Nazarov Cyclization Research Articles

Expansion of Structure Property in Cascade Nazarov Cyclization and Cycloexpansion Reaction to Diverse Angular Tricycles and Total Synthesis of Nominal Madreporanone.

A cascade Nazarov cyclization/dicycloexpansions reaction was developed for the precise synthesis of the angularly fused M/5/N (M=5, 6; N=4-9, 13) tricyclic skeletons. The prioritized expansion of the first ring played a critical role in the transformations, due to the release of ring strain, and the nature of the substituents present on the substrate is another influencing factor. This pioneering cascade reaction features broad substrates scope (33 examples), short reaction time, exceptional yields (up to 95 %), and remarkable regioselectivities (>20 : 1). Exploiting the synthetic application of this cascade reaction, we successfully executed a succinct total synthesis of nominal madreporanone for the first time.

--Steric Activation in the Nazarov Cyclization of Fully Substituted Divinyl Ketones.

Fully substituted divinyl ketones (fsDVKs) have long been regarded as resistant to Nazarov cyclization (NC) unless they contain strategically positioned electronically-activating substituents. Here, however, we show that fsDVKs bearing only electronically neutral alkyl or aryl groups actually undergo facile NC due to steric-crowding in the pentadienyl cation intermediate, which raises its energy and reduces the barrier height to cyclization. Strongly ionizing and suitably bulky acid moieties further increase the energy of this intermediate cation, favoring cyclization. These features enable NCs of fsDVKs to be employed in the ready construction of multiple contiguous all-carbon quaternary stereocenters under mild conditions, in the absence of electronically activating groups.

Asymmetric Photoinduced Excited-State Nazarov Reaction.

We report herein the first asymmetric photoinduced excited-state Nazarov reaction of non-aromatic dicyclic divinyl ketones by using hydrogen-bonding catalysis. The enantioselectivity of photoinduced electrocyclization is highly dependent on the structural features of the substrate and its interaction with chiral catalysts. For the simple dicyclic divinyl ketone substrates, there is no discernible selectivity of the hydrogen bond coordination between the thiourea and carbonyl groups of the substrates in the ground state. However, we found that the direction of the electrocyclization was well controlled in each coordination model and the N,N'-dimethylamine motif acts as a base in the regioselective deprotonation process, which leads to the formation of two stereoisomers with high enantioselectivity. Photolysis of dicyclic divinyl ketones bearing a 1,3-dioxolane motif in the presence of bifunctional hybrid peptide-thiourea chiral catalysts gave the tricyclic cis-hydrofluorenones with good enantioselectivity. Mechanistic and DFT studies suggested that the amide and thiourea groups in the bifunctional chiral catalysts play a key role as H-bond donors, which coordinate with both the carbonyl group and the 1,3-dioxolane motif to provide a more favorable chiral species, and control the direction of the electrocyclization. Due to the presence of the rigid 1,3-dioxolane ring, the deprotonation/protonation process occurs regiospecifically with high driving force. This photo-electrocyclization is mild (room temperature and neutral solution), which results a broad reaction scope and functional group tolerance and demonstrates its synthetic potential in organic synthesis.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide

AbstractHere we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu‐promoted dienyl enolization, intramolecular Diels–Alder reaction and enol‐ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide.

Here we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu-promoted dienyl enolization, intramolecular Diels-Alder reaction and enol-ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Exploring Interrupted Nazarov Cyclizations Using Tethered Sulfonamide Nucleophiles: Insights into Capture Pathways

This manuscript describes a study of diverse reaction outcomes that stem from the ionization of aza‐alkynyl‐Prins adducts. Experimental results have demonstrated unexpected behavior in the nitrogen‐containing systems compared to the analogous oxygen derivatives derived from oxa‐Prins/halo‐Nazarov sequences. In‐depth experimental studies and computational analysis revealed an intricate mechanism involving competing halo‐Nazarov and imino‐Nazarov pathways. These findings further elucidate the reaction chemistry of 3‐halo‐pentadienyl cation intermediates, and expand their utility in synthetic transformations.

Site-selective synthesis of indanyl-substituted indole derivatives via 1,3-dithiane induced Nazarov cyclization.

We report an efficient site-selective synthetic method to C2 and C3 indanyl-substituted indole derivatives via 1,3-dithianyl induced Nazarov-type cyclization. In particular, C2-selective indanyl-substituted indoles were directly obtained by a BF3·Et2O-promoted sequence of intramolecular C3-C2 migration and Nazarov-type cyclization process.

