Regio- and Enantioselective Synthesis of Pyrrolidines Bearing a Quaternary Center by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethanes

Abstract

Herein we describe the first use of disubstituted donors in the palladium-catalyzed trimethylenemethane (TMM) cycloaddition resulting in an enantioselective synthesis of highly substituted pyrrolidines. These cyanoalkyl donors 1 form all-carbon quaternary centers in a catalytic, asymmetric, and intermolecular manner uniquely using diamidophosphite ligands L2 and L3, generating synthetically important chiral building blocks in good yields and selectivities.

3-Aryl-2,5-Dihydropyrroles via Catalytic Carbonyl-Olefin Metathesis

“…1). Additional strategies rely on transition-metal catalyzed asymmetric α-arylation and alkylation procedures 11–14 ( 3 and 4 , Fig. 1).…”

Utilizing Palladium‐Stabilized Zwitterions for the Construction of N‐Heterocycles

“…The primary challenges in developing this dipolar reagent for efficient synthesis are: 1) ensuring the zwitterionic intermediate is reactive enough to add to the imine acceptors; 2) allowing the process to be conducted selectively with regards to regiocontrol, enantiodiscrimination and diastereoselectivity . In the event, the use of N ‐tosylimines proved efficient, however, the previously reported phosphoramidite ligand L3 was not so successful in this case.…”

“…As an alternative to using ketimines to generate chiral quaternary stereocenters in the pyrrolidine products, it has been demonstrated thatm ore congested Pd-TMM donors can also be used in cycloadditions. [16] The synthesis of the requisite Pd-TMM precursors is achieved through addition of the Grignard reagent 16 to the required Weinreb amide 17.T hen, treatment with ZnI 2 andT MSCN, followed by acetylation of the silyl-protected cyanohydrin gives the required substrates (Scheme8).…”

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

“…Ther esults are summarized in Scheme 3. [12] The1 ,3-, 1,4-, and 1,5-alkanediol-based ligands (L1-L3)i nduced moderate enantioselectivity (58-60 % ee) with high substrate conversion. TheP h-TRAP again gave complete substrate conversion, albeit with poor enantioselectivity (19 % ee).…”

“…Further ligand screening revealed bis(diamidophosphite)-type ligands as promising candidates. [12] The1 ,3-, 1,4-, and 1,5-alkanediol-based ligands (L1-L3)i nduced moderate enantioselectivity (58-60 % ee) with high substrate conversion. Among bis(diamidophosphite) ligands derived from chiral 1,4-butanediols (L4-L6), the d-isomannide derivative (L6), having ar igid bicyclic backbone,was the most favorable for both product yield and enantioselectivity (91 %yield, 60 % ee).…”