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  • Tricyclic Sesquiterpenes from Marine Origin Franck Le Bideau,*,† Mohammad Kousara,†,‡ Li Chen,† Lai Wei,† and Franco̧ise Dumas*,†

    †BioCIS, Faculty of Pharmacy, Universite ́ Paris-Sud, CNRS, Universite ́ Paris-Saclay, 92290, Chat̂enay-Malabry, France ‡Faculty of Pharmacy, Al Andalus University, P.O. Box 101, Tartus, Al Qadmus, Syria

    *S Supporting Information

    ABSTRACT: The structure elucidation, biosynthesis, and biological activity of marine carbotricyclic sesquiterpene compounds are reviewed from the pioneering results to the end of 2015. Their total syntheses with a particular emphasis on the first syntheses, enantiomeric versions, and syntheses that led to the revision of structures or stereochemistries are summarized. Overall, 284 tricyclic compounds are classified into fused, bridged, and miscellaneous structures based on 54 different skeletal types. Tricyclic sesquiterpenes constitute an important group of natural products. Their structural diversity and biological activities have generated further interest in the field of drug discovery research, although the exact mechanisms of action of these species are not well known. Furthermore, these tricyclic structures, according to their chemical complexity, are a source of inspiration for chemists in the field of total synthesis for the development of innovative methodologies.

    CONTENTS

    1. Introduction 6111 2. Isolation, Structural Determination, and Biosyn-

    thesis 6111 2.1. Fused Carbocycles 6111

    2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbo- nane and Kelsoane 6111

    2.1.2. 5/5/5 Tricyclic Skeletons: Hirsutane, Iso- hirsutane, Capnellane, and Silphiperfo- lane 6112

    2.1.3. 6/5/3, 5/6/3, 5/3/6 Tricyclic Skeletons: Cycloeudesmane, Calenzanane, Sha- gane, and Cubebane 6114

    2.1.4. 6/5/4 Tricyclic Skeletons: Viridiane, Punc- taporane and Perforetane 6116

    2.1.5. 6/5/5 Tricyclic Skeleton: Probotryane 6116 2.1.6. 6/6/3 Tricyclic Skeletons: Aristolane,

    Maaliane, and Laurobtusane 6116 2.1.7. 6/6/4 Tricyclic Skeleton: Paralemnane 6118 2.1.8. 7/5/3 Tricyclic Skeletons: Africanane,

    Aromadendrane, and Neomerane 6118 2.1.9. 7/6/3 Tricyclic Skeleton: Capillosanane 6120 2.1.10. 8/4/3 Tricyclic Skeleton: Norantipa-

    thane 6121 2.2. Bridged Carbocycles 6121

    2.2.1. Tricyclic Decane Skeletons: Ylangane, Copaane, Sinularane, Trachyopsane, Pu- pukeanane, Allopupukeanane, Abeopu- pukeanane, Neopupukeanane, Sativane, and Isosativane 6121

    2.2.2. Tricyclic Undecane Skeletons: Acantho- dorane, Isotenerane, Quadrane or Sub- erosane, Paesslerane, Longibornane, Rumphellane, Strepsesquitriane, and Cedrane 6123

    2.2.3. Tricyclic Dodecane Skeletons: Caryolane, Isocaryolane, Clovane, Penicibilane, Lemnafricanane, Isoparalemnane, Rho- dolaurane, Gomerane, and Omphalane 6124

    2.3. Miscellaneous Carbocycles: Inflatane, Cyclo- laurane, and Cyclococane 6125

    3. Biological Activity 6126 3.1. Cytotoxic and Antitumor Activity 6126 3.2. Antibacterial Activity 6130 3.3. Other Biological Activities 6132

    4. Synthesis 6133 4.1. Fused Carbocycles 6133

    4.1.1. Kelsoene 6133 4.1.2. Capnellene and Corresponding Diols 6133 4.1.3. Silphiperfolanes 6135 4.1.4. Cycloeudesmanes and Cubebanes 6136 4.1.5. Aristolanes and Maalianes 6138 4.1.6. Africananes and Aromadendranes 6138

    4.2. Bridged Tricyclic Sesquiterpenes 6141 4.2.1. Tricyclic Decane Skeleton 6141 4.2.2. Tricyclic Undecane Skeleton 6143 4.2.3. Tricyclic Dodecane Skeleton 6146

