to this area, the simple para-alkylation of an appropriately substituted phenol derivative to generate a cross conjugated 2, 5-cyclohexadienone has not been reported. This strategy would avoid the low-yielding phenolic oxidation reaction and the product would merely require a double reductive amination of the aromatic aldehyde and the latent aldehyde (in the acetal) to produce narwedine, the synthetic precursor to (-)-galanthamine. On the other hand, the same intermediate can be elaborated to (±)-morphine via a Henry reaction, followed by reduction and reductive amination. Following the aforementioned methodology, we have successfully completed the synthesis of both these alkaloids via the common intermediate, a 2, 5-cross-conjugated cyclohexadienone. A demonstration of the use of this methodology towards achieving an enantioselective synthesis of these compounds has also been made. The overall yield of the 8 step procedure for galanthamine proceeds in 65% yield, which is approximately five times the yield of the current manufacturing process for this molecule. The synthesis of (±)-morphine, for the first time, allows access to codeine without having to reduce codeinone and, with an overall yield of 20% for the 14 step process, makes this the shortest synthesis of morphine.