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Special Issue "Synthesis around Marine Natural Products"

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 October 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Yoshihide Usami

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
E-Mail
Fax: +81 726 90 1005
Interests: natural product; anti-cancer; bioactive; structure determination; total synthesis; chemical modification

Keywords

  • marine natural product
  • bioactive
  • total synthesis
  • structural assignment
  • chemical transformation
  • chemical modification

Published Papers (16 papers)

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Research

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Open AccessArticle Synthesis of the Oligosaccharides Related to Branching Sites of Fucosylated Chondroitin Sulfates from Sea Cucumbers
Mar. Drugs 2015, 13(2), 770-787; doi:10.3390/md13020770
Received: 1 December 2014 / Revised: 29 December 2014 / Accepted: 22 January 2015 / Published: 2 February 2015
Cited by 9 | PDF Full-text (666 KB) | HTML Full-text | XML Full-text
Abstract
Natural anionic polysaccharides fucosylated chondroitin sulfates (FCS) from sea cucumbers attract great attention nowadays due to their ability to influence various biological processes, such as blood coagulation, thrombosis, angiogenesis, inflammation, bacterial and viral adhesion. To determine pharmacophore fragments in FCS we have started
[...] Read more.
Natural anionic polysaccharides fucosylated chondroitin sulfates (FCS) from sea cucumbers attract great attention nowadays due to their ability to influence various biological processes, such as blood coagulation, thrombosis, angiogenesis, inflammation, bacterial and viral adhesion. To determine pharmacophore fragments in FCS we have started systematic synthesis of oligosaccharides with well-defined structure related to various fragments of these polysaccharides. In this communication, the synthesis of non-sulfated and selectively O-sulfated di- and trisaccharides structurally related to branching sites of FCS is described. The target compounds are built up of propyl β-d-glucuronic acid residue bearing at O-3 α-l-fucosyl or α-l-fucosyl-(1→3)-α-l-fucosyl substituents. O-Sulfation pattern in the fucose units of the synthetic targets was selected according to the known to date holothurian FCS structures. Stereospecific α-glycoside bond formation was achieved using 2-O-benzyl-3,4-di-O-chloroacetyl-α-l-fucosyl trichloroacetimidate as a donor. Stereochemical outcome of the glycosylation was explained by the remote participation of the chloroacetyl groups with the formation of the stabilized glycosyl cations, which could be attacked by the glycosyl acceptor only from the α-side. The experimental results were in good agreement with the SCF/MP2 calculated energies of such participation. The synthesized oligosaccharides are regarded as model compounds for the determination of a structure-activity relationship in FCS. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle Design, Synthesis and Biological Evaluation of Novel Bromophenol Derivatives Incorporating Indolin-2-One Moiety as Potential Anticancer Agents
Mar. Drugs 2015, 13(2), 806-823; doi:10.3390/md13020806
Received: 31 December 2014 / Accepted: 27 January 2015 / Published: 2 February 2015
Cited by 3 | PDF Full-text (1301 KB) | HTML Full-text | XML Full-text
Abstract
A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g4i, 5h
[...] Read more.
A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g4i, 5h, 6d, 7a, 7b) showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure–activity relationships (SARs) of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle Design, Synthesis and Evaluation of New Marine Alkaloid-Derived Pentacyclic Structures with Anti-Tumoral Potency
Mar. Drugs 2015, 13(1), 655-665; doi:10.3390/md13010655
Received: 4 November 2014 / Revised: 10 December 2014 / Accepted: 9 January 2015 / Published: 19 January 2015
Cited by 3 | PDF Full-text (460 KB) | HTML Full-text | XML Full-text
Abstract
This work describes the synthesis and biological evaluation of a new heterocyclic hybrid derived from the ellipticine and the marine alkaloid makaluvamine A. Pyridoquinoxalinedione 12 was obtained in seven steps with 6.5% overall yield. 12 and its intermediates 111 were evaluated
[...] Read more.
This work describes the synthesis and biological evaluation of a new heterocyclic hybrid derived from the ellipticine and the marine alkaloid makaluvamine A. Pyridoquinoxalinedione 12 was obtained in seven steps with 6.5% overall yield. 12 and its intermediates 111 were evaluated for their in vitro cytotoxic activity against different cancer cell lines and tested for their inhibitory activity against the human DNA topoisomerase II. The analysis by electrophoresis shows that the pentacycle 12 inhibits the topoisomerase II like doxorubicine at 100 µM. Compound 9 was found to have an interesting profile, having a cytotoxicity of 15, 15, 15 and 10 μM against Caco-2, HCT-116, Pc-3 and NCI cell lines respectively, without any noticeable toxicity against human fibroblast. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle Development of Highly Selective Kv1.3-Blocking Peptides Based on the Sea Anemone Peptide ShK
Mar. Drugs 2015, 13(1), 529-542; doi:10.3390/md13010529
Received: 12 November 2014 / Accepted: 7 January 2015 / Published: 16 January 2015
Cited by 7 | PDF Full-text (1285 KB) | HTML Full-text | XML Full-text
Abstract
ShK, from the sea anemone Stichodactyla helianthus, is a 35-residue disulfide-rich peptide that blocks the voltage-gated potassium channel Kv1.3 at ca. 10 pM and the related channel Kv1.1 at ca. 16 pM. We developed an analog of this peptide, ShK-186, which is
[...] Read more.
