The application of the structural correlation method to determine the reaction coordinate for a putative ring closure reaction

The cr ystal structure of the compound 2-benzoylethylidene-3-(2,4- dibromophenyl)-2,3-dihydro-5-phenyl-l,3,4-thiadiazole* C23H16Br2NZOS (BRMEO) has been determined by using three dimensiona l x-ray diffraction data. The crys tal form is monoclinic, space group P21/c, a = 17.492(4), o -.t' 0 R 0 b =: 16.979(1), c = 14.962(1) A, "X. =o= 90 ',= 106.46(1) , z = 8, graphite-monochromatized Mo~ rad iation, Jl= 0.710J3~, D = 1.62g/cc and o D = 1.65g/cc. The data were col lected on ~ Nonius CAD-4 c diffractometer. The following atoms were made anisotropic: Br, S, N, 0, C7, and C14-C16 for each i ndependent molecu le ; the rest were left isotropic. For 3112 independent refl ec tions with F > 6G\F), R == 0.057. The compound has two independent molecules within the asymmetric unit. Two different conformers were observed which pack well together. /l The S---O interaction distances of 2.493(6) and 2 . 478(7) A were observed for molecules A and B respectively. These values are consistent with earlier findings for 2-benzoylmethylene-3-(2,4-dibromophenyl)- ~~ 2,3-dihydro-5-phenyl-l,3,4-thiadiazole C22H14Br2N20S (BRPHO) and 2-benzoylpropylidene-3-(2,4-dibromophenyl)-2,3-dihydroiii ,'r 5-phenyl-l,3,4-thiadiazole C24H18Br2N20S (BRPETO ) where S---O distances are l ess than the van der Waals (3.251\) but greater than those expected for () a single bond (1.50A). From the results and the literature it appears obvious that the energy/reaction coordinate pathway has a minimum between the end structures (the mono- and bicyclic compounds). * See reference (21) for nomenclature.

The preparation and reactions of some 1, 2-dipolar species /|nI. D. Brindle. -- 260 St. Catharines, Ont. : [s. n.],

This research was directed mainly towards the investigation of the reactions of allylic amineimides. The work can be divided into two main sections. Section 1 of the thesis deals mainly with thermolysis studies of amineimides. Sections 1a and 1b represent a comprehensive survey of amineimide literature up to 1971. N-A1ly1-N,N-dirnethylarnine-benzirnide was prepared and rearranged at 1400 to l-allyl-1-benzoyl-2,2-dimethylhydrazine. A tentative mechanism involving an initial migration to the carbonyl oxygen was disproved by incorporating the amineimide system into a five-membered ring. N,N~Dimethyl-N-propargylamine-benzimidedid not rearrange on heating; but the hydrobromide, on heating, disproportionated to give 1-benzoyl~2,2,2-trimethylhydraziniumbromide and I-benzoyl-2,2~ dimethylhydrazine. l-Ally'l--l, I-dimethyl-2-benzoy-lhydrazinium bromide and 1~benzoy-1-2,2, 2-trimethy-lhydrazinium iodide both disproportionated to give l~benzoyl-2,2-dimethylhydrazine. Section 1 concludes with a discussion of the mechanisms of ally'lic migrations in amineimides proposed by J. E. Baldwin. Section 2 deals with the formation of five-membered heterocyclic compounds from amineimides by bromination. 1,1-Dimethyl-2benzoyl- 4-bromopyrazolidinium bromide was formed from N-allyl-N,Ndime thy-lamtne-benzimide , 1,1-dimethyl-2-benzoyl-4-bromopyrazol-3enium bromide from N,N~dimethyl-N-propargylamine~benzimidevia the unusual acetylenic "bromonium" ion. Hydrogenolysis of both heterocyclic compounds gave the same product. The preparation was extended by forming 2,2-dimethyl-4-bromoisoxazolinium bromide from N-allylN, N-dimethylamine-N-oxide. Sections 3 and 4 cover a number of unsuccessful attempts to synthesise other amineimides and l,2-dipolar species.

