In this report, three studies are presented that utilize computations to predict transformations, identities, and properties of environmental organic molecules. Each study shows how computations can lead to models of chemical behavior. The importance of this research is rooted in the need for understanding how human behavior and health intersect...
Xanthohumol [XN, (E)-6´-methoxy-3´-(3-methylbuten-2-yl)-2´,4´,4´´-trihydroxychalcone], the principal prenylated chalcone from hops, and its 2,3-dihydro- (DXN) and O6-desmethyl-2,3-dihydro- (DDXN) congeners, are of potential utility for the amelioration of metabolic syndrome; however, their complex bioactivity profiles cannot be properly studied and understood without access to appropriately produced synthetic materials.
In the first part of...
Part 1: A Diels-Alder Approach to the Synthesis of Novel Analogues of the Natural
Product Siamenol
Due to the prevalence of biaryl motifs in natural product synthesis, the Carter
research group has been exploring the utility of a Diels-Alder approach to biaryl
synthesis. The Diels-Alder approach involves a [4+2] cycloaddition...
7,7'-Dihydroxy-8,8'-biquinolyl (azaBINOL) was prepared from 7-hydroxyquinoline via N,N-dimethyl O-quinol-7-yl carbamate by directed ortho-metallation followed by FeCl₃-mediated oxidative coupling of the 8-lithioquinoline intermediate. Saponification of the resulting dicarbamate provided crystalline (±)-azaBINOL in 56% overall yield. 6,6'-Bis(dimethylaminocarbonyl)-7,7'-dihydroxy-8,8´-biquinolyl was prepared from the same dicarbamate by a double anionic-Fries rearrangement in 43% yield. 7,7'-Bis(diethylamino-carbonyloxy)-6,6'-diiodo-8,8´-biquinolyl...
Sulfoxide-ligand exchange (SLE) and asymmetric halogen-metal exchange (AHME) processes were separately examined for the enantioselective synthesis of functionalized alpha-haloalkylmetal (carbenoid) reagents. Carbenoids derived from SLE were used to effect stereospecific reagent-controlled homologation (StReCH) of boronic esters and those generated via AHME were engaged in Darzens-type chemistry with aldehydes.
Abstract for...
In this report, three studies are presented that aid in the development of drug discovery and their synthesis. In each, the importance of the marriage between computations and experiments is highlighted. Continued efforts in this vein are essential for future efforts towards improving human health.
The first case study investigated...
Many D2d-symmetric 2,2',6,6'-tetrasubstituted biphenyls are
readily prepared via net oxidative dimerization of appropriate
1,3-disubstituted benzenes. Conversion of such proprochiral
compounds to useful C2-symmetric chiral biphenyls requires
formal replacement of two substituents on opposing aryl ring
units with alternate groups. This under exploited
desymmetrization tactic has been demonstrated for the
generation...
Two distinct strategies were explored for the enantioselective synthesis of α-heteroatom substituted alkyl boronic esters by stereoselective reagent-controlled homologation using transient chiral carbenoid reagents CHYMX (Y = heteroatom, X = nucleofuge, M = electrofuge). In the first case, a stereospecific reagent-controlled homologation (sStReCH) approach to α-alkoxyalkylboronates using α-metalated S,O- and...
Enantioenriched sp³-hybridized carbenoid reagents CR1R2MX (X = nucleofuge, M = electrofuge) of different types were investigated for the synthesis of polysubstituted alkyl chains by iterative stereospecific reagent-controlled homologation (StReCH) and for the stereospecific connective synthesis of alkenes by eliminative cross-coupling.
In the first part, putative enantioenriched α-chloroalkyllithiums (CHRLiCl) were employed...
My work has focused on investigating synthetic organic reactions using applied computational methods. Non-covalent interactions are critical to catalysis, mechanism, and stereoselectivity, with the most prominent interaction for isothioureas being the S···O contact between the catalyst sulfur atom and the oxygen of the acyl group. A comprehensive joint experimental and...
In Part I, (4S,5R)-4,5-dimethyl-4-phenylcyclohex-2-enone (19a) was prepared in 73% yield with high enantio- and diastereo-selectivity (er > 98:2, dr > 20:1) on a multigram scale by a Yamada-Otani condensation between (E)-pent-3-en-2-one and 2-phenylpropanal catalyzed by a sulfonimide derivative of (S)-proline (18, HuaCat®). Synthetically useful transformations of the cyclohexenone product 19a...