ShK, from the sea anemone Stichodactyla helianthus, is a 35-residue disulfide-rich peptide that blocks the voltage-gated potassium channel Kv1.3 at ca. 10 pM and the related channel Kv1.1 at ca. 16 pM. We developed an analog of this peptide, ShK-186, which is currently in Phase 1b-2a clinical trials for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. While ShK-186 displays a >100-fold improvement in selectivity for Kv1.3 over Kv1.1 compared with ShK, there is considerable interest in developing peptides with an even greater selectivity ratio. In this report, we describe several variants of ShK that incorporate p-phophono-phenylalanine at the N-terminus coupled with internal substitutions at Gln16 and Met21. In addition, we also explored the combinatorial effects of these internal substitutions with an alanine extension at the C-terminus. Their selectivity was determined by patch-clamp electrophysiology on Kv1.3 and Kv1.1 channels stably expressed in mouse fibroblasts. The peptides with an alanine extension blocked Kv1.3 at low pM concentrations and exhibited up to 2250-fold selectivity for Kv1.3 over Kv1.1. Analogs that incorporates p-phosphono-phenylalanine at the N-terminus blocked Kv1.3 with IC50s in the low pM range and did not affect Kv1.1 at concentrations up to 100 nM, displaying a selectivity enhancement of >10,000-fold for Kv1.3 over Kv1.1. Other potentially important Kv channels such as Kv1.4 and Kv1.6 were only partially blocked at 100 nM concentrations of each of the ShK analogs. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
Open AccessArticle Synthesis and Antiproliferative Activity of Thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, Nortopsentin Analogues
Mar. Drugs 2015, 13(1), 460-492; doi:10.3390/md13010460
Received: 14 November 2014 / Accepted: 4 January 2015 / Published: 16 January 2015
Cited by 15 | PDF Full-text (983 KB) | HTML Full-text | XML Full-text
Abstract
Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging
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Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle Synthesis of Enantiopure Reversed Structured Ether Lipids of the 1-O-Alkyl-sn-2,3-diacylglycerol Type
Mar. Drugs 2015, 13(1), 173-201; doi:10.3390/md13010173
Received: 22 October 2014 / Accepted: 17 December 2014 / Published: 7 January 2015
Cited by 2 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
This report describes the synthesis of reversed structured 1-O-alkyl-2,3-diacyl-sn-glycerols (DAGEs) possessing a pure saturated even number fatty acid (C6:0–C16:0) at the sn-2 position along with a pure EPA or DHA located at the terminal sn-3 position of
[...] Read more.
This report describes the synthesis of reversed structured 1-O-alkyl-2,3-diacyl-sn-glycerols (DAGEs) possessing a pure saturated even number fatty acid (C6:0–C16:0) at the sn-2 position along with a pure EPA or DHA located at the terminal sn-3 position of the glycerol backbone of chimyl, batyl and selachyl alcohols. These adducts were synthesized by a highly efficient two-step chemoenzymatic process involving an immobilized Candida antarctica lipase to introduce pure EPA and DHA activated as oxime esters exclusively to the sn-3 terminal position of enantiopure chimyl, batyl and selachyl alcohols in excellent yields. The saturated fatty acids were subsequently incorporated to the remaining sn-2 position of the resulting 3-monoacylglyceryl ethers (3-MAGEs) using EDAC coupling agent in the presence of DMAP in very high to excellent yields (85%–98%). No losses of enantiomeric composition were observed during these processes. The multiple utilities of the resulting focused library of reversed structured DAGEs are discussed including how such compounds may possibly be utilized within the pharmaceutical area. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle Total Synthesis and Absolute Configuration of the Marine Norditerpenoid Xestenone
Mar. Drugs 2009, 7(4), 654-671; doi:10.3390/md7040654
Received: 2 November 2009 / Revised: 19 November 2009 / Accepted: 23 November 2009 / Published: 24 November 2009
Cited by 5 | PDF Full-text (333 KB) | HTML Full-text | XML Full-text
Abstract
Xestenone is a marine norditerpenoid found in the northeastern Pacific sponge Xestospongia vanilla. The relative configuration of C-3 and C-7 in xestenone was determined by NOESY spectral analysis. However the relative configuration of C-12 and the absolute configuration of this compound were
[...] Read more.
Xestenone is a marine norditerpenoid found in the northeastern Pacific sponge Xestospongia vanilla. The relative configuration of C-3 and C-7 in xestenone was determined by NOESY spectral analysis. However the relative configuration of C-12 and the absolute configuration of this compound were not determined. The authors have now achieved the total synthesis of xestenone using their developed one-pot synthesis of cyclopentane derivatives employing allyl phenyl sulfone and an epoxy iodide as a key step. The relative and absolute configurations of xestenone were thus successfully determined by this synthesis. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessArticle New Azaphilones, Seco-Chaetomugilins A and D, Produced by a Marine-Fish-Derived Chaetomium globosum
Mar. Drugs 2009, 7(2), 249-257; doi:10.3390/md7020249
Received: 18 May 2009 / Revised: 11 June 2009 / Accepted: 15 June 2009 / Published: 16 June 2009
Cited by 14 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
Abstract
Seco-chaetomugilins A and D were isolated from a strain of Chaetomium globosum that was originally isolated from the marine fish Mugil cephalus, and their absolute stereostructures were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR techniques, along
[...] Read more.
Seco-chaetomugilins A and D were isolated from a strain of Chaetomium globosum that was originally isolated from the marine fish Mugil cephalus, and their absolute stereostructures were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR techniques, along with the chemical transformation from known chaetomugilins A and D. Seco-chaetomugilin D exhibited growth inhibitory activity against cultured P388, HL-60, L1210, and KB cells. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)

