Bicyclo Pentane Research Articles

Achieving C(sp2)-C(sp3) Coupling with BCP-F2 Building Blocks via Barluenga Coupling: A Comparative Approach.

We report our efforts toward achieving C(sp2)-C(sp3) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. By comparing the reactivities of matching pairs of bicyclo[1.1.1]pentane (BCP) and BCP-F2 analogues, we discovered that the Barluenga coupling reaction was the only cross-coupling protocol that translated well between the two structural motifs in contrast to other reported protocols. In this chemistry, a BCP-F2 bearing a tosylhydrazone functional group is cross-coupled with an arylboronic acid. These results further expanded the scope of BCP-F2 building blocks for potential applications in organic chemistry as well as medicinal chemistry.

Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP).

In flow photochemical addition of propellane to diacetyl allowed construction of the bicyclo[1.1.1]pentane (BCP) core in a 1 kg scale within 1 day. Haloform reaction of the formed diketone in batch afforded bicyclo[1.1.1]pentane-1,3-dicarboxylic acid in a multigram amount. Representative gram scale transformations of the diacid were also performed to obtain various BCP-containing building blocks—alcohols, acids, amines, trifluoroborates, amino acids, etc.—for medicinal chemistry.

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation.

The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon-carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP-aryl compounds for late-stage functionalization, but these typically require reactive organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor-acceptor complex are reported.

Radical Carbosulfonylation of Propellane: Synthesis of Sulfonyl β-Keto-bicyclo[1,1,1]pentanes

AbstractThe construction of multiply functionalized bicyclo[1.1.1]pentanes (BCPs) is of high synthetic value, as they are frequently harnessed as bioisosteres of 1,3-disubstituted benzene rings, alkynes, and tert-butyl groups in medicinal chemistry. Herein, we disclose a practical radical-mediated carbosulfonylation of propellane for the synthesis of sulfonyl β-keto-substituted BCPs by using vinyl sulfonates as dual-function reagent. This protocol features broad functional group tolerance and excellent atom-economy, leading to a variety of valuable difunctionalized BCP derivatives under mild photochemical conditions.

Enantioselective Synthesis of Bicyclopentane-Containing Alcohols via Asymmetric Transfer Hydrogenation.

Compounds a containing bicyclo[1.1.1]pentane (BCP) adjacent to a chiral center can be prepared with high enantiomeric excess through asymmetric transfer hydrogenation (ATH) of adjacent ketones. In the reduction step, the BCP occupies the position distant from the η6-arene of the catalyst. The reduction was applied to the synthesis of a BCP analogue of the antihistamine drug neobenodine.

Direct catalytic asymmetric synthesis of \u03b1-chiral bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.

Visible-Light-Induced 1,3-Aminopyridylation of [1.1.1]Propellane with N-Aminopyridinium Salts.

Through the formation of an electron donor-acceptor (EDA) complex, strain-release aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3-aminopyridylated BCPs under mild and metal-free conditions is highlighted by the late-stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P-centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three-component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4-pyridine-functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP-type bioisosteres for applications in drug discovery.

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

AbstractThrough the formation of an electron donor–acceptor (EDA) complex, strain‐release aminopyridylation of [1.1.1]propellane with N‐aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3‐aminopyridylated BCPs under mild and metal‐free conditions is highlighted by the late‐stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P‐centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three‐component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4‐pyridine‐functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP‐type bioisosteres for applications in drug discovery.

α-Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane.

The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.

α‐Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane

AbstractThe bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α‐cyclodextrin (α‐CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3‐diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non‐polar solvents. The combination of these methodologies enables simple, on‐demand preparation of [1.1.1]propellane in various solvents under mild conditions from α‐CD capsules containing 1,3‐diiodo BCP.

A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives.

A continuous flow process to generate [1.1.1]propellane on demand is presented rendering solutions of [1.1.1]propellane that can directly be derivatised into various bicyclo[1.1.1]pentane (BCP) species. This was realised in throughputs up to 8.5 mmol h-1 providing an attractive and straightforward access to gram quantities of selected BCP building blocks. Lastly, a continuous photochemical transformation of [1.1.1]propellane into valuable BCPs bearing mixed ester/acyl chloride moieties was developed.

An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold.

