Mountain Scholar :: Browsing by Author "Williams, Robert M., advisor"

Browsing by Author "Williams, Robert M., advisor"

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Open Access
A concise total synthesis of the TMC-95A and TMC-95B proteasome inhibitors
(Colorado State University. Libraries, 2004) Albrecht, Brian Keith, author; Williams, Robert M., advisor
A concise total synthesis of the TMC-95A/B proteasome inhibitors is presented. The synthesis features the use of an L-serine derived E-selective modified Julia olefination reaction that ultimately controls the stereochemical outcome of the highly oxidized tryptophan fragment. A diastereoselective dihydroxylation, a Suzuki coupling, macrocyclization and cis-propenyl amide formation were also employed. In the process of the total synthesis, a suitable intermediate was converted to a late stage intermediate in the Danishefsky total synthesis, effectively completing a formal synthesis. The limited use of protecting groups allowed for an efficient route that is amenable to the preparation of a variety of analogs due to its convergency.
Open Access
A divergent synthesis of secologanin derived natural products
(Colorado State University. Libraries, 2010) English, Brandon Joel, author; Williams, Robert M., advisor; Ferreira, Eric M., committee member; Eckstein, Torsten, committee member; Elliot, C. Michael, committee member; Finke, Richard G., committee member
This dissertation documents the racemic total synthesis of the natural products oleocanthal, geissoschizol, corynantheidol, dihydrocorynantheol, protoemetinol, and 3-epi-protoemetinol from a single synthetic intermediate. Also described are efforts to produce an optically pure supply of the common synthetic intermediate of the above described natural products. The work described herein represents the first steps toward the development of a general strategy capable of synthesizing several structurally diverse members of the family of compounds derived from secologanin.
Open Access
Approaches towards the synthesis of saxitoxin alkaloids
(Colorado State University. Libraries, 2013) Pearson, Aaron Daniel, author; Williams, Robert M., advisor; Wood, John L., committee member; Kennan, Alan J., committee member; Fisher, Ellen R., committee member; Woody, Robert W., committee member
Zetekitoxin AB is a toxin isolated from the Panamanian golden frog (Atelopus zeteki). The structure and activity of zetekitoxin AB was a mystery for 30 years until 2004 when it was elucidated by Yamashita and coworkers. It was found to be a potent analog of Saxitoxin, a marine neurotoxin. Saxitoxin is a sodium channel blocker and has been used extensively as a research probe. Zetekitoxin AB shows an affinity profile similar to saxitoxin, but is considerably more potent. Due to the endangerment of the Panamanian golden frog there is no source of zetekitoxin AB, preventing further studies. Presented herein is a concise synthesis of 4,5-epi-11-hydroxy-saxitoxinol, which utilizes D-ribose to direct an asymmetric Mannich reaction. This approach allows many modes of reactivity, which can be used to potentially access various analogs of saxitoxin with novel bioactivity.
Open Access
Asperparaline A: biosynthetic studies and synthetic efforts
(Colorado State University. Libraries, 2008) Gray, Chandele Ramsey, author; Williams, Robert M., advisor; Kennan, Alan, committee member; Szamel, Grzegorz, committee member; Parkinson, Bruce, committee member; Brennan, Patrick, committee member
Asperparaline A, a fungal metabolite isolated from Aspergillus japonicus, is of interest due to anthelmintic activity and structural similarities to the paraherquamides and brevianamides owing to the presence of bicyclo [2.2.2] diazaoctane core proposed to be derived from a biosynthetic [4+2] cycloaddition. This communication details two aspects of research regarding asperparaline A. The first goal involves the elucidation of asperparaline A as being biosynthetically composed of dimethylallylpyrophosphate and the amino acids, tryptophan and L-isoleucine, analogous to the paraherquamides. The second goal addresses the desire to develop synthetic methodology amenable to the introduction of isotopic labels for further biosynthetic studies. The proposed retrosyntheses envision the spiro-succinimide ring of asperparaline A being introduced by the photooxidation of a suitably oxidized pyrrole ring. Synthetic approaches toward asperparaline A presented include peptide coupling of β-methylproline with a prenylated pyrolylalanine, and Horner-Wadsworth-Emmons olefination of a diketopiperazine phosphonate with various aldehydes designed to allow for late stage pyrrole synthesis.
