Retrosynthetic Analysis Research Articles

Impact of C-H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules.

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

BracketMaker: Visualization and optimization of chemical protein synthesis.

Chemical protein synthesis (CPS), in which custom peptide segments of ~20-60 aa are produced by solid-phase peptide synthesis and then stitched together through sequential ligation reactions, is an increasingly popular technique. The workflow of CPS is often depicted with a "bracket" style diagram detailing the starting segments and the order of all ligation, desulfurization, and/or deprotection steps to obtain the product protein. Brackets are invaluable tools for comparing multiple possible synthetic approaches and serve as blueprints throughout a synthesis. Drawing CPS brackets by hand or in standard graphics software, however, is a painstaking and error-prone process. Furthermore, the CPS field lacks a standard bracket format, making side-by-side comparisons difficult. To address these problems, we developed BracketMaker, an open-source Python program with built-in graphic user interface (GUI) for the rapid creation and analysis of CPS brackets. BracketMaker contains a custom graphics engine which converts a text string (a protein sequence annotated with reaction steps, introduced herein as a standardized format for brackets) into a high-quality vector or PNG image. To aid with new syntheses, BracketMaker's "AutoBracket" tool automatically performs retrosynthetic analysis on a set of segments to draft and rank all possible ligation orders using standard native chemical ligation, protection, and desulfurization techniques. AutoBracket, in conjunction with an improved version of our previously reported Automated Ligator (Aligator) program, provides a pipeline to rapidly develop synthesis plans for a given protein sequence. We demonstrate the application of both programs to develop a blueprint for 65 proteins of the minimal Escherichia coli ribosome.

Synthesis of Marine (-)-Pelorol and Future Perspectives.

Meroterpenoid-type marine natural compounds have attracted an increasing amount of attention due to their peculiar chemical structures and their potential for the development of therapeutically important probes. Within this group of substances pelorol stands out; it is a natural compound isolated from marine organisms with a unique structure and an interesting biological profile. In this article, we summarize and highlight the most interesting aspects of the synthetic procedures towards this compound, which have two common key steps. The first is the coupling of a drimanyl derivative with a compound derived from an arene. The second is a Friedel-Crafts cyclization which forms the C ring of the natural product. Despite the synthetic advances achieved so far, we consider that a more efficient synthetic procedures could be carried out, since their synthetic routes are difficult to scale up due to numerous reaction steps and the limitations imposed by the use of some reagents. In this article, we present a new and versatile retrosynthetic analysis of (-)-pelorol and analogs, which is highly desirable for their easy preparation and subsequent broad study of their biological activities. This is a retrosynthetic route that could improve those reported in the literature in terms of cost-effectiveness.

Estimation of the Vaporization Enthalpies and Vapor Pressures of α-Tocopherol and Δ9-Tetrahydrocannabinol via the Use of a Surrogate, Correlation Gas Chromatography, and Synthetic and Retrosynthetic Analysis.

A protocol is proposed that combines the use of the known properties of a surrogate containing various functional groups together with n-alkanes as standards to evaluate the properties of much larger related substances using correlation gas chromatography. An objective of this work is to develop options that circumvent the lack of appropriate vaporization enthalpy standards that can be used for evaluation of various thermodynamic properties of larger complex molecules using gas chromatography. The surrogate in this case is 2,2,5,7,8-pentamethylchroman-6-ol (PMC) and is used to evaluate the vaporization enthalpies and vapor pressures of α-tocopherol (α-TOC) and Δ9-tetrahydrocannabinol (Δ9-THC). The results are compared to the available literature data and to estimated properties. Vaporization enthalpies are also evaluated by a proposed method that involves the use of synthetic and retrosynthetic analysis.

Molecular complexity as a driving force for the advancement of organic synthesis.