Bicyclo[1.1.1]pentane (BCP) is studied extensively as a bioisosteric component of drugs. Not found in nature, this molecular unit approximates the distance of a para‐disubstituted benzene which is replaced in medicines as a method of improving treatments. Predicting interactions of these drugs with specific active sites requires knowledge of the non‐covalent interactions engaged by this subunit. Structure determinations and computational analysis (Hirshfeld analysis, 2D fingerprint plots, DFT) of seven BCP derivatives chosen to probe specific and directional interactions. X‐ray analysis revealed the presence of various non‐covalent interactions including I ⋅⋅⋅ I, I ⋅⋅⋅ N, N−H ⋅⋅⋅ O, C−H ⋅⋅⋅ O, and H−C ⋅⋅⋅ H−C contacts. The preference of halogen bonding (I ⋅⋅⋅ I or I ⋅⋅⋅ N) in BCP 1–4 strictly depends upon the electronic nature and angle between bridgehead substituents. The transannular distance in co‐crystals 2 and 4 was longer as compared to monomers 1 and 3. Stronger N−H ⋅⋅⋅ O and weaker C−H ⋅⋅⋅ O contacts were observed for BCP 5 while the O ⋅⋅⋅ H interaction was a prominent contact for BCP 6. The presence of 3D BCP units prevented the π ⋅⋅⋅ π stacking between phenyl rings in 3, 4, and 7. The BCP skeleton was often rotationally averaged, indicating fewer interactions compared to bridgehead functional groups. Using DFT analysis, geometries were optimized and molecular electrostatic potentials were calculated on the BCP surfaces. These interaction profiles may be useful for designing BCP analogs of drugs.

Investigation of the Reactivity of 1-Azido-3-iodobicyclo[1.1.1]pentane under “Click” Reaction Conditions

The bicyclo[1.1.1]pentane (BCP) unit is under scrutiny as a bioisostere in drug molecules. We employed methodologies for the synthesis of different BCP triazole building blocks from one precursor, 1-azido-3-iodobicyclo[1.1.1]pentane, by "click" reactions and integrated cycloaddition-Sonogashira coupling reactions. Thereby, we accessed 1,4-disubstituted triazoles, 5-iodo-1,4,5-trisubstituted triazoles, and 5-alkynylated 1,4,5-trisubstituted triazoles. This gives entry to the synthesis of multiply substituted BCP triazoles on either a modular or a one-pot basis. These methodologies were further utilized for appending porphyrin moieties onto the BCP core.

Chemists bring substituted bicyclopentanes into reach

Chemists bring substituted bicyclopentanes into reach

Selective Synthesis of 1-Dialkylamino-2-alkylbicyclo-[1.1.1]pentanes

Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), the synthetic accessibility of BCPs with substitutions at the methylene position has been limited. Herein, we report a selective synthesis of 1-dialkylamino-2-alkylbicyclo[1.1.1]pentanes from prefunctionalized starting materials. We also achieved further functionalizations of these 1,2-disubstituted BCPs and developed a synthesis of these compounds with minimum necessity of chromatographic purifications starting from 1,3-dichloroacetone. Finally, we also detailed the synthesis of a 1,2,3-trisubstituted BCP analogue.

Development of Scalable Routes to 1-Bicyclo[1.1.1]pentylpyrazoles

The application of bicyclo[1.1.1]pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. De...

Highly Regioselective Addition of Allylic Zinc Halides and Various Zinc Enolates to [1.1.1]Propellane.

We report a range of highly regioselective openings of [1.1.1]propellane with various allylic zinc halides, as well as zinc enolates of ketones, esters and nitriles. The resulting zincated bicyclopentanes (BCPs) were trapped with a range of electrophiles including acyl chlorides, sulfonothioates, hydroxylamino benzoates, tosyl cyanide as well as aryl and allyl halides, generating highly functionalized BCP‐derivatives. The unusually high regioselectivity of these reactions has been rationalized using DFT calculations. A bioisostere of the synthetic opioid pethidine was prepared in 95 % yield in one step using this method.

Cubane, Bicyclo[1.1.1]pentane and Bicyclo[2.2.2]octane: Impact and Thermal Sensitiveness of Carboxyl-, Hydroxymethyl- and Iodo-substituents.

With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.1]pentane (BCP), and bicyclo[2.2.2]octane (BCO) were evaluated via hammer test and sealed cell differential scanning calorimetry, respectively. Iodo-substituted systems were found to be more impact sensitive, whereas hydroxymethyl substitution led to more rapid thermodecomposition. Cubane was more likely to be impact sensitive with these substituents, followed by BCP, whereas all BCOs were unresponsive. The majority of derivatives were placed substantially above Yoshida thresholds-a computational indicator of sensitivity.

Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.

Iridium-Catalyzed Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes by 1,3-Difunctionalization of [1.1.1]Propellane.

Bicyclo[1.1.1]pentanes (BCPs) have found application as bioisosteres of aromatic rings in drug development. However, catalytic construction of this motif with adjacent stereocenters with high enantioselectivity from readily available starting materials still constitutes a significant synthetic challenge. Herein we report a direct stereoselective synthesis of α-chiral allylic BCPs by 1,3-difunctionalization of [1.1.1]propellane with Grignard reagents and allyl carbonates using iridium catalysis. This mild protocol proceeds via initial organometallic addition to [1.1.1]propellane followed by asymmetric allylic substitution, providing the products with high enantioselectivities over a broad range of substrates. Further derivatization of the products demonstrates the applicability of this method to the preparation of structurally diverse libraries of chiral BCP derivatives.