Total Synthesis of Dragocins A-C through Electrochemical Cyclization.

The first total synthesis of dragocins A-C, remarkable natural products containing an unusual C4' oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C-H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful.

Three-Component Asymmetric Ni-Catalyzed 1,2-Dicarbofunctionalization of Unactivated Alkenes via Stereoselective Migratory Insertion.

An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array of aryl and alkenyl nucleophiles are tolerated, furnishing the products in good yield and with high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted internal alkenes participate in the reaction, establishing two contiguous stereocenters with high diastereoselectivity and moderate enantioselectivity. A combination of experimental and computational techniques shed light on the mechanism of the catalytic transformation, pointing to a closed-shell pathway with an enantiodetermining migratory insertion step, where stereoinduction arises from synergistic interactions between the sterically bulky achiral sulfonamide directing group and the hemilabile bidentate ligand.

Mapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via PdII /PdIV Catalysis.

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under PdII /PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3-5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII /PdIV mechanism involving Wacker-type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation.

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free -NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.