Open Access
Asymmetric syntheses of cyclopropane-containing amino acids
(Colorado State University. Libraries, 1994) Fegley, Glenn Jeffery, author; Williams, Robert M., advisor
Chiral, non-racemic (D)-erythro-4-(tert-butoxycarbonyl)-3-(dimethoxyphosphoryl)- 5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one was efficiently condensed with various alkyl and aryl aldehydes via the Emmons-Horner-Wadsworth procedure to provide the corresponding (E)-α,β-dehydrolactones. These compounds were smoothly cyclopropanated by racemic sodium [(diethylamino)phenyl]oxosulfonium methylide to furnish in high chemical and optical yields the desired cyclopropyllactones. Interestingly, the ylide consistently delivered the methylene unit almost exclusively syn to the C-5 and C-6 phenyl rings of the α,β-dehydrolactones. Removal of the chiral auxiliary was accomplished by dissolving-metal reduction using lithium metal and liquid ammonia to afford the corresponding t-BOC-protected 2-alkyl-1-aminocyclopropane-1-carboxylic acids in good yield. Sequential treatment of these protected amino acids with anhydrous methanolic HCl (or aqueous HCl) and propylene oxide provided the corresponding free amino acids in high chemical and optical yields. In this fashion the asymmetric syntheses of (1S)-[2,2-2H2]ACC, (1S,2S)-MeACC (norcoronamic acid), (1S,2S)-EtACC (coronamic acid), (1S,2S)-PrACC, and three diastereomers of cyclopropyldiaminopimelic acid (cyclopropylDAP) were achieved in 83-99% de. Deblocking of a phenyl-substituted cyclopropyllactone was accomplished via a stepwise sequence involving the lead tetraacetate cleavage of the chiral auxiliary as the key step. This protocol furnished (1S,2R)-2-phenyl-1-aminocyclopropane-1-carboxylic acid in greater than 95% de, and revealed a potential route to other aromatic-substituted cyclopropane amino acids. Finally, several (E)- α,β-dehydrolactones were treated with the azomethine ylide of N-benzyl-N-(methoxymethyl)-N-[(tlimethylsilyl)methyl]amine to furnish the corresponding spiropyrrolidine lactones in moderate to excellent yields and in high diastereomeric excesses. Deprotection of one spiropyrrolidine adduct by palladium-catalyzed hydrogenolysis resulted in the synthesis of enantiomerically pure (S)-(-)-cucurbitine.
Open Access
Asymmetric total syntheses of (+)- and (-)-spirotryprostatins A and B
(Colorado State University. Libraries, 2003) Sebahar, Paul Richard, author; Williams, Robert M., advisor
The first published total synthesis of (+)- and (-)-spirotryprostatin B is presented. The synthesis features an asymmetric azomethine ylide [1,3]-dipolar cycloaddition reaction. Additionally, a Barton-modified Hunsdiecker reaction was demonstrated as means of affecting an oxidative decarboxylation. Intermediates along the synthesis were studied for their biological activity as G2/M phase cell cycle inhibitors and microtubule assembly inhibitors. The asymmetric azomethine ylide [1,3]-dipolar cycloaddition was also studied in greater detail. Varying the aldehyde component of the reaction resulted in the formation three different cycloadducts. Theoretical calculations for the reaction were compared with observed results. Attempts to synthesize (-)-spirotryprostatin A are also presented. Two different strategies based on the synthesis of (+)- and (-)-spirotryprostatin B were explored.
