Academic literature on the topic 'Diversity-oriented synthesi'

A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels–Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.

La seguente dissertazione è un riassunto di un progetto di dottorato della durata di tre anni, condotto con lo scopo di esplorare nuove regioni dello spazio chimico, che potrebbero contenere interessanti molecole bioattive. Infatti, al giorno d’oggi, solo una porzione molto limitata dello spazio chimico è stata investigata. Oltretutto, tale porzione diventa ancora più ristretta se si considerano solo molecole caratterizzate da attività biologica. In questa tesi sono state considerate due diverse strategie per consentire un’ulteriore esplorazione dello spazio chimico: si tratta della diversity-oriented synthesis (DOS) e di un particolare approccio chemoenzimatico, sviluppato durante sei mesi trascorsi presso l’Università di Warwick (UK), sotto la supervisione della Professoressa Manuela Tosin. Capitolo 1. Il primo capitolo della tesi contiene un’introduzione generale ai principi della diversity-oriented synthesis, che costituirà il tema principale della dissertazione. Successivamente viene presentata una overview dettagliata, riguardante un approccio DOS sviluppato negli ultimi anni nel gruppo Passarella. Tale approccio si basa sull’utilizzo del 2-piperidinetanolo (1) come precursore per ottenere una libreria di derivati piperidinici diversificati. Alla fine del capitolo, viene presentata la progettazione di un’ulteriore espansione di tale libreria, tramite la sintesi dei prodotti riportati in Figura 1 (La figura può essere visionata nella versione dell'abstract riportata nel file della tesi). Capitolo 2. Questo capitolo riguarda la sintesi enantioselettiva di otto prodotti polieterociclici, caratterizzati da tre scaffolds altamente diversificati. La diversificazione strutturale è stata ottenuta a partire da un intermedio comune, sfruttando la diversa reattività dei suoi diastereoisomeri syn e anti, che, posti nelle medesime condizioni di reazione, hanno portato a prodotti strutturalmente diversi. In tal modo, analoghi di alcaloidi naturali sono stati ottenuti. Capitolo 3. In questo capitolo viene presentata la sintesi di una libreria di potenziali inibitori dell’hedgehog signalling pathway. La struttura degli inibitori è stata disegnata sulla base di studi di docking, prendendo ispirazione da una classe di prodotti naturali, i withanolidi. Gli elementi chiave del design sviluppato sono un carbammato biciclico, ottenibile da 1, e un lattone α,β-insaturo. La struttura presenta tre stereocentri e, ad oggi, due su quattro stereoisomeri racemi sono stati sintetizzati. I test biologici hanno rivelato due intermedi attivi, che sono stati sintetizzati anche in versione enantiopura. Inoltre, studi preliminari, volti allo sviluppo di inibitori di seconda generazione, sono attualmente in corso. Capitolo 4. In questo capitolo viene presentata la sinesi di un prodotto naturale, la (-)-anaferina, ottenuta come ulteriore ramificazione del nostro approccio DOS. L’idea è nata prendendo ispirazione dall’intermedio 10, già usato per la sintesi degli inibitori hedgehog. Infatti, il suo alcol omoallilico può essere convertito in un lattame α,β-insaturo (usando una procedura analoga a quella impiegata per la sintesi del primo prodotto presente nel riquadro rosa in Figura 1). Una volta ottenuto il lattame, questo può essere ridotto a piperidina. La successiva ossidazione del ponte 2-idrossipropanico a chetone permette poi di completare la sintesi della (-)-anaferina. Il Capitolo 5 riporta la sintesi di coniugati bivalenti, potenzialmente in grado di interagire con le tubuline in modo sinergico. Gli elementi chiave di tali coniugati sono un composto ibrido, precedentemente sintetizzato nel gruppo Passarella a partire da 1, e la N-10-deacetiltiocolchicina, noto legante di β-tubulina. Il prodotto ibrido contiene invece i motivi fondamentali della struttura della pironetina, noto legante di α –tubulina. Le due funzionalità attive sono state connesse da linkers diversi. Tuttavia i test biologici hanno evidenziato come la scelta di impiegare linkers lipofilici abbia reso i nostri coniugati migliori substrati per la P-glicoproteina, coinvolta nello sviluppo della resistenza ai farmaci, sviluppata da diverse cellule tumorali. Per questo motivo, nuovi coniugati verranno presto prodotti nel nostro laboratorio, testando linkers diversi. Infine, il Capitolo 6 ha riguardato la generazione di versioni non naturali e diversificate di due antibiotici, lasaloside A e salinomicina. A tal fine, un approccio simile alla mutasintesi, basato sulla somministrazione di probes chimiche, mimiche del malonato, ai microrganismi produttori di tali antibiotici, è stato impiegato. In particolare, diverse strategie, per un facile recupero e analisi dei prodotti non naturali presenti nei complessi brodi di fermentazione, sono state considerate. Quattro probes sono state sintetizzate e diversi esperimenti sono stati sviluppati per verificare la loro applicabilità in tale contesto.
This dissertation is an overview of a three-years project, aimed at the exploration of new regions of the chemical space, that could contain new unusual bioactive compounds. The already discovered small molecules cover only a small portion of the chemical universe, that becomes even narrower when bioactive compounds are considered. In this context, two different strategies for the investigation of the chemical space have been considered: the diversity oriented-synthesis (DOS), that constitute the major topic of the work, and a chemoenzymatic approach, developed during a period spent at the University of Warwick (UK), in the laboratory of Professor M. Tosin. Chapter 1 deals with the general principles of the DOS approach, focusing then the attention on a library of piperidine-based compounds previously synthesised in Professor Passarella’s research group, starting from a common precursor, 2-piperidine ethanol (1). An overview of the main results previously accessed in this field is reported. At the end of the chapter, the planning of a further expansion of this library is presented. The structure of the newly accessed piperidine-based products is appreciable in Figure 1 (see Figure 1 in the abstarct version reported in the thesis file); their obtainment was the main goal of this thesis. Chapter 2 is focused on the stereoselective synthesis of eight highly diversified polyheterocyclic compounds, characterized by three different scaffolds. In particular, the different scaffolds were originated by the same precursor, considering that its different syn- or anti- stereocenter configuration, influenced the reaction outcome. This project opens the possibility of accessing analogs of some natural products, such as lupin and lycopodium alkaloids. Chapter 3 concerned the obtainment of a library of potential Hedgehog (Hh) signalling pathway inhibitors, rationally designed exploiting docking simulations and taking inspiration from a class of natural products, the withanolides. The designed scaffold contains two key motif, a bicyclic carbamate and an α,β-unsaturated lactone, and presents three stereocenters. So far, two out of the four racemic isomers have been accessed and biological evaluation revealed two interesting intermediates, that have been synthesised also as separate enantiomers. Moreover, preliminary studies toward the obtainment of 2nd generation inhibitors have been performed in our laboratory. Biological evaluation of these compounds is currently in progress and will orient the future development of this work. Chapter 4 is aimed at the synthesis of (-)-anaferine as an unexpected further ramification of our DOS approach. Key intermediate 10, already exploited for the synthesis of the inhibitors of chapter 3, has been employed as starting material, converting its homoallylic alcohol into an α,β-unsaturated lactam. To this extent, the same approach used in chapter 1, to transform 9 into a similar lactam (left compound in the pink box of Figure 1) was applied. After that, the synthesis of (-)-anaferine was accomplished in few steps, reducing the lactam to piperidine and oxidizing the 2-hydoxypropane bridge to the corresponding ketone. Chapter 5 deals with the synthesis of thiocolchicine-based bivalent compounds, possibly acting as microtubules binders. A hybrid compound, bearing the key structural features of pironetin (one of the few known α-tubulin binder), previously synthesised on our laboratory from 2-piperidine ethanol, was exploited as key building block. In fact, it was connected through different linkers to N-10-deacteyl-thiocolchicine, a model of β-tubulin binder. Biological tests revealed that the lipophilic nature of the linkers rendered our conjugates better substrates for P-glycoprotein, leading to a drop in activity on resistant cancer cells. Therefore, new bivalent compounds will be soon produced in our laboratory, changing linkers chemo-physical properties. Structures of the new compounds resulting from the expansion of the DOS-approach from 2-piperidine ethanol 1. Finally, chapter 6 concerned a project aimed at the generation of unnatural, diversified derivatives of lasalocid A and salinomycin, through feeding experiments of malonate-mimicking chemical probes to the natural Streptomyces producers, in an approach resembling mutasynthesis. The efforts were focused on the devopment of different strategies for an easier recovery and analysis of the unnatural products from the complex mixtures of the fermentation broths. To this extent, four chemical probes have been synthesised and proof on concept experiments were performed to verify their applicability in this field.

