A Versatile, Functional Group-Tolerant, and Bench-Stable Iron Precatalyst for Building Arene and Triazine Rings by [2+2+2] Cycloadditions.

We report an efficient iron-catalyzed cycloaddition procedure leading to the construction of (hetero)aromatic rings by alkyne [2+2+2] cycloisomerization. This method relies on the use of an air-stable (N,N)Fe(II) precursor easily prepared from a commercially available ligand derived from 1,10-phenanthroline, reduced in situ into a catalytically active non-innocent (N,N ⋅-)2Fe(II) species. This system displays a large scope application, operates under mild conditions and at low catalytic charges (25 cycloadducts formed, up to 1.5 mol% catalyst). Moreover, this method also enables access to 29 cycloadducts by cross-cycloisomerization between 1,6- or 1,7-diynes and alkynes in near-equimolar conditions. 1,3,5-Triazines can also be prepared with this procedure starting from the corresponding cyanamides. Scale-up reactions and post-functionalization of several cycloadducts also show that this [2+2+2] cycloaddition can be used in multistep sequences.

Asymmetric Transfer Hydrogenation of gem-Difluorocyclopropenyl Ketones: The Synthesis and Functionalization of Enantioenriched cis gem-Difluorocyclopropyl Ketones.

The asymmetric transfer hydrogenation of gem-difluorocyclopropenyl ketones, catalyzed by a Noyori-Ikariya ruthenium complex, was developed to access substituted optically enriched cis-disubstituted gem-difluorocyclopropyl ketones, and the value of these latter building blocks was illustrated by the synthesis of heterocycles fused to the difluorocyclopropyl moiety.

Straightforward Access to Enantioenriched cis-3-Fluoro-dihydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution.

Herein we report a practical method for the asymmetric transfer hydrogenation/dynamic kinetic resolution of N-Boc 3-fluoro-dihydrotetrahydroquinolin-4-ones into the corresponding cis-fluoro alcohols in 70-96% yields, up to 99:1 diastereomeric ratio (dr) and up to >99% ee (enantiomeric excess) by using the ruthenium complex Ts-DENEB and a formic acid/triethylamine (1:1) mixture as the hydrogen donor under mild conditions.

Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols through Dynamic Kinetic Resolution.

Enantioenriched cis-3-fluoro-chroman-4-ol derivatives were conveniently prepared by the ruthenium-catalyzed asymmetric transfer hydrogenation of a new family of 3-fluoro-chromanones through a dynamic kinetic resolution process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (1:1) as the hydrogen source, affording the reduced fluorinated alcohols in good yields (80-96%), high diastereomeric ratios (up to 99:1 dr), and excellent enantioselectivities (up to >99% ee).

Asymmetric Transfer Hydrogenation of (Hetero)arylketones with Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Complexes: Scope and Limitations.

A series of new tethered Rh(III)/Cp* complexes containing the N-(p-tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine ligand have been prepared, characterized, and evaluated in the asymmetric transfer hydrogenation (ATH) of a wide range of (hetero)aryl ketones. The reaction was performed under mild conditions with the formic acid/triethylamine (5:2) system as the hydrogen source and provided enantiomerically enriched alcohols with good yields and high to excellent enantioselectivities. Although the nature of the substituents on the phenyl tethering ring did not alter the stereochemical outcome of the reaction, complexes bearing electron-donating groups exhibited a higher catalytic activity than those having electron-withdrawing groups. A scale-up of the ATH of 4-chromanone to the gram scale quantitatively delivered the reduced product with excellent enantioselectivity, demonstrating the potential usefulness of these new complexes.

Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation: Sustainable Chemistry to Access Bioactive Molecules.

Over the last few decades, the development of new and highly efficient synthetic methods to obtain chiral compounds has become an increasingly important and challenging research area in modern synthetic organic chemistry. In this account, we review recent work from our laboratory toward the synthesis of valuable chiral building blocks through transition-metal-catalyzed asymmetric hydrogenation and transfer hydrogenation of C=O, C=N and C=C bonds. Application to the synthesis of biologically relevant products is also described.

General asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by iridium-difluorphos: unusual halide effect and synthetic application.

A general asymmetric hydrogenation of a wide range of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by an iridium-difluorphos complex has been developed. Under mild reaction conditions, the corresponding biologically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units were obtained in high yields and good to excellent enantioselectivities up to 95%. With a catalyst ratio of S/C = 1000 and on a gram scale, the catalytic activity of the Ir-difluorphos complex was maintained showing its potential value. Finally, we demonstrated the application of our process in the synthesis of compound (S)-9, which is an inhibitor of cholesteryl ester transfer protein (CETP).

Identification of Chemical Probes Targeting MBD2.

Epigenetics has received much attention in the past decade. Many insights on epigenetic (dys)regulation in diseases have been obtained, and clinical therapies targeting them are in place. However, the readers of the epigenetic marks are lacking enlightenment behind this revolution, and it is poorly understood how DNA methylation is being read and translated to chromatin function and cellular responses. Chemical probes targeting the methyl-CpG readers, such as the methyl-CpG binding domain proteins (MBDs), could be used to study this mechanism. We have designed analogues of 5-methylcytosine to probe the MBD domain of human MBD2. By setting up a protein thermal shift assay and an AlphaScreen-based test, we were able to identify three fragments that bind MBD2 alone and disrupt the MBD2-methylated DNA interactions. Two-dimensional NMR experiments and virtual docking gave valuable insights into the interaction of the ligands with the protein showing that the compounds interact with residues that are important for DNA recognition. These constitute the starting point for the design of potent chemical probes for MBD proteins.

Rhodium-Catalyzed Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution of 3-Benzylidene-Chromanones.

Straightforward access to enantiomerically enriched cis-3-benzyl-chromanols from (E)-3-benzylidene-chromanones was developed through Rh-catalyzed asymmetric transfer hydrogenation. This transformation allowed the reduction of both the C═C and C═O bonds and the formation of two stereocenters in high yields with excellent levels of diastereo- and enantioselectivities (up to >99:1 dr, up to >99% ee) in a single step through a dynamic kinetic resolution process using a low catalyst loading and HCO2H/DABCO as the hydrogen source.

Synthesis of Enantioenriched ß-Hydroxy-γ-Acetal Enamides by Rhodium-Catalyzed Asymmetric Transfer Hydrogenation.

The asymmetric reduction of ß-keto-γ-acetal enamides has been investigated. A wide range of enantioenriched ß-hydroxy-γ-acetal enamides were obtained through asymmetric transfer hydrogenation catalyzed by a tethered Rh(III)-DPEN complex with yields up to quantitative and enantioselectivities up to 99%. The reaction proved to be highly chemoselective toward the reduction of the carbonyl group over the C═C bond.

Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors.

A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α'-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99 : 1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.

Rh-Mediated Asymmetric-Transfer Hydrogenation of 3-Substituted Chromones: A Route to Enantioenriched cis-3-(Hydroxymethyl)chroman-4-ol Derivatives through Dynamic Kinetic Resolution.

Enantioenriched cis-3-(hydroxymethyl)chroman-4-ol derivatives were conveniently prepared by rhodium-catalyzed asymmetric transfer hydrogenation of 3-formylchromones through a dynamic kinetic resolution process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (5:2) as the hydrogen source, delivering the reduced compounds in good yields, high diastereomeric ratio (up to 98:2 dr), and excellent enantioselectivities (up to >99% ee).

RhIII -Catalyzed Asymmetric Transfer Hydrogenation of α-Methoxy ß-Ketoesters through DKR in Water: Toward a Greener Procedure.

