Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process

Alachouzos, Georgios; Frontier, Alison J.

doi:10.1021/jacs.8b11713

Cited by 37 publications

(13 citation statements)

References 31 publications

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“…Following this lead, research directions focused on 3- halo -Nazarov cyclizations are currently being pursued in the lab. Some of this work has been disclosed already, − and new findings will be reported in due course.…”

Section: Resultsmentioning

confidence: 88%

New Twists in Nazarov Cyclization Chemistry

Frontier

Hernandez

2020

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The defining feature of the Nazarov cyclization is a 4πconrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process. The first stage involves a 4π-electrocyclization leading to the formation of an allylic cation, and the second stage corresponds to the fate of this cationic intermediate. With a complete understanding of the discrete events that characterize the overall process, one can optimize reactivity and control the selectivity of the different Stage 2 pathways.In this Account, we describe the development of methods that render the Nazarov cyclization catalytic and chemoselective, focusing specifically on advances made in our lab between 2002 and 2015. The initial discovery made in our lab involved reactions of electronically asymmetric ("polarized") substrates, which cyclize efficiently in the catalytic regime using mild Lewis acidic reagents. These cyclizations also exhibit selective eliminative behavior, increasing their synthetic utility. Research directed toward catalytic asymmetric Nazarov cyclization led to the serendipitous discovery of a 4π-cyclization coupled to a well-behaved Wagner−Meerwein rearrangement, representing an underexplored Stage 2 process. With careful choice of promoter and loading, it is possible to access either the rearrangement or the elimination pathway. Additional experimental and computational studies provided an effective model for anticipating the migratory behavior of substiutents in the rearrangements. Problem-solving efforts prompted investigation of alternative methods for generating pentadienyl cation intermediates, including oxidation of allenol ethers and addition of nucleophiles to dienyl diketones. These Nazarov cyclization variants afford cyclopentenone products with vicinal stereogenic centers and a different arrangement of substituents around the ring. A nucleophilic addition/cyclization/elimination sequence can be executed enantioselectively using catalytic amounts of a nonracemic chiral tertiary amine. In summary, the discovery and development of several new variations on the Nazarov electrocyclization are described, along with synthetic applications. This work illustrates how strongly substitution patterns can impact the efficiency of the 4π-electrocyclization (Stage 1), allowing for mild Lewis acid catalysis. Over the course of these studies, we have also identified new ways to access the critical pentadienyl cation intermediates and demonstrated strategies that exploit and control the different cationic pathways available post-electrocyclization (Stage 2 processes). These advances in Na...

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Section: Resultsmentioning

confidence: 88%

New Twists in Nazarov Cyclization Chemistry

Frontier

Hernandez

2020

Acc. Chem. Res.

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“…The study began when experiments in our laboratory focused on the alkynyl halo -Prins cyclization yielded an unexpected result . The treatment of enyne 1a with TBAI (2 equiv) and Tf 2 NH (2.4 equiv) in the presence of Ts-protected hemiaminal 2 gave 3a in 82% yield (Table , entry 1).…”

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confidence: 99%

One-Pot Double-Annulation Strategy for the Synthesis of Unusual Fused Bis-Heterocycles

et al. 2020

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A novel metal-free double-annulation cascade for the construction of unusual fused heterocyclic systems is described. This simple protocol enables the sequential assembly of two rings in one pot from two simple precursors. Acidic conditions promote the condensation and the intramolecular alkynyl Prins reaction of an enyne or arenyne alcohol with a cyclic hemiaminal to form a five-, six-, or seven-membered oxacycle followed by a seven- or eight-membered azacycle. In this transformation, chemical complexity is rapidly generated with the formation of three new bonds (one C–O, one C–C, and one C–N) in one synthetic operation. The strategy is modular and relatively general, providing access to a series of unique fused bicyclic scaffolds.

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“…Our penultimate demonstration of the utility of this method is shown in our recent study involving our multicomponent halo‐ Prins/arene‐interrupted halo‐ Nazarov cascade [89] . In this study, we took aldehydes or ketones bearing a pendent electron‐rich arene 159 , enyne alcohols 160 and tetrabutylammonium halide salts TBAX and combined them under acidic conditions to effect a cascade reaction that ultimately furnishes polycycles 162 containing up to three potential QSCs (see Scheme 36).…”

Section: Cyclization Strategiesmentioning

confidence: 99%

Cyclization Strategies for the Concurrent Installation of Multiple Quaternary Stereogenic Centers

Alachouzos

Frontier

2021

Israel Journal of Chemistry

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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 multiple Quaternary 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 21st century. 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.

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Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process

Cited by 37 publications

References 31 publications

New Twists in Nazarov Cyclization Chemistry

New Twists in Nazarov Cyclization Chemistry

One-Pot Double-Annulation Strategy for the Synthesis of Unusual Fused Bis-Heterocycles

Cyclization Strategies for the Concurrent Installation of Multiple Quaternary Stereogenic Centers

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