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction.

We describe the use of bismuth(III) triflate as an efficient and environmentally friendly catalyst for the Nazarov reaction of aryl vinyl ketones, leading to the synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones. By changing the temperature and reaction time, it was possible to modulate the reactivity, allowing the synthesis of two distinct product classes (3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells.

Recent Developments in Asymmetric Nazarov Reactions

Abstract: The Nazarov reaction involves the cyclization of divinyl ketones into cyclopentenones under the influence of strong acids. The prevalence of five-membered carbocycles in a multitude of natural and bioactive products has triggered an intense development of efficient methods for their construction. In particular, asymmetric versions of the Nazarov reaction are achieved by using either a chiral auxiliary or a chiral catalyst, which can be an organocatalyst, a metal catalyst, or a multicatalytic system. This review aims to update the field of asymmetric Nazarov reactions published since 2017. It is divided into four sections, dealing successively with Nazarov reactions of chiral auxiliaries, organocatalytic enantioselective Nazarov reactions, metal/boron-catalyzed enantioselective Nazarov reactions, and multicatalytic enantioselective Nazarov reactions. Each section of the review is subdivided into simple asymmetric Nazarov reactions and Nazarov-based domino/tandem reactions, which have allowed numerous more complex functionalized chiral molecules to be synthesized in one-pot procedures.

Expanding the Scope of Alkynes in C-H Activation: Weak Chelation-Assisted Cobalt-Catalyzed Synthesis of Indole C(4)-Acrylophenone via C-O Bond Cleavage of Propargylic Ethers.

Herein, we report the facile synthesis of indole C(4)-acrylophenone using a C-H bond activation strategy. For this conversion, an unsymmetrical alkyne (phenylethynyl ether) in the presence of cobalt(III)-catalyst works efficiently. In this process, alkyne gets oxidized in the presence of in situ generated water, which is the key step for this method, for which trifluoroethanol is the water source. The pivaloyl directing group chelates effectively to generate the cobaltacycle intermediate, which was detected through high-resolution mass spectrometry (HRMS). Also, the formation of bis(2,2,2-trifluoroethyl) ether has been confirmed and quantified using 19F NMR. In addition, the applicability of obtained indole C(4)-acrylophenone product has been demonstrated by performing the Nazarov cyclization and conjugate addition to the α,β-unsaturated ketone moiety.

Collective total synthesis of fusicoccane diterpenoids via Yu [5+2+1] cycloaddition and oxidative Nazarov cyclization

Collective total synthesis of fusicoccane diterpenoids via Yu [5+2+1] cycloaddition and oxidative Nazarov cyclization

Total Synthesis of Laurane and Guaiane Sesquiterpenoids via Oxidative Nazarov Reaction

Comprehensive SummaryAs one of the most common structural motifs in natural products, cyclopentenones usually can be fabricated by Nazarov cyclization using divinyl ketones or functionalized tertiary divinyl carbinols (TDCs) as substrates. However, straightforward method for transforming unfunctionalized TDCs to their corresponding cyclopentenones is currently lacking. Herein, we wish to report the total syntheses of four structurally distinct terpenoids, namely laurane‐type marine sesquiterpenoids isolaurene, debromoaplysin and aplysin, and guaiane sesquiterpenoid guaiadienone A, all using a novel synthetic method, named oxidative Nazarov cyclization, as the key step. This work demonstrated our robust method is suitable for synthesizing various highly substituted cyclopentenones.

Total Synthesis of Daphniphyllum Alkaloids: (+)-Daphlongamine E, (+)-Calyciphylline R, and (–)-10-Deoxydaphnipaxianine A

AbstractHere, we wish to describe our detailed efforts in the total synthesis of three calyciphylline A-type alkaloids, namely (+)-daphlongamine E, (+)-calyciphylline R, and (–)-10-deoxydaphnipaxianine A. Important steps in our approach include a Pt-catalyzed nitrile hydration, a Babler–Dauben rearrangement, a novel selective amide reduction tactic, and an oxidative Nazarov cyclization via an unfunctionalized tertiary divinyl carbinol (TDC).

