CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted beta-methyl-alpha-homophenylalanines

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a convenient two-step synthesis of anti-beta-methylhomophenylalanines is also described.     

Indolyl substituted 4-oxobut-2-enoic acids. Synthesis and aza-Michael additions

The synthesis of three new substituted 4-hetereoaryl-4-oxobut-2-enoic acids with indole ring substitutedin positions 3-, 5- and 7- is described. The addition of these Michael acceptors to 4-(1-phenylsulphonylpyrrol-3-yl)-4-oxobut-2-enoic acid in conjugate addition was explored using both racemic and chiral amines. In tandem with the crystallization-induced asymmetric transformation (CIAT) protocol the effective methodology for the synthesis of enantiomerically highly enriched substituted 2-amino-4-heteroaryl-4-oxobutanoic acids as multifunctional homotryptophan analogues was developed.      

Crystallisation induced asymmetric transformation (CIAT) in the synthesis of furoylalanines and furylcarbinols

A new synthesis of enantiomerically highly enriched N-substituted furoylalanines has been developed. This process involves the combination of crystallisation induced asymmetric transformation (CIAT) and a conjugate addition of N-nucleophiles to furoylacrylic acids. Further transformations to furoylalanines and substituted furylcarbinols are also described.     

Tandem retro-aldol/Wittig/Michael and related cascade processes

A number of novel tandem sequences initiated by a retro-aldol process are described along with preliminary scope and limitation studies. These include (i) retro-aldol/Wittig trapping/intramolecular Michael addition, (ii) retro-aldol/aza-Wittig/intramolecular imine addition, (iii) retro-aldol/Henry/intramolecular Michael addition and (iv) retro-aldol/Knoevenagel/intramolecular Michael addition sequences. A range of novel functionalised cyclopentanes, and related systems, are described which should prove to be useful synthetic building blocks.     

In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge

A reversible Michael addition reaction between thiol nucleophiles and cyanoenones has been previously postulated to be the mechanism‐of‐action of a new family of reversible covalent drugs. However, the hypothetical Michael adducts in this mechanism have only been detected by spectroscopic methods in solution. Herein, the crystallographic observation of reversible Michael addition with a potent cyanoenone drug candidate by means of the crystalline‐sponge method is reported. After inclusion of the cyanoenone substrate, the sponge crystal was treated with a thiol solution. Subsequent crystallographic analysis confirmed the single‐crystal‐to‐single‐crystal transformation of the substrate into the impermanent Michael adduct.     

A convenient synthesis of polysubstituted 2-amino-4,5-dihydrofuran-3-nitriles from benzoins or benzaldehydes

A convenient assembly of polysubstituted 2-amino-4,5-dihydrofuran-3-nitriles from a tandem Michael addition/cyclization reaction between benzoins and arylidenemalononitriles is described. The products are also obtained from readily available benzaldehydes via a sequential N-heterocyclic carbene–catalyzed benzoin condensation and Michael addition/cyclization process in a one-pot tandem procedure.     

Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.     

Metal-free Michael addition initiated multicomponent oxidative cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonyls

A simple metal-free, step-economic and selective access to pyridines from readily available substrates is reported, involving a flexible 4 A molecular sieves promoted Michael addition initiated domino three-component reaction between a 1,3-dicarbonyl, a Michael acceptor and a synthetic equivalent of ammonia.     

Enantioselective organocatalytic Michael addition reactions between N-heterocycles and nitroolefins

[reaction: see text] A method for Michael addition of N-heterocycles to nitroolefins has been developed. The process is promoted by a cinchona alkaloid derivative to give Michael adducts in moderate to high enantioselectivities.     

Synthesis of a novel crown ether derived from chiro-inositol and its catalytic activity on the asymmetric Michael addition

A novel 18-membered chiral crown ether was prepared in four steps starting from L-quebrachitol, a chiro-inositol, and its catalytic activity in the Michael addition reaction of glycine imine with several Michael acceptors was studied.     

Asymmetric Michael Addition of Activated Alkenes to Nitro Alkenes Catalyzed by Organic Catalyst

Enantioselective Michael addition is one of the most powerfulbond-forming reaction in organic synthesis. [1] A mong the Michael acceptors, nitro alkenes are very attractive, because the nitro group is the most electron-withdrawing group known and it can serve as masked functionality to be further transformed after the addition has taken place. [2] Recently, asymmetric Michael reactions catalyzed by organic catalyst have draw much attention.[3]     

Michael addition of allenoates to electron-deficient olefins: facile synthesis of 2-alkynyl-substituted glutaric acid derivatives

A Michael addition of allenoates to electron-deficient olefins was mediated efficiently by a catalytic amount of commercial tetra-n-butylammonium fluoride (TBAF) under mild conditions. And 2-alkynyl substituted glutaric acid derivatives, which may be potential building blocks in organic synthesis, were obtained in good to excellent yields from these reactions. The mechanism for the Michael addition reaction may involve the formation of an alkynylenolate intermediate.     

Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones: cocatalyst effects and evidence for an enamine intermediate

An enantioselective intermolecular Michael addition of aldehydes to enones catalyzed by imidazolidinones has been achieved. Chemoselectivity (Michael addition vs aldol) can be controlled through judicious choice of hydrogen-bond-donating cocatalysts. The optimal imidazolidinone/hydrogen-bond-donor pair affords Michael addition products in excess of 90% ee. Furthermore, we have isolated and characterized an enamine intermediate and demonstrated its efficacy as a nucleophile in the observed Michael addition reactions.     

Fluorapatite: efficient catalyst for the Michael addition

A Michael addition assisted by fluorapatite in heterogeneous media is described. Reaction between mercaptans and chalcone derivatives was studied at room temperature in methanol as solvent. By-products of usual undesirable reactions in Michael addition such as 1,2-addition, bis-addition and polymerisation are not observed. The yields obtained are good to excellent.     

Copper(II)-catalyzed enantioselective conjugate addition of nitro esters to 2-enoyl-pyridine N-oxides

A highly enantioselective Michael addition of nitro esters to 2-enoyl-pyridine N-oxides was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields and with up to 96% ee.     

Artificial transmembrane signal transduction mediated by dynamic covalent chemistry

Reversible formation of covalent adducts between a thiol and a membrane-anchored Michael acceptor has been used to control the activation of a caged enzyme encapsulated inside vesicles. A peptide substrate and papain, caged as the mixed disulfide with methane thiol, were encapsulated inside vesicles, which contained Michael acceptors embedded in the lipid bilayer. In the absence of the Michael acceptor, addition of thiols to the external aqueous solution did not activate the enzyme to any significant extent. In the presence of the Michael acceptor, addition of benzyl thiol led to uncaging of the enzyme and hydrolysis of the peptide substrate to generate a fluorescence output signal. A charged thiol used as the input signal did not activate the enzyme. A Michael acceptor with a polar head group that cannot cross the lipid bilayer was just as effective at delivering benzyl thiol to the inner compartment of the vesicles as a non-polar Michael acceptor that can diffuse across the bilayer. The concentration dependence of the output signal suggests that the mechanism of signal transduction is based on increasing the local concentration of thiol present in the vesicles by the formation of Michael adducts. An interesting feature of this system is that enzyme activation is transient, which means that sequential addition of aliquots of thiol can be used to repeatedly generate an output signal.

Reversible formation of covalent adducts between a thiol and a membrane-anchored Michael acceptor has been used to control the activation of a caged enzyme encapsulated inside vesicles.     

Aza‐Michael addition reaction: Post‐polymerization modification and preparation of PEI/PEG‐based polyester hydrogels from enzymatically synthesized reactive polymers

The utility of aza‐Michael addition chemistry for post‐polymerization functionalization of enzymatically prepared polyesters is established. For this, itaconate ester and oligoethylene glycol are selected as monomers. A Candida Antarctica lipase B catalyzed polycondensation reaction between the two monomers provides the polyesters, which carry an activated carbon‐carbon double bond in the polymer backbone. These electron deficient alkenes represent suitable aza‐Michael acceptors and can be engaged in a nucleophilic addition reaction with small molecular mono‐amines (aza‐Michael donors) to yield functionalized linear polyesters. Employing a poly‐amine as the aza‐Michael donor, on the other hand, results in the formation of hydrophilic polymer networks. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 745–749     

Enantioselective organocatalytic Michael addition of malonate esters to nitro olefins using bifunctional cinchonine derivatives

A family of 9-amino(9-deoxy) epicinchonine derivatives, possessing a range of mono- and bidentate hydrogen bond donor groups at the 9-position, were synthesised and evaluated for asymmetric organocatalytic activity in the dimethyl malonate Michael addition to beta-nitrostyrene; thiourea derivative was identified as the most effective bifunctional organic catalyst and found to induce high enantioselectivity in the malonate ester Michael addition reaction to a range of nitro olefins.     

Asymmetric total synthesis of (-)-alkaloid 223A and its 6-epimer

The enantiopure gamma-amino alcohols 7 and 18 are prepared by using the diastereoselective Michael addition of lithium N-benzyl (R)-alpha-methylbenzylamide to alpha,beta-unsaturated esters as a key step. The Michael addition of 7 or 18 to an alkynone 8 followed by an intramolecular cyclization afford the cyclic enamine 10 or 20, which are subjected to the diastereoselective hydrogenation, and the subsequent transformations provide 6-epi-alkaloid 223A and alkaloid 223A, respectively.     

Pyrrolidinyl-sulfamide derivatives as a new class of bifunctional organocatalysts for direct asymmetric Michael addition of cyclohexanone to nitroalkenes

A series of chiral pyrrolidinyl-sulfamide derivatives have been identified as efficient bifunctional organocatalysts for the direct Michael addition of cyclohexanone to a wide range of nitroalkenes. The desired Michael adducts were obtained in high chemical yields and excellent stereoselectivities (up to 99/1 dr and 95% ee).