Attempted asymmetric synthesis of Lactobacillic acid / |nFawzy F. Z. Georges. -- 260 St. Catharines, Ont. : [s. n.],

This research work has been planned with the intention of proving the absolute configuration of lactobacillc acid. During the course of this work, attempts have been made to synthesize cis-2-carboxycyclopropane- l-.acetic acid as,v,a suitable resolvable material. As the results were not satisfactory, the synthesis of ci,s-2-carboxycyclopropane-l-propionic acid has been alternatively attempted by ring opening of bicyclo- [4.1.~-heptan-2-onewithout much success. Attempts to resolve or prepare bicyclo[ 4.1.~-hePtan-2-one optically active are also reported. On the other hand, a complete scheme is described for the possible synthesis of optically active lactobacillic acid. If only bicyclo- ~.1.~ -heptan-2-one can be resolved or prepared optically active, this described scheme can be applied smoothly to the synthesis of enant~omeric lactobacillic acid.

A Bicyclic L-Proline Derived Chiral Auxiliary for Asymmetric Synthesis

This thesis describes the use of an L−proline-derived chiral auxiliary for diastereoselective lithiation and ligand synthesis. Such compounds have been utilized in the Metallinos research group previously for the synthesis of N−substituted planar chiral ferrocenes. The first project describes the use of this chiral auxiliary as a directing group for N−benzyl substitution, providing products in up to 10:1 diastereomeric ratio (dr). These derivatives may serve as chiral ylidene precursors to serve as ligands in transition metal catalysis. In addition, an N−substituted planar chiral ferrocene ylidene ligand derived from the same chiral auxiliary was used to prepare rhodium complexes that were explored as potential catalysts for asymmetric hydroformylation.

Design and synthesis of new monoterpenoid derived ligands for asymmetric catalysis /

The work to be presented herein illustrates several important facts. First, the synthesis of BIBOL (19), a 1,4-diol derived from the monoterpene camphor has allowed us to demonstrate that oxidative dimerizations of enolates can, and do proceed with nearly complete diastereoselectivity under kinetically controlled conditions. The yield of BIBOL is now 50% on average, with a 10% yield of a second diastereomer, which is likely the result of a non-kinetic hydride reduction, thereby affording the epimeric alcohol, 20, coupled on the exo face of camphor. This implies the production of 60% of a single coupling diastereomer. No other diastereomers from the reduction were observed. The utility of BEBOL has been illustrated in early asymmetric additions of diethylzinc to aryl aldehydes, with e.e.'s as high as 25-30%. '^' To further the oxidative coupling work, the same methodology which gave rise to BIBOL was applied to the chiral pool ketone, menthone. Interestingly, this gave an excellent yield of the a-halohydrin (31), which is the result of a chlorination of menthone. This result clearly indicates the high stereoselectivity of the process regardless of the outcome, and has illustrated an interesting dichotomy between camphor and menthone. The utility of the chlorination product as a precursor other chiral ligands is currently being investigated. > ' Finally, a new series of 1,3-diols as well as a new aminoalcohol have successfully been synthesized from highly diastereoselective aldol/mannich reactions. Early studies have indicated their potential in asymmetric catalysis, while employing pi-stack interactions as a means of controlling enantioselective aldol reactions.

Synthesis of chiral homoallylic alcohols and phthalans through the asymmetric allylation of carbonyl compounds /

The implementation of chiral centres within biologically active compounds has been a perplexing yet motivational force in chemistry. This work presents the attempted formation of a concurrent or sequential tandem catalyzed methodology of enantioselective nucleophilic addition and electrophilic cyclization. The 2'- arylalkynyl- aldehyde, ketone, and imine substrates used within were adeptly chosen with a dually activated structure; 1) for nucleophilic addition to the electrophilic substituents; and 2) for carbophilic activation of the alkyne substituent to undergo cyclization. To accomplish the nucleophilic addition, two distinct allylation methodologies were pursued: (/?)-BINOL catalyzed-allylboration and (5)- BINAP-AgF catalyzed-allylsilylation. BINAP catalyzed enantioselective allylation of 2'-arylalkynyl-aldehydes, to form chiral homoallylic alcohols, was successful. Homoallylic alcohols were isolated with high enantio-purity (>80%), which then underwent sequential cyclization to form chiral allylic phthalans, in moderate yields. An application of this methodology towards the construction of biologically active compounds was included with the partial synthesis of the natural product and H. pylori inhibitor, (+)-Spirolaxine methyl ether.

