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The total synthesis of racemic merrilactone A is described, which has featured a simultaneous and stereospecific creation of the C4 and C5 stereocenters via silyloxyfuran Nazarov cyclization. The results have suggested the participation of Lewis acidic silicon species in the Nazarov cyclization.

Research is presented concerning the total synthesis of racemic hispidospermidin. The four important steps leading up to the synthesis and the results of a preliminary SAR profile are discussed.

The total syntheses of aglafolin, rocagloic acid, and rocaglamide are described by using Nazarov cyclization. The generation of the oxyallyl cation intermediate is accomplished by peracid oxidation of allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization.

The effects of the dienone substitution pattern on the reactivity and selectivity of the Nazarov cyclization are discussed.

A Nazarov cyclization/Wagner-Meerwein rearrangement pathway that produces unusual spirocyclic products is described. The transformations are found to be highly stereoselective, efficient for a range of substrate types and are capable of creating adjacent quaternary centers.

The synthesis of a ring-expanded bryostatin analogue is described, which has retailed all the functionalities in the byrostatins and their biological activities against many cancer cell lines. The main features of this analogue include a Ru-catalyzed tandem tetrahydropyran formation, a Pd-catalyzed tandem dihydropyran formation and a ring-closing metathesis.

An efficient stereoselective synthesis of (plusmin)-merrilactone A via catalytic Nazarov cyclization is described. The method involves Nazarov cyclization of a silyloxyfuryl enone as the key step.

The successful development of Michael addition reaction sequence, which gives cyclopentenones directly from precursors alkylidene beta-ketoester substrates in high yield, creating three contiguous stereocenters with excellent diastereoselectivity, is reported. The sequence is efficiently catalyzed by Ir[Me(CO)(dppe)(DIB)](super 2 +) and occurs with high diastereoselectivity, creating new stereocenters.

The electrophilic Ir(III) complex having a labile DIB chelate is a very reactive catalyst for promoting the Nazarov cyclization of aryl and divinyl ketones. This is the first example of catalysis of the Nazarov cyclization using a well-defined cationic metal complex having two adjacent substrate sites.

A mild, Lewis acid-catalyzed procedure for Nazarov cyclization of polarized divinyl ketones is reported. Polarization in the cyclization, by utilizing Lewis acid with chiral ligands to promote enentioselective cyclization and synthetic applications of the methodology is highlighted.

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]

Oxygen heterocycles were synthesized via tandem palladium-catalyzed reactions.

The stereocontrolled total synthesis of hispidospermidin, a phospholipase C inhibitor, was reported. It was found that the 400MHz nuclear magnetic resonance spectrum of a true sample and that of the synthetic racemate were comparable. The total synthesis venture is believed to be of great potential for the generation of a wide range of analogs that will eliminate delicate SAR profiles.

It has been possible to obtain two concise syntheses of the interleukin-8 receptor antagonist (+/-)-frondosin B from commercially available 5-methoxysalicylaldehyde. The absolute configuration of the secondary methyl centre in frondosin B was established as R.

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]

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]

A correction is presented to the article "Cyclization Cascades Initiated by 1,6-Conjugate Addition" published in a 2012 issue.

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.

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.

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.

This article is a comprehensive report describing our studies in the field of aza-alkynyl Prins chemistry, comparing and contrasting the different reaction partners and reactivities observed during method development. The synthetic strategies combine an alkynyl aza-Prins coupling with an annulation, enabling the preparation of different nitrogen-containing heterocycles. Different iminium ions are explored as viable electrophiles for an alkynyl Prins cyclization, terminated by capture with a halogen nucleophile to form a vinyl halide. The synthetic utility of this functional handle is exploited through a number of Suzuki cross-couplings, allowing for the preparation of a modest library of compounds. In most cases, the Prins couplings are highly selective for the vinyl halides with E geometry, resulting from anti-addition across the alkyne.