Review

Jump to: Research

Open AccessReview Recent Advances in the Synthesis of 2-Pyrones
Mar. Drugs 2015, 13(3), 1581-1620; doi:10.3390/md13031581
Received: 1 November 2014 / Revised: 9 March 2015 / Accepted: 11 March 2015 / Published: 23 March 2015
Cited by 7 | PDF Full-text (3477 KB) | HTML Full-text | XML Full-text
Abstract The present review summarizes the recent progresses in the synthesis of 2-pyrones and the application to the synthesis of marine natural products. Especially, much attention was placed on the transition metal catalyzed synthetic methodologies in this review. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
Open AccessReview Synthetic Approaches to the Lamellarins—A Comprehensive Review
Mar. Drugs 2014, 12(12), 6142-6177; doi:10.3390/md12126142
Received: 3 November 2014 / Revised: 1 December 2014 / Accepted: 5 December 2014 / Published: 18 December 2014
Cited by 6 | PDF Full-text (5436 KB) | HTML Full-text | XML Full-text
Abstract
The present review discusses the known synthetic routes to the lamellarin alkaloids published until 2014. It begins with syntheses of the structurally simpler type-II lamellarins and then focuses on the larger class of the 5,6-saturated and -unsaturated type-I lamellarins. The syntheses are grouped
[...] Read more.
The present review discusses the known synthetic routes to the lamellarin alkaloids published until 2014. It begins with syntheses of the structurally simpler type-II lamellarins and then focuses on the larger class of the 5,6-saturated and -unsaturated type-I lamellarins. The syntheses are grouped by the strategy employed for the assembly of the central pyrrole ring. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessReview Synthetic Strategies to Terpene Quinones/Hydroquinones
Mar. Drugs 2012, 10(2), 358-402; doi:10.3390/md10020358
Received: 26 December 2011 / Revised: 3 February 2012 / Accepted: 3 February 2012 / Published: 14 February 2012
Cited by 11 | PDF Full-text (632 KB) | HTML Full-text | XML Full-text
Abstract
The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of
[...] Read more.
The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of the most relevant quinones/hydroquinones are described. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessReview Generating a Generation of Proteasome Inhibitors: From Microbial Fermentation to Total Synthesis of Salinosporamide A (Marizomib) and Other Salinosporamides
Mar. Drugs 2010, 8(4), 835-880; doi:10.3390/md8040835
Received: 28 February 2010 / Revised: 19 March 2010 / Accepted: 22 March 2010 / Published: 25 March 2010
Cited by 31 | PDF Full-text (377 KB) | HTML Full-text | XML Full-text
Abstract
The salinosporamides are potent proteasome inhibitors among which the parent marine-derived natural product salinosporamide A (marizomib; NPI-0052; 1) is currently in clinical trials for the treatment of various cancers. Methods to generate this class of compounds include fermentation and natural products chemistry,
[...] Read more.
The salinosporamides are potent proteasome inhibitors among which the parent marine-derived natural product salinosporamide A (marizomib; NPI-0052; 1) is currently in clinical trials for the treatment of various cancers. Methods to generate this class of compounds include fermentation and natural products chemistry, precursor-directed biosynthesis, mutasynthesis, semi-synthesis, and total synthesis. The end products range from biochemical tools for probing mechanism of action to clinical trials materials; in turn, the considerable efforts to produce the target molecules have expanded the technologies used to generate them. Here, the full complement of methods is reviewed, reflecting remarkable contributions from scientists of various disciplines over a period of 7 years since the first publication of the structure of 1. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessReview Synthesis of 3-Alkyl Pyridinium Alkaloids from the Arctic Sponge Haliclona viscosa
Mar. Drugs 2010, 8(3), 483-497; doi:10.3390/md8030483
Received: 21 January 2010 / Revised: 2 March 2010 / Accepted: 2 March 2010 / Published: 5 March 2010
Cited by 11 | PDF Full-text (390 KB) | HTML Full-text | XML Full-text
Abstract
3-Alkyl pyridinium alkaloids (3-APAs) are common secondary metabolites in marine sponges of the order Haplosclerida. In recent years, our laboratory has isolated and synthesized several new members of this family such as haliclamines C–F, viscosamine, viscosaline and a cyclic monomer. All of them
[...] Read more.
3-Alkyl pyridinium alkaloids (3-APAs) are common secondary metabolites in marine sponges of the order Haplosclerida. In recent years, our laboratory has isolated and synthesized several new members of this family such as haliclamines C–F, viscosamine, viscosaline and a cyclic monomer. All of them were isolated from the Arctic sponge Haliclona viscosa collected in Spitsbergen, Norway. In this article we report the syntheses of these secondary metabolites from Haliclona viscosa and related compounds and give a short overview of the bioactivity. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
Open AccessReview Calyculins and Related Marine Natural Products as Serine- Threonine Protein Phosphatase PP1 and PP2A Inhibitors and Total Syntheses of Calyculin A, B, and C
Mar. Drugs 2010, 8(1), 122-172; doi:10.3390/md80100122
Received: 21 December 2009 / Revised: 12 January 2010 / Accepted: 13 January 2010 / Published: 21 January 2010
Cited by 32 | PDF Full-text (2365 KB) | HTML Full-text | XML Full-text
Abstract
Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role
[...] Read more.
Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control. Calyculins express potent protein phosphatase 1 and 2A inhibitory activity, and have therefore become valuable tools for cellular biologists studying intracellular processes and their control by reversible phosphorylation. Calyculins might also play an important role in the development of several diseases such as cancer, neurodegenerative diseases, and type 2-diabetes mellitus. The fascinating structures of calyculins have inspired various groups of synthetic organic chemists to develop total syntheses of the most abundant calyculins A and C. However, with fifteen chiral centres, a cyano-capped tetraene unit, a phosphate-bearing spiroketal, an anti, anti, anti dipropionate segment, an α-chiral oxazole, and a trihydroxylated γ-amino acid, calyculins reach versatility that only few natural products can surpass, and truly challenge modern chemists’ asymmetric synthesis skills. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Open AccessReview A Submarine Journey: The Pyrrole-Imidazole Alkaloids
Mar. Drugs 2009, 7(4), 705-753; doi:10.3390/md7040705
Received: 30 October 2009 / Revised: 20 November 2009 / Accepted: 26 November 2009 / Published: 27 November 2009
Cited by 102 | PDF Full-text (426 KB) | HTML Full-text | XML Full-text
Abstract
In his most celebrated tale “The Picture of Dorian Gray”, Oscar Wilde stated that “those who go beneath the surface do so at their peril”. This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize
[...] Read more.
In his most celebrated tale “The Picture of Dorian Gray”, Oscar Wilde stated that “those who go beneath the surface do so at their peril”. This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity − from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
Open AccessReview Recent Synthetic Studies Leading to Structural Revisions of Marine Natural Products
Mar. Drugs 2009, 7(3), 314-330; doi:10.3390/md7030314
Received: 15 June 2009 / Revised: 7 July 2009 / Accepted: 13 July 2009 / Published: 13 July 2009
Cited by 32 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
Because of the highly unique structures of marine natural products, there are many examples of structures that were originally proposed based on spectral analyses but later proven incorrect. In many cases, the total syntheses of the originally proposed structures of marine natural products
[...] Read more.
Because of the highly unique structures of marine natural products, there are many examples of structures that were originally proposed based on spectral analyses but later proven incorrect. In many cases, the total syntheses of the originally proposed structures of marine natural products has confirmed their incorrectness and the subsequent total syntheses of the newly proposed structures proved the revised structures. This review will show such cases appearing after 2005 and demonstrate how the true structures were elucidated. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)

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