Direct Catalytic Asymmetric Aldol Reaction Research Articles

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

Abstractα‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.

Direct Catalytic Asymmetric Aldol Reaction of α-Alkoxyamides to α-Fluorinated Ketones.

α-Oxygen-functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α-fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn- and anti-aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2-dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.

Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl Acetamide

A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted by a cooperative acid/base catalyst in a stereodivergent manner. The key structural element, a 7-azaindoline moiety, facilitated catalytic enolization, allowing for subsequent stereoselective aldol addition. Enantioselective synthesis of the key intermediate of blumiolide C and kainic acid supported the synthetic utility of this protocol.

Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α-Vinyl Appendage.

The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.

Direct Catalytic Asymmetric Aldol Reaction of α-Alkylamides.

A catalytic asymmetric aldol reaction directly employing amides as latent enolates has remained elusive because of the resistance of amides to enolization. A direct aldol reaction of α-alkylamides without any electron-withdrawing group harnessed by specific activation of 7-azaindoline amides under soft Lewis acid/Brønsted base cooperative catalysis is reported. Diastereo- and enantioselective coupling with ynals and aromatic aldehydes as well as divergent functional group interconversion of the amide provided expeditious access to a variety of aliphatic and aromatic chiral building blocks.

ChemInform Abstract: Managing the Retro‐Pathway in Direct Catalytic Asymmetric Aldol Reactions of Thioamides.

ChemInformVolume 47, Issue 9 Preparative Organic Chemistry ChemInform Abstract: Managing the Retro-Pathway in Direct Catalytic Asymmetric Aldol Reactions of Thioamides. Youmei Bao, Youmei Bao Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author Youmei Bao, Youmei Bao Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorNaoya Kumagai, Naoya Kumagai Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this authorMasakatsu Shibasaki, Masakatsu Shibasaki Inst. Microb. Chem., Shinagawa, Tokyo 141, JapanSearch for more papers by this author First published: 11 February 2016 https://doi.org/10.1002/chin.201609089Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue9February, 2016 RelatedInformation

Direct Catalytic Asymmetric Aldol Reaction of an α‐Azido Amide

AbstractA direct aldol reaction of an α‐azido 7‐azaindolinylamide, promoted by a Cu‐based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7‐azaindolinylamide moiety furnished enantioenriched β‐hydroxy‐α‐azido carboxylic acid derivatives.

Direct Catalytic Asymmetric Aldol Reaction of an α-Azido Amide.

A direct aldol reaction of an α-azido 7-azaindolinylamide, promoted by a Cu-based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7-azaindolinylamide moiety furnished enantioenriched β-hydroxy-α-azido carboxylic acid derivatives.

Managing the retro-pathway in direct catalytic asymmetric aldol reactions of thioamides.

Thioamides are the preferred pronucleophiles for direct catalytic asymmetric aldol reactions in the context of soft Lewis acid/hard Brønsted base cooperative catalysis. In-depth investigation of this proton-transfer catalysis, which is virtually in equilibrium, revealed that the prominence of the retro-aldol reaction depended on the substrate combination. The retro-aldol reaction is a serious issue in direct aldol reactions because the product distribution, including enantiomers and diastereomers, is governed by thermodynamic parameters, and the aldol products are obtained in much lower stereoselectivity compared with the kinetically controlled process. Herein we report the beneficial effect of an additive with a functional group architecture similar to that of the aldol adduct that suppresses the retro-aldol reaction by competitively binding to the catalyst. Strategic use of the additive led to high stereoselectivity, even when the combination of substrates was prone to the retro-aldol reaction.

ChemInform Abstract: A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction.

AbstractThe azaindolylamido group is found to trigger exclusive formation of the amide enolate in the presence of enolizable aldehydes.

A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction

AbstractThe direct catalytic asymmetric aldol reaction offers efficient access to β‐hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α‐sulfanyl 7‐azaindolinylamide, thus affording both aromatic and aliphatic β‐hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Brønsted base.

A designed amide as an aldol donor in the direct catalytic asymmetric aldol reaction.

The direct catalytic asymmetric aldol reaction offers efficient access to β-hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α-sulfanyl 7-azaindolinylamide, thus affording both aromatic and aliphatic β-hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Brønsted base.

Streamlined Catalytic Asymmetric Synthesis of Atorvastatin

An efficient enantioselective synthetic route to atorvastatin was developed based on a direct catalytic asymmetric aldol reaction. The expensive chiral ligand used in the initial aldol reaction was readily recovered (91 %) and reused. Implementation of an oxy-Michael reaction for the construction of the syn-1,3-diol unit eliminated several redundant steps, allowing for rapid access to the common intermediate in six steps.

ChemInform Abstract: The Direct Catalytic Asymmetric Aldol Reaction of α‐Substituted Nitroacetates with Aqueous Formaldehyde under Base‐Free Neutral Phase‐Transfer Conditions.

AbstractTitle reaction proceeds readily in the presence of a bifunctional chiral phase‐transfer organocatalyst.

Anti-Selective Direct Catalytic Asymmetric Aldol Reaction of Thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.

Concise Enantioselective Synthesis of Duloxetine via Direct Catalytic Asymmetric Aldol Reaction of Thioamide

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH(4) reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.

A Direct Catalytic Asymmetric Aldol Reaction of α‐Sulfanyl Lactones: Efficient Synthesis of SPT Inhibitors

Es geht auch sanft: Die Titelreaktion mit dem Katalysatorsystem AgPF6/(R)-Biphep/DBU bietet einen enantioselektiven Zugang zu syn-konfigurierten α-Thio-β-hydroxylactonen (siehe Schema). In einem speziellen Fall wurde die Sulfidgruppe stereospezifisch durch eine Hydroxygruppe ersetzt, und aus dem resultierenden tertiären Alkohol konnte eine Klasse von dicht funktionalisierten SPT-Inhibitoren erzeugt werden.

A Direct Catalytic Asymmetric Aldol Reaction of α‐Sulfanyl Lactones: Efficient Synthesis of SPT Inhibitors

The scalable and not moisture sensitive [indicated by the reaction with the compound (IId)] title aldol reaction is developed.

The direct catalytic asymmetric aldol reaction of α-substituted nitroacetates with aqueous formaldehyde under base-free neutral phase-transfer conditions

Enantioselective direct aldol reaction of α-substituted nitroacetates with aqueous formaldehyde for the synthesis of α-alkyl serines has been achieved under base-free neutral phase-transfer conditions with a bifunctional chiral phase-transfer catalyst.

ChemInform Abstract: A Simplified Catalytic System for Direct Catalytic Asymmetric Aldol Reaction of Thioamides; Application to an Enantioselective Synthesis of Atorvastatin.

AbstractA new second generation lithium‐free Cu catalyst is developed that exhibits an enhanced catalytic efficiency over the previously applied first generation catalyst (Cu(MeCN)4PF6/BPE/LiOAr), which required a tedious preparation process.