Synthesis Of Complex Natural Products Research Articles

Chemoenzymatic Oxidation of Labdane and Formal Synthesis of Nimbolide.

In nature, basic terpene skeletons are produced and subsequently undergo enzymatic or nonenzymatic oxidative transformations, leading to diverse structural variations. To date, thousands of natural products featuring a variety of oxidation patterns have been isolated solely from the labdane family. This work describes a strategy for the comprehensive introduction of oxidation states into the labdane core by employing a combination of enzyme library screening, directed evolution, and sequential chemical oxidation processes. Furthermore, we showcase the functional viability of our chemoenzymatic approach by accomplishing a formal synthesis of nimbolide, highlighting its potential for streamlining the synthesis of complex natural products.

Generation and Coupling of Radical Species from α-Alkoxy Bridgehead Carboxylic Acid, Selenide, Telluride, Acyl Selenide, and Acyl Telluride.

α-Alkoxy bridgehead radicals enable intermolecular construction of sterically congested C-C bonds due to their sterically accessible nature. We implemented these radical species into total syntheses of various densely oxygenated natural products and demonstrated their exceptional versatility. Herein, we employed different precursors to generate the same α-alkoxy bridgehead radical and compared the efficacy of the precursors for coupling reactions. Specifically, the bridgehead radical of the trioxaadamantane structure was formed from α-alkoxy carboxylic acid, selenide/telluride, and acyl selenide/acyl telluride, and reacted with 4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-one and 5-oxo-1-cyclopentene-1-carbonitrile. The efficiency of the bridgehead radical formation and subsequent coupling reaction significantly depended on the structures of the precursors and acceptors as well as the reaction conditions. Our findings provide new insights for selecting the appropriate substrates of key coupling reactions in the total synthesis of complex natural products.

Organic Electrosynthesis: A Promising Green Tool in Solving Key Steps for the Total Synthesis of Complex Natural Products

Abstract: Electro-organic synthesis, an atom-efficient, sustainable, mild process, permits an ecofriendly and elegant green path to synthesize structurally complex, still valuable molecules, avoiding the use of conventional harsh oxidizing and reducing agents and long-route reaction protocols. Being one of the oldest forms of reaction setups in a laboratory, it deals with fundamental redox chemistry through the direct application of electrical potential. Here flow of electrons acts as an oxidizing agent at the anode at the same time reducing agent at the cathode, depending upon the requirement of the reaction. Simultaneously, it minimizes the generation of reagent waste during the reaction. However, electrifying organic synthesis plays more than preventing the waste footprint. This technology provides an alternative roadmap through nonclassical bond disconnections to access desired target molecules by cutting down a number of steps with the formation of apparently looking difficult bonds with excellent regio-, chemo-and stereoselectivity. Hence, it emerges as an alternative and attractive technique for the contemporary synthetic communities. Consequently, in recent years, multiple milestones have been achieved in the electro-organic synthesis of fascinating natural products through oxidative C-C bond formation, C-H/N-H functionalization, very rare oxidative N-N dimerization, RCDA dimerization, etc. Thus, synthesis of extremely complex natural products through finding new electro-synthetic route as a key methodology have become one of the alluring synthetic targets to synthetic chemists because of their versatile utilities in medicine, agriculture, food, and cosmetic industry. This review presents advances in electrochemistry in the total synthesis of 20 complex natural products reported since 2013. Enabling synthetic steps are analyzed alongside innate advantages as well as future prospects are speculated.

Gold-Catalyzed Oxidative Rearrangement Strategy to Yield 2-Hydroxycyclohepta-1,3-diene-1-carbonyl Compounds.

A gold-catalyzed oxidative rearrangement of propargyl alcohols, derived from commercially available cyclohex-2-en-1-ones and alkynes, was successfully developed for the efficient synthesis of seven-membered rings. Thorough investigations were conducted to optimize the reaction conditions and evaluate its compatibility with various functional groups. Additionally, this methodology was applied to the formal total synthesis of guanacastepene A, demonstrating its practical utility in complex natural product synthesis. This versatile and efficient approach opens up new possibilities for the construction of diverse seven-membered ring systems, providing valuable building blocks for further exploration in drug discovery and the synthesis of intricate molecules.

Concise Total Synthesis of (-)-Bipolarolide D.