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.

Asymmetric cyclopropanation via catalysts incorporating the 1,4-diol ligands and the newly designed dioxaborolane /

The development of new methodology for the asymmetric synthesis of chiral organic compounds is a major focus in modem organic chemistry. The use of chiral catalysts is replacing chiral auxiliaries as a new tool for synthetic chemists. An efficient chiral catalyst allows for large quantities of optically active product to be obtained on use of relatively small amount of enantiopure material, without the need for the removal and recovery of a chiral auxiliary. Furthermore, the most practical catalytic methods utilize an inexpensive and readily available chiral ligand that can provide high and predictable enantioselectivity across a wide range of substrates. In our project, two type of versatile, upgraded chiral ligands have been designed and synthesized. Their application in Simmons-Smith type cyclopropanation is investigated, and the pleasing results suggest that they are the potential catalytic enantioselective candidates to build C-C bonds.

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.

Diastereoselective Synthesis of Planar Chiral N-Substituted Ferrocenes Derived from Epimeric Imidazolones and their Application to Asymmetric Hydrogenation of Quinolines

This thesis describes the synthesis and use of an N-substituted ferrocene bearing a proline-derived chiral directing group and diastereoselective lithiation-electrophile quench of the pro-Sp hydrogen of the ferrocene to give planar chiral products in >95:5 dr. The auxiliary group is found to be stable to lithium bases of types RLi and R2NLi giving the same diastereoselectivity. The anti- epimer of the previously mentioned syn auxiliary induces lithiation of pro Rp rather than pro Sp hydrogen in >95:5 dr. Upon electrophile quench and elimination, the enantiomer of the syn-derived planar chiral imidazolone is obtained. Hence, this method provides a practical way to prepare planar chiral enantiomers in this series without the use of a more expensive D-proline derived starting material. The syn and anti epimers have β, γ-stereogenic centers and the origin of stereoselectivity in lithiation appears to be driven by the conformational bias exerted by the β-silyloxy moiety in each chiral auxiliary. In the thesis, this conclusion is supported using insensitivity of lithiation selectivity to the bulkiness of the base, comparison of enantiomers, deuteration experiments, nOe difference studies and computational modeling of the ground states and lithiation transition states for both substrates. The products are then converted to ligand precursors to make iridium and rhodium complexes. Among them, one of the cationic iridium complex is found to be effective in the asymmetric hydrogenation of 2-substituted quinolines with enantioselectivities up to 80% at pressures as low as 5 atm.

Attemped asymmetric dehydration with chiral carbodiimides /|nMin-jen Shiao. -- 260 0 St. Catharines [Ont. : s. n.],

This research work has been planned with the intention of synthesizing optically active bicyclo[3,l,0]-hexan-2-one using chiral carbodiimides. Several carbodiimides have been prepared for practice and for attempts at asymmetric induction. The total synthesis of dibenzo[e,g]- (l:3)diazonine and the partial synthesis of l:13-dimethyldibenzo[e,g]- (l:3)diazonine are reported. Attempts to resolve 6,6f-dimethyl-2,2t-diphenic acid were not successful. The NMR spectra of carbodiimides and the related thioureas are compared. The reaction transition state of the 4-hydroxycyclohexanone with optically pure R,R(+)-di(a-phenylethyl)-carbodiimide has been considered. The ORD application to chiral cyclohexanones is discussed.