Open Access
Carbohydrates as chiral templates
(Colorado State University. Libraries, 1987) Stewart, Andrew O., author; Williams, Robert M., advisor
Carbohydrates can serve as a source of functionalized asymmetric carbon atoms. The synthesis of a carbon fragment derived from 2-deoxy-glucose is described as an optically pure intermediate (34) for the synthesis of the antibiotic thienamycin. Natural products containing sugar moieties are direct targets for synthetic strategems utilizing carbohydrate precursors. The synthesis of naturally occurring C-glycosides from readily available sugars require carbon bond formation at the acetal carbon. Reported, herein, is methodology for the conversion of hemiacetals to the corresponding 2'-thiopyridyl acetals and subsequent metal activation toward nucleophilic displacement by carbon species resulting in efficient C-glycosidation. A glucosyl substrate (122) and two ribosyl substrates (147, 154) are described and their stereoselective reactions with different carbon nucleophiles are examined. The glucose substrate (122) shows general α-selectivity in carbon-carbon bond formation. The selectivity in the ribosyl substrates is quite good but, exhibits a large dependence on the particular nucleophile. The total synthesis of (+)- showdomycin is achieved employing a β-selective coupling of trimethoxybenzene and the ribosyl thioacetal (154) utilizing silver (I) activation. Preparation of other useful C-nucleoside precursors containing the required β-stereochemistry are reported. The use of these metal activated thiopyridyl acetals for intramolecular O-glycosidations are also investigated. Approaches to the [3.1.1) bycyclic oxetane of the thromboxane A2 nucleus using this methodology are examined. The use of a polymer bound mercury(II) salt (226) for activation of the thio-residue is shown to be useful in an intramolecular O-glycosidation resulting in the 1,5 anhydro-furanose (186). This polymer bound reagent should potentially represent an advantageous heterogeneous alternative to the homogeneous metal salts; particularly for glycosidations of sensitive substrates. In general, these thiopyridyl-acetals are stable precursors that may be readily activated by thiophilic metal salts for efficient nucleophilic substitution reactions.
Open Access
Concise asymmetric syntheses of the cylindrospermopsin alkaloids
(Colorado State University. Libraries, 2004) Looper, Ryan Edward, author; Williams, Robert M., advisor
Presented herein is a concise 18 step asymmetric synthesis of the hepatotoxic cyanobacterial alkaloids cylidrospermopsin, 7-epi-cylindrospermopsin, and the purported structure of 7-deoxycylindrospermopsin. Born from a simple amino acid, an intramolecular [1,3]-dipolar cycloaddition of an α-alkoxycarbonyl nitrone and a nitroaldol reaction serve to construct these natural products from a single stereocenter. The brevity of the synthesis, and the incorporation of the uracil moiety in a late-stage approach, proffers the ability to generate synthetic analogues that have been deployed for biomechanistic evaluation.
Open Access
Concise enantioselective synthesis of (+)-FR66070 and (+)-FR900482 and the synthesis and biochemical studies of a photo-triggered FR900482 mitosene progenitor
(Colorado State University. Libraries, 2003) Judd, Ted Charles, author; Williams, Robert M., advisor
The total synthesis of the natural products (+)-FR66979 and (+)-FR900482 is presented. The synthesis features a novel dimethyldioxirane-mediated reaction for construction of the hydroxylamine hemiketal functionality and represents the shortest total synthesis reported to date. The synthesis of a photo-triggered mitosene progenitor based on the natural products (+)-FR66979 and (+)-FR900482 has also been described. Biochemical studies demonstrate the capacity of the mitosene progenitor to form DNA interstrand cross-links upon photo-activation. Furthermore, the cross-links have been shown to share the identical sequence specificity as the natural products.
Open Access
Design and synthesis of analogs of the peptidylnucleoside antibiotics: the mureidomycins
(Colorado State University. Libraries, 1998) Bender, David Michael, author; Williams, Robert M., advisor
The recent emergence of strains of bacteria which are resistant to many commercially available antibiotics requires a continual search for new drugs to combat infection. A new family of antibiotics, the mureidomycins, has recently been reported. These compounds have been shown exhibit activity against Pseudomonas aeruginosa through inhibition of phospho-N-acetylmuramyl translocase, an enzyme involved in the lipid cycle of peptidolycan biosynthesis. Progress toward the total synthesis of this series of natural products is described. Specifically, methodology for the production of 4',5'-unsaturated enamine nucleosides has been investigated. In addition, two unnatural amino acids, (S)-m-tyrosine and 2-amino-3-N-methylaminobuyric acid, have been synthesized in optically pure form. Molecular modeling was used to predict structural analogs of the mureidomycin antibiotics. These compounds are simple peptidylnucleosides and are derived from coupling of small amino acid subunits to an aminonucleoside core. The synthesis of these analogs is described, including a novel route to 3',5' -dideoxy-5'aminouridine.
