Synthetic Building Blocks Research Articles

Adventures in the Chemistry of 1,1-Diacylcyclopropanes

AbstractThe present personalized account aims to highlight 1,1-diacylcyclopropanes as synthetic building blocks or target molecules. The chemistry presented includes cyclization reactions of 1,1-diacylcyclopropanes with free and masked dianions to give spirocyclopropanes as products or reactive intermediates that readily undergo ring-cleavage reactions. In addition, the synthesis of cyclopropylated 1,3,5-tricarbonyl compounds, containing two 1,1-diacylcyclopropane moieties, is discussed. Based on this work also other syntheses of cyclopropanes were developed.1 Introduction2 Reactions of Masked Dianions3 Reactions of Free Dianions4 Cyclopropylated 1,3,5-Tricarbonyl Compounds5 Miscellaneous6 Conclusions

Synthesis and Reactivity of an Anti-van't Hoff/Le Bel Compound with a Planar Tetracoordinate Silicon(II) Atom.

For a long time, planar tetracoordinate carbon (ptC) represented an exotic coordination mode in organic and organometallic chemistry, but it is now a useful synthetic building block. In contrast, realization of planar tetracoordinate silicon (ptSi), a heavier analogue of ptC, is still challenging. Herein we report the successful synthesis and unusual reactivity of the first ptSi species of divalent silicon present in 3, supported by the chelating bis(N-heterocyclic silylene)bipyridine ligand, 2,2'-{[(4-tBuPh)C(NtBu)]2SiNMe}2(C5N)2, 1]. The compound resulted from direct reaction of 1 with Idipp-SiI2 [Idipp = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]. Alternatively, it can also be synthesized by a two-electron reduction of the corresponding Si(IV) precursor 2 with 2 molar equiv of KC10H8. Density functional theory calculations show that the lone pair at the ptSi(II) resides almost completely in its 3pz orbital, very different from known four-coordinate silylenes. Oxidative addition of MeI to the ptSi(II) atom affords the corresponding pentacoordinate Si(IV) compound 4, with the methyl group located in an apical position. Remarkably, the reaction of 2 with [CuOtBu] leads to the regeneration of the bis(silylene) arms via Si-Si bond scission and induces the Si(II) → Si(IV) oxidation of the central Si(II) atom and concomitant two-electron reduction of the bipyridine moiety to form the neutral bis(silylene)silyl Cu(I) complex 5.

Amido-ene(amido) Ni(II)-Catalyzed Highly Enantioselective Transfer Hydrogenations of Ketone: Dual Functions of the Ene(amido) Group

Catalytic asymmetric transfer hydrogenation (ATH) reactions of ketones have become an important tool for producing enantiomerically pure alcohols that are widely used in the syntheses of bioactive compounds. However, the high toxicities and low abundances of traditionally employed precious metals serving as catalyst centers have impeded widespread application of precious metal-based catalysts in asymmetric synthesis. Development of catalysts from abundant and less toxic 3d metals is highly desirable but still challenging. We report herein the development of structurally well-defined (R,R)-amido-ene(amido) nickel catalysts for ATH of ketone substrates, facilitating access to a wide range of secondary (S)-configuration alcohols, many of which are synthetic building blocks of biologically relevant molecules, with up to 95% enantiomeric excess (e.e.) and broad scope of functional group tolerance. Catalytic intermediate isolation and density functional theory calculation ascribed the catalytic activity to stabilization of the electron-rich nickel center with the ene(amido) group via a π-backdonation interaction within the catalytic intermediates, while the stereoinduction mainly arises from a catalyst–substrate π–π interaction in the transition state for enantioselective hydride transfer.

Chemically Fueled Dissipative Cross-Linking of Protein Hydrogels Mediated by Protein Unfolding.

