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Application of Two-Dimensional Nmr Spectroscopy in the Structural Determination of Marine Natural Products. Isolation and Total Structural Assignment of 4-Deoxyasbestinin Diterpenes from the Caribbean Gorgonian Briareum asbestinum
Abstract
The structures of four novel asbestinin diterpenes isolated in the toxic extracts of the Caribbean gorgonian Briareum asbestinum are discussed. The major metabolite 11-acetoxy-4-deoxyasbestinin B was subjected to a total structural assignment through the concerted application of several 2D nmr techniques that included 1H-1H COSY, RCT-COSY, RCT2 COSY, HC COSY (HMQC), NOESY, proton-detected long range heteronuclear chemical shift correlation (HMBC) and 13C-13C chemical shift correlation spectroscopy (INADEQUATE).
... The studies performed about their biological activities are scarce, but shows important cytotoxicity against several tumor cellular lines at micromolar and nanomolar levels. [1][2][3][4][5][6][7] Several comprehensive reviews covering the isolation, biological activity and synthesis of these marine metabolites have been published since the first report in 1980. [8][9][10][11][12][13]. ...
... A close inspection of all the NOE contacts in the 2D-PSNOE spectra of Asbestinin 15, showed the typical ones of the Asbestinin carbon skeleton [3,92] and when we tested them on the optimized calculated molecule, they matched quite well. ...
The structure of the marine natural products Asbestinin 7, Asbestinin 15, Labiatin C (5), Labiatin E, and Sclerophytin F were reassigned. The structure of Sclerophytin E (11) was confirmed.
A methodology that involved carefully analyses of the experimental 1H-NMR, 13C-NMR data, key NOE correlations and computed geometries at MPW1PW91/631G(d) and calculated GIAO 13C-NMR chemical shifts at MPW1PW91/631G(d,p) levels of theory was used to propose the reassignment of the structure of all the five compounds.
... [1] The 39 asbestinins that have been isolated and characterized to date partitioni nto two distinct structural groups: members that lack aC -4 substituent, such as 11-acetoxy-deoxyasbestinin D( 1)a nd 4-deoxyasbestinin C ( 2), and those that are oxidiseda tC -4, such as asbestinin-12( 3)a nd asbestinin-2 (4) ( Figure 1). [2][3][4][5][6][7][8] Ab iosynthetic route to the asbestininsf rom related briarellin naturalp roductsh as been proposed in which Wagner-Meerwein rearrangement transfers am ethyl group from C-11t oC -12. [1,9] Theb riarellin naturalp roducts are, in turn, thought to be derived from the simpler cladiellins (eunicellins). ...
... At the outset, we intended to synthesize 11-acetoxy-4-deoxyasbestinin D( 1)a nd 4-deoxyasbestinin C( 2), andp repare several other asbestinins from these natural products thereafter. [3] The retrosynthetic analysiso ft he natural products 1 and 2 began with the cleavage of the ester andf ormationo fak etone at C-11 and removal of the C-12 methyls ubstituent to give advancedt etracyclic intermediate i (Scheme1). Sequential opening of the oxepane by scission of the CÀOb ond distal to the quaternary centre at C-3, conversion of the methyl substituent into am ethylene group and the C-11k etonei nto an enol ether,f ollowed by removal of the C-3 methyl substituent led to the tricyclick etone ii.S ubsequent conversion of the sidechain allylic ether into am ethyl ketone produced intermediate iii,a na nalogue of as ynthetic intermediate used in our total syntheses of members the cladiellin natural products. ...
Six members of the asbestinin family of marine diterpene natural products have been synthesized in an efficient and stereoselective manner from a single oxa‐bridged intermediate. Five of these natural products have not been synthesized previously and the structures of four of them have been confirmed as those proposed originally or following revisions to the original structures. The fifth natural product—asbestinin‐21—has been shown to be a diastereomer of the compound that had been proposed previously.
