Intramolecular aza-Michael Reaction Research Articles

Hypervalent Chalcogen Bonds Catalysis on the Intramolecular Aza-Michael Reaction of Aminochalcone: Catalytic Performance and Chalcogen Bond Properties.

Chalcogen bond (ChB) catalysis, as a new type in the field of non-covalent bond catalysis, has become a hot research topic in the field of organocatalysis in recent years. In the present work, we investigated the catalytic performance of a series of hypervalent ChB catalysis based on the intramolecular Aza-Michael reaction of aminochalcone. The reaction includes the carbon-nitrogen bond coupling step (key step) and the proton transfer step. The catalytic performance of mono-dentate pentafluorophenyl chalcogen bond donor ChB1 was comparable to that of bis-dentate chalcogen bond donor ChB4, and stronger than that of mono-dentate chalcogen bond donors ChB2 and ChB3. The formation of the chalcogen bond between the catalyst and the carbonyl oxygen atom of the reactant, causing the charge rearrangement of the reactant and C(1) charge of the -C-Ph group to become more positive, thereby the ChB catalysis promoted the nucleophile reaction. The electron density of the chalcogen bond of the pre-complex, the most positive electrostatic potentials of the catalyst, and the NPA charge of the key atom are proportional to the Gibbs energy barrier of the C-N bond coupling process, which provides an idea to predict the catalytic activity of the ChB catalysis.

Identification of Dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones as Cyclic Products of β-Amidomethyl Vinyl Sulfone Alphavirus Cysteine Protease Inhibitors.

Optimized syntheses of (E)-5-(2-ethoxyphenyl)-N-(3-(methylsulfonyl)allyl)-1H-pyrazole-3-carboxamide (RA-0002034, 1), a promising antiviral covalent cysteine protease inhibitor lead, were developed. The syntheses avoid the contamination of 1 with the inactive cyclic dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 2, which is formed by the intramolecular aza-Michael reaction of the vinyl sulfone warhead under basic conditions and slowly at pH 7.4 in phosphate buffer. The pure cysteine protease inhibitor 1 could be synthesized using either modified amide coupling conditions or through the introduction of a MOM-protecting group and was stable as a TFA or HCl salt. Although acyclic 1 demonstrated poor pharmacokinetics with high in vivo clearance in mice, inactive cyclic 2 showed improved plasma exposure. The potential use of cyclic dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones as prodrugs for the acyclic β-amidomethyl vinyl sulfone warhead was demonstrated by GSH capture experiments with an analog of 2.

The synthesis, carbonic anhydrase and acetylcholinesterase inhibition effects of sulfonyl chloride moiety containing oxazolidinones using an intramolecular aza-Michael addition

Oxazolidinones are used as various potent antibiotics, in organisms it acts as a protein synthesis inhibitor, focusing on an initial stage that encompasses the tRNA binding process. Novel intramolecular aza-Michael reactions devoid of metal catalysts have been introduced in an oxazolidone synthesis pathway, different from α,β-unsaturated ketones. Oxazolidinone derivatives were tested against acetylcholinesterase (AChE), carbonic anhydrase I and II (hCA I and hCA II) enzymes. All the synthesized compounds had potent inhibition effects with Ki values in the range of 13.57 ± 0.98 − 53.60 ± 6.81 µM against hCA I and 9.96 ± 1.02 − 46.35 ± 3.83 µM against hCA II in comparison to the acetazolamide (AZA) (Ki = 50.46 ± 6.17 µM for hCA I) and for hCA II (Ki = 41.31 ± 5.05 µM). Also, most of the compounds demonstrated potent inhibition ability towards AChE enzyme with Ki values 78.67–231.75 nM and compared to tacrine (TAC) as standard clinical inhibitor (Ki = 142.48 nM). Furthermore, ADMET analysis and molecular docking were calculated using the AChE, hCA I and hCA II enzyme proteins to correlate the data with the experimental data. In this work, recent applications of a stereoselective aza-Michael reaction as an efficient tool for of nitrogen-containing heterocyclic scaffolds and their useful to pharmacology analogs are reviewed and summarized. Communicated by Ramaswamy H. Sarma

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Rh(III)-Catalyzed C8-Spiroannulation of 1-Aminonaphthalenes with Maleimides.

The rhodium(III)-catalyzed C8-spiroannulation of 1-aminonaphthalenes with maleimides is described herein. Initially formed C8-alkenylated 1-aminonaphthalenes can intercept nucleophilic 1-amino groups through the intramolecular aza-Michael reaction, resulting in the formation of spirofused tetracyclic frameworks. This protocol displayed a wide substrate scope and a broad functional group compatibility. The synthetic utility of this process is demonstrated by the gram-scale synthesis, late-stage modification, and synthetic transformations.