Experimental and Computational Studies on Copper and Hydrobenzoin Derivatives in Catalytic Asymmetric Reactions

The use of theory to understand and facilitate catalytic enantioselective organic transformations involving copper and hydrobenzoin derivatives is reported. Section A details the use of theory to predict, facilitate, and understand a copper promoted amino oxygenation reaction reported by Chemler et al. Using Density Functional Theory (DFT), employing the hybrid B3LYP functional and a LanL2DZ/6-31G(d) basis set, the mechanistic details were studied on a N-tosyl-o-allylaniline and a [alpha]-methyl-[gamma]-alkenyl sulfonamide substrate. The results suggest the N-C bond formation proceeds via a cisaminocupration, and not through a radical-type mechanism. Additionally, the origin of diastereoselection observed with [alpha]-methyl-[gamma]-alkenyl sulfonamide arises from avoidance of unfavourable steric interactions between the methyl substituent and the N -protecting group. Section B details the computationally guided, experimental investigation of two hydrobenzoin derivatives as ligands/ catalysts, as well as the attempted synthesis of a third hydrobenzoin derivative. The bis-boronic acid derived from hydrobenzoin was successful as a Lewis acid catalyst in the Bignielli reaction and the Conia ene reaction, but provided only racemic products. The chiral diol derived from hydrobenzoin successfully increased the rate of the addition of diethyl zinc to benzaldehyde in the presence of titanium tetraisopropoxide, however poor enantioinduction was obseverved. Notably, the observed reactivity was successfully predicted by theoretical calculations.

A DFT Guided/Experimental Approach to Asymmetric Allylation and Phase-Transfer Catalysis

The Dudding group is interested in the application of Density Functional Theory (DFT) in developing asymmetric methodologies, and thus the focus of this dissertation will be on the integration of these approaches. Several interrelated subsets of computer aided design and implementation in catalysis have been addressed during the course of these studies. The first of the aims rested upon the advancement of methodologies for the synthesis of biological active C(1)-chiral 3-methylene-indan-1-ols, which in practice lead to the use of a sequential asymmetric Yamamoto-Sakurai-Hosomi allylation/Mizoroki Heck reaction sequence. An important aspect of this work was the utilization of ortho-substituted arylaldehyde reagents which are known to be a problematic class of substrates for existing asymmetric allylation approaches. The second phase of my research program lead to the further development of asymmetric allylation methods using o-arylaldehyde substrates for synthesis of chiral C(3)-substituted phthalides. Apart from the de novo design of these chemistries in silico, which notably utilized water-tolerant, inexpensive, and relatively environmental benign indium metal, this work represented the first computational study of a stereoselective indium-mediated process. Following from these discoveries was the advent of a related, yet catalytic, Ag(I)-catalyzed approach for preparing C(3)-substituted phthalides that from a practical standpoint was complementary in many ways. Not only did this new methodology build upon my earlier work with the integrated (experimental/computational) use of the Ag(I)-catalyzed asymmetric methods in synthesis, it provided fundamental insight arrived at through DFT calculations, regarding the Yamamoto-Sakurai-Hosomi allylation. The development of ligands for unprecedented asymmetric Lewis base catalysis, especially asymmetric allylations using silver and indium metals, followed as a natural extension from these earlier discoveries. To this end, forthcoming as well was the advancement of a family of disubstituted (N-cyclopropenium guanidine/N-imidazoliumyl substituted cyclopropenylimine) nitrogen adducts that has provided fundamental insight into chemical bonding and offered an unprecedented class of phase transfer catalysts (PTC) having far-reaching potential. Salient features of these disubstituted nitrogen species is unprecedented finding of a cyclopropenium based C-H•••πaryl interaction, as well, the presence of a highly dissociated anion projected them to serve as a catalyst promoting fluorination reactions. Attracted by the timely development of these disubstituted nitrogen adducts my last studies as a PhD scholar has addressed the utility of one of the synthesized disubstituted nitrogen adducts as a valuable catalyst for benzylation of the Schiff base N-diphenyl methylene glycine ethyl ester. Additionally, the catalyst was applied for benzylic fluorination, emerging from this exploration was successful fluorination of benzyl bromide and its derivatives in high yields. A notable feature of this protocol is column-free purification of the product and recovery of the catalyst to use in a further reaction sequence.