Introduction of Fluorine and Fluorine-Containing Functional Groups

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C[BOND]F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal—fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.Chemistry and Chemical Biolog

Evaluation of In-Batch and In-Flow Synthetic Strategies towards the Stereoselective Synthesis of a Fluorinated Analogue of Retro-Thiorphan

A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio

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

Transition-metal catalyzed redox triggered C-C bond forming reactions via carbonyl addition

Carbon-carbon (C–C) bonds construct the skeleton of all organic molecules. Hence, the development of new efficient methods of C–C bond formation is of great significance in organic chemistry. Since the discovery of the Grignard reaction, carbonyl addition has been an established method for C–C bond formation. In classical carbonyl additions, premetalated reagents or stoichiometric metallic reductants are required. By taking advantage of the native reducing capability of alcohols, our lab has developed methods that exploit alcohols and π-unsaturates to generate transient electrophile-nucleophile pairs to directly convert lower alcohols to higher alcohol. Efforts have been focused on the development of transition metal-catalyzed redox-triggered coupling reactions of primary alcohols and aldehydes to π-unsaturates as well as aryl iodides. Modern methods to construct new C-C bonds in highly selective manner via carbonyl addition were undertaken.Chemistr

The Aza-Silyl-Prins Reaction: Development and Application to the Total Synthesis of (±)-Pipecolic Acid and (±)-Cannabisativine

The focus of this thesis is to develop new methods towards the synthesis of nitrogen-containing heterocycles. Chapter one contains a brief introduction into previous work by the Dobbs group, involving the optimisation of the silyl-Prins reaction and aza-silyl-Prins reaction, which afford substituted dihydropyrans and tetrahydropyridines respectively. Chapter two initially provides a literature overview towards the synthesis of piperidines using this methodology. Following this, our results demonstrate that using different substitution patterns in the homoallylic amine precursors has quite a significant regiochemical effect on the reaction. These effects include the formation of pyrrolidine structures, which can be isolated and characterised. Chapter three presents the utilization of the previously optimised silyl-Prins and aza-silyl-Prins reaction to obtain oxa- and aza-cycles containing a trifluoromethyl group, a functionality known to have significant effects on the lipophilicity of drug molecules. Next in chapter four, again the advantages of using the aza-silyl-Prins reaction to obtain high functionality in a simple coupling reaction are presented, with the formation of pipecolate and pipecolic acid analogues. Chapter five includes attempts to use the aza-silyl-Prins to form tetrasubstituted tetrahydropyridines using precedent from studies in the silyl-Prins reaction. However, although the similarities between these two coupling reactions are obvious, the differences in heteroatom in the substrates and products have a significant effect. Following previous attempts in the group to form nitrogen heterocycles in high enantiopurity with little success, chapter six discusses the optimisation of a new Lewis acid mediated imine-vinylsilane cyclisation reaction. The formation of 2-substituted free amine tetrahydropyridines was successful for racemic examples, but the studies into utilising this methodology towards an asymmetric synthesis are yet to be finalised. Finally, chapter seven investigates the use of the aza-silyl-Prins reaction into forming more complex natural products such as cannabisativine. Part of this work has been published in: 1) A.P.Dobbs, R.J.Parker, J.Skidmore, Tetrahedron Letters, 2008, 49, 827-831

Amphiphilic [pi]-allyliridium catalyzed nucleophilic and electrophilic allylation

Transition metal-catalyzed allylic substitution has emerged as a powerful method for stereoselective C-N bond formation. Chiral iridium-phosphoramidite complexes have proven especially effective as catalysts for regio- and enantioselective allylic amination, but are limited to aryl-substituted π-allyl electrophiles. With commercially available π-allyliridium C,O-benzoates, which are stable to air, water and SiO₂ chromatography, and are well known to catalyze allylic acetate mediated carbonyl allylation, highly regio- and enantioselective electrophilic allylation of aliphatic amines, primary and secondary aromatic or heteroaromatic amines were demonstrated. Furthermore, indoles and related azoles can also undergo the amination and generate enantiomerically enriched N-allyl indoles with completely N-selective and exclusive branched regioselectivity, which are an unmet challenge in this field. Moreover, indoles and related azoles are prevalent structural motifs in clinical candidates and FDA approved drugs, so these results also show the utility and importance of asymmetric allylic alkylation.Chemistr