The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (??)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

Amines are ubiquitous in nature and serve a variety of functions in living organisms. Because of this fact amines are of great biological and pharmaceutical interest. The iridium catalyst (pentamethylcyclopentadienyl) iridium dichloride dimer ([Cp*IrCl2]2) has been used in a number of ways to synthesize new carbon-nitrogen bonds. These studies were directed toward the development of a method for the iridium catalyzed N-alkylation of alpha-amino acid esters as well as the development of a strategy for synthesis of the natural product 275A. We have optimized a method for the N-alkylation for alpha-amino acid esters. Using this method, we have N-alkylated a series of alpha-amino acid esters with a variety of alcohols. We have shown that the N-alkylation of the alpha-amino acid esters works consistently and gives the desired products in moderate to high yields. We have examined the effect of this method on the chiral center of the obtained products by analyzing their optical rotation. Evaluation of these specific rotations indicated racemization was occurring but it is believed that any loss of the chiral center is due to the reaction conditions. Amphibian alkaloids are of great interest to the pharmaceutical and academic communities due to their biological activities. Unfortunately, they are not naturally available in large quantities which makes total synthesis the most common method of generating these compounds for evaluation. One amphibian alkaloid class of interest to us are the Lehmizidines. These are bicyclic ring structures consisting of a 7-member and 5-member ring with a nitrogen bridgehead. The alkaloid, 275A, was selected as a target for a general synthetic approach. This synthetic approach required the synthesis of novel diols. The construction of these diols along with a method for the synthesis of the azepane ring is presented here.

No description available.

Direct generation of enantioenriched mono-α-alkylated aldehydes by intermolecular nucleophilic substitution is a general and long-standing problem in synthesis, and is of importance due to the diverse reactions such aldehydes undergo for introducing asymmetry into molecules. The work described in this thesis initially details the development of the first lithium amide capable of efficiently converting terminal epoxide into enamine functionality, where the latter also demonstrates effective C-alkylation activity. Not only addition to Michael acceptors, but more notably substitution using activated organohalides (α-bromoacetates, benzyl, allyl and propargyl bromide) gave the corresponding α-substituted aldehydes in good to excellent yields. Alkylation with propargyl bromide yielded only the propargyl-substituted aldehyde with none of the corresponding allene observed; this result shows that N-alkylation followed by [3,3] sigmatropic rearrangement is not occuring. Importantly, a range of short-, longer-chain and secondary unactivated alkyl iodides also proved viable. Significantly, with chiral lithium amides, the corresponding chiral enamines could be alkylated with strongly electrophilic benzyl, allyl and propargyl (no allene seen) bromides in very good yields, and with short chain alkyl iodides – MeI and EtI in satisfactory yields, to provide the first direct access to α-alkylated aldehydes with high asymmetric induction by intermolecular nucleophilic substitution.

Azetidine is a four-membered nitrogen-containing heterocyclic ring that has recently received a great deal of attention as a molecular scaffold for the design and preparation of biologically active compounds. Structure-activity studies employing functionalized azetidines have led to the development of variety of drug molecules and clinical candidates encompassing a broad spectrum of biological activities. Herein, the synthesis a novel series of 3-aryl-3-arylmethoxyazetidines is described. Selected 3-aryl-3-arylmethoxyazetidines were evaluated for their binding affinity to multiple monoaminergic transporters for the potential treatment of methamphetamine addiction. It was discovered that this scaffold exhibits high binding affinity (nM) for both the serotonin and dopamine transporters. In addition, a new method was developed for the synthesis of 3,3-diarylazetidines. This new approach provides a facile and efficient method to synthesize a variety of diaryl heterocycles including 3,3-diarylazetidines, 3,3-diarylpyrrolidines, and 4,4-diarylpiperidines in moderate to good yields.

