Mukaiyama-Michael Reaction Research Articles

Total Synthesis of (−)‐Daphenylline by Gold‐Catalyzed Intramolecular Dearomatization Reaction of Methoxynaphthalene

AbstractDaphenylline, a structurally unique triterpenoid Daphniphyllum alkaloid, has attracted considerable attention from the synthetic community since its isolation. Herein, we delineate an enantioselective total synthesis of (−)‐daphenylline, which is based on a gold‐catalyzed dearomatization reaction of β‐methoxynaphthalene. Other features include installation of the initial chiral stereocenter via an enantioselective rhodium‐catalyzed hydrogenation of an alkylidene‐indane derivative; construction of the other vital stereocenter by organocatalytic asymmetric Mukaiyama–Michael reaction of a structurally complex benzofused cyclohexanone; and a tandem reductive amination/amidation double cyclization reaction to assemble the distinctive azapolycyclic cage‐like architecture.

Synthesis of Electrophilic Cyclopent‐2‐enone Conjugates With Modulatory Effects on Inflammatory Responses Mediated by Nrf2/Keap1, NF‐κB and IL‐6

AbstractCyclopent‐2‐enone bearing natural products possess anti‐inflammatory, cytotoxic, antiproliferative, and antimicrobial activities attributed to the presence of a Michael acceptor enone group acting as a bait for protein targets. To explore the biological activity of synthetic small molecules bearing the cyclopent‐2‐enone moiety, a collection of 4‐substituted cyclopent‐2‐enones (3 a–3 i) was prepared synthetically using Lewis acid‐catalyzed Mukaiyama‐Michael reaction (MMR) in modest to high yields. These derivatives were screened for their effect on inflammatory response mediators, namely Nrf2, NF‐κB, and IL‐6 through cell‐based reporter assays. The results show that 5‐(4‐oxocyclopent‐2‐en‐1‐yl)furan‐2(5H)‐one (3 g) is a potent Nrf2 activator in HaCaT cells. The mechanism of Nrf2 activation by 3 g was investigated through an MS/MS‐directed proteomic analysis and have shown the formation of a Michael adduct via cysteine‐613 on Keap1, an inhibitor of Nrf2. Density functional theory calculations show favorable Michael adduct formation between 3 g and the truncated Keap1 tripeptide Pro‐Cys613‐Ala at the β‐carbon of the cyclopent‐2‐enone moiety. On the other hand, the derivative 4‐(2‐oxo‐2‐phenylethyl)cyclopent‐2‐en‐1‐one (3 a) exhibited selective Nrf2 inhibition in the cancer cell line Huh7, and inhibitory activity along with 3 g against NF‐κB, and IL‐6 in RAW 264.7 cells. This points to the cyclopent‐2‐enone group being an effective scaffold for anti‐inflammatory drug designs.

Fe-BPsalan complex catalyzed asymmetric vinylogous Mukaiyama–Michael reaction of silyloxyfuran and α, β-unsaturated acyl imidazoles with high enantioselectivity and diastereoselectivity

An efficient iron catalyzed asymmetric vinylogous Mukaiyama–Michael reaction of silyloxyfuran and α, β-unsaturated acyl imidazoles was developed to afford chiral γ-butenolide derivatives (25 examples) in moderate to good yields (up...

Preparation of New Chiral Building Blocks by a Mukaiyama–Michael Reaction of 2-(Phenylsulfonyl)cyclopent-2-en-1-one

AbstractA highly enantio- and diastereoselective Mukaiyama–­Michael reaction of 2-(phenylsulfonyl)cyclopent-2-en-1-one by using an enol silane of tert-butyl thiopropionate is described. The product was formed in 87% yield with a dr of 27:1 and 91% ee under stoichiometric conditions, whereas the yield, dr, and ee were 89%, 49:1, and 88% ee, respectively, under catalytic conditions. A highly stereoselective epimerization of the product of the Mukaiyama–Michael reaction which proceeds in 77% yield with a dr of 22:1 is also described. Because both enantiomers of the ligand for this Mukaiyama–Michael reaction are available, a method for the synthesis of all four stereoisomers of the product as useful chiral building blocks has been established.

Enantioselective Formal Total Synthesis of Damsin

AbstractEnantioselective formal total synthesis of damsin, which was isolated from Compositae Ambrosia maritima L., is described. The highly enantio- and diastereoselective catalytic Mukaiyama–Michael reaction and subsequent highly stereoselective epimerization shorten the synthetic steps. It is also reported that the enolate, which was formed by the reaction of β-keto sulfone with lithium naphthalenide, reacted with methyl cyanoformate to form a quaternary stereogenic center in high yield with high stereoselectivity. This finding extends the synthetic chemistry starting from β-keto sulfones.

