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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. [ABSTRACT FROM AUTHOR]

A diastereoselective two-step strategy for the synthesis of densely functionalized 1-halocyclopentenes with several chiral centers has been developed. In the first step, a multicomponent alkynyl halo-Prins reaction joins an enyne, a carbonyl derivative, and either a chloride, bromide, or iodide to produce a cyclic ether intermediate. In the subsequent step, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo-Nazarov cyclization. The products contain three new contiguous stereogenic centers, generated with a high level of stereocontrol, as well as a vinyl halide allowing for additional functionalization. The strategy creates two new carbon-carbon bonds, one carbon-halide bond, and one carbon-oxygen bond. [ABSTRACT FROM AUTHOR]

A 1,6 conjugate addition/Nazarov electrocyclization/internal redox cyclization sequence was developed. Various 5-hydroxycyclopentenones were made through the 1,6-conjugate addition initiated Nazarov reaction with excellent diastereoselectivities. Under thermal conditions, these underwent a through-space 1,5-hydride-transfer/ring-closure reaction to form bridged bicyclic N-heterocyclic compounds with up to four stereogenic centers. It was also possible to convert simple acyclic dienyl diketones into the bicyclo[3.2.1] products in a one-pot process (with a solvent switch). [ABSTRACT FROM AUTHOR]

Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s - cis conformation. [ABSTRACT FROM AUTHOR]

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum-based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization. [ABSTRACT FROM AUTHOR]

The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in 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 intermediates central to the cyclization. Methods reviewed include carbon-heteroatom ionization, double bond functionalization, nucleophilic addition, or electrocyclic ring opening. Additional variations, such as iso- and imino-Nazarov cyclization, employ unconventional substrates to produce new pentacycles. Here we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article focuses on a study which reviewed catalytic advances in Nazarov cyclization including the catalyst designs, new condition formulation and electrocyclization variations. The Nazarov reaction allows stereospecific construction of a carbon-carbon bond in the pentadienyl cation of divinyl ketones via a 4φ electrocyclic process. As a reaction mechanism, the coordination of a Brønsted or a Lewis acid promoter to the dienone leads to electrocyclization of the pentadienyl cation.

Dienyl diketones containing tethered acetates selectively undergo two different 1,6-conjugate addition-initiated cyclization cascades. One is a 1,6-conjugate addition/cyclization sequence with incorporation of the nucleophile, and the other is catalyzed by DABCO and is thought to proceed via a cyclic acetoxonium intermediate. The reaction behavior of substrates lacking the tethered acetate was also studied. The scope of both types of cyclization cascades, the role of the amine additive, and the factors controlling reactivity and selectivity in the two different reaction pathways is discussed. [ABSTRACT FROM AUTHOR]

The article describes the development of a Nazarov cyclization/Wagner-Meerwein rearrangement pathway sequence that produces unusual spirocyclic products. The efficient synthesis of richly functionalized spirocycles using an inexpensive promoter was demonstrated. Most promising for potential synthetic application was the finding that adjacent stereocenters, including adjacent quaternary centers, could be installed with high selectivity using the protocol.

Diene-diones of type (I) undergo an 1,6-addition/Nazarov cyclization/elimination reaction in the presence of Hatkeyama′s chiral cinchona alkaloid catalyst to give functionalized cyclopentenones in good yields and enantioselectivities. [ABSTRACT FROM AUTHOR]

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. [ABSTRACT FROM AUTHOR]

A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization. [ABSTRACT FROM AUTHOR]

Studies the total synthesis and determination of the absolute configuration of frondosin B. Facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin; Demonstration of the efficacy of the stepwise approach to the frondosin ring-system.

The article describes the total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization. According to the authors, the generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. Moreover, it mentions that the synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.

This article presents a study on the efficient catalysis of Nazarov cyclization using a cationic iridium complex possessing adjacent labile coordination sites. The formation of five-membered carbocycles in natural products and bioactive molecules has stimulated interest in utilizing Nazarov cyclization strategies for their synthesis. This reaction is a 4π electrocyclization that can convert divinyl ketones into cyclopentenones stereoselectively via conrotatory cyclization. The Nazarov cyclization is generally promoted by one or more equivalents of a protic or Lewis acid and most often involves the intermediacy of a 3-oxypentadienyl cation.

Nazarov cyclization is a 4π-electrocyclization that converts divinyl ketones to cyclopentenones by activation with a Lewis acid. The potential synthetic utility of the reaction is considerable, given the stereospecific nature of the cyclization and the ability of existing stereocenters to effect diastereoselective ring closure. In contrast, Diels-Alder, Aldol, Michael, and ene-like reactions can be effected using mild Lewis acids as catalysts. These reaction types involve addition of an electron-rich π-system to an electron-poor π-system, a bond-forming process similar to the Nazarov cyclization. This article reporta a mild, Lewis acid-catalyzed procedure for Nazarov cyclization of polarized divinyl ketones.

An abstract of the article "No Acid Required: 4π and 6π Electrocyclization Reactions of Dienyl Diketones for the Synthesis of Cyclopentenones and 2H-Pyrans" by J. L. Brooks and A. J. Frontier is presented.

Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key to this work was the use of [3+2] cycloaddition/oxidative extrusion methodology to furnish functionalized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were identified that enabled installatiion of the requisite C14–N bond. [ABSTRACT FROM AUTHOR]

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. [ABSTRACT FROM AUTHOR]

A heterogeneous gold catalyst withremarkable activity for promotingthe electrophilic reactions of aryl vinyl ketones and aryl dienylketones is described. The catalyst is easy to prepare, is robust,and can be recycled. Low loadings are effective for different typesof cationic reactions, including Nazarov cyclizations, lactonizations,and [1,2] shifts. [ABSTRACT FROM AUTHOR]

The article presents a chemical diagram which shows the application of reagent control of [1,2]-Wagner—Meerwein shift chemoselectivity after Nazarov cyclization to the total synthesis pf enokipodin B (X).

Highly functionalized cyclopentenones can be generated by a chemoselective copper(II)-mediated Nazarov/Wagner-Meerwein rearrangement sequence of divinyl ketones. A detailed investigation of this sequence is described including a study of substrate scope and limitations. After the initial 4π electrocyclization, this reaction proceeds via two different sequential [1,2]-shifts, with selectivity that depends upon either migratory ability or the steric bulkiness of the substituents at C1 and C5. This methodology allows the creation of vicinal stereogenic centers, including adjacent quaternary centers. This sequence can also be achieved by using a catalytic amount of copper(II) in combination with NaBAr4f, a weak Lewis acid. During the study of the scope of the reaction, a partial or complete E/Z isomerization of the enone moiety was observed in some cases prior to the cyclization, which resulted in a mixture of diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the isomerization, allowing high diastereoselectivity to be obtained in all substrate types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent with the proposed sequences observed, including E/Z isomerizations and chemoselective Wagner-Meerwein shifts. [ABSTRACT FROM AUTHOR]

This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, anti-inflammatory, and insecticidal natural products (±)-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 hamessed in a successful second-generation approach using an oxidation-initiated Nazarov cylization of a heteroaryl alkoxyallene. Full details of these two approaches are giving, 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. [ABSTRACT FROM AUTHOR]

Abstract: A mild, convenient reaction sequence for the synthesis of Nazarov cyclization substrates is described. The [3+2] dipolar cycloaddition of a nitrone and an electron-deficient alkyne gives an isolable isoxazoline intermediate, which upon oxidation undergoes stereoselective extrusion of nitrosomethane to give aryl vinyl or divinyl ketones. [Copyright &y& Elsevier]

The impact of dienone substitution on the Nazarov cyclization has been examined in detail. Substrates bearing different substituents at each of four positions on the dienone backbone were systematically probed in order to identify trends leading to higher reactivity and better selectivity. Desymmetrization of the pentadienyl cation and oxyallyl cation intermediates through placement of polarizing groups at both the C-2 and C-4 positions was found to be particularly effective. These modifications allowed cyclizations to occur in the presence of catalytic amounts of mild Lewis acids. It was also found that stereoconvergent cyclization of mixtures of E and Z isomers of alkylidene β-ketoesters occurred via an efficient isomerization process that occurred under the reaction conditions. [ABSTRACT FROM AUTHOR]

The total synthesis of racemic merrilactone A (a neurotrophic agent) is described, featuring simultaneous and stereospecific creation of the C4 and C5 stereocenters via a notable silyloxyfuran Nazarov cyclization. Full details of the successful synthetic strategy are given, as well as several examples of the interesting reactivity of intermediates that were prepared and studied during the execution of the total synthesis. A detailed investigation of the Lewis acid-catalyzed Nazarov cyclization of silyloxyfurans was conducted, including a systematic study of substrate scope and limitations. In addition, experiments were conducted that suggest the participation of Lewis acidic silicon species in the Nazarov cyclization. [ABSTRACT FROM AUTHOR]

The article features the total synthesis of merrilactone A via catalytic Nazarov cyclization. Merrilactone A was identified as a potent nonpeptidal neurotrophic factor that promotes neurite outgrowth in the culture of fetal rat cortical neurons. The first examples of Nazarov cyclizations of a silyloxyfuran component involved the elaboration of an intermediate type 3 into intermediate 2, which Birman and Danishefsky were able to convert into merrilactone A in two steps.

The article reports on the successful development of a reaction sequence, which gives cyclopentenones directly from precursors in high yield, creating three contiguous stereocenters with excellent diastereoselectivity. It discusses the catalytic Nazarov cyclizations using several different Lewis acid promoters. The optimization of tandem Nazarov cyclization/Michael addition sequence is described.

The catalyst is effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts. [ABSTRACT FROM AUTHOR]

The AuCl3-catalyzed 6-endo-trig oxa-Michael addition of cyclic β-iodoallenoates is developed to give a diverse range of polycyclic tetrahydropyranones. [ABSTRACT FROM AUTHOR]

The article presents chemical diagram for the study which examines the synthesis of 4-alkylidene cyclopentenones with the use of Nazarov Cyclization/Wagner-Meerwein rearrangement techniques.