Retrosynthetic Analysis Research Articles

A Multidimensional Journal Club Activity for an Undergraduate Advanced Organic Chemistry Course

Discussions of the primary literature are an important part of undergraduate education, and much work has been done to develop methods of integrating the literature into the curriculum. Examples include individual single-article discussion activities, literature-based courses, and regular journal club events. While many published examples focus on the use of these activities to gain experience in reading the literature and identifying specific content, fewer examples describe intentionally incorporating a more holistic discussion of the process, particularly in synthetic organic chemistry. The multidimensional journal club activity described here provides a space for students to continue practicing reading the literature, retrosynthetic analysis, synthesis development, and reaction mechanisms while also placing the process of organic synthesis as well as the target molecule (morphine) into a broader historical and societal context. Out-of-class preparation was done both individually and in small groups. The in-class portion included a group discussion of the broader context and strategies, followed by small-group presentations of synthetic steps. After the activity, the course’s take-home exam required students to consider other syntheses of morphine and their place within the greater body of work. This activity has been carried out in three separate sections of a small, condensed-format upper division organic chemistry course but can be implemented in a longer course format or potentially at the end of a second-semester organic chemistry course. Insight into the process behind the choice of materials is also provided.

An update on liquid heat capacity estimations of cyclic organic compounds by group additivity and their application in estimations of complex molecules by synthetic and retrosynthetic analysis

Group additivity is very useful technique for estimating heat capacities of organic substances. This contribution examines a concern regarding the use of this technique when estimating the heat capacities of large molecules. The concern addresses the observation of a tendency of group values, particularly liquids, to overestimate heat capacities of large cyclic or highly branched liquid compounds of a commonly used group method. Group values for estimating cyclic liquids have been updated. In addition, a protocol is also described for the estimations of both liquid and solid heat capacities of large complex molecules at T = 298.15 K that takes advantage of currently available experimental data of potential precursors. The materials estimated using this protocol include several natural products, a statin and a number of steroids. Results are compared to available experimental data.

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres.

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)-C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

Synthetic Approaches Towards Taxol; from Holton to Chida

Abstract: Nature is an inspiring source in drug discovery which constantly reveals new complex chemical structures of natural products that inherit attractive chemical challenges for organic chemists to synthesize them. Taxol is a unique natural product that impressive biological properties and a very tempting chemical structure that motivated organic chemists all over the world to enter the race for synthesizing it. The total synthesis of this highly oxygenated diterpene was completed by 11 different research groups starting from Holton (1994) to Chida (2022). This review article demonstrates the various retrosynthetic analysis of Taxol, the actual synthetic routes to it and highlights the key steps in each synthesis. It also provides a critical review of the advantages and disadvantages in all the synthetic routes in terms of number of steps, yields and the synthetic challenges.

Computer-aided key step generation in alkaloid total synthesis.

Efficient chemical synthesis is critical to satisfying future demands for medicines, materials, and agrochemicals. Retrosynthetic analysis of modestly complex molecules has been automated over the course of decades, but the combinatorial explosion of route possibilities has challenged computer hardware and software until only recently. Here, we explore a computational strategy that merges computer-aided synthesis planning with molecular graph editing to minimize the number of synthetic steps required to produce alkaloids. Our study culminated in an enantioselective three-step synthesis of (-)-stemoamide by leveraging high-impact key steps, which could be identified in computer-generated retrosynthesis plans using graph edit distances.

Six-Step Synthesis of (±)-Lysergic Acid.

This article describes a concise synthesis of lysergic acid from simple aromatic precursors. The successful strategy relies on the coupling, dearomatization, and cyclization of a halopyridine with a 4-haloindole derivative in 6 total synthetic steps from commercial starting materials. In addition to highlighting the advantages of employing dearomative retrosynthetic analysis, the design is practical and anticipated to enable the synthesis of novel neuroactive compounds as exemplified by the synthesis of a novel natural product derivative, 12-chlorolysergic acid.

A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach.

Infection of hepatitis C (HCV) is a major threat to human health throughout the world. The current therapy program suffers from restricted efficiency and low tolerance, and there is serious demand frr novel medication. NS3/4A protease is observed to be very effective target for the treatment of HCV. A data set of the already reported HCV NS3/4A protease inhibitors was first docked into the NS3/4A protease (PDB ID: 4A92A) active sites of both protease and helicase sites for calculating the docking score, binding affinity, binding mode, and solvation energy. Then the data set of these reported inhibitors was used in a computer-based program "RECAP Analyses" implemented in MOE to fragment every molecule in the subset according to simple retrosynthetic analysis rules. The RECAP analysis fragments were then used in another computer-based program "RECAP Synthesis" to randomly recombine and generate synthetically reasonable novel chemical structures. The novel chemical structures thus produced were then docked against HCV NS3/4A. After a thorough validation of all undertaken steps, based on Lipinski's rule of five, docking score, binding affinity, solvation energy, and Van der Waal's interactions with HCV NS3/4A, 12 novel chemical structures were identified as inhibitors of HCV NS3/4A. The novel structures thus designed are hoped to play a key role in the development of new effective inhibitors of HCV.