Here we report the first and concise total synthesis of a complex ophiobolin-derived sesterterpene, bipolarolide D, which hinges on two strategic applications of pentafulvene: (1) enantioselective pentafulvene-involved [6+2] cycloaddition; (2) regioselective and diastereoselective pentafulvene-involved Heck cyclization. Late-stage selective allylic addition to the ketone moiety facilitates the successful installation of the side chain. This strategy enabled the accomplishment of its first enantioselective total synthesis through a modular approach. This synthesis will facilitate the investigation of relevant biological activities and provide a synthetic blueprint for utilizing fulvenes as versatile synthons in other complex natural product synthesis.

Total Synthesis of Keramaphidin B and Ingenamine by Base-Catalyzed Diels-Alder Reaction Using Dynamic Regioselective Crystallization.

The control of the selectivity is a central issue in the total synthesis of complex natural products. In this paper, we report the total synthesis of (±)-keramaphidin B and (±)-ingenamine. The key reaction is a DMAP-catalyzed Diels-Alder reaction in which the regioselectivity is completely controlled by dynamic crystallization. Our synthesis successfully demonstrates that dynamic crystallization can be an alternative when the selectivity is not controlled by either kinetic or thermodynamic approaches in solution.

Exploring the synthetic potential of epoxide ring opening reactions toward the synthesis of alkaloids and terpenoids: a review.

Epoxides are oxygen containing heterocycles which are significantly employed as crucial intermediates in various organic transformations. They are considered highly reactive three-membered heterocycles due to ring strain and they undergo epoxide ring opening reactions with diverse range of nucleophiles. Epoxide ring-opening reactions have gained prominence as flexible and effective means to obtain various functionalized molecules. These reactions have garnered substantial attention in organic synthesis, driven by the need to comprehend the synthesis of biologically and structurally important organic compounds. They have also found applications in the synthesis of complex natural products. In this review article, we have summarized the implementation of epoxide ring opening reactions in the synthesis of alkaloids and terpenoids based natural products reported within the last decade (2014-2023).

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

Direct trifluoromethylselenolations of electron-rich (hetero)aromatic rings with N-trifluoromethylselenolating saccharin.

A novel, easily synthesizable, shelf-stable electrophilic trifluoromethylselenolating reagent, N-trifluoromethylselenosaccharin, has been developed. This reagent can be synthesized in good yield by a two-step one-pot reaction from BnSeCF3, SO2Cl2, and silver saccharin. N-Trifluoromethylselenosaccharin proves to be an efficient trifluoromethylselenolating reagent, enabling the direct trifluoromethylselenolation of various electron-rich aromatic and heteroaromatic rings under mild reaction conditions. It exhibits excellent chemoselectivity and excellent compatibility with various functional groups, making it suitable for late-stage trifluoromethylselenolation applications in complex natural product and drug synthesis.

The Intermolecular Pauson‐Khand Reaction: Applications, Challenges, and Opportunities

AbstractThe rapid assembly of complex organic molecules from simple and structurally diverse building blocks is a prevalent challenge in organic synthesis. The Pauson‐Khand reaction (PKR) is a method of choice for the construction of five membered rings that has historically been popularized as a late‐stage intramolecular cyclization method. The intermolecular version of the PKR, on the other hand, constitutes a powerful approach for the rapid assembly of densely functionalized cyclopentanic cores at early stages of a synthetic sequence. Despite its potential, the intermolecular PKR is much less prevalent in the organic synthesis literature due to several historical limitations, most importantly a reduced scope with respect to the alkene component of the reaction. The last decade has witnessed important developments in the area including a) experimental and theoretical studies that provide a good mechanistic understanding of the reaction and its selectivity, b) methodological developments that have broadened the scope of potential alkene partners, and c) the development of catalytic enantioselective versions that provide useful levels of enantioselectivity. In parallel, remarkable synthetic applications of the intermolecular PKR have emerged, including (enantioselective) total syntheses of complex natural products (polycyclic terpenes, alkaloids, prostanes) as well as examples of industrial relevance. A fundamental limitation of the PKR that needs to be addressed in the future is the current lack of a ligand‐accelerated version of the reaction, which would be a promising advance towards developing more efficient and general catalytic (enantioselective) reactions.

