Synthesis Of Complex Molecules Research Articles

Biased photo cleavage of N1-/N6-nitrobenzyl from 2’-hydroxyethyl-adenosine and their DNA/RNA Caged-analogues

The protection and deprotection of functional groups are critical steps during the synthesis of complex molecules. The chemo-selective and regio-selective protection-deprotection under mild conditions are always preferred. The photolabile protecting groups have such qualities. For example, o-nitrobenzyl is a versatile photolabile protecting group of amine, alcohol, and carboxylic acid. This report describes the regio-selective N-nitrobenzylation of 2′-tethered-adenosine nucleoside analogue with o-nitrobenzyl bromide, as resultant two new protected nucleosides such as 2′-hydroxylethyl-NBn1A/2′-hydroxylethyl-NBn6A are prepared. Importantly, N-nitrobezylation occurs only at adenine residue, though it is protected. This analogue has a free tethered hydroxyl group at 2′-position and remained unaffected with nitrobenzylation. Furthers, these analogues are incorporated into DNA/RNA oligonucleotides using DNA synthesizer. This report also demonstrates the photocleavage of those nitrobenzyl groups in a regio-specific manner by UV-light (λ365nm). The nitrobenyl of only NBn6A derivatives are cleavable regio-specifically with UV-light. Surprisingly, unusual chemical cleavage of nitrobenzyl of NBn1A-DNA/RNA has found during oligo syntheses. Also, the isomerization of NBn1A-DNA into NBn6A-DNA occurs. Thus only NBn6A derivatives are caged-adenosine analogues. Hence 2′-tethered-NBn6A/-NBn1A derivatives are potential analogues for regulating the biochemical activities with light.

C-C Bond Cleavage Approach to Complex Terpenoids: Development of a Unified Total Synthesis of the Phomactins.

The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C-C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C-C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C-C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.

Multiple Catalytic C-H Bond Functionalization for Natural Product Synthesis.

In the past decade, multiple catalytic C-H bond functionalization has been successfully applied in natural product synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This minireview presents selected examples making use of multiple C-H bond functionalization in conceptually different ways. First, linear syntheses are discussed, wherein multiple C-H functionalization is employed either from simple (hetero)cyclic cores, at a late stage, or to build polycyclic systems. Second, the use of multiple C-H functionalization as a strategic tool in convergent synthesis to access and couple complex fragments is discussed. Information on the scalability of the employed methods is provided when available. The presented cases indicate that multiple C-H functionalization strategies should play a great role to shape the future synthesis of functional complex molecules with improved sustainability.

Forging Odd-Membered Rings: Palladium-Catalyzed Asymmetric Cycloadditions of Trimethylenemethane.

The catalytic asymmetric synthesis of complex molecules has been the focus of our research program for several decades because such strategies have significant utility for the construction of chiral building blocks for drug development as well as the total synthesis of natural products. Cycloaddition reactions are very powerful transformations in organic synthesis providing access to highly functionalized motifs from simple starting materials. In concert with this central interest, four decades ago, we reported the palladium-catalyzed trimethylenemethane (TMM) cycloaddition for forging odd-membered ring systems. In recent years, we focused our attention on the development of powerful ligand scaffolds which enable the preparation of valuable products with complete control of chemo-, regio-, diastereo-, and enantioselectivity, thereby addressing several limitations in the field of palladium-catalyzed asymmetric cycloadditions. The first section of this Account will outline the discovery of a new class of highly modular pyrrolidine-based phosphoramidite and diamidophosphite chiral ligands which facilitate [3 + 2] cycloadditions of TMM donors, opening a new area in asymmetric construction of five-membered rings.The formation of the Pd-TMM zwitterionic intermediates is driven by the unique charge distribution of the cationic π-allyl motif, in which the most electropositive central carbon stabilizes the neighboring carbanion generated by either desilylation or deprotonation. The second section of this Account summarizes the scope of cycloadditions between Pd-TMM zwitterionic intermediates generated via desilylation and a variety of electron-deficient acceptors to access cyclopentanes, pyrrolidines and tetrahydrofurans. This section also includes the use of nitrile-, vinyl-, alkynyl- and allene-substituted TMM donors to rapidly generate cycloadducts with high molecular complexity. The extension of this strategy to include [6 + 3] cycloadditions and dearomative processes will also be presented. The third section will discuss a new generation of TMM donors substituted with electron-withdrawing groups such as nitrile, benzophenone imine, trifluoromethyl, and phosphonate, where the Pd-TMM zwitterionic intermediates are generated via deprotonation of the acidic C-H bond adjacent to the π-allyl motif. This new strategy has enabled the synthesis of heterocycles with increased numbers of functional groups in highly asymmetric and atom-economic fashion.Throughout this Account, we will describe the implementation of these transformations toward the rapid assembly of drug candidates and the total synthesis of natural products such as (-)-marcfortine C. We will also give details of mechanistic studies regarding relevant intermediates within the catalytic cycles of the different strategies, which allowed us to better understand the origin of selectivity with various donors.

