Synthesis Of Complex Molecules Research Articles

Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles

Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C–O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp3)–C(sp2) cross-coupling via asymmetric activation of aromatic C–O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp3)–C(sp2) cross-coupling via enantioselective activation of aromatic C–O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2’-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.

Enantioselective Cobalt-Catalyzed Hydroboration of Ketone-Derived Silyl Enol Ethers.

Catalytic asymmetric hydroboration of alkenes is a powerful tool for the synthesis of natural products, agrochemicals, and pharmaceuticals via the versatile transformations of chiral alkyl boronic esters. However, the scope of available alkenes is limited to styrenes, activated alkenes, and compounds with directing groups. The catalytic enantioselective hydroboration of heteroatom-substituted alkenes is rarely explored and those catalyzed by earth-abundant metals are yet to be reported. Herein, we report a cobalt-catalyzed asymmetric hydroboration of ketone-derived silyl enol ethers and provide a convenient approach to access valuable enantiopure β-hydroxy boronic esters. This protocol features mild reaction conditions, a broad substrate scope, and excellent enantioselectivities (up to 99 % ee). This approach was applied in the successful synthesis of salmeterol and albuterol, demonstrating its potential to streamline complex molecule synthesis.

Green protocols for Tsuji–Trost allylation: an overview

Abstract Since its inception in 1960s, the Tsuji–Trost reaction, an allylic substitution reaction with diverse nucleophiles such as phenols, amines, thiols, and active methylene compounds, has remained as one of the most useful and widely used organic reactions for the construction of C–C and C–heteroatom bonds. Allylic compounds such as allylic acetates, alcohols, halides, and carbonates undergo this transformation which plays an important role in the total synthesis of various natural products. The competence to incorporate synthetically demanding allylic functionalities makes it a beneficial tool for the synthesis of complex molecules. Over the last two decades, major advancements for this unique and facile Tsuji–Trost allylation reaction have been made with special emphasis to develop greener and sustainable protocols. This chapter presents an update on the significant progress focusing on the newly designed catalytic systems with high efficiency, the use of eco-friendly solvents or solvent-free conditions, low or room temperature conditions and waste management, along with future outlook.

Enantioselective Cobalt‐Catalyzed Hydroboration of Ketone‐Derived Silyl Enol Ethers

Catalytic asymmetric hydroboration of alkenes is a powerful tool for the synthesis of natural products, agrochemicals, and pharmaceuticals via the versatile transformations of chiral alkyl boronic esters. However, the scope of available alkenes is limited to styrenes, activated alkenes, and compounds with directing groups. The catalytic enantioselective hydroboration of heteroatom-substituted alkenes is rarely explored and those catalyzed by earth-abundant metals are yet to be reported. Herein, we report a cobalt-catalyzed asymmetric hydroboration of ketone-derived silyl enol ethers and provide a convenient approach to access valuable enantiopure β-hydroxy boronic esters. This protocol features mild reaction conditions, a broad substrate scope, and excellent enantioselectivities (up to 99 % ee). This approach was applied in the successful synthesis of salmeterol and albuterol, demonstrating its potential to streamline complex molecule synthesis.

Remote B-Ring Oxidation of Sclareol with an Engineered P450 Facilitates Divergent Access to Complex Terpenoids.

Though chiral pool synthesis is widely accepted as a powerful strategy in complex molecule synthesis, the effectiveness of the approach is intimately linked to the range of available chiral building blocks and the functional groups they possess. To date, there is still a pressing need for new remote functionalization methods that would allow the installation of useful chemical handles on these building blocks to enable a broader spectrum of synthetic manipulations. Herein, we report the engineering of a P450BM3 variant for the regioselective C-H oxidation of sclareol at C6. The synthetic utility of the resulting product was demonstrated in a formal synthesis of ansellone B, the first total synthesis of the 2,3-seco-labdane excolide B, and a model study toward (+)-pallavicinin.

Methane as a reddish coating agent

Experiments in quartz ampoules that simulate the saltation of quartz grains in a methane atmosphere show that the solid phase acquires a reddish color, reminiscent of the color observed on Triton, Pluto, and Charon. Reflection spectroscopy of the coated grains show a wide, continuous absorption spectrum peaking at near-UV wavelengths, in line with the reddish color. X-ray photoelectron spectroscopy indicates the grains are coated with a substance containing CC and CO bonds, and estimates the average thickness of the surface layer to 2.3 Å. Solid state Raman measurements of the coating shows a transition at 1540 cm−1. A model is proposed to describe these measurements. The model is a polydiene, anchored to the quartz surface. Electron structure calculations show that a polydiene with around 8 CH units reproduces the measurements. AFM-IR experiments support this result. Our findings suggest a pathway for synthesis of complex molecules with CC bonds on planets and moons with a solid surface and a methane-containing atmosphere.

