Photocatalyzed Cascade Hydrogen Atom Transfers for Assembly of Multi-substituted α-SCF3 and α-SCF2H Cyclopentanones.

A photocatalyzed formal (3+2) cycloaddition has been developed to construct original polysubstituted α-SCF3 cyclopentanones in a regio- and diastereoselective manner. This building block approach leverages trifluoromethylthio alkynes and branched / linear aldehydes, as readily available reaction partners, in consecutive hydrogen atom transfers and C-C bond formations. Difluoromethylthio alkynes are also compatible subtrates. Furthermore, the potential for telescoped reaction starting from alcohols instead of aldehydes was demonstrated, as well as process automatization and scale-up under continuous microflow conditions. This prompted density functional theory calculations to support a free radical-mediated cascade hydrogen atom transfer process.

Stereoselective Nucleophilic Halogenation at CF3-Substituted Nonclassical Carbocation.

CF3-substituted cyclopropyl carbinol derivatives undergo regioselective and diastereoselective nucleophilic halogenation at the quaternary carbon center to provide acyclic products as a single diastereomer. The selectivity of the substitution is rationalized by the formation of a nonclassical cyclopropylcarbinyl cation intermediate, reacting at the most-substituted carbon center. Tertiary alkyl chlorides, bromides, and fluorides adjacent to a stereogenic C-CF3-motif are diastereomerically pure and can be obtained in few catalytic steps from commercially available alkynes.

10-Phenylphenothiazine-Organophotocatalyzed Bromo-Perfluoroalkylation of Unactivated Olefins.

In this study, we have developed a smooth metal-free visible-light-induced bromo-perfluoroalkylation of unactivated olefins with the aid of 10-phenylphenothiazine (PTH) as an organic photoredox catalyst. The reaction is 100% atom-economic redox-neutral and proceeds with stoichiometric amounts of olefin and perfluoroalkyl bromide. To show the potential of these unexplored motifs, we carried out various postfunctionalizations taking advantage of the bromine atom, including gram-scale experiments.

Expanding Radical Chloropentafluorosulfanylation of Alkynes.

The chloropentafluorosulfanylation of alkynes is a delicate but crucial operation for accessing SF5-alkynes that serve as substrates in numerous transformations. Dolbier's procedure using Et3B/O2 was the most efficient approach, while recent efforts make use of other initiators and light activation. We found that THF, as a single stimulus, is sufficient to trigger the reaction of SF5Cl with alkynes. We determined the configuration of Cl/SF5 products and clarified the structure of side-products.

Tracking SF5 I in the Iodopentafluorosulfanylation of Alkynes.

In the vibrant field of SF5 chemistry, SF5 X reagents (X=F, Cl, Br) are at the heart of current investigations in radical pentafluorosulfanylation reactions. SF5 I is the missing link whose existence has not been reported despite its potential as SF5 donor. This study reports the formal addition of the hitherto unknown SF5 I reagent to alkynes by means of a combination of SF5 Cl/KI/18-crown-6 ether. The exclusive regio- and stereoselective synthesis of unprecedented (E)-1-iodo-2-(pentafluoro-λ6 -sulfanyl) alkenes was achieved. A consensus was reached through computational and mechanistic studies for the realistic formation of SF5 - anion but not SF5 I in solution and the rational involvement of SF5 ⋅ and iodine radicals in the iodo pentafluorosulfanylation reaction.

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 µg/mL for most Gram-positive strains and 4-16 µg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.

Structure-property relationships of fluorinated carboxylic acid bioisosteres.

Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pKa), lipophilicity (logD7.4), and permeability (PAMPA). The results presented can help estimate the relative changes in physicochemical properties that may be attainable by replacing the carboxylic acid functional group with fluorine containing surrogate structures.

N-Fluoro Ammonium Salts of Cinchona Alkaloids in Enantioselective Electrophilic Fluorination.

From 2000, our two research groups independently and simultaneously designed and developed a novel family of electrophilic fluorinating reagents based on the use of Cinchona alkaloids. The chiral N-fluoro ammonium salts demonstrated the highest efficiency compared to prior art in enantioselective electrophilic fluorination for a wide range of substrates. In this account, we tell our respective stories, how the same idea germinated in our laboratories, the characterization of the chiral reagents, the use in stoichiometric quantity then the development of a catalytic version, the application to the synthesis of chiral fluorinated molecules of pharmaceutical interest, and finally the exploitation of our reagents by other teams and for other applications.

Stereoselective Preparation of CF3-Containing Cyclopropanes.

A regio- and diastereoselective carbometalation of easily accessible CF3-substituted cyclopropenes is developed with a diastereoselectivity of the addition opposite to the CF3 group. This simple strategy allows the preparation of polysubstituted (up to penta-) cyclopropyl rings possessing two adjacent quaternary carbon stereocenters with excellent diastereoselectivities.

Amphiphilic Polyfluorinated Amino Ethers from Cyclic Sulfamidates.

Regioselective ring opening of cyclic sulfamidates was achieved by means of nucleophilic polyfluorinated alkoxides to access achiral and chiral ß- and γ-ORF amines and α-amino esters. Subsequent transformations provide free amines ready for incorporation into bioactive substances through amide bond formation or nucleophilic aromatic substitution.

Catalytic Stereoconvergent Synthesis of Homochiral ß-CF3, ß-SCF3, and ß-OCF3 Benzylic Alcohols.