... In fact, during the 1990s, crude extracts from Briareum asbestinum, a common inhabitant of shallow Caribbean reefs, were shown to be highly toxic to CHO-K1 cells at concentrations <25 μg/mL. Furthermore, four derivatives were significantly cytotoxic to the same cells with ED 50 values of 3.35, 2.50, 3.55, and 4.82 μg/mL, respectively as well as active against Klebsiella pneumoniae [82]. Diterpenes 2β-acetoxy-2-(debutyryloxy)stecholide E, 9-deacetylstylatulide lactone, 4β-acetoxy-9-deacetylstylatulide lactone, brianthein W and 9-deacetylbriareolide H were isolated from the gorgonian Briareum sp.; their derivatives were found to be cytotoxic to P-388, KB, A-549, and HT-29 cancer cell lines [83]. ...
The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested in order to evaluate some fundamental parameters, such as the activity on cell survival, functioning and metabolism, and to improve the knowledge about the mechanisms of action of these compounds. In agreement with the modern tendency aimed to avoid the utilization of living animals in the experiments and to substitute them with in vitro systems, established cell lines or primary cultures have been employed to test cnidarian extracts or derivatives. Several cnidarian venoms have been found to have cytotoxic properties and have been also shown to cause hemolytic effects. Some studied substances have been shown to affect tumour cells and microorganisms, so making cnidarian extracts particularly interesting for their possible therapeutic employment. The review aims to emphasize the up-to-date knowledge about this subject taking in consideration the importance of such venoms in human pathology, the health implications and the possible therapeutic application of these natural compounds.
Los cembranoides 2.11-cicüzados son una familia de diterpenoides altamente funcionalizados aislados may oritar i ámente de octocoralcs del mar caribe. Biogenéticamente se proponen como derivados de la ciclacion de la molécula del cembrano, con posteriores ciclaciones oxidativas que originan el esqueleto carbonado de asbestinino, briaicllina, eunicelina y saicodictina. Sesenta y nueve cembranoides 2,11 ciclizados se han aislado hasta diciembre do 2009 de tres gorgonios del caribe mesoamericano, treinta y nueve Asbestininos, veintidós Briarellinas, siete Sarcodictinas y una Eunicelma, dejos cuales cuarenta y cuatro son de Bria retan asbeslinum, dieciocho de Bria retan polyajiíhes y siete de Eritliropodium caribaeorum. Estos metabolites poseen diversidad de actividades biológicas que van desde citotóxicas, antimmorales hasta antibacterianas y anti -inflamatorias. El número importante de estos metabolites, aunado a su variada y sorprendente actividad biológica y aspectos estructurales únicos, los hacen moléculas que deben ser sujetas a estudios profundos, tanto en su potencial farmacológico, como en el análisis de la relación entre su estructura y actividad biológica. El origen biosintético/estructura y actividad biológica de estos sesenta y nueve cembranoides se describen en este artículo.
Gorgonios caribeños del género Briareum (Cnidaria, Gorgonaceae), son una fuente importante de metabolites secundarios bioactivos. Biosintetizan tres tipos básicos de diterpenos; asbestininos, briarellinas y briareinas. Las briarellinas A-R y las briarellinas D y K peróxidos, son los únicos metabolites que poseen el esqueleto de briarellina, que han sido aislados de un organismo marino de la región del Caribe. Estos diterpenos altamente funcionalizados forman parte de la familia de Cembranoides 2,11 ciclizados, cuyo origen biosintético se propone deriva del esqueleto carbonado del cembrano, vía diversas ciclizaciones oxidativas y transposiciones de metilo. En este trabajo se discuten ampliamente las propiedades de Resonancia Magnética Nuclear RMN- del esqueleto carbonado de Briarellina y la comparación entre los dos tipos de briarellinas existentes, y de éstas, con el de los asbestininos. Mediante la aplicación concertada y exhaustiva de técnicas de RMN de una y dos dimensiones, se muestran sus cuatro sub-sistemas de espín y la conectividad entre ellos para estructurar el esqueleto carbonado de las Briarellinas. Mediante comparación de los espectros de RMN-'H y RMN- 13C entre asbestininos y los distintos tipos de briarellinas, se documentan diferencias claras que permiten diferenciar entre estos tipos de metabolites secundarios e inclusive, la estereoquímica sobre determinados centros quinales al rededor del esqueleto carbonado de estos compuestos.