Dihydro-10H-indeno[1,2-b]benzofurans and Tetrahydroindeno[1,2-c]isochromenes via Stereoselective Intramolecular Carbocation Cascade Cyclization.

Nazarov cyclization of the (E)-(2-stilbenyl)methanols under the catalysis of p-TsOH immobilized on silica (PTS-Si) proceeded to give the corresponding indanyl cation with the exclusive trans relationship at the two newly formed adjacent stereogenic centers. The ensuing intramolecular nucleophilic addition by the MOM-protected phenol (m = 0) or benzyl alcohol (m = 1) furnished the Indane-fused benzofuran [5/5] or isochroman [5/6] system, respectively, with the exclusive cis stereocontrol at the two-carbon ring junction. Thus, in a single step, from nonchiral starting materials, the intramolecular cascade carbocation cyclization (CCC) furnished the [5/5] or [5/6] oxygen-containing Indane fused-ring systems in moderate to good yields with excellent stereoselectivity on all three contiguous stereogenic centers.

Convergent and Efficient Total Synthesis of (+)-Heilonine Enabled by C-H Functionalizations.

We report a convergent and efficient total synthesis of the C-nor D-homo steroidal alkaloid (+)-heilonine with a hexacyclic ring system, nine stereocenters, and a trans-hydrindane moiety. Our synthesis features four selective C-H functionalizations to form key C-C bonds and stereocenters, a Stille carbonylative cross-coupling to connect the AB ring system with the DEF ring system, and a Nazarov cyclization to construct the five-membered C ring. These enabling transformations significantly reduced functional group manipulations and delivered (+)-heilonine in 11 or 13 longest linear sequence (LLS) steps.

Nazarov reaction triggered by active lithium salts in cyclopentyl methyl ether

Abstract In this study, we developed a lithium-activated Nazarov reaction of highly activated divinyl ketones in the presence of mixed lithium salts by combining LiClO4 with either LiOMe or LiI in cyclopentyl methyl ether (CPME). This reaction produces LiOPh in the reaction mixture, exhibiting aspects of a Nazarov reaction in the presence of base. The additives LiOMe and LiI not only facilitated the dissolution of LiClO4 aggregates but also promoted the addition–elimination mechanism, thereby accelerating the reaction and preventing side reactions.

Neutral Nazarov reaction using protic solvents as activators

Abstract Herein, we report a neutral Nazarov reaction using protic solvents instead of strong acids as activators. The key to the success of this reaction lies in the rational design of the divinyl ketone substrates. In particular, the introduction of electron-donating groups (EDGs) at the β- and β′-positions of the carbonyl group in the divinyl ketone increases the Lewis basicity dramatically, an EDG at α-position promotes the cyclization, and the presence of a phenoxy group at β-position enables the irreversible elimination of phenol from the cyclized intermediate, thus shifting the reversible cyclization to the product side. This phenol-releasing reaction can be applied to clip chemistry to target acidic biological environments.

Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Superacid-Promoted synthesis of spirooxindoles

Isatins and acetophenones provide Aldol products (3-hydroxy-3-(2-oxo-2-arylethyl)indolin-2-ones) from reaction with triethylamine and these substrates react in excess superacid to provide good yields of spirooxindoles. The resulting spirooxindoles are shown to be useful scaffolds in the syntheses of related urea, carbamate, amido, and benzyl derivatives. A mechanism of cyclization is proposed involving a superelectrophilic Nazarov cyclization.

Mechanistic Basis for Oxoammonium Salt‐Mediated Tertiary Alcohol Oxidative Transformation Decoded by Computations and Experiments

AbstractOxoammonium salts have demonstrated superior efficacy as reagents in mediating various reactions involving tertiary alcohols, including the eliminative functionalization of tertiary benzylic alcohols, oxidative rearrangement of tertiary allylic alcohols, and oxidative Nazarov cyclization. These reactions have been believed to be triggered by the addition of alcohols to the N−O double bonds of oxoammonium cations. However, in this work, a combination of density functional theory (DFT) and ab initio molecular dynamics (AIMD) calculations shows that the formation of this adduct is thermodynamically unfavorable. A thorough exploration of the possible mechanisms has shown that the reaction occurs through the ring opening of the oxoammonium cation. The oxoammonium cation acted as a masked tertiary carbocation and triggered the subsequent reactions. The computational results were further supported by control experiments and high‐resolution mass spectroscopy (HRMS) characterization.