Enantioselective formal total synthesis of dihydrospirotryprostatin B.

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

Enantioconvergent Palladium-Catalyzed Alkylation of Tertiary Allylic C-H Bonds.

Enantioconvergent catalysis enables the conversion of racemic molecules into a single enantiomer in perfect yield and is considered an ideal approach for asymmetric synthesis. Despite remarkable advances in this field, enantioconvergent transformations of inert tertiary C-H bonds remain largely unexplored due to the high bond dissociation energy and the surrounding steric repulsion that pose unparalleled constraints on bond cleavage and formation. Here, we report an enantioconvergent Pd-catalyzed alkylation of racemic tertiary allylic C-H bonds of α-alkenes, providing a unique approach to access a broad range of enantioenriched γ,δ-unsaturated carbonyl compounds featuring quaternary carbon stereocenters. Mechanistic studies reveal that a stereoablative event occurs through the rate-limiting cleavage of tertiary allylic C-H bonds to generate σ-allyl-Pd species, and the achieved E/Z-selectivity of σ-allyl-Pd species effectively regulates the diastereoselectivity via a nucleophile coordination-enabled SN 2'-allylation pathway.

Pd-Catalyzed Asymmetric 5-exo-trig Cyclization/Cyclopropanation/Carbonylation of 1,6-Enynes for the Construction of Chiral 3-Azabicyclo[3.1.0]hexanes.

We herein disclose a mild and efficient access to chiral 3-azabicyclo[3.1.0]hexanes via a Pd-catalyzed asymmetric 5-exo-trig cyclization/cyclopropanation/carbonylation of 1,6-enynes. Various nucleophiles, such as alcohols, phenols, amines and water, are well compatible with the reaction system. This reaction forms three C-C bonds, two rings, two adjacent quaternary carbon stereocenters as well as one C-O/C-N bond with excellent regio- and enantioselectivities. The products could be further functionalized to generate a library of 3-azabicyclo[3.1.0]hexane frameworks.

Organocatalytic Synthesis of Highly Functionalized Heterocycles by Enantioselective aza-Morita-Baylis-Hillman-Type Domino Reactions.

Organocatalytic enantioselective domino reactions are an extremely attractive methodology, as their use enables the construction of complex chiral skeletons from readily available starting materials in two or more steps by a single operation under mild reaction conditions. Thus, these reactions can save both the quantity of chemicals and length of time typically required for the isolation and/or purification of synthetic intermediates. Additionally, no metal contamination of the products occurs, given that organocatalysts include no expensive or toxic metals. The aza-Morita-Baylis-Hillman (aza-MBH) reaction is an atom-economical carbon-carbon bond-forming reaction between α,ß-unsaturated carbonyl compounds and imines mediated by Lewis base (LB) catalysts, such as nucleophilic phosphines and amines. aza-MBH products are functionalized chiral ß-amino acid derivatives that are highly valuable as pharmaceutical raw materials. Although various enantioselective aza-MBH processes have been investigated, very few studies of aza-MBH-type domino reactions have been reported due to the complexity of the aza-MBH process, which involves a Michael/Mannich/H-transfer/ß-elimination sequence. Accordingly, in this review article, our recent efforts in the development of enantioselective domino reactions initiated by MBH processes are described. In the domino reactions, chiral organocatalysts bearing Brønsted acid (BA) and/or LB units impart synergistic activation to substrates, leading to the easy synthesis of highly functionalized heterocycles (some of which have tetrasubstituted and/or quaternary carbon stereocenters) in high yield and enantioselectivity.

Enantioselective Synthesis of Quaternary Carbon Stereocenters: Addition of 3-Substituted Oxindoles to Vinyl Sulfone Catalyzed by Pentanidiums.

A pentanidium-catalyzed highly enantioselective conjugate addition of 3-alkyloxindoles to phenyl vinyl sulfone has been demonstrated. This approach allows the construction of 3,3-dialkyl-substituted oxindole frameworks with high yield and excellent enantioselectivity (up to 99%) under simple phase-transfer conditions. A variety of oxindoles bearing all-carbon quaternary stereogenic centers were obtained in the presence of 0.25 mol% pentanidium. Meanwhile, practicality was illustrated by a gram-scale asymmetric synthesis of two 3,3-dialkyl-substituted oxindoles. The resulting adduct can be smoothly transformed to the natural product analogue in a short synthetic route.