Enantioselective Mukaiyama-Michael Reaction of β,γ-Unsaturated α-Keto Esters with Silyl Ketene Acetals Catalyzed by a Chiral Magnesium Phosphate.

We would like to describe an efficient and highly enantioselective Mukaiyama-Michael reaction of silyl ketene acetals with β,γ-unsaturated α-keto esters catalyzed by a chiral magnesium BINOL-derived phosphate. The resulting functionalized 1,5-dicarbonyl adducts are obtained in high yields (up to 96%) and with excellent enantioselectivities (up to 98%) under mild conditions. Two plausible mechanistic pathways were proposed, including a 1,4-addition and a hetero Diels-Alder [4 + 2] cycloaddition.

Concise Enantioselective Total Synthesis of Daphenylline Enabled by an Intramolecular Oxidative Dearomatization.

Daphenylline is a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids, which exhibit intriguing biological activities. Six total syntheses have been reported, five of which utilize aromatization approaches. Herein, we report a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, which concurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notable transformations include a tandem reductive amination/amidation double cyclization reaction, to assemble the cage-like architecture, and installation of the other two chiral stereocenters via a highly enantioselective rhodium-catalyzed challenging hydrogenation of the diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complex benzofused cyclohexanone (13:1 d.r.).

Silyldienolates in Organocatalytic Enantioselective Vinylogous Mukaiyama-Type Reactions: A Review.

Mukaiyama aldol, Mannich, and Michael reactions are arguably amongst the most important C–C bond formation processes and enable access to highly relevant building blocks of various natural products. Their vinylogous extensions display equally high potential in the formation of important key intermediates featuring even higher functionalization possibilities through an additional conjugated C–C double bond. Hence, it is much desired to develop highly selective vinylogous methods in order to enable unconventional, more efficient asymmetric syntheses of biologically active compounds. In this regard, silyl-dienolates were discovered to display high regioselectivities due to their tendency toward γ-additions. The control of the enantio- and diastereoinduction of these processes have been for a long time dominated by transition metal catalysis, but it received serious competition by the application of organocatalytic approaches since the beginning of this century. In this review, the organocatalytic applications of silyl-dienolates in asymmetric vinylogous C–C bond formations are summarized, focusing on their scope, characteristics, and limitations.

Chemical Synthesis Reveals the Odorous Principle of Vetiver Oil

Key words vetiver oil - fragrances - Mukaiyama–Michael reaction - imidophosphoimidates - enones

Asymmetric One‐Pot Mukaiyama Michael/Michael Reaction Catalyzed by Diphenylprolinol Silyl Ether

The asymmetric catalytic Mukaiyama Michael reaction between α,β‐unsaturated aldehydes and silyl enol ether derived from a cyclic ketone was catalyzed by diphenylprolinol silyl ether to afford Michael products with excellent diastereo‐ and enantioselectivities. Bicyclo[2.2.2]octanone derivatives can be synthesized as a single isomer in a nearly optically pure form via a two‐step, one‐pot reaction, comprising the sequential Mukaiyama Michael reaction and intramolecular Michael reaction starting from dienol silyl ether and α,β‐unsaturated aldehydes, catalyzed by diphenylprolinol silyl ether. In the second Michael reaction, positive kinetic resolution occurred to increase the enantioselectivity.

Catalytic Enantioselective Total Synthesis of (+)-Lycoperdic Acid.

A concise enantio- and stereocontrolled synthesis of (+)-lycoperdic acid is presented. The stereochemical control is based on iminium-catalyzed Mukaiyama-Michael reaction and enamine-catalyzed organocatalytic α-chlorination steps. The amino group was introduced by azide displacement, affording the final stereochemistry of (+)-lycoperdic acid. Penultimate hydrogenation and hydrolysis afforded pure (+)-lycoperdic acid in seven steps from a known silyloxyfuran.

Enantioselective Mukaiyama-Michael Reaction Catalyzed by a Chiral Rhodium Complex Based on Pinene-Modified Pyridine Ligands.

The rhodium complex Λ-Rh1 containing chiral pinene-modified pyridine ligands is prepared through a two-step synthetic procedure; it exhibits excellent reactivity and enantiocontrol towards the enantioselective Mukaiyama-Michael reaction of α,β-unsaturated 2-acyl imidazoles with silyl enol ethers, affording enantioenriched 1,5-dicarbonyl compounds in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee).

