Palladium and Amino Acid Co-Catalyzed Highly Regio- and Enantioselective Hydroarylation of Unbiased Alkenes

Abstract

A practical palladium and amino acid co-catalyzed hydroarylation of unbiased alkenes has been developed. Using the transient-directing strategy, this chemistry could construct isolated chiral Csp2–Csp3 bonds with good regio- and enantioselectivity. The potential synthetic utility of a representative product was well-illustrated by further transformations. Furthermore, the mechanism of this reaction was intensively studied through control experiments and DFT calculations.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification**

“…A limitation is that the other type of trisubstituted alkene (α,α,β-trisubstituted), gave only the corresponding Heck byproduct (see mechanistic discussion below). Importantly, we were able to expand the alkenyl aldehyde scope beyond ortho-alkenylbenzaldehydes to a non-conjugated aldehyde containing purely aliphatic tether (3 ka) [18,30] and conjugated dienyl aldehydes (3 la-3 pa), establishing that the aromatic linker is not necessary for reactivity. The product derived from an aliphatic aldehyde (3 ka) was obtained in moderate yield and 96 : 4 er.…”

“…On the other hand, other factors such as the rigidity and distortion of the TDGs may play more important roles on the enantioselectivity. However, how the substituents affect the TDG rigidity and the mode of enantioinduction is still not well understood [16, 18] …”

“…Next, we performed DFT calculations to investigate why L-tert-leucine is a uniquely effective TDG in controlling the enantioselectivity in hydroarylation, hydroalkenylation, and hydroalkynylation reactions, whereas other α-amino-acidbased TDGs, such as L-alanine, lead to much lower selectivity. Prior DFT studies of Pd/TDG 1 -catalyzed hydroarylation have shown that C(sp 3 )À H reductive elimination is the turnover-limiting step, while migratory insertion is the selectivity-determining step, [16,18] so our efforts focused on migratory insertion with different TDGs and migrating groups. Understanding the origin of TDG effects on enantioselectivity is particularly intriguing because the α-substituent on the TDG is placed far away from the new chiral center formed during migratory insertion (see below), yet high enantioselectivity was observed across different migrating groups (alkenyl, alkynyl and aryl) that have vastly different steric profiles.…”

“…[12][13][14][15] Notably, in an elegant series of studies, Li has applied a monodentate directing group strategy to achieve rhodiumand iridium-catalyzed enantioselective hydroalkynylation of activated and unactivated alkenes with terminal alkynes. [14] Our group's continued interest in developing a chiral transient directing group strategy for regio-and stereoselective alkene functionalization [16][17][18][19] led us to question whether a complementary approach for asymmetric hydroalkenylation and hydroalkynylation could be developed by employing alkenyl and alkynyl halides in a reductive Heck reaction paradigm (Scheme 1B). [20,21] Palladium-catalyzed reductive Heck hydrofunctionalization of olefins is characterized by its broad functional group compatibility, tolerance for air and moisture, and operational simplicity, [22] which would make the envisioned methodology a practically useful addition to the modern hydroalkenylation/hydroalkynylation toolkit.…”

Mechanistic Investigation into the Regio-Controllable Hydroallylations of Alkynes with Allylborons under Pd-Based Synergetic Catalyses

“…The experimental phenomena indicate that judicious combination of promoters and ligands has a unique effect on the product-divergence. The importance of these transformations has encouraged the researchers to develop massive related catalytic reactions …”