Network Effects Lead to Self-Organization in Metabolic Cycles of Self-Repelling Catalysts.

Mixtures of particles that interact through phoretic effects are known to aggregate if they belong to species that exhibit attractive self-interactions. We study self-organization in a model metabolic cycle composed of three species of catalytically active particles that are chemotactic toward the chemicals that define their connectivity network. We find that the self-organization can be controlled by the network properties, as exemplified by a case where a collapse instability is achieved by design for self-repelling species. Our findings highlight a possibility for controlling the intricate functions of metabolic networks by taking advantage of the physics of phoretic active matter.

Self-organization of primitive metabolic cycles due to non-reciprocal interactions.

One of the greatest mysteries concerning the origin of life is how it has emerged so quickly after the formation of the earth. In particular, it is not understood how metabolic cycles, which power the non-equilibrium activity of cells, have come into existence in the first instances. While it is generally expected that non-equilibrium conditions would have been necessary for the formation of primitive metabolic structures, the focus has so far been on externally imposed non-equilibrium conditions, such as temperature or proton gradients. Here, we propose an alternative paradigm in which naturally occurring non-reciprocal interactions between catalysts that can partner together in a cyclic reaction lead to their recruitment into self-organized functional structures. We uncover different classes of self-organized cycles that form through exponentially rapid coarsening processes, depending on the parity of the cycle and the nature of the interaction motifs, which are all generic but have readily tuneable features.

Non-equilibrium phase separation in mixtures of catalytically active particles: size dispersity and screening effects.

Biomolecular condensates in cells are often rich in catalytically active enzymes. This is particularly true in the case of the large enzymatic complexes known as metabolons, which contain different enzymes that participate in the same catalytic pathway. One possible explanation for this self-organization is the combination of the catalytic activity of the enzymes and a chemotactic response to gradients of their substrate, which leads to a substrate-mediated effective interaction between enzymes. These interactions constitute a purely non-equilibrium effect and show exotic features such as non-reciprocity. Here, we analytically study a model describing the phase separation of a mixture of such catalytically active particles. We show that a Michaelis-Menten-like dependence of the particles' activities manifests itself as a screening of the interactions, and that a mixture of two differently sized active species can exhibit phase separation with transient oscillations. We also derive a rich stability phase diagram for a mixture of two species with both concentration-dependent activity and size dispersity. This work highlights the variety of possible phase separation behaviours in mixtures of chemically active particles, which provides an alternative pathway to the passive interactions more commonly associated with phase separation in cells. Our results highlight non-equilibrium organizing principles that can be important for biologically relevant liquid-liquid phase separation.

Design of iodinated radioligands for SPECT imaging of central human 5-HT4R using a ligand lipophilicity efficiency approach.

A series of iodinated ligands for the SPECT imaging of 5-HT4 receptors was designed starting from the previously reported hit MR-26132. We focused on the modulation of the piperidine-containing lateral chain by introducing hydrophilic groups in order to decrease the liphophilicity of the new ligands. All the synthesized compounds were tested for their binding affinities on 5-HT4Rs and based on the Ligand Lipophilicity Efficiency approach, compound 13 was further selected for radioiodination with iodine-125 and imaging experiments. Compound 13 showed its ability to displace the specific signal of the reference compound [125I]SB-207710 but no significant detection of [125I]13 was observed in vivo in SPECT experiments.

Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal Diazirines and 15N2-Diazirines and Their Application as Hyperpolarized Markers.

A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDA-mediated transformation occurs via three consecutive reactions and involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it is operationally simple, and it can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that this transformation could be applied to dipeptides without racemization. Furthermore, 14N2 and 15N2 isotopomers can be obtained, emphasizing a key trans-imination step when using 15NH3. In addition, we report the first experimental observation of 14N/15N isotopomers directly creating an asymmetric carbon. Finally, the 15N2-diazirine from l-tyrosine was hyperpolarized by a parahydrogen-based method (SABRE-SHEATH), demonstrating the products' utility as hyperpolarized molecular tag.