Cells assemble dynamic protein-based nanostructures far from equilibrium, such as microtubules, in a process referred to as dissipative assembly. Synthetic analogues have utilized chemical fuels and reaction networks to form transient hydrogels and molecular assemblies from small molecule or synthetic polymer building blocks. Here, we demonstrate dissipative cross-linking of transient protein hydrogels using a redox cycle, which exhibit protein unfolding-dependent lifetimes and mechanical properties. Fast oxidation of cysteine groups on bovine serum albumin by hydrogen peroxide, the chemical fuel, formed transient hydrogels with disulfide bond cross-links that degraded over hours by a slow reductive back reaction. Interestingly, despite increased cross-linking, the hydrogel lifetime decreased as a function of increasing denaturant concentration. Experiments showed that the solvent-accessible cysteine concentration increased with increasing denaturant concentration due to unfolding of secondary structures. The increased cysteine concentration consumed more fuel, which led to less direction oxidation of the reducing agent and affected a shorter hydrogel lifetime. Increased hydrogel stiffness, disulfide cross-linking density, and decreased oxidation of redox-sensitive fluorescent probes at a high denaturant concentration provided evidence supporting the unveiling of additional cysteine cross-linking sites and more rapid consumption of hydrogen peroxide at higher denaturant concentrations. Taken together, the results indicate that the protein secondary structure mediated the transient hydrogel lifetime and mechanical properties by mediating the redox reactions, a feature unique to biomacromolecules that exhibit a higher order structure. While prior works have focused on the effects of the fuel concentration on dissipative assembly of non-biological molecules, this work demonstrates that the protein structure, even in nearly fully denatured proteins, can exert similar control over reaction kinetics, lifetime, and resulting mechanical properties of transient hydrogels.

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures.

This review covers the synthetic applications of 1,4-dithianes, as well as derivatives thereof at various oxidation states. The selected examples show how the specific heterocyclic reactivity can be harnessed for the controlled synthesis of carbon-carbon bonds. The reactivity is compared to and put into context with more common synthetic building blocks, such as 1,3-dithianes and (hetero)aromatic building blocks. 1,4-Dithianes have as yet not been investigated to the same extent as their well-known 1,3-dithiane counterparts, but they do offer attractive transformations that can find good use in the assembly of a wide array of complex molecular architectures, ranging from lipids and carbohydrates to various carbocyclic scaffolds. This versatility arises from the possibility to chemoselectively cleave or reduce the sulfur-heterocycle to reveal a versatile C2-synthon.

Ir-Catalyzed Regioselective Dihydroboration of Thioalkynes toward Gem-Diboryl Thioethers.

While 1,1-diboryl (gem-diboryl) compounds are valuable synthetic building blocks, currently, related studies have mainly focused on those 1,1-diboryl alkanes without a hetero functional group in the α-position. gem-Diboryl compounds with an α-hetero substituent, though highly versatile, have been limitedly accessible and thus rarely utilized. Herein, we have developed the first α-dihydroboration of heteroalkynes leading to the efficient construction of gem-diboryl, hetero-, and tetra-substituted carbon centers. This straightforward, practical, mild, and atom-economic reaction is an attractive complement to the conventional multistep synthetic strategy relying on deprotonation of gem-diborylmethane by a strong base. Specifically, [Ir(cod)(OMe)]2 was found to be uniquely effective for this process of thioalkynes, leading to excellent α-regioselectivity when delivering the two boryl groups, which is remarkable in view of the many competitive paths including monohydroboration, 1,2-dihydroboration, dehydrodiboration, triboration, tetraboration, etc. Control experiments combined with DFT calculations suggested that this process involves two sequential hydroboration events. The second hydroboration requires a higher energy barrier due to severe steric repulsion in generating the highly congested α-sulfenyl gem-diboryl carbon center, a structural motif that was almost unknown before.

Self-assembly of achiral building blocks into chiral cyclophanes using non-directional interactions.

The diastereoselective assembly of achiral constituents through a single spontaneous process into complex covalent architectures bearing multiple stereogenic elements still remains a challenge for synthetic chemists. Here, we show that such an extreme level of control can be achieved by implementing stereo-electronic information on synthetic organic building blocks and templates and that non-directional interactions (i.e., electrostatic and steric interactions) can transfer this information to deliver, after self-assembly, high-molecular weight macrocyclic species carrying up to 16 stereogenic elements. Beyond the field of supramolecular chemistry, this proof of concept should stimulate the on-demand production of highly structured polyfunctional architectures.

Chloroacetyl boronate N-tosylhydrazone as a versatile synthetic building block.

Chloroacetyl boronate N-tosylhydrazone (CABT) has been synthesized as a reagent to generate a diverse range of molecular skeletons. CABT can undergo a series of transformations involving nucleophilic substitution of the chloride and coupling of the N-tosylhydrazones, followed by boryl group functionalization. We further demonstrated that this CABT reagent could enable a diversity-oriented synthesis.

