α,β-Unsaturated γ-Oxo Carboxylic Acids in Heterocylic Synthesis II. Behavior of 4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic Acid Towards Carbon Nucleophiles under Michael Reaction Condition

4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic acid ( 1 ) was condensed with compounds containing active methylene groups under Michael reaction conditions to form the Michael adducts 2a-c , 3a-c , and 4a-b . The behavior of Michael adduct towards the action of hydrazine hydrate was investigated. The compounds were tested for biological properties.     

Direct asymmetric organocatalytic Michael reactions of alpha,alpha-disubstituted aldehydes with beta-nitrostyrenes for the synthesis of quaternary carbon-containing products

[reaction: see text] Direct asymmetric catalytic Michael reactions have been performed using chiral-amine/acid bifunctional catalysts. Performed with 0.3 equiv of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and 0.3 equiv of trifluoroacetic acid as the catalyst, the reaction of alpha,alpha-dialkylaldehydes with (E)-beta-nitrostyrene provided the alpha,alpha-dialkyl Michael products in up to 96% yield with up to 91% ee. With respect to enantioselectivity, l-proline was a poor catalyst of this class of Michael reactions.     

Organocatalytic enantioselective conjugate addition of ketones to isatylidine malononitriles

An enantioselective Michael addition of ketones to alkylidenemalononitriles catalyzed by chiral primary amine I with (R)-5c as a co-catalyst in good yields (>90%) and with good enantioselectivities (85-96% ee) has been developed. The strategy has also been extended to a three-component version through a domino Knoevenagel/Michael sequence with similar or better outcomes.     

一步法合成取代-1,2-苯醌类化合物

应用固定化多酚氧化酶催化的氧化-迈克尔加成反应,一步合成了4,5-二取代-1,2-苯醌类化合物:4,5-N,N-二(苯胺基)-1,2-苯醌,4,5-N,N-二(对甲苯胺基)-1,2-苯醌,4,5-N,N-二(间氯苯胺基)-1,2-苯醌,4,5-N,N-二(对溴苯胺基)-1,2-苯醌。用化学法(I_2—KI)进行氧化-迈克尔加成反应也成功地合成了4,5-二取代-1,2-苯醌类化合物。应用紫外光谱方法证明了氧化-迈克尔加成反应的机制。     

Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea

We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and dimethylamino groups was revealed to be highly efficient for the asymmetric Michael reaction of 1,3-dicarbonyl compounds to nitroolefins. Furthermore, we have developed a new synthetic route for (R)-(-)-baclofen and a chiral quaternary carbon center with high enantioselectivity by Michael reaction. In these reactions, we assumed that a thiourea moiety and an amino group of the catalyst activates a nitroolefin and a 1,3-dicarbonyl compound, respectively, to afford the Michael adduct with high enantio- and diastereoselectivity.     

Organophosphorus Reagents in Organocatalysis: Synthesis of Optically Active α-Methylene-δ-lactones and δ-Lactams

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner-Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2,?3-a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.     

Colorimetric and fluorimetric detection of cysteine: Unexpected Michael addition–elimination reaction

The synthesis of three isomers based on Michael addition mechanism for the detection of sulfurcontaining species in aqueous solution is described. These compounds are constructed by conjugating an enone to a coumarin fluorophore. A substituted-phenyl (o, m, or p-) was appended at the carbonyl carbon to adjust the reactivity. The experimental results showed that (E)-7-(diethylamino)-3-(3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (m-QPS) and (E)-7-(diethylamino)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (p-QPS) barely react with sulfur-containing nucleophiles, while (E)-7-(diethylamino)-3-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (o-QPS) exhibited a fast response toward sulfite, sulfide and thiols in DMSO/phosphate buffer (2:1). The above results are probably due to the intramolecular H-bonding activated Michael addition. More interestingly, cysteine triggered unusual photophysical responses of o-QPS:the original absorption (488 nm) and emission peaks (573 nm) underwent significant blue shifts initially and then recovered, which might be caused by the Michael addition and elimination reaction, respectively.     