As one of the most common marine sponges in tropical and subtropical oceans, the sponges of the genus Agelas, have emerged as unique and yet under-investigated pools for discovery of natural products with fabulous molecular diversity and myriad interesting biological activities. The present review highlights the chemical structure and biological activity of 355 compounds that have been isolated and characterized from the members of Agelas sponges, over the period of about five decades (from 1971 to November 2021). For a better understanding, these numerous compounds are firstly classified and presented according to their carbon skeleton as well as their biosynthetic origins. Relevant summaries focusing on the source organism and the associated bioactivity of these compounds belonging to different chemical classes are also provided. This review highlights sponges of the genus Agelas as exciting source for discovery of intriguing natural compounds.
An overview on the heterocyclic natural products of gorgonian octocorals of genus Briareum is presented. Based on previous studies, most of the heterocyclic natural products from Briareum are diterpenoid metabolites, including eunicellin, asbestinane, cembrane, and briarane-type derivatives. The structures, names, biological activities, and references of these natural products exclusive of briaranes are described in this review.
The structure of eunicillin (89), a carbobicyclic diterpenoid isolated from the Mediterranean gorgonian Eunicella stricta, was reported in 1968 (1). At that time chlorine-containing diterpenoids had been discovered in the gorgonian Briareum asbestinum (2, 3), but it was not until 1977 that the structure of the first briaran, briarein A (211), was resolved by X-ray analysis (4). The first trinervitane diterpenoid (26), which was isolated from Trinervitermes termites, was reported in 1976 (5).
Cycloaddition is a member of pericyclic reactions in which reactive components possessing conjugated π-electrons (e.g., diene/dienophile, 1,3-dipole/dipolarophile, and ketene/imine) transform into cyclic molecules. These reactions proceed in a concerted mechanism with a high degree of regio- and stereoselectivity. Thus, they have been widely used for the construction of cyclic skeletons of numerous natural products and pharmacologically active molecules. Based on the π-electron systems of reactants, they can be further classified into [4 + 2], [3 + 2], and [2 + 2] cycloadditions that produce six-, five-, and four-membered rings, respectively. On the other hand, whereas natural products and designed synthetic molecules may offer a starting point in drug development, improvement of their structures and properties is frequently needed to optimize their biological efficacy. To this end, solid-phase synthesis is a powerful tool for generating a large number of compounds with synthetic convenience and many solid-phase cycloaddition reactions have been reported to date. This review, in particular, summarizes stereoselective cycloaddition reactions and their solid-phase versions carried out on polymer supports for the synthesis of natural products and their analogs, focusing on the reactions that were employed as key steps.Keywords:cycloaddition reaction;stereoselective;pericyclic reaction;CC bond formation;total synthesis;regioselectivity;stereoselectivity;[4+2] cycloaddition;[3+2] cycloaddition;[2+2] cycloaddition;solid-phase synthesis
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The full details for our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 micromolar). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy we have determined that neither alkaloid affects tubulin dynamics within cells.
Six new diterpenes, (1–3 and 5–7), were isolated from Briareum asbestinum collected off the coast of Tobago, West Indies. Their structures were determined by a combination of 2D NMR experiments.
The crystal structure of 11-acetoxy-4-deoxyasbestinin B (C22H34O4, Mr=362.49) crystallized in the orthorhombic space group P212121 with a=10.923(5)Å, b=11.127(5)Å, c=17.047(5)Å, V=2072(3)Å3, Z=4, Dx=1.163g/cm-3. Mo Kα radiation was used for data collection at room temperature. The final R=0.042 for 2464 observed reflections. The stereochemical assignments of the molecule from the 2-D NMR data are verified totally by the overall geometry of the molecule obtained from the X-ray diffraction analysis.
The concerted application of two-dimensional phase-sensitive COSY, RELAY, ROESY and 13C-1H shift correlation spectroscopy in the structural elucidation and stereochemical assignment of a new asbestinin diterpene, (Z-11-acetoxy-4-deoxyasbestinin-(D), is reported. The results reveal that these two-dimensional techniques are invaluable for the stereochemical assignment of proton resonances in the 4-deoxyasbestinin series which overlap in 1H NMR and homonuclear correlation spectra.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Three novel diterpenoids named pachyclavulariaenones A–C (1–3) have been isolated from the soft coral Pachyclavularia violacea. Their structures have been established by spectroscopic methods. The structure of 3 was further confirmed by a single crystal X-ray analysis.
