Bicyclic Scaffold Research Articles

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products.

Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp3 character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp3 features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

Synthesis of a novel tripeptidomimetic scaffold and biological evaluation for CXC chemokine receptor 4 (CXCR4) antagonism

We here report the preparation of a new 2,6,8-trisubstituted bicyclic tripeptidomimetic scaffold through TFA-mediated cyclization of a linear precursor containing three side chains. The introduction of a triphenylmethyl-protected thiol into carboxylic acid containing building blocks through sulfa Michael additions onto α,β-unsaturated hexafluoroisopropyl esters is described. The stereoselectivity of the bicycle formation was found to be somewhat lower than that previously reported for analogous 3,6,8-trisubstituted scaffolds. Moreover, the configuration of the linear precursor directs the stereochemical outcome of the cyclization differently when the R1 side chain is positioned on C2 in the bicycles (present work) instead of C3 (previous work). Tripeptidomimetic compounds based on the new scaffold were synthesized and evaluated for antagonistic potency toward CXCR4, and one compound (45a) displayed similar activity to earlier reported 3,6,8-tripeptidomimetic bicycles.

Epoxides as Precursors to 1-Hydroxymethyl Indolizidine and Pyrrolizidine

Herein we describe the synthesis of 1-hydroxymethyl pyrrolizidine and indolizidine alkaloids from epoxy-tethered pyrrole precursors. Two titanium-based methods are evaluated for the construction of the bicyclic scaffold: the Lewis acid mediated cyclization developed by Tanis and Raggon and the titanocene(III)-catalyzed reaction proceeding via radical intermediates. The former method, after hydrogenation of the pyrrole moiety, ultimately gives rise to enantiopure (–)-tashiromine, being the most concise and atom-economic procedure reported to date.

Stereoselective Synthesis of Functionalized Bicyclic Scaffolds by Passerini 3-Center-2-Component Reactions of Cyclic Ketoacids.

We report the use of bifunctional starting materials (ketoacids) in a diastereoselective Passerini three‐center‐two‐component reaction. Study of the reaction scope revealed the required structural features for stereoselectivity in the isocyanide addition. In this system, an interesting isomerization of the primary Passerini product – the α‐carboxamido lactone – into an atypical product, an α‐hydroxy imide, was found to occur under acidic conditions. Furthermore, enantioenriched Passerini products can be generated from an enantioenriched ketoacid obtained by chemoenzymatic synthesis.

Highly Constrained Bicyclic Scaffolds for the Discovery of Protease-Stable Peptides via mRNA Display.

Highly constrained peptides such as the knotted peptide natural products are promising medicinal agents because of their impressive biostability and potent activity. Yet, libraries of highly constrained peptides are challenging to prepare. Here, we present a method which utilizes two robust, orthogonal chemical steps to create highly constrained bicyclic peptide libraries. This technology was optimized to be compatible with in vitro selections by mRNA display. We performed side-by-side monocyclic and bicyclic selections against a model protein (streptavidin). Both selections resulted in peptides with mid-nanomolar affinity, and the bicyclic selection yielded a peptide with remarkable protease resistance.

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene.

Lactols in an asymmetric aldol-desymmetrization sequence: access to tetrahydro-4H-furo[2,3-b]pyran-2-one and tetrahydro-4H-furo[2,3-b]furan-2-one derivatives.

An asymmetric aldol-desymmetrization sequence was developed which provided highly efficient access to important bicyclic oxygen-containing scaffolds with multiple chiral centers and one is a quaternary stereogenic center containing a free hydroxy group. Moreover, starting from racemic precursors, the final products were obtained as two separable diastereomers by flash chromatography. Several other heterocycles could also be easily generated with this strategy.

Identification of a Dolabellane Type Diterpene Synthase and other Root-Expressed Diterpene Synthases in Arabidopsis.

Arabidopsis thaliana maintains a complex metabolism for the production of secondary or specialized metabolites. Such metabolites include volatile and semivolatile terpenes, which have been associated with direct and indirect defensive activities in flowers and leaves. In comparison, the structural diversity and function of terpenes in Arabidopsis roots has remained largely unexplored despite a substantial number of root-expressed genes in the Arabidopsis terpene synthase (TPS) gene family. We show that five root-expressed TPSs of an expanded subfamily-a type clade in the Arabidopsis TPS family function as class I diterpene synthases that predominantly convert geranylgeranyl diphosphate (GGPP) to different semi-volatile diterpene products, which are in part detectable at low levels in the ecotypes Columbia (Col) and Cape Verde Island (Cvi). The enzyme TPS20 produces a macrocyclic dolabellane diterpene alcohol and a dolabellane-related diterpene olefin named dolathaliatriene with a so far unknown C6-C11 bicyclic scaffold besides several minor olefin products. The TPS20 compounds occur in all tissues of Cvi but are absent in the Col ecotype because of deletion and substitution mutations in the Col TPS20 sequence. The primary TPS20 diterpene products retard the growth of the root rot pathogen Pythium irregulare but only at concentrations exceeding those in planta. Together, our results demonstrate that divergence and pseudogenization in the Arabidopsis TPS gene family allow for structural plasticity in diterpene profiles of above- and belowground tissues.

A deconjugative alkylation/Diels-Alder cycloaddition strategy to synthesize 2-substituted bicyclic scaffolds

Knoevenagel adducts derived from α,β-unsaturated aldehydes and a malonic acid derivative can undergo deconjugative alkylation using dienophile-functionalized alkyl iodides. The single step reaction is two-fold significant: (a) The electron-deficient diene (α,β-unsaturated aldehyde Knoevenagel adduct) is deconjugated from the esters, resulting in an electronically neutral diene and (b) tethers the diene and dienophile, which allow for intramolecular cycloaddition to bicyclic systems bearing a malonic acid derivative at the 2-position. The sequence thus converts simple reagents into natural product relevant bicyclic scaffolds. We also disclose an unexpected Diels-Alder cycloaddition/aromative CC cleavage reaction that results due to the malonate's location at the 2-position.