    4.3. Miscellaneous Tricyclic Sesquiterpenes 6146 5. Conclusion 6146 Associated Content 6147

    Received: July 29, 2016 Published: April 5, 2017

    Review

    pubs.acs.org/CR

    © 2017 American Chemical Society 6110 DOI: 10.1021/acs.chemrev.6b00502 Chem. Rev. 2017, 117, 6110−6159

    pubs.acs.org/CR http://dx.doi.org/10.1021/acs.chemrev.6b00502

  • Supporting Information 6147 Author Information 6147

    Corresponding Authors 6147 ORCID 6147 Notes 6147

    Acknowledgments 6147 Abbreviations 6148 References 6148

    1. INTRODUCTION

    Sesquiterpenes could be seen as a class of very old compounds, especially when looking to their terrestrial members. However, their occurrence is still expanding due to growing interest in the marine biodiversity and the importance of natural products in drug discovery.1 They thus represent an important class of natural products,2 identified from all kingdoms of life.3 Many of these compounds display a wide range of biological activities such as anti-HIV, antitumor, antibiotic, antiviral, immunosup- pressive, cytotoxic, insecticidal, and antifungal activities and have stimulated research for druggable analogs.4−11 Known sesqui- terpenes are derived metabolically from some 300 distinct C15- hydrocarbon skeletons, which in turn are produced from the single substrate farnesyl diphosphate (FPP) by the action of sesquiterpene synthases.12,13 Each cyclization reaction in these biosynthetic cascades is initiated by the formation and propagation of highly reactive carbocation intermediates.14,15

    Not surprisingly, covering 70% of the surface of the planet, oceans are the source of an extremely rich biodiversity. Life appearance in the marine environment is dated approximately 4 billion years ago, whereas the first known terrestrial species are aged 400 million years, and consequently, this difference leads today to a greater diversity of phyla in the marine world. In addition to this longer evolution timeline, the huge variations in temperature, pressure, and light from the sea surface to the seabed16 may also explain the richness of the marine world in comparison with the terrestrial world. A large number of living organisms shows biochemical

    properties that could lead to major advances in the field of medicinal chemistry and understanding of human diseases and their treatments. In the same way as terrestrial plants, which have inspired numerous drug discoveries, marine organisms represent an impressive source of original molecules which have the potential to lead to new therapeutic findings.17 Currently, few of them are commercially available as drugs, and others are at an advanced stage of clinical trials.18,19

    More than 25 000 marine natural substances have been described,20 a limited number in comparison with their terrestrial counterparts. This is due to the late development in diving technologies and subsequent difficult access to marine species. Marine metabolites often display peculiar structures due to their environment. They incorporate elements such as chlorine, bromine, and to a lesser extent boron, silicon, phosphorus, iodine, and arsenic, as well as the chemical functions such as isonitrile, thiocyanate, or formamide.21 Most of them were isolated from sponges, algae, corals, and other invertebrates, which mainly adopt biologically active compounds as chemical defenses owing to their lack of physical protection against predators. Because they rapidly dilute when in the marine environment, these chemical defenses need to be highly toxic, which could give them an advantage in the field of drug discovery. Among these compounds, tricyclic sesquiterpenes constitute

    an important group of natural products showing structural

    diversity and for some of them interesting biological activities.7,9,22−24

    In this review, tricyclic sesquiterpenes from marine environ- ment will be considered, excluding their heterocyclic counter- parts.25 Halogenated sesquiterpenes of marine origin were, in part, recently compiled.26,27 Structural characterization, biosyn- thesis, and biological activity of the species will be commented on when appropriate. Total syntheses, either racemic or asymmetric, with particular emphasis on the first syntheses and syntheses that led to the revision of structures or stereochemistry attributions will be described focusing on the key step and/or introduction of chirality. The present review covers the subject from the pioneering results (early 1970s) to the end of 2015. In the second and fourth parts of this review, fused carbocycles

    were classified according to the increasing sizes of their rings (5/ 5/4, 5/5/5, 6/5/3, ...), whatever their relative positions. For instance, 5/5/4 and 5/4/5 tricyclic structures are reported in the same section, even if they are separately treated and appear in different schemes. Bridged carbocycles are sorted according to the number of carbon atoms found in their skeletons: tricyclic decane, undecane, and dodecane. Both bridged and fused all- carbon carbocycle structures reported in this review can be described in accordance with IUPAC atom numbering28 as illustrated in Figures 1 and 2, but numbering resulting from biosynthetic considerations or from common usage29 is also utilized in the manuscript. Skeleton family names (Figures 1 and 2) are given when known (in black). Since the authors did not coin names for several skeletons, we herewith named them (in blue) based on the corresponding metabolite names or on the names of the species they are extracted from. Compound structures described all along this manuscript whose ACs have not been determined are arbitrarily drawn under one enantiomeric form. In these cases, the associated optical rotation signs, when specified, are those of the corresponding isolated products, irrespective of their ACs.

    2. ISOLATION, STRUCTURAL DETERMINATION, AND BIOSYNTHESIS

    2.1. Fused Carbocycles

    2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbonane and Kelsoane. From the dichloromethane solubles of the tropical marine sponge Cymbastela hooperi collected at Kelso reef (Great Barrier Reef, Australia), novel terpenoid metabolites were isolated after repeated HPLC separations.30 One of these, (−)-bourbon-11-ene 1, named inconveniently prespa

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