Total synthesis of (-)-4-desacetoxy-1-oxovindoline: Single atom exchange of an embedded core heteroatom in vindoline.

A concise total synthesis of (-)-4-desacetoxy-1-oxovindoline is disclosed, bearing a single heteroatom exchange in the core structure of the natural product 4-desacetoxyvindoline. Central to the synthesis is powerful oxadiazole intramolecular [4+2]/[3+2] cycloaddition cascade that formed four C-C bonds, created three new rings, and established five contiguous stereocenters about the new formed central 6-membered ring.

Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline: Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope.

A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16' stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.

Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Alkynes: The Transannular Pauson-Khand Reaction.

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2 + 2 + 1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Macrocyclic enyne and dienyne complexes were readily synthesized by palladium(II)-catalyzed oxidative macrocyclizations of bis(vinyl boronate esters) or ring-closing metathesis reactions followed by complexation with dicobalt octacarbonyl. Several reaction modalities of these macrocyclic complexes were uncovered. In addition to the first successful transannular Pauson-Khand reactions, other intermolecular and transannular cycloaddition reactions included intermolecular Pauson-Khand reactions, transannular [4 + 2] cycloaddition reactions, intermolecular [2 + 2 + 2] cycloaddition reactions, and intermolecular [2 + 2 + 1 + 1] cycloaddition reactions. The structural and reaction requirements for each process are presented.

Using Ring Strain to Control 4π-Electrocyclization Reactions: Torquoselectivity in Ring Closing of Medium-Ring Dienes and Ring Opening of Bicyclic Cyclobutenes.

Syntheses of strained cyclic dienes were accomplished via palladium(II)-catalyzed oxidative cyclizations of terminal bis(vinylboronate esters). The reactions generate strained (E,E)-1,3-dienes that undergo spontaneous 4π-electrocyclizations to form bicyclic cyclobutenes. Formation of the cyclobutenes is driven by the strain in the medium-ring (E,E)-1,3-diene intermediate. Thermal ring openings of the cyclobutenes give (Z,Z)-1,3-diene products, again for thermodynamic reasons. DFT calculations verified the thermodynamic versus kinetic control of the reactions, and kinetic studies are in excellent agreement with the calculated energy changes. An extension of the tandem coupling/4π-electrocyclization pathway was demonstrated by a palladium(II)-catalyzed oxidative homocoupling/8π-electrocyclization cascade.

Cyclization strategies to polyenes using Pd(II)-catalyzed couplings of pinacol vinylboronates.

As a complement to Pd(0)-catalyzed cyclizations, seven Pd(II)-catalyzed cyclization strategies are reported. α,ω-Diynes are selectively hydroborated to bis(boronate esters), which cyclize under Pd(II)-catalysis producing a diverse array of small, medium, and macrocyclic polyenes with controlled E,E, Z,Z, or E,Z stereochemistry. Various functional groups are tolerated including aryl bromides, and applications are illustrated.