Unusual Skeletal Reorganization of Oxetanes for the Synthesis of 1,2‐Dihydroquinolines

AbstractSkeletal reorganization is a type of fascinating transformations owing to their intriguing mechanisms and utility in complex molecule synthesis. However, only a limited amount of examples are known for most functional groups. Herein, we describe such an unusual process of oxetanes. In the presence of In(OTf)3 as catalyst, oxetane‐tethered anilines reacted unexpectedly to form 1,2‐dihydroquinolines. This process not only provides expedient access to dihydroquinolines, but also represents a new reaction of oxetane. Mechanistically, it is believed that the reaction proceeds through initial nitrogen attack rather than arene attack followed by a series of bond cleavage and formation events. Control experiments provided important insights into the mechanism.

Unusual Skeletal Reorganization of Oxetanes for the Synthesis of 1,2-Dihydroquinolines.

Skeletal reorganization is a type of fascinating transformations owing to their intriguing mechanisms and utility in complex molecule synthesis. However, only a limited amount of examples are known for most functional groups. Herein, we describe such an unusual process of oxetanes. In the presence of In(OTf)3 as catalyst, oxetane-tethered anilines reacted unexpectedly to form 1,2-dihydroquinolines. This process not only provides expedient access to dihydroquinolines, but also represents a new reaction of oxetane. Mechanistically, it is believed that the reaction proceeds through initial nitrogen attack rather than arene attack followed by a series of bond cleavage and formation events. Control experiments provided important insights into the mechanism.

Transfer Learning: Making Retrosynthetic Predictions Based on a Small Chemical Reaction Dataset Scale to a New Level.

Effective computational prediction of complex or novel molecule syntheses can greatly help organic and medicinal chemistry. Retrosynthetic analysis is a method employed by chemists to predict synthetic routes to target compounds. The target compounds are incrementally converted into simpler compounds until the starting compounds are commercially available. However, predictions based on small chemical datasets often result in low accuracy due to an insufficient number of samples. To address this limitation, we introduced transfer learning to retrosynthetic analysis. Transfer learning is a machine learning approach that trains a model on one task and then applies the model to a related but different task; this approach can be used to solve the limitation of few data. The unclassified USPTO-380K large dataset was first applied to models for pretraining so that they gain a basic theoretical knowledge of chemistry, such as the chirality of compounds, reaction types and the SMILES form of chemical structure of compounds. The USPTO-380K and the USPTO-50K (which was also used by Liu et al.) were originally derived from Lowe’s patent mining work. Liu et al. further processed these data and divided the reaction examples into 10 categories, but we did not. Subsequently, the acquired skills were transferred to be used on the classified USPTO-50K small dataset for continuous training and retrosynthetic reaction tests, and the pretrained accuracy data were simultaneously compared with the accuracy of results from models without pretraining. The transfer learning concept was combined with the sequence-to-sequence (seq2seq) or Transformer model for prediction and verification. The seq2seq and Transformer models, both of which are based on an encoder-decoder architecture, were originally constructed for language translation missions. The two algorithms translate SMILES form of structures of reactants to SMILES form of products, also taking into account other relevant chemical information (chirality, reaction types and conditions). The results demonstrated that the accuracy of the retrosynthetic analysis by the seq2seq and Transformer models after pretraining was significantly improved. The top-1 accuracy (which is the accuracy rate of the first prediction matching the actual result) of the Transformer-transfer-learning model increased from 52.4% to 60.7% with greatly improved prediction power. The model’s top-20 prediction accuracy (which is the accuracy rate of the top 20 categories containing actual results) was 88.9%, which represents fairly good prediction in retrosynthetic analysis. In summary, this study proves that transferring learning between models working with different chemical datasets is feasible. The introduction of transfer learning to a model significantly improved prediction accuracy and, especially, assisted in small dataset based reaction prediction and retrosynthetic analysis.

