Organometallic Bridge Diversification of Bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1-electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron "late stage" approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched "chiral-at-BCP" bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.

Ficini Reaction with Acrylates for the Stereoselective Synthesis of Aminocyclobutanes.

The first Ficini reaction between ynamides and acrylates is reported herein. The reaction is catalyzed by B(C6F5)3 acting as a Lewis acid and is giving access to stable tri-substituted aminocyclobutenes in high yield. The resulting products can be hydrogenated and epimerized under basic conditions or in presence of a Lewis acid, providing two distinct trans- aminocyclobutane monoester stereoisomers in high yield and diastereoisomeric ratio (up to quantitative yield and >99:1 dr).

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Rapid and Scalable Halosulfonylation of Strain-Release Reagents.

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non-classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one-pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl-substituted bioisosteres and cyclobutanes, on up to multidecagram scale.

α-Lactam Electrophiles for Covalent Chemical Biology.

Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α-lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo- and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α-lactam-based electrophilic probes in covalent chemical biology.

Transformations of Strained Three-Membered Rings a Common, Yet Overlooked, Motif in Heavy-Atom Tunneling Reactions.

Quantum mechanical tunneling has long been recognized as an important phenomenon when considering transformations dominated by a lightweight hydrogen atom. Tunneling of heavier atoms like carbon, initially dismissed as negligible, has seen a quickly increasing number of computationally predicted and/or experimentally confirmed examples over the last decade, thus highlighting its importance for a wide variety of reactions. However, no common structural motif has been pointed out within these seemingly unconnected examples, strongly limiting the predictability of the impact of heavy-atom tunneling on a given reaction. This Concept article will provide this perspective and showcase how the recognition of the formation and cleavage of three-membered rings as common motif can inform the prediction of and research into heavy-atom tunneling reactions.

New antiproliferative agents derived from tricyclic 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine scaffold: Synthesis and pharmacological effects.

A series of novel 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine (BIT) derivatives were designed and synthesized. In vitro antiproliferative activity was detected toward two human colorectal adenocarcinoma cell lines (CaCo-2 and HT-29) and one human dermal microvascular endothelial cell line (HMVEC-d). The most active compounds, namely 2-4 and 8, were further investigated to clarify the mechanism behind their biological activity. Through immunofluorescence assay, we identified the target of these molecules to be the microtubule cytoskeleton with subsequent formation of dense microtubule accumulation, particularly at the periphery of the cancer cells, as observed in paclitaxel-treated cells. Overall, these results highlight BIT derivatives as robust and feasible candidates deserving to be further developed in the search for novel potent antiproliferative microtubule-targeting agents.

Ultrafast Photo-ion Probing of the Ring-Opening Process in Trans-Stilbene Oxide.

The ultrafast photo-induced ring opening of the oxirane derivative trans-stilbene oxide has been studied through the use of ultrafast UV/UV pump-probe spectroscopy by using photo-ion detection. Single- and multiphoton probe paths and final states were identified through comparisons between UV power studies and synchrotron-based vacuum ultraviolet (VUV) single-photon ionization studies. Three major time-dependent features of the parent ion (sub-450 fs decay, (1.5±0.2) ps, and >100 ps) were observed. These decays are discussed in conjunction with the primary ring-opening mechanism of stilbene oxide, which occurs through C-C dissociation in the oxirane ring. The appearance of fragments relating to the masses of dehydrogenated diphenylmethane (167 amu) and dehydrogenated methylbenzene (90 amu) were also investigated. The appearance of the 167 amu fragment could suggest an alternative ultrafast ring-opening pathway via the dissociation of one of the C-O bonds within the oxirane ring.

Ladderane Natural Products: From the Ground Up.

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.

Synthesis of ß-Lactams and ß-Homoprolines by Fragmentative Rearrangement of 5-Spirocyclopropaneisoxazolidines Mediated by Acids.

