New Cytotoxic 14-Membered Macrolides from Marine-Derived Fungus <i>Aspergillus ostianus</i>

Kito, Keijiro; Ookura, Ryuhei; Yoshida, Sanae; Namikoshi, Michio; Ooi, Takashi; Kusumi, Takenori

doi:10.1021/ol702598q

Cited by 138 publications

(87 citation statements)

References 8 publications

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“…46 These compounds were identified as the secondary metabolites of the marine fungus Aspergillus ostianus strain 01F313, cultured in a bromine-modified medium. The Uenishi group demonstrated through total synthesis that the originally assigned structures of aspergillides A and B needed to be reconsidered.…”

Section: Synthesis Of Oxacycles By Harnessing Unique Reactivity Of Rumentioning

confidence: 99%

“…Although Kusumi and co-workers described that direct interconversion of aspergillides A and B via a retro-oxa-Michael reaction was not possible, 46 we envisioned a unified total synthesis of these macrolides by exploiting a divergent synthesis of 2,6-cis-and 2,6-trans-substituted tetrahydropyrans via an intramolecular oxa-Michael reaction 50 of the ζ-hydroxy α,β-unsaturated ester 47, as shown in Figure 8.…”

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Exploiting Ruthenium Carbene-Catalyzed Reactions in Total Synthesis of Marine Oxacyclic Natural Products

Fuwa¹,

Sasaki²

2016

Bulletin of the Chemical Society of Japan

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Olefin metathesis has emerged as an indispensable means to create complex natural products by the virtue of its powerful carboncarbon bond-forming ability, compatibility with a range of functional groups, and ready availability of highly reactive ruthenium carbene catalysts. Furthermore, Grubbs-type ruthenium carbene complexes originally developed for olefin metathesis reactions also mediate a variety of non-metathetic reactions and found their use in tandem metathetic/nonmetathetic processes. This account summarizes our recent efforts on total synthesis of oxacyclic natural products by means of ruthenium carbene-catalyzed reactions.

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Section: Synthesis Of Oxacycles By Harnessing Unique Reactivity Of Rumentioning

confidence: 99%

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confidence: 99%

Exploiting Ruthenium Carbene-Catalyzed Reactions in Total Synthesis of Marine Oxacyclic Natural Products

Fuwa¹,

Sasaki²

2016

Bulletin of the Chemical Society of Japan

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“…1 These novel macrolides exhibit significant cytotoxic activity against mouse lymphocytic leukemia cells with LD 50 values ranging from 2-70 μg/mL. Structurally, the aspergillide macrolides bear a 14-membered lactone ring with 2,6-cis-or 2,6-trans-trisubstituted dihydro-or tetrahydropyran subunits and an E-alkene bond at C8-C9.…”

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Total Synthesis of the Z-Isomers of the Proposed and Revised Structures of Aspergillide B via an Iodocyclization and Ring-Closing Metathesis Strategy

2014

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The synthesis of Z-isomers of both the proposed and revised structures of aspergillide B is described. A divergent route is employed that involves kinetically controlled ring-closing metathesis for the construction of a 14-membered macrocyclic ring, ester formation under Yamaguchi conditions, a Wacker-type oxidative cyclization for creation of the C4 stereogenic center and a previously reported diastereoselective isomerization-iodocyclization strategy for the construction of the 2,6-trans-disubstituted tetrahydropyran subunit.Kusumi and co-workers isolated aspergillides A-C from the marine derived fungus, Aspergillus ostianus strain 01F313, cultured in a potato-dextrose (1/2PD) medium containing bromine-modified artificial sea water, and thereby launched an exciting chapter in natural product synthesis. 1 These novel macrolides exhibit significant cytotoxic activity against mouse lymphocytic leukemia cells with LD 50 values ranging from 2-70 μg/mL. Structurally, the aspergillide macrolides bear a 14-membered lactone ring with 2,6-cis-or 2,6-trans-trisubstituted dihydro-or tetrahydropyran subunits and an E-alkene bond at C8-C9. Though the structures and stereochemistry were established on the basis of detailed NMR studies and by employing a modified Mosher's ester method, there were some discrepancies in the structures of aspergillides A and B. However, Kusumi and Uenishi assigned the corrected structures via X-ray crystallographic analysis of the benzoate ester derivatives, and by total synthesis. 2,3 The proposed and confirmed structures of aspergillides A and B are shown in Figure 1. Because of their potent cytotoxic activity and unique structural features, the aspergillides have attracted interest from the synthetic community. 2,4-6 Due to these structural ambiguities, we have focused our attention on the syntheses of the Z-isomers of both the enantiomers (revised and proposed) of aspergillide B. Our group has previously developed an efficient and novel iodocyclization strategy for the synthesis of trans-2,6-dihydropyrans, which are building blocks of many complex bioactive natural products. The versatility of this methodology has resulted in the synthesis of complex natural products such as the bicyclic core of (+)-sorangicin A, 7a the macrolactone core of leucascandrolide A, 7c the total synthesis of polyrachitides 7b and the formal total synthesis of cladosporin. 7d In continuation of our efforts toward the synthesis of pyran-containing complex natural products, herein, we report a divergent synthesis of the proposed and revised structures of aspergillide B, with cis-alkene geometry at C8-C9, by employing an iodocyclization and ring-closing metathesis (RCM) based strategy. In our retrosynthetic analysis (Scheme 1), we envisaged that the target molecules could be prepared from macrolactones 3 and 4, which in turn could be synthesized from dienes 7a and 7b, respectively, following ring-closing metathesis 8 and tert-butyldimethylsilyl ether deprotection. Dienes 7a or 7b could be obtained by coupling of acid 10...