Diversity-oriented synthesis of cyclohexenes by combining enzymatic intermolecular Diels-Alder reactions and decarboxylative functionalizations

Substituted cyclohexanes are common scaffolds found in both natural products and drug molecules. Diels-Alderases that can efficiently catalyze intermolecular Diels-Alder reactions to generate cyclohexene ring systems have received considerable interest. However, the synthetic power of Diels-Alderases is incomparable with chemo-catalysts due to their limited substrate scopes. Here, we report a new chemo-enzymatic strategy for the diversity-oriented syntheses of functionalized cyclohexenes. We first applied focused rational iterative site-specific mutagenesis to generate a natural Diels-Alderase variant M3, which shows a 34-fold increase in catalytic efficiency, broad substrate scope, and good to perfect stereoselectivity. Then, we used diverse transition-metal-catalyzed decarboxylative coupling reactions to functionalize the enzymatic Diels-Alder products. This work offers an efficient synthetic route to structurally diverse cyclohexenes that are not accessible by solely using biocatalysis or chemo-catalysis and illustrates how chemo-catalysis can cooperate with biocatalysis to expand the synthetic application of biocatalysts. • Rapid engineering of the intermolecular Diels-Alderase has expanded its substrate scope • A new chemo-enzymatic strategy for the synthesis of cyclohexenes has been developed • Many structurally diverse cyclohexenes have been efficiently prepared Selectivity and structural diversity are the two important factors chemists need to manipulate precisely in their synthetic designs. Despite their exceptionally high chemo-, regio-, and stereoselectivity, biocatalysts are typically featured with limitations in both substrate scope and reaction types, which, on the contrary, are the innate advantages of chemo-catalysts. Thus, combining biocatalysis and chemo-catalysis is one of the most promising ways to overcome the synthetic challenges in the efficient synthesis of structurally complex and diverse molecules. To enhance the synthetic power of the intermolecular Diels-Alderase, protein engineering was performed to increase the catalytic efficiency toward dienophiles containing an ester group as a functional handle. After enzymatic transformation, the optically pure Diels-Alder (D-A) products were further functionalized by several decarboxylative cross-coupling reactions, thus rapidly generating a panel of structurally diverse cyclohexene scaffolds. Wang et al. describe a new chemo-enzymatic strategy toward the diversity-orientated synthesis of enantiopure cyclohexenes. This strategy features an intermolecular Diels-Alder reaction catalyzed by an engineered Diels-Alderase followed by various transition-metal-catalyzed decarboxylative functionalizations. Both stereoselectivity and structural diversity have been achieved by this chemo-enzymatic strategy, enabling efficient access to useful synthetic building blocks, natural products, and privileged structures for drug discovery that are difficult to be obtained by solely using biocatalyst or chemo-catalyst.

Colloidosomes as a Protocell Model: Engineering Life‐Like Behaviour through Organic Chemistry

AbstractThe bottom‐up synthesis of self‐assembled micro‐compartmentalised systems that mimic basic characteristics of living cells is rapidly evolving. These types of systems are termed “protocells” and can be chemically programmed to grow and divide, to send and receive chemical signals, to transcript and translate chemical information, to adhere to surfaces or to other protocells, and to perform rudimental enzyme‐mediated metabolic processes. An emerging protocell model that is attracting great attention is the colloidosome. Colloidosomes are microcapsules with a chemically crosslinked, semipermeable membrane composed of amphiphilic nanoparticles. Colloidosomes display important advantages over other protocell models (e. g., vesicles and coacervate micro‐droplets) due to their physical‐chemical properties that can be easily tuned through the careful engineering of their synthetic building blocks. In this review, we deliver an overview of the different types of colloidosomes that have been developed thus far and discuss how organic chemistry contributes to the design and bottom‐up synthesis of novel types of colloidosomes endowed with advanced chemically programmed bio‐inspired functions.

Access to Enantiomerically Pure P-Stereogenic Primary Aminophosphine Sulfides under Reductive Conditions.

