Exploration of Carbon-oxygen and Carbon-nitrogen Bond Formation Utilizing Trichloroacetimidates and Investigations of New Reactions Mediated By Oxoammonium Salts

Mono-O-alkylated 1,1′-bi-2-naphthols (BINOLs) are often used as the source of chirality for catalysts or ligand systems that are employed in asymmetric organic transformations. However, these BINOLs can be hard to synthesize. The O-alkylation of BINOL can be accomplished with primary and secondary alkyl halides or under Mitsunobu conditions, the yields of these alkylations with tertiary halides or alcohols are very low. A new protocol was developed utilizing trichloroacetamide electrophiles to install bulky groups onto one of the phenolic oxygens. Trichloroacetimidates are also shown to be useful reactions for the synthesis of esters. These reagents proceeded through a symbiotic activation pathway. Under these conditions sensitive substrates did not decompose, which often is observed with other conditions using Lewis or Brønsted acids. These reactions have been broadened to benzyl esters without electron donating groups on the benzylic ring. The trichloroacetimidates therefore provide inexpensive and convenient methods that should find use in the formation of esters in complex substrates. Benzylic amines are important structural features in pharmaceuticals, food additives, and insecticides. Many methods to synthesize benzylic amines have been developed but many of these protocols generate significant waste by-products. Additionally, the benzylic amines are often protected as amides or carbamates in a second step, which requires further resources and produces more waste. Alternatively, the rearrangement of benzylic trichloroacetimidates to acetamides may provide direct access to protected benzylic amine containing systems in a single step. The activity of palladium catalysts in the rearrangement of benzylic trichloroacetimidates to acetamides was explored. Using tris(dibenzylideneacetone)dipalladium(0) gave promising results. The exploration of chiral ligands to access enantioenriched products from this reaction has been investigated. N-Alkylated pyrazoles and benzotriazoles are present in a number of natural products and pharmaceuticals. However, methods of synthesizing pyrazoles and benzotriazoles generally use hydrazine derivatives and limited regioselectivity. N-Alkylated pyrazole utilizing trichloroacetimidate electrophiles under Bronsted acid catalyzed conditions has been developed. Both primary and secondary imidates provided good yields. Benzylic primary imidates provided significantly better yields than phthalimidomethyl imidate. Structurally different pyrazoles were also studied in this transformation. Changing the halogen was tolerated, however, iodine provided the lowest yield. When adding methyl groups at the 3 and 5 position on the pyrazole, product was isolated in moderate yield. Interestingly, when using benzotriazole, a single product was isolated in good yield. This was the dearomatized alkylated product. Further substrate scope investigations and mechanism studies need to be performed to better understand these results. Oxoammonium salts are commonly used to oxidize alcohols to aldehydes or ketones, but these reagents may also be used in a number of other oxidative transformations which are useful in organic chemistry. Taking advantage of these reagents, a new tandem elimination-oxidation process of tertiary alcohols has been discovered, synthesizing a protected allylic alcohol. Data suggests that the transformation first proceeds through elimination of the alcohol mediated by the oxoammonium salt. Then the allylic oxidation proceeds through an ene type mechanism. Additionally, the tetramethylpiperidine derived from the oxoammonium salt also serves as a protecting group for the newly generated allylic alcohol, resulting in a process with high atom economy. The optimization and scope of the reaction has been investigated. N-Oxoammonium salts are also shown to be useful reagents for the metal free 1,2-difunctionalizations of alkenes with heteroatom nucleophiles. While many transformations for the 1,2-addition of heteroatoms to alkenes have been developed, most are dependent on transition metals. Rarer are alkene difunctionalizations that utilize nonmetallic reagents, with most of these reactions relying on photochemical or radical conditions. Investigating these N-oxoammonium salt mediated additions provides a new method for the elaboration of alkenes into molecules with significantly greater complexity. The determination of the stereochemistry of the products of an amino-oxidation with N-oxoammonium salts was also accomplished. Attempts to improve the diastereoselectivity of this process were explored. Investigations have also been initiated to perform these alkene difunctionalizations in an enantioselective manner utilizing anionic phase transfer catalysis. Expansion of the N-oxoammonium salt mediated additions of alkenes with primary alcohols, water, and isatin was also initiated

Trichloroacetimidates as Alkylating Reagents and Their Application in the Synthesis of Pyrroloindoline Natural Products and Synthesis of Small Molecule Inhibitors of Src Homology 2 Domain- Containing Inositol Phosphatase (SHIP)