The asymmetric reduction of α-methoxy ß-ketoesters through transfer hydrogenation with a new rhodium(III) complex was developed. The reaction was efficient in 2-MeTHF with formic acid/triethylamine or in water with sodium formate. The corresponding syn α-methoxy ß-hydroxyesters were obtained with high diastereoselectivities and excellent levels of enantioselectivity through a dynamic kinetic resolution process.

Synthesis of Enantioenriched α,α-Dichloro- and α,α-Difluoro-ß-Hydroxy Esters and Amides by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation.

A mild and convenient approach was developed to prepare a series of α,α-dihalogeno ß-hydroxy esters or amides by using commercially available Noyori's complex [RuCl( p-cymene)( R, R)-TsDPEN] as a catalyst (S/C = 100-200) in the asymmetric transfer hydrogenation of the corresponding ketones. Moderate to high yields (up to 99%) and excellent enantioselectivities (up to >99% ee) were achieved for a series of variously substituted dichloro and difluoro ß-hydroxy esters and amides.

Rhodium-mediated asymmetric transfer hydrogenation: a diastereo- and enantioselective synthesis of syn-α-amido ß-hydroxy esters.

The preparation of syn α-benzoylamido ß-hydroxy esters through asymmetric transfer hydrogenation (ATH) with a tethered Rh(iii)-DPEN complex via dynamic kinetic resolution (DKR) has been developed for the first time starting from α-benzoylamido ß-keto esters. A variety of α-benzoylamido ß-keto esters were converted under mild conditions into the corresponding syn α-benzoylamino ß-hydroxy esters with high yields (up to 98%) and diastereomeric ratios (up to >99 : 1 dr) as well as excellent enantioselectivities (up to >99% ee).

RuCl3/PPh3: an efficient combination for the preparation of chiral 1,3-anti-diols through catalytic hydrogenation.

[reaction: see text] An efficient economical alternative to the commonly used Evans' reagent for the diastereoselective reduction of beta-hydroxy ketones is reported. Thus, ruthenium-mediated hydrogenation of enantioenriched beta-hydroxy ketones using RuCl3 associated to achiral monophosphines allowed the preparation of a series of 1,3-anti-diols in good yields and with a high level of diastereoselectivity. A short screening of ligands pointed out PPh3 as the most effective phosphine, and PCy3 afforded the 1,3-diols with an unexpected moderate syn selectivity.

Enantioselective Synthesis of α-Acetal-ß'-Amino Ketone Derivatives by Rhodium-Catalyzed Asymmetric Hydrogenation.

A range of ß-keto-γ-acetal enamides has been synthesized and transformed into the corresponding enantioenriched α-acetal-ß'-amino ketones with enantioinductions of up to 99% by using rhodium/QuinoxP*-catalyzed enantioselective hydrogenation under mild conditions. This method also proved to be highly chemoselective toward the reduction of the C-C double bond.

Synthetic Studies toward the C14-C29 Fragment of Mirabalin.

A convergent synthesis of one isomer of the C14-C29 fragment of mirabalin is disclosed. The key steps include a Marshall allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization, which allow the control of 10 out of 25 stereogenic centers present in the molecule.

Heck coupling using a vinyliodo-MIDA boronate: an efficient and modular access to polyene frameworks.

A simple Heck coupling between an alkenyl iodo-boronate and a variety of terminal olefins is disclosed. This method gives access to a wide range of dienic moieties including valuable bis-functionalized dienes. The synthetic potential of the coupling reaction is demonstrated by a short and modular preparation of several tetraenic compounds.

New efficient construction of the ABC core of the taxoids via a sequence of consecutive cobalt(I)-mediated [2 + 2 + 2] and [4 + 2] cyclizations.

[reaction: see text] A new and efficient sequence of two consecutive cyclizations, a cobalt(I)-mediated [2 + 2 + 2] cyclotrimerization and a Diels-Alder reaction, is proposed to allow the formation of the ABC core of the taxoids in 65% overall yield, starting from an acyclic polyunsaturated precursor.