Total Synthesis of the Proposed Structure for Pyragonicin

Takahashi, Shigetoshi; Ogawa, Narihito; Koshino, Hiroyuki; Nakata, Tadashi

doi:10.1021/ol0508126

Cited by 40 publications

(31 citation statements)

References 36 publications

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“…In the event, exposure to SmI 2 provided the desired pyran 12 in 69% yield for the three steps. The relative stereochemistry of 12 was assigned by NMR and nOe analysis, and in agreement with literature precedent 5-10…”

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confidence: 87%

Total Synthesis of Brevisamide

Fadeyi

Lindsley

2009

Org. Lett.

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The second total synthesis of Brevisamide, a marine cyclic ether alkaloid from Karenia brevis is reported. This streamlined synthesis proceeds in 21 steps, 14 steps longest linear sequence, in 5.2% overall yield and features a key SmI 2 reductive cyclization step to access the tetrasubstituted pyran core.Recently, Satake, Tachibana, Wright and co-workers reported on the isolation and characterization of brevisamide (1), an unprecendented monocylic ether alkaloid, from the dinoflagellate Karenia brevis, a species known to produce polycyclic ether toxins such as the brevetoxins. 1 Identification of 1, containing the same conjugated 3,4-dimethyl-2,4-dienal side chain as the more complex polycylic ether brevenal, 2 provided further support for the model of ladder-frame initiation in the synthesis of polycyclic ether natural products, and thus has garnered significant synthetic interest. 1 Within months of the publication of the isolation and characterization of brevisamide (1), the first total synthesis and structural confirmation of 1 was reported by the same group. 3 The synthesis proceeded in 28 steps, with the longest linear sequence of 21 steps, for an overall yield of 1 from cis-but-2-ene diol of 0.23%. 3 In this letter, we wish to report our efforts on the total synthesis of brevisamide (1) employing a fundamentally different synthetic strategy that afforded 1 in 21 total synthetic steps and an overall yield of 5.2%.Scheme 1 illustrates our retrosynthetic analysis of 1, providing a convergent synthetic strategy. Inspired by the elegant synthesis of brevenal by Takamura and coworkers, 4 we envisioned the western C 1 -C 4 side chain would be installed through a Horner-Emmons-Wadsworth reaction utilizing 2, prepared from commercially available 4. Key pyran 3, the C 5 -C 15 fragment, was conceived to be derived from 5 through a SmI 2 -mediated reductive cyclization reaction. [5][6][7][8][9][10] The synthesis of pyran 3 is described in Scheme 2. Mono-benzyl protected-1,4-butane diol 6 was oxidized under Swern conditions to the corresponding aldehyde which was then subjected to a Brown crotylation reaction to afford 7 as a single diastereomer in 87% ee. 11,12 Hydroboration and chemoselective TBS protection of the primary alcohol provided 8 in 89% yield for the two steps. 1,4-addition of 8 to ethyl propiolate proved difficult, resulting in craig.lindsley@vanderbilt.edu. Supporting Information Available: Experimental procedures, characterization data, and 1 H and 13 C NMR spectra for all new compounds. This material is avaialble free of charge via the internet at http://pubs.acs.org. complex mixtures under a number of reaction conditions. 13 Ultimately, slow addition of ethyl propiolate via syringe pump over 24 hours delivered the key intermediate 9 in 93% isolated yield. Removal of the TBS group proved equally problematic. Upon exposure to TBAF, a 1:1 mixture of the desired 10 and an unanticipated 1,3-dioxepane 11 formed. While separable, this undesired side product was detrimental at this stage of the synth...

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confidence: 87%

Total Synthesis of Brevisamide

Fadeyi

Lindsley

2009

Org. Lett.

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“…Carbon-carbon double bond or triple bond reduction using Wilkinson's catalyst were used in synthesis of 10-hydroxyasimicin [323], murisolins [324], tuberostemonines [688], eupomatilones [211], guanacastepene A [942], pyragonicin [943], mucocin [944], 3-hydroxy-4-methyl-2-tetradecyl-4-butenolide [945], gleenol and axeenol [946], (−)-jimenezin [947], epi-(+)-SCH-642305 [948], methionine aminopeptidase-2-inhibitor [949] and the tricyclic core of cyathin diterpenoids [455]. Crabtree's iridium catalyst was used in synthesis of prodigiosines [198], batzelladine alkaloids (Eq.…”

Section: Formation Of Carbon-hydrogen Bonds From Alkenes Alkynes Camentioning

confidence: 99%

Transition metals in organic synthesis: Highlights for the year 2005

Söderberg

2008

Coordination Chemistry Reviews

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“…however, research on the inhibition of acetogenins against pol and topo activities is limited, probably due to the small quantities of natural products. Since the total synthesis of bioactive acetogenins, such as compound 5, is possible (17)(18)(19)(20)(21)(22)(23)(24)(25), these compounds should be provided and studied in pharmaceutical research throughout the world. compound 5 directly inhibited animal pol and human topo activities (table ii), but did not bind to dna.…”

Section: Discussionmentioning

confidence: 99%

“…1) was achieved (17)(18)(19)(20)(21)(22)(23)(24)(25). Since mclaughlin et al and mata et al reported that some acetogenins have cytotoxicity against human cancer cell lines (4-7), the purpose of this review is to investigate the biochemical action of the compounds against dna metabolic enzymes such as pols and topos, and to use the compound as an antineoplastic agent.…”

Section: Introductionmentioning

confidence: 99%

The relationship between the molecular structure of natural acetogenins and their inhibitory activities which affect DNA polymerase, DNA topoisomerase and human cancer cell growth

Matsui

Takeuchi²,

Kumamoto-Yonezawa³

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. acetogenins from the annonaceous plant are a fatty acid-derived natural product. chemically synthesized natural acetogenins, such as mucocin (compound 1), jimenezin (compound 2), muconin (compound 4), pyranicin (compound 5) and pyragonicin (compound 6) were investigated. concomitantly, 19-epi jimenezin (compound 3), 10-epi pyragonicin (compound 7) and a γ-lactone (compound 8), which is estimated to be a biosynthetic precursor of acetogenins, were synthesized and investigated. compounds 5 and 6 strongly inhibited, and compound 7 moderately inhibited the activities of mammalian dna polymerases (pols), such as replicative pol α and repair/recombination-related pol β and λ, and also inhibited human dna topoisomerase (topos) i and ii activities. On the other hand, compounds 1-4 and 8 did not influence the activities of any pols and topos. Compound 5 was the strongest inhibitor of the pols and topos tested, and the ic 50 values were 5.0-9.6 µm, respectively. these compounds also suppressed human cancer cell growth with almost the same tendency as the inhibition of pols and topos. compound 5 was the strongest suppressor of the proliferation of the promyelocytic leukemia cell line, hl-60, in human cancer cell lines tested with an ld 50 value of 9.4 µm, and arrested the cells at G1 phases, indicating that it blocks dna replication by inhibiting the activity of pols rather than topos. this compound also induced cell apoptosis. the relationship between the three-dimensional molecular structure of acetogenins and these inhibitory activities is discussed. the results suggested that compound 5 is a lead compound of potentially useful cancer chemotherapy agents.

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Total Synthesis of the Proposed Structure for Pyragonicin

Cited by 40 publications

References 36 publications

Total Synthesis of Brevisamide

Total Synthesis of Brevisamide

Transition metals in organic synthesis: Highlights for the year 2005

The relationship between the molecular structure of natural acetogenins and their inhibitory activities which affect DNA polymerase, DNA topoisomerase and human cancer cell growth

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