Total synthesis of (S)-4-hydroxy-[a]-Lapachone

(S)-4-Hydroxy-a-lapachone has been prepared for the first time. The commercially available compound 2-acetyl-1-naphthol was used as the starting material. The synthesis involved methylation, followed by Baeyer-Villiger oxidation, and hydrolysis of the acetate to give 1-methoxy-2-naphthol. After protecting of the hydroxyl group, t-BuLi was used to form 3-(3',3'-dimethyl-acryloyl)-1- meth oxy-2- (meth oxymethoxy)-naphthalen e. eycl izationand oxidation then gave 4-keto-a-lapachone. Finally enzymic biotransformation by Mortierella isabellina ATCC 42613 was used to yield the target compound. The enantiomeric excess of the product was determined to be ~98% by using 1H NMR chiral shift analysis. The overall yield is 80/0. The biological activity of (S)-4-hydroxy-alapachone and its acetate are under investigation.

Modifications to the Suzuki reaction and mechanistic insights on the NBS mediated cleavage of benzylidene acetals /

One of the most challenging tasks for a synthetic organic chemist today, is the development of chemo, regio, and stereoselective methodologies toward the total synthesis of macromolecules. r . The objective of my thesis was to develop methodologies towards this end. The first part of my project was to develop highly functionalized chirons from D-glucose, a cheap, chiral starting material, to be utilized in this capacity. The second part of the project dealt with modifying the carbon-carbon bond forming Suzuki reaction, which is utilized quite often as a means of combining molecular sub units in total synthesis applications. As previously stated the first area of the project was to develop high value chirons from D-glucose, but the mechanism of their formation was also investigated. The free radical initiated oxidative fragmentation of benzylidene acetals was investigated through the use of several test-case substrates in order to unravel the possible mechanistic pathways. This was performed by reacting the different acetals with N-bromosuccinimide and benzoyl peroxide in chlorobenzene at 70^C in all cases. Of the three mechanistic pathways discussed in the literature, it was determined, from the various reaction products obtained, that the fragmentation of the initial benzylic radical does not occur spontaneously but rather, oxidation proceeds to give the benzyl bromide, which then fragments via a polar pathway. It was also discovered that the regioselectivity of the fragmentation step could be altered through incorporation of an allylic system into the benzylidene acetal. This allows for the acquisition of a new set of densely functionalized. chiral, valuable synthetic intermediates in only a few steps and in high yields from a-Dglucose. The second part of the project was the utilization of the phosphonium salt room temperature ionic liquid tetradecyltrihexylphosphonium chloride (THPC) as an efficient reusable medium for the palladium catalyzed Suzuki cross-coupling reaction of aryl halides, including aryl chlorides, under mild conditions. The cross-coupling reactions were found to proceed in THPC containing small amounts of water and toluene using potassium phosphate and 1% Pd2(dba)3. Variously substituted iodobenzenes, including electron rich derivatives, reacted efficiently in THPC with a variety of arylboronic acids and afforded complete conversion within 1 hour at 50 ^C. The corresponding aryl bromides also reacted under these conditions with the addition of a catalytic amount of triphenylphosphine that allowed for complete conversion and high isolated yields. The reactions involving aryl chlorides were considerably slower, although the addition of triphenylphosphine and heating at 70 ^C allowed high conversion of electron deficient derivatives. Addition of water and hexane to the reaction products results in a triphasic system in which the top hexane phase contained the biaryl products, the palladium catalyst remained fully dissolved in the central THPC layer, while the inorganic salts were extracted into the lower aqueous phase. The catalyst was then recycled by removing the top and bottom layers and adding the reagents to the ionic liquid which was heated again at 50 ^C; resulting in complete turnover of iodobenzene. Repetition of this procedure gave the biphenyl product in 82-97% yield (repeated five times) for both the initial and recycled reaction sequences.