Introduction to Retrosynthesis: Strategies and Approaches

Chemical synthesis is a powerful tool for human being as it provides many useful products, especially those that do not exist or only exist in a small quantity in nature. Since it is often hard to design and visualize the reactions of organic synthesis, retrosynthesis is often used to achieve a desired product. This review is an introduction of the concepts of retrosynthetic analysis and how it can be established, including the basic steps and strategies. It also discuss the guiding principles of retrosynthesis (simplification, complexity, yield) along with some possible problems and coping strategies in the analyses, including functional group disconnections, fine tuning, and illogical disconnections.

Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline.

A concise strategy to prepare polycyclic heteroaromatics involving a deaminative contraction cascade is detailed. The efficient deaminative ring contraction involves the in situ methylation of a biaryl-linked dihydroazepine to form a cyclic ammonium cation that undergoes a base-induced [1,2]-Stevens rearrangement/dehydroamination sequence. The presence of pseudosymmetry guides the retrosynthetic analysis of pyridyl-containing polycyclic heteroaromatics, enabling their construction by the reductive cyclization and deaminative contraction of tertiary amine precursors.

Prediction of High-Yielding Single-Step or Cascade Pericyclic Reactions for the Synthesis of Complex Synthetic Targets.

Pericyclic reactions, which involve cyclic concerted transition states without ionic or radical intermediates, have been extensively studied since their definition in the 1960s, and the famous Woodward-Hoffmann rules predict their stereoselectivity and chemoselectivity. Here, we describe the application of a fully automated reaction-path search method, that is, the artificial force induced reaction (AFIR), to trace an input compound back to reasonable starting materials through thermally allowed pericyclic reactions via product-based quantum-chemistry-aided retrosynthetic analysis (QCaRA) without using any a priori experimental knowledge. All categories of pericyclic reactions, including cycloadditions, ene reactions, group-transfer, cheletropic, electrocyclic, and sigmatropic reactions, were successfully traced back via concerted reaction pathways, and starting materials were computationally obtained with the correct stereochemistry. Furthermore, AFIR was used to predict whether the identified reaction pathway can be expected to occur in good yield relative to other possible reactions of the identified starting material. In order to showcase its practical utility, this state-of-the-art technology was also applied to the retrosynthetic analysis of a natural product with a relatively high number of atoms (52 atoms: endiandric acid C methyl ester), which was first synthesized by Nicolaou in 1982 and provided the corresponding starting polyenes with the correct stereospecificity via three pericyclic reaction cascades (one Diels-Alder reaction as well as 6π and 8π electrocyclic reactions). Moreover, not only systems that obey the Woodward-Hoffmann rules but also systems that violate these rules, such as those recently calculated by Houk, can be retrosynthesized accurately.

Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV-1 Entry Inhibitor NBD-14270.

The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small-molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule's flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD-14270 by retrosynthetic analysis approach, their anti-HIV-1 activity, cellular toxicity, and structure-activity relationships. The study revealed that Scaffold A provided the best HIV-1 inhibitors with higher potency and better selectivity index (SI).

Recyclable and malleable thermosets enabled by activating dormant dynamic linkages.

Chemical recycling of polymers is critical for improving the circular economy of plastics and environmental sustainability. Traditional thermoset polymers have generally been considered permanently crosslinked materials that are difficult or impossible to recycle. Herein, we demonstrate that by activating 'dormant' covalent bonds, traditional polycyanurate thermosets can be recycled into the original monomers, which can be circularly reused for their original purpose. Through retrosynthetic analysis, we redirected the synthetic route from forming conventional C-N bonds via irreversible cyanate trimerization to forming the C-O bonds through reversible nucleophilic aromatic substitution of alkoxy-substituted triazine derivatives by alcohol nucleophiles. The new reversible synthetic route enabled the synthesis of previously inaccessible alkyl-polycyanurate thermosets, which exhibit excellent film properties with high chemical resistance, closed-loop recyclability and reprocessing capability. These results show that 'apparently dormant' dynamic linkages can be activated and utilized to construct fully recyclable thermoset polymers with a broader monomer scope and increased sustainability.

