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In this paper is described the competition and transition between hydrogen bonding and protonation of alkynes connected, on one side, to various aromatic rings and to chiral amino ester appendages on the other side. While the first mode of activation induced the cyclization into pyrrolidines, the protonation of the alkyne led preferentially to tetrahydropyridines due to the higher level of the highest occupied molecular orbital (HOMO) of the considered arylogous ynolethers and ynamines. The transition between H-bonding and protonation was observed with the alkyne substituted with 2-methoxyphenyl, for which the cyclization delivered either five- or six-membered rings depending on the temperature of the experiment. From there, the cyclization of dialkoxy- and trialkoxyphenyl-substituted alkynes into six-membered rings, i.e., tetrahydropyridines, was developed. When next applied to alkynylindoles, the same pattern of cyclization provided six-membered rings as an illustration of the reactivity of arylogous ynamines. Thanks to the high reactivity of the intermediate cationic species, weak nucleophiles such as NH-oxazolidinone participated efficiently in the hydroamination reaction of alkynylindoles. Pyrrolidines, tetrahydropyridines, and piperidines decorated with various aromatics and substituents were thus prepared in enantio- and stereoselective manner. Capitalizing on the enamine moiety of the azaheterocycles, the molecular diversity was extended through stereoselective oxidation and ring contraction processes.

Amenable to late-stage preparation of analogues, a flexible and convergent total synthesis of (±)-aureothin is presented. The strategy was based on a desymmetrization of α,α'-dimethoxy-γ-pyrone by a process combining 1,4-addition and alkylation of vinylogous enolate to stereoselectively reach the backbone of the target. Palladium-catalyzed cyanation of an elaborated and isomerizable E,Z dienyl motif followed by Pinner cyclization enabled the construction of the tetrahydrofuran motif while a first approach based on a late-stage oxidation was unsuccessful.

Carbohydrates typically have low affinities to protein binding sites, and the development of carbohydrate mimetics with improved binding is therefore of interest. Tetrafluorination of monosaccharides is one of the strategies currently under investigation for that purpose. The synthesis of the required tetrafluorinated monosaccharides is achieved by a fluorinated building block approach. The enantioselective synthesis of tetrafluorinated hexose derivatives is described here, in both pyranose and furanose forms. In particular, the optimization of the enantioselective synthesis of the previously reported 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose 3, 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexofuranose 4, and 2,3-dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexopyranose 5 is described as is the synthesis of two novel sugar derivatives, 3,4-dideoxy-3,3,4,4-tetrafluoro-d-threo-hexopyranose 6 and 3,4-dideoxy-3,3,4,4-tetrafluoro-d-erythro-hexopyranose 7. The key step of all syntheses is a perfluoroalkyl lithium-mediated C-C bond formation, either intramolecular or intermolecular, which proceeds in good to excellent yields. NMR and X-ray crystallographic analyses of the tetrafluorinated methyl pyranoside derivatives confirm their (4)C1 conformation.

In cold THF and in the presence of LiCl, a lithium pyrrolidinylamide forms a 1:1 mixed aggregate, which is observed directly by ESI-MS. Gas-phase protonation of this species leads to selective transfer of H(+) to the chlorine, suggesting that LiCl shields the amide nitrogen and prevents its direct protonation.

A theoretical study of the intramolecular 5-exo-dig carbolithiation of substituted propargyl o-lithioaryl ethers, leading to dihydrobenzofurans, has been performed. The results show that a DFT description of the reaction (B3P86, 6-31G**) matches the experimental data provided that an explicit solvation by two molecules of THF is considered. To take place, the cyclization also implies that the acetylenic chain adopts a conformation in which a significant interaction arises between the lithium and the C≡C triple bond. Reaching the cyclization TS requires the passage of an activation barrier that should not be higher than 12-13 kcal mol(-1). From a thermodynamic point of view, the reaction is exothermic whatever the substituent R (from approximately -40 to -62 kcal mol(-1)). In the starting substrate, a supplementary interaction between the Li and a substituent at the propargylic position can develop, influencing the future double-bond configuration. Thus, derivatives exhibiting an R-Li interaction tend to provide E olefins. In contrast, when no coordination between the lithium cation and the terminal R occurs, syn carbolithiation takes place, and the configuration of the exocyclic olefin is likely to be Z. This hypothesis accounts for most of the experimental results published before.

A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.

A versatile and practical methodology to access β-amino and β-hydroxy α,α-difluoro carbonyl compounds using indium metal is described. This methodology has been successfully applied to a broad range of substrates including aldehydes, ketones, and imines, affording the corresponding and highly valuable gem-difluoro esters. The wide substrate scope highlights the chemoselectivity of the process.

Herein is disclosed an efficient catalytic enantioselective protonation of enol acetates by means of a readily implementable transition-metal-free chemical process. By making use of simple hygrogenocarbonates as the proton source and hydroquinine anthraquinone-1,4-diyl diether as the chiral proton shuttle, a series of cyclic enol trifluoroacetates are protonated under mild conditions to yield the corresponding ketones in up to 93% ee.

A highly trans and regioselective anionic formal [3 + 2] cycloaddition was achieved with allylic sulfones having an MBH acrylamide backbone under phase transfer organocatalytic conditions giving rise to the formation of unprecedented densely substituted cyclopentene derivatives.

In the present work, enantioselective protonation of silyl enol ethers is reported by means of a variety of chiral nitrogen bases as catalysts, mainly derived from cinchona alkaloids, in the presence of various protic nucleophiles as proton source. A detailed study of the most relevant reaction parameters is disclosed allowing high enantioselectivities of up to 92% ee with excellent yields to be achieved under mild and eco-friendly conditions. The synthetic utility of this organocatalytic protonation was demonstrated during the preparation of two homoisoflavones 4a and 4b, isolated from Chlorophytum Inornatum and Scilla Nervosa, which were obtained with 81% and 78% ee, respectively.

The structure of the aggregates formed when mixing methyllithium and lithium chloride in THF has been studied by multinuclear magnetic resonance at 170 K. The data suggest that only one new entity is observed, that is the dimer [(MeLi)(LiCl)], in equilibrium (K approximately 0.6) with [MeLi](4) and [LiCl](2). NMR diffusion measurements lead to the conclusion that this dimer is trisolvated in THF at 170 K, a solvation scheme in agreement with DFT computations.

A efficient methodology allowing the one-pot stereoselective synthesis of alpha-fluoroacrylates, based on the addition of ethyl dibromofluoroacetate to a carbonyl derivative using diethylzinc as organometallic mediator, is described. Two different pathways have been identified depending on the involved carbonyl partner. In the case of aldehydes, an E2-type mechanism has been identified, whereas ketones go through an E1cb-type mechanism.

The first transition-metal-free addition of alkyl nitriles to unactivated imines was developed using a catalytic combination of 4-MeOC(6)H(4)ONa and TMSCH(2)CO(2)Et to promote the reaction. The corresponding beta-amino nitriles are obtained in good to almost quantitative isolated yields under mild conditions. A mechanism involving an autocatalytic pathway is proposed on the basis of experimental observations.

Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs), and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi's turned out to be also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at -78 degrees C in THF. In all cases, the sense of induction depends on the absolute configuration of C(8) on the 3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence of organolithium species.

A methodology allowing the synthesis alpha-CF(2)-mannosides, based on the addition of a difluoroenoxysilane to a glycal followed by a dihydroxylation reaction, is described. The resulting 2,2-difluoro-2-mannosylacetate is converted into two pseudoglycopeptides which may act as E- and P-selectin inhibitors.

The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal.mol(-1) provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.

A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).

The first deprotonations of oxazole and benzoxazole using lithium magnesates are described. The reactions occurred in tetrahydrofuran at room temperature using 1/3 equiv of lithium tributylmagnesate. As 2-lithiooxazole and 2-lithiobenzoxazole, lithium tri(2-oxazolyl)magnesate and lithium tri(2-benzoxazolyl)magnesate very rapidly and completely isomerized to the more stable 2-(isocyano)enolate and 2-(isocyano)phenolate type structures, respectively, a result shown by NMR analysis. The isolation of 2-substituted oxazoles and benzoxazoles in medium to good yields after electrophilic trapping was interpreted in two ways: (1) the equilibration between the open and closed structures is faster than the trapping of the open isomers, and the closed isomers are more reactive than the open ones, or (2) the open isomers react with electrophiles in a intramolecular Passerini type reaction. The nonreactivity of the 2-(isocyano)enolate type structure toward anisaldehyde in the absence of lithium bromide makes the intramolecular Passerini type reaction more plausible.

A highly diastereoselective and straightforward synthesis for (Z)-2-fluoroallylic alcohols via a Nozaki-Hiyama-Kishi-type reaction with the corresponding bromofluoroolefins was developed, providing an easy access to highly interesting fluorinated synthons.