Dissertations / Theses on the topic 'A -hydroxy ketones'

Chiral polyfunctionalized 1,5-dicarbonyl compounds are important synthetic intermediates and starting materials for many biologically active compounds so their synthesis has a great importance in the literature. In the first step, 1,3-cyclohexandione and other b-diketone derivatives are protected under acid catalyzation and their corresponding b-keto enol ether derivatives are obtained. These b-keto enol ethers are then converted to a-acetoxy enones in racemic form by Mn(OAc)3 mediated oxidation. Enzymatic kinetic resolution is applied to the racemic acetoxy enones by using different lipases and enantiomerically pure a-acetoxy and hydroxy enones are obtained. Then, dicarbonyl derivatives are obtained by hydrolizing racemic a-acetoxy enones. Oxidative cleavage of racemic a-acetoxy diketones in the presence of oxone gives corresponding racemic 1,5-dimethyl ester derivatives. By using this reaction as a reference, same reactions are applied to the chiral a-acetoxy and hydroxy diketones in order to synthesize chiral a-acetoxy and hydroxy 1,5-diester derivatives.

The objective of the study presented here was to develop either enzymatic or whole cell mediated green procedures for the syntheses of a-hydroxy ketones. Production of optically active synthons is crucial for the preparation of fine chemicals. Enzymes and whole-cell biocatalysts have proven to be excellent vehicles with their chiral nature for the biotransformations. Under the light of this discussion, firstly benzaldehyde lyase [BAL, (EC 4.1.2.38)] was used in novel C-C bond formation reactions to obtain interesting and biologically important precursors
2-Hydroxy-1-arylethan-1-ones and functionalized aliphatic acyloin derivatives. All the compounds were obtained with high yields and in the case of aliphatic acyloin derivatives with high enantiomeric excesses (ee&rsquo
s). Another strategy was to use whole cell biocatalysis. A.flavus 200120 was found to be a promising biocatalyst with the ability to catalyze a broad range of reactions
reduction, hydrolysis and deracemization, while another fungus
A. oryzae 5048 was utilized in bioreduction reactions of benzil and its derivatives. Each reaction was investigated, optimized and thus enhanced via medium design. Products were obtained with high yields and ee&rsquo
s. To sum up, in this study novel efficient green procedures were developed to synthesize various ahydroxy ketones with high yield and stereoselectivity. These newly established methods present promising alternatives to classical chemical methodologies.

Abstract The synthesis of α-hydroxy aldehydes and hydroxymethyl ketones as well as their interconversion to each other are discussed in this thesis. The literature survey of the monograph reviews the synthetic methods for the preparation of 1,2-bifunctionalized hydroxy aldehydes and ketones. The keto-aldehyde isomerisation reaction catalyzed by Triosephosphate isomerase enzyme (TIM) and organic compounds that interact with the TIM are also introduced. In addition, the microwave heating techniques in organic syntheses are reviewed. The practical work consists of two entities: The synthesis of new substrate candidates and transition state analogues for a mutated monomeric TIM. These compounds are model compounds for the catalytic activity and the structural studies of the mutated monomeric TIM. The synthesis of the sulphonyl α-hydroxy ketone-based substrate candidates consists of four successive syntheses. The microwave-activation was utilized in the preparation of a carbon-sulphur bond and the synthesis of hydroxymethyl ketones. The improved synthesis of the terminal α-hydroxy ketone functionality with microwave activation is presented. The formation of charged compounds was utilized to improve the absorption of microwave energy of reaction mixtures. The design and the synthetic work were carried out in accordance to principles of green chemistry. The second part of the practical work is the development of an organocatalytic α-oxybenzoylation reaction of aldehydes with high enantiomeric selectivity. This novel method generated enantiomerically pure α-hydroxy aldehydes in the stable benzoate-protected form from achiral starting materials under mild conditions at the presence of air and moisture.