This review covers the literature published in 2005 for marine natural products, with 704 citations (493
for the period January to December 2005) referring to compounds isolated from marine microorganisms
and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs,
tunicates and echinoderms. The emphasis is on new compounds (812 for 2005), together with their
relevant biological activities, source organisms and country of origin. Biosynthetic studies, first
syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.
The hexane extract of the Caribbean gorgonian octocoral Briareum asbestinum was found to contain traces of a novel seco-asbestinin diterpenoid. The structure of 1, the first representative of this novel class of diterpenoids, was assigned on the basis of extensive NMR analyses and by comparison with analogous spectral data from related asbestinane diterpenoids. Confirmation of structure 1 was achieved by partial synthesis from known asbestinin-6 (2).
Compound 1, the first representative of a novel class of ether-cyclized asbestinane diterpenes known as seco-asbestinins, was found in the lipid soluble extract of the Caribbean gorgonian Briareum asbestinum. The structure of 1 was confirmed by partial synthesis.
Five new diterpenoids representatives from the rare skeletal class asbestinins have been isolated from the Caribbean gorgonian octocoral Briareum asbestinum. The structures of these secondary metabolites, named asbestinin-6 (1), asbestinin-7 (4), asbestinin-8 (5), asbestinin-9 (10) and asbestinin-10 (11), were defined by chemical and spectroscopic methods. The specimens of B. asbestinum collected in Puerto Rico yielded exclusively diterpenoids possessing the asbestinane carbon skeleton thus suggesting lack of biosynthetic versatility for this gorgonian. Diterpenoids 1, 4, 510 and 11 showed significant cytotoxicity when screened against a panel of five human tumor cell lines.The extraction of several specimens of the Caribbean gorgonian octocoral produced five new diterpenoids possessing the rare asbestinane carbon skeleton. Most of the new compounds exhibited in vitro antitumor activity against a panel of five human tumor cell lines. The complete structural assignments of these new metabolites have been accomplished exclusively from in-depth NMR spectral analyses.
Ten new diterpenoid representatives from the briarane skeletal class have been isolated from shallow water colonies of the Caribbean gorgonian octocoral Briareum asbestinum collected at Mona Island near Puerto Rico. The structures of the new secondary metabolites, named briareins C−L (3−12), were defined by chemical and spectroscopic methods. In addition, two known diterpenoids, briareins A (1) and B (2), were among the most abundant compounds isolated. Traces of another known diterpenoid, briarane methyl ester (13), were also isolated from the same gorgonian extracts. In this paper we also establish unambiguously structure 2 for the known diterpene briarein B.
For Abstract see ChemInform Abstract in Full Text.
The Caribbean gorgonian Briareum asbestinum has been shown to contain representatives from three skeletal classes, asbestinins, briareins, and eunicellins. The structural diversity of the diterpenoids isolated suggest a common biosynthetic pathway. Briarellins -A (1), -B (3), -C (5), and -D (6) are members of a new class of tetracyclic diterpenoids of the eunicellin family distinguished by the presence of a seven-membered lactone ring formed between C-3 and C-16. Seco-briarellin (7), which possesses a novel carbon skeleton, is the first representative of a new class of ether-cyclized eunicellin diterpenes known as seco-eunicellins. The briarellins are also unique among the compounds in this series in having the opposite relative stereochemistry at C-11 to that found in eunicellin-based compounds isolated from South Pacific soft corals. The structures of the new eunicellin-type diterpenoids were established after extensive analysis of spectral data and those of 3 and 5 were confirmed by chemical interconversions. Briarellin-A (1) displayed modest in vitro cytotoxicity against HeLa cells.
The total syntheses of (+)-vigulariol and (-)-sclerophytin A are reported in 15 steps and 16 steps, respectively, from a known compound. The flexible, readily scalable synthetic strategy allows for rapid construction of a critical tricyclic intermediate and is demonstrated via the synthesis of these two marine natural products. A key reaction in this synthetic protocol is a combination Wittig/intramolecular Diels-Alder cycloaddition.