Trichloroacetimidates are known to be excellent alkylating agents when activated by a catalytic amount of a Brønsted or Lewis acid. Work described herein involved taking advantage of the favorable reactivity of trichloroacetimidates to establish several different synthetic protocols, including the application of these reagents in the synthesis of pyrroloindoline based natural products, 3,3\u27-disubstituted indolenines and benzylic trichloroacetamides. Initial investigations on the utilization of the reactivity of trichloroacetimidates found that diphenylmethyl trichloroacetimidate, which is a precursor to a highly stabilized carbocation, undergoes facile displacement with carboxylic acids providing the ester product without the need of any exogenous catalyst. Both hindered and unhindered carboxylic acids were esterified with high yields, with no preference for aromatic or aliphatic carboxylic acids. Carboxylic acids with unprotected hydroxyl groups or β-lactam rings were esterified efficiently. Substrates that are highly prone to elimination or retro-aldol were also esterified in high yields. Carboxylic acids with highly enolizable α-stereocenters were esterified without any racemization. Mechanistic studies indicate that the carboxylic acid substrate itself is acidic enough to be effective at promoting the esterification reaction. During our studies on esterification with imidates it was found that these imidates also showed a tendency to undergo rearrangement to the corresponding trichloroacetamides. Two different sets of conditions, thermal and Lewis acid catalyzed, were established which provided these rearranged products with high yields. Various benzylic trichloroacetimidates were shown to undergo these transformations under the established conditions. Based on the observations discussed in this work a cationic mechanism is proposed. After the preliminary studies on alkylation of benzylic trichloroacetimidate with different nucleophiles, this chemistry was applied towards the synthesis of natural products and their analogs. The pyrroloindoline ring system is found in many alkaloids and cyclic peptides which mainly differ in the substitution at the C3a position. To provide rapid access to these natural products a diversity-oriented strategy was established via displacement of C3a-trichloroacetimidate pyrroloindoline. Carbon, oxygen, sulfur and nitrogen nucleophiles were all shown to undergo substitution reactions with these trichloroacetimidates in the presence of a Lewis acid catalyst. In order to demonstrate the utility of this new method it was applied towards the synthesis of arundinine and a formal synthesis of psychotriasine. Current investigations involve the application of this method towards the synthesis of a complex pyrroloindoline natural product kapakahine C and the progress made therein has been discussed. The reactivity of trichloroacetimidates was also investigated for the selective C3-alkylation of 2,3-disubstituted indoles to provide indolenines. Indolenines serve as useful intermediates in the synthesis of many complex alkaloids. Different benzylic and allylic trichloroacetimidates were shown to provide 3,3’-disubstituted indolenines with high yields in the presence of catalytic amounts of Lewis acids. Various substituted indoles were evaluated under these reaction conditions. This methodology was also applied towards the synthesis of the core tetracyclic ring system found in communesin natural products. In addition to the above work, synthesis of small molecule inhibitors of Src Homology 2 Domain-Containing Inositol Phosphatase (SHIP) has also been described. Aberrations in the phosphoinositide 3-kinase (PI3K) cellular signaling pathway can lead to diseased cellular states like cancer. Herein we have reported stereoselective synthesis of two quinoline based small molecule SHIP inhibitors. The lead compounds and their analogs were tested for their activities against SHIP by Malachite green assay and the discoveries made therein are discussed. In addition to this synthesis of a tryptamine based SHIP inhibitor has also been reported

Applying Trichloroacetimidates to the Synthesis of Benzylic Trichloroacetamides & Functionalized Indoles

Allylic trichloroacetimidates have been previously shown to be versatile substrates for the synthesis of C-N bonds through [3,3]-sigmatropic rearrangements. This work explores a similar reaction, the rearrangement of benzylic trichloroacetimidates to access benzylic trichloroacetamides. The benzylic rearrangement was shown to proceed under two different sets of conditions: thermal and Lewis-acid catalyzed (TMSOTf). The corresponding secondary benzylic trichloroacetamides were produced in good to high yields with either protocol. The convenience of having two protocols was demonstrated in the study as it allows for extensibility and flexibility of the substrate scope. The usefulness of the benzylic rearrangement of trichloroacetimidates was demonstrated in the synthesis of trichloroacetamide derivatives, such as the corresponding benzyl amine. A cationic pathway is proposed for this reaction based on the available data. The alkylation of many heteroatom nucleophiles with trichloroacetimidates has recently been demonstrated by the Chisholm group, proving that trichloroactimidates are competent alkylating agents. This work has now been extended using benzylic trichloroacetimidates as electrophiles for the Friedel-Crafts alkylation reaction with indoles under Lewis acid catalysis. These reactions proceeded well even with electron-deficient benzyl structures. C3-Monobenzylated indoles were produced in excellent yields with high regioselectivity, an important feature since a common challenge with indoles is polyalkylation. The development of this facile procedure to access C3-monoalkylated indoles facilitated the formation of several interesting indole frameworks, which are known to possess important medicinal and pharmacological properties. Studies towards the selective C3-alkylation of indoles showed that a small amount of the 3,3’-indolenine was being formed as a competing side product. Progress towards an efficient protocol that takes advantage of the nucleophilicity of the C3 position of indoles to build a quaternary center directly with trichloroacetimidates has been discussed. The modular synthesis of indoles with different trichloroacetimidates was possible using Lewis acid-catalyzed conditions was also investigated. While there are reports on the electrophilic addition of electrophiles to indoles for the synthesis of 3,3’-indolenines, this method is differentiated because it does not use any transition-metal catalyst or strong base. Additionally, this methodology is envisioned to be applied in the synthesis of spirocycles from bis-trichloroacetimidates, which are three-dimensional in structure and prominent in medicinal chemistry

