Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

Abstract

Exploration of novel, three-dimensional chemical space is of growing interesti nt he drug discoveryc ommunity and with this comest he challenge for synthetic chemists to devisen ew stereoselective methods to introduce chirality in ar apid and efficient manner.T his Minireview provides a timely summary of the development of palladium-catalyzed asymmetric redox-relay Heck-type processes. These reactions represent an important class of transformation for the selective introduction of remote stereocenters, and have risen to prominence overt he past decade. Within this Minireview, the vast scope of theset ransformationsw ill be showcased, alongside applications to pharmaceutically relevant chiral buildingb locks and drug substances.T oc omplementt his overview,amechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation. Scheme1.Scopeo fr edox-relay Heck-type transformations coveredi nthis Minireview.

Catalytic Cage BH Functionalization of Carboranes via “Cage Walking” Strategy

“…The cage-walking strategy can provide BH functionalization at positions different from those where initial bond activation occurs to achieve functionalized carboranes that are difficult to access by conventional methods. In comparison to the rich literature on chain-walking/ring-walking, − cage-walking remains a young, developing realm. We anticipate that our discussion herein can provide a better understanding of the catalytic selective carborane functionalization via the cage-walking strategy.…”

“…The “walking” process of a transition-metal catalyst along a carbon skeleton has inspired the development of remote functionalization at unfunctionalized sites which are otherwise difficult to access in an organic molecule. − In these “chain-walking” and “ring-walking” processes, the transition-metal catalyst migrates along the sp 3 carbon chain or the conjugated π-system of the substrate until a specific favorable reaction site is reached. In comparison to the extensively studied chain-/ring-walking processes on alkyl chain or aromatics, the “cage-walking” phenomenon is much less investigated.…”

Mechanistically guided survey of enantioselective palladium-catalyzed alkene functionalization

“…In 2012, the arylation of homoallylic and bishomallylic alcohols (11) with excellent levels of regio-and enantioselectivity to yield remotely functionalized ketones (13) was reported (Figure 2E). These types of transformations have come to be known as Heck redox-relay reactions, where a chain-walking [37][38][39] process featuring a series of β-hydrogen eliminations and migratory insertions leads to the thermodynamically driven formation of a ketone or an aldehyde product [40]. Key to the development of this transformation is to maintain the coordination of the Pd complex to the substrate during the chain-walking process [41][42][43].…”

“…The oxidation of alcohols to aldehydes and ketones is the most commonly used strategy for Heck redox-relay processes. However, other thermodynamic driving forces like the formation of α,β-unsaturated carbonyl groups or other Michael acceptors [65,66], styrene derivatives [67], or cyclopropane ring openings [68,69] have been reported [40]. Recently, the Sigman group has reported the use of homoallylic phthalimides and other electron-poor amine-protecting groups in an interrupted Heck redox-relay process.…”

Relay‐Heck Cross‐Coupling Between Alkenyl Halides and Unsaturated Alcohols in the Synthesis of Open‐Chain Analogues of Musk Odorant Vulcanolide

“…The relay‐Heck cross‐coupling of alkenyl precursors with allylic alcohols would be a straightforward manner of preparing a series of cyclohexene‐propanal derivatives with different substitution patterns from a common intermediate. Among different conditions already published in the aromatic series, [18] our attention was drawn to Xiao's catalytic system [19] involving electron‐rich phosphine ligand L . It has already been used for the synthesis of odorant aldehydes from aryl bromides by us [20] and our competitors, [21] but its extension to alkenyl halides has remained unexplored.…”