The focus of these studies was directed towards the synthesis of novel N-heterocyclic compounds and pharmacological evaluation of these compounds for activity at monoamine transporters. A series of novel piperidine and pyrrolidine analogues were prepared from commercially available starting material with a three and four step synthetic method, respectively. A variety of substituents on the aromatic ring were incorporated to achieve a diverse library of compounds. The preliminary binding studies of piperidine molecules showed strong affinity towards serotonin transporters and moderate affinity towards dopamine transporters. The focus of further studies was directed towards utilization of iridium catalysis for the development of new synthetic methods for biologically important molecules. This research has led to the development of a new synthetic strategy for the construction of nicotine and its analogues. In addition, the iridium catalysis was also used for alkylation of amides with primary and secondary alcohols under microwave conditions.

The solvent-free (Cp*IrCl2)2 catalyzed N-alkylation of urea with benzyl alcohol has been studied. A variety of reaction conditions were studied and optimized to produce a high yield (82%) of N,N-dibenzylurea. A series of substituted benzyl alcohols were examined at the optimal reaction conditions. However, the preparation of substituted benzyl urea derivatives using conditions optimized for benzyl alcohol gave poor yields or intractable mixtures.

The pyrrolidine and piperidine ring systems are present in a variety of different classes of amphibian alkaloids. We have found the iridium catalyzed N-heterocylization reaction of diols with amines to be very useful for the construction of novel pyrrolidine, piperidine and piperazine derivatives. The scope and utility of the iridium catalyzed N-heterocyclization reaction for the construction of novel anuran scaffolds using amino diols and triols are presented. Studies directed towards the total synthesis of 4,6-disubstituted quinolizidine and (±)-epiquinamide are discussed. The second study is focused on the selective conversion of terminal dienes to primary diols. This conversion has always had problems with regioselectivity and low yields due to polymer formation with carbon chains having more than 7 carbon atoms. An improvement in the yield and regioselectivity was observed with disiamylborane prepared in situ using 2-methyl-2-butene and BH3•DMS. The scope of this method with 7, 8 and 9 carbon chains and different alcohol protecting groups for synthesis of triols is presented.

Thesis advisor: Amir H. Hoveyda / Chapter 1. In this chapter, the ability of chiral bidentate N-heterocyclic carbenes (NHCs) to activate alkylmetal reagents directly in order to promote C&#8210;C bond forming reactions in the absence of a Cu salt is presented. Highly regio- and enantioselective Cu-free allylic alkylation reactions of di- and trisubstituted allylic substrates with organomagnesium, organozinc, and organoaluminum reagents are demonstrated. Chiral bidentate sulfonate-bearing NHC-Zn and NHC-Al complexes are isolated and fully characterized. Based on crystal structures of these catalytic complexes, mechanistic details regarding Cu-free allylic alkylations with alkylmetal reagents are proposed. Chapter 2. New methods for efficient and highly enantioselective Cu-catalyzed allylic alkylation reactions of a variety of trisubstituted allylic substrates with alkylmagnesium and alkyl-, aryl-, 2-furyl-, and 2-thiophenylaluminum reagents are presented. Transformations are promoted by a chiral NHC complex in the presence of commercially available, inexpensive and air stable CuCl2*H2O. Enantiomerically enriched compounds containing difficult-to-access all-carbon quaternary stereogenic centers are obtained. Chapter 3. New methods for highly site- and enantioselective Cu-catalyzed allylic alkylation reactions of allylic phosphates with vinylaluminum reagents are presented. The requisite vinylaluminums are prepared by reaction of readily accessible terminal alkynes with DIBAL-H and used directly without further purification. Vinyl additions are promoted in the presence of a chiral bidentate sulfonate-based NHC complex and a Cu salt. The desired SN2' products are obtained in >98% E selectivities, >98% SN2' selectivities, >98% group selectivities (<2% i-Bu addition) and high enantioselectivities. The enantioselective total synthesis of the natural product bakuchiol highlights the versatility of the one-pot hydroalumination/Cu-catalyzed enantioselective allylic vinylation process. Chapter 4. Efficient and highly site-selective Cu-catalyzed hydroboration reactions of 1,2-disubstituted aryl olefins with bis(pinacolato)diboron (B2(pin)2) are presented. Transformations are promoted by an NHC-Cu complex in the presence of MeOH, affording only secondary &#946;-boronate isomers. A Cu-catalyzed method for the synthesis of enantiomerically enriched secondary alkylboronates promoted by chiral NHC complexes is disclosed. Chapter 5. A new method for efficient and site-selective tandem Cu-catalyzed copper-boron additions to terminal alkynes with B2(pin)2 in the presence of an NHC-Cu complex is demonstrated. In a one-pot process, Cu-catalyzed hydroboration of alkynes provides vinylboronates in situ, which undergo a second site-selective hydroboration to afford vicinal diboronates. Highly Enantiomerically enriched diboronates obtained through Cu-catalyzed enantioselective dihydroboration in the presence of chiral bidentate sulfonate-based NHC-Cu complex are obtained. The control of site selectivity in the first-stage hydroboration of alkynes is critical for efficient and highly enantioselective reactions in the tandem dihydroboration. Functionalizations of the vicinal diboronates described herein underline the significance of the current method. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