In this report, we describe an alkynyl halo - aza -Prins cyclization of 3-hydroxyisoindolones to prepare aza -Prins products. These Prins adducts undergo oxidation at the 3-isoindolone position after activation of the amide by triflic anhydride and 2-chloropyridine to form a pentadienyl cation capable of undergoing a halo -Nazarov cyclization. Using this methodology, angular-fused N-heterocyclic small molecules with two new rings, two new carbon-carbon bonds, a vinyl halide, and an aza -tertiary stereocenter can be obtained in good yields.

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.

A stereocontrolled halo -Prins/ halo -Nazarov cyclization protocol is reported, where chiral information from a secondary alcohol is relayed through several intermediates yielding halocyclopentene products diastereoselectively. An enantiopure product is obtained when a nonracemic secondary alcohol is used. Experimental and computational studies are described, enabling the design and synthesis of systems that ionize and cyclize with >95% chirality transfer through a mechanism involving the creation and preservation of transient helical chirality in a pentadienyl cation intermediate. First, a diastereoselective alkynyl Prins cyclization is executed to synthesize a conformationally distorted dihydropyran intermediate with a curved backbone and high reactivity. This chiral precursor adopts a specific helical alignment early in the subsequent cationic ionization/ halo -Nazarov cyclization process, dictating the direction of conrotation in the electrocyclization. Notably, despite the ablation of an sp 3 stereogenic center during ionization, the low halo -Nazarov barrier enables efficient capture of a cationic intermediate with dynamic conformational chirality. The ionization and electrocyclization thus occur with "memory of chirality".

Cobalt-mimochrome VI*a (CoMC6*a) is a synthetic mini-protein that catalyzes aqueous proton reduction to hydrogen (H 2 ). In buffered water, there are multiple possible proton donors, complicating the elucidation of the mechanism. We have found that the buffer p K a and sterics have significant effects on activity, evaluated via cyclic voltammetry (CV). Protonated buffer is proposed to act as the primary proton donor to the catalyst, specifically through the protonated amine of the buffers that were tested. At a constant pH of 6.5, catalytic H 2 evolution in the presence of buffer acids with p K a values ranging from 5.8 to 11.6 was investigated, giving rise to a potential-p K a relationship that can be divided into two regions. For acids with p K a values of ≤8.7, the half-wave catalytic potential ( E h ) changes as a function of p K a with a slope of -128 mV/p K a unit, and for acids with p K a of ≥8.7, E h changes as a function of p K a with a slope of -39 mV/p K a unit. In addition, a series of buffer acids were synthesized to explore the influence of steric bulk around the acidic proton on catalysis. The catalytic current in CV shows a significant decrease in the presence of the sterically hindered buffer acids compared to those of their parent compounds, also consistent with the added buffer acid acting as the primary proton donor to the catalyst and showing that acid structure in addition to p K a impacts activity. These results demonstrate that buffer acidity and structure are important considerations when optimizing and evaluating systems for proton-dependent catalysis in water.

Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6- endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.

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).

A heterogeneous gold catalyst with remarkable activity for promoting the electrophilic reactions of aryl vinyl ketones and aryl dienyl ketones is described. The catalyst is easy to prepare, is robust, and can be recycled. Low loadings are effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts.

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid triggered cyclization of a β-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor.

In contrast to 2-substituted pyrrole enones, furyl and benzofuryl enones do not undergo the Nazarov electrocyclization. Instead, these furyl and benzofuryl enones exhibit unusual rearrangement sequences in the presence of catalytic amounts of [IrBr(CO)(DIM)((R)-(+)-BINAP)](SbF(6))(2) (1; DIM = diethylisopropylidene malonate) and AgSbF(6) (1:1). A 1,2-H shift followed by intramolecular Friedel-Crafts alkylation leads to synthetically valuable cyclohexanones with furanylic quaternary centers. The electrophilicity of 1 is essential for this rearrangement.

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.