Enantioselective Synthesis of Fluorinated Indolizidinone Derivatives

The enantioselective synthesis of fluorinated indolizidinone derivatives has been developed. The process involved an enantioselective intramolecular aza-Michael reaction of conjugated amides bearing a pendant α,β-unsaturated ketone moiety, catalyzed by the (S)-TRIP-derived phosphoric acid, followed by dimethyltitanocene methylenation and ring closing metathesis (RCM). Final indolizidine-derived products comprise a fluorine-containing tetrasubstituted double bond generated by the RCM reaction, which is a challenging task. The whole synthetic sequence took place in acceptable overall yields with excellent enantioselectivities.

Asymmetric Total Synthesis of Senepodine F.

The first asymmetric total synthesis of the Lycopodium alkaloid senepodine F, which contains a decahydroquinoline ring (AB-ring) and a quinolizidine ring (CD-ring) connected by a methylene tether, has been achieved. The key steps of this synthesis include an organocatalytic asymmetric Diels-Alder reaction, a diastereoselective intramolecular aza-Michael reaction, and an intramolecular SN2 cyclization to construct multisubstituted nitrogen-containing heterocycles. In addition, our total synthesis led to the stereochemical reassignment on the decahydroquinoline ring of senepodine F.

Total Synthesis of Fused Polycyclic Alkaloids Based on Oxidative Phenolic Couplings and Aza-Michael Reactions

AbstractAlkaloids with fused polycyclic frameworks are attractive targets for synthetic organic chemists because of their structural complexity and biological activities, and a variety of strategies for their synthesis have been developed. Herein, we describe our strategy of utilizing oxidative phenolic coupling and a regioselective intramolecular aza-Michael reaction to generate fused polycyclic structural frameworks, and its application for the total syntheses of (+)-gracilamine and various hasubanan alkaloids.1 Introduction2 Total Synthesis of (+)-Gracilamine3 Synthetic Studies on Monoterpene Indole Alkaloids4 Total Synthesis of Hasubanan Alkaloids5 Summary

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

Rapid synthesis of polyester based single-chain polymeric nanoparticles via an intra-molecular aza-Michael addition reaction

An alternative method to produce single-chain polymeric nanoparticles using the aza-Michael addition reaction of a linear polyester containing in-chain reactive triple bonds is introduced.

Rhodium-Catalyzed Oxidative Annulation of 2- or 7-Arylindoles with Alkenes/Alkynes Using Molecular Oxygen as the Sole Oxidant Enabled by Quaternary Ammonium Salt.

Developing an efficient catalytic system using molecular oxygen as the oxidant for rhodium-catalyzed cross-dehydrogenative coupling remains highly desirable. Herein, rhodium-catalyzed oxidative annulation of 2- or 7-phenyl-1H-indoles with alkenes or alkynes to assemble valuable 6H-isoindolo[2,1-a]indoles, pyrrolo[3,2,1-de]phenanthridines, or indolo[2,1-a]isoquinolines using the atmospheric pressure of air as the sole oxidant enabled by quaternary ammonium salt has been accomplished. Mechanistic studies provided evidence for the fast intramolecular aza-Michael reaction and aerobic reoxidation of Rh(I)/Rh(III), facilitated by the addition of quaternary ammonium salt.

Two Decades of Progress in the Asymmetric Intramolecular aza-Michael Reaction.

The asymmetric intramolecular aza-Michael reaction (IMAMR) is a very convenient strategy for the generation of heterocycles bearing nitrogen-substituted stereocenters. Due to the ubiquitous presence of these skeletons in natural products, the IMAMR has found widespread applications in the total synthesis of alkaloids and biologically relevant compounds. The development of asymmetric versions of the IMAMR are quite recent, most of them reported in this century. The fundamental advances in this field involve the use of organocatalysts. Chiral imidazolidinones, diaryl prolinol derivatives, Cinchone-derived primary amines and quaternary ammonium salts, and BINOL-derived phosphoric acids account for the success of those methodologies. Moreover, the use of N-sulfinyl imines with a dual role, as nitrogen nucleophiles and as chiral auxiliaries, appeared as a versatile mode of performing the asymmetric IMAMR.

Domino imino-aldol-aza-Michael and imino-aldol-aza-Michael-imino-aldol reactions: Diastereoselective synthesis of highly functionalized 2,6-disubstituted piperidines

Enolate mediated domino imino-aldol-aza-Michael and domino imino-aldol-aza-Michael-imino-aldol reactions of α-(aryl/alkyl)methylidene-β-diketones with activated N-aryl aldimines (1.0 and 2.0 equiv., respectively) have been developed for the diastereoselective (de >99%) synthesis of two sets of highly functionalized 2,6-disubstituted piperidines. The reaction course follows an intermolecular imino-aldol reaction followed by an intramolecular aza-Michael reaction with 1.0 equiv. of imine; whereas another intermolecular imino-aldol reaction takes place when 2.0 equiv. of imine is present in the reaction medium. The formation of the piperidine derivatives has been explained by plausible reaction mechanisms.

Enantioselective Total Synthesis of (+)-Stephadiamine through Bioinspired Aza-Benzilic Acid Type Rearrangement.

We report the first enantioselective total syntheses of the hasubanan alkaloid (-)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (-)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.

Double asymmetric intramolecular aza-Michael reaction: a convenient strategy for the synthesis of quinolizidine alkaloids.

A new methodology to access the quinolizidine skeleton in an asymmetric fashion was devised. It involves two consecutive intramolecular aza-Michael reactions of sulfinyl amines bearing a bis-enone moiety, in turn generated by a monodirectional cross metathesis reaction. The sequence, which takes place with excellent yields and diastereocontrol, was applied to the total synthesis of alkaloids lasubine I and myrtine.

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters.

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

Diastereoselective direct amidation/aza-Michael cascade reaction to synthesize cis-1,3-disubstituted isoindolines

A convenient and efficient base-promoted cascade reaction for the synthesis of cis-1,3-disubstituted isoindolines has been reported herein. We discovered that various N-protected imines bearing a Michael acceptor react smoothly with several nitrogenous nucleophiles in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene under mild conditions. cis-1,3-Disubstituted isoindolines bearing aminal functionality were assembled as a single diastereomer in moderate to good yields (52%–94%). This cascade process features the direct amidation of imines followed by the intramolecular aza-Michael reaction.

A multicomponent palladium-catalyzed carbonylative approach to imidazopyridinyl-N,N-dialkylacetamides

A novel, multicomponent approach to 2-(imidazo[1,2-a]pyridin-3-yl)-N,N-dialkylacetamides (very important class of fused heterocyclic derivatives, known to act on central nervous system by enhancing the activity of the GABA) is reported. It is based on the carbonylation reaction of N-Boc-(prop-2-yn-1-yl)pyridin-2-amines carried out in the presence of secondary amines (2–3 equiv) under oxidative conditions, using oxygen (from air) as oxidant (4:1 CO-air, total pressure 20 atm) and PdI2/KI as the catalytic system (0.33–1 mol% of PdI2 and 0.5 equiv of KI) in MeCN as the solvent at 100 °C. The process leads to the target compounds in good to high yields (67–90%) through an ordered sequence of steps, occurring in situ under the reaction conditions: Boc-deprotection of the substrate is followed by PdI2/KI-catalyzed oxidative monoaminocarbonylation of the terminal triple bond (or vice versa) to give a 2-ynamide intermediate, which then undergoes intramolecular aza-Michael reaction and isomerization.

Asymmetric Construction of Alkaloids by Employing a Key ω-Transaminase Cascade.

An ω-transaminase-triggered intramolecular aza-Michael reaction has been employed for the preparation of cyclic β-enaminones in good yield and excellent enantio- and diastereoselectivity, starting from easily accessible prochiral ketoynones and commercially available enzymes. The powerful thermodynamic driving force associated with the spontaneous aza-Michael reaction effectively displaces the transaminase reaction equilibrium towards product formation, using only two equivalents of isopropylamine. To demonstrate the potential of this methodology, this biocatalytic aza-Michael step was combined with annulation chemistry, affording unique stereo-defined fused alkaloid architectures.

Stereoselective Synthesis of the A,E-Ring Bicyclic Core of Calyciphylline B-Type Alkaloids

A stereoselective synthesis of the bicyclic unit constituting the A and E rings of calyciphylline B-type alkaloids is disclosed. The propionate ester of (1R)-cyclohex-2-en-1-ol, obtained by enzymatic resolution, is subjected to an Ireland–Claisen rearrangement. Subsequent reduction of the acid, Mitsunobu reaction to introduce a nitrogen functionality, oxidative cleavage to a dialdehyde, and intramolecular aldol and aza-Michael reactions afford the bicyclic subunit.