Synthesis of indoles via alkylidenation of acyl hydrazides

Indoles have been synthesised via alkylidenation of acyl phenylhydrazides using phosphoranes and the Petasis reagent, followed by in situ thermal rearrangement of the product enehydrazines. The Petasis reagent provides an essentially neutral equivalent of the [acid-catalysed] Fischer indole synthesis, but with acyl phenylhydrazides as starting substrates. Alkylidene triphenylphosphoranes convert aroyl phenylhydrazides to indoles, but acyl phenylhydrazides derived from aliphatic carboxylic acids undergo a Brunner reaction to form indolin-2-ones

Synthesis of highly substituted allenylsilanes by alkylidenation of silylketenes

BACKGROUND: Allenylsilanes are useful intermediates in organic synthesis. An attractive, convergent but little used approach for their synthesis is the alkylidenation of stable silylketenes. Reactions thus far have been limited to the use of unsubstituted silylketenes (or equivalents) with stabilised or semi-stabilised ylides only. The current study explores the reactions of substituted ketenes prepared through rhodium(II)-mediated rearrangement of silylated diazoketones. RESULTS: A range of novel 1,3-disubstituted and 1,3,3-trisubstituted allenylsilanes were prepared using stabilised and semi-stabilised ylides. Alkylidenation with non-stabilised phosphorus ylides was not viable, but the use of titanium-based methylenating reagents was successful, allowing access to 1-substituted allenylsilanes. CONCLUSION: Many novel allenylsilanes may be accessed by alkylidenation of substituted silylketenes. Importantly, for the first time, simple methylenation of silylketenes has been achieved using titanium carbenoid-based reagents

Stereoselective synthesis of piperidines

EDITED ABSTRACT. This thesis is divided into two parts. The first part describes the production of a small stereodiverse library of 2-substituted piperidines. Novel chiral titanium alkylidene reagents ii alkylidenated resin-bound esters i to give acid-labile resin-bound enol ethers iii. These were cleaved to give amino ketones iv. The switch in the nature of the resin from acid-stable to acid-labile is key to the purity of the amino ketones iv, as during cleavage only the acid-sensitive enol ethers iii are cleaved, leaving the unreacted esters i on the resin. The amino ketonse iv were cyclized using TMSC1 to give cyclic iminium salts v. Diastereoselective reduction of the iminium salts v with NaBH(OAc)[sub]3 gave piperidines vi which, after cleavage of the chiral protecting group gave the desired enantiomerically-enriched, 2-substituted piperidines vii. [Illustrated] The piperidines vii were produced in good overall yield, high purity, and good to excellent stereochemical purity. By switching the enantiomer of the phenylethylamine chiral protecting group used, either enantiomer of the desired piperidine could be produced at will. The second part of the thesis describes a solution-phase route to 2,6-syn substituted piperidin-4-ones xii inspired by the Petasis-Ferrier rearrangement. Imino esters x derived from [Beta]-amino acids viii were methylenated using the Petasis reagent, dimethyltitanoce, to give imino enol ethers xi containing nucleophilic and electrophilic functionality in the same molecule. The mild microwave conditions used for the methylenation geve the enol ethers xi in minutes. Potentially, the reaction takes advantage of selective heating of the polar Petasis reagent in a non polar solvent system so that the rate determining decomposition of the Petasis reagent is accelerated without affecting any sensitive substrate. Acidic conditions activated the imine and induced cyclization to give the desired 2,6-syn piperidin-4-ones xii in good yield and excellent diastereoselectivity. A small library of piperidinones was produced to demonstrate the method. [Illustrated

Total Synthesis of Kingianins A, D, and F

A synthesis fit for a king: The total synthesis of (±)-kingianinsA, D, and F has been achieved in ten steps. Key features include the gram-scale synthesis and partial reduction of a conjugated tetrayne to a (Z,Z,Z,Z)-tetraene, the domino 8π-6π electro

Synthesis of spiroacetals using functionalised titanium carbenoids

Alkylidenation of lactones with functionalised titanium carbenoid reagents (Schrock carbenes) followed by acid-induced cyclisation of the resulting enol ethers constitutes a new method for the preparation of [4.4], [4.5] and [5.5] spiroacetals (1,6-dioxaspiro[4.4]nonanes, 1,6-dioxaspiro[4.5]decanes and 1,7-dioxaspiro[5.5]undecanes, respectively, sometimes termed 5,5-, 5,6- and 6,6-spiroketals). The titanium carbenoids are easily generated from readily available thioacetals