Chiral Hydroxamic Acid Ligands in the Asymmetric Synthesis of Natural Products

Chiral hydroxamic acid (HA) and bis-hydroxamic acid (BHA) ligands have made significant contributions to the field of asymmetric synthesis, particularly in the synthesis of natural products. These ligands possess unique molecular structures that allow for exceptional stereochemical control, leading to their widespread use in catalytic systems. This review highlights the advancements made in asymmetric synthesis using chiral hydroxamic acid and bis-hydroxamic acid ligands and their impact on the synthesis of complex natural products. This discussion encompasses their role in enantioselective C–C bond formation, the functionalization of C–H bonds, the asymmetric transformations involving heteroatoms, and their application in the total synthesis of natural products. The versatility and efficiency of chiral hydroxamic acid ligands and bis-hydroxamic acid ligands make them invaluable tools for synthetic chemists working towards the efficient and selective synthesis of natural products. This review provides a comprehensive overview of their contributions, showcasing their potential to expand the boundaries of chemical synthesis and access the diverse array of natural product scaffolds.

Biomimetic tail-to-head terpene cyclizations using the resorcin[4]arene capsule catalyst.

The tail-to-head terpene (THT) cyclization is a biochemical process that gives rise to many terpene natural product skeletons encountered in nature. Historically, it has been difficult to achieve THT synthetically without using an enzyme. In this protocol, a hexameric resorcin[4]arene capsule acts as an artificial enzyme mimic to carry out biomimetic THT cyclizations and related carbocationic rearrangements. The precursor molecule bears a leaving group (usually an alcohol or acetate group) and undergoes the THT reaction in the presence of the capsule catalyst and HCl as a cocatalyst. Careful control of several parameters (including water content, amount of HCl cocatalyst, temperature and solvent) is crucial to successfully carrying out the reaction. To facilitate the application of this unique capsule-catalysis methodology, we therefore developed a very detailed procedure that includes the preparation and analysis of all reaction components. In this protocol, we describe how to prepare two different terpenes: isolongifolene and presilphiperfolan-1β-ol. The two procedures differ in the water content required for efficient product formation, and thus exemplify the two common use cases of this methodology. The influence of other crucial reaction parameters and means of precisely controlling them are described. A commercially available substrate, nerol, can be used as simple test substrate to validate the reaction setup. Each synthetic procedure requires 5-7 d, including 1-5 h of hands-on time. The protocol applies to the synthesis of many complex terpene natural products that would otherwise be difficult to access in synthetically useful yields.

Establishing Modular Cell‐Free Expression System for the Biosynthesis of Bicyclomycin from a Chemically Synthesized Cyclodipeptide†

Comprehensive SummaryCell‐free expression systems have emerged as a versatile and powerful platform for metabolic engineering, biosynthesis and synthetic biology studies. Nevertheless, successful examples of the synthesis of complex natural products using this system are still limited. Bicyclomycin, a structurally unique and complex diketopiperazine alkaloid, is a clinically promising antibiotic that selectively inhibits the transcription termination factor Rho. Here, we established a modular cell‐free expression system with cascade catalysis for the biosynthesis of bicyclomycin from a chemically synthesized cyclodipeptide. The six cell‐free expressed biosynthetic enzymes, including five iron‐ and α‐ketoglutarate‐dependent dioxygenases and one cytochrome P450 monooxygenase, were active in converting their substrates to the corresponding products. The co‐expressed enzymes in the cell‐free module were able to complete the related partial pathway. In vitro biosynthesis of bicyclomycin was also achieved by reconstituting the entire biosynthetic pathways (i.e., six enzymes) using the modular cell‐free expression system. This study demonstrates that the modular cell‐free expression system can be used as a robust and promising platform for the biosynthesis of complex antibiotics.

Total synthesis of cassane‐type diterpenoid pikrosalvin

AbstractThis paper presents the first successful total synthesis of pikrosalvin, a compound naturally derived from Salvia officinalis, grounded on the structural framework delineated by Brieskorn and Fuchs. Our synthetic approach was underpinned by a biomimetic strategy inspired by the Stork–Eschenmoser hypothesis for the biosynthesis of terpenes via polyene cyclization. Starting with commercially available vanillic acid and geraniol, we strategically assembled pikrosalvin's structural core, consisting of a decalin A/B ring, an aromatic C ring, and a butyrolactone D ring. Challenges related to protective groups and specific catalytic conditions were effectively addressed, resulting in high product yields. We further demonstrated the efficacy and broad applicability of a combined‐acid‐catalyzed polyene cyclization methodology in the context of complex natural product synthesis. This study sets the stage for future biological and pharmacological investigations of pikrosalvin.