Synthesis of α-tertiary amines by polysulfide anions photocatalysis via single-electron transfer and hydrogen atom transfer in relays

α,α,α-Trisubstituted amines (α-tertiary amines) are an important class of compounds in drug discovery programs. Herein, we report a photocatalytic method to synthesize α-tertiary amines using polysulfide anions as photocatalysts that facilitate single-electron transfer (SET) and hydrogen atom transfer (HAT) in relays to enable α-C–H functionalization of α-secondary benzylamines with cyanoarenes or aryl ketones under irradiation with visible light. The keys enabling advance in the present protocol take advantage of highly negative photoexcited oxidation potential of polysulfide dianions (S n 2− , n = 4 or 6) to cover a range of cyanoarenes and aryl ketones for their SET reduction as well as the catenated structure of polysulfide anion radicals (S n ⋅– , n = 4 or 6) capable of polarity-driven HAT at the hindered α-amino benzylic C–H bond. Thus, ensuing coupling of cyanoarene radical anions or ketyl anion radicals with α-amino benzylic radicals allows for facile construction of sterically congested α-tertiary amine scaffolds. • Readily available polysulfide anions serve as photocatalysts • Single-electron transfer and hydrogen atom transfer in relays • Protecting group-free approaches toward the synthesis of α-tertiary amines Visible light photocatalysis has made tremendous advancement in contemporary chemical synthesis of complex molecules. In most cases, precious transition metal complexes or organic dyes of heavier molecular weight have been employed as the photocatalyst to drive the desired molecular transformations. In this work, we adopted readily available polysulfide anions as the photocatalysts that perform single-electron transfer and hydrogen atom transfer in relays, enabling the synthesis of α-tertiary amines. The photocatalytic protocol streamlines the coupling of cyanoarenes or aryl ketones with α-secondary benzylamines to afford various α-tertiary amines, which are otherwise difficult to be constructed. A photocatalytic method to synthesize α-tertiary amines has been developed using polysulfide anions as photocatalysts that facilitate single-electron transfer and hydrogen atom transfer in relays to enable α-C–H functionalization of α-secondary benzylamines with cyanoarenes or aryl ketones under irradiation with visible light.

Coordination‐Controlled Nickel‐Catalyzed Benzylic Allylation of Unactivated Electron‐Deficient Heterocycles

AbstractHeterocycles are widespread in pharmaceuticals but methods for their transition metal‐catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel‐catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3‐dimethyl‐indoles. The exquisite selectivity for benzylic sites at the 2‐position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP)2 subverting generally presumed pKa’s of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

Coordination-Controlled Nickel-Catalyzed Benzylic Allylation of Unactivated Electron-Deficient Heterocycles.

Heterocycles are widespread in pharmaceuticals but methods for their transition metal-catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel-catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3-dimethyl-indoles. The exquisite selectivity for benzylic sites at the 2-position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP)2 subverting generally presumed pKa 's of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

Industrially Relevant Enzyme Cascades for Drug Synthesis and Their Ecological Assessment.

Environmentally friendly and sustainable processes for the production of active pharmaceutical ingredients (APIs) gain increasing attention. Biocatalytic synthesis routes with enzyme cascades support many stated green production principles, for example, the reduced need for solvents or the biodegradability of enzymes. Multi-enzyme reactions have even more advantages such as the shift of the equilibrium towards the product side, no intermediate isolation, and the synthesis of complex molecules in one reaction pot. Despite the intriguing benefits, only a few enzyme cascades have been applied in the pharmaceutical industry so far. However, several new enzyme cascades are currently being developed in research that could be of great importance to the pharmaceutical industry. Here, we present multi-enzymatic reactions for API synthesis that are close to an industrial application. Their performances are comparable or exceed their chemical counterparts. A few enzyme cascades that are still in development are also introduced in this review. Economic and ecological considerations are made for some example cascades to assess their environmental friendliness and applicability.

