Hydroxy Enones Research Articles

Development of an α'-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein.

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.

Organocatalytic Asymmetric Cascade Reaction between o‐Hydroxycinnamaldehydes and γ/δ‐Hydroxyenones: A Route to Tetrahydrofuran/Tetrahydropyran‐Fused 3,4‐Dihydrocoumarins

AbstractThe first organocatalytic asymmetric synthesis of tetrahydrofuran/tetrahydropyran‐fused 3,4‐dihydrocoumarin has been developed via a cascade reaction between 2‐hydroxy cinnamaldehydes and γ/δ‐hydroxy enones followed by pyridinium chlorochromate oxidation. Diphenylprolinol silyl ether catalyst in combination with acetic acid was found to be the most effective for the cascade reaction. With 10 mol% of the catalyst and the additive, the desired products were obtained in high enantio‐ and diastereoselectivities.magnified image

ChemInform Abstract: Enantioselective Construction of Tetrasubstituted Stereogenic Carbons Through Broensted Base Catalyzed Michael Reactions: α′‐Hydroxy Enones as Key Enoate Equivalent.

Abstractα‐Hydroxy enones undergo asymmetric Michael reactions with a broad variety of Michael donors catalyzed by varying chiral catalysts.

Enantioselective construction of tetrasubstituted stereogenic carbons through Brønsted base catalyzed michael reactions: α'-hydroxy enones as key enoate equivalent.

Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α'-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α'-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α'-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.

ChemInform Abstract: α‐Hydroxy Ketones as Useful Templates in Asymmetric Reactions

AbstractReview: 56 refs.

α-Hydroxy ketones as useful templates in asymmetric reactions

Approaching the Nature's efficiency in controlling both reactivity and stereoselectivity of organic reactions by means of a catalyst species remains a formidable challenge for chemists to face. Despite impressive advances in the design of novel catalysts and activation modes, current catalytic and asymmetric methodologies rarely meet desirable standards of robustness, substrate scope, and selectivity altogether. One trick to improve catalyst behaviour is to identify adequate substrate template-catalyst combinations so that optimum performance of the reaction system could be achieved. During the last couple of years α-hydroxy ketones, and most particularly α'-hydroxy enones, have emerged as useful templates with applications in a number of metal-catalyzed as well as organocatalyzed C-C and C-X bond-forming stereoselective reactions. The first review of these accomplishments is presented here along with a brief historical introduction.

ChemInform Abstract: Ring A Modifications of Podocarpic Acid: Towards the Synthesis of Quassinoids.

Efficient methods for the formation of the hydroxy enone moieties in (17), (18), (45) and (46) from podocarpic acid (1) have been developed. The exocyclic alkene (13) has been converted into the α-hydroxy enones (17) and (18) in six steps and high overall yield. Oxidation of the enones (7) and (44) with manganese(III) acetate gave high yields of the α-acetoxy enones (10) and (47) and (48), respectively. Hydrolysis of (10), (47) and (48) afforded the α-hydroxy enones (11), (45) and (46), respectively. Hydroboration-oxidation of the alkene mixture (38) and (41) provided the alcohol (53) (53%) which was readily oxidized to the ketone (21) (92%). This ketone (21) was converted in three steps into the hydroxy enone (57) in 39% overall yield. Hydroxylation of the enone (44) via the silyl dienol ether (58) gave the α- hydroxy enones (45) (16%) and (46) (33%). The stereochemistry of 12-methoxy-19-nor-5β-podocarpa-3,8,11,13-tetraen-2-one (44) was established by X-ray crystallography.

ChemInform Abstract: Stereoselective Epoxidation of Hydroxy Enones. The Synthesis of the Side Chain of Clerocidin.

ChemInform 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.

ChemInform Abstract: Chiral Broensted Acid Directed Iron‐Catalyzed Enantioselective Friedel—Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones.

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.

(1R)-(+)-Camphor and Acetone Derived α′-Hydroxy Enones in Asymmetric Diels−Alder Reaction: Catalytic Activation by Lewis and Brønsted Acids, Substrate Scope, Applications in Syntheses, and Mechanistic Studies

The Diels-Alder reaction constitutes one of the most powerful and convergent C-C bond-forming transformations and continues to be the privileged route to access cyclohexene substructures, which are widespread within natural products and bioactive constituents. Over the recent years, asymmetric catalytic Diels-Alder methodologies have experienced a tremendous advance, but still inherently difficult diene-dienophile combinations prevail, such as those involving dienes less reactive than cyclopentadiene or dienophiles like beta-substituted acrylates and equivalents. Here the main features of alpha'-hydroxy enones as reaction partners of the Diels-Alder reaction are shown, with especial focus on their potentials and limitations in solving the above difficult cases. Alpha'-hydroxy enones are able to bind reversibly to both Lewis acids and Brønsted acids, forming 1,4-coordinated species that are shown to efficiently engage in these inherently difficult Diels-Alder reactions. On these bases, a convenient control of the reaction stereocontrol can be achieved using a camphor-derived chiral alpha'-hydroxy enone model (substrate-controlled asymmetric induction) and either Lewis acid or Brønsted acid catalysis. Complementing this approach, highly enantio- and diastereoselective Diels-Alder reactions can also be carried out by using simple achiral alpha'-hydroxy enones in combination with Evans' chiral Cu(II)-BOX complexes (catalyst-controlled asymmetric induction). Of importance, alpha'-hydroxy enones showed improved reactivity profiles and levels of stereoselectivity (endo/exo and facial selectivity) as compared with other prototypical dienophiles in the reactions involving dienes less reactive than cyclopentadiene. A rationale of some of these results is provided based on both kinetic experiments and quantum calculations. Thus, kinetic measurements of Brønsted acid promoted Diels-Alder reactions of alpha'-hydroxy enones show a first-order rate with respect to both enone and Brønsted acid promoter. Quantum calculations also support this trend and provide a rational explanation of the observed stereochemical outcome of the reactions. Finally, these fundamental studies are complemented with applications in natural products synthesis. More specifically, a nonracemic synthesis of (-)-nicolaioidesin C is described wherein a Brønsted acid catalyzed Diels-Alder reaction involving a alpha'-hydroxy enone substrate is the key step toward the hitherto challenging trisubstituted cyclohexene subunit.

