Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Design methodologies of microwawe integrated circuits for satellite telecommunications

The running innovation processes of the microwave transistor technologies, used in the implementation of microwave circuits, have to be supported by the study and development of proper design methodologies which, depending on the applications, will fully exploit the technology potentialities. After the choice of the technology to be used in the particular application, the circuit designer has few degrees of freedom when carrying out his design; in the most cases, due to the technological constrains, all the foundries develop and provide customized processes optimized for a specific performance such as power, low-noise, linearity, broadband etc. For these reasons circuit design is always a “compromise”, an investigation for the best solution to reach a trade off between the desired performances. This approach becomes crucial in the design of microwave systems to be used in satellite applications; the tight space constraints impose to reach the best performances under proper electrical and thermal de-rated conditions, respect to the maximum ratings provided by the used technology, in order to ensure adequate levels of reliability. In particular this work is about one of the most critical components in the front-end of a satellite antenna, the High Power Amplifier (HPA). The HPA is the main power dissipation source and so the element which mostly engrave on space, weight and cost of telecommunication apparatus; it is clear from the above reasons that design strategies addressing optimization of power density, efficiency and reliability are of major concern. Many transactions and publications demonstrate different methods for the design of power amplifiers, highlighting the availability to obtain very good levels of output power, efficiency and gain. Starting from existing knowledge, the target of the research activities summarized in this dissertation was to develop a design methodology capable optimize power amplifier performances complying all the constraints imposed by the space applications, tacking into account the thermal behaviour in the same manner of the power and the efficiency. After a reminder of the existing theories about the power amplifier design, in the first section of this work, the effectiveness of the methodology based on the accurate control of the dynamic Load Line and her shaping will be described, explaining all steps in the design of two different kinds of high power amplifiers. Considering the trade-off between the main performances and reliability issues as the target of the design activity, we will demonstrate that the expected results could be obtained working on the characteristics of the Load Line at the intrinsic terminals of the selected active device. The methodology proposed in this first part is based on the assumption that designer has the availability of an accurate electrical model of the device; the variety of publications about this argument demonstrates that it is so difficult to carry out a CAD model capable to taking into account all the non-ideal phenomena which occur when the amplifier operates at such high frequency and power levels. For that, especially for the emerging technology of Gallium Nitride (GaN), in the second section a new approach for power amplifier design will be described, basing on the experimental characterization of the intrinsic Load Line by means of a low frequency high power measurements bench. Thanks to the possibility to develop my Ph.D. in an academic spin-off, MEC – Microwave Electronics for Communications, the results of this activity has been applied to important research programs requested by space agencies, with the aim support the technological transfer from universities to industrial world and to promote a science-based entrepreneurship. For these reasons the proposed design methodology will be explained basing on many experimental results.

Design and development of new green catalytic methodologies for the synthesis of enantiomerically enriched molecules

The following Ph.D work was mainly focused on catalysis, as a key technology, to achieve the objectives of sustainable (green) chemistry. After introducing the concepts of sustainable (green) chemistry and an assessment of new sustainable chemical technologies, the relationship between catalysis and sustainable (green) chemistry was briefly discussed and illustrated via an analysis of some selected and relevant examples. Afterwards, as a continuation of the ongoing interest in Dr. Marco Bandini’s group on organometallic and organocatalytic processes, I addressed my efforts to the design and development of novel catalytic green methodologies for the synthesis of enantiomerically enriched molecules. In the first two projects the attention was focused on the employment of solid supports to carry out reactions that still remain a prerogative of omogeneous catalysis. Firstly, particular emphasis was addressed to the discovery of catalytic enantioselective variants of nitroaldol condensation (commonly termed Henry reaction), using a complex consisting in a polyethylene supported diamino thiopene (DATx) ligands and copper as active species. In the second project, a new class of electrochemically modified surfaces with DATx palladium complexes was presented. The DATx-graphite system proved to be efficient in promoting the Suzuki reaction. Moreover, in collaboration with Prof. Wolf at the University of British Columbia (Vancouver), cyclic voltammetry studies were reported. This study disclosed new opportunities for carbon–carbon forming processes by using heterogeneous, electrodeposited catalyst films. A straightforward metal-free catalysis allowed the exploration around the world of organocatalysis. In fact, three different and novel methodologies, using Cinchona, Guanidine and Phosphine derivatives, were envisioned in the three following projects. An interesting variant of nitroaldol condensation with simple trifluoromethyl ketones and also their application in a non-conventional activation of indolyl cores by Friedel-Crafts-functionalization, led to two novel synthetic protocols. These approaches allowed the preparation of synthetically useful trifluoromethyl derivatives bearing quaternary stereocenters. Lastly, in the sixth project the first γ-alkylation of allenoates with conjugated carbonyl compounds was envisioned. In the last part of this Ph.D thesis bases on an extra-ordinary collaboration with Prof. Balzani and Prof. Gigli, I was involved in the synthesis and characterization of a new type of heteroleptic cyclometaled-Ir(III) complexes, bearing bis-oxazolines (BOXs) as ancillary ligands. The new heteroleptic complexes were fully characterized and in order to examine the electroluminescent properties of FIrBOX(CH2), an Organic Light Emitting Device was realized.