Transfer C–H borylation of alkenes under Rh(I) catalysis: Insight into the synthetic capacity, mechanism, and selectivity control

Transfer C–H borylation of alkenes bears the potential to unlock a range of attractive transformations for modular synthesis and late-stage derivatization of complex molecules. However, its scarce precedence and a limited mechanistic understanding hinders the development of practical synthetic protocols. Here, we report a Rh(I)-catalyzed transfer C–H borylation that is applicable to various terminal and internal alkenes and compatible with a plethora of functional groups, including often problematic motifs. The successful late-stage borylation of bioactive molecules, including derivatives of macrocyclic zearalenol and the drug brompheniramine, underscores its synthetic capacity. A thorough mechanistic investigation involving a series of catalytic and stoichiometric experiments as well as computational studies gave insight into the full catalytic cycle employing a β-boryl elimination, which is unprecedented for Rh-catalysis, and elucidated the features controlling the activity and the selectivity. This work sets the stage for the development of other hydrogen-for-functional group exchange reactions undergoing similar pathways.

Boosting Mass Exchange between Pd/NC and MoC/NC Dual Junctions via Electron Exchange for Cascade CO2 Fixation.

Merging existing catalysts together as a cascade catalyst may achieve "one-pot" synthesis of complex but functional molecules by simplifying multistep reactions, which is the blueprint of sustainable chemistry with low pollutant emission and consumption of energy and materials only when the smooth mass exchange between different catalysts is ensured. Effective strategies to facilitate the mass exchange between different active centers, which may dominate the final activity of various cascade catalysts, have not been reached until now, even though charged interfaces due to work function driven electron exchange have been widely observed. Here, we successfully constructed mass (reactants and intermediates) exchange paths between Pd/N-doped carbon and MoC/N-doped carbon induced by interfacial electron exchange to trigger the mild and cascade methylation of amines using CO2 and H2. Theoretical and experimental results have demonstrated that the mass exchange between electron-rich MoC and electron-deficient Pd could prominently improve the production of N,N-dimethyl tertiary amine, which results in a remarkably high turnover frequency value under mild conditions, outperforming the state-of-the-art catalysts in the literature by a factor of 5.9.

C-C Bond Cleavage of α-Pinene Derivatives Prepared from Carvone as a General Strategy for Complex Molecule Synthesis.

The preparation of complex molecules (e.g., biologically active secondary metabolites) remains an important pursuit in chemical synthesis. By virtue of their sophisticated architectures, complex natural products inspire total synthesis campaigns that can lead to completely new ways of building molecules. In the twentieth century, one such paradigm which emerged was the use of naturally occurring "chiral pool terpenes" as starting materials for total synthesis. These inexpensive and naturally abundant molecules provide an easily accessed source of enantioenriched material for the enantiospecific preparation of natural products. The most common applications of chiral pool terpenes are in syntheses where their structure can, entirely or largely, be superimposed directly onto a portion of the target structure. Less straightforward uses, where the structure of the starting chiral pool terpene is not immediately evident in the structure of the target, can be more challenging to implement. Nevertheless, these "nonintuitive" approaches illustrate the ultimate promise of chiral pool-based strategies: that any single chiral pool terpene could be applied to syntheses of an indefinite number of structurally diverse complex synthetic targets.By definition, such strategies require carefully orchestrated sequences of C-C bond forming and C-C cleaving reactions which result in remodeling of the terpene architecture. The combination of traditional rearrangement chemistry and transition-metal-catalyzed C-C cleavage methods, the latter of which were primarily developed in the early twenty-first century, provide a rich and powerful toolbox for implementing this remodeling approach. In this Account, we detail our efforts to use a variety of C-C cleavage tactics in the skeletal remodeling of carvone, a chiral pool terpene. This skeletal remodeling strategy enabled the reorganization of the carvone scaffold into synthetic intermediates with a variety of carboskeletons, which we, then, leveraged for the total syntheses of structurally disparate terpene natural products.We begin by describing our initial investigations into various, mechanistically distinct C-C cleavage processes involving cyclobutanols synthesized from carvone. These initial studies showcased how electrophile-mediated semipinacol rearrangements of these cyclobutanols can lead to [2.2.1]bicyclic intermediates, and how Rh- and Pd-catalyzed C-C cleavage can lead to a variety of densely functionalized cyclohexenes pertinent to natural product synthesis. We, then, present several total syntheses using these synthetic intermediates, beginning with the bridged, polycyclic sesquiterpenoid longiborneol, which was synthesized from a carvone-derived [2.2.1]bicycle following a key semipinacol rearrangement. Next, we discuss how several members of the macrocyclic phomactin family were synthesized from a cyclohexene derivative prepared through a Rh-catalyzed C-C cleavage reaction. Finally, we describe our synthesis of the marine diterpene xishacorene B, which was prepared using a key Pd-catalyzed C-C cleavage/cross-coupling that facilitated the assembly of the core [3.3.1]bicycle that is resident in the natural product structure.

Minimal mechanism for cyclic templating of length-controlled copolymers under isothermal conditions.

