Cyclic Enones Research Articles

Helical foldamer-catalyzed enantioselective 1,4-addition reaction of dialkyl malonates to cyclic enones

The introduction of a five-membered ring α,α-disubstituted α-amino acid into l-Leu-based heptapeptides preferentially induced right-handed (P) helical structures. Using 5 ∼ 20 mol% of a single helical foldamers-catalyst, enantioselective 1,4-addition reactions of dialkyl malonates to cycloalk-2-enones (5 ∼ 7 rings) proceeded to give chiral 3-substituted cycloalkanones with 94 ∼ 99% ee in moderate chemical yields, regardless of the ring size of substrates.

Rh(III)-Catalyzed Tandem Bicyclization of 2-Arylimidazo[1,2-a]pyridines with Cyclic Enones for the Construction of Bridged Scaffolds.

An efficient Rh(III)-catalyzed bicyclization of 2-arylimidazo[1,2-a]pyridine with cyclic enones has been developed for the synthesis of bridged imidazopyridine derivatives in excellent yields up to 95%. The reaction proceeds through a sequential conjugate addition of ortho-C-H bond of aryl group followed by an intramolecular C3-alkylation of imidazopyridine ring in a highly regioselective manner.

(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction

Bis(NHC) ligand precursors, L1, based on trans-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of L1, a chiral β-amino alcohol, such as enantiopure leucinol, was used. Cu-catalyzed asymmetric conjugate addition reactions of cyclic and acyclic enones with Et2Zn were selected to evaluate the performance of L1 as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (±)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (rac; S,S)-L1, which was prepared from (S)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (3) with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 afforded (R)-3-ethylcyclohexanone ((R)-4) with 97% ee. Similarly, use of (rac; R,R)-L1, which was prepared from (R)-leucinol, produced (S)-4 with 97% ee. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (−)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (R,R; S,S)-L1, worked efficiently. For example, 3-nonen-2-one (5) was reacted with Et2Zn using the CuOAc/(R,R; S,S)-L1 catalytic system to afford (R)-4-ethylnonan-2-one ((R)-6) with 90% ee. Furthermore, initially changing the counterion of the Cu precatalyst between an OAc and a ClO4 ligand on the metal reversed the facial selectivity of the approach of the substrates. Thus, the conjugate addition reaction of 5 with Et2Zn using the Cu(ClO4)2/(R,R; S,S)-L1 catalytic system, afforded (S)-6 with 75% ee.

Remote Friedel-Crafts Reaction with α-Heteroaryl-Substituted Cyclic Ketones via HOMO Activation of Lewis Bases.

Under the catalysis of Lewis bases, cyclic enones bearing an α-(2-furyl) motif can undergo remote Friedel-Crafts reaction with electrophilic reagents via a HOMO-activation strategy, proceeding in a formal vinylogous Rauhut-Currier or Morita-Baylis-Hillman-type reaction pattern. Moreover, even less reactive α-(2-benzofuranyl)-substituted cyclopeten-2-ones can be similarly HOMO-raised and furnish [4 + 2] products with alkylidenemalononitriles in a cascade Friedel-Crafts/Michael addition process.

Construction of Spirofused Tricyclic Frameworks by NHC-Catalyzed Intramolecular Stetter Reaction of a Benzaldehyde Tether with a Cyclic Enone.

Various benzaldehyde tethers with a cyclic enone were prepared from commercially available 2-hydroxybenzaldehydes via a three-step sequence involving triflate formation, Sonogashira cross-coupling, and regioselective hydrogenation. These substrates were then exposed to an N-heterocyclic carbene, whereupon intramolecular Stetter reaction proceeded smoothly to give various spirofused tricyclic 1,4-diketones in 30-87% yields. Furaldehyde and nicotinaldehyde derivatives also participated in the reaction under the Stetter conditions.

Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine.

An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.

BINOL Phosphoric Acid-Catalyzed Asymmetric Mannich Reaction of Cyclic N-Acyl Ketimines with Cyclic Enones.

A highly enantio- and diastereoselective Mannich reaction of cyclic N-acyl ketimines generated in situ from 3-hydroxyisoindolin-1-ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin-1-ones bearing adjacent quaternary and tertiary stereogenic centers.

Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion.

Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX3 (X = F, Cl, Br) and B(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002( Corey et al. J. Am. Chem. Soc. 2002 , 124 , 3808 ), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004-2006, Diels-Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid-base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,β-unsaturated aldehydes through 1,2-addition reactions resulting in chiral β-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active β-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π-π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective β-hydride shift pathway afforded the β-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the β-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

Intramolecular [2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications.

