Tanguy Saget

Cyclobutanes in catalysis.

The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. The most prominent and most frequently used compound classes in this respect are oxiranes and cyclopropanes. For rather a long time, cyclobutanes lagged behind these three-membered-ring compounds in their development as reactive substrates, but during the past decade an increasing number of useful reactions of four-membered-ring substrates have emerged. This Minireview examines corresponding catalytic reactions ranging from Lewis or Brønsted acid catalyzed processes to enzymatic reactions. The main focus is placed on transition-metal-catalyzed C-C bond-insertion and β-carbon-elimination processes, which enable exciting downstream reactions that deliver versatile building blocks.

Chiral Monodentate Phosphines and Bulky Carboxylic Acids: Cooperative Effects in Palladium‐Catalyzed Enantioselective C(sp3)–H Functionalization

Keywords: asymmetric catalysis ; C?H activation ; cooperative effects ; palladium ; phosphines ; C-H Activation ; Quaternary Stereogenic Centers ; Intramolecular Alkane Arylation ; Unactivated C(Sp(3))-H Bonds ; Asymmetric Hydrogenation ; Mild Conditions ; Methyl-Groups ; Ligands ; Derivatives ; Indolines Reference EPFL-ARTICLE-176461doi:10.1002/anie.201108511View record in Web of Science Record created on 2012-04-26, modified on 2017-12-03

Palladium(0)‐Catalyzed Enantioselective CH Arylation of Cyclopropanes: Efficient Access to Functionalized Tetrahydroquinolines

Keywords: asymmetric catalysis ; C?H activation ; cyclopropanes ; palladium ; tetrahydroquinolines Reference EPFL-ARTICLE-185275doi:10.1002/anie.201207959View record in Web of Science Record created on 2013-03-28, modified on 2017-12-03

Access to β-lactams by enantioselective palladium(0)-catalyzed C(sp3)-H alkylation.

β-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd(0)-catalyzed C-H functionalization for aryl-aryl couplings, related reactions involving the formation of saturated C(sp(3))-C(sp(3)) bonds are elusive. Reported here is an asymmetric C-H functionalization approach to β-lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp(3))-C(sp(3)) and strain-building reductive eliminations to for the four-membered ring. In general, the β-lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.

Enantioselective CH Arylation Strategy for Functionalized Dibenzazepinones with Quaternary Stereocenters

Tada! Highly functionalized chiral dibenzazepinones are obtained by a mild palladium(0)-catalyzed enantioselective C-H arylation with excellent selectivities by using simple taddol phosphoramidite ligands. The amide tether allows exclusive regioselectivity through a rare eight-membered palladacycle intermediate.

Formal Homo‐Nazarov and Other Cyclization Reactions of Activated Cyclopropanes

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.

Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation.

The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed C-H functionalization of a methine C(sp(3))-H bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access functionalized indoline scaffolds in a single step.

Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral β‐Fluoroamines

Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of β-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C-F centers.

Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters

Herein, we report a Zn-ProPhenol catalyzed Mannich reaction using α-branched ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of quaternary carbon stereocenters. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, the Mannich adducts can be further elaborated with complete diastereocontrol to access molecules possessing complex stereotriads.

Heteroatom-nucleophile-induced C-C fragmentations: synthesis of allenes and entry to domino reactions.

Heteroatom nucleophiles (NuH) induce Grob-type fragmentations of cyclic vinyl triflates under mild conditions and provide ω-allene-functionalized carboxylic acid derivs. These products are a versatile starting point for domino and one-pot reactions accessing a range of structurally diverse scaffolds in good yields.