Intramolecular Michael Cyclization Research Articles

Reagent-Controlled Regiodivergent Annulations of Achmatowicz Products with Vinylogous Nucleophiles: Synthesis of Bicyclic Cyclopenta[b]pyrans and 8-Oxabicyclo[3.2.1]octane Derivatives.

Two reagent-controlled regiodivergent annulation protocols for Achmatowicz products with vinylogous nucleophiles have been developed, which furnished a series of bicyclic cyclopenta[b]pyrans and 8-oxabicyclo[3.2.1]octane derivatives in 28-90% yields. Plausible mechanisms were proposed to involve either Pd-catalyzed Tsuji-Trost allyl-allyl coupling and concomitant Michael cyclization or quinine-promoted cascade stepwise [5 + 2] cycloaddition and intramolecular Michael cyclization.

Umpolung Chemo- and Regioselective Cascade Addition of Diethylzinc to α-Diketones Followed by Intramolecular Michael Reaction: Stereoselective Synthesis of Highly Substituted 1- Indanones.

Herein we report an efficient stereoselective umpolung 1,2-addition of Et2Zn onto α-diketones followed by intramolecular cascade Michael cyclization. This strategy effectively delivers a broad range of substituted 1-indanones in excellent yields in a chemo- and regioselective fashion. Additionally, we performed a variety of synthetic transformations on the 1-indanone products. Furthermore, a hitherto-unexplored asymmetric variant of this methodology that provides up to 94:6 er using an easily accessible cinchona alkaloid ligand has been addressed.

Synthesis of Chromeno[4,3-b]pyrrol-4(1H)-ones through a Multicomponent Reaction and Cyclization Strategy.

A novel three-component reaction of 2-oxo-2H-chromene-3-carbaldehydes with isocyanides and anilines was developed for one-pot assembly of biologically intriguing chromeno[4,3-b]pyrrol-4(1H)-ones, which can also be transferred into diverse polycyclic fused scaffolds through further synthetic manipulations. The described method tolerates a broad substrate scope and proceeds in moderate to good yield via a sequential multicomponent reaction and intramolecular Michael cyclization.

ChemInform Abstract: Three‐Step Synthesis of Substituted Isochromenes.

AbstractA novel three‐step approach to substituted isochromenes consisting of Henry reaction, aerobic Wacker‐type oxidation, and intramolecular Michael cyclization is developed.

Three-step synthesis of substituted isochromenes

A synthetic route toward isochromenes 6, starting with aldehydes 3, in good to excellent yield is described herein. This novel approach was carried out by the Henry reaction of 3 with NH4OAc and nitroalkanes (MeNO2 or EtNO2), aerobic Wacker-type oxidation of the resulting nitroalkenes 4, followed by K2CO3-promoted intramolecular Michael cyclization in modest to good yields.

ChemInform Abstract: A Route to Benzo‐Annelated δ‐Sultams Through Michael Cyclization.

A new approach to benzo-annelated δ-sultams containing an aryl–nitrogen bond is described. The method, which involves the intramolecular Michael cyclization of tert-butyl ortho-[N-(methoxycarbonylmethyl)sulfonylamino]cinnamates, allows the synthesis of secondary sultams as well as their tertiary analogues and bridged tricyclic derivatives efficiently and diastereoselectively.

A Route to Benzo‐Annelated δ‐Sultams through Michael Cyclization

AbstractA new approach to benzo‐annelated δ‐sultams containing an aryl–nitrogen bond is described. The method, which involves the intramolecular Michael cyclization of tert‐butyl ortho‐[N‐(methoxycarbonylmethyl)sulfonylamino]cinnamates, allows the synthesis of secondary sultams as well as their tertiary analogues and bridged tricyclic derivatives efficiently and diastereoselectively.

Enantiodivergent strategy for the synthesis of polyhydroxylated pyrrolizidines and evaluation of their inhibitory activities against glycosidases

The enantiodivergent synthesis of polyhydroxylated pyrrolizidines has been achieved, starting from common intermediate 1. The synthesis involved the stereoselective construction of the pyrrolizidine core unit by using intramolecular Michael cyclization reaction as the key reaction. The synthesized eight isomers were evaluated for various glycosidase inhibition effects. Compound 15 showed a moderate inhibitory activity against α-l-fucosidase and a high selectivity compared from the other glycosidases.

ChemInform Abstract: Asymmetric Synthesis of 1,2,3‐Trisubstituted Indanes via an Enantioselective Copper(II)‐Catalyzed Asymmetric Nitroaldol Reaction Followed by an Intramolecular Michael Cyclization.

Abstract Herein we describe a novel approach for the synthesis of a chiral 1,2,3-trisubstituted indane, a privileged substructure in medicinal chemistry, via an enantioselective nitroaldol reaction and subsequent intramolecular Michael addition. The asymmetric copper(II)-catalyzed reactions of ortho -formyl cinnamates, ortho -formyl cinnamonitrile, or ortho -formyl α-benzalketones with nitromethane were carried out using the C1-symmetric chiral secondary diamine L1 as a ligand, which afforded the nitroaldol products in high yields (up to 92%) and with good to excellent enantioselectivities (up to 97%) under mild conditions. The notable effect of the base and the dosage of nitromethane on the reaction are also discussed.