The intramolecular [2+2] photocycloaddition of 3‐alkenyl‐2‐cycloalkenones was performed in an enantioselective fashion (nine representative examples, 54–86 % yield, 76–96 % ee) upon irradiation at λ=366 nm in the presence of an AlBr3‐activated oxazaborolidine as the Lewis acid. An extensive screening of proline‐derived oxazaborolidines showed that the enantioface differentiation depends strongly on the nature of the aryl group at the 3‐position of the heterocycle. DFT calculations of the Lewis acid–substrate complex indicate that attractive dispersion forces may be responsible for a change of the binding mode. The catalytic [2+2] photocycloaddition was shown to proceed on the triplet hypersurface with a quantum yield of 0.05. The positive effect of Lewis acids on the outcome of a given intramolecular [2+2] photocycloaddition was illustrated by optimizing the key step in a concise total synthesis of the sesquiterpene (±)‐italicene.

Cover Picture: A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones (Chin. J. Chem. 4/2019)

The cover picture shows a typical building within the Campus of Xiamen University displaying Chen Jiageng (Tan Kah Kee)'s style. Just like many beautiful buildings designed and constructed by human, Nature “designs and constructs” a huge number of useful molecules with fascinating structures called natural products. Many natural products possess a fused six or seven‐membered carbocyclic unity. On page 315–322, the Huang's group disclosed a three‐step “[2+n]” annulation method for the construction of fused six and seven‐membered carbocyclic enimines and enones. The method starts from simple cyclic ketones and terminal olefinic amides, and relies on both the Suzuki coupling reaction and the olefin‐amide based Friedel‐Crafts type acylating reaction, a method developed by Huang and coworkers. image

A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones

Summary of main observation and conclusionThe efficient construction of functionalized polycyclic structures is an important objective in organic synthesis. Herein, we disclose a three‐step “[2 + n]” annulation method for the transformation of cyclic ketones to fused enimines and enones. The method relies on the Suzuki coupling reaction and the amide reductive alkenylation reaction. A series of fused bicyclic (6/6, 6/7, 8/7) and tricyclic (6/6/6; 6/6/7, 6/5/7) ring systems bearing an α,β‐enimine or an α,β‐enone functionality have been synthetized in good overall yields.

Vinylogous acyl triflates as an entry point to α,β-disubstituted cyclic enones via Suzuki-Miyaura cross-coupling.

An alternative protocol for the B-alkyl Suzuki-Miyaura reaction to produce cyclic α,β-disubstituted enones is reported. The use of β-triflyl enones as coupling partners in lieu of their halogenated analogs provides enhanced substrate stability to light and chromatography without adversely affecting reactivity. This protocol allows efficient access to the synthetically challenging α,β-disubstituted enone motif under mild conditions.

Pyridine‐Hydrazone Ligands in Asymmetric Palladium‐Catalyzed 1,4‐ and 1,6‐Additions of Arylboronic Acids to Cyclic (Di)enones

AbstractCatalysts generated by combinations of Pd(TFA)2 and enantiomerically pure pyridine‐hydrazone ligands have been applied to the 1,4‐addition of arylboronic acids to β‐substituted cyclic enones, building all‐carbon quaternary stereocenters in high yields and enantioselectivities (up to 93% ee). The developed methodology allows the efficient introduction of ortho‐substituted aryl groups in β‐position of cyclopentanone cores, giving scaffolds present in a broad range of biologically active natural products. These Pd(II)‐complexes served also as catalysts in the 1,6‐addition of arylboronic acids to cyclic dienones, affording complete regioselectivities, moderate yields and good enantioselectivities (up to 80% ee).magnified image

Metal-Organic Layers Catalyze Photoreactions without Pore Size and Diffusion Limitations.

Metal-organic frameworks (MOFs) have emerged as promising single-site solid catalysts for organic reactions. However, MOF catalysts suffer from pore size limitation and slow diffusion, which are detrimental for photoreactions. Metal-organic layers (MOLs) have unique ultrathin 2D monolayer structures and overcome pore size and diffusion limitations. Here, the synthesis of photoactive Zr-RuBPY MOL based on Zr-oxo clusters and [Ru(bpy)3 ]2+ -containing linkers is reported as well as its application in photocatalytic [2+2] cyclizations of enones and Meerwein addition reactions between aryl diazonium salts, styrenes, and nitriles.

Scalable and Chemoselective Synthesis of γ-Keto Esters and Acids via Pd-Catalyzed Carbonylation of Cyclic β-Chloro Enones

The Pd-catalyzed carbonylation of cyclic β-chloro enones using simple phosphine ligands is described. Screening identified P(Me)(t-Bu)2 as the most general ligand for an array of chloro enone electrophiles. The reaction scope has been evaluated on a milligram scale across 80 examples, with excellent reactivity observed in nearly every case. Carbonylation can be achieved even in the presence of potentially sensitive or inhibitory functional groups, including basic nitrogens as well as aryl chlorides or bromides. Twenty examples have been run on a gram scale, demonstrating scalability and practical utility. Using P(Me)(t-Bu)2, the reaction rate depends on both nucleophile and electrophile identity, with completion times varying between 3 and >18 h under a standard set of conditions. Switching to P(t-Bu)3 for the carbonylation of 3-chlorocyclohex-2-enone with methanol results in a dramatic rate increase, enabling effective catalysis with kinetics consistent with rate-limiting mass transfer. Stoichiometric ox...