The applications of the most recently developed asymmetric Diels-Alder (D-A) reactions, [n + m] cycloaddition reactions, molecular rearrangements, free-radical reactions and transition-metal-catalyzed cyclization reactions toward the syntheses of APIs and natural products with bridge-containing ring systems were studied. The Diels-Alder cycloaddition reaction is one of the most fundamental synthetic transformations and has been the cornerstone in countless total syntheses. Lewis-acid-catalyzed asymmetric DA reactions have attracted great attention due to their ability to construct complex carbocyclic frameworks. 2,5-disubstituted cyclopentadiene is highly competent in Diels-Alder cycloadditions with a wide variety of dienophiles under very mild reaction condition. A combination of intramolecular Diels-Alder cycloaddition with intermolecular Diels-Alder cycloaddition, developed by Baran's group, constitutes a powerful tool to access a key tricyclic carbon skeleton.
Enantioselective total syntheses of briarellin E (12) and briarellin F (13), as well as the structure originally proposed for the cladiellin diterpene alcyonin (10), have been realized. Comparison of the spectral data for synthetic 10, natural alcyonin, cladiellisin (33), and cladiellaperoxide (34), as well as chemical transformations of 10 and natural alcyonin, suggest that the structure of this coral metabolite is allylic peroxide 11. The unified approach detailed herein can be used to access both C4-deoxygenated and C4-oxygenated cladiellins and briarellins. The central step in these syntheses is acid-promoted condensation of (Z)-alpha,beta-unsaturated aldehydes 17 with cyclohexadienyl diols 18 to form intermediates 16 incorporating the hexahydroisobenzofuran core and five stereocenters of these marine diterpenes (Scheme 1 ).
This review covers the literature published since the report of the first compound to December 2006, for marine natural 2,11-cyclized cembranoids isolated from Caribbean sources, with 30 citations, most of them from 2000 to 2006, referring to compounds isolated from the Caribbean gorgonian octocorals Briareum asbestinum, Briareum polyanthes, and Erithropodiun caribaeorum. The emphasis is on all of these natural compounds isolated to date, with an overview of their biogenetic pathway and relevant biological activity.
Recent reports of the syntheses of heterocyclic natural products that are isolated from bacteria, fungi, plants and marine sources are discussed. This review emphasizes new developments in synthetic methodology and strategies for such products, and the potential biological activity of the metabolites that are described is highlighted. Concepts of conformational analysis, stereoelectronic control and reaction mechanism are all used in the development of new methodology. Despite the variety and scope of synthetic efforts, the synthesis of new organic molecules and the improved synthesis of known molecules remains a major task for organic chemists.
A number of strategies for the total synthesis of C2-C11 cyclized cembranoids were discussed. The C2-C11 cyclized cembranoids include the eunicellins, asbestinins are secondary metabolites isolated from gorgonian octocorals and soft corals. The first total synthesis of a C2-C11 hinges upon the formation of the hydroisobenzofuran functionality through a prins-pinacol condensation-rearrangement, employed for the stereoselective synthesis of tetrahydrofurans. The next extended Prins-pinacol condensation-rearrangement approach to a cladiellin of potential pharmocological utility. Each of the described synthesis have targeted cembranoids containing a (Z)-oxozene or lacking an endocyclic olefin within the nine-membered ring of the natural products. Diverse strategies can be found within the literature that approach these molecular skeletons.
Sixteen new diterpenoids, representative of the asbestinane skeletal class, have been isolated from shallow water colonies of the Caribbean gorgonian octocoral Briareum asbestinum. The structures of these secondary metabolites, named asbestinin-11 [1], asbestinin-12 [3], asbestinin-13 [4], asbestinin-14 [5], asbestinin-15 [7], asbestinin-16 [8], asbestinin-17 [9], asbestinin-18 [10], asbestinin-19 [11], asbestinin-20 [12], asbestinin-21 [13], asbestinin-22 [14], asbestinin-23 [15], 11-acetoxy-4-deoxyasbestinin E [16], 11-acetoxy-4-deoxyasbestinin F [17] and 4-deoxyasbestinin G [18], were defined by chemical and spectroscopic methods. These specimens of B. asbestinum, collected in Puerto Rico, yielded almost exclusively diterpenoids possessing the asbestinane carbon skeleton thus suggesting minor biosynthetic variations for this gorgonian. In this paper, we also revise the structures of the known asbestinin-6 and asbestinin-7 to asbestinanes 2 and 6, respectively.