Inner- and Outer-Sphere Cross-Coupling of High Fsp3 Fragments.

Natural product research originates from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful and creative problem solving. Often this means bold disconnections that would simplify access to complex structures, if only the methods existed to bridge these theoretical gaps. Whereas biological interrogations provide long-term intellectual value and impetus, methods come as attractive fringe benefits of natural product synthesis. This Account describes strategic, methodological solutions to the syntheses of natural products [(-)-eugenial C, Galbulimima alkaloids GB18, GB22, GB13, and himgaline] featuring new, convergent disconnections as important problem-solving steps, which themselves were inspired by recent methods that arose from our group. Each target required the invention of first-row transition metal-catalyzed cross-coupling procedures to satisfy the biological goals of the project. In these cases, synthetic strategy identified the methodological gap (the absence of stereo- and chemoselective couplings of appropriate fragments), but the tactical advantage conferred by first-row metals met the challenge. These methods were competent to handle the dense, sterically encumbered motifs common to natural products due to, in many cases, elementary steps that did not require bond formation between the hindered substrate and the metal center. Instead, these sterically lenient reactions appeared to involve metal-ligand-substrate reactions (i.e., outer-sphere steps), in contrast to the metal-substrate, coordinative reactions of precious metals (i.e., inner-sphere steps). Key observations from our previous studies, combined with the observations in seminal publications from other laboratories (Mattay, Weix, and MacMillan), led to the optimization of ligand-controlled, stereoselective reactions and the introduction of complementary catalytic cycles that revealed new modes of reactivity and generated novel structural motifs. Optimized access to bioactive natural product space accelerated our timeline of biological characterization, fulfilling a common premise of natural products research. The integration of methodology, complex natural product synthesis, diversification, and bioassay into a single Ph.D. dissertation would have been unmanageable in a prior era. The unique ability of first-row transition metals to effect Csp3-Csp3 cross-coupling with high chemo- and stereoselectivity has significantly lowered the barrier to reach the avowed goal of natural product synthesis and reduced the burden (real or perceived) of integrating natural products into functional campaigns.

Charting the Evolution of Chemoenzymatic Strategies in the Syntheses of Complex Natural Products.

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase in popularity and utility. This Perspective explores the integration of enzymes into multistep chemical syntheses, highlighting the unique potential of biocatalytic transformations to streamline the synthesis of complex natural products. In particular, we identify four primary conceptual approaches to chemoenzymatic synthesis and illustrate each with a number of landmark case studies. Future opportunities and challenges are also discussed.

Applications of Flow Chemistry in Total Synthesis of Natural Products

Abstract: A vital driving force for chemists to discover novel synthetic protocols is the improvement of more effective synthetic technologies and sustainable methodologies. This is associated with the development of innovative research that stimulates the creative reevaluating of known conceptions. Currently, these robust methodologies, as well as green synthetic procedures, have been designed for the total synthesis of secondary metabolites. Flow chemistry and flow photochemistry have emerged as powerful tools to promote valuable transformations in the total synthesis of natural products as key step(s). Flow chemistry development offers many merits over a traditional batch format, namely a round-bottom flask. The advantages of this green tool comprise waste minimization, simple scale-up, reduction of reaction time, safety betterment as, well as energy and cost efficiency. Flow chemistry comprises a fascinating prospect for the synthesis of promising organic molecules and bioactive complex natural products as it represents a suitable modern synthetic technology for the improvement of sustainable chemistry. Continuous flow chemistry is an assembly of chemical processes carried out in continuous flowing streams. Compared to conventional organic synthesis, it is a process that strengthens technology and is superior in enhancing and scaling up synthesis, accurately controlling reaction rate, and providing the desired products with maximum yields. In the past and likely in the future natural products and their analogue will continue to deliver the stimulation for drug discovery and development programs. Total synthesis of natural products is very useful to synthesize natural products in the laboratory as many secondary metabolites are available in low quantities from their sources of origin. So, this review wishes to cover the brilliant applications of flow chemistry in the total synthesis of natural products in the field of novel technological advances.