Total Synthesis of (-)-Enigmazole A

The dissertation contained herein presents a total synthesis of (-)-enigmazole A utilizing a late-stage large-fragment Petasis-Ferrier union/rearrangement protocol. Chapter One details the isolation, structural elucidation and subsequent biological studies of (-)-enigmazole A. The previous synthetic studies of (-)-enigmazole A are also introduced. The chapter then outlines the Smith three-step Petasis-Ferrier union/rearrangement protocol, as well as a number of the successful total syntheses achieved over the years by the Smith group utilizing this protocol. Herein, a late-stage large-fragment Petasis-Ferrier union/rearrangement will be utilized as the synthetic cornerstone for the Smith total synthesis of (-)-enigmazole A. Chapter Two describes the retrosynthetic strategy toward (-)-enigmazole A and subsequent total synthesis. The late-stage large-fragment Petasis-Ferrier union/rearrangement, which generates the entire carbon skeleton of (-)-enigmazole A, is described after the construction of the requisite eastern and western hemispheres. The chapter then describes the subsequent macrolactonization studies and the end game of the total synthesis. In addition to the Smith three-step Petasis-Ferrier union/rearrangement protocol, highlights of the total synthesis includes a Negishi cross-coupling, a dithiane-epoxide union, a Type I ARC multicomponent coupling, a Yamaguchi macrolactonization and chemoselective oxidation/reduction strategies the details of which are also described in Chapter Two

Chemical tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) bioconjugation of Peptides and Proteins

Chemical protein synthesis is an invaluable tool that enables the construction of novel protein design, incorporation of non-native functionalities, elucidation of structure-function relationships and enable a wide diversity of modifications (such as Post Translation Modification) to study protein functions. Native Chemical Ligation (NCL) in conjunction with Fmoc Solid Phase Peptide Synthesis (SPPS) is the most used method for synthesis of functional peptides and proteins. The synthesis relies on the reaction of a C-terminal peptide thioester and a N-terminal cysteine peptide. Fmoc SPPS of peptide thioester for chemical protein synthesis via NCL is a challenge. Methods that exist for the synthesis of peptide thioester by Fmoc SPPS require special resins, linkers, additional chemistry and is difficult and time consuming. Therefore, a simple and robust method to synthesize peptide thioester is highly desirable. Chapter two of this thesis describes the development of a versatile approach for direct synthesis of peptide thioesters from a solid support utilizing Fmoc chemistry. The method utilizes a cyclic urethane activation technique for the synthesis of peptide thioesters directly from solid support. The resulting thioester is stable and free of epimerization. The usefulness of this methodology was demonstrated by the synthesis of a 19 amino acid peptide thioester, which was utilized for the synthesis of a 29 amino acid long peptide derived from rabies virus glycoprotein (Rvg) using NCL. This accessible and robust Fmoc-based thioesterication technique provides a significant advance to chemical protein synthesis due to its uncomplicated nature, whereby eliminating special precautions and additional steps typically needed for synthesis of peptide thioesters. This approach can be used to incorporate post-translational modifications for the synthesis of complex post translational peptides and proteins in milligram quantities that can be used to study their structure and function. This modification approach can also be used for the synthesis of other complex protein modifications through residue specific N-terminal chemical modification by NCL. Chemical modification of protein is a critically important tool for various biological applications such as probing protein dynamics, elucidating protein structure and functions, enhancing protein stability in biological system and construction of protein-drug conjugates. Traditional modification techniques utilize non-specific lysine and cysteine conjugation strategies that produces a heterogenous mixture of conjugates. Over the last two decades there has been an increasing need to developed methods which would modify protein in a controlled manner. Chapter three describes the development of a novel site-specific Secondary Amine Selective Petasis (SASP) bioconjugation strategy using Petasis reaction to modify secondary amines and N-terminal proline. The SASP reaction has been shown to modify a wide variety of peptides and proteins with high selectivity for N-terminal proline. The resulting bioconjugate is highly stereoselective (de \u3e99%) which can be useful in drug discovery. Also, the multicomponent nature of this conjugation technique enables dual labeling of complex proteins in one pot with various cargoes such as dye, biotin and alkynes. The applicability of the SASP bioconjugation technique was demonstrated on a variety of different peptides and proteins with various aldehyde and organoboronate derivatives. The chemo-, regio- and site-specific nature of this method will enable the construction of biomolecular hybrids that can be used to study protein functions, identify new drug targets, deliver potent therapeutics to cellular targets, and engineer new materials. This strategy also provides a powerful tool to study the function and dynamics of post-translational modification such as mono methylated lysine that regulates transcription factor function

