3,3-Difluorooxetane - A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery.

Functional group (FG) is one of the cornerstone concepts in organic chemistry and related areas. The wide spread of bioisosterism ideas in medicinal chemistry and beyond caused a striking rise in demand for novel FGs with a defined impact on the developed compound properties. In this work, the evaluation of the 3,3-difluorooxetane unit (3,3-diFox) as a functional group for bioisosteric replacements is disclosed. A comprehensive experimental study (including multigram building block synthesis, quantification of steric and electronic properties, measurements of pKa, LogP, chemical stability, and biological evaluation of the 3,3-diFox-derived bioisostere of a drug candidate) revealed a prominent behavior of the 3,3-diFox fragment as a versatile substituent for early drug discovery programs.

Identification of readily available pseudo-natural products.

Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synthesis programs. We employed an improved version of the previously reported natural product fragment combination (NPFC) tool to analyze the full library of 3.5 M synthetic small molecules and screening libraries from Enamine for PNP content, assessed the spatial complexity of Enamine-PNPs using the recently developed normalized spatial score (nSPS) and evaluated the bioactivity of a selected subset of Enamine-PNPs in the unbiased morphological cell painting assay. A major fraction (32%; 1.1 million compounds) of the Enamine library are PNPs which contain a significant number of compounds with unexpected and probably new bioactivity.

Parallel Minisci Reaction of gem-Difluorocycloalkyl Building Blocks.

Parallel Minisci reactions of nonfluorinated and gem-difluorinated C4-C7 cycloalkyl building blocks (trifluoroborates and carboxylic acids) with a series of electron-deficient heterocycles were studied. A comparison of the reaction's outcome revealed better product yields in the case of carboxylic acids as the radical precursors in most cases, albeit these reagents were used with three-fold excess under optimized conditions. The nature of the heterocyclic core was found to be important for successful incorporation of the cycloalkyl fragment. The impact of the CF2 moiety on the oxidation potential of fluorinated cycloalkyl trifluoroborates and the reaction outcome, in general, was also evaluated.

Generation of multimillion chemical space based on the parallel Groebke-Blackburn-Bienaymé reaction.

Parallel Groebke-Blackburn-Bienaymé reaction was evaluated as a source of multimillion chemically accessible chemical space. Two most popular classical protocols involving the use of Sc(OTf)3 and TsOH as the catalysts were tested on a broad substrate scope, and prevalence of the first method was clearly demonstrated. Furthermore, the scope and limitations of the procedure were established. A model 790-member library was obtained with 85% synthesis success rate. These results were used to generate a 271-Mln. readily accessible (REAL) heterocyclic chemical space mostly containing unique chemotypes, which was confirmed by comparative analysis with commercially available compound collections. Meanwhile, this chemical space contained 432 compounds that already showed biological activity according to the ChEMBL database.

3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.

SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that SNAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the SNAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control. Further sulfur-fluoride exchange (SuFEx) is also possible, which can be especially valuable for some sulfonyl halide classes. The developed two-step parallel double amination protocol provides access to a 6.67-billion compound synthetically tractable REAL-type chemical space (76% expected synthesis success rate).

(Diazomethyl)dimethylphosphine Oxide - A Diazoalkane Reagent for [3+2] Cycloadditions.

A safe and efficient method for the in-situ preparation of (diazomethyl)dimethylphosphine oxide - a hereto unexplored diazoalkane reagent - is developed. The method is based on the diazotization of the corresponding P(O)Me2-substituted amine (readily available in multigram quantities) in non-aqueous media. The protocol provides the target product as ca. 1.5 M CHCl3 solution which is stable at -18 °C. The utility of the synthesized diazoalkane is illustrated by its [3+2] cycloaddition with electron-poor alkynes and alkenes providing the corresponding P(O)Me2-substituted pyrazoles and pyrazolines with moderate to good efficiency. In this view, the title compound represents and an important extension of medicinally relevant phosphine oxide reagents.

Organocatalytic Decarboxylative Borylation of Cyclopropane N-Hydroxyphthalimide Esters.

