Design and Synthesis of Estrarubicin: a Novel Class of Estrogen-Anthracenedione Hybrids

Riccardis, Francesco De; Meo, D.; Izzo, Irene; Filippo, Marcello Di; Casapullo, Agostino

doi:10.1002/(sici)1099-0690(199809)1998:9<1965::aid-ejoc1965>3.0.co;2-s

Cited by 30 publications

(18 citation statements)

References 22 publications

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“…Acceptable yield of the diene 50 was obtained by Stille reaction of the vinyltriflate prepared from the ketone 48 using Commin’s reagent. 40 From a practical perspective we realized that these reactions can be carried out in a single pot from 48 giving 86% yield of the diene 50. …”

Section: Resultsmentioning

confidence: 99%

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

et al. 2018

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A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products including di- and tri-terpenes and steroids. Installation of these centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serrulatanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinylation (HV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provide an exceptionally facile way of introducing these chiral centers. This manuscript documents our efforts to demonstrate the generality of the asymmetric HV to access not only the natural products, but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phosphoramidite Ni(II)-complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for HV reactions are excellent, and selectivities are in the range of 92–99% for the desired isomers. Discovery of novel, configurationally fluxional, yet sterically less demanding, 2,2′-biphenol-derived phosphoramidite Ni-complexes (fully characterized by X-ray) turned out to be critical for success in several HV reactions. We also report, a less spectacular, yet equally important role of solvents in a metal-ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives we iteratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)-p-benzoquinone natural product, elisabethadione, nor-elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin] and amphilectane [e.g., A–F, G–J and K,L- pseudopterosins] derivatives. Our attempts to synthesize a hither-to elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A–F aglycone.

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Section: Resultsmentioning

confidence: 99%

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

et al. 2018

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“…Wittig olefination of estrone benzyl ether, 23 followed by epoxidation with mCPBA gave the known 24 epoxide 1 as a mixture of diastereomers (Scheme 1). Deprotonation of 1 with lithium diisopropylamine, followed by cleavage of the benzyl ether under dissolving metal conditions gave the allylic alcohol 2 .…”

Section: Resultsmentioning

confidence: 99%

“…A PolarStar Galaxy fluorescent plate reader was used and controlled with FLUOStar Galaxy software (version 4.30-0). Estrone benzyl ether 23 and compounds 3 , 25 5 , 26 8 , 26 and 17 28 were prepared by the literature procedures.…”

Section: Methodsmentioning

confidence: 99%

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

McCullough¹,

Neumann²,

Gone³

et al. 2014

Bioorganic & Medicinal Chemistry

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Various estrogen analogs were synthesized and tested for binding to human ERα using a fluorescence polarization displacement assay. Binding affinity and orientation were also predicted using docking calculations. Docking was able to accurately predict relative binding affinity and orientation for estradiol, but only if a tightly bound water molecule bridging Arg394/Glu353 is present. Di-hydroxyl compounds sometimes bind in two orientations, which are flipped in terms of relative positioning of their hydroxyl groups. Di-hydroxyl compounds were predicted to bind with their aliphatic hydroxyl group interacting with His524 in ERα. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ERβ over ERα, and was also 25-fold specific for agonist ERβ versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ERβ, versus with Thr299 in the antagonist form. But, the presence of this aliphatic hydroxyl is not required in all compounds, since mono-hydroxyl (phenolic) compounds bind ERα with high affinity, via hydroxyl hydrogen bonding interactions with the ERα Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.

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“…The cyanide 9 was hydrolyzed to an acid and subsequently converted into an acid chloride, which was cyclized under Friedel-Crafts conditions to form 10 . The diene 11 was synthesized in 86% yield from 10 via a Stille reaction 14 of a vinyltriflate generated in situ from the ketone. The compound 11 is set up for the installation of the chiral center at C 3 via a second hydrovinylation , this time that of a 1,3-diene.…”

Section: Enantioselective Synthesis Of Pseudopterosin Corementioning

confidence: 99%

Ethylene in Organic Synthesis. Repetitive Hydrovinylation of Alkenes for Highly Enantioselective Syntheses of Pseudopterosins

2011

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In this report we highlight the significant potential of ethylene as a reagent for the introduction of a vinyl group with excellent stereoselectivity at three different stages in the synthesis of a broad class of natural products, best exemplified by syntheses of pseudopterosins. The late-stage applications of the asymmetric hydrovinylation reaction further illustrate the compatibility of the catalyst with complex functional groups. We also show that depending on the choice of the catalyst, it is possible to either enhance or even completely reverse the inherent diastereoselectivity in the reactions of advanced chiral intermediates. This should enable the synthesis of diastereomeric analogs of several classes of medicinally relevant compounds that are not readily accessible by the existing methods, which depend on ‘substrate-control’ for the installation of many of the chiral centers, especially in molecules of this class.

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Design and Synthesis of Estrarubicin: a Novel Class of Estrogen-Anthracenedione Hybrids

Cited by 30 publications

References 22 publications

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

Ethylene in Organic Synthesis. Repetitive Hydrovinylation of Alkenes for Highly Enantioselective Syntheses of Pseudopterosins

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