Over the past 20 years, the asymmetric synthesis of acyclic tetrasubstituted stereocenters by Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) strategies has seen considerable growth. Despite the inherent difficulty in accessing acyclic tetrasubstituted stereocenters, creative approaches toward this problem have resulted in high stereoinduction on both electrophilic and nucleophilic reaction partners. Much of this chemistry has paved the way for unique solutions in Mo-, Ir-, and Rh-AAA, with many complimentary methods arising due to the unique regiochemical outcomes of AAA outside of Pd catalysis.1 Introduction2 Stereocontrol on Prochiral Electrophiles3 Stereocontrol on Prochiral Nucleophiles4 Temporary Cyclic Pronucleophiles5 Allylic Alkylation with Other Metals6 Conclusions and Outlook

The C19-oxo-functionalized eburnane alkaloids display unique chemical structure and interesting biological activity. Herein, we report a divergent enantioselective strategy to access these alkaloids by use of a challenging palladium-catalyzed asymmetric allylic alkylation of an N-alkyl-α,β-unsaturated lactam. 19-(S)-OH-Δ14-vincamone (phutdonginin), (−)-19-OH-eburnamine, (+)-19-oxoeburnamine, and (+)-19-OH-eburnamonine (1–4) have been concisely synthesized for the first time in 11 to 13 steps.

The efficient and selective synthesis of functionalized seven‐membered rings remains an important pursuit within synthetic organic chemistry, as this motif appears in numerous drug‐like molecules and natural products. Use of cycloaddition reactions remains an attractive approach for their construction within the perspective of atom and step economy. Additionally, the ability to combine multiple components in a single reaction has the potential to allow for efficient combinatorial strategies of diversity‐oriented synthesis. The inherent entropic penalty associated with achieving these transformations has impressively been overcome with development of catalysis, whereby the reaction components can be pre‐organized through activation by transition‐metal‐catalysis. The fine‐tuning of metal/ligand combinations as well as reaction conditions allows for achieving chemo‐, regio‐, diastereo‐ and enantioselectivity in these transformations. Herein, we discuss recent advances in transition‐metal‐catalyzed construction of seven‐membered rings via combination of 2–4 components mediated by a variety of metals. An emphasis is placed on the mechanistic aspects of these transformations to both illustrate the state of the science and to highlight the unique application of novel processes of transition‐metals in these transformations.

We describe the development of a Pdcatalyzed asymmetric allylic alkylation (Pd-AAA) of acyclic α-hydroxyketones using boronic acids as traceless templates. Condensation of boronic acids with hydroxyketones generates 1,3-dioxaboroles, which can be used directly as pronucleophiles in Pd-AAA reactions. This strategy enables control of the enolate geometry, while removing the issue of O-alkylation. Allylic alcohols can be directly ionized in the presence of Pd(0) and chiral ligands to afford alkylation products with regio-and enantioselectivity. Additionally, a dynamic kinetic asymmetric transformation of allenyl electrophiles affords Calkylation products in high regio-, diastereo-, and enantioselectivity. To the best of our knowledge, this method represents the first example in Pd-AAA for setting point chirality on a nucleophile simultaneous to stereoinduction on an axial chiral allene.

We describe the development of aP d-catalyzed decarboxylative asymmetric allylic alkylation of a-nitro allyl esters to afforda cyclic tetrasubstituted nitroalkanes.O ptimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo-and enantioselective C-alkylation of electronically challenging benzylic nitronates and sterically encumbered 2-allyl esters.S ubstrates were efficiently accessed in acombinatorial fashion by across-Claisen/ a-arylation sequence.The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for a-tertiary amine synthesis.

Quaternary carbon stereocenters are ubiquitous in a wide variety of organic compounds and drug molecules. Highly enantioselective construction of such quaternary carbon centers poses a singular challenge due to the steric repulsion between the four different carbon substituents. Herein, we report a novel strategy to control the enantioselective construction of chiral α-quaternary aldehydes from racemic α-branched aldehydes. Distinct from the established chiral α-quaternary aldehyde synthesis, this project employed a chiral π-allyl–Pd complex neighboring the enolate to determine both the enantio- and diastereoselectivity. The synthetic utility of the products has been highlighted by a series of derivatizations, and the potential of this method has been extended to the synthesis of chiral α-quaternary ketones. Furthermore, this reaction exemplifies the themes of step and atom economy, in addition to the principles of diversity-oriented synthesis.

A palladium-catalyzed allylation of ester-derived boron enolates, which is prepared through 1,4-reduction of α,β-unsaturated ester analogues.

We describe the development of a Pd‐catalyzed decarboxylative asymmetric allylic alkylation of α‐nitro allyl esters to afford acyclic tetrasubstituted nitroalkanes. Optimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo‐ and enantioselective C‐alkylation of electronically challenging benzylic nitronates and sterically encumbered 2‐allyl esters. Substrates were efficiently accessed in a combinatorial fashion by a cross‐Claisen/ α‐arylation sequence. The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for α‐tertiary amine synthesis.