Trichloroacetimidates as Alkylating Reagents in C-N Bond Formation and Synthesis of Aminosteroid and Quinoline Inhibitors of Src Homology 2 Domain-Containing Inositol Phosphatase (SHIP)

Trichloroacetimidates have frequently been used in the formation of glycosidic bonds and other ethers, which is especially useful for the introduction of ether protecting groups. Trichloroacetimidates have also been used as electrophiles in Friedel-Crafts alkylation reactions. The formation of C-N bonds has also been accomplished utilizing trichloroacetimidates. Most frequently C-N bond formation with trichloroacetimidates is associated with sigmatropic rearrangement of an allylic trichloroacetimidate to an allylic trichloroacetamide. This reaction can proceed thermally or through the use of Lewis acid or transition metal catalysts. Recently, the direct substitution of trichloroacetimidates using nitrogen nucleophiles has been accomplished utilizing transition metal catalysts, which indicates that trichloroacetimidates may be suitable alkylation partners for certain nitrogen nucleophiles. Trichloroacetimidates are now shown to be effective alkylating reagents for the monosubstitution of anilines using the Brønsted acid catalyst (±)-camphorsulfonic acid. The reaction is especially efficient for electron deficient anilines while electron rich anilines provided lower yields due to competing Friedel-Crafts reactions. A one-pot procedure for generating the trichloroacetimidate in situ followed by displacement with the aniline is also described, and the yields for this one-step process are similar to the two-step protocol. The displacement of a chiral imidate by 4-chloroaniline led to significant racemization which indicates that the reaction may proceed through a carbocation intermediate. The alkylation of sulfonamides with trichloroacetimidates under thermal conditions is also described. Primary and secondary trichloroacetimidates are found to be suitable electrophiles under these conditions, while tertiary trichloroacetimidates provide reduced yields. Aryl and alkyl sulfonamides with varying electronic properties were well tolerated under the reaction conditions. A bioactive analog of the analgesic ketoprofen is synthesized using the described methodology. Complete racemization of a chiral trichloroacetimidate is observed under these reaction conditions which is evidence that the reaction proceeds through an SN1 type mechanism. Pyrroloindoline trichloroacetimidates may react with amine nucleophiles in the presence of catalytic BF3ˑOEt2 to generate pyrroloindoline systems decorated with amines at the C3a position. The natural product kapakahine C is a complex heterocyclic compound containing a substituted pyrroloindoline-pyridoindoline core that may be accessed using this method. A route to the synthesis of the substituted pyridoindoline core of kapakahine C was investigated. Optimization of key reactions in this sequence, including a peptide coupling reaction and oxidative cyclization, was performed. Investigation into completing the synthesis of kapakahine C is ongoing. The inhibition of the SH2-containing inositol 5’-phosphatase (SHIP) can modulate the dephosphorylation of phosphoinositols. These molecules act as second messengers in a signal transduction cascade, with the placement of phosphorylation on the inositol acting to convey information in the transmission of signals from the cell membrane to the cell nucleus. The concentration of these phosphates has an effect on cellular function such as cell proliferation, survival, and differentiation. The synthesis of six aminosteroid SHIP inhibitors is described. Optimization of the key steps in the synthetic sequence was conducted. The synthesis of two quinoline based SHIP inhibitors, which were identified in a high-throughput screening conducted by the National Cancer Institute (NCI), was also completed. Studies were conducted to synthesize these molecules on multi-gram scale. The synthesized compounds were tested for inhibitory activity in a Malachite Green assay

