Bicyclo Pentane Research Articles

Synthesis of All‐Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron‐Catalyzed Kumada Cross‐Coupling

Abstract1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.

Synthesis of All-Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada Cross-Coupling.

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.

A practical access to fluoroalkylthio(seleno)-functionalized bicyclo[1.1.1]pentanes

Rational design of new bioisosteres through introduction of high-value functional groups to bicyclo[1.1.1]pentane (BCP) is of particular use for drug discovery. Disclosed herein is the first access to valuable fluoroalkylthio(seleno)-functionalized BCPs. A range of SCF3, SCF2H, SCFH2, SeCF3, SeC4F9, and SeC8F17 groups are readily incorporated to BCPs under mild conditions. Concomitant installation of a sulfone provides a platform for incorporation of the BCP motif to bioactive molecules. This practical protocol features novel BCP scaffolds, broad substrate scope, excellent atom-economy, simple operation, and gram-scale preparation.

Recent advances in the applications of [1.1.1]propellane in organic synthesis

As a highly strained small molecule, [1.1.1]propellane has been widely used in various synthetic transformations owing to the exceptional reactivity of the central bond between the two bridgehead carbons. Utilizing strain-release approaches, the rapid development of strategies for the construction of bicyclo[1.1.1]pentane (BCP) and cyclobutane derivatives using [1.1.1]propellane as the starting material has been witnessed in the past few years. In this review, we highlight the most recent advances in this field. Accordingly, the reactivity of [1.1.1]propellane can be divided into three pathways, including radical, anionic and transition metal-catalyzed pathways under appropriate conditions.

Copper-mediated synthesis of drug-like bicyclopentanes.

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable 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. Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3-13. The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

1,3‐Difunctionalizations of [1.1.1]Propellane via 1,2‐Metallate Rearrangements of Boronate Complexes

Abstract1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para‐substituted aromatic rings. The most direct route to these structures is via multicomponent ring‐opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP‐halide intermediates. Herein, we report three‐ and four‐component 1,3‐difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP‐metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile‐induced 1,2‐metallate rearrangement chemistry enables a broad range of C−C bond‐forming reactions.

1,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate Rearrangements of Boronate Complexes.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings. The most direct route to these structures is via multicomponent ring-opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP-halide intermediates. Herein, we report three- and four-component 1,3-difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP-metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile-induced 1,2-metallate rearrangement chemistry enables a broad range of C-C bond-forming reactions.

Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles that have fascinated the chemical community for decades because of their unique structure. Despite the immense interest in this scaffold and extensive synthetic efforts, the construction of BCP derivatives still relies substantially on the manipulation of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate. Furthermore, BCPs that contain a proximal stereocentre are underrepresented in the literature and their generation requires stoichiometric chiral auxiliaries. Here we explore enantioselective C–H functionalization of BCPs as a conceptually innovative strategy that provides access to chiral substituted BCPs. For this purpose, enantioselective intermolecular sp3 C–H insertion reactions of donor/acceptor diazo compounds catalysed by the chiral dirhodium complex, Rh2(TCPTAD)4, were employed to forge new C–C bonds at the tertiary position of a variety of BCPs. This work also establishes that highly strained molecules can undergo direct C–H insertion without losing the integrity of their carbocyclic framework. Bicyclo[1.1.1]pentanes are of interest to the pharmaceutical and chemical communities, due largely to their metabolic stability and potential as bioisosteres. Here the enantioselective C–H activation of these carbocycles is reported, giving access to enantioenriched, substituted products while maintaining the carbocyclic framework.

Bridging and Conformational Control of Porphyrin Units through Non-Traditional Rigid Scaffolds.

