UNIVERSITÀ DEGLI STUDI DI MILANO Scuola di Dottorato in Scienze e Tecnologie Chimiche Dipartimento di Chimica Corso di Dottorato di Ricerca in Chimica Industriale – XXV ciclo Settore disciplinare: CHIM/06 - CARBON NITROGEN DOUBLE BOND STEREOSELECTIVE REDUCTION Tesi di Dottorato di Martina Bonsignore Matricola R08780 Tutor: Prof. Maurizio Benaglia Coordinatore: Prof. Dominique Roberto Anno Accademico 2011-2012 Index INDEX CHAPTER I - Enantioselective Organocatalytic Reductions of C=N Double Bonds ......................................................................................... 1 1.1 Introduction ............................................................................................................... 1 1.2 Catalytic hydrogenation with Frustrated Lewis Pairs ................................................ 3 1.3 Enantioselective reductions promoted by chiral phosphoric acid ........................... 11 CHAPTER II - Silicate-mediated Stereoselective Reductions Catalysed by Chiral Lewis Bases ........................................................................... 25 2.1 Hypervalent bonding analysis ................................................................................. 26 2.2 Stereoselective C-H bond formation ........................................................................ 34 2.2.1 Reactions catalyzed by amino acids-derived chiral Lewis bases. .............. 34 2.2.2 Reactions catalyzed by amino alcohol derived chiral Lewis bases .............. 39 2.2.3 Reactions catalyzed by other chiral Lewis bases .......................................... 45 CHAPTER III - Proline-based Catalysts for the Reduction of Carbon-Nitrogen Double Bond ............................................................ 47 3.1 Reduction of ketimine .............................................................................................. 48 3.2 Reduction of b -enamino esters and a -imino esters ................................................. 60 i Index CHAPTER IV - Trichlorosilane-mediated Stereoselective Synthesis of β-amino Esters................................................................................... 65 CHAPTER V - New Chiral Organocatalysts for the Reduction of Carbon-Nitrogen Double Bond ............................................................... 75 CHAPTER VI - (S)-Proline-derived Organocatalysts for the Lewis Acid-mediated Lewis Base-catalysed Stereoselective Aldol Reactions of Activated Thioesters ..................... 89 CHAPTER VII - Stereoselective Reduction of Heteroaromatic Compounds .............. 99 7.1 Hantzsch esters....................................................................................................... 100 7.2 Trichlorosilane ....................................................................................................... 105 CHAPTER VIII - Experimental Section ..................................................................... 117 8.1 Synthesis of catalysts ............................................................................................ 119 8.2 Synthesis of substrates .......................................................................................... 155 8.3 Trichlorosilane-mediated C-N double bond reductions ........................................ 172 8.4 Deprotection protocols ........................................................................................... 187 8.5 Synthesis of β-lactam ............................................................................................. 189 8.6 Synthesis of substrates for reductive amination .................................................... 191 8.7 Reductive aminations ............................................................................................. 195 8.8 Synthesis of thioesters............................................................................................ 198 8.9 Aldol condensation of thioesters with aldehydes ................................................... 200 APPENDIX - Cyclopropenone ....................................................................................... 203 Experimental Section ................................................................................................... 215 BIBLIOGRAPHY .......................................................................................................... 221 LIST OF COMMON ABBREVIATIONS ................................................................... 229 ii Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds CHAPTER I Enantioselective Organocatalytic Reductions of C=N Double Bonds 1.1 Introduction The reduction of C=N bonds represents a powerful and widely used transformation which allows new nitrogen-containing molecules to be generated. Specifically, the carbon-nitrogen double bond enantioselctive reduction is of paramount importance in a variety of bioactive molecules such as alkaloids, natural products, drugs, and medical agents.[1] The employment of a “chiral technology” is, in principle, the most attractive procedure to perform this transformation.[2] Catalytic enantioselective reactions provide the most efficient method for the synthesis of chiral compounds, because large quantities of chiral compounds are expected to be prepared using small amounts of chiral sources.[3] Recent market analyses have shown that global revenues from chiral technologies soared from $6.63 billion in 2000 to $16.03 billion in 2007, growing at a compounded annual rate of 13.4%, and approximately 80% of all products currently in development for the 1 Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds pharmaceutical industry are based on chiral building blocks.[4] In addition, over 90% of chemicals derive from a catalytic process.[5] Over the years, the replacement of metal-based catalysts with equally efficient metal-free counterparts have attracted increasing interest for their low toxicity and for their environmental and economic advantages.[6] Organic catalysis represents now an established possibility of using an organic molecule of relatively low molecular weight, simple structure and low cost to promote a reaction in substoichiometric quantity. Noteworthy, it is also possible to work in the absence of any metal and under non-stringent reaction conditions that are typical of organometallic catalytic process.[7] The organocatalytic approach also satisfies many of the well-known twelve principles of green chemistry.