O presente trabalho teve como objetivo central estudar, sob condições de Catálise de Transferência de Fase, as reações de C-alquilação de diversos compostos contendo em sua estrutura molecular os grupos &#945;-fenil ou &#945;-naftilacetila: (Ver arquivo PDF). Nas várias reações efetuadas, foram empregados o hidrogenossulfato de tetrabutilamônio (TBAH) e catalisadores quirais derivados de alcalóides da cinchona. Foram investigadas, para cada substrato, várias condições experimentais, tanto em sistema sólido-líquido como líquido-líquido. Nas reações dos ésteres (24), (25) e (26) foram observados produtos derivados da hidrólise do grupo éster. No entanto, para os ésteres (27), (28) e (29) a reação de C-alquilação era preponderante, o que permitiu a extrapolação ao uso de catalisadores quirais. Para estes substratos, apenas o produto de C-alquilação do éster (28) apresentou excesso enantiomérico (8-12%). Os resultados insatisfatórios obtidos para os 6 ésteres estudados foram atribuídos à baixa acidez dos prótons metilênicos, à enolização do produto ou a fatores estruturais. O produto da C-benzilação da amida (31) foi isolado em baixo rendimento e 30% de excesso enantiomérico. Uma comparação com os resultados obtidos para amida (30) permitiu inferir que a substituição de um grupo fenila por um grupo naftila produz um aumento de reatividade e uma melhor interação com o catalisador quiral. No caso da acil-imina (32) e das acil-hidrazonas (33) e (34) os produtos foram obtidos em rendimentos de médios a bons e apresentavam atividade óptica. No entanto, a dificuldade técnica de determinar seu excesso enantiomérico impossibilitou a avaliação da enantiosseletividade das reações de C-alquilação efetuadas com estes substratos. O conjunto dos resultados obtido foi analisado à luz dos modelos atualmente propostos para reações de CTF assimétrica. / The present work focussed on the alkylation reactions, via Phase Transfer Catalysis, of several acyl derivatives: (See files PDF). In order to evaluate the extension of the backgroud reaction, several blank experiments were performed, in the absence of catalyst. The efficiency of the catalitic process was determined using as catalyst an achiral ammonium salt (TBAH). Experimental conditions were optimized using liquid-liquid or solid-liquid systems. In reactions performed with the ester derivatives (24), (25) and (26), hydrolytic acyl cleavage could be observed. However, for compounds (27), (28) and (29), C-alkylated products could be isolated in reasonable yields. Reactions conducted under asymmetric PTC conditions led, in most cases, to racemic products. Esters were considered inadequate substrates for C-alkylation as a consequence of three main factors: (i) low reactivity under PTC conditions, (ii) product racemization or (iii) formation of loose ion-pairs, or diastereomeric intermediates of equal thermodynamic stability. Asymmetric PTC alkylation of amide (31) afforded a C-benzylated optically active product in low yield (ee= 30%). Improved reactivity could be observed for this substrate as compared to amide (30), as a result of increasing acidity and a more favorable interaction between the catalyst and the corresponding enolate. For compounds (32), (33) and (34), the enantiomeric excess of the corresponding C-benzylated products could not be determined, precluding a comparison of the efficiency of the stereoselective catalytic process. For each case, results were discussed in terms of currently accepted models for the enolate/catalyst interaction.