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International audience; A rapid synthesis of enantioenriched 2,3,4-trisubstituted tetrahydropyrans in good yields and stereoselectivities is reported. The first step is a domino organocatalytic reaction between ambident electrophilic and 1,4-bis-nucleophilic 1,2-ketoamides and 1,3-bis-electrophilic enals, leading to aza-oxa-bicyclo[3.2.1]octane. Then, the TiCl4/Et3SiH system ensures a chemoselective cleavage of the C−N bond and affords the desired trisubstituted tetrahydropyran in good yield and with conservation of the precursors optical purity. This final synthetic operation includes two consecutive oxocarbenium ion formation and reductions.

N-aryl γ-lactams react intermolecularly with acceptor–acceptor diazo reagents, usually dicarbonyl compounds, in a copper-catalyzed process to yield functionalized pyrrolidines with α-pseudoquaternary centers. As 1,2-acyl or -phosphoryl migration is preferred, single regioisomers are obtained. Furthermore, in the presence of a Lewis acid, subsequent Friedel–Crafts reactions yield tricyclic pyrrolizidines in excellent yields (90–96 %) and diastereoselectivities (up to >20:1).

International audience; A new strategy for the synthesis of optically active pyrrolo[ 1,4]benzo- diazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction–double cyclization sequence leading to the desired substituted benzodiazepine.

Polycyclic indoline‐benzodiazepines can be accessed through the intermolecular reaction of Tröger bases with N‐sulfonyl‐1,2,3‐triazoles. Under RhII catalysis, α‐imino carbenes are generated and a subsequent cascade of [1,2]‐Stevens, Friedel–Crafts, Grob, and aminal formation reactions yield the polycyclic heterocycles as single isomers (d.r.>49:1, four stereocenters including two bridgehead N atoms). Further ring expansion by insertion of a second α‐imino carbene leads to elaborated polycyclic 9‐membered‐ring triazonanes.

International audience; α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences. This new reactivity has been applied to the synthesis of enantioenriched azaspiro[4,5]decanone ring systems by a formal [3+3]spiroannulation, constituting a rare example of synthesis of glutarimides in an optically active form.

Polysubstituted chiral cyclohexanes and cyclohexenes are important building blocks in organic synthesis. From historical and pioneering reports to the most recent accounts, this review focuses on domino enantioselective organocatalytic methodologies that have allowed the control of the relative and absolute configurations of up to six stereogenic centers in the construction of these versatile molecular architectures. 1 Introduction 2 Two-Component Transformations 2.1 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 2.2 Michael-Initiated Domino Reactions with Nitroolefins 2.3 Non Michael-Initiated Domino Reactions 3 Multicomponent and Related Transformations 3.1 Pseudo-Three-Component Reactions 3.1.1 Michael-Initiated Domino Reactions with Nitroolefins 3.1.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.2 Consecutive Reactions 3.2.1 Michael-Initiated Domino Reactions with Nitroolefins 3.2.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.3 Multicomponent Reactions 3.3.1 Michael-Initiated Domino Reactions with Nitroolefins 3.3.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 4 Conclusion

In this feature article, a general perspective of the research program aimed towards the preparation of polycyclic heterocycles by the means of enantioselective organocatalytic multicomponent reactions is presented. Guidelines for reaction design, including the selection of substrates and organocatalysts are discussed. For all transformations, scope and limitations are presented, along with post-functionalization to afford diversified heterocyclic scaffolds. 1 Introduction 2 Type I Products: 1,4,5,6-Tetrahydropyridines 3 Type II Products: 1,2,3,4-Tetrahydropyridines 4 Type III Products: Bridged Perhydropyridines 5 Conclusion and Perspective

A new strategy for the synthesis of optically active pyrrolo[1,4]benzodiazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction–double cyclization sequence leading to the desired substituted benzodiazepine.

We report the first enantioselective organocatalyzed domino synthesis of azepane moieties. This temporary-bridge strategy is based on a conceptually original annulation of ambident electrophilic and 1,4-bis-nucleophilic α-ketoamides with 1,3-bis-electrophilic enals. The obtained oxygen-bridged azepanes can be selectively transformed into optically active azepanone, azepanol or azepanedione derivatives of high synthetic value.

International audience; We report the first enantioselective organocatalyzed domino synthesis of azepane moieties. This temporary-bridge strategy is based on a conceptually original annulation of ambident electrophilic and 1,4-bis-nucleophilic a-ketoamides with 1,3-bis-electrophilic enals. The obtained oxygen-bridged azepanes can be selectively transformed into optically active azepanone, azepanol or azepanedione derivatives of high synthetic value.

α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences. This new reactivity has been applied to the synthesis of enantioenriched azaspiro[4,5]decanone ring systems by a formal [3+3]spiroannulation, constituting a rare example of synthesis of glutarimides in an optically active form.

Several reactive sites of 1,2- and 1,3-ketoamides were successively exploited in two complementary domino transformations for the synthesis of polysubstituted monocyclic or bridged bicyclic cyclohexanes, with the creation of up to six stereogenic centers. In both cases, a chiral bifunctional thiourea organocatalyst allowed efficient control of chirality in the final carbocycle.

Polysubstituted chiral cyclohexanes and cyclohexenes are important building blocks in organic synthesis. From historical and pioneering reports to the most recent accounts, this review focuses on domino enantioselective organocatalytic methodologies that have allowed the control of the relative and absolute configurations of up to six stereogenic centers in the construction of these versatile molecular architectures. 1 Introduction 2 Two-Component Transformations 2.1 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 2.2 Michael-Initiated Domino Reactions with Nitroolefins 2.3 Non Michael-Initiated Domino Reactions 3 Multicomponent and Related Transformations 3.1 Pseudo-Three-Component Reactions 3.1.1 Michael-Initiated Domino Reactions with Nitroolefins 3.1.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.2 Consecutive Reactions 3.2.1 Michael-Initiated Domino Reactions with Nitroolefins 3.2.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.3 Multicomponent Reactions 3.3.1 Michael-Initiated Domino Reactions with Nitroolefins 3.3.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 4 Conclusion

International audience; Several reactive sites of 1,2- and 1,3-ketoamides were successively exploited in two complementary domino transformations for the synthesis of polysubstituted monocyclic or bridged bicyclic cyclohexanes, with the creation of up to six stereogenic centers. In both cases, a chiral bifunctional thiourea organocatalyst allowed efficient control of chirality in the final carbocycle.

Cyclopentanones and cyclohexanones tethered to α,β-unsaturated ketones are treated with TiCl4 to afford mostly Michael-aldol products.

The addition of 0.5 equiv of TiCl(4) to (cyclo)alkanones tethered to α,β-unsaturated ketones afforded polyfunctionalized diquinanes, hydrindanes, and decalines. These products, resulting from a Michael-aldol or a Baylis-Hillman reaction, can be obtained with high or total diastereoselectivity in moderate to high yields. These scaffolds represent interesting building blocks for the synthesis of complex natural products.

International audience; We are reporting on the utility of commercial vinyl isocyanate for a practical synthetic route from adenosine to N(6)-bis-demethylpuromycin in seven steps and 65% overall yield. A clean one-pot conversion of 3'-bromo-2'-carbamoyl derivative 8 to 3'-amino-3'-deoxyadenosine derivative 10 is the main feature of this synthetic pathway. This synthesis is the shortest synthetic route toward 3'-(aminoacylamido)deoxyadenosines to date.