This thesis explores two approaches to fragment-based drug discovery. First, protein target CK2 was chosen due to its importance in the cancer phenotype. A literature fragment, NMR154L, proved to be a promising compound for fragment development, due to its binding at the interface site of the protein rather than the highly conserved ATP pocket. Analogues were synthesised of this fragment leading to a candidate with a better IC50. Additionally, computer modelling of the interface site suggested that a series of spirocyclic compounds would inhibit this protein. These were synthesised and tested in vitro. Results from these tests were analysed and informed the synthesis of new inhibitors with the aid of crystal structures and computer modelling. Secondly, to address the lack of spirocyclic scaffolds in fragment screening libraries a number of diversity-orientated synthetic campaigns were undertaken. The first of these utilised glycine as starting material. Two terminal alkenes were installed. The alkenes were linked and the amino and acidic residues cyclised. This allowed for the formation of a diverse range of spirocyclic scaffolds from this one starting material. Having established chemistry for linking amino and acidic residues a campaign with dehydroalanine was under taken. This would allow for the installation of the second ring by pericyclic chemistry as well as using chemistry previously established. This pericyclic chemistry was also applied to synthesising spirocycles from rings with exocyclic double bonds. These being readily installed from Wittig chemistry, this allowed utilisation of starting materials which contained a cyclic ketone. Of these azetidinone was a good candidate due to the fact it was a commercially available building block and allowed access to spirocycles containing a 4-membered ring; an underrepresented ring size. Finally, computation analysis was carried out on the library to assess it diversity and any potential biological targets which these fragments may inhibit.