The generation of molecular complexity is a primary goal in the field of synthetic chemistry. In the context of retrosynthetic analysis, the concept of molecular complexity is central to identifying productive disconnections and the development of efficient total syntheses. However, this field-defining concept is frequently invoked on an intuitive basis without precise definition or appreciation of its subtleties. Methods for quantifying molecular complexity could prove useful for characterizing the state of synthesis in a more rigorous, reliable and reproducible fashion. As a first step to evaluating the importance of these methods to the state of the field, here we present our perspective on the development of molecular complexity quantification and its implications for chemical synthesis. The extension and application of these methods beyond computer-aided synthesis planning and medicinal chemistry to the traditional practice of 'complex molecule' synthesis could have the potential to unearth new opportunities and more efficient approaches for synthesis.

Synthesis of pyrazole and 1,3,4-oxadiazole derivatives of pharmaceutical potential

Heterocyclic compounds are important molecules that serve as scaffolds or linkers for the core structure of numerous drug substances. In particular, pyrazole and 1,3,4-oxadiazole are compounds of great interest due to their comprehensive biological activities and interesting structural features. Here, we described an efficient and economical synthetic route leading to N-phenyl substituted pyrazole and 1,3,4-oxadiazole derivatives. Retrosynthetic disconnective analysis showed that the N-phenyl substituted pyrazole can be obtained from chalcone, accessible from the respective aldehyde, and acetophenone. The disubstituted 1,3,4-oxadiazole can be constructed from the respective aldehyde, which originates from pyrrole-containing compound, and formyl chloride. Based on our retrosynthetic analysis, N-phenyl substituted pyrazole was obtained by cyclization of the respective chalcone with phenylhydrazine to give pyrazoline which was in turn converted into pyrazole by oxidative aromatization. Potassium carbonate and a catalytic amount of molecular iodine were used to oxidatively cyclize semicarbazones into 1,3,4-oxadiazoles in a transition metal-free process. Novel pyrazole and 1,3,4-oxadiazoles with potential biological activity are investigated as antituberculosis, anticonvulsant, antidiabetic, anticancer, and tyrosinase inhibitory agents.

Anodic Cyclization Reactions and an Approach to the Chrysosporazine Family of Natural Products

Electrochemistry has long offered new opportunities for the construction of biologically relevant molecules. Many of these opportunities are based on the ability that electrochemistry provides for reversing the polarity of known functional groups. For example, consider the brief retrosynthetic analysis shown in the Scheme below. The analysis proposes a route to the Chrysosporazine family of natural products (specifically Chrysosporazine D in this case) from readily available amino acid and lignin derived starting materials. The Chrysosporazines are efflux inhibitors that improve the effectiveness of chemotherapy agents.1 The plan calls for a coupling of the two starting materials to afford a cyclization substrate. However, the proposed cyclization reaction would combine a nucleophilic amide nitrogen with a nucleophile electron rich styrene derivative. In principle, an anodic oxidation reaction can solve this issue by either converting the amide nitrogen into a radical or oxidizing the styrene derivative to form a radical cation. Either mode would effectively reverse the polarity of one of the nucleophilic groups and allow for the cyclization. Previous efforts examining these cyclizations have focused on the generation of a N-radical intermediate.2 Yet while these efforts have been very successful, they require the presence of a phenyl ring on the amide nitrogen in order to lower its pKa. This is essential for the formation of an amide anion that is in turn oxidized to the desired N-radical. Such a plan is not compatible with the synthesis of the Chrysosporazines that simply do not have a phenyl ring on the nitrogen of the amide. Placing one there would prevent the intramolecular cyclization. So, how can this problem be resolved? There are two possible answers to this question. One involves a change in the overall strategy that converts the amide into an electron-rich olefin equivalent that can be oxidized to from a radical cation. The second involves finding an alternative method for dropping the pKa of the amide so that the anion and subsequent N-radical can still be made. In the chemistry to be discussed, both strategies will be examined and the propensity for the cyclic product to undergo over-oxidation shown to be the determining factor for which pathway is preferred; a preference that has led to a new approach to N-based radical cyclizations. 1. Elbanna, A. H., Khalil, Z. G., Bernhardt, P., V., Capon, R. J. Org. Lett. 2019, 21, 8097–8100. 2. Xiong, P.; Xu, H-C. Acc. Chem. Res. 2019, 52, 3339-3350. Figure 1