Reactions of steroidal epoxides with strong organic bases and an investigation into the syntheses of some labelled pregnane derivatives

Reactions of 5,6- and 4,5-epoxycholestane derivatives with strong bases were investigated. Epoxidation of 3a-acetoxycholest-5-ene also gave a new compound along with the anticipated epoxides. Interconversions of the latter were observed. Some possible mechanisms of its formation and rearrangements have been pIioposed. No reaction was observed with any of the 5,6- and 4,5-steroidal epoxides employed in the present study, using potassium tertiary butoxide under refluxing conditions. n-Butyllithium reacted only with 5,6-epoxycholestanes bearing a ketal moiety at the C3 carbon. Opening of the ketal group was observed with n-butyllithium in the case of a ~-epoxide. The reaction was also investigated in the absence of epoxide functionality. A possible mechanism for the opening of ketal group has been proposed. Lithium diethylamide (LDEA) was found effective in rearranging 5,6- and 4,5-epoxides to their ~orresponding allylic alcohols. These rearrangements presumably proceed via syn-eliminations, however the possibility of a corresponding anti-elimination has not been eliminated. A substituent effect of various functional groups (R = H, OH, OCH2CH20) at C3 has-been observed on product distribution in the LDEApromoted rearrangements of the corresponding epoxides. No reaction of these epoxides was observed with lithium diisopropylamide (LDA) • In the second part of the project, several attempts were made towards the sYRthesis of deoxycorticoste~one~17,2l,2l~d3' a compound desirable for the 2l-dehydroxylation studies of deoxycorticosterone. Several routes were investigated, and some deuterium labelled pregnane derivatives were prepared in this regard. Microbial 21-hydroxylation of progesteronel7,21,21,2l- d4 by ~ niger led to loss of deuterium from C21 of the product. An effort was made to hydroxylate progesterone microbially under neutral condtions.

Iridium(I) complexes of phenanthroline-derived benzimidazolylidenes : synthetic, structural and catalytic studies

N-heterocyclic carbenes (NHCs) have undergone rapid development in recent years. Due to their strong a-electron donation and structural variability properties, NHCs are becoming a major class of ligands in organometallic chemistry. Compared with the other two types of NHCs (imidazolylidenes and imidazolinylidenes), benzimidazolylidenes have not been well represented. Limited synthetic approaches may impede the development ofbenzimidazolylidenes. This thesis is focused on the synthesis of phenanthroline-derived benzimidazolylidene ligands and their metal complexes. A series of benzimidazolylidene-iridium complexes were synthesized and characterized spectroscopically and crystallographic ally. All of the new complexes showed varying degrees of catalytic activity and enantioselectivity toward transfer hydrogenation and asymmetric hydrogenation. The best results were achieved in hydrogenation of methyl-2-acetamidoacrylate, which afforded (-)-(R)-methyl-2-acetamidopropanoate in 97% yield and 81 % ee.

Stereoselective synthesis of substituted hexahydro-3a,4a-diazacyclopentaphenanthren-4-ones and aminoferrocenes

This thesis explored the development of several methodologies for the stereoselective construction of ligand frameworks and some of their applications. The first segment concerns the application of an enantioselective lithiation at an Sp3_ hybridized position adjacent to nitrogen by means of the widely used and typically highly effective enantioselective lithiation with ( -)-sparteine. This investigation was intended to develop a method to install chirality into a system that would be converted into a family of diaminoylidenes for use as phosphine mimics in transition metal catalysis or as nucleophilic reagents. Molecular modeling of the system revealed some key interactions between the substrate and (-)-sparteine that provided general insight into the diamine's mode of action and should lend some predictive value to its future applications. The second portion focuses on the development of methods to access 1,2- disubstituted aminoferrocenes, an underexplored class of metallocenes possessing planar chirality. Two routes were examined involving a diastereoselective and an enantioselective pathway, where the latter method made use of the first BF3-mediated lithiation-substitution to install planar chirality. Key derivatives such as 1,2- aminophosphines, made readily accessible by the new route, were evaluated as ligands for Pd(II), Pt(II) and Ir(I). These complexes show activity in a number of transformations with both achiral and prochiral substrates. Optimization experiments were conducted to prepare enantiomerically enriched 2-substituted-I-aminoferrocenes by direct asymmetric lithiation of BF3-coordinated tertiary aminoferrocenes. A predictive computational model describing the transition state of this reaction was developed in collaboration with Professor Travis Dudding's group (Department of Chemistry, Brock University). The predicted stereochemistry of the process was confirmed by single-crystal X-ray analysis of a 2-phosphino-l-dimethylaminoferrocene derivative. Enantiomerically pure samples of the aminophosphine ligands derived from this new process have given promising preliminary results in the enantioselective hydrogenation of prochiral alkenes and warrant further stUdy in metal-mediated catalysis.

