TRULLI, LAURA
Reactivity of trifluoromethyl aldimines with active methylene compounds [Tesi di dottorato]
In this thesis the reactivity of N-protected trifluoromethyl (E)-aldimines towards different active methylene compounds in the Mannich-type and aza-Reformatsky reactions was studied. At first, suitable trifluoromethyl aldimines were reacted with ?-dicarbonyl compounds, including diethyl malonate and several ?-keto esters. The presence of a trifluoromethyl group, lowering both nitrogen basicity and carbon electrophilicity of the imine C=N group, greatly affects the Mannich-type addition of ?-dicarbonyl compounds. In fact, the most common organic or inorganic bases, such as some organocatalysts (cinchonidine, L-proline or their derivatives), frequently used to promote Mannich-type reactions between aromatic aldimines and ?-dicarbonyl compounds,1 did not give the expected results. Excellent results were obtained only through a Lewis acid catalysis, indeed an efficient solvent-free Zr-catalyzed Mannich-type reaction has been developed for the synthesis of fluorinated ?-amino ?-dicarbonyl compounds starting from N-protected trifluoromethyl aldimines and cyclic or acyclic ?-keto esters bearing different ester residues. The presence of an alkyl substituent on the nucleophilic carbon and the use of Zr as coordinating metal lead to a high stereoselective control of reactions. Instead, contrary to what reported in the literature for similar reaction, the ester residue did not affect the reaction outcome: in fact, no difference in reactivity was found by changing the ester moiety. Then, in order to develop a catalytic asymmetric Mannich-type reaction, failing all attempts using an added chiral catalyst, we successfully developed a new asymmetric Zr-catalyzed Mannich-type reaction at low cost starting from the optically pure aldimine derived by the inexpensive chiral (R)-?-methylbenzylamine. A complete facial and geometric stereoselective induction with formation of a chiral quaternary center was so obtained, the same chiral substrate acting as chiral ligand. The nucleophilic attack takes place only on the sterically less hindered prochiral Re face of optically pure aldimine, giving R,R,S pure diastereomeric compounds bearing a quaternary chiral center. In addition, the diastereoselective catalytic Mannich-type reaction represents, thanks to a diastereoselective decarboxylation reaction of the new obtained ?-keto esters, a valid approach to obtain optically active trifluoromethyl ?-amino ketones. Extending my studies, the interest has been directed towards the possibility to synthesize attractive trifluoromethylated 2-imidazolines by Mannich-type addition/cyclization cascade reaction of isocyano acetates on trifluoromethyl aldimines. Silver(I) oxide is turned out to be a very efficient catalyst for the reaction performed under solvent-free conditions between methyl 2-isocyanoacetate and trifluoromethyl aldimines. High cis/trans stereoselective control was obtained, the reaction affording only trans imidazolines. Subsequently, the study has been extended to the reactivity of ?-isocyano esters bearing a tertiary carbon center. Though the silver(I) catalysis appeared once again to be a good reaction catalyst, the use of dichloromethane as solvent was required and the total loss of geometric selectivity was recorded because of the steric hindrance on the nucleophilic site. Excellent stereoselectivity was obtained starting from the trifluoromethyl (E)- aldimines deriving from L-?-amino esters, leading to the formation of the only optically pure trans isomers. To explain the high diastereoselectivity observed and the stereochemical outcome, a transition state can be proposed in which the coordination of the imine ester group to the silver promotes the enolate attack preferentially to the Re imine face, obtaining enantiopure valuable trifluoromethyl imidazolines enriched by an ?-amino ester residue. As a further and last class of active methylene compounds, ?-bromo esters have been considered in the aza-Reformatsky reactions, always with different trifluoromethyl aldimines. The reactions were studied under two different conditions: heterogeneous conditions, using activated metal zinc as catalyst, and homogenous conditions, using Et2Zn as source of the metal. Working under heterogeneous conditions, only ?-lactams in good yields and high trans geometric selectivity were achieved when the reactions were performed starting from ?-bromo esters. However, adding (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol as chiral ligand no enantioselective control was obtained. Even the presence of a chiral center on the aldimine does not seem able to control the facial attack selectivity. Then, we moved on to study the homogeneous reaction outcome. Under optimal conditions, the additions lead to the only ?-amino esters, in good isolated yields and high geometric selectivity, the syn or anti isomer formation depending from the R substituent. In fact, while a complete syn selectivity was achieved starting from methyl substituted ?-bromo ester, the anti ?-amino ester was obtained starting from phenyl substituted ?-bromo ester. Subsequently, the first example of a convenient enantioselective aza- Reformatsky reaction on trifluoromethyl aldimines has been successfully developed. Using diethyl zinc and substoichiometric amount of (1R,2S)-1-phenyl-2-(1- pyrrolidinyl)propan-1-ol as chiral ligand, trifluoromethyl enantioenriched ?-amino esters in good yields and enantioselectivities (up to 91% ee) were synthesized. ?-Amino esters, keto esters, and malonates obtained through aza-Reformatsky and Mannich type-reactions respectively, allow to approach, through appropriate chemical transformations, new ?[CH(CF3)NH]-peptidomimetics. In fact, the [CH(CF3)] group is a known isoster of the carbonyl group. Similarly, the synthesis of bioisoster has been the aim of the project carried out at the University of Oxford (UK) under the supervision of Professor Darren J. Dixon and in collaboration with the SGC (Structural Genomics Consortium). I have turned the attention on the development of potential epigenetic probes, characterized by a portion of acetyl lysine bioisoster, in order to draw conclusions about the binding elements, which are important for affinity with the bromodomain module of PCAF. A library of 20 compounds was developed and improvements in terms of affinity, compared to the lead compound, were obtained..
diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/11573/924571
PELLACANI, Lucio
FIORAVANTI, Stefania
Valutatori esterni: Prof. Dr. Bartolo Gabriele
Prof. Enrico Marcantoni
LANZALUNGA, Osvaldo
Settore CHIM/06 - - Chimica Organica


Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18047815