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In this review we highlight the general cyclization strategies currently available to organic chemists for the concurrent and stereoselective installation of multipleQuaternary Stereogenic Centers(QSC) atoms in cyclic or polycyclic architectures. QSCs embedded in rigid cyclic architectures are motifs found in many blockbuster drugs and important bioactive natural product classes, and yet, direct access to these structures stereoselectively from simple precursors remains a significant challenge. Underscoring the difficulty associated with their synthesis, such topologically three‐dimensional molecules are underrepresented in existing small molecule compound libraries, which are instead dominated by linear or flat molecules. This review focuses on methods disclosed in both natural product synthesis and methodology studies since the turn of the 21^stcentury. The cases to be examined successfully achieve these challenging transformations: (1)one‐step assembly of the cyclized architecture; and (2)concurrent stereoselective installation of multiple (≥2) new QSCs. These cyclization strategies, which address the aforementioned fundamental challenges in complex molecule synthesis, have been categorized into five broad groups: i) Biomimetic Polyene Cyclization Cascades; ii) Cyclization Cascades of Prochiral Alkenes; iii) Cycloadditions; iv) Dearomatizations; v) Electrocyclizations.

 

The nitrogen-interrupted Nazarov cyclization can be a powerful method for the stereocontrolled synthesis of sp 3 -rich N -heterocycles. However, due to the incompatibility between the basicity of nitrogen and the acidic reaction conditions, examples of this type of Nazarov cyclization are scarce. Herein, we report a one-pot nitrogen-interrupted halo -Prins/ halo -Nazarov coupling cascade that joins two simple building blocks, an enyne and a carbonyl partner, to furnish functionalized cyclopenta[ b ]indolines with up to four contiguous stereocenters. For the first time, we provide a general method for the alkynyl halo -Prins reaction of ketones, thus enabling the formation of quaternary stereocenters. Additionally, we describe the outcomes of secondary alcohol enyne couplings, which exhibit helical chirality transfer. Furthermore, we investigate the impact of aniline enyne substituents on the reaction and evaluate the tolerance of different functional groups. Finally, we discuss the reaction mechanism and demonstrate various transformations of the prepared indoline scaffolds, highlighting their applicability in drug discovery campaigns. 

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