Michael addition reactions between various nucleophilic glycine equivalents and (S,E)-1-enoyl-5-oxo-N-phenylpyrrolidine-2-carboxamide,an optimal type of chiral Michael acceptor in the asymmetric synthesis of β-phenyl pyroglutamic acid and related compounds

(S)-5-Oxo-N-phenyl-1-[(E)-3-phenylacryloyl]pyrrolidine-2-carboxamide, easily prepared from inexpensive and readily available, in both enantiomeric forms, glutamic/pyroglutamic acid was designed as an optimal type of chiral Michael acceptor for reactions with a series of nucleophilic glycine equivalents. A study of the corresponding Michael addition reactions revealed that the new generation of modular glycine derivatives, as a counterpart to the Michael acceptor, provides for operationally convenient preparation of β-phenyl pyroglutamic acids and related compounds with virtually complete chemical and stereochemical outcomes.     

Asymmetric Michael addition of a recyclable chiral amine: inversion of stereoselectivity caused by the difference of ethereal solvents

The Michael addition of a chiral amine [(-)- 6] to alpha,beta-unsaturated esters ( 4) was attained and the stereoselectivity was inverted by changing the solvent from diethyl ether to tetrahydrofuran when alpha,beta-unsaturated esters having an aromatic ring at the beta-position were employed. In addition, the chiral auxiliary in the Michael adducts ( 9A) was facilely removed with N-iodosuccinimide to afford beta-amino esters ( 10A) and 2-methoxy- d-bornylaldehyde ( 11), which can be reclaimed to the chiral amine ( 6) by reductive amination.     

Development of new DMAP-related organocatalysts for use in the Michael addition reaction of β-ketoesters in water

A general and efficient protocol for the Michael addition reactions of β-ketoesters in pure water has been developed. The reactions are successfully catalyzed by newly designed DMAP-related organocatalysts such as 4-(didecylamino)pyridine, and the desired Michael adducts are obtained in good to high yields     

Asymmetric synthesis of succinic semialdehyde derivatives

The nucleophilic Michael addition of 2-(diphenylmethoxymethyl)-1-methyleneamino pyrrolidine 1Dto prochiral aliphatic and aromatic alkylidene malonates 2 takes place in the presence of MgI(2) to afford the corresponding Michael adducts 3 in excellent yields and good selectivities. In the aromatic series, optically pure (de > 98%) major diastereomers (S,S)-3 were isolated in good yields (77-93%) after chromatographic separation. Direct, racemization-free BF(3).OEt(2)-catalyzed thiolysis of compounds 3 afforded dithioacetals 7. These compounds were transformed into malonates 8 and succinic semialdehyde derivatives 9 by Raney Nickel mediated desulfuration or decarboxylation, respectively.     

Highly enantioselective Michael addition of acetone to nitroolefins catalyzed by chiral bifunctional primary amine-thiourea catalysts with acetic acid

Highly enantioselective Michael reaction of acetone with a variety of nitroolefins catalyzed by N-[(1R,2R)-2-aminocyclohexyl]-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-thiourea (1b) together with acetic acid is described. The Michael addition products were obtained in high yields (76-94%) and up to 96% ee.     

Organocatalytic asymmetric synthesis of polyfunctionalized cyclohexene-carbaldehydes via dominom reaction between 3-(benzyloxy)propanal and β-nitroalkenes

A novel domino Michael/retro-oxa-Michael/Michael/Aldol condensation reaction was developed via the reaction of 3-(benzyloxy)propanal with β-nitroalkenes catalyzed by secondary amine. Using this methodology, optically pure polyfunctionalized cyclohexene-carbaldehydes were prepared straightforwardly from two simple starting materials in good yield with excellent stereoselectivity.     

A stereoselective total synthesis of (−)-seychellene

A stereoselective total synthesis of the tricyclic sesquiterpene (−)-seychellene, starting from (R)-carvone via (R)-3-methylcarvone has been accomplished, employing a combination of intermolecular Michael addition-intramolecular Michael addition sequence, a stereoselective hydrogenation, and an intramolecular alkylation reaction.     

