Intermolecular Michael Reaction Research Articles

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between β-oxo esters and β-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

AbstractHerein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one‐carbon introduction and ring expansion operations, we have successfully converted cephalotane‐type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid‐type C19 norditerpenoids and intact cephalotane‐type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13‐oxo‐cephinoid H, 7‐oxo‐cephinoid H, fortalpinoid C, 7‐epi‐fortalpinoid C, cephanolide E, and 13‐epi‐cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between β‐oxo esters and β‐substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Organocatalytic One‐Pot Synthesis of Pseudo‐Terpenoids

AbstractStructurally complex cedrane scaffolds were synthesized in very good yields with high chemo‐ and diastereoselectivities in a sequential one‐pot manner. A combination of intermolecular olefination, intramolecular Michael and Michael reactions or intermolecular olefination, intramolecular Michael and aldol reactions were used as the key steps from the readily available hydroxy‐p‐quinone butanals and phosphoranes with catalytic amounts of quinine at ambient temperatures for a few hours. This is a unique one‐pot combination of coupling and annulation routes for the green synthesis of a library of tricyclic pseudo‐terpenoids (cedrane scaffolds) with high selectivity and yields. Organocatalytic ring isomerization was highlighted through transforming one ring into another one by retro‐cyclization. We have discussed thoroughly mechanistic aspects of these tandem coupling/annulation and ring isomerization reactions based on control experiments and X‐ray crystal structure analysis.

A Molecular Iodine-Mediated Synthesis of Cyclopenta[c]furo[3,2-b]furan-5,6-diones: Assembly of an Angular Dioxatriquinane Core.

A molecular iodine-mediated synthesis of angular oxatriqinane core from 3-acetyl-2H-chromen-2-ones, β-bromo-β-nitrostyrenes, and pyridine in the presence of Et3N in MeCN containing a trace amount of water was developed. The reaction proceeds via intermolecular Michael reaction of 2-oxo-2-(2-oxo-2H-chromen-3-yl)-1-(pyridin-1-ium-1-yl)ethan-1-ide with bromonitrostyrene followed by intramolecular Michael reaction and elimination steps. Evidence for the stereochemistry of a typical product is obtained from single-crystal X-ray analyses. The important feature of this strategy is the fact that it forms three stereogenic centers with good selectivity.

Annulation of a Highly Functionalized Diazo Building Block with Indoles under Sc(OTf)3/Rh2(OAc)4 Multicatalysis through Michael Addition/Cyclization Sequence.

A highly functionalized and easily accessible six-carbon diazo building block has been developed and utilized as a 1,4-diacceptor for an efficient synthesis of functionalized tetrahydrocarbazoles, carbazoles, and tetrahydropyrido[1,2- a]indoles. The synthesis involves concurrent tandem catalysis by Sc(OTf)3 and Rh2(OAc)4. The role of Sc(OTf)3 is critical as it facilitates both the initial intermolecular Michael reaction of the indole and the subsequent Rh(II)-catalyzed intramolecular annulation. The products, tetrahydrocarbazoles and tetrahydropyridoindoles, are equipped with a β-ketoester and ester functionalities which can be utilized for further synthetic elaborations.

ChemInform Abstract: Pd0‐Catalyzed Intramolecular α‐Arylation of Sulfones: Domino Reactions in the Synthesis of Functionalized Tetrahydroisoquinolines.

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials.

Pd(0)-catalyzed intramolecular α-arylation of sulfones: domino reactions in the synthesis of functionalized tetrahydroisoquinolines.

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials.

Biomimetic Synthesis of Zeylanone and Zeylanone Epoxide by Dimerization of 2-Methyl-1,4-naphthoquinone

A biomimetic synthesis of zeylanone and zeylanone epoxide, which are natural dimeric naphthoquinones, has been accomplished starting from plumbagin, a natural monomeric naphthoquinone. The key features of our synthesis are cascade intermolecular and intramolecular Michael reactions, followed by epoxidation of the resultant hydroquinone with molecular oxygen.

Studies Towards the Synthesis of Crotogoudin

An effective synthesis of the tricyclic core structure of the new diterpene crotogoudin was achieved. The synthesis features an intermolecular domino Michael reaction to construct a bicyclo[2.2.2]octane motif and an aldol condensation to close ring B. Stork reductive alkylation with allyl bromide proceeded from the β side, resulting in the wrong stereochemistry at C-10.