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“…According to MS and 1 H and 13 C NMR spectral data, the other isolated compounds were identified to be cytosporones A-C (3, 4, 7) [9], M (5), and N (6) [8], pestalotiopsones A (8), B (9), and F (10) [10], and 14-membered macrolides aspergillides A (11) and C (12) [11]. Previously, a total of 19 cytosporones has been identified from cultures of Cytospora sp.…”

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“…Antimicrobial and/or cytotoxic activities were observed with some of these polyketides [14]. In particular, cytosporone B, which has been totally synthesized, was shown to be an excellent agonist for a nuclear orphan receptor Nur77 [17][18][19], and aspergillides A and C were disclosed to be promising cytotoxic agents against mouse lymphocytic leukemia cells (L1210) [11].…”

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Two new cytosporones from the culture of endophytic Phomopsis sp.

Guo

Zhong

et al. 2013

Chem Nat Compd

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Two new steroids, (14b,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (1) and (5a,6b,15b,22E)-6-ethoxy-5,15-dihydroxyergosta-7,22-dien-3-one (2), together with three known steroids, calvasterols A and B (3 and 4, resp.), and ganodermaside D (5), were isolated from the culture broth of an endophytic fungus Phomopsis sp. isolated from Aconitum carmichaeli. The structures of these compounds were elucidated on the basis of spectroscopic analysis, and their inhibitory activities against six pathogenic fungi were evaluated. Most of the compounds showed moderate or weak antifungal activities in a brothmicrodilution assay.Introduction. -Endophytic fungi of the genus Phomopsis are a rich source of bioactive secondary metabolites with diverse structures [1] [2]. In the course of our studies on chemical constituents of the endophytic fungi of medicinal plants, several new compounds had been obtained previously [3 -5], including two new tenmembered lactones from a Phomopsis strain. During our ongoing research on endophytic fungi, one strain of Phomopsis sp. was isolated from the traditional Chinese medicinal plant Aconitum carmichaeli Debx. The AcOEt extract of the culture broth of this strain showed potent antifungal activity. A follow-up fractionation led to the isolation of two new steroids, (14b,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (1) and (5a,6b,15b,22E)-6-ethoxy-5,15-dihydroxyergosta-7,22-dien-3-one (2), together with three known steroids, calvasterols A and B (3 and 4, resp.), and ganodermaside D (5). Several articles on chemical constituents, pharmaceutical uses, and toxicities of the Aconitum plants had been reported previously. However, few work has been conducted on the endophytic fungi of the plant. Here, we report the isolation and structure elucidation of the new compounds, as well as their antifungal activities. We describe the secondary metabolites from an endophytic fungi of the plant A. carmichaeli for the first time.

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New Cytotoxic 14-Membered Macrolides from Marine-Derived Fungus Aspergillus ostianus

Cited by 138 publications

References 8 publications

Exploiting Ruthenium Carbene-Catalyzed Reactions in Total Synthesis of Marine Oxacyclic Natural Products

Exploiting Ruthenium Carbene-Catalyzed Reactions in Total Synthesis of Marine Oxacyclic Natural Products

Total Synthesis of the Z-Isomers of the Proposed and Revised Structures of Aspergillide B via an Iodocyclization and Ring-Closing Metathesis Strategy

Two new cytosporones from the culture of endophytic Phomopsis sp.

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