Synthetic study of leptosperol A

Leptosperol A, isolated from the leaves of L. scoparium in 2020 together with leptosperol B, possesses a unique 1-benzyl-2-(2-phenylethyl) cyclodecane framework. A synthetic study of leptosperol A was performed based on a retrosynthetic analysis that indicated that leptosperols A and B could be synthesized efficiently via a common intermediate. Our study showed that unexpected transannular reactions easily occurred to give bicyclo [4.4.0] ring systems instead of the desired cyclodecane ring with a diene moiety. The results communicated here offers useful information to organic chemists involved in medium-sized ring systems.

RDCanon: A Python Package for Canonicalizing the Order of Tokens in SMARTS Queries.

SMARTS is a widely used language in cheminformatics for defining substructural queries for database lookups, reaction templates for chemical transformations, and other applications. As an extension to SMILES, many SMARTS patterns can represent the same query. Despite this, no canonicalization algorithm invariant of the line notation sequence or atomic numbering is publicly available. Here, we introduce RDCanon, an open-source Python package that can be used to standardize SMARTS queries. RDCanon is designed to ensure that the sequence of atomic queries remains consistent for all graphs representing the same substructure query and to ensure a canonical sequence of primitives within each individual atom query; furthermore, the algorithm can be applied to canonicalize the order of reactants, agents, and products and their atom map numbers in reaction SMARTS templates. As part of its canonicalization algorithm, RDCanon provides a mechanism in which the canonicalized SMARTS is optimized for speed against specific molecular databases. Several case studies are provided to showcase improved efficiency in substructure matching and retrosynthetic analysis.

The Role of Base in Reaction Performance of Photochemical Synthesis of Thiazoles: An Integrated Theoretical and Experimental Study.

Artificial intelligence (AI)/machine learning (ML) is emerging as pivotal in synthetic chemistry, offering revolutionary potential in retrosynthetic analysis, reaction conditions and reaction prediction. We have combined chemical descriptors, primarily based on Density Functional Theory (DFT) calculations, with various AI/ML tools such as Multi-Layer Perceptron (MLP) and Random Forest (RF), to predict the synthesis of 2-arylbenzothiazole in photoredox reactions. Significantly, our models underscore the critical role of the molecular structure and physicochemical characteristics of the base, especially the total atomic polarizabilities, in the rate-determining steps involving cyclohexyl and phenethyl moieties of the substrate. Moreover, we validated our findings in articles through experimental studies. It showcases the power of AI/ML and quantum chemistry in shaping the future of organic chemistry.

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.

The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators-small molecules acting on the basic molecular defect in CF-have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA's) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.

Efficient enzymatic synthesis of theaflavin and its production mechanism.

In this study, a novel preparation method of theaflavin (TF) has been established. Our findings indicated that the formation of TF was significantly enhanced by using an ice bath (2-3°C). Additionally, increasing the ratio of (-)-epigallocatechin (EGC) under the ice bath could further improve its yield. This approach prevented the appearance of a dark solution within 3h, effectively protecting TF from oxidation. Our study on the generation mechanism of TF suggested that EGC-quinone I (EGC-Q-I) with two carbanions could potentially serve as one of synthons based on the retrosynthetic analysis of the bicyclo[3.2.1]octane-type intermediate. Subsequently, quantum mechanical calculations further supported this hypothesis. Practical Application: In this study, we have developed a novel method for the synthesis of theaflavin (TF), demonstrating that the use of ice bath significantly enhanced its yield. Increasing the ratio of (-)-epigallocatechin (EGC) under the ice bath further improved TF yields and prevented darkening of the solution for at least 3h, thereby protecting TF from oxidation. Our study suggested that EGC-quinone I is a potential synthon based on the retrosynthetic analysis of the bicyclo[3.2.1]octane-type intermediate (BOI). This hypothesis is supported by QM calculations.

