Michael Initiated Ring Closure Reactions Research Articles

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles.

Herein, we present the first ever use of 3-isopropylidene oxindoles as electrophiles in vinylogous Michael initiated ring closure reaction (MIRC). Among the various alkylidene oxindoles used in enantioselective spirocyclization reactions, isopropylidene oxindoles are the least explored to date. The competing reactivity of isopropylidene oxindoles (electrophilicity vs nucleophilicity) in the presence of a chiral organocatalyst is controlled by the logical selection of a more reactive nucleophile. The methodology produces a library of densely substituted highly enantioenriched spirocyclopropyl oxindoles with excellent yield and stereoselectivities. Moreover, the first enantioselective synthesis of HIV-1 NNRT inhibitor indicates the importance of our synthesized spiro-cyclopropyl oxindole core.

Asymmetric Synthesis of Spiro-3,3'-cyclopropyl Oxindoles via Vinylogous Michael Initiated Ring Closure Reaction.

A novel organocatalytic cascade approach for the synthesis of spiro-cyclopropyl oxindole derivatives has been developed. The methodology is based on asymmetric vinylogous Michael addition of 4-nitroisoxazole derivatives to N-Boc isatylidene malonates followed by intramolecular alkylation. Its remarkable stereocontrol, wide substrate scope, and scalability highlight this new developed strategy. Moreover, this work represents the first example of vinylogous Michael initiated ring closure (MIRC) reaction for the synthesis of chiral 3,3'-cyclopropyl oxindole.

Asymmetric Synthesis of Fluoro, Fluoromethyl, Difluoromethyl, and Trifluoromethylcyclopropanes.

Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,β-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.

Carbohydrate-Based Azacrown Ethers in Asymmetric Syntheses

Carbohydrate-based crown ethers represent a special group of chiral phase transfer catalysts. Several derivatives of these macrocycles have been synthesized in our research group. Among these compounds, monoaza-15-crown-5 lariat ethers proved to be effective phase transfer and enantioselective catalysts in certain reactions. Those chiral azacrown ethers incorporating various carbohydrate moieties in the macrocyclic structure are reviewed, which generated asymmetric induction in reactions, such as Michael addition, epoxidation of enones, Darzens condensation and Michael-initiated ring-closure (MIRC) reaction. Effects on the catalytic activity of the structural changes are the focus.

Synthesis of Spirocyclopropane Oxindoles via Michael-Initiated Cyclopropanation of Pyridinium Salts with 3-Ylidene Oxindoles

AbstractA Michael-initiated ring-closure reaction of pyridinium salts with arylidene oxindoles has been developed. A wide range of aryl-substituted spirocyclopropane oxindoles has been achieved in moderate to good yields (41–99%). This efficient strategy exhibits good functional group compatibility and may serve as an attractive method for the synthesis of diverse cyclopropanes.

Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

Epoxides of d-fructose and l-sorbose: A convenient class of “click” functionality for the synthesis of a rare family of amino- and thio-sugars

The strained epoxide ring of oxirane-derived furanoside and pyranoside of d-fructose are regioselectively opened by various primary and secondary amines as well as azide to yield C4-alkylamino-C4-deoxy and the corresponding azido derivatives. The epoxide ring of a furanoside derived from l-sorbose, a C-5 epimer of d-fructose also afforded C4-amino and C4-azido analogues. All three epoxides generated piperazine linked disaccharides. These epoxides are also easily opened by p-tolylthiol to access thiosugars. One such thiosugar was converted to vinylsulfone-modified fructofuranoside and subjected to nucleophillic addition. A suitably designed vinyl sulfone-modified fructofuranoside having a leaving group at C-6, act as an efficient substrate for MIRC (Michael Initiated Ring Closure) reactions to construct cyclopropane skeleton in d-fructose. The strategy is general in nature and provides an easy access to cyclopropanated sugar derivatives. Thus, the easily accessible “spring loaded” epoxides of d-fructose and l-sorbose have been used as pivotal starting point for the synthesis of hitherto unknown modified carbohydrates.

3-Nitroacrylates as promising substrates for the construction of carbo- and heterocyclic structures

The review analyzes and summarizes methods for the synthesis of carbo- and heterocycles based on alkyl 3-nitroacrylates that were described over the past decade. The scope of the review includes cycloaddition reactions and tandem processes, in particular Michael-initiated ring closure (MIRC) reactions, giving functionalized carbo- and heterocycles, mainly five- and six-membered derivatives.

