Mukaiyama Mannich Research Articles

An aromatic ion platform for enantioselective Brønsted acid catalysis.

Chiral acid catalysts are useful for the synthesis of enantioenriched small molecules, but the standard catalysts require laborious and expensive preparations. Here, we describe a chiral Brønsted acid prepared in one step from naturally occurring (-)-menthol and readily available 1,2,3,4,5-pentacarbomethoxycyclopentadiene. Aromatic stabilization serves as a key contributing factor to the potent acidity of the resulting compound, which is shown to catalyze both Mukaiyama-Mannich and oxocarbenium aldol reactions with high efficiency and enantioselectivity. Catalyst loadings as low as 0.01 mole percent and preparative scalability (25 grams) are demonstrated. Alternative amide catalysts are also shown to be promising platforms. In addition to proton catalysis, a chiral anion pathway is demonstrated to be viable with this catalyst system.

Competition for binaphthyl catalysts

Organic Chemistry The binaphthyl framework has proven extremely effective in biasing a broad range of chemical reactions toward just one of two mirror-image products. The motif was first applied as a ligand in metal catalysis, and more recently as a conjugate base in acid catalysis. Gheewala et al. report a class of chiral carbon acids based around a cyclopentadiene framework that are easily accessible from readily available precursors. The compounds are showcased as highly selective catalysts for asymmetric Mukaiyama Mannich and oxocarbenium aldol reactions. Science , this issue p. [961][1] [1]: /lookup/doi/10.1126/science.aad0591

Calcium catalyzed Mukaiyama–Mannich addition of silyl enol ethers to nitrones

A method for synthesizing β-(silyloxy)amino carbonyls through the addition of ketone-derived silyl enol ethers to N-phenyl nitrones has been developed. The transformation is catalyzed by a commercially available calcium(II) complex affording β-(silyloxy)amino carbonyls in good to excellent yield.

One‐Pot Silyl Ketene Acetal‐Formation Mukaiyama–Mannich Additions to Imines Mediated by Trimethylsilyl Trifluoro­methanesulfonate

AbstractIn the presence of trimethylsilyl trifluoromethanesulfonate and trialkylamine base, thioesters are readily converted into silyl ketene acetals in situ and undergo Mukaiyama–Mannich addition to N‐phenylimines in one pot. The silyl triflate appears to play two roles, activating both the thioester and the imine. This process also works well when thioesters are replaced with amides, esters, or ketones. Products are isolated as desilylated anilines without the necessity of a deprotection step. Yields range from 65 to 99 %.

ChemInform Abstract: Unified Approach to Isoindolinones and THIQs via Lewis Acid Catalyzed Domino Mukaiyama—Mannich Lactamization/Alkylations: Application in the Synthesis of (.+‐.)‐Homolaudanosine.

AbstractElectron‐deficient amines, e.g. Tos‐NH2 and Cbz‐NH2, do not react in this procedure.

Unified Approach to Isoindolinones and THIQs via Lewis Acid Catalyzed Domino Mukaiyama-Mannich Lactamization/Alkylations: Application in the Synthesis of (±)-Homolaudanosine.

A novel and efficient synthesis of a variety of isoindolinones and tetrahydroisoquinolines via a Lewis acid catalyzed domino Mukaiyama-Mannich lactamization/alkylation is achieved. This transformation comprises a sequential formation of three new bonds through a one-pot, three-component procedure to afford product in moderate to high yields. A concise synthesis of (±)-homolaudanosine (2b) has been achieved using this method.

ChemInform Abstract: Asymmetric Disulfonimide‐Catalyzed Synthesis of δ‐Amino‐β‐Ketoester Derivatives by Vinylogous Mukaiyama—Mannich Reactions.

An organocatalytic asymmetric synthesis of δ-amino-β-ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama–Mannich reaction of readily available dioxinone-derived silyloxydienes with N-Boc-protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new CC bond-forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (−)-lasubin.

A highly efficient Mukaiyama-Mannich reaction of N-Boc isatin ketimines and other active cyclic ketimines using difluoroenol silyl ethers catalyzed by Ph3PAuOTf.

Ph3PAuOTf is identified as a powerful catalyst for the addition of difluoroenol silyl ethers to N-Boc isatin ketimines and other two kinds of active cyclic ketimines. This represents the first Au(i)-catalyzed Mukaiyama-Mannich reaction, and the corresponding non-fluorinated enol silyl ether proves to be even much more reactive under the same conditions. This method paves the way to the total synthesis of difluoromethylated analogues of AG-041R, a gastrin/CCK-B receptor antagonist.

Asymmetric disulfonimide-catalyzed synthesis of δ-amino-β-ketoester derivatives by vinylogous Mukaiyama-Mannich reactions.

An organocatalytic asymmetric synthesis of δ-amino-β-ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama-Mannich reaction of readily available dioxinone-derived silyloxydienes with N-Boc-protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new CC bond-forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (-)-lasubin.

ChemInform Abstract: Aqueous and Solvent‐Free Uncatalyzed Three‐Component Vinylogous Mukaiyama—Mannich Reactions of Pyrrole‐Based Silyl Dienolates.

AbstractA catalyst and additive‐free environmentally benign Mukaiyama—Mannich reaction of silyl dienolate (I) with a wide variety of aromatic and aliphatic aldehydes and o‐methoxyaniline (III) is presented.

ChemInform Abstract: Diastereo‐ and Enantioselective Catalytic Vinylogous Mukaiyama—Mannich Reactions of Pyrrole‐Based Silyl Dienolates with Alkyl‐Substituted Aldehydes.

AbstractTreatment of the pyrrole (I) with aliphatic aldehydes and the aniline (III) in the presence of AgOAc and the chiral ligand allows a highly efficient and stereoselective access to diamines of type (IV), (VII), and (IX).

A Combined Vinylogous Mannich/Diels–Alder Approach for the Stereoselective Synthesis of Highly Functionalized Hexahydroindoles

AbstractA versatile strategy for the formation of hydroindole derivatives is reported. The molecules synthesized are highly functionalized and bear up to six stereogenic centers. We were able to develop a stereoselective route starting from nonchiral commercially available materials. Key steps in the formation of the bicyclic products are an organocatalytic vinylogous Mukaiyama–Mannich and a Diels–Alder reaction. The former uses a 1,1′‐bi‐2‐napthol (BINOL)‐based chiral Brønsted acid catalyst to build the first stereogenic center. The [4+2] cycloaddition proceeds highly diastereoselectively and furnishes one main stereoisomer, which represents the scaffold of the mycotoxins Rostratin B–D. Other transformations include iodolactonization, a Curtius rearrangement, additions, oxidations, and reductions.

Anti-Selective, Catalytic Asymmetric Vinylogous Mukaiyama Mannich Reactions of Pyrrole-Based Silyl Dienolates with N-Aryl Aldimines

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda-Snapper amino acid-derived silver(I) catalysts. The Mannich products-α,β-unsaturated δ-amino-γ-butyrolactams-are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.