Diversity-oriented Synthetic Strategy Research Articles

A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters.

The palladium-catalyzed Sonogashira coupling of α, β-unsaturated acid derivatives offers a diversity-oriented synthetic strategy for cross-conjugated enynones. However, the susceptibility of the unsaturated C-C bonds adjacent to the carbonyl group toward Pd catalysts makes the direct conversion of α, β-unsaturated derivatives as acyl electrophiles to cross-conjugated ketones rare. This work presents a highly selective C-O activation approach to prepare cross-conjugated enynones using α, β-unsaturated triazine esters as acyl electrophiles. Under base and phosphine ligand-free conditions, NHC-Pd(II)-Allyl precatalyst alone catalyzed the cross-coupling of α, β-unsaturated triazine esters with terminal alkynes efficiently, yielding 31 cross-conjugated enynones with diverse functional groups. This method demonstrates the potential of triazine-mediated C-O activation for preparing highly functionalized ketones.

High Value-Added Application of Natural Products in Crop Protection: Semisynthesis and Acaricidal Activity of Limonoid-Type Derivatives and Investigation of Their Biocompatible O/W Nanoemulsions as Agronanopesticide Candidates.

The increasingly serious resistance of Tetranychus cinnabarinus Boisduval to a wide range of insecticides/acaricides poses a major challenge to their control. The citrus processing industry generates a huge quantity of various wastes that contain many limonoids. To effectively utilize these byproducts and discover more potent green acaricidal molecules as sustainable alternatives for traditional resistant pesticides, various limonoid-type derivatives (halogenated/seven-membered lactam derivatives of obacunone and halogenated/oxime esters/oxime ethers/seven-membered lactam derivatives of limonin) were synthesized based on a diversity-oriented synthetic strategy. The key steric configurations of 10 derivatives were further confirmed by X-ray crystallography. Compound 9m, which displayed greater than 9.7-fold potent acaricidal activity of limonin, was of preeminence. In addition, some interesting structure-activity relationships were observed. Moreover, a biocompatible O/W nanoemulsion delivery system was used to prepare the limonin-based agronanoacaricide, which exhibited pronounced control efficiency against T. cinnabarinus Boisduval in the greenhouse. This systematic investigation will provide valuable information and guidance for future value-added applications of novel eco-friendly natural product-based nanopesticides.

Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N -Aryl Indoles via Vinylidene Ortho -Quinone Methides

An atroposelectively diversity-oriented synthetic strategy was developed for the divergent synthesis of axially chiral heterocycles through organocatalytic asymmetric intramolecular annulation of a...

Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis

Polyfunctional building blocks are essential for the implementation of diversity-oriented synthetic strategies, highly demanded in small molecule libraries’ design for modern drug discovery. Acyl(imidoyl)ketenes are highly reactive organic compounds, bearing both oxa- and aza-diene moieties, conjugated symmetrically to the ketene fragment, enabling synthesis of various skeletally diverse heterocycles on their basis. The highlights of reactions utilizing acyl(imidoyl)ketenes are high yields, short reaction time (about several minutes), high selectivity, atom economy, and simple purification procedures, which benefits the drug discovery. The present review focuses on the approaches to thermal generation of acyl(imidoyl)ketenes, patterns of their immediate transformations via intra- and intermolecular reactions, including the reactions of cyclodimerization, in which either symmetric or dissymmetric heterocycles can be formed. Recent advances in investigations on mechanisms, identifications of intermediates, and chemo- and regioselectivity of reactions with participation of acyl(imidoyl)ketenes are also covered.

Diversity-oriented synthesis of polymer membranes with ion solvation cages.