Open Access
Design and synthesis of biologically active Largazole derivatives, including development of improved syntheses of Largazole analogs
(Colorado State University. Libraries, 2018) Dunne, Christine E., author; Williams, Robert M., advisor; Shi, Yian, committee member; Prieto, Amy, committee member; Thamm, Douglas, committee member
Natural product histone deacetylase inhibitor, Largazole, has been developed into a streamlined synthetic pathway for the development of a complex library of analogs. The library developed within the Williams laboratory encompasses an array of derivatives, including but not limited to: thiazole modification and macrocycle substitutions. The cap group of Largazole, portion of the molecule extending outside of the enzyme binding pocket, was successfully modified to install new chemical handles for biologic and dual therapeutic conjugation. Biological conjugates of Largazole, as well as its derivatives, aid in increasing selectivity and potency of the compound. Largazole has been conjugated to both biotin and folic acid for further studies. Additionally, a streamlined synthesis towards Wnt inhibitor 3289-5066 and a developed path for conjugation have been explored. Modified procedures were developed to aid in scale up and improvement of synthetic pathways. Scale up is crucial for development of sufficient material for biological testing and further development of conjugative therapeutics. One main impediment in the synthesis of Largazole peptide isostere is towards the southern fragment, specifically the Grubbs olefin metathesis. Multiple routes were explored to combat this low yielding step. Further exploration of these synthetic routes are underway.
Open Access
Efforts toward the total synthesis of quinine, synthesis of largazole analogs, and progress toward potential biosynthetic intermediates of taxol
(Colorado State University. Libraries, 2012) Bubb, Jennifer Marie, author; Williams, Robert M., advisor; Wood, John L., committee member; McNaughton, Brian R., committee member; Prieto, Amy L., committee member; Ishii, Douglas N., committee member
Herein we discuss our work involving three different projects, namely (1) efforts toward the total synthesis of quinine, (2) synthesis of largazole analogs, and (3) progress toward potential biosynthetic intermediates of taxol. Our efforts toward the synthesis of quinine have led us toward a route toward a pipecolic acid derivative that was further elaborated to a late-stage intermediate. Following an intramolecular cyclization and deoxygenation protocol, a formal synthesis of quinine could be realized. In the second project, we have successfully synthesized and tested analogs of the known HDAC inhibitor, largazole. These analogs have demonstrated good potency towards a series of HDAC isoforms. In the third project, efforts have been made to synthesis potential biosynthetic intermediates of taxol. Utilizing highly oxygenated intermediates isolated from the heartwood of the Japanese yew tree, we have explored the reactivities of these complex natural products in hope of devising a method to construct mono-acetylated derivatives.
Open Access
Elucidating the biosynthetic pathway of taxol
(Colorado State University. Libraries, 1996) Rubenstein, Steven Marc, author; Williams, Robert M., advisor
The total synthesis of (±)-taxa-4(5),11(12)-diene, (±)-taxa-4(20),11(12)-diene, (±)-taxa-4(20), 11(12)-diene-5(β)-ol, and (±)-taxa-4(20),11(12)-diene-5(α)-ol is described. The syntheses rely upon selenium-based methodology developed by Krief for the introduction of the tetrasubstituted double bond in diene 201 and an intramolecular Diels-Alder reaction, methodology developed by Shea and Jenkins, to form the AB ring system of taxol in compound 208. The synthetic route was used to introduce stable and radiolabeled atoms into the target compounds. The incubation of 13C labeled (±)-taxa-4(20),11(12)-diene with taxadiene synthase has helped confirm the first committed biosynthetic step to taxol, in Taxus brevifolia, as being the direct cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. The incubation of tritium labeled (±)-taxa-4(5),11(12)-diene with a cytochrome P-450 microsomal cell-free extract produced a new mono-oxygenated product that had the same g.l.c. retention time and mass spectral fragmentation pattern as taxa-4(20),11(12)-diene-S(α)-ol. Taxa-4(20),11(12)-diene-5(β)-ol could not be found in this assay. Tritium labeled taxa-4(20),11(12)-diene-S(a)-ol was subsequently incubated with Taxus brevifolia stem discs and was incorporated into taxol. In addition, taxa-4(20),11(12)-diene-S(α)-acetate acted as a better substrate than taxa-4(20),11(12)-diene-5(α)-ol in the conversion to the more polar product(s) when incubated with the cytochrome P-450 microsomal cell-free extract. The more polar product(s) is/are presumed to be more highly hydroxylated biosynthetic intermediates enroute to taxol.
