Alma Mater Studiorum – Università di Bologna DOTTORATO DI RICERCA IN SCIENZE CHIMICHE Ciclo XXV NOVEL SYNTHETIC PROCEDURES IN ORGANOCATALYSIS Presentata da:! ! ! ! ! ! ! ! Diego Petruzziello Coordinatore Dottorato:!! ! ! ! ! ! Relatore: Adriana Bigi ! ! ! ! ! Pier Giorgio Cozzi Esame finale anno 2013 Index PART 1 3 Design of new catalysts in organocatalysis 3 Asimmetric Catalysis 3 Asimmetric Organocatalysis 4 References 16 New Ferrocenyl Pyrrolidine for Enamine Catalysis 18 Introduction 18 Results and Discussion 19 Conclusions 30 Experimental Section 31 References 45 Towards novel organocatalytic strategies 47 Electrophiles and nucleophiles: a new reactivity profile 47 Introduction 49 Results and Discussion 51 Conclusions 58 Experimental Section 59 References 82 PART 2 84 Direct Formylation of Organoboron Aromatic Compounds 84 The benzodithiolylium tetrafluoroborate salt 84 1 The Suzuki Reaction 86 Results and Discussion 89 Trifluoroborate salts 91 Conclusions 97 Experimental Section 99 References 111 Stereoselective Alkylation of α-Substituted Aldehydes. 113 Introduction 113 Results and Discussion 114 Conclusions 121 Experimental Section 122 References 128 2 PART 1 Design of new catalysts in organocatalysis The main aim of my PhD project was to design and synthesize new pirrolidine organocatalysts. Asimmetric Catalysis The term “asymmetric catalysis” refers to the set of chemical processes that allow a high stereochemical control of the reactions, by the use of sub-stoichiometric amount of enantiomerically pure chiral molecules as catalyst. The chirality of the molecules plays an important role in nature, science and technology: indeed, most of the physiological phenomena are driven by highly selective molecular interactions, where a chiral molecule (host) selectively recognizes two enantiomeric molecules (guest). The principle of asymmetric catalysis is based on the use of small amounts of a chiral catalyst able to give, in a stereoselective way, the desired product. The chiral catalyst promotes a reaction path where the two diastereoisomeric transition states have different activation energy, due to the discrimination between atoms, groups or faces of the molecule. Knowles, Noyori and Sharpless, awarded with the Nobel Prize for chemistry in 2001, were among the first researchers to explore the field of asymmetric catalysis, demonstrating its usefulness in the processes for the synthesis of pharmaceuticals. In 1968, W. S. Knowles discovered that rhodium metal can be coordi- nated by a diphosphinic binder to carry out a chiral asymmetric catalysis of the hidrogenation reaction:[1] this observation rapidly led up to the development of an industrial process for the synthesis of L-DOPA, an amino acid used in the therapy of Parkinson's disease (Scheme 1.1). Scheme 1.1. Industrial sinthesys of L-DOPA Once understood the importance of identifying excellent chiral ligands for highly selective asymmetric catalysis, Ryoji Noyori in 1974 developed the synthesis of BINAP (2,2'-bis(diphenylphosphino)-1,1'- binaphthyl), a di-phosphine with C2 symmetry. A new catalyst was developed, the Ru-BINAP, which is used for the synthesis of chemical compounds, pharmaceuticals, as well as new materials. Particularly important is its application to the synthesis of (R)1,2-propanediol in the production of the antibiotic Levofloxacin (Scheme 1.2).[2] Scheme 1.2. Synthesis of (R)-1,2-propanediol. 3 In parallel with the development of catalytic asymmetric hydrogenation reactions, Barry Sharpless syn- thesized a new catalyst for another important class of transformations: the oxidation reactions.[3] Among the many discoveries made in this field, a special attention should be given to the asymmetric epoxidation reac- tion, catalyzed by a chiral titanium complex (Scheme 1.3). The epoxides are important intermediates for many syntheses, including those of drugs for blood pressure reduction. Scheme 1.3. Asymmetric epoxidation reaction. Starting from these early pioneering works, research on asymmetric catalysis has encountered an explo- sive growth especially in the last decade, in both academic and industrial sectors. To date, asymmetric ca- talysis represents an important branch of stereoselective synthesis and its high practicality is exploited in more and more industrial processes. Asimmetric Organocatalysis The use of small organic molecules as chiral catalysts is called ‘organocatalysis’. At present, organo- catalysis is considered an efficient and reliable strategy for the stereoselective preparation of a wide range of organic compounds: indeed, with respect to the classical methods (such as metal-catalysis, enzymatic cataly- sis and separation of enantiomers from racemic mixtures), it provides objective advantages in obtaining enantiopure products, since the catalysts: • do not exhibit the toxicity problems associated with the use of metals (particularly advantageous in pharmaceutical chemistry); • are readily available or synthesized from simple natural molecules; • are stable to the air. The high compatibility with aerobic conditions makes the reaction methodologies simple and safe, since the use of anhydrous solvents or inert atmosphere are not needed (the water and the air pose a serious risk when working with metal catalysts). Although it was already known that small organic molecules can promote several changes in a stereose- lective way,[4] the wherewithal of this approach was realized only in 2000 when, totally independently, List, Lerner and Barbas[5] on one side, and MacMillan and coworkers[6] on the other, published two different ex- amples of organocatalysis promoted by chiral secondary amines, now known as “asymmetric aminocataly- sis”. List, Lerner and Barbas showed that a catalytic amount acid L-proline (I) was capable of promoting a di- rect aldol reaction between a non-functionalized ketone, such as acetone, and a wide variety of aldehydes (Scheme 1.4). It was, thus, demonstrated that small organic molecules are able to promote the same reac- tions catalyzed by bio-organic molecules much larger (enzymes), in a similar manner. 4 Scheme 1.4. Aldol reaction promoted by L-proline. Simultaneously, MacMillan described the first asymmetric Diels-Alder reaction catalyzed by a secondary amine, and demonstrated the efficiency of the imidazolidinone (II) in catalyzing the activation of aldehydes, α,β-unsaturated aldehydes (Scheme 1.5). In this circumstance, the term ‘organocatalysis’ was reintroduced in the literature, and the benefits of this newborn branch of catalysis were also described. Scheme 1.5. Diels-Alder asymmetric reaction catalyzed by imidazolidinone (II). The interest aroused by these two works has led to an exponential growth of studies on catalysis by sec- ondary amines all over the world and the competition has accelerated the process of innovation and discovery.[7] New synthetic tools, that a few years earlier were considered inaccessible, were now revealed. Due to its characteristics of generality, affordability, stability and non-toxicity, organocatalysis has en- countered a wide acceptance not only in academia but also in industry, particularly in medicinal chemistry. Critical for the success of organocatalysis in these fields was the identification of general protocols for the activation, induction and reactivity of the organic catalysts employed. An accurate study of these activa- tion strategies has led to the discovery of new reactions and reactive species formed with a peculiar func- tional group able to participate in different stereoselective processes. The importance of general methods of activation lies in their ease in being chosen and applied to new enantioselective synthesis or in the development of new catalysts families. This becomes evident when we consider that the 130 organocatalytic reactions published since 1998, are based on only four or five activa- tion modes. At the same time, it is clear that the discovery of new strategies of activation is very important in all fields of catalysis. The four major activation procedures identified in aminocatalysis, able to promote so stereoselective formation of new bonds, are the following:[7] Enamine catalysis: The wide applicability of this activation comes from the studies of Barbas, Lerner and List,[5] that used the enamine to functionalize a carbonyl compound in α position. The reactive species is obtained by con- densation of the reversible secondary chiral amine (organocatalyst) with the carbonyl compound. This reac- tion leads to the initial formation of the iminium cation, with a consequent lowering of the LUMO (Low Un- 5 occupied Molecular Orbital) energy of the system; this leads to an increase of the proton acidity, therefore generating the nucleophilic enamine equivalent of the enolate (Scheme 1.6a). A second contribution to activation is given by the coordination of the electrophilic partner, through hy- drogen bonding or electrostatic interaction, by the carboxyl function present in the chiral catalyst, that sta- bilizes the transition state of the process and determines the stereoselectivity of the electrophilic attack (Scheme 1.6b). Scheme 1.6. Enamine activation: a) activation HOMO b) coordination of the electrophilic. The enamine catalysis promotes two different types of reactions depending on the class of electrophiles used.[8] The electrophiles containing one double bond, such as aldehydes, imines, Mannich acceptors, are inserted in the C-H bond of the carbonyl compound through a nucleophilic addition reaction (Scheme 1.7a). Instead, single bonds with electrophiles, such as alkyl halides, react in a nucleophilic substitution re- action, giving a stoichiometric amount of co-product (Scheme 1.7b). a b Scheme 1.7. Mechanisms of enamine catalysis. The concept of enamine catalysis was developed starting from two important observations in the fields of organic chemistry and biochemistry. 6 The first one is represented by the pioneering research of two industrial laboratories in the early '70s, that developed the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction, a stereoselective intramolecular aldol cyclization reaction catalyzed by a proline (Scheme 1.8).[9] This was the first demonstration that natural small molecules can act as highly enantioselective chiral catalysts in fundamental chemical transformations. Scheme 1.8. Intramolecular stereo selective aldol reaction of cyclization. The second observation comes from the studies of Lerner and Barbas, aimed at finding a new catalyst to promote intramolecular aldol reactions, similarly to the mechanism used by the natural enzyme aldolase type I.[10] The objective of the research was to to enhance the versatility of the enzyme aldolase, while preserving their exceptional catalytic efficiency. Once elucidated the mechanistic aspect of the reaction, the principle of asymmetric enamine catalysis has been extended over the aldol reactions replacing the aldehyde with other electrophilic components, such as imines. The first reaction of asymmetric Mannich is reported from List in 2000: in this reaction, the com- patibility between the conditions of catalysis via enamine was exploited together with the ability to generate in situ the imine, achieving with good results a direct three components reaction and a reversed stereoselec- tivity compared to that observed in the aldol condensation reaction (Scheme 1.9).[11] Scheme 1.9. Asymmetric Mannich reaction. The demonstration of the efficiency of proline in activating different types of electrophiles promoting highly selective processes, strongly incentivated the search for new organic transformations applicable to catalysis via enamine, such as the Michael reaction.[12] Thanks to Barbas’ paper describing the autocondensation of acetaldehyde catalyzed by proline,[13] alde- hydes quickly acquired a central role as donors in the organocatalysis, due to their high reactivity and versa- tility as building blocks. Following these observations, Jørgensen published the first asymmetric intermolecular addition of alde- hydes to activated ketones (Scheme 1.10):[14] in his paper, indeed, he demonstrated that differently substi- tuted ketones can be used for the fast synthesis of compounds with a quaternary center. 7 Scheme 1.10. Intermolecular and asymmetric direct aldol addition. Secondarily, the range of applicability of proline to catalysis was extended beyond the formation process of the C-C bond, through a direct functionalization of aldehydes and ketones with different heteroatomic nucleophiles (α-amination, α-oxygenation, α-halogenation, α-sulfenilation). The formation of optically active molecules with one stereocenter directly bonded to a heteroatom in position adjacent to the carbonyl function, plays a key role in all the areas of organic chemistry. The first examples reported in literature, re- garding effective and simple methods for a direct α-amination of highly enantioselective aldehydes,[15] were extended to ketones and α di-substituted aldehydes, then applied to the total synthesis of biologically active compounds. Following the excellent results with pyrrolidine skeleton catalysts, in recent years similar molecules with different substituents have been studied and developed. Among these, the Jørgensen catalyst catalyzes dif- ferent types of nucleophilic attack ensuring good yields and excellent enantiomeric excesses.[16] The versa- tility of this catalyst, as well as the possibility to exploit it in a variety of reactions, favoured the use of Jør- gensen catalyst in some processes so called "domino" (Scheme 1.11).[17] Scheme 1.11. Domino process promoted by Jørgensen catalyst Thanks to the formation of the active enaminic species and the high enantioselectivity of the catalyst, the domino reaction allows the formation of cyclic products containing up to five stereocenters, with an excel- lent stereocontrol. Another alternative to catalysis mediated by proline is represented by the use of MacMillan’s imidazolidi- none II and IV, which, in addition to activating carbonyl compounds as iminium ions, was found to be also a highly stereoselective enaminic catalyst (Scheme 1.12).[18] 8 Scheme 1.12. Application of MacMillan catalyst IV. Computational studies indicated that the formation of an imine transition state precedes the formation of the C-C bond. On this basis, MacMillan suggested that the ability of a chiral amine to control the iminium geometry in the transition state is a crucial factor in the discrimination of the enantiofacial addition of the enamine. The limited applicability of the enamine catalysis to electrophiles possessing a lone pair available, to al- low the stereocontrol by the catalyst, was overcome by Vignola and List. Indeed, the two researchers discov- ered the first asymmetric intramolecular α-alkylation of halo-aldehydes via enamine catalysis, a highly useful unprecedented organocatalytic transformation. The proline and its derivative α-methylproline (III) are ca- pable of cyclizing 6-halo-aldehydes to give cyclopentancarbaldehyde in excellent yields and enantiomeric excesses (Scheme 1.13).[19] Scheme 1.13. Asymmetric catalysis via intramolecular enamine alkylation This first reaction of nucleophilic substitution opened a new line of research on catalysis by proline, con- temporary solving the problems related to catalyst deactivation via the N-alkylation or possible racemization products. Iminium catalysis: This catalytic activation concept was introduced by MacMillan and co-workers with the asymmetric Diels-Alder reaction between α,β-unsaturated aldehydes and various dienes catalyzed by imidazolidinone (II). This new approach led to the development of a large number of asymmetric transformations involving unsaturated carbonyl compounds.[6] The kind of organocatalytic activation derives from the reversible condensation of a secondary amine with an aldehyde to generate an unsaturated iminium ion intermediate. The latter induces an electronics redistribution that lowers the energy of the LUMO, increasing its susceptibility towards nucleophilic addi- tion reactions, such as conjugated and pericyclic (LUMO activation). The success of this process lies in the catalytic ability of the iminium ion intermediate to discriminate effectively between the two faces of the elec- trophile: either through a control of the double bond configuration, favoring the E configuration with re- 9