Synthesis and utilization of guanidine catalysts for applications directed towards the preparation of butenolide and modified amino acid derivatives

Development of guanidine catalysts is explored through direct iminium chloride and amine coupling, alongside a 2-chloro-l,3-dimethyl-IH-imidazol-:-3-ium chloride (DMC) induced thiourea cyclization. Synthesized achiral catalyst N-(5Hdibenzo[ d,t][1,3]diazepin-6(7H)-ylidene)-3,5-bis(trifluoromethyl) aniline proved unsuccessful towards O-acyl migrations, however successfully catalyzed the vinylogous aldol reaction between dicbloro furanone and benzaldehyde. Incorporating chirality into the guanidine catalyst utilizing a (R)-phenylalaninol auxiliary, generating (R)-2-((5Hdibenzo[ d,t] [1,3 ]diazepin-6(7H)-ylidene ) amino )-3 -phenylpropan-l-ol, demonstrated enantioselectivity for a variety of adducts. Highest enantiomeric excess (ee) was afforded between dibromofuranone and p-chlorobenzaldehyde, affording the syn conformation in 96% ee and the anti in 54% ee, with an overall yield of30%. Attempts to increase asymmetric induction were focused on incorporation of axial chirality to the (R)phenylalaninol catalyst using binaphthyl diamine. Incorporation of (S)-binaphthyl exhibited destructive selectivity, whereas incorporation of (R)-binaphthyl demonstrated no effects on enantioselectivity. Current studies are being directed towards identifying the catalytic properties of asymmetric induction with further studies are being aimed towards increasing enantioselectivity by increasing backbone steric bulk.

Racemic and Enantioselective Total Syntheses of Mosquito Oviposition Pheromone from a Naturally Available Unsaturated Fatty Acid

The unnatural threo-6-acetoxy-5-hexadecanolide and the natural mosquito oviposition pheromone erythro-6-acetoxy-5-hexadecanolide were synthesized in a diastereodivergent fashion in 44% and 33% overall yield respectively from 5-bromovaleric acid and undecanal. The key step utilized a chemoenzymatic epoxidation-lactonization of a naturally available fatty acid to form the 6-hydroxy-5-hexadecanolide core.17 The epoxidation strategy was later adapted to allow for an asymmetric synthesis. Shi epoxidation afforded highly enantioenriched (5R, 6R)-6-hydroxyhexadecanolide (er = 10) in 70 % overall yield. Other derivatives of the chiral ketone catalyst were also screened. Finally, attempts were made to obtain the correct stereochemistry at C(6) of the target with a dynamic kinetic transformation using lipase and a transfer hydrogenation catalyst. Epimerization of the lactol with the transfer hydrogenation catalyst was successful, but lipase mediated reactions halted at <10 % conversion.

DFT Studies of the Organocatalytic Aldol Reaction and a Frustrated Lewis Pair

The computational study, and in particular the density functional theory (DFT) study of the organocatalytic α-chlorination-aldol reaction and the chiral backbone Frustrated Lewis Pair (FLP) system served as a valuable tool for experimental purposes. This thesis describes methods to consider different transition states of the proline- catalyzed α-chlorination aldol reaction to determine the reasonable transition state in the reaction between the enamine and α-chloro aldehydes. Moreover, the novel intramolecular Frustrated Lewis pair based on a chiral backbone for the asymmetric hydrogenation of imines and enamines was designed and the ability of hydrogen splitting by this new FLP system was examined by computational modeling and calculating the hydrogen activation energy barrier.