A convenient protocol for the two-step organocatalytic decarboxylative borylation of 1,1-disubstituted, 1,2-disubstituted, and bicyclic cyclopropane carboxylic acids via the corresponding N-hydroxyphthalimide esters is described, using tert-butyl or ethyl isonicotinate as an inexpensive and readily available catalyst. The scope of the method was demonstrated, being limited mainly by electron-poor substrates. The reaction sequence showed good scalability (up to 51.5 g) and excellent trans diastereoselectivity (for the case of 1,2-disubstituted substrates). Therefore, the proposed approach is a very promising alternative to other existing (i.e., metal-catalyzed) methods for borodecarboxylation.

Chemistry in Ukraine.

In this special issue, we highlight recent advances in chemical research by scientists in Ukraine, as well as by their compatriots and collaborators outside the country. Besides spotlighting their contributions, we see our task in fostering global partnerships and multi-, inter-, and trans-disciplinary collaborations, including much-needed co-funded projects and initiatives. The three decades of the renewed Ukraine independence have seen rather limited integration of Ukrainian (chemical) science into global research communities.[1] At the same time, the recent surge of collaborative science initiatives between European Union (EU) and Ukraine echoes the unfolding steps towards Ukraine's full research participation to the Horizon Europe Program. This recently implemented step opens enormous possibilities for Ukrainian researchers to apply for diverse EU research grants. Moreover, a number of journal special issues and collections were launched to highlight Ukrainian chemistry (i. e., by Chemistry of Heterocyclic Compounds[2] and ChemistrySelect[3] ). Other scientific initiatives include 'European Chemistry School for Ukrainians'[4] and 'Kharkiv Chemical Seminar'[5] as voluntary projects aimed at engaging Ukrainian scientists into European and international chemical research.

[3+2] Cycloaddition of Alkynyl Boronates and in†situ Generated Azomethine Ylide.

Scalable [3+2] cycloaddition of alkynyl boronates and in situ generated unstabilized azomethine ylide is reported for the first time. The selective formation of either 1 : 1 or 1 : 2 cycloaddition products was achieved by carefully optimizing the reaction conditions, mainly by controlling the reactant stoichiometry, catalyst loading, and internal temperature. The developed protocol tolerated many valuable functional groups, including TMS, protected alcohol (as ether or THP derivatives), or aldehyde (as acetal). Further common C-C and C-heteroatom bond-forming reactions, as well as scaled-up procedures demonstrate the utility of the prepared compounds as building blocks for organic synthesis and drug discovery.

Insights into Modeling Approaches in Chemistry: Assessing Ligand-Protein Binding Thermodynamics Based on Rigid-Flexible Model Molecules.

In the field of chemistry, model compounds find extensive use for investigating complex objects. One prime example of such object is the protein-ligand supramolecular interaction. Prediction the enthalpic and entropic contribution to the free energy associated with this process, as well as the structural and dynamic characteristics of protein-ligand complexes poses considerable challenges. This review exemplifies modeling approaches used to study protein-ligand binding (PLB) thermodynamics by employing pairs of conformationally constrained/flexible model molecules. Strategically designing the model molecules can reduce the number of variables that influence thermodynamic parameters. This enables scientists to gain deeper insights into the enthalpy and entropy of PLB, which is relevant for medicinal chemistry and drug design. The model studies reviewed here demonstrate that rigidifying ligands may induce compensating changes in the enthalpy and entropy of binding. Some "rules of thumb" have started to emerge on how to minimize entropy-enthalpy compensation and design efficient rigidified or flexible ligands.

Bypassing Sulfonyl Halides: Synthesis of Sulfonamides from Other Sulfur-Containing Building Blocks.

This review disclosed synthetic approaches to sulfonyl amides from non-sulfonyl halogenated precursors. Known methods were systematized into groups and subgroups according to the type of starting organosulfur compound. Thiols, disulfides, and sulfonamides form a group of S(II)-containing precursors, which are used in oxidative amination reactions. An important and versatile group for oxidative amination is represented with S(IV)-containing compounds, i. e., sufinates, sulfinamides, DMSO, N-sulfinyl-O-(tert-butyl)hydroxylamine, etc. A series of S(VI)-containing precursors for amination reactions (except sulfonyl halides) include sulfonic acids, sulfonyl azides, thiosulfonates, and sulfones. All approaches are represented with the most prominent examples of the resulting sulfonamides, which could be obtained in high yields mostly via short reaction sequences. Promising electrochemical methods for the preparation of sulfonamides from thiols, disulfides, sulfonamides, sulfinic acid derivatives, and dimethyl sulfoxide under mild and green conditions are also highlighted.