Unravelling the Nucleophilicity of Butenolides for 1,6-Conjugate Addition to p-Quinone Methides: A Direct Access to Diversely Substituted Butenolide-Derived Diarylmethanes.

A Lewis acid catalyzed regioselective C-C bond is constructed through β-addition of deconjugated butenolides with p-quinone methides in a 1,6-conjugate addition manner. Interestingly, Lewis acid catalyzed vinylogous Mukaiyama-Michael reaction of silyloxyfurans with p-QMs proceeds selectively through the α or γ position exclusively. The reaction is mild with broad substrate scope, thus allowing easy access to a wide range of bis-arylated α-/β-/γ-substituted butenolides.

Metal-Controlled Switching of Enantioselectivity in the Mukaiyama-Michael Reaction of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Metal-Pybox Complexes.

Metal-directed switching of enantioselectivity in the Mukaiyama-Michael reaction of silyl enol ethers to α,β-unsaturated 2-acyl imidazoles using the same chiral indapybox ligand has been reported. The utility of this approach has been portrayed in the synthesis of both enantiomers of optically active δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of the tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

Asymmetric Synthesis of 1,5-Diesters by Mukaiyama–Michael Reaction

Key words α,β-unsaturated esters - Mukaiyama–Michael reaction - silyl ketene acetals - diesters

The Catalytic Asymmetric Mukaiyama-Michael Reaction of Silyl Ketene Acetals with α,β-Unsaturated Methyl Esters.

α,β-Unsaturated esters are readily available but challenging substrates to activate in asymmetric catalysis. We now describe an efficient, general, and highly enantioselective Mukaiyama-Michael reaction of silyl ketene acetals with α,β-unsaturated methyl esters that is catalyzed by a silylium imidodiphosphorimidate (IDPi) Lewis acid.

Asymmetric synthesis of Rauhut-Currier-type esters via Mukaiyama-Michael reaction to acylphosphonates under bifunctional catalysis.

A highly enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy dienes and α,β-unsaturated acyl phosphonates under bifunctional organocatalysis is presented. The new reactivity triggered by the catalyst conducted to Rauhut-Currier type esters, via a formal conjugate addition to α,β-unsaturated esters. This protocol proceeds under mild conditions with complete regioselectivity and excellent enantiocontrol.

Switchable Diastereoselectivity in the Fluoride-Promoted Vinylogous Mukaiyama–Michael Reaction of 2-[(Trimethylsilyl)oxy]furan Catalyzed by Crown Ethers

The fluoride-promoted vinylogous Mukaiyama-Michael reaction of 2-[(trimethylsilyl)oxy]furan with diverse α,β-unsaturated ketones is described. The TBAF-catalyzed VMMR afforded high anti-diastereoselectivity irrespective of the solvents used. The KF/crown ethers catalytic systems proved to be highly efficient in terms of yields and resulted in a highly diastereoselective unprecedented solvent/catalyst switchable reaction. Anti-adducts were obtained as single diastereomers or with excellent diastereoselectivities when benzo-15-crown-5 in CH2Cl2 was employed. On the other hand, high syn-diastereoselectivities (from 73:27 to 96:4) were achieved by employing dicyclohexane-18-crown-6 in toluene. On the basis of DFT calculations, the catalysts/solvent-dependent switchable diastereoselectivities are proposed to be the result of loose or tight cation-dienolate ion pairs.

Enantioselective Mukaiyama-Michael Reaction of Cyclic α-Alkylidene β-Keto Phosphine Oxide and Phosphonate and Asymmetric Synthesis of (R)-Homosarkomycin.

The asymmetric Mukaiyama-Michael reaction of cyclic α-alkylidene β-oxo phosphates and phosphine oxides that proceeds in a highly enantioselective manner is described. It is possible to carry out these reactions using a catalytic amount of a bisoxazoline-Cu(II) complex without decreasing the enantioselectivity, and one of the products has been successfully used for the first enantioselective synthesis of (R)-homosarkomycin.

An asymmetric vinylogous Mukaiyama-Michael reaction of α,β-unsaturated 2-acyl imidazoles catalyzed by chiral Sc(iii)- or Er(iii)-pybox complexes.

A highly diastereo- and enantioselective vinylogous Mukaiyama-Michael reaction of silyloxyfurans with α,β-unsaturated 2-acyl imidazoles catalyzed by either chiral Sc(iii) or Er(iii) complexes of a pybox ligand has been reported. The enantioenriched γ-butenolides formed in the reaction were further transformed into highly functionalized γ-lactones found as important structural frameworks in a wide range of biologically active natural products.