Chiral a -hydroxy ketones are important structural units in many natural products, biologically active compounds and the hydroxyl group has frequently been used as a reagent directing group, such as for the selective elaboration of aldol products. In this work, enzymatic synthesis of both enantiomers of the a -hydroxy ketones (2-hydroxy indanone, 2-hydroxy tetralone) using Aspergillus niger by selective &
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-oxidation of ketones (1-indanone, 1-tetralone) was studied. The &
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-oxidation of ketones was carried out by using whole cells of Aspergillus niger in different growth media. A. niger whole cell catalyzed reactions afforded (S)-configurated 2- hydroxy-1-tetralone with %87 e.e. in DMSO at pH 5.0. In addition to this,while (S)-configurated 2-hydroxy-1-indanone with %33 e.e. in pH 8.0 (in DMSO) was synthesized, (R)-configurated-2-hyroxy-1-indanone with %32 e.e. in pH 7.0 ( in DMSO) was synthesized.

Optically active &
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-hydroxy ketones are important subunits of many biologically active compounds and indispensable synthons for asymmetric synthesis. Benzaldehyde Lyase from Pseudomonas fluorescens Biovar I is a novel ThDP-dependent enzyme that catalyzes the synthesis of benzoin type chiral &
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-hydroxy ketones starting from both benzaldehyde and racemic benzoin derivatives. Benzaldehyde Lyase is the first example of enzymes in the literature which leads to a chemical resolution of enantiomers of benzoin derivatives through a C-C bond cleavage reaction. Chiral 2-hydroxypropiophenone derivatives are formed by benzaldehyde lyase (BAL), catalyzing C-C bond formation after a selective C-C bond cleavage of a benzoin derivative accepted as a substrate. The enzyme uses only the (R)-benzoin derivatives as substrate for the formation of (R)-HPP derivatives and it is highly stereoselective. Thus, in the presence of the acetaldehyde as the acceptor aldehyde, the C-C bond cleavage of the benzoin molecule followed by the carboligation of the acetaldehyde to yield chiral 2-hydroxy propiophenone derivatives. Given the racemic benzoin to the enzyme as the substrate in the presence of acetaldehyde, both the racemic resolution of the substrate, revealing the unreacted (S)-Benzoin and the formation of the corresponding R-HPP occur.

Chiral cyclic polyoxo-ketones are important structural units in many natural products, biologically active compouds, such as prostaglandins, didemnenones, sarkomycin, punaglandin, clavulone, etc. In this work, a chemoenzymatic synthesis of both enantiomers of the &
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&rsquo
-acetoxy-&
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-methyl and &
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-hydroxy-&
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-methyl cyclic enones starting from &
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-methyl-&
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-methoxy cyclic enone is described. Manganese (III) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of &
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-acetoxy enone provides acetoxy enones. The reduction of the hydroxy enone, obtained from hydrolysis, furnished both enantiomers of 4-hydroxy enone or &
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-hydroxy enone by using LiAlH4. This study is a model for the synthesis of these type compounds

&
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-Hydroxy phosphonates are versatile building blocks for the synthesis of many biologically active compounds that display antiviral, antibacterial, anticancer, pesticide activities beside their enzyme inhibitory activities such as they are the inhibitors of rennin or human immunodeficiency virus (HIV) protease and polymerase. Benzaldehyde lyase is able to catalyze not only C-C bond formation reactions but also C-C bond breaking reactions with high enantioselectivity that brings about the development of new synthetic methodologies for the synthesis of hydroxy ketones which are the key intermediates in the synthesis of many biologically active compounds due to the versatility of stereogenic center for developing structural diversity. There are several synthetic methodologies for the synthesis of hydroxy phoshonates however, in this work we have achieved the synthesis of hydroxy phoshonates through C-C bond forming reactions catalyzed by Benzaldehyde lyase that offers the use of green methodologies. Moreover, we have achieved the synthesis of hydroxy ketones which are versatile building blocks in the synthesis of many biologically active compounds via the immobilization of BAL enzyme on superparamagnetic solid support with high yield and high enantioselectivity.

Ketosis is a metabolic condition that occurs during heat stress, prolonged exercise, fasting, and in obese and diabetic individuals. The major ketone body, β-OH butyrate, affects cellular signaling pathways in a hormone-like manner through its receptor GPR109a. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of diabetes. To understand how β-OH butyrate signaling affects hepatic metabolism we compared the fasting response in control and 3-hydroxy-3-methylglutaryl-CoA Synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production, and in GPR109a +/+ and -/- mice. To directly assess the response to ketone signaling we gave intraperitoneal injections of the GPR109a agonists niacin (0.8mmol/kg) and β-OH butyrate (5.7mmol/kg) to HMGCS2 knockdown mice over the final 9 hours of a 16 hour fast. Ketogenic deficient mice showed a more robust increase in hepatic carnitine palmitoyltransferase 1 (CPT1) and uncoupling protein 2 (UCP2) mRNA than control mice in response to fasting. Accordingly, niacin and β-OH butyrate administration decreased fasting CPT1 mRNA expression in knockdown mice, while fasting knockdown UCP2 mRNA and control HMGCS2 mRNA were lowered by β-OH butyrate. GPR109a knockout did not alter the hepatic response to fasting, although the effect of niacin on fasting HMGCS2 mRNA expression was dependent on GPR109a expression. While the role of GPR109a and how chronic hyperketonemia alters β-OH butyrate signaling require further study, these data suggest that endogenous β-OH butyrate signaling during a fast regulates the transcript levels of hepatic genes directly involved in its own synthesis.

Benzoin is an important a-hydroxy ketone which can be used as chiral intermediate for the synthesis of several drugs. In this study, it was aimed to synthesize this compound by high stereoslectivity and yield by the use of fungal bioconversions. For this purpose, whole cells of four different Fusarium spp. (F. anguoides, F. roseum, F. solanii, F.bulbigenum) were used for reduction of readily available achiral compound benzil. The reaction conditions were optimized as glucose peptone broth consisting of 30g/L glucose and 10 g/L peptone, inoculum size as 20 mg/L and substrate concentration as 200 mg/L. A complete set of derivatives substituted with electron donating and electron withdrawing groups of the benzils were also reduced to the corresponding benzoin derivatives with the same optimized condition with up to 98% ee.

A novel method for asymmetric synthesis of α-hydroxy ketone with excellent regio- and stereoselectivity has been established by the systematic investigation of asymmetric dihydroxylation of allenes. The efficiency of kinetic resolution of racemic allenes was also investigated by using the AD reaction on both 1,3-disubstituted and trisubstituted allenes. Steric effects, electronic effects and allene substitution are also discussed. Aziridines were formed by copper-catalyzed intramolecular nitrene addition to alkenes. The carbamate group was used as the tether between the alkene and the nitrene. Subsequent nucleophilic attack of the aziridine was accomplished using RSH, R2NH, N3-,or ROH as the nucleophile. This addition was found to be regio- and stereoselective. This methodology has provided a new strategy for the stereoselective construction of three adjacent functional groups, in particular the 1,2 diamino-3-hydroxy unit. The rhodium-catalyzed intramolecular aziridination of allenic N-sulfonyloxy carbamates has been established. Efficient ring opening of these bicyclic compounds may provide synthetic utility in organic chemistry. The intramolecular aziridination of allenic sulfamate esters was tested on a single example to afford in situ a ring opened product.

The objective of this presented study was to synthesize optically active compounds considered to be key intermediates in the synthesis of Oseltamivir (Tamiflu) by performing chemical and biotechnological methods. Thereof, the carboethoxy cyclohexenone skeleton first was synthesized utilizing easily available substances. The synthesis of alpha-hydroxy ketones in enantiomerically pure form offers a great importance in the synthesis of biologically active compounds. Toward this fact, the enantioselective synthesis of alpha-hydroxy carboethoxy cyclohexenone scaffold has been accomplished by following the routes which were manganese(III) acetate-mediated chemical oxidation followed by enzyme-mediated hydrolysis and additionally microbial direct biooxidation by whole cells of fungi expressly A. oryzae and A. flavus. A very satisfying results have been obtained by both of the methods.