Hydrobiological Aspects of Fatty Acids: Unique, Rare, and Unusual Fatty Acids Incorporated into Linear and Cyclic Lipopeptides and Their Biological Activity

The study of lipopeptides and their related compounds produced by various living organisms from bacteria to marine invertebrates is of fundamental interest for medicinal chemistry, pharmacology, and practical clinical medicine. Using the principles of retrosynthetic analysis of linear and cyclic peptides, the pharmacological activity of unique, unusual, and rare fatty acids (FA) that are part of natural lipopeptides was investigated. To search for new biologically active natural metabolites from natural sources, more than 350 FA incorporated into linear and cyclic peptides isolated from bacteria, cyanobacteria, microalgae, marine invertebrates, fungal endophytes, and microorganisms isolated from sediments are presented. Biological activities have been studied experimentally in various laboratories, as well as data obtained using QSAR (Quantitative Structure-Activity Relationships) algorithms. According to the data obtained, several FA were identified that demonstrated strong antibacterial, antimicrobial, antifungal, or antitumor activity. Along with this, FA have been found that have shown rare properties such as antiviral, antidiabetic, anti-helmintic, anti-inflammatory, anti-psoriatic, anti-ischemic, and anti-infective activities. In addition, FA have been found as potential regulators of lipid metabolism, as well as agents for the treatment of acute neurological disorders, as well as in the treatment of atherosclerosis and multiple sclerosis. For 36 FA, 3D graphs are presented, which demonstrate their predicted and calculated activities.

Efficient Production of L-Homophenylalanine by Enzymatic-Chemical Cascade Catalysis.

L-Homophenylalanine (L-HPA) is a vital building block for the synthesis of numerous chiral drugs. However, the high cost of starting materials limits the industrial production of L-HPA. In this study, an enzymatic-spontaneous chemical cascade route for L-HPA production was designed based on retrosynthetic analysis. This route, using simple benzaldehyde and pyruvate as starting materials, is extremely cost-effective. The enzymes were screened and further assembled in E. coli, and TipheDH was identified as the rate-limiting enzyme. Therefore, TipheDH was engineered to improve its specific activity (by 82 %) and expression level (by 254 %), thus generating the best strain (W14). W14 exhibited the optimum enzyme activity ratio (1.7 : 1.1 : 1 : 1.8) and demonstrated production of 100.9 g L-1 of L-HPA (with 94 % conversion, >99 % ee) in a 5-L reactor. This route effectively exploits the power of cascades and offers insight into avenues for synthesizing other valuable chemicals from inexpensive building blocks.

Efficient Production of L‐Homophenylalanine by Enzymatic‐Chemical Cascade Catalysis

AbstractL‐Homophenylalanine (L‐HPA) is a vital building block for the synthesis of numerous chiral drugs. However, the high cost of starting materials limits the industrial production of L‐HPA. In this study, an enzymatic‐spontaneous chemical cascade route for L‐HPA production was designed based on retrosynthetic analysis. This route, using simple benzaldehyde and pyruvate as starting materials, is extremely cost‐effective. The enzymes were screened and further assembled in E. coli, and TipheDH was identified as the rate‐limiting enzyme. Therefore, TipheDH was engineered to improve its specific activity (by 82 %) and expression level (by 254 %), thus generating the best strain (W14). W14 exhibited the optimum enzyme activity ratio (1.7 : 1.1 : 1 : 1.8) and demonstrated production of 100.9 g L−1 of L‐HPA (with 94 % conversion, >99 % ee) in a 5‐L reactor. This route effectively exploits the power of cascades and offers insight into avenues for synthesizing other valuable chemicals from inexpensive building blocks.

Design, Synthesis, and Applications of ortho -Sulfur Substituted Arylphosphanes

Design, Synthesis, and Applications of <i>ortho</i> -Sulfur Substituted Arylphosphanes

Organocatalyzed Cross-Nucleophile Couplings: Umpolung of Catalytic Enamines.

The concept of umpolung, or polarity reversal, introduced by Seebach and Corey nearly half a century ago, ushered a new paradigm into synthetic chemistry. Novel connections were able to be forged among functional groups that were typically inaccessible. Conceptually, an umpolung reaction is identified only upon retrosynthetic analysis. Stoichiometric examples have served as a platform to develop and refine elegant methodologies into catalytic processes. The advent of these unconventional arrangements of canonical synthons into new points of diversity has expanded the repertoire of the synthetic toolbox. Within this context, asymmetric organocatalyzed methodologies remain rare, and there are even fewer aminocatalyzed variants.Recent years have witnessed a renaissance in α-functionalizations of aldehydes, specifically in the context of oxidative umpolung strategies. Unlike previous open-shell approaches, application of a quinone-based oxidant in conjunction with an aminocatalyst leads to a discrete, substitutionally labile quinone adduct. These have proven to be valuable building blocks toward polar reactivity─auguring the advent of new avenues to construct tetrasubstituted tertiary stereocenters through the application of conventional nucleophiles to form C-C, C-N, C-O, and C-S bonds through an organocatalyzed cross-nucleophile coupling (organo-CNC) reaction. The resulting nonepimerizable stereocenter demonstrates high optical fidelity and provides a significant advancement in many applications that suffer from racemization, such as in vivo studies.This strategy harnesses a trifunctional aminocatalyst to promote an unusual SN2 reaction at a highly congested center. The selection of the quinone oxidant and nucleophile converges to a continuum of reactivity ranging from enantioselective oxidation to stereoselective substitution. A remarkable aspect of these developments is the identification of an asymmetric SN2 dynamic kinetic resolution (SN2-DKR) manifold. These organo-CNC reactions are highly modular and demonstrate complete stereocontrol from the catalyst with minimal influence from incoming chiral nucleophiles. Leveraging this facet, these technologies have been extended to peptidic bioconjugations bearing bio-orthogonoal linker molecules.This Account aims to highlight the progress, from an internal perspective, toward directing the initial result into established methodologies. Within this construct, the underlying principles of each reaction will be disseminated with specific content on inherent challenges and opportunity. Combined, these will serve as an instructive tool to stimulate applications in cross-disciplinary interfaces.

MegaSyn: Integrating Generative Molecular Design, Automated Analog Designer, and Synthetic Viability Prediction.

Generative machine learning models have become widely adopted in drug discovery and other fields to produce new molecules and explore molecular space, with the goal of discovering novel compounds with optimized properties. These generative models are frequently combined with transfer learning or scoring of the physicochemical properties to steer generative design, yet often, they are not capable of addressing a wide variety of potential problems, as well as converge into similar molecular space when combined with a scoring function for the desired properties. In addition, these generated compounds may not be synthetically feasible, reducing their capabilities and limiting their usefulness in real-world scenarios. Here, we introduce a suite of automated tools called MegaSyn representing three components: a new hill-climb algorithm, which makes use of SMILES-based recurrent neural network (RNN) generative models, analog generation software, and retrosynthetic analysis coupled with fragment analysis to score molecules for their synthetic feasibility. We show that by deconstructing the targeted molecules and focusing on substructures, combined with an ensemble of generative models, MegaSyn generally performs well for the specific tasks of generating new scaffolds as well as targeted analogs, which are likely synthesizable and druglike. We now describe the development, benchmarking, and testing of this suite of tools and propose how they might be used to optimize molecules or prioritize promising lead compounds using these RNN examples provided by multiple test case examples.

Driving Aspirational Process Mass Intensity Using Simple Structure-Based Prediction

An important metric for gauging the impact that a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step-PMI for a given synthesis from a process description is more and more common across the pharmaceutical industry, especially in process chemistry departments. As with other pharmaceutical companies, our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with eight EPA Green Chemistry Challenge Awards in the last 15 years, and we show how these routes help define aspirational PMI targets. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what a “good” PMI for a molecule looks like given its structure alone. An existing tool that chemists have at their disposal to predict PMI requires the synthetic route be provided or proposed (e.g., via retrosynthetic analysis) which then enables practitioners to compare predicted PMIs between routes. We have developed SMART-PMI (in-Silico MSD Aspirational Research Tool) to complement existing tools by predicting PMI from molecular structure alone. Using only a 2D chemical structure, we can generate a predicted SMART-PMI from a measure of molecular complexity and molecular weight. We show how these predictions correlate with historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges which we termed “Successful”, “World Class”, and “Aspirational” PMI. The goal of this range is to set the floor for what is a “good” PMI for a given molecule and provide ambitious targets to drive innovative green chemistry. Using this model, chemists can develop synthetic strategies that make the biggest impact on PMI. As innovation in chemistry and processes leads to better and better PMIs, in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI, in combination with other existing PMI tools, to set industry-wide aspirational PMI targets is discussed.

Green P(AAm-co-DADMAC) Copolymeric Material as Catalyst for Synthesis of Potential Phytohormones of Phenylazophenoxy-acetic Acids by Phase Transfer

Several phenylazophenoxyacetic acid derivatives were obtained starting from azophenols and ethyl chloroacetate by an environmentally friendly approach. The synthesis reaction was carried out in heterogeneous medium using P(AAm-co-DADMAC) copolymer. Good results have been obtained thanks to phase transfer catalysis. Retrosynthetic and structural analysis were performed.