Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Abstract

Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.

1 Introduction

2 Synthesis

2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole

2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization

2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange

2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition

2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation

3 Reactivity

3.1 Use of Uhle’s Ketone for Lysergic Acid

3.2 Use of Uhle’s Ketone for Rearranged Clavines

3.3 Use of Uhle’s Ketone for Medicinal Chemistry

4 Conclusion and Outlook

Keywords

Uhle’s ketone - 3,4-fused tricyclic indole - ergot alkaloids - natural products - bioactive substances

Publication History

Received: 05 November 2020

Accepted after revision: 18 December 2020

Accepted Manuscript online:
18 December 2020

Article published online:
25 January 2021

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