Chemoselective Reactions of Functionalized Sulfonyl Halides.

Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2 F group - from amide and ester formation to directed ortho-lithiation and transition-metal-catalyzed cross-couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of "another click reaction". On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2 Cl moiety.

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization.

Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.

Photochemical [2+2] Cycloaddition of Alkynyl Boronates.

A photochemical [2+2] cycloaddition of alkynyl boronates and maleimides is reported. The developed protocol provided 35-70 % yield of maleimide-derived cyclobutenyl boronates and demonstrated wide compatibility with various functional groups. The synthetic utility of the prepared building blocks was demonstrated for a range of transformations, including Suzuki cross-coupling, catalytic or metal-hydride reduction, oxidation, and cycloaddition reactions. With aryl-substituted alkynyl boronates, the products of double [2+2] cycloaddition were obtained predominantly. Using the developed protocol, a cyclobutene-derived analogue of Thalidomide was prepared in one step. Mechanistic studies supported the participation of the triplet-excited state maleimides and ground state alkynyl boronates in the key step of the process.

Mono- and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties.

A comprehensive study of physicochemical properties (pKa , LogP, and intrinsic microsomal clearance) within the series of mono- and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both pKa and LogP values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of "Janus face" (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis-3,5-difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3-difluoroazetidine derivative). According to pKa - LogP plots, the title compounds provide a valuable extension of the fluorine-containing (e. g., fluoroalkyl-substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes.

An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH2/NHBoc, OH, SH, or SO2F groups attached to the carbocycle either directly or via a CH2 unit) relying on the divergent strategy is described. This class of compounds provides sp3-enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis- and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer-Pople puckering parameters and exit vector (EVP) plots.

Screening of Palladium/Charcoal Catalysts for Hydrogenation of Diene Carboxylates with Isolated-Rings (Hetero)aliphatic Scaffold.

A series of seven palladium-containing composites, i.e., four Pd/C and three Pd(OH)2/C (Pearlman's catalysts), was prepared using modified common approaches to deposition of Pd or hydrated PdO on charcoal. All the composites were tested in the catalytic hydrogenation of diene carboxylates with the isolated-ring scaffold, e.g., 5,6-dihydropyridine-1(2H)-carboxylates with 2-(alkoxycarbonyl)cyclopent-1-en-1-yl and hex-1-en-1-yl substituents at the C(4)-position. The performance of the composites was also studied via the hydrogenation of quinoline as a model reaction. The composites were characterized by transmission and scanning electron microscopy (TEM and SEM), powder X-ray diffraction, and low-temperature N2 adsorption. It was found that the composites containing Pd nanoparticles (NPs) of 5-40 nm size were the most efficient catalysts for the hydrogenation of dienes, providing the reduced products with up to 90% yields at p(H2) = 100 atm, T = 30 °C for 24 h. The method of Pd NPs formation had more effect on the catalyst performance than the size of the NPs. The catalytic performance of Pearlman's catalysts (Pd(OH)2/C) in the hydrogenation of dienes was comparable to or lower than the performance of the Pd/C systems, though the Pearlman's catalysts were more efficient in the hydrogenation of quinoline.

C-C Coupling through Nitrogen Deletion: Application to Library Synthesis.

Invited for the cover of this issue are Oleksandr Grygorenko and his Ukrainian colleagues at Enamine Ltd., Taras Shevchenko National University of Kyiv, National Academy of Sciences of Ukraine, and ChemSpace, as well as Mark Levin at the University of Chicago. The image depicts application of a nitrogen-deleting anomeric amide to parallel C(sp3 )-C(sp3 ) coupling. Read the full text of the article at 10.1002/chem.202203470.