Theses and Dissertations

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Open Access
The constituents of Castilleja rhexifolia, Mahonia repens and Oncidium cebolleta
(Colorado State University. Libraries, 1981) Suess, Terry R., author; Stermitz, Frank R., advisor
A total of 54 species of plants from 21 different plant families were collected throughout the subalpine region of the Colorado Rocky Mountains. These plants were tested for antitumor activity, alkaloid content and grasshopper antifeedant activity. Although none of the plants showed significant antitumor activity, 13 showed the presence of alkaloids and eight showed activity in the grasshopper antifeedant screen. One of the plants that showed the presence of alkaloids was Castilleja rhexifolia Rydb. Investigation of C. rhexifolia extracts led to the isolation of senecionine, a previously reported hepatoxic, pyrrolizidine alkaloid. This is the first report of a pyrrolizidine alkaloid in the Scrophulariaceae, and the first alkaloid isolated from Castilleja. The constituents of Mahonia repens (Lindl.) G. Don, a plant used by the Ramah Navajo of the Southwest in folk medicine, were also investigated. The leaves of M. repens contained four known aporphine alkaloids: isocorydine, corydine, thaliporphine and glaucine. The stems and roots of M. repens contained one known aporphine alkaloid (magnoflorine), four known bisbenzylisoquinoline alkaloids (obaberine, thalrugosine, oxyacanthine and obamegine), four known protoberberine alkaloids (palmatine, berberine, jatrorrhizine and columbamine), the known lignan, syringaresinol, and the sugar, sucrose. The isolation of these secondary metabolites allows a chemotaxonomic comparison of M. repens to the other Mahonia sp. studied, and also to the closely related genus, Berberis. As part of a continuing study to clarify the spectral data of 1,2,10,11-dihydroxydimethoxyaporphines, N-methylisocorytuberine was synthesized by the Pomeranz-Fritsch reaction and Pschorr cyclization. Spectral and thin layer chromatography data for N-methylisocorytuberine were then compared to two other reported isomers, magnoflorine and N,N-dimethyllindcarpine. The orchid, Oncidium cebolleta (Jacq.) Sw., is used by the Tarahumara Indians of Mexico as an important substitute for peyote. The chloroform extract of O. cebolleta was found to contain five previously unreported phenanthrenes and 9,10-dihydrophenanthrenes. Four of these compounds were identified as 2,3-dihydroxy-4,6,7 -trimethoxyphenanthrene, 2,3-dihydroxy-4,6,7-trimethoxy-9,10-dihydrophenanthrene, 2,7-dihydroxy-3,4-dimethoxyphenanthrene and 2,8- dihydroxy-4,7-dimethoxyphenanthrene. Although it is not known if these compounds are responsible for the hallucinogenic activity of O. cebolleta, their structural similarity to tetrahydrocannabinol makes this conceivable.
Open Access
The total synthesis of (±)- and (+)-biocyclomycin
(Colorado State University. Libraries, 1984) Armstrong, Robert W., author; Williams, Robert M., advisor
The completely regio- and stereocontrolled total synthesis of bicyclomycin (1) is described in 12 chemical steps. A new carbon-carbon bond-forming reaction of 1,4-dibenzyl- and 1,4-di-p-methoxybenzyl-3,6'-bis-(2'-thiopyridyl)-2,5-piperazinediones (234 and 275) has been discovered involving complexation of 234 or 275 with silver(I)triflate followed by addition of the trimethylsilyl ketene acetal of γ-butyrolactone to afford 1,4-dibenzyl- and l,4-di-p-methoxybenzyl-3-(2'-thiopyridyl)-6-(2"- γ-butyrolactonyl)-2,5-piperazinediones (236, 237, and 276-279) in good yield. The reaction proceeds in THF at 25°C with predominant syn-stereospecificity. LiA1H4 reduction of lactones 276-279 provides the corresponding diols 280-282 which are cyclized to the bicyclo[4.2.2]nucleus 284 in the presence of silver(I)triflate in THF at 25°C. Dehydration of 284 in three steps affords the key olefinic intermediate 8,10-di-p-methoxybenzyl-8,10-diaza-5-(methylene)-2-oxabicyclo[4.2.2]decane-7,9-dione (294) which is regio- and stereoselectively elaborated at the bridgehead positions via: 1) C-6-bridgehead carbanion formation followed by quenching with O2; and 2) C-1-bridgehead carbanion formation followed by aldol condensation with 2,2,4-trimethyl-l,3-dioxolane-4-carboxyaldehyde to afford a single diastereomer (279a) possessing the correct relative configuration at C-1', C-2'. Protection of the secondary hydroxyl at C-1' as the trifluoroacetate followed by oxidative removal of all the protecting groups with ceric ammonium nitrate in MeCN/H2O affords directly, totally synthetic bicyclomycin. Condensation of the racemic bicyclic nucleus 296 with optically active S-2,2,4-trirnethyl-1,3-dioxolane-4-carboxaldehyde (83% ee) provides after protection and deprotection, (+)-bicyclornycin in 78% ee. Preliminary results establishing a structure-activity correlation requiring an obligate partnership of the C-6 hydroxyl and the C-4, C-5 exomethylene are described.
Open Access
Structural variations in metal ion complexes of the ligand EGTA⁴-
(Colorado State University. Libraries, 1985) Schauer, Cynthia Karen, author; Anderson, Oren, advisor; Elliott, C. Michael, committee member
Structural studies of several metal ion complexes with the tetraanion of the octadentate ligand, H^4EGTA (3,12-bis(carboxymethyl)-6, 9-dioxa-3, 12-diazatetradecanedioic acid), as well as the structure of H^4EGTA, have been performed by single crystal X-ray diffraction. Of particular interest was the structural basis for the large preference for EGTA^4- to bind calcium ion rather than (K(CaL^2-) ~= 10^6 magnesium ion = 10^6 (K(MgL^2-)), a preference which is similar to that exhibited by intracellular calcium binding proteins. The alkaline earth compounds, Ca[Ca(EGTA)]·(22/3)H2o, Sr[Ca(EGTA)] ·6H2O, Mg[Sr(EGTA)(OH2 )]·7H2o, Mg(Ba-(EGTA)]·(8/3)H2O·(1/3) (CH3) 2CO, and (Mg2(EGTA)(OH2 )6]·5H2O, have been structurally characterized. [Ca(EGTA)]2- is eight-coordinate and utilizes the full octadentate chelating capability of the EGTA^4- ligand. The ether oxygen atoms are bound at a shorter distance than the amine nitrogen atoms. EGTA^4 - is octadentate toward both the strontium and barium ions, which are nine- and ten-coordinate, respectively. The magnesium complex is dinuclear, utilizing each end of the EGTA^4- ligand as a tridentate iminodiacetate ligand; the ether oxygen atoms are not involved in coordination to the metal ion. Structures of EGTA^4 - chelates of metal ions that are commonly used as spectroscopic probes for calcium ion binding sites have also been determined. The cadmium chelate in Sr[Cd(EGTA)]·7H2 o is eight-coordinate, li k e [Ca(EGTA)]^2 -, but the amine nitrogen atoms are bound at shorter distances than the ether oxygen atoms. The metal ions in the structures of tripositive lanthanide ion complexes, Ca[Er(EGTA)(OH2)]2·12H2O and Ca[Nd(EGTA)- (OH 2 )]2·9H2O, are nine- and ten-coordinate, respectively. To further explore coordination modes of the EGTA^4 - ligand with smaller metal ions, where the ligand is not likely to be octadentate, structures of manganese and copper complexes of were determined. Sr[Mn(EGTA)] ·7H2O is isomorphous with the cadmium compound. As a result, the Mn(II) ion is eight-coordinate. The copper complex crystallizes as a dinuclear species, [CU2(EGTA)(OH2)2] ·2H2O, in which each end of the EGTA^4- ligand binds a copper(II) ion in a tetradentate fashion; the ether oxygen atom is bound in the apical position of the square pyramidal coordination sphere.
Open Access
Spin dynamics in solids
(Colorado State University. Libraries, 1986) Bronnimann, Charles E., author
The work described in this thesis falls into two largely unrelated categories. Part I of the thesis reports unusually fast 13C spin diffusion in adamantane. A calculation of the 13C spin-diffusion rate from first order perturbation theory is presented and compared to the experimental data. There is good agreement between calculation and experiment for relatively small mixing times. Motional averaging of 13C- 1H dipolar coupling is found to be responsible for the unusually efficient 13C spin-diffusion in adamantane. Further enhancement of 13C spin-diffusion should be possible by carrying out mixing in the rotating frame. This is experimentally verified for adamantane. Part II discussed 13C NMR of methanol adsorbed on HY zeolite. Three species were distinguished on the basis of their different spin-lattice, spin-spin (spin diffusion) and chemical properties shift. These were: a species exhibiting liquid-like mobility, a species chemically adsorbed onto the wall of the large cage of the zeolite, and a species chemically adsorbed onto the wall of the small cage of the zeolite.
Open Access
Synthesis and study of bicyclomycin analogs
(Colorado State University. Libraries, 1987) Maruyama, Lynn K., author; Williams, Robert M., advisor
The synthetic utility of a key electrophilic coupling reaction developed in the total synthesis of bicyclomycin was explored in the hope that this methodology could be applied to the synthesis of homologs of this unique antibiotic. The coupling reaction was a carbon-carbon bond forming reaction which utilized an electrophilic glycine anhydride derivative and a trimethylsilylketeneacetal in the presence of a Lewis acid. A number of substituted diketopiperazines were made by this route and their elaboration to bicyclomycin homologs attempted. Carbocyclic bicyclomycin derivatives which lacked the oxygen heteroatom in the bicyclic bridge were synthesized as a complementary series of analogs. Various [2.2.2) and [3.2.2) carbocyclic systems were made containing and lacking the structural functionalities believed necessary for biological activity. The desired structural features were based on proposed mechanisms of action for bicyclomycin. These features included: 1) an OR or SR type leaving group at the C-6 position of the piperazinedione, 2) an olefinic moiety alpha to the leaving group at C-6, 3) secondary (-NH-) amides. Methodology was developed for synthesis of these carbocycles, of particular significance was an intramolecular enolate/epoxide opening reaction which yielded both the [2 .2.2) (178, 182, 184) and [3.2.2) (179, 183, 185) carbocyclic skeletons. The regiochemistry displayed by this reaction could be explained by a consideration of Baldwin's Rules for Ring Closure. Attempted deprotonation at the bridgehead position of these carbocycles proved unsuccessful in achieving heteroatom substitution. Consequently, these bridgehead substituted bicyclic compounds (162, 205) were obtained by functionalization of the C-6 position prior to cyclization. The carbocycles obtained through this synthetic work were submitted for biological testing.
Open Access
The asymmetric synthesis of amino acids via electrophilic glycinates
(Colorado State University. Libraries, 1987) Sinclair, Peter John, author; Williams, Robert M., advisor
A new asymmetric synthesis of α-monosubstituted-α-amino acids using D- and L-erythro-4-benzy loxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-1,4-oxazin-2-ones 108 as amino acid templates is described. Bromination of 108 with NBS generates the key electrophilic glycinate 132 which couples with a variety of carbon nucleophiles with high diastereoselectivity to afford the amino acid precursors 134. Catalytic hydrogenation of homologated heterocycles 134 directly furnishes the zwitterionic α-amino acids in high enantiomeric excess. Dissolving metal reduction of 134 permits the preparation of unsaturated amino acids while use of erythro-4-t-butoxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-1,4-oxazin-2-one 160 allows the direct preparation of t-BOC protected α-amino acids. The synthetic approaches to a number of biologically interesting amino acids are described and mechanistic aspects of the coupling reaction are discussed.
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
Novel polynuclear copper compounds of halides and pseudo-halides
(Colorado State University. Libraries, 1987) Reibenspies, Joseph Henry, author; Anderson, Oren, advisor; Elliott, C. Michael, committee member
Mixed-valence compounds (one trinuclear (4) and two polymeric (5,6)) of copper(I,II) containing bridging cyano ligands and the ligands 1 (Pre-H) and 2 (cyclops) have been synthesized and characterized by single crystal X-ray diffraction. For 4, [Cu(1)(μ-NC)]2Cu(CN) · H2O, a= 9.723(2) Å, b = 10.908(2) A, c = 16.184(3) A, ɑ = 97.82(1) ᵒ, β = 103.64(2)ᵒ, γ= 92.21(2)ᵒ. Compound 5 ([Cu(1)(μ-NC)Cu(μ-CN)]n) occurs in three structural modifications. For 5a, a= 7 .755(2) Å, b = 13.179(3) Å, c = 16.508(5) A. For 5b, a= 7.878(2) Å, b = 8.418(2) Å, c = 25.874(4) Å, ~= 94.15(2)ᵒ. For 5c, a= 8.85(1) Å, b = 20.755(8) Å, c = 23.081(8) Å. For 6, [Cu(2)(μ-NC)Cu(μ- CN)·(l/2C6H6)]n, a= 11.667(2) Å, b = 8.962(2) Å, c = 19.895(5) Å,~= 97.58(2)ᵒ. The discrete molecules of 4 contain a trigonal planar [Cu(CN)3]^2- unit, which bridges between two [Cu(l)]+ complexes through two cyano ligands. Each of the polymeric species 5a, 5b, 5c, and 6 consists of a chain of [Cu(CN)2]- units joined by bridging cyano ligands. A cyano ligand also bridges between the copper(I) atoms of the chain and [Cu(1)]+ or [Cu(2)]+ complexes. The structures of three dinuclear copper(II) complexes, in which the Cu(II) atoms are bridged by azido and hydroxo ligands and by either the phenolate oxygen atom of N6OH or N6'OH have been determined by single crystal X-ray diffraction. The compound [Cu2(μ-l,3-N3)(N6O)](ClO4)2·THF (7) crystallized in the orthorhombic space group P 212121, with a= 12.977(2) Å, b = 13.188(3) Å, c = 22.033(6) Å. The compound [Cu2(μ-1,1-N3)(N6'O)](BF4)2·THF (8) crystallized in the orthorhombic space group P21cn, with a= 10.222(2) Å, b = 16.683(4) Å, c = 23.517(7) Å. The compound [Cu2(μ- OH)(N6'O)](BF4)i · THF (9a) crystallized in the monoclinic space group ?21/n, with a= 12.457(3) Å, b = 10.222(3) Å, c = 30.397(10) Å, β= 91.63(2). In these complexes each copper(II) atom is five-coordinate and is bound to three nitrogen atoms and the bridging phenoxo oxygen atom of either N60- or N6'0-. The fifth coordination site on each copper(II) atom is occupied by an atom of the bridging azido or hydroxo ligand. A dinuclear copper(II) complex which contains a bridging iodo ligand and two [Cu(2)]+ moieties has been characterized by X-ray crystallography. [Cu2(2)2I](ClO4) · 2MeOH (10) crystallized in the monoclinic system, space group C2/c, with Z = 4 and a= 21.564(3) Å, b = 11.920(2) Å, c = 14.831(2) Å, β = 96.83(1)ᵒ. Each of the copper(II) atoms in the dimer is coordinated to four nitrogen atoms of ligand 2 and to the bridging iodo ligand. The structures of two phases of the perchlorate salt of the copper(II) complex of 1 and methanol have been characterized by X-ray crystallography. For the room temperature phase {[Cu(1)]C1O4 · 1/2 MeOH}n (11a), a= 23.018(3) Å, b = 6.903(1) Å, c = 22.511(3) Å, β= 105.48(1)ᵒ. For the low temperature phase { [Cu(l)]ClO4 · 1/2 MeOH}i ((llb), a= 6.850(2) A, b = 11.886(3) A, c = 22.303(5) A, a= 75.26(2)0 , β= 88.97(2)ᵒ, γ= 73.38(2)ᵒ. When cooled, the crystalline solid 11 undergoes a reversible structural change. 11a is polymeric in nature, with bridging between copper atoms accomplished by an oxime oxygen atom of ligand 1. 11b is best described as dimeric.
Open Access
Synthetic and pharmacophoric studies of quinocarcin
(Colorado State University. Libraries, 1990) Ehrlich, Paul P., author; Williams, Robert M., advisor
A new synthetic approach to the stereoselective total synthesis of the structurally unique antitumor antibiotic quinocarcin (1) is described. The utilization of model studies in this approach has led to novel methodologies concerning the construction of 1-(hydroxymethyl)-8-methoxy-1,2,3,4-tetrahydroisoquinolin-4-one (195) and several variably substituted pyrrolidines (180, 181, 182 and 183). These methodologies are discussed in terms of their synthetic utility as well as their mechanistic aspects. The synthetic approach to quinocarcin described herein allowed for the construction of several oxazolidine containing alkaloids which incorporate various aspects of the 8-11- iminoazepinotetrahydroiso-quinoline skeleton of quinocarcin. To this end the synthesis of a new tetracyclic oxazolidine moiety (240), which mimics quinocarcin's DNA nicking capabilities and represents the isolation of the pharmacophore of this novel antibiotic was achieved. The significance of the chemical stability and biological activity of 240 relative to quinocarcin is discussed.
Open Access
The asymmetric synthesis of amino acids via glycine enolates
(Colorado State University. Libraries, 1991) Im, Myeong-Nyeo, author; Williams, Robert M., advisor
The enolates derived from the optically active D-e rythro-4- (tertbutyloxycarbonyl)-5,6-di phenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (166a) and D- and L-erythro-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6- tetrahydro-4H-1,4-oxazin-2-ones (167a/b) efficiently couple with alkyl halides to afford the corresponding anti-α-monosubstituted oxazinones. The enolate alkylation of the a-monosubstituted oxazinones provides the corresponding α-disubstituted oxazinones. Dissolving-metal reduction of the homologated oxazinones allows the direct preparation of t-BOC protected α-amino acids. In the case of dissolving metal-reducible functionality, hydrogenation over a Pd° catalyst furnishes the zwitterionic amino acids. By employing this protocol the syntheses of complex amino acids such as 2-(tert-butyloxycarbonyl)amino-6-(p-methoxybenzyI)thionohexanoic acid and 2,6-diamino-6-hydroxymethylpimelic acid are discussed.
Open Access
The asymmetric synthesis of arylglycines
(Colorado State University. Libraries, 1992) Hendrix, James A., author; Williams, Robert M., advisor
The asymmetric synthesis of several arylglycines is discussed. Several methods for the coupling of an aromatic group to the chiral bromoglycinates (171, 172) were developed. It was found that the cuprate and Friedel-Crafts couplings provided the desired aryl-coupled glycinates in the greatest yield with excellent selectivity. An oxidative protocol was employed to unmask the oxazinone chiral auxiliary which provided the desired free α-amino acids. A reductive deprotection method was also employed in two unique cases which efficiently gave the arylglycine products. The % ee's ranged from 82 to 94 %. This methodology was further utilized in an approach to the asymmetric synthesis of the bis-arylglycine, actinoidic acid. This study explored the scope of the Stille biphenyl cross-coupling reaction and produced methodology for the synthesis of biphenyl amino acid precursors.
