The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in the study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediate central to the cyclization. Methods reviewed include carbon-heteroatom ionization, functionalization of a double bond, nucleophilic addition, or electrocyclic ring opening. Additional variations employ unconventional substrates to produce novel pentacycles, such as the iso- and imino-Nazarov. Herein, we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization.
A mild method for the diastereoselective formation of C 4 , C 5 -disubstituted cyclopentenones has been developed, involving formation of a pentadienyl cation via diastereoselective oxidation of a vinyl alkoxyallene. Conrotatory electrocyclization provides the cyclopentenone product. The broad scope, mild conditions, and uncommon substitution pattern accessible through this transformation make it a useful addition to the existing repertoire of cyclopentenone synthetic methods.Cyclopentenones are an architectural underpinning of a wide range of natural products and medicinal agents. Moreover, their practical use as intermediates en route to these compounds of interest makes the development of methods for their synthesis of perennial importance.The Nazarov cyclization has, in recent times, played a increasingly prominent role in this capacity.1 The prototypical version employs the Lewis acid activation of a divinyl ketone to generate a pentadienyl cation, which undergoes π4 a conrotatory electrocyclization to form an oxyallyl cation. Subsequent elimination forms the cyclopentenone. Less commonly, access to the requisite pentadienyl cation is gained via routes that do not conform to this conventional rubric.2 Such an approach is exemplified in our laboratory's recent synthesis of (±)-Rocaglamide,3 wherein the key step employs a novel Nazarov cyclization triggered by the oxidation of a vinyl alkoxyallene (Scheme 1). In this case, a pentadienyl cation is generated upon oxidation, instead of via exposure to an acidic promoter. Cyclization gives the cyclopentenone, and both stereocenters created during the electrocyclization are retained in the product. 4This transformation is suspected to follow the same basic mechanism as the metabolic conversion of polyunsaturated fatty acids to jasmonates in plants, wherein the enzymatic conversion of a vinyl allene to a vinyl allene oxide is followed by formation of a pentadienyl cation that cyclizes to the cyclopentenone.5 Synthetic studies on the rearrangements of simple vinyl allene oxides to cyclopentenones have also been conducted.6 Observations included formation of side products resulting from poor epoxidation selectivity6a and undesired trapping of the pentadienyl cation intermediate by nucleophiles present in the reaction mixture.6d frontier@chem.rochester.edu. Supporting Information Available: Experimental procedures for the preparation of all compounds and characterization data. This material is available free of charge via the internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2012 February 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTo expand the utility of the oxidation-initiated cyclization utilized in the rocaglamide synthesis, we sought to explore the oxidation/cyclization of type 2 allenes, which have an alkoxy group on the internal allene terminus (Table 1). Oxidation of these allenes should occur preferentially at the electron rich internal double bond. Our c...
This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)–rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide.
The synthesis of 3-pyridyl biaryl systems can be readily achieved by means of palladium-catalyzed Suzuki cross-coupling reactions between aryl halides and 3-pyridylboroxin. A series of cross-couplings were conducted in order to investigate the scope and limitations of this protocol.
The scope of the cycloaromatization of propargylic ethers was explored using operationally simple air- and moisture-insensitive conditions. Highly substituted phenol derivatives were obtained in high yields. Mechanistic experiments indicate that the reaction occurs by an electrocyclization followed by 1,3-proton transfer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.