Tandem aza-Claisen rearrangement and ring closing metathesis reactions: the stereoselective synthesis of functionalised carbocyclic amides

A one-pot, tandem process has been developed for the efficient synthesis of functionalised carbocyclic amides. A substituted cyclopentenyl trichloroacetamide was synthesised using a tandem thermal aza-Claisen rearrangement and RCM process, while an analogous cyclohexenyl trichloroacetamide was generated with high diastereoselectivity using a tandem MOM-ether directed metal-catalysed aza-Claisen rearrangement and RCM process

One-pot multi-reaction processes: synthesis of natural products and drug-like scaffolds

One-pot multi-reaction processes involving Overman rearrangements, metathesis cyclizations, and Diels–Alder reactions have been developed for the rapid and efficient synthesis of amino-substituted carbocyclic and heterocyclic compounds. This account describes the development and optimization of these processes, as well as their applications in the synthesis of natural products and drug-like scaffolds

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

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

Thioetherification and Etherification Utilizing Trichloroacetimidates Under Thermal Conditions & Progress Towards an Efficient Synthesis of AQX-1125

The synthesis of ethers and thioethers is necessary as the motifs are ubiquitous in natural products, pharmaceuticals, and are quite useful in numerous synthetic applications. While common methodologies prepare simple ether and thioether substrates, the harsh conditions of these techniques make them unsuitable for complex molecules. The requirement for these functional groups to be prepared by facile and efficient means has led to an investigation into O - and S – alkylations occurring solely under thermal conditions utilizing trichloroacetimidates. The alkylation of thiols by the direct displacement of trichloroacetimidates has been accomplished under thermal conditions (heating in refluxing THF). These reactions proceed to the corresponding thioetherification product without the requirement of an added acid, base, or metal catalyst. This facile procedure provides the sulfide in excellent yields with only the formation of the neutral trichloroacetamide as the side product. Formation of the trichloroacetimidate in situ has also been studied, which provides a convenient method for the formation of sulfides from alcohols in a single flask. A similar methodology towards obtaining etherification products has also been investigated. O – Diphenylmethyl and para-methoxybenzyl trichloroacetimidates in refluxing solvent has shown to effectively convert a variety of alcohols to their corresponding ether without disturbing pre-existing functionality. This methodology provides the subsequent etherification products in moderate to excellent yields with only the formation of the neutral trichloroacetamide as the side product. Additionally, the development of a more efficient and concise total synthesis towards the SHIP1 activator AQX-1125 from trans-dehydroandrosterone has been studied. The synthetic approach features an allylic oxidation of the C7 position and ozonolysis to generate key intermediates. Alternative routes have also been proposed and future investigations will aim to complete this project in the future

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

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

New methodology for the stereoselective synthesis of unnatural alpha-amino acids

New general methodology for the stereoselective synthesis of unnatural alpha-amino acids has been developed. Early work focussed on investigating methods for the generation of chiral allylic alcohols using cross-metathesis of a simple enone with various terminal alkenes, followed by an asymmetric ketone reduction. The allylic alcohols were then converted to protected allylic amines via Overman rearrangement chemistry. Oxidative alkene cleavage and hydrolysis of these intermediates generated a range of alpha-amino acid targets. Attempts were also made to apply the developed methodology to the synthesis of a simple alpha,alpha-disubstituted alpha-amino acid target. The Overman rearrangement was also applied to the generation of a late-stage intermediate which could be used in the synthesis of (2S,3S)-capreomycidine, a component of a number of peptides which exhibit antibacterial activity

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

Investigation of metal mediated reactions for natural product synthesis

During the course of the studies outlined in this thesis, an ether-directed Pd(II)-catalysed aza-Claisen rearrangement reaction that had previously been developed by the Sutherland group was expanded to include more functionalised rearrangement substrates. This methodology has been applied for the synthesis of several natural products including dihydroxylated-amino acids. Further investigation of substrates for the rearrangement led to the synthesis of other substituted trichloroacetimidates. Rearrangement of these compounds demonstrated the role of steric strain on the stereocontrol of the rearrangement and also highlighted the role that solvent can have upon the diastereoselectivity of ether-directed rearrangements. In addition to this, a novel tandem aza-Claisen rearrangement and ring closing metathesis reaction has been developed. This reaction allows the synthesis of cyclic allylic trichloroacetamides in excellent yields from simple allylic alcohols. The use of commercially available chiral rearrangement catalysts allowed a highly enantioselective tandem process to be developed. Further development of this process has provided an ether-directed tandem aza-Claisen rearrangement and RCM reaction which occurs with high yield and diastereoselectivity to provide functionalised cyclic products. The use of these compounds for the total synthesis of the amaryllidaceae alkaloid (+)-gamma-lycorane was also investigated