Terminal Diazirines Enable Reverse Polarization Transfer from 15 N2 Singlets.

Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The 15 N2 labeled diazirines are appealing motifs for hyperpolarization supporting relaxation protected states with long-lived lifetimes. The (-CH15 N2 ) diazirine groups investigated here are analogues to methyl groups, which provides the opportunity to transfer polarization stored on a relaxation protected (-CH15 N2 ) moiety to 1 H, thus combining the advantages of long lifetimes of 15 N polarization with superior sensitivity of 1 H detection. Despite the proximity of 1 H to 15 N nuclei in the diazirine moiety, 15 N T1 times of up to (4.6±0.4) min and singlet lifetimes Ts of up to (17.5±3.8) min are observed. Furthermore, we found terminal diazirines to support hyperpolarized 1 H2 singlet states in CH2 groups of chiral molecules. The singlet lifetime of 1 H singlets is up to (9.2±1.8) min, thus exceeding 1 H T1 relaxation time (at 8.45 T) by a factor of ≈100.

One-Pot Synthesis of Aryl- and Alkyl S-Perfluoroalkylated NH-Sulfoximines from Sulfides.

A general efficient one-pot synthesis of S-perfluoroalkylated NH-sulfoximines from sulfides has been developed using phenyliodine diacetate (PIDA) and ammonium carbamate. Remarkable rate enhancement with trifluoroethanol was observed, presumably due to H-bonding effects. These mild and metal-free conditions are compatible with -CH2 F, -CFCl2 , -CF2 H, -CF2 Br, -C4 F9 , and -CF3 groups, in both the alkyl- and aryl series. Based on a 19 F NMR analysis, a λ6 -acetoxysulfanenitrile intermediate was proposed.

Mechanistic investigation of the NH-sulfoximination of sulfide. Evidence for λ6-sulfanenitrile intermediates.

We report a new procedure for the preparation of NH-sulfoximines from sulfides using PIDA as an oxidant and ammonium carbamate as the ammonia source. Excellent yields were obtained with a wide range of sulfides. The formation of acetoxy- and methoxy-λ6-sulfanenitrile as intermediates was proposed, both of which were converted to the NH-sulfoximine by the action of the solvent. The structure of these intermediates was confirmed by 1H, 13C and 15N NMR and HRMS analysis.

Asymmetric three-component domino reaction: an original access to chiral nonracemic 1,3-thiazin-2-ones.

A new asymmetric three-component domino process, based on a diastereoselective hetero-Diels-Alder reaction, involving an aldehyde, an alkene, and a chiral thiocarbamate was developed. The chiral auxiliary is directly removed during this process, leading to enantioenriched 2H-1,3-thiazin-2-ones with up to 96% ee.

Catalytic generation of cesium acetylide by CsF: synthesis of 1,3-benzothiazines from cyclic sulfenamides.

An efficient synthesis of enantiopure 1,3-benzothiazines has been achieved by reaction of cyclic sulfenamides and alkylpropiolate or tosylacetylene catalyzed by cesium fluoride.

Fluoride ion and phosphines as nucleophilic catalysts: synthesis of 1,4-benzothiazepines from cyclic sulfenamides.

A new methodology, using fluoride ion as a nucleophilic catalyst, was applied for the synthesis of enantiopure 1,4-benzothiazepine from cyclic sulfenamide and electron-deficient acetylene, with high efficiency and atom economy.

A novel synthesis of 1-nosyl 3,3-dichloro-beta-lactams and derivatives.

We report herein an efficient and simple route to synthesize 1-nosyl 3,3-dichloro-beta-lactams using a Staudinger reaction between N-nosyl imines and dichloroketene. The resulting dichloroazetidines were opened to afford highly functionalized building blocks.