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

Stereoconvergent catalysis is an important subset of asymmetric synthesis that encompasses stereoablative transformations, dynamic kinetic resolutions, and dynamic kinetic asymmetric transformations. Initially, only enzymes were known to catalyze dynamic kinetic processes, but recently various synthetic catalysts have been developed. This Review summarizes major advances in nonenzymatic, transition-metal-promoted dynamic asymmetric transformations reported between 2005 and 2015

Alkylation of Carboxylic Acids And 1,2,3-Triazoles Using Imidates

Imidate alkylating reagents are known to be effective for a wide range of nucleophiles under acidic or thermal conditions. These alkylation reactions may even proceed spontaneously in some cases, as has been observed with the formation of esters from carboxylic acids. This work is focused on further exploring the synthetic utility of imidate alkylating reagents. A general overview of imidate is given in Chapter 1. Some of the important transformations using imidates are briefly discussed. This background provides a basis for understanding the reactivity of this functional group, as both a nucleophile and a leaving group. Building on this work, some esterifications using N-aryl trifluoroacetimidates under promoter free condition was explored. This involved the synthsis of a number of N-aryl trifluoroacetimidates and the evaluation of their reactivity with some carboxylic acids. In Chapter 2, a general method for preparing 2-trimethylsilylethyl (TMSE) esters using 2-(trimethylsilyl)ethyl 2,2,2-trichloroacetimidate under thermal conditions is described. The 2-(trimethylsilyl)ethyl 2,2,2-trichloroacetimidate was easily formed under mild conditions with catalytic DBU from 2-(trimethylsilyl)ethanol. The use of TMSE protecting group was advantageous during some total syntheses, as this protecting group may be easily cleaved using fluoride ions under mild conditions that do not affect other alkyl and benzyl esters. Previously a number of studies on the use of 2,2,2-trichloroacetimidates as electrophiles in N-alkylation reactions have been disclosed. More recently, alkylation of ambident nucleophiles using imidates has been shown to lead to unusual selectivity under some reaction conditions. Building on this work, a new alkylation method for 1,2,3-triazoles using 2,2,2-trichloroacetimidate electrophiles is described in Chapter 3. This alkylation is catalyzed by a Brønsted acid and is regioselective with a strong preference for the N2 alkylation product. This unusual regioselectivity as the N2 alkylation product is typically the minor product from alkylations under basic conditions employing alkyl halides. The isomeric ratio is sensitive to both the reaction solvent and reaction concentration. Optimal results were obtained with a non-polar solvent at low concentrations

Reactions for rapid access to C3a oxygenated pyrroloindolines and its application towards a novel route to pestalazine A

Alkaloids containing a hexahydropyrrolo[2,3-b] indole (pyrroloindoline) core constitute a sizeable group of natural products. In these systems the most common functionality at the C3a position is perhaps the hydroxyl group. In this work oxoammonium salt 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (Bobbitt’s salt) rapidly reacts with tryptamine and tryptophan derivatives to provide the C3a oxygenated pyrroloindolines. These conditions exclude the use of expensive transition metal catalyst, LED lamps and long reaction times. This new method wasa then utilized in a synthetic study on the natural product pestalazine A. 1,1′-diaryl ethanes are an important functionality in many biologically active compounds. A pioneering study was done to access these systems by displacement of tricholoracetimidates with stoichiometric amounts of alkylmetal reagent (trimethylaluminium). Most benzylic substrates except the electron poor substrates undergo ready displacement. In case of an enantiopure imidate, a significant racemization was observed, implicating the formation of a cationic intermediate in the transformation. The success of trimethylaluminium was further extended with allyltributylstannane to synthesize 1, 1’-diarylbutyl. The 1,1’-diarylbutyl group is a common structural motif found in many pharmaceutically active compounds. Commonly a strong base, transition metal catalyst, Brønsted acid or Lewis acid promoter is required to affect the displacement of diarylmethyl leaving groups. However, in this work simply heating diarylmethyl trichloroacetimidates with the allyltributylstannane gives easy access to these systems. Electron rich benzylic trichloroacetimidate systems gave the best results, where excellent yields are achieved just by refluxing the reactants together in nitromethane. Mechanistic studies conducted suggests both cationic and radical pathways may be active in this transformation. Application of trichloroacetimidates for the synthesis of esters under mild conditions in the absence of an exogenous promoter is explored in this study. These conditions avoid the undesired decomposition of substrates with sensitive functional groups. With heating, these reactions have been extended to benzyl esters without electron donating groups. Ghrelin is a peptide hormone which plays a key role in regulating hunger and energy balance within the body. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential target for controlling ghrelin signaling. Through screening a small molecule library by our collabrators, a class of synthetic triterpenoids (CDDO) was identified that efficiently inhibit ghrelin acylation. To verify which functional group was responsible for hGOAT activity, some minimally functionalized steroid derivatives were synthesized in this project. These compounds act as covalent reversible inhibitors, providing the first evidence of the involvement of a nucleophilic cysteine residue in hGOAT catalysis. The Michael acceptor group plays the most important role in inhibition. This study may lead to a viable treatment for diabetes and obesity in future