Open Access
The total synthesis of (+)-paraherquamide B
(Colorado State University. Libraries, 1993) Cushing, Timothy D., author; Williams, Robert M., advisor
The first stereocontrolled total synthesis of (+)-paraherquamide B is described in 42 chemical steps. The synthesis is a convergent one, starting from S-proline and vanillin. Vanillin was acylated, nitrated and hydrolyzed to supply o-nitrovanillin (131). This was converted to the azlactone, hydrolyzed to the α-ketocarboxylic acid, oxidatively decarboxylated and reductively cyclized to afford the oxindole 142. The oxindole was demethylated, regioselectively prenylated, epoxidized, and subjected to a key seven-membered ring forming procedure to provide the unique dioxepin 124. This ring forming methodology was explored in detail with two alternative procedures (epoxidation/SnCl4; PhSeCl, N-PSP) culminating in the synthesis of the dioxepins 148, 154, 188, 189, 192 , 195, 193, and 196. 124 was reduced, protected and subjected to a Mannich reaction to afford the gramine 220 in 4% overall yield. S-proline was condensed with pivaldehyde and allylated to give the key (Seebach) heterocycle, which was amidolyzed, cyclized, ozonolyzed and homologated to grant the (Williams) piperazinedione 91. This was oxidatively N-deprotected, reduced, O-silylated and dimethoxycarbonylated to afford the piperazinedione 271 in 20% yield from proline. This piperazinedione was alkylated with 220 to yield the indole 272, which was demethoxycarbonylated to provide two separable diastereomers 273 and 274. These were individually treated with Me3OBF4, (BOC)2O, and n-BU4NF to afford the diols 276 and 293. The allylic alcohols were converted to the chlorides, and resilylated to supply 290 and 295, which were subjected to a key regioselective SN2' cyclization. The resulting bicyclic piperazinedione 291 was cyclized, selectively reduced, N-methylated and deprotected to provide the indolepiperazinone 311. This indole-piperazinone 311 was oxidatively spiro-cyclized and dehydrated to afford (+)-paraherquamide B (3) in 1.4% yield from S-proline.
Open Access
The total synthesis of (+/-)-aspirochlorine
(Colorado State University. Libraries, 1993) Miknis, Gregory Francis, author; Williams, Robert M., advisor
Aspirochlorine is a unique epidithiodioxopiperazine isolated from Aspergillus oryzae, Asp. tamarii and Asp. flavus. The molecule contains a highly unusual bicyclo [3.2.2]disulfide ring system which has previously never been prepared. The first total synthesis of (±)-Aspirochlorine was achieved from commercially available 5-chlororesorcinol 324 in 16 steps. The key step in the synthesis was an efficient intramolecular cycloaddition reaction of hydroxamic ester 344 to form the parent spiro [benzofuran-2(3H),2'-piperazine] ring system 345 as a single stereoisomer. In addition the synthesis employed a 2-nitrobenzyl moiety as a novel amide protecting group. The 2-nitrobenzyl group could be removed in 72% yield under photolytic conditions. Synthetic aspirochlorine was identical to natural material in comparison by 1H NMR, IR and HPLC. Comparison of the biological activity of aspirochlorine versus other epidithiodioxopiperazines was investigated as a function of superoxide production. Although aspirochlorine was shown to be capable of producing superoxide as evidenced in DNA plasmid nicking and NBT reduction assays, the observed activity was less than the 6-membered epidithiodioxopiperazines.