Connecting two porphyrin units in a rigid linear fashion, without any undesired electron delocalization or communication between the chromophores, remains a synthetic challenge. Herein, a broad library of functionally diverse multi‐porphyrin arrays that incorporate the non‐traditional rigid linker groups cubane and bicyclo[1.1.1]pentane (BCP) is described. A robust, reliable, and versatile synthetic procedure was employed to access porphyrin‐cubane/BCP‐porphyrin arrays, representing the largest non‐polymeric structures available for cubane/BCP derivatives. These reactions demonstrate considerable substrate scope, from utilization of small phenyl moieties to large porphyrin rings, with varying lengths and different angles. To control conformational flexibility, amide bonds were introduced between the bridgehead carbon of BCP/cubane and the porphyrin rings. Through varying the orientation of the substituents around the amide bond of cubane/BCP, different intermolecular interactions were identified through single crystal X‐ray analysis. These studies revealed non‐covalent interactions that are the first‐of‐their‐kind including a unique iodine‐oxygen interaction between cubane units. These supramolecular architectures indicate the possibility to mimic a protein structure due to the sp3 rigid scaffolds (BCP or cubane) that exhibit the essential conformational space for protein function while simultaneously providing amide bonds for molecular recognition.

Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

AbstractThis Minireview focuses on selected topics in the syntheses of bicyclo[1.1.1]pentane (BCP) analogues. A brief historical introduction was included. The content covers various synthetic routes of 1‐substituted and 1,3‐disubstituted BCPs. Selective examples of synthetically useful building blocks are summarized for each category for synthetic organic chemists’ and medicinal chemists’ reference. A compare‐and‐contrast analysis is also applied to evaluate these routes and to demonstrate the progress of strategic functional group transformations using modern organic methodologies. By systematically analyzing the synthetic strategies to access these strained molecules, we also hope that this Minireview will provide inspirations for future developments in this area.

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

AbstractThe 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.

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.

Reactions of 2-Aryl-1,3-Dithianes and [1.1.1]Propellane.

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.

A Selective Synthesis of 2,2-Difluorobicyclo[1.1.1]pentane Analogues: "BCP-F2".

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other "ortho/meta-substituted" BCPs via similar mechanisms.

Insertion of [1.1.1]propellane into aromatic disulfides.

Herein we present the synthesis of symmetrically and unsymmetrically substituted 1,3-bissulfanylbicyclo[1.1.1]pentanes from disulfides and [1.1.1]propellane. Bicyclo[1.1.1]pentanes (BCPs) recently gained interest as rigid linkers and as bioisosters of para-substituted benzene and alkyne moieties. The most promising precursor for BCPs is [1.1.1]propellane (1). The available methods to synthesize BCPs are quite limited and many groups contribute to the development of novel methods. The insertion of 1 into disulfide bonds is known, but has never been thoroughly investigated. In this study, we show that an UV initiated radical reaction can be used to synthesize symmetrically and unsymmetrically substituted BCP sulfides by reaction of [1.1.1]propellane (1) with disulfides. Depending on the ratio of 1 to the disulfide, only the BCP product (with up to 98% yield) or a mixture of BCP and [2]staffane can be obtained. The reaction tolerates functional groups such as halogens, alkyl and methoxy groups. The separation of the corresponding BCP and [2]staffane products is challenging but possible by column chromatography and preparative TLC in most cases. Single crystal X-ray diffraction analysis confirms the rod-like structure of the [2]staffanes that is often required in material applications.

Synthesis of Enantioenriched α-Chiral Bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentanes (BCPs), useful surrogates for para-substituted arenes, alkynes, and tert-butyl groups in medicinal chemistry, are challenging to prepare when featuring stereogenic centers adjacent to the BCP. We report the development of an efficient route to α-chiral BCPs, via highly diastereoselective asymmetric enolate functionalization. We also describe the application of this chemistry to the synthesis of BCP analogues of phenylglycine and tarenflurbil, the single enantiomer of the NSAID flurbiprofen.

Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane

Utilization of three-dimensional cyclic scaffolds is important in modern drug discovery, both to provide greater opportunities for optimizing drug candidates and to expand the available chemical space of drugs. Among these scaffolds, bicyclo[1.1.1]pentane (BCP) is a high-value bioisostere for 1,4-disubstituted phenyl rings, internal alkynes, and the tert-butyl group, generally offering high passive permeability, high water solubility, and improved metabolic stability. However, the lack of methods for functionalizing BCP remains a significant challenge, and in particular, a versatile strategy for synthesizing a wide range of unsymmetrically 1,3-difunctionalized BCP derivatives has been lacking. In this account, we review recent advances in the synthetic chemistry of BCP, focusing especially on our recently developed radical multicomponent carboamination of [1.1.1]propellane.1 Introduction2 Overview of the Synthetic Chemistry of [1.1.1]Propellane, the Most Promising Precursor of Bicyclo[1.1.1]pentane3 Recent Advances in the Synthetic Chemistry of Unsymmetrically 1,3-Disubstituted Bicyclo[1.1.1]pentane Derivatives4 Radical Multicomponent Carboamination of [1.1.1]Propellane Permits Direct Synthesis of 3-Substituted Bicyclo[1.1.1]pent-1-ylamine Derivatives5 Conclusion

Synthesis of BCP Benzylamines From 2-Azaallyl Anions and [1.1.1]Propellane.

For bioactive molecules, bicyclo[1.1.1]pentanes (BCPs) are an emerging isostere of rigid spacer groups that have shown potential to improve drug-like qualities. As BCPs become an increasingly popular motif for evaluation in drug candidates, organic chemists must meet the demand to reliably incorporate them into new targets. To provide access to BCP analogues of diaryl methanamines, a ubiquitous scaffold in medicinal chemistry, we report the synthesis of BCP benzylamines through reactivity of [1.1.1]propellane with 2-azaallyl anions, which are generated in situ from N-benzyl ketimines. The reaction proceeds rapidly at room temperature and tolerates a broad substrate scope, providing straightforward access to 23 new BCP benzylamine derivatives. Initial experiments support the intermediacy of a BCP anion. Additionally, the reaction can be promoted by substoichiometric loadings of base, highlighting an unusual reactivity of both 2-azaallyls and [1.1.1]propellane.

Synthesis of BCP Benzylamines From 2‐Azaallyl Anions and [1.1.1]Propellane

AbstractFor bioactive molecules, bicyclo[1.1.1]pentanes (BCPs) are an emerging isostere of rigid spacer groups that have shown potential to improve drug‐like qualities. As BCPs become an increasingly popular motif for evaluation in drug candidates, organic chemists must meet the demand to reliably incorporate them into new targets. To provide access to BCP analogues of diaryl methanamines, a ubiquitous scaffold in medicinal chemistry, we report the synthesis of BCP benzylamines through reactivity of [1.1.1]propellane with 2‐azaallyl anions, which are generated in situ from N‐benzyl ketimines. The reaction proceeds rapidly at room temperature and tolerates a broad substrate scope, providing straightforward access to 23 new BCP benzylamine derivatives. Initial experiments support the intermediacy of a BCP anion. Additionally, the reaction can be promoted by substoichiometric loadings of base, highlighting an unusual reactivity of both 2‐azaallyls and [1.1.1]propellane.

Asymmetric Choreography in Pairs of Orthogonal Rotors.

An asymmetric mechanism for correlated motion occurring in noninteracting pairs of adjacent orthogonal 1,4-bis(carboxyethynyl)bicyclo[1.1.1]pentane (BCP) rotators 1 in the solid state is unraveled and shown to play an important role in understanding the dynamics in the crystalline rotor, Bu4N+[1–]·H2O. Single crystal X-ray diffraction and calculation of rotor–rotor interaction energies combined with variable-temperature, variable-field 1H spin–lattice relaxation experiments led to the identification and microscopic rationalization of two distinct relaxation processes.