We describe an efficient catalytic strategy for enantio- and diastereoselective synthesis of homochiral ß-CF3, ß-SCF3, and ß-OCF3 benzylic alcohols. The approach is based on dynamic kinetic resolution (DKR) with Noyori-Ikariya asymmetric transfer hydrogenation leading to simultaneous construction of two contiguous stereogenic centers with up to 99.9% ee, up to 99.9:0.1 dr, and up to 99% isolated yield. The origin of the stereoselectivity and racemization mechanism of DKR is rationalized by density functional theory calculations. Applicability of the previously inaccessible chiral fluorinated alcohols obtained by this method in two directions is further demonstrated: As building blocks for pharmaceuticals, illustrated by the synthesis of heat shock protein 90 inhibitor with in vitro anticancer activity, and in particular, needle-shaped crystals of representative stereopure products that exhibit either elastic or plastic flexibility, which opens the door to functional materials based on mechanically responsive chiral molecular crystals.

KHMDS/Triglyme Cryptate as an Alternative to Phosphazene Base in Stereodivergent Pentafluoroethylation of N-Sulfinylimines Using HFC-125.

A protocol for the stereodivergent pentafluoroethylation of N-sulfinylimines using HFC-125 with KHMDS/triglyme has been developed. Both diastereomers of the pentafluoroethylated amines can be selectively synthesized based on the presence or absence of triglyme. This additive-controlled protocol allows the KHMDS/triglyme cryptate to be a straightforward and cheap alternative to previously reported base-controlled stereodivergent trifluoromethylation using potassium hexamethyldisilazide (KHMDS) versus P4-tBu.

Radical 1,5-Chloropentafluorosulfanylation of Unactivated Vinylcyclopropanes and Transformation into α-SF5 Ketones.

The radical 1,5-chloropentafluorosulfanylation of vinyl cyclopropanes (VCPs) initiated by Et3B/O2 affords allylic pentafluorosulfanyl/homoallylic chloride products through the ring-strain release of the cyclopropane. The VCP substitution pattern was investigated. The utility of this reaction was illustrated in post-transformation of the C═C bond by ozonolysis, giving access to valuable α-SF5 carbonyl compounds.

Enantioselective catalytic synthesis of α-aryl-α-SCF3-ß2,2-amino acids.

We herein report a novel entry towards chiral α-SCF3-ß2,2-amino acids by carrying out the ammonium salt-catalyzed α-trifluoromethylthiolation of isoxazolidin-5-ones. This approach allowed for high enantioselectivities and high yields and the obtained heterocycles proved to be versatile platforms to access other targets of potential interest.

Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based ß-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides.

The first electrophilic diastereoselective direct introduction of the difluoromethylthio group is described. We used a chiral auxiliary-based approach to illustrate the versatility of our recently developed difluoromethanesulfonyl hypervalent iodonium ylide reagents for the difluoromethylthiolation of indanone-based ß-keto esters. Chiral SCF2H-featuring compounds were obtained in up to 93% ee value.

Telescoping Reactions with Trifluorodiazoethane-Derived Aza-Wittig Reagents and Allenyl esters.

A telescoping process involving the consecutive addition of four reagents (trifluorodiazoethane, phosphine, allenyl ester, and acetic acid) into a single reactor was developed for the novel functionalization of allenyl esters. First, new phosphazenes derived from trifluorodiazoethane and phosphines were generated and reacted with allenyl esters to give unexpected α-iminophosphoranes through the creation of C=P, C=N, and C-H bonds at the α-, ß-, and γ-carbon atoms, respectively, of the allenyl esters. The α-iminophosphoranes did not react with aldehydes in a classic Wittig reaction, but instead ß-enamino esters were obtained. The overall sequence of reactions offered a formal hydrohydrazonation of allenyl esters. The method was extended to other related diazo compounds and applied to the preparation of novel 5-pyrazolone derivatives. Not only is the telescoping process described herein an effective approach for truncating the multistep synthesis, but also each step has been dissected to understand and support the reaction mechanisms.

Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access to Chiral ß- and γ-SCF3 Amines and α-Amino Esters.

The regio- and stereoselective ring opening of 1,2- and 1,3-sulfamidates with trifluoromethanethiolate anion is reported. This direct introduction of the whole SCF3 motif is a straightforward synthetic route toward ß- and γ-SCF3 amines and α-amino acid derivatives. The utility of this reaction was further illustrated by incorporation of Cys(S-CF3) into di- and tripeptides.

CF3SO2X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF3SO2Na.

Sodium trifluoromethanesulfinate, CF3SO2Na, and trifluoromethanesulfonyl chloride, CF3SO2Cl, are two popular reagents that are widely used for the direct trifluoromethylation of a large range of substrates. Further, these two reagents are employed for the direct trifluoromethylsulfenylation and trifluoromethylsulfinylation, the introduction of the SCF3 and the S(O)CF3 group, respectively. In addition to the aforementioned reactions, the versatility of these two reagents is presented in other reactions such as sulfonylation and chlorination. This first part is dedicated to sodium trifluoromethanesulfinate.

CF3SO2X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF3SO2Cl.

The recent progresses of the application of trifluoromethanesulfonyl chloride, CF3SO2Cl, in the formation of C-CF3, C-SCF3, C-SOCF3, and C-Cl bonds are summarised in this second part of a two-part review published back-to-back on both sodium trifluoromethanesulfinate, CF3SO2Na, (Part 1) and trifluoromethanesulfonyl chloride, CF3SO2Cl (Part 2). There are many reactions in common between these two reagents but it should be noted that CF3SO2Cl reacts under reductive conditions while CF3SO2Na requires oxidative conditions. Electrophilic chlorination is obviously the exclusive preserve of CF3SO2Cl that has been exploited with emphasis in enantioselective chlorination.

Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation.

The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes.