Enantioselective Palladium‐Catalyzed [3+2] Cycloaddition of Trimethylenemethane and Fluorinated Ketones

A nitrile‐substituted trimethylenemethane (TMM) donor undergoes palladium‐catalyzed [3+2] cycloadditions with fluorinated ketones to generate tetrasubstituted trifluoromethylated centers in high enantioselectivity under mild conditions. The generation of the palladium–TMM complex was achieved by a self‐deprotonation strategy, which shows remarkable improvements in regiocontrol, efficiency, and atom economy of asymmetric [3+2] cycloadditions. Moreover, the versatility of the nitrile group provides direct access to a variety of synthetically useful intermediates, including amides, aldehydes, and esters. The developed reaction conditions allow for the synthesis of a wide variety of aromatic, heteroaromatic, and aliphatic fluorinated dihydrofurans in excellent regio‐ and enantioselectivities.     

Enantio‐ and Diastereoselective Synthesis of Chiral Allenes by Palladium‐Catalyzed Asymmetric [3+2] Cycloaddition Reactions

A protocol for the asymmetric synthesis of highly substituted chiral allenes with control of point and axial chirality has been developed. A palladium‐catalyzed [3+2] cycloaddition using readily available racemic allenes gives access to densely functionalized chiral allenes with excellent yields and functional group tolerance. The catalytic asymmetric protocol utilizes a broad range of allenyl TMM (trimethylenemethane) donors to form cyclopentanes, pyrrolidines, and spirocycles with very good control of regio‐, enantio‐, and diastereoselectivity. The chiral allene moiety is shown to be a valuable functional group for rapid elaboration towards complex targets.     

DYKAT of vinyl aziridines: total synthesis of (+)-pseudodistomin D

A concise total synthesis of (+)-pseudodistomin D was developed. The absolute stereochemistry was established through a dynamic kinetic asymmetric cycloaddition of an isocyanate to a vinyl aziridine. The piperidine core was constructed through a silver(I)-catalyzed hydroamination of an alkyne and subsequent diastereo- and regioselective reduction. [reaction: see text]     

Regio- and enantioselective Pd-catalyzed allylic alkylation of ketones through allyl enol carbonates

The Pd-catalyzed reorganization of enol allyl carbonates to allylated ketones occurs asymmetrically in the presence of chiral ligands previously developed in this group. With 2-methylcyclohexanone, asymmetric regioselective alkylation occurs at the more substituted carbon without complications of polyalkylation. Alkylation to create quaternary centers in indanones and benzonabenone occurs in much higher ee than using tin or lithium enolates. The sense of enantioinduction in tetralones is opposite from the tin and lithium enolate examples. For the first time, asymmetric creation of tertiary centers occurs with high ee (78-99%). The different results between this reaction and the use of lithium or tin enolates suggest different mechanisms may be involved.     

AAA in KAT/DYKAT processes: first- and second-generation asymmetric syntheses of (+)- and (-)-cyclophellitol

Kinetic resolutions and kinetic asymmetric transformations (KAT) as well as dynamic kinetic resolutions and dynamic kinetic asymmetric transformations (DYKAT) are important synthetic protocols. The feasibility of KAT and DYKAT processes for asymmetric allylic alkylations (AAA) is explored utilizing a single substrate--conduritol B tetraesters. Both processes can be performed resulting in excellent enantioselectivity. The impact of nucleophile and leaving group on the effectiveness of each is outlined. The ability to differentiate the various hydroxyl groups is also described. For this purpose, 4-tert-butyldimethylsiloxy-2,2-dimethylbutyric acid was developed as a nucleophile. The utility of effecting KAT/DYKAT processes through the Pd-catalyzed AAA reaction is demonstrated by efficient syntheses of both enantiomers of the potent glycosidase inhibitor cyclophellitol.