Polycyclic Natural Products Research Articles

Collective total synthesis of stereoisomeric yohimbine alkaloids

Stereoisomeric polycyclic natural products are important for drug discovery-based screening campaigns, due to the close correlation of stereochemistry with diversified bioactivities. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the ten-carbon building block. In this work, we reset the stage by the development of a bioinspired coupling, in which the rapid construction of the entire pentacyclic skeleton and the complete control of all five stereogenic centers are achieved through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate. The stereochemical diversification from a common intermediate allows for the divergent and collective synthesis of all four stereoisomeric subfamilies of yohimbine alkaloids through orchestrated tackling of thermodynamic and kinetic preference.

Structurally Diverse Macrolactams from an Antarctic Streptomyces Species.

Twelve new polyenic macrolactams, cyclamenols G-R (1 and 3-13), together with the known analogue cyclamenol A (2), were isolated from Streptomyces sp. OUCMDZ-4348. Their structures were elucidated by spectroscopic analysis, quantum chemical calculations, chemical derivatizations, and Mosher's methods. The sequenced genome of OUCMDZ-4348 revealed the putative biosynthetic gene cluster of cyclamenols. It was proposed that the polycyclic natural products, cyclamenols H-R, might be formed from cyclamenols A and G through nonenzymatic intramolecular cycloadditions and oxidative cyclizations.

Use of Emerging C-H Functionalization Methods to Implement Strategies for the Divergent Total Syntheses of Bridged Polycyclic Natural Products

Use of Emerging C-H Functionalization Methods to Implement Strategies for the Divergent Total Syntheses of Bridged Polycyclic Natural Products

Two-phase terpenoid biosynthesis-inspired divergent total syntheses of bridged polycyclic natural products

Two-phase terpenoid biosynthesis-inspired divergent total syntheses of bridged polycyclic natural products

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P.

The asymmetric total syntheses of cephalotaxus C19 diterpenoids, bearing a unique cycloheptene A ring with a chiral methyl group at C-12, were disclosed based on a universal strategy. Six members, including cephinoid P, cephafortoid A, 14-epi-cephafortoid A and fortalpinoids M-N, P, were accomplished for the first time. The concise approach relies on two crucial steps: (1) a Nicholas/Hosomi-Sakurai cascade reaction was developed to efficiently generate the cycloheptene ring bearing a chiral methyl group; (2) an intramolecular Pauson-Khand reaction was followed to facilitate the construction of the complete skeleton of target molecules. Our studies provide a new strategy for the synthetic analysis of cephalotaxus diterpenoids and structurally related polycyclic natural products.

Biosynthesis of Polycyclic Natural Products from Conjugated Polyenes via Tandem Isomerization and Pericyclic Reactions.

We report biosynthetic pathways that can synthesize and transform conjugated octaenes and nonaenes to complex natural products. The biosynthesis of (-)-PF1018 involves an enzyme PfB that can control the regio-, stereo-, and periselectivity of multiple reactions starting from a conjugated octaene. Using PfB as a lead, we discovered a homologous enzyme, BruB, that facilitates diene isomerization, tandem 8π-6π-electrocyclization, and a 1,2-divinylcyclobutane Cope rearrangement to generate a new-to-nature compound.

Palladium‐Catalyzed Regioselective peri‐ and ortho‐Halogenation of 1‐Naphthaldehydes: Application to the Synthesis of Polycyclic Natural Product Skeletons

AbstractHerein, a regioselective bromination or chlorination reaction of 1‐naphthaldehydes is described. Without additive, the palladium‐catalyzed C−H halogenation showed a C8‐regioselectivity, whereas the formation of an aromatic imine intermediate allowed a switch to a C2‐reactivity. Mechanistic studies and DFT calculations were performed to explain the regioselectivity and the synthesized halogenated products were used as key building blocks to access polycyclic natural product skeletons.