Azetidinones and ß-amino acids serve as useful building blocks in synthetic organic chemistry and their structural motifs are often found in biologically active compounds. Due to the importance of these compounds, several synthetic strategies have been developed and availability of new synthetic approaches is highly desirable. In this account, we describe the development of an original method that allows the preparation of ß-lactam and ß-homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a ß-lactam by heating a mixture of an alkylidenecyclopropane tethered to a formyl group with N-methylhydroxylamine hydrochloride. Investigation of the process resulted in disclosing an alternative synthetic method of azetidinones based on an acid induced fragmentative rearrangement of cycloadducts of nitrones with suitable methylenecyclopropane derivatives. Herein, the scope of this process is reviewed. In addition, both experimental and computational studies of the mechanism for this peculiar fragmentative rearrangement are presented.

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives.

"Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well-documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.

Cyclo-Dipnictadialanes.

Using the AlI precursor Cp3t Al in conjunction with triphosphiranes (PAr)3 (Ar=Mes, Dip, Tip) we have succeeded in preparing Lewis base-free cyclic diphosphadialanes with both the Al and P atoms bearing three substituents. Using the sterically more demanding Dip and Tip substituents the first 1,2-diphospha-3,4-dialuminacyclobutanes were obtained, whereas with Mes substituents [Cp3t Al(µ-PMes)]2 is formed. This divergent reactivity was corroborated by DFT studies, which indicated the thermodynamic preference for the 1,2-diphospha-3,4-dialuminacyclobutane form for sterically more demanding groups on phosphorus. Using Cp*Al we could extend this concept to the corresponding cyclic diarsadialanes [Cp*Al(µ-AsAr)]2 (Ar=Dip, Tip) and additionally add the phosphorus variants [Cp*Al(µ-PAr)]2 (P=Mes, Dip, Tip). The reactivity of one variant [Cp3t Al(µ-PPh)]2 towards NHCs was tested and resulted in double NHC-stabilised [Cp3t (IiPr2 )Al(µ-PPh)]2 .

Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1-Methylimidazolium Thiocyanate.

We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Brønsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate-based protic ionic liquids for the ring-opening of donor-acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time-efficient step. The ability of 1-methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane, epoxide ring-opening and other organic transformations.

Engineering Crystals Using sp3 -C Centred Tetrel Bonding Interactions.

1,1,2,2-Tetracyanocyclopropane derivatives 1 and 2 were designed and synthesized to probe the utility of sp3 -C centred tetrel bonding interactions in crystal engineering. The crystal packing of 1 and 2 and their 1,4-dioxane cocrystals is dominated by sp3 -C(CN)2 ⋅⋅⋅O interactions, has significant C⋅⋅⋅O van der Waals overlap (≤0.266 Å) and DFT calculations indicate interaction energies of up to -11.0 kcal mol-1 . A cocrystal of 2 with 1,4-thioxane reveals that the cyclopropane synthon prefers interacting with O over S. Computational analyses revealed that the electropositive C2 (CN)4 pocket in 1 and 2 can be seen as a strongly directional 'tetrel-bond donor', similar to halogen bond or hydrogen bond donors. This disclosure is expected to have implications for the utility of such 'tetrel bond donors' in molecular disciplines such as crystal engineering, supramolecular chemistry, molecular recognition and medicinal chemistry.

Silylium-Ion-Promoted (5+1) Cycloaddition of Aryl-Substituted Vinylcyclopropanes and Hydrosilanes Involving Aryl Migration.

A transition-metal-free (5+1) cycloaddition of aryl-substituted vinylcyclopropanes (VCPs) and hydrosilanes to afford silacyclohexanes is reported. Catalytic amounts of the trityl cation initiate the reaction by hydride abstraction from the hydrosilane, and further progress of the reaction is maintained by self-regeneration of the silylium ions. The new reaction involves a [1,2] migration of an aryl group, eventually furnishing 4- rather than 3-aryl-substituted silacyclohexane derivatives as major products. Various control experiments and quantum-chemical calculations support a mechanistic picture where a silylium ion intramolecularly stabilized by a cyclopropane ring can either undergo a kinetically favored concerted [1,2] aryl migration/ring expansion or engage in a cyclopropane-to-cyclopropane rearrangement.

