Asymmetric synthesis of benzylic and heterobenzylic amines

C2-Symmetrical, enantiopure 2,6-di[1-(1-aziridinyl)alkyl]pyridines (DIAZAPs) were prepared by a high-yielding, three-step sequence starting from 2,6-pyridinedicarbaldehyde and (S)-valinol or (S)-phenylglycinol. The new compounds were tested as ligands in palladium-catalyzed allylation of carbanions in different solvents. Almost quantitative yield and up to 99% enantiomeric excess were obtained in the reactions of the enolates derived from malonate, phenyl- and benzylmalonate dimethyl esters with 1,3-diphenyl-2-propenyl ethyl carbonate. Asymmetric synthesis of 2-(2-pyridyl)aziridines from chiral 2-pyridineimines bearing a stereogenic center at the nitrogen atom was development. The envisioned route involves the addition of chloromethyllithium to the imine derived from 2-pyridinealdehyde and (S)-valinol, protected as O-trimethylsilyl ether. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring as well as the α-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines, e.g. 3-pyridineimine and benzaldimine, which are not capable of bidentate chelation. The N-substituent could not be removed, but aziridine underwent ring-opening by attack of nitrogen, sulfur, and oxygen nucleophiles. Complete or prevalent regioselectivity was obtained using cerium trichloride heptahydrate as a catalyst. In some cases, the N-substituent could be removed by an oxidative protocol. The addition of organometallic (lithium, magnesium, zinc) reagents to 2-pyrroleimines derived from (S)-valinol and (S)-phenylglycinol gave the N-substituted-1-(2-pyrrolyl)alkylamines with high yields and diastereoselectivities. The (S,S)-diastereomers were useful intermediates for the preparation of enantiopure 1-[1-(2-pyrrolyl)alkyl]aziridines by routine cyclization of the β-aminoalcohol moiety and of (S)-N-benzoyl 1-[1-(2-pyrrolyl)alkyl]amines and their N-substituted derivatives by oxidative cleavage of the chiral auxiliary. 1-Allyl-2-pyrroleimines obtained from (S)-phenylglycinol and (S)-valinol underwent highly diastereoselective addition of allylmetal reagents, used in excess amounts, to give the corresponding secondary amines with concomitant allyl to 1-propenyl isomerisation of the 1-pyrrole substituent. Protection of the 2-aminoalcohol moiety as oxazolidinone, amide or Boc derivate followed by ring closing metathesis of the alkene groups gave the unsaturated bicyclic compound, whose hydrogenation afforded the indolizidine derivative as a mixture of separable diastereomers. The absolute configuration of the main diastereomer was assessed by X-ray crystallographic analysis.

Dynamic resolution of alpha-substituted dihydrocinnamic aldehydes. A new asymmetric synthesis of pharmaceutically important amine building blocks.

Crystallization-induced diastereoisomer transformation (CIDT) was successfully employed in the enantioselective synthesis of 2-alkyl-3-aryl-propan-1-amines. These products are seen as potentially useful building blocks in the field of asymmetric organic chemistry, notably for pharmaceutically relevant compounds. The procedure was based on a recently reported protocol for deracemization of dihydrocinnamic aldehydes in which enantiomerically enriched 1-(amino(phenyl)methyl)naphthalen-2-ol (Betti base) is employed as a resolving agent. Additionally, fenpropimorph, a biologically active substance which contains the 2-alkyl-3-aryl-propan-1-amine moiety was synthetized, as an attempt to assess the usefulness of the enantiomerically enriched amines.

Regiocontrolled Synthesis of Pyrazole Derivatives Through 1,3-Dipolar Cycloaddition Reaction And Synthesis of Helicene-Thiourea based and Polymer Supported Soos's Catalyst for Asymmetric Synthesis

In first part we have developed a simple regiocontrolled protocol of 1,3-DC to get ring fused pyrazole derivatives. These pyrazole derivatives were synthesized using 1,3-DC between nitrile imine and various dipolarophiles such as alkynes, cyclic α,β-ketones, lactones, thiocatones and lactums. The reactions were found to be highly regiospecific. In second part we have discussed about helicene, its properties, synthesis and applications as asymmetric catalyst.Due to inherent chirality, herein we have made an attempt to synthesize the helicene-thiourea based catalyst for asymmetric catalysis. The synthesis involved formation of two key intermediates viz, bromo-phenanthrene 5 and a vinyl-naphthalene 10. The coupling of these two intermediates leads to formation of hexahelicene.

Cinchona alkaloids and BINOL derivatives as privileged catalysts or ligands in asymmetric synthesis

During the last fifteen years organocatalysis emerged as a powerful tool for the enantioselective functionalization of the most different organic molecules. Both C-C and C-heteroatom bonds can be formed in an enantioselective fashion using many types of catalyst and the field is always growing. Many kind of chiral catalysts have emerged as privileged, but among them Proline, cinchona alkaloids, BINOL, and their derivatives showed to be particularly useful chiral scaffolds. This thesis, after a short presentation of many organocatalysts and activation modes, focuses mainly on cinchona alkaloid derived primary amines and BINOL derived chiral Brønsted acids, describing their properties and applications. Then, in the experimental part, these compounds are used for the catalysis of new transformations. The enantioselective Friedel-Crafts alkylation of cyclic enones with naphthols using cinchona alkaloid derived primary amines as catalysts is presented and discussed. The results of this work were very good and this resulted also in a publication. The same catalysts are then used to accomplish the enantioselective addition of indoles to cyclic enones. Many catalysts in combination with many acids as co-catalysts were tried and the reaction was fully studied. Selective N-alkylation was obtained in many cases, in combination with quite good to good enantioselectivities. Also other kind of catalysis were tried for this reaction, with interesting results. Another aza-Michael reaction between OH-free hydroxylamines and nitrostyrene using cinchona alkaloid derived thioureas is briefly discussed. Then our attention focused on Brønsted acid catalyzed transformations. With this regard, the Prins cyclization, a reaction never accomplished in an enantioselective fashion until now, is presented and developed. The results obtained are promising. In the last part of this thesis the work carried out abroad is presented. In Prof. Rueping laboratories, an enantioselective Nazarov cyclization using cooperative catalysis and the enantioselective desymmetrization of meso-hydrobenzoin catalyzed by Brønsted acid were studied.

Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-benzylated L-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.

Palladium and organocatalysis: an excellent recipe for asymmetric synthesis

The dual activation of simple substrates by the combination of organocatalysis and palladium catalysis has been successfully applied in a variety of different asymmetric transformations. Thus, the asymmetric a-allylation of carbonyl compounds, a-fluorination of acyl derivatives, decarboxylative protonation of β-dicarbonyl compounds, cyclization reactions of alkynyl carbonyl compounds and β-functionalization of aldehydes have been efficiently achieved employing this double-catalytic methodology.

Asymmetric Synthesis and Absolute Configuration of (+)- and (–)-Perhexiline

Peer reviewed

Asymmetric Synthesis and Absolute Configuration of (+)- and (–)-Perhexiline

Peer reviewed

New methods for the asymmetric synthesis of α-alkylated ketones and 1,3-amino alcohols

A large number of optically active drugs and natural products contain α-functionalised ketones or simple derivatives thereof. Furthermore, chiral α-alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. This is discussed in Chapter 1, which also provides a background of other key topics discussed throughout the thesis. Expanding on the existing methodology of chiral auxiliaries, Chapter 2 details the synthesis of a novel chiral auxiliary containing a pyrrolidine ring and its use in the asymmetric preparation of α-alkylated ketones with good enantioselectivity. The synthesis of racemic α-alkylated ketones as reference standards for GC chromatography is also reported in this chapter. Chapter 3 details a new approach to chiral α-alkylated ketones using an intermolecular chirality transfer methodology. This approach employs the use of simple non-chiral dimethylhydrazones and their asymmetric alkylation using the chiral diamine ligands, (+)- and (-)-sparteine. The methodology described represents the first example of an asymmetric alkylation of non-chiral azaenolates. Enantiomeric ratios up to 83 : 17 are observed. Chapter 4 introduces the first aldol-Tishchenko reaction of an imine derivative for the preparation of 1,3-aminoalcohol precursors. 1,3-Aminoalcohols can be synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Our approach offers an alternative highly diastereomeric route to the synthesis of this important moiety utilising N-tert-butanesulfinyl imines in an aldol-Tishchenko-type reaction. Chapter 5 details the experimental procedures for all of the above work. Chapter 6 discusses the results of a separate research project undertaken during this PhD. 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the role of Pseudomonas quinolone signal (PQS) in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules.

Rational design of a (S)-selective-Transaminase for asymmetric synthesis of (1S)-1-(1,1'-biphenyl 2-yl)ethanamine

Amine transaminases offer an environmentally sustainable synthesis route for the production ofpure chiral amines. However, their catalytic efficiency towards bulky ketone substrates isgreatly limited by steric hindrance and therefore presents a great challenge for industrialsynthetic applications. Hereby we report an example of rational transaminase enzyme design tohelp alleviate these challenges. Starting from the Vibrio fluvialis amine transaminase that has nodetectable catalytic activity towards the bulky aromatic ketone 2-acetylbiphenyl, we employed arational design strategy combining in silico and in vitro studies to engineer the transaminaseenzyme with a minimal number of mutations, achieving an high catalytic activity and highenantioselectivity. We found that by introducing two mutations W57G/R415A detectableenzyme activity was achieved. The rationally designed best variant,W57F/R88H/V153S/K163F/I259M/R415A/V422A, showed an improvement in reaction rateby > 1716-fold towards the bulky ketone under study, producing the corresponding enantiomericpure (S)-amine (ee value of > 99%). 

Rhodium-catalysed enantioselective C-H functionalization in asymmetric synthesis

Catalytic asymmetric synthesis of alfa,alfa-disubstituted alfa-thio- and alfa-amino acid derivatives

449 p.

Exploring the scope of asymmetric synthesis of β-Hydroxy-γ-lactams via Noyori-type reductions

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.