Three distinct methods to achieve the stereoselective synthesis of carbon-carbon bonds were investigated, encompassing: (i) the formation of axially chiral biaryl molecules by enantioselective Suzuki cross-coupling, (ii) the synthesis of α-phenylalkylboronic esters by enantioselective chain extension, and (iii) the stereospecific synthesis of alkenes by eliminative cross-coupling of enantioenriched sp³-hybridized carbenoids....
Traditional approaches for the direct preparation of alkenes are unable to fully control either the stereochemical configuration of the carbon-carbon double bond or else the regiochemistry of the substituents surrounding it. The recently introduced concept of carbenoid eliminative cross-coupling (CEXC) offers a remedy to these deficiencies by providing for a...
The stereospecific reagent-controlled homologation (StReCH) of boronic esters with enantioenriched carbenoid species generated in situ by the addition of organolithium initiators to stereodefined α-chloroalkyl aryl sulfoxides was previously reported. The reaction of an organolithium with an α-chloroalkyl aryl sulfoxide ostensibly generates an α-chloroalkyllithium via sulfoxide-lithium exchange; however, the true nature...
The bimolecular reaction of two carbenoid species resulting in the formation of a carbon-carbon double bond (pi-system), referred to herein as carbenoid eliminative cross-coupling (CEXC), involves a series of three fundamental steps: (i) ate-complex formation (transmetalation), (ii) 1,2-metalate rearrangement, and (iii) beta-elimination. All three steps are stereospecific and so the...
Chalaniline A, an unusual xanthone-like aminofulvene with modest cytotoxicity, and chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibacterial aminoxanthone, were previously isolated by Loesgen and coworkers from vorinostat-treated Chalara sp. 6661. Of note, the anilino moiety found within both chalaniline structures originates from biotransformation of the HDAC inhibitor vorinostat (SAHA, suberanilohydroxamic acid) by...
Put generally, the work I have conducted in my time at Oregon State University has been to answer two questions. The first of these is “Why do I get this particular product from this particular chemical reaction?” and the second is “How do the reagents in this chemical reaction lead...
In this Dissertation, the mechanism and stereomechanics of complex organocatalysis and reaction processes are disclosed. The technologies and protocols currently being developed and utilized to efficiently investigate these systems using theory are highlighted.
A detailed computational study of peptide-catalyzed acylations is disclosed. In particular, the magnitude of all possible non-bonding...
The stereospecific reagent-controlled homologation (StReCH) of boronic esters with putative lithiooxiranes generated in situ from appropriate precursors via sulfoxide-lithium exchange, tin-lithium exchange, and direct lithiation is described with an emphasis on the first lithiation technique which allows for the regio- and stereo-specific generation of all types of lithiooxirane isomer. Transient...
The work presented here is the culmination of efforts in describing complex chemical systems with statistical methods, thereby providing relatively simple quantitative models and easily comprehensible qualitative insights. The following investigations have various goals, such as development of new methods, fundamental understanding, molecular control of chemical species, and advancement of...
An intramolecular variant of the modified-Julia olefination was demonstrated by the synthesis of α,β-unsaturated lactones in a mild and (Z)-selective fashion. The lynchpin reagent (benzothiazol-2-sulfonyl) acetic acid was synthesized in a straightforward fashion in 86% overall yield from commercially available 2-mercaptobenzothiazole via conversion to ethyl (benzothiazol-2-ylthio)acetate by base mediated alkylation...
My work on computing complex catalyzed organic transformations reveals that only a few subtle chemical factors, e.g. non-classical hydrogen bonding, (hyper)conjugation and steric effects, common across different catalyst manifolds are critical for catalysis and selectivity. Rational manipulation and exploitation of these factors has led to improved catalyst designs, which has...
In this report, two studies are presented that utilize computations to predict and elucidate the reaction mechanisms of two different copper catalyzed reactions. Each study provides insight into the various chemical transformations, as well as the how and why behind regioselectivity and isotopic selectivity. The importance of this research is...