A straightforward asymmetric synthesis of 1,2-disubstituted ferrocenylalkyl amines with the unusual (S(Fc),S) configuration.

A useful synthesis of rare 1,2-disubstituted ferrocenylalkyl amines with (S(Fc),S) configuration has been achieved in a sequential one-pot methodology from (S)-p-tolylsulfinylferrocene.

Diastereoselective addition of enantiopure lithium tert-butylsulfinylferrocene to imines.

(S)-tert-Butylsulfinylferrocene was submitted to ortho-metalation, and the corresponding lithium derivative was trapped by alkyl or aryl imines bearing various electron-withdrawing groups on the nitrogen atom (Ts, Dpp, Boc). New aminosulfoxides were obtained with complete diastereocontrol when Dpp or Boc groups were used. The absolute configuration (SS,SFc,S) has been determined by single-crystal X-ray analysis and chemical correlation. An unusual pseudocyclic boatlike transition state has been proposed to explain the stereochemical course of this reaction.

ortho-Metalation of enantiopure aromatic sulfoxides and stereocontrolled addition to imines.

Enantiopure aromatic (phenyl, naphthyl) and heteroaromatic (pyridyl, quinolyl, diazinyl) sulfoxides have been synthesized by reaction of (S)-tert-butyl tert-butanethiosulfinate with aryl- or heteroaryllithium derivatives. The ortho-directed metalation of the sulfoxides was performed with lithium bases. Subsequent addition of the lithiated intermediates to N-tosylimines afforded tosylaminoalkyl tert-butylsulfinyl arenes. In most cases a complete asymmetric induction was highlighted in favor of (S,S) isomers. Heating the aminosulfoxides provided an original cyclization to form novel cyclic sulfenamides. A novel enantiopure synthesis of a benzylamine was described. An application of an enantiopure aminosulfoxide as N,S ligand for the asymmetric catalysis of allylic nucleophilic substitution has been successfully tested.

Asymmetric induction of the iodolactonization reaction of alpha-sulfurated gamma-unsaturated amides.

The 1,3-asymmetric iodolactonization reaction of enantiopure alpha-sulfurated gamma-unsaturated amides has been investigated. With sulfinyl and sulfonyl groups, a poorly stereoselective reaction was observed, whereas with a sulfanyl moiety, the diastereoselectivity can be high as 96:4. The role of the oxygen atom on the sulfur moiety is discussed.

First enantioselective synthesis of vinyl oxiranes from aldehydes and ylides generated from allyl halides and chiral sulfides.

Asymmetric allylidenation of aldehydes with sulfur ylides is possible with proper substitution of the initial sulfide, to avoid the [2,3] sigmatropic rearrangement of the unsaturated ylides. One-pot reaction of (2R,5R)-dimethylthiolane with allyl halides, aldehydes, and sodium hydroxide in tert-butyl alcohol affords vinyl oxiranes in good yields. Enantiomeric excesses up to 90% and trans selectivities have been achieved with methallyl-type halides.

First use of axially chiral thioamides for the stereocontrol of C-C bond formation.

Several N-aryl-substituted thioamides with an axis of chirality along the N-C(aryl) bond were prepared in good to excellent yields. NMR spectra revealed preferences for the E rotamer (along the N-C(=S) bond). X-ray crystallographic analysis showed that the planes of the aryl and thioamide groups were almost perpendicular (79 degrees). For the first time, these atropisomeric thioamides were used for an asymmetric Claisen rearrangement. LDA deprotonation led selectively to the enethiolates of Z stereochemistry, and subsequent reaction with a variety of allyl halides furnished S-allyl keteneaminothioacetals. These intermediates were not detected as they rearranged readily to gamma-unsaturated thioamides in good to high yields and diastereoselectivities up to 88:12. Chemical correlation allowed the assignment of the (aR*,2R*) configuration to the major diastereoisomer. A model was proposed to explain the stereochemical course of the thio-Claisen rearrangement.