Peptide-phospholipid cross-linking reactions: Identification of leucine enkephalin-alka(e)nal-glycerophosphatidylcholine adducts by tandem mass spectrometry

The covalent interactions between peptides and lipid oxidation products, with formation of Schiff and Michael adducts, are known to occur during free radical oxidative damage. In this study, leucine-enkephalin-glycerophosphatidylcholine alka(e)nal adducts were analyzed by electrospray tandem mass spectrometry (MS/MS). Upon collision-induced dissociation of the Leucine enkephalin-2-(9-oxo-nonanoyl)-1-palmitoyl-3-glycerophosphatidylcholine, an alkanal Schiff adduct observed at m/z 1187.7, the main product ions were attributed to the phosphocholine polar head and loss of the peptide. Also, product ions resulting from characteristic losses of phosphatidylcholines and cleavages of the peptide chain (mainly b-type) were observed. Additional product ions formed by combined peptide and phosphatidylcholine fragmentations were identified. The fragmentation pattern of the leucine enkephalin-alkanal Schiff adduct and the leucine enkephalin-alkenal phosphatidylcholine Schiff and Michael adducts were similar, although the loss of the peptide for the Michael adduct should occur through a distinct mechanism. These fragmentation pathways differ greatly from those described for peptide-lipid Schiff and Michael adducts, in which only peptide chain cleavages are reported, probably due to charge retention in the glycerophosphatidylcholine polar head in peptide-glycerophosphatidylcholine adducts.     

Cu(I)- and Cu(II)-catalyzed cyclo- and Michael addition reactions of unsaturated β-ketoesters

The α-alkylidene β-ketoesters 2-carbethoxycyclopentenone (1a) and ethyl 2-benzoylacrylate (1b) react with 1,2-dimethylbutadiene (2) (Diels-Alder), N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (3) (Ficini reaction), ethynyl(phenyl)sulfane (4) ([2 + 2] cycloaddition), and 1,2,5-trimethyl-1H-pyrrole (5) (Michael addition) in the presence of copper(I) (6) or copper(II) triflate (7) (1-2 mol %) in dichloromethane. This convenient protocol converts 1a and 1b to the corresponding cycloaddition (8-10) or Michael addition (11) products in good yields after reaction times of 0.5-3 h without requiring purified solvents or inert gas atmosphere.     

Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene: efficient access to gamma2-amino acids

Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene catalyzed by (S)-diphenylprolinol silyl ether provides beta-substituted-delta-nitroalcohols in nearly optically pure form (96-99% ee). The Michael adducts bear a single substituent adjacent to the carbonyl and can be efficiently converted to protected gamma2-amino acids, which are essential for the systematic conformational studies of gamma-peptide foldamers.     

New auxiliaries for copper-catalyzed asymmetric Michael reactions: generation of quaternary stereocenters at room temperature

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.     

A formal total synthesis of (±)-9-isocyanoneopupukeanane

A formal total synthesis of the marine sesquiterpene (±)-9-isocyanoneopupukeanane starting from the readily available monoterpene carvone has been accomplished employing a combination of intermolecular Michael addition-intramolecular Michael addition reaction and an intramolecular rhodium carbenoid C-H insertion reaction as key steps, and identifying the isopropenyl group as a masked hydroxy group.     

Nitroalkenes as electrophiles in the asymmetric Michael reaction involving chiral imines/enamino esters

Addition of 2-nitropropene to the chiral imine derived from 2-methylcyclopentanone and (S)-1-phenylethylamine furnished the expected Michael adduct. The latter compound was then efficiently converted into (R)-pentalenone through a Nef reaction. Condensation of the enamino ester derived from 2-carbethoxycyclopentanone and (S)-1-phenylethylamine with 1-nitropropene gave with excellent diastereo- and enantioselectivity the corresponding Michael adduct.