Seven new briariane diterpene lactones were isolated from the gorgonian Solenopodium excavatum collected in New Guinea. One structure (4) was determined by X-ray diffraction and the remainder were elucidated by spectroscopic analysis. Six of the new briareolides, 4-9, exist in a conformation that is quite uncommon for representatives of this fairly large family of compounds, namely one in which the bonds joining the 10-membered ring to the 6-membered ring are nearly diaxially oriented. Conformational energy calculations are discussed as are the structural features that are responsible for the uncommon conformation. Mild cytotoxic activity was confirmed for 4.
Three new briaran diterpenes, 2 beta-acetoxy-2-(debutyryloxy) stecholide E (3), 9 -deacetylstylatulide lactone (4), and 4 beta-acetoxy-9-deacetylstylatulide lactone (5), and two known diterpenes, brianthein W (1) and 9-deacetylbriareolide H (2), have been isolated from a Briareum sp. of gorgonian. The structures and relative stereochemistry of these compounds were determined by spectroscopic and chemical methods. Diterpenes 2-4 and the corresponding 9-acetyl derivatives 6, 7, and 12 exhibited cytotoxicity toward various cancer cell lines.
The chemistry of Briareum excavatum, a Formosan gorgonian coral, was investigated. This study has led to the isolation of five novel marine natural products, excavatolides A-E (1-5), together with brianolide (6). The structures of the above compounds were established by spectral and chemical methods. The relative configuration of excavatolide B (2) was further confirmed by a single-crystal X-ray structure analysis. Cytotoxicity of these compounds toward various cancer cell lines also is described.
An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structure assigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequential Tebbe-Claisen rearrangement of lactones 29 and 30, which originated from the Diels-Alder cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introduced into the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methyl group to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. The superfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means of oxymercuration chemistry. Only then was the exocyclic methylene group unmasked via elimination. An alternative approach to the alpha-carbinol diastereomer proceeds by initial alpha-oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerization at C10. Through deployment of oxymercuration chemistry, it was again possible to elaborate the dual oxygen-bridge network of the target ring system. Oxidation of the organomercurial products with O(2) in the presence of sodium borohydride furnished 72, which was readily separated from its isomer 73 after oxidation to 61. Hydride attack on this ketone proceeded with high selectivity from the beta-direction to deliver (-)-60. Comparison of the high-field (1)H and (13)C NMR properties and polarity of synthetic 5 with natural material required that structural revision be made. Following a complete spectral reassessment of the structural assignments to many sclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytin B was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absolute configurations were properly determined. Key elements of the strategy include dihydroxylation of a medium-ring double bond, oxidation of the secondary hydroxyl in the two resulting diols, unmasking of an exocyclic methylene group at C-11, and stereocontrolled 1,2-reduction of the alpha-hydroxy ketone functionality made available earlier.
A new chemical study of the hexane extract of the gorgonian Briareum polyanthes collected in Puerto Rico afforded 10 new diterpenes of the eunicellin class, briarellins 1-9 and polyanthellin A (10), along with the known diterpene briarellin D (11). The structures and relative stereochemistry of metabolites 1-10 were assigned on the basis of NMR studies, chemical methods, and comparisons to the spectral properties of 11. A reassessment of prior structural assignment for briarellin A and two known sclerophytin-type diterpenes, 13 and 14, is proposed. Antimalarial tests on 1-6 and 8-12 indicated that they were active against Plasmodium falciparum.
A total synthesis of the laurencia metabolite (+)-obtusenyne has been completed. The key steps include a Sharpless kinetic resolution and an asymmetric glycolate alkylation to establish the stereogenic centers adjacent to the ether linkage and a ring-closing metathesis reaction to construct the nine-membered ether without the aid of a cyclic conformational constraint. The synthesis was completed in 20 linear steps from commercially available 1,5-hexadiene-3-ol.
A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products.
Our extended chemical investigation of the crude MeOH-CHCl3 extract of the gorgonian octocoral Briareum polyanthes from Puerto Rico has led to the isolation of three eunicellin-type diterpenoids, 1-3, along with five (4-8) diterpenoids of the asbestinane-type and one (9) of the briarane-type of polycyclized diterpenes. The structures and relative stereochemistry of the new compounds 1-9 were established on the basis of spectroscopic analysis (1H NMR, 13C NMR, HMQC, HMBC, NOESY). The biological activity of these compounds against pathogenic microbes responsible for various human infectious diseases was investigated. In addition, new data recorded for four known asbestinin diterpenes also isolated during this investigation and further analysis through chemical reactions have prompted us to revise our original structural assignments for these compounds.
The enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12 have been completed. A glycolate aldol reaction provided a diene useful for ring-closing metathesis to form an oxonene, which was ultimately employed as a template to execute a highly stereoselective intramolecular Diels-Alder cycloaddition, forming the hydroisobenzofuran moiety. The absolute configuration of the asbestinin subclass was confirmed via these synthetic efforts.
A method is described for obtaining pure absorption phase spectra in four quadrants in a two-dimensional nuclear magnetic resonance spin exchange experiment. It is shown that phase correction results in a substantial increase in resolution and discrimination while maintaining a signal-to-noise ratio comparable to that of the usual magnitude spectrum. Experimental results are presented for the application of the method to a biological macromolecule, the bovine pancreatic trypsin inhibitor.
The principles of compensation of pulse imperfections in N.M.R. coherence transfer experiments are explained. The INADEQUATE technique in which 13C-13C satellites are observed through a double quantum filter is chosen for detailed theoretical analysis. The results are verified by proton and by carbon-13 experiments.
Fourteen 4α-methyl sterols have been isolated from the gorgonians Briareum asbestinum, Gorgonia mariae, Muriceopsis flavida and Pseudoplexaura wagenaari, including the following five new sterols: 4α-methyl-24-methylene-5α-cholestan-3β-ol, (24R)-4α, 24-dimethyl-5α-cholesta-7,22-dien-3,β-ol, 4α,24S(or 23ξ)-dimethyl-5α-cholest-7-en-3β-ol, (22E, 24R)-4α,23,24-trimethyl-5α-cholesta-7,22-dien-3β-ol and (24R)-4α,24-dimethyl-5α-cholesta-8(14),22-dien-3β-ol. There is strong evidence that these 4α-methyl sterols are synthesized by the algal (dinoflagellate) symbionts (zooxanthellae) of the gorgonians. It is suggested that analysis of 4Δ-methyl sterol mixtures isolated from a zooxanthellae-bearing invertebrate, collected in several different geographic locations, might give information on the specificity of the symbiotic association between a given animal species and a particular strain of zooxanthellae.
The optimization of the recently introduced two-dimensional homonuclear RELAY experiment is described. Practical guidelines for optimization of experimental parameters and data processing are presented. The effectiveness of relayed magnetization transfer is found to be strongly dependent on the type of spin system. Explicit calculations predict the relative intensities of RELAY cross peaks for a number of commonly occurring systems. The feasibility of doubly relayed magnetizatioin transfer experiments is discussed and demonstrated for a sample of gramacidin-S and for the trinucleotides A2′--5′A2′-5Á.
Experimental techniques used for homonuclear 2D 1H NMR studies of proteins are described. A brief survey of the general strategy for structural studies of proteins by 2D NMR is included. The main part of the paper discusses guidelines for the selection of experimental techniques, the elimination of artifacts and unwanted peaks in protein 2D 1H NMR spectra, suppression of the solvent line in H2O solutions, experimental parameters, numerical data processing before and after Fourier transformation, and suitable presentations of complex 2D NMR spectra.
A method is given for identifying families of signals belonging to the same network of coupled spins in NMR. The method exploits the existence of a coupling network to prove the connectivity between 2 remote nuclei A and X in the AMX system. Two or more consecutive steps are employed where transverse magnetization is relayed from nucleus to nucleus along a path defined by a sequence of resolved couplings. The spectrum of crotonaldehyde is discussed. [on SciFinder (R)]
1.1. The sterols of a number of coelenterates and of their zooxanthellae have been examined by mass spectrometry. The sterols, with C27, C28, C29 and C30 skeletons, occur as complex mixtures.2.2. The occurrence of the “gorgosterol” of Bergmann in coelenterates has been confirmed; its molecular weight has been determined by mass spectrometry to be 426, corresponding to C30H50O.3.3. The occurrence of gorgosterol in coelenterates is associated with the occurrence of symbiotic zooxanthellae.4.4. Zooxanthellae from Anthopleura elegantissima, a sea anemone, and from Tridacna gigas, the giant clam, do not contain gorgosterol.5.5. Unfer anaerobic conditions gorgosterol is reduced in the zooxanthellae to a C30H52O compound, “dihydrogorgosterol”.