Diastereoselectivity in unusual intermolecular tandem Michael reactions

Highly stereoselective consecutive or tandem Michael (MIMI) reactions are reported. A variety of initial nucleophiles react with chiral acylated 1,3-oxazolidin-2-ones to generate a reactive enolate. The enolate then reacts stereoselectively with a second equivalent of the acylated 1,3-oxazolidin-2-one to afford ‘dimeric’ adducts. The adducts have three new contiguous stereogenic centers formed with a high level of control. Single crystal X-ray crystallographic analysis confirmed this controlled formation of novel tandem acyclic conjugate addition or MIMI products in several examples.

Facile Synthesis of 3-(Succinimid-3-yl)-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine Derivatives by Sequential Intra- and Intermolecular Michael Reactions between 2-Aminopyridines and Maleimides

Facile Synthesis of 3-(Succinimid-3-yl)-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine Derivatives by Sequential Intra- and Intermolecular Michael Reactions between 2-Aminopyridines and Maleimides

Convenient Synthesis of Substituted Piperidinones from α,β-Unsaturated Amides: Formal Synthesis of Deplancheine, Tacamonine, and Paroxetine

[reaction: see text] An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from simple starting materials has been developed. The method allows alpha,beta-unsaturated amides to be used as a synthon of the piperidine nucleus. In addition, the utility of this methodology is demonstrated by its application to a formal synthesis of the indolo[2,3-a]quinolizidine alkaloids, (+/-)-deplancheine, (+/-)-tacamonine, and the antidepressant paroxetine.

A “Chiral Aldehyde” Equivalent as a Building Block Towards Biologically Active Targets

Chiral gamma-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6 % overall yield.

A Direct Entry to Substituted Piperidinones from α,β‐Unsaturated Amides by Means of Aza Double Michael Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A direct entry to substituted piperidinones from α,β-unsaturated amides by means of aza double Michael reaction

An intermolecular aza-double Michael reaction has been developed leading to functionalized piperidin-2-ones from simple starting materials. The method allows to utilize α,β-unsaturated amides as a synthon of piperidine nucleus. The short synthesis of anti-depressant paroxetine was demonstrated by using the new methodology.

ChemInform Abstract: Synthesis of Pyrrolidin‐2‐ones and of Staurosporine Aglycon (K‐252c) by Intermolecular Michael Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Pyrrolidin-2-ones and of Staurosporine Aglycon (K-252c) by Intermolecular Michael Reaction.

Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-, and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.

Diastereoselective synthesis of (−)-1-methyl-(3 S,4 R)-3,4-bis((2 S)- N-( tert-butyloxycarbonyl)pyrrolidin-2-yl)-2-pyrrolidinone by an asymmetric Michael reaction

Beginning with enantiomerically pure L-proline, (−)-1-methyl-(3 S,4 R)-3,4-bis((2 S)- N-( tert-butyloxycarbonyl)pyrrolidin-2-yl)-2-pyrrolidinone was prepared in diastereomerically pure form. Taking advantage of the chiral induction of the L-proline derivatives, the intermolecular Michael reaction, used to build the pyrrolidinone ring, was carried out stereoselectively.

Sequential “double-Michael” additions of dienolates to fulvene: Rapid access to the tricyclo[5.3.0.n 2,5]alkane systems

A highly efficient and stereoselective approach to the tricyclo[5.3.0.n 2,5]alkan-4-one system has been achieved via the intermolecular double Michael reaction of lithium dienolates to fulvene.

Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction

AbstractThe one‐pot intramolecular double Michael reaction of compounds having two different α, β‐unsaturated carbonyl groups to form polycyclic compounds can be carried out by three different methods: in the first the substrate is treated with lithium hexamethyldisilazide, in the second with chlorotrimethylsilane, triethylamine, and zinc chloride at an elevated temperature, and in the third with tert‐butyldimethylsilyl trifluoromethanesulfonate and triethylamine. The reaction proceeds with complete regioselectivity and high stereoselectivity following a stepwise mechanism. Spiro‐fused bicyclo[2.2.2]octane derivatives can be constructed with high stereoselectivity by the intromolecular double Michael reaction by using the first method. Enantiomerically pure atisine and the enantiomer of atisirene were synthesized stereoselectively by application of this methodology. The syntheses of steroids and angular triquinane‐type sesquiterpenoids were possible with the second method. Heterocyclic compounds with a bridgehead nitrogen atom were obtained by the reaction of α, β‐unsaturated amides following the second and third methods. The asymmetric synthesis of tylophorine with diastereofacial control was achieved by the intramolecular reaction according to the third method. The sulfur‐mediated intramolecular double Michael reaction utilizing the third method produced trans‐hydroindane derivatives. Furthermore, the intramolecular Michael‐aldol reaction can be employed in synthesizing polycyclic systems with cyclobutane units by treatment with tert‐butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine. The intermolecular double Michael reaction and related reactions will also be described.