The production of sequence-specific copolymers using copolymer templates is fundamental to the synthesis of complex biological molecules and is a promising framework for the synthesis of synthetic chemical complexes. Unlike the superficially similar process of self-assembly, however, the development of synthetic systems that implement templated copying of copolymers under constant environmental conditions has been challenging. The main difficulty has been overcoming product inhibition or the tendency of products to adhere strongly to their templates-an effect that gets exponentially stronger with the template length. We develop coarse-grained models of copolymerization on a finite-length template and analyze them through stochastic simulation. We use these models first to demonstrate that product inhibition prevents reliable template copying and then ask how this problem can be overcome to achieve cyclic production of polymer copies of the right length and sequence in an autonomous and chemically driven context. We find that a simple addition to the model is sufficient to generate far longer polymer products that initially form on, and then separate from, the template. In this approach, some of the free energy of polymerization is diverted into disrupting copy-template bonds behind the leading edge of the growing copy copolymer. By additionally weakening the final copy-template bond at the end of the template, the model predicts that reliable copying with a high yield of full-length, sequence-matched products is possible over large ranges of parameter space, opening the way to the engineering of synthetic copying systems that operate autonomously.

Cover Feature: Asymmetric Direct/Stepwise Dearomatization Reactions Involving Hypervalent Iodine Reagents (Chem. Asian J. 4/2022)

Cyclic unsaturated ketone frameworks, which are obtained as the dearomatized products of phenols and their derivatives, are valuable to the synthesis of complex molecules and also contribute to the generation of products that can be readily employed for further transformations. Herein, the use of hypervalent iodine compounds to access enantioenriched compounds through direct and stepwise dearomatization reactions have been elaborated. More information can be found in the Review by Ravi Kumar, Fateh V. Singh, Naoko Takenaga, and Toshifumi Dohi.

Controlled and Predictably Selective Oxidation of Activated and Unactivated C(sp3)-H Bonds Catalyzed by a Molybdenum-Based Metallomicellar Catalyst in Water.

The synthesis of carbonyl derivatives from renewable feedstocks, by direct oxidation/functionalization of activated and unactivated C(sp3)-H bonds under a controlled and predictably selective fashion, especially in late stages, remains a formidable challenge. Herein, for the first time, cost-effective and widely applicable protocols for controlled and predictably selective oxidation of petroleum waste and feedstock ingredients like methyl-/alkylarenes to corresponding value-added carbonyls have been developed, using a surfactant-based oxodiperoxo molybdenum catalyst in water. The methodologies use hydrogen peroxide (H2O2) as an environmentally benign green oxidant, and the reactions preclude the need of any external base, additive, or cocatalyst and can be operated under mild eco-friendly conditions. The developed protocols show a wide substrate scope and eminent functional group tolerance, especially oxidation-liable and reactive boronic acid groups. Upscaled multigram synthesis of complex steroid molecules by late-stage oxidation proves the robustness and practical utility of the current protocol since it employs an inexpensive recyclable catalyst and an easily available oxidant. A plausible mechanism has been proposed with the help of few controlled experiments and kinetic and computational studies.

Recent Progress in Chromium-Mediated Carbonyl Addition Reactions

AbstractOrganochromium(III) species are versatile nucleophiles in complex molecule synthesis due to their high functional group tolerance and chemoselectivity for aldehydes. Traditionally, carbonyl addition reactions of organochromium(III) species were performed through reduction of organohalides either using stoichiometric chromium(II) salts or catalytic chromium salts in the presence of stoichiometric reductants [such as Mn(0)]. Recently, alternative methods emerged involving organoradical formation from readily available starting materials (e.g., N-hydroxyphthalimide esters, alkenes, and alkanes), followed by trapping the radical with stoichiometric or catalytic chromium(II) salts. Such methods, especially using catalytic chromium(II) salts, will lead to the development of sustainable chemical processes minimizing salt wastes and number of synthetic steps. In this review, methods for generation of organochromium(III) species for addition reactions to carbonyl compounds, classified by nucleophiles are described.1 Introduction2 Alkylation2.1 Branch-Selective Reductive Alkylation of Aldehydes Using Unactivated Alkenes2.2 Linear-Selective Alkylation of Aldehydes2.2.1 Catalytic Decarboxylative Alkylation of Aldehydes Using NHPI ­Esters2.2.2 Catalytic Reductive Alkylation of Aldehydes Using Unactivated Alkenes2.2.3 Alkylation of Aldehydes via C(sp3)–H Bond Functionalization of Unactivated Alkanes2.3 Catalytic α-Aminoalkylation of Carbonyl Compounds3 Allylation3.1 Catalytic Allylation of Aldehydes via Three-Component Coupling3.2 Catalytic Allylation of Aldehydes via C(sp3)–H Bond Functionalization of Alkenes4 Propargylation: Catalytic Propargylation of Aldehydes via Three-Component Coupling5 Conclusion

Selenonium ylides: synthesis, characterization, and applications to photo-induced cyclopropanation reactions.