[8] Any process based on a catalytic methodology is green by definition, because it minimizes waste and increase energy efficiency compared to process that employ stoichiometric reagents. In particular, by employing less hazardous solvents and promoting safer reaction conditions, organocatalysts might represent a solution to the problems related to the presence of toxic metal, whose leaching could contaminate the product and may lead to the design of safer processes and products. In fact, the enantioselective metal-catalyzed hydrogenations suffer from several drawbacks:[9] they are generally quite expensive species, typically constituted by an enantiomerically pure ligands (whose synthesis may be costly, long and difficult), and a metal species, in many cases a precious element and there is the possibility of the deactivation or poisoning of catalysts by compounds containing nitrogen and sulfur atoms. Thus, the replacement of metal-based catalysts with equally efficient metal-free counterparts is very appealing in view of future possible applications in non-toxic, low cost, and more environmentally friendly processes on industrial scale. Therefore, it’s not surprising that in recent years this field of research have attracted the attention of many research groups who are putting extraordinary efforts in studying and developing novel and alternative synthetic organocatalytic stereoselective methodologies.[10] In addition, catalysis in pharmaceutical R&D has been attracting increasing attention due to the competitive pressure to reduce drug development cost and time, the increasing 2 Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds regulatory requirements that force the companies to develop and study single-enantiomer drugs,[11] and environmental protection laws. The picture is completed by the continue discovery of new practical catalysts from both academia and industry, that make new solutions available for production.[12] Catalysis can also be a solution for companies that are exploring ways to address the problem of the increasing complexity of the chemical targets. The average number of manipulations required to synthesize an active pharmaceutical ingredient (API) continues to grow and currently amounts to an average of 12 synthetic steps. In this context, it is clear how the stereoselective reduction can be considerate a fundamental process and in this chapter the enantioselective reduction of carbon-nitrogen double bond promoted by organocatalysts was briefly discussed. In particular, the FLP (Frustrated Lewis Pair) method and binaphthol-derived phosphoric acids in the presence of a dihydropyridine-based compound were described, while the use of trichlorosilane for CN reduction will be deeply discussed in the next chapter. 1.2 Catalytic hydrogenation with Frustrated Lewis Pairs The use of H as a reducing agent for unsaturated substrates is very well known procedure 2 and it can be considered as perhaps the most important catalytic method in synthetic organic chemistry. Indeed, hydrogenation catalysis is the most common transformation used in the chemical industry and is employed in the preparation of scores of commercial targets, including natural products and commodity and fine chemicals.[13]Several studies led to a number of important developments including the transition metal dihydrogen complexes, transition metal systems that effect the heterolytic cleavage of hydrogen and metal-based catalysts for asymmetric hydrogenation; the fundamental importance of these studies has been clearly recognized by the award of the Nobel Prize to Knowles and Noyori. Recent studies have been directed to the exploitation of non-transition metal systems for the activation of H and the subsequent use in hydrogenation. A novel and promising 2 approach to the utilization of hydrogen in catalysis has emerged from studies related to the use of a proper combination of a Lewis acid and a Lewis base, in which steric 3 Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds demands preclude classical adduct formation, called ‘‘frustrated Lewis pairs’’ or ‘‘FLPs’’.[14]In these unique Lewis acid–base (LA–LB) adducts, the steric hindrance precludes the formation of stable donor–acceptor complexes on account of which these pairs are kinetically able to promote various unprecedented reactions with organic and inorganic molecules. Their most remarkable reactivity is the heterolytic cleavage of hydrogen at ambient temperature (Eq. 1), a process that was long thought to be the exclusive characteristic of transition metals. Equation 1 Computational studies suggest the generation of a phosphine-borane “encounter complex”, stabilized by H··F interactions.[15]In this species the boron and phosphorus centers are close but fail to form P to B dative bond as a result of steric congestion. Interaction of H in the reactive pocket between the donor and acceptor sites (Figure 1) 2 results in heterolytic cleavage of H ; according to the proposal FLPs fulfill a similar 2 function as the frontier orbitals on transition metals. However very recent computational studies[16] of the (quasi)linear P···H-H···B activation mechanism of the system cast some doubt on the corresponding transition state. According to these new results, a transition state in a linear arrangement only appears for rather large P···B distances over 4.5 Å. Such values seem to be artificially induced by the quantum chemical method (B3LYP) which is well known to overestimate steric congestion. With properly dispersion-corrected density functional no linear transition state exists and only one minimum with a rather large H–H distance of about 1.67Åcould be found. This points to an alternative bimolecular mechanism in which H access into the 2 frustrated P···B bond is the rate-determining step. Further theoretical studies to address this important question are needed in order to fully elucidate the mechanism. 4 Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds Figure 1 Several inter- and intramolecular combinations of bulky Lewis acid–base pairs were effectively tested for the heterolytic cleavage of hydrogen. Highly active FLPs 2-3 of Figure 2 with a linked design were reported from the groups of Erker, Repo, Rieger and Tamm.[17] Subsequently, this methodology was exploited in metal-free hydrogenation procedures. First, Stephan and co-workers reported a structurally bifunctional phosphine–borane 1 for the metal-free hydrogenation catalysis (Figure 2).[18] Figure 2 Thus, using a catalytic amount of 1*and heating to 80–120 °C under 1–5 atm H resulted 2 in the hydrogenation of a variety of imines in high isolated yields. Similarly, the N-aryl 5 Chapter I - Enantioselective Organocatalytic Reductions of C=N Double Bonds aziridines were catalytically hydrogenated. Mechanistic studies point to the initial protonation of the imine, followed by hydride transfer to the carbon of the iminium salt (Scheme 1). Scheme 1 Then, more focus was placed on the development of intermolecular and easily available FLPs for hydrogen activation and relied on the tris(pentafluorophenyl)borane as the LA component.[14] Following these initial studies about metal-free catalytic hydrogenation of imines, the authors thought to use the substrate as the base-partner of an FLP, requiring only a catalytic amount of tris-pentafluorophenyl borane. Indeed, a series of differently substituted imines were reduced under hydrogen using just a catalytic amount of B(C F ) (Scheme 2).[19] In case of poorly basic imines, addition of 6 5 3 catalytic amount of sterically encumbered phosphine accelerated the reductions. This presumably results from the greater ease with which phosphine/borane heterolytically cleaves hydrogen. 6