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents.

Copper-catalysed asymmetric C–C bond-forming reactions using organometallic reagents have developed into a powerful tool for the synthesis of complex molecules with single or multiple stereogenic centres over the past decades. Among the various acceptors employed in such reactions, those with a heterocyclic core are of particular importance because of the frequent occurrence of heterocyclic scaffolds in the structures of chiral natural products and bioactive molecules. Hence, this review focuses on the progress made over the past 20 years for heterocyclic acceptors.

Sensitivity of gas-grain chemical models to surface reaction barriers

Context. The feasibility of contemporary gas-grain astrochemical models depends on the availability of accurate kinetics data, in particular, for surface processes. Aims. We study the sensitivity of gas-grain chemical models to the energy barrier Ea of the important surface reaction between some of the most abundant species: C and H2 (surface C + surface H2 → surface CH2). Methods. We used the gas-grain code ALCHEMIC to model the time-dependent chemical evolution over a 2D grid of densities (nH ∈ 103, 1012 cm−3) and temperatures (T ∈ 10, 300 K), assuming UV-dark (AV = 20 mag) and partly UV-irradiated (AV = 3 mag) conditions that are typical of the dense interstellar medium. We considered two values for the energy barrier of the surface reaction, Ea = 2500 K (as originally implemented in the networks) and Ea = 0 K (as measured in the laboratory and computed by quantum chemistry simulations). Results. We find that if the C + H2 → CH2 surface reaction is barrierless, a more rapid conversion of the surface carbon atoms into methane ice occurs. Overproduction of the CHn hydrocarbon ices affects the surface formation of more complex hydrocarbons, cyanides and nitriles, and CS-bearing species at low temperatures ≲10−15 K. The surface hydrogenation of CO and hence the synthesis of complex (organic) molecules become affected as well. As a result, important species whose abundances may change by more than a factor of two at 1 Myr include atomic carbon, small mono-carbonic (C1) and di-carbonic (C2) hydrocarbons, CO2, CN, HCN, HNC, HNCO, CS, H2CO, H2CS, CH2CO, and CH3OH (in either gas and/or ice). The abundances of key species, CO, H2O, and N2 as well as O, HCO+, N2H+, NH3, NO, and most of the S-bearing molecules, remain almost unaffected. Conclusions. Further accurate laboratory measurements and quantum chemical calculations of the surface reaction barriers will be crucial to improve the accuracy of astrochemical models.

Blue LED‐Promoted Oxathiacetalization of Aldehydes and Ketones

In synthetic chemistry, the protection of aldehydes and ketones is crucial during multistep synthesis of complex molecules. Organic chemists have paid substantial attention to the synthesis of 1,3‐oxathiolanes and 1,3‐oxathianes because of their considerable stability under acidic conditions and ease of removal of protecting groups. In this paper, we report the mild and efficient oxathiacetalization of aldehydes with 2‐mercaptoethanol and 3‐mercaptopropan‐1‐ol through visible‐light‐promoted eosin‐Y catalyzed C–S and C–O bond formation at ambient temperature under metal‐free conditions. This catalytic system also affords oxathiacetalization of ketones through photoredox catalysis.

Photocatalytic Oxidative Dearomatization of Orcinaldehyde Derivatives.

For decades, oxidative dearomatization has been employed as a key step in the synthesis of complex molecules. Challenges in controlling the chemo- and site-selectivity of this transformation have sparked the development of a variety of specialized oxidants; however, these result in stoichiometric amounts of organic byproducts. Herein, we describe a photocatalytic method for oxidative dearomatization using molecular oxygen as the stoichiometric oxidant. This provides environmentally benign entry to highly substituted o-quinols, reactive intermediates which can be elaborated to a number of natural product families.

Application of Chiral Isocyanides in Multicomponent Reactions

As one of the most important building blocks in organic synthesis, isocyanides come in for a wide range of transformations owing mostly to their unusual terminal carbon center adsorbed electrophiles, reacted with nucleophiles, get involved in radical reactions and coordinated with metal centers. The distinctive feature of isocyanide is its ready willingness to participate in multicomponent reactions (MCRs). MCRs represent a great tool in organic synthesis for the construction of new lead structures in a single procedure introducing both structural diversity and molecular complexity in only one step. Isocyanide-based multicomponent reactions (IMCRs) have become a powerful approach for the synthesis of complex molecules providing high degree of atom and bond economy under very mild reaction conditions. The use of enantiomerically pure isocyanides can, in principle, bring about two advantages: (i) the possibility to obtain a stereochemically diverse adduct, controlling the absolute configuration of the starting isocyanide; and (ii) the possibility to induce diastereoselection in the multicomponent reaction. The most commonly-used IMCRs are the Ugi and Passerini reactions. Many published reviews have focused on the Ugi and Passerini reactions from different viewpoints, but this review describes advances in the application of chiral isocyanides in MCRs. The rationale for applying such diversity generating chemistries is also discussed.

Ruthenium-Catalyzed Intermolecular Coupling of Vinylic 1,2-Bisboronates with Alkynes: Stereoselective Access to Boryl-Substituted Homoallylic Alcohols.

The ruthenium catalytic addition of alkenes to alkynes has been demonstrated as a powerful synthetic tool to form diene motifs and widely applied in the synthesis of complex molecules. However, except for the intramolecular coupling, trisubstituted alkenes are unsatisfactory coupling partners with alkynes, presumably due to the increased steric hindrance. Herein, we discovered that substituted vinyl 1,2-bisboronate derivatives can serve as the trisubstituted alkene equivalents to couple with alkynes, generating various boryl-substituted homoallylic alcohol motifs with good stereoselectivity through the sequential allylboration with aldehydes. In contrast to carbon substituents on the double bond, boron substituents accelerate the alkyne coupling.

Expanding the Use of Tyrosine Phenol Lyase in the Enzymatic Synthesis of Unnatural Amino Acids

The use of enzymes in the synthesis of pharmaceuticals and biochemical tools offers an attractive approach to generating complex structures, as enzymatic reactions often lead to the formation of specific products in high yields. Tyrosine phenol lyase (TPL), an enzyme biologically involved in the degradation of tyrosine, has been used to synthesize a variety of substituted tyrosines including fluorotyrosines for biochemical studies. In addition to fluorotyrosines, expanding the scope of substrates to naphthol‐based compounds offers an attractive target for enzymatic synthesis of complex molecules, as substituted naphthols can be used as biochemical probes and as building blocks in potential pharmaceuticals. Using Citrobacter freundii TPL we enzymatically synthesized the naphthol‐analog of tyrosine, but the unnatural amino acid was generated in low yield. The simplest model for the low conversion is that the larger substrate is poorly accommodated by the enzyme active site and this poor binding leads to the low yield in the enzymatic reaction. To test this hypothesis, we mutated several bulky residues near the substrate‐binding site (M288, M397, F448) to open space for substrate binding and facilitate synthesis of the unnatural amino acid. A series of mutant plasmids were generated using site‐directed mutagenesis and sequenced to confirm the mutation. The wild type and mutant enzymes were recombinantly expressed in E. coli, purified by affinity and ion‐exchange chromatography, and purity was analyzed by gel electrophoresis. Enzyme activity with tyrosine in an NADH‐dependent coupled enzyme was first used to determine that the wild type and mutants are active, and initial results for the first mutants generated (M228S and M379A) indicate that the mutants are active. We are currently surveying reaction conditions using high‐performance liquid chromatography (HPLC) to evaluate the reactions of the TPL mutants with naphthols as substrates. HPLC is being used to determine the generation of product to calculate yields and provides a method to test if additional products are formed. While a goal of this study is aimed at the more efficient production of tyrosine derivatives, a larger goal is to better understand the features important for substrate binding in enzymatic reactions. This understanding may aid in the development of enzymes with a broad range of substrates efficiently converted to products in the biochemical generation of complex molecules.Support or Funding InformationFunding by NIH/NIGMS T34GM008074

Intermolecular Radical C-H Bond Activation: A Powerful Tool for Late Stage Functionalization.

The synthesis of complex molecules via radical reactions involving carbon-carbon and carbon-heteroatom bonds has become a very successful approach. Radical chemistry has long been dominated by the use of tin-based reagents. Those strongly contributed to the development of the field, allowing one to achieve spectacular transformations, most of which being difficult or impossible to achieve under ionic conditions, and giving access to invaluable kinetics data that paved the way for the development of improved protocols and the design of new synthetic strategies. However, tin reagents and tin byproducts are often toxic and they proved to make purification steps sometimes tedious. In this context, tin-free methods have progressively gained in interest. This short review aims at providing the reader with alternative methods employing C-H bonds in place of the classical alkyl halides to generate, via an intermolecular hydrogen atom transfer (HAT), the radical species. Examples of carbon-carbon and carbon-heteroatom bond formation using this type of C-H bond activation approach will be provided, from early reports to the more recent developments.

Reworking Organic Synthesis for the Modern Age: Synthetic Strategies Based on Continuous-Flow Addition and Condensation Reactions with Heterogeneous Catalysts.

While organic synthesis carried out in most laboratories uses batch methods, there is growing interest in modernizing fine chemical synthesis through continuous-flow processes. As a synthetic method, flow processes have several advantages over batch systems in terms of environmental compatibility, efficiency, and safety, and recent advances have allowed for the synthesis of several complex molecules, including active pharmaceutical ingredients (APIs). Nevertheless, due to several reasons related to the difficulties arising from byproduct formation during the flow process, such as lower yields, poor selectivities, clogging of columns due to poor solubility, catalyst poisoning, etc., successful examples of continuous-flow synthesis of complex organic molecules are still limited. In order to solve this bottleneck, the development of selective and atom-economical continuous-flow organic transformations are needed. This perspective highlights examples of atom-economical addition and condensation reactions with heterogeneous catalysts under continuous-flow conditions and their applications for the synthesis of complex organic molecules such as natural products and APIs. In order to realize new continuous-flow methodologies, based on addition and condensation reactions, in place of substitution reactions, the development of novel reactions and heterogeneous catalysts is required.

Remote Chirality Transfer through Medium Cycle Formation/Intramolecular Hydride Transfer Cascade

Intramolecular hydride transfer has long been recognized as a powerful method to generate new stereogenic centers induced by the existing stereogenic center(s). Synthetically significant selectivities are usually obtained through 1,5‐hydride transfer within six‐ membered ring. This mini‐review focuses on a transannular hydride transfer generating up to three stereocenters simultaneously from a single stereogenic center through formation of medium rings, mostly eight‐membered rings, in mild reaction conditions. The corresponding linear products with multiple stereocenters are potentially useful building blocks for synthesis of complex molecules including polyketide natural products.

Oxalyl-CoA Decarboxylase Enables Nucleophilic One-Carbon Extension of Aldehydes to Chiral α-Hydroxy Acids.

The synthesis of complex molecules from simple, renewable carbon units is the goal of a sustainable economy. Here we explored the biocatalytic potential of the thiamine‐diphosphate‐dependent (ThDP) oxalyl‐CoA decarboxylase (OXC)/2‐hydroxyacyl‐CoA lyase (HACL) superfamily that naturally catalyzes the shortening of acyl‐CoA thioester substrates through the release of the C1‐unit formyl‐CoA. We show that the OXC/HACL superfamily contains promiscuous members that can be reversed to perform nucleophilic C1‐extensions of various aldehydes to yield the corresponding 2‐hydroxyacyl‐CoA thioesters. We improved the catalytic properties of Methylorubrum extorquens OXC by rational enzyme engineering and combined it with two newly described enzymes—a specific oxalyl‐CoA synthetase and a 2‐hydroxyacyl‐CoA thioesterase. This enzymatic cascade enabled continuous conversion of oxalate and aromatic aldehydes into valuable (S)‐α‐hydroxy acids with enantiomeric excess up to 99 %.

Frontispiece: Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

Frontispiece: Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

Exploring Homogeneous Conditions for Mild Buchwald–Hartwig Amination in Batch and Flow

Cross-couplings are among the most frequently used reactions in complex molecule synthesis. However, the requirement of stoichiometric base can cause challenges. Harsh, insoluble inorganic bases ca...