Chiral Brønsted Acid Directed Iron‐Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones

A cooperative catalytic system established by the combination of an iron salt and a chiral Brønsted acid has proven to be effective in the asymmetric Friedel-Crafts alkylation of indoles with beta-aryl alpha'-hydroxy enones. Good to excellent yields and enatioselectivities were observed for a variety of alpha'-hydroxy enones and indoles, particularly for the beta-aryl alpha'-hydroxy enones bearing an electron-withdrawing group at the para position of the phenyl ring (up to 90 % yield and 91 % ee). The proton of the chiral Brønsted acid, the Lewis acid activation site, as well as the inherent basic site for the hydrogen-bonding interaction of the Brønsted acid are responsible for the high catalytic activities and enantioselectivities of the title reaction. A possible reaction mechanism was proposed. The key catalytic species in the catalytic system, the phosphate salt of Fe(III), which was thought to be responsible for the high activity and good enantioselectivity, was then confirmed by ESIMS studies.

Catalytic Michael Reactions of Ketoesters with a Camphor-Derived Acrylate Equivalent: Stereoselective Access to All-Carbon Quaternary Centers

A camphor-based alpha'-hydroxy enone reagent acts as a chiral acrylate equivalent in copper-catalyzed Michael reactions of beta-keto esters and affords products that possess all-carbon quaternary stereocenters of high enantiomeric purity.

Enantioselective Conjugate Radical Addition to α′‐Hydroxy Enones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Catalytic Enantioselective Conjugate Addition of Nitromethane to α′‐Hydroxy Enones as Surrogates of α,β‐Unsaturated Carboxylic Acids and Aldehydes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Enantioselective Conjugate Radical Addition to α‘-Hydroxy Enones

Enantioselective conjugate radical addition to alpha'-hydroxy alpha,beta-unsaturated ketones, compounds containing bidentate donors, has been investigated. It has been found that radical additions to alpha'-hydroxy alpha,beta-unsaturated ketones in the presence of Mg(NTf2)2 and bisoxazoline ligand 5a proceeded cleanly, yielding the addition products in high chemical yields and good enantiomeric excesses.

Catalytic Enantioselective Conjugate Addition of Nitromethane to α′‐Hydroxy Enones as Surrogates of α,β‐Unsaturated Carboxylic Acids and Aldehydes

AbstractNo base is required for the Mg(II)‐catalyzed conjugate addition of nitromethane to α′‐hydroxy enones in the presence of molecular sieves. Good enantioselectivities are attained using 3 or 4 Å MS and about 10 mol % of Mg(OTf)2‐chiral bisoxazoline complexes. Elaboration of the adducts through oxidative cleavage of the ketol moiety provides an entry to enantioenriched γ‐nitro carboxylic acids, while a sequential carbonyl reduction‐diol oxidation yields the corresponding aldehydes.

A new and efficient chemoenzymatic route to both enantiomers of α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones

A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones starting from α-hydroxy cyclic enones is described. Protection of 1,2-diketones, manganese(III) acetate-mediated acetoxylation followed by enzyme-mediated hydrolysis of α′-acetoxy enones gives acetoxy enones 3a– d and hydroxy enones 4a– d with high enantiomeric excesses (up to 99%) and good yields. The transesterification of rac- 4b in the presence of DMAP afforded (+)- 4b and (−)- 3b in high enantiomeric excesses (91–94%) and good chemical yields.

Lewis Acid Catalyzed Asymmetric Cycloadditions of Nitrones: α′‐Hydroxy Enones as Efficient Reaction Partners.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lewis Acid Catalyzed Asymmetric Cycloadditions of Nitrones: α′‐Hydroxy Enones as Efficient Reaction Partners

A fine pair: Excellent levels of regio-, endo/exo-, diastereo-, and/or enantioselectivity are attained in the Cu-catalyzed cycloaddition of nitrones with α′-hydroxy enones (see scheme). The resulting adducts can be further elaborated to the corresponding isoxazolidines bearing aldehyde, ketone, and carboxylic acid functions. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z502308_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Lewis Acid Catalyzed Asymmetric Cycloadditions of Nitrones: α′‐Hydroxy Enones as Efficient Reaction Partners

Lewis Acid Catalyzed Asymmetric Cycloadditions of Nitrones: α′‐Hydroxy Enones as Efficient Reaction Partners