Total Synthesis of Pinnatoxin A

Nakamura, Seiichi; Kikuchi, Fumiaki; Hashimoto, Shunichi

doi:10.1002/anie.200802729

Cited by 41 publications

(29 citation statements)

References 56 publications

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“…In contrast, the non-natural (−)-PnTx-A is inactive in mouse assays (Munday R, 2008). Identification of successful strategies for the synthesis of (+)-PnTx-A and PnTx-G, and subsequent electrophysiological, competition binding and computational analyses established PnTx-A as a potent antagonist of nicotinic acetylcholine receptors (nAChR), with high selectivity for the human neuronal α7 subtype (Stivala and Zakarian, 2008; Nakamura et al, 2008; Aráoz et al, 2011). In contrast, a synthetic aminoketone derivative of PnTx-A (PnTx-A AK) with an open imine ring shows no action on various nAChR subtypes, a feature supporting the central role of the imine ring for potent nAChR antagonism previously observed for the related toxins, 13-desmethyl spirolide C (SPX) and gymnodimine A (GYM) (Aráoz et al, 2011; Bourne et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α12βγδ nAChRs

et al. 2015

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Pinnatoxins are macrocyclic imine phycotoxins associated with algal blooms and shellfish toxicity. Functional analysis of pinnatoxin-A and pinnatoxin-G, by binding and electrophysiology on membrane-embedded neuronal α7, α4β2 and α3β2 and muscle-type α12βγδ nicotinic acetylcholine receptors (nAChRs), reveals high-affinity binding and potent antagonism for the α7 and α12βγδ subtypes. The toxins also bind to the nAChR surrogate, acetylcholine-binding protein (AChBP), with low Kd’s reflecting slow dissociation. Crystal structures of pinnatoxin-AChBP complexes (1.9–2.2Å resolution) picture the multiple anchoring points of the hydrophobic portion, the cyclic imine and the substituted bis-spiroketal and cyclohexene ring systems of the pinnatoxins that dictate tight binding between the opposing loops C and F at the receptor subunit interface, as observed for the 13-desmethyl-spirolide-C and gymnodimine-A congeners. Uniquely however, the bulky bridged EF-ketal ring specific to the pinnatoxins extends radially from the interfacial-binding pocket to interact with the sequence-variable loop F and govern nAChR-subtype selectivity and central neurotoxicity.

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Section: Introductionmentioning

confidence: 99%

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α12βγδ nAChRs

et al. 2015

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“…Initial efforts were dedicated to exploring an intramolecular reaction to forge the macrocycle, since to date only three examples of intramolecular Ru-catalyzed alkene-alkyne couplings have been reported. These have appeared in the total syntheses of (+)-amphidinolide A, (+)-pinnatoxin A, 49 and laulimalide. However, in each of these examples only branched products were generated.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of (−)-Lasonolide A

et al. 2016

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The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products, however through a detailed investigation we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.

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“…[xii] The formation of highly functionalized macrocycles which highlights the chemoselectivity has also been illustrated in the case of the synthesis of amphidinolide A by our group, albeit with lower efficiency. [xiii] The synthesis of pinnatoxin A [xiv] through this method further illustrates the power of the Ru-catalyzed coupling reaction which wherein the alkene-alkyne macrocyclization proceeded in 79% yield represents a new opportunity to form macrocycles in an atom economical fashion.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Laulimalide: Assembly of the Fragments and Completion of the Synthesis of the Natural Product and a Potent Analogue

Trost

Amans

Seganish

et al. 2012

Chemistry A European J

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In this manuscript, we report the full account of our efforts to couple the northern and the southern building blocks, whose synthesis were described in the preceding paper, along with the modifications required which ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report in this paper a second generation route which provided a more concise synthesis of the natural product.

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Total Synthesis of Pinnatoxin A

Cited by 41 publications

References 56 publications

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α12βγδ nAChRs

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α12βγδ nAChRs

Total Synthesis of (−)-Lasonolide A

Total Synthesis of Laulimalide: Assembly of the Fragments and Completion of the Synthesis of the Natural Product and a Potent Analogue

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