Open Access
Elucidation of the biogenesis of the paraherquamides, malbrancheamides, citrinalins, and brevianamides
(Colorado State University. Libraries, 2019) Klas, Kimberly R., author; Williams, Robert M., advisor; Shi, Yian, committee member; Chen, Eugene, committee member; Crick, Dean, committee member
Various fungi of the genera Aspergillus, Penicillium and Malbranchea produce prenylated indole alkaloids that possess a bicyclo[2.2.2]diazaoctane ring system and a variety of biological activities such as insecticidal, cytotoxic, anthelmintic, and antibacterial properties. After the discovery of distinct enantiomers of the natural alkaloids Stephacidin A, Notoamide B and their corresponding diastereomers, from Aspergillus protuberus MF297-2, Aspergillus amoenus NRRL 35660 and Aspergillus taichungensis, the structurally diverse metabolites became of particular biosynthetic interest. The bicyclo[2.2.2]diazaoctane core of the divergent natural metabolites may be enzymatically derived via a putative intramolecular hetero-Diels-Alder cycloaddition. We completed the total synthesis of ZwtP and MeZwtP, unveiling the role of a newly discovered Diels-Alderase. We are also undergoing further synthetic efforts to access other novel natural products, as well as further understand additional unprecedented transformations in nature.
Open Access
Epidithiodioxopiperazines: synthetic studies of (+)-chetomin and (-)-sporidesmin A
(Colorado State University. Libraries, 2012) Welch, Timothy R., author; Williams, Robert M., advisor; Rovis, Tomislav, committee member; Wood, John L., committee member; Ackerson, Chris, committee member; Thamm, Douglas H., committee member
This dissertation documents efforts toward the asymmetric total syntheses of the natural products (+)-chetomin and (-)-sporidesmin A. Synthetic methods have been developed to efficiently construct the dioxopiperazine core of both molecules. Additionally, a simple epidithiodioxopiperazine has been synthesized to demonstrate a general method for the addition of a sulfur bridge to a dioxopiperazine ring. The work described herein, while not totally successful, provides a basis for future completion of the asymmetric total syntheses of these two epidithiodioxopiperazines and other related fungal metabolites.
Open Access
Investigating biosynthetic pathways of the Aspergillus genus through biomimetic total synthesis of secondary metabolites
(Colorado State University. Libraries, 2022) Benson, Brooke, author; Williams, Robert M., advisor; Kennan, Alan J., advisor; Paton, Robert, committee member; Crans, Debbie, committee member; Crick, Dean, committee member
The prenylated indole alkaloids are a class of secondary metabolites containing a unique bicyclo[2.2.2]diazaoctane core and a wide range of biological activity. This complex structure has prompted extensive investigation into the biochemical synthesis of these compounds. Currently, three disparate biochemical strategies are known to be used by producing fungi to construct the bicyclic core: (1) NADPH-dependent bifunctional reductase/Diels-Alderase-mediation in formation of the monooxopiperazines; (2) brevianamide assembly through cofactor-independent pinacolase resulting in spontaneous intramolecular Diels-Alder (IMDA) generation of the bicyclo[2.2.2]diazaoctane core; (3) Diels-Alderase mediated enantiodivergent generation of the dioxopiperazines via cytochrome P450 oxidation to achiral azadienes and successive enzyme-mediated stereoselective IMDA reaction. This work aimed to employ biomimetic total synthesis to aid in elucidation of the biosynthetic pathways in the Aspergillus genus, which utilizes the third strategy. This author reports the first total syntheses of 6-epi-Notoamides T10-12 and Notoamide T2, as well as an improved total synthesis of 6-epi-Notoamide T. Also reported are synthetic efforts towards 6-epi-Notoamide T9, Notoamide TI, and Citrinalin C.