Asymmetric cyclopropanation reactions catalyzed by carbohydrate-based crown ethers

Optically active cyclopropane derivatives were prepared by a novel, simple and green approach in high enantioselectivities using monosaccharide-based chiral crown ethers as phase transfer catalysts. The crown ethers having d-glucopyranoside, d-mannopyranoside and d-altropyranoside units proved to be efficient catalyst in a few asymmetric phase transfer cyclopropanation reactions. The Michael-initiated ring closure (MIRC) reactions of diethyl bromomalonate with chalcones took place with complete diastereoselectivity and up to 99% ee. Using benzylidenemalononitrile, 2-arylidenemalononitriles, 2-benzylidene-1,3-indandione, substituted 2-benzylidene-1,3-indandiones, 2-arylidene-1,3-indandiones and 2-benzylidene-1,3-diphenyl-1,3-propanediones enantioselectivities up to 92%, 99%, 54% 93%, 89% and 72%, respectively, were achieved, in the presence of chiral lariat ethers derived from different monosaccharides. The absolute configuration of a cyclopropane diester product was determined by a combined CD spectroscopic and theoretical study.

Highly Enantioselective Synthesis of Chiral Cyclopropyl Nucleosides via Catalytic Asymmetric Intermolecular Cyclopropanation.

An efficient route to construct chiral cyclopropyl purine nucleoside analogues has been established via the catalytic asymmetric Michael-initiated ring-closure reactions of α-purine acrylates with α-bromo-carboxylic esters. Using (DHQD)2AQN as the catalyst, various chiral cyclopropyl purine nucleoside analogues with a chiral quaternary stereocenter were obtained in 72-98% yields, excellent diastereoselectivities, and 93-97% ee. Through simple functional group transformations, diverse chiral cyclopropyl purine nucleosides with hydroxymethyl group or carboxyl group were obtained.

N,N′‐Dioxide–Lanthanum(III)‐Catalyzed Asymmetric Cyclopropanation of 2‐Cyano‐3‐arylacrylates with 2‐Bromomalonates

AbstractAn efficient N,N′‐dioxide–lanthanum(III) complex catalytic system has been developed for the diastereo‐ and enantioselective Michael‐initiated ring‐closure (MIRC) reaction of 2‐cyano‐3‐arylacrylates with 2‐bromomalonates. Various chiral cyclopropanes with multiple substitutions were obtained in high yields (up to 93%) with excellent dr (>95:5 dr) and good ee values (up to 91% ee). The catalytic system also worked for the tandem halogenation/asymmetric MIRC reaction of α,β‐unsaturated nitriles, malonates and NBS. Besides, a possible catalytic model has been proposed to explain the origin of the stereoselectivity.magnified image

ChemInform Abstract: Catalytic One‐Pot Diastereoselective Michael‐Initiated Ring‐Closure of Methyl Ketones with 3‐Bromochromones: Synthesis of Cyclopropa[b]chromanones.

A one-pot diastereoselective base-catalyzed Michael-initiated ring-closure (MIRC) of activated methyl ketones with 3-bromochromones to give cyclopropa[b]chromanones is described. Three asymmetric centres are generated in the new cyclopropa[b]chromanone skeleton. Stereochemistry studies based on NMR spectroscopy and single-crystal X-ray diffraction analysis revealed the trans configuration of the cyclopropane ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as was further confirmed by chiral HPLC. The use of acetone in our reaction produced a 1-acetyl-substituted cyclopropa[b]chromanone that can undergo a subsequent MIRC reaction with a second molecule of 3-bromochromone to give the first described 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers as a meso form.

Catalytic One‐Pot Diastereoselective Michael‐Initiated Ring‐Closure of Methyl Ketones with 3‐Bromochromones: Synthesis of Cyclopropa[b]chromanones

A one‐pot diastereoselective base‐catalyzed Michael‐initiated ring‐closure (MIRC) of activated methyl ketones with 3‐bromochromones to give cyclopropa[b]chromanones is described. Three asymmetric centres are generated in the new cyclopropa[b]chromanone skeleton. Stereochemistry studies based on NMR spectroscopy and single‐crystal X‐ray diffraction analysis revealed the trans configuration of the cyclopropane ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as was further confirmed by chiral HPLC. The use of acetone in our reaction produced a 1‐acetyl‐substituted cyclopropa[b]chromanone that can undergo a subsequent MIRC reaction with a second molecule of 3‐bromochromone to give the first described 1,1′‐carbonylbis(cyclopropa[b]chromanone) dimers as a meso form.