Theoretical investigations of Rh-catalyzed asymmetric 1,4-addition to enones using planar-chiral phosphine-olefin ligands.

Recently, planar-chiral phosphine-olefin ligands based on (η6 -arene)chromium(0) and (η5 -cyclopentadienyl)manganese(I), which are known as first- and second-generation, respectively, have been developed. These ligands were employed for Rh-catalyzed asymmetric 1,4-addition to enones. First-generation ligands involve high enantioselectivity for cyclic enones (>98% ee). Second-generation ligands involve high enantioselectivity for not only cyclic enones but also for acyclic enones (>98% ee). In this study, we have performed DFT calculations to investigate the origin of enantioselectivity. The theoretical values of enantioselectivities were found to be in good agreement with the experimental values obtained for a cyclic enone, 2-cyclopenten-1-one, using both the first- and second-generation ligands. Regarding an acyclic enone, 3-penten-2-one, it was found that the s-cis type decreases the enantioselectivity because the transition states in the s-cis type have a large steric repulsion. Energy decomposition analysis (EDA) and natural bond orbital (NBO) analysis indicate that it is important to study the orbital interactions in the transition states of the insertion step for the acyclic enone attacked from si-face with the second-generation ligand. © 2018 Wiley Periodicals, Inc.

Enantioselective radical conjugate additions driven by a photoactive intramolecular iminium-ion-based EDA complex

The photochemical activity of electron donor–acceptor (EDA) complexes provides a way to generate radicals under mild conditions. This strategy has found application in chemical synthesis and recently in enantioselective catalysis. Reported methods classically relied on the formation of intermolecular EDA complexes, generated upon aggregation of two suitable reagents. Herein, we further expand the synthetic utility of this strategy demonstrating that an intramolecular EDA complex can trigger a photochemical catalytic enantioselective radical process. This approach enables radical conjugate additions to β-substituted cyclic enones to form quaternary carbon stereocenters with high stereocontrol using visible light irradiation. Crucial for success is the use of an amine catalyst, adorned with a carbazole moiety, which generates, upon condensation with enones, chiral iminium ions that show a broad absorption band in the visible region. This optical property originates from an intramolecular charge transfer π–π interaction between the electron-rich carbazole nucleus and the electron-deficient iminium double bond.

Synthesis of Highly Enantioenriched Propelladienes and their Application as Ligands in Asymmetric Rh-Catalyzed 1,4-Additions.

The first synthesis of highly enantioenriched [4.3.3]propelladienes is reported. The novel bridged bicyclo[3.3.0] dienes were applied as steering ligands in the rhodium-catalyzed asymmetric arylation of cyclic enones. The catalytic system showed high catalytic activity, and the 1,4-adducts were obtained in good to excellent yields (46-99%) with enantioselectivities up to 96% ee.

Electronic and Steric Tuning of an Atropisomeric Disulfoxide Ligand Motif and Its Use in the Rh(I)-Catalyzed Addition Reactions of Boronic Acids to a Wide Range of Acceptors.

A novel chiral disulfoxide ligand pair bearing fluorine atoms at the 6 and 6' position of its atropisomeric backbone, ( M, S, S)- and ( P, S, S)- p-Tol-6F-BIPHESO, was synthesized. Complexation to a rhodium(I) precursor gave rise to μ-Cl- and μ-OH-bridged rhodium dimer complexes incorporating the new ( M, S, S)- p-Tol-6F-BIPHESO ligand, while its sibling ( P, S, S)- p-Tol-6F-BIPHESO was not complexed efficiently to the rhodium precursor. The performance of this disulfoxide ligand [( M, S, S)- p-Tol-6F-BIPHESO] in catalysis was tested in both 1,4- and 1,2-addition reactions of arylboronic acids. We show that addition to both cyclic and acyclic enones as well as N-tosylarylimines proceeds with high yields and high enantioselectivities to give the corresponding products. The synthesis of enantiomerically pure p-Tol-6F-BIPHESO is straightforward and inexpensive which, together with the high catalytic performance and wide substrate scope for these addition reactions, makes it a very attractive alternative to more classical chiral ligand entities.

OZONOLYTIC TRANSFORMATIONS OF (R)-4-MENTHENE-3-ONE AND ITS DERIVATIVES IN DIRECTION TO LOW MOLECULAR WEIGHT BIOREGULATORS

The author’s data on ozonolytic decyclization (ring opening) of (R)-4- menthene-3-one and its alkylated analogues and application of non-peroxide ozonolysis products in the synthesis of optically active low molecular weight bioregulators including the insects pheromones and juvenoids were generalized. The results of comparative reactivity of the mentioned above mono-terpenoid in the set of α, β-unsaturated cyclic enones were represented.