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We report a Brønsted acid-catalyzed carbocyclization cascade, featuring condensation of an alcohol/sulfonamide with an aldehyde followed by an intramolecular three-component coupling involving an alkyne, an oxocarbenium/iminium ion, and an arene. A formal cycloaddition is embedded in the cationic cascade, which enables the synthesis of a wide range of fused heterotricycles. The diastereoselectivity of the cascade is studied using secondary alcohols/sulfonamides with different carbonyl partners. The described method results in the preparation of synthetically versatile scaffolds with ample opportunity for further derivatization at the resulting tetrasubstituted olefin, or by inclusion of other functionalizable motifs from the starting materials. It is worth noting that this chemistry also facilitates the synthesis of piperidines and 1,4-oxazepanes, as well as the inclusion of indoles and benzofurans, which are privileged motifs for medicinal chemistry. Herein we present the generality of this approach and some chemical transformations that can be achieved with our substrates.
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Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications
This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019. 1 Introduction 1.1 Alkyne-Carbonyl Coupling Pathways 1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction 2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles) 2.1 Early Work 2.2 Halide as Terminal Nucleophile 2.3 Oxygen as Terminal Nucleophile 2.4 Arene as Terminal Nucleophile (Intermolecular) 2.5 Arene Terminal Nucleophile (Intramolecular) 2.6 Cyclizations Terminated by Elimination 3 Synthetic Utility of Alkynyl Prins Annulation 3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo- addition-Oxidation Sequence 3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors 3.3 Alkynyl Prins Cyclization in Natural Product Synthesis 4 Alkynyl Aza-Prins Annulation 4.1 Iminium Electrophiles 4.2 Activated Iminium Electrophiles 5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis 6 Summary and Outlook
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- Award ID(s):
- 1900050
- PAR ID:
- 10181816
- Date Published:
- Journal Name:
- Synthesis
- Volume:
- 52
- Issue:
- 14
- ISSN:
- 0039-7881
- Page Range / eLocation ID:
- 1991 to 2007
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1055/s-0039-1690869