Microporous polymers feature shape-persistent free volume elements (FVEs), which are permeated by small molecules and ions when used as membranes for chemical separations, water purification, fuel cells and batteries1-3. Identifying FVEs that have analyte specificity remains a challenge, owing to difficulties in generating polymers with sufficient diversity to enable screening of their properties. Here we describe a diversity-oriented synthetic strategy for microporous polymer membranes to identify candidates featuring FVEs that serve as solvation cages for lithium ions (Li+). This strategy includes diversification of bis(catechol) monomers by Mannich reactions to introduce Li+-coordinating functionality within FVEs, topology-enforcing polymerizations for networking FVEs into different pore architectures, and several on-polymer reactions for diversifying pore geometries and dielectric properties. The most promising candidate membranes featuring ion solvation cages exhibited both higher ionic conductivity and higher cation transference number than control membranes, in which FVEs were aspecific, indicating that conventional bounds for membrane permeability and selectivity for ion transport can be overcome4. These advantages are associated with enhanced Li+ partitioning from the electrolyte when cages are present, higher diffusion barriers for anions within pores, and network-enforced restrictions on Li+ coordination number compared to the bulk electrolyte, which reduces the effective mass of the working ion. Such membranes show promise as anode-stabilizing interlayers in high-voltage lithium metal batteries.

Diversity-oriented approach to functional thiophene dyes by Suzuki coupling-lithiation one-pot sequences

Functional thiophenes, e.g. for organic metal-free dye sensitized solar cells (DSSC), are accessible efficiently via a divergent and diversity-oriented synthetic strategy.

The First Racemic Total Syntheses of the Antiplasmodials Watsonianones A and B and Corymbone B.

The first biomimetic total syntheses of three biologically meaningful acylphloroglucinols, watsonianones A and B and corymbone B, with potent antiplasmodial activity, were performed. Their total syntheses were carried out through a diversity-oriented synthetic strategy from congener 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione with high step efficiency. The spontaneous enolization/air oxidation of the precursor 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione through a singlet O2-induced Diels-Alder reaction pathway to assemble the key biosynthetic peroxide intermediate is also discussed.

Total Synthesis of (+)-Lycoricidine and Conduramine B-1, ent-C-1, C-4, D-1, ent-F-1, and ent-F-4, and Formal Synthesis of (-)-Laminitol: a C2-Symmetric Chiral-Pool-Based Flexible Strategy.

A facile and diversity-oriented synthetic strategy toward aminocyclitol natural products from inexpensive C2-symmetric l-tartaric acid was developed. The pivotal epoxide was used as a common intermediate to accomplish eight diverse target molecules in six to eleven steps. Various allyl-amine-type conduramines were synthesized in a diastereoselective manner. Heck arylation was explored to construct aphenanthridone ring in a concise synthesis of (+)-lycoricidine. In addition, a highly efficient formal synthesis of (-)-laminitol was developed.

Enantioselective total synthesis of (-)-kainic acid and (+)-acromelic acid C via Rh(i)-catalyzed asymmetric enyne cycloisomerization.

A diversity-oriented synthetic strategy was developed for the total synthesis of kainoid amino acids, which led to the enantioselective synthesis of (-)-kainic acid and the first total synthesis of (+)-acromelic acid C. Rh(i)-catalyzed asymmetric enyne cycloisomerization served as the key reaction in this strategy for the rapid construction of highly functionalized lactam, and the resulting vinyl acetate moiety was further utilized as a versatile building block for the installation of both isopropylidene and 2-pyridone units existing in natural kainoids.

A diversity oriented synthesis of natural product inspired molecular libraries.

Natural products are the source of innumerable pharmaceutical drug candidates and also form an important aspect of herbal remedies. They are also a source of various bioactive compounds. Herein we have leveraged the structural attributes of several natural products in building a library of architecturally diverse chiral molecules by harnessing R-tryptophan as the chiral auxiliary. It is converted to its corresponding methyl ester 1 which in turn provided a bevy of 1-aryl-tetrahydro-β-carbolines 2a-d, which were then converted to chiral compounds via a diversity oriented synthetic strategy (DOS). In general, intermolecular and intramolecular ring rearrangements facilitated the formation of the final compounds. Four different classes of molecules with distinct architectures were generated, adding up to nearly twenty-two individual molecules. Phenotypic screening of a representative section of the library revealed two molecules that selectively inhibit MCF7 breast cancer cells with IC50 of ∼5 μg mL-1 potency.

Diversity-oriented synthetic strategy for developing a chemical modulator of protein-protein interaction.

Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

ChemInform Abstract: Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity‐Oriented Synthesis

AbstractReview: 38 refs.

Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis.

