Michael-aldol Reaction Research Articles

Enantioselective Organocatalytic Tandem Michael−Aldol Reactions: One-Pot Synthesis of Chiral Thiochromenes

A highly enantioselective (S) diphenylpyrrolinol silyl ether promoted tandem Michael-aldol reaction of alpha,beta-unsaturated aldehydes with 2-mercaptobenzaldehydes has been developed. The method affords one-pot access to chiral and synthetically useful thiochromenes in high yields and high enantioselectivities from readily available compounds.

Tandem Intramolecular Michael-Aldol Reaction as a Tool for the Construction of the C-Ring of Hexacyclinic Acid

[reaction: see text] The tandem intramolecular Michael-aldol reaction was studied as a tool for the construction of the C-ring of hexacyclinic acid. By changing the reaction conditions it was possible to selectively obtain either the kinetic or the thermodynamic product. Retro-aldol reaction and subsequent epimerization provides four individual cyclopentane derivatives that can be incorporated as building blocks in natural product syntheses.

An acid-catalyzed Michael–aldol reaction

A tricyclic ketone is formed from cyclohexanone and cyclohexenone in strong acid solutions. The structure is confirmed by X-ray crystallography.

Synthesis of 3‐Sulfanylpropanols Containing Three Consecutive Stereocenters via Tandem Michael—Aldol Reaction of Enoylthioamides with Acetals as Key Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Diastereoselective Sequential Michael-Aldol Reactions of Methyl 2-Chloro-2-cyclopropylideneacetate with Grignard Reagents and Aldehydes

Grignard reagents, especially isopropylmagnesium chloride, smoothly undergo Michael addition onto methyl 2-bromo- and 2-chloro-2-cyclopropylideneacetate (1-Cl), and the thus formed magnesium enolates are particularly efficiently trapped with aromatic aldehydes. This one-pot reaction provides highly substituted chlorohydrines, mostly in high yields (10 out of 18 examples with 72-92%) and as pure (2S*,3R*)-diastereomers (anti-aldols). These chlorohydrines can be transformed to Darzens-type α,β-epoxyesters in good yields, as demonstrated for one example.

Selective Michael—Aldol Reaction by Use of Sterically Hindered Aluminum Aryloxides as Lewis Acids: An Easy Approach to Cyclobutane Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Practical synthesis of (2 S,3 R)-3-hydroxy-3-methylproline, a constituent of papuamides, using a diastereoselective tandem Michael-aldol reaction

(2 S,3 R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthesized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naphthylsulfonylglycine ( R)-binaphthyl ester and subsequent hydrolysis of the product in 39% overall yield and five steps.

Synthesis of 3-sulfanylpropanols containing three consecutive stereocenters via tandem Michael–aldol reaction of enoylthioamides with acetals as key reaction

(2 S,3 S,1′ R)-2-(α-Methoxybenzyl)-3-phenyl-3-sulfanylpropionamides were diastereoselectively prepared by the reactions of N-cinnamoyl-4 S-isopropyl-5,5-dimethyloxazolidinethione with acetals in the presence of SnCl 4. The absolute configuration of the three newly created contiguous stereocenters was determined by the X-ray analysis of the disulfide. The amides were transformed into propanols by the reductive removal of the oxazolidinone moiety.

Organocatalytic Transformation of 1,3‐Diketones into Optically Active Cyclohexanones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chalcogenide—Lewis Acid Mediated Tandem Michael Aldol Reaction — An Alternative to the Morita—Baylis—Hillman Reaction and a New Development

AbstractFor Abstract see ChemInform Abstract in Full Text.

Organocatalytic transformation of 1,3-diketones into optically active cyclohexanones

The domino Michael-aldol reaction of 1,3-diketones with MVK in the presence of l-proline furnished highly substituted cyclohexanones in a regio- and stereocontrolled manner. When the reaction was performed in NMP, high yields (up to 93%) and enantioselectivities up to 80% were observed.