Recent Applications of Ammonium Ylide Based [2,3]-Sigmatropic and [1,2]-Stevens Rearrangements To Transform Amines into Natural Products

AbstractAmmonium ylide based [2,3]-sigmatropic and [1,2]-Stevens rearrangements enable the transformation of tertiary amines into rearranged and functionalized intermediates en route to many polycyclic natural product targets. Herein, we summarize recent applications of these rearrangement reactions in formal and total synthesis endeavors while highlighting innovative improvements to these transforms.1 Introduction2 Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements in Natural Product Synthesis2.1 (–)-Cephalotaxine2.2 (±)-Amathaspiramide F2.3 (–)-Cephalezomine G and Its C3 Epimer2.4 (±)-Strictamine2.5 (–)-Doxycycline3 [1,2]-Stevens Rearrangements Toward Natural Products3.1 Ring-Expanding [1,2]-Stevens Rearrangements en route to (±)-Tylophorine, (±)-7-Methoxycryptopleurine, and (±)-Xylopinine3.2 Enantioselective Synthesis of Iboga Alkaloids and (+)-Vinblastine4 Selected Methodology4.1 Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements To Form Natural Product Cores4.2 Cascade Reactions Involving [1,2]-Stevens Rearrangement/ Hofmann-Type Elimination Events5 Conclusions

Microwave-Assisted Cu-Catalyzed Diaryletherification for Facile Synthesis of Bioactive Prenylated Diresorcinols

Prenylated diresorcinols exhibit various bioactivities, including cytotoxic, antibacterial, and antifungal activities. Therefore, establishing facile and efficient synthetic routes for prenylated diresorcinols facilitates their development as chemical probes or drugs with a novel mode of action. In this study, microwave-assisted copper catalysis was explored as a cost-effective and environmentally friendly method for the cross-coupling of sterically hindered ortho-prenylated phenols and aryl halides to produce bioactive prenylated diresorcinols, diorcinol I and leotiomycene B. Notable advantages of microwave-assisted catalysis include not only operational simplicity and rapid heating but also shorter reaction times and higher chemical yields. In addition, highly regioselective prenylation of phenol was achieved for the preparation of ortho-prenyl phenol via directed lithiation and subsequent alkylation. This study provides valuable insights for the preparation of other bioactive prenylated diresorcinols. Furthermore, considering that prenylated benzenoids are biosynthetic precursors of various polycyclic natural products, this synthetic route could be expanded to more complex bioactive compounds possessing diaryl ethers.

Synthetic Studies to Fused 5/5/6‐Tricyclic Frameworks: Access to Presilphiperfolanol Analogues and A, B, C‐Ring System of Lycopodium Alkaloids and Cyclopiane Diterpenes

AbstractHerein, we describe new synthetic approaches to fused 5/5/6‐carbocyclic frameworks present in various polycyclic natural products such as presilphiperfolanols, lycopodium alkaloids, and cyclopiane diterpenes. Our work features, a strategically introduced hydroxy group at thetert‐carbon center of the tricyclic system which is present in presilphiperfolanols. In addition, one presilphiperfolanol analogue is reported to show the potential of strategies disclosed in this work. All the new compounds are characterized by high‐resolution NMR spectral data. The structures of critical compounds were confirmed by various chemical transformations and further supported by single‐crystal X‐ray diffraction data. Overall, our approach is simple and rely on readily available starting materials and involves a tandem‐metathesis sequence. The synthetic studies disclosed here are applicable to the synthesis of natural products and to design medicinally important targets.

Research on the Efficient Enantioselective Total Synthesis of Useful Bioactive Polycyclic Compounds

Abstract Useful bioactive polycyclic natural products are important targets in academic research, wherein their mechanisms of action and total syntheses are commonly investigated. In addition, polycyclic compounds that exhibit highly selective biological activities through multipoint recognition are valuable as biochemical reagents and lead compounds for pharmaceuticals. However, when such compounds are difficult to obtain, their supply depends on appropriate chemical preparations. Unfortunately, polycyclic natural products pose difficult synthetic problems, such as the construction of distorted ring structures, contiguous stereogenic centers, and quaternary asymmetric carbon atoms in their fused ring moieties. Moreover, since polycyclic natural products have a large number of bonds, their total syntheses inevitably become multi-step procedures, and when enantioselective total synthesis is required, the number of steps tends to increase, since such routes require the use of commercially available chiral compounds. Hence, their efficient total synthesis is challenging. In our group, we have demonstrated the preparation of chiral synthetic intermediates, especially those bearing a quaternary stereogenic center, through novel asymmetric catalysis procedures, as well as the incorporation of logically designed cascade reactions to reduce the number of transformations. This route can ultimately lead to the efficient enantioselective total syntheses of useful bioactive polycyclic natural products.