During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4-O-C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB' three-component reaction for PVEs; A2BB' four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β,γ-unsaturated esters and acids, and fused polycycles. They can be transformed into more elaborated molecular skeletons by the use of chemical handles generated in their own domino reactions or by appending different functionalities to the pluripotent molecular platform (secondary reactivity principles).

Synthesis of novel imidazole-based triheterocycles via a domino Ugi/Michael reaction and silver-catalyzed heteroannulation

An efficient and diversity-oriented synthetic strategy for novel triheterocyclic imidazo-pyrrolo-pyrazine/diazepine/diazocine derivatives is elaborated.

Efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc) and sp2-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme

Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-iminosugars have been widely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta β-N-acetylglucosaminidase (β-hexosaminidase) among the epimeric series, is here described. This novel procedure can be easily scaled up, providing enough material for structural modifications and further biological tests. Thus, two series of sp2-iminosugar conjugates derived from DAJNAc have been prepared, namely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory activity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic strategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory potencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of the compounds towards β-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor form) were encountered. The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase.

Diversity-oriented approach for chemical biology.

Synthetic molecules that modulate and probe biological events are critical tools in chemical biology. Utilizing combinatorial and diversity-oriented synthetic strategies, access to large numbers of small molecules is becoming more and more feasible, and research groups in this field can take advantage of the power of chemical diversity. Since the majority of early studies were focused on the discovery of compounds that perturb protein functions, diversity-based approaches are often considered as therapeutic lead discovery tactics. However, the diversity-oriented approach can also be applied to advance distinct aims, such as target protein identification, or the development of imaging probes and sensors. This review provides a personal perspective of the chemical-diversity-based approach and how this principle can be adapted to various chemical biology studies.

Diversity-oriented synthetic strategies applied to cancer chemical biology and drug discovery.

How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery.

ChemInform Abstract: Diversity‐Oriented Synthesis of Enantiopure Furofurans from Carbohydrates: An Expedient Approach with Built‐in Michael Acceptor, Masked Aldehyde and Leaving Group in a Single Sugar Derivative.

A single sugar molecule containing three functional groups, namely a masked aldehyde, a Michael acceptor and a leaving group, reacts with a series of β-dicarbonyl compounds and related reagents to form up to three new bonds and up to three new stereocenters. The configuration of the sugar derivative controls the diastereoselectivity in the formation of all the new bonds without a requirement for any external reagent for asymmetric induction. This Chiral pool based diversity-oriented synthetic strategy has led to the formation of a series of furofurans based on different scaffolds and with appendage variations, and also to a hitherto unknown family of bicyclic 3,8-dioxabicyclo[4.2.1]nonanes.

ChemInform Abstract: Catalytic Formation of Ketones from Unactivated Esters Through Rhodium Chelation‐Assisted C—O Bond Activation.

A new method for building aryl aryl ketones containing heterocyclic rings through chelation-assisted C–O bond activation catalyzed by a rhodium complex has been developed. In this reaction, methyl quinoline-8-carboxylate, methyl quinoxaline-5-carboxylate, and their derivatives were reacted with an excess amount of a substituted phenyl boronic acid in the presence of a rhodium(I) complex to give substituted phenyl(quinolin-8-yl)methanone, phenylquinoxalin-5-ylmethanone, and their derivatives in medium to high yields. The current method offers a highly favorable synthetic pathway to efficiently build related drugs with an 8-benzoylquinoline core structure. This method may prove especially valuable for medicinal chemists for the late-stage introduction of versatile ketone moieties into complex scaffolds for diversity-oriented synthetic strategies.

Towards the realisation of lead-oriented synthesis

Sourcing large numbers of lead-like molecules - compounds that would serve as good starting points for drug discovery programmes - is currently very challenging. The concept of lead-oriented synthesis has recently been articulated to capture the specific problem of preparing diverse small molecules with lead-like molecular properties. In this Feature, some methods that might be used to prepare lead-like molecular scaffolds are described, and presented in the context of diversity-oriented synthetic strategies that allow wide variation in molecular scaffold. It is concluded that the development of a wider toolkit of reactions that is reliable with more polar substrates will be required to allow genuine combination of molecular scaffold within lead-like chemical space.