Stereochemically pure phosphines with phosphorus-heteroatom bonds and P-centered chirality are a promising class of functional building blocks for the design of chiral ligands and organocatalysts. A route to enantiomerically pure primary aminophosphine sulfides was opened through stereospecific reductive C-N bond cleavage of phosphorus(V) precursors by lithium in liquid ammonia. The chemoselectivity of the reaction as a function of reaction time, substrate pattern, and chiral auxiliary was investigated. In the presence of exclusively aliphatic groups bound to the phosphorus atom, all competing reductive side reactions are totally prevented. The absolute configurations of all P-stereogenic compounds were determined by single-crystal X-ray diffraction analysis. Their use as synthetic building blocks was demonstrated. The lithium salt of (R)-BINOL-dithiophosphoric acid proved to be a useful stereochemical probe to determine the enantiomeric purity. Insights into the coordination mode of the lithium-based chiral complex formed in solution was provided by NMR spectroscopy and DFT calculations.

Preparation of 2,3-Dibromo-1H-indenes and Tetrabromodihydro-s-indacenes as Synthetic Building Blocks.

The acid-induced intramolecular cyclization of 1,1-disubstituted 3-aryl-2,3-dibromoallylalcohols affords 2,3-dibromo-1H-indene derivatives. This method is also applicable to the preparation of tetrabromodihydro-s-indacenes. The thus obtained multi-brominated compounds can serve as versatile synthetic building blocks to obtain a variety of indene and indacene derivatives, as demonstrated by the synthesis of dialkylmethylene-bridged oligo(phenylenevinylene)s, which feature attractive photophysical properties.

3,4-Bis-O-propargyl-1,2:5,6-di-O-isopropylidene-D-mannitol: a study of multiple weak hydrogen bonds in the solid state.

The title homochiral compound, C18H26O6, 1, was examined by single-crystal X-ray crystallography in order to understand its potential as a synthetic building block, particularly in inter- and intramolecular cyclocondensation reactions. It has also proven to be an excellent model for understanding multiple weak donor-acceptor D-H...A interactions involving terminal acetylenes as donors and as acceptors. The asymmetric unit of 1 comprises three almost identical independent molecules, each with the mannitol 2R,3R,4R,5R configuration and different conformations. Like independent molecules align in strands through acetylenic donor C-H...O contacts with equivalent dioxolanyl acceptor groups. Two of the strands are aligned unidirectionally, in parallel, while the third strand aligns perpendicular to the first two, to give interwoven layers in the supramolecular structure. A detailed study of the interdigitation of the second propargyl group from each independent molecule between strands, and of other short interstrand C-H...O contacts, provides new insight into the application of weak hydrogen-bond theory within the context of a conformationally flexible symmetrical molecule. Analyses of the Cambridge Structural Database using Crystal Packing Features and ConQuest search motifs support the importance of the D...A distance parameter, demonstrate the different influences of donor and acceptor types, and reveal the interplay between H...A and D...A contributions in different contact types.

Dendrimersome Synthetic Cells Harbor Cell Division Machinery of Bacteria.

The integration of active cell machinery with synthetic building blocks is the bridge toward developing synthetic cells with biological functions and beyond. Self-replication is one of the most important tasks of living systems, and various complex machineries exist to execute it. In Escherichia coli, a contractile division ring is positioned to mid-cell by concentration oscillations of self-organizing proteins (MinCDE), where it severs membrane and cell wall. So far, the reconstitution of any cell division machinery has exclusively been tied to liposomes. Here, the reconstitution of a rudimentary bacterial divisome in fully synthetic bicomponent dendrimersomes is shown. By tuning the membrane composition, the interaction of biological machinery with synthetic membranes can be tailored to reproduce its dynamic behavior. This constitutes an important breakthrough in the assembly of synthetic cells with biological elements, as tuning of membrane-divisome interactions is the key to engineering emergent biological behavior from the bottom-up.

Medial packing and elastic asymmetry stabilize the double-gyroid in block copolymers

Triply-periodic networks are among the most complex and functionally valuable self-assembled morphologies, yet they form in nearly every class of biological and synthetic soft matter building blocks. In contrast to simpler assembly motifs – spheres, cylinders, layers – networks require molecules to occupy variable local environments, confounding attempts to understand their formation. Here, we examine the double-gyroid network phase by using a geometric formulation of the strong stretching theory of block copolymer melts, a prototypical soft self-assembly system. The theory establishes the direct link between molecular packing, assembly thermodynamics and the medial map, a generic measure of the geometric center of complex shapes. We show that “medial packing” is essential for stability of double-gyroid in strongly-segregated melts, reconciling a long-standing contradiction between infinite- and finite-segregation theories. Additionally, we find a previously unrecognized non-monotonic dependence of network stability on the relative entropic elastic stiffness of matrix-forming to tubular-network forming blocks. The composition window of stable double-gyroid widens for both large and small elastic asymmetry, contradicting intuitive notions that packing frustration is localized to the tubular domains. This study demonstrates the utility of optimized medial tessellations for understanding soft-molecular assembly and packing frustration via an approach that is readily generalizable far beyond gyroids in neat block copolymers.