Radical Decarboxylative Carbon-Nitrogen Bond Formation.

The carbon-nitrogen bond is one of the most prevalent chemical bonds in natural and artificial molecules, as many naturally existing organic molecules, pharmaceuticals, agrochemicals, and functional materials contain at least one nitrogen atom. Radical decarboxylative carbon-nitrogen bond formation from readily available carboxylic acids and their derivatives has emerged as an attractive and valuable tool in modern synthetic chemistry. The promising achievements in this research topic have been demonstrated via utilizing this strategy in the synthesis of complex natural products. In this review, we will cover carbon-nitrogen bond formation via radical decarboxylation of carboxylic acids, Barton esters, MPDOC esters, N-hydroxyphthalimide esters (NHP esters), oxime esters, aryliodine(III) dicarboxylates, and others, respectively. This review aims to bring readers a comprehensive survey of the development in this rapidly expanding field. We hope that this review will emphasize the knowledge, highlight the proposed mechanisms, and further disclose the fascinating features in modern synthetic applications.

Recent advances in total synthesis of natrual products containing contiguous all carbon quaternary stereocenters

<p indent="0mm">Contiguous all carbon quaternary stereocenters are common structural units in bioactive natural products with significant synthetic challenges. In this paper, we reviewed our recent progresses in total synthesis of complex natural products containing contiguous all carbon quaternary stereocenters firstly. Then, four different synthetic strategies concerning the construction of contiguous all carbon quaternary stereocenters (≥3) were summarized. Finally, the total synthesis of waihoensene and crinipellins reported by us and other groups were taken as examples to clarify the advantages and disadvantages of various synthetic methodologies and synthetic strategies.

Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis.

ConspectusBenzo-fused skeletons are ubiquitous in agrochemicals, medicines, natural products, catalysts, and other organic function materials. The assembly of these skeletons in an efficient manner is an actively explored field in organic synthesis. Palladium/norbornene (Pd/NBE) cooperative catalysis is a powerful tool for the expeditious assembly of polysubstituted arenes through bis-functionalization of the ortho and ipso positions of aryl iodides in one operation. Owing to the efforts of Lautens, Catellani, and others, an array of Pd/NBE-promoted annulations for the syntheses of diversified benzo-fused rings have been developed. However, these methods have not been broadly applied in total synthesis yet.Our group is interested in efficient and practical total synthesis of biologically active molecules. In the past 7 years, we have been devoted to the development of new annulation strategies for the assembly of common benzo-fused skeletons through Pd/NBE-promoted reactions of aryl iodides with novel bifunctional reagents. In this Account, we summarize our laboratory's systematic efforts in this direction. First, readily available epoxides and aziridines were exploited as versatile bifunctional alkylating reagents, which enables quick assembly of a series of valuable benzo-fused heterocycles, including isochromans, dihydrobenzofurans, 1,3-cis-tetrahydroisoquinolines (THIQs), 1,3-trans-THIQs, etc. Second, a convergent access to 5-7-membered benzo-fused carbocycles (including indanes and tetrahydronaphthalenes) was developed by Pd/NBE-promoted annulation of aryl iodides with simple olefinic alcohol-containing alkylating reagents. Third, a Pd/NBE-promoted annulation between aryl iodides and cyclohexanone-containing amination reagents was developed for the construction of benzo-fused N-containing bridged scaffolds. Thus, we have established a practical and versatile toolbox for the quick assembly of diversified benzo-fused skeletons. These new annulation reactions are of high chemo-, regio-, and stereoselectivities with good step and atom economy. Moreover, they are able to rapidly increase molecular complexity from simple building blocks. Finally, their synthetic value has been demonstrated by immediate adoption in several efficient total syntheses of medicines and complex natural products. Compared to conventional synthetic logics, the Pd/NBE-promoted annulation toolbox allows the development of highly convergent strategies, which significantly improves the overall synthetic efficiency.We believe the results presented in this Account will have significant implications beyond our research. It can be envisaged that new Pd/NBE-promoted annulations as well as new applications in complex total synthesis will be revealed in the near future.