Formal Synthesis of Antiplatelet Drug, Beraprost

Reddy, Naredla Kesava; Vijaykumar, B.V.D.; Chandrasekhar, Srivari

doi:10.1021/ol203060v

Cited by 25 publications

(3 citation statements)

References 35 publications

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“…Due to the unique tricyclic core of 1 , which bears four contiguous stereocenters, various approaches for the synthesis of key intermediate 2 (Scheme 1) have been reported [14–23], including a few asymmetric syntheses relying on the optical resolution of racemic intermediates [16–18 23]. Herein we report the first catalytic asymmetric synthesis of the key intermediate 2 through organocatalyzed-enantioselective intramolecular oxa-Michael reaction [24–26].…”

Section: Introductionmentioning

confidence: 99%

Catalytic asymmetric formal synthesis of beraprost

Kobayashi¹,

Kuramoto²,

Takemoto³

2015

Beilstein J. Org. Chem.

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SummaryThe first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C–H insertion and the subsequent reduction from the convex face.

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Section: Introductionmentioning

confidence: 99%

Catalytic asymmetric formal synthesis of beraprost

Kobayashi¹,

Kuramoto²,

Takemoto³

2015

Beilstein J. Org. Chem.

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“…After examining a reductive Claisen rearrangement that afforded allenes as a product, we next examined the reductive rearrangement involving an allene as a substrate, the allylic 2,3-allenoates, a substrate type that has been even less studied, which could react to yield 1,5-diene as products. Previous reports on Ireland-Claisen rearrangements that generated 1,5-dienes were based solely on deprotonations of α,β- − or β,γ-unsaturated esters . One problem with this protocol for conducting the Ireland–Claisen rearrangement was a possible side reaction of the isomerization of the original rearrangement product to the more stable conjugated acid under the reaction conditions (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Copper-Catalyzed Reductive Ireland–Claisen Rearrangements of Propargylic Acrylates and Allylic Allenoates

et al. 2021

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The copper-catalyzed reductive Ireland–Claisen rearrangement of propargylic acrylates led to 3,4-allenoic acids. The use of silanes or pinacolborane as stoichiometric reducing agents and triethylphosphite as a ligand facilitated the divergent and complementary selectivity for the synthesis of diastereomeric anti- and syn-rearranged products, respectively. Copper-catalyzed reductive Ireland–Claisen rearrangement of allylic 2,3-allenoates proceeded effectively only when pinacolborane was used as a reductant to generate various 1,5-dienes in excellent yields and with good diastereoselectivities in some cases. Mechanistic studies showed that the silyl and boron enolates, rather than the copper enolate, underwent a stereospecific rearrangement via a chairlike transition state to afford the corresponding Claisen rearrangement products.

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“…Most strategies for the enantioselective synthesis of beraprost have focused on using either resolution strategies, or the enantiopure (−)-Corey lactone . Recently, Hayashi, reported an asymmetric organocatalytic synthesis of beraprost through a formal [3+2] cycloaddition reaction catalyzed by diphenylprolinol silyl ether as the key step to construct the cyclopentane core .…”

Section: Introductionmentioning

confidence: 99%

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost

et al. 2023

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Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels−Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination− aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost's dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels−Alder reaction.

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Formal Synthesis of Antiplatelet Drug, Beraprost

Abstract: The first stereocontrolled and enantiospecific formal synthesis of antiplatelet drug beraprost has been achieved from readily available 1-tetralone.

Cited by 25 publications

References 35 publications

Catalytic asymmetric formal synthesis of beraprost

Catalytic asymmetric formal synthesis of beraprost

Copper-Catalyzed Reductive Ireland–Claisen Rearrangements of Propargylic Acrylates and Allylic Allenoates

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost

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