Ru(II)-Catalyzed Enantioselective Transfer Hydrogenation of α-Ketophosphonates: Straightforward Access to Valuable Chiral α-Hydroxy Phosphonates.

Asymmetric transfer hydrogenation (ATH) is arguably one of the most powerful tools for the synthesis of chiral compounds. Despite tremendous advances in this field, the reduction of α-ketophosphonates remains largely unexplored. Herein, we report an efficient Ru-catalyzed ATH on a broad range of α-ketophosphonates. Compared with existing methods, our approach offers as advantages mild conditions, operational simplicity, limited waste generation, broad substrate scope (26 examples), good to excellent yields (75-93%), and excellent levels of stereoinduction (from 90% to >99% ee).

Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated ß-Iminophosphonates-Spectroscopic and Theoretical Studies.

The efficient one-pot halofluorination of a ß-enaminophosphonate/ß-iminophosphonate tautomeric mixture resulting in α,α-halofluorinated ß-iminophosphonates is reported. Subsequent imine reduction gave the corresponding ß-aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of N-inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the cis/trans geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of cis/trans-fluoroaziridine mixture 24, allows us to isolate chiral trans-aziridines 24 as well as cis-aziridines 27 that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the SN2 intramolecular cyclization of vicinal haloamines have been modeled.

Beyond the Limits of Atropochirality: Design of Highly Conformationally Restrained Biaryls with Bridgehead Phosphine Oxide.

In the last three decades, reacting sterically congested ortho-substituted arenes to form atropochiral biaryls is an appealing venture and a challenging subject that has garnered significant attention. Therefore, there is interest in developing methods to prepare these compounds. In this study, an efficient approach to produce a new class 2,2' disubstituted biaryls bridgehead phosphine oxides with an unusual topology and exceptional conformational stability is presented. Our methodology demonstrates that depending on the substitution pattern on the aryl moieties, the methanophosphocine backbone could be rigid enough to observe a double atropochirality, resulting in an under covered class of molecules. Notably, our studies revealed that replacing only one hydrogen at the ortho position by a fluorine atom led to sufficiently restricted rotation at temperatures below 80 °C, extending "far away" the limits of atropostability. Finally, our investigations, which employed variable-temperature NMR spectroscopy and DFT calculations, yielded unique insights into the isomerisation mechanism, indicating that the two biaryl motifs are fully independent in spite of their proximity.

New Approaches toward Building Csp -P bond: A Two-Decade Overview.

Since the review of Savignac, the past 20 years have seen significant progresses on the synthesis of alkynylphosphorus compounds considerably expanding the original and rather limited organic toolbox. This comprehensive review explores the latest and potentially greener methodologies using sustainable catalysis or direct metal-free couplings from stable and easy to handle precursors. Recent progress and mechanistic insights for metal-catalyzed reactions with a particular emphasis on copper, palladium, nickel and silver catalytic systems, photocatalytic and metal-free reactions are detailed covering most of the publications related to this field since 2000 until March 2022.

Gold-Catalyzed Access to Isophosphinoline 2-Oxides.

Gold(I)-catalyzed reactions of electron-poor alkynes are still a challenging process. A straightforward synthesis of phosphorus-based heterocycles, namely, 2-phenyl 1H-isophosphinoline 2-oxides 1, is reported. The reaction used PPh3AuCl precatalyst in combination with triflic acid under microwave activation and afforded isophosphinoline 2-oxides 1 in moderate to quantitative yields through a fully regioselective 6-endo-dig hydroarylation cyclization, paving the way toward an effective synthesis of phosphorus heterocycles.

Diversity-Oriented Synthesis toward Aryl- and Phosphoryl-Functionalized Imidazo[1,2-a]pyridines.

We report herein an efficient synthesis of diversely polysubstituted imidazo[1,2-a]pyridines, a family of aza-heterocycles endowed with numerous biological properties, through a sequence involving two consecutive palladium-catalyzed cross-coupling reactions. First, we demonstrated that a Hirao coupling occurred straightforwardly in high yields at positions 3, 5, and 6 of imidazopyridine derivatives, giving access to a wide variety of substituted phosphonates, phosphinates, and phosphine oxides. In a second step, direct CH-arylation of phosphorylimidazopyridines with aryl halides was found to be effective and fully selective, leading to 3-aryl-substituted imidazopyridines in moderate to high yields depending on steric hindrance.

Golden Face of Phosphine: Cascade Reaction to Bridgehead Methanophosphocines by Intramolecular Double Hydroarylation.

Reported herein is the first example of a gold-catalyzed cyclization of bis(arylmethyl)ethynylphosphine oxides. This represents an original approach to bridgehead methanophosphocines 1, eight-membered heterocycles. Gold catalyst in combination with triflic acid activates alkyne and induces a double hydroarylation. Mechanistic studies suggest that the reaction proceeds stepwise, forming first the 1 H-isophosphinoline 2-oxide 5. Reduction and protection of the corresponding phosphine oxides 1 described herein also highlight the effectiveness of our approach to this new class of electron-rich ligands.

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.

Synthesis and Antiproliferative and Metabolic Evaluations of Novel Securinine Derivatives.

New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

Synthesis and biological evaluation of new securinine analogues as potential anticancer agents.

A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.

Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted ß-Ketoesters.

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-ß-ketoesters in the presence of well-defined, commercially available, chiral catalyst Ru(II) -(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α-alkoxy-ß-hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru(II) - and Rh(III) -tethered precatalysts extended this process to more-challenging substrates that bore alkenyl-, alkynyl-, and alkyl substituents to provide the corresponding syn α-alkoxy-ß-hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoate, which is an important pharmacophore in a number of peroxisome proliferator-activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type-II diabetes.

Enantioselective ruthenium(II)/Xyl-SunPhos/Daipen-catalyzed hydrogenation of γ-ketoamides.

A series of γ-hydroxy amides were synthesized with high enantioselectivities (up to 99%) using asymmetric hydrogenation of the corresponding γ-ketoamides in the presence of Ru-Xyl-SunPhos-Daipen catalyst providing key building blocks for a variety of naturally occurring and biologically active compounds.

Enantioselective rhodium-catalyzed synthesis of α-chloromethylene-γ-butyrolactams from N-allylic alkynamides.

The first enantioselective cycloisomerization with intramolecular halogen migration of various 1,6-enynes promoted by a cationic Rh-Synphos catalyst is reported. This method provides an efficient route to enantiomerically enriched γ-butyrolactam derivatives, which are important core scaffolds found in numerous natural products and biologically active molecules. Good yields and enantiomeric excesses up to 96% are achieved.

Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation.

Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl](2)/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.

Ru-catalyzed highly chemo- and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-ß-keto esters under neutral conditions.

Finely-tuned ruthenium-catalyzed highly chemoselective and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-ß-keto esters at the carbonyl group was achieved under neutral reaction conditions (ee up to 97%). Both olefin and alkenyl halogen moieties, which are labile under hydrogenation conditions, remained untouched during the reaction.

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).

Ruthenium-catalyzed enantioselective hydrogenation of aryl-pyridyl ketones.

Various substituted aryl-pyridyl ketones were hydrogenated in the presence of Ru-XylSunPhos-Daipen bifunctional catalytic system with enantiomeric excesses up to 99.5%. Upon introduction of a readily removable ortho-bromo atom to the phenyl ring, enantiomerically enriched 4-chlorophenylpyridylmethanol was obtained by hydrogenation method with 97.3% ee, which provided an important chiral intermediate for some histamine H(1) antagonists.

Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,ß-unsaturated ketones with DIFLUORPHOS and SYNPHOS analogues.

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,ß-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF(3)-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.