Recent Advances on the Catalytic Asymmetric Allylic α-Alkylation of Carbonyl Derivatives Using Free Allylic Alcohols.

During the last years, the development of more sustainable and straightforward methodologies to minimize the generation of waste organic substances has acquired high importance within synthetic organic chemistry. Therefore, it is not surprising that many efforts are devoted to ameliorating already well-known successful methodologies, that is, the case of the asymmetric allylic allylation reaction of carbonyl compounds. The use of free alcohols as alkylating agents in this transformation represents a step forward in this sense since it minimizes waste production and the substrate manipulation. In this review, we aim to gather the most recent methodologies describing this strategy by paying special attention to the reaction mechanisms, as well as their synthetic applications.

Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes.

A catalytic methodology for the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes is reported here. The versatile and readily accessible chiral Ph-BINMOL ligand, in the presence of Ti(OiPr)4 and a zinc salt, facilitates the reaction, which proceeds under mild conditions and is compatible with functionalized nucleophiles. The alkylzirconium reagents are conveniently generated in situ by hydrozirconation of alkenes with the Schwartz reagent. This work is a continuation of our previous work on aromatic aldehydes.

Asymmetric Construction of Alkaloids by Employing a Key ω-Transaminase Cascade.

An ω-transaminase-triggered intramolecular aza-Michael reaction has been employed for the preparation of cyclic ß-enaminones in good yield and excellent enantio- and diastereoselectivity, starting from easily accessible prochiral ketoynones and commercially available enzymes. The powerful thermodynamic driving force associated with the spontaneous aza-Michael reaction effectively displaces the transaminase reaction equilibrium towards product formation, using only two equivalents of isopropylamine. To demonstrate the potential of this methodology, this biocatalytic aza-Michael step was combined with annulation chemistry, affording unique stereo-defined fused alkaloid architectures.

Synthesis of Optimized Molecularly Imprinted Polymers for the Isolation and Detection of Antidepressants via HPLC.

Antidepressants such as amitryptiline and fluoxetine are on the list of modern essential medicines of the World Health Organization. However, there are growing concerns regarding the ecological impact of these pharmaceuticals, leading to a great need to improve current wastewater treatment procedures. In this contribution, we will report on the use of molecularly imprinted polymers (MIPs) for the extraction of antidepressants in water samples. MIPs were developed for fluoxetine and duloxetine, antidepressants belonging to the class of selective serotonin reuptake inhibitors (SSRIs). The binding capacity of these microparticles was evaluated using ultraviolet-visible (UV-Vis) spectroscopy. A new high-performance liquid chromatography (HPLC) procedure coupled to UV detection was developed, which enabled the study of mixtures of fluoxetine and duloxetine with other nitrogen-containing compounds. These results indicate that it is possible to selectively extract SSRIs from complex samples. Therefore, these versatile polymers are a promising analytical tool for the clean-up of water samples, which will benefit aquatic life and reduce the ecological impact of pharmaceuticals.

Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides.

The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquinolines 12 as single diastereomers.

Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes.

A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes.

Transaminase Triggered Aza-Michael Approach for the Enantioselective Synthesis of Piperidine Scaffolds.

The expanding "toolbox" of biocatalysts opens new opportunities to redesign synthetic strategies to target molecules by incorporating a key enzymatic step into the synthesis. Herein, we describe a general biocatalytic approach for the enantioselective preparation of 2,6-disubstituted piperidines starting from easily accessible pro-chiral ketoenones. The strategy represents a new biocatalytic disconnection, which relies on an ω-TA-mediated aza-Michael reaction. Significantly, we show that the reversible enzymatic process can power the shuttling of amine functionality across a molecular framework, providing access to the desired aza-Michael products.

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 ß-dicarbonyl compounds, cyclization reactions of alkynyl carbonyl compounds and ß-functionalization of aldehydes have been efficiently achieved employing this double-catalytic methodology.

Electrically driven directional motion of a four-wheeled molecule on a metal surface.

Propelling single molecules in a controlled manner along an unmodified surface remains extremely challenging because it requires molecules that can use light, chemical or electrical energy to modulate their interaction with the surface in a way that generates motion. Nature's motor proteins have mastered the art of converting conformational changes into directed motion, and have inspired the design of artificial systems such as DNA walkers and light- and redox-driven molecular motors. But although controlled movement of single molecules along a surface has been reported, the molecules in these examples act as passive elements that either diffuse along a preferential direction with equal probability for forward and backward movement or are dragged by an STM tip. Here we present a molecule with four functional units--our previously reported rotary motors--that undergo continuous and defined conformational changes upon sequential electronic and vibrational excitation. Scanning tunnelling microscopy confirms that activation of the conformational changes of the rotors through inelastic electron tunnelling propels the molecule unidirectionally across a Cu(111) surface. The system can be adapted to follow either linear or random surface trajectories or to remain stationary, by tuning the chirality of the individual motor units. Our design provides a starting point for the exploration of more sophisticated molecular mechanical systems with directionally controlled motion.

Light-induced disassembly of self-assembled vesicle-capped nanotubes observed in real time.

Molecular self-assembly is the basis for the formation of numerous artificial nanostructures. The self-organization of peptides, amphiphilic molecules composed of fused benzene rings and other functional molecules into nanotubes is of particular interest. However, the design of dynamic, complex self-organized systems that are responsive to external stimuli remains a significant challenge. Here, we report self-assembled, vesicle-capped nanotubes that can be selectively disassembled by irradiation. The walls of the nanotubes are 3-nm-thick bilayers and are made from amphiphilic molecules with two hydrophobic legs that interdigitate when the molecules self-assemble into bilayers. In the presence of phospholipids, a phase separation between the phospholipids and the amphiphilic molecules creates nanotubes, which are end-capped by vesicles that can be chemically altered or removed and reattached without affecting the nanotubes. The presence of a photoswitchable and fluorescent core in the amphiphilic molecules allows fast and highly controlled disassembly of the nanotubes on irradiation, and distinct disassembly processes can be observed in real time using fluorescence microscopy.

Copper-catalyzed enantioselective synthesis of trans-1-alkyl-2-substituted cyclopropanes via tandem conjugate addition-intramolecular enolate trapping.

Cu-TolBINAP-catalyzed conjugate addition of Grignard reagents to 4-chloro-α,ß-unsaturated esters, thioesters, and ketones leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to 84% yield and up to 96% ee upon protonation of the corresponding enolates at low temperature. Tandem conjugate addition-enolate trapping, however, yields trans-1-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee. The versatility of this reaction is illustrated by the formation of key intermediates for the formal syntheses of cascarillic acid and grenadamide.

Catalytic asymmetric conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones.

An efficient method is reported for the highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones using a monodentate phosphoramidite ligand.

Catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones.

The catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones with good enantioselectivities and moderate to good yields is reported. A readily available BINOL derivative is used as a chiral catalyst, and the reactions are performed with ethyl iodoacetate as a nucleophile and Me2Zn as the zinc source. The presence of air was found to be crucial to achieve an effective C-C bond formation pointing to a radical mechanism.

Catalytic enantioselective Reformatsky reaction with ketones.

Chiral tertiary alcohols were obtained with good yields and enantioselectivities via a catalytic Reformatsky reaction with ketones, including the challenging diaryl ketones, using chiral BINOL derivatives.