N-Heterocyclic Carbene Stabilized Dicarbondiphosphides: Strong Neutral Four-Membered Heterocyclic 6π-Electron Donors.

In contrast to cyclic π-conjugated hydrocarbons, the coordination chemistry of inorganic heterocycles is less developed. Dicarbondiphosphides stabilized by N-heterocyclic carbenes (NHCs) NHC→C2 P2 ←NHC (1 a,b) (NHC=IPr or SIPr) contain a four-membered C2 P2 ring with an aromatic 6π-electron configuration. These heterocycles coordinate to a variety of complex fragments with metals from groups 6, 9, and 10, namely [M0 (CO)3 ] (M=Cr, Mo), [CoI (CO)2 ]+ , or [NiII Br2 ], through an η4 -coordination mode, leading to complexes 2 a,b, 3 a,b, 5 a,b, and 6 a,b, respectively. These complexes were characterized by X-ray diffraction methods using single crystals, IR spectroscopy, and DFT calculations. In combination these methods indicate that 1 a,b behave as exceptionally strong 6π-electron donors.

A Flexible Method for Covalent Double Functionalization of Graphene Oxide.

A method for the double functionalization of graphene oxide (GO) under mild alkaline conditions has been developed. Two functional groups were covalently linked to GO in two steps: the first group was attached by an epoxide ring-opening reaction and the second, bearing an amine function, was covalently conjugated to benzoquinone attached to the GO. The doubly functionalized GO was characterized by several techniques, confirming the sequential covalent modification of the GO surface with two different functional groups. This method is straightforward and the reaction conditions are mild, allowing preservation of the structure and properties of GO. This strategy could be exploited to prepare multifunctional GO conjugates with potential applications in many fields ranging from materials science to biomedicine.

Silaboration of [1.1.1]Propellane: A Storable Feedstock for Bicyclo[1.1.1]pentane Derivatives.

The silaboration of [1.1.1]propellane enables direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive-free conditions. The silaborated BCP can be obtained on a gram-scale in a single step without the need for column-chromatographic purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives. We also describe various conversions of the C-B/C-Si bonds on the BCP scaffold, including development of a modified Suzuki-Miyaura cross-coupling reaction at the highly sterically hindered bridgehead sp3 carbon center of the BCP skeleton using a combination of highly activated BCP boronic esters, copper(I) oxide, and a PdCl2 (dppf) catalyst system.

Convenient Access to 2,3-Disubstituted-cyclobut-2-en-1-ones under Suzuki Conditions and Their Synthetic Utility.

A regioselective synthesis of general applicability has been designed for the one-pot preparation of 2,3-disubstituted-cyclobutenones from iodoalkynes through cyclobutenylation, Suzuki CC coupling, and ketone formation. This one-pot methodology has been applied to the selective synthesis of an orally active cyclooxygenase II inhibitor. Furthermore, the obtained cyclobut-2-en-1-ones were used as synthons in several transformations, such as, the preparation of ß-lactams, phthalazines, cyclohexa-2,5-dien-1-ones, and cyclopent-3-en-1-ones.

The Shape of the Archetypical Oxocarbon Squaric Acid and Its Water Clusters.

Herein, a full structural description is presented for the archetypical supramolecular synthone squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione), placed in the gas phase by laser ablation and characterized by chirped pulse Fourier transform microwave technique. Free from natural environmental disturbances, two different anti-anti and syn-anti planar forms and the corresponding water clusters have been revealed in a supersonic expansion. The substitution structure of the most stable anti-anti conformer has also been extracted from the analysis of the rotational spectra of the 13 C and 18 O isotopic species in their natural abundance. The interplay between inter- and intramolecular interactions involving hydroxy and carbonyl groups has been analyzed by QTAIM (quantum theory of atoms in molecules) methods for squaric acid and its water clusters to understand their chemical behavior and further rationalize their role in the stabilization of these molecular systems.