Navigating Excess Complexity: Total Synthesis of Daphenylline.

Retrosynthetic analysis is a framework for designing synthetic routes to complex molecules that generally prioritizes disconnections which reduce molecular complexity. However, strict adherence to this principle can overlook pathways involving highly complex intermediates that can be easily prepared through powerful bond-forming transformations. Herein, we demonstrate this tactic of generating excess complexity, followed by strategic bond-cleavage, as a highly effective approach for the 11-step total synthesis of the Daphniphyllum alkaloid daphenylline. To implement this strategy, we accessed a bicyclo[4.1.0]heptane core through a dearomative Buchner cycloaddition, which enabled construction of the seven-membered ring after C-C bond cleavage. Installation of the synthetically challenging quaternary stereocenter methyl group was achieved through a thia-Paternò-Büchi [2 + 2] photocycloaddition followed by stereospecific thietane reduction, further illustrating how building excess complexity can enable desired synthetic outcomes after strategic bond-breaking events. This strategy leveraging bond cleavage transformations should serve as a complement to traditional bond-forming, complexity-generating synthetic strategies.

Advances in the self-organized total synthesis of natural products.

Natural product total synthesis has trailblazed in the era of multistep synthesis. The strategic application of existing synthetic methodologies and the stepwise construction that revolves around newly developed, tailored key steps, are two basic tactics in the principle of classic retrosynthetic analysis. However, a new synthetic model, termed self-organized total synthesis, has emerged in recent years, enabling the rapid creation of specific natural products by a one-pot reaction. Distinct from conventional analysis associated with certain bond disconnections, the design of self-organized total synthesis focuses on seeking a series of self-organized reaction sequences which can be integrated compatibly under a uniform condition, therefore allowing the entire sequence to proceed in one pot, and most importantly, starting from commercially available feedstocks or biomass materials. Whilst dauntingly challenging, this synthetic strategy is more consistent with the biogenetic pathway of natural products compared with conventional counterparts, and will hopefully provide the shortest synthesis for such natural products. Through this rational analysis, one-pot total synthesis is no longer in the way of serendipity but can be precisely designed and manipulated. In this review, we account for the definition, delimitation, and categorization of self-organized total synthesis and then elucidate a comprehensive understanding of this synthetic strategy based on our intensive explorations. We also highlight the contributions of other research groups in this growing field and anticipate that it will give rise to advancing new methodologies, as well as new concepts within organic synthesis.

Django Unleashed: A Deep Dive into the Features and Advantages of the Django Framework

Django is a powerful framework for developing web applications enabling researchers and students to efficiently access and analyse organic compound data contributing to improved patient care and safety. Its security data modelling integration capabilities and user friendly interfaces make it an excellent choice for building systems that assist in reaction planning and retro synthesis enhancing the efficiency and effectiveness of chemical research and development. This paper presents a comprehensive review on the core features user friendliness and extensive documentation of the framework providing guidance and instructions on how to integrate it with these and other technologies empowering developers to create robust and innovative web applications.

Design of new dipeptide inhibitors against SARS-CoV 3CLpro: 3D-QSAR, molecular docking, MD simulation, ADMET studies and retrosynthesis strategy