Cyclopropanation of Various Substrates via Simmons-Smith and Michael-Initiated Ring Closure (MIRC) Reactions

Cyclopropanation of various electron rich and electron deficient olefins via Simmons-Smith and Michael-initiated ring closure reactions was studied in our research. Cinnamyl alcohol 18 was succesfully cyclopropanated in a good to excellent yield using Simmons-Smith reactions. Methyl and benzyl crotonate 14 and 16 were labile in MIRC reaction condition indicated by the detection of starting material degradation in the NMR spectra of the crude reactions, and allowed a low to moderate product yield. The other starting materials, i.e., cinnamaldehyde 19 , methyl cinnamate 20 , mono- and di-protected cross-coupled product (4 R ,5 R , E )-methyl 5-( tert -butyldimethylsilyloxy)-4-hydroxyhepta-2,6-dienoate 25 and (4 R ,5 R , E )-methyl 5-( tert -butyldimethylsilyloxy)-4-(methoxymethoxy)hepta-2,6-dienoate 26 , were apparently incompatible to the reaction condition set in our study.

ChemInform Abstract: A Straightforward and Highly Diastereoselective Access to Functionalized Monofluorinated Cyclopropanes via a Michael Initiated Ring Closure Reaction.

AbstractA tandem Michael addition/ring closure sequence is developed to yield fluorinated cyclopropanes from a reaction of ammonium salts (I) derived from bromofluoroacetate and DABCO with electron deficient alkenes.

Regio- and Stereocontrol in the Michael-Initiated Ring-Closure Reactions of γ,δ-Epoxy-α,β-unsaturated Esters, Ketones, Sulfones, and Amides

Organozincates or Grignard reagents in the presence of zinc catalysts undergo Michael initiated ring closure (MIRC) reactions with γ,δ-epoxy-α,β-enoates, enones, enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of diastereoselectivity is solvent dependent for alkyl Grignard reagents reacting with epoxy enoates, ensulfones, and enamides but solvent independent for the enones. Excellent diastereoselectivity can be achieved for the epoxy enoates, enones, and ensulfones, while the enamides afford modest diastereoselectivity under optimal conditions. The MIRC reaction can be achieved with phenylmagnesium chloride and these substrates under reaction conditions designed to minimize biphenyl formation.

A Straightforward and Highly Diastereoselective Access to Functionalized Monofluorinated Cyclopropanes via a Michael Initiated Ring Closure Reaction

The synthesis of highly functionalized monofluorinated cyclopropanes based on a Michael Initiated Ring Closure (MIRC) reaction has been developed. The addition of quaternary ammonium salts derived from ethyl bromofluoroacetate on a panel of electron deficient alkenes followed by cyclization gave rise to an efficient access to monofluorinated cyclopropanes with good yields and remarkable diastereoselectivity.

ChemInform Abstract: Stereoselective Cyclopropanation of α‐Bromochalcone with Diethyl Malonate Promoted by K2CO3.

AbstractBesides good yields for the exclusive formation of the trans‐isomers (III), this Michael‐initiated ring closure reaction also provides the first access to the cis‐isomers (IV) of the depicted densely substituted cyclopropanes.

Regio- and Diastereoselective Synthesis of trans-2,3-Dihydrofuran Derivatives in an Aqueous Medium

A wide variety of fused<i> trans</i>-2,3-dihydrofuran derivatives were synthesized through a one-pot three-component reaction of an aromatic aldehyde, a cyclic β-diketo compound, and an <i>in situ</i>-generated pyridinium ylide in refluxing. The pyridinium ylide was formed from either 2-bromo-1-phenylethanone or 4-nitrobenzyl bromide and pyridine in the presence of 10 mol% of sodium hydroxide. Pyridine plays crucial role in forming the pyridinium salt, which, in turn, forms a nitrogen ylide in the presence of sodium hydroxide. The ylide assists a Michael-initiated ring-closure reaction, but is not itself incorporated in the final product. The protocol is environmentally acceptable because no organic solvent is involved at any stage. Furthermore, the method is highly diastereoselective, gives good yields, and does not involve extensive workup procedures or chromatographic separations, as the desired products can be isolated by filtration and drying.

Asymmetric Synthesis of Cyclopropanes with a Monofluorinated Quaternary Stereocenter

New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer.