Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters.

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).

Catalytic Reversible (De)hydrogenation To Rotate a Chemically Fueled Molecular Switch.

We report here the development of a rotating molecular switch based on metal-catalyzed reversible (de)-hydrogenation. Under an argon atmosphere, acceptorless dehydrogenation induces a switch from an alcohol to a ketone, while reversing to a hydrogen pressure switches back the system to the alcohol. Based on a tolane scaffold, such reversible (de)-hydrogenation enables 180° rotation. The absence of waste accumulation in a switch relying on chemical stimuli is of great significance and could potentially be applied to the design of efficient complex molecular machines.

Trichloroacetic acid fueled practical amine purifications.

Amine purification have for long been dominated by tedious stepwise processes involving the generation of large amounts of undesired waste. Inspired by recent work on out of equilibrium molecular machinery, using trichloroacetic acid (TCA), we disclose a purification technique considerably decreasing the number of operations and the waste generation required for such purifications. At first, TCA triggers the precipitation of the amines through their protonated salt formation, enabling the separation with the impurities. From these amine salts, simple decarboxylation of TCA liberates volatile CO2 and chloroform affording directly the pure amines. Through this approach, a broad range of diversely substituted amines could be isolated with success.

Chemically Fueled Three-State Chiroptical Switching Supramolecular Gel with Temporal Control.

The recent discovery of temporally controlled gels opens broad perspectives to the field of smart functional materials. However, to obtain fully operative systems, the design of simple and robust gels displaying complex functions is desirable. Herein, we fuel dissipative gelating materials through iterative additions of trichloroacetic acid (TCA). This simple fuel enables to switch over time an acid/base-dependent commercially available amino acid gelator/DBU combination between three distinct states (anionic, cationic, and neutral), while liberating volatile CO2 and CHCl3 upon fuel consumption. Of interest, the anionic resting state of the system is obtained through trapping of 1 equiv of CO2 through the formation of a carbamate. The system is tunable, robust, and resilient over time with over 25 consecutive sol-gel-sol cycles possible without significant loss of properties. Most importantly, because of the chiral nature of the amino acid gelator, the system features chiroptical switching properties moving reversibly between three distinct states as observed by ECD. The described system considerably enhances the potential of smart molecular devices for logic gates or data storage by adding a time dimension based on three states to the gelating materials. It is particularly simple in terms of chemical components involved, but it enables sophisticated functions.

Iron-Based Multi-Catalysis: Eco-Compatible Alternative for Complex Molecules Synthesis.

In the last decade, multi-catalysis has emerged as an excellent alternative to classical methods, rapidly elaborating complex organic molecules while considerably decreasing steps and waste generation. In order to further decrease costs, the application of cheaper and more available iron-based catalysts has recently arisen. Through these iron-based multi-catalytic combinations, greener transformations have been developed that generate complex organic scaffolds from simple building blocks at lower costs. In addition to the decrease in catalysts costs, it was also demonstrated that in many cases, the application of iron complexes could also lead to unique reactivity features, expanding chemist's available toolbox. All the advantages observed in terms of costs and reactivity, should make iron-based multi-catalysis one of the leading technology of the future.

Copper Catalyzed Decarboxylative Functionalization of Ketoacids.

Selective copper catalyzed activation of ketoacids and notably bio-sourced 1,3-acetonedicarboxylic acid, represents an attractive strategy to solve key synthetic challenges. Condensation with aldehydes under exceedingly mild conditions can create more rapidly known natural products scaffolds such as 1,3 polyols. In this account, the recent progress in this field, notably through multicatalytic combination with organocatalysis is described. In addition to the rapid preparation of natural product fragments, cascade incorporation of fluorine also provided new type of synthetic analogues of improved properties in a broad range of applications.

Mössbauer Spectroscopic and Computational Investigation of An Iron Cyclopentadienone Complex.

(Cyclopentadienone)iron carbonyl complexes have recently received particular attention for their use as catalysts in hydrogenation or transfer hydrogenation reactions including the N-alkylation of amines with alcohols. This is due to their easy synthesis from simple and cheap materials, air and water stabilities, and the crucial metal-ligand cooperation giving rise to unique catalytic properties. Here, we report a Mössbauer spectroscopic and computational investigation of such a complex and its corresponding activated species for dehydrogenation and hydrogenation reactions. This study affords a deeper understanding of the species formed by the reaction with Me3NO and their distribution upon the added amount of an oxidant.

Impact of the Difluoromethylene Group in the Organocatalyzed Acylative Kinetic Resolution of α,α-Difluorohydrins.

Due to the omnipresence of chiral organofluorine compounds in pharmaceutical, agrochemical, and material chemistry, the development of enantioselective methods for their preparation is highly desirable. In the present study, the enantioselective organocatalyzed acylation of α,α-difluorohydrins using a commercially available chiral isothiourea is reported through a kinetic resolution (KR) process. It reveals that the difluoromethylene moiety (C(sp3 )F2 ) can serve as a directing group through electrostatic fluorine-cation interactions, greatly improving the enantioselectivity of the KR. In this context, a broad range of fluorinated alcohols such as valuable 4,4-difluoro-1,3-diols could be synthesized with exquisite enantiocontrol (typically >99:1 er). Turning to 2,2-difluoro-1,3-diols, we also demonstrated that aromatic and fluorinated groups were mutually compatible to provide the expected enantioenriched adducts with >99:1 er.

Organocatalytic carbon dioxide fixation to epoxides by perfluorinated 1,3,5-triols catalysts.

In order to improve epoxides conversion to carbonates by fixation of CO2 a new type of perfluorinated triol catalysts was developed. These simple acyclic scaffolds of enhanced acidity are efficient for catalysis through selective H-bonding activation of the epoxide. In combination with TBAI as co-catalyst, this useful transformation is performed under only 1 atmosphere of CO2 and between 30 to 80 °C. Both the 1,3,5-triol motif and the perfluorinated side chains are crucial in order to observe this epoxide opening under such mild conditions. In addition, the stereochemistry of the starting epoxide can efficiently be conserved during the carbonate formation.

Catalytic strategies towards 1,3-polyol synthesis by enantioselective cascades creating multiple alcohol functions.

This review highlights the different enantioselective catalyst-controlled cascades creating multiple alcohol functions through the formation of several carbon-carbon bonds. Through subsequent simple derivatization, these strategies ensure the rapid preparation of 1,3-polyols. Thanks to the use of efficient metal- or organo-catalysts, these cascades enable the selective assembly of multiple substrates considerably limiting operations and waste generation. For this purpose, several mono- or bi-directional approaches have been devised allowing successive C-C bond-forming events. The considerable synthetic economies these cascades enable have been demonstrated in the preparation of a wide variety of complex bioactive natural products, notably polyketides.

Strategic Stereoselective Halogen (F, Cl) Insertion: A Tool to Enhance Supramolecular Properties in Polyols.

To improve the supramolecular properties of organic compounds, chemists continuously need to identify new tools. Herein, the influence of the stereoselective insertion of halogen atoms (F or Cl) on different supramolecular properties is analyzed. Inserting anti-halohydrins in polyols considerably strengthens the H-bonding networks and other supramolecular interactions. This behavior resulted in improved anion binding, H-bonding catalysis, or organogel properties of the designed polyols with strong perspectives for applications in other classes of substrates.

Discovery of Eco-compatible Synthetic Paths by a Multi-catalysis Approach.

This article summarizes our recent developments in the discovery of multi-catalytic reactions. By efficiently taking the best from different worlds, the combination of several catalytic principles allows the invention of eco-compatible transformations rapidly assembling simple building blocks into elaborated enantioenriched molecules. This type of approach was successfully illustrated in the synthesis of cyclohexenones, keto-diols or in the direct functionalization of allylic alcohols by an enantioselective borrowing hydrogen. In addition, mechanistic understanding of the role of the different constituents enabled the fine-tuning of the catalytic systems considerably improving the efficiency notably in terms of enantiocontrol.

Recent Achievements in Enantioselective Borrowing Hydrogen by the Combination of Iron- and Organocatalysis.