Nickel-Catalyzed Chemo- and Enantioselective Coupling between Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bicycles.

Herein an intramolecular nickel-catalyzed (4+2) coupling between cyclobutanones and allenes, by C-C cleavage, is reported. The reaction provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches. The reaction is efficient, chemoselective, and pH/redox neutral. Room temperature conditions and low catalyst loadings can be adopted. Excellent enantioselectivity is also achieved.

Nickel‐Catalyzed Chemo‐ and Enantioselective Coupling between Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bicycles

AbstractHerein an intramolecular nickel‐catalyzed (4+2) coupling between cyclobutanones and allenes, by C−C cleavage, is reported. The reaction provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches. The reaction is efficient, chemoselective, and pH/redox neutral. Room temperature conditions and low catalyst loadings can be adopted. Excellent enantioselectivity is also achieved.

1,4-Addition Ugi Reaction Using Cyclic α,β-Unsaturated Ketone as Substrate.

A four-component, 1,4-addition Ugi reaction using cyclic α,β-unsaturated ketones, carboxylic acids, amines, and isocyanides was developed for the first time. By combining this reaction with Michael addition, nucleophilic substitution, and C-N bond formation reactions, bicyclic and tricyclic scaffolds with pyridinone and quinolinone moieties, two basic units among a variety of natural products and pharmaceuticals, were constructed.

Partially Saturated Bicyclic Heteroaromatics as an sp(3) -Enriched Fragment Collection.

Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection

AbstractFragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

ChemInform Abstract: Diastereo‐ and Enantioselective Synthesis of Polyfunctionalized Diquinanes, Hydrindanes, and Decalins Bearing a Hydroxyl Group at the Ring Junction

AbstractReview: [30 refs.

Diastereo- and Enantioselective Synthesis of Polyfunctionalized Diquinanes, Hydrindanes, and Decalins Bearing a Hydroxyl Group at the Ring Junction

Bicyclo[3.3.0]octan-1-ol (diquinane ring system), bicyclo[4.3.0]nonan-1-ol (hydrindane ring system), and bicyclo[4.4.0]decan-1-ol (decalin ring system) belong to the medium-sized rings family which represent important scaffolds of numerous natural products. Thus, the development of new routes leading to such scaffolds is of importance because such carbocycles are ubiquitous in numerous biologically active compounds. This short review will focus on the main approaches reported since 2000, leading to these bicyclic scaffolds with high diastereo- and/or enantioselectivities. 1 Introduction 2 Diastereoselective Approaches 3 Diastereo- and Enantioselective Catalytic Approaches 4 Conclusion

Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides.

Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.

ChemInform Abstract: Calcium‐Catalyzed Dynamic Multicomponent Reaction.

AbstractAn air and moisture insensitive calcium‐based catalytic system is developed for the reversible formation of covalent bonds allowing for the diastereoselective amplification of a pharmacologically relevant bicyclic amine scaffold.

Determinative role of ring size and substituents in highly selective synthesis of functionalized bicyclic guanidine and tetra substituted thiophene derivatives based on salt adducts afforded by cyclic thioureas and ketene dithioacetal

The condensation of organic salt adducts generated by cyclic thioureas and 2-di(methylsulfanyl)methylenemalononitrile with dialkyl acetylenedicarboxylates selectively leads to either tetrasubstituted thiophenes (2 examples) or hitherto unreported bicyclic guanidine (13 examples) derivatives, with controlling factors being ring size, the substituent on the S-methylisothiourea and the bulk of the substituent on the dialkyl acetylenedicarboxylates. Green solvents, short reaction time; easy purification, high yield and selectivity, are key feature of this protocol in the condensation step. The performances of the reactions in the presence of free-base and a catalyst at room temperature is unprecedented in the synthesis of thiophene frameworks and functionalized bicyclic guanidine scaffolds.

Oxadendralenes in asymmetric organocatalysis for the construction of tetrahydroisochromenes.

Oxadendralenes are integrated in a novel manner into a one-pot cascade utilizing synergistic catalysis for the construction of valuable and complex bicyclic heterocyclic scaffolds. The construction is based on the organocatalytic activation of the oxadendralenes generating a vinylogous iminium-ion intermediate which is set-up for a 1,6-addition with an enamine formed from an aldehyde and the same organocatalyst. This reaction generates a cyclic oxadendralenic intermediate, which acts as an electron-deficient heterodiene reacting in a Lewis-acid catalyzed hetero-Diels-Alder reaction with vinyl ethers to form tetrahydroisochromenes with five continuous stereocenters in high yields, >20 : 1 dr and 99% ee. This synergistic organo- and Lewis-acid catalysed system also displays high tolerance for variation in oxadendralenes and aldehydes, which provides tetrahydroisochromenes with high diversity in the substituent pattern and the same excellent stereoselectivities. Mechanistic studies have been performed to account for the activation modes and stereochemical outcome of the reaction. The reaction concept has been extended to also include a sequential organocatalytic reaction of oxadendralenes with aldehydes, in which the enamine formed from the aldehyde and the organocatalyst act both in the first catalytic cycle forming the cyclic oxadendralenic intermediate and in a second catalytic cycle leading to tetrahydroisochromenes in good yields and excellent stereoselectivities. Mechanistic studies reveal that the stereochemistry of the organocatalyst has an influence on the diastereoselectivity of the reaction sequence. Some transformations of the tetrahydroisochromenes are also presented. The chiral tetrahydroisochromenes formed might be applied in the diversified synthesis of important drugs.