Complex organic transformations, such as the addition of pyrrole to ketene using planar chiral organocatalyst (*PPY), the four-component anhydride- Manniach reactions, and the site-selective desymmetrization of meso-1,2-diol, are remarkable synthetic reactions that provide high yield and high selectivity. However, the exact mechanism and origins of stereocontrol for theses synthetic organic...
Ambifunctional axially chiral 2,2',6,6'-tetrasubstituted biphenyls containing nucleophilic (or basic) functional groups juxtaposed with hydrogen-bond donors were synthesized and their properties studied. Applications for the prepared biaryls as potential organocatalysts for enantioselective carbon-carbon bond forming reactions were examined. Processes investigated included: aldol, Michael, nitroaldol (Henry), and Baylis-Hillman reactions.
The novel amidoamine...
In previous work (Blakemore et al. Org. Lett. 2005, 7, 4721; Heterocycles 2006, 70, 609), successful elaborations of the lupine alkaloids (±)-α-isosparteine (dl-2) and (±)-β-isosparteine (dl-3) were realized from a common tetraoxobispidine precursor, 3,7-diallyl -2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (93). Herein, the tetraoxobispidine approach to lupine alkaloids was extended to a total synthesis of...
My work has focused on using density functional theory to elucidate mechanisms of organocatalytic and transition metal catalyzed reactions by considering competing mechanisms. In each of the three presented studies computational investigation complemented experimental work by predicting stereoselectivity or revealing origins of stereo, regio, or chemoselectivity.
A study on the...
My work has focused on streamlining the study of organic compound structure, properties, and reactions by 1) understanding and using available computational software, 2) developing software packages to facilitate data manipulation as well as augment public programs, and 3) applying public and in-house developed software to further the understanding of...
In this dissertation, the process of computational modeling of amorphous oxide materials is studied. Amorphous oxides have random atomic arrangements with no long-range structural order which makes it difficult to study structure-property relationships. Despite the difficulties, amorphous oxides have great uses as semiconductors and dielectrics in thin-film transistors. The ability...
The synthesis of axially chiral polyfunctional derivatives of 8,8'-biquinolyl was explored and the catalytic action of appropriate derivative types investigated in three separate processes: (1) the silylcyanation of carbonyl groups and imines, (2) alkylation of a glycine Schiff-base via phase transfer-catalysis, and (3) direct amide bond formation from simple amines...
White muscle disease or muscular dystrophy of sheep is a selenium
responsive malady common to many areas with an inherent natural
deficiency of selenium in the forage. The disease can be prevented in
lambs by adding trace amounts (approximately 0.1 ppm) of selenium to
the otherwise selenium deficient, forage fed...
In an attempt to find a laboratory species which develops an
experimental myopathy similar to white muscle disease (WMD) in
lambs, comparative studies of nutritional muscular dystrophy of
chicks were initiated. This condition was grossly visible as white
striations running parallel with the fibers of the pectoral muscles and
was...
In this dissertation, a novel method for analyzing computed transition states (TS) for organic reactions is disclosed. It introduces the use of localization-delocalization matrices as parameters in a linear free energy relationship to determine the transition state interactions responsible for differences in energy between the major and minor TS in...
Automation of computational chemistry, while only an engineering feat, has the potential to accelerating computational research be removing all by the science. The work in this thesis mainly discusses fundamental understanding of complex chemical systems. What is not obvious are the numerous tasks necessary for this fundamental understanding. Under the...
Copper in blood and liver can be divided into several fractions.
Copper in blood is about evenly divided between erythrocytes and
plasma. Normal concentrations for most species range between one and
two parts per million. Plasma copper is mainly a copper protein,
ceruloplasmin and a loosely bound form, reacting directly...
The preparation and characterization of thin film oxides and chalcogenides by pulsed laser deposition (PLD) is presented. An overview of fundamental PLD concepts are presented and are followed by a description implementation and development of the PLD systems at OSU. We present the results of thin film growth of high...
A total synthesis of the fungal hormones, trisporic acids A and B, is described, starting from a -methyltetronic acid 34. A Robinson annelation of 34 with ethyl vinyl ketone affords the lactone 33. Treatment of 33 with N-bromosuccinimide gave 97, which was hydrolyzed to the lactol 103. The reaction of...