Open Access
Mechanism of action studies on the FR-9000482 class of antitumor antibiotics
(Colorado State University. Libraries, 1997) Rajski, Scott Raymond, author; Williams, Robert M., advisor
The interactions of members of the FR-900482 class of antitumor antibiotic agents with DNA has been examined. Importantly, the first in vitro demonstration of nucleic acid interstrand cross-linking has been reported and the DNA base pair sequence specificity of the cross-linking event has been elucidated. These agents demonstrate a high degree of selectivity for 5'-CG-3' sequences of DNA. As such, bio-mechanistic analogy between these compounds and the clinically employed compound Mitomycin Chas been shown. Efforts have also examined extensively the ability of these agents to give rise to orientation isomers of each respective cross-link and their different properties. DNA-protein cross-linking by these agents has also been examined. A sequence-specific DNA-peptide binding motif has been identified which undergoes drug-mediated DNA-protein cross-linking. This is the first reported instance of a mitosene based-minor groove DNA-protein cross-link event. Significantly, the motif examined is characteristic of tissues which bear striking similarity to those of cancerous cell lines.
Open Access
Mitomycin alkaloids: synthetic studies
(Colorado State University. Libraries, 2009) Gubler, Daniel Alan, author; Williams, Robert M., advisor; Rovis, Tomislav, committee member; Kennan, Alan J., committee member; Elliott, C. Michael, committee member; Luger, Karolin, committee member
Documented herein are efforts towards the first asymmetric total synthesis of the mitomycin family of natural products. Methods have been developed that efficiently construct eight-membered ring precursors of the natural products. Additionally, a tetracyclic mitosane compound containing all the core features of the mitomycins except the C9a methyl aminal has been constructed. The above-mentioned synthetic efforts help set the stage for future completion of the asymmetric total synthesis of this family of compounds. The studies mentioned herein, while not totally successful, shed new light on the reactivity of the mitomycins as well as the remarkable electronic effect of the electron-rich arene ring.
Open Access
Panning peptide libraries on filamentous phage
(Colorado State University. Libraries, 1996) Travers, Jennifer A., author; Williams, Robert M., advisor
This Ph.D. project involved using the filamentous phage as a tool to express peptide libraries on its external appendage called the pIII protein. The peptide libraries were designed based on a motif of the honeybee toxin Apamin. Apamin is expressed on the end of the pIII protein and a portion of the apamin section is randomized to produce all possible combinations of amino acids to give a peptide library. The library phage are then panned on a derivatized solid support to determine if any library members have an affinity to a target ligand. The target chosen is a portion of the peptidoglycan layer in bacterial cells called L-lysine-D-alanine-D-alanine. This is the site for binding of the antibiotic vancomycin. Library members that bind to this site should have vancomycin-like activity. This project entailed preparing the libraries, synthesizing the ligand, and derivatizing a variety of solid supports for panning. Many different panning experiments were performed on several libraries and the results are described herein.
Open Access
Part I. Asymmetric synthesis of 2,6-diaminopimelic acids (DAP) and γ-D(L)-glutamyl-L-meso-diaminopimelic acid dipeptide. Part II. Total synthesis of TAN-1057 and analogues
(Colorado State University. Libraries, 1997) Yuan, Chenguang, author; Williams, Robert M., advisor
Part I. An asymmetric and stereochemically unambiguous construction of diaminopimelic acid and related system using the chiral, non-racemic diphenyl oxazinones glycinate templates has been developed. The preparations of (R,R)-DAP, (S,S)-DAP, (S,S)-2,7-diaminosuberic acid, and mono-N-protected (S,R)-DAP are described. The synthesis of γ-D(L)-glutamyl-L-meso-diaminopimelic acid dipeptide, a subunit of both FK-156 and FK-565, is also described. The availability of both optical antipodes of the glycinate templates renders this chemistry adaptable to prepare all possible diastereoisomers of substances based on the DAP skeleton in optically pure form.