Enhanced Molecular Recognition through Substrate–Additive Complex Formation in N-Heterocyclic-Carbene-Catalyzed Kinetic Resolution of α-Hydroxythioamides

We describe a new way of understanding enhanced molecular recognition through substrate–additive complex formation and the development of the first catalytic kinetic resolution of α-hydroxythioamides, which are versatile synthetic building blocks, using chiral N-heterocyclic carbene-catalyzed enantioselective acylation assisted by a carboxylate additive. Mass spectrometry provided evidence for the role of the additive, which forms a hydrogen-bonded complex with α-hydroxythioamide, resulting in both rate and selectivity enhancements. The synthetic applications of the resolved α-hydroxythioamides highlight the usefulness of the developed method.

Electrochemical Sulfoxidation of Thiols and Alkyl Halides.

Sulfoxides are actively engaged as versatile synthetic building blocks, chiral ligands, bioactive molecules, and function materials. However, their oxidative syntheses from thioethers are inevitably impeded by overoxidation, excess oxidants, and the tedious preparation of thioethers. To address these shortcomings, we report herein a highly selective electrochemical sulfoxidation reaction featuring the use of simple starting materials, i.e., thiols and alkyl halides, in a single operation.

Catalytic Asymmetric Chlorination of Isoxazolinones

AbstractOrganic compounds featuring a chlorine substituted stereocenter are frequently found in nature and are interesting for pharmaceutical applications and as synthetic building blocks. Catalytic methods to generate such stereocenters by C,H bond functionalization are still relatively rare. Here we report the first catalytic asymmetric chlorination of isoxazolinones, a synthetically and biologically interesting class of heterocycles, which can be considered as precursors for β‐aminoacids. The title reaction was catalyzed with high enantioselectivity by a planar chiral ferrocene based palladacycle in high to excellent yields. It is showcased that the products are valuable for post‐synthetic transformations. An SN2 reaction proceeded with smooth inversion of the absolute configuration. The substitution product could then be transformed into an α‐azido β‐aminoacid derivative via a reductive, diastereoselective ring opening.

Assembly of Bioactive Nanoparticles via Metal–Phenolic Complexation

The integration of bioactive materials (e.g., proteins and genes) into nanoparticles holds promise in fields ranging from catalysis to biomedicine. However, it is challenging to develop a simple and broadly applicable nanoparticle platform that can readily incorporate distinct biomacromolecules without affecting their intrinsic activity. Herein, a metal-phenolic assembly approach is presented whereby diverse functional nanoparticles can be readily assembled in water by combining various synthetic and natural building blocks, including poly(ethylene glycol), phenolic ligands, metal ions, and bioactive macromolecules. The assembly process is primarily mediated by metal-phenolic complexes through coordination and hydrophobic interactions, which yields uniform and spherical nanoparticles (mostly <200nm),while preserving the function of the incorporated biomacromolecules (siRNA and five different proteins used). The functionality of the assembled nanoparticles is demonstrated through cancer cell apoptosis, RNA degradation, catalysis, and gene downregulation studies. Furthermore, the resulting nanoparticles can be used as building blocks for the secondary engineering of superstructures via templating and cross-linking with metal ions. The bioactivity and versatility of the platform can potentially be used for the streamlined and rational design of future bioactive materials.

Synthesis and Use of Bicyclo[1.1.1]pentylaldehyde Building Blocks.

The bicyclo[1.1.1]pentane (BCP) motif is an emerging scaffold in medicinal chemistry because of its bioisosterism to 1,4-phenylene and 1,2-alkynyl functions. The current drawback of its use is the lack of stable versatile synthetic building blocks. Aldehydes are among the most useful functionalities in organic chemistry. In this paper, a simple one-pot procedure from aryl-halides and [1.1.1]propellane is described. Preparation of various BCP molecules is conducted to showcase the versatility of these stable intermediates.