Mukaiyama Mannich Reaction Research Articles

Chiral Diselenophosphoric Acids for Ion Pair Catalysis: A Novel Approach to Enhance Both Proton Donating and Proton Accepting Properties.

The activation of poorly reactive substrates via strong chiral acids is a central topic in asymmetric ion pair catalysis these days. Despite highly successful scaffolds such as N-triflylphosphoramides, these catalysts either lack C2-symmetry or provide multiple H-bond acceptor sites, leading to lower ee values for certain reactions. We present BINOL-based diselenophosphoric acids (DSA) as an extremely promising alternative. Using an intertwined approach of synthesis and NMR studies, we developed a synthetic approach to DSA with up to 98 % NMR yield. The obtained acids provide both very high proton donor and proton acceptor properties, a bifunctionality, which is key to catalytic applications. Indeed, first reactivity test proved the much higher acidity of DSA and its ability to initiate Mukaiyama-Mannich reaction and protodesilylation of silyl ethers. Together with their C2-symmetry, the single donor and single acceptor situation, the decreased tendency of self-association, and the straightforward synthesis with potential 3,3'-substitution, the DSA provide all features ideal for the further development of ion pair catalysis.

Chiral Carborane Acids Decorated with Binol-Based Phosphonates: Synthesis, Characterization, and Application.

The syntheses of hexabrominated closo-carborates decorated with different chiral Binol-derived phosphonates and their conjugate acids are described. X-ray diffraction analysis reveals a polymeric structure for the sodium salt with the anionic units connected by [B-Br-Na-O═P]+ linkages. For the acid, coordination of the proton to the phosphonate's P═O oxygen atom is assumed. The pKa value was estimated by combining experiments and computations. Application of these Brønsted acids as chiral catalysts in an imino-ene and a Mukaiyama-Mannich reaction was moderately successful.

A Powerful Chiral Super Brønsted C-H Acid for Asymmetric Catalysis.

A new type of chiral super Brønsted C-H acids, BINOL-derived phosphoryl bis((trifluoromethyl)sulfonyl) methanes (BPTMs), were developed. As compared to widely utilized BINOL-derived chiral phosphoric acids (BPAs) and N-triflyl phosphoramides (NTPAs), BPTMs displayed much higher Brønsted acidity, resulting in dramatically improved activity and excellent enantioselectivity as demonstrated in catalytic asymmetric Mukaiyama-Mannich reaction, allylic amination, three-component coupling of allyltrimethylsilane with 9-fluorenylmethyl carbamate and aldehydes, and protonation of silyl enol ether. These new strong Brønsted C-H acids have provided a platform for expanding the chemistry of asymmetric Brønsted acid catalysis.

The Co(ii)/spiroBox-catalyzed enantioselective Mukaiyama-Mannich reaction for the synthesis of quaternary α-amino acid derivatives

Co(ii)/spiroBox-catalyzed Mukaiyama-Mannich reactions of enol silyl ethers with cyclic N-sulfonyl ketimino esters were examined and showed excellent yields and enantioselectivity values.

Stereoselective Synthesis of the Decahydroquinoline Alkaloid cis-195J.

The first enantioselective synthesis of two C-5 diastereomers of the proposed structure of the decahydroquinoline alkaloid cis-195J has been achieved. The key step of our strategy is the highly stereoselective vinylogous Mukaiyama-Mannich reaction (VMMR), which gave rise to the first two stereogenic centers at the ring fusion with excellent diastereo- and enantiocontrol. Through alkyne cyclization and enamine reduction the correct cis-configuration between C-2, C-4a, and C-8a in the decahydroquinoline backbone was established. Subsequently, a radical cyclization of a tethered alkyl iodide onto the enoate assembled the bicyclic cis-decahydroquinoline as a mixture of two C-5 diastereomers. Further elaboration of the C-5 side chain eventually provided both diastereomers of cis-195J, which were readily separated, and their constitution and configuration were thus unambiguously proven for the first time.

Catalytic Enantioselective Synthesis of Difluoromethylated Tetrasubstituted Stereocenters in Isoindolones Enabled by a Multiple-Fluorine System.

A poly trifluoromethylated chiral spirocyclic phosphoric acid was developed and employed with hexafluoroisoproyl alcohol (HFIP) to render the catalytic asymmetric Mukaiyama-Mannich reaction of difluoroenoxysilanes with in situ formed ketimines. This unique multiple-fluorine system provides rapid access to difluoromethylated tetrasubstituted stereocenters in isoindolones with wide substrate scope under mild conditions. Further synthetic transformations to enantioenriched CF2H-isoindolones and CF2-decorated fused isoindolones were also implemented with good efficiency.

Short Synthesis of Alkaloid (-)-205B.

The alkaloid (-)-205B has in the past served as a testing ground for novel approaches in nitrogen heterocycle synthesis. We herein report a highly straightforward synthesis of (-)-205B in just six synthetic steps, making it the shortest route currently known. The central steps of our approach are a vinylogous Mukaiyama-Mannich reaction to establish the first two stereogenic centers with excellent diastereo- and enantiocontrol followed by zinc-mediated Barbier allylation to set the third chiral center with high substrate control. Upon cyclization of the Barbier product to lactam and enolate methylation, the third ring is annulated by a one-pot sequence of lactam reduction and aza-Prins cyclization to directly set the final stereogenic center with complete cis-stereoselectivity. As the iminium ion undergoing the aza-Prins cyclization rapidly isomerized to a planar enamine intermediate, the alkaloid was eventually obtained as a 1:1 mixture of C6 diastereomers, which were readily separated by chromatography. Yet, the target natural product was obtained isomerically pure in an overall yield of 12%, which compares favorably with all previous syntheses.

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin‐Derived Ketimines for the Synthesis of Oxindolyl‐β3, 3‐Amino Acid Esters

Mukaiyama-Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama-Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β3, 3 -amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.

Asymmetric Vinylogous Mukaiyama‐Mannich Reactions of Heterocyclic Siloxy Dienes with Ellman's Fluorinated Aldimines

AbstractVinylogous Mukaiyama Mannich reactions of furan and pyrrole based dienoxy silanes with α‐fluoroalkyl sulfinyl imines provide a powerful synthetic access to a variety of amino fluoroalkyl γ‐butenolide‐type and butyrolactam frameworks with high regio‐ and diastereoselectivity. Anti‐configured adducts were obtained in all cases, independent of the nature of the heteroatom (O or N) present in the dienoxy silane. The absolute configuration of the adducts prepared was unequivocally established by X‐ray crystallographic analysis. It is noteworthy that the introduction of substituents at the γ‐position of the heterocyclic partner allows the generation of adducts bearing chiral quaternary centers.magnified image

One-pot Mukaiyama–Mannich reaction of aldehydes, amines and silyl enol diazoacetate catalyzed by MgI2 etherate

Three-component Mukaiyama–Mannich reaction of aldehydes, amines, and silyl enol diazoacetoacetate was efficiently carried out to afford δ-amino substituted-α-diazoacetoacetate derivatives catalyzed by 5 mol% of MgI2 etherate (MgI2•(OEt2)n) under mild and neutral reaction conditions in good to excellent yields.

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

AbstractA new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/ZnII complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.

Chiral Zinc(II)-Catalyzed Enantioselective Tandem α-Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines.

A new catalytic asymmetric tandem α-alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N'-dioxide/ZnII complexes. The proton shift preferentially proceeded instead of a silyl shift after α-alkenyl addition of silyl enol ether to the ketimine. A wide range of β-amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama-Mannich reaction and tandem α-alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β-amino silyl enol ethers were easily transformed into β-fluoroamines containing two vicinal tetrasubstituted carbon centers.

Internally reuse by-product as promoter: A catalyst-free imine formation/Mukaiyama-Mannich sequence of α-amido sulfones with fluorinated silyl enol ethers

Described herein is a catalyst-free tandem imine formation/Mukaiyama-Mannich sequence of fluorinated silyl enol ethers and α-amido sulfones, allowing the efficient synthesis of value-added β-amino α-fluorinated ketones in good to excellent yields. Noticeably, the key for high efficacy of the catalyst-free reaction is attributed to the in situ generated acidic by-product PhSO2X (X = TMS or H) that can act as an promoter for the subsequent Mukaiyama-Mannich reaction.

A Sc(OTf)3 catalyzed Mukaiyama–Mannich reaction of difluoroenoxysilanes with unactivated ketimines

The first example of a Mukaiyama–Mannich reaction of difluoroenoxysilanes with unactivated ketimines catalyzed by Sc(OTf)3 is described.

Modular Synthesis of Dipyrroloquinolines: A Combined Synthetic and Mechanistic Study.

A straightforward synthesis of [1,2-a][3',2'-c]dipyrroloquinolines has been developed generating up to eight new σ-bonds and five new stereogenic centers in a simple and modular one-pot operation. Generally good to excellent yields and moderate to good stereoselectivities in favor of the all-cis stereoisomer were observed. A detailed investigation combining synthetic studies, analytical measurements, and theoretical calculations has been conducted to elucidate the reaction mechanism using ESI- and liquid-beam IR-laser desorption mass spectrometry as well as DFT calculations. Key steps of this sequential transformation include a Lewis acid-catalyzed vinylogous Mukaiyama-Mannich reaction of bis(silyl) dienediolate 1 and a Brønsted acid-promoted Mannich-Pictet-Spengler reaction cascade reaction to complete the synthesis of the dipyrroloquinoline core of the target compounds.

Catalytic Asymmetric Mukaiyama-Mannich Reaction of Cyclic C-Acylimines with Difluoroenoxysilanes: Access to Difluoroalkylated Indolin-3-ones.

A catalytic enantioselective Mukaiyama-Mannich reaction of cyclic C-acylimines with difluoroenoxysilanes is reported. (S)-TRIP enables the enantioselective synthesis of a series of novel difluoroalkylated indolin-3-ones bearing a quaternary stereocenter in up to 97% yield and 98% ee. The synthetic utility of this protocol is highlighted by efficient conversion of the products to the corresponding indolin-3-one derivatives without any erosion of the enantiopurity.

A Highly Efficient Gold(I)-Catalyzed Mukaiyama–Mannich Reaction of α-Amino Sulfones with Fluorinated Silyl Enol Ethers To Give β-Amino α-Fluorinated Ketones

Ph3PAuOTf was identified as a powerful catalyst for the ­Mukaiyama–Mannich reaction of fluorinated silyl enol ethers with α-amino sulfones. This provides ready access to β-amino α-fluorinated ketones in good to excellent yields.

Stereoselective Synthesis and Biological Evaluation of C1-Epimeric and Desmethyl Monomeric Nuphar Analogues.

A class of monomeric nuphar analogues that are either epimeric at C1 and C1' or lack the naturally occurring methyl group at those positions were synthesized and evaluated for biological activity. The syntheses feature enantioselective vinylogous Mukaiyama-Mannich (vM-Mannich) reactions catalyzed by chiral phosphoric acids that proceed with excellent diastereoselectivity. Biological assays reveal that both the desmethyl and C1-epimeric monomeric nuphar analogous are able to induce rapid apoptosis.

In situ generation of N-Boc-protected alkenyl imines: controlling the E/Z geometry of alkenyl moieties in the Mukaiyama–Mannich reaction

Readily available Boc-protected Z-alkenyl aminals could be used as Z-alkenyl and E-alkenyl imine precursors under acidic conditions. In the Mukaiyama-Mannich reaction of Z-alkenyl Boc-aminals, the E/Z geometry of the products was controlled by the catalyst used. The present method was also applied to asymmetric Mukaiyama-Mannich reactions.

Ni(ii)-Catalyzed enantioselective Mukaiyama–Mannich reaction between silyl enol ethers and cyclic N-sulfonyl α-ketiminoesters

The first Ni(ii)-catalyzed Mukaiyama–Mannich reaction of cyclic N-sulfonyl α-ketiminoesters with silyl enol ethers was realized and provided enantioenriched benzofused sultams containing a quaternary α-amino ester.