This article summarizes our recent developments in allylic alcohol functionalization by the interconnection of two catalytic cycles. By combining an iron-catalyzed borrowing hydrogen with an organocatalytic enantioselective nucleophilic addition, allylic alcohols can be converted to enantioenriched chiral aliphatic alcohols in up to 92% ee. This eco-compatible one-operation multi-catalytic process allows the classical oxidation-addition-reduction steps usually required for this transformation to be bypassed. Synthetic applications in the synthesis of different fragments of some important natural products have highlighted the great potential of this transformation.

Didecarboxylative Iron-Catalyzed Bidirectional Aldolization towards Diversity-Oriented Ketodiol Synthesis.

1,3-Acetonedicarboxylic acid was selectively activated by Fe(acac)3 , providing a synthetic platform for rapid synthesis of keto-3,3'-diols. The bidirectional aldol reaction was efficient for challenging aliphatic aldehydes, providing a rapid route to potentially bioactive complex structures.

Origin of the enantioselectivity in organocatalytic Michael additions of ß-ketoamides to α,ß-unsaturated carbonyls: a combined experimental, spectroscopic and theoretical study.

The organocatalytic enantioselective conjugate addition of secondary ß-ketoamides to α,ß-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

Iron cyclopentadienone complexes: discovery, properties, and catalytic reactivity.

Iron cyclopentadienone complexes have recently received particular attention in organic chemistry. This is due to their easy synthesis from simple and cheap materials, air-water stability, and most importantly for their unique catalytic features arising from the presence of a non-innocent ligand, triggering powerful redox properties. Herein we discuss the properties of such complexes from synthetic and mechanistic points of view, and their applications in original redox-neutral transformations in both racemic and enantioselective series.

Iron- and Organo-Catalyzed Borrowing Hydrogen for the Stereoselective Construction of Tetrahydropyrans.

Stereocontrolled oxa-Michael additions are challenging, given the high reversibility of the process, which ultimately leads to racemization of the newly formed stereocenters. When iron-catalyzed borrowing hydrogen from allylic alcohols was combined with a stereocontrolled organocatalytic oxa-Michael addition, a wide array of chiral tetrahydropyrans were efficiently prepared. The reaction could be performed in a diastereoselective manner from pre-existing stereocenters or enantioselectively from achiral substrates. The key to success was the reactivity of the iron complex, which was selective for allylic alcohol dehydrogenation and irreversibly led the reaction to the final product.

An iron/amine-catalyzed cascade process for the enantioselective functionalization of allylic alcohols.

Three is a lucky number: An enantioselective transformation of allylic alcohols into ß-chiral saturated alcohols has been developed by combining two distinct metal- and organocatalyzed catalytic cycles. This waste-free triple cascade process merges an iron-catalyzed borrowing-hydrogen step with an aminocatalyzed nucleophilic addition reaction.

Catalysis Driven Six-Step Synthesis of Apratoxin A Key Polyketide Fragment.

Apratoxin A is a potent anticancer natural product whose key polyketide fragment constitutes a considerable challenge for organic synthesis, with five prior syntheses requiring 12 to 20 steps for its preparation. By combining different redox-economical catalytic stereoselective transformations, the key polyketide fragment could be rapidly prepared. Followed by a site-selective protection of the diol, this strategy enables the preparation of the apratoxin A fragment in only six steps, representing the shortest route to this polyketide.

Dissipative Acid-Fueled Reprogrammable Supramolecular Materials.

Smart materials reversibly changing properties in response to a stimuli are promising for a broad array of applications. In this article, we report the use of trichloroacetic acid (TCA) as fuel to create new types of time-controlled materials switching reversibly from a gel to a solution (gel-sol-gel cycle). Applying various neutral amines as organogelators, TCA addition induces amine protonation, switching the system to a solution, while TCA decarboxylation over time enables a return to the initial gel state. Consequently, the newly obtained materials possess interesting time-dependent properties applied in the generation of remoldable objects, as an erasing ink, as chiroptical switches, or for the generation of new types of electrical systems.