Chasing Polycyclic Natural Products: 5/6/5‐ or 5/6/6‐Carbotricyclic Scaffold Construction via Stereodivergent Diels‐Alder Reaction of Chiral Hydrindanes and Their Boron Complexes

AbstractChiral trans‐hydrindanes (bicyclo[4.3.0]nonanes) are important building blocks of polycyclic natural products. In order to access 5/6/5‐ and 5/6/6‐carbotricyclic scaffolds scope and limitation of [4+2] cycloadditions of tetrahydroindanones with various dienes were studied. Cyclopentadiene gave a tetracylic endo‐(R,R)‐diastereomer under acid‐catalysis, whereas thermal conditions provided the endo‐(S,S)‐diastereomer with the opposite diastereofacial selectivity. The stereodivergent outcome was rationalized by high‐level quantum‐chemical computations which revealed the acid‐catalysis to be a kinetically controlled reaction and the thermal cycloaddition to be under thermodynamic control. Stereochemical assignment of the cycloadducts was facilitated by conversion of the 1,3‐dicarbonyls with BF3 ⋅ OEt2 into BF2‐chelate complexes. Subsequent thermal Diels‐Alder reaction of BF2‐ or BBN‐chelates (from 9‐BBN‐OTf) gave endo/exo‐mixtures of the (R,R)‐ and (S,S)‐diastereomers, while more elevated temperatures yielded primarily the endo/exo‐(S,S)‐diastereomers. Thermal [4+2] cycloadditions with 2,3‐dimethylbutadiene proceeded with lower diastereoselectivity as the reaction was kinetically controlled according to calculations. Attempted Diels‐Alder‐reactions with furan gave furyl‐substituted indanones rather than cycloadducts.

Chiral Pool Guided Syntheses of Polycyclic Natural Products

Comprehensive SummaryChiral pools have been commonly utilized as inexpensive and versatile building blocks in organic synthesis. In this account, we provide an overview of our recent synthetic efforts toward polycyclic natural products using chiral natural small molecules (chiral pool) as starting materials. Key achievements during our syntheses include intermolecular Diels‐Alder/intramolecular hetero‐Diels‐Alder cascade to enable modification of previously proposed biosynthetic pathway of bolivianine, Diels‐Alder‐type dimerization through a conjugated furanyl diene intermediate to achieve three types of lindenane [4+2] dimers, Iron‐catalyzed reductive aldol reaction to construct core of rumphellclovane E and [3,3]‐rearrangement along with vinylogous Pummerer rearrangement to make epoxyquinol substructure of JBIR‐23/‐24. In the final, the outlook is also presented. What is the most favorite and original chemistry developed in your research group?Biomimetic and/or convergent synthetic strategies leading to concise natural product synthesisHow do you get into this specific field? Could you please share some experiences with our readers?I have become interested in natural product synthesis (NPS) since I was a senior undergraduate student, encouraging me to enter this field in my PhD study. NPS is both fascinating and challenging to make complex molecules from simple starting materials, and construct different chemical bonds with proper stereochemistry. In my opinion, solid knowledge in reaction mechanism and structural conformation and persistent passion to pursue dreams are the two key elements aiming at successful and beautiful natural product synthesis.How do you supervise your students?Persuade them that it is important to be cautious with experiments, to be curious with new development and to be open with minds.What is the most important personality for scientific research?Passion, creativity, persistence and honesty.What are your hobbies?Music, reading and sight‐seeing.How do you keep balance between research and family?To tell the truth, I actually owe a lot to my family.

Regioisomers Salviprolin A and B, Unprecedented Rosmarinic Acid Conjugated Dinorditerpenoids from Salvia przewalskii Maxim.

Salvia przewalskii Maxim is a perennial plant from the genus Salvia (family Lamiaceae). The roots of S. przewalskii were long used as a traditional herb to treat blood circulation related illnesses in China. As part of our continuing interest in polycyclic natural products from medicinal plants, two unprecedented adducts comprised of a dinor-diterpenoid and a 9′-nor-rosmarinic acid derivative, linked by a 1,4-benzodioxane motif (1 and 2), were isolated from the roots of S. przewalskii. Their structures were established by extensive spectroscopic approaches including 1D, 2D NMR, and HRFABMS. Their cytotoxic activities against five human tumor cell lines were evaluated.

Synthetic Study of Polycyclic Natural Products Based on Development of New Strategy

On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.

Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin.

Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (e.g. plumarellide, verrillin, and bielschowskysin). These architecturally complex metabolites are thought to originate from site-selective oxidation of the macrocycle backbone and a series of intricate transannular reactions. Yet the development of a common biomimetic route has been hampered by a lack of synthetic methods for the pivotal furan dearomatization in a regio- and stereoselective manner. To address these shortcomings, a concise strategy of epoxidation followed by a kinetically controlled furan dearomatization is reported. The surprising switch of facial α:β-discrimination observed in the epoxidation of the most strained E-acerosolide versus E-deoxypukalide and E-bipinnatin J derived macrocycles has been rationalized by the variation of the 3D conformational landscape between macrocyclic scaffolds. A careful conformational analysis of these macrocycles by VT-NMR and NOESY experiments at low temperature was supported by DFT calculations to characterize these equilibrating macrocyclic conformers. The shift in conformational topology associated with a swing of the butenolide ring in E-deoxypukalide is in general agreement with the reversal of β-selectivity observed in the epoxidation. We also describe the downstream functionalization of FBC-macrocycles and how the C-7 epoxide configuration is retentively translated to the C-3 stereogenicity in dearomatized products under kinetic control to secure the requisite 3S,7S,8S configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a E-(Δ7,8)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.

Asymmetric Total Synthesis of (−)-Spirochensilide A, Part 2: The Final Phase and Completion

The final phase of the total synthesis of (-)-spirochensilide A is described. A tungsten-mediated cyclopropene-based Pauson-Khand reaction was developed to form the spiral CD ring system with desired stereochemistry at the C13 quaternary center. Other important steps enabling completion of this synthesis included an intermolecular aldol condensation to link the ABCD core with the EF fragment and a Cu-mediated 1,4-addition to stereoselectively install the C21 stereogenic center. The chemistry developed for this total synthesis of (-)-spirochensilide A (1) will aid the synthesis of polycyclic natural products bearing this unique spiral ring system.

Strategies for the Total Synthesis of the Furanosteroids: wortmannin and viridin

Furanosteroids are polycyclic natural products isolated from fungus, which consist of wortmannin and viridin containing a [5,6,6,6]-tetracyclic skeleton in addition to a furan ring. They inhibit phosphoinositide 3-kinases, suggesting drug potential. This highlight review describes strategies that have been reported for building the tetracyclic ring skeleton and the all-carbon quaternary center in order to achieve total syntheses of wortmannin and viridin.

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products.

Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C-H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors.During the last two decades, a series of remarkable advances in C-H functionalization have led to the emergence of many new approaches to directly functionalize C-H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step- and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C-H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C-H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.Recently, we have also completed the total syntheses for a number of skeletally diverse tetracyclic Isodon diterpenoids inspired by their biogenesis and radical-based retrosynthetic disconnections. Radical transformations are strategically and tactically utilized in our syntheses, and radical-based reactions, including organo-SOMO catalysis, Birch reduction, regioselective 1,6-dienyne reductive cyclization, visible-light-mediated Schenck ene reaction, and photoradical-mediated late-stage skeletal rearrangement, play significant roles in our synthetic endeavors. Protecting-group-free and scalable syntheses are also built into our work to achieve the "ideal" synthesis. Furthermore, our synthetic work reveals that late-stage skeletal rearrangement through a photo radical process is possible in a biological setting in complement with nature's carbocation chemistry in complex natural product biosynthesis.Lycopodium alkaloids are a large family of structurally unique polycyclic natural products with impressive biological activities. Owing to their fascinating polycyclic architectures and diverse biological activities, these alkaloids have continued to serve as targets as well as inspirations for the synthetic community for decades. To access these bioactive natural products or natural product-like molecules for biological exploration and drug discovery, we applied a novel functional group pairing strategy to furnish the total syntheses for several Lycopodium alkaloids and obtained numerous skeletally diverse compounds with structural complexity comparable to natural products.

Recent Advances in Construction of Polycyclic Natural Product Scaffolds via One-Pot Reactions Involving Alkyne Annulation

Polycyclic scaffolds are omnipresent in natural products and drugs, and the synthetic strategies and methods toward construction of these scaffolds are of particular importance. Compared to simple cyclic ring systems, polycyclic scaffolds have higher structure complexity and diversity, making them suitable for charting broader chemical space, yet bringing challenges for the syntheses. In this review, we surveyed progress in the past decade on synthetic methods for polycyclic natural product scaffolds, in which the key steps are one-pot reactions involving intermolecular or intramolecular alkyne annulation. Synthetic strategies of selected polycyclic carbocycles and heterocycles with at least three fused, bridged, or spiro rings are discussed with emphasis on the synthetic efficiency and product diversity. Recent examples containing newly developed synthetic concepts or toolkits such as collective and divergent total synthesis, gold catalysis, C–H functionalization, and dearomative cyclization are highlighted. Finally, several “privileged synthetic strategies” for “privileged polycyclic scaffolds” are summarized, with discussion of remained challenges and future perspectives.