碩士
國立清華大學
化學系
102
This thesis dealt with the synthesis and application of novel prolinamide-camphor organocatalysts that derived from the coupling of trans-4-hydroxy-L-proline and camphorsulfonamide. Organocatalyst 11d is proven to be an efficient catalyst for the asymmetric Michael reaction of ketone and a series of chalcone-derived. Treatment of cyclohexanone with chalcone- deriveds which have electron-withdrawing group using organocatalyst 11d provided the desired Michael products with high chemical yields (up to 97% yield), excellent diastereoselectivities (up to 99/1 dr) and high levels of enantioselectivities (up to 93% ee) for syn- products.

碩士
國立暨南國際大學
應用化學系
104
The application of asymmetric aza-Michael addition reactions by utilizing organic catalyst is one of the important synthesis methods to create a carbon-nitrogen bond. And it is useful for nature product and medicine synthesis. It has economic benefits and is environmentaly friendly in asymmetric synthesis. In this thesis, aza-Michael addition reaction’s product is 1,3-oxazolidine. 1,3-Oxazolidines are important structural moieties that exist in many biologically active compound. For example, quinocarcin and its analogue terazomine are polycyclic tetrahydroisoquinoline alkaloids with remarkable activities against several tumor cell lines. Therefore, we synthesised the new type of organocatalysts 59、60 containing camphor derived [3.2.1] bicyclic thiourea has also been designed and prepared. It shows low [α]D values to cyclize 3,4-dihydroisoquinolines and γ-hydroxy-α,β-unsaturated phenyl ketone. But, the cyclization took only 15 min at room temperature without any catalyst and addition agent. Then, we examined a wide variety of 3,4-dihydroisoquinolines substates. The results showed that the reaction tolerated both electron-donating and –withdrawing groups at the various positions on the phenyl ring of 3,4-dihydroisoquinolines. The reaction provides the various products in good to excellent yields (82-98%).

La plupart des conditions détectées par le dépistage néonatal sont reliées à l'une des enzymes qui dégradent les acyls-CoA mitochondriaux. Le rôle physiopathologique des acyls-CoA dans ces maladies est peu connue, en partie parce que les esters liés au CoA sont intracellulaires et les échantillons tissulaires de patients humains ne sont généralement pas disponibles. Nous avons créé une modèle animal murin de l'une de ces maladies, la déficience en 3-hydroxy-3-methylglutaryl-CoA lyase (HL), dans le foie (souris HLLKO). HL est la dernière enzyme de la cétogenèse et de la dégradation de la leucine. Une déficience chronique en HL et les crises métaboliques aigües, produisent chacune un portrait anormal et distinct d'acyls-CoA hépatiques. Ces profils ne sont pas prévisibles à partir des niveaux d'acides organiques urinaires et d'acylcarnitines plasmatiques. La cétogenèse est indétectable dans les hépatocytes HLLKO. Dans les mitochondries HLLKO isolées, le dégagement de 14CO2 à partir du [2-14C]pyruvate a diminué en présence de 2-ketoisocaproate (KIC), un métabolite de la leucine. Au test de tolérance au pyruvate, une mesure de la gluconéogenèse, les souris HLLKO ne présentent pas la réponse hyperglycémique normale. L'hyperammoniémie et l'hypoglycémie, des signes classiques de plusieurs erreurs innées du métabolisme (EIM) des acyls-CoA, surviennent de façon spontanée chez des souris HLLKO et sont inductibles par l'administration de KIC. Une charge en KIC augmente le niveau d'acyls-CoA reliés à la leucine et diminue le niveau d'acétyl-CoA. Les mitochondries des hépatocytes des souris HLLKO traitées avec KIC présentent un gonflement marqué. L'hyperammoniémie des souris HLLKO répond au traitement par l'acide N-carbamyl-L-glutamique. Ce composé permet de contourner une enzyme acétyl-CoA-dépendante essentielle pour l’uréogenèse, le N-acétylglutamate synthase. Ceci démontre un mécanisme d’hyperammoniémie lié aux acyls-CoA. Dans une deuxième EIM des acyls-CoA, la souris SCADD, déficiente en déshydrogénase des acyls-CoA à chaînes courtes. Le profil des acyls-CoA hépatiques montre un niveau élevé du butyryl-CoA particulièrement après un jeûne et après une charge en triglycérides à chaîne moyenne précurseurs du butyryl-CoA.
Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-CoA esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Measures of Krebs cycle flux diminished following incubation of HLLKO mitochondria with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which bypasses an acetyl-CoA-dependent reaction essential for urea cycle function, thus demonstrating an acyl-CoA-related mechanism for this complication. In a second animal model of an inborn error of acyl-CoA metabolism, short chain acyl-CoA dehydrogenase (SCAD)-deficient mice, the main finding in liver acyl-CoAs is increased butyryl-CoA, particularly during fasting or after enteral loading with medium chain triglyceride precursor of butyryl-CoA.