Thesis advisor: Marc L. Snapper
Cyclobutadiene cycloadditions provide rapid access to rigid polycyclic systems with high strain energy and unusual molecular geometries. Further functionalization of these systems allows entry into unexplored chemical space. A tricarbonylcyclobutadiene iron complex on solid support enables exploration of these cycloadditions in a parallel format amenable to diversity oriented synthesis. Modeling of the cycloaddition transition states with density functional calculations provides a theoretical basis for analysis of the regioselectivity observed in generation of these substituted bicyclo[2.2.0]hexene derivatives. The high strain energy accessible in cyclobutadiene cycloadducts and their derivatives renders them useful synthons for access to medium-ring natural products through ring expansion. Torilin, a guaiane sesquiterpene isolated from extracts of the fruits of Torilis japonica, exhibits a range of biological activities including testosterone 5α-reductase inhibition, hKv1.5 channel blocking, hepatoprotective, anti-inflammatory and anti-cancer effects. These activities are reviewed and analyzed from the perspective of a common biochemical target. Tandem oxidation and acid-catalyzed rearrangement of a highly strained tetracyclo[5.3.0.01,5.02,4]decane in the presence of tetrapropylammonium perruthenate provides the bicyclo[5.3.0]decane core of this natural product with complete control of relevant stereochemistry. The complex precursor required for this rearrangement is rapidly accessed by cyclopropanation of an intramolecular cyclobutadiene cycloadduct. Synthetic studies are reported which provide preliminary access to 8-deoxytorilolone
Thesis (PhD) — Boston College, 2010
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.

The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.

The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.

This thesis describes the development of a novel methodology to allow the synthesis of skeletally diverse alkaloid-like unnatural compounds. Enantiomerically enriched building blocks are iteratively assembled onto a purification handle using reliable coupling reactions. Subsequently, ring-opening-ring-closing metathesis cascade reactions are used as a complexity generating step to restitch the molecular framework. Chapter 1 introduces the concept of diversity-oriented synthesis, with particular emphasis on strategies used to introduce skeletal diversity. The conceptual idea behind the project is explained, and placed into context using leading examples as the benchmark for success in diversity-oriented synthesis. Chapter 2 describes the synthesis of a range of building blocks, many of which are enantiomerically enriched, on multigram scale. The design of a solid phase 'linker' is described in Chapter 3, as are the solution phase studies used to explore suitable methodologies to couple the building blocks. The use of solid phase chemistry is described in Chapter 4, as well as the use of light fluorous tags as an alternative purification handle. Chapter 5 describes the synthesis and subsequent metathesis of a range of fluorous-tagged metathesis substrates using one building block iteration. The Thesis concludes with the preparation of 45 metathesis precursors using combinations of two building blocks assembled onto a fluoroustagged linker in Chapter 6. Metathesis cascades were carried out, allowing the isolation of 33 complex and skeletally diverse products.

This thesis describes a novel approach to diversity-oriented synthesis. The approach involves the iterative assembly of building blocks onto a purification handle using temporary diisopropylsilylene tethers; this approach yields substrates for a ring-c1osing-ring-opening olefin metathesis cascade. The metathesis cascade results in a skeletal transformation and a range of scaffolds have been generated using only a few simple building blocks and a small number of common reactions. The use of a fluorous tag as a purification handle minimised labour-intensive purification steps and rendered the approach appropriate for library synthesis. The structures ofthe diverse final compounds are reminiscent ofpolyketide natural products. Chapter 1 describes alternative approaches for varying molecular scaffolds and places our generic approach in context. In Chapter 2, .the syntheses of.enant.iome~cally enriched building . blocks are described in· which an enzymatic desymmetrisation· is often used to induce asymmetry. Our investigations to conduct our methodology on solid support our described in Chapter 3. The potential of individual building blocks to participate in simple metathesis cascades is described in Chapter 4. In addition, this Chapter describes our studies to optimise the formation of unsymmetrical silaketals using diisopropylsilyl ethers as storable precursors. The thesis culminates with the preparation of36 metathesis substrates in which pairs of building blocks have been appended to the fluorous tag. The metatheses of some ofthese substrates are described and leads to natural product-like ligands.

There is a growing interest in using diversity-oriented synthesis (DOS) to generate small molecule libraries that are inspired by bioactive natural products. Over the years they have proven to be quite valuable chemical probes for understanding protein functions. Of particular interest is the design of natural product-like chiral scaffolds in which one could explore the three dimensional space around the building block by having several chiral diversity sites. A novel synthesis to reach an indoline scaffold is described. This template is then utilized to synthesize a seven-membered ring tricyclic derivative through an olefin ring-closing metathesis (RCM) approach. As well, asymmetric diversity-oriented reactions (e.g. asymmetric benzenethiol addition and intramolecular free radical cyclization) were explored with the tricyclic compound with the intention of utilizing these reactions on solid phase for generating a library.