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

Stereoconvergent catalysis is an important subset of asymmetric synthesis that encompasses stereoablative transformations, dynamic kinetic resolutions, and dynamic kinetic asymmetric transformations. Initially, only enzymes were known to catalyze dynamic kinetic processes, but recently various synthetic catalysts have been developed. This Review summarizes major advances in nonenzymatic, transition-metal-promoted dynamic asymmetric transformations reported between 2005 and 2015

Trichloroacetimidates As Outstanding Electrophiles for the Carbon-nitrogen, Carbon-oxygen and Carbon-carbon Bonds Formation and Synthetic Studies of Protein Phosphatase-5 (pp5) Small Molecule Inhibitors

Trichloroacetimidates have been previously used for glycosidic bond formation in carbohydrate chemistry and in Friedel-Craft reactions. Traditionally, trichloroacetimidates had be synthesized using an alcohol and strongly basic conditions, but in recent years milder preparation methods have been reported. Given the ease of preparation of these versatile reagents, their chemistry has been explored intensely in recent years. While few reported methods suggest they can react under promoter free conditions, activation by Lewis or Brønsted acid leads to a formation of a carbocation from benzylic trichloroacetimidates. Work described herein makes use of these convenient carbocation precursors for new reactions.Isatin is an ambidentate nucleophile and commonly can be N-alkylated using harsh conditions and specialized reaction conditions, while O-alkylation is uncommon and has only been reported utilizing silver salts. These important structures can be alkylated using trichloroacetimidates with a Lewis acid catalyst and the regioselectivity of the alkylation can be varied by changing the solvent. A plethora of secondary trichloroacetimidates participate providing excellent yields of N-alkyl product, while switching the solvent showed a preference for O-alkylation. Substitution of electron donating and withdrawing groups on the isatin ring is also tolerated except at the isatin 7-position, which lowers the yield. Studies have been performed to understand the divergence in the observed selectivity when the solvent was switched and explain the mechanistic pathway this reaction may undergo. Structures containing indolenine core are of great importance to the pharmaceutical and medicinal chemistry research areas. Established methods for the synthesis of 3,3-dialkyl indolenines often require a 3-substituted indole structure. A direct 3,3-dialkylation protocol has been developed by using trichloroacetimidates with Lewis acid catalyst taking advantage of the nucleophilic nature of the C3 position of indole. This method does not depend on the use of transition metal catalyst and two consecutive reactions take place in a single flask providing good yields with a wide substrate scope regarding the imidates and indole substrates. A spirocyclic derivative have also been synthesized to demonstrate the utility of the this developed protocol. Pyrazoles are a group of resourceful heterocyclic compounds with their presence seen in a variety of current medications, potential illness treatments, natural products, and pharmaceutical intermediates. However, N-alkylation of these systems can be done using strongly basic conditions or using transition metal catalyst. Trichloroacetimidates activated by Brønsted acid provide an easy alternative for these N-alkyl pyrazole derivatives. Alkylation using both primary and secondary benzylic imidates provided product in good to excellent yields. While symmetric pyrazoles such as 4-substitute or 3,5-disusbtitued pyrazole showed good reactivity with product formation in moderate yields and good functionality tolerance, unsymmetric pyrazole showed multiple product formation with higher preference to the least sterically hindered one. In addition to the work described above, synthetic studies of small molecule inhibitors for protein phosphatase-5 (PP5) were also undertaken. In recent years, overactivation of PP5 has been linked to the renal cancer and a great need of therapeutic treatment development is necessary. Two previously identified potent inhibitors were synthesized and coupled with biotin and BODIPY dye for pulldown assays and binding data respectively. With the help of docking trials, more structures are actively being developed as potent inhibitors. The results of these studies are also discussed

Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro-Sphinganine, (+)-spisulosine and D-ribo-phytosphingosine

Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM-ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, while the Overman rearrangement of chiral allylic trichloroacetimidates generated by asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access to both D-ribo-phytosphingosine and L-arabino-phytosphingosine