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

Ze-Shu Wang, Steven h. Bennett, Bilal Kicin, Changcheng Jing, Johan a. Pradeilles, Karen Thai, James r. Smith, P. david Bacoş, Valerio Fasano, Carla m. Saunders, Varinder k. Aggarwal*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)

Abstract

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-1,1-dioxide 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.
Original languageEnglish
Pages (from-to)14124–14132
Number of pages9
JournalJournal of the American Chemical Society
Volume145
Issue number25
Early online date16 Jun 2023
DOIs
Publication statusPublished - 28 Jun 2023

Bibliographical note

Funding Information:
We thank EPSRC (EP/M012530/1) for financial support. V.F. thanks the University of Bristol for awarding the EPSRC Doctoral Prize Fellowship (EP/R513179/1). Z.-S.W. thanks the Foundation of Wenzhou Science and Technology Bureau (No. ZY2020027) for financial support. We thank Dr. Hazel A. Sparkes and Dr. Natalie E. Pridmore for X-ray analysis and Dr. Natalie Fey for helpful discussions of the computational results. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/ .

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

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