Macrophomate Synthase: QM/MM Simulations Address the Diels−Alder versus Michael−Aldol Reaction Mechanism

Macrophomate synthase (MPS) of the phytopathogenic fungus Macrophoma commelinae catalyzes the transformation of 2-pyrone derivatives to the corresponding benzoate analogues. The transformation proceeds through three separate chemical reactions, including decarboxylation of oxalacetate to produce pyruvate enolate, two C-C bond formations between 2-pyrone and pyruvate enolate that form a bicyclic intermediate, and final decarboxylation with concomitant dehydration. Although some evidence suggests that the second step of the reaction catalyzed by MPS is a Diels-Alder reaction, definite proof that the C-C bond formations occur via a concerted mechanism is still required. An alternative route for formation of the C-C bonds is a stepwise Michael-aldol reaction. In this work, mixed quantum and molecular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation (FEP) calculations were performed to investigate the relative stabilities of the transition states (TS) for both reaction mechanisms. The key results are that the Diels-Alder TS model is 17.7 and 12.1 kcal/mol less stable than the Michael and aldol TSs in the stepwise route, respectively. Therefore, this work indicates that the Michael-aldol mechanism is the route used by MPS to catalyze the second step of the overall transformation, and that the enzyme is not a natural Diels-Alderase, as claimed by Ose and co-workers (Nature 2003, 422, 185-189; Acta Crystallogr. 2004, D60, 1187-1197). A modified link-atom treatment for the bonds at the QM/MM interface is also presented.

Chalcogenide–Lewis Acid Mediated Tandem Michael Aldol Reaction — an Alternative to the Morita–Baylis–Hillman Reaction and a New Development

AbstractA tandem Michael aldol reaction mediated by a chalcogenide and Lewis acid was developed in three different types. Reactions of electron‐deficient alkenes with aldehydes or α‐keto esters in the presence of a sulfide and TiCl4 gave α‐chloromethyl aldols. Reactions of chalcogenide–enones with carbonyl compounds gave α‐(α‐hydroxyalkyl)enones (Mori‐ta–Baylis–Hillman adducts) after the work‐up of the reaction mixture with triethylamine. The intramolecular Michael aldol reactions of N‐enoylthioamides with aldehydes in the presence of BF3Et2O produced tricyclic compounds bearing a bridgehead bound to four heteroatoms and induced four stereocenters in one step, three of which were consecutive. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A Short‐Step Synthesis of (2S,3R)‐3‐Hydroxy‐3‐methylproline, a Component of Polyoxypeptins, Using a Tandem Michael—Aldol Reaction and Optical Resolution.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New Synthesis of a Pyrroloquinoline Skeleton, the Martinelline Core, Using a Tandem Michael-Aldol Strategy

Correction to:New Synthesis of a Pyrroloquinoline Skeleton, the Martinelline Core, Using a Tandem Michael-Aldol StrategySynlett 2004; 2004(09): 1625-1627DOI: 10.1055/s-2004-829085

A Short-Step Synthesis of (2S,3R)-3-Hydroxy-3-methylproline, a Component of Polyoxypeptins, Using a Tandem Michael–Aldol Reaction and Optical Resolution

Abstract A short-step synthesis of (2S,3R)-3-hydroxy-3-methylproline, a component of polyoxypeptins, using a tandem Michael–aldol reaction followed by its optical resolution using (−)-cinchonidine has been achieved.

Highly Enantio‐ and Diastereoselective Organocatalytic Asymmetric Domino Michael—Aldol Reaction of β‐Ketoesters and α,β‐Unsaturated Ketones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Domino Michael-Aldol reactions on 1,4-diarylbut-2-ene-1,4-diones with methyl acetoacetate furnish methyl 2-aroyl-4- hydroxy-6-oxo-4-arylcyclohexane-1-carboxylate derivatives.

Domino Michael-Aldol reactions on 1,4-diaryl-2-butene-1,4-diones with methyl acetoacetate in the presence of activated Ba(OH)(2) furnished methyl (1R*,2S*,4S*)-2-aroyl-4-hydroxy-6-oxo-4-arylcyclohexane-1-carboxylate derivatives in a stereo- and regiospecific manner. While treatment of these cyclohexanecarboxylate products with TsOH resulted in the dehydrated and decarbomethoxylated cyclohexenone derivatives, the reaction with NaOMe furnished 3,5-disubstituted phenols via dehydration, decarbomethoxylation, and dehydrogenation. NaCl/DMSO under microwave irradiation transformed the cyclohexanecarboxylate products to the 7-hydroxyisobenzofuranone derivatives.

Efficient Construction of 1,2‐Dihydroquinoline and 1,2,3,4‐Tetrahydroquinoline Rings Using Tandem Michael‐Aldol Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly enantio- and diastereoselective organocatalytic asymmetric domino Michael-aldol reaction of beta-ketoesters and alpha,beta-unsaturated ketones.

Highly enantio- and diastereoselective organocatalytic asymmetric domino Michael-aldol reaction of beta-ketoesters and alpha,beta-unsaturated ketones.