Carbenes are important and highly reactive intermediates for the synthesis of various complex molecules. They are now an indispensable chemical species in organic chemistry and are used frequently to synthesize complex compounds in drug discovery chemistry. In general, carbenes are synthesized by a combination of transition metal catalysts and diazo compounds or by the decomposition reactions of diazo compounds. This paper reports the development of the visible light for the photochemical generation of carbenes from a novel C,Se-selenonium ylide. Overall, this photochemical carbene generation method using C,Se-selenonium ylide does not require a catalyst, is simple to perform, and enables highly efficient cyclopropanation reactions with alkenes.

Emergence of Pyrimidine-Based meta-Directing Group: Journey from Weak to Strong Coordination in Diversifying meta-C–H Functionalization

C-H activation has emerged as a powerful transformative synthetic tool to construct complex molecular frameworks, which are ubiquitous in natural products, medicines, dyes, polymers, and many more. However, reactivity and selectivity, arising from the inertness of C-H bonds and their overabundance in organic molecules, are the two major fundamental challenges in developing various carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation reactions via C-H activation technique. Functional groups with coordinating capacity to the transition metal catalysts, profoundly known as directing groups (DGs), have shown great promise in exerting selective C-H activation, often called site-selective or regioselective transformation of a target molecule. Advent of directing group (DG)-assisted strategies not only has resolved the selectivity issues but also offers a unique solution to the rapid synthesis of complex molecules in a convenient and predictable manner. Our laboratory, in this regard, is fascinated by the prospect of DG-assisted distal C-H functionalization of arenes, in which the target C-H bond is remotely located from the existing directing group. Notably, in opposition to proximal ortho-C-H activation, which proceeded via an energetically favorable five- to seven-membered metallacycle, distal C-H activation remained a formidable challenge as it required formation of a large macrocyclic metallacycle. Therefore, designing a suitable directing template that would maintain the required distance and geometric relationship between the target C-H bond and the appended directing auxiliary in order to ensure the prolific delivery of the metal catalyst to the closest proximity of targeted distal C-H bond was the key to success. In this regard, the Yu group devised an elegant "U-shaped" template for the first time to execute distal meta-C-H activation recruiting a cyano-based directing group. Our initial effort to diversify the scope of meta-C-H functionalization using a cyano-based template led us to realize that the "cyano-based DGs" are intrinsically limited with weak coordinating ability, competitive binding mode (end-on vs side-on), and incompatibility with acidic and basic reaction conditions. In search of a robust directing auxiliary, we were intrigued by the possibility of using the strongly coordinating ability of pyrimidine and quinoline-based DGs.In this Account, we describe our journey from the weakly coordinating cyano-based DG to the strongly coordinating pyrimidine-based DG to achieve diverse meta-C-H functionalization of electronically and sterically unbiased arenes. While some of the functionalizations were achieved by finding suitable reaction conditions, others were led by mechanistic understanding. Notably, initial development in this realm was constrained with short linkers, in which the DG was attached to the arene of interest through 2-4 atoms. In later studies, we demonstrated that the selective meta-C-H activation can be attained even though the DG is 10-atoms away from the targeted arene. More importantly, a transient DG was successfully utilized to deliver meta-C-H olefination of arenes via in situ imine formation, which provided a step-economic route to meta-C-H activation.We hope that this Account will stimulate further template design and will provide a guiding platform for the future development of distal meta-C-H functionalization.

Selective Degradation of Lignosulfonate and Lignin with Periodate to 5‐Iodovanillin

AbstractThis work represents a new method that uses electrochemically generated periodate to oxidize side‐stream lignins. Using periodate, a lignin‐derived product other than vanillin becomes accessible. The development of an eco‐friendly method for generating 5‐iodovanillin from lignin is reported and is of significant interest for the wood‐based industry. Wider utilization of lignin can substitute fossil‐based chemicals and fuels, reduce the emission of greenhouse gases, and facilitate the dependence on fossil energy. The reaction conditions are easy to conduct, the lignin is modified, and no specific setup is required. This one‐pot cost‐efficient method does not use toxic or harmful metals and yields more than 15 wt% 5‐iodovanillin. 5‐Iodovanillin represents an advanced building block for the synthesis of complex molecules, such as active pharmaceutical ingredients.