Chemical tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) bioconjugation of Peptides and Proteins

Chemical protein synthesis is an invaluable tool that enables the construction of novel protein design, incorporation of non-native functionalities, elucidation of structure-function relationships and enable a wide diversity of modifications (such as Post Translation Modification) to study protein functions. Native Chemical Ligation (NCL) in conjunction with Fmoc Solid Phase Peptide Synthesis (SPPS) is the most used method for synthesis of functional peptides and proteins. The synthesis relies on the reaction of a C-terminal peptide thioester and a N-terminal cysteine peptide. Fmoc SPPS of peptide thioester for chemical protein synthesis via NCL is a challenge. Methods that exist for the synthesis of peptide thioester by Fmoc SPPS require special resins, linkers, additional chemistry and is difficult and time consuming. Therefore, a simple and robust method to synthesize peptide thioester is highly desirable. Chapter two of this thesis describes the development of a versatile approach for direct synthesis of peptide thioesters from a solid support utilizing Fmoc chemistry. The method utilizes a cyclic urethane activation technique for the synthesis of peptide thioesters directly from solid support. The resulting thioester is stable and free of epimerization. The usefulness of this methodology was demonstrated by the synthesis of a 19 amino acid peptide thioester, which was utilized for the synthesis of a 29 amino acid long peptide derived from rabies virus glycoprotein (Rvg) using NCL. This accessible and robust Fmoc-based thioesterication technique provides a significant advance to chemical protein synthesis due to its uncomplicated nature, whereby eliminating special precautions and additional steps typically needed for synthesis of peptide thioesters. This approach can be used to incorporate post-translational modifications for the synthesis of complex post translational peptides and proteins in milligram quantities that can be used to study their structure and function. This modification approach can also be used for the synthesis of other complex protein modifications through residue specific N-terminal chemical modification by NCL. Chemical modification of protein is a critically important tool for various biological applications such as probing protein dynamics, elucidating protein structure and functions, enhancing protein stability in biological system and construction of protein-drug conjugates. Traditional modification techniques utilize non-specific lysine and cysteine conjugation strategies that produces a heterogenous mixture of conjugates. Over the last two decades there has been an increasing need to developed methods which would modify protein in a controlled manner. Chapter three describes the development of a novel site-specific Secondary Amine Selective Petasis (SASP) bioconjugation strategy using Petasis reaction to modify secondary amines and N-terminal proline. The SASP reaction has been shown to modify a wide variety of peptides and proteins with high selectivity for N-terminal proline. The resulting bioconjugate is highly stereoselective (de \u3e99%) which can be useful in drug discovery. Also, the multicomponent nature of this conjugation technique enables dual labeling of complex proteins in one pot with various cargoes such as dye, biotin and alkynes. The applicability of the SASP bioconjugation technique was demonstrated on a variety of different peptides and proteins with various aldehyde and organoboronate derivatives. The chemo-, regio- and site-specific nature of this method will enable the construction of biomolecular hybrids that can be used to study protein functions, identify new drug targets, deliver potent therapeutics to cellular targets, and engineer new materials. This strategy also provides a powerful tool to study the function and dynamics of post-translational modification such as mono methylated lysine that regulates transcription factor function

Engineered structures for the profiling and enrichment of the phosphoproteome

Dissertação para obtenção do Grau de Doutor em Bioengenharia (MIT-Portugal)O capítulo 1 foi parcialmente reproduzido de um artigo previamente publicado sob permissão dos editores originais e sujeito às restrições de cópia impostos pelos mesmos.Fundação para a Ciência e a Tecnologia - (SFRH/BD/64427/2009) and the project PTDC/EBB-BIO/102163/2008 assigned to Prof. Cecília Roque, and also to the Associate Laboratory REQUIMTE (PEst-C/EQB/LA0006/2013