Collective Asymmetric Total Syntheses of Marine Decahydroquinoline Alkaloid Lepadins A–E, H, and <i>ent</i>-I

Ma, Foqing; He, Chenxi; Wang, Eryu; Tong, Rongbiao

doi:10.1021/acs.orglett.1c02435

Cited by 20 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These AchR-based strategies are usually more efficient and more flexible than the related previous syntheses, as exemplified by our syntheses of (i) a series of 6,8-dioxabicyclo-[3.2.1]octane (6,8-DOBCO) complex natural products (Figure 1C) 1,54 and (ii) decahydroquinoline alkaloid lepadins (Figure 1F). 55 Additionally, the AchR-based strategy allowed us to address the synthetic challenge of diastereoselective construction of trans-2,6tetrahydropyran present in many natural products 52a,56 (i.e., musellarins, Figure 1B). By using the AchR-based strategy, we have accomplished the total syntheses of >28 natural products, including the structurally complex uprolides 57 and paspalines 1 (Figure 1).…”

Section: Application Of Achmatowicz Rearrangement In Total Synthesis ...mentioning

confidence: 99%

“…In the last section of this Account, we demonstrate the utility of aza-AchR in the total synthesis of lepadins A−K (Scheme 16). 55 Lepadins are a family of decahydroquinoline (DHQ) alkaloids isolated from marine invertebrate animals and they exhibit significant biological activities. We proposed a new synthetic strategy that exploited aza-AchR and intramolecular nitrile oxide cyclization to construct the DHQ core (Scheme 16).…”

Section: Collective Total Syntheses Of Lepadins A−e H and Ent-i (Pipe...mentioning

confidence: 99%

See 1 more Smart Citation

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

2022

Self Cite

View full text Add to dashboard Cite

Metrics & MoreArticle Recommendations CONSPECTUS:The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, smallmolecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges. This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries. We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck−Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

show abstract

Section: Application Of Achmatowicz Rearrangement In Total Synthesis ...mentioning

confidence: 99%

Section: Collective Total Syntheses Of Lepadins A−e H and Ent-i (Pipe...mentioning

confidence: 99%

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the synthesis of lepadins requires a conspicuous number of highly stereoselective synthetic steps which represents a not easily accessible route for obtaining the native metabolites. Indeed, only recently, Tong et al have reported a more attractive synthetic strategy for constructing the common cis-fused decahydroquinoline ring of several lepadins by a green chemistry approach [17]. For this reason, the isolation of new examples of lepadin alkaloids remains a key factor to enlarge the great chemodiversity associated to this chemical class, and to provide further new structural motifs that can represent a valuable resource both to grow up the knowledge on their bioactivities and to assess accordingly structure-activity relationships.…”

Section: Introductionmentioning

confidence: 99%

Insights into Cytotoxic Behavior of Lepadins and Structure Elucidation of the New Alkaloid Lepadin L from the Mediterranean Ascidian Clavelina lepadiformis

et al. 2022

View full text Add to dashboard Cite

The chemical investigation of the Mediterranean ascidian Clavelina lepadiformis has led to the isolation of a new lepadin, named lepadin L, and two known metabolites belonging to the same family, lepadins A and B. The planar structure and relative configuration of the decahydroquinoline ring of lepadin L were established both by means of HR-ESIMS and by a detailed as extensive analysis of 1D and 2D NMR spectra. Moreover, microscale derivatization of the new alkaloid lepadin L was performed to assess the relative configuration of the functionalized alkyl side chain. Lepadins A, B, and L were tested for their cytotoxic activity on a panel of cancer cell lines (human melanoma [A375], human breast [MDA-MB-468], human colon adenocarcinoma [HT29], human colorectal carcinoma [HCT116], and mouse myoblast [C2C12]). Interestingly, a deeper investigation into the mechanism of action of the most cytotoxic metabolite, lepadin A, on the A375 cells has highlighted its ability to induce a strongly inhibition of cell migration, G2/M phase cell cycle arrest and a dose-dependent decrease of cell clonogenity, suggesting that it is able to impair self-renewing capacity of A375 cells.

show abstract

“…Lepadins are cis -fused decahydroquinoline (DHQ) marine alkaloids that have shown diverse biological activities and have attracted extensive synthetic interest [ 41 ]. In this study we found that lepadin A shows cytotoxic effect against cancer cells together with maturation of mouse DCs at micromolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death

et al. 2022

View full text Add to dashboard Cite

Natural products and their synthetic analogs and derivatives are a traditional source of bioactive molecules with potential development as drug candidates. In this context, Marine Natural Products (MNPs) represent a rich reservoir of diverse molecular skeletons with potential pharmacological activity that, so far, has been mostly explored in cancer and infectious diseases. Starting from the development of a novel bioassay-guided screening platform for immunomodulatory compounds from an in-house MNPs library, we report the identification of the alkaloid lepadin A as a new model compound for immune-based anticancer activity with characteristics that suggest a possible mechanism as Immunogenic Cell Death inducer. The work describes the molecular-based bioprospecting in the Gulf of Naples together with the bioassay-guided fractionation, the chemical characterization of the alkaloid, and the biological activity in mouse dendritic cells (D1).

show abstract

Collective Asymmetric Total Syntheses of Marine Decahydroquinoline Alkaloid Lepadins A–E, H, and ent-I

Cited by 20 publications

References 50 publications

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

Insights into Cytotoxic Behavior of Lepadins and Structure Elucidation of the New Alkaloid Lepadin L from the Mediterranean Ascidian Clavelina lepadiformis

Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death

Contact Info

Product

Resources

About