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
Synthesis and biomechanistic studies of quinocarcin and structural analogs
(Colorado State University. Libraries, 1995) Flanagan, Mark Edward, author; Williams, Robert M., advisor
The formal total synthesis of the antitumor antibiotic quinocarcin is presented. The synthesis is characterized by a novel NBS oxidative azomethine ylide cycloaddition reaction for the diastereoselective construction of the tetracyclic framework of this substance. A novel mechanism for the reduction of molecular oxygen that results in the O2-dependent cleavage of DNA by quinocarcin, tetrazomine and synthetic structural analogs is presented. The results are discussed in the context of a redox self-disproportionation of the oxazolidine moieties of these compounds which produces superoxide by a previously unrecognized mechanism discovered herein. Stereoelectronic control elements of superoxide production have been elucidated through the use of structural analogs prepared by total synthesis. The synthesis of a structurally less complex water soluble analog of quinocarcin which exhibits most of the physical properties associated with the parent compound is presented. By covalently attaching known DNA binding molecules to this substance, the ability to vary the mechanism and DNA-cleavage specificity of this compound has been demonstrated and is presented herein along with a proposed binding model derived from molecular mechanics.
Open Access
Preparation of azidobrevianamide A and synthetic and biological studies of tetrazomine
(Colorado State University. Libraries, 1995) Tippie, Tracy N., author; Williams, Robert M., advisor
The regioisomers 5-azidobrevianamide A and 7-azidobrevianamide A were synthesized from natural (+)-brevianamide A. The synthesis involved nitration, reduction to the amine, formation of the diazonium ion, and reaction with azide ion. These compounds might be of potential use as photo-affinity labeling agents for the isolation of a potential enzyme catalyzing a Diels-Alder reaction in the proposed biosynthesis of brevianamide A and B. Synthetic studies were conducted towards the total synthesis of tetrazomine. A methodology was devised which allows regioselective introduction of nitrogen functionality to the aromatic ring of an isoquinolone system which is an intermediate in a synthetic pathway to the structurally related quinocarcin. The methodology involves the use of a chloride atom as a "blocking" group, followed by regioselective nitration, and simultaneous cleavage of the chloride and reduction of the nitro moiety furnishing the desired amine. The synthesis of the P-hydroxypipecolinic acid (1 R, 2 R)-1-carboxy-2-hydroxypiperidine was achieved via a stereoselective aldol condensation with a chiral glycine template and 4-pentenal. Following reductive ozonolysis the amino acid was generated by a novel one pot transformation in which a protecting group was cleaved, reductive amination realized and the chiral auxiliary of the template cleaved to furnish the substituted piperidine. It was found that under anaerobic conditions tetrazomine undergoes a redox self-disproportionation of the oxazolidine moiety in an analogous manner to quinocarcin. The oxidized and reduced products were isolated by HPLC and characterized. It was proposed that under aerobic conditions tetrazomine generates superoxide via the proposed disproportionation which could ultimately generate hydroxyl radical by Haber- Weiss/Fenton chemistry. Elucidation of this mechanism provided the first evidence of the relative stereochemical configuration of tetrazomine. It was also shown using a 32P-5'-end labeled synthetic oligionucleotide and high-resolution polyacrylamide gel electrophoresis that tetrazomine is capable of DNA nicking in a non-sequence-specific oxygen dependent fashion characteristic of Fenton-mediated DNA damage.
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
Studies toward the total synthesis of Fusarin C
(Colorado State University. Libraries, 1996) Esslinger, Christopher Sean, author; Williams, Robert M., advisor
The development of the synthesis of the heterocyclic proposed pharmacaphore of the natural mutagenic fungal metabolite fusarin C is discussed with the result of a short and elegant synthesis for this portion of the molecule. The structural integrity of this compound was studied giving rise to a method of diastereomeric preference. Studies to further the synthesis of the natural product are discussed which result in successful alkylation of the heterocycle. The alkylation procedure then produced two new non-natural products which when tested for mutagenic activity along with the heterocycle, may provide information as to the function of the penta-ene side chain of fusarin C in regard to mutagenic activity.
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
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.