Enantioselective Catalytic Aldehyde α-Alkylation/Semipinacol Rearrangement: Construction of α-Quaternary-δ-Carbonyl Cycloketones and Total Synthesis of (+)-Cerapicol

An enantioselective aldehyde α-alkylation/semipinacol rearrangement was achieved through organo-SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring-expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α-quaternary-δ-carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)-cerapicol.     

α,α‐Diarylprolinol Ethers: New Tools for Functionalization of Carbonyl Compounds

α,α‐Diaryl(dialkyl)prolinol ethers constitute a potent organocatalyst family which has been shown to be very general for a broad range of reactions involving enamine and iminium ion activation or a combination of both. The reactions are characterized by an efficient steric control approach and can lead to a variety of α‐, β‐, γ‐, and α,β‐functionalized carbonyl compounds with excellent stereocontrol. As a full expression of their catalytic activity, these compounds are also excellent promoters of elegant cascade processes and valuable catalysts in water‐compatible systems.     

A Facile Approach to Oximes and Ethers by a Tandem NO+‐Initiated Semipinacol Rearrangement and H‐Elimination

An efficient oximation method has been developed on the basis of NO⁺‐initiated semipinacol rearrangement and subsequent proton elimination. The procedure enabled the rapid construction of a series of oximes and oxime ethers with spiro quaternary stereocenters from allylic silyl ethers. Additional features of this reaction include wide substrate tolerance as well as the commercial availability of the safe nitrosation reagent NOBF₄. The key N‐heterotricyclic cores of three natural alkaloids, tuberostemoninol B, (+)‐quebrachidine, and an insecticide, were also constructed efficiently by this method.     

Cu‐Catalyzed Diastereo‐ and Enantioselective Reactions of γ,γ‐Disubstituted Allyldiboron Compounds with Ketones

A catalytic diastereo‐ and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1‐diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.     

Catalytic Enantioselective Synthesis of α‐Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation

The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl‐substituted N‐heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza‐Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N‐heterocycles, nucleophiles, and substituents on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst‐induced LUMO lowering, with site‐selective, rate‐limiting, intramolecular asymmetric proton transfer from the ion‐paired prochiral intermediate.     

Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

An enantioselective cyclopropanation of α‐substituted α,β‐unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/α‐alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the α‐position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and α,β‐unsaturated aldehydes previously reported by other groups. Very good yields (up to 81 %) and enantioselectivities (up to 97 % ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.     

Catalytic Enantioselective Synthesis of N,Cα,Cα‐Trisubstituted α‐Amino Acid Derivatives Using 1H‐Imidazol‐4(5H)‐ones as Key Templates

1H‐Imidazol‐4(5H)‐ones are introduced as novel nucleophilic α‐amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N‐substituted (alkyl, allyl, aryl) α‐amino acid derivatives.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (?)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (?)‐quebrachamine, are reported herein.     

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

The asymmetric palladium‐catalyzed decarboxylative allylic alkylation of differentially N‐protected piperazin‐2‐ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine‐2‐ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.     

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective,Catalytic Michael Reaction for the Formation of α,α‐Disubstituted α‐Amino Acid Derivatives

Direct and enantioselective : Diphenylprolinol silyl ether was found to catalyze the direct, asymmetric Michael reaction of 4‐substituted 2‐aryl‐2‐oxazoline‐5‐one and α,β‐unsaturated aldehydes, affording the chiral α,α‐disubstituted α‐amino acid derivatives with excellent enantioselectivity.