Asymmetric synthesis of 1,2,3-trisubstituted indanes via an enantioselective copper(II)-catalyzed asymmetric nitroaldol reaction followed by an intramolecular Michael cyclization

Herein we describe a novel approach for the synthesis of a chiral 1,2,3-trisubstituted indane, a privileged substructure in medicinal chemistry, via an enantioselective nitroaldol reaction and subsequent intramolecular Michael addition. The asymmetric copper(II)-catalyzed reactions of ortho-formyl cinnamates, ortho-formyl cinnamonitrile, or ortho-formyl α-benzalketones with nitromethane were carried out using the C1-symmetric chiral secondary diamine L1 as a ligand, which afforded the nitroaldol products in high yields (up to 92%) and with good to excellent enantioselectivities (up to 97%) under mild conditions. The notable effect of the base and the dosage of nitromethane on the reaction are also discussed.

ChemInform Abstract: Phosphine‐Triggered Tandem Annulation Between Morita—Baylis—Hillman Carbonates and Dinucleophiles: Facile Syntheses of Oxazepanes, Thiazepanes, and Diazepanes.

AbstractThe title reactions are proposed to proceed through a phosphine‐catalyzed allylic alkylation followed by an intramolecular Michael cyclization.

ChemInform Abstract: Stereoselective Synthesis of Indanylglycine Derivatives by a Tandem Michael—Michael Reaction.

The construction of 1,2,3-trisubstituted indane rings by the Michael addition of a glycinate followed by an intramolecular Michael cyclization is reported. The tandem process affords indanylglycine derivatives with high regio- and diastereoselectivity.

Phosphine-Triggered Tandem Annulation between Morita–Baylis–Hillman Carbonates and Dinucleophiles: Facile Syntheses of Oxazepanes, Thiazepanes, and Diazepanes

A new phosphine-triggered tandem [3 + 4] annulation reaction between Morita-Baylis-Hillman carbonates and 1,4-diheteroatom dinucleophiles has been developed, which provides a facile synthetic method for saturated seven-membered 1,4-heterocycles such as 1,4-oxazepanes, 1,4-thiazepanes, and 1,4-diazepanes. Mechanistic investigation implies that this reaction takes place through a phosphine-catalyzed allylic alkylation followed by a general base-catalyzed intramolecular Michael cyclization.

Stereoselective Synthesis of Indanylglycine Derivatives by a Tandem Michael–Michael Reaction

The construction of 1,2,3-trisubstituted indane rings by the Michael addition of a glycinate followed by an intramolecular Michael cyclization is reported. The tandem process affords indanylglycine derivatives with high regio- and diastereoselectivity.

Studies toward the total synthesis of (+)-gelsemine and synthesis of spirocyclopentaneoxindole through intramolecular Michael cyclization

During the approach to the total synthesis of (+)-gelsemine, two novel spirocyclopentaneoxindole compounds 2 and 3 were obtained. Starting from compound 9, spirocyclopentaneoxindole 3 was efficiently and unexpectedly obtained through a Boc migration–intramolecular Michael cyclization cascade procedure. This intramolecular Michael addition strategy allows conveniently access to complex spirooxindole and spirocyclopentaneoxindole derivatives.

Synthesis of (±)-oleocanthal via a tandem intramolecular Michael cyclization–HWE olefination

A synthesis of racemic oleocanthal has been accomplished in 11 steps from 1,3 propanediol by a key tandem intramolecular Michael cyclization–Horner–Wadsworth–Emmons olefination.

Diastereoselective Route to Piperidine and Indolizidine Scaffolds From Enantiopure Vinylsulfinyl-Containing Amino Alcohols

A new route to functionalized piperidine and indolizidine scaffolds, based on the diastereoselective intramolecular Michael cyclization of vinylsulfinyl-containing amino alcohols 1−3, has been developed. Pyrolytic elimination of the resulting cycloadducts resulted in the regioselective formation of the corresponding tetrahydropyridines and indolizidines. The observed regiochemical course of this process can be explained mainly in terms of the steric bias imposed by the disposition of the arylsulfinyl group and the concerted syn mechanism accepted for this kind of elimination. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Synthesis of a Novel Sesquiterpene Isolated from the Pheromone Gland of a Stink Bug, Tynacantha marginata Dallas

A novel sesquiterpene, isolated as the putative sex pheromone of a stink bug ( Tynacantha marginata Dallas) and proposed to have an unprecedented carbon framework, was synthesized as its racemate by using an intramolecular double Michael cyclization as the key step. Comparison of the spectral data of the synthetic sample with those of the natural material confirmed the proposed structure.

Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides. A novel class of antibiotics.

A novel class of 2-fluoro-6-O-propargyl-11,12-carbamate ketolide derivatives of erythromycin has been synthesized for antibacterial SAR studies. Replacement of the C2-hydrogen by a fluorine atom allows the synthesis of 6-O-propargylic ketones and electron-deficient 6-O-propargylic aromatic derivatives by preventing intramolecular C2-enolate Michael cyclization.

The use of furans in natural product syntheses

Abstract