Innis Lecture: Can the Theory of Incentives Explain Decentralization?

This survey presents within a single model three theories of decentralization of decision-making within organizations based on private information and incentives. Renegotiation, collusion, and limits on communication are three sufficient conditions for decentralization to be optimal.

A Prudent Central Banker

This paper studies monetary policy in an economy where the central banker's preferences are asymmetric around optimal inflation. In particular, positive deviations from the optimum can be weighted more, or less, severely than negative deviations in the policy maker's loss function. It is shown that under asymmetric preferences, uncertainty can induce a prudent behavior on the part of the central banker. Since the prudence motive can be large enough to override the inflation bias, optimal monetary policy could be implemented even in the absence of rules, reputation, or contractual mechanisms. For certain parameter values, a deflationary bias can arise in equilibrium.

Upper Semicontinuous Extensions of Binary Relations.

Suzumura shows that a binary relation has a weak order extension if and only if it is consistent. However, consistency is demonstrably not sufficient to extend an upper semi-continuous binary relation to an upper semicontinuous weak order. Jaffray proves that any asymmetric (or reflexive), transitive and upper semicontinuous binary relation has an upper semicontinuous strict (or weak) order extension. We provide sufficient conditions for existence of upper semicontinuous extensions of consistence rather than transitive relations. For asymmetric relations, consistency and upper semicontinuity suffice. For more general relations, we prove one theorem using a further consistency property and another with an additional continuity requirement.

Does the Barro-Gordon Model Explain the Behavior of US Inflation? a Reexamination of the Empirical Evidence

This paper tests the predictions of the Barro-Gordon model using US data on inflation and unemployment. To that end, it constructs a general game-theoretical model with asymmetric preferences that nests the Barro-Gordon model and a version of Cukierman’s model as special cases. Likelihood Ratio tests indicate that the restriction imposed by the Barro-Gordon model is rejected by the data but the one imposed by the version of Cukierman’s model is not. Reduced-form estimates are consistent with the view that the Federal Reserve weights more heavily positive than negative unemployment deviations from the expected natural rate.

Risk Aversion, Intertemporal Substitution, and Option Pricing

This paper develops a general stochastic framework and an equilibrium asset pricing model that make clear how attitudes towards intertemporal substitution and risk matter for option pricing. In particular, we show under which statistical conditions option pricing formulas are not preference-free, in other words, when preferences are not hidden in the stock and bond prices as they are in the standard Black and Scholes (BS) or Hull and White (HW) pricing formulas. The dependence of option prices on preference parameters comes from several instantaneous causality effects such as the so-called leverage effect. We also emphasize that the most standard asset pricing models (CAPM for the stock and BS or HW preference-free option pricing) are valid under the same stochastic setting (typically the absence of leverage effect), regardless of preference parameter values. Even though we propose a general non-preference-free option pricing formula, we always keep in mind that the BS formula is dominant both as a theoretical reference model and as a tool for practitioners. Another contribution of the paper is to characterize why the BS formula is such a benchmark. We show that, as soon as we are ready to accept a basic property of option prices, namely their homogeneity of degree one with respect to the pair formed by the underlying stock price and the strike price, the necessary statistical hypotheses for homogeneity provide BS-shaped option prices in equilibrium. This BS-shaped option-pricing formula allows us to derive interesting characterizations of the volatility smile, that is, the pattern of BS implicit volatilities as a function of the option moneyness. First, the asymmetry of the smile is shown to be equivalent to a particular form of asymmetry of the equivalent martingale measure. Second, this asymmetry appears precisely when there is either a premium on an instantaneous interest rate risk or on a generalized leverage effect or both, in other words, whenever the option pricing formula is not preference-free. Therefore, the main conclusion of our analysis for practitioners should be that an asymmetric smile is indicative of the relevance of preference parameters to price options.