The 3CL protease plays a crucial role in the life cycle of SARS-CoV. This protease is considered an important antiviral target. In the present work, the 3D-QSAR study was performed on a set composed of twenty-six dipeptide SARS-CoV 3CLpro inhibitors in order to propose the new potent anti-SARS agents with a high predicted activity value. The model of CoMSIA/SH is the optimal, with good statistical results presenting a high value of the cross-validation coefficient Q2 = 0.796 and a good value of the determination coefficient R2 = 0.887, the external validation of this model is justified by the high value of the prediction coefficient R2pred = 0.884 and the validation of Globraikh, Roy and Tropsha criteria. The exploitation of the different results provided key information about the structures favored to improve the inhibitory activity against 3CLpro, and has enabled us to propose seven new potent inhibitors with significant predictive activity values, notably compound M−1 with pKipred = 7.080. Then, a molecular docking study was performed to determine the binding energy and to identify the key interactions between the receptor (PDB ID: 1WOF) and the ligands. All the newly designed compounds showed low binding energy values as compared to the Remdesivir −8.144 kcal. mol−1 especially for compounds M−5 and M−4 with the binding affinity values −10.022 kcal. mol−1 and −9.727 kcal.mol−1 respectively. In addition, these inhibitors were verified for in silico pharmacokinetic proprieties and toxicity profile using ADMET. Two compounds M−4 and M−5 with potential results in the molecular docking were selected for the molecular dynamic simulation of 100 ns. The MM-GBSA results show that the predicted compound M−5 has the lowest free energy with −38.200 KJ/mol. We exploited the computer-aided synthesis technology using the ASKCOS website to perform a retrosynthetic analysis of compound M−5.

Novel Divinyl-Flanked Diketopyrrolopyrrole Polymer, Based on a Dimerization Strategy for High-Performance Organic Field-Effect Transistors.

In this communication, we report a novel acceptor structural unit, TVDPP, that can be distinguished from classical materials based on TDPP structures. By designing a synthetic route via retrosynthetic analysis, we successfully prepared this monomer and further prepared polymer P2TVDPP with high yield using a Stille-coupling polymerization reaction. The polymer showed several expected properties, such as high molecular weight, thermal stability, full planarity, small π-π stacking distance, smooth interface, and so on. The absorption spectra and energy levels of the polymer were characterized via photochemical and electrochemical analysis. The organic field-effect transistor (OFET), which is based on P2TVDPP, exhibited excellent carrier mobility and an on/off current ratio of 0.41 cm2 V-1 s-1 and ~107, respectively, which is an important step in expanding the significance of DPP-based materials in the field of optoelectronic devices and organic electronics.

Retrosynthetic Analysis of the Synthetic Pathway for Antineocyclocitrinol A.

With the discovery and exploration of deep-sea fungal metabolites, researchers have found that these abundant metabolites have a wide range of therapeutic effects on human diseases. Mutagenesis, purification and structural analysis of diverse deep-sea fungal metabolites have led to a new molecule named Antineocyclocitrinol A. This molecule is difficult to synthesize because it contains a complex structure such as the unusual bicyclo [4.4.1] A/B ring system with a bridgehead double bond. This paper explains an analytical strategy for retrosynthesis concretely and provides a theoretically feasible new synthetic pathway for synthesizing Antineocyclocitrinol A. This pathway fills a gap in the specific retrosynthetic analysis of Antineocyclocitrinol A and also serves as an application idea for a more detailed synthesis of cyclocitrinols analogs. Furthermore, this pathway promotes the development of the biopharmaceutical field by using deep-sea fungal metabolites.

Cover Picture: Retrosynthetic Analysis Applied to Clip‐off Chemistry: Synthesis of Four Rh(II)‐Based Complexes as Proof‐of‐Concept (Angew. Chem. Int. Ed. 48/2023)

Cover Picture: Retrosynthetic Analysis Applied to Clip‐off Chemistry: Synthesis of Four Rh(II)‐Based Complexes as Proof‐of‐Concept (Angew. Chem. Int. Ed. 48/2023)

Titelbild: Retrosynthetic Analysis Applied to Clip‐off Chemistry: Synthesis of Four Rh(II)‐Based Complexes as Proof‐of‐Concept (Angew. Chem. 48/2023)

Titelbild: Retrosynthetic Analysis Applied to Clip‐off Chemistry: Synthesis of Four Rh(II)‐Based Complexes as Proof‐of‐Concept (Angew. Chem. 48/2023)