Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity.
ABSTRACT: Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.
Project description:To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.
Project description:Bicyclo[1.1.1]pentanes (BCPs) have sparked the interest of medicinal chemists due to their recent discovery as bioisosteres of aromatic rings. To study the biological activity of this relatively new class of bioisosteres, reliable methods to incorporate BCPs into target molecules are in high demand, as reflected by a flurry of methods for BCP synthesis in recent years. In this work, we disclose a general method for the synthesis of BCP-containing dithianes which, upon deprotection, provide access to BCP analogues of medicinally abundant diarylketones. A broad scope of 2-aryl-1,3-dithianes, including several heterocyclic derivatives, react with [1.1.1]propellane to afford 26 new derivatives in good to excellent yields. Further transformation of the dithiane portion into a variety of functional groups demonstrates the robustness of the products. A computational study indicates that the reaction of 2-aryl-1,3-dithianes and [1.1.1]propellane proceeds via a two-electron pathway.
Project description:Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen-radicals to undergo strain-release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open-shell intermediates and the presence of strong polar effects in the transition-state for C-N bond formation/ring-opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain-release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino-functionalized building blocks with potential application in medicinal chemistry programs as p-substituted aniline bioisosteres.
Project description:Substituting heteroatoms into nanostructured graphene elements, such as graphene nanoribbons, offers the possibility for atomic engineering of electronic properties. To characterize these substitutions, functionalized atomic force microscopy (AFM)-a tool to directly resolve chemical structures-is one of the most promising tools, yet the chemical analysis of heteroatoms has been rarely performed. We synthesized multiple heteroatom-substituted graphene nanoribbons and showed that AFM can directly resolve elemental differences and can be correlated to the van der Waals radii, as well as the modulated local electron density caused by the substitution. This elemental-sensitive measurement takes an important step in the analysis of functionalized two-dimensional carbon materials.
Project description:Human urine, otherwise potentially polluting waste, is an universal unused resource in organic form disposed by the human body. We present for the first time "proof of concept" of a convenient, perhaps economically beneficial, and innovative template-free route to synthesize highly porous carbon containing heteroatoms such as N, S, Si, and P from human urine waste as a single precursor for carbon and multiple heteroatoms. High porosity is created through removal of inherently-present salt particles in as-prepared "Urine Carbon" (URC), and multiple heteroatoms are naturally doped into the carbon, making it unnecessary to employ troublesome expensive pore-generating templates as well as extra costly heteroatom-containing organic precursors. Additionally, isolation of rock salts is an extra bonus of present work. The technique is simple, but successful, offering naturally doped conductive hierarchical porous URC, which leads to superior electrocatalytic ORR activity comparable to state of the art Pt/C catalyst along with much improved durability and methanol tolerance, demonstrating that the URC can be a promising alternative to costly Pt-based electrocatalyst for ORR. The ORR activity can be addressed in terms of heteroatom doping, surface properties and electrical conductivity of the carbon framework.
Project description:Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.
Project description:Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, ?-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.
Project description:The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.
Project description:We report a modular synthetic strategy for accessing heteroatom-containing polycyclic aromatic hydrocarbons (PAHs). Our approach relies on the controlled generation of transient heterocyclic alkynes and arynes. The strained intermediates undergo in situ trapping with readily accessible oxadiazinones. Four sequential pericyclic reactions occur, namely two Diels-Alder/retro-Diels-Alder sequences, which can be performed in a stepwise or one-pot fashion to assemble four new carbon-carbon (C-C) bonds. These studies underscore how the use of heterocyclic strained intermediates can be harnessed for the preparation of new organic materials.
Project description:Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).