Ottimizzazione di un protocollo di anticoagulazione regionale con citrato in CRRT

Ottimizzazione di un protocollo di anticoagulazione regionale con citrato in CRRT Introduzione: La necessità di un'anticoagulazione continua e l'ipofosforemia in corso di trattamento sono problemi costranti in corso di CRRT. Il nostro studio ha cercato di dimostrare l'efficacia e la sicurezza dell'anticoagulazione regionale con citrato in CVVH basato sull'utilizzo di una soluzione di citrato (18 mmol/L) associata ad una soluzione di reinfusione contenente fosfato, recentemente disponibile in commercio, al fine di ridurre l'ipofosfatemia in corso di CRRT. Metodi: Abbiamo utilizzato il nostro protocollo basato sull'utilizzo di una concentrazione di citrato contenente 18 mmol/l associata ad una soluzione di reinfusione contenente fosfato in un piccolo gruppo di pazienti ricoverati in terapia intensiva post-cardiochirurgica, sottoposti a CRRT per insufficienza renale acuta. Risultati: Il nostro protocollo ha garantito un'adeguata durata del circuito ed un ottimo controllo dell'equilibrio acido-base in ogni paziente. E' stata necessaria solo una minima supplementazione di fosforo in alcuni dei pazienti trattati. Conclusioni: Il nostro protocollo basato sull' utilizzo di una soluzione a concentrazione di citrato maggiore (18 mmol/l), permette un miglior controllo dell'equilibrio acido-base rispetto all'utilizzo della soluzione a più bassa concentrazione di citrato. L'uso di una minore dose di citrato ed il mantenimento di un target maggiore di calcio ionizzato all'interno del circuito sono comunque associati ad un'adeguata durata del circuito. I livelli di fosforemia sono rimasti sostanzialmente stabili nella maggior parte dei pazienti trattati, grazie alla presenza di fosfato nella soluzione utilizzata come reinfusione in post-diluizione.

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).