An Organocatalytic and Stereoselective Vinylogous Domino Process towards Thiochromans.

A highly diastereoselective organocatalyzed domino vinylogous sulfa-Michael-aldol-cyclocondensation (VMAC) reaction has been developed using alkylidene Meldrum's acid as dienes highlighting two vinylogous steps, an unprecedented sulfa-1,6-conjugate addition and a diastereoselective aldol reaction triggering a formal (4+2) cycloaddition. This work opens a new route towards bio-relevant and original tricyclic thiochroman derivatives.

Turning the Imidazole Core into Three-Dimensional Ring Systems: Mild Organocatalytic Entry to Enantiopure 6,7-Dihydrobenzimidazoles.

Organocatalytic asymmetric transformation of common aromatic heterocycles via in situ formation of highly reactive dearomatized ortho-quinodimethane diene species and subsequent [4+2] cycloaddition with suitable dienophiles has become a powerful tool to enter cyclohexane-fused heterocycles. Most of these reactions were previously applied to benzo-fused heterocycles or poorly aromatic rings. Herein, we disclose how previously intractable aromatic imidazole rings, equipped with removable methylidene malononitrile activating handle, could be involved as competent cycloaddends with ß-aryl enals in efficient eliminative [4+2] cycloadditions under mild organocatalytic conditions. This method allowed the efficient and direct preparation of scantly represented 6,7-dihydrobenzo[d]imidazoles with optimal enantio- and regioselectivities. Post-cycloaddition chemical editing provided imidazole-based ring systems with diverse oxidation state and functional groups.

Organocatalyzed Modular Synthesis of Polycyclic Dihydropyridines and Pyridines through Sulfamate Linchpin.

The cascade annulation between alkylidene malononitriles and cyclic sulfamidate imines has been controlled by leveraging the sulfamate functionality under organocatalysis, which allows selective access to polycyclic and densely functionalized dihydropyridines and pyridines in high yields. The protocol is scalable and shows broad substrate scope. The products were also engaged in the preparation of tetracyclic pyridopyrimidines, showcasing the synthetic versatility.

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials.

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.

Alkylidene Meldrum's Acids as Platforms for the Vinylogous Synthesis of Dihydropyranones.

Upon Brønsted base organocatalysis, ketone-derived alkylidene Meldrum's acids proved to be competent vinylogous platforms able to undergo a formal (4+2) cycloaddition reaction with dihydro-2,3-furandione, providing an unprecedented route to 3,6-dihydropyran-2-ones as spiro[4.5]decane derivatives with up to 98 % ee thanks to the commercially available Takemoto catalyst. Preliminary investigation showed that this reaction could be extended to other activated ketones, establishing these alkylidene Meldrum's acids as a novel C4-synthon in the vinylogous series.

Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a ß-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C-C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016-2019.

Organocatalytic Desymmetrization Reactions for the Synthesis of Axially Chiral Compounds.

The enantioselective synthesis of atropisomers is an emerging field, that in recent years reached fundamental results and put the bases for innovative applications. Organocatalysis is playing a central role in the realization of original synthesis for novel atropisomeric scaffolds.[1] In this short review, we would like to highlight the results obtained by our group and others in the field of axially enantioselective desymmetrization reactions using organocatalysis as main strategy.

Exploiting the Distal Reactivity of Indolyl Methylenemalononitriles: An Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles.

An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles by amine-mediated remote C(sp(3) )-H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures through a formal asymmetric [4+2] eliminative cycloaddition governed by a α,α-diphenylprolinol trimethylsilyl ether catalyst.

Site-Selective Conjugate Addition Through Catalytic Generation of Ion-Pairing Intermediates.

Site-selectivity in conjugate addition reactions is tightly associated with the principle of vinylogy. Various vinylogous nucleophiles and electrophiles have been applied to stereoselective conjugate additions directed by chiral small-molecule catalysts. This chapter focuses on the systems that control site- and stereoselectivity via chiral ion-pairing intermediates under organocatalytic conditions and describes individual vinylogous substrates in a separate section. Although site-selectivity originates largely from the intrinsic stereoelectronic nature of individual substrates, catalyst-controlled site-selectivity can be attained in certain cases.

Pushing the boundaries of vinylogous reactivity: catalytic enantioselective mukaiyama aldol reactions of highly unsaturated 2-silyloxyindoles.

The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reaction utilizes a chiral Lewis base-catalyzed Lewis acid-mediated technology to deliver homoallylic 3-polyenylidene 2-oxindoles with extraordinary levels of regio-, enantio-, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the (13) C NMR chemical shifts of the C-ω remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor.

Favoring trienamine activation through unconjugated dienals: organocatalytic enantioselective remote functionalization of alkenes.

Unconjugated 2,5-dienals are more reactive substrates than the corresponding fully conjugated α,ß,γ,δ-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This difference in reactivity has been demonstrated in the Diels-Alder reaction with nitroalkenes, a reaction that proceeds with clean ß,ε-selectivity to afford the final products in high yields and stereoselectivities, the related polyconjugated 2,4-dienals being completely unreactive.