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.
This thesis consists of two parts: Part 1: Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents FTY720 is presently marketed as a drug (GilenyaTM) for the treatment of relapsing-remitting multiple sclerosis. It functions as an immunosuppressant due to its effect on sphingosine-1-phosphate (S1P) receptors. At higher doses, FTY720 also has antineoplastic actions. However, at such doses it induces bradycardia due to the activation of the S1P1 and S1P3 receptors. This limits its potentical to be used as a cancer therapy in humans. Our previous studies have shown that some constrained pyrrolidine analogues of FTY720 have anticancer activity but no activity toward S1P1 and S1P3 receptors. We reasoned that a study of the structure-activity relationships (SARs) could lead to the discovery of new effective antitumor agents. Thus, two series of constrained analogues (O-arylmethyl-substituted pyrrolidines and C-aryl-substituted pyrrolidines) were designed and synthesized (Chapter 1). These analogues showed excellent cytotoxic activity against various human cancer cells (prostate, colon, breast, pancreas and leukemia). Especially, several active analogues, which cannot be phosphorylated by SphK, have the potency to be further studied in the treatment of cancer without inducing bradycardia. Mechanistic studies suggest that these constrained analogues trigger down-regulation of nutrient transporters, which induce a bioenergetic crisis and the cancer cells starve to death. To further investigate their target receptors, we have designed and synthesized diazirine based photo-affinity labeling (PAL) probes (Chapter 2). Aided by the PAL technique, information regarding the target receptor could be obtained through LC/MS/MS protein analysis. These tests are in progress and the preliminary results appear promising. Part 2: Metal coordination-controlled and bifunctional catalysis toward tertiary β-ketols The Barbier and Grignard reactions are classical methods to form carbon-carbon bonds, and generally used to prepare secondary or tertiary alcohols. In an attempt to perform a Grignard reaction with n-butyl iodide under Barbier one-pot conditions, we obtained major product β-hydroxyl ketol from the self-aldol reaction of 5-hexen-2-one, rather than the expected addition alcohol product (Chapter 3). The unusual β-ketol formation was also observed using other methyl ketone substrates. Interestingly, in an intramolecular reaction of a triketone substrate, which is well known to give the Hajos-Parrish ketone, the favored product was a rarely studied β-ketol with the hydroxyl group at axial position. Intrigued by these results, after systematic reaction condition studies, we developed two new methods toward the catalytic synthesis of specific β-ketols by intramolecular cylcization in high yield and selectivity (Chapter 4). The reaction can be catalyzed either by a suitable base and lithium bromide as the additive, through a lithium pre-organized transition state or by a bifunctional catalyst TBD (triazabicyclodecene), through a TBD mediated bidentate transition state. The proposed mechanisms were corroborated by DFT computation. These catalytic reactions were also extended to other triketone and diketone substrates. Although the initial efforts to achieve enantioselectivity were not successful, they merit further study of the synthesis and investigation of new chiral catalysts.