Reactivity of trifluoromethyl aldimines with active methylene compounds

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 β-dicarbonyl compounds, including diethyl malonate and several β-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 β-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 β-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 β-amino β-dicarbonyl compounds starting from N-protected trifluoromethyl aldimines and cyclic or acyclic β-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)-α-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 β-keto esters, a valid approach to obtain optically active trifluoromethyl β-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 α-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-α-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 α-amino ester residue. As a further and last class of active methylene compounds, α-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 β-lactams in good yields and high trans geometric selectivity were achieved when the reactions were performed starting from α-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 β-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 α-bromo ester, the anti β-amino ester was obtained starting from phenyl substituted α-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 β-amino esters in good yields and enantioselectivities (up to 91% ee) were synthesized. β-Amino esters, keto esters, and malonates obtained through aza-Reformatsky and Mannich type-reactions respectively, allow to approach, through appropriate chemical transformations, new ψ[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

Stereospecific synthesis of α-hydroxy-cyclopropylboronates from allylic epoxides

This is the peer reviewed version of the following article: Angewandte Chemie - International Edition 58.10 (2019): 3188-03192, which has been published in final form at https://doi.org/10.1002/anie.201812836. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsWe report a catalytic and stereospecific method for the preparation of enantioenriched α-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon–boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediateWe thank the European Research Council (ERC-337776) and MINECO (CTQ2016-78779-R) for financial suppor

Harnessing the elusive 1,4-reduction of vinyl epoxides through copper catalysis

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acscatal.9b02005We present an efficient strategy for the formal 1,4-reduction of vinyl epoxides that does not require superstoichiometric amounts of a strong reductant. Using a readily available copper catalyst and a diboron compound, a wide variety of enantioenriched allylic alcohols have been prepared. Additionally, epoxyenynes have been reduced in a 1,4-manner to selectively afford skipped enynes or skipped dienes.We thank the European Research Council (ERC-337776) and MINECO (CTQ2016-78779-R) for financial suppor

Regioselective monoborylation of spirocyclobutenes

We present a strategy for the synthesis of spirocyclic cyclobutanes with modulable exit vectors based on the regioselective monoborylation of spirocyclobutenes. Using an inexpensive copper salt and a commercially available bidentate phosphine, a broad variety of borylated spirocycles have been prepared with complete regiocontrol. The boryl moiety provides a synthetic handled for further functionalization, allowing access to a wide array of spirocyclic building blocks from a common intermediateWe thank the European Research Council (ERC-337776) and MINECO and MICIIN (CTQ2016-78779-R and PID2019-107380GB-I00 to M.T.; PID2019106184GB-I00 and RED2018-102387-T to I.F.) for financial support. L.N. thanks Comunidad de Madrid for a predoctoral fellowship. We acknowledge Dr. Josefina Perles (UAM) for X-ray structure análisi

L'innovazione di prodotto per la transizione ecologica: Il riciclo del laterizio e del vetro

Nel contesto tematico dell’uso consapevole e del riciclo delle risorse materiche, il Dipartimento di Architettura dell’Università di Roma Tre ha in corso una linea di ricerca improntatasui temi dell’innovazione ambientale di prodotto. Tale linea è rappresentata da due ricerche applicative che coinvolgono aziende produttrici del settore delle costruzioni. Entrambe le ricerche affrontano il tema della additivazione delle miscele, rispettivamente del laterizio e del calcestruzzo, per la realizzazione di prodotti con prestazioni migliorate. Gli esiti conducono alla prototipazione di due prodotti: un blocco in laterizio, realizzato con scarti che sostituiscono una frazione di argilla con una miscela di fanghi bentonitici e residui metallici, e una miscela di calcestruzzo per massetti, realizzata con scarti e rifiuti in vetro da costruzione e demolizione che sostituiscono gli aggregati naturali. --- In the thematic environment of conscious use and material resource recycling, the Department of Architecture of the Roma Tre University is currently conducting a research line focused on environmental product innovation. This line consists of two application studies involving manufacturing companies in the construction sector. Both types of research address the issue of additives in the mix design of bricks and concrete, respectively, to achieve better-performing products. The results led to the prototyping of two products: a brick,made from waste replacing a fraction of clay with a mixture of bentonite sludge and metal residues, and a concrete screed mix, made from construction and demolition glass waste replacing natural aggregates

Risk stratification of neck lesions detected sonographically during the follow-up of differentiated thyroid cancer

Context: The European Thyroid Association (ETA) has classified post-treatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence. Objective: To assess this classification's ability to predict the growth and persistence of such lesions during active post-treatment surveillance of patients with differentiated thyroid cancer (DTC). Design: Retrospective, observational study Setting: Thyroid cancer center, large Italian teaching hospital. Patients: Center referrals (2005–2014) were reviewed and patients selected with pathologically confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on ≥2 consecutive post-treatment neck sonograms; subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with ≥1 lesion classified as ‘suspicious’) and group I (‘indeterminate’ lesions only). We recorded baseline and follow-up clinical data through 30 June 2015. Main Outcomes: Patients with growth (> 3 mm, largest diameter) of ≥1 lesion during follow-up, patients with ≥1 persistent lesion at the final visit. Results: The cohort included 58 (9%) of the 637 DTC cases screened. A total of 113 lesions were followed (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 years), group I had significantly lower rates than group S of lesion growth (8% vs. 36%, p=0.01) and persistence (64% vs. 97%, p=0.014). Median time to scan normalization: 2.9 years. Conclusions: The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify PTC patients eligible for more relaxed follow-up

Copper, Boron and Vinyl Epoxides: from 1,4-Diols to Cyclopropylboronates

Herein we describe the reactivity found between vinyl epoxides and catalytically generated copper-boryl complexes. By tuning the substituents of the alkene and/or the reaction conditions, 1,4-diols, allylic alcohols or cyclopropylboronates can be prepared. The stereochemical information of the vinyl epoxide is transferred to the products with high levels of stereocontrol

Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O catalyzed Mannich-type reaction

Trifluoromethyl aldimines derived from a-amino esters have proven to be very good starting materials to obtain the title compounds. A Ag2O-catalyzed Mannich-type/cyclization cascade reaction starting from suitable a-isocyano acetates leads to enantiopure valuable trans-carboxylic trifluoromethyl substituted 2-imidazolines by a highly stereoselective addition without the need to add organocatalyst

Trifluoromethyl syn- or anti-γ-amino alcohols by one-pot solvent-free mannich-type reactions under temperature control

Starting from trifluoroacetaldehyde ethyl hemiacetal, chiral amines and suitable aldehydes, diastereomerically pure fluorinated syn- or anti-γ-amino alcohols